The authors would like to thank Ivan Hanigan for his support in extracting and interpreting the ultraviolet radiation satellite data. The work was supported by the NHMRC Career Development Award (Clinical) to HB [ID628856], NHMRC Project Grant [1032484], NHMRC Center for Research Excellence [Grant ID 1001216] and the MSBase Foundation. The MSBase Foundation is a not-for-profit organization that receives support from Merck Serono, Biogen Idec, Novartis Pharma, Bayer-Schering, Sanofi-Aventis and BioCSL. RL is supported by a NHMRC Career Development Award [ID 1004898].

注：所述对应的Stata的代码段在提供的代码文件相同数目的每个步骤。 Stata的命令名称已被斜体在以下协议。 1.准备并绘制观察到的复发发病数据<ol><li>通过点击“新建待办事项文件编辑器”按钮，打开一个做文件，并使用生成的命令来计算追溯至每十二个日历月为三个地理层次的复发起始点的号码为蓝本：位置，半球和全球性的。通过点击DO-文件中的“执行（做）”做文件操作按钮的动作命令。 </li><li>使用swilk或sktest命令测试复发计数使用夏皮罗-威尔克或修改Jarque-Bera检验的位置总复发数据的基础分布正常或分别分解患者水平复发的数据。选择的代码，然后单击“执行（做）”。 38,39。 </li><li>使用生成命令创建一个新的变量“north_month”的南半球日历个月+6偏移，允许北部和南半球复发绘制季节沿同一水平轴线。选择的代码，然后单击“执行（做）”。 <ol><li>图的观察每月复发起始点与y轴和日历月份对x轴为使用双向散射命令每个半球复发频率的散点图。重复每个位置。通过查看图查看器中自动打开屏幕的每个情节观察波峰和波谷的复发发生在历年的模式。 </li></ol></li><li>使用雷达命令绘制雷达图复发次数的按日历月的分布，每个雷达捕捉轴单月下令以顺时针方式。选择的代码，然后单击“执行（做）”。 <ol><li>重复的所有网站。通过查看图查看器中自动打开屏幕的每个情节观察波峰和波谷的复发发生在历年的模式。 </li></ol></li><li>运行SEAST命令跨越观测数据复发申请季节性的爱德华的考验。40-42重复所有地理层面。 </li></ol> 2.模型的建立与选择<ol><li>使用生成命令来指定在回归中使用的年周期的正弦和 ​​余弦三角函数。选择的代码，然后单击“执行（做）”。 </li><li>使用回归命令指定与复发数为因变量的结果，并计算正弦和 ​​余弦项基本模型的形式在步骤2.1作为主要解释变量。 <ol><li>添加特定位置的紫外线辐射37的基本模型作为一个额外的调整协变量和使用分析重aweight选择加权模式，为患者贡献的各位置的号码。选择的代码，然后单击“执行（做）”。 注：记录确定（R 2），并在结果窗口自动打开筛选剩余误差的模型系数。紫外线辐射：日均红斑加权环境紫外线辐射的每月1979至2004年包括由美国国家航空和航天局地球探测臭氧总量绘图系统，发布包含在分析中的所有个别位置37。 </li></ol></li><li>存储使用预测命令的模型预测每月日志（复发）。转换日志复发回整复发计数使用根儿 exponentiating日志（复发）项吃了命令。选择的代码，然后单击“执行（做）”。重复的所有网站。 </li><li> 2.3在使用双向散射命令观察到的月度复发的数据叠加的指数化预测月度复发的估计。选择的代码，然后单击“执行（做）”。 <ol><li>重复的所有网站。在图形显示浏览器的每个情节。 </li></ol></li><li>使用回归命令通过添加附加的谐波正弦/余弦对扩大在2.2中指定的模型。选择的代码，然后单击“执行（做）”。 注：记录残差和决心的系数。保存和转换模型的估计按2.3和打印模型估计出的观测数据按2.4。重复的所有网站。 </li><li>使用回归命令通过增加两个额外的谐波正弦/余弦对，以进一步扩大在2.2指定的型号。选择的代码，然后单击“执行（做）”。 注：记录残差和系数决心。直接使用似然比检验的基础模型进行比较这一模式。使用ESTAT IC后估计命令生成赤池和贝叶斯信息准则。保存和转换模型的估计按2.3和打印模型估计出的观测数据按2.4。重复所有地理层面。 </li></ol> 3.估算峰值复发概率<ol><li>使用的估计功能（nlcom）非线性组合来计算点估计和95％置信区间的相移，通过使用2.6确定从步骤2.1最佳拟合模型。选择的代码，然后单击“执行（做）”。 <ol><li>将这些点估计和相关的置信区间为代表的峰值复发次数（T max）和波谷复发次数（T 分），日历日期的编号，其中1 = 1 月1日和365 = 12月31日和T最大=相移+ （四分之三百六十五）和T最小=相移+（（四分之三百六十五）* 3）。重复所有地理层面。比赛T最大和T 分钟，以通过Excel查找文件中的日历日期。 </li></ol></li><li>使用生成命令来计算峰值到低谷的差别（T最大减T 分）的每个位置，标准为每每个站点100例。使用Wilcoxon秩和检验比较规范的纬度范围内的峰值到低谷的差别。选择的代码，然后单击“执行（做）”。 </li></ol> 4.模拟紫外辐射数据<ol><li>运行使用命令加载的紫外线辐射数据。计算平均每月紫外线辐射的使用EGEN命令的每个位置。选择的代码，然后单击“执行（做）”。 </li><li>绘制每月紫外线辐射（Y轴），按日历月（X轴）的散点图使用的双向散射作用的每个位置。在图形显示查看器中自动打开屏幕的每个情节。 </li><li>众议员吃步骤1.2的紫外线辐射数据，并使用该回归命令指定的，其中每月UVR被指定为因结果变量，并且在步骤2.1中指定的正弦和 ​​余弦三角函数位置级年度UVR趋势基础模型被结合到模型中作为解释变量。 </li><li>重复步骤2.4至2.6的紫外线辐射模型并仅限于该特定位置的模型。这涉及到重新运行双向散射命令覆盖预测估计的观测数据，并使用回归命令来运行扩展的谐波模型的替代品。 </li><li>通过4.4使用的步骤4.2确定特定地点的月度紫外线辐射的最佳拟合模型中使用的生成命令再次申请步骤3.1中指定的双角公式来计算相移点估计和相关的95％置信区间紫外线辐射。计算T最小（槽紫外线辐射的日期），使用日每个位置在步骤3.1Ë公式来描述。选择的代码，然后单击“执行（做）”。 </li></ol> 5.模拟紫外线辐射谷底到复发峰值滞后<ol><li>从步骤4.5，并从使用合并命令每个位置步3.1复发高峰日期追加的紫外线辐射的季节性低谷模型估计的日期。使用生成命令来计算失效的紫外线辐射低谷日期和随后的复发高峰日期间个月的时间。选择的代码，然后单击“执行（做）”。 </li><li>使用sktest命令使用夏皮罗-威尔克测试选择的代码，从正态性检验紫外线辐射低谷到复发高峰期滞后变量显著出发，然后单击“执行（做）”。 </li><li>使用合并命令追加位置级别的纬度数据集。相对纬度转换为使用ABS（x）函数绝对纬度。选择的代码，然后单击“执行（做）”。 </li><li>使用回归命令，测试线性Ôf显示运行线性和二次回归和残差比较滞后，绝对的纬度之间的关系。选择的代码，然后单击“执行（做）”。 </li><li>使用倒退 ，指定线性意味着与紫外线辐射谷底到复发峰值滞后作为因变量的结果，绝对的纬度在10度的预测变量单位回归模型。重量的模型的患者贡献的使用aweights倒退选项的每个位置的数目。选择的代码，然后单击“执行（做）”。 </li><li>使用双向散射命令绘制关于对UVR-槽到复发滞后y轴的绝对纬度在月上的x轴。叠加线使用lfit图选择最适合的。 Visualise每个位置的使用aweight分析权重的选择相对患者体重。选择的代码，然后单击“执行（做）”。 </li></ol>患者级复发第6页。敏感性分析ropensities <ol><li>使用mepossion命令来指定一个混合效应泊松回归，其中每月的复发次数是因结果变量，在步骤2.1规定的正弦和 ​​余弦三角函数再次纳入模型作为固定变量，基线EDSS，年龄在MS发病和事先接触到MS特定疾病修饰治疗被包括作为潜在的混杂因素和独特的患者标识符被指定为随机效应。选择的代码，然后单击“执行（做）”。 </li><li>重复步骤2.4至2.6，以确定最佳拟合泊松模型。这涉及到重新运行双向散射命令覆盖预测估计的观测数据，并使用回归命令来运行扩展的谐波模型的替代品。 </li><li>使用的估计量函数（nlcom）的非线性组合来计算点估计和95％置信区间为相移和计算日期高峰复发次数。比较与主要的分析结果。 </li><li>使用生成命令如步骤5.1中所述，使用高峰期复发日期衍生步骤6.3病人级泊松模型估计重新计算紫外线辐射谷底到复发峰值滞后几个月的每个位置。选择的代码，然后单击“执行（做）”。 </li><li>使用回归命令步骤5.5描述和比较的初步分析结果重塑绝对纬度滞后的预测。选择的代码，然后单击“执行（做）”。 </li></ol>

蒂姆·斯佩尔曼收到酬金咨询和从Biogen Idec公司公司差旅资金;奥尔拉灰色收到的差旅补助从Biogen Idec公司，默克雪兰诺和诺华;补偿服务从Biogen Idec公司，Genzyme公司，诺华公司和默克雪兰诺公司的科学顾问委员会;罗宾·卢卡斯并没有透露任何利益争夺和赫尔穆特Butzkueven得到报酬担任科学顾问委员会，并担任顾问的Biogen Idec公司和诺华公司;从Biogen Idec公司澳大利亚，默克雪兰诺澳大利亚和诺华澳大利亚扬声器酬金;旅行从Biogen Idec公司澳大利亚和默克雪兰诺澳大利亚的支持;研究支持中国社会科学院基金会（澳大利亚），默克雪兰诺澳大利亚皇家墨尔本医院友神经科学基金会和墨尔本大学。

这里所描述的协议的细节进行系统回归基础的技术，通过可视化图分析全球MS复发发作的数据，指导。它需要为出发点，从整个两个半球20个国家的复发数据的相对简单的描述性分析，使用户能够探索复发发作时间在MS的时间性，并通过使用三角模型正式测试这些理论理论。通过第一绘制全局复发发作的数据，然后系统地作图和评估观察到的数据的候补几何配合的逐步过程，被观察到的季节槽UVR和?...

多发性硬化的最常见的形式（MS）被复发缓解多发性硬化（RRMS）。 RRMS的特征在于发作恶化神经功能，随后部分或完全恢复。全球范围内，MS的发病率和患病率增加而增加距离赤道两个半球1-3复发事件的发生特别是在RRMS的频率是否也随纬度而变化，以及是否有任何潜在的季节性变化在该等联想，仍不清楚。迄今为止的研究探索季节性复发时间被限制在单一临床中心，限制就季节性趋势复发时机孤立的地理位置，从而无法 ​​开拓更广阔的纬度影响的任何推论4-14这些研究通过小样本被进一步限制大小和稀疏复发的数据。从欧元临床中心2000年的一份荟萃分析10项研究OPE，美国和加拿大，其中每个研究包括至少30例报告复发的的发病季节，说明复发发作的时间明显的季节性趋势，复发高峰在春季和冬季槽4 。类似周期性年度趋势发病在随后的已观察到，虽然小，研究在日本15和西班牙16。然而，可比美国研究未能证实这一图案 17。迄今为止，这些研究和观察被限制在北半球。该MSBase研究小组最近分析了在这两个南半球和北半球MS复发的一个大的全球数据，探讨除了峰复发概率和季节紫外线（紫外线辐射）槽18之间的关系纬度影响，季节性趋势复发发病时间。中央对这些方法是三角回归的应用可视化和复发发作和紫外线辐射分布的时机评价的发展趋势。 这项研究的总体目标是测试复发发作MS的时刻在时间上的变化可预测变化与季节北部和南半球的假设，这是季节性的影响纬度。对于使用三角函数模型来调查这些问题的理由是它的灵活性用于表征已知或怀疑来描述离散的，可预测的和一致的形状或图案，如波峰和波谷通常的年度周期二维或三维现象在生物或流行病学现象具有季节性变化。19-22常规时间序列的缺点的分析，包括傅立叶分析，是假定，时间序列的特点往往是随机过程。21,23,24相比之下，结合三角函数我NTO回归型模型的定期和系统结构的周期性数据既便于开采利用的同时回归模型结构，开拓其他相关因素或调整季节性因素的混杂因素的优势。 三角函数回归以前已广泛应用于医学流行病学文献，探讨时间性的主题多种多样传染病疫情检测，昼夜节律的，一切从植物神经系统功能紊乱早产胎盘早剥通过先天畸形和时间的季节性相关因素的作用急症的演示。25-32这种建模通常要求较大的样本量超过常规的时间序列分析和因此这是第一次已经被施放到MS的复发发作全局数据集。这里所描述的三角回归是合适的工具，研究者探索任何pH值enomena这是众所周知的或可疑的骑自行车的系统随着时间的推移。不仅可这种建模帮助检定和可视化这些模式，进一步允许探索潜在的驱动程序，以及这些趋势相互关联的用户。 至于MS复发发作这里提出，利用散射和剩余地块具体的例子来可视化和评估如何接近一个假设三角模型形式拟合数据构成确定关键步骤：1）是否观察到的数据提供足够的证据支持季节性或其他时间趋势在复发发作的定时的假说;和2）是否正弦和余弦函数限定特定三角函数模型的频率和排列是足够以允许使用该模型用于随后的推理和预测的。回归模型还允许控制任何观察到的季节性或纬度的影响重要的混杂因素如病人级倾向为复发，这在本身随时间变化的诸如预复发暴露于疾病修饰药（DMD）治疗持续时间特别因素。分离独立地理和时间预测以及在MS复发发作定时相关因素有引导生物调查的复发事件而这又可以通知将来的治疗干预，以防止或延缓疾病发作的发展机制的潜力。 该MSBase注册 MS患者造成复发的数据这一分析国际MSBase注册表进行采购。成立于2004年，注册纵向整理人口，疾病活动度，临床检查和调查的特点和使用一个基于互联网的，医生拥有和经营系统同意参加MS患者的临床指标，33个会员中心遵循一个共同的protoc醇，定义所需的最小数据集以商定定期上载以保证结果的数据，如复发事件一致地和前瞻性编译。复发发作的日期是作为一个强制性的最低数据集变量。除了这些复发事件相关联的相关临床数据通常收集包括皮质类固醇治疗和受影响的功能系统。使用通用IMED数据输入系统进一步确保了中心的一个统一的方法来收集数据和报告。该项目包含人类研究伦理委员会每届促进中心批准或豁免。根据来自所有患者的当地法律的知情同意包括在分析中是强制性的。 纳入标准 总共有9811例患者造成32762复发事件被纳入分析。临床MS用最少的20例患者登记中心同意，uploaDED和跟踪在注册表中的1日2013年12月（资料整理的日）有资格列入分析。为了确保包含在分析中所有复发事件进行前瞻性观察，仅复发声母日之后的第一个记录，患者残疾评估（使用Kurtzke扩展残疾状态评分（EDSS））被包括在分析中。这些都有助于复发的数据来分析患者满意正规的诊断标准MS。34,35 结果措施 这项研究考虑了两个主要结果：1）是否有复发发作的地理位置，半球和/或全球水平的概率随时间的变化;和2）是否有在几个月纬度和滞后，之间的关系，季节性UVR波谷的定时和随后的峰复发概率日期之间。该MSBase研究组hypothe大小，作为绝对维生素D水平较低的区域中进一步远离赤道和特定位置的季节性群体水平的维生素D最低点更早有可能达到以下冬至在这种远侧位置，维生素D水平低的则上增加MS的效果复发的概率将同样描述了这样的时间和纬度分布格局。 复发的定义和日期 甲复发被定义为发生的新的症状或现有的症状至少持续24小时，在不存在的并发疾病或发烧的发作，和先前的攻击后发生至少30天。这个定义以前在MSBase复发的表型分析中得到应用。36随访时间为每个符合条件的患者横跨其复发的事件可以被观察到的定义是通过跨越第一EDSS评估日期的最近日期起计EDSS评估记录之前，数据提取和汇编的数据注册表。在情况下复发发作的确切日期是不可用或者不能被特定月份确定的，诊所使用，也可以在1日或者一个月的默认日期的第 15天。在32762复发本报告中分析中，有7913（24.2％）和4594（14.0％）被记录在每月的1日和15日当天分别显著高于比例记录在其范围在每月的任何一天从0.8％至5.6％。为了校正此，记录于复发任一月份的第 15天第 1次被随机分配到一个天15天都这些默认日期的时间间隔任一侧内。这种方法的内部效度是通过敏感性分析证实了这证明，峰值复发日起在默认的日期随机模拟的估计是不显著不同于模无论使用EL原来的报道日期，但不包括默认的日期完全。

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			<td height="42" style="height:42px;width:216px;">Stata SE Version 13</td>
			<td style="width:136px;">StataCorp, College Station, Texas</td>
			<td style="width:119px;">Version 13</td>
			<td style="width:345px;">Statistical analysis software used for analysis</td>
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		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Microsoft Excel 2010</td>
			<td style="width:136px;">Microsoft</td>
			<td style="width:119px;">2010</td>
			<td>Spreadsheet program for calendar date look-up</td>
		</tr>
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a method of trigonometric modelling of seasonal variation demonstrated with multiple sclerosis relapse data

This report describes a novel Stata-based application of trigonometric regression modelling to 55 years of multiple sclerosis relapse data from 46 clinical centers across 20 countries located in both hemispheres. Central to the success of this method was the strategic use of plot analysis to guide and corroborate the statistical regression modelling. Initial plot analysis was necessary for establishing realistic hypotheses regarding the presence and structural form of seasonal and latitudinal influences on relapse probability and then testing the performance of the resultant models. Trigonometric regression was then necessary to quantify these relationships, adjust for important confounders and provide a measure of certainty as to how plausible these associations were. Synchronization of graphing techniques with regression modelling permitted a systematic refinement of models until best-fit convergence was achieved, enabling novel inferences to be made regarding the independent influence of both season and latitude in predicting relapse onset timing in MS. These methods have the potential for application across other complex disease and epidemiological phenomena suspected or known to vary systematically with season and/or geographic location.

三角函数回归到来自全国各地20个国家的46个临床中心采购的32762复发事件该应用程序的基础是提供观察，复发发作的MS时机周期性和季节性的跨越南北半球和季节之间的持续时间可辩护的统计参数紫外线辐射槽和随后的复发高峰期与相关的自由度。关键这是依赖于情节的分析来指导模型开发，评估和细化的必然反复的过程。 复发次数由一个月散点图观测数据的分析建议以年为...

Watch this Scientific Journal Video about A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data at JoVE.com

A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data

Combining plot analysis with trigonometric regression is a robust method for exploring complex, cyclical phenomena such as relapse onset timing in multiple sclerosis (MS). This method enabled unbiased characterisation of seasonal trends in relapse onset permitting novel inferences around the influence of seasonal variation, ultraviolet radiation (UVR) and latitude.

季节变化的三角建模的方法证明与多发性硬化症复发数据

This report describes a novel Stata-based application of trigonometric regression modelling to  55 years of multiple sclerosis relapse data from 46 ...

a-method-trigonometric-modelling-seasonal-variation-demonstrated-with

Research

JoVE Journal

Medicine

10.6K 次观看.  Royal Melbourne Hospital. Combining plot analysis with trigonometric regression is a robust method for exploring complex, cyclical phenomena such as relapse onset timing in multiple sclerosis (MS). This method enabled unbiased characterisation of seasonal trends in relapse onset permitting novel inferences around the influence of seasonal variation, ultraviolet radiation (UVR) and latitude. 

视频: A Method of Trigonometric Modelling of Seasonal Variation Demonstrated with Multiple Sclerosis Relapse Data

A Protocol for Comprehensive Assessment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis (ALS)

Improved methods for assessing bulbar impairment are necessary for expediting diagnosis of bulbar dysfunction in ALS, for predicting disease progression across speech subsystems, and for addressing the critical need for sensitive outcome measures for ongoing experimental treatment trials. To address this need, we are obtaining longitudinal profiles of bulbar impairment in 100 individuals based on a comprehensive instrumentation-based assessment that yield objective measures. Using instrumental approaches to quantify speech-related behaviors is very important in a field that has primarily relied on subjective, auditory-perceptual forms of speech assessment1. Our assessment protocol measures performance across all of the speech subsystems, which include respiratory, phonatory (laryngeal), resonatory (velopharyngeal), and articulatory. The articulatory subsystem is divided into the facial components (jaw and lip), and the tongue. Prior research has suggested that each speech subsystem responds differently to neurological diseases such as ALS. The current protocol is designed to test the performance of each speech subsystem as independently from other subsystems as possible. The speech subsystems are evaluated in the context of more global changes to speech performance. These speech system level variables include speaking rate and intelligibility of speech.
The protocol requires specialized instrumentation, and commercial and custom software. The respiratory, phonatory, and resonatory subsystems are evaluated using pressure-flow (aerodynamic) and acoustic methods. The articulatory subsystem is assessed using 3D motion tracking techniques. The objective measures that are used to quantify bulbar impairment have been well established in the speech literature and show sensitivity to changes in bulbar function with disease progression. The result of the assessment is a comprehensive, across-subsystem performance profile for each participant. The profile, when compared to the same measures obtained from healthy controls, is used for diagnostic purposes. Currently, we are testing the sensitivity and specificity of these measures for diagnosis of ALS and for predicting the rate of disease progression. In the long term, the more refined endophenotype of bulbar ALS derived from this work is expected to strengthen future efforts to identify the genetic loci of ALS and improve diagnostic and treatment specificity of the disease as a whole. The objective assessment that is demonstrated in this video may be used to assess a broad range of speech motor impairments, including those related to stroke, traumatic brain injury, multiple sclerosis, and Parkinson disease.

A Protocol for Comprehensive Assessment of Bulbar Dysfunction in Amyotrophic Lateral Sclerosis ALS

Objective assessments of the physiological mechanisms that support speech are needed to monitor disease onset and progression in persons with ALS and to quantify treatment effects in clinical trials. In this video, we present a comprehensive, instrumentation-based protocol for quantifying speech motor performance in clinical populations.

延髓功能障碍肌萎缩性脊髓侧索硬化症（ALS）的综合评估议定书

Improved methods for assessing bulbar impairment are necessary for expediting diagnosis of bulbar dysfunction in ALS, for predicting disease progression ...

科研

医学

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 years for the sporadic disease and around 50 years for the familial disease. Due to its progressive course, 50% of the patients die within 30 months of symptom onset. In order to evaluate novel treatment options for this disease, genetic mouse models of ALS have been generated based on human familial mutations in the SOD gene, such as the SOD1 (G93A) mutation. Most important aspects that have to be evaluated in the model are overall survival, clinical course and motor function. Here, we demonstrate the clinical evaluation, show the conduction of two behavioural motor tests and provide quantitative scoring systems for all parameters. Because an in depth analysis of the ALS mouse model usually requires an immunohistochemical examination of the spinal cord, we demonstrate its preparation in detail applying the dorsal laminectomy method. Exemplary histological findings are demonstrated. The comprehensive application of the depicted examination methods in studies on the mouse model of ALS will enable the researcher to reliably test future therapeutic options which can provide a basis for later human clinical trials.

Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis ALS

A mouse model for amyotrophic lateral sclerosis (ALS) is examined clinically and behaviorally. As a prerequisite for an accompanying immunohistological analysis the preparation of the spinal cord is depicted in detail.

临床试验和脊髓去除在肌萎缩性侧索硬化症的小鼠模型（ALS）

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in progressive degeneration of motoneurons. Peak of onset is around 60 ...

Utility of Dissociated Intrinsic Hand Muscle Atrophy in the Diagnosis of Amyotrophic Lateral Sclerosis

The split hand phenomenon refers to predominant wasting of thenar muscles and is an early and specific feature of amyotrophic lateral sclerosis (ALS). A novel split hand index (SI) was developed to quantify the split hand phenomenon, and its diagnostic utility was assessed in ALS patients. The split hand index was derived by dividing the product of the compound muscle action potential (CMAP) amplitude recorded over the abductor pollicis brevis and first dorsal interosseous muscles by the CMAP amplitude recorded over the abductor digiti minimi muscle. In order to assess the diagnostic utility of the split hand index, ALS patients were prospectively assessed and their results were compared to neuromuscular disorder patients. The split hand index was significantly reduced in ALS when compared to neuromuscular disorder patients (P&#60;0.0001). Limb-onset ALS patients exhibited the greatest reduction in the split&#160;hand index, and a value of 5.2 or less reliably differentiated ALS from other neuromuscular disorders. Consequently, the split&#160;hand index appears to be a novel diagnostic biomarker for ALS, perhaps facilitating an earlier diagnosis.

Dissociated atrophy of intrinsic hand muscles, termed the split hand, appears to be a specific feature of amyotrophic lateral sclerosis (ALS).&#160;Consequently, a novel neurodiagnostic test, termed the split hand&#160;index, was developed to quantify the clinical phenomenon of the split hand, which differentiated ALS from mimic disorders.

在肌萎缩侧索硬化症的诊断游离本质手部肌肉萎缩实用工具

The split hand phenomenon refers to predominant wasting of thenar muscles and is an early and specific feature of amyotrophic lateral sclerosis (ALS). A ...

The Multiple Sclerosis Performance Test (MSPT): An iPad-Based Disability Assessment Tool

Precise measurement of neurological and neuropsychological impairment and disability in multiple sclerosis is challenging. We report a new test, the Multiple Sclerosis Performance Test (MSPT), which represents a new approach to quantifying MS related disability. The MSPT takes advantage of advances in computer technology, information technology, biomechanics, and clinical measurement science. The resulting MSPT represents a computer-based platform for precise, valid measurement of MS severity. Based on, but extending the Multiple Sclerosis Functional Composite (MSFC), the MSPT provides precise, quantitative data on walking speed, balance, manual dexterity, visual function, and cognitive processing speed. The MSPT was tested by 51 MS patients and 49 healthy controls (HC). MSPT scores were highly reproducible, correlated strongly with technician-administered test scores, discriminated MS from HC and severe from mild MS, and correlated with patient reported outcomes. Measures of reliability, sensitivity, and clinical meaning for MSPT scores were favorable compared with technician-based testing. The MSPT is a potentially transformative approach for collecting MS disability outcome data for patient care and research. Because the testing is computer-based, test performance can be analyzed in traditional or novel ways and data can be directly entered into research or clinical databases. The MSPT could be widely disseminated to clinicians in practice settings who are not connected to clinical trial performance sites or who are practicing in rural settings, drastically improving access to clinical trials for clinicians and patients. The MSPT could be adapted to out of clinic settings, like the patient&#8217;s home, thereby providing more meaningful real world data. The MSPT represents a new paradigm for neuroperformance testing. This method could have the same transformative effect on clinical care and research in MS as standardized computer-adapted testing has had in the education field, with clear potential to accelerate progress in clinical care and research.

The Multiple Sclerosis Performance Test MSPT: An iPad-Based Disability Assessment Tool

Precise measurement of neurological and neuropsychological impairment and disability in multiple sclerosis is challenging. We report methodologic details on a new test, the Multiple Sclerosis Performance Test (MSPT). This new approach to the objective of quantification of MS related disability provides a computer-based platform for precise, valid measurement of MS severity.

多发性硬化症性能测试（MSPT）：一个iPad为基础的残疾评估工具

Precise measurement of neurological and neuropsychological impairment and disability in multiple sclerosis is challenging. We report a new test, the ...

Adapted Resistance Training Improves Strength in Eight Weeks in Individuals with Multiple Sclerosis

Hip weakness is a common symptom affecting walking ability in people with multiple sclerosis (MS). It is known that resistance strength training (RST) can improve strength in individuals with MS, however; it remains unclear the duration of RST that is needed to make strength gains and how to adapt hip strengthening exercises for individuals of varying strength using only resistance bands. This paper describes the methodology to set up and implement an adapted resistance strength training program, using resistance bands, for individuals with MS. Directions for pre- and post-strength tests to evaluate efficacy of the strength-training program are included. Safety features and detailed instructions outline the weekly program content and progression. Current evidence is presented showing that significant strength gains can be made within 8 weeks of starting a RST program. Evidence is also presented showing that resistance strength training can be successfully adapted for individuals with MS of varying strength with little equipment.

Hip weakness is a common symptom affecting walking ability in people with multiple sclerosis. Isolated muscle strengthening is a useful method to target specific weaknesses. This protocol describes a progressive resistance-training program using exercise bands to increase hip muscle strength.

改编阻力训练提高力量在八周内的个人与多发性硬化症

Hip weakness is a common symptom affecting walking ability in people with multiple sclerosis (MS). It is known that resistance strength training (RST) can ...

A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation (tDCS) in Multiple Sclerosis (MS)

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low amplitude direct currents to alter cortical excitability. With well-established safety and tolerability, tDCS has been found to have the potential to ameliorate symptoms such as depression and pain in a range of conditions as well as to enhance outcomes of cognitive and physical training. However, effects are cumulative, requiring treatments that can span weeks or months and frequent, repeated visits to the clinic. The cost in terms of time and travel is often prohibitive for many participants, and ultimately limits real-world access. 
Following guidelines for remote tDCS application, we propose a protocol that would allow remote (in-home) participation that uses specially-designed devices for supervised use with materials modified for patient use, and real-time monitoring through a telemedicine video conferencing platform. We have developed structured training procedures and clear, detailed instructional materials to allow for self- or proxy-administration while supervised remotely in real-time. The protocol is designed to have a series of checkpoints, addressing attendance and tolerability of the session, to be met in order to continue to the next step. The feasibility of this protocol was then piloted for clinical use in an open label study of remotely-supervised tDCS in multiple sclerosis (MS). This protocol can be widely used for clinical study of tDCS.

A Protocol for the Use of Remotely-Supervised Transcranial Direct Current Stimulation tDCS in Multiple Sclerosis MS

The goal of this pilot study is to describe a protocol for the remotely-supervised delivery of transcranial direct current stimulation (tDCS) so that the procedure maintains standards of in-clinic practice, including safety, reproducibility, and tolerability. The feasibility of this protocol was tested in participants with multiple sclerosis (MS).

一个协议，用于远程监督经颅直流电刺激（TDCS）在多发性硬化症的使用（MS）

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that uses low amplitude direct currents to alter cortical ...

Bioluminescence and Near-infrared Imaging of Optic Neuritis and Brain Inflammation in the EAE Model of Multiple Sclerosis in Mice

Experimental autoimmune encephalomyelitis (EAE) in SJL/J mice is a model for relapsing-remitting multiple sclerosis (RRMS). Clinical EAE scores describing motor function deficits are basic readouts of the immune-mediated inflammation of the spinal cord. However, scores and body weight do not allow for an in vivo assessment of brain inflammation and optic neuritis. The latter is an early and frequent manifestation in about 2/3 of MS patients. Here, we show methods for bioluminescence and near-infrared live imaging to assess EAE evoked optic neuritis, brain inflammation, and blood-brain barrier (BBB) disruption in living mice using an in vivo imaging system. A bioluminescent substrate activated by oxidases primarily showed optic neuritis. The signal was specific and allowed the visualization of medication effects and disease time courses, which paralleled the clinical scores. Pegylated fluorescent nanoparticles that remained within the vasculature for extended periods of time were used to assess the BBB integrity. Near-infrared imaging revealed a BBB leak at the peak of the disease. The signal was the strongest around the eyes. A near-infrared substrate for matrix metalloproteinases was used to assess EAE-evoked inflammation. Auto-fluorescence interfered with the signal, requiring spectral unmixing for quantification. Overall, bioluminescence imaging was a reliable method to assess EAE-associated optic neuritis and medication effects and was superior to the near-infrared techniques in terms of signal specificity, robustness, ease of quantification, and cost.

We show a technique for in vivo live bioluminescence and near-infrared imaging of optic neuritis and encephalitis in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis in SJL/J mice.

多发性硬化症的小鼠模型EAE视神经炎及脑部炎症的生物发光和近红外成像

Experimental autoimmune encephalomyelitis (EAE) in SJL/J mice is a model for relapsing-remitting multiple sclerosis (RRMS). Clinical EAE scores describing ...

Precision Implementation of Minimal Erythema Dose (MED) Testing to Assess Individual Variation in Human Inflammatory Response

Minimal erythema dose (MED) testing is frequently used in clinical settings for determining the smallest amount of ultraviolet (UV) irradiation necessary to produce erythema (inflammatory reddening) on the surface of the skin. In this context, the MED is regarded as a key factor in determining starting doses for UV phototherapy for common skin conditions such as psoriasis and eczema. In research settings, MED testing also has potential to be a powerful tool for assessing within- and between-persons variation in inflammatory responses. However, MED testing has not been widely adopted for use in research settings, likely owing to a lack of published guidelines, which is a barrier to obtaining reproducible results from this assay. Also, protocols and equipment for establishing MED vary widely, making it difficult to compare results across laboratories. Here, we describe a precise and reproducible method to induce and measure superficial erythema using newly designed protocols and methods that can easily be adapted to other equipment and laboratory environments. The method described here includes detail on procedures that will allow extrapolation of a standardized dosage schedule to other equipment so that this protocol can be adapted to any UV radiation source.

Precision Implementation of Minimal Erythema Dose MED Testing to Assess Individual Variation in Human Inflammatory Response

Minimal erythema dose (MED) testing is used to establish dosage schedules for ultraviolet radiation phototherapy. It can assess individual variation in inflammatory response but lacks methodology for achieving reproducible results. Here, we present a precision implementation of MED and demonstrate its ability to capture individual variation in inflammatory response.

精确实施最小红斑剂量（MED）测试，以评估人体炎症反应中的个体变异

Minimal erythema dose (MED) testing is frequently used in clinical settings for determining the smallest amount of ultraviolet (UV) irradiation necessary ...

A Pre-clinical Rat Model for the Study of Ischemia-reperfusion Injury in Reconstructive Microsurgery

Ischemia-reperfusion injury is the main cause of flap failure in reconstructive microsurgery. The rat is the preferred preclinical animal model in many areas of biomedical research due to its cost-effectiveness and its translation to humans. This protocol describes a method to create a preclinical free skin flap model in rats with ischemia-reperfusion injury. The described 3 cm x 6 cm rat free skin flap model is easily obtained after the placement of several vascular ligatures and the section of the vascular pedicle. Then, 8 h after the ischemic insult and completion of the microsurgical anastomosis, the free skin flap develops the tissue damage. These ischemia-reperfusion injury-related damages can be studied in this model, making it a suitable model for evaluating therapeutic agents to address this pathophysiological process. Furthermore, two main monitoring techniques are described in the protocol for the assessment of this animal model: transit-time ultrasound technology and laser speckle contrast analysis.

Here, we describe a pre-clinical animal model for studying the pathophysiology of ischemia-reperfusion injury in reconstructive microsurgery. This free skin flap model based on the superficial caudal epigastric vessels in the rat may also allow for the evaluation of different therapies and compounds to counteract ischemia-reperfusion injury-related damage.

重建显微外科缺血再灌注损伤研究的临床前大鼠模型

Ischemia-reperfusion injury is the main cause of flap failure in reconstructive microsurgery. The rat is the preferred preclinical animal model in many ...

Imaging Features of Systemic Sclerosis-Associated Interstitial Lung Disease

Early diagnosis of systemic sclerosis-related interstitial lung disease (SSc-ILD) is important to enable treatment to be administered with minimal delay. However, diagnosing SSc-ILD is challenging because key symptoms are non-specific. High-resolution computed tomography (HRCT) of the chest is recognized as a sensitive imaging method for diagnosing and assessing SSc-ILD. Exposure of patients to ionizing radiation may be considered as a limitation, although methodological steps may be taken to moderate this. We present practical recommendations for performing HRCT scans and interpreting the results. Key features of SSc-ILD on HRCT include a non-specific interstitial pneumonia (NSIP) pattern with peripheral ground-glass opacities and extensive traction bronchiectasis. Despite similarities between SSc-ILD and idiopathic pulmonary fibrosis (IPF), HRCT can be used to differentiate between these conditions: in SSc-ILD compared with IPF, there is a greater proportion of ground-glass opacity and fibrosis is less coarse. A dilated, air-filled esophagus with diameter &#62;10 mm, suggestive of esophageal dysmotility is commonly seen in SSc-ILD. Pulmonary artery size greater than the adjacent ascending aorta suggests coexistent pulmonary hypertension. Nodules must be monitored due to the increased risk of lung cancer. A large extent of disease on HRCT (&#8805;20%) or a high fibrosis score suggests an increased risk of mortality. HRCT is central to diagnosing SSc-ILD, and serial assessments can be helpful in monitoring disease progression or treatment response.

Here, we present practical recommendations for performing thoracic high-resolution computed tomography for diagnosing and assessing systemic sclerosis-related interstitial lung disease.

全身硬化-相关间交性肺病的成像特征

Early diagnosis of systemic sclerosis-related interstitial lung disease (SSc-ILD) is important to enable treatment to be administered with minimal delay. ...