托珠单抗联合改善病情抗风湿药治疗中重度类风湿关节炎短期临床观察

目的:研究托珠单抗联合改善病情抗风湿药（DMARDs）治疗中重度活动性类风湿关节炎（RA）12周临床疗效及不良反应。方法: 20例中重度活动的RA患者分别在0周、4周、8周接受托珠单抗8 mg/kg治疗,同时予以DMARDs治疗,在4周、8周、12周观察疗效及不良反应。观察指标为血沉、C反应蛋白（CRP）、类风湿因子（RF）、血红蛋白、血小板、疾病活动度评分（DAS28）、肝功能、肾功能、患者对疾病总体评价和医生对疾病总体评价及美国风湿病学会疗效评价指标（ACR20、ACR50）。结果: 与治疗前相比,20例RA患者在4周、8周、12周时血沉、CRP、RF、血小板均明显下降,差异均有统计学意义（P<0.01）;DAS28在治疗4周时明显改善,在治疗8周时进一步改善,差异均有统计学意义（P<0.01）;而血红蛋白在4周时明显上升,到12周时进一步上升,差异均有统计学差异（P<0.01）;患者和医生总体评价评分持续性下降,差异有统计学意义（P<0.01）;在8周和12周时达到ACR20者达90%、95%,达到ACR50者达80%、90%;20例患者中有1例出现上呼吸道感染,但无严重感染、肝肾损害及过敏反应发生。结论: 托珠单抗联合DMARDs治疗RA短期之内即改善患者的症状体征及炎症指标,且无明显不良反应发生。     

托珠单抗与依那西普治疗多关节炎型幼年特发性关节炎临床研究

目的:探讨托珠单抗与依那西普治疗多关节炎型幼年特发性关节炎（polyarticular juvenile idiopathic arthritis,pJIA）患儿的临床疗效,免疫调节作用及安全性差异。方法:选择2017年1月至2019年3月在浙江大学医学院附属儿童医院诊治的24例重度活动性pJIA患儿,分为托珠单抗组12例和依那西普组12例,分别记录两组患儿治疗前、治疗3个月、6个月、12个月时的临床症状、实验室指标及不良反应情况,并进行对比分析。结果:治疗3个月时,托珠单抗组和依那西普组的关节肿胀数、关节压痛或活动时疼痛数、C反应蛋白（CRP）、红细胞沉降率（ESR）及JADAS 27评分均较治疗前有明显改善（P<0.05）;且托珠单抗组的CRP、ESR、JADAS 27评分比依那西普组下降更明显（P<0.05）。治疗6个月时,托珠单抗组CD19+B、CD4+T细胞比例、IgG、IgA、IgM、C3、C4下降和CD8+T细胞比例升高,比较治疗前差异有统计学意义;依那西普组IgG和IgA较治疗前明显下降;托珠单抗组IgG、IgA、IgM、C3、C4比依那西普组下降更明显（P<0.05）。治疗12个月时,托珠单抗组和依那西普组的JADAS 27低疾病活动度率分别为36.4%和37.5%;两组的ACR Pedi 30/50/70/90分别达到100%/100%/87.5%/62.5%和100%/100%/81.9%/45.5%的缓解。两组患儿的不良反应最常见为感染,无严重不良事件发生。结论:托珠单抗与依那西普治疗pJIA疗效确切,托珠单抗能更快降低炎症指标,改善疾病活动度,并可调节亢进的体液免疫及调节CD4+T、CD19+B细胞。     

HER2阳性乳腺癌辅助治疗中帕妥珠单抗和曲妥珠单抗的个体化给药研究

目的:为一个亚裔早期乳腺癌患者制定并实施曲妥珠和帕妥珠单抗的个体化治疗方案。方法:曲妥珠和帕妥珠单抗是HER2阳性乳腺癌患者的重要治疗药物。尽管药动学相似,但推荐的给药方案不同：帕妥珠单抗为固定剂量,而曲妥珠单抗剂量取决于体重;帕妥珠单抗给药为每三周一次,但曲妥珠单抗给药为每周一次或每三周一次。当两种药与化药物合并使用时,执业医师对给药方案的选择有限。剂量-暴露量-效应关系是决定给药方案的重要依据。为了解个体患者的剂量-暴露量-效应关系,我们审查了群体药动学分析文献以了解对暴露量有影响的协变量（疾病状态和体重等）,另外考虑了有效和安全性因素如最低有效性浓度,亚洲患者的不良事件发生率,及给药方便性等。结果:基于对帕妥珠和曲妥珠单抗的群体药动学及药动和协变量关系的了解,对该患者制定并实施了曲妥珠和帕妥珠单抗的每两周一次的个体化给药方案。结论:个体化给药方案的制定需个体化剂量-暴露量-效应关系支持,而群体分析是了解个体化剂量-暴露量-效应关系的重要工具。     

药物临床试验不良事件监管问题分析

目的: 研究药物临床试验不良事件监管过程中存在的问题。方法: 通过查阅机构临床试验相关资料,分析2011年至2016年承担的完成临床部分的Ⅱ-Ⅳ期及上市后再评价药物临床试验中不良事件的监管质量。结果: 对165项药物临床试验的所有不良事件及其中的39人次严重不良事件整理后,获得实验室检查类不良事件有无漏记、原始病历和病例报告表的不良事件记录一致性、不良事件跟踪及复查情况、不良事件记录的及时率、严重不良事件是否按规定时间上报5个监控问题影响因素的相关数据。结论: 现有药物临床试验安全性评价体系尚存在一定问题,要解决这些问题,必须加强研究者的培训和全方位的过程管理。     

临床药师参与诊断或发现药品不良事件的典型病例分析

目的: 探讨临床药师基于药品不良事件开展临床药学服务的方式。方法: 通过典型案例分析,介绍临床药师从不同的角度识别药物不良事件,协助医生制订合理、有效的治疗方案。结果: 临床药师可通过采集用药史、关注药物相互作用、监测血药浓度及检索国内外文献等方面鉴别药物不良事件。结论: 临床药师应积极参与到临床医疗实践中,提高专业水平,及时为临床医疗提供科学有效的参考依据,使临床药师在临床合理治疗,提高疗效,保障安全和促进医患和谐的实践中发挥作用和体现价值。     

临床试验中严重不良事件一致性核对的优化

目的:利用SAS程序实现安全性数据库与临床数据库严重不良事件一致性核对的半自动化,减轻人工工作量,提高核对的准确性。方法:以某CRO公司的严重不良事件一致性核对为例,通过SAS的Proc import程序将安全性数据库严重不良事件报告读入,与临床数据库中的严重不良事件合并,需进行核对的严重不良事件通过受试者号、不良事件编号或名称排序并导入EXCEL中,而后对两份不良事件中的同一数据点逐条进行比较,通过SAS DDE语言对EXCEL中不一致的数据点进行定位标记,使一致性核对更有针对性且更直观。结果:半自动化方法能够准确定位不一致的数据点,减轻人工核对的工作量,同时通过程序进行筛选匹配,减少了人工操作可能出现的随机错误。结论:此方法能一定程度上辅助人工核查,实现人工核查的半自动化,减少此类核查的人工依赖,保证核对的质量,具有较高的实际应用价值。     

基于美国FAERS数据库的依维莫司不良反应分析

目的:通过对美国FAERS数据库中依维莫司不良事件的统计分析,揭示依维莫司不良事件发生的规律,为依维莫司安全风险控制和临床合理用药提供参考。方法:采用回顾性研究方法,对美国FAERS数据库中1 868例依维莫司不良事件报告信息进行统计分析。结果:1 868例依维莫司不良事件报告中,导致死亡、有生命危险、致残、导致住院或住院时间延长的,合计达到67.71%;消费者报告的不良事件接近半数,报告国家以美国、日本、法国、德国为主;不良事件的临床表现排名前三位的分别是死亡382例（20.45%）;口腔炎168例（8.99%）;恶性肿瘤恶化154例（8.24%）结论:提示依维莫司不良反应相对较为严重,临床使用过程中需要高度关注;不良反应事件报告数与上报国家的经济水平有一定的相关性。     

KDR基因遗传变异对贝伐珠单抗一线治疗晚期非小细胞肺癌患者临床疗效的影响

目的: 本研究旨在探讨激酶插入区受体（KDR）基因遗传变异对贝伐珠单抗联合化疗治疗晚期非小细胞肺癌（NSCLC）患者疗效的影响。方法:本研究纳入135例一线接受贝伐珠单抗治疗的NSCLC患者,收集外周血及活检癌组织标本分别用来进行基因分型及表达测定。多态性位点的基因型和其他变量的相关性通过logistic回归模型进行分析。基因型和预后的单变量分析用Kaplan-Meier生存分析方法,并通过Cox风险比例模型对其他变量进行校正。结果:在KDR的标记多态性位点中,只发现了V297I位点的临床意义。V297I位点位于该基因的编码区,在研究人群的基因分布频率为：CC型99例（73.33%）,CT型33例（24.44%）,TT型3例（2.23%）,最小等位基因频率为0.14,三种基因型分布频率符合哈迪温伯格平衡（P=0.898）。后期比较将TT型和CT型患者合并,对不同基因型患者进行疗效分析发现：CT/TT基因型患者和野生型CC型患者的客观缓解率（ORR）分别为41.67%和47.47%（P=0.549）。CT/TT和CC基因型患者的中位无进展生存期（mPFS）分别为6.2和8.6个月,差异具有统计学意义（P=0.003）。在总生存期（OS）方面,两种基因型患者的中位总生存期（mOS）分别为18.9和21.5个月,差异具有统计学意义（P=0.017）。对无进展生存期（PFS）构建多变量的Cox模型校正之后发现CT/TT基因型对PFS的影响仍然具有统计学意义（OR=1.95,P=0.019）。另外,进一步在68例癌组织标本的表达分析中发现,CT/TT基因型患者相对于野生型的CC型患者,癌组织中KDR的表达明显较高,且差异具有统计学意义（P<0.01）。结论:在接受贝伐珠单抗治疗的非小细胞肺癌患者中,KDR基因V297I位点可能通过影响KDR基因的表达从而影响贝伐珠单抗一线治疗非小细胞肺癌患者的疗效。     

基于LabVIEW的砂带磨削力检测系统

针对砂带磨削工艺过程,基于LabVIEW虚拟仪器开发平台,设计了砂带磨削力监控及信号分析系统。该系统包括一系列硬件设备与LabVIEW软件结合,构建了磨削力测试实验平台,具有实时检测砂带磨削过程和磨削力信号采集、分析、显示与储存记录等功能。通过磨削力标定实验,得出了磨削力的标定公式。实际测试表明:该系统磨削力检测精度可以达到0.4N。     

基于小波分析的汽车EPS扭矩传感器故障检测

针对扭矩传感器正常工作信号、发生故障时信号和噪声信号在小波变换下的不同传播形式,利用小波变换的多分辨率分析特性,提出一种EPS扭矩传感器信号消噪和故障检测的方法,建立各种信号的模型,并进行仿真分析.结果表明,该方法能有效抑制噪声信号并检测出故障发生的时刻和故障信息,对汽车EPS系统的安全运行及故障诊断具有重要的工程应用意义.     

Titanium sintering science: A review of atomic events during densification

The sintering densification trajectory for titanium powder is identified in terms of the interaction between mass transport processes and microstructure evolution. During initial heating, as surface oxides dissolve, surface diffusion forms bonds between contacting particles without densification. Grain boundaries form in the bonds due to random crystal orientations at the contacts. Except for mixed powder Kirkendall swelling, subsequent diffusion in these interparticle grain boundaries leads to densification. Most importantly, the alpha-beta transformation provides strain, defects, and interfaces that accelerate densification in the 800–1100 °C temperature range. This is below a typical peak sintering temperature. Final densification involves beta phase volume diffusion and grain boundary diffusion. Densification slows due to grain growth and the loss of grain boundary area. Pores close near 92% density to trap impurities and reaction products inside the closed pores, often limiting sintered density to about 95% of theoretical. High final density requires slow heating or long holds at intermediate temperatures to evaporate impurities prior to pore closure. The master sintering curve is a means to link densification to process parameters without concern over detailing this cascade of transport mechanisms and microstructure changes.     

Life-cycle analysis of automobiles: A critical review of methodologies

Life-cycle analysis (LCA) has been described by its proponents as an environmental panacea, capable of providing engineers, designers, and managers with everything that they need to make environmentally correct decisions. Unfortunately, the goals of the technique and the reality of its application are very different. Like any analytical technique, its application requires the imposition of assumptions to accommodate limitations in budgets, resources, and know-how. Furthermore, the evaluation of the analytical results introduces questions of strategy and priority that are currently unresolved. Thus, while the concepts underlying LCA are readily understandable, the practical application of the method has substantial problems.     

On the load-bearing efficiency of open-cell foams: A comparison of two architectures related to two processes

Using a simple beam element, this study estimates the elastic stiffness of two isotropic open-cell foam architectures that approximate, respectively, the space between tightly packed fluid bubbles and that defined between densified solid particles, and finds little difference between the two microstructures above a relative density of a few per cent.     

Effect of calendering on paper surface micro-structure: A multi-scale analysis

Paper is a complex composite material. Its structure and surface greatly influence its end use properties. Calendering is a finishing process applied to paper to provide a shiny surface and to improve the smoothness. Hence, the control of the efficiency of calendering and the characterization of the final product necessitate the measure of the surface modification. Furthermore the relationship between the surface and the obtained level of gloss has to be further developed. The main purpose of this study is to describe the modification of the micro-structure at various scales of the paper surface due to the calendering process (under various processing conditions). The characterization of the paper surface was carried out thanks to an optical device allowing the topographic measurement to be taken at various scales. The equipment combines topographical imaging with a high definition camera, allowing measurement on the exact same area of the sample after each pass in the nip. We therefore introduce a new way to perform multi-scale analysis of the paper surface modification based on fractal theory.     

我国治疗新冠肺炎药物临床研究现状浅析

目的：分析疫情期间我国开展的新型冠状病毒肺炎（以下简称“新冠肺炎”）治疗药物临床试验的特点,提出防治新冠肺炎药物研发的建议。方法：在中国临床试验注册中心网站检索关于新冠肺炎的药物临床试验项目,对药物类别、研究目标、方案设计等进行分析。结果：截至2020年7月1日,与药物相关的临床试验项目共有271项。注册进行临床试验的药物主要是已上市药物,包括化学药、中药及生物制品,有些是药物联合应用。这些研究主要采取了随机或非随机平行对照试验设计,另外还有些是单臂、连续入组、析因分组等。结论：疫情期间应急开展药物临床试验、尽快发现有效的防治药物是应对疫情的重要措施,但同时本次新冠肺炎药物临床试验也暴露出在试验设计、实施及监管等方面存在的一些不足和短板,建议采取加强候选药物的科学性评价、规范研究者发起药物临床研究、建立由多学科组成的国家级抗病毒药物研发平台及协同创新攻关机制等措施,提升我国抗病毒药物的研发能力和水平。     

Materials analysis: A key to unlocking the mystery of the Columbia tragedy

Materials analyses of key forensic evidence helped unlock the mystery of the loss of space shuttle Columbia that disintegrated February 1, 2003 while returning from a 16-day research mission. Following an intensive four-month recovery effort by federal, state, and local emergency management and law officials, Columbia debris was collected, catalogued, and reassembled at the Kennedy Space Center. Engineers and scientists from the Materials and Processes (M&P) team formed by NASA supported Columbia reconstruction efforts, provided factual data through analysis, and conducted experiments to validate the root cause of the accident. Fracture surfaces and thermal effects of selected airframe debris were assessed, and process flows for both nondestructive and destructive sampling and evaluation of debris were developed. The team also assessed left hand (LH) airframe components that were believed to be associated with a structural breach of Columbia. Analytical data collected by the M&P team showed that a significant thermal event occurred at the left wing leading edge in the proximity of LH reinforced carbon carbon (RCC) panels 8 and 9. The analysis also showed exposure to temperatures in excess of 1,649°C, which would severely degrade the support structure, tiles, and RCC panel materials. The integrated failure analysis of wing leading edge debris and deposits strongly supported the hypothesis that a breach occurred at LH RCC panel 8. Authors’ Note: This document was prepared under the sponsorship of the National Aeronautics and Space Administration. Neither the United States government nor any person acting on behalf of the United States government assumes any liability resulting from the use of the information contained in this document, or warrants that such use will be free from privately owned rights. Editor’s Note: A hypertext-enhanced version of this article is available on-line at www.tms.org/pubs/journals/JOM/0402/Mayeaux-0402.html. Brian M. Mayeaux is with NASA Johnson Space Center; Thomas E. Collins is with The Boeing Company; Robert S. Piascik is with NASA Langley Research Center; Richard W. Russell is with the United Space Alliance; Gregory A. Jerman and Sandeep R. Shah are with NASA Marshall Space Flight Center, and Steven J. McDanels is with NASA Kennedy Space Center.     

Hydride-induced degradation of hoop ductility in textured zirconium-alloy tubes: A theoretical analysis

Hydride-induced degradation of hoop ductility in Zr-alloy tubular components has been studied for many years because of its importance in the nuclear industry. In this paper the role of intergranular and intragranular δ-hydrides in the degradation of ductility of the textured Zr-alloy tubes is investigated. The correlation among hydride distribution, orientation and morphology in the tubes is formulated based on thermodynamic modeling, and then analyzed. The results show that the applied stress, the crystallographic texture of α-Zr matrix, the grain-boundary structure, and the morphology and size of Zr grains simultaneously govern the site preference and the orientation of hydrides. A criterion is proposed to determine the threshold stress of hydride reorientation. The hoop ductility of the hydrided Zr tubes is discussed using the concept of macroscopic fracture strain. It is shown that the intergranular hydrides may be more deleterious to ductility than the intragranular ones. This work defines a general framework for understanding the relation of the microstructure of hydride-forming materials to embrittlement.     

The Interdependence model of grain nucleation: A numerical analysis of the Nucleation-Free Zone

Predictions by a 1-D analytical model and a 3-D numerical model of the formation of the Nucleation-Free Zone (NFZ) surrounding each growing grain during the initial transient of equiaxed solidification are compared. The extent of NFZ formation was studied under different solidification conditions in 1-D, 2-D and 3-D for both single-grain and multiple-grain growth scenarios with different geometric grain arrangements. The previously hypothesised NFZ concept presented by the analytic Interdependence model has been clearly demonstrated to exist for a range of solidification conditions. While there is good agreement between the 1-D numerical and analytic models, the 2-D and 3-D simulations of NFZ formation demonstrate that for some conditions the analytic model should be rederived in spherical coordinates. Further, the strong influence of the overlap of the diffusion fields between neighbouring grains was clearly demonstrated, revealing that the effect of competition between the rate of solute accumulation and cooling rate determines whether or not additional nucleation events are able to occur. It is also shown that a judicious choice of the growth rate term is essential for the analytical model to provide an accurate prediction of NFZ. Application of the computationally intensive 3-D simulations has allowed an improved solution to be derived that can be run at very low computational cost.     

Dependence of Strain Rate Sensitivity on the Slip System: A Molecular Dynamics Simulation

The strain rate of deformation might affect mechanical properties of metallic materials, especially at elevated temperatures. Due to the nature of dislocation slip, it is anticipated that strain rate sensitivity (SRS) depends on the slip system. While the dependency of SRS on the temperature and strain rate of the deformation is well recognized, its dependence on the slip system is not well understood. Accordingly, the molecular dynamics simulation was used to investigate the dependence of strain rate sensitivity of pure Al single crystals on the slip system. In this study, the embedded atom method (EAM) potential for Al was employed. SRS and shear strength of the material were studied in four different slip systems and at two temperatures of 300 and 500 K. It was found that SRS of the material depends on the slip system in addition to the temperature, and SRS was higher in less compact systems with more difficult slip. The dislocation theories were used to rationalize the simulation results.