Specifying Compositional Units for Correct Program Development
仿制药晶型研究的技术指导原则英文
仿制药晶型研究的技术指导原则英文Technical Guidance Principles for the Study of Generic Drug Polymorphs1. Comprehensive Literature Review:Conduct a thorough review of existing literature on the polymorphic forms of the reference drug substance. Identify the different polymorphs reported and their characterization methods, including X-ray diffraction, thermal analysis, and spectroscopic techniques.2. Sample Preparation:Ensure that the sample preparation technique maintains the integrity and purity of the reference drug substance. Use appropriate methods such as crystallization, recrystallization, or solvent evaporation to obtain the desired polymorphs for characterization.3. Controlled Crystallization Conditions:Conduct crystallization experiments under controlled conditions to promote the formation of specific polymorphs. Factors such as temperature, solvent selection, cooling rate, and agitation should be considered and optimized to achieve reproducible results.4. Polymorph Characterization:Employ a combination of analytical techniques to characterize the obtained polymorphs. X-ray diffraction is essential to confirm the crystalline nature and determine the crystal structure. Use thermal analysis techniques such as differential scanning calorimetry and thermogravimetric analysis to investigate thermal behavior. Complement these techniques with spectroscopic tools like infrared spectroscopy and solid-state nuclear magnetic resonance to confirm structural differences.5. Physical Property Comparison:Compare the physical properties (e.g., melting point, solubility, density) of the newly formed polymorphs with those of the reference drug substance. Any significant differences may indicate a new polymorphic form.6. Stability Studies:Conduct stability studies to evaluate the stability of the polymorphs under different environmental conditions, including temperature, humidity, and light exposure. Monitor changes in physical properties and assess any potential degradation or transformation.7. Bioavailability Studies:Perform bioavailability studies to determine if the newly formedpolymorphs exhibit similar or improved bioavailability compared to the reference drug substance. In vitro dissolution testing and in vivo pharmacokinetic studies can provide valuable insights into the drug's performance.8. Regulatory Compliance:Ensure that the research and development of generic drug polymorphs adhere to applicable regulatory guidelines, such as those set by the Food and Drug Administration (FDA) or European Medicines Agency (EMA). Demonstrate the equivalence or superiority of the polymorphs through rigorous scientific evidence.9. Documentation and Reporting:Maintain detailed records of all experimental procedures, data, and observations. Prepare comprehensive reports that summarize the research findings and provide sufficient evidence to support the conclusions drawn.10. Intellectual Property Considerations:Respect existing patents and intellectual property rights when conducting research on generic drug polymorphs. Ensure compliance with applicable legal requirements and consider seeking legal advicewhen necessary.Note: It is important to consult specific guidelines and requirements from regulatory authorities or professional organizations when conducting research on generic drug polymorphs.。
能源环境用富氮共轭微孔聚合物材料研究进展
㊀第40卷㊀第9期2021年9月中国材料进展MATERIALS CHINAVol.40㊀No.9Sep.2021收稿日期:2021-04-01㊀㊀修回日期:2021-06-09基金项目:国家自然科学基金资助项目(52073046,51873036,51673039,52103106);教育部长江学者奖励计划青年项目(Q2019152);上海市曙光人才计划项目(19S-G28);上海市自然科学基金项目(19D3859);中央高校基本科研业务资助项目(2232019A3-01,2232020D-08)第一作者:滕砺宽,男,1998年生,硕士研究生刘永盛,男,1998年生,硕士研究生通讯作者:吕㊀伟,女,1989年生,讲师,硕士生导师,Email:wlyu@廖耀祖,男,1982年生,研究员,博士生导师,Email:yzliao@DOI :10.7502/j.issn.1674-3962.202104005能源环境用富氮共轭微孔聚合物材料研究进展滕砺宽1,刘永盛1,吕㊀伟1,吴子豹2,廖耀祖1(1.东华大学材料科学与工程学院纤维材料改性国家重点实验室,上海201620)(2.南通斐腾新材料科技有限公司,南通226334)摘㊀要:共轭微孔聚合物(conjugated microporous polymers,CMPs)是一类由刚性芳香结构单元组成㊁自具微孔结构㊁具有三维网络骨架的有机多孔材料,具有稳定的多孔性和半导体特征,在电化学和热能存储㊁氢能转化㊁CO 2捕获和存储㊁污染物吸附和分离纯化等能源环境领域有着重要应用㊂其中,富氮共轭微孔聚合物因富含极性氮原子,具有强吸附位点和富电子结构,拥有独特的氧化还原电化学活性和一定的润湿性,显现出独特的应用优势㊂系统概述了富氮共轭微孔聚合物的制备及其在能源环境领域的应用研究进展,分析了各种制备方法的优缺点以及在应用方面存在的主要问题,并指出了富氮共轭微孔聚合物材料未来的发展方向 开发绿色㊁廉价的合成新方法以及相关高性能膜或块体材料的制备新路径等㊂关键词:有机多孔材料;富氮共轭微孔聚合物;制备方法;能源存储与转化;污染物吸附分离中图分类号:TQ317㊀㊀文献标识码:A㊀㊀文章编号:1674-3962(2021)09-0645-14Research Progress in Preparation of Nitrogen-RichConjugated Microporous Polymers for Energyand Environmental ApplicationsTENG Likuan 1,LIU Yongsheng 1,LYU Wei 1,WU Zibao 2,LIAO Yaozu 1(1.State Key Laboratory for Modification of Fibers and Polymer Materials,College of Material Science andEngineering,Donghua University,Shanghai 201620,China)(2.Nantong Feiteng New Matrials Technology Co.,Ltd.,Nantong 226334,China)Abstract :Conjugated microporous polymers (CMPs)are a class of porous polymers with three-dimensional network skeletonand microporous structure,which consist of rigid aromatic structural units.Owing to their characteristics of stable porosity and semiconductor,they have shown significant potentials in the applications of energy and environmental areas such as electro-chemical and thermal energy storage,hydrogen energy conversion,the capture and storage of CO 2and the adsorption,separa-tion and purification of pollutants.Among these CMPs,nitrogen-rich conjugated microporous polymers (NCMPs)possess extra adsorption active sites and electrons and therefore show the unique redox electrochemical activity and wettability because of their plentiful polar N atoms,endowing NCMPs with excellent performance in energy and environmental applications.In this review,the research progress in preparation of NCMPs for energy and environmental applications is summarized.The meritsand demerits of these preparation methods are analyzed.The main problems existing in the preparation methods and their applications are summarized.The future development direc-tions including developing new,green and cost-efficient syn-thetic method and new routes of high-performance membraneand bulk materials of NCMPs are finally proposed.Key words :organic porous materials;nitrogen-rich conjugated microporous polymers;preparation method;en-ergy storage and conversion;adsorption and separation of pollutants1㊀前㊀言多孔材料如沸石㊁金属有机框架㊁共价有机骨架㊁博看网 . All Rights Reserved.中国材料进展第40卷有机多孔聚合物等已广泛应用于能源存储与转化和污染物分离与吸附等能源环境领域㊂其中,有机多孔聚合物(porous organic polymers,POPs)由轻质元素组成,具有化学和热稳定性良好㊁比表面积高㊁孔隙率高㊁骨架密度低㊁分子可设计和易于功能化等优点㊂随着能源短缺和环境污染问题日益严重,设计合成性能优异的有机多孔聚合物材料成为当下的研究热点[1]㊂共轭微孔聚合物(conjugated microporous polymers, CMPs)作为一种新型有机多孔聚合物材料,是一类由π-π键连接的刚性芳香结构单元组成,自具微孔结构的三维骨架材料[2]㊂CMPs首次被报道于2007年,Cooper 课题组[3]通过Sonogashira偶联反应将芳香炔烃和芳香卤化物连接起来,进而制得共轭微孔聚乙炔撑芳基(PAEs)网络结构,其比表面积高达834m2㊃g-1㊂随后,一系列不同网络结构和性能的CMPs被陆续合成出来㊂其中,芳香环和共价键为CMPs骨架提供刚性和方向性,可防止微孔结构坍塌,赋予聚合物优异的热稳定性和化学稳定性;而共轭结构可为CMPs提供半导体特性[4],以上特性使得CMPs在电㊁热能源存储㊁氢能转化㊁CO2捕获和存储㊁环境污染物吸附和分离纯化等能源环境领域具有巨大的应用潜力[5]㊂通过向聚合物本体引入极性官能团或者杂原子可使CMPs进一步功能化㊂如引入氮原子,不仅能为CMPs提供额外的吸附活性位点㊁金属键合位点,并且这些氮原子中心还可以提供额外电子,使CMPs具有独特的氧化还原性和一定的润湿性,使其在能源环境相关领域中显现出更为优异的性能㊂本文旨在对能源环境用富氮共轭微孔聚合物的制备方法和应用进行系统归纳,并对目前该研究领域存在的问题进行分析和展望㊂2㊀富氮共轭微孔聚合物的制备方法因绝大多数具有共轭结构的单体都可作为CMPs的构筑单元,因此CMPs在结构单元的选择性上具有高度灵活性,从而具有很强的分子设计性㊂通常,富氮CMPs 的制备方法主要分为含氮原子共轭结构单元的C C偶联反应(如Suzuki,Sonogashira,Yamamoto偶联反应)㊁直接以胺基为聚合反应位点的C N偶联反应(如席夫碱缩合反应㊁Buchwald-Hartwig偶联反应)以及其它种类的反应(如Chichibabin吡啶合成反应㊁氧化聚合反应㊁氰基环化反应)等㊂2.1㊀含氮共轭结构的C C偶联反应(Suzuki,Sono-gashira,Yamamoto偶联反应)㊀㊀Suzuki和Sonogashira偶联反应是在钯催化作用下,卤代芳烃分别与硼酸芳烃或端炔芳烃进行C C键合的偶联反应㊂合理设计富氮共轭单体拓扑结构是构筑高性能富氮CMPs的关键㊂Jiang等设计合成具有类似化学组成,但构型和刚性不同的两种富氮型单体:2,2 -二氨基-3,3 ,5,5 -四溴联苯(单体1)和2,4,7,9-四溴苯并[C]噌啉(单体2),采用Suzuki和Sonagashira偶联聚合得到二氨基CMPs(DA-CMPs)和偶氮基CMPs(Azo-CMPs)的系列富氮型CMPs(图1)㊂研究表明,单体1中侧链的胺基占据了部分孔道致使最终聚合物的比表面积降低,而由单体2聚合所得的刚性偶氮基CMPs具有较高的比表面积(1146m2㊃g-1)㊂此外,胺基和偶氮基的引入都有效地增加了孔道与CO2的亲和力,而增加单体的刚性可以提高聚合物的比表面积,两者协同作用后使聚合物的气体吸附能力提高[6]㊂图1㊀Suzuki和Sonagashira偶联反应制备二氨基和偶氮基富氮共轭微孔聚合物[6]Fig.1㊀Synthetic route for DA-CMPs and Azo-CMPs by Suzuki and Sona-gashira crosslinking method[6]㊀㊀Yamamoto偶联反应是在镍催化剂作用下,双卤代芳烃或多卤代芳烃通过C C键合的偶联反应㊂该偶联方法的优点在于仅需要单个卤素官能化的单体,反应路线简单㊂因芳基卤化物单体种类繁多,故可通过Yamamoto偶联设计合成系列富氮CMPs㊂2017年,作者课题组[7]采用Yamamoto反应对聚咔唑进行吡啶㊁双吡啶㊁氰基功能化处理(图2)㊂相对于单纯的聚咔唑,极性氮功能化聚咔唑对CO2的选择性吸附显著增强,吸附焓由22.3提升到31.8kJ㊃mol-1㊂646博看网 . All Rights Reserved.㊀第9期滕砺宽等:能源环境用富氮共轭微孔聚合物材料研究进展图2㊀聚咔唑网络(PCZN)的反应路线[7]Fig.2㊀Synthetic route for polycarbazole network (PCZN)[7]2.2㊀席夫碱(Schiff base )缩合反应由芳香胺和芳香醛碳氮偶联缩合形成亚胺或甲亚胺特性基团( RC N )的席夫碱反应是制备富氮CMPs 的一种常用手段(图3)[8],该类富氮CMPs 在CO 2选择性吸附应用方面受到了研究者的广泛关注[9,10]㊂因该反应不使用金属催化剂,故而具有绿色㊁低成本㊁无二次污染的优点㊂合理选择芳香胺和芳香醛单体,席夫碱反应可以促使聚合物在水热条件下凝胶化,进而使生成的聚合物作为高性能氮掺杂炭气凝胶的前驱体㊂作者课题组[11]采用价格低廉的工业副品红碱和均苯三甲醛为原料,通过多次试验筛选溶剂类型㊁调控单体浓度及反应温度,设计合成富氮有机多孔聚合物纳米球凝胶,通过简单的高温热处理,一步法成功地制备得到了具有极高比表面积(2356m 2㊃g -1)的新型氮掺杂炭气凝胶,其CO 2/N 2选择性系数高达47.8㊂图3㊀席夫碱反应制备富氮共轭微孔聚合物[8]Fig.3㊀Nitrogen-rich CMPs synthesized via Schiff base reaction [8]2.3㊀Buchwald -Hartwig 偶联反应在少量钯的催化作用下,由芳香卤化物和芳香胺进行C N 偶联的Buchawald-Hartwig(BH)反应是制备富含亚胺氮CMPs 的又一常用方法㊂作者课题组于2014年首次将BH 偶联反应拓展到富氮CMPs 的高效制备上[12]㊂所制备的富氮CMPs 具有类似于导电高分子聚苯胺的独特氧化还原电活性,兼具微孔结构和优异电活性的特点,在电化学能源存储领域显现出了独特的优势㊂通过优化芳香胺的共轭长度和刚性,BH 偶联反应制备的富氮CMP 比表面积最高可达600m 2㊃g -1(图4)[13]㊂2019年以来,利用不同阴离子尺寸的盐(如NaF,NaCl,NaBr 和NaI)和阳离子尺寸的盐(如LiNO 3,NaNO 3,KNO 3和Ba(NO 3)2),对合成溶剂的Hansen 溶度进行调控并使之与聚合物的溶度常数匹配,可以将该类型CMPs 的比表面积提高到1152m 2㊃g -1㊂该方法对制备具有均一微孔孔径分布㊁高比表面积的富氮CMPs 具有指导意义[14,15]㊂2.4㊀Chichibabin 吡啶合成反应Chichibabin 吡啶合成是一种利用醛和氨发生缩合,得到2,3,5-取代吡啶的反应㊂该反应简单㊁易操作㊁反应时间短㊁反应条件温和且不使用任何金属催化剂,是一种绿色制备吡啶基富氮CMPs 的合成路径㊂作者课题组[16]于2020年首次选用对苯二甲醛和均苯三甲醛分别与苯乙酮和三乙酰基苯在醋酸铵/醋酸的混合溶剂中120ħ下回流1h(图5),制得纳米球状吡啶基富氮CMPs,即PCMPs㊂PCMPs 特有的电子结构使其在光催化产氢领域具有潜在的应用价值㊂进一步地,通过调控单体的几何拓扑结构和氮含量,实现了对PCMPs 能带和光催化制氢性能的调节,最高可实现1198.9μmol㊃g -1㊃h-1的光催化产氢速率(紫外光照射)[17]㊂Chichibabin 吡啶合成反应为光催化产氢聚合物催化剂提供了一种绿色的制备新途径㊂746博看网 . All Rights Reserved.中国材料进展第40卷图4㊀Buchawald-Hartwig偶联反应合成氨基蒽醌型共轭微孔聚合物(PAQ)网络[13] Fig.4㊀Synthetic route for the formation of PAQ networks via Buchawald-Hartwig cross-coupling reaction[13]图5㊀纳米球状吡啶基富氮共轭微孔聚合物(PCMPs)合成路径[16] Fig.5㊀Synthetic route to PCMPs[16]2.5㊀氧化聚合反应氧化聚合反应是富氮CMPs制备的另一常见手段,通常选用含苯胺㊁吡咯或咔唑单元的单体,在化学氧化剂如FeCl3的作用下进行化学氧化聚合或电化学氧化聚合㊂作者课题组[18,19]于2017年以FeCl3为氧化剂,硝基甲烷/氯仿混合溶液为反应溶剂分别对星状咔唑㊁苯胺单体进行化学氧化聚合,制备得到氮含量(质量分数)分别为6.1%和11.84%的富氮CMPs(图6和图7),比表面积高达1200m2㊃g-1(PTCT)㊂其中,由于PTCT的刚性交联结构,咔唑基富氮CMPs热解制备氮掺杂炭材料的产率可高达75%~80%㊂得益于其较高的微孔孔隙率㊁比表面积以及氮含量,该氮掺杂炭材料具有优异的CO2存储(19.6%, 0ħ,0.1MPa)和电化学储能性能(558F㊃g-1,1A㊃g-1)㊂与化学氧化聚合相比,电化学氧化聚合虽然产量较低,但却能通过调节扫描速率和氧化电位精准制备厚度图6㊀聚咔唑网络及其衍生炭的合成路径[18] Fig.6㊀Synthetic route to polycarbazole networks and their derived car-bons[18]846博看网 . All Rights Reserved.㊀第9期滕砺宽等:能源环境用富氮共轭微孔聚合物材料研究进展图7㊀富氮共轭微孔聚合物(NCMP1,NCMP2,NCMP3)网络的合成路径[19]Fig.7㊀Synthetic route to nitrogen-rich CMPs (NCMP1,NCMP2,NC-MP3)networks [19]可控的富氮CMPs 薄膜㊂相较于不溶不熔㊁难以加工的粉末状富氮CMPs,薄膜状材料更具实际使用价值,便于高性能分离膜和膜器件的开发和应用㊂2013年,Ma 等[20]以四(4-咔唑基苯基)甲烷为单体,通过电化学氧化聚合法制备了相应的CMPs 薄膜材料,用作聚合物太阳能电池的阳极层;2015年,该课题组[21]以Zn(II)-5,10,15,20-四[(咔唑-9-基)苯基]卟啉为单体,通过电化学氧化聚合得到厚度为60nm 的Zn-卟啉基CMPs 薄膜,并将其用作超级电容器电极材料;2017年,他们又以1,2-双(4-(9 H-[3,6-三咔唑]-9 -基)苯基)二氮烯为单体,采用电化学氧化聚合制备了光刺激响应型的CMPs 薄膜材料[22]㊂江东林㊁Scherf 等也通过电化学氧化聚合法合成了系列咔唑基CMPs 薄膜[23,24]㊂电化学氧化聚合法具有简单易行的特点,并可以拓展材料的功能性,但是其适用的单体分子具有一定的局限性㊂2.6㊀氰基环化反应将氰基单体和ZnCl 2在离子热条件下熔融,当温度超过400ħ时即可发生腈基环化反应,可将氰基单体链接形成C 3N 3的三嗪环网络,是另一种制备富氮CMPs 的方法㊂该类CMPs 又称为共价三嗪框架(CTFs),具有一定的结晶性㊂Kuo 等[25]利用自制的1,3,6,8-四氰基芘进行环化反应制备了一种芘基CTFs(图8),该材料的比表面积最高可达1019m 2㊃g -1,具有出色的电化学性能和CO 2吸附能力,在电化学能源存储和气体吸附分离中具有很大的应用潜力㊂相对其他制备方法而言,该方法的反应条件较苛刻,不利于后期的规模化制备及功能拓展㊂图8㊀芘基共价三嗪框架的合成路径[25]Fig.8㊀Synthetic route to pyrene-CTFs [25]3㊀富氮CMPs 在能源环境领域的应用富氮CMPs 因具有较高的氮含量㊁丰富的微孔结构㊁高孔隙率㊁π-π共轭体系㊁优良的化学和热稳定性等优点,在电能㊁热能等能源储存[13,26-38]㊁光电催化产氢等能源转化[39-47]㊁CO 2存储㊁环境污染物吸附与分离[7,11,12,18,19,48-60]等领域表现出了良好的应用潜力㊂3.1㊀电化学能源存储通过合理的分子结构设计可制备出具有高比表面积的CMPs,而掺杂的氮原子可以带来额外的氧化还原电化学活性㊂因此,富氮CMPs 可同时具备双电层电容和赝电容特性,作为超级电容器电极材料用于电化学储能,具有很大优势㊂基于BH 偶联反应制备的富氮CMPs 即保留了CMPs 的微孔特性,亚胺基的引入同时赋予了CMPs 类似聚苯胺的电化学活性,而进一步通过引入其他官能团,可显著增加材料的电化学储能性质[13,26,27]㊂作者课题组[13]通过BH 偶联反应将2,6-二氨基蒽醌(DAQ)和不同芳基溴化物进行交联,合成氨基蒽醌型共轭聚合物网络,并加工成柔性电极(图9),所制备的PAQs 柔性电极具有高比电容和良好的循环稳定性㊂将PAQs 组装成不对称双电极超级电容器,在0~1.6V 的工作电位下,该电容器表现出168F㊃g-1的比电容,并且在60Wh㊃kg-1的能量密度下具有1300W㊃kg-1的功率密度㊂组装的不对称超级电容器经过2000次循环后仍可保留高达97%的库伦效率和95.5%的比电容㊂该工作在高性能电化学储能用CMPs 的网络分子设计上提出了新颖且有前途的方法㊂进一步地,为了探究不同氮结构对电化学储能性能的影响,作者课题组[26]选择了带有不同取代基的吡啶基构件作为单体,通过BH 反应合成了一种富氮共轭微孔聚三苯胺(PTPA)网络,制备的CMPs 孔隙率可调,且具备氧化还原活性㊂电化学表征结果表明,在1.0mol㊃L-1H 2SO 4中,在0.5A㊃g-1的电流密度下,使用2,5-二氨基946博看网 . All Rights Reserved.中国材料进展第40卷图9㊀PAQs电极在0.5mol㊃L-1H2SO4中不同电流密度下的电化学存储容量曲线(a),2A㊃g-1电流密度下PAQs电极的电化学存储稳定性(b),PAQs电极组装的超级电容器阵列(c)[13]Fig.9㊀Specific capacitance of PAQs electrodes obtained at different current densities conducted in0.5mol㊃L-1H2SO4(a),electrochemical storage stability of PAQs electrodes(2A㊃g-1)(b),photograph of PAQs electrodes asymmetric supercapacitor arrays(c)[13]吡啶二盐酸盐制得的PTPA-25共轭微孔聚合物显示出最高的比电容,达到335F㊃g-1,并且具有出色的循环稳定性㊂利用BH反应,Patra等[28]制备了一种苯胺/芘连接的共轭微孔聚合物(pyrene aniline-based CMP,PYBDA),也表现出了良好的电化学存储性能㊂三嗪环网络中含有大量氮原子,以三嗪基化合物为原料,也可得到具有高比表面积和比电容的富氮CMPs㊂Bhaumik等[29]通过1,3,5-三(4-氨基苯基)三嗪与2,6-二甲酰基-4-甲基苯酚的溶剂热席夫碱缩合反应制备了一种新型CMPs,表现出了极好的能量存储能力㊂Dutta 等[30]在高温下合成了富含氮原子的三嗪基聚酰亚胺框架(TPI-P/TPI-N),其中TPI-P-700氮含量高达6.3% (质量分数),比表面积可达1650m2㊃g-1,其组装的对称超级电容器在0.5A㊃g-1的电流密度下能量密度为10.5Wh㊃kg-1㊂Wei等[31]用合成的三嗪基CMPs与石墨烯气凝胶复合,制备出的N-GA/CMPs具有更高的含氮量,其组装的超级电容器能量密度可得到进一步提高㊂与三嗪环结构相似,三苯胺基衍生物也具有星形结构㊂Zhang等[32]通过Suzuki反应和FeCl3化学氧化聚合反应合成了三苯胺基CMPs,其充放电速率快且循环稳定性好,可用于锂离子电池的正极材料㊂此外,作者课题组[33]利用Chichibabin交叉偶联反应,不添加金属催化剂,利用芳香醛和酮为单体㊁乙酸铵为氮源合成了吡啶基CMPs,即PCMPs㊂以PCMPs为前驱体,碳化得到氮掺杂多孔炭微球材料(NCM),比表面积高达1232m2㊃g-1㊂此NCM作为超级电容器电极材料时,表现出高的比电容和高功率密度㊂随着研究的进行,柔性可穿戴电子器件逐渐走进了人们的视野,为了满足人们对可穿戴电子设备小型化㊁灵活性和兼容性不断增长的需求,供能器件的柔性和可穿戴性成为了新的挑战[61]㊂由于其柔性和可编织性,一维纤维状超级电容器(FSCs)得到了广泛的关注[62]㊂在前有研究的基础上,作者课题组[27]通过BH反应在溴功能化的碳纳米管纤维(CNF)上进行CMPs的原位交叉偶联聚合,首次制备了宏观尺度的纤维状CMPs,即CNF@CMPs,该材料在1mA㊃cm-2电流密度下表现出高面积比电容(671.9mF㊃cm-2)㊂以CNF@CMPs作为电极,PVA/H3PO4为凝胶电解质,制备得到了全固态对称扭曲纤维状CNF@PTPA对称超级电容器,其在0.28mA㊃cm-2电流密度下,具有高面积比电容(398mF㊃cm-2);在1.4V的最大工作电压下,表现出高能量密度(18.33μWh㊃cm-2)㊂该纤维状对称超级电容器具有出色的柔韧性和机械稳定性,在10000次弯曲循环后,可保留初始比电容的84.5%㊂该研究为高性能可穿戴超级电容器(HPWS)的制备提供了一个新思路(图10)㊂056博看网 . All Rights Reserved.㊀第9期滕砺宽等:能源环境用富氮共轭微孔聚合物材料研究进展图10㊀对称纤维状超级电容器(FSCs)的制备示意图(a),CNT@CMPs 的合成示意图(b),FSCs 编织表带点亮手表的照片(c)及FSCs 十字绣点亮发光二极管的照片(d)[27]Fig.10㊀Schematic illustration of the fabrication for symmetrical fiber-shaped supercapacitors (FSCs)(a),synthetic route of CNT@CMPs(b),photographs of a knitted watchband containing FSCs powering a digital watch (c),photographs of a cross-stitched logo con-taining FSCs powering LED bubbles (d)[27]3.2㊀相变储热近年来,为了解决能源危机这一全球性问题,以减少化石燃料的消耗为目标,除了电化学器件,热能存储材料也得到了广泛的关注[63]㊂其中相变材料(phase change materials,PCMs)是潜热储能系统中最有效的储能系统之一㊂相变储热材料的机理是通过在发生相变过程中的吸热和放热来实现存储和释放热能,因具有储热密度高且在充放热过程中温度可控的优点,受到研究者的广泛关注[64],目前相变材料已经充分应用在太阳能存储[65]和建筑节能[66]等领域中㊂然而,在相变过程中熔融的PCMs 泄露问题严重限制了其应用性,为了解决这一问题,使用多孔材料的封装技术来制备形状稳定的PCMs 是一种有效方法[67]㊂作者课题组在2017年首次采用富氮多孔聚合物(N-POP)封装1-十八烷醇(ODA ),解决了相变材料泄露问题(图11a)[34]㊂富氮卟啉基多孔聚合物能够吸收红外光并将其转化为热能,具有优异的光热性质㊂以之为PCMs 的封装材料在某种程度上可显著提高材料的热稳定性㊂2021年,作者课题组[35]采用Diels-Alder 反应制备得到最高比表面积为650m 2㊃g -1的卟啉-二茂铁基富氮CMPs(PFCMP)(图11b),封装ODA 后所得的复合材料ODA@PFCMP 具有153.8J㊃g-1的高熔融潜热(图11c),并且具有长达425s 的储热稳定时间㊂采用多孔炭对PCMs 进行封装不仅可以有效防止PCMs 泄漏,并且在某种程度上可提高热传导效应[36]㊂研究表明,对多孔炭材料进行氮原子掺杂可有效改变材料的结构性质,进而提高封装PCMs 的形状稳定性和热传导效应[37]㊂设计合成富氮CMPs 则是制备氮掺杂多孔炭的一种有效途径㊂2020年,作者课题组[38]通过BH 反应制得螺旋芴和苯胺连接的CMPs(SACMPs)㊂以之为前驱体,热解得到高比表面积的多孔空心炭球(HCSPs),并对ODA 相变材料进行了有效的包封(图11d 和11e)㊂所得到的HCSPs /ODA 具有180~190J㊃g-1的高熔融潜热,加热速率与纯ODA 相当,并且具有良好的形状稳定性和热循环稳定性(图11f),有望应用于太阳能光热转化工程中㊂156博看网 . All Rights Reserved.中国材料进展第40卷图11㊀富氮多孔聚合物封装1-十八烷醇储热示意图(a)[34];卟啉-二茂铁基富氮共轭微孔聚合物的合成路径(b)及其封装1-十八烷醇的复合材料的热红外照片(c)[35];多孔空心炭球/1-十八烷醇复合物的合成路径(d),多孔空心炭球的TEM 照片(e),复合物的热红外照片(f)[38]Fig.11㊀Scheme showing the heat storage of ODA encapsulated by N-POP (a)[34];synthetic route to PFCMP (b)and the thermal infrared photosof composite material of ODA encapsulated by PFCMP (c)[35];synthetic route to HCSPs /ODA composite (d),TEM image of HCSPs(e),thermal infrared photo of HCSPs /ODA composite (f)[38]3.3㊀光催化制氢氢气燃烧无污染㊁释放热量高,是一种可替代化石燃料的绿色清洁燃料㊂作为可再生能源,氢气可通过光催化分解水获得㊂光催化析氢材料的研究主要集中在氮化碳材料或无机半导体材料上,但这些材料通常仅在紫外光区域展现出光催化活性,对可见光利用率低㊁活性较差[68,69]㊂CMPs 具有半导体特性,且氮的掺杂可对其电子结构进行调控,因此可以合理设计得到在可见光下具有一定光催化产氢活性的富氮CMPs [70]㊂Cooper 等[39]合成了一系列无定形的CMPs,比表面积最高可达1700m 2㊃g -1,在可见光下,无需添加金属助催化剂就可以进行光催化产氢㊂通过调整聚合单体结构,可以有效调控CMPs 的带隙宽度,赋予其可见光吸收的能力,与其它光催化剂相比具有显著的优势㊂该课题组[40]在低温下合成了一种具有层状结构的CTFs,在可见光下分解水析氢的速率最高可达2647μmol㊃g -1㊃h -1㊂此后,他们又通过Suzuki 反应合成了结构多样的系列CTFs,研究发现催化剂中残留的钯可以提高光催化活性㊂其中,采用2,5溴-苄腈单体合成的CTFs 光催化析氢速率最高,高达2946μmol㊃g -1㊃h-1[41]㊂任世杰等[42]通过Suzuki 偶联反应分别合成了具有噻吩单元和芴单元的4种三嗪基共轭微孔聚合物(TCMPs)㊂研究表明,TCMPs 具有较大的比表面积和与光催化分解水相匹配的光学带隙㊂该研究表明,通过改变功能单元结构和连接体的长度可以有效改变聚合物的能带带隙,进而调节聚合物的产氢性能㊂Yu 等[43]发现联吡啶基团的加入可提高CMPs 对可见光的吸收,进而显著提高CMPs 的光催化活性㊂作者课题组[16]通过芳基醛和酮之间的Chichibabin 反应合成了PCMPs,反应过程中不添加任何金属催化剂,合成快速且成本低廉㊂PCMPs 的电子结构适合可见光驱动水分解产氢,为开发新型绿色低廉聚合物光催化剂的制备提供了新思路㊂Xiang 等[44]设计了含双吡啶基团的CMPs (COP-PB-N2),双吡啶结构能够降低氢吸附和活化的能垒(图12a 和12b)㊂研制的COP-PB-N2的表观量子产率可达1mg㊃mL -1,是迄今为止CMPs 可达到的最高值㊂Maji 等[45]选用三(4-氨基苯基)胺(TAPA)和不同取代基的对苯撑乙炔(OPE)基于席夫碱反应合成了两种新型具有氧化还原活性的富氮CMPs (TAPA-OPE-mix 和TAPA-OPE-gly)(图12c)㊂两种富氮CMPs 对电催化还原O 2和光催化制H 2都显示出良好的多相催化活性和循环稳定性㊂此外,两种富氮CMPs 的氧化还原活性可用于铂纳米粒子的原位生成和固定,并且这些Pt@CMPs 表现出显著增强的光催化活性(图12d 和12e)㊂2021年,作者课题组[46]首次利用吡啶基PCMPs 锚定非贵金属Ni 或Co 原子,构建了单原子光催化剂(图13)㊂所制备的Ni@PCMPs 和Co@PCMPs 光催化剂具有适合可见光催化析氢活性的电子结构㊂其中,30%Co@PCMPs 的光催化析氢活性最高,析氢速率为1.72mmol㊃g -1㊃h -1,是纯PCMPs 的2倍,并具有良好的稳定性㊂这一研究为能源环境相关的CMPs 负载非贵金属单原子光催化剂的设计合成及制备提供了一种新的思路㊂256博看网 . 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翻译
多孔硅的超声表征使用遗传算法逆向解决问题关键词:遗传算法 ,逆向问题的解决,超声无损检测,多孔硅摘要:这篇文章写的是多孔硅超声表征的一种方法,利用遗传算法来选择解决逆问题的最优化方法。
使用描述水波通过浸在水中的样品的一维模型来计算透射光谱。
然后,通过使用插入法或者替代法测量水浸的带宽,样品的光谱通过快速傅立叶变换法来计算。
为了获得厚度,纵向黏度或密度等参数,需要使用以最优化为基础的基因算法。
做两个不同厚度的铝板做为对照实验来确认这个方法,尽管在超声波信号发生重叠的情况下,听觉上的参数仍非常符合。
最后,两个样品,晶体硅和硅表面的多孔硅被评价。
实际值与理论值比较符合。
为了解释一些小的矛盾需要做一些假设。
1.引言对于通过样品的超声波的分析允许声学参数,因此也需要被提取样品的力学参数。
大多数情况下,信号不会有重叠。
时间范围和频度范围的分析可以用来决定参数,例如波速,衰减时间或密度。
在某些情况下,在频度范围内的声波透射系数被用来计算这些参数。
当样品的厚度与波长的分步一致时,或者在多层样品中会发生重叠时,直接测量参数是不可能的。
然而,超声无损表征材料已在薄层的情况下进行了广泛的研究。
由于接收到的信号的复杂性,需要建立模型。
利用逆问题的解决方法,可以得到所需的参数。
但是,多数的最优化方法需要假设初使值。
在材料的参数变化较大的情况下,很难精确的设定初使值来得到正确的解决方案。
在这项研究中,提出一各遗传算法来限制初使值的影响。
事实上,这各优化方法收敛于全部解,并确定解的唯一性。
选择一个一维波传播模型来计算通过一个多层样品信号的波谱。
这个波谱段依赖于每层的几何性质和声学性质,比如,厚度,波速和波的密度。
为了验证的目的,对透射谱的理论浸渍铝合金板进行了计算并与经验值比较以获取样本的声学参数。
然后,对包含表面被侵蚀形成多孔硅层的样品进行研究。
波速和硅的密度是已知的。
多孔硅层被认为是均匀的,通过用遗传算法解决逆部里的方法来估计它的参数。
sci中平均免疫荧光强度英文
sci中平均免疫荧光强度英文Average Immunofluorescence Intensity (AIFI) in Scientific Research.Introduction:Immunofluorescence (IF) is a widely used technique in biomedical research to visualize and quantify the expression and localization of proteins within cells. It involves labeling specific proteins with fluorescent antibodies, allowing for their detection and measurement using microscopy. Average immunofluorescence intensity (AIFI) is a common parameter used to assess the expression levels of proteins in IF experiments. It provides a quantitative measure of the overall fluorescence intensity associated with a specific protein of interest.Measurement of AIFI:AIFI is typically determined using image analysissoftware, which quantifies the fluorescence intensity within a defined region of interest (ROI) containing the labeled protein. The ROI can be a cell, a subcellular compartment, or a specific structure within the cell. The software calculates the average pixel intensity within the ROI, excluding any background fluorescence. The resulting value represents the AIFI for the protein of interest.Factors Affecting AIFI:Several factors can influence the AIFI measured in IF experiments:Antibody Concentration: The concentration of the fluorescent antibody used affects the intensity of the signal. Higher antibody concentrations lead to increased binding and, consequently, higher fluorescence intensity.Protein Expression Levels: The abundance of the protein of interest directly affects the AIFI. Cells with higher protein expression levels exhibit stronger fluorescence signals and thus higher AIFI values.Background Fluorescence: Non-specific binding of antibodies or autofluorescence from cellular components can contribute to background fluorescence, which can reduce the AIFI of the target protein.Microscope Settings: The settings of the microscope, such as exposure time and gain, can influence the measured fluorescence intensity. Proper optimization of these settings is essential for accurate AIFI quantification.Applications of AIFI:AIFI is a valuable parameter in various scientific applications:Protein Expression Analysis: AIFI provides a quantitative assessment of protein expression levels in different cell types, experimental conditions, or disease states. It allows researchers to compare protein expression across samples and identify changes associated withspecific treatments or interventions.Subcellular Localization: AIFI can be used todetermine the subcellular localization of proteins. By quantifying fluorescence intensity in specific compartments, such as the nucleus or cytoplasm, researchers can gain insights into protein function and trafficking.Colocalization Studies: AIFI can assist in colocalization studies, where the overlap between different proteins is investigated. By measuring the AIFI of multiple proteins within the same ROI, researchers can determine the extent of colocalization and assess potential interactions between proteins.Drug Screening: AIFI can be used in drug screening assays to evaluate the effects of compounds on protein expression or subcellular localization. Changes in AIFI can indicate the efficacy of drugs or provide insights intotheir mechanisms of action.Conclusion:Average immunofluorescence intensity (AIFI) is a versatile and informative parameter widely employed in immunofluorescence experiments. It provides a quantitative measure of protein expression levels, subcellular localization, and colocalization. By carefully controlling experimental conditions and optimizing image analysis methods, researchers can obtain accurate and reliable AIFI measurements, enabling a deeper understanding of protein biology and cellular processes.。
98 德国 缺陷 正电子湮没
Appl.Phys.A66,599–614(1998)Applied Physics AMaterialsScience&Processing©Springer-Verlag1998 Invited paperReview of defect investigations by means of positron annihilationin II−VI compound semiconductorsR.Krause-Rehberg,H.S.Leipner,T.Abgarjan,A.PolityFachbereich Physik,Martin-Luther-Universität Halle-Wittenberg,06099Halle,Germany(Fax:+49-345/5527160,E-mail:krause@physik.uni-halle.de)Received:19November1997/Accepted:20November1997Abstract.An overview is given on positron annihilation stud-ies of vacancy-type defects in Cd-and Zn-related II−VI com-pound semiconductors.The most noticeable results among the positron investigations have been obtained by the study of the indium-or chlorine-related A centers in as-grown cad-mium telluride and by the study of the defect chemistry of the mercury vacancy in Hg1−x Cd x Te after post-growth an-nealing.The experiments on defect generation and annihila-tion after low-temperature electron irradiation of II−VI com-pounds are also reviewed.The characteristic positron life-times are given for cation and anion vacancies.PACS:61.70;78.70BII−VI compound semiconductors are considered for appli-cations in fast-particle detectors and can cover the whole wavelength range from the far infrared to the near ultraviolet in optoelectronic devices.The width of the band gap can be adjusted in pseudo-ternary compounds such as Hg1−x Cd x Te by varying the composition x.The II−VI semiconductors appeared promising for emitter or detector devices because of their excellent optical features together with the pre-dicted favorable transport properties.However,no techno-logical breakthrough has been achieved.This is mainly be-cause no II−VI compound,except CdTe,can be amphoteri-cally doped.Bulk crystals of ZnSe,CdSe,ZnS,and CdS are always n-type,independent of impurities[1].ZnTe appears only as p-type[2].A number of theoretical approaches for this behavior exists but nofinal experimental proofs for these theories have been given.The reason for the compensation could be the existence of extrinsic defects introduced during crystal growth.However,intrinsic defects or complexes of in-trinsic defects with dopants have also been discussed.The research on II−VI compounds was greatly stimulated by the growth of nitrogen-doped,p-type ZnSe layers by mo-lecular beam epitaxy(MBE)[3,4].p–n junctions were made, andfirst ZnSe-based blue lasers could be fabricated[5,6]. Nevertheless,the doping behavior of nitrogen-doped ZnSe layers is also not fully understood.It is not clear why only the nitrogen doping during MBE works for p-type conductiv-ity and why other epitaxial growth techniques provide hole densities of one order of magnitude lower[7].Obviously,the understanding of point defects in II−VI semiconductors is far from being complete.Vacancy-type defects,for example monovacancies and complexes contain-ing a vacancy,play an important role.A prominent defect in doped CdTe is the A center,identified by electron para-magnetic resonance measurements as a cadmium vacancy paired off with a dopant atom at the nearest neighbor site[8]. The dominant defect in Hg1−x Cd x Te is the mercury mono-vacancy,acting as an acceptor.A high concentration of V Hg may be the reason for the p-conductivity.These examples show the importance of experimental tools for the detection of vacancy-type defects.Such a method is positron annihila-tion,which was successfully applied for the investigation of the structure and the concentration of such defects in elemen-tal and compound semiconductors[9–11].Significant contri-butions have been made by positron annihilation to revealing the structure of such important defects in III−V compounds as the EL2defect and the DX center[12–14].The aim in this paper is to review available experimen-tal data on defect studies in II−VI compounds by positron annihilation.The paper is organized as follows.The relevant methods of positron annihilation spectroscopy and theoretical calculations of the positron lifetime in II−VI compounds are introduced in Sect.1.The experimental results on cadmium mercury telluride,cadmium telluride,and zinc-related II−VI compounds are reviewed in Sect.2.Section3summarizes positron data on irradiation-induced defects.1Basics of positron annihilation in semiconductors1.1Positron lifetime and Doppler-broadening spectroscopy The detection of defects by means of positron annihilation is based on the capture of prehensive treatments of positron annihilation in solids can be found elsewhere[15–18].Attractive potentials for positrons exist for open-volume defects,e.g.vacancies,and for negatively charged non-open600volume defects,e.g.acceptor-type impurities.The potential is based in the latter case only on the Coulomb attraction be-tween the positron and the negative defect[19].The main reason for the binding of positrons to an open-volume defect is the lack of the repulsive force of the nucleus.Additional Coulombic contributions,which enhance or inhibit the trap-ping owing to a negative or a positive charge,respectively, occur for charged vacancies[18].The positrons in a typical conventional positron experi-ment are generated in an isotope source.They penetrate the sample,thermalize and diffuse.They can be trapped in de-fects during diffusion over a mean distance of about100nm. This may result in characteristic changes of annihilation pa-rameters.The positron lifetime for open-volume defects is increased in relation to the undisturbed bulk.This is due to the reduced electron densities in these defects.The clustering of vacancies in larger agglomerates can be observed as an in-crease in the defect-related positron lifetime.The lifetime of a positron is monitored in positron lifetime spectroscopy(PO-LIS)as the time difference between the birth of the particle in the radioactive source,indicated by the almost simultan-eous emission of a1.27-MeVγquantum,and the annihilation in the sample,resulting inγrays with an annihilation energy of0.511MeV.The lifetime spectrum is formed by the col-lection of several million annihilation events.In general,the spectrum consists of several exponential decay components, which can be numerically separated(see Sect.1.3).Doppler-broadening spectroscopy(DOBS),as another positron technique,utilizes the conservation of momentum during annihilation.The total momentum of the positron and the electron is practically equal to the momentum of the annihilating electron.This momentum is transferred to the annihilationγquanta.The momentum component in the propagation direction,p z,results in a Doppler shift of the an-nihilation energy of∆E=p z c/2(where c is the speed of light).The accumulation of several million events for a whole Doppler spectrum in an energy-dispersive system leads to the registration of a Doppler-broadened line,which is caused by the contributions of electron momentums in all space di-rections.The distribution of electron momentums may be different close to defects,and this is reflected in characteris-tic changes of the shape of the annihilation line.Annihilations with core electrons having higher momentums are reduced, for example,for a vacancy,and thus the annihilation line be-comes narrower.The annihilation line is usually specified by shape parameters,such as the S parameter,which is defined as the area of afixed central region of the Doppler peak normal-ized to the whole area under the peak,i.e.to the total number of annihilation events.Another parameter is the W parameter, defined in the wing parts of the annihilation line.This param-eter is determined mainly by the annihilations of the positrons with core electrons.The W parameter is thus more sensitive to the chemical nature of the surrounding of the annihilation site.A plot of the W parameter versus the S parameter may be used for the identification of defect types[20,21].The slope of the line corresponds to the R parameter,which is charac-teristic for a certain defect type,independent of the defect concentration.If the pairs of(S,W)values plotted for differ-ent sample conditions lie on a straight line running through the bulk values(S b,W b),one has to conclude that one sin-gle defect type having different concentrations dominates the positron trapping.Positrons from an isotope source have a broad energy dis-tribution of up to several hundred keV.This leads to a mean penetration depth of some10µm,and thin epitaxial layers cannot be studied.Therefore,the slow positron beam tech-nique[22]was developed.It is based on the moderation of positrons,i.e.the generation of monoenergetic positrons with energies in the eV range.The energy of the positron beam can be adjusted in an accelerator stage.This allows the registra-tion of annihilation parameters as a function of the penetra-tion depth.Hence,depth profiling is possible with a variable information depth of up to a fewµm.The basics of the defect profiling by slow positrons in comparison with other methods was presented by Dupasquier and Ottaviani[23].A main result of the positron experiments is the positron trapping rateκ,which is proportional to the defect concentra-tion C,κ=µC.(1) The proportionality constantµis the trapping coefficient (specific trapping rate),which must be determined in correla-tion to an independent reference method.The determination of the trapping coefficient for semiconductors has been re-viewed by Krause-Rehberg and Leipner[24].Equation(1) holds strictly only in the case of a rate-limited transition of the positron from the delocalized bulk state into the deep bound state of the defect[18].This case describes well the positron trapping in vacancies.The trapping coefficient for small vacancy clusters(n≤5)increases with the number of incorporated vacancies n,µn=nµv,(2) whereµv is the trapping coefficient of monovacancies[25].1.2Temperature dependence of positron trapping in chargeddefectsThe trapping coefficientµin(1)is always a specific con-stant for a given temperature.The attractive potential is su-perimposed by a long-range Coulomb potential in the case of a charged defect.A positive charge causes a strong repul-sion of the positron,and trapping is practically impossible.In contrast,a negative charge promotes positron trapping com-pared to a neutral defect by the formation of a series of attractive shallow Rydberg states[26].The positron bind-ing energy to the shallow Rydberg states is of the order of some10meV and,therefore,the enhancement of positron trapping is especially effective at low temperatures,where the positron may not escape by thermal activation.Thus,a dis-tinct temperature-dependent trapping rate was obtained for negatively charged vacancies in Si[27]and in GaAs[28].A detailed description of the temperature dependence of positron trapping in negatively charged vacancies was given by Le Berre et al.[28].Non-open volume defects,such as acceptor-type impuri-ties or negatively charged antisite defects,may also act as positron traps provided that they carry a negative charge.The extended shallow Rydberg states are exclusively responsible for positron trapping.The binding energy of the positron is small and therefore these defects are called shallow positron traps.The positron–position probability density at the defect601 nucleus is vanishingly small because of the repulsion fromthe positive nucleus.Therefore,the positron is located andannihilates in the bulk surrounding the defect.The electrondensity felt by the positron equals the density in the bulkand hence the positron lifetime of the shallow trap is closeto the bulk lifetime.Positron trapping to these shallow trapsis important at low temperatures in practically all compoundsemiconductors.Manninen and Nieminen[29]calculated thetemperature dependence of the positron detrapping rateδ:δ=κCmk B T2πh23/2exp−E bk B T.(3)Here,κand C are the trapping rate and the concentration of the shallow positron traps.m is the effective positron mass,k B the Boltzmann constant,and E b the positron binding energy.The description of the trapping in charged defects shows that in the presence of several charged defect types in the ma-terial the temperature dependence of positron trapping may be rather complex and a quantitative evaluation of the annihi-lation parameters as a function of the temperature T is often not possible.1.3Trapping modelA phenomenological description of positron trapping was given by Berlotaccini and Dupasquier[30]and was later gen-eralized[31,32].The model is referred to as the“trapping model”.The aim is the quantitative analysis of lifetime spec-tra in order to calculate the trapping rates and the correspond-ing defect concentrations.Only one extended model that is sufficient for the interpretation of the experimental results is discussed in this paper.This model(Fig.1)includes two dif-ferent types of non-interacting open-volume defects and one shallow positron trap exhibiting thermal detrapping with the detrapping rateδ.The corresponding differential equations ared n b(t) d t =−(λb+κd1+κd2+κd3)n b(t)+δn d1(t),d n d1(t) d t =−(λd1+δ)n d1(t)+κd1n b(t),d n d2(t) d t =−λd2n d2(t)+κd2n b(t),d n d3(t)d t=−λd3n d3(t)+κd3n b(t).(4)Defect d1is the shallow positron trap,and d2and d3are open-volume defects,such as vacancies and vacancy agglom-erates.b denotes the bulk state.The n i are the normalized numbers of positrons in the state i(i=b,d1,d2,d3)at the time t,andλi are the corresponding annihilation rates(inverse positron lifetimes).The starting conditions are n b(0)=1and n d1(0)=n d2(0)=n d3(0)=0.The solution of(4)is a sum of four exponential decay terms,the prefactors of which are the intensities I1to I4.The lifetimesτ1toτ4are found in the exponents.The lifetimes and intensities are obtained asτ1=2Λ+Ξ,τ2=2Λ−Ξ,τ3=1λd2,τ4=1λd3,andFig.1.Scheme of a trapping model including two types of open-volumedefects,d2and d3,and one shallow positron trap,d1.The latter exhibitsthermally induced detrapping with the temperature-dependent detrappingrateδ.The individual trapping ratesκd1,κd2,andκd3and the correspond-ing annihilation ratesλd1,λd2,andλd3are drawn as arrows.λb is the bulkannihilation rateI1=1−(I2+I3+I4),I2=δ+λd1−12(Λ−Ξ)Ξ×1+κd1δ+λd1−12(Λ−Ξ)+κd2λd2−12(Λ−Ξ)+κd3λd3−12(Λ−Ξ),I3=κd2(δ+λd1−λd2)λd2−12(Λ+Ξ)λd2−12(Λ−Ξ),I4=κd3(δ+λd1−λd3)λd3−12(Λ+Ξ)λd3−12(Λ−Ξ).(5)The abbreviations in(5)areΛ=λb+κd1+κd2+κd3+λd1+δ,Ξ=(λb+κd1+κd2+κd3−λd1−δ)2+4δκd1.(6)The two long-lived lifetimes are equal to the defect-related lifetimes:τ3=τd2andτ4=τd3,and they are inde-pendent of the defect concentrations.The average positronlifetimeτfor this model is given byτ=4j=1I jτj.(7)The result(5)represents the components of the lifetime spec-trum.The experimental spectrum may be decomposed in suchcomponents,and the lifetimes and their intensities can beused to determine the corresponding trapping and detrappingrates.Equation(1)then provides the defect concentrations.Cases where the number of independent defects is smallerthan three can easily be obtained from(5)by setting the cor-responding trapping rates to zero.6021.4Theoretical calculation of positron lifetimesThe positron lifetimes in the bulk and in lattice defects of II −VI compounds were first theoretically calculated by Puska [33]who used the linear muffin-tin orbital band-structure method within the atomic sphere approximation.Monovacancies were treated in different charge states by the corresponding Green’s function method.More recent calcu-lations from the same group [34,35]used the superimposed-atom model [36].A supercell approach with periodic bound-ary conditions for the positron wave function retaining the three-dimensional character of the crystal was employed.The electron–positron correlation potential was treated with the local-density approximation (LDA)[37].The results of pure LDA calculations provided lifetimes,which were too low compared to experimental values.The calculation method was hence modified in such a way that the d-electron en-hancement factors for Zn ,Cd ,and Hg were scaled to provide the correct lifetimes for the pure metals [34,35].Another ap-proach used the enhancement factors for d electrons in Ag and Au [38].Calculations of positron lifetimes of vacan-cies were carried out with unscaled LDA [34,35],providing values that are obviously too small compared to the bulk life-times of the scaled LDA calculations.In order to compare the theoretical defect-related lifetimes to the experimental ones and to the bulk lifetimes (Table 1),the vacancy lifetimes given by Plazaola et al.[34,35]were multiplied by the ratio of the bulk lifetimes calculated for the pure and scaled LDA,respec-tively.No relaxation effects and Jahn-Teller distortions were taken into account in these computations.Although the positron lifetimes for almost all II −VI com-pound semiconductors have been calculated,only materials for which experimental data exist are included in Table 1.The calculated bulk lifetimes agree reasonably well with the ex-perimental values.However,the lifetimes calculated for the vacancies are always distinctly smaller than the measured ones.Table 1.Calculated and experimental positron lifetimes for II −VI semiconductors.The bulk lifetimes were calculated using a modified semi-empirical local density approximation (LDA)[34,35].The LDA lifetimes for the vacancies given by Plazaola et al.[34,35]are scaled by a factor to allow a more realistic comparison to the experiments (see text).The experimental values of the cation vacancies (vacancies of group II atoms)are related to the A centers in In -or Cl -doped CdTe ,to the mercury vacancies in Hg 1−x Cd x Te ,and to the Zn vacancies as part of complexes in Zn -related compounds,respectively.The only experimental value for anion vacancies (vacancies of group VI atoms)is that of the tellurium vacancy in Hg 1−x Cd x Te MaterialBulk lifetime /psCation-vacancy lifetime /ps Anion-vacancy lifetime /ps Calculated Experimental Calculated Experimental Calculated Experimental CdTe286291[104]298320±5[45,46]312–281[68]330±15[44,52,68]283±1[44]285±1[45,46]280±1[52]HgTe274274[68]285–300–Hg 0.8Cd 0.2Te –274[68]–309[69]–325±5[93]286[69]305[54,70]275[54]319[97]278[70]282[97]ZnO –169±2[88]–255±16[86,87]––183±4[86,87]211±6[102]ZnS 225230[78,80]240290[80]237–ZnSe 240240[79]253–260–ZnTe260266[78]266–297–2Characterization of defects in as-grown II –IV compounds 2.1Cadmium tellurideCadmium telluride can be amphoterically doped.However,the doping and compensation behavior are still not com-pletely understood.Important defects for the understanding of the compensation are the impurity-vacancy complexes called “A centers”[39].These centers consist of a group-II vacancy paired off with either a group-VII donor (F ,Cl ,Br ,I )on the Te site,or with a group-III donor (e.g.Ga ,In )the Cd site [40].The ionization level of the Cl -related A center,(V Cd Cl Te )−/0,was determined by photolumines-cence measurements to be located at 150meV above the va-lence band [41].The levels for the isolated monovacancies were also investigated experimentally.The 2−/−level of the Cd vacancy was found with electron paramagnetic resonance at E d −E v <470meV [42]and the 0/+level of the Te va-cancy (F center)at E d −E v <200meV (E d defect ionization level,E v position of the top of the valence band)[43].2.1.1The A center.Weakly In -doped cadmium telluride was studied by positron lifetime spectroscopy as a func-tion of the temperature [44–46].Distinct positron trapping in a monovacancy-type defect was found.The defect-related lifetime was given first as 330±5ps [44],but was corrected later to 320±5ps [45,46].The lifetime was interpreted to be either due to isolated Cd monovacancies in a double negative charge state or due to (V Cd In Cd )−complexes.The average positron lifetime exhibited a distinct decrease with decreasing temperature,which was attributed to the presence of shal-low positron traps,i.e.negatively charged non-open volume defects.The compensation mechanism in iodine-doped CdTe lay-ers grown by MBE was investigated by photoluminescence (PL),conductivity measurements,and Doppler-broadening603spectroscopy [47].The DOBS S parameter increased dis-tinctly with increasing iodine concentration,i.e.with the free-electron concentration.The iodine doping obviously induced vacancy-type defects.This result is in agreement with the proposed microscopic structure of the iodine-related A center [40].Kauppinen and Baroux [48]investigated CdTe crystals doped with In or Cl with positron lifetime and Doppler-broadening spectroscopy.The Doppler measurements were carried out in a background-reducing coincidence setup [49,50].Vacancy-type defects were found in all samples.Defect-related lifetimes of 323and 370ps were separated in CdTe :In and in CdTe :Cl ,respectively.The indium-or chlorine-related A centers were assumed to be the positron traps responsible.This interpretation was supported by the Doppler measure-ments in the high-momentum range of the spectrum,where the annihilation with core electrons dominates.It was con-cluded that the annihilation takes place in the cadmium va-cancy that is part of the A center.The distinct difference in the positron lifetime for In -and Cl -related A centers was ascribed to different open volumes.A stronger outward lat-tice relaxation was assumed for V Cd Cl Te .However,the ob-served longer lifetime may also be interpreted by the occur-rence of an additional defect with larger open volume (see discussion of Fig.3).In contrast to In doping,chlorine impurities lead to high-resistance CdTe material.A series of CdTe samples contain-ing chlorine in a concentration range from 100to 3000ppm was studied by positron lifetime measurements [51,52].The average positron lifetime measured as a function of the sam-ple temperature is shown in Fig.2.The reference sample exhibited a single-component spectrum with a temperature-independent lifetime of 280±1ps that was attributed to the bulk lifetime.The average lifetime increased strongly with in-100200280300320340360380300Sample temperature [K]A v e r a g e l i f e t i m e [p s ]Fig.2.Average positron lifetime as a function of the sample temperature measured in cadmium telluride with a chlorine content in a range from 100to 3000ppm [52].A nominally undoped sample is included for reference.The full lines are fits according to the trapping model of Fig.1and (5)L i f e t i m e [p s ]Cl content [ppm]10101T r a p p i n g r a t e [s ]-1Cl content [ppm]Fig.3a,b.Decomposition of the positron lifetime spectra measured in chlorine-doped cadmium telluride at room temperature as a function of the chlorine content [52].a Positron lifetime components.The two long-lived lifetimes (and ◦)represent the lifetimes τd2and τd3related to two de-fects with different open volumes.The shortest lifetime ()is the reduced positron bulk lifetime τ1,which corresponds reasonably to the lifetime (full line)calculated from a trapping model with two open-volume defects (ob-tained from (5)by setting κd1=0).b Trapping rates of the defects d2(A center)and d3calculated from the decomposition of the spectra.The dashed lines in a and b are drawn to guide the eyecreasing Cl content,showing that open-volume defects,prob-ably in a complex with chlorine,were present.It should be noted that the observed change of 100ps in τat T ≥250K is exceptionally large,indicating that the defect-related positron lifetime must be high.The open volume of the defects should thus be distinctly larger than that of a monovacancy.The lifetime spectra were decomposed at first into two components yielding a defect-related positron lifetime of 350to 395ps ,which increased with increasing Cl content [51].These results correspond well to the characteristic lifetime of 370ps found in CdTe :Cl by Kauppinen and Baroux [48].However,the variance of the fit in the experiments by Polity et al.[51]was rather poor,indicating the presence of an-other unresolved lifetime component.Indeed,repeated meas-urements with a higher figure of 2×107annihilation events allowed the decomposition of three components at tempera-tures above 250K for the same samples [52].Two lifetimes with τd2=(330±10)ps and τd3=(450±15)ps were sepa-rated (Fig.3a).Hence,the previously obtained defect-related lifetime of 370ps must be regarded as an unresolved mixture of τd2and τd3.The defect d2represents a monovacancy-related defect and is attributed to the chlorine A center,V Cd Cl Te .Defect d3obviously exhibits an open volume dis-tinctly larger than that of a monovacancy.The ratio τd3/τb =1.6indicates that d3comprises at least the open volume of a divacancy.For comparison,this ratio equals 1.34for the nearest-neighbor divacancy in CdTe according to the calcula-tions of Puska [38].In contrast to the earlier results [51],the reduced bulk lifetimes τ1calculated according to a trapping model with two open-volume defects (solid line in Fig.3a)agreed reasonably well with the measured values.This trap-ping model is obtained from (5)by setting κd1=0,i.e.neg-lecting the shallow traps in this temperature range.The trapping rates κd2and κd3calculated from the de-composition of the lifetime spectra are shown in Fig.3b.The trapping rates of both open-volume defects increase with the Cl content,leading us to the conclusion that not only d2,but604also d3,represents a complex containing Cl.The concentra-tions C d2and C d3can be estimated according to(1).When the Cl content is increased from100to3000ppm,the d2(A cen-ter)density increases from3×1016to4×1017cm−3and the d3density from1×1016to1×1017cm−3.Hence,the total chlorine content in the defects d2and d3amounts to less than2%of the Cl added during crystal growth.Trapping coeffi-cients ofµ=9×1014s−1and1.8×1015s−1were used for these estimations[52].Samples from the same set were stud-ied in correlated photoluminescence measurements.The con-centration of the A centers was determined from the shift of the zero-phonon line of the1.4-eV band,which is character-istic for the A center.The concentrations obtained in this way were within the error limits of the positron measurements.The temperature dependence of the average lifetimeshown in Fig.2exhibits a decrease towards lower T,indi-cating the presence of shallow positron traps.The trapping model analysis(solid line in Fig.2)including the tempera-ture dependence(3)of the detrapping rateδrevealed that the concentration of the shallow traps did not depend on the chlorine content.The shallow traps were attributed to neg-atively charged acceptor-type impurities in agreement with photoluminescence results[52].2.1.2Silver diffusion experiments.The diffusion of silver in p-type cadmium telluride results in an increase in the degree of compensation as detected by photoluminescence and Halleffect measurements[53].This is illustrated in the upper part of Fig.4,where the hole concentration is plotted against the time after silver was injected by dipping the crystal into anAgNO3solution.When the silver diffusion was carried out in p-type CdTe crystals,the concentration of Ag Cd impurities increased.This was indicated by the enhancement of the corresponding (A0,X)bound exciton line in the PL spectra.It was supposed that the interstitially diffusing silver interacts with vacanciesaccording to the defect reactionV Cd+Ag i→Ag Cd.(8)In order to confirm this assumption,positron lifetime meas-urements were carried out.As the native concentration of vacancies was too low to be detected by positron annihilation, post-growth annealing at820◦C under equilibrium condi-tions in a Te atmosphere was performed in a two-zone fur-nace over a period of6weeks.The annealing conditions were chosen in such a way as to increase the concentration of Cd vacancies to a level of several1016cm−3.An average positron lifetime of294.5ps was found after this procedure[54].The increase of about10ps in the positron lifetime compared to the bulk value was attributed to these cadmium vacan-cies.A silver diffusion experiment was carried out thereafter under conditions comparable to those used by Zimmermann et al.[53].The result is shown in the lower part of Fig.4. The average positron lifetime decreased markedly during the diffusion experiment carried out at room temperature.This decrease was taken as a proof of the dominance of the defect reaction(8),resulting in a decrease in the V Cd concentration.A similar experiment was performed by Grillot et al.[55]in CdS,where cadmium vacancies were alsofilled by diffusing silver.However,the time constants of the diffusion process mon-itored by the change in the hole concentration and by the change inτare distinctly different(Fig.4).Although the electrical measurement shows the activation of the silver in-terstitials acting as donors in the bulk CdTe,the decrease in the average positron lifetime reflects reaction(8).Since the silver diffusion should be much faster than the kinetics of(8), it was concluded that an additional barrier has to be overcome for the Ag i in order for cadmium vacancy sites to become occupied[54].2.2Mercury cadmium tellurideThe intermixing of the semiconductor CdTe with the semi-metal HgTe allows the adjustment of the width of the band gap by variation of the composition x in Hg1−x Cd x Te. The material with a composition of about x=0.2becomes a narrow-gap semiconductor and is of interest for infrared de-tector applications in the atmospheric transmission window around10µm.The Hg vacancy is the most important point defect because of its electrical activity as an acceptor and the high diffusivity of mercury[56,57].Furthermore,the Hg partial pressure is already rather high at low temperatures. The stoichiometry,i.e.the content of mercury vacancies,can be influenced by post-growth annealing under defined vapor pressure conditions[58].The Hg vacancy is negatively charged and is thus an in-teresting subject for the application of positron annihilation techniques.Thefirst positron experiments on Hg1−x Cd x Te were reported by V oitsekhovskii et al.[59],Dekhtyar et al.[60],and Andersen et al.[61].The positron annihilation results of post-growth annealing and diffusion experiments Averageholedensity[cm]-3Averagelifetime[ps]Time[h]210´110´Fig.4.Hole density determined by Hall effect measurements and average positron lifetime as a function of the time after silver injection into a p-type cadmium telluride sample.The upper part of the plot was taken from Zim-mermann et al.[53],the lower part from Krause-Rehberg et al.[54].The decrease in the hole concentration corresponds to a diffusion constant D Ag of interstitial silver of1×10−8cm2/s[53]。
Learning new compositions from given ones
Learning New Compositions from Given OnesJi DonghongDepartment of Computer ScienceTsinghua UniversityBeijing, 100084, P. R. ChinaEmail: jdh@He JunDepartment of Computer ScienceHerbin Institute of TechnologyEmail: hj@Huang ChangningDepartment of Computer ScienceTsinghua UniversityBeijing, 100084, P. R. ChinaEmail: hcn@Abstract:In this paper, we study the problem of learning new compositions of words from given ones with a specific syntactic structure, e.g., A-N or V-N structures. We first cluster words according to the given compositions, then construct a cluster-based compositional frame for each word cluster, which contains both new and given compositions relevant with the words in the cluster. In contrast to other methods, we don’t pre-define the number of clusters, and formalize the problem of clustering words as a non-linear optimization one, in which we specify the environments of words based on word clusters to be determined, rather than their neighboring words. To solve the problem, we make use of a kind of cooperative evolution strategy to design an evolutionary algorithm.Key words: word compositions, evolutionary learning, clustering, natural language processing.1. IntroductionWord compositions have long been a concern in lexicography(Benson et al. 1986; Miller et al. 1995), and now as a specific kind of lexical knowledge, it has been shown that they have an important role in many areas in natural language processing, e.g., parsing, generation, lexicon building, word sense disambiguation, and information retrieving, etc.(e.g., Abney 1989, 1990; Benson et al. 1986; Yarowsky 1995; Church and Hanks 1989; Church, Gale, Hans, and Hindle 1989). But due to the huge number of words, it is impossible to list all compositions between words by hand in dictionaries. So an urgent problem occurs: how to automatically acquire word compositions?In general, word compositions fall into two categories: free compositions and bound compositions, i.e., collocations. Free compositions refer to those in which words can be replaced by other similar ones, while in bound compositions, words cannot be replaced freely(Benson 1990). Free compositions are predictable, i.e., their reasonableness can be determined according to the syntactic and semantic properties of the words in them. While bound compositions are not predictable, i.e., their reasonableness cannot be derived from the syntactic and semantic propertiesof the words in them(Smadja 1993).N ow with the availability of large-scale corpus, automatic acquisition of word compositions, especially word collocations from them have been extensively studied(e.g., Choueka et al. 1988; Church and Hanks 1989; Smadja 1993). The key of their methods is to make use of some statistical means, e.g., frequencies or mutual information, to quantify the compositional strength between words. These methods are more appropriate for retrieving bound compositions, while less appropriate for retrieving free ones. This is because in free compositions, words are related with each other in a more loose way, which may result in the invalidity of mutual information and other statistical means in distinguishing reasonable compositions from unreasonable ones.In this paper, we start from a different point to explore the problem of automatic acquisition of free compositions. Although we cannot list all free compositions, we can select some typical ones as those specified in some dictionaries(e.g., Benson 1986; Zhang et al. 1994). According to the properties held by free compositions, we can reasonably suppose that selected compositions can provide strong clues for others. Furthermore we suppose that words can be classified into clusters, with the members in each cluster similar in their compositional ability, which can be characterized as the set of the words able to combined with them to form meaningful phrases. Thus any given composition, although specifying the relation between two words literally, suggests the relation between two clusters. So for each word(or cluster), there exist some word clusters, the word (or the words in the cluster) can and only can combine with the words in the clusters to form meaningful phrases. We call the set of these clusters compositional frame of the word (or the cluster).A seemingly plausible method to determine compositional frames is to make use of pre-defined semantic classes in some thesauri(e.g., Miller et al. 1993; Mei et al. 1996). The rationale behind the method is to take such an assumption that if one word can be combined with another one to form a meaningful phrase, the words similar to them in meaning can also be combined with each other. But it has been shown that the similarity between words in meaning doesn’t correspond to the similarity in compositional ability(Zhu 1982). So adopting semantic classes to construct compositional frames will result in considerable redundancy.An alternative to semantic class is word cluster based on distributional environment (Brown et al., 1992), which in general refers to the surrounding words distributed around certain word (e.g., Hatzivassiloglou et al., 1993; Pereira et al., 1993), or the classes of them(Bensch et al., 1995), or more complex statistical means (Dagan et al., 1993). According to the properties of the clusters in compositional frames, the clusters should be based on the environment, which, however, is narrowed in the given compositions. Because the given compositions are listed by hand, it is impossible to make use of statistical means to form the environment, the remaining choices are surrounding words or classes of them.Pereira et al.(1993) put forward a method to cluster nouns in V-N compositions, taking the verbs which can combine with a noun as its environment. Although its goal is to deal with the problem of data sparseness, it suffers from the problem itself. A strategy to alleviate the effects of the problem is to cluster nouns and verbs simultaneously. But as a result, the problem of word clustering becomes a bootstrapping one, or a non-linear one: the environment is also to be determined. Bensch et al. (1995) proposed a definite method to deal with the generalized version of the non-linear problem, but it suffers from the problem of local optimization.In this paper, we focus on A-N compositions in Chinese, and explore the problem of learningnew compositions from given ones. In order to copy with the problem of sparseness, we take adjective clusters as nouns’ environment, and take noun clusters as adjectives’ environment. In order to avoid local optimal solutions, we propose a cooperative evolutionary strategy. The method uses no specific knowledge of A-N structure, and can be applied to other structures.The remainder of the paper is organized as follows: in section 2, we give a formal description of the problem. In section 3, we discuss a kind of cooperative evolution strategy to deal with the problem. In section 4, we explore the problem of parameter estimation. In section 5, we present our experiments and the results as well as their evaluation. In section 6, we give some conclusions and discuss future work.2. Problem SettingGiven an adjective set and a noun set, suppose for each noun, some adjectives are listed as its compositional instances1. Our goal is to learn new reasonable compositions from the instances. To do so, we cluster nouns and adjectives simultaneously and build a compositional frame for each noun.Suppose A is the set of adjectives, N is the set of nouns, for any a symbol 206 \f "Symbol" \s 10.5∈}A, let f(a)symbol 205 \f "Symbol" \s 10.5⊆}N be the instance set of a, i.e., the set of nouns in N which can be combined with a, and for any n symbol 206 \f "Symbol" \s 10.5∈}N, let g(n)symbol 205 \f "Symbol" \s 10.5⊆}A be the instance set of n, i.e., the set of adjectives in A which can be combined with n. We first give some formal definitions in the following:Definition 1 partitionSuppose U is a non-empty finite set, we call <U1, U2, ..., U k> a partition of U, if:i) for any U i, and U j, i symbol 185 \f "Symbol" \s 10.5≠}j, U i symbol 199 \f "Symbol" \s10.5∩}U j•symbol 102 \f "Symbol" \s 10.5φ,ii) U=U ii k1≤≤UWe call U i a cluster of U.Suppose U•< A1, A2, ..., A p > is a partition of A, V•<N1, N2, ..., N q> is a partition of N, f and g are defined as above, for any N i, let g(N i)•{A j:_symbol 36 \f "Symbol" \s 10.5∃n symbol 206 \f "Symbol" \s 10.5∈}N i, A j symbol 199 \f "Symbol" \s 10.5∩}g(n)symbol 185 \f "Symbol" \s 10.5≠}symbol 102 \f "Symbol" \s 10.5φ}, and for anyn, let δ<>U V n,()•symbol 124 \f "Symbol" \s 10.5|{a:_symbol 36 \f "Symbol" \s 10.5∃A j, A j symbol 206 \f "Symbol" \s 10.5∈}g(N k), a symbol 206 \f "Symbol" \s 10.5∈}A j}symbol 45 \f "Symbol" \s 10.5−g(n)symbol 124 \f "Symbol" \s 10.5|, where n symbol 206 \f "Symbol" \s 10.5∈}N k. Intuitively,δ<>U V n,()is the number of the new instances relevant with n. We define the general learning amount as the following:Definition 2 learning amountδ<>U V,1 The compositional instances of the adjectives can be inferred from those of the nouns.δ<>U V ,•δ<>∈∑n N n ,()Based on the partitions of both nouns and adjectives, we can define the distance between nouns and that between adjectives.Definition 3 distance between wordsfor any a symbol 206 \f "Symbol" \s 10.5∈}A , let f a ()={N i :_1symbol 163 \f "Symbol" \s 10.5≤}i symbol 163 \f "Symbol" \s 10.5≤}q , N i symbol 199 \f "Symbol" \s 10.5∩}f(a)symbol 185 \f "Symbol" \s 10.5≠}symbol 102 \f "Symbol" \s 10.5φ}, for any n symbol 206 \f "Symbol" \s 10.5∈}N , let g n U ()={A i :_1symbol 163 \f "Symbol" \s 10.5≤}i symbol 163 \f "Symbol" \s 10.5≤}p , A i symbol 199 \f "Symbol" \s 10.5∩}g(n)symbol 185 \f "Symbol" \s 10.5≠}symbol 102 \f "Symbol" \s 10.5φ}, for any two nouns n 1 and n 2, any two adjectives a 1 and a 2, we define the distances between them respectively as the following: i) dis n n U (,)12=1-g n g n g n g n U U U U ()()()()1212∩∪ii) dis a a V (,)12=1-f a f a f a f a V V V V ()()()()1212∩∪According to the distances between words, we can define the distances between word sets .Definition 4 distance between word setsGiven any two adjective sets X 1, X 2symbol 205 \f "Symbol" \s 10.5⊆}A , any two noun sets Y 1, Y 2symbol 205 \f "Symbol" \s 10.5⊆}N , their distances are:i) dis X X V (,)12=a X a X V dis a a 112212∈∈,max{(,)}ii) dis Y Y U (,)12 =n Y n Y dis n n 112212∈∈,max {(,)}Intuitively, the distance between word sets refer to the biggest distance between words respectively in the two sets.We formalize the problem of clustering nouns and adjectives simultaneously as an optimization problem with some constraints. (1)To determine a partition U •<A 1, A 2, ..., A p > of A , and a partition V •<N 1, N 2, ..., N q > of N , where p , q symbol 62 \f "Symbol" \s 10.5>0, which satisfies i) and ii), and minimize δ<>U V ,.i) for any a 1, a 2symbol 206 \f "Symbol" \s 10.5∈}A i , 1symbol 163 \f "Symbol" \s 10.5≤}i symbol 163 \f "Symbol" \s 10.5≤}p , dis a a (,)12<t 1; for A i and A j , 1symbol 163 \f "Symbol" \s 10.5≤}i symbol 185 \f "Symbol" \s 10.5≠}j symbol 163 \f "Symbol" \s 10.5≤}p , dis A A V i j (,)symbol 179 \f "Symbol" \s 10.5≥} t 1;ii) for any n 1, n 2symbol 206 \f "Symbol" \s 10.5∈}N i , 0symbol 163 \f"Symbol" \s 10.5≤}i symbol 163 \f "Symbol" \s 10.5≤}q , dis n n U (,)12<t 1; for N i and N j , 1symbol 163 \f "Symbol" \s 10.5≤}i symbol 185 \f "Symbol" \s 10.5≠}j symbol 163 \f "Symbol" \s 10.5≤}q , dis N N i j (,)symbol 179 \f "Symbol" \s 10.5≥} t 2;where 0symbol 163 \f "Symbol" \s 10.5≤}t 1, t 2symbol 163 \f "Symbol" \s 10.5≤}1.Intuitively, the conditions i) and ii) make the distances between words within clusters smaller, and those between different clusters bigger, and to minimize δ<>U V ,means to minimize the distances between the words within clusters. In fact, (U , V ) can be seen as an abstraction model over given compositions, and t 1, t 2 can be seen as its abstraction degree . Consider the two special case: one is t 1=t 2 =0, i.e., the abstract degree is the lowest, when the result is that one noun forms a cluster and on adjective forms a cluster, which means that no new compositions are learned. The other is t 1=t 2 =1, the abstract degree is the highest, when a possible result is that all nouns form a cluster and all adjectives form a cluster, which means that all possible compositions, reasonable or unreasonable, are learned. So we need estimate appropriate values for the two parameters, in order to make an appropriate abstraction over given compositions, i.e., make the compositional frames contain as many reasonable compositions as possible, and as few unreasonable ones as possible.3. Cooperative EvolutionSince the beginning of evolutionary algorithms, they have been applied in many areas in AI(Davis et al., 1991; Holland 1994). Recently, as a new and powerful learning strategy,cooperative evolution has gained much attention in solving complex non-linear problem. In this section, we discuss how to deal with the problem (1) based on the strategy.According to the interaction between adjective clusters and noun clusters, we adopt such a cooperative strategy: after establishing the preliminary solutions, for any preliminary solution, we optimize N ’s partition based on A ’s partition, then we optimize A ’s partition based on N ’s partition, and so on, until the given conditions are satisfied.3.1 Preliminary SolutionsWhen determining the preliminary population, we also cluster nouns and adjectives respectively.However, we see the environment of a noun as the set of all adjectives which occur with it in given compositions, and that of an adjective as the set of all the nouns which occur with it in given compositions. Compared with (1), the problem is a linear clustering one.Suppose a 1, a 2symbol 206 \f "Symbol" \s 10.5∈}A , f is defined as above, we define the linear distance between them as (2):(2) dis (a 1, a 2)•1-f a f a f a f a ()()()()1212∩∪Similarly, we can define the linear distance between nouns dis (n 1, n 2) based on g . In contrast, we call the distances in definition 3 non-linear distances .According to the linear distances between adjectives, we can determine a preliminary partition of N : randomly select an adjective and put it into an empty set X , then scan the otheradjectives in A , for any adjective in A -X, if its distances from the adjectives in X are all smaller than t 1, then put it into X , finally X forms a preliminary cluster. Similarly, we can build another preliminary cluster in (A -X ). So on, we can get a set of preliminary clusters, which is just a partition of A . According to the different order in which we scan the adjectives, we can get different preliminary partitions of A .Similarly, we can determine the preliminary partitions of N based on the linear distances between nouns. A partition of A and a partition of N forms a preliminary solution of (1), and all possible preliminary solutions forms the population of preliminary solutions, which we also call the population of 0th generation solutions.3.2 Evolution OperationIn general, evolution operation consists of recombination, mutation and selection. Recombination makes two solutions in a generation combine with each other to form a solution belonging to nextgeneration. Suppose <U i 1(); V i 1()> and <U i 2(); V i 2()> are two ith generation solutions, whereU i 1() and U i 2() are two partitions of A , V i 1() and V i 2() are two partitions of N , then <U i 1()•V i 2()>and <U i 2(); V i 1()> forms two possible (i +1)th generation solutions.Mutation makes a solution in a generation improve its fitness , and evolve into a new onebelonging to next generation. Suppose <U i (); V i ()> is a ith generation solution, whereU i ()•<A 1, A 2, ..., A p >•V i ()•<N 1, N 2, ..., N q > are partitions of A and N respectively, the mutation is aimed at optimizing Vi () into V i ()£«1 based on U i (), and makes V i ()£«1 satisfy the condition ii)in (1), or optimizing U i () into Ui ()£«1 based on V i (), and makes U i ()£«1 satisfy the condition i)in (1), then moving words across clusters to minimize δ<>U V ,.We design three steps for mutation operation: splitting , merging and moving , the former two are intended for the partitions to satisfy the conditions in (1), and the third intended to minimizeδ<>U V ,. In the following, we take the evolution of V i ()£«1 as an example to demonstrate the three steps.symbol 183 \f "Symbol" \s 10.5•} Splitting Procedure . For any N k , 1symbol 163 \f "Symbol"\s 10.5≤}k symbol 163 \f "Symbol" \s 10.5≤}q , if there exist n 1, n 2symbol 206 \f "Symbol" \s 10.5∈}N k , such that dis n n U i ()(,)12symbol 179 \f "Symbol" \s 10.5≥} t 2, then splitting N k into two subsets X and Y . The procedure is given as the following:i) Put n 1 into X , n 2 into Y ,ii) Select the noun in (N k -(X symbol 200 \f "Symbol" \s 10.5∪}Y )) whose distance from n 1is the smallest, and put it into X ,iii) Select the noun in (N k -(X symbol 200 \f "Symbol" \s 10.5∪}Y )) whose distance from n 2is the smallest, and put it into Y,iv) Repeat ii) and iii), until X symbol 200 \f "Symbol" \s 10.5∪}Y = N k .For X (or Y ), if there exist n 1, n 2symbol 206 \f "Symbol" \s 10.5∈}X (or Y ), dis n n U i ()(,)12symbol 179 \f "Symbol" \s 10.5≥} t 2, then we can make use of the above procedure to split it into moresmaller sets. Obviously, we can split any N k in V i () into several subsets which satisfy thecondition ii) in (1) by repeating the procedure.symbol 183 \f "Symbol" \s 10.5•} Merging procedure . If there exist N j and N k , where1symbol 163 \f "Symbol" \s 10.5≤}j,k symbol 163 \f "Symbol" \s 10.5≤}q , such that dis N N U j k i ()(,)symbol 60 \f "Symbol" \s 10.5<t 2, then merging them into a new cluster.It is easy to prove that U i () and V i () will meet the condition i) and ii) in (1) respectively, after splitting and merging procedure.symbol 183 \f "Symbol" \s 10.5•} Moving procedure . We call moving n from N j to N k a word move , where 1symbol 163 \f "Symbol" \s 10.5≤}j symbol 185 \f "Symbol" \s 10.5≠}k symbol 163 \f "Symbol" \s 10.5≤}q , denoted as (n , N j , N k ), if the condition (ii) remains satisfied. The procedure is as the following:i) Select a word move (n , N j , N k ) which minimizes δ<>U V ,,ii) Move n from N j to N k ,iii) Repeat i) and ii)•until there are no word moves which reduce δ<>U V ,.After the three steps, U i ()and V i () evolve into U i ()£«1and V i ()£«1 respectively.Selection operation selects the solutions among those in the population of certain generation according to their fitness. We define the fitness of a solution as its learning amount.We use J i to denote the set of ith generation solutions, H (i , i+1), as in (3), specifies the similarity between ith generation solutions and (i +1)th generation solutions.(3) H (i , i+1)=Min U V J Min U V J U V i i i U V i i i i i i i {:_(,)}{:_(,)}()()()(),()(),()()δδ<>+++<>++∈∈11111Let t 3 be a threshold for H (i , i+1), the following is the general evolutionary algorithm:Procedure Clustering (A , N , f , g );begini) Build preliminary solution population I 0,ii) Determine 0th generation solution set J 0 according to their fitness,iii) Determine I i+1 based on J i :a) Recombination: if (U i 1(),V i 1()), (U i 2(),V i 2())symbol 206 \f "Symbol" \s10.5∈}J i , then (U i 1(),V i 2()), (U i 2(),V i 1())symbol 206 \f "Symbol" \s10.5∈}I i+1,b) Mutation: if (U i (),V i ())symbol 206 \f "Symbol" \s 10.5∈}J i , then(U i (),V i ()£«1), (U i ()£«1,V i ())symbol 206 \f "Symbol" \s 10.5∈}I i+1,iv) Determine J i+1 from I i+1 according to their fitness,v) If H (i ,i+1)>t 3, then exit, otherwise goto iii),end •After determining the clusters of adjectives and nouns, we can construct the compositional frame for each noun cluster or each noun. In fact, for each noun cluster N i , g (N i )={A j :_symbol 36 \f "Symbol" \s 10.5∃n symbol 206 \f "Symbol" \s 10.5∈}N i , A j symbol 199 \f "Symbol" \s 10.5∩}g (n )symbol 185 \f "Symbol" \s 10.5≠}symbol 102 \f"Symbol" \s 10.5φ} is just its compositional frame, and for any noun in N i , g (N i ) is also its compositional frame. Similarly, for each adjective (or adjective cluster), we can also determine its compositional frame.4. Parameter EstimationThe parameters t 1 and t 2 in (1) are the thresholds for the distances between the clusters of A and N respectively. If they are too big, the established frame will contain more unreasonable compositions, on the other hand, if they are too small, many reasonable compositions may not be included in the frame. Thus, we should determine appropriate values for t 1 and t 2, which makes the fame contain as many reasonable compositions as possible, meanwhile as few unreasonable ones as possible.Suppose F i is the compositional frame of N i , let F =<F 1, F 2, ..., F q >, for any F i , let A F i •{a :_symbol 36 \f "Symbol" \s 10.5∃X symbol 206 \f "Symbol" \s 10.5∈}F i , a symbol 206 \f "Symbol" \s 10.5∈}X }. Intuitively, A F i is the set of the adjectives learned as the compositionalinstances of the noun in N i . For any n symbol 206 \f "Symbol" \s 10.5∈}N i , we use A n to denote the set of all the adjectives which in fact can modify n to form a meaningful phrase, we now define deficiency rate and redundancy rate of F . For convenience, we use symbol 100 \f "Symbol" \s 10.5δF to represent symbol 100 \f "Symbol" \s 10.5δ(, ).Definition 5 Deficiency rate symbol 97 \f "Symbol" \s 10.5αFsymbol 97 \f "Symbol" \s 10.5αF = n N n F i q nn N i iA A A∈≤≤∈∑∑∑−1Intuitively, symbol 97 \f "Symbol" \s 10.5αF refers to the ratio between the reasonable compositions which are not learned and all the reasonable ones.Definition 6 Redundancy rate symbol 98 \f "Symbol" \s 10.5βFsymbol 98 \f "Symbol" \s 10.5βF •n N F ni q Fi i A A ∈≤≤∑∑−1δIntuitively, symbol 98 \f "Symbol" \s 10.5βF refers to the ratio between unreasonable compositions which are learned and all the learned ones.So the problem of estimating t 1 and t 2 can be formalized as (5):(5) to find t 1 and t 2, which makes symbol 97 \f "Symbol" \s 10.5αF =0, and symbol 98 \f "Symbol" \s 10.5βF =0.But, (5) may exists no solutions, because its constraints are two strong, on one hand, the sparseness of instances may cause symbol 97 \f "Symbol" \s 10.5αF not to get 0 value, even if t 1and t 2 close to 1, on the other hand, the difference between words may cause symbol 98 \f "Symbol" \s 10.5βF not to get 0 value, even if t 1 and t 2 close to 0. So we need to weaken (5).In fact, both symbol 97 \f "Symbol" \s 10.5αF and symbol 98 \f "Symbol" \s 10.5βF can be seen as the functions of t 1 and t 2, denoted as symbol 97 \f "Symbol" \s 10.5αF (t 1, t 2) and symbol 98 \f "Symbol" \s 10.5βF (t 1,t 2) respectively. Given some values for t 1 and t 2, we can compute symbol 97\f "Symbol" \s 10.5αF and symbol 98 \f "Symbol" \s 10.5βF . Although there may exist no values (t 1*, t 2*) for (t 1, t 2), such that symbol 97 \f "Symbol" \s 10.5αF (t 1*, t 2*)=symbol 98 \f "Symbol" \s 10.5βF (t 1*, t 2*)=0, but with t 1 and t 2 increasing, symbol 97 \f "Symbol" \s 10.5αF tends to decrease, while symbol 98 \f "Symbol" \s 10.5βF tends to increase. So we can weaken (5) as (6).(6) to find t 1 and t 2, which maximizes (7). (7) ααF t t T t t F t t T t t t t T t t t t T t t (,)(,)(,)(,)(,)(,)**(,)(,)******12112122121211212212∈∈∑∑−whereT 1(t 1*, t 2*)={(t 1, t 2):_0symbol 163 \f "Symbol" \s 10.5≤}t 1symbol 163\f "Symbol" \s 10.5≤}t 1*, 0symbol 163 \f "Symbol" \s 10.5≤}t 2symbol 163 \f "Symbol" \s 10.5≤}t 2*}, T 2(t 1*, t 2*)={(t 1, t 2):_t 1*<t 1symbol 163 \f "Symbol" \s 10.5≤}1, t 2*<t 2symbol 163 \f "Symbol" \s 10.5≤}1}Intuitively, if we see the area ([0, 1]; [0, 1]) as a sample space for t 1 and t 2, T 1(t 1*, t 2*) and T 2(t 1*, t 2*) are its sub-areas. So the former part of (7) is the mean deficiency rate of the points in T 1(t 1*, t 2*), and the latter part of (7) is the mean deficiency rate of the points in T 2(t 1*, t 2*). To maximize (7) means to maximize its former part, while to minimize its latter part. So ourweakening (5) into (6) lies in finding a point (t 1*, t 2*), such that the mean deficiency rate of thesample points in T 2(t 1*, t 2*) tends to be very low, rather than finding a point(t 1*, t 2*), such that its deficiency rate is 0.5 Experiment Results and EvaluationWe randomly select 30 nouns and 43 adjectives, and retrieve 164 compositions(see Appendix I)between them from Xiandai Hanyu Cihai (Zhang et al. 1994), a word composition dictionary of Chinese. After checking by hand, we get 342 reasonable compositions(see Appendix I), among which 177 ones are neglected in the dictionary. So the sufficiency rate 2(denoted as symbol 103 \f "Symbol" \s 10.5γ) of these given compositions is 47.9%.We select 0.95 as the value of t 3, and let t 1=0.0, 0.1, 0.2, …, 1.0, t 2=0.0, 0.1, 0.2, …, 1.0respectively, we get 121 groups of values for symbol 97 \f "Symbol" \s 10.5αF and symbol 98 \f "Symbol" \s 10.5βF . Fig.1 and Fig.2 demonstrate the distribution of symbol 97 \f "Symbol" \s 10.5αF and symbol 98 \f "Symbol" \s 10.5βF respectively.2 Sufficiency rate refers to the ratio between given reasonable compositions and all reasonable ones.19deficiencyratet2t1 Fig. 1 The distribution of symbol 97 \f "Symbol" \s 10.5αF.19redundancerate(%)t2(1/10)t1(1/10)Fig. 2 The distribution of symbol 98 \f "Symbol" \s 10.5βF.For any given t1, and t2,we found (7) get its biggest value when t1=0.4 and t2=0.4, so we select 0.4 as the appropriate value for both t1 and t2. The result is listed in Appendix II. From Fig.1 and Fig.2, we can see that when t1=0.4 and t2=0.4, both symbol 97 \f "Symbol" \s 10.5αF and symbol 98 \f "Symbol" \s 10.5βF get smaller values. With the two parameters increasing, symbol 97 \f "Symbol" \s 10.5αF decreases slowly, while symbol 98 \f "Symbol" \s 10.5βF increases severely, which demonstrates the fact that the learning of new compositions from the given ones has reached the limit at the point: the other reasonable compositions will be learned at a cost of severely raising the redundancy rate.From Fig.1, we can see that symbol 97 \f "Symbol" \s 10.5αF generally increases as t1 and t2 increase, this is because that to increase the thresholds of the distances between clusters means to raise the abstract degree of the model, then more reasonable compositions will be learned. On the other hand, we can see from Fig.2 that when t1symbol 179 \f "Symbol" \s 10.5≥}0.4, t2symbol 179 \f "Symbol" \s 10.5≥}0.4, symbol 98 \f "Symbol" \s 10.5βF roughly increases as t1 and t2 increase3,3 On some points, it may be not the case.。
欧洲药典嗜血流感杆菌Hib疫苗制药规范
Haemophilus type b conjugate vaccine EUROPEAN PHARMACOPOEIA5.0Sterility (2.6.1).The vaccine complies with the test for sterility.ASSAY Carry out one of the prescribed methods for the assay of diphtheria vaccine (adsorbed)(2.7.6).The lower confidence limit (P =0.95)of the estimated potency is not less than 2IU per single human BELLING The label states:—the minimum number of International Units per single human dose,—the name and the amount of the adsorbent,—that the vaccine must be shaken before use,—that the vaccine is not to be frozen.01/2005:1219HAEMOPHILUS TYPE b CONJUGATE VACCINE Vaccinum haemophili stirpe b coniugatum DEFINITION Haemophilus type b conjugate vaccine is a liquid orfreeze-dried preparation of a polysaccharide,derived from a suitable strain of Haemophilus influenzae type b,covalently bound toa carrier protein.The polysaccharide,polyribosylribitol phosphate,referred to as PRP,is a linear copolymer composed of repeated units of3-β-D -ribofuranosyl-(1→1)-ribitol-5-phosphate [(C 10H 19O 12P)n ],with a defined molecular size.The carrier protein,when conjugated to PRP,is capable of inducing a T-cell-dependent B-cell immune response to the polysaccharide.PRODUCTION GENERAL PROVISIONS The productionmethod shallhave been shown to yield consistently haemophilus type b conjugate vaccines of adequate safety and immunogenicity in man.The production of PRP and of the carrier are based on seed-lot systems.The production method is validated to demonstrate that the product,if tested,would comply with the test for abnormal toxicity for immunosera and vaccines for human use (2.6.9).During development studies and wherever revalidation of themanufacturing processis necessary,it shall be demonstrated by tests in animals that the vaccine consistently induces a T-cell-dependent B-cell immune response.The stability of the final lot and relevant intermediates is evaluated using one or more indicator tests.Such tests may include determination of molecular size,determination of free PRP in the conjugate and the immunogenicity test in mice.Takingaccount of the results of the stability testing,release requirements are set for these indicator tests to ensure that the vaccine will be satisfactory at the end of the period of validity.BACTERIAL SEED LOTSThe seedlots of H.influenzae type b are shown to be free from contamination by methods of suitable sensitivity.These may include inoculation into suitable media,examination of colony morphology,microscopic examination of Gram-stained smears and culture agglutination with suitable specific antisera.No complexproductsof animal origin are included in themenstruum used for preservation of strain viability,eitherfor freeze-drying or for frozen storage.Itis recommended that PRP produced by the seed lot be characterised using nuclear magnetic resonance spectrometry (2.2.33).H.INFLUENZAE TYPE b POLYSACCHARIDE (PRP)H.influenzae type b is grown in a liquid medium thatdoesnot contain high-molecular-mass polysaccharides;if any ingredient of the medium contains blood-group substances,the process shall be validated to demonstrate thatafter the purificationstep theyare no longer detectable.The bacterial purity of the culture is verified by methods of suitable sensitivity.These may include inoculation into suitable media,examination of colony morphology,microscopic examination of Gram-stained smears and cultureagglutination with suitable specific antisera.The culturemay be inactivated.PRP is separated from the culture medium and purified by a suitable method.Volatile matter,including water,in the purified polysaccharide is determinedby a suitable method such as thermogravimetry (2.2.34);theresult is used to calculate the results of certain tests withreference to the dried substance,as prescribed below.Only PRP that complies with the following requirementsmay be used inthe preparation of the conjugate.Identification .PRP is identified by an immunochemical method (2.7.1)or other suitable method,for example 1H nuclear magnetic resonance spectrometry (2.2.33).Molecular-size distribution .The percentage of PRP elutedbefore a given K 0value or within arange of K 0values isdetermined by size-exclusion chromatography (2.2.30);anacceptable value is established for the particular product and each batch of PRP must be shown to comply with this limit.Limits for currently approved products,using the indicated stationaryphases,are shownforinformationin Table 1219.-1.Where applicable,the molecular-size distribution is also determined after chemical modificationof the polysaccharide.Liquid chromatography (2.2.29)with multiple-angle laser light-scattering detection may also be used for determination of molecular-size distribution.A validated determination of the degree of polymerisation or of the weight-average molecular weight and the dispersion ofmolecular masses may be used instead of the determination of molecular size distribution.Ribose (2.5.31).Not less than 32per cent,calculated withreference to the dried substance.Phosphorus (2.5.18):6.8per cent to 9.0per cent,calculatedwith reference to the dried substance.Protein (2.5.16).Not more than 1.0per cent,calculated with reference to the dried e sufficient PRP to allow detection of proteins at concentrations of 1per centor greater.Nucleic acid (2.5.17).Not more than 1.0per cent,calculated with reference to the dried substance.Bacterial endotoxins (2.6.14):less than 25IU per microgram of PRP.Residualreagents .Where applicable,tests are carried outto determine residues of reagents used during inactivation and purification.An acceptable value for each reagent is established for the particular product and each batch of PRPmust be shown to comply with this limit.Where validation studies have demonstrated removal of a residual reagent,thetest on PRP may be omitted.662See the information section on general monographs (cover pages)EUROPEAN PHARMACOPOEIA 5.0Haemophilus type b conjugatevaccine Table 1219.-1.–Product characteristics and specifications for PRP and carrier protein in currently approved productsCarrier Haemophilus polysaccharideConjugationType Purity Nominal amount per dose Type of PRP Nominal amount per dose Coupling method Procedure Diphtheria toxoid >1500Lf per milligram of nitrogen 18µg Size-reduced PRP K 0:0.6-0.7,using cross-linked aga-rose for chroma-tography R 25µg cyanogenbromide activation of PRPactivateddiphtheria toxoid(D-AH +),cyanogenbromide-activated PRPTetanus toxoid >1500Lf per milligram of nitrogen 20µg PRP ≥50%≤K 0:0.30,usingcross-linked aga-rose for chroma-tography R10µg carbodi-imidemediated ADH-activatedPRP (PRP-cov.-AH)+tetanus toxoid +EDACCRM 197diphtheria protein >90%of diphtheria protein 25µg Size-reduced PRP Dp =15-35or 10-3510µg reductive amina-tion (1-step meth-od)or N -hydrox-ysuccinimide ac-tivation directcoupling ofPRP to CRM 197(cyanoborohydride activated)Meningococcal group B outer membrane protein (OMP)outer membrane protein vesicles:≤8%of lipopolysaccharide 125µg or 250µg Size-reduced PRP K 0<0.6,usingcross-linked aga-rose for chroma-tography R or M w >50×1037.5µg or 15µg thioether bond PRP activation by CDI PRP-IM +BuA2+BrAc =PRP-BuA2-BrAc +thioactivated OMPADH =adipic acid dihydrazide BrAc =bromoacetyl chloride BuA2=butane-1,4-diamide CDI =carbonyldiimidazole Dp =degree of polymerisationEDAC =1-ethyl-3-(3-dimethylaminopropyl)carbodiimideIM =imidazoliumM w =weight-average molecular weightCARRIER PROTEIN The carrier protein is chosen so that when the PRP is conjugated it is able to induce a T-cell-dependent B-cell immune response.Currently approved carrier proteins and coupling methods are listed for information in Table 1219.-1.The carrier proteins are produced by culture of suitable micro-organisms;thebacterialpurity of the culture is verified;the culture may be inactivated;the carrier protein is purified by a suitable method.Only a carrier protein that complies with the following requirements may be used in the preparation of theconjugate.Identification .The carrier protein is identified by a suitable immunochemical method (2.7.1).Sterility (2.6.1).Carry out the test using for each medium10ml or the equivalent of one-hundred doses,whichever is less.Diphtheria toxoid .Diphtheria toxoid is produced as described in Diphtheria vaccine (adsorbed)(0443)and complies with the requirements prescribed therein for bulk purified toxoid.Tetanus toxoid .Tetanus toxoid is produced as described in Tetanus vaccine (adsorbed)(0452)and complies with the requirements prescribedtherein for bulk purified toxoid,except that the antigenic purity is not less than 1500Lf per milligram of protein nitrogen.Diphtheria protein CRM 197.It contains not less than 90per cent of diphtheria CRM 197protein,determinedby asuitable method.Suitable tests are carried out,for validation or routinely,to demonstrate that the product is nontoxic.OMP (meningococcal group B Outer Membrane Proteincomplex).OMP complies with the following requirements for lipopolysaccharide and pyrogens.Lipopolysaccharide .Not more than 8per cent of lipopolysaccharide,determined by a suitable method.Pyrogens (2.6.8).Inject into each rabbit 0.25µg of OMP per kilogram of body mass.BULK CONJUGATEPRPis chemicallymodified to enable conjugation;it is usually partly depolymerised either before or during this procedure.Reactive functional groups or spacers may be introducedinto the carrier protein or PRP prior to conjugation.As a measure of consistency,the extent of derivatisation is monitored.The conjugate is obtained bythe covalentbinding of PRP and carrier protein.Where applicable,unreacted but potentially reactogenic functional groups are made unreactive by means of capping agents;the conjugate is purified to remove reagents.Onlya bulk conjugatethat complies with the following requirements may be used in the preparation of the final bulkvaccine.For each test and for each particular product,limitsofacceptance are established and each batch of conjugate must be shown to comply with these limits.Limits applied tocurrently approved products for some of these tests are listed for information in Table 1219.-2.For a freeze-dried vaccine,some of the tests may be carried out on the final lot rather than on the bulk conjugate where the freeze-drying process may affect the component being tested.PRP.The PRPcontentis determinedby assay of phosphorus (2.5.18)or by assay of ribose (2.5.31)or by animmunochemical method (2.7.1).Protein.The protein content is determined by a suitablechemical method (for example,2.5.16).PRP to protein ratio .Determine the ratio by calculation.Molecular-size distribution .Molecular-size distribution is determined by size-exclusion chromatography (2.2.30).FreePRP .Unbound PRP is determined afterremoval of theconjugate,for example by anion-exchange,size-exclusion or hydrophobic chromatography,ultrafiltration or othervalidated methods.Freecarrier protein .Determine the content by a suitable method,eitherdirectly or byderiving the content bycalculation from the results of other tests.The amount iswithin the limits approved for the particular product.General Notices (1)apply to all monographs and other texts 663Hepatitis A(inactivated)and hepatitis B(rDNA)vaccine EUROPEAN PHARMACOPOEIA5.0Table1219.-2.–Bulk conjugate requirements for currently approved products Test Protein carrierDiphtheria toxoid Tetanus toxoid CRM197OMP Free PRP<37%<20%<25%<15% Free protein<4%<1%,where applicable<1%or<2%,dependingon the coupling methodnot applicable PRP to protein ratio 1.25-1.80.30-0.550.3-0.70.05-0.1Molecular size(Ko):cross-linked agarose forchromatography R95%<0.7560%<0.250%0.3-0.685%<0.3cross-linked agarose forchromatography R10.6-0.785%<0.5Unreacted functional groups.No unreacted functional groups are detectable in the bulk conjugate unless process validation has shown that unreacted functional groups detectable at this stage are removed during the subsequent manufacturing process(for example,owing to short half-life). Residual reagents.Removal of residual reagents such as cyanide,EDAC(ethyldimethylaminopropylcarbodi-imide) and phenol is confirmed by suitable tests or by validation of the process.Sterility(2.6.1).Carry out the test using for each medium 10ml or the equivalent of100doses,whichever is less. FINAL BULK VACCINEAn adjuvant,an antimicrobial preservative and a stabiliser may be added to the bulk conjugate before dilution to the final concentration with a suitable diluent.Only a final bulk vaccine that complies with the following requirements may be used in preparation of the final lot. Antimicrobial preservative.Where applicable,determine the amount of antimicrobial preservative by a suitable chemical or physico-chemical method.The content is not less than85per cent and not greater than115per cent of the intended amount.Sterility(2.6.1).It complies with the test for sterility,carried out using10ml for each medium.FINAL LOTOnly a final lot that is satisfactory with respect to each of the requirements given below under Identification and Tests may be released for use.Provided the test for antimicrobial preservative has been carried out on the final bulk vaccine, it may be omitted on the final lot.pH(2.2.3).The pH of the vaccine,reconstituted if necessary, is within the range approved for the particular product. Free PRP.Unbound PRP is determined after removal of the conjugate,for example by anion-exchange,size-exclusionor hydrophobic chromatography,ultrafiltration or other validated methods.The amount of free PRP is not greater than that approved for the particular product. IDENTIFICATIONThe vaccine is identified by a suitable immunochemical method(2.7.1)for PRP.TESTSPRP.Not less than80per cent of the amount of PRP stated on the label.PRP is determined either by assay of ribose (2.5.31)or phosphorus(2.5.18),by an immunochemical method(2.7.1)or by anion-exchange liquid chromatography with pulsed amperometric detection(2.2.29).Aluminium(2.5.13):maximum1.25mg per single human dose,if aluminium hydroxide or hydrated aluminium phosphate is used as the adsorbent.Antimicrobial preservative.Where applicable,determine the amount of antimicrobial preservative by a suitable chemical or physico-chemical method.The content is not less than the minimum amount shown to be effective and not greater than115per cent of the quantity stated on the label. Water(2.5.12):maximum3.0per cent for freeze-dried vaccines.Sterility(2.6.1).It complies with the test for sterility. Pyrogens(2.6.8).It complies with the test for pyrogens. Inject per kilogram of the rabbit’s mass a quantity of the vaccine equivalent to:1µg of PRP for a vaccine with diphtheria toxoid or CRM197diphtheria protein as carrier;0.1µg of PRP for a vaccine with tetanus toxoid as carrier;0.025µg of PRP for a vaccine with OMP as carrier. LABELLINGThe label states:—the number of micrograms of PRP per human dose,—the type and nominal amount of carrier protein per single human dose.01/2005:1526 HEPATITIS A(INACTIVATED)ANDHEPATITIS B(rDNA)VACCINE(ADSORBED)Vaccinum hepatitidis A inactivatum ethepatitidis B(ADNr)adsorbatum DEFINITIONHepatitis A(inactivated)and hepatitis B(rDNA)vaccine (adsorbed)is a suspension consisting of a suitable strainof hepatitis A virus,grown in cell cultures and inactivated by a validated method,and of hepatitis B surface antigen (HBsAg),a component protein of hepatitis B virus obtained by recombinant DNA technology;the antigens are adsorbed on a mineral carrier,such as aluminium hydroxide or hydrated aluminium phosphate.PRODUCTIONGENERAL PROVISIONSThe two components are prepared as described inthe monographs on Hepatitis A vaccine(inactivated, adsorbed)(1107)and Hepatitis B vaccine(rDNA)(1056) and comply with the requirements prescribed therein.The production method is validated to demonstrate that the product,if tested,would comply with the test for abnormal toxicity for immunosera and vaccines for human use(2.6.9). Reference preparation.The reference preparation is part of a representative batch shown to be at least as immunogenic in animals as a batch that,in clinical studies in young healthy664See the information section on general monographs(cover pages)。
ImperialCollege,
ImperialCollege,Component-based Modeling, Analysis and AnimationJeff KramerProfessor of Distributed ComputingDepartment of Computing,Imperial College,London SW7 2AZ, UKE-mail: j.kramer@ /doc/c5661349.htmlAbstractComponent-based software construction is widely used in a variety of applications, from embedded environments to grid computing. However, errors in these applications and systems may have severe financial implications or may even be life threatening. A rigorous software engineering approach is necessary.We advocate a model-based tool-supported approach to the design of concurrent component-based systems. Component behaviour is modeled as a finite state process and specified in a process algebra FSP. In the same way that components can be composed according to an architecture so as to provide (sub-)system functionality, so component models can be composed to construct a system behaviour model. These models can be analysed using model checking against required properties specified in FSP or Linear Temporal Logic. Furthermore, these models can be animated to demonstrate and validate their behaviour and to replay counterexamples to illustrate their misbehaviour.In order to facilitate model construction early in the design process, the behaviour models can be synthesised from scenarios, captured as message sequence charts (MSC). Models described in this way can be used as an initial basis for validating requirements and as a specification that must be satisfied by more detailed models.By using a model-based design process early in the software lifecycle we hope that users gain the greatest benefit from model building and analysis. By providing techniques to generate models from scenarios and by associating the models with the proposed software architecture, we embed modeling into the software process. The ability to associate animation with models provides an accessible means for interpreting both model behavior and misbehavior to users. Analysis and animation can be carried out at any level of the architecture. Consequently, component models can be designed and debugged before composing them into larger systems.The model-based approach and analysis and animation techniques will be described and demonstrated through a series of examples and using the Labelled Transition System Analyser (LTSA) toolkit, which has been extended to deal with animation and MSCs.BiodataProfessor Jeff Kramer was Head of the Department of Computing at Imperial College from 1999 to 2004. He is currently Head of the Distributed Software Engineering Section. His research work is on behaviour analysis, the use of models in requirements elaboration and architectural approaches to self-organising software systems. He was a principal investigator in the various research projects that led to the development of the CONIC and DARWIN environments for distributed programming and the associated research into software architectures and their analysis. The work on the Darwin Software Architecture led to its commercial use by Philips in their new generation of consumer television products.Jeff Kramer is a Chartered Engineer, Fellow of the IEE and Fellow of the ACM. He was program co-chair of the 21st ICSE (International Conference on Software Engineering) in Los Angeles in 1999, Chair of the Steering Committee for ICSE from 2000 to 2002. He was associate editor and member of the editorial board of ACM TOSEM from 1995 to 2001 and is currently Editor in Chief of IEEE TSE. He was awarded the IEE Informatics Premium prize for 1998/99, the Most Influential Paper Award at ICSE 2003 and the 2005 ACM SIGSOFTOutstanding Research Award Award for significant and lasting research contributions to software engineering. He is co-author of a recent book on Concurrency, co-author of a previous book on Distributed Systems and Computer Networks, and the author of over 150 journal and conference publications.Bibliography[1] S. C. Cheung and J. Kramer, “Checking Safety Properties Using Compositional Reachability Analysis”, ACM Transactionson Software Engineering and Methodology, Vol. 8, No. 1, pp. 49-78, 99.[2] H. Foster, S. Uchitel, J. Magee and J. Kramer, “LTSA-WS: A Tool for Model-Based Verification of Web Service Compositions and Choreography”, (Formal Research Demo, 28th IEEE/ACM Int. Conf. on Software Engineering (ICSE-2006), Shanghai, May 2006).[3] D. Giannakopoulou and J. Magee, “Fluent Model-checking for Event-based Systems”, ESEC/FSE, Helsinki, Sept. 2003.[4] D. Giannakopoulou, J. Magee and J. Kramer, “Checking Progress with Action Priority: Is it Fair?”, 7th European Software Engineering Conference held jointly with the 7th ACM SIGSOFT Symposium on the Foundations of Software Engineering (ESEC/FSE'99), Toulouse, France, 1687, pp. 511-527, September 1999.[5] J. Kramer and J. Magee, “Exposing the Skeleton in the Coordination Closet”, Coordination'97, Second International Conference on Coordination Models and Languages, Berlin, Germany, 1282, pp. 18-31, September 1997.[6] J. Magee, N. Dulay, S. Eisenbach and J. Kramer, “Specifying Distributed Software Architectures”, 5th European Software Engineering Conference (ESEC'95), Sitges, Spain, 989, pp. 137-153, September 1995.[7] J. Magee, N. Dulay and J. Kramer, Regis, “A Constructive Development Environment for Parallel and Distributed Programs”, Distributed Systems Engineering Journal, Special Issue on Configurable Distributed Systems, Vol. 1, No. 5, pp. 304-312, 94.[8] J. Magee and J. Kramer, Concurrency - State Models & Java Programs, Chichester, John Wiley & Sons, 1999.[9] J. Magee, J. Kramer, D. Giannakopoulou and N. Pryce, “Graphical Animation of Behavior Models”, 22nd International Conference on Software Engineering (ICSE'00), Limerick, pp. 499-508, June 2000.[10] K. Ng, J. Kramer and J. Magee, “Automated Support for the Design of Distributed Systems”, Journal of Automated Software Engineering (JASE), Vol. 3, No. 4, pp. 261-284, 1996.[11] S. Uchitel, J. Kramer and J. Magee, “Detecting Implied Scenarios in Message Sequence Chart Specifications”, Joint 8th European Software Engineering Conference (ESEC'01) and 9th ACM SIGSOFT Symposium on the Foundations of Software Engineering (FSE'01), Vienna, pp. 74-82.[12] S. Uchitel, J. Kramer and J. Magee, “Negative Scenarios for Implied Scenario Elicitation”, ACM SIGSOFT 10th International Symposium on the Foundations of Software Engineering (FSE-10), Charleston, South Carolina, November 18-22, 2002).[13] S. Uchitel, J. Kramer and J. Magee, “Synthesis of Behavioural Models from Scenarios”, IEEE Transactions on Software Engineering, Vol. 29, No. 2, pp. 99-115, 2003.[14] J. Kramer, J. Magee and S. Uchitel, “Software Architecture Modeling and Analysis: A Rigorous Approach”, Formal Methods for Software Architectures (SFM-03:SA Lectures), Marco Bernardo and Paola Inverardi, Springer, LNCS 2804, 2003, 45-52.[15] S. Uchitel, J. Kramer and J. Magee, “Incremental Elaboration of Scenario-based Specifications and Behaviour Models usingImplied Scenarios”, ACM Transactions on Software Engineering Methodology TOSEM, 13 (1), January 2004.[16] S. Uchitel, R. Chatley, J. Kramer and J. Magee, “Fluent-Based Animation: Exploiting the Relation between Goals and Scenarios for Requirements Validation”, Requirements Engineering (RE ’04), Kyoto, September 2004.)[17] S. Uchitel S., R. Chatley, J. Kramer, and J. Magee, “System Architecture: the Context for Scenario-based Model Synthesis”,ACM SIGSOFT 12th International Symposium on the Foundations of Software Engineering (FSE-12), Newport Beach, California, October 31 – November 5, 2004.。
ABSTRACT Speci cation of Components in a Proposition Solver
Hale Waihona Puke 1. Introduction
The objective of this paper is to provide a library of speci cations of components for generic solver tools for logical propositions. These components may serve as building blocks for solvers that can be tailored for a wide range of applications, such as proof checkers, constraint solvers and generators of transition systems. The style of speci cation we use is brief and functional, so that the component and data type designs are easy to carry over to any potential programmer. Various implementation details are omitted, and left to the programmer. A proposition solver solves equations such as p~ = true, where ~ stands for the free boolean x x variables in proposition p. The satis ability of the proposition p is checked and a solution of the equation is computed, provided that p is satis able. The core system or main component of the solver tools we aim at is the satis ability checker HeerHugo Gro97 , which was originally developed at Utrecht University and the CWI for checking railway safety systems GKV95 . It is possible to build totally di erent applications from the same components. We summarise the advantages of dividing applications in components and specifying them before they are implemented. - Development time can be saved by rst building the components simultaneously and assembling them afterwards. - In any application, components may easily be replaced by other components with the same functional speci cations. - Components may be reused in di erent applications. We use the term manager for the process which takes care of scheduling issues and correct transport of the various data structures that ow between the components that are connected to it. A number of components, together with a manager process, de ne a solver tool. For the components that will be speci ed here, we require that they only communicate with the manager process, and not with other
翻译
不同气氛(N2/CO2/H2O)对厘米级木质颗粒在800℃脱挥发分的影响强调研究了不同气氛下(N2/H2O/CO2)对生物质碳脱挥发份的影响。
不同有机气体的产量取决于气氛。
这可能是由于水煤气转换中颗粒内部的二次反应。
气氛影响无机物的释放,特别是主要的元素K和Ca。
煤焦中剩余的无机物起主要的催化作用影响它的反应。
摘要研究了不同气氛(纯氮,氮气与二氧化碳和水蒸气混合,水蒸气)下对厘米级生物质碳脱挥发分的影响。
实验在自行设计的分析仪器中进行,可以限制颗粒外部的二次反应。
其产量和组分是确定的。
水煤气转化中不同有机气体的产量取决于脱挥发分的气氛,它可以决定粒子内部的二次反应可能对煤焦起催化作用。
气氛影响无机物的释放,特别是主要的元素K和Ca,因此还有煤焦的灰分含量。
煤焦中剩余的无机元素显示出它在二氧化碳,水或二者混合的气化反应起主要的催化作用。
这个结果显示出在气化反应器中,煤焦气化收到气氛的影响,不仅是因为二氧化碳和水蒸气气化反应不同的动力学原因,而且因为不同无机物含量的反应性不同。
关键词:热解脱挥发分水蒸气二氧化碳反应性1.引言生物质气化反应过程中产生液体或气体燃料,二氧化碳是在合成步骤前必须除去的副产品。
二氧化碳是温室气体,而且它的释放应限制到满意的范围。
因此,有意愿考虑替代工艺操作可以使二氧化碳部分消耗掉。
目前的研究正在构建RECO2项目的框架。
这个项目的目的是研究两段流化床中生物质气化反应过程产生的二氧化碳的回收,目标是生产气体燃料(bioSNG:合成天然气)或Fischer–Tropsch法(表1)合成液体燃料。
两段流化床由气化炉和燃烧室组成。
在气化炉中,一般只有水蒸气作为流化气体。
水蒸气在焦油重整和煤焦气化反应中充当气化剂。
二氧化碳也是一种氧化剂,可以与焦油和煤焦通过焦炭熔损反应发生相类似的反应。
因此项目的目的是研究气化炉中水蒸气被全部或部分替代二氧化碳的回收。
在实际工业的两段流化床气化炉中,木质生物质通常用厘米级别的木屑。
开启片剂完整性的窗户(中英文对照)
开启片剂完整性的窗户日本东芝公司,剑桥大学摘要:由日本东芝公司和剑桥大学合作成立的公司向《医药技术》解释了FDA支持的技术如何在不损坏片剂的情况下测定其完整性。
太赫脉冲成像的一个应用是检查肠溶制剂的完整性,以确保它们在到达肠溶之前不会溶解。
关键词:片剂完整性,太赫脉冲成像。
能够检测片剂的结构完整性和化学成分而无需将它们打碎的一种技术,已经通过了概念验证阶段,正在进行法规申请。
由英国私募Teraview公司研发并且以太赫光(介于无线电波和光波之间)为基础。
该成像技术为配方研发和质量控制中的湿溶出试验提供了一个更好的选择。
该技术还可以缩短新产品的研发时间,并且根据厂商的情况,随时间推移甚至可能发展成为一个用于制药生产线的实时片剂检测系统。
TPI技术通过发射太赫射线绘制出片剂和涂层厚度的三维差异图谱,在有结构或化学变化时太赫射线被反射回。
反射脉冲的时间延迟累加成该片剂的三维图像。
该系统使用太赫发射极,采用一个机器臂捡起片剂并且使其通过太赫光束,用一个扫描仪收集反射光并且建成三维图像(见图)。
技术研发太赫技术发源于二十世纪九十年代中期13本东芝公司位于英国的东芝欧洲研究中心,该中心与剑桥大学的物理学系有着密切的联系。
日本东芝公司当时正在研究新一代的半导体,研究的副产品是发现了这些半导体实际上是太赫光非常好的发射源和检测器。
二十世纪九十年代后期,日本东芝公司授权研究小组寻求该技术可能的应用,包括成像和化学传感光谱学,并与葛兰素史克和辉瑞以及其它公司建立了关系,以探讨其在制药业的应用。
虽然早期的结果表明该技术有前景,但日本东芝公司却不愿深入研究下去,原因是此应用与日本东芝公司在消费电子行业的任何业务兴趣都没有交叉。
这一决定的结果是研究中心的首席执行官DonArnone和剑桥桥大学物理学系的教授Michael Pepper先生于2001年成立了Teraview公司一作为研究中心的子公司。
TPI imaga 2000是第一个商品化太赫成像系统,该系统经优化用于成品片剂及其核心完整性和性能的无破坏检测。
新疆汉代羊毛织物染料的飞行时间二次离子质谱表征
ZHANG Hongying. Comparative studies on secretory glandular trichome morphology and leaf surface chemi-stry between tobacco varieties[J]. Tobacco Science & Technology, 2021, 54(1): 10-16(in Chinese).SEVERSON R F, ARRENDALE R F, CHORTYK O T, JOHNSON A W, JACKSON D M, GWYNN G R, CHAPLIN J F, STEPHENSON M G. Quantitation of the major cuticular components from green leaf of different tobacco types[J]. Journal of Agricultural and Food Chemistry, 1984, 32(3): 566-570.[5]XIA Y, JOHNSON A W, CHORTYK O T. Enhanced toxicity of sugar esters to the tobacco aphid (homoptera: Aphididae) using humectants[J]. Journal of Economic Entomology, 1997, 90(4): 1 015-1 021.[6]ASHRAF-KHORASSANI M, NAZEM N, TAYLOR L T, COLEMAN W M III. Separation and identification of sucrose esters from Turkish tobacco using liquid chro-matography-mass spectrometry[J]. Beiträ ge Zur Tabak-forschung International, 2005, 21(7): 381-389.[7]ASHRAF-KHORASSANI M, NAZEM N, TAYLOR L T, COLEMAN W M III. Isolation, fractionation, and identification of sucrose esters from various oriental tobaccos employing supercritical fluids[J]. Beiträ ge Zur Tabakforschung International, 2008, 23(1): 32-45.[8]范若静, 陈秀萍, 张芳, 张菁, 郭寅龙. 液相色谱-离子淌度-四极杆/飞行时间串联质谱法快速检测烟叶中蔗糖酯[J]. 质谱学报, 2016, 37(4): 301-309.FAN Ruojing, CHEN Xiuping, ZHANG Fang, ZHANG Jing, GUO Yinlong. Fast detection of sucrose esters in tobacco leaf using liquid chromatography coupled with ion mobility-quadrupole/time of flight mass spectrome-try[J]. Journal of Chinese Mass Spectrometry Society, 2016, 37(4): 301-309(in Chinese).[9]EINOLF W N, CHAN W G. Estimation of sucrose esters in tobacco by direct chemical ionization mass spectrome-try[J]. Journal of Agricultural and Food Chemistry, 1984, 32(4): 785-789.[10]DING L, XIE F, ZHAO M, WANG S, XIE J, XU G.Rapid quantification of sucrose esters in oriental tobacco by liquid chromatography-ion trap mass spectrometry[J].Journal of Separation Science, 2007, 30(1): 35-41. [11]DING L, XIE F, ZHAO M, XIE J, XU G. Rapid charac-[12]terization of the sucrose esters from oriental tobacco using liquid chromatography/ion trap mass spectrometry[J]. Rapid Communications in Mass Spec-trometry, 2006, 20(19): 2 816-2 822.DING L, XIE F, XU G, LIU K, WANG S, XIE J. Sepa-ration and detection of polar cuticular components from Oriental tobacco leaf by integration of normal-phase liq-uid chromatography fractionation with reversed-phase liquid chromatography-mass spectrometry[J]. Journal of Separation Science, 2010, 33(21): 3 429-3 436.[13]JIA C, WANG Y, ZHU Y, XU C, MAO D. Preparative isolation and structural characterization of sucrose ester isomers from oriental tobacco[J]. Carbohydrate Research, 2013, 372: 73-77.[14]ZHU H, FENG Y, YANG J, PAN W, LI Z, TU Y, ZHU X, HUANG G. Separation and characterization of sucrose esters from Oriental tobacco leaves using accel-erated solvent extraction followed by SPE coupled to HPLC with ion-trap MS detection[J]. Journal of Separa-tion Science, 2013, 36(15): 2 486-2 495.[15]SHINOZAKI Y, MATSUZAKI T, SUHARA S, TOBITA T, SHIGEMATSU H, KOIWAI A. New types of glycolipids from the surface lipids of nicotiana umbratica[J]. Agricultural and Biological Chemistry, 1991, 55(3): 751-756.[16]MATSUZAKI T, SHINOZAKI Y, SUHARA S, SHIGE-MATSU H, KOIWAI A. Isolation and characterization of tetra- and triacylglucose from the surface lipids of nico-tiana miersii[J]. Agricultural and Biological Chemistry, 1989, 53(12): 3 343-3 345.[17]SCHUMACHER J N. The isolation of 6-O-acetyl-2, 3, 4-tri-O-[(+)-3-methylvaleryl]-β-d-glucopyranose from toba-cco[J]. Carbohydrate Research, 1970, 13(1): 1-8.[18]贾春晓, 王瑞玲, 王莹莹, 毛多斌. 超声萃取-气相色谱-质谱法测定烟叶中的葡萄糖四酯[J]. 分析试验室, 2013, 32(12): 55-60.JIA Chunxiao, WANG Ruiling, WANG Yingying, MAO Duobin. Determination of glucose tetra-esters in tobac-cos by ultrasonic extraction coupled with gas chromatog-raphymass spectrometry[J]. Chinese Journal of Analysis Laboratory, 2013, 32(12): 55-60(in Chinese).[19](收稿日期:2023-07-25;修回日期:2023-09-07)第 3 期袁凯龙等:白肋烟中糖酯类化合物的分离与鉴定385第 45 卷 第 3 期质 谱 学 报Vol. 45 No. 3 2024 年 5 月Journal of Chinese Mass Spectrometry Society May 2024新疆汉代羊毛织物染料的飞行时间二次离子质谱表征刘 婕1,2,陈相龙3,梁汉东1,2,铁 偲1,李展平4(1. 煤炭精细勘探与智能开发全国重点实验室,北京 100083;2. 中国矿业大学(北京)地球科学与测绘工程学院,北京 100083;3. 中国社会科学院考古研究所,北京 100101;4. 清华大学化学系,有机光电子与分子工程教育部重点实验室,北京 100084)摘要:汉代女性干尸着鲜艳的红-蓝-浅黄三色羊毛纤维编制的华丽服饰,本研究以织物片段作为研究样本,主要采用飞行时间二次离子质谱(TOF-SIMS)法对其染料进行表征。
社区获得型肺炎英国指南
347Downloaded from at Library of Medical Center of Fudan University on April 21, 2014/348Bartlett et al.CID2000;31(August)is not available initially but is subsequently reported,changing to the antimicrobial agent that is most cost-effective,least toxic, and most narrow in spectrum is encouraged.Recommendations for treating patients who require empirical antibiotic selection are based on severity of illness,pathogen probabilities,resis-tance patterns of S.pneumoniae(the most commonly implicated etiologic agent),and comorbid conditions.The recommendation for outpatients is administration of a macrolide,doxycycline,orfluoroquinolone with enhanced ac-tivity against S.pneumoniae.For patients who are hospitalized, the recommendation is administration of afluoroquinolone alone or an extended-spectrum cephalosporin(cefotaxime or ceftriaxone)plus a macrolide.Patients hospitalized in the in-tensive care unit(ICU)should receive ceftriaxone,cefotaxime, ampicillin-sulbactam,or piperacillin-tazobactam in combina-tion with afluoroquinolone or macrolide.b-lactams,other than those noted,are not recommended.Intravenous antibiotics may be switched to oral agents when the patient is improving clin-ically,is hemodynamically stable,and is able to ingest drugs. Most patients show a clinical response within3–5days. Changes evident on chest radiographs usually lag behind the clinical response,and repeated chest radiography is generally not indicated for patients who respond.The failure to respond usually indicates an incorrect diagnosis;host failure;inappro-priate antibiotic;inappropriate dose or route of administration; unusual or unanticipated pathogen;adverse drug reaction;or complication,such as pulmonary superinfection or empyema. Prognosis.The most frequent causes of lethal community-acquired pneumonia are S.pneumoniae and Legionella.The most frequent reason for failure to respond is progression of pathophysiological changes,despite appropriate antibiotic treatment.Pneumococcal pneumonia.S.pneumoniae,the most com-mon identifiable etiologic agent of pneumonia in virtually all studies,accounts for about two-thirds of bacteremic pneumonia cases,and pneumococci are the most frequent cause of lethal community-acquired pneumonia.Management has been com-plicated in recent years by the evolution of multidrug resistance. b-lactams(amoxicillin,cefotaxime,and ceftriaxone)are gen-erally regarded as the drugs of choice,although pneumonia caused by resistant strains(MIC,у2m g/mL)may not respond as readily as pneumonia caused by more susceptible strains. The activity of macrolides and doxycycline or other b-lactams, including cefuroxime,is good against penicillin-susceptible strains but less predictable with strains that show reduced pen-icillin-susceptibility.Vancomycin,linezolid,and quinupristin/ dalfopristin are the only drugs with predictable in vitro activity. Fluoroquinolones are generally active against strains that are susceptible or resistant to penicillin,but recent reports indicate increasing resistance in selective locations that correlate with excessivefluoroquinolone use.Prevention.The major preventive measures are use of in-fluenza vaccine and use of pneumococcal vaccine,according to guidelines of the Advisory Council on Immunization Practicesof the Centers for Disease Control and Prevention(CDC). Performance indicators.Recommendations for perform-ance indicators include the collection of blood culture speci-mens before antibiotic treatment and the institution of anti-biotic treatment within8h of hospitalization,since both aresupported on the basis of evidence-based trials.Additional per-formance indicators recommended are laboratory tests for Le-gionella in patients hospitalized in the ICU,demonstration ofan infiltrate on chest radiographs of patients with an ICD-9 (International Classification of Diseases,9th edition)code for pneumonia,and measurement of blood gases or pulse oximetrywithin24h of admission.IntroductionLower respiratory tract infections are the major cause ofdeath in the world and the major cause of death due to infec-tious diseases in the United States.Recent advances in thefieldinclude the identification of new pathogens(Chlamydia pneu-moniae and hantavirus),new methods of microbial detection (PCR),and new antimicrobial agents(macrolides,b-lactamagents,fluoroquinolones,oxazolidinones,and streptogramins).Despite extensive studies,there are few conditions in medicinethat are so controversial in terms of management.Guidelinesfor management were published in1993by the American Tho-racic Society[1],the British Thoracic Society[2],and the Ca-nadian Infectious Disease Society[3],as well as the InfectiousDiseases Society of America(IDSA)in1998[4].The presentguidelines represent revised recommendations of the IDSA. Compared with previous guidelines,these guidelines are in-tended to reflect updated information,provide more extensive recommendations in selected areas,and indicate an evolutionof opinion.These therapeutic guidelines are restricted to com-munity-acquired pneumonia(CAP)in immunocompetentadults.Recommendations are given alphabetical ranking to reflecttheir strength and a Roman numeral ranking to reflect thequality of supporting evidence(table1).This is customary forquality standards from the IDSA[5].It should be acknowledgedthat no set of standards can be constructed to deal with themultitude of variables that influence decisions regarding site ofcare,diagnostic evaluation,and selection of antibiotics.Thus,these standards should not supplant good clinical judgement.EpidemiologyMagnitudeCAP is commonly defined as an acute infection of the pul-monary parenchyma that is associated with at least some symp-toms of acute infection,accompanied by the presence of anacute infiltrate on a chest radiograph or auscultatoryfindingsconsistent with pneumonia(such as altered breath sounds and/at Library of Medical Center of Fudan University on April 21, 2014/Downloaded fromCID2000;31(August)IDSA Guidelines for CAP in Adults349Table1.Categories for ranking recommendations in the therapeutic guidelines.Category DescriptionStrength of recommendationA Good evidence to support a recommendation for useB Moderate evidence to support a recommendation for useC Poor evidence to support a recommendationD Moderate evidence to support a recommendation against useE Good evidence to support a recommendation against useQuality of evidenceI Evidence from at least1randomized,controlled trialII Evidence from at least1well-designed clinical trial without randomizationIII Evidence from opinions of respected authorities,based on clinical experi-ence,descriptive studies,or reports of expert committeesor localized rales),in a patient not hospitalized or residing in a long-term-care facility forу14days before onset of symp-toms.Symptoms of acute lower respiratory infection may in-clude several(in most studies,at least2)of the following:fever or hypothermia,rigors,sweats,new cough with or without sputum production or change in color of respiratory secretions in a patient with chronic cough,chest discomfort,or the onset of dyspnea.Most patients also have nonspecific symptoms, such as fatigue,myalgias,abdominal pain,anorexia,and headache.Pneumonia is the sixth most common cause of death in the United States.From1979through1994,the overall rates of death due to pneumonia and influenza increased by59%(on the basis of ICD-9codes on death certificates)in the United States[6].Much of this increase is due to a greater proportion of persons agedу65years;however,age-adjusted rates also increased by22%,which suggests that other factors may have contributed to a changing epidemiology of pneumonia,includ-ing a greater proportion of the population with underlying med-ical conditions at increased risk of respiratory infection. Annually,2–3million cases of CAP result in∼10million physician visits,500,000hospitalizations,and45,000deaths in the United States[7,8].The incidence of CAP that requires hospitalization is estimated to be258persons per100,000pop-ulation and962per100,000persons agedу65years[8].Al-though mortality has ranged from2%to30%among hospi-talized patients in a variety of studies,the average is∼14%[9]. Mortality is estimated to be!1%for patients not hospitalized [9,10].The incidence of CAP is heavily weighted toward the winter months.Prognosis,Risk Stratification,and the Initial Site-of-Treatment DecisionKnowledge about the prognosis of a disease allows physi-cians to inform their patients about the expected natural history of an illness,the likelihood of potential complications,and the probability of successful treatment.Understanding the prog-nosis of CAP is of particular clinical relevance,since it ranges from rapid recovery from symptoms without functional im-pairment to serious morbid complications and death.The abil-ity to accurately predict medical outcomes in cases of CAP hasa major impact on management.The decision to hospitalize apatient or to treat him or her as an outpatient(figure1)isperhaps the single most important clinical decision made by physicians during the entire course of illness,which has directbearing on the location and intensity of laboratory evaluation,antibiotic therapy,and costs.The estimated total treatment costfor an episode of CAP managed in the hospital is$7500(USdollars)[11],120-fold higher than the cost of outpatient treatment.Numerous studies have identified risk factors for death incases of CAP[9,10,12].These factors were well-defined in thepre–penicillin era;studies of adults showed an increased riskwith alcohol consumption,increasing age,the presence of leu-kopenia,the presence of bacteremia,and radiographic changes[12].More recent studies have confirmed thesefindings[2,13–18].Independent associations with increased mortality havealso been demonstrated for a variety of comorbid illnesses,suchas active malignancies[10,16,19],immunosuppression[20,21], neurological disease[19,22,23],congestive heart failure[10,17,19],coronary artery disease[19],and diabetes mellitus[10,19,24].Signs and symptoms independently associated with in-creased mortality consist of dyspnea[10],chills[25],alteredmental status[10,19,23,26],hypothermia or hyperthermia[10,16,17,20],tachypnea[10,19,23,27],and hypotension(diastolic and systolic)[10,19,26–28].Laboratory and radiographicfindings independently asso-ciated with increased mortality are hyponatremia[10,19],hy-perglycemia[10,19],azotemia[10,19,27,28],hypoalbumi-nemia[16,19,22,25],hypoxemia[10,19],liver function test abnormalities[19],and pleural effusion[29].Infections due togram-negative bacilli or S.aureus,postobstructive pneumonia,and aspiration pneumonia are also independently associatedwith higher mortality[30].Despite our knowledge regarding the associations of clinical, laboratory,and radiographic factors and patient mortality,there is wide geographic variation in hospital admission ratesfor CAP[31,32].This variation suggests that physicians donot use a uniform strategy to relate the decision to hospitalizeto the prognosis.In fact,physicians often overestimate the riskof death for patients with CAP,and the degree of overesti-at Library of Medical Center of Fudan University on April 21, 2014/Downloaded from350Bartlett et al.CID2000;31(August)Figure1.Evaluation for diagnosis and management of community-acquired pneumonia,including site,duration,and type of treatment. b-Lactam:cefotaxime,ceftriaxone,or a b-lactam/b-lactamase inhibitor.Fluoroquinolone:levofloxacin,moxifloxacin,or gatifloxacin or another fluoroquinolone with enhanced antipneumococcal activity.Macrolide:erythromycin,clarithromycin,or azithromycin.CBC,complete blood cell count;ICU,intensive care unit.*Other tests for selected patients:see text,Diagnostic Evaluation:Etiology.**See table15for special considerations.mation is independently associated with the decision to hos-pitalize[30].Over the past10years,at least13studies have used multi-variate analysis to identify predictors of prognosis for patients with CAP[10,16–20,25–27,33–35].The Pneumonia PORT developed a methodologically sound clinical prediction rule that quantifies short-term mortality for patients with this illness [10].Used as a guideline,this rule may help physicians make decisions about the initial location and intensity of treatment for patients with this illness(table2).The Pneumonia PORT prediction rule was derived with 14,199inpatients with CAP;it was independently validated with 38,039inpatients with CAP and2287inpatients and outpatients prospectively enrolled in the Pneumonia PORT cohort study. With this rule,patients are stratified into5severity classes by means of a2-step process.In step1,patients are classified as risk class I(the lowest severity level)if they are agedр50years,have none of5important comorbid conditions(neoplastic dis-ease,liver disease,congestive heart failure,cerebrovascular dis-ease,or renal disease),and have normal or only mildly derangedvital signs and normal mental status.In step2,all patients whoare not assigned to risk class I on the basis of the initial historyand physical examinationfindings alone are stratified into clas-ses II–V,on the basis of points assigned for3demographicvariables(age,sex,and nursing home residence),5comorbidconditions(listed above),5physical examinationfindings(al-tered mental status,tachypnea,tachycardia,systolic hypoten-sion,hypothermia,or hyperthermia),and7laboratory or ra-diographicfindings(acidemia,elevated blood urea nitrogen, hyponatremia,hyperglycemia,anemia,hypoxemia,or pleuraleffusion;table3).Point assignments correspond with the fol-lowing classes:р70,class II;71–90,class III;91–130,class IV;and1130,class V.In the derivation and validation of this rule,mortality wasat Library of Medical Center of Fudan University on April 21, 2014/Downloaded fromCID2000;31(August)IDSA Guidelines for CAP in Adults351 parison of risk class–specific mortality rates in the derivation and validation cohorts.Risk class a (total points)MedisGroups MedisGroupsPneumonia PORT validation cohortderivation cohort validation cohort Inpatients Outpatients All patientsn Mortality,%n Mortality,%n Mortality,%n Mortality,%n Mortality,%I13720.430340.11850.55870.07720.1II(р70)24120.757780.62330.92440.44770.6III(71–90)2632 2.86790 2.8254 1.2720.03260.9IV(91–130)46978.513,1048.24469.04012.54869.3V(1130)308631.1933329.222527.110.022627.0 Total14,19910.238,03910.613438.09440.62287 5.2 NOTE.No statistically significant differences in overall mortality or mortality within risk class existed among patients in the MedisGroups derivation,MedisGroups validation,and overall Pneumonia Patient Outcome Research Team(PORT)validation cohorts(n denotes the no.of patients within each risk class in the derivation and validation cohorts).P values for the comparisons of mortality across risk classes are as follows:class I,;class II,;class III,;class IV,;and class V,.P p.22P p.67P p.12P p.69P p.09a Risk class I was determined by the absence of all predictors identified in step1of the prediction rule.Risk classes II–V were determined by a patient’s total risk score,which is computed by use of the point scoring system shown in table3.low for risk classes I–III(0.1%–2.8%),intermediate for class IV(8.2%–9.3%),and high for class V(27.0%–31.1%).Increases in risk class were also associated with subsequent hospitaliza-tion and delayed return to usual activities for outpatients and with rates of admission to the ICU and length of stay for inpatients in the Pneumonia PORT validation cohort.On the basis of these observations,Pneumonia PORT investigators suggest that patients in risk classes I or II generally are can-didates for outpatient treatment,risk class III patients are po-tential candidates for outpatient treatment or brief inpatient observation,and patients in classes IV and V should be hos-pitalized(table4).Estimates from the Pneumonia PORT cohort study suggest that these recommendations would reduce the proportion of patients receiving traditional inpatient care by 31%and that there would be a brief observational inpatient stay for an additional19%.The effectiveness and safety of applying the Pneumonia PORT prediction rule to the initial site of care for an indepen-dent population of patients with CAP have been examined with use of a modified version of the Pneumonia PORT prediction rule[36].Emergency room physicians were educated about the rule and were encouraged to treat those in risk classes I–III as outpatients,with close,structured follow-up and provision of oral clarithromycin at no cost to the patient,if desired.The outcomes for those treated at home during this intervention phase were compared with the outcomes for historical control subjects from the time period immediately preceding the intervention.During the intervention period,there were166eligible pa-tients classified as“low risk”for short-term mortality(risk classes I–III)for comparison with147control subjects.The percentage treated initially as outpatients was higher during the intervention period than during the control period(57%vs. 42%;relative increase of36%;).When initial plus sub-P p.01sequent hospitalization was used as the outcome measure,there was a trend toward more outpatient care during the interven-tion period,but the difference was no longer statistically sig-nificant(52%vs.42%;).None of those initially treatedP p.07in the outpatient setting during the intervention period diedwithin4weeks of presentation.A second multicenter controlled trial subsequently assessedthe effectiveness and safety of using the Pneumonia PORT pre-diction rule for the initial site-of-treatment decision[37].In thistrial,19emergency departments were randomly assigned eitherto continue conventional management of CAP or to implementa critical pathway that included the Pneumonia PORT predic-tion rule to guide the admission decision.Emergency room physicians were educated about the rule and were encouragedto treat those in risk classes I–III as outpatients with oral levo-floxacin.Overall,1743patients with CAP were enrolled in this6-month e of the prediction rule resulted in an18%reduction in the admission of low-risk patients(31%vs.49%;).Use of the rule did not result in an increase in mor-P p.013tality or morbidity and did not compromise patients’30-dayfunctional status.These studies support use of the PneumoniaPORT prediction rule to help physicians identify low-risk pa-tients who can be safely treated in the outpatient setting.The IDSA panel endorses thefindings of the PneumoniaPORT prediction rule,which identifies valid predictors for mor-tality and provides a rational foundation for the decision re-garding hospitalization.However,it should be emphasized thatthe PORT prediction rule is validated as a mortality predictionmodel and not as a method to triage patients with CAP.Newstudies are required to test the basic premise underlying the useof this rule in the initial site-of-treatment decision,so that pa-tients classified as“low risk”and treated in the outpatient set-ting will have outcomes equivalent to or better than those ofsimilar“low-risk”patients who are hospitalized.It is important to note that prediction rules are meant tocontribute to rather than to supersede physicians’judgment.Another limitation is that factors other than severity of illnessmust also be considered in determining whether an individualpatient is a candidate for outpatient care.Patients designatedas“low risk”may have important medical and psychosocial contraindications to outpatient care,including expected com-pliance problems with medical treatment or poor social supportat Library of Medical Center of Fudan University on April 21, 2014/Downloaded from352Bartlett et al.CID 2000;31(August)Table 3.Scoring system for step 2of the prediction rule:assignment to risk classes II–V .Patient characteristicPoints assignedaDemographic factor Age Male No.of years of age FemaleNo.of years of age Ϫ10Nursing home resident ϩ10Comorbid illnessesNeoplastic diseasebϩ30Liver diseasecϩ20Congestive heart failuredϩ10Cerebrovascular diseaseeϩ10Renal diseasefϩ10Physical examination findingAltered mental statusgϩ20Respiratory rate 130breaths/min ϩ20Systolic blood pressure !90mm Hg ϩ20Temperature !35ЊC or 140ЊC ϩ15Pulse 1125beats/minϩ10Laboratory or radiographic finding Arterial pH !7.35ϩ30Blood urea nitrogen 130mg/dL ϩ20Sodium !130mEq/L ϩ20Glucose 1250mg/dL ϩ10Hematocrit !30%ϩ10Arterial partial pressure of oxygen !60mm Hg hϩ10Pleural effusionϩ10aA total point score for a given patient is obtained by adding the patient’s age in years (age Ϫ10,for females)and the points for each applicable patient char-acteristic.Points assigned to each predictor variable were based on coefficients obtained from the logistic regression model used in step 2of the prediction rule.bAny cancer except basal or squamous cell cancer of the skin that was active at the time of presentation or diagnosed within 1year of presentation.cA clinical or histologic diagnosis of cirrhosis or other form of chronic liver disease such as chronic active hepatitis.dSystolic or diastolic ventricular dysfunction documented by history and physical examination,as well as chest radiography,echocardiography,Muga scanning,or left ventriculography.eA clinical diagnosis of stroke,transient ischemic attack,or stroke docu-mented by MRI or computed axial tomography.fA history of chronic renal disease or abnormal blood urea nitrogen and creatinine values documented in the medical record.gDisorientation (to person,place,or time,not known to be chronic),stupor,or coma.hIn the Pneumonia Patient Outcome Research Team cohort study,an oxygen saturation value !90%on pulse oximetry or intubation before admission was also considered abnormal.Table 4.Risk-class mortality rates.Risk class No.of points Validation cohortRecommended site of care No.of patientsMortality,%I —a30340.1Outpatient II р7057780.6Outpatient III 71–906790 2.8Outpatient or brief inpatient IV 91–13013,1048.2Inpatient V1130933329.2InpatientNOTE.Table is adapted from [10].aAbsence of predictors.at home.Ability to maintain oral intake,history of substance abuse,cognitive impairment,and ability to perform activities of daily living must be considered.In addition,patients may have rare conditions,such as severe neuromuscular disease or immunosuppression,which are not included as predictors in these prediction rules but increase the likelihood of a poor prognosis.Prediction rules may also oversimplify the way physicians interpret important predictor variables.For example,extreme alterations in any one variable have the same effect on risk stratification as lesser changes,despite obvious differences in clinical import (e.g.,a systolic blood pressure of 40mm Hg vs.one of 88mm Hg).Furthermore,such rules discount the cu-mulative importance of multiple simultaneous physiological de-rangements,especially if each derangement alone does not reach the threshold that defines an abnormal value (e.g.,systolicblood pressure of 90/40mm Hg,respiratory rate of 28breaths/min,and pulse of 120beats/min).Finally,prediction rules often neglect the importance of patients’preferences in clinical de-cision-making.This point is highlighted by the observation that the vast majority of low-risk patients with CAP do not have their preferences for site of care solicited,despite strong pref-erences for outpatient care [38].Role of Specific Pathogens in CAPProspective studies evaluating the causes of CAP in adults have failed to identify the cause of 40%–60%of cases of CAP and have detected у2etiologies in 2%–5%[2,7,26,39,40].The most common etiologic agent identified in virtually all studies of CAP is S.pneumoniae,which accounts for about two-thirds of all cases of bacteremic pneumonia cases [9].Other pathogens implicated less frequently include H.influenzae (most strains of which are nontypeable),Mycoplasma pneumoniae,C.pneumoniae,S.aureus,Streptococcus pyogenes,N.meningitidis,Moraxella catarrhalis,Klebsiella pneumoniae and other gram-negative rods,Legionella species,influenza virus (depending on the season),respiratory syncytial virus,adenovirus,parainflu-enza virus,and other microbes.The frequency of other etiol-ogies is dependent on specific epidemiological factors,as with Chlamydia psittaci (psittacosis),Coxiella burnetii (Q fever),Francisella tularensis (tularemia),and endemic fungi (histo-plasmosis,blastomycosis,and coccidioidomycosis).Comparisons of relative frequency of each of the etiologies of pneumonia are hampered by the varying levels of sensitivity and specificity of the tests used for each of the pathogens that they detect;for example,in some studies,tests used for legi-onella infections provide a much higher degree of sensitivity and possibly specificity than do tests used for pneumococcal infections.Thus,the relative contribution of many causes to the incidence of CAP is undoubtedly either exaggerated or un-derestimated,depending on the sensitivity and specificity of tests used in each of the studies.Etiology-Specific Diagnoses and the Clinical SettingNo convincing association has been demonstrated between individual symptoms,physical findings,or laboratory test re-sults and specific etiology [39].Even time-honored beliefs,suchat Library of Medical Center of Fudan University on April 21, 2014/Downloaded fromCID2000;31(August)IDSA Guidelines for CAP in Adults353Table5.Diagnostic studies for evaluation of community-acquired pneumonia.Baseline assessmentChest radiography to substantiate diagnosis of pneumonia,to detect associated lung diseases,to gain insightinto causative agent(in some cases),to assess severity,and as baseline to assess responseOutpatientsSputum Gram stain and culture for conventional bacteria are optionalInpatientsDetermination of complete blood cell and differential countsSerum creatinine,urea nitrogen,glucose,electrolyte,bilirubin,and liver enzyme valuesHIV serological status for persons aged15–54yearsO2saturation arterial blood gas values for selected patientsBlood cultures(ϫ2;before treatment)Gram stain and culture of sputum aTest for Mycobacterium tuberculosis,with acid-fast bacilli staining and culture for selected patients,especiallythose with cough for11mo,other common symptoms,or suggestive radiographic changesTest for Legionella in selected patients,including all seriously ill patients without an alternative diagnosis,es-pecially if aged140years,immunocompromised,or nonresponsive to b-lactam antibiotics,if clinicalfeatures are suggestive of this diagnosis,or in outbreak settingsThoracentesis with stain,culture,and determination of pH and leukocyte count differential(pleuralfluid)Alternative specimens to expectorated sputumAspirates of intubated patients,tracheostomy aspirates,and nasotracheal aspirates:manage as with expec-torated sputumInduced sputum:recommended for detection of M.tuberculosis or Pneumocystis cariniiBronchoscopy(see text under Special Considerations:Pnemococcal Pneumonia)Transtracheal aspiration:recommended only in cases of enigmatic pneumonia,to be done by personsskilled in the technique,preferably before antibiotic treatmentOptionalAdditional cytological or microbiological tests,as listed in table8,depending on clinical features,availableresources,underlying conditions,and/or epidemiological associations of the patientSerum:to be frozen and saved for serological analysis,if needed ba Should be deep-cough specimen obtained before antibiotic therapy.Gram stain should be interpreted by trainedpersonnel and culture done only if specimen is adequate by cytological criteria,except for Legionella and myco-bacteria.Consider diagnostic studies for endemic fungi and mycobacteria when clinical features suggest infectionwith these.For hospitalized patients with severe pneumonia or clinical features that suggest legionnaires’disease,perform culture and urinary antigen testing for Legionella.Inability to obtain specimens for diagnostic studiesshould not delay antibiotic treatment of acutely ill patients.b Serological tests would include those for Mycoplasma pneumoniae,Legionella pneumophila,Chlamydia pneu-moniae,or others(i.e.,viruses,Chlamydia psittaci,or Coxiella burnetii),depending on the circumstances.as the absence of productive cough or inflammatory sputum in pneumonia due to Mycoplasma,Legionella,or Chlamydia species,have not withstood close inspection.On the other hand, most comparisons have involved relatively small numbers of patients and have not evaluated the potential for separating causes by use of constellations of symptoms and physical findings.In one study,as yet unconfirmed,that compared patients identified in a prospective standardized fashion,a scoring sys-tem using5symptoms and laboratory abnormalities was able to differentiate most patients with legionnaires’disease from the other patients[41].A similar type of system has been devised for identifying patients with hantavirus pulmonary syndrome (HPS)[42].If validated,such scoring systems may be useful for identifying patients who should undergo specific diagnostic tests(which are too expensive to use routinely for all patients with CAP)and be empirically treated with specific antimicrobial drugs while test results are pending.Certain pathogens cause pneumonia more commonly among persons with specific risk factors.For instance,pneumococcal pneumonia is especially likely to occur in the elderly and in patients with a variety of medical conditions,including alco-holism,chronic cardiovascular disease,chronic obstructed air-way disease,immunoglobulin deficiency,hematologic malig-nancy,and HIV infection.However,outbreaks occur amongyoung adults under conditions of crowding,such as in armycamps or prisons.S.pneumoniae is second only to Pneumocystiscarinii as the most common identifiable cause of acute pneu-monia in patients with AIDS[43–45].Legionella is an oppor-tunistic pathogen;legionella pneumonia is rarely recognized inhealthy young children and young adults.It is an importantcause of pneumonia in organ transplant recipients and in pa-tients with renal failure and occurs with increased frequency inpatients with chronic lung disease,smokers,and possibly thosewith AIDS[46].Although M.pneumoniae historically has beenthought primarily to involve children and young adults,someevidence suggests that it causes pneumonia in healthy adultsof any age[8].There are seasonal differences in incidence of many of thecauses of CAP.Pneumonia due to S.pneumoniae,H.influenzae,and influenza occurs predominantly in winter months,whereasC.pneumoniae appears to cause pneumonia year-round.Al-though there is a summer prevalence of outbreaks of legion-naires’disease,sporadic cases occur with similar frequency dur-ing all seasons[8,46].Some studies suggest that there is noseasonal variation in mycoplasma infection;however,otherdata suggest that its incidence is greatest during the fall andwinter months[47].at Library of Medical Center of Fudan University on April 21, 2014/Downloaded from。
分析检验管路维修英语作文
In the realm of industrial and mechanical systems,the analysis and inspection of pipeline maintenance is a critical task that ensures the smooth operation and safety of various processes.Here is an essay discussing the importance and steps involved in pipeline maintenance:Title:Analysis and Inspection of Pipeline MaintenanceIntroductionPipelines are the lifelines of many industries,transporting essential fluids,gases,and materials across vast distances.Over time,these pipelines can suffer from wear and tear, corrosion,and other forms of damage,necessitating regular analysis and maintenance to prevent leaks,failures,and environmental disasters.Importance of Pipeline Maintenance1.Safety:Regular inspections prevent accidents and ensure the safety of both workers and the public.2.Efficiency:Maintained pipelines operate more efficiently,reducing the risk of process interruptions.3.CostEffectiveness:Proactive maintenance is more costeffective than reactive repairs following a failure.pliance:Adhering to regulatory standards and avoiding fines or legal issues. Steps in Pipeline Maintenance1.Visual Inspection:The initial step involves a thorough visual examination for obvious signs of damage or wear.2.Pressure Testing:Pipelines are subjected to pressure tests to identify any weak points or leaks.3.Ultrasound Testing:This nondestructive testing method uses sound waves to detect internal corrosion or damage.4.Magnetic Particle Inspection:Particularly useful for detecting surface and nearsurface defects in ferromagnetic materials.5.Dye Penetrant Testing:A method used to highlight surfacebreaking defects by using a visible or fluorescent dye.6.Radiographic Testing:Xrays or gamma rays are used to inspect the internal structure of the pipeline for cracks or inclusions.7.Pigging:A device known as a pig is inserted into the pipeline to clean and inspect the interior without the need for excavation.8.Condition Monitoring:Using sensors to monitor pipeline conditions in realtime, providing data for predictive maintenance.9.Data Analysis:Collected data is analyzed to identify trends,predict potential issues, and schedule maintenance accordingly.10.Repair and Rehabilitation:Once issues are identified,repairs are carried out,which may include patching,lining,or full replacement of sections of the pipeline.ConclusionEffective pipeline maintenance is a multistep process that combines various inspection techniques with data analysis to ensure the continued safe and efficient operation of pipelines.By investing in regular maintenance,industries can prevent costly downtimes and protect the environment from potential hazards.This essay provides a comprehensive overview of the process and importance of pipeline maintenance,highlighting the various inspection methods and the role of data in ensuring the integrity and longevity of pipeline systems.。
TSI AeroTrak+ 迷你级别粒子计数器 A100 系列应用文档 CC-120(A4)版本B说
Sampling Compressed Gases Using the TSI AeroTrak ™+ Portable Particle Counter A100 SeriesApplication Note CC-120 (A4)Rev B IntroductionCompressed air is used abundantly inpharmaceutical and electronics cleanrooms.Some uses of compressed gases includede-dusting, spray-coating tablets, over-pressurizing mixing and holding tanks,driving liquids through fill lines and filters,and operating control valves. However,compressed gases can be a source ofcontamination if not sufficiently clean.Leading facilities will therefore routinely testtheir compressed gases.Measuring the cleanliness of compressedgas is challenging. The high pressure of acompressed gas system can overwhelm aparticle counter, forcing more air throughthe particle counter than it was designedfor. The higher flow rate will cause errors inthe particle measurements and could evendamage the particle counter. Gases alsohave different densities, but particlecounters are generally calibrated for sampling air. This results in an inaccurate result because, unless corrected for, the sample volume is incorrect.To obtain accurate particle counts for a compressed gas requires two considerations:•Reducing the flow rate using a high-pressure diffuser •Correcting for the specific gravity of the gas being sampledSelecting a High Pressure DiffuserGas pressures above ambient room pressure require theuse of pressure-reducing equipment specificallydesigned for particle counting applications. TSI HighPressure Diffusers (HPDs) allow sampling with a particlecounter of non-reactive gas with pressures up to 120 PSI(8.3 bar) without introducing contaminants into thesample.There are two TSI HPD models that can be used with theAeroTrak+ Portable Particle Counter A100 Series. TheModel 7960 HPD is suitable for use for most gases,being used with sample flow rates of 1 CFM, 50 LPMand 100 LPM.However, for sampling very low humidity gases used inelectronic manufacturing, the TSI Model 7955 HPD mustbe used. This is because extremely dry air can abradethe fan and optics of the particle counter. The Model 7955 HPD uses HEPA-filtered room air to add moisture to the sampled air to allow the air to flow smoothly, without damaging the particle counter. It can only be used with a sample flow rate of 1 CFM.Correcting for Specific GravityParticle counters are calibrated to measure volumetric flow based on a specific gas, normally air. If other gases are sampled, the results will not reflect the programmed sample volume because of varying gas densities. Specific gravity, also known as relative density, of gases is defined as the ratio of the density of the gas to the density of the air at a specified temperature and pressure.Specific Gravity can be calculated asSG = ρgas/ ρairwhereSG = specific gravity of gasρgas = density of gas [kg/m3]ρair = density of air (normally at NTP - 1.204 [kg/m3])NTP - Normal Temperature and Pressure - defined as 20oC (293.15 K, 68oF) and1 atm (101.325 kN/m2, 101.325 kPa, 14.7 psia, 0 psig, 30 in Hg, 760 torr)Molecular weights can be used to calculate specific gravity if the densities of the gas and the air are evaluated at the same pressure and temperature.(Source: https:///density-specific-weight-gravity-d_290.html)Depending on the flow control method of the particle counter, a gas sample other than air can be normalized to the correct result for the actual sample volume desired by use of a correction factor based on specific gravity. For example, a 1 cubic foot sample result for nitrogen taken in a particle counter calibrated for air would have to be multiplied by 0.972 to obtain the equivalent result if an actual cubic foot of nitrogen is sampled. Because the particle counter is flow calibrated to the density of air, it would actually be taking a slightly larger sample of nitrogen because of the lower density of nitrogen.Other gases have similar correction factors, some larger or smaller, depending on the actual gas density. The AeroTrak+ Portable Particle Counter A100 Series can automatically apply the applicable correction factor for the gases listed in Table 1.Table 1: Gas Specific GravityAir 1Argon (Ar) 1.379Carbon Dioxide (CO2) 1.519Nitrogen (N2) 0.972To apply the correction factor, simply select the appropriate Sample Gas from the Sample Parameters dropdown menu in the Manual Mode Quick Settings or Monitor Zone creation screens. The selected sample volume is automatically programmed for the selected gas and results are corrected to obtain and accurate result.Figure 1 — Selecting a Sample Gas on the Sampling Parameters Screen_____________________ TSI and the TSI logo are registered trademarks of TSI Incorporated in the United States and may be protected under other country’s trademark registrations. TSI Incorporated – Visit our website for more information.USATel: +1 800 680 1220 UKTel: +44 149 4 459200 FranceTel: +33 4 91 11 87 64 GermanyTel: +49 241 523030 India Tel: +91 80 67877200 China Tel: +86 10 8251 6588 Singapore Tel: +65 6595 6388 CC-120 Rev B (4/25/2023) A4 ©2023 TSI Incorporated Printed in U.S.AEvaluating Results and Industry StandardsLife Sciences and other established cleanroom manufacturing operators typically use cleanroomstandards, notably ISO 14644-1, as guidelines for compressed air and gas particulate levels. SEMI E49 contains material pertinent to the electronics/semiconductor industry. ISO 8573 addresses compressed air (but not any other gas) limits and procedures for various types of contamination. The particulate limits for compressed gases in ISO 8573-1:2010 differ from the particulate limits for cleanrooms from ISO 14644-1:2015.Cleanroom personnel should determine the appropriate particulate contamination limits of compressed air or gas used in a cleanroom based on established risk assessment tools for the process taking place in the cleanroom. Specifying compressed air to be cleaner than the surrounding clean space may not be cost-effective, whereas specifying insufficiently clean air may introduce contamination. Forpharmaceutical applications, the US Food and Drug Administration requires compressed gases to be at least as clean as the area into which the gases are introduced.。
血透患者:司维拉姆的存活率是否优于含钙磷结合剂?
Original InvestigationSevelamer Versus Calcium Carbonate in Incident Hemodialysis Patients:Results of an Open-Label24-Month RandomizedClinical TrialBiagio Di Iorio,MD,1Donald Molony,MD,2Cynthia Bell,MS,3Emanuele Cucciniello,MD,1†Vincenzo Bellizzi,MD,4Domenico Russo,MD,5and Antonio Bellasi,MD,6on behalf of the INDEPENDENT Study Investigators* Background:Whether the use of sevelamer rather than a calcium-containing phosphate binder improves cardiovascular(CV)survival in patients receiving dialysis remains to be elucidated.Study Design:Open-label randomized controlled trial with parallel groups.Settings&Participants:466incident hemodialysis patients recruited from18centers in Italy.Intervention:Study participants were randomly assigned in a1:1fashion to receive either sevelamer or a calcium-containing phosphate binder(although not required by the protocol,all patients in this group received calcium carbonate)for24months.Outcomes:All individuals were followed up until completion of36months of follow-up or censoring.CV death due to cardiac arrhythmias was regarded as the primary end point.Measurements:Blind event adjudication.Results:At baseline,patients allocated to sevelamer had higher serum phosphorus(mean,5.6Ϯ1.7[SD] vs4.8Ϯ1.4mg/dL)and C-reactive protein levels(mean,8.8Ϯ13.4vs5.9Ϯ6.8mg/dL)and lower coronary artery calcification scores(median,19[IQR,0-30]vs30[IQR,7-180]).At study completion,serum phosphate levels were lower in the sevelamer arm(median dosages,4,800and2,000mg/d for sevelamer and calcium carbonate,respectively).After a mean follow-up of28Ϯ10months,128deaths were recorded(29and88due to cardiac arrhythmias and all-cause CV death).Sevelamer-treated patients experienced lower CV mortality due to cardiac arrhythmias compared with patients treated with calcium carbonate(HR,0.06;95%CI,0.01-0.25;PϽ0.001).Similar results were noted for all-cause CV mortality and all-cause mortality,but not fornon-CV mortality.Adjustments for potential confounders did not affect results.Limitations:Open-label design,higher baseline coronary artery calcification burden in calcium carbonate–treated patients,different mineral metabolism control in sevelamer-treated patients,overall lower than expected mortality.Conclusions:These results show that sevelamer compared to a calcium-containing phosphate binder improves survival in a cohort of incident hemodialysis patients.However,the better outcomes in the sevelamer group may be due to better phosphate control rather than reduction in calcium load.Am J Kidney Dis.62(4):771-778.©2013by the National Kidney Foundation,Inc.INDEX WORDS:Cardiovascular mortality;sevelamer;coronary artery calcification;chronic kidney disease.O bservational studies have documented that in-creased serum phosphorus levels are associated with excessive cardiovascular(CV)disease risk in incident and prevalent dialysis patients(chronic kid-ney disease[CKD]stage5D).1-3This body of evi-dence has prompted recommendations that correction of hyperphosphatemia should be attempted through a balanced approach of dietary phosphate restriction and phosphate-binder administration.4,5A recent pro-spective study cohort of10,044incident hemodialysis patients corroborates this recommendation,showing a significant survival improvement in thefirst year of dialysis for patients treated with phosphate binders compared with peers not using phosphate binders.6From the1UOC di Nefrologia,PO“A Landolfi,”Solofra(AV), Italy;2Division of Renal Disease and Hypertension,Department of Medicine,and3Division of Pediatric Nephrology,Department of Pediatrics,University of Texas Houston Medical School,Hous-ton,TX;4UOC di Nefrologia,AO Ruggi d’Aragona,Salerno; 5Department of Nephrology,School of Medicine,University“Fed-erico II”Napoli;and6UOC di Nefrologia,Dialisi,Ospedale Sant’Anna,Azienda Ospedaliera Sant’Anna,Como,Italy.†Deceased.*A list of the INDEPENDENT Study Investigators appears in the Acknowledgements.Received July1,2012.Accepted in revised form March7,2013. Originally published online May20,2013.Corrected online July 30,2013.See Item S1in“Supplementary Material”online for an explanation of the corrections.The errors have been corrected in the print,PDF,and HTML versions of this article.Trial registration:;study number: NCT00710788.Address correspondence to Biagio Di Iorio,UOC Nefrologia, PO“A Landolfi,”Via Melito,snc,I-83029Solofra(AV),Italy (e-mail:br.diiorio@)or Antonio Bellasi,UOC Nefrolo-gia e Dialisi,Azienda Ospedaliera S.Anna(CO),Via Ravona, 22020San Fermo della Battaglia(Como),Italy(e-mail: antonio.bellasi@).©2013by the National Kidney Foundation,Inc.0272-6386/$36.00/10.1053/j.ajkd.2013.03.023These results were largely independent of serum phos-phorus levels and type of phosphate binders.6A few previous clinical trials7-14and systematic reviews15-17have investigated the impact of different phosphate-binder regimens on clinical outcomes.De-spite similar phosphate-lowering ability,sevelamer is associated in numerous,although not all,studies with lower risk of coronary artery calcification(CAC), arterial stiffening,and electrocardiogram(ECG)abnor-malities compared with calcium-based phosphate bind-ers.18Nonetheless,the impact of sevelamer on CV survival is uncertain.19,20Based on a previous report that document an inde-pendent association between CAC and QT interval prolongation on ECGs,18we postulated that sevelamer may lower the risk of death due to cardiac arrhyth-mias.Hence,we conducted an open-label randomized controlled clinical trial to evaluate the impact of sevelamer compared with calcium-based phosphate binders on CV death due to arrhythmias,all-cause CV death,and all-cause death.The impact of treatment assignment on markers of vascular damage(ie,CAC, corrected QT interval,and pulse wave velocity)will be reported separately.METHODSStudy ParticipantsA detailed description of the INDEPENDENT(Reduce Cardio-vascular Calcifications to Reduce QT Interval in Dialysis)Study has been published elsewhere.21Study participants were randomly assigned in a1:1fashion to receive either sevelamer hydrochloride or a calcium-containing phosphate binder(although not required by the protocol,all patients in this group received calcium carbon-ate;Fig1).Adult(agedϾ18years)patients with CKD stage5new to hemodialysis(requiring dialysisϽ120days)were enrolled at18 dialysis centers in Italy(Table S1,available as online supplemen-tary material).Exclusion criteria include age older than75years, history of cardiac arrhythmia(reported history of cardiac arrhyth-mias,evidence of arrhythmias on an ECG,or presence of a pacemaker),syndrome of congenital prolongation of the QT seg-ment interval,corrected QT interval longer than440milliseconds or increased QT dispersion,history of coronary artery bypass,liver dysfunction(elevation of liver enzyme levelsϾ2-fold higher than the upper limits of the normal range),hypothyroidism,and use of drugs known to prolong the QT interval.22Enrollment began in January2007and continued through September2008.Study follow-up ended in September2011(Table S2).To maintain allocation concealment,randomization was per-formed centrally.Patients were assigned to treatment with either sevelamer or a calcium-containing phosphate binder(aluminum hydroxide was used as rescue therapy only as per the National Kidney Foundation–Kidney Disease Outcomes Quality Initiative [NKF-KDOQI]recommendations4)in a1:1fashion(Fig1).Study participants were stratified by age(Ն65andϽ65years),sex, diabetes status,and recruitment site prior to randomization.Due to the unavailability of computed tomography in most study centers during patient recruitment,participants were not stratified by baseline CAC score prior to randomization.CAC scores subse-quently were obtained for all participants enrolled in the study in a single central location.Investigators were instructed to adjust phosphate-binder dosage to achieve a serum phosphorus level of2.7-5.5mg/dL,as recom-mended by the NKF-KDOQI guidelines available at the time of the study design.4Similarly,investigators were instructed to control blood pressure(Յ130/80mm Hg),anemia(hemoglobinϾ11g/dL and transferrin saturationϾ20%),acidosis(bicarbonate,20-24 mmol/L),diabetes(hemoglobin A1cϽ7.0%),dyslipidemia(total cholesterolϽ200mg/dL,low-density lipoprotein cholesterolϽ100 mg/dL,and triglyceridesϽ180mg/dL),and the other parameters of bone mineral metabolism(ie,calcium and intact parathyroid hormone[iPTH]at8.0-9.9mg/dL and150-300pg/mL,respec-tively)per NKF-KDOQI guidelines.4Investigators were free to adjust medication dosages to achieve these therapeutic targets. Both sevelamer and calcium carbonate were provided by the central pharmacy at each study center as part of the standard care of hemodialysis patients.Figure1.Studyflow chart.Abbreviation:CT,computed tomographic.Di Iorio et alWritten informed consent was obtained from all participants prior to study entry and after approval from each institutional ethical review board.The study was conducted in adherence to the Declaration of Helsinki ethical principles for medical research involving human subjects.Laboratory Measurements and Markers of CV Disease Routine biochemical laboratory and imaging measurements were obtained at baseline and at6-month intervals until comple-tion of24months of follow-up.All blood samples were fasting and obtained before the midweek dialysis session.Serum parameters of mineral metabolism,electrolytes,inflammation,anemia,and dialysis adequacy were performed by each facility’s usual labora-tory.The Nichols second-generation immunoradiometric iPTH assay was used to determine iPTH levels.CAC score was assessed by multislice lightspeed(GE Medical Systems)equipment at one center(Solofra,A V),as previously described.23All scans were reviewed by a single reader blinded to patients’characteristics and group allocation.Primary and Secondary Study End PointsAll patients were followed up for36months or censored earlier in the case of a lethal event or study discontinuation.The primary end point of the study was CV mortality due to cardiac arrhyth-mias,defined as death attributed to either cardiac arrhythmia or sudden cardiac death defined as any death coded as cardiac arrest, cause unknown or cardiac arrhythmia.Secondary end points were: (1)all-cause mortality,defined as any fatal event;(2)all-cause CV mortality,defined as the composite of fatal event due to sudden cardiac death,cardiac arrhythmias,acute myocardial infarction, cerebral vascular accident,and heart failure;and(3)non-CV mortality,defined as all deaths not classified by the predetermined definition for CV mortality.All patient charts were reviewed for correct adjudication of any lethal events by a committee masked to group allocation.Statistical MethodsDemographic,clinical,and laboratory characteristics were col-lected at enrollment.Continuous variables are presented as meanϮstandard deviation or median(interquartile range[IQR])when appropriate.Categorical variables are presented as proportion.To gauge the association between phosphate binder and the primary and secondary end points,wefirst plotted the incidence of these end point curves according to phosphate-binder assignment using the Kaplan-Meier product-limit method.We then used2-sided log-rank test to calculate overall P values for survival differ-ences.24Finally,we calculated the multivariable-adjusted hazard ratio(HR)byfitting the data to Cox models.HRs were calculated initially without adjustments.Subsequent models included adjust-ment for all clinically relevant measured characteristics that dem-onstrated a significant imbalance at baseline.CAC scores were entered in the model as log(CAC scoreϩ1)to normalize CAC score distribution and avoid zero score exclusion.The proportional hazards assumption of the Cox models was tested by the distribu-tion of Schoenfeld residuals.If proportionality assumptions were violated,time-varying covariates were added to the models to account for nonproportional associations across time.All analyses were conducted as intention-to-treat analyses.All probability values are2tailed.PՅ0.05was considered statisti-cally significant.All analyses were completed using R statistical software,version2.9.2(R Foundation for Statistical Computing), and Stata/SE12(StataCorp LP).Sample Size CalculationProviding that the aim of the study was to assess the impact of sevelamer versus calcium-based phosphate binders on CV mortal-ity due to arrhythmias that are assumed to result from CAC and QTinterval prolongation,sample size calculation was based on thefollowing assumption:(1)time-dependent exponential distributionof coronary calcifications(this is the days during Agatston Unit Ͼ400multiplied for the value of calcium content in the coronary artery),(2)HR according to median survival time at36months insevelamer-versus calcium-treated patients equal to0.6678,(3)assignment fraction of0.5,(4)statistical test:a2-tailed test withtype I error of5%,(5)statistical test power of80%,and(6)dropout rate of10%per year.According to these assumptions,itwas anticipated that a total of194fatal events and360studyparticipants would be required.Because a lower than expectedoverall mortality rate was observed in the total study populationwithout consideration of group allocation after12months of study,an8-month extension of the recruitment phase was obtained,and atotal of466individuals were recruited into the INDEPENDENTStudy.EaST3.1software(Cytel Statistical Software&Services)was used for this calculation.RESULTSA total of466patients were randomly assigned to treatment with either sevelamer(nϭ232)or a calcium-containing phosphate binder(nϭ234).Of these,33 (14.2%)in the sevelamer arm and36(15.3%)in the calcium carbonate arm exited the study for various reasons prior to study completion,for a drop-out rate Ͻ5%per year(Fig1).Enrollment and drop-out rates were well balanced across all sites(Table S1).Mean age of the study cohort was65Ϯ14years.Men and women were represented equally;hypertension(79%), atherosclerotic CV disease(36%),and diabetes(29%) were the most common comorbid conditions.Base-line clinical characteristics of study participants are listed in Table1.Serum phosphorus levels were higher in the sevelamer group versus the calcium carbonate group(mean, 5.6Ϯ 1.7vs 4.8Ϯ 1.4 mg/dL).Otherwise,there were no significant differ-ences in clinical characteristics between sevelamer-and calcium carbonate–treated participants at study entry.CAC was highly prevalent in this study cohort of incident hemodialysis patients.Only137(29.4%) individuals did not show evidence of CAC at baseline. Mild(CAC score,1-29),moderate(CAC score,30-99),high(CAC score,100-400),and extremely high (CAC score,Ͼ400)CAC was detected in108(23.1%), 117(25.1%),40(8.6%),and64(13.7%)study partici-pants,respectively.A lower CAC score was noted in patients randomly assigned to the sevelamer versus calcium carbonate group(median,19[IQR,0-30]vs 30[IQR,7-180];Fig S1).Throughout the study,no significant differences in the use of3-hydroxy-3-methylglutaryl coenzyme A(HMG CoA)reductase in-hibitors,angiotensin-converting enzyme inhibitors,-blockers,cinacalcet,or vitamin D sterols could be detected between treatment groups.Average dosages of sevelamer and calcium carbonate administered wereSevelamer and Mortality4,300Ϯ1,400(median,4,800)mg/d and2,200Ϯ1,000 (median,2,000)mg/d,respectively.Despite higher serum phosphorus levels in patients allocated to sevelamer,serum phosphorus levels were controlled better in this group by study completion (Table2).Serum phosphorus level reduction was coupled with a significant reduction in iPTH levels in the sevelamer but not in the calcium carbonate study arm(comparisons between groups at study comple-tion:PϽ0.001).Finally,serum calcium levels tended to be higher in calcium carbonate–treated patients, consistent with adherence to their prescribed binders (comparisons between groups at study completion: PϽ0.001;Table2).Patients were followed up on average for28Ϯ10 months for the occurrence of any fatal CV or non-CVTable1.Demographic,Clinical,and Laboratory Characteristics at Baseline and by Phosphate-Binder AssignmentTotal (N؍466)Sevelamer(n؍232)Calcium Carbonate(n؍234)PMale sex4950480.7 Age(y)65.6Ϯ14.866.6Ϯ14.164.6Ϯ15.40.1 Atherosclerotic CVD3636340.7 Hypertension797880.50.6 Diabetes2930290.9 Body weight(kg)69.2Ϯ14.170.8Ϯ15.267.6Ϯ12.70.01 SBP(mm Hg)137Ϯ18137Ϯ18137Ϯ170.9 DBP(mm Hg)76Ϯ976Ϯ976Ϯ90.9 Use of vitamin D4242410.9 Use of cinacalcet5350540.4 Use of EPO8887880.9 Creatinine(mg/dL)7.8Ϯ2.57.9Ϯ2.37.7Ϯ2.70.4 Sodium(mmol/L)139Ϯ3138Ϯ3139Ϯ3Ͻ0.001 Phosphorus(mg/dL) 5.2Ϯ1.5 5.6Ϯ1.7 4.8Ϯ1.4Ͻ0.001 Calcium(mg/dL)8.9Ϯ0.79.0Ϯ0.88.8Ϯ0.70.004 Hemoglobin(g/dL)11.0Ϯ1.511.1Ϯ1.511.0Ϯ1.50.5 Intact PTH(pg/mmol)274Ϯ207265Ϯ187283Ϯ2260.4 Albumin(g/dL) 3.8Ϯ0.4 3.9Ϯ0.5 3.7Ϯ0.4Ͻ0.001 LDL cholesterol(mg/dL)99Ϯ2998Ϯ30100Ϯ280.5 CRP(mg/dL)7.4Ϯ10.78.8Ϯ13.4 5.9Ϯ6.80.003 Kt/V 1.2Ϯ0.3 1.2Ϯ0.4 1.3Ϯ0.30.002 Note:Values for categorical variables are given as percentages;values for continuous variables are given as meanϮstandard deviation.Conversion factors for units:creatinine in mg/dL tomol/L,ϫ88.4;phosphorus in mg/dL to mmol/L,ϫ0.3229;calcium in mg/dL to mmol/L,ϫ0.2495;LDL cholesterol in mg/dL to mmol/L,ϫ0.02586.Abbreviations and definitions:atherosclerotic CVD,atherosclerotic cardiovascular disease(defined as cerebrovascular disease, peripheral vascular disease,angina pectoris,history of myocardial infarction,aortic aneurysm,history of percutaneous coronary angioplasty with or without stenting);CRP,C-reactive protein;DBP,diastolic blood pressure;EPO,erythropoietin;LDL,low-density lipoprotein;PTH,parathyroid hormone;SBP,systolic blood pressure.Table2.Mineral Metabolism Control at Study Entry and Completion Between Study ArmsSevelamer (n؍232)Calcium Carbonate(n؍234)Sevelamer vs CalciumCarbonateBaseline24mo Baselinevs24mo Baseline24moBaseline vs24mo Baseline24moPhosphorus(mg/dL) 5.6Ϯ1.7 4.2Ϯ1.2Ϫ1.37Ϯ1.93;PϽ0.0014.8Ϯ1.4 4.8Ϯ1.1Ϫ0.10Ϯ1.67;Pϭ0.40.75Ϯ0.14Ϫ0.65Ϯ0.12;PϽ0.001Calcium(mg/dL)8.9Ϯ0.88.2Ϯ0.5Ϫ0.70Ϯ0.91;PϽ0.0018.8Ϯ0.79.6Ϯ1.10.84Ϯ1.21;PϽ0.0010.15Ϯ0.07Ϫ1.37Ϯ0.09;PϽ0.001Intact PTH(pg/mL)208[135-265]120[78-137]Ϫ153.7Ϯ188.4;PϽ0.001218[135-283]240[142-398] 2.1Ϯ313.5;Pϭ0.417.5Ϯ19.2Ϫ173.7Ϯ15.85;PϽ0.001Note:Values are given as meanϮstandard deviation or median[interquartile range].Conversion factors for units:phosphorus in mg/dL to mmol/L,ϫ0.3229;calcium in mg/dL to mmol/L,ϫ0.2495.Abbreviation:PTH,parathyroid hormone.Di Iorio et alevent.Specifically,11.4%of participants were fol-lowed up for less than 12months;14.6%,for 13-24months;14.6%,for 24-35months;and 59.4%,for at least 36months.At the end of follow-up,128deaths (event rate,113[95%confidence interval (CI),95-135]per 1,000patients/y)were recorded.Of these,29(22%)and 88(68.7%)were adjudicated as CV due to cardiac arrhythmias (event rate,25[95%CI,17-37]per 1,000patients/y)or all-CV deaths (event rate,78[95%CI,63-96]per 1,000patients/y).Survival analyses showed that sevelamer-treated patients exhibited a significant reduction in risk of CV death due to cardiac arrhythmias (P Ͻ0.001)com-pared with calcium carbonate–treated patients (Fig 2A).Two (event rate,3.3[95%CI,0.8-13]per 1,000patients/y)and 27(event rate,50[95%CI,34-73]per 1,000patients/y)CV deaths due to cardiac arrhyth-mias were recorded in sevelamer-and calcium car-bonate–treated patients,respectively,that corre-sponded to a greater than 10-fold reduction in the risk of experiencing a lethal cardiac arrhythmia (HR,0.06;95%CI,0.01-0.25;P Ͻ0.001;Table 3).A similar 10-fold risk reduction (HR,0.09;95%CI,0.05-0.19;P Ͻ0.001)was noted when all-cause CV deaths were considered:9(event rate,15[95%CI,8-29]per 1,000patients/y)versus 80(event rate,147[95%CI,118-184]per 1,000patients/y)all-cause CV deaths in sevelamer-and calcium carbonate–treated patients,respectively (Fig 2B;Table 3).All-cause mortality,but not non-CV mortality,also was attenuated in sevelamer-treated patients (HRs of 0.23[95%CI,0.15-0.31;P Ͻ0.001]and 0.75[95%CI,0.39-1.40;P ϭ0.4)for all-cause and non-CV mortality,respectively;Fig 2C and D;Table 3),sug-gesting that the survival benefit possibly is driven by the impact on the CV system.To explore whether the survival benefit associated with sevelamer was independent of and not modu-lated by clinically relevant differences between groups at baseline,we adjusted our results for baseline CAC score,serum phosphorus level,and C-reactive protein level.To control for a lack of proportionality,the fully adjusted Cox models for CV death due to cardiac arrhythmias,all-cause CV death,all-cause mortality,and non-CV mortality,all models were adjusted for time-varying serum phosphorus levels,C-reactive protein levels,and CAC scores (Table 3).All assump-tions of proportional hazards were met when the time-varying covariates were added and none of these covariates affected the significant relationship be-tween binder assignment and risk of any of the end points except for non-CV mortality.There was a lack of proportionality with respect to the relationship between binder allocation andnon-CVFigure 2.Kaplan-Meier (A)cardiovascular (CV)survival due to cardiac arrhythmias,(B)all-cause CV survival,(C)all-cause survival,and (D)non-CV survival according to phosphate-binder assignment.Sevelamer and Mortalitymortality.The time-varying covariate approach did not ameliorate this lack of proportionality.When data were divided for participants followed up for24or fewer months versus those followed up for25months or longer,a significant relationship between sevelamer and improved survival was seen in the latter period, whereas in the earlier period,a nonsignificant trend favoring calcium for reduced non-CV death was ob-served(Table3).DISCUSSIONIn this study,a large cohort of incident hemodialy-sis patients was randomly assigned to receive either sevelamer or calcium carbonate for treatment of hyper-phosphatemia.The primary objective of the study was to test the impact of phosphate-binder assignment on CV mortality due to cardiac arrhythmias and second-arily on all-cause CV mortality and all-cause mortal-ity.Previous randomized clinical trials have shown that sevelamer may significantly attenuate the progres-sion of CV calcification in both incident and prevalent dialysis patients.Additionally,observational studies support an association of sevelamer use with signifi-cantly lower arterial stiffness,25another marker of CV disease.26Providing that CAC burden is linked to QT interval prolongation on a standard ECG,18,27it is conceivable that sevelamer might lower the risk of sudden cardiac death/arrhythmic death.Nonetheless, prior to the present study,a beneficial impact of sevelamer on hard patient-centered outcomes has been uncertain.A secondary analysis of the Renagel in New Dialy-sis(RIND)Study showed a substantial3.1-fold reduc-tion in all-cause mortality in incident hemodialysis patients receiving sevelamer.8This benefit became evident after2years of treatment and persisted after multivariable adjustment(HR for death associated with calcium carbonate vs sevelamer treatment,3.1; 95%CI,1.23-7.61;Pϭ0.02).The generalizability of these results is limited by the small sample size of the RIND Study and the inconclusive results of the Dialy-sis Clinical Outcomes Revisited(DCOR)Study.11 DCOR failed to demonstrate a mortality reduction with sevelamer treatment for the entire population (HR of sevelamer vs calcium-based phosphate-binder treatment,0.93;95%CI,0.79-1.10;Pϭ0.4).Signifi-cantly better survival was noted for patients older than 65years assigned to treatment with sevelamer(rela-tive risk,0.77;95%CI,0.61-0.96;Pϭ0.02).28The prevalent rather than incident to dialysis population randomly assigned,the high dropout rate(ϳ50%of the entire DCOR Study cohort),the lower than ex-pected event rate for the entire study population,and the relatively short follow-up(38%of participants were treated forϽ12months;20%,for12-24months; 25%,for25-36months;and only17%forϾ36 months)may partly explain the failure of DCOR to demonstrate conclusively an overall survival benefit with sevelamer similar to that observed in RIND and the present study.A post hoc analysis of DCOR demonstrated that patients who received sevelamer for at least24months had significantly better survival (relative risk for sevelamer vs calcium-based phos-phate-binder treatment,0.66;95%CI,0.48-0.94;Pϭ0.02).28The present study,the INDEPENDENT Study,adds to the existing body of evidence by showing that sevelamer is associated with significantly lower CV and all-cause mortality in a large aging cohort of (overall mean age,65.6Ϯ14.8years)incident dialy-sis patients treated for a relatively longer period(74% of study participants were treated for at least24Table3.HRs for Primary and Secondary End Points inSevelamer Versus Calcium Carbonate GroupsOutcome Value PCV mortality from cardiac arrhythmiasNo.of deathsSevelamer2Calcium carbonate27HR(95%CI)Unadjusted model0.06(0.01-0.25)Ͻ0.001Adjusted model0.08(0.02-0.34)Ͻ0.001All-cause CV mortalityNo.of deathsSevelamer9Calcium carbonate80HR(95%CI)Unadjusted model0.09(0.05-0.19)Ͻ0.001Adjusted model0.11(0.05-0.22)Ͻ0.001All-cause mortalityNo.of deathsSevelamer28Calcium carbonate100HR(95%CI)Unadjusted model0.23(0.15-0.35)Ͻ0.001Adjusted model0.26(0.17-0.41)Ͻ0.001Non-CV mortalityNo.of deathsSevelamer19Calcium carbonate20HR(95%CI),unadjusted model0.75(0.39-1.40)0.4HR(95%CI),adjusted modelPatients with f/uϽ25mo 2.74(0.81-9.30)0.3Patients with f/uՆ25mo0.19(0.06-0.61)0.01Note:HR is for sevelamer versus calcium carbonate.Adjustedmodel was adjusted for C-reactive protein level,serum phospho-rus level and coronary artery calcification at baseline and time-varying C-reactive protein level;serum phosphorus level andcoronary artery calcification.Abbreviations:CI,confidence interval;CV,cardiovascular;f/u,follow-up;HR,hazard ratio.Di Iorio et almonths).Notably,the INDEPENDENT Study results for all-cause mortality(the least susceptible to misclas-sification)are consistent with the3-fold reduction in mortality previously documented in the RIND Study. Furthermore,that either no or only a modest effect after24months on non-CV mortality was demon-strated suggests that the positive impact of sevelamer on all-cause mortality is driven mainly by the signifi-cantly lower CV mortality.Additionally,overall mor-tality in this cohort of incident dialysis patients was lower than expected;the study likely was insuffi-ciently powered to demonstrate an impact of treat-ment on the less common causes of mortality. Finally,the lower incidence of lethal cardiac arrhyth-mias in sevelamer-treated patients may be due to slowing of damage to the conduction system.Previ-ous observational studies suggest that abnormalities in the QT interval are associated significantly with CAC burden18,27,29,and CAC progression18and that sevelamer reduces CAC progression.It therefore is plausible that by attenuating CAC and QT interval prolongation,sevelamer reduces the risk of cardiac arrhythmias and hence CV mortality.The INDEPENDENT Study exhibits limitations worth noting.One limitation is the higher baseline CAC burden in patients allocated to calcium-contain-ing phosphate binders,because CAC is a marker of CV disease risk in patients with CKD stage5.30Nonethe-less,adjustment for baseline CAC did not change the strengths of the association between sevelamer treatment and CV survival,supporting the conclusion that the effect is independent of CAC burden.The open-label design represents another possible limitation that might have distorted the observation of the true treatment effect.Effective blinding was deemed impossible due to the predictable lowering of serum total and low-density lipoprotein cholesterol levels by sevelamer.An impact of unblinding on the differential care of patients by group allocation was minimized by protocolizing all aspects of patient management according to NKF-KDOQI guidelines. Additionally,outcomes were adjudicated independently by investigators masked to treatment allocation.Patients allocated to sevelamer had poorer initial mineral metab-olism control.However,after therapy was established, serum phosphorus levels were controlled better in the sevelamer arm,and this difference persisted for the rest of the study.Hence,it is possible that the better out-comes observed in the sevelamer group could be due to better phosphate control rather than reduction in calcium load.Finally,the overall lower mortality observed in this study was consistent with mortality rates reported for cohorts of incident dialysis patients with normal cor-rected QT interval values and hence less advanced CV disease.Thus,it is possible that the beneficial effects of sevelamer observed in this randomized controlled trial might not be seen in patients with more advanced CV disease.However,in most clinical conditions,the con-verse is observed:the magnitude of benefit increases, and hence the number needed to treat decreases,when baseline risks are higher.In summary,we have demonstrated in an Italian cohort of incident patients with CKD stage5D that sevelamer treatment attenuates CV and all-cause mortal-ity.The present study differs importantly from previous published studies in that it is larger,evaluates a hard patient-centered outcome,and has achieved significantly more complete follow-up of substantially longer dura-tion.In keeping with the existing evidence,data from the present study lend support to the view that older and/or incident dialysis patients may benefit from treatment of hyperphosphatemia with the non–calcium-containing phosphate binder sevelamer compared with treatment with calcium-based binders.ACKNOWLEDGEMENTSThe INDEPENDENT Study Investigators are as follows:Fil-ippo Aucella(S.Giovanni Rotondo),Pasquale Guastaferro,An-gela Di Gianni(S.Angelo DèLombardi),Luigi Chiuchiulo(Avel-lino,Dyalysis),Roberto Rubino(Ariano Irpino),Lucia Di Micco (Napoli),Vincenzo Tedesco(Montella),Mario Migliorati(S.Gior-gio A Cremano),Walter De Simone,Bruno Zito(Avellino),Er-nesto D’avanzo,Francesco Saverio Iannaccone(Solofra:Radiolo-gia),Maria Luisa Sirico(Caserta),Patrizia Veniero,Maria Capuano, Raffaele Genualdo(Napoli:Pellegrini),Magda Lorenzo,Do-menico Santoro,Ferdinando Avella(Nola),Luigi Morrone,Vini-cio Martignetti(Benevento),Andrea Pota(Maddaloni),Carmine Piscopo,Lorella Berardino(Solofra:Cardiologia),Domenico Ma-tarese,Domenico Vigilante(Lucera),Assunta Aquino(Avellino), Rosa Martino,Struzziero Giuseppe,Alfonso Frallicciardi,and Raffaele Tortoriello(Solofra:Laboratorio Analisi).This report is dedicated to the memory of Dr Cucciniello,who prematurely died during the INDEPENDENT trial.We thank the doctors,nurses,and administrative staff who assisted in conducting the INDEPENDENT Study project.Some preliminary results were presented as oral communication at the European Renal AssociationϪEuropean Dialysis and Trans-plant Association meeting in Paris,France,May24-27,2012. Support:All costs connected to the INDEPENDENT Study were covered by the Italian National Health Care System through the local ASLs(Azienda Sanitaria Locale).The coordinating center was UOC di Nefrologia,PO“A Landolfi”-Solofra(A V), Italy Requirement for Registration of Clinical Trials.Financial Disclosure:Antonio Bellasi received speaking hono-raria from Amgen,Genzyme,and Sanofi.Biagio Di Iorio received speaking honoraria from Genzyme,Shire,and Plada.Vincenzo Bellizzi received speaking honoraria from Genzyme,Shire,and Plada.Domenico Russo received speaking honoraria from Abbott, Genzyme,Amgen,Roche,Fresenius Medical Care,Novartis,and Bristol-Myers Squibb and a research grant from Amgen.Donald Molony received speaking honoraria from Genzyme,Amgen,and Novartis.Dr Cucciniello died before this article was accepted,the corresponding author affirms that to his knowledge,Dr Cucciniello had no relevantfinancial interests;the other authors declare that they have no other relevantfinancial interests.Sevelamer and Mortality。
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durometer”(relatively soft)or “high durometer”(relativelyhard).3.2.4edge clearance —the distance between the bottom of achannel of a lock-strip gasket and the edge of material installedin the channel.3.2.5elongation —increase in length (expressed as a per-centage of the original length).3.2.6filler strip —see lock-strip,the preferred term.3.2.7flange —that part of a lock-strip gasket which extendsto form one side of a channel (see Fig.1and Fig.2).3.2.8gasket —any preformed deformable device designedto be placed between two adjoining parts to prevent the passageof liquid or gas between the parts.3.2.9gasket,lock-strip —a gasket in which the sealingpressure is produced internally by forcing a keyed lock-stripinto a groove (referred to as the lock-strip cavity)in one faceof the gasket.3.2.9.1H-type —two channel recesses,of equal or unequalsizes,one on either side of a central web (see Fig.1).3.2.9.2reglet-type —a channel recess on the inner edge anda tongue,or spline,on the outer edge,the latter being designedfor insertion in a reglet (see Fig.2).3.2.10gasket,structural —see gasket,lock-strip,the pre-ferred term.3.2.11gasket,zipper —see gasket,lock-strip,the preferredterm.3.2.12H-gasket —see gasket,lock-strip,H-type.3.2.13hinge —the minimum thickness of gasket materialbetween the channel recess and the lock-strip cavity;the planeat which bonding occurs when the flange is bent open toreceive or release installed material.3.2.14ladder gasket —a lock-strip gasket in the form of asubdivided frame having one or more integrally formed inter-mediate cross members.3.2.15lip —the inner face of the tip of a flange on alock-strip gasket (see Fig.1and Fig.2).3.2.16lip pressure —the pressure exerted by the lip of alock-strip gasket on material installed in the channel,when thelock-strip is in place. 3.2.17lip seal pressure —the lip pressure required to effect a seal against the passage of water and air.3.2.18lock-strip or locking strip —the strip which is de-signed to be inserted in the lock-strip cavity to force the lips against material placed in the channel.3.2.19lock-strip cavity —the groove in the face of a lock-strip gasket,designed to receive and retain the lock-strip.3.2.20reglet —a groove or recess formed in material such as concrete or masonry to receive the spline,or tongue,of a reglet-type lock-strip gasket.3.2.21reglet gasket —see gasket,lock-strip,reglet type.3.2.22setting block —a short length of suitable material placed in the gasket channel to maintain proper edge clearance.3.2.23spline or tongue —that part of a reglet-type lock-strip gasket which is designed to be installed in a reglet in supporting material.3.2.24web —that part of an H-type lock-strip gasket which extends between the flanges,forming two channels.4.Materials and Manufacture 4.1All materials and workmanship shall be in accordance with good commercial practice.4.2Gaskets shall be manufactured from an ozone-resistant compound and shall not be dependent for ozone resistance on surface protection which can be removed by abrasion,deter-gents,or other means.4.3Gaskets shall be free of porosity,surface defects,and dimensional irregularities,particularly in the sealing area.4.4Unless otherwise specified,the material shall be black.4.5Lubricants used in installation,shall be as recommended by the gasket manufacturer.5.Physical Properties 5.1The physical properties of the gasket shall conform to the requirements specified in Table 1.6.Dimensions and Permissible Variations 6.1Minimum thickness of material between the locking strip cavity and the panel or rail channel shall be 0.10in.(2.5mm).AHinge H Glass or panel BLock-strip I Bite CLock-strip cavity J Edge clearance DLip (sealing edge)K Frame to glass or panel dimension EChannel recess L Frame lug FFlange M FrameG Web FIG.1Basic H-Type Gasket,Its Functional Principles andNomenclature6.2All cross-sectioned dimensions shall have an RMAClass 2tolerance,as specified in Table 2unless otherwiseagreed by the purchaser and seller.7.Sampling7.1When proof of conformance with this specification is required,the samples shall be taken from the finished product whenever possible.7.2When the thickness or shape of the finished product makes sampling,as specified in Section 7,impossible,the manufacturer shall,upon request of the purchaser at the timeofAHinge H Glass or panel BLock-strip I Bite CLock-strip cavity J Edge clearance DLip (sealing edge)K Frame to glass or panel dimension EChannel recess L Spline FFlange M RegletG Web FIG.2Reglet Type Gasket,Its Functional Principles and NomenclatureTABLE 1Physical Requirements and Test Methods for GasketsPropertyRequirements Test Method Tensile strength,min A2000psi (14MPa)D 412Elongation at rupture,min,%175D 412Tear resistance,min120lbf/linear in.(214N/linear cm)D 624(Die C)Hardness,durometer A A7565D 2240Compression set,max,%,22h at 212°F (100°C)35D 395(Method B)Brittleness temperature,min−40°F (−40°C)D 746Ozone resistance,100mPa ozone......100h at 40°C (104°F),20%elongationno cracks @73magnification D 1149(Specimen A)Heat aging,70h at 212°F (100°C)D 573Change in hardness,maxLoss in tensile strength,max,%Loss in elongation,max,%0to +10Durometer points 1540Flame propagation B100mm (4in.),max.C 1166Lip pressure CExtruded section,minCorners,min4lbf/linear in.(7N/linear cm)4lbf/linear in.(7N/linear cm)as specified (see 8.9)A If a separate stock is used for the locking strip,it may have a hardness of 8065durometer points,and a minimum tensile strength of 1800psi (12.5MPa).In all other respects,it must meet these specifications.B This requirement may be waived (see Note 1).C In the case of molded corners with integral sealing devices,the requirement for corner lip pressure may be lowered by the architect or professional engineer.TABLE 2Cross-Sectional Tolerances Lock-Strip GasketsRMA Class 2,Schedule I,Commercial ADimension,in.Tolerance,plus or minus Dimension,in.Dimension,mm Tolerance,plus or minus Over 0to0.10incl 0.0130to 3⁄32Over 0to 2.5incl 0.32Over 0.10to 0.16incl 0.0163⁄32to 5⁄32Over 2.5to 4.0incl 0.40Over 0.16to 0.25incl 0.0205⁄32to 1⁄4Over 4.0to 6.3incl 0.50Over 0.25to 0.40incl 0.0251⁄4to 13⁄32Over 6.3to 10.0incl 0.63Over 0.40to 0.63incl 0.03213⁄32to 5⁄8Over 10.0to 16.0incl 0.80Over 0.63to 1.00incl 0.0405⁄8to 1Over 16.0to 25.0incl 1.00Over 1.00to 1.60incl 0.0501to 15⁄8Over 25.0to 40.0incl 1.25Over 1.60to 2.50incl 0.06315⁄8to 21⁄2Over 40.0to 63.0incl 1.60A Rubber Handbook ,Specifications for Rubber Products ,Table12.ordering,furnish a sufficient number of test slabs or blocksprepared in accordance with Methods D 15for the properperformance of the required tests.The slabs or blocks shall beprepared from the compound of the same source production lotused in the gasket.8.Test Methods8.1Tensile Strength and Elongation —Test in accordancewith Test Methods D 412.Determine percentage change intensile strength and elongation after oven aging for 70h at 21262°F (10061°C).8.2Tear Resistance —Test in accordance with Test MethodD 624using Die C.8.3Hardness —Test in accordance with Test MethodD 2240,using a Type A durometer.If size or shape of thespecimen precludes testing of the finished surface,makemeasurements on a squarely cut end or on a flat sliced or buffedsurface.Determine change in hardness after oven aging for 70h at 21262°F (10061°C).8.4Compression Set —Test in accordance with Test Meth-ods D 395,Method B.Hold the sample under test for 22h at21262°F (10061°C).Buffed specimen,taken from material1⁄16in.(1.5mm)minimum thickness may be superimposed to atotal thickness of 1⁄2in.(13.0mm).8.5Brittleness Temperature —Test in accordance with TestMethod D 746.8.6Ozone Resistance —Test in accordance with TestMethod D 1149(Specimen A).Use an ozone concentration of100mPa,an exposure time of 4062°C (10463.6°F),and aspecimen elongation of 20%.8.7Heat Aging —Test the effects of heat aging in accor-dance with Test Method D 573.8.8Flame Propagation —Test Method C 1166.8.8.1This test is designed to differentiate the flame propa-gation characteristics of candidate materials used in lock-stripgaskets.It is a small-scale test which enables the specifier toexercise engineering prudence in the selection of materials.Itshould not be used to predict the performance of the testedmaterial in an actual fire situation.It should not be used topredict fuel contribution,rate of flame spread,smoke genera-tion,or the nature of the products of combustion.Testconditions are those most conducive to flame propagation andthe method simulates the worst possible exposure condition.The specimen is mounted vertically.The igniting flame is hot;the fuel supply is unlimited;and the flame is not removed fromthe specimen throughout the test.8.9Lip Pressure:78.9.1This test method determines the pressure exerted bythe gasket on collateral material positioned within the gasketchannel or channels.It simulates actual use conditions andprovides a measurement of the force required to open the lipsof the gasket channel to that distance representing the thicknessof material for which the gasket is designed.In the case ofdouble channel gaskets,this measurement is made with a solidmaterial of the intended thickness in position in the channelopposite to that being tested.Thus these measurements reflect the forces to be encountered during application.8.9.2Apparatus :8.9.2.1The testing machine shall be a power-driven tension-testing machine of the movable cross-head type,equipped with adjustable cross-head speed and a suitable dynamometer and indicating or recording device for measuring the applied force within 62%.8.9.2.2The grips to be used with the testing machine described in 8.9.2.1shall be of a type similar to those shown in Fig.3.They shall exert a uniform pressure across the gripping surface,increasing as the tension increases,so as to prevent uneven slipping.8.9.2.3The lip dividers used to separate the lips of the test specimen shall be made of stainless steel as shown in Fig.4.Their length shall be at least equal to that of the test specimen.8.9.2.4The metal spacer to be used when testing double-channel gaskets,as shown in Fig.3,shall be the same length as 7Supporting data are available from ASTM Headquarters.Request RR:C24-1009.FIG.3Tension Tester for LipPressurethe test specimen,the same thickness as the material the gasketis designed to hold,and at least 0.50in.(13mm)wider than thedepth of the channel.8.9.3Test Specimen :8.9.3.1The extruded test specimen shall be a piece of the actual gasket at least 1in.(25mm)in length.A minimum of four specimens from each lot shall be tested.8.9.4Procedure :8.9.4.1Place the test specimen in the testing machine as shown in Fig.3,ensuring that the locking strip is in place and that,if it is a double-channel-type gasket,the specified spacer is properly positioned in the channel opposite from that being tested.Provide means of supporting the test assembly so that when tension is applied to the channel lips,the assembly will remain in a horizontal position (Note 5).It is important to ensure that the lip dividers have a secure hold on the gasket lips and that they are also securely held by the grips of the machine.Conduct the test at 73.461.8°F (2361°C).N OTE 3—When testing single channel gaskets,the spacers obviously cannot be used.However,some means must be provided to hold the test specimen in a horizontal position during testing.8.9.4.2Separate the lips of the gasket channel at a uniform rate of 0.20in.(5.1mm)/min,until the distance between the lips is equal to the minimum thickness of the material they are designed to hold.8.9.4.3When the lips have been separated the specified distance,stop the testing machine and record the amount of force in lbf (or kgf)required to produce this opening.8.9.4.4Repeat 8.9.4.1-8.9.4.3until all of the extruded chan-nels of a minimum of four specimens of each type have been tested.8.9.4.5Calculate the lip pressure of each channel tested as follows:Lip pressure,lbf/linear in.~N/linear cm !5F /L (1)where:F =force required to open the lips the specified distance,lbf (or N),and L =length of test specimen in in.(or cm),to the nearest 0.1in.(0.2cm).8.9.5Report—The following test information shall be reported:8.9.5.1Date of test,8.9.5.2Type of testing machine used,8.9.5.3Description or numbers of the lot or lots tested,8.9.5.4The width of the filler strip to the nearest 0.001in.(0.025mm),and 8.9.5.5Lip pressure for each gasket channel tested.9.Keywords 9.1compression;elastomer;elastomeric;gasket;locking;lock-strip;preformed;seal;strip;zipperFIG.4LipDividersThe American Society for Testing and Materials takes no position respecting the validity of any patent rights asserted in connection with any item mentioned in this ers of this standard are expressly advised that determination of the validity of any such patent rights,and the risk of infringement of such rights,are entirely their own responsibility.This standard is subject to revision at any time by the responsible technical committee and must be reviewed everyfive years and if not revised,either reapproved or withdrawn.Your comments are invited either for revision of this standard or for additional standards and should be addressed to ASTM Headquarters.Your comments will receive careful consideration at a meeting of the responsible technical committee,which you may attend.If you feel that your comments have not received a fair hearing you should make your views known to the ASTM Committee on Standards,at the address shown below.This standard is copyrighted by ASTM,100Barr Harbor Drive,PO Box C700,West Conshohocken,PA19428-2959,United States. Individual reprints(single or multiple copies)of this standard may be obtained by contacting ASTM at the above address or at 610-832-9585(phone),610-832-9555(fax),or service@(e-mail);or through the ASTM website().。
2022年分析化学考研面试问题
药物分析实验典型问题1、鉴别检查在药物质量控制中旳意义及一般杂质检查旳重要项目是什么? What are thepurposes of drug identification and test? What are the usual items of drug tests?.2、比色比浊操作应遵循旳原则是什么? What are the standard operation procedures forthe clarity test?3、试计算葡萄糖重金属检查中原则铅溶液旳取用量。
How much of the lead standardsolution should be taken for the limit test for heavy metals in this experiment?4、古蔡氏试砷法中所加各试剂旳作用与操作注意点是什么? What precautions shouldbe taken for the limit test for arsenic(Appendix VIII J,method 1)? And what is the function for each of the test solutions added?5、根据样品取用量、杂质限量及原则砷溶液旳浓度,计算原则砷溶液旳取用量。
Figure outthe amount of the arsenic standard solution that should be taken for the limit test for arsenic(Appendix VIII J,method 1) (0.0001%) in this experiment with the specified quantity of 2.0 g of sample.6、炽灼残渣测定旳成败核心是什么?什么是恒重?What is the key step during thedetermination of residue on ignition? What does ‘ignite or dry to constant weight’mean?7、盐酸普鲁卡因旳鉴别原理是什么?What are the principles of the identification ofProcaine Hydrochloride.8、盐酸普鲁卡因注射液中为什么要检核对氨基苯甲酸?Why is the limit of4-aminobenzoic acid tested for Procaine Hydrochloride?9、薄层色谱法检查药物中有关物质旳措施一般有哪几种类型?本实验属于哪种?与其他措施有何异同点? How many kinds of the limit tests for related compounds are there?What are the differences between them? Which one is used for the limit test of 4-amino-benzoic acid in Procaine Hydrochloride Injection?10、醋酸氢化可旳松旳鉴别原理是什么?What are the principles of the identification ofhydrocortisone acetate?11、甾体激素中“其他甾体”检查旳意义和常用措施是什么?What are the commonly usedmethod for and the significance of the limit test for other steroids for the steroidal drugs?12、哪类甾体激素可与四氮唑蓝产生反映,是构造中旳何种基团参与了反映,反映式是什么?What kind of steroidal drugs can react with the alkaline tetrazolium blue TS?What is the chemical reaction equation?13、氯贝丁酯旳鉴别原理是什么?What are the principles of the identification ofclofibrate?14、氯贝丁酯中为什么要检核对氯酚?其措施及原理是什么?Why is the limit ofp-Chlorophenol tested for clofibrate? What kind of method is employed for the test and what is the principle?15、气相色谱法检查杂质有哪些措施,试比较多种措施旳特点?How many types ofmethods are there for the test of related compounds by the gas chromatography?What are the differences between them?16、抗生素类药物旳鉴别和检查有何特点?What are the characteristics for theidentification and tests of antibiotics?17、钠盐旳焰色反映应注意什么?What precautions should be taken during the flamereaction of sodium salts?18、本品吸取度检查旳意义是什么?What is the purpose of the light absorption tests forbenzylpenicillin sodium?19、药物晶型测定旳常用措施有哪些,各有什么特点?What are the commonly usedmethods for the test of polymorphism? And what are the characteristics of each of them?20、吸取系数测定措施与规定?What are the standard operation procedures for theestablishment of specific absorbance?21、写出异烟肼与溴酸钾旳滴定反映式和滴定度旳计算过程。
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Specifying Compositional Units for Correct Program Development in Computational LogicKung-Kiu Lau1and Mario Ornaghi21Department of Computer Science,University of ManchesterManchester M139PL,United Kingdomkung-kiu@2Dipartimento di Scienze dell’Informazione,Universita’degli studi di MilanoVia Comelico39/41,20135Milano,Italyornaghi@dsi.unimi.itAbstract.In order to provide a formalism for defining program cor-rectness and to reason about program development in ComputationalLogic,we believe that it is better to distinguish between specificationsand programs.To this end,we have developed a general approach tospecification that is based on a model-theoretic semantics.In our pre-vious work,we have shown how to define specifications and programcorrectness for open logic programs.In particular we have defined a no-tion of correctness called steadfastness,that captures at once modularity,reusability and correctness.In this paper,we review our past work andwe show how it can be used to define compositional units that can becorrectly reused in modular or component-based software development.1IntroductionIn software engineering,requirements analysis,design and implementation are distinctly separate phases of the development process[18],as they employ dif-ferent methods and produce different artefacts.In requirements analysis and design,specifications play a central role,as a frame of reference capturing the requirements and the design decisions.By contrast,data and programs only ap-pear in the implementation phase,towards the end of the development process. There is therefore a clear distinction between specifications and programs.In Computational Logic,however,this distinction is usually not maintained. This is because there is a widely held view that logic programs are executable specifications and therefore there is no need to produce specifications before the implementation phase of the development process.We believe that undervalu-ing specifications in this manner is not an ideal platform for program devel-opment.If programs are indistinguishable from specifications,then how do we define program correctness,and how do we reason about program development? We hold the view that the meaning of correctness must be defined in terms of something other than logic programs themselves.We are not alone in this,see e.g.,[17,p.410].In our view,the specification should axiomatise all our rele-vant knowledge of the problem context and the necessary data types,whereas,M.Bruynooghe and u(Eds.):Program Development in CL,LNCS3049,pp.1–29,2004.c Springer-Verlag Berlin Heidelberg20042Kung-Kiu Lau and Mario Ornaghifor complexity reasons,programs rightly capture only what is strictly neces-sary for computing.In the process of extracting programs from specifications, a lot of knowledge is lost,making programs much weaker axiomatisations.This suggests that specifying and programming are different activities,involving dif-ferent methodological aspects.Thus,we take the view that specifications should be clearly distinguished from programs,especially for the purpose of program development.Indeed,we have shown(in[28,29])that in Computational Logic, not only can we maintain this distinction,but we can also define various kinds of specifications for different purposes.Moreover,we can also define correctness with respect to these specifications.Our semantics for specification and correctness is model-theoretic.The declar-ative nature of such a semantics allows us to define steadfastness[34],a notion of correctness that captures at once modularity,reusability and correctness.Open programs are incomplete pieces of code that can be(re)used in many different admissible situations,by closing them(by adding the missing code)in many different ways.Steadfastness of an open program P is pre-proved correctness of the various closures of P,with respect to the different meanings that the spec-ification of P assumes in the admissible situations.For correct reuse,we need to know when a situation is admissible.This knowledge is given by the prob-lem context.We have formalised problem context as a specification framework [27],namely,afirst-order theory that axiomatises the problem context,charac-terises the admissible situations as its(intended)models,and is used to write specifications and to reason about them.In this paper,we review our work in specification and correctness of logic pro-grams,including steadfastness.Our purpose is to discuss the role of steadfastness for correct software development.In particular,we are interested in modularity and reuse,which are key aspects of software development.Our work is centred on the notion of a compositional unit.A compositional unit is a software com-ponent,which is commonly defined as a unit of composition with contractually specified interfaces and context dependencies only[46].The interfaces declare the imported and exported operations,and the context dependencies specify the constraints that must be satisfied in order to correctly(re)use them.Through-out the paper,we will not refer to compositional units as software components, however,for the simple reason that as yet there is no standard definition for the latter(although the one we used above[46]is widely accepted).So we prefer to avoid any unnecessary confusion.In our compositional units,the interfaces and the context dependencies are declaratively specified in the context of the specification framework F axiomatising the problem context.F gives a precise semantics to specifications and allows us to reason about the correctness of pro-grams,as well as their correct reuse.Thus,in our formalisation,a compositional unit has a three-tier structure,with separate levels for framework,specifications and programs.We introduce compositional units in Section2,and consider the three levels separately.We focus on model-theoretic semantics of frameworks and specifica-tions,and on steadfastness(i.e.,open program correctness).Specifying Compositional Units for Correct Program Development 3InSection 3,we show how the proposed formalisation of compositional units can be used to support correct reuse.Our aim is to highlight the aspects related to specifications,so we consider only the aspects related to the framework and the specification levels,while assuming the possibility of deriving (synthesising)steadfast programs from specifications.At the end of each section we briefly discuss and compare our results with related work,and finally in the conclusion we comment on future developments.2Compositional UnitsIn our approach,compositional units represent correctly reusable units of specifi-cations and correct open programs .Our view is that specifications and programs are not stand-alone entities,but are always to be considered in the light of a problem context.The latter plays a central role:it is the semantic context in which specifications and program correctness assume their appropriate mean-ing,and it contains the necessary knowledge for reasoning about correctness and correct reuse.This is reflected in the three-tier structure (with model-theoretic semantics)of a compositional unit,as illustrated in Figure 1.Fig.1.A three-tier formalism.At the top level of a compositional unit K ,we have a specification framework F ,or framework for short,that embodies an axiomatisation of the problem context.F has a signature Σ,a set X of axioms ,a set T of theorems ,a list ΠF of open symbols ,and a list ∆F of defined symbols .The syntax ΠF ⇒∆F indicates that the axioms of F fix (the meaning of)the symbols ∆F whenever F is composed with frameworks that fix ΠF .The defined and open symbols belong to the signature Σ,which may also contain closed symbols ,namely symbols4Kung-Kiu Lau and Mario Ornaghidefined completely by the axioms(i.e.,independently fromΠF).Frameworks are explained in Section2.1,and framework composition is explained in Section 3.1.In the middle,we have the specification section.Its role is to bridge the gap between the framework F and the chosen programming language.So far,we have considered only logic programs,and the corresponding specification formalism is explained in Section2.2.The specification section contains the specificationsS p1,...,S pnof the program predicates occurring in the program section.It mayalso contain a set of specification reduction theorems theorems RD1,...,RD k, that are useful to reason about correct reuse.Specification reduction is explained in Section3.2.At the bottom,we have the program section.Programs are open logic(or con-straint logic)programs.An open program P idi :Sπi⇒Sδi{C i}(1≤i≤h)hasan identifier id i,an interface specification Sπi ⇒Sδiand a set{C i}of implemen-tation clauses.Sπi and Sδiare lists of specifications defined in the specificationsection.An interface specification contains all the information needed to correctly reuse a correct program.Programs and correctness are explained in Section2.3. Correct reuse is explained in Section3.3.2.1Specification FrameworksA specification framework F is defined in the context offirst-order logic,and contains the relevant knowledge of the necessary concepts and data types for building a model of the application at hand.We distinguish between closed and open frameworks.A closed framework F= Σ,X,T has a signatureΣ,a set X of axioms,and a set T of theorems. It has no open and defined symbols,that is,all the symbols ofΣare closed.Example1.An example of closed framework isfirst-order arithmetic NAT= ΣNat,X Nat,T Nat ,introduced by the following syntax:3Framework NAT;decls:Nat:sort;0:[]→Nat;s:[Nat]→Nat;+,∗:[Nat,Nat]→Nat;axs:Nat:construct(0,s:Nat);+:i+0=i;i+s(j)=s(i+j);:i∗0=0;i∗s(j)=i∗j+i;thms:i+j=j+i;...3In all the examples,we will omit the outermost universal quantifiers,but their omni-presence should be implicitly understood.Specifying Compositional Units for Correct Program Development5 The signatureΣNat,introduced in the declaration section decls,is the signature of Peano’s arithmetic.The axioms X Nat,introduced in the axs section,are the usual ones offirst-order arithmetic.0and s are the constructors of Nat and their axioms,which we call the constructor axioms for Nat,are collectively indicated by construct(0,s:Nat).The latter contains Clark’s equality theory[35]for0 and s,as well as all the instances of thefirst-order induction schema.NAT has been widely studied,and there are a lot of known theorems(in section thms), including for example the associative,commutative and distributive laws.Theorems are an important part of a framework.However,they are not relevant in the definitions that follow,so we will not refer to them explicitly here.For closed frameworks we adopt isoinitial semantics,that is,we choose the intended model of F= Σ,X to be a reachable isoinitial model,defined as follows:Definition1(Reachable Isoinitial Model[5]).Let X be a set ofΣ-axioms. AΣ-structure i is an isoinitial model of X iff,for every model m of X,there is a unique isomorphic embedding i:i→m.A model i is reachable if its elements can be represented by ground terms. Definition2(Adequate Closed Frameworks[30]).A closed framework F= Σ,X is adequate iffthere is a reachable isoinitial model i of X that we call‘the’intended model of F.In fact i is one of many intended models of F,all of which are isomorphic. So i is unique up to isomorphism,and hence our(ab)use of‘the’.As shown in[5],adequacy entails the computability of the operations and predicates of the signature.Example2.NAT is an adequate closed framework.Its intended model is the standard structure N of natural numbers(N is a reachable isoinitial model of X Nat).N interprets Nat as the set of natural numbers,and s,+and∗as the successor,sum and product function,respectively.The adequacy of a closed framework is not a decidable property.We have the following useful proof-theoretic characterisation,which can be seen as a“richness requirement”implicit in isoinitial semantics[31]:Definition3(Atomic Completeness).A framework F= Σ,X is atomi-cally complete iff,for every ground atomic formula A,either X A or X ¬A.Theorem1(Adequacy Condition[38]).A closed framework F= Σ,X is adequate iffit has at least one reachable model and is atomically complete.Closed adequate frameworks can be built incrementally,starting from a closed adequate kernel,by means of adequate extensions.6Kung-Kiu Lau and Mario OrnaghiDefinition4(Adequate Extensions[30]).An adequate extension of an ad-equate closed framework F= Σ,X is an adequate closed framework Fδ= Σ∪δ,X∪Dδ such that:a)Dδis a set of(Σ∪δ)-axioms,axiomatising a set of new(i.e.,not inΣ)symbolsδ;b)theΣ-reduct i|Σof the intended model i of Fδis the intended model of F.The notions of reduct and expansion are standard in logic[4].TheΣ-reduct i =i|Σforgets the interpretation of the symbols not inΣ,in our case the new symbolsδ.Conversely,i is said to be a(Σ∪δ)-expansion of i ,that is,a (Σ∪δ)-expansion is a(Σ∪δ)-interpretation that preserves the meaning of the oldΣ-symbols,and interprets the newδarbitrarily.In Definition4,by b),the intended model i of an adequate extension is an expansion of the old intended model,that is,adequacy entails that the meaning of the old symbols is preserved.If the axioms Dδof an adequate extension are explicit definitions,we say that they are adequate explicit definitions.Since they are important in our approach, we briefly recall them.An explicit definition of a new relation r has the form∀x•r(x)↔R(x), where x indicates a tuple of variables and(as usual)“•”extends the scope of a quantifier to the longest subformula next to it.The explicit definition of a new function f has the form∀x•F(x,f(x)),where R(x)and F(x,y)are formulas of the framework that contain free only the indicated variables.The explicit definition of f has the proof obligation X ∀x•∃!y•F(x,y),where X are the framework axioms(as usual,∃!y means unique existence).R(x)is called the definens(or defining formula)of r,and F(x,y)the definiens(or defining formula)of f.Explicit definitions have nice properties.They are purely declarative,in the following sense:they define the new symbols purely in terms of the old ones, that is,in a non-recursive way.This declarative character is reflected by the following eliminability property,whereΣis the signature of the framework and δare the new explicitly defined symbols:the extension is conservative(i.e.,no newΣ-theorem is added)and every formula ofΣ+δis provably equivalent to a corresponding formula of the old signatureΣ.Moreover,if we start from a sufficiently expressive kernel,most of the relevant relations and functions can be explicitly defined.Finally,we can prove:Proposition1.If the definiens of an explicit definition is quantifier-free,then the definition is adequate.If the definiens is not quantifier-free,adequacy must be checked.To state the adequacy of closed frameworks and of explicit definitions,we can apply proof methods based on logic program synthesis[26,27]or constructive logic[38]. Example3.The kernel NAT of Example1is sufficiently expressive in the fol-lowing sense.Every recursively enumerable relation r can be introduced by anSpecifying Compositional Units for Correct Program Development7 explicit definition.4For example,we can define the ordering relations≤and< by the explicit definitions:D≤:i≤j↔∃k•i+k=j;D<:i<j↔i≤j∧¬i=j.Since the outermost universal quantifiers are implicitly present,D≤is the closed formula∀i,j•i≤j↔∃k•i+k=j(similarly,D<is understood to be univer-sally closed).Since the definiens∃k•i+k=j of≤is quantified,adequacy of D≤must be checked.It can be proved by logic program synthesis,as follows.(a)We derive the following clauses in NAT+D≤:P≤:0≤i←s(i)≤s(j)←i≤j.(b)In NAT+D≤we prove the only-if part of the completed definition[35]of≤in P≤(the if part is guaranteed by a)).(c)Finally,we prove that P≤existentially terminates,i.e.,for every ground atomA,the goal←Afinitely fails or has at least one successful derivation(with program P≤).By(a),(b)and(c)we get([27],Theorem11)that the extension by D≤is adequate.By the way,adequacy entails that the new predicate≤is computable. We do not have to check the adequacy of D<,because its definiens is quantifier free.D<uses≤.However,an explicit definition of<and a proof of its adequacy can be given directly in NAT,by the eliminability of explicit definitions.Thus we could define<first,prove its adequacy,and then define≤on top of<.That is,the order of explicit definitions is not relevant.We can explicitly define functions,for example the integer square root sqrt:D sqrt:sqrt(i)∗sqrt(i)≤i∧i<s(sqrt(i))∗s(sqrt(i)).The proof obligation∀i•∃!j•j∗j≤i∧i<s(j)∗s(j)can be proved in NAT by induction.Adequacy follows from the fact that the definiens j∗j≤i∧i< s(j)∗s(j)is quantifier free.An open framework F(Π⇒∆)= Σ,X represents an incomplete axioma-tisation.It has a non-empty import listΠ,containing the symbols left open by the axioms,and a(possibly empty)disjoint export list∆,containing the symbols that are defined by the axioms,in terms of the open ones.The closed symbols are the symbols of the signature that are not inΠ∪∆,and their meaning is fixed in a unique way by the axioms.We distinguish three sets of axioms,where ΣK is the sub-signature of the closed symbols:4Every recursively enumerable relation is Diophantine(Matijacevic theorem[37]).8Kung-Kiu Lau and Mario Ornaghi–the kernel axioms X K=X|ΣK(...|ΣK is the subset of the axioms with symbols fromΣk);the kernel axioms axiomatise the closed symbols,that is,F K= ΣK,X K must be an adequate closed framework,that we call theclosed kernel;–the constraints X C=(X|(ΣK∪Π))\X K,which constrain the possible interpretations of the open symbolsΠ;–and the definition axioms X D=X\(X K∪X C),whichfix the meaning of the defined symbols∆,in terms of the open and closed symbols.Example4.The following open framework axiomatises lists with generic ele-ments X and a generic total ordering¡on X.From now on,in the examples, the variables of sort X will begin with x,y,z,w,those of sort Nat with i,j,h,k, and those of sort ListX with l,m,n,o.Framework LIST(X,¡⇒ListX,nil,.,@,nocc);kernel:NAT;decls:X:sort;ListX:sort;¡:[X,X];nil:[]→ListX;.:[X,ListX]→ListX;@(,):[X,Nat,ListX];nocc:[X,ListX]→Nat;defaxs:ListX:construct(nil,.:ListX);@:x@(0,l)↔∃y,m•l=y.m∧x=y;x@(s(i),l)↔∃y,m•l=y.m∧x@(i,m);nocc:nocc(x,nil)=0;x=y→nocc(x,y.l)=nocc(x,l)+1;¬x=y→nocc(x,y.l)=nocc(x,l);constrs:¡:TotalOrdering(¡).The signatureΣNat,the axioms X Nat and the theorems T Nat of the imported ker-nel NAT are automatically included.In the definition axioms defaxs,nil and “.”are the list constructors,as indicated by construct(nil,.:ListX),which con-tains Clark’s equality theory and structural induction on constructors;x@(i,l) means that the element x occurs at position i in the list l,where positions start from0;nocc(x,l)is the number of occurrences of the element x in the list l;by the constraint axioms constrs,¡is a total ordering relation.To specify the basic operations on the ADT of lists,the closed kernel NAT is not necessary.We have imported it for specification and reasoning purposes. Indeed,by using natural numbers we can introduce@and nocc.The resulting language and axiomatic system give a rich starting framework,which allows us to explicitly define the usual operations on lists and ordered lists,and to reason about them(see Example6).Specifying Compositional Units for Correct Program Development9An open framework F has a class of not necessarily isomorphic intended models,since X K∪X C allows many(ΣK∪Π)-interpretations,that we call pre-models.The semantics considered here is a variant of the one presented in[30].A pre-model is an expansion of the intended model of the kernel that satisfies the constraints X C.For every pre-model p,the axioms of Ffix a corresponding intended p-model i p,defined as follows.A p-model of F is aΣ-model m of X such that m|(ΣK∪Π)=p,that is,m coincides with p over the closed and open symbols.SinceΠmay contain open sorts,we considerΠ-reachable models,whereΠ-reachability is reachability in an expansion containing a new constant for each element of each open sort.Definition5(p-isoinitial Models).A p-model i is a p-isoinitial model of F iff,for every p-model m,there is a unique isomorphic embedding i:i→m such that i is the identity over the open sorts.Definition6(Adequate Open Frameworks and Intended Models).An open framework F is adequate iff,for every pre-model p of F,there is aΠ-reachable p-isoinitial model i p,that we call the intended p-model of F.m is an intended model of F iffthere is a pre-model p of F such that m is the intended p-model of F.For every pre-model p,the intended p-model is unique up to isomorphism. Intended models with non-isomorphic pre-models are,of course,non-isomorphic. We consider closed frameworks as a limiting case,where the kernel coincides with the whole framework and the unique intended model coincides with the unique pre-model.Example5.LIST is an adequate open framework.In it,a pre-model p coincides with N for the kernel signatureΣNat and interprets X as any set with a total ordering¡.The intended p-model of LIST interprets ListX as the set of the finite lists with elements from X,and the other defined symbols in the way already explained in Example4.Adequate open frameworks can be built incrementally,by adequate exten-sions,where the intended models of an adequate extension F of a framework F are expansions of intended models of F.Definition7(Adequate Extensions).A framework F is an adequate ex-tension of an adequate open framework F iffF is an adequate open or closed framework,the signature and the axioms of F contain those of F,the kernel signature of F contains the kernel signature of F,and for every intended model i of F ,the reduct i |Σis an intended model of F.In the limiting case,an adequate extension F of an open framework F may be a closed framework.In this case,we say that F is an instance of F,and the axioms that“instantiate”(i.e.,close)the open symbols are called closure axioms.A set of closure axioms is called a closure.Closures will be considered in Section3.1,together with other framework operations.10Kung-Kiu Lau and Mario OrnaghiIn general,the adequacy of an extension is not decidable,but we may havedifferent kinds of extensions,with different adequacy conditions.In particular,we distinguish:–Parameter extensions.In this case new parameters and/or new constraintsare added.Parameter extensions are adequate iff,adding new constraints,consistency is preserved.–Defined symbol extensions.In this case new defined symbols,together withthe corresponding definition axioms,are added.Adequate explicit definitionsare still useful for introducing new defined symbols,and adequacy can be stated in a way similar to those mentioned before for closed framework ex-tensions(by program synthesis or constructive logic[27,38]).Proposition1still holds.–Kernel extensions.In this case the closed kernel is extended by new closedsymbols,as already shown for closed frameworks.Example6.The framework LIST(X,¡⇒ListX,nil,.,@,nocc)can be ob-tained by extending the framework LIST(X⇒ListX,nil,.,@,nocc),without ¡and without constraint axioms,by the parameter¡:[X,X]constrained by TotalOrdering(¡).The kernel NAT can be extended by explicitly defining themost useful operations and predicates on natural numbers.The defined symbolscan be extended by the relevant operations on lists,by means of explicit defi-nitions.For example,the definitions of list membership,length,concatenation and permutation are:5D∈:x∈l↔nocc(x,l)>0D len:∀i•(∃x•x@(i,l))↔i<len(l)D|:∀i,x•(i<len(l)→(x@(i,l)↔x@(i,l|m)))∧(len(l)≤i→(x@(i,m)↔x@(i+len(l),l|m)))D perm:perm(l,m)↔∀x•nocc(x,l)=nocc(x,m)D∈gives rise to an adequate extension,because its definiens is quantifier free.The definiens of D len is∀i•(∃x•x@(i,l))↔i<k and the proof obligation re-quires a proof of∀l•∃!k•∀i•(∃x•x@(i,l))↔i<k.Since the definiens is quan-tified,adequacy must be checked(and can be proved),by constructive proofs or by program synthesis.Adequacy must be checked(and can be proved)also for D|and D perm.Using¡:[X,X],we can also define operations on ordered lists,like l¡L m(lexicographic ordering on lists),ord(l)(l is an ordered list),and so on.Their properties can be proved using the total ordering constraints.For example,we can prove that the lexicographic ordering¡L is,in turn,a total ordering.2.2SpecificationsIn a compositional unit K,specifications assume their proper meaning only in the context of the framework F.In this section we define formally what we 5In Dand D|,the universal quantifiers of the definiens have not been omitted.lenSpecifying Compositional Units for Correct Program Development11 mean by specifications in F and we show some examples.We maintain a strict distinction between specification frameworks and(program)specifications and, to distinguish the function and relation symbols of the framework from thosecomputed by programs,the latter will be called(program)operations.Definition8(Specifications and S-expansions).Let F(Π⇒∆)= Σ,X be a framework.A specification Sωin(the context of)F is a set of closed (Σ+ω)-formulas,that define a set of operationsωin terms of F.An Sω-expansion of a model m of F is a(Σ+ω)-expansion m of m such that m |=Sω.That is,Sωcan be interpreted as an expansion operator that associates with every intended model of F the corresponding Sω-expansions,namely the expan-sions that interpret the specified operations according to Sω.Definition9(Strict Specifications).A specification Sωis strict in a frame-work F,if,for every model m of F,there is only one Sω-expansion.It is non-strict otherwise.Now we list different kinds of strict and non-strict specifications considered in[28],essentially based on explicit definitions.The specification formalism con-sidered here is tailored to logic programs with definite clauses in a many-sortedsignature.Program semantics is based on minimum Herbrand models,where program data(those used in programs)coincide with ground terms.We as-sume that the signatureΣD of program data is pre-defined by the framework F,and that,for every closed or defined sort s ofΣD,F contains the axioms construct(c1,...,c n:s),where c1,...,c n are the constructors of s.They are theunique operations of sort s that can be used in logic programs.This assump-tion concerns Herbrand models of standard logic programs,where construct(...) holds,but our treatment readily extends to the specification formalism for con-straint logic programs by assuming thatΣD is the constraint signature,and is pre-defined by the framework.Since in logic programs only program predicates are not pre-defined,we have to specify only them.There are different forms of specifications.If-and-Only-if Specifications.An if-and-only-if specification in a framework F is an explicit definition of a new predicate r:S r:∀x•r(x)↔R(x)By the well known properties of explicit definitions,for every model m of the framework F,there is only one S r-expansion of m,that is,S r is strict. Example7.In NAT we can specify,for example,the following predicates: S div:div(i,j,h,k)↔i=j∗h+k∧k<j;S divides:divides(i,j)↔∃h•div(j,i,h,0);S prime:prime(i)↔∀j•divides(j,i)→j=1∨j=i;12Kung-Kiu Lau and Mario OrnaghiSuper-and-sub Specifications.A super-and-sub specification in a framework F is of the formS r:∀x•(R s ub(x)→r(x))∧(r(x)→R s uper(x))where R s ub(x)and R s uper(x)are two formulas of F such that F ∀x•R s ub(x)→R s uper(x).The implication∀x•R s ub(x)→R s uper(x)is satisfied by the models of F. Therefore,in every intended model i,the relation R s ub in i,i.e.,the set of values x such that i|=R s ub(x),is a sub-relation of the relation R s uper,and the specified relation r is any relation that is a super-relation of R s ub but is a sub-relation of R s uper.Conditional Specifications.A conditional specification of a new relation r in a framework F has the form:∀x,y•I C(x)→(r(x,y)↔R(x,y))(1) where I C(x)is the input condition,and R(x,y)is the input-output condition. Both I C(x)and R(x,y)are formulas of F.(1)specifies r(x,y)only when the input condition I C(x)is true,while nothing is required if the input condition is false.That is,I C(x)states that r(x,y)is to be called only in contexts that make it true.This fact allows us to assume I C(x)when reasoning about correct reuse,as shown in Section3.2.(1)is equivalent to the following super-and-sub specification,which allows us to apply the results of[34]in correctness proofs:∀x,y•(I C(x)∧R(x,y)→r(x,y))∧(r(x,y)→¬I C(x)∨R(x,y)) Example8.In the open framework LIST(X,¡⇒ListX,nil,.,@,nocc),we have for example the following specification:S s ort:s ort(l,m)↔p erm(l,m)∧o rd(m);S m erge:o rd(l)∧o rd(m)→(m erge(l,m,o)↔o rd(o)∧perm(l|m,o));S s plit:(len(l)>1∧s plit(l,m,n)→perm(l,m|n)∧len(m)<len(l)∧len(n)<len(l))∧(len(l)>1→∃m,n•s plit(l,m,n));S s ort is an if-and-only-if specification,S m erge is a conditional specification.By the input condition,m erge(l,m)is to be called only in contexts where the input lists are ordered.If they are not,o is not required to be ordered.S s plit is an ex-ample of another form of non-strict specification(called a selector specification) that we do not discuss here(see[28]).2.3Interface Specifications,Programs,and CorrectnessHere we consider correctness of(logic)programs with respect to interface spec-ifications.In Section3.2,we will consider the role of interface specifications in correct reuse.We start by introducing some terminology.。