Aston_Martin_Guide_2006
Unit 1 Factory Tour
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rejects? Richard: Only 1% in normal operations. Thomas: It’s amazing. How do you control the quality? Richard: All products go through three checks during the whole
assembly line. Thomas: That’s fine. I’ll just follow you.
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Opening
This course is not traditional listening & viewing English course, we should construct a multidimensional interaction (audio-visual) learning mode.
临床化学分析方法:Albumin_in_Urine
Kaplan: Clinical Chemistry, 5th EditionClinical References - Methods of AnalysisAlbumin in UrineGraham Jones iName: Albumin in urineClinical Significance: A marker of renal damage in diabetes and other conditions. Also amarker of risk for cardiovascular disease.Common name: MicroalbuminuriaRefer to Chapter 30, Renal Function, in the 5th edition of Clinical Chemistry: Theory, Analysis, Correlation.Students’ Quick Hyperlink Review•Measurand•Principles of analysis and current usage•Reference and preferred methods•Specimen•Interferences•Urine albumin reference intervals•Interpretation•Urine albumin performance goals•References•Urine albumin methods tableMeasurandHuman albumin is a single polypeptide chain of 585 amino acids with 17 internal disulphide bonds but without carbohydrate side chains. Albumin in the circulation has microheterogeneity due to structural flexibility, ligand binding, and other factors. The transition of albumin from the serum to the urine has the potential to markedly increase the structural variability by fragmentation, internal cleavage, oxidation, or selective tubular resorption, and multiple forms of albumin have been identified in urine [1,2]. This variability in albumin has the potential to lead to standardization difficulties with assays and is known to produce different results for individual patients using different assays [3,4]. The development of assays for albumin fragments detectable by HPLC but not by standard immunoassays, the so-called immunochemical non-reactive albumin, has raised the possibility of improved sensitivity for detection of early renal damage [2]. There is a need to identify a measurand which is the most clinically relevant andi Albumin in UrineNew methodFifth edition: Graham Jonesanalytically suitable to provide standardized assays for urine albumin [5]. The structure of albumin in urine and its possible effect on various assays has been the subject of an extensive review [6].Principles of Analysis and Current UsageAssays for albumin in urine can be divided into three main categories: routine laboratory assays, point-of-care assays, and other reference or developmental assays. Owing to the issues mentioned above with regard to variability in the structure of urine albumin, there are some systematic and patient-specific differences between results from different assays, depending on the measurement technology and the antibody specificity.The vast majority of routine laboratories use immunoassays to quantitate albumin in urine. These may be structured as nephelometric or turbidimetric homogenous immunoassays or heterogenous competitive or noncompetitive immunoassays and may use monoclonal or polyclonal antibodies. These assays are generally purchased from diagnostic companies and are available for use on high-volume chemistry or immunoassay analyzers, as well as in manual assay formats such as enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay. These commercial assays generally provide sufficient sensitivity to measure urine albumin down to concentrations found in healthy individuals, often with limits of detection below 5 mg/L, and are able to separate patients with normal albumin excretion from those with increased excretion. In addition, these assays have precision characteristics able to meet biological variation criteria with claimed coefficient of variation (CV) values for total precision of < 5%. For determination of the albumin-creatinine ratio, there is also the need to measure urine creatinine concentrations. Because the presence of noncreatinine chromogens in urine is much less than in plasma, routine creatinine assays are generally acceptable for this purpose. If a timed sample is received for calculation of the albumin excretion rate, the urine volume must be measured using appropriate scales or a volumetric flask. Given the high prevalence of diabetes, most laboratories need a method with high capacity to meet the clinical needs.There are a number of point-of-care methods available for urine albumin measurement using different assay formats and technologies. These may be semiquantitative or quantitative, and some also measure creatinine to allow calculation of the albumin-creatinine ratio. Point-of-care testing is of particular use in the clinical setting where a rapid return of laboratory results is difficult [7], although in any setting, the provision of a result for use within the same medical consultation as the sample collection can be beneficial. Since positive results can be referred to a laboratory for further analysis, a point-of-care test used as a screening test should have sufficient sensitivity to avoid missing positive results. The use of a high-quality quantitative point-of-care analyzer may avoid the need for referral of positive samples. Below are examples of point-of-care devices for measurement of urine albumin.The Siemens DCA Vantage analyzer (previously known as the DCA 2000) uses a monoclonal antibody agglutination technique for albumin, with a simultaneous chemical creatinine assay. These tests are performed on a single 40 µL sample; results are available in 7 minutes, using a disposable cartridge and a portable analyzer. The system achieves good precision, with CV < 5% for albumin and < 3% for creatinine, with quantitation of albumin down to 5 mg/L in a laboratory evaluation [8] with similar performance when used in remote locations [7].The Haemocue instrument is small, portable analyzer which uses disposable cuvettes preloaded with reagents. The system uses immunoturbidimetry and produces a result in 90 seconds from 18 µL of sample. The reporting range is 5 to 150 mg/L; however, precision was poorer than seen in laboratory methods at all concentrations tested, with within-run CVs of between 10% and 13% for patient samples with albumin concentrations above 20 µg/L [9,10], although overall a good correlation with routine laboratory methods has been achieved [10].The Siemens Clinitek system provides semiquantitative results for both albumin concentration and the albumin/creatinine ratio, using a regent strip with dye-binding techniques. The strips may be read in a small reader device, and results higher than 20 mg/L are reported as positive. Precision for the system cannot be easily determined, because the results are reported in large increments. A number of interferences are listed in the product information, including hematuria, soaps, dyes, and some drugs, as well as high levels of urine protein. An evaluation of patient samples showed that approximately 12% of patients with laboratory urine albumin results below 20 mg/L were falsely reported as elevated and 11% of samples with low-positive lab results (20 to 55 μg/L) were reported as negative [11]. A higher false-positive rate has been described in children [12], and it has been recommended that low-positive results be confirmed with laboratory testing [10].The Roche Micral reagent strips are dipped into a urine sample and the resultant immunologically-mediated color formation visually compared with a semiquantitative chart. The method has demonstrated acceptable between-user correlation [13].The lowest positive result is a color intensity associated with a nominal value of 20 mg/L. This decision point has been shown to have a high false-positive rate in two studies, indicating the need for laboratory follow-up if available [14,15].Measurement of urine albumin by HPLC detects different fragments of albumin, compared to immunoassay as described above. This leads to higher results, especially in the low range, with consequent higher detection rates for microalbuminuria when standard decision points are used [16,17]. More recent work has indicated possible co-elution of other proteins with albumin leading to overestimation of albumin by this method [18]. The differences between HPLC and immunoassay highlights the need for agreed reference methods and materials.Reference and Preferred MethodsThere are currently no reference methods or reference materials for urine albumin listed on the Joint Committee for Traceability in Laboratory Medicine (JCTLM) database [19]. In the absence of specific reference materials for urine albumin, most manufacturers reference their assays to human serum albumin—for example, using CRM470.The preferred methods for routine use are immunoassays for urine albumin with additional measurement of urine creatinine to allow calculation of the albumin/creatinine ratio. For many routine laboratories, this type of technology has the advantages of high throughput and performance on a routine chemistry or immunoassay analyzer. The required key performance characteristics are described further below.SpecimenThe amount of albumin in urine can be expressed in a number of different formats which require different samples [6]. These reporting formats include the following:Albumin Excretion Rate (AER)Albumin excretion rate is commonly expressed as mg per 24 hours or micrograms per minute. The former requires a 24-hour sample, whereas the latter may use a 24-hour sample or other timed period, such as an overnight collection. Both samples require close attention to start and finish times, as well as avoiding over- and under-collection from other causes. AER is considered to be the gold standard but is not generally recommended for routine use because of these collection difficulties.Urine Albumin/Creatinine Ratio (ACR)Expressing the albumin concentration in a spot sample as a ratio to urine creatinine is a method to reduce the effect of patient hydration on the albumin concentration. ACR is measured in a spot sample, preferably a first morning sample; a random sample is acceptable, but daily activity may lead to false-positive results. The units are mg/g creatinine or mg/mmol creatinine. The use of creatinine to correct for hydration also adds an influence of muscle mass to the result with larger people, who produce more creatinine, giving lower results for the same albumin excretion. This is seen with the different decision points for males and females recommended by some bodies. The ACR is recommended by the American Diabetes Association (ADA) for urine albumin testing [20]. These recommendations also indicate that results from at least 2 out of 3 samples over a 6-month period are used to confirm significant changes in albumin excretion status. Urine Albumin Concentration (UAC)The UAC is reported as mg/L or the equivalent µg/mL and is measured in a spot sample—like the ACR, preferably a first morning sample, but a random sample is acceptable. Some studies have shown minimal difference between the sensitivity of ACR and UAC for increased AER, so some authors recommend the use of UAC for general purposes, because this removes the requirement for creatinine measurement [21].No preservatives are usually required for urine albumin collections, and manufacturers recommendations should be consulted if a preservative is required. The sample may be stored at room temperature for up to 7 days and 1 month at 4°C to 8°C, according to World Health Organization (WHO) guidelines [22]. It is possible that bacterial contamination may affect stability at room temperature, so earlier cooling may be preferred. Storage at −20°C causes breakdown to fragments which are measured in some assays but not others, but this is not seen at −80°C, and long-term storage is possible at this temperature [3,23].InterferencesBiological causes for increased urine albumin excretion other than kidney damage include fever, exercise, heart failure, marked hyperglycemia, and hypertension [20]. Additionally, collection shortly after ejaculation may elevate results owing to the albumin content of semen. If these causes are identified, repeat testing at an appropriate time may be indicated to further evaluate positive results.Homogenous immunoassays such as turbidimetry are at risk of producing falsely low results due to a prozone effect [24]. Routine procedures to identify this problem may include (1) measurement of all samples neat and in dilution to confirm linear dilution, (2) measurement neat and with additional albumin added to confirm complete recovery, or (3) testing for high total protein with a dipstick to identify samples where excess albumin is likely [25].Attention should also be given to the possibility of carry-over effects when serum and urine are run on the same analyzer, given the > 1000-fold difference in albumin concentrations in the two sample types.Reference IntervalsDecision points for interpretation of urine albumin are not based on population reference intervals but rather on outcome-based consensus decision points. Different professional bodies have made slightly different recommendations, and the table below is based on the data from the American Diabetes Association nephrology guidelines [26]. Laboratories are encouraged to adopt their national guidelines where these are available. Of note, the decision point of 30 mg/g creatinine is also recommended as an indication of renal damage in the nondiabetic population [27].TABLE 1: Decision Points for Interpretation of Urine Albumin.*Spot Samples Timed SamplesAlbumin/Creatinine Ratio Albumin Excretion Rate AlbuminConcentration**mg/mol mg/24 hours µg/minmg/L mg/g orµg/mgNormal <30 <30 <2.5 (male)<30 <20<3.5 (female)30 -299 20-199 Microalbuminuria 30-299 2.5-29 (male)3.5-29(female)Macroalbuminuria ≥300 ≥30 ≥300 ≥200*Based on ADA Nephropathy guidelines [26].**Albumin concentration decision point from KDOQI [27].InterpretationUrine albumin is primarily measured as a marker of the risk of development of renal damage in diabetic patients. It is now becoming established as a marker for renal damage in nondiabetic patients, owing to vascular disease associated with hypertension, elevated lipids, and other standard risk factors. An elevated urine albumin is also an established marker of cardiovascular risk in the diabetic and nondiabetic populations [28], and this risk may extend down to results within the currently accepted “normal” range [29]. The benefit of urine albumin in the microalbumin range compared to measurement of total protein is the increased sensitivity provided by albumin. Once a result is in the macroalbumin range, the significance is the same as frank proteinuria.The response to the finding of an elevated urine albumin should be increased attention to risk factors, with the aim of reducing the risk of further damage to the kidneys or other organs. Performance GoalsLike many other analytes in urine, the concentration of albumin may vary considerably from day to day. A CV for within-subject biological variation of 36% is listed on the Biological Variation database on the Westgard website [30], although a recent review has shown marked variation in the estimates for this parameter, with the central tertile for all studies showing a range of 28% to 47% [6]. Thus assays with values for total analytical CVs below 7% will meet optimal precision requirements of less than a quarter of the within-subject variation for most estimates of this parameter. Given that urine albumin/creatinine ratios continue to provide information down to 10 mg/g (1.1 mg/mmol), the ability to measure albumin down below 5 mg/L is an advantage when measuring dilute samples. These criteria can be met by most laboratory-based immunoassays, including immunoturbidimetric assays that may be run on routine chemistry analyzers. By contrast, most point-of-care analyzers, particularly the semiquantitative methods, are unable to provide good analytical performance near upper limit of normal, although they are clearly able to identify higher levels of albumin within the “microalbuminuria” range.References1 Candiano G, Musante L, Bruschi M, Petretto A, Santucci L, Del Boccio P et al. Repetitivefragmentation products of albumin and alpha-1-antitrypsin in glomerular disease associated with nephrotic syndrome. J Am Soc Nephrol 2006:17:3139-3148.2 Osicka TM, Comper WD. Characterization of immunochemically nonreactive urinaryalbumin. Clin Chem 2004;50:2286-2291.3 Svridov D, Drake SK, Hortin GL. Reactivity of urinary albumin (microalbumin) assayswith fragmented or modified albumin. Clin Chem 2008;54:61-68.4 Comper WD, Jerums G, Osika TM. Differences in urinary albumin detected by fourimmunoassays and high-performance liquid chromatography. Clin Biochem 2004;37:105-111.5 Becker GJ. Which albumin should we measure? Kidney Int 2004;66(suppl 92):S16-17.6 Miller WG, Bruns DE, Hortin GL et al. Current issues in measurement and reporting ofurinary albumin. Clin Chem 2009;55:24-38.7 Shephard MDS, Gill JP. An innovative Australian point-of-care model for urinealbumin/creatinine ratio testing that supports diabetes management in indigenous medical services and has international application. Ann Clin Biochem 2005;42:208-215.8 Parsons MP, Newman DJ, Newall RG, Price CP. Validation of a point-of-care assay for theurinary albumin/creatinine ratio. Clin Chem 1999;45:414-417.9 Von Schenck H. Validation of albumin determined in urine with the HemoCue point-of-care analyzer. Scand J Clin Lab Invest 2003;63:119-126.10 Sarafidis PA, Riehle J, Bogojevic Z, Basta E, Chugh A, Bakris GL. A comparativeevaluation of various methods for microalbuminuria screening. Am J Nephrol2008;28:324-329.11 Pugia MJ, Lott JA, Luke KE, Shihabi ZK, Wians FH, Phillips L. Comparison of instrumentread dipsticks for albumin and creatinine in urine with visual results and quantitativemethods. J Clin Lab Analysis 1998;12:280-284.12 Meinhardt U, Ammann RA, Fluck C, Diem P, Mullis PE. Microalbuminuria in diabetesmellitus. Efficacy of a new screening method in comparison with timed overnight urinecollection. J Diabetes Complications 2003;17:254-257.13 Mogensen CE, Viberti GC, Peheim E et al. Multicenter evaluation of the Micral Test- IItest strip, an immunological rapid test for the detection of microalbuminuria. Diabetes Care1997;20:1642-1646.14 Parikh CR, Fischer MJ, Estacio R, Schrier RW. Rapid microalbuminuria screening in type2 diabetes mellitus: simplified approach with Micral test strips and specific gravity.Nephrol Dial Transplant 2004;19:1881-1885.15 Incerti J, Zelmaovitz T, Camargo JL, Gross JL, de Azevedo MJ. Evaluation of tests formicroalbuminuria screening in patients with diabetes. Nephrol Dial Transplant2005:20:2402-2407.16 Brinkman JW, Bakker SJ, Gansevoort RT, Hillege HL, Kema IP, Gans RO et al. Whichmethod for quantifying urinary albumin excretion gives what outcome? A comparison ofimmunonephelometry with HPLC. Kidney Int 2004;66:S69-S7517 Polkinhorne KR, Su Q, Chadban SJ, Shaw JE, Zimmet PZ, Atkins RC. Populationprevalence of albuminuria in the Australian Diabetes, Obesity, and Lifestyle (AusDiab)Study: immunonephelometry compared with high-performance liquid chromatography.Am J Kidney Dis 2006:47:604-613.18 Denis Sviridov D, Meilinger B, Drake SK, Hoehn GT, Hortin GL. Coelution of otherproteins with albumin during size-exclusion HPLC: implications for analysis of urinaryalbumin. Clin Chem 2006;52:389-397.19 Joint Committee for Traceability in Laboratory Medicine website. Available at</en/committees/jc/jctlm/> Accessed 05.28.2008.20 American Diabetes Association. Standards of medical care in diabetes. Diabetes Care2008;31(suppl 1):S12-S5421 Gansevoort RT, Verhave JC, Hillege HL, Burgerhof JGM, Bakker SJL, De Zeeuw D, DeJong PE. The validity of screening based on spot morning urine samples to detect subjectswith microalbuminuria in the general population. Kidney Int 2005;67:S28-S35.22 World Health Organization. Use of anticoagulants in diagnostic laboratory investigations.Available at<http://whqlibdoc.who.int/hq/2000/WHO_DIL_00.4.pdf>23 Parekh RS, Kao WH, Meoni LA, Ipp E, Kimmel PL, La Page J et al. Family Investigationof Nephropathy and Diabetes Research Group.Reliability of urinary albumin, total protein,and creatinine assays after prolonged storage: the family investigation of nephropathy anddiabetes. Clin J Am Soc Nephrol 2007;2:1156-1162.24 Jury DR, Mikkelsen DJ, Dunn PJ. Prozone effect and the immunoturbidimetricmeasurement of albumin in urine. Clin Chem 1990;36:1518-1519.25 Bakker AJ, Bierma-Ram A, Keidel H, Syperda H, Zijlstra A. (Micro)albuminuria: antigenexcess detection in the Roche Modular analyser. Clin Chem 2005;51:1070-1071.26 Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH, SteffesMW. American Diabetes Association.Nephropathy in diabetes. Diabetes Care2004;27(Suppl 1):S79-83.27 Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J et al. Definition andclassification of chronic kidney disease: a position statement from Kidney Disease:Improving Global Outcomes (KDIGO). Kidney Int 2005;67:2089-2100.28 Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL et al. Kidneydisease as a risk factor for development of cardiovascular disease: American HeartAssociation scientific statement. Circulation. 2003;108:2154-2169.29 Xu J, Knowler WC, Devereux RB, Yeh J, Umans JG, Begum M et al. Albuminuria withinthe “normal” range and risk of cardiovascular disease and death in American Indians: the Strong Heart Study. Am J Kid Dis 2007;49:208-216.30 Ricos C. Biological variation database. Available at <> Accessed05.02.2008.Clinical References - Methods of Analysis 5-9 Table 1: Albumin in Urine Methods Summary TableMethod 1: ImmunoturbidimetrySensitivity (mg/L): Typically < 10Principle: Anti-albumin antibodies react with albumin in the sample to scatter light,reducing transmitted light. Absorbance change can be measured at a range ofwavelengths in the visible range. A homogenous immunoassay.Usage: Widely used on routine chemistry analyzers and in Haemocue point-of-caredeviceComments: Prozone effect must be consideredMethod 2: ImmunonephelometrySensitivity (mg/L): Typically < 10Principle: Anti-albumin antibodies react with albumin in the sample to scatter light.Light is detected at an angle to the incident light.Usage: In common useComments: Requires specific analyzer with nephelometric capacityMethod 3: RadioimmunoassaySensitivity (mg/L): <5Principle: Competitive immunoassayUsage: Uncommon in routine use.Comments: The first measurement system for urine albumin in the microalbuminuricrangeMethod 4: HPLC (AusAM technologies)Sensitivity (mg/L): <5Principle: Zorbax preparative GF-250 HPLC columnUsage: Uncommon in routine useComments: Detects both immuno and non-immunoreactive intact albumin with possible detection of other proteinsMethod 5: Semiquantitative dipstick – dye binding (Clinitek)Sensitivity (mg/L): Approximately 20Principle: Binding to high-affinity sulfonephthalein dye with color change. Quantitation by comparison with color chart or Clinitek Reader using reflectometry. Colour chart is10, 30, 80, 150 mg/L. Creatinine can also be measured on the same system.Usage: Point-of-care deviceComments: Semiquantitative only. Visible hemoglobin or myoglobin in sample canaffect result. Colored drugs or dyes may mask true response. Low-positive results require confirmation.Method 6: Semiquantitative immunological dipstick (Micral)Sensitivity (mg/L): Approximately 20Principle: Detection of albumin with albumin-enzyme complex with substrate to formcolored pad. Comparison with color chart at 0, 10, 20, 50, 100 mg/L.Usage: Common in point-of-care settingComments: Useful screening test. No equipment required.Time of expose to urine iscritical. Low-positive results require confirmation.。
马波斯产品
ACQ System
7
Microsoft and Windows are either registered trademarks or trademarks of Microsoft Corporation in the United States and/or other countries.
- dedicated, that means designed for the measurement of a single part type, or
- modular, that means reconfigurable for the measurement of different part types.
For a full list of address locations, please consult the Marposs official website D6G00001G0 - Edition 07/2006 - Specifications are subject to modifications © Copyright 2006 MARPOSS S.p.A. (Italy) - All rights reserved. MARPOSS, and Marposs product names/signs mentioned or shown herein are registered trademarks or trademarks of Marposs in the United States and other countries. The rights, if any, of third parties on trademarks or registered trademarks mentioned in the present publication are acknowledged to the respective owners. Marposs has an integrated system to manage the Company quality, the environment and safety, attested by ISO 9001, ISO 14001, OHSAS 18001 and QS9000 T&E certifications. Marposs has further been qualified EAQF 94 and has obtained the Q1-Award.
METHOD AND APPARATUS FOR STORING, TRANSMITTING AND
专利名称:METHOD AND APPARATUS FOR STORING, TRANSMITTING AND RETRIEVINGGRAPHICAL AND TABULAR DATA发明人:ROZMANITH, A. MARTIN,ROZMANITH,ANTHONY I.,FULOP, GABOR F.,BERENSON,NEIL,FABIAN, EGON STEPHEN,TRILLING, TEDR.申请号:EP91902355申请日:19901213公开号:EP0506842A4公开日:19930901专利内容由知识产权出版社提供摘要:A kind of method and apparatus, for quickly searching the system (20) with the display of lake figure and tabular data two parts (10) and distributed computer. The method selects and shows rapidly (12) relevant figure and text information by graphic user interface, interface (16) (GUI) from two graphics relationship databases (GRDB) and large list type database. Operator enters inquiry and selects being coded and stored within graphic element before, by controlling program, from local mass storage device (22) and display (12) and related text information, local display (12). This method provides intelligent selection and show the analysis of (12) graph data, any graphic element is based on by system (10) or image needs to meet operator's inquiry, and how these elements show (12) together with related table (text) data.申请人:ARACO地址:118 WEST RIDING ROAD; CHERRY HILL, NJ 08003更多信息请下载全文后查看。
Guideline for Structural Health Monitoring F08b
SAMCO Final Report 2006 F08b Guideline for Structural Health Monitoring
CONTENTS
1 2 3 3.1 3.1.1 3.1.1.1 3.1.1.2 3.1.2 3.1.2.1 3.1.2.2 3.1.3 3.2 3.3 3.3.1 3.3.2 3.3.2.1 3.3.2.2 3.3.2.3 3.3.2.4 3.3.2.5 3.3.2.6 3.3.2.7 3.3.2.8 3.3.2.9 3.3.3 3.3.4 3.3.5 3.3.5.1 4 4.1 4.2 4.2.1 4.2.2 4.2.3 4.2.4 4.2.4.1 4.2.4.2 4.2.4.3 4.2.5 Introduction........................................................................................ 5 Objectives and outline of the guideline............................................ 6 Analysis of actions ............................................................................ 7 Classification of actions ........................................................................7 Type of actions .........................................................................................7 Static loads.........................................................................................7 Dynamic loads....................................................................................7 Character of actions .................................................................................8 Dead loads .........................................................................................8 Live loads ...........................................................................................8 Loads and load effects .............................................................................8 Objectives and approach to action analysis ........................................8 Determination of actions based on dimension, duration and local effect .......................................................................................................9 Measurands for characterisation of actions ..............................................9 Determination of actions.........................................................................10 Monitoring pattern ............................................................................10 Wind loads .......................................................................................11 Wave loads and swell loads .............................................................11 Traffic loads......................................................................................11 Loading by displacements ................................................................12 Weight loads ....................................................................................12 Impact and collision loads; vibrations ...............................................12 Temperature loads ...........................................................................13 Effects caused by physical - chemical processes .............................13 Load combinations .................................................................................13 Use and analysis of measurement data..................................................14 Load models...........................................................................................14 Calibration of load models ................................................................15 Diagnostic of structures.................................................................. 16 Preamble ...............................................................................................16 Structural Condition Analysis .............................................................16 Description of design and construction of the structure...........................16 Determination of threshold values for position stability, serviceability and load bearing capacity.......................................................................17 Structural identification ...........................................................................18 Application of NDT techniques ...............................................................19 Steel structures ................................................................................19 Reinforced and prestressed structures .............................................19 Masonry structures...........................................................................20 Field tests...............................................................................................20
METHOD FOR IMPROVING THE FUNCTIONAL PROPERTIES OF
专利名称:METHOD FOR IMPROVING THEFUNCTIONAL PROPERTIES OF A GLOBULARPROTEIN, PROTEIN THUS PREPARED, USETHEREOF AND PRODUCTS CONTAININGTHE PROTEIN发明人:LEONARD, MARTIN, CORNELIASAGIS,HENDERICUS, GERARDUS, MARIABAPTIST,ERIK VAN DER LINDEN,SUZANNE,GODELIEVE BOLDER,WILLIAM KLOEK,CECILEVEERMAN申请号:AU2003293761申请日:20031128公开号:AU2003293761A1公开日:20040623专利内容由知识产权出版社提供摘要:The invention relates to a method for improving the functional properties of globular proteins, comprising the steps of providing a solution of one or more globular proteins, in which solution the protein(s) is/are at least partially aggregated in fibrils; and performing one or more of the following steps in random order: increasing the pH; increasing the salt concentration; concentrating the solution; and changing the solvent quality of the solution. Preferably, the solution of the one or more globular protein is provided by heating at a low pH or the addition of a denaturing agent. The invention also relates to the protein additive thus obtained, to the use thereof for food and non-food applications and to the food and non-food products containing the protein additive.申请人:CAMPINA B.V.更多信息请下载全文后查看。
实验动物学——参考文献-附录
主要参考文献1.李厚达. 实验动物学. 北京:中国农业科学出版社.20032.贺争鸣.李冠明.动物实验替代方法概论.北京:学苑出版社.20033.孙敬方.动物实验方法学.北京:人民卫生出版社.20014. 钟品仁.哺乳类实验动物.北京:人民卫生出版社.19835.魏泓.医学实验动物学.成都:四川科学技术出版社.19986.邵义祥.医学实验动物学教程.南京: 东南大学出版社.20037.中华人民共和国国家科学技术委员会发布.实验动物管理条例.19888.北京市人大委员会.北京市实验动物管理条例.20049.孙靖.实验动物学基础.北京科学技术出版社.200510.Jann Hau and Gerald L.Van Hoosier Jr. Handbook of Laboratory Animal Science.(Second Edition).Boca Raton:CRC PRESS.200211.王建飞,陈筱侠. 实验动物饲养管理和使用手册.上海:上海科学技术出版社.199812.Michael F.W.Festing, Philip Overend, Rose Gaines Das, Mario Cortina Borja and Manuel Berdoy. The design of Animal Experiments.Oxfordshire: The Royal Society of medicine Press Limited 200013.霍金龙,张娟,罗古月,张美,李小梅,曾养志. 近交系实验动物在生物医学等领域中的研究和应用. 动物医学进展.2003,20(12):59-6014.郑继奎,岳秉飞. 日本动物实验替代法研究.中国比较医学杂志.2005,15(3):193-19415.贺争鸣,李冠民,岳秉飞,张宝旭,赵德明.我国动物实验替代方法研究工作的现状与发展. 实验动物科学与管理.2003,(增刊)53-5516. Nadia Belmatoug, Bruno Fantin. Contribution of animal models of infection for the evaluation of the activityof antimicrobial agents, International Journal of Antimicrobial Agents 1997(9):73-8217.Jan Buer, Rudi Balling. Mice, Microbes and Models of Infection ,Nature Reviews, 2003(40):195-20518 Trevor Poole, Pauline English. The UFAW Handbook on the care and management of Laboratory Animals. Seventh Edition. Lodon:Blackwell Science Ltd .199919.石岩,梅世昌.医学动物实验实用手册.中国农业出版社.200220.Jones J.C.主编.程鸿 主译.人类疾病动物模型.上海医科大学出版社.198921.朱愉.实验动物的疾病模型.天津科技翻译出版公司.199722.刘福英, 吕占军. 实验动物学.北京: 中国农业科技出版社,199723.中华人民共和国卫生部. 微生物和生物医学实验室生物安全通用准则(WS 233-2002),200324. WHO. 实验室生物安全手册第二版(修订版),200325.军事医学科学院实验动物中心译.加拿大动物管理委员会编. 实验用动物管理与使用指南.原子能出版社.199326.国家医药管理局实验动物管理委员会.医药实验动物简明教程.北京: 中国医药科技出版社,199627.卢耀增.实验动物学.北京:北京医科大学 中国协和医科大学联合出版社.199628.中华人民共和国国家标准 中国标准出版社 2001年实验动物 环境及设施 GB 14925-2001实验动物 哺乳类实验动物的遗传质量控制 GB 14923-2001实验动物 近交系小鼠、大鼠生化标记检测法 GB 14927-2001实验动物 微生物学等级及监测 GB 14922.2-2001实验动物 寄生虫学等级及监测 GB 14922.1-2001实验动物 配合饲料通用质量标准 GB 14924.1-2001附录一中英文专业对照AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care) 国际实验动物评估和认可管理委员会AALAS (American Association for Laboratory Animal Science) 美国实验动物学会AAALAC (American Association for Accreditation of Laboratory Animal Care)美国实验动物饲养管理认可委员会ABSL (Animal Biosafety Levels) 动物生物安全级别Adjuvant 佐剂AFSTAL (French Association of Laboratory Animal Sciences and Techniques) 法国实验动物科学和技术协会Air cleanliness level空气洁净度Allergy (to animals) 过敏Alternatives 替代Anesthesia 麻醉Animal Experiment Technique动物实验技术Animal Research Ethics动物实验伦理学Antibody production 产生抗体ANZCCART (Australian and New Zealand Council for the Care of Animals in Research and Teaching) 澳大利亚和新西兰研究、教学用动物管理委员会ANZLAS (Australian and New Zealand Society for Laboratory Animal Science) 澳大利亚和新西兰实验动物管理委员会ASLAP (American Society of Laboratory Animal Practitioners) 美国实验动物临床学会。
“翻译理论与实践”系列课程参考文献目录
“翻译理论与实践”系列课程参考文献目录[1]Arnold, D. et al. 1994. Machine Translation: An Introductory Guide [M]. London: Blackwells NCC.[2]Baker, Mona. 1992, 2000. In Other Words: A Course-book on Translation [Z]. London: Taylor&Francis Ltd.; Beijing: Foreign Language Teaching and Research Press.[3]Bell, Roger. T. 1991, 2001. Translation and Translating: Theory and Practice [M]. London: Longman Group UK Ltd.; Beijing: Foreign Language Teaching and Research Press. [4]Benjamin, W. 1993. The Task of the Translator[A]. In: L. Venuti ed. 2000. The Translation Studies Reader [C]. London & New York: Routledge.[5] Dann, Graham M.S. 1996. The Language of Tourism [M]. A Sociolinguistic Perspective.Wallingford: CAB International.[6]Davis, K. 2004. Deconstruction and Translation [M]. Shanghai: Shanghai Foreign Language Education Press.[7]Delisle, J. 1988. Translation: An Interpretive Approach [M]. Ottawa: University of Ottawa Press.[8]Hatim, Basil and Mason, Ian. 1990, 2001. Discourse and the Translator [M]. London: Longman Group UK Ltd.; Shanghai: Shanghai Foreign Language Education Press. [9]Jin Di and Eugene Nida. 1984. On Translation [M]. Beijing: China Translation and Publishing Corporation.[10]Lawson V. 1982. Machine Translation and People [A]. In: V. Lawson ed. 1982. Practical Experience of Machine Translation [C]. Amsterdam & New York & Oxford: NorthHolland Publishing Company.[11] Mellinkoff, David. 1963. The Language of the Law [M]. Boston /Toronto: Little Brown &Co. Law & Business.[12] Newmark, Peter. 1981, 2001. Approaches to Translation [M]. Oxford: Pergamon Press;Shanghai: Shanghai Foreign Language Education Press.[13] Newmark, P. 1988. A Textbook of Translation [Z]. New York: Prentice Hall International.[14] Nida, E. A. 1964. Toward a Science of Translating, with Special Reference to Principlesand Procedures Involved in Bible Translating [M]. Leiden: Brill.[15] Nida, E. A. and C. Taber. 1969. The Theory and Practice of Translation [M]. Leiden: E.J.Brill.[16] Nida, E. A. 1993. Language, Culture, and Translating [M]. Shanghai: Shanghai ForeignLanguage Education Press.[17] Robinson, D. 2001. Who Translates? Translator Subjectivities Beyond Reason [M]. NewYork: State University of New York Press.[18] Savory, T. 1957. Translation Through the Ages[A]. In: 申雨平ed. 2002.西方翻译理论精选[C]. 北京:外语教育与研究出版社.[19] Shuttleworth, M. and M. Cowie. 2004. Dictionary of Translation Studies [Z]. Shanghai:Shanghai Foreign Language Education Press.[20] Snell Hornby, M. 1995. Translation Studies: An Integrated Approach [M]. Amsterdam &Philadelphia: John Benjamins Publishing Company.[21] Sofer, M. 1999. The translator’s Handbook [Z]. Rockville: Schreiber Publishing Inc.[22] Toury, G. 1980. In Search of a Theory of Translation[M]. Tel Aviv: Porter Institute forPoetics and Semiotics.[23] Tytler, A. F. 1790. Essay on The Principles of Translation [M]. Edinburgh: Cadell &Davies.[24] Venuti, L. 1995. The Translator’s Invisibility: A History of Translation [M]. London :Routledge.[25] Wilss, W. 1982. The Science of Translation: Problems and Methods [M]. Tübingen: GunterNarr.[26] 陈刚. 旅游翻译与涉外导游[M]. 北京:中国对外翻译出版公司,2004.[27] 陈浩然. 外贸英语翻译[M]. 北京:知识产权出版社,1987[28] 陈荣东. 一篇不该忽视的译论[J].中国翻译, 1997(4).[29] 戴炜栋. 中国外语教学法回顾、探索与展望——首届中国外语教学法国际研讨会论文集[C]. 上海:上海外语教育出版社,2006.[30] 丁大刚. 旅游英语的语言特点与翻译[M].上海:上海交通大学出版社,2008.[31] 冯庆华主编.实用翻译教程[Z]. 上海:上海外语教育出版社,2002.[32] 冯志伟. 机器翻译——从梦想到现实[J]. 中国翻译, 1999(4).[33] 丰子义. 主体论——新时代新体制呼唤的新人学[M]. 北京:北京大学出版社,2002.[34] 冯国华. 英译汉别裁[M]. 北京:外文出版社, 2001.[35] 顾大僖,金辉主编.简明英汉语翻译教程[Z].北京:外文出版社,2005.[36] 金隄. 等效翻译探索[M]. 北京:中国对外翻译出版公司,1998.[37] 何善芬. 英汉语言对比研究[M]. 上海:上海外语教育出版社,2002.[38] 黄伯荣. 现代汉语[M]. 北京:高等教育出版社, 1991.[39] 黄凯. 科技英语结构与翻译模式[M]. 广州: 华南工学院出版社, 1987.[40] 李克兴、张新红.法律文本与法律翻译. 北京:中国对外翻译出版公司, 2006.[41] 李静滢. Machine Translation[MA]. Nan Ling: Guangxi University, 2003.[42] 李长栓. 汉英口译入门[Z].北京:外语教学与研究出版社,2000.[43] 李照国. 中医英语教程[Z]. 西北大学出版社,1995.[44] 李照国. 中医英语翻译技巧[M]. 北京:人民卫生出版社,1997.[45] 李照国. 中医英语[M]. 上海:上海科学技术出版社,2002.[46] 李照国. 译海心语——中国古典文化翻译别论[M]. 上海中医药大学出版社,2007.[47] 李照国. 熵化·耗散·重构——汉英翻译理法探微[M].上海科学技术出版社,2008.[47] 李照国. 中医英语翻译技巧问难[M].上海:第二军医大学出版社,2009.[49] 李忠初. 现代汉语纲要[M]. 长沙:湖南教育出版社,1998.[50] 林相周. 英语理解与翻译[M]. 上海: 上海外语教育出版社,2005.[51] 刘宓庆. 翻译与语言哲学[M]. 北京:中国对外翻译出版公司, 2001.[52] 刘士聪. 汉英·英汉美文翻译与鉴赏[M].(中英对照)译林出版社, 2003.[53] 刘重德.文学翻译十讲[M]. 北京:中国对外翻译出版公司. 1991.[54] 陆文惠.法律翻译——从实践出发. 北京:中国法律出版社. 2004.[55] 卢敏. 英语法律文本的语言特点与翻译. 上海:上海交通大学出版社,2008.[56] 吕俊. 英汉翻译教程[M]. 上海:上海外语教育出版社. 2001.[57] 吕叔湘.中诗英译比录[M]. 上海:上海外语教育出版社. 1980.[58] 梅德明.英语口译教程.北京:高等教育出版社,2003.[59] 苗玲玲. 译可译,无常译[J]. 学术研究, 2002(8).[60] 潘文国. 汉英语对比纲要[M]. 北京:北京语言文化大学出版社,1997.[61] 彭长江. 英汉—汉英翻译教程[Z]. 长沙:湖南师范大学出版社,2002.[62] 邵志洪. 结构、语义、关系:英汉微观对比研究[C].上海:上海外语教育出版社,2008.[63] 申雨平. 西方翻译理论精选[M]. 北京:外语教学与研究出版社,2002.[64] 孙会军. 译论研究中的文化倾向[J].中国翻译, 2001(5).[65] 孙致礼. 译者的克己意识与创造意识[J]. 上海科技翻译, 2000(1).[66] 孙万彪.高级翻译教程[Z]. 上海:外语教育出版社, 2000.[67] 谭卫国. 最新报刊英语教程[Z]. 长沙:中南工业大学出版社, 2004.[68] 谭卫国、蔡龙权.新编英汉互译教程[Z].上海:华东理工大学出版社,2005.[69] 谭卫国. 英语背诵范文精华[Z]. 上海:华东理工大学出版社. 2005.[70] 谭卫国. 英语广告的语言特点与翻译[M].上海:上海交通大学出版社,2009.[71] 谭载喜. 翻译学[M]. 武汉:湖北教育出版社. 2000.[72] 倜西. 英汉翻译手册[Z]. 北京:商务印书馆. 2002.[73] 田德蓓.论译者的身份[J]. 中国翻译, 2000(6).[74] 王卫平. 英语科技文献的语言特点与翻译[M].上海:上海交通大学出版社,2009.[75] 王佐良. 文学翻译中的语言问题[J]. 中国翻译, 1993(2).[76] 谢天振. 翻译本体研究与翻译研究本体[J]. 中国翻译,2008(5).[77] 许建平.英汉互译实践与技巧[M]. 北京:清华大学出版社, 2000.[78] 许明武. 英语新闻与翻译[M]. 北京:中国对外翻译出版公司, 2003.[79] 许渊冲. 谈重译[J]. 外语与外语教学, 1996(6).[80] 许钧. 文学翻译的理论与实践——翻译对话录[M]. 南京:译林出版社. 2001.[81] 许钧. “创造性叛逆”和翻译主体性的确立[J]. 中国翻译, 2003(1).[82] 严俊仁. 科技阅读与翻译[M]. 北京: 国防工业出版社, 2006.[83] 杨自俭. 语篇和语境[J]. 解放军外国语学院学报, 2003(2).[84] 张南峰.艾克西拉的文化专有项翻译策略评介[J]. 中国翻译, 2004(1).[85] 张培基. 英汉翻译教程[Z]. 上海:上海外语教育出版社,1980.[86] 张培基译注.英译中国现代散文选[Z].上海:上海外语教育出版社,1999.[87] 张炜. 外贸英语的语言特点与翻译[M]. 上海:上海交通大学出版社,2008.[88] 赵志恒. 国际贸易实物[Z]. 北京:机械工业出版社,2006.[89] 郑海凌.文学翻译过程中的“距离”问题[J]. 中国翻译, 2002(3).[90] 周仪. 翻译与批评[M]. 武汉:湖北教育出版社. 1999.[91] 朱伊革. 英语新闻的语言特点与翻译[M].上海:上海交通大学出版社,2008.[92] 庄绎传. 英汉翻译简明教程[Z]. 北京:外语教学与研究出版社,2002.。
ch03The Consumer Decision Process
The Consumer Decision Process
The CDP represents a road map of consumers’ minds that marketers and managers can use to help guide product mix, communications, and sales strategies
M E M O R Y
Need Recognition
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色谱分析法专业知识培训
俄国植物学家 茨维特
➢ Tswett植物色素分离 试验图示:
样 品:植物色素 固定相:CaCO3颗粒 流动相:石油醚
色谱柱
固定相 碳酸钙
流动相 石油醚
混合色素 叶绿素 叶黄素 胡萝卜素
分离组分
表1 色谱法旳发展简史 年代 发明者 发明旳色谱措施或主要应用
1906 Tswett
用碳酸钙作吸附剂分离植物色素。最先 提杰出谱概念。
蒂塞利乌斯(Tiselius)因电泳分析和分析措施旳研究,发觉 血清蛋白组分,获1948年诺贝尔化学奖
1941,马丁(Martin)和辛格(Synge)创始分配色谱尤其是纸 色谱而共获1952年诺贝尔化学奖
氨基酸自动分析仪发明人S.穆尔(Stanford Moore)和W.H. 斯坦(William Howard Stein),定量分析措施处理了有关 氨基酸、多肽、蛋白质等复杂旳生物化学问题,获1972年 诺贝尔化学奖
12.1 概述>>
一、色谱法简介
➢ 1923年,俄国植物学家M.Tswett刊登了他旳试验 成果:为了分离植物色素,他将具有植物色素旳 石油醚提取液倒入装有碳酸钙粉末旳玻璃管中, 并用石油醚自上而下淋洗,因为不同旳色素在 CaCO3颗粒表面旳吸附力不同,伴随淋洗旳进行, 不同色素向下移动旳速度不同,从而形成一圈圈 不同颜色旳色带,使各色素成份得到了分离。他 将这种分离措施命名为色谱法(chromatography)。 在今后旳20数年里,几乎无人问津这一技术。到 了1931年,德国旳Kuhn等用一样旳措施成功地分 离了胡萝卜素和叶黄素,从此色谱法开始为人们 所注重,相继出现了多种色谱措施。
2. 基本术语
➢ 保存值是色谱定性分析 和色谱过程热力学特征 旳主要参数。
细胞信号转导的分子机制PPT课件
1936年 神经冲动的化学传递
Henry Hallett Dale Otto Loewi
1950年 肾上腺皮质激素
Edward Calvin Kendall Philip Showalter Hench Tadeus Reichstein
1970年 1971年
神经末梢的神经递质的合成、释 放及灭活
激素作用的第二信使机制
目录
膜受体识别细胞外信号分子并转换信号 膜受体识别并结合细胞外信号分子,将细胞外
信号转换成为能够被细胞内分子识别的信号, 通过信号转导通路将信号传递至效应分子,引 起细胞的应答。
目录
(三)受体与配体的相互作用具有共同的特点
•高度专一性 • 高度亲和力
• 可饱和性 • 可逆性 • 特定的作用模式
细胞针对外源信息所发生的细胞内生物化学变 化 及 效 应 的 全 过 程 称 为 信 号 转 导 ( signal transduction)。
目录
年度 重要发现
诺贝尔奖获得者
1923年 胰岛素
Frederick Grant Banting John James Richard Macleod
The General Information of Signal Transduction
目录
细胞信号转导的基本路线 细胞外信号
受体
细胞内各种分子数量、分布 或活性变化
改变细胞内的某些代谢过程,或 改变生长速度,或改变细胞迁移
或进入细胞凋亡等生物学行为
目录
一、细胞外化学信号有可溶型和 膜结合型两种形式
这种细胞通讯方式称为膜表面分子接触通讯。
目录
• 属于这一类通讯的有: 相邻细胞间黏附因子 的相互作用、T淋巴细 胞与B淋巴细胞表面分 子的相互作用等。
国际制药协会ISPE基本指南05卷
A GUIDE FOR NEW FACILITIES VOLUME 5: COMMISSIONING AND QUALIFICATIONEXECUTIVE SUMMARYJUNE 2000A DOCUMENT DEVELOPED IN PARTNERSHIP BY:23ISPE PHARMACEUTICAL ENGINEERING GUIDECOMMISSIONING AND QUALIFICATIONFOREWORDAs noted in the Baseline® Guides, Volume 1, the pharmaceutical industry has experienced a ratcheting effect in the cost of new facilities. This increase in cost has been driven in part by uncertainty about the requirements for regulatory compliance. Some significant areas of concern are validation, particularly related to automation systems, and the trend to validate back to source utilities, architectural and HVAC. The absence of a consistent and widely accepted interpretation of regulatory requirements has led to one-upmanship. This practice of building increasingly technically advanced facilities has led to increased cost, longer lead times and, in some cases, delays in bringing new products to market.In May 1994, engineering representatives from the pharmaceutical industry engaged in a discussion with the International Society for Pharmaceutical Engineering (ISPE) and the Food and Drug Administration (FDA). That first discussion allowed for the creation of 10 facility engineering guides, now known as the Baseline® Pharmaceutical Engineering Guides. These guides are intended to assist pharmaceutical manufacturers in the design, construction and commissioning of facilities that comply with the requirements of the FDA. Volume 1, covering Bulk Pharmaceutical Chemicals (BPC), was published in June of 1996. This Guide, for Commissioning and Qualification, is the fifth volume in the series.As with the BPC Guide, the Commissioning and Qualification Guide, has been sponsored by ISPE’s Pharmaceutical Advisory Council, made up of senior pharmaceutical engineering executives from owner companies, the FDA and ISPE senior management. Overall planning, direction and technical guidance in the preparation of the Commissioning and Qualification Guide was provided by a Steering Committee most of whom were involved in the BPC Guide. The Commissioning and Qualification Guide itself was produced by a task force of around 60 individuals who expended a great deal of their own time in its preparation and development.Editors’ Disclaimer:This guide is meant to assist pharmaceutical manufacturers in the design and construction of newfacilities that comply with the requirements of the Food and Drug Administration (FDA). TheInternational Society for Pharmaceutical Engineering (ISPE) cannot ensure, and does not warrant,that a facility built in accordance with this guide will be acceptable to FDA.4ISPE PHARMACEUTICAL ENGINEERING GUIDECOMMISIONING AND QUALIFICATIONACKNOWLEDGEMENTSThis guide was developed by an integrated US-European team under the co-leadership of Alan Philips of Pfizer and Christopher Wood of Glaxo Wellcome.The Core Team on the guide was comprised:Alan Philips PfizerChristopher Wood Glaxo WellcomeBob Myers KvaernerGeorgia Keresty, Ph.D. Bristol Myers SquibbThe Extended Review Team was comprised the Core Team plusJan Gustafsson Novo NordiskGraham Shewell SmithKline BeechamTodd Troutman KvaernerSimon Shelley Glaxo WellcomeGene Yuan Hoffman LaRocheThe Chapter Credits are as follows:Introduction Alan PhilipsGeorgia Keresty, Ph.D. PfizerBristol-Myers SquibbKey Concepts & Philosophy Chris WoodGeorgia Keresty, Ph.D. Glaxo Wellcome Bristol-Myers SquibbImpact Assessment Bob MyersSimon ShelleyTodd Troutman KvaernerGlaxo WellcomeKvaerner5Good Engineering Practice John FadoolGraham Shewell Glaxo Wellcome SmithKline BeechamCommissioning Mark E. Miller1Chris WoodGraham Shewell GenentechGlaxo Wellcome SmithKline BeechamQualification Practices Jan GustafssonGene YuanSue Bacso Novo Nordisk Hoffman LaRoche MerckEnhanced Design Review Graham ShewellChris Wood SmithKline Beecham Glaxo WellcomeInstallation Qualification Bob MyersBob AdamsonTodd Troutman Kvaerner Foster Wheeler KvaernerOperational Qualification Bob MyersTodd Troutman Kvaerner KvaernerPerformance Qualification Chris Dell Cioppia KvaernerRelated Programs Georgia Keresty, Ph.D.Todd Troutman Bristol-Myers Squibb KvaernerIllustrative Examples Bob Myers KvaernerThe guide co-team leaders would also like to acknowledge the contributions made by the following part-time members of the guide team:Flemming Steen Jensen (then of) Novo NordiskSteve Heidel MerckCecilia Luna Novartis1 With the support of John Hughes (TVS Inc,), Jon Sheh (Alza Inc.) and Gary Schoenhouse (Genentech)6Tony deClaire APDC ConsultingFDA Reviewers:We would like to thank the following FDA review team for their input to this guide:Robert Sharpnack InvestigatorEric S. Weilage NDA/ANDA Pre-approval Inspection ManagerRobert Coleman National Drug Expert, DEIOBrian Nadel Compliance Officer, CDERWe also appreciate FDA support from the following representatives:Sharon Smith-Holston Deputy Commissioner for External AffairsSusan Setterberg Regional Director, Mid-Atlantic RegionJoe Phillips Deputy Regional Manager, Mid-Atlantic RegionIn addition, we would like to acknowledge the support and contribution of the ISPE Technical Documents Steering Committee, in particular the following members:Paul D’Eramo Committee Chairman, Johnson & JohnsonMel Crichton Eli LillyBruce Davis Astra ZenecaPaul Lorenzo (Retired)71. INTRODUCTION1.1 BACKGROUNDThe design, construction, commissioning and qualification of manufacturing facilities regulated by FDA or other regulatory authorities pose significant challenges to manufacturers, engineering professionals and equipment suppliers. These facilities are required to meet cGMP regulations while remaining in compliance with all other governing codes, laws, and regulations.The cost and time required to bring such facilities on line has been increasing, in many cases due to inconsistent interpretation of regulatory requirements. The ISPE and engineering representatives from a broad base of healthcare companies (e.g. pharmaceutical, device, biotechnology, etc.) have entered into a partnership with the Food and Drug Administration (FDA) to enhance understanding of Baseline cGMP requirements for facilities. This Guide is intended to define key terms and offer a consistent interpretation, while still allowing a flexible and innovative approach to facility design, construction, commissioning and qualification. A fundamental goal of the Guide is to provide value added guidance to industry that will facilitate timely and cost effective commissioning and qualification of facilities.This guide is one in a series of Baseline® Guides being planned and produced by ISPE. The majority of these are specific to one functional area (e.g. Oral Solid Dosage Forms). However, this guide provides advice and guidance that may be applied to all types of facilities, utilities and equipment found in the healthcare industry.This Guide was prepared by the ISPE, and has incorporated comments from:Industry representatives from all areas and disciplinesFDA Field Investigators and personnel from The Center for Drug Evaluation and ResearchIt is recognized that industry standards evolve and this document reflects the understanding of these standards, as of publication date.1.2 SCOPE OF THIS GUIDEThis is a Guide to be used by industry for the design, construction, commissioning and qualification of new or newly renovated manufacturing facilities that are regulated by FDA or other health authorities. It is neither a standard nor a GMP. It is not intended to replace governing laws, codes, standards or regulations that apply to facilities of this type. These are mentioned only for completeness and where their impact affects facility, equipment and utility design relative to cGMP’s. The use of this document for new or existing facilities, equipment or utilities is at the discretion of the owner or operator.This Guide focuses on the engineering approaches and practices involved in providing cost effective manufacturing facilities in a timely manner that meet their intended purposes. Specifically, the Guide addresses the process of designing, constructing, commissioning and qualifying the facilities, utilities and equipment regulated by FDA or other health authorities.This Guide is not intended to address any aspect of process/product validation. This is a subject that has been well defined by FDA and other authorities and for which substantial guidance documentation exists.It must be recognized, however, that Commissioning and Qualification activities are the foundation upon which Process Validation is built. Furthermore, these activities play a crucial role in delivering operationally effective, safe and efficient facilities, utilities and equipment. Therefore, it is important to ensure that a comprehensive approach is 8undertaken during the commissioning and qualification process. A well conceived and executed commissioning and qualification plan can greatly facilitate a timely and cost effective validation effort.Where non-engineering issues are covered (e.g. support systems, documentation, decision processes), the guidance is provided to show engineers the importance of such topics and the impact they have on the commissioning and qualification process. Consequently, non-engineering topics are not covered comprehensively. Specialist advice from QA Departments should be sought where additional information is required.The Guide is intended primarily for facilities, equipment and utilities meeting regulatory requirements to supply the United States (US) market and is aligned with US standards and references. The Guide may also be helpful to manufacturers needing to meet European requirements.91.3 KEY FEATURES AND CHAPTERS OF THIS GUIDEThe following key concepts are defined and used as a basis for guidance:• Direct Impact Systems• Indirect Impact Systems• System Impact Assessment• Good Engineering Practice• Commissioning• Qualification Practices• Enhanced Design Review• Installation Qualification• Operational Qualification• Performance Qualification• Consistent Terminology• Documentation RequirementsSOME BRIEF EXPLANATION OF THESE IS AS FOLLOWS:It is the function of the facility, equipment or utility that determines what level of commissioning and qualification are needed.• ‘Direct Impact’ systems are expected to have an impact on product quality• ‘Indirect Impact’ systems are not expected to have an impact on product qualityBoth types of systems will require commissioning, however, the “Direct Impact” systems will be subject to supplementary qualification practices to meet the additional regulatory requirements of the FDA and other regulatory authorities.The determination of a system as either ‘Direct Impact’ or ‘Indirect Impact’ is critical. It is this differentiation between system types that determines the degree of effort and level of resources required for each system. System Impact Assessment provides the thought process and some key questions that must be asked in making the determination.During the production of this guide, regulatory authorities have expressed concern that designating a system “Indirect Impact” might be a means of doing less than full testing on a system that may actually require it. This is not the intention. The objective is that through a comprehensive impact assessment process, those systems presenting a risk to product quality are identified and given the attention appropriate to this level of risk, and by the right people (e.g. QA Departments).For this process to work it is essential that an explicit rationale is provided for the indirect/direct impact assessment and that the rationales are fully understood, documented and endorsed by QA Departments. This places a responsibility upon engineers to communicate clearly the nature of operation of engineering systems, and their potential impact on product quality.It will also be seen that throughout the Guide, the application of Good Engineering Practice is essential to the commissioning and qualification activities. Good Engineering Practice, commonly referred to as GEP, is proven and accepted, cost-effective, engineering methods and practices that ensure the effective satisfaction of stakeholder requirements. As such, GEP ensures that an engineering project meets the requirements of the user while being cost effective, compliant with regulations and well documented. Guidance and standards that have been defined by engineering institutes and other learned bodies support GEP. For direct impact systems, GEP is supplemented by enhanced documentation and qualification practices with the active participation of Quality Assurance personnel.The guide also attempts to clarify some misconceptions about how activities are defined, which activities are the subject of regulatory oversight and the sequence, if any, of these activities. For example, the guide discusses “Enhanced Design Review” and the components and criteria of this activity. The intent is to identify design aspects that are key to manufacturing facilities regulated by the FDA or other health authorities. How this enhanced design review is accomplished, either with a formal or informal process, is at the discretion of the individual company. The intent is not to establish new administrative requirements, especially for those activities not regulated by FDA or other regulatory authorities. The design review activities are part of GEP and are unregulated by FDA, i.e. these are good engineering practices, not regulatory requirements.Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ) are activities that FDA may have an interest in, since these are the final activities before process validation can begin. IQ/OQ in many instances is done concurrently with commissioning and requires the enhanced documentation, QA involvement and additional tests and checks known as Qualification Practices.An overview of the Chapter structure is given in Figure 1-2.Figure 1-2: Chapter Structure1.4 GOALS OF THIS GUIDEThere are two primary goals of the Commissioning and Qualification Baseline® Guide. The first is to bring a common terminology and methodology to the commissioning and qualification process that can be used by manufacturers, facility designers, contractors and equipment suppliers. The second is to provide a system impact assessment process to bring structure and consistency to determining a direct and indirect impact system. An important secondary goal is to foster an interdisciplinary team approach to commissioning and qualification. Such an approach will help establish an effective basis for master planning and execution of facility projects. Specifically, the Guide is focused upon value added approaches that will eliminate duplication of effort and the costly practices of:• Repeating qualification steps during process validation• Qualifying systems that only require commissioning• Generating insufficient or excessive documentation• Excessively long project schedules• Delays which can result in product supply interruptions or delayed product launches2. GUIDE PHILOSOPHY AND KEY CONCEPTSThis Chapter describes the purpose and philosophy of the Commissioning and Qualification Baseline® Guide, and the differences between the commissioning and qualification processes in the context of this Guide. It is important to understand and apply the approaches outlined in this Baseline® Guide in a sound and well-reasoned manner, since every facility and project is different.The key terms used in the Guide are defined, including:• Direct Impact System• Indirect Impact System• No Impact System• Design for Impact• Good Engineering Practice• Enhanced Design Review• CommissioningAn overview of Qualification Practices is given, including Enhanced Design Review, Installation Qualification, Operational Qualification, and Performance Qualification. V-models are provided for both Direct Impact systems and Indirect Impact systems and the role of Quality Assurance is discussed.3. IMPACT ASSESSMENTImpact Assessment is the process of determining which systems and/or system components should be subject to Qualification Practices in addition to Good Engineering Practices (GEP). Impact Assessment assists in defining the Commissioning and Qualification scope of a project.This Chapter considers the Impact Assessment process. Terms specific to Impact Assessment are defined. A method is suggested for defining the steps of a system assessment process, including a discussion of the benefits, and a list of the criteria for determining system impact and component criticality.4. GOOD ENGINEERING PRACTICEThis Chapter provides an overview of the various project phases and sequence, from inception through commissioning, qualification, and operation. Concepts associated with “Good Engineering Practice” (GEP), the types of activities that occur, and documentation that is created through GEP are discussed. Overviews are provided of both effective project controls, and project team concepts and organization.The Requirements phase is considered in detail, including:• Project Purpose and Justification• User Requirements Brief• Requirements Specifications• Project Execution Plan• Maintenance and Technical Support Requirements• Compliance Requirements• DeliverablesStages in the design process are described with specific consideration of Piping and Instrumentation Diagrams, Specifications, and Construction drawings. Construction involves several elements, which are crucial to every project, including project site logistics and project quality control. This Chapter details typical requirements and elements of construction.The information given in the Chapter aims to demonstrate how GEP, as applied throughout the project lifecycle, provides a basis for effective qualification.5. COMMISSIONINGThis Chapter defines the term “commissioning” in the context of the Guide and describes the organization and content of the Commissioning Plan document. Commissioning is positioned within the context of the Qualification effort and guidance is provided in the management and execution of the commissioning activities. Typical commissioning deliverables and the associated commissioning team responsibilities are considered.Commissioning activities described include:• Inspection• Setting-to-Work• Regulation and Adjustment• Testing and Performance Testing• Training• Turnover• Commissioning Plan Close-Out6. QUALIFICATION PRACTICESDirect impact systems are subject to qualification practices that incorporate the enhanced review, control and testing against specifications and requirements necessary for compliance with current Good Manufacturing Practice. The purpose of this chapter is to introduce a high level overview of qualification practices that are required for direct impact systems. The Validation Master Plan and Qualification Rationale are described in detail. This Chapter contains detailed consideration of Enhanced Documentation.7. ENHANCED DESIGN REVIEWEnhanced Design Review (EDR) is the term adopted by this guide to describe the process by which engineering designs for pharmaceutical facilities, systems and equipment are evaluated. This process compliments Good Engineering Practice.This Chapter gives the regulatory perspective on EDR and relates EDR to the V-Model for Direct Impact systems. The EDR process is detailed. A structured design review method and a failure modes analysis method are suggested for evaluating designs.8. INSTALLATION QUALIFICATIONInstallation Qualification (IQ) is an activity that is regulated by the FDA, and is a part of final qualification activities before process validation begins.The primary objectives of this chapter are to:• Provide an overview of the Installation Qualification process• Describe the types of activities that occur and documentation that is needed for the Installation Qualification Process• Describe how Installation Qualification fits in with the overall qualification process• Describe how Commissioning integrates within the Installation Qualification process9. OPERATIONAL QUALIFICATIONOperational Qualification (OQ) is an activity that is regulated by the FDA, and is a part of final qualification activities before Performance Qualification or Process Validation begins.The primary objectives of this chapter are to:• Provide an overview of the Operational Qualification process• Describe the types of activities that occur and documentation that is needed for the Operational Qualification Process• Describe how Operational Qualification fits in with the overall qualification process• Describe how the commissioning process integrates within Operational Qualification10. PERFORMANCE QUALIFICATIONPerformance Qualification (PQ) is an activity that is regulated by the FDA, and is the final qualification activity before the remainder of Process Validation begins. For pharmaceutical grade utilities and certain support systems, PQ is the final qualification step.Once the system (or systems) have gone through IQ and OQ execution and have been approved/accepted the PQ can be performed.The primary objectives of this chapter are to:• Provide an overview of the Performance Qualification process• Describe the types of activities that occur and documentation that is needed for the Performance Qualification Process• Describe how Performance Qualification fits in with the overall qualification process• Describe how the commissioning process integrates within Performance Qualification11. RELATED PROGRAMSThis Chapter provides details of those programs that are undertaken to provide assistance and information in support of the qualification activities. Some of these programs can be applied to ‘Direct’, ‘Indirect’ and ‘No Impact’ systems and their components. Where these programs are undertaken in support of qualification activities, the appropriate qualification practices must be followed to ensure that the compliance of the over-all qualification effort is not compromised. Related programs considered include:• Safety• Standard Operating Procedures• Training• Preventative Maintenance and Calibration• Computer Systems Validation• Cleaning Validation• Analytical Method Validation• Process Validation• Revalidation12. GLOSSARYTerms and concepts used throughout the Commissioning and Qualification Baseline® Guide are defined and cross-referenced.13. ILLUSTRATIVE EXAMPLESThe illustrative examples given in this Chapter provide one interpretation of how the key concepts of this guidecan be applied in preparing for commissioning and qualification activities. Depending upon company policies or the intended use of the equipment listed, there may be additions or deletions to the listed activities. APPENDIXThe Appendix provides detail and references for Failures Modes Analysis.。
Some Recent Aspects of Differential Game Theory
Dyn Games Appl(2011)1:74–114DOI10.1007/s13235-010-0005-0Some Recent Aspects of Differential Game TheoryR.Buckdahn·P.Cardaliaguet·M.QuincampoixPublished online:5October2010©Springer-Verlag2010Abstract This survey paper presents some new advances in theoretical aspects of dif-ferential game theory.We particular focus on three topics:differential games with state constraints;backward stochastic differential equations approach to stochastic differential games;differential games with incomplete information.We also address some recent devel-opment in nonzero-sum differential games(analysis of systems of Hamilton–Jacobi equa-tions by conservation laws methods;differential games with a large number of players,i.e., mean-field games)and long-time average of zero-sum differential games.Keywords Differential game·Viscosity solution·System of Hamilton–Jacobi equations·Mean-field games·State-constraints·Backward stochastic differential equations·Incomplete information1IntroductionThis survey paper presents some recent results in differential game theory.In order to keep the presentation at a reasonable size,we have chosen to describe in full details three topics with which we are particularly familiar,and to give a brief summary of some other research directions.Although this choice does not claim to represent all the recent literature on the R.Buckdahn·M.QuincampoixUniversitéde Brest,Laboratoire de Mathématiques,UMR6205,6Av.Le Gorgeu,BP809,29285Brest, FranceR.Buckdahne-mail:Rainer.Buckdahn@univ-brest.frM.Quincampoixe-mail:Marc.Quincampoix@univ-brest.frP.Cardaliaguet( )Ceremade,UniversitéParis-Dauphine,Place du Maréchal de Lattre de Tassigny,75775Paris Cedex16, Francee-mail:cardaliaguet@ceremade.dauphine.frmore theoretic aspects of differential game theory,we are pretty much confident that it cov-ers a large part of what has recently been written on the subject.It is clear however that the respective part dedicated to each topic is just proportional to our own interest in it,and not to its importance in the literature.The three main topics we have chosen to present in detail are:–Differential games with state constraints,–Backward stochastic differential equation approach to differential games,–Differential games with incomplete information.Before this,we also present more briefly two domains which have been the object of very active research in recent years:–nonzero-sum differential games,–long-time average of differential games.Thefirst section of this survey is dedicated to nonzero-sum differential games.Although zero-sum differential games have attracted a lot of attention in the80–90’s(in particular, thanks to the introduction of viscosity solutions for Hamilton–Jacobi equations),the ad-vances on nonzero-sum differential games have been scarcer,and mainly restricted to linear-quadratic games or stochastic differential games with a nondegenerate diffusion.The main reason for this is that there was very little understanding of the system of Hamilton–Jacobi equations naturally attached to these games.In the recent years the analysis of this sys-tem has been the object of several papers by Bressan and his co-authors.At the same time, nonzero-sum differential games with a very large number of players have been investigated in the terminology of mean-field games by Lasry and Lions.In the second section we briefly sum up some advances in the analysis of the large time behavior of zero-sum differential games.Such problems have been the aim of intense re-search activities in the framework of repeated game theory;it has however only been re-cently investigated for differential games.In the third part of this survey(thefirst one to be the object of a longer development) we investigate the problem of state constraints for differential games,and in particular,for pursuit-evasion games.Even if such class of games has been studied since Isaacs’pioneer-ing work[80],the existence of a value was not known up to recently for these games in a rather general framework.This is mostly due to the lack of regularity of the Hamiltonian and of the value function,which prevents the usual viscosity solution approach to work(Evans and Souganidis[63]):Indeed some controllability conditions on the phase space have to be added in order to prove the existence of the value(Bardi,Koike and Soravia[18]).Following Cardaliaguet,Quincampoix and Saint Pierre[50]and Bettiol,Cardaliaguet and Quincam-poix[26]we explain that,even without controllability conditions,the game has a value and that this value can be characterized as the smallest supersolution of some Hamilton–Jacobi equation with discontinuous Hamiltonian.Next we turn to zero-sum stochastic differential games.Since the pioneering work by Fleming and Souginidis[65]it has been known that such games have a value,at least in a framework of games of the type“nonanticipating strategies against controls”.Unfortunately this notion of strategies is not completely satisfactory,since it presupposes that the players have a full knowledge of their opponent’s control in all states of the world:It would be more natural to assume that the players use strategies which give an answer to the control effectively played by their opponent.On the other hand it seems also natural to consider nonlinear cost functionals and to allow the controls of the players to depend on events of the past which happened before the beginning of the game.The last two points have beeninvestigated in a series of papers by Buckdahn and Li[35,36,39],and an approach more direct than that in[65]has been developed.Thefirst point,together with the two others,will be the object of the fourth part of the survey.In the last part we study differential games with incomplete information.In such games, one of the parameters of the game is chosen at random according to some probability mea-sure and the result is told to one of the players and not to the other.Then the game is played as usual,players observing each other’s control.The main difference with the usual case is that at least one of the players does not know which payoff he is actually optimizing.All the difficulty of this game is to understand what kind of information the informed player has interest in to disclose in order to optimize his payoff,taking thus the risk that his opponent learns his missing information.Such games are the natural extension to differential games of the Aumann–Maschler theory for repeated games[11].Their analysis has been developed in a series of papers by Cardaliaguet[41,43–45]and Cardaliaguet and Rainer[51,52].Throughout these notes we assume the reader to be familiar with the basic results of dif-ferential game theory.Many references can be quoted on this subject:A general introduction for the formal relation between differential games and Hamilton–Jacobi equations(or sys-tem)can be found in the monograph Baçar and Olsder[13].We also refer the reader to the classical monographs by Isaacs[80],Friedman[67]and Krasovskii and Subbotin[83]for early presentations of differential game theory.The recent literature on differential games strongly relies on the notion of viscosity solution:Classical monographs on this subject are Bardi and Capuzzo Dolcetta[17],Barles[19],Fleming and Soner[64],Lions[93]and the survey paper by Crandall,Ishii and Lions[56].In particular[17]contains a good introduc-tion to the viscosity solution aspects of deterministic zero-sum differential games:the proof of the existence and the characterization of a value for a large class of differential games can be found there.Section6is mostly based on the notion of backward stochastic differential equation(BSDE):We refer to El Karoui and Mazliak[60],Ma and Yong[96]and Yong and Zhou[116]for a general presentation.The reader is in particular referred to the work by S.Peng on BSDE methods in stochastic control[101].Let usfinally note that,even if this survey tries to cover a large part of the recent literature on the more theoretical aspects of differential games,we have been obliged to omit some topics:linear-quadratic differential games are not covered by this survey despite their usefulness in applications;however,these games have been already the object of several survey ck of place also prevented us from describing advances in the domain of Dynkin games.2Nonzero-sum Differential GamesIn the recent years,the more striking advances in the analysis of nonzero-sum differential games have been directed in two directions:analysis by P.D.E.methods of Nash feedback equilibria for deterministic differential games;differential games with a very large number of small players(mean-field games).These topics appear as the natural extensions of older results:existence of Nash equilibria in memory strategies and of Nash equilibria in feedback strategies for stochastic differential games,which have also been revisited.2.1Nash Equilibria in Memory StrategiesSince the work of Kononenko[82](see also Kleimenov[81],Tolwinski,Haurie and Leit-mann[114],Gaitsgory and Nitzan[68],Coulomb and Gaitsgory[55]),it has been knownthat deterministic nonzero-sum differential games admit Nash equilibrium payoffs in mem-ory strategies:This result is actually the counterpart of the so-called Folk Theorem in re-peated game theory[100].Recall that a memory(or a nonanticipating)strategy for a player is a strategy where this player takes into account the past controls played by the other play-ers.In contrast a feedback strategy is a strategy which only takes into account the present position of the system.Following[82]Nash equilibrium payoffs in memory strategies are characterized as follows:A payoff is a Nash equilibrium payoff if and only if it is reach-able(i.e.,the players can obtain it by playing some control)and individually rational(the expected payoff for a player lies above its min-max level at any point of the resulting trajec-tory).This result has been recently generalized to stochastic differential games by Buckdahn, Cardaliaguet and Rainer[38](see also Rainer[105])and to games in which players can play random strategies by Souquière[111].2.2Nash Equilibria in Feedback FormAlthough the existence and characterization result of Nash equilibrium payoffs in mem-ory strategies is quite general,it has several major drawbacks.Firstly,there are,in general, infinitely many such Nash equilibria,but there exists—at least up to now—no completely satisfactory way to select one.Secondly,such equilibria are usually based on threatening strategies which are often non credible.Thirdly,the corresponding strategies are,in general, not“time-consistent”and in particular cannot be computed by any kind of“backward in-duction”.For this reason it is desirable tofind more robust notions of Nash equilibria.The best concept at hand is the notion of subgame perfect Nash equilibria.Since the works of Case[54]and Friedman[67],it is known that subgame perfect Nash equilibria are(at least heuristically)given by feedback strategies and that their corresponding payoffs should be the solution of a system of Hamilton–Jacobi equations.Up to now these ideas have been successfully applied to linear-quadratic differential games(Case[54],Starr and Ho[113], ...)and to stochastic differential games with non degenerate viscosity term:In thefirst case,one seeks solutions which are quadratic with respect to the state variable;this leads to the resolution of Riccati equations.In the latter case,the regularizing effect of the non-degenerate diffusion allows us to usefixed point arguments to get either Nash equilibrium payoffs or Nash equilibrium feedbacks.Several approaches have been developed:Borkar and Ghosh[27]consider infinite horizon problems and use the smoothness of the invari-ant measure associated to the S.D.E;Bensoussan and Frehse[21,22]and Mannucci[97] build“regular”Nash equilibrium payoffs satisfying a system of Hamilton–Jacobi equations thanks to elliptic or parabolic P.D.E techniques;Nash equilibrium feedbacks can also be built by backward stochastic differential equations methods like in Hamadène,Lepeltier and Peng[75],Hamadène[74],Lepeltier,Wu and Yu[92].2.3Ill-posedness of the System of HJ EquationsIn a series of articles,Bressan and his co-authors(Bressan and Chen[33,34],Bressan and Priuli[32],Bressan[30,31])have analyzed with the help of P.D.E methods the system of Hamilton–Jacobi equations arising in the construction of feedback Nash equilibria for deter-ministic nonzero-sum games.In state-space dimension1and for thefinite horizon problem, this system takes the form∂V i+H i(x,D V1,...,D V n)=0in R×(0,T),i=1,...,n,coupled with a terminal condition at time T(here n is the number of players and H i is the Hamiltonian of player i,V i(t,x)is the payoff obtained by player i for the initial condition (t,x)).Setting p i=(V i)x and deriving the above system with respect to x one obtains the system of conservation laws:∂t p i+H i(x,p1,...,p n)x=0in R×(0,T).This system turns out to be,in general,ill-posed.Typically,in the case of two players(n= 2),the system is ill-posed if the terminal payoff of the players have an opposite monotonicity. If,on the contrary,these payoffs have the same monotony and are close to some linear payoff (which is a kind of cooperative case),then the above system has a unique solution,and one can build Nash equilibria in feedback form from the solution of the P.D.E[33].Still in space dimension1,the case of infinite horizon seems more promising:The sys-tem of P.D.E then reduces to an ordinary differential equation.The existence of suitable solutions for this equation then leads to Nash equilibria.Such a construction is carried out in Bressan and Priuli[32],Bressan[30,31]through several classes of examples and by various methods.In a similar spirit,the papers Cardaliaguet and Plaskacz[47],Cardaliaguet[42]study a very simple class of nonzero-sum differential games in dimension1and with a terminal payoff:In this case it is possible to select a unique Nash equilibrium payoff in feedback form by just imposing that it is Pareto whenever there is a unique Pareto one.However,this equilibrium payoff turns out to be highly unstable with respect to the terminal data.Some other examples of nonlinear-quadratic differential games are also analyzed in Olsder[99] and in Ramasubramanian[106].2.4Mean-field GamesSince the system of P.D.Es arising in nonzero-sum differential games is,in general,ill-posed,it is natural to investigate situations where the problem simplifies.It turns out that this is the case for differential games with a very large number of identical players.This problem has been recently developed in a series of papers by Lasry and Lions[87–90,94] under the terminology of mean-field games(see also Huang,Caines and Malhame[76–79] for a related approach).The main achievement of Lasry and Lions is the identification of the limit when the number of players tends to infinity.The typical resulting model takes the form⎧⎪⎨⎪⎩(i)−∂t u−Δu+H(x,m,Du)=0in R d×(0,T),(ii)∂t m−Δm−divD p H(x,m,Du)m=0in R d×(0,T),(iii)m(0)=m0,u(x,T)=Gx,m(T).(1)In the above system,thefirst equation has to be understood backward in time while the second one is forward in time.Thefirst equation(a Hamilton–Jacobi one)is associated with an optimal control problem and its solution can be regarded as the value function for a typical small player(in particular the Hamiltonian H=H(x,m,p)is convex with respect to the last variable).As for the second equation,it describes the evolution of the density m(t)of the population.More precisely,let usfirst consider the behavior of a typical player.He controls through his control(αs)the stochastic differential equationdX t=αt dt+√2B t(where(B t)is a standard Brownian motion)and he aims at minimizing the quantityET12LX s,m(s),αsds+GX T,m(T),where L is the Fenchel conjugate of H with respect to the p variable.Note that in this cost the evolving measure m(s)enters as a parameter.The value function of our average player is then given by(1-(i)).His optimal control is—at least heuristically—given in feedback form byα∗(x,t)=−D p H(x,m,Du).Now,if all agents argue in this way,their repartition will move with a velocity which is due,on the one hand,to the diffusion,and,one the other hand,to the drift term−D p H(x,m,Du).This leads to the Kolmogorov equation(1-(ii)).The mean-field game theory developed so far has been focused on two main issues:firstly,investigate equations of the form(1)and give an interpretation(in economics,for instance)of such systems.Secondly,analyze differential games with afinite but large num-ber of players and interpret(1)as their limiting behavior as the number of players goes to infinity.Up to now thefirst issue is well understood and well documented.The original works by Lasry and Lions give a certain number of conditions under which(1)has a solution,discuss its uniqueness and its stability.Several papers also study the numerical approximation of this solution:see Achdou and Capuzzo Dolcetta[1],Achdou,Camilli and Capuzzo Dolcetta[2], Gomes,Mohr and Souza[71],Lachapelle,Salomon and Turinici[85].The mean-field games theory has been used in the analysis of wireless communication systems in Huang,Caines and Malhamé[76],or Yin,Mehta,Meyn and Shanbhag[115].It seems also particularly adapted to modeling problems in economics:see Guéant[72,73],Lachapelle[84],Lasry, Lions,Guéant[91],and the references therein.As for the second part of the program,the limiting behavior of differential games when the number of players tend to infinity has been understood for ergodic differential games[88].The general case remains mostly open.3Long-time Average of Differential GamesAnother way to reduce the complexity of differential games is to look at their long-time be-havior.Among the numerous applications of this topic let us quote homogenization,singular perturbations and dimension reduction of multiscale systems.In order to explain the basic ideas,let us consider a two-player stochastic zero-sum dif-ferential game with dynamics given bydX t,ζ;u,vs =bX t,ζ;u,vs,u s,v sds+σX t,ζ;u,v,u s,v sdB s,s∈[t,+∞),X t=ζ,where B is a d-dimensional standard Brownian motion on a given probability space (Ω,F,P),b:R N×U×V→R N andσ:R N×U×V→R N×d,U and V being some metric compact sets.We assume that thefirst player,playing with u,aims at minimizing a running payoff :R N×U×V→R(while the second players,playing with v,maximizes). Then it is known that,under some Isaacs’assumption,the game has a value V T which is the viscosity solution of a second order Hamilton–Jacobi equation of the form−∂t V T(t,x)+Hx,D V T(t,x),D2V T(t,x)=0in[0,T]×R N,V T(T,x)=0in R N.A natural question is the behavior of V T as T→+∞.Actually,since V T is typically of linear growth,the natural quantity to consider is the long-time average,i.e.,lim T→+∞V T/T.Interesting phenomena can be observed under some compactness assumption on the un-derlying state-space.Let us assume,for instance,that the maps b(·,u,v),σ(·,u,v)and (·,u,v)are periodic in all space variables:this actually means that the game takes place in the torus R N/Z N.In this framework,the long-time average is well understood in two cases:either the dif-fusion is strongly nondegenerate:∃ν>0,(σσ∗)(x,u,v)≥νI N∀x,u,v,(where the inequality is understood in the sense of quadratic matrices);orσ≡0and H= H(x,ξ)is coercive:lim|ξ|→+∞H(x,ξ)=+∞uniformly with respect to x.(2) In both cases the quantity V T(x,0)/T uniformly converges to the unique constant¯c forwhich the problem¯c+Hx,Dχ(x),D2χ(x)=0in R Nhas a continuous,periodic solutionχ.In particular,the limit is independent of the initial condition.Such kind of results has been proved by Lions,Papanicoulaou and Varadhan[95] forfirst order equations(i.e.,deterministic differential games).For second order equations, the result has been obtained by Alvarez and Bardi in[3],where the authors combine funda-mental contributions of Evans[61,62]and of Arisawa and Lions[7](see also Alvarez and Bardi[4,5],Bettiol[24],Ghosh and Rao[70]).For deterministic differential games(i.e.,σ≡0),the coercivity condition(2)is not very natural:Indeed,it means that one of the players is much more powerful than the other one. However,very little is known without such a condition.Existing results rely on a specific structure of the game:see for instance Bardi[16],Cardaliaguet[46].The difficulty comes from the fact that,in these cases,the limit may depend upon the initial condition(see also Arisawa and Lions[7],Quincampoix and Renault[104]for related issues in a control set-ting).The existence of a limit for large time differential games is certainly one of the main challenges in differential games theory.4Existence of a Value for Zero-sum Differential Games with State Constraints Differential games with state constraints have been considered since the early theory of differential games:we refer to[23,28,66,69,80]for the computation of the solution for several examples of pursuit.We present here recent trends for obtaining the existence of a value for a rather general class of differential games with constraints.This question had been unsolved during a rather long period due to problems we discuss now.The main conceptual difficulty for considering such zero-sum games lies in the fact that players have to achieve their own goal and to satisfy the state constraint.Indeed,it is not clear to decide which players has to be penalized if the state constraint is violated.For this reason,we only consider a specific class of decoupled games where each player controls independently a part of the dynamics.A second mathematical difficulty comes from the fact that players have to use admissible controls i.e.,controls ensuring the trajectory to fulfilthe state constraint.A byproduct of this problem is the fact that starting from two close initial points it is not obvious tofind two close constrained trajectories.This also affects the regularity of value functions associated with admissible controls:The value functions are,in general,not Lipschitz continuous anymore and,consequently,classical viscosity solutions methods for Hamilton–Jacobi equations may fail.4.1Statement of the ProblemWe consider a differential game where thefirst player playing with u,controls afirst systemy (t)=gy(t),u(t),u(t)∈U,y(t0)=y0∈K U,(3) while the second player,playing with v,controls a second systemz (t)=hz(t),v(t),v(t)∈V,z(t0)=z0∈K V.(4)For every time t,thefirst player has to ensure the state constraint y(t)∈K U while the second player has to respect the state constraint z(t)∈K V for any t∈[t0,T].We denote by x(t)= x[t0,x0;u(·),v(·)](t)=(y[t0,y0;u(·)](t),z[t0,z0;v(·)](t))the solution of the systems(3) and(4)associated with an initial data(t0,x0):=(t0,y0,z0)and with a couple of controls (u(·),v(·)).In the following lines we summarize all the assumptions concerning with the vectorfields of the dynamics:⎧⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎨⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎪⎩(i)U and V are compact subsets of somefinitedimensional spaces(ii)f:R n×U×V→R n is continuous andLipschitz continuous(with Lipschitz constant M)with respect to x∈R n(iii)uf(x,u,v)andvf(x,u,v)are convex for any x(iv)K U={y∈R l,φU(y)≤0}withφU∈C2(R l;R),∇φU(y)=0ifφU(y)=0(v)K V={z∈R m,φV(z)≤0}withφV∈C2(R m;R),∇φV(z)=0ifφV(z)=0(vi)∀y∈∂K U,∃u∈U such that ∇φU(y),g(y,u) <0(vii)∀z∈∂K V,∃v∈V such that ∇φV(z),h(z,v) <0(5)We need to introduce the notion of admissible controls:∀y0∈K U,∀z0∈K V and∀t0∈[0,T]we defineU(t0,y0):=u(·):[t0,+∞)→U measurable|y[t0,y0;u(·)](t)∈K U∀t≥t0V(t0,z0):=v(·):[t0,+∞)→V measurable|z[t0,z0;v(·)](t)∈K V∀t≥t0.Under assumptions(5),the Viability Theorem(see[9,10])ensures that for all x0= (y0,z0)∈K U×K VU(t0,y0)=∅and V(t0,z0)=∅.Throughout the paper we omit t0in the notations U(t0,y0)and U(t0,y0)whenever t0=0.We now describe two quantitative differential games.Let us start with a game with an integral cost:Bolza Type Differential Game Given a running cost L:[0,T]×R N×U×V→R and afinal costΨ:R N→R,we define the payoff associated to an initial position(t0,x0)= (t0,y0,z0)and to a pair of controls(u,v)∈U(t0,y0)×V(t0,z0)byJt0,x0;u(·),v(·)=Tt0Lt,x(t),u(·),v(·)dt+Ψx(T),(6)where x(t)=x[t0,x0;u(·),v(·)](t)=(y[t0,y0;u(·)](t),z[t0,z0;v(·)](t))denotes the solu-tion of the systems(3)and(4).Thefirst player wants to maximize the functional J,while the second player’s goal is to minimize J.Definition1A mapα:V(t0,z0)→U(t0,y0)is a nonanticipating strategy(for thefirst player and for the point(t0,x0):=(t0,y0,z0)∈R+×K U×K V)if,for anyτ>0,for all controls v1(·)and v2(·)belonging to V(t0,z0),which coincide a.e.on[t0,t0+τ],α(v1(·)) andα(v2(·))coincide almost everywhere on[t0,t0+τ].Nonanticipating strategiesβfor the second player are symmetrically defined.For any point x0∈K U×K V and∀t0∈[0,T]we denote by A(t0,x0)and by B(t0,x0)the sets of the nonanticipating strategies for thefirst and the second player respectively.We are now ready to define the value functions of the game.The lower value V−is defined by:V−(t0,x0):=infβ∈B(t0,x0)supu(·)∈U(t0,y0)Jt0,x0;u(·),βu(·),(7)where J is defined by(6).On the other hand we define the upper value function as follows:V+(t0,x0):=limε→0+supα∈A(t0,x0)infv(·)∈V(t0,z0)Jεt0,x0;αv(·),v(·)(8)withJεt0,x0;u(·),v(·):=Tt0Lt,x(t),u(t),v(t)dt+Ψεx(T),where x(t)=x[t0,x0;u(·),v(·)](t)andΨεis the lower semicontinuous function defined byΨε(x):=infρ∈R|∃y∈R n with(y,ρ)−x,Ψ(x)=ε.The asymmetry between the definition of the value functions is due to the fact that one assumes that the terminal payoffΨis lower semicontinuous.WhenΨis continuous,one can check that V+can equivalently be defined in a more natural way asV+(t0,x0):=supα∈A(t0,x0)infv(·)∈V(t0,z0)Jt0,x0;αv(·),v(·).We now describe the second differential game which is a pursuit game with closed target C⊂K U×K V.Pursuit Type Differential Game The hitting time of C for a trajectory x(·):=(y(·),z(·)) is:θCx(·):=inft≥0|x(t)∈C.If x(t)/∈C for every t≥0,then we setθC(x(·)):=+∞.In the pursuit game,thefirst player wants to maximizeθC while the second player wants to minimize it.The value functions aredefined as follows:The lower optimal hitting-time function is the mapϑ−C :K U×K V→R+∪{+∞}defined,for any x0:=(y0,z0),byϑ−C (x0):=infβ(·)∈B(x0)supu(·)∈U(y0)θCxx0,u(·),βu(·).The upper optimal hitting-time function is the mapϑ+C :K U×K V→R+∪{+∞}de-fined,for any x0:=(y0,z0),byϑ+ C (x0):=limε→0+supα(·)∈A(x0)infv(·)∈V(z0)θC+εBxx0,αv(·),v(·).By convention,we setϑ−C (x)=ϑ+C(x)=0on C.Remarks–Note that here again the definition of the upper and lower value functions are not sym-metric:this is related to the fact that the target assumed to be closed,so that the game is intrinsically asymmetric.–The typical pursuit game is the case when the target coincides with the diagonal:C= {(y,z),|y=z}.We refer the reader to[6,29]for various types of pursuit games.The formalism of the present survey is adapted from[50].4.2Main ResultThe main difficulty for the analysis of state-constraint problems lies in the fact that two trajectories of a control system starting from two—close—different initial conditions could be estimated by classical arguments on the continuity of theflow of the differential equation. For constrained systems,it is easy to imagine cases where the constrained trajectories starting from two close initial conditions are rather far from each other.So,an important problem in order to get suitable estimates on constrained trajectories,is to obtain a kind of Filippov Theorem with ly a result which allows one to approach—in a suitable sense—a given trajectory of the dynamics by a constrained trajectory.Note that similar results exist in the literature.However,we need here to construct a constrained trajectory in a nonanticipating way[26](cf.also[25]),which is not the case in the previous constructions.Proposition1Assume that conditions(5)are satisfied.For any R>0there exist C0= C0(R)>0such that for any initial time t0∈[0,T],for any y0,y1∈K U with|y0|,|y1|≤R,。
手册:统计分析使用R - 第2版 - 布兰·S·埃维里特和托尔斯坦·豾伯恩说明书
A Handbook of Statistical Analyses Using R—2nd EditionBrian S.Everitt and Torsten HothornCHAPTER11Survival Analysis:Glioma Treatment andBreast Cancer Survival11.1Introduction11.2Survival Analysis11.3Analysis Using R11.3.1Glioma RadioimmunotherapyFigure11.1leads to the impression that patients treated with the novel radioimmunotherapy survive longer,regardless of the tumour type.In order to assess if this informalfinding is reliable,we may perform a log-rank test viaR>survdiff(Surv(time,event)~group,data=g3)Call:survdiff(formula=Surv(time,event)~group,data=g3)N Observed Expected(O-E)^2/E(O-E)^2/Vgroup=Control64 1.49 4.23 6.06group=RIT112 4.51 1.40 6.06Chisq= 6.1on1degrees of freedom,p=0.01which indicates that the survival times are indeed different in both groups. However,the number of patients is rather limited and so it might be danger-ous to rely on asymptotic tests.As shown in Chapter4,conditioning on the data and computing the distribution of the test statistics without additional assumptions are one alternative.The function surv_test from package coin (Hothorn et al.,2006,2008)can be used to compute an exact conditional test answering the question whether the survival times differ for grade III patients. For all possible permutations of the groups on the censored response variable, the test statistic is computed and the fraction of whose being greater than the observed statistic defines the exact p-value:R>library("coin")R>logrank_test(Surv(time,event)~group,data=g3,+distribution="exact")Exact Two-Sample Logrank Testdata:Surv(time,event)by group(Control,RIT)Z=-2,p-value=0.03alternative hypothesis:true theta is not equal to134SURVIVAL ANALYSIS R>data("glioma",package ="coin")R>library("survival")R>layout(matrix(1:2,ncol =2))R>g3<-subset(glioma,histology =="Grade3")R>plot(survfit(Surv(time,event)~group,data =g3),+main ="Grade III Glioma",lty =c(2,1),+ylab ="Probability",xlab ="Survival Time in Month",+legend.text =c("Control","Treated"),+legend.bty ="n")R>g4<-subset(glioma,histology =="GBM")R>plot(survfit(Surv(time,event)~group,data =g4),+main ="Grade IV Glioma",ylab ="Probability",+lty =c(2,1),xlab ="Survival Time in Month",+xlim =c(0,max(glioma$time)*1.05))02040600.00.20.40.60.81.0Grade III Glioma Survival Time in Month P r o b a b i l i ty 0204060..2.40.6.81.0Grade IV GliomaSurvival Time in MonthP ro bab i l i ty Figure 11.1Survival times comparing treated and control patients.which,in this case,confirms the above results.The same exercise can be performed for patients with grade IV gliomaR>logrank_test(Surv(time,event)~group,data =g4,+distribution ="exact")Exact Two-Sample Logrank Testdata:Surv(time,event)by group (Control,RIT)Z =-3,p-value =2e-04alternative hypothesis:true theta is not equal to 1which shows a difference as well.However,it might be more appropriate toANALYSIS USING R5 answer the question whether the novel therapy is superior for both groups of tumours simultaneously.This can be implemented by stratifying,or blocking,with respect to tumour grading:R>logrank_test(Surv(time,event)~group|histology,+data=glioma,distribution=approximate(B=10000)) Approximative Two-Sample Logrank Testdata:Surv(time,event)bygroup(Control,RIT)stratified by histologyZ=-4,p-value=1e-04alternative hypothesis:true theta is not equal to1Here,we need to approximate the exact conditional distribution since the exact distribution is hard to compute.The result supports the initial impression implied by Figure11.1.11.3.2Breast Cancer SurvivalBeforefitting a Cox model to the GBSG2data,we again derive a Kaplan-Meier estimate of the survival function of the data,here stratified with respect to whether a patient received a hormonal therapy or not(see Figure11.2).Fitting a Cox model follows roughly the same rules as shown for linear models in Chapter6with the exception that the response variable is again coded as a Surv object.For the GBSG2data,the model isfitted viaR>GBSG2_coxph<-coxph(Surv(time,cens)~.,data=GBSG2)and the results as given by the summary method are given in Figure11.3.Sincewe are especially interested in the relative risk for patients who underwent a hormonal therapy,we can compute an estimate of the relative risk and a corresponding confidence interval viaR>ci<-confint(GBSG2_coxph)R>exp(cbind(coef(GBSG2_coxph),ci))["horThyes",]2.5%97.5%0.7070.5490.911This result implies that patients treated with a hormonal therapy had a lowerrisk and thus survived longer compared to women who were not treated this way.Model checking and model selection for proportional hazards models are complicated by the fact that easy-to-use residuals,such as those discussed in Chapter6for linear regression models,are not available,but several possibil-ities do exist.A check of the proportional hazards assumption can be done by looking at the parameter estimatesβ1,...,βq over time.We can safely assume proportional hazards when the estimates don’t vary much over time.The null hypothesis of constant regression coefficients can be tested,both globally aswell as for each covariate,by using the cox.zph functionR>GBSG2_zph<-cox.zph(GBSG2_coxph)R>GBSG2_zph6SURVIVAL ANALYSIS R>data("GBSG2",package ="TH.data")R>plot(survfit(Surv(time,cens)~horTh,data =GBSG2),+lty =1:2,mark.time =FALSE,ylab ="Probability",+xlab ="Survival Time in Days")R>legend(250,0.2,legend =c("yes","no"),lty =c(2,1),+title ="Hormonal Therapy",bty ="n")050010001500200025000.00.2.4.6.81.Survival Time in DaysP r o babi l it y Hormonal TherapyyesnoFigure 11.2Kaplan-Meier estimates for breast cancer patients who either receiveda hormonal therapy or not.chisq df phorTh 0.23910.6253age 10.43810.0012menostat 5.40610.0201tsize 0.19110.6620tgrade 10.71220.0047pnodes 0.80810.3688progrec 4.38610.0362estrec 5.89310.0152GLOBAL 24.42190.0037There seems to be some evidence of time-varying effects,especially for age and tumour grading.A graphical representation of the estimated regression coeffi-ANALYSIS USING R7 R>summary(GBSG2_coxph)Call:coxph(formula=Surv(time,cens)~.,data=GBSG2)n=686,number of events=299coef exp(coef)se(coef)z Pr(>|z|)horThyes-0.3462780.7073160.129075-2.680.00730age-0.0094590.9905850.009301-1.020.30913menostatPost0.258445 1.2949150.183476 1.410.15895tsize0.007796 1.0078270.003939 1.980.04779tgrade.L0.551299 1.7355060.189844 2.900.00368tgrade.Q-0.2010910.8178380.121965-1.650.09920pnodes0.048789 1.0499980.007447 6.55 5.7e-11progrec-0.0022170.9977850.000574-3.870.00011estrec0.000197 1.0001970.0004500.440.66131exp(coef)exp(-coef)lower.95upper.95horThyes0.707 1.4140.5490.911age0.991 1.0100.973 1.009menostatPost 1.2950.7720.904 1.855tsize 1.0080.992 1.000 1.016tgrade.L 1.7360.576 1.196 2.518tgrade.Q0.818 1.2230.644 1.039pnodes 1.0500.952 1.035 1.065progrec0.998 1.0020.9970.999estrec 1.000 1.0000.999 1.001Concordance=0.692(se=0.015)Likelihood ratio test=105on9df,p=<2e-16Wald test=115on9df,p=<2e-16Score(logrank)test=121on9df,p=<2e-16Figure11.3R output of the summary method for GBSG2_coxph.cient over time is shown in Figure11.4.We refer to Therneau and Grambsch (2000)for a detailed theoretical description of these topics.The tree-structured regression models applied to continuous and binary responses in Chapter9are applicable to censored responses in survival analysis as well.Such a simple prognostic model with only a few terminal nodes might be helpful for relating the risk to certain subgroups of patients.Both rpart and the ctree function from package party can be applied to the GBSG2 data,where the conditional trees of the latter select cutpoints based on log-rank statisticsR>GBSG2_ctree<-ctree(Surv(time,cens)~.,data=GBSG2)and the plot method applied to this tree produces the graphical representation in Figure11.6.The number of positive lymph nodes(pnodes)is the most important variable in the tree,corresponding to the p-value associated with this variable in Cox’s regression;see Figure11.3.Women with not more than three positive lymph nodes who have undergone a hormonal therapy seem to have the best prognosis whereas a large number of positive lymph nodes and a small value of the progesterone receptor indicates a bad prognosis.8SURVIVAL ANALYSIS R>plot(GBSG2_zph,var ="age")−0.6−.4−0.20.00.2.4TimeBe ta(t)f o r age2704405607701100140018002300Figure 11.4Estimated regression coefficient for age depending on time for theGBSG2data.ANALYSIS USING R 9R>layout(matrix(1:3,ncol =3))R>res <-residuals(GBSG2_coxph)R>plot(res ~age,data =GBSG2,ylim =c(-2.5,1.5),+pch =".",ylab ="Martingale Residuals")R>abline(h =0,lty =3)R>plot(res ~pnodes,data =GBSG2,ylim =c(-2.5,1.5),+pch =".",ylab ="")R>abline(h =0,lty =3)R>plot(res ~log(progrec),data =GBSG2,ylim =c(-2.5,1.5),+pch =".",ylab ="")R>abline(h =0,lty =3)20406080−2−101age Ma r t i ngal eResi d uals010********−2−101pnodes 02468−2−11log(progrec)Figure 11.5Martingale residuals for the GBSG2data.10SURVIVAL ANALYSIS R>plot(GBSG2_ctree)050015002500050015002500050015002500050015002500Figure 11.6Conditional inference tree for the GBSG2data with the survival func-tion,estimated by Kaplan-Meier,shown for every subgroup of patientsidentified by the tree.BibliographyHothorn,T.,Hornik,K.,van de Wiel,M.,and Zeileis,A.(2008),coin: Conditional Inference Procedures in a Permutation Test Framework,URL /package=coin,R package version1.0-21. Hothorn,T.,Hornik,K.,van de Wiel,M.A.,and Zeileis,A.(2006),“A Lego system for conditional inference,”The American Statistician,60,257–263. Therneau,T.M.and Grambsch,P.M.(2000),Modeling Survival Data:Ex-tending the Cox Model,New York,USA:Springer-Verlag.。
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低剂量ICS 加长效2激动剂 中/高剂量ICS
加用一种 或多种
中/高剂量ICS 加长效2-激动剂 白三烯调节剂
肺功能‡ (PEF or FEV1) 恶化
任何急性加重出现均应重新评估维持治疗,以确保治疗足够达到控制哮喘 † 任意一周内的一次恶化即可认为该周内哮喘未得到控制 ‡ 对5岁及5岁以下的儿童,肺功能并不是一项可靠的测试指标
Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention 2006
根据严重程度
•间歇性 •轻度持续 •中度持续 •重度持续
GINA 2006 根据控制水平
•控制 •部分控制 •未控制
Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention 2006
哮喘临床控制
2006年版GINA解读
卫生部中日友好医院 林江涛
GINA回顾
1993年GINA专家组成立 1995年发表GINA系列文件 1998年修订(强调哮喘应根据严重程度进行分级治疗)
2002年再次修订(早期治疗和联合治疗),此后每年内容补 充
2006年版(强调哮喘的控制)
Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention 2006
欧洲术后镇痛指南
PostoperativePain Management –Good Clinical PracticeGeneral recommendationsand principles forsuccessful pain managementProduced in consultation with theEuropean Society of Regional Anaesthesiaand Pain TherapyPostoperativePain Management –Good Clinical PracticeGeneral recommendationsand principles forsuccessful pain managementProduced in consultation with theEuropean Society of Regional Anaesthesiaand Pain TherapyContents ContentsContents11. Introduction and objectives1 Although the choice of drugs shown here is indicative, adjustments will be required to take account ofindividual patient variation and are the responsibility of the prescribing physician.Effective postoperative pain management has a humanitarian role, but there are additional medical and economic benefits for rapid recovery and discharge from hospital. A number of factors contribute to effective postoperative pain management including a structured acute pain management team, patient education, regular staff training, use of balanced analgesia, regular pain assessment using specificassessment tools and adjustment of strategies to meet the needs of special patient groups, such as children and the elderly.Recent advances in pain control provide greater potential for effective postoperative management. This document reflects the opinions of a panel of European anaesthesiologists. Its aims are to raise awareness of recent advances in pain control and to provide advice on how toachieve effective postoperative analgesia. The recommendations and advice are general principles of pain management and do not provide detailed advice for specific surgical procedures.1Effective pain management is now an integral part of modern surgical practice. Postoperative pain management not only minimises patient suffering but also can reduce morbidity and facilitate rapid recovery and early discharge from hospital (see section 8, page 33), which can reduce hospital costs.23Pain is a personal, subjective experience that involves sensory,emotional and behavioural factors associated with actual or potentialtissue injury. What patients tell us about their pain can be very revealing,and an understanding of how the nervous system responds and adaptsto pain in the short and long term is essential if we are to make sense ofpatients’ experiences. The wide area of discomfort surrounding awound, or even a wound that has healed long ago, such as anamputation stump, is a natural consequence of the plasticity of thenervous system. An understanding of the physiological basis of pain ishelpful to the sufferer, and the professionals who have to provideappropriate treatment.According to the International Association for the Study of Pain (IASP),pain is defined as"An unpleasant sensory and emotional experience associated withactual or potential tissue damage, or described in terms of suchdamage."(IASP 1979)There is individual variation in response to pain, which is influenced bygenetic makeup, cultural background, age and gender. Certain patientpopulations are at risk of inadequate pain control and require specialattention. These include:G Paediatric patientsG Geriatric patientsG Patients with difficulty in communicating (due to critical illness,cognitive impairment or language barriers)Postoperative pain can be divided into acute pain and chronic pain:G Acute pain is experienced immediately after surgery (up to 7 days)G Pain which lasts more than 3 months after the injury is considered tobe chronic pain3. Physiology of pain 2. Goals of pain treatmentAcute and chronic pain can arise from cutaneous, deep somatic orvisceral structures. Surgery is typically followed by acute pain and correct identification of the type of pain enables selection of appropriate effective treatment. The type of pain may be somatic (arising from skin, muscle, bone), visceral (arising from organs within the chest and abdomen), or neuropathic (caused by damage or dysfunction in the nervous system). Patients often experience more than one type of pain.3.a. Positive role of painAcute pain plays a useful "positive" physiological role by:G Providing a warning of tissue damageG Inducing immobilisation to allow appropriate healing3.b. Negative effects of painShort term negative effects of acute pain include:G Emotional and physical suffering for the patientG Sleep disturbance(with negative impact on mood and mobilisation)G Cardiovascular side effects(such as hypertension and tachycardia)G Increased oxygen consumption(with negative impact in the case of coronary artery disease)G Impaired bowel movement(while opioids induce constipation or nausea, untreated pain mayalso be an important cause of impaired bowel movement or PONV*)G Negative effects on respiratory function(leading to atelectasis, retention of secretions and pneumonia)G Delays mobilisation and promotes thromboembolism(postoperative pain on mobilisation is one of the major causes fordelayed mobilisation)Long term negative effects of acute pain:G Severe acute pain is a risk factor for the development of chronicpain1G There is a risk of behavioural changes in children for a prolongedperiod (up to 1 year) after surgical painThere are two major mechanisms in the physiology of pain:G Nociceptive (sensory):Inflammatory pain due to chemical,mechanical and thermal stimuli at the nociceptors (nerves thatrespond to painful stimuli).G Neuropathic:Pain due to neural damage in peripheral nervesor within the central nervous system.During normal physiology, pain sensations are elicited by activity in unmyelinated (C-) and thinly myelinated (Ad-) primary afferent neurons that synapse with neurons is the dorsal horn of the spinal cord. Sensory information is then relayed to the thalamus and brainstem.Repetitive activation of C- nociceptive receptors produces alterations in central as well as peripheral nervous systems.3.c. The mechanism of peripheral pain sensitisationNormally, C- fibres (slow-conducting fibres that transmit dull aching pain) are silent in the absence of stimulation, but following acute tissue injury in the presence of ongoing pathophysiology, these nociceptors become sensitised and release a complex mix of pain and inflammatory mediators leading to pain sensations (Figure 1, page 6).1Several investigations into chronic pain have concluded that 20% to 50% of all patients with chronic pain syndromes started with acute pain following trauma or surgery, but the role of effective pain treatment in preventing this risk is not clear.* PONV = Postoperative Nausea and Vomiting.Figure 1.Mechanism of peripheral sensitisation3.d. The mechanism of central sensitisationThe responses in the CNS are primarily physiological. Centralsensitisation is a physiological process and, only if there is continual firing of C-nociceptors over time, will these processes leads to more chronic pain syndromes.Sustained or repetitive C-nociceptor activity produces alterations in the response of the central nervous system to inputs from the periphery.When identical noxious stimuli are repeatedly applied to the skin at a certain rate, there is a progressive build-up in the response of spinalcord dorsal horn neurons (known as ‘wind up’). This allows the size of the dorsal horn neuron’s receptive field to grow (Figure 2). This process,called central sensitisation, occurs with any tissue damage. As with sensitisation of primary afferent nociceptors, this sensitisation of central pain transmission is a normal physiological response of the undamaged nervous system.Figure 2.Pain mediatorsGUnexpected intense pain, particularly if associated with altered vital signs, (hypotension, tachycardia, or fever), is immediately evaluated. New diagnoses, such as wound dehiscence, infection, or deep venous thrombosis, should be considered.GImmediate pain relief without asking for a pain rating is given to patients in obvious pain who are not sufficiently focused to use a pain rating scale.GFamily members are involved when appropriate.4.a. Specific tools for pain assessmentSpecific pain assessment scales are used to quantify pain. The use of one scale within a hospital ensures that everyone in the team "speaks the same language"regarding the intensity of pain. The patient's own report is the most useful tool. The intensity of pain should therefore be assessed as far as possible by the patient as long as he/she is able tocommunicate and express what pain feels like. Always listen to and believe what the patient says.A number of different patient self-assessment scales are available (Figure 3, page 12):A. Facial expressions: a pictogram of six faces with differentexpressions from smiling or happy through to tearful. This scale is suitable for patients where communication is a problem, such as children, elderly patients, confused patients or patients who do not speak the local language.B. Verbal rating scale (VRS): the patient is asked to rate their pain on a five-point scale as "none, mild, moderate, severe or very severe".Assessment of pain is a vital element in effective postoperative pain management. The principles of successful pain assessment are shown in Table 1.44. Assessment of pain4G The treatment strategy to be continued is discussed by the physician responsible for the patient in conjunction with the ward nurses.GThe physician and nurses pay attention to the effects and side effects of the pain treatment.C. Numerical rating scale (NRS): This consists of a simple 0 to 5 or 0 to 10 scale which correlates to no pain at zero and worst possible pain at 5 (or 10). The patient is asked to rate his/her pain intensity as a number.D. Visual analogue scale (VAS): This consists of an ungraduated,straight 100 mm line marked at one end with the term " no pain" and at the other end "the worst possible pain". The patient makes a cross on the line at the point that best approximates to their pain intensity.The VRS and NRS are the most frequently used assessment tools in the clinical setting while the VAS scale is primarily used as a research tool.4.b. Selection of suitable assessment tool (Figure 3, page 12):When selecting a pain assessment tool ensure that:GIt is appropriate for the patient's developmental, physical, emotional, and cognitive statusGIt meets the needs of both the patient and the pain management team4.c. DocumentationDocument pain regularly, take appropriate action and monitor efficacy and side effects of treatment. Record the information in a well-defined place in the patient record, such as the vital sign sheet or a purpose-designed acute pain chart.GThe nurse responsible for the patient reports the intensity of pain and treats the pain within the defined rules of the local guidelines. GThe physician responsible for the patient may need to modify theintervention if evaluation shows that the patient still has significant pain.44Faces painassessmentscale(Fig A) Patientable to communicatewell ?VRS painassessmentscale(Fig B)NRSassessmentscale(Fig C)VASassessmentscale(Fig D) NoYesChoice of assessment tool12Fig A. Alternatecoding Fig B.Fig C. Fig D.G Select a pain assessment tool, and teach the patient to use it.Determine the level of pain above which adjustment of analgesia or other interventions will be considered.G Provide the patient with education and information about pain control.GEmphasise the importance of a factual report of pain, avoiding stoicism or exaggeration.The "Patient Information Project" is a useful source of information for patients who require information about anaesthesia and postoperative pain management. This is a joint project between the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland, together with patient representative groups. The website is:Patients are unlikely to be aware of postoperative pain treatment techniques and as the success of pain relief is influenced by theirknowledge and beliefs, it is helpful to give patients (and parents in case of children) detailed information about postoperative pain and pain treatment. Adequate information gives the patient realistic expectations of the care that can be provided (pain relief, not a "pain free status"). This information can include:G The importance of treating postoperative pain G Available methods of pain treatment G Pain assessment routinesG Goals (optimum pain scoring) (see section 2, page 2)GThe patient's participation in the treatment of painInformation for the patient can be given in different ways (in combination):G Verbal informationGWritten and/or audiovisual information -Brochures -Wall posters -Video films -Web pagesA preoperative discussion with the patient and relatives can include the following:GDiscuss the patient's previous experiences with pain and preferences for pain assessment and management.GGive the patient information about pain management therapies that are available and the rationale underlying their use.GDevelop with the patient a plan for pain assessment and management.141555. Patient education51716Effective treatment of postoperative pain includes a number of factors,including good nursing, non-pharmacological techniques, such as distraction, and balanced (multimodal) analgesia to provide adequate pain relief with optimal drug combinations used at the lowest effective doses.6.a. Pharmacological methods of pain treatment 1Postoperative pain management should be step-wise and balanced (Figure 4, page 18). The four main groups of analgesic drugs used for postoperative pain management are shown in Table 2 opposite, with examples of drugs listed in each group.6.a.i. Balanced (multimodal) analgesiaBalanced (multimodal) analgesia uses two or more analgesic agents that act by different mechanisms to achieve a superior analgesic effect without increasing adverse events compared with increased doses of single agents. For example, epidural opioids can be administered in combination with epidural local anaesthetics; intravenous opioids can be administered in combination with NSAIDs, which have a dose sparing effect for systemically administered opioids.Balanced analgesia is therefore the method of choice wherever possible,based on paracetamol and NSAIDs for low intensity pain with opioid analgesics and/or local analgesia techniques being used for moderate and high intensity pain as indicated (Figure 4, page 18).66. Treatment optionsTable 2Pharmacological options of pain managementNon-opioid analgesicsParacetamolNSAIDs, including COX-2 inhibitors*Gabapentin, pregabalin 2Weak opioidsCodeine TramadolParacetamol combined with codeine or tramadol Strong opioidsMorphine Diamorphine Pethidine Piritramide Oxycodone Adjuvants**Ketamine Clonidine* At the time of writing, COX-2 inhibitor drugs are subject to scrutiny by international regulatory bodies with regard to adverse outcomes when used for long-term oralprescription or for pain relief in patients with cardiovascular problems such as myocardial infarction, angina pectoris, hypertension. Rofecoxib has been withdrawn fromsales and prescription of valdecoxib has been suspended pending further research into its adverse events profile for cardiovascular morbidity and the occurrence of severemuco-cutaneous side effects. The injectable COX-2 inhibitor, parecoxib remains available for short-term use in treating postoperative pain. All NSAIDs should be used with care in patients with cardiovascular disease.** These adjuvants are not recommended for routine use in acute pain management because of their adverse side effects. Their use should be restricted to specialists in managing pain problems.62Gabapentin and pregabalin are approved for pain management but at the time of writing there is little published data to recommend the use of these drugs for acute pain management.1The example doses given are indicative and do not take account of individual patient variation.196.a.ii. Opioids 1Severeintensity painFor example:ThoracotomyUpper abdominal surgery Aortic surgery Knee replacementModerateintensity painFor example:Hip replacement Hysterectomy Jaw surgeryMildintensity painFor example:Inguinal hernia VaricesLaparoscopy(i) Paracetamol and wound infiltration with local anaesthetic (ii) NSAIDs (unless contraindicated) and(iii) Regional block analgesiaAdd weak opioid or rescue analgesia with small increments of intravenous strong opioid if necessary(i) Paracetamol and wound infiltration withlocal anaesthetic (ii) NSAIDs (unless contraindicated) and (iii) Peripheral nerve block(single shot or continuous infusion) or opioid injection (IV PCA)(i) Paracetamol and woundinfiltration with local anaesthetic (ii) NSAIDs (unlesscontraindicated) and (iii) Epidural local analgesia ormajor peripheral nerve or plexus block or opioid injection (IV PCA)1 The examples given here represent levels of pain commonly experienced and are subject to individual variation and contra-indications may apply.Figure 4Treatment options in relation to magnitude of postoperative pain expected following different types of surgery 1Table 3Morphine and weak opioidsMorphine Administration(i) Intravenous.(ii) Subcutaneous by continuous infusion or intermittent boluses via indwelling cannula.(iii) Intramuscular (not recommended due to incidence of pain. 5-10 mg 3-4 hourly).Dosage:IV PCABolus: 1-2 mg, lockout: 5-15 min (usually 7-8 min),no background infusion.Subcutaneous0.1-0.15 mg/kg 4-6 hourly, adapted in relation to pain score, sedation and respiratory rate.Monitoring Pain score, sedation, respiratory rate, side mentsSide effects such as nausea, vomiting, sedation and apnoea.No other opioid or sedative drug should be administered.18continued overleaf1 The doses and routes of administration of drugs described above are general examples and each patient should beassessed individually before prescribing.2120 6.a.iii. Non-opioids 1Table 5Combination of codeine + paracetamolAdministration Oral.DosageParacetamol 500 mg + codeine 30 mg. 4 x 1 g paracetamol/day.Monitoring Pain score, sedation, side effects.CommentsAnalgesic action is likely to be due to conversion to morphine. A small number of patients derive no benefit due to absence of the converting enzyme.NV = nausea and vomitingTramadol Administration(i) Intravenous: inject slowly (risk of high incidence of NV).(ii) Intramuscular.(iii) Oral administration as soon as possible.Dosage 50-100 mg 6 hourly.Monitoring Pain score, sedation, respiratory rate, side mentsTramadol reduces serotonin and norepinephrine reuptake and is a weak opioid agonist.In analgesic efficiency, 100 mg tramadol is equivalent to 5-15 mg morphine.Sedative drugs can have an additive effect.Table 4ParacetamolAdministration(i) Intravenous: Start 30 min before the end of surgery.(ii) Oral administration as soon as possible.Duration: as long as required.Dosage4 x 1 g paracetamol/day (2 g propacetamol/day).Dose to be reduced (e.g. 3 x 1 g/day) in case of hepatic insufficiency.Monitoring Pain scores.CommentsShould be combined with NSAID and/or opioids or loco-regional analgesia for moderate to severe pain.1 The doses and routes of administration of drugs described above are general examples and each patient should beassessed individually before prescribing.1 The doses and routes of administration of drugs described above are generally examples and each patient should be assessed individually before prescribing.Table 3 (continued)Codeine Administration OralDosage3 mg/kg/day combined with paracetamol.A minimum of 30 mg codeine/tablet is required.Monitoring Pain score, sedation, side effects.CommentsAnalgesic action is likely to be due to conversion to morphine. A small number of patients derive no benefit due to absence of the converting enzyme.6.a.iv. AdjuvantsIn addition to systemic administration of NSAIDs or paracetamol, weak opioids and non-opioid analgesic drugs may be administered "on request" for moderate or severe pain. These include ketamine and clonidine. Clonidine can be administered orally, intravenously orperineurally in combination with local anaesthetics. However, the side effects could be significant. The most important ones are hypotension and sedation. Ketamine can be administered via oral, intramuscular or intravenous routes. It has also significant side effects.6.a.v. Regional analgesiaContinuous Central Neuraxis Blockade (CCNB)CCNB is one of the most effective forms of postoperative analgesia, but it is also one of the most invasive. However, CCNB remains the first choice for a number of indications, such as abdominal, thoracic, and major orthopaedic surgery, where adequate pain relief cannot be achieved with other analgesia techniques NB can be achieved via two routes:G Continuous epidural analgesia - the recommended first choice GContinuous spinal analgesia - should be limited to selected cases only, as there is less experience with this techniquePostoperative epidural analgesia is usually accomplished with acombination of a long-acting local anaesthetic and an opioid, in dilute concentrations. Long-acting local anaesthetics are preferred because they are associated with less tachyphylaxis. Maintenance techniques in epidural analgesia include:GContinuous Infusion (CI): An easy technique that requires littleintervention. The cumulative dose of local anaesthetic is likely to be higher and side effects are more likely than with the other two techniques.2322Table 6NSAIDs 1Administration(i) Intravenous: administration should start at least 30-60 min before end of surgery.(ii) Oral administration should start as soon as possible.Duration: 3-5 days.Dosage examples(i) Conventional NSAIDs include:ketorolac: 3 x 30-40 mg/day (only IV form)diclofenac: 2 x 75 mg/day ketoprofen: 4 x 50 mg/day (ii) Selective NSAIDs include:meloxicam 15 mg once dailyCOX-2 inhibitors are now licensed for postoperative pain management. They are as efficient as ketorolac but reduce GI side effects. Examples include: parecoxib: 40 mg followed by 1-2 x 40 mg/day (IV form) or celecoxib: 200 mg/day. However, there is some debate due to cardiovascular risks in patients witharteriosclerosis. *See note below Table 2, page 17MonitoringPain scores.Renal function in patients with renal or cardiac disease, elderly patients, or patients with episodes of severe hypotension. Gastrointestinal side effects. Non-selective NSAIDs would be combined with proton inhibitors (i.e. omeprasol) in patients at risk of gastrointestinal side effects.CommentsCan be added to the pre-medication.Can be used in association with paracetamol and/or opioids or local regional analgesia for moderate to severe pain.1 The doses and routes of administration of drugs described above are general examples and each patient should beassessed individually before prescribing.2524Continuous Peripheral Nerve Blockade (CPNB)Continuous peripheral nerve blocks are being increasingly used since they may provide more selective but still excellent postoperative analgesia with reduced need for opioids over an extended period.Peripheral nerve blocks (PNBs) avoid the side effects associated with central neuraxial blockade, such as hypotension and wide motorblockade with reduced mobility and proprioception, and complications such as epidural haematoma, epidural abscess and paraparesis.After major orthopaedic lower limb surgery, clinical studies showperipheral nerve blocks are as effective as epidural and that both are better than IV opioids. Examples of drugs and dosages for use in continuous peripheral analgesia are shown in Table 8.Table 8Examples of local anaesthetics and doses in continuous peripheral nerve analgesiaG Intermittent Top-up: Results in benefits due to frequent patient/staff contact but can produce a high staff workload and patients may have to wait for treatment.GPatient-Controlled Epidural Analgesia (PCEA): This technique produces high patient satisfaction and reduced dose requirements compared with CI. However, sophisticated pumps are required and accurate catheter position is important for optimal efficacy.Examples of drugs and dosages for use in continuous epidural analgesia are shown in Table 7.Table 7Examples of local anaesthetics and opioids and doses in epidural analgesia 1LocalRopivacaineSufentanil 0.5-1 µg/ml anaesthetics/opioids0.2% (2 mg/ml) or orFentanyl 2-4 µg/mlLevobupivacaine or Bupivacaine0.1-0.2% (1-2 mg/ml)Dosage for continuous 6-12 ml/hinfusion (thoracic or lumbar level)Dosage for patient Background: 4-6 ml/h controlled infusion Bolus dose: 2 ml (2-4 ml)(lumbar or thoracic)2Minimum lockout interval 10 min (10-30 min)Recommended maximum hourly dose (bolus + background): 12 ml1 The tip of the catheter should be placed as close as possible to the surgical dermatomes: T6-T10 for majorintra-abdominal surgery, and L2-L4 for lower limb surgery.2 There are many possible variations in local anaesthetic/opioid concentration yielding good results, the examples givenhere should be taken as a guideline; higher concentrations than the ones mentioned here are sometimes required but cannot be recommended as a routine for postoperative pain relief.Site of catheterLocal anaesthetics and dosage*Ropivacaine 0.2%Bupivacaine 0.1-0.125%Levobupivacaine 0.1-0.2%Interscalene5-9 ml/h Infraclavicular 5-9 ml/h Axillary 5-10 ml/h Femoral 7-10 ml/h Popliteal3-7 ml/h*Sometimes, higher concentrations are required in individual patients. As a standard, starting with a low concentration/dose is recommended to avoid sensory loss or motor block.2726Patient Controlled Regional Analgesia (PCRA) can be used to maintain peripheral nerve block. A low basal infusion rate (e.g. 3-5 ml/h)associated with small PCA boluses (e.g. 2.5-5 ml - lockout: 30-60 min) is the preferred technique.Infiltration blocksPain relief may be achieved by infiltration of the wound with localanaesthetic. The technique is easy to perform by the surgeon at the time of surgery. The efficacy and duration of analgesia depend on the length of the wound and the type of local anaesthetic used (Table 9).The advantages and disadvantages of various techniques of regional analgesia are shown in Table 10.Table 9Local anaesthetic infiltrationLocal anaestheticVolumeAdditivesIntraarticular instillation Knee arthroscopy0.75% Ropivacaine 20 ml Morphine 1-2 mg 0.5% Bupivacaine20 ml Morphine 1-2 mgShoulder arthroscopy 0.75% Ropivacaine10-20 mlIntraperitoneal instillation Gynaecological 0.75% Ropivacaine 20 ml Cholecystectomy 0.25% Ropivacaine40-60 mlWound infiltration Inguinal hernia0.25-0.5% Ropivacaine 30-40 ml 0.25-0.5% Levobupi*30-40 ml0.25-0.5% Bupivacaine Up to 30 mlTable 10Advantages of different techniques of regional analgesiaAdvantagesDisadvantagesContinuous Very effective.Motor block and urinary Epiduralretention may develop Analgesia (CEA)Much experience.or persist depending on the concentrations used.Differential block withDrugs used must have motor sparing is possible.low risk of systemic toxicity and produce as little motor Excellent postoperative block as possible.pain control over an extended period.Requires regular clinical monitoring on surgical Useful for rehabilitation wards or ICU.and physiotherapy.There are no universal Reduces the quantity of guidelines for monitoring.opioid analgesics needed.May mask a haematoma or abscess resulting in damage to spinal nerves.continued overleafThyroid surgery0.25-0.5% Ropivacaine 10-20 ml 0.25-0.5% Levobupi*10-20 ml0.25-0.5% Bupivacaine Up to 20 mlPerianal surgery0.25-0.5% Ropivacaine 30-40 ml 0.25-0.5% Levobupi*30-40 ml0.25-0.5% Bupivacaine Up to 30 mlcontinued opposite* Levobupi = Levobupivacaine.* Levobupi = Levobupivacaine.Please consult the manufacturer’s full prescribing information before use.。
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ASTON MARTIN - A GUIDEAston Martin Lagonda Limited, Banbury Road, Gaydon, Warwickshire, CV35 0DB EnglandTelephone +44(0)1908 610620 Facsimile +44(0)1926 644222 IMPORTANT NOTICE: Aston Martin Lagonda Limited is consistantly seeking ways to improve the specificxation, design and production of its vehicles and alterations take place continually. Whilstevery effort is made to produce up to date literature, this brochure should not be regarded as an infallible guide to current specifications, nor does it constitute an offer for sale of any particularvehicle. The contents of this brochure represent the Company’s business as a whole. Text and photographs may relaye to models not available for sale in some countries. Performance resultsmay vary depending on the specification of the particular vehicle, road and envirronmental conditions and driving style. Published figures should be used for comparison purposes only andverification should not be attempted on public roads. Aston Martin Lagonda Limited strongly urges that all speed laws be obeyed and that safety belts be worn at all times. Distributors anddealers are not agents of Aston Martin Lagonda Limited and have absolutely no authority to bind Aston Martin Lagonda Limited by any express or implied undertaking or representation.The first of the company’s many changes of ownership took place in 1925. Lionel Martin’s heavy concentration on competition and consequent lack of production preparation – only around 50 cars were built between 1921-1925 – found the company in serious financial problems. Martin left the company he had founded, handing the reins to the Charnwood family, but it was too late and the company went into receivership.Augustus Cesare Bertelli, one of Martin’s competitors,visited the Kensington workshop in 1925. Greatly impressed with the quality of the cars remaining, he arranged a meeting between himself, his business partner William Somerville Renwick and Lord Charnwood. It was decided that Lord Charnwood,using the considerable engineering talents of Bertelli and Renwick, would form Aston Martin Motors Ltd and move to new premises in Feltham, Middlesex.Renwick and Bertelli had already designed an advanced single overhead camshaft 1.5-litre engine which, when placed in a new Aston Martin chassis,helped create the legendary International. The International and later Le Mans and Ulster models became regular race winners with class victories at Le Mans among the highlights.In 1932, there was another change of ownership when Sir Arthur Sutherland took over, placing his son Gordon in control. More motor racing successes ensued though Sutherland was also keen to show that Aston Martin could produce more than just competition cars.Bamford Martin. It doesn’t have quite the right ring to it, yet if things had been just a little different, that is how we would know this most British of performance sports cars.It was back before the Great War that Robert Bamford and Lionel Martin joined forces to sell Singer cars, and to prepare them for hill climbing and racing.Successfully too: it was Martin’s performances with these cars at the hillclimb course in Aston Clinton,Buckinghamshire that was to provide the inspiration for a name when the pair started making their own car.In 1914, Bamford & Martin Ltd moved into premises in London’s West Kensington and announced the intention to build its first car: the ‘Coal Scuttle’, as it was affectionately known, was powered by a Coventry Simplex side valve engine and was registered in March 1915.Further growth was, of course, halted by the war. But once peace was restored Bamford and Martin returned to making cars at new premises in Kensington. Once again, competition success proved the product: in May 1922, an Aston Martin nick-named Bunny broke ten world speed records at Brooklands, averaging more than 76 mph for over 16hours of continuous running.In the same year, Aston Martin entered international racing. With backing from racing driver and Brooklands legend Count Zborowski, Aston Martin built two cars for the French Grand Prix.Lionel Martin Robert BamfordThe DB7 marked a significant change in Aston Martin’s fortunes and work practices. For starters it was built not at Newport Pagnell but at a new facility near Bloxham in Oxfordshire with far more automation than had traditionally been the case.Production of the DB7 started in late 1994, the same year that Ford acquired a 100 per cent holding in the company, and the rewards were immediate. In 1995,the first full year of the DB7, Aston Martin produced more than 700 cars – an all-time record for the company.With the arrival of the convertible DB7 Volante in 1996, production has continued at similarly high levels making the DB7 easily the most successful model in Aston Martin’s history. By the end of 2001,total DB7 production had passed the 5,000 milestone and outstripped the combined total production of DB5and DB6 models.This same period saw a new V8 model developed from the Virage, culminating in the hugely powerful V8 Vantage, the last example of which was delivered in October 2000. The ‘V’car traditional continued at Newport Pagnell with the 2001 launch of the V12-powered Vanquish.In 2002 Aston Martin unveiled the first purpose-built facility in the history of the company at Gaydon inWarwickshire. The DB9 was the first car to be built atthe facility, which will be the home of all future AstonMartins. In 1987 when Ford Motor Company acquired 75 percent of the shares – the remainder was split evenlybetween the Livanos family and Gauntlett – and longterm stability, finally, arrived. That same year, JamesBond was reunited with Aston Martin, driving an AMV8 in The Living Daylights , while the following year,1988, the new Virage appeared.Over the next five or six years, life at Aston Martincontinued largely unchanged, but things werehappening behind the scenes as Ford plannedthe future for its new acquisition. Long-servingexecutive chairman Victor Gauntlett handed overcontrol to another legend, Walter Hayes CBE, aformer Ford of Europe Vice-Chairman. There wasalso another return to competition, with a creditable6th overall for the AMR1 in the 1989 WorldEndurance Championship and plans were hatched fora new small Aston Martin.The new car could not come soon enough. The early1990s saw a recession hit the UK and sales of thebig V8-powered Virage and Virage Volante dwindled:in 1992, just 46 cars were built. So it was that in 1993at the Geneva Show, Aston Martin proudly showedthe new DB7, a model imbued with the spirit of thoseclassic DB models of the 1960s. Indeed, the entireproject was encouraged by Sir David Brown, who died at the end of 1993.A 1970s AM V8 VantageThere is no such thing as a zero-mile Vanquish.Every car is given a 40 mile shakedown test drive at the demanding Millbrook proving ground before being given the all clear by Aston Martin’s Quality Inspector,who personally checks every finished car before signing it off. It’s his name that adorns the famous plaque placed on every finished car signifying it is ready for its new owner.In the trim shop a team of dedicated professionals hand cut and stitch the leather hides that help give every Aston Martin its unique ambience.Its cars might be at the leading edge of 21st Century automotive engineering, but there is still plenty of room for traditional skills to play their part at Aston Martin.That said, there is a consistency and uniformity about the Superform panels ensuring far greater accuracy,build quality and panel fit than has been enjoyed by Aston Martins in the past. As a result, production quality is more consistent than before which ensures that the latest generation of Aston Martin cars are the best yet.Great advances have been made in the paint processes, too. Aston Martins are available in any colour requested by the customer and spend a total of up to three hours in the paint bay being given no fewer than eight coats of paint and lacquer.Once the body has been assembled, painted and partially trimmed, it is made ready to accept the powertrain. Such is the size of the engine and transmission assembly, however, that the old way of lowering the powertrain into the car can no longer be undertaken. Instead the body/chassis is lowered onto the powertrain.After final trimming, with leather covered panels and trimmed seats created in house, each car undergoes a quality inspection – indeed, three cars in every eight are picked at random for a detailed quality audit – before it is ready for the final stage of the build process: the test drive.A typical modern car factory is a soulless place where cars are churned out as if they were white goods…fridges on wheels. Things aren’t like that at Newport Pagnell, home of the Aston Martin Vanquish S. Here in the very same buildings that produced such enduring classics as the DB4/5/6 and the later ‘V’cars – like the V8 and the Vantage – the Vanquish is assembled.In the not-too-distant past, Aston Martins created at Newport Pagnell were largely built by hand. Panels were hand formed, lovingly smoothed into shape by a combination of trained eye and experienced hand.In contrast, production of the Vanquish S bristles with modern techniques and space age materials. But the Vanquish S remains far from mass-produced. Each car takes between six to eight weeks to build and each is built to individual customer specification: no two cars are exactly alike. In a typical year, Aston Martin expects to make only a few hundred examples of the Vanquish S.The body structure and panels are preformed mixing lightweight aluminium with the latest composite materials, but even so, a large degree of hand finishing is required before the Vanquish S can take shape – each Superform aluminium front wing, for example, takes some five hours of hand smoothing and detail shaping before it is ready to be offered, by hand, to the body.Accurate measuring of every chassis built at Gaydon ensures each car is built to within the smallesttolerance levels. Only by using precision measuring equipment can we ensure that every car will enjoy the same high standards of handling, road holding and refinement.Rather than entrust the painting of an Aston Martin to a machine, every car is painted by experts using the latest quality equipment. Achieving the finish of an Aston Martin is one of the most labour intensive aspects of its production.Unlike most car factories – where cars sit on amoving line and production is completed against the clock – building an Aston Martin takes place at a less frenetic pace. Approximately 200 man-hours are involved in building each DB9 and V8 Vantage. Cars are made at a series of work stations, where technicians hand-build the cars. Once work iscompleted at one station, the bodies are moved to the next station on the small indexed line: the key word is quality and we take our time to achieve it.Although today’s Aston Martins are built in far greater numbers than their predecessors, Aston Martin remains a long way from being a mass-producer.Each car remains hand built by craftsmen with decades of experience beneath their fingertips.Gaydon symbolises the future of Aston Martin. A combination of cutting-edge technology, hand-craftsmanship and tradition ensure the facility is probably amongst the best of its type in the world. The new facility at Gaydon has been set in the gently undulating landscape of an English country estate –reflected in the stone of the reception elevation.Gaydon’s sweeping curves and lack of decoration suggest a company that is dynamic and contemporary.The offices are immediately adjacent to theproduction building separated by the double-height ‘street’which acts as an informal meeting area and a light well to the back of the deep, open-plan offices. The production facility provides a clean, clutter free,modern environment where ease of communication is paramount and all members of staff, production and office, can work together. It has silver clad walls, a gently barrel-vaulted roof and a polished concrete floor slab containing the production lines in one large room.The dramatic architecture of Aston Martin’s new Gaydon home and the elegant materials used in its construction reflect the quality of the design and finish of the cars themselves.LEFT:Gaydon - the first purpose built facility in Aston Martin’s historyAll the exterior body panels are constructed from aluminium with each individual panel hand tailored to the central structure to ensure a perfect panel fit.Every carefully detailed feature provides graphic evidence of the painstaking craftsmanship and quality, which is invested in its construction.Now further developed as the Vanquish S, the Aston Martin designed and developed 6.0-litre V12 engine produces a prodigious 520 bhp, (388 kW) enough to power the Vanquish S to a maximum speed over 200mph (321km/h) and a sub 5.0 second 0-62 mph (100km/h) acceleration time.It is coupled to a class leading Formula 1 style six-speed sequential manual transmission and electro-hydraulic clutch that operates without the use of a conventional clutch pedal. Gear changing is performed via levers behind the steering wheel.This superb performance is matched by a supremely luxurious interior and a complete standard equipment list.Since its introduction in 2001, the Vanquish hasproved to be one of the most significant Aston Martin models ever, pioneering the use of advancedtechnologies and materials such as aluminium and carbon fibre. Furthermore, its on-screen appearance in the James Bond film ‘Die Another Day ’has ensured the Vanquish has created international appeal for the Aston Martin brand.With the capacity to continue to turn heads, the design of the Vanquish is already established as a modern classic. Perfectly proportioned from every aspect, design confirms the promise of outstanding “Supercar” performance and an impeccable pedigree that makes the Vanquish the flagship Aston Martin model.The aluminium and carbon fibre technology developed for the car’s structure is a world firstcombining dimensional accuracy, durability, efficiency,safety and best-in-class torsional strength for superior handling.LEFT:Vanquish SAmong the many technological firsts is the 'message centre' in the dashboard. It is an organicelectroluminescent display (OEL), as opposed to the more common LCD. OELs have a higher resolution and better contrast and are easier to read, especially when viewed at an angle. Of course, no Aston Martin would be an Aston Martin without a beautiful body.The DB9 is modern and clean but retains much of its heritage. It is a modern interpretation of a traditional Aston Martin, the successor to benchmark designs such as the DB4 and DB5. The aluminium bonnet is long and extends all the way to the car’s leading edge. There is a minimum number of 'cut' or 'shut'lines, to aid styling simplicity and beauty. The design of an Aston Martin is integral to its appeal. Taking styling cues from the past, butreinterpreting them for the future forms the central theme of every new Aston Martin currently under development.The DB9 manages to combine all facets of style,quality and usability of a traditional Aston Martin without relying on retrospective detail or design. It is a totally modern Aston Martin.All body panels are either aluminium or lightweight composites with magnesium being used on the steering column and inner door frames. Even the gear selector paddles are made from magnesium alloy. The total weight is 1710kgs, extremely light for a V12-powered prestige 2+2 seater sports car with every imaginable luxury feature. This has a hugely beneficial effect on performance. Top speed of the manual is 186mph and 0-100 km/h (62mph)acceleration takes just 4.9 seconds. Othertechnologically radical features include a ZF 'drive-by-wire' six-speed automatic gearbox that dispenses with a traditional gear lever. Instead, the drive, park,neutral and reverse controls are selected by buttons. Touchtronic manual mode enables the driver to change gear using paddles mounted behind thesteering wheel. The automatic gearchange has been tuned to provide the perfect balance between super-fast operation and comfortably smooth shifts. A conventional six-speed manual transmission is also offered.The agility of the car is boosted by the perfect 50:50weight distribution. This has been achieved partly by putting the gearbox at the rear. A carbon fibre drive shaft, running in a cast aluminium tube, delivers torque from the engine to the gearbox. Handling is further improved by the light aluminium wishbone suspension and aluminium bodied dampers. The whole DB9 cabin is hand-finished in premium quality materials giving it a simple and functional feel.Aluminium is used in the interior, reflecting the most commonly used material in the structure and body.Even details such as the instrument dials are made from aluminium. Features include full leather Bridge of Weir upholstery of the highest quality and a state of the art music system specially developed for Aston Martin by British audio specialists Linn.The future of Aston Martin is epitomised by the DB9,a 2+2 seater sports car that sets new standards in its class due to its astonishing combination of agility,V12 power, smoothness, beautiful design and hand build.Using a radical new aluminium-bonded body frame,the DB9 is one of the most sophisticated andtechnically advanced sports cars in the world. It is powered by the latest version of Aston Martin's own designed and developed 6.0-litre V12, producing 450bhp and a top speed of 186mph. Yet the DB9 is significant well beyond being a class-leading sports car. It is the beginning of a new era for Aston Martin.It is the first car to be hand-made at Aston Martin's new high technology facility in Gaydon, Warwickshire,where all future Aston Martin models will be developed and built.The body frame is one of the most structurally efficient in the world, taking into account strength,torsional rigidity and weight. It has double the rigidity of many rivals, as well as being lighter, resulting in superior handling and agility.The elegant DB9 VolanteLEFT:The DB9 - a totally modern Aston MartinASTON MARTINDB9The DBRS9 race car (pictured left) was unveiled at Le Mans 2005, and provides a competition car for club and national racing series, and a bridge for teams and drivers looking towards international GT racing.The DBRS9 is based on the DB9 road car, but shares many design features from the full GT1 specification DBR9. It uses the road car’s aluminium bonded chassis with a DBR9-based roll cage. Aston Martin Racing’s engineers have tuned the standard six litre V12 engine to produce approximately 550bhp (an increase of 20%) and reduced the overall weight by 480kg, to increase the power to weight ratio to nearly 430 bhp/tonne.Positioned between the road going DB9 and the full race DBR9, the DBRS9 makes a racing experience more accessible to Aston Martin race enthusiasts,whilst reinforcing the DB9’s performance potential and inherent racing qualities.Aston Martin returned to international motor sport in 2005 with an exciting new programme focused on the DBR9 - a stunning GT based entirely on the road going sister car - the DB9.The DBR9 was unveiled at Aston Martin’s state-of-the-art facility at Gaydon, near Warwick on 4November 2004 finished in the same evocative shade of Aston Martin Racing Green as the Works cars of the 1950’s.Though billed as a ‘test and development year’, the DBR9 made an instant impact, taking class honours on its debut at 12 Hours of Sebring in March 2005and then winning the famous Tourist Trophy - today a round of the FIA GT Championship - at Silverstone.Aston Martin’s eagerly-anticipated return to Le Mans followed and with it came further podium success -the DBR9 shared by David Brabham, StephaneSarrazin and Darren Turner posting a top ten overall result on the car’s maiden appearance at the Sarthe circuit and finishing third in its GT1 category.Already the DBR9 is taking up where the DB3S and DBR1 left off by combining outstanding performance with the beauty and integrity of a true, thoroughbred Aston Martin.ASTON MARTIN RACINGLEFT:The DBR9 scores a winning debut at SebringThe DBRS9 race car。