Comparison and Evaluation Between MODIS Vegetation Indices in Northwest China

组间和组内比较结果的英文注释Between-Group and Within-Group Comparisons.In an analysis of variance (ANOVA), the researcher partitions the variability of a quantitative dependent variable into two sources: between-group and within-group variability.Between-Group Variability.Between-group variability refers to the variability in the dependent variable that is due to differences between the groups being compared. This variability is captured by the sum of squares between groups (SSbetween), which is calculated by subtracting the sum of squares within groups (SSwithin) from the total sum of squares (SStotal).The between-group variability can be further broken down into the variability due to the main effects of each independent variable and the variability due to theinteraction effects between the independent variables.Within-Group Variability.Within-group variability refers to the variability inthe dependent variable that is within each group being compared. This variability is captured by the sum ofsquares within groups (SSwithin), which is calculated by subtracting the sum of squares between groups (SSbetween) from the total sum of squares (SStotal).The within-group variability can be further broken down into the variability due to random error and thevariability due to individual differences within each group.Comparing Between-Group and Within-Group Variability.The ratio of between-group variability to within-group variability is known as the F-ratio. The F-ratio is used to test the statistical significance of the differences between the groups being compared.If the F-ratio is statistically significant, then it can be concluded that there is a significant difference in the dependent variable between the groups being compared.Post-Hoc Tests.If the overall ANOVA is statistically significant, then post-hoc tests can be used to determine which specific groups are different from each other. Post-hoc tests are multiple comparison procedures that control for the increased risk of Type I error that is associated with making multiple comparisons.Some of the most common post-hoc tests include:Tukey's HSD test.Scheffé's test.Bonferroni correction.Assumptions of ANOVA.The following assumptions must be met in order for ANOVA to be valid:The dependent variable is normally distributed.The variances of the dependent variable are equal across all groups.The groups are independent of each other.If these assumptions are not met, then the results of the ANOVA may be biased.Example.Suppose a researcher wants to compare the mean test scores of three different groups of students. The three groups are:Group A: Students who studied for the test for 1 hour.Group B: Students who studied for the test for 2 hours.Group C: Students who did not study for the test.The researcher conducts an ANOVA and finds that the F-ratio is statistically significant. This means that thereis a significant difference in the mean test scores of the three groups.The researcher then conducts post-hoc tests todetermine which specific groups are different from each other. The post-hoc tests show that Group A and Group Bhave significantly higher mean test scores than Group C. There is no significant difference in the mean test scoresof Group A and Group B.Conclusion.ANOVA is a powerful statistical technique that can be used to compare the means of two or more groups. By understanding the concepts of between-group and within-group variability, researchers can use ANOVA to gaininsights into the relationships between different variables.。

CERAMICSINTERNATIONALAvailable online at Ceramics International 40(2014)2047–2056Chemically modi fied boron nitride-epoxy terminated dimethylsiloxanecomposite for improving the thermal conductivityKiho Kim,Myeongjin Kim,Yongseon Hwang,Jooheon Kim nSchool of Chemical Engineering &Materials Science,Chung-Ang University,Seoul 156-756,KoreaReceived 30May 2013;received in revised form 22July 2013;accepted 24July 2013Available online 21August 2013AbstractThe thermal conductivities of composites with an epoxy-terminated dimethylsiloxane (ETDS)matrix and boron nitride (BN)powder fillers were investigated.Two surface curing agents,3-glycidoxypropyltrimethoxysilane (KBM-403)and 3-chloropropyltrimethoxysilane (KBM-703),were doped onto the surfaces of hydroxyl-functionalized boron nitride using a simple sol –gel process to act as fillers in the thermally conducting composites.These synthesized materials were embedded in epoxy resin via a solvent casting method.The surface modi fication had an appreciable effect on the thermal conductivity resulting in increased thermal conductivity up to 70wt%.The thermal conductivities of the composites containing 70wt%BN particles treated with the KBM-403and KBM-703curing agents were 4.11and 3.88W/mK,respectively,compared to 2.92W/mK for the composite without surface treatment.&2013Elsevier Ltd and Techna Group S.r.l.All rights reserved.Keywords:posites;C.Thermal conductivity;D.Nitrides;Surface treatment1.IntroductionDemands for the miniaturization and continuous perfor-mance improvements of electronic packages have led to the development of new microelectronic packaging techniques.The typical characteristics of future microelectronic packaging include high density,high frequency,and high speed [1–3].It is well known that the reliability of an electronic device is exponentially dependent on the operating temperature of the junction,whereby a small difference of the operation tempera-ture can result in a two-fold reduction of the lifespan of a device [4].Improvements of size and performance are likely to result in the generation of a greater amount of heat in a smaller volume of space.To ensure proper device operation,the unwanted heat must be removed as quickly and effectively as possible to maintain the operation temperature,suggesting that the packaging materials of the product needs to have good thermal conductivity [5,6].Epoxy resin has been widely applied in electronics,paints,electrical insulators,printed circuit boards,and packaging materials as a matrix [7,8].Unfortunately,epoxy used alone as an electronic packaging material cannot effectively dissipate the heat generated from high packing and power-density devices,given the relatively low thermal conductivity range of epoxy of 0.1–0.3W/mK.Several studies have been conducted to improve the thermal conductivity of epoxy.For example,polymers filled with thermally conductive fillers are emerging as a cost-effective means of coping with thermal management issues.Many researchers have investigated the thermal conductivity enhancement of composite materials including oxides (Al 2O 3,SiO 2,ZnO)[9–11],carbide (SiC)[12],and nitrides (AlN,BN,Si 3N 4)[13,14].The properties of these epoxy/inorganic filler composites depend on the nature of the inorganic filler including their chemical and physical composition,size,shape and dispersion in the epoxy matrix.Thermally conductive fillers,like those mentioned above,have attracted attention due to their high thermal and low electrical conductivities,while metallic particles have high thermal and electrical conductiv-ities.Among the fillers,boron nitride has been considered as/locate/ceramint0272-8842/$-see front matter &2013Elsevier Ltd and Techna Group S.r.l.All rights reserved./10.1016/j.ceramint.2013.07.117nCorresponding author.Tel.:þ8228205763.E-mail address:jooheonkim@cau.ac.kr (J.Kim).an attractive candidate due to its significantly high thermal conductivity($300W/mK),lack of toxicity,superior chemi-cal stability,electrical insulation properties,and relatively low cost.In order to obtain a higher thermal conductivity while maintaining the existing properties,filler loadings of60wt% or higher have traditionally been incorporated to form a heat conduction path in the matrix that is as continuous as possible. However,a highfiller content becomes rather inflexible with voids and cracks forming betweenfillers.Moreover,the BN/ epoxy slurry has a relatively low viscosity before drying, which facilitates the sedimentation of the BNfiller.As a result, BNfillers settle to the bottom of the compositefilm,the heat-conductive path is cut off,and the thermal conductivity decreases.In response to this issue,many studies have suggested fabrication of a surface-modified BN particle to preventfiller sedimentation[15,16].Recently,BN has been coated with a surface-curing agent to further enhance the thermal conductivity of polymer compo-sites,resulting in a reduction of sedimentation due to the lone-pair electron interaction of particle surfaces into the matrix.Gu et al.achieved a thermal conductivity of1.052W/mK using a hot disk instrument for epoxyfilled with silane-modified BN at a solid loading of60wt%[17].Yung et al.reported the effect of multi-modal particle size mixing on the formation of a thermally conductive network[18].Unfortunately,these previous experiments used nano-scale BN particles($1μm). Due to the small size of thefiller-containedfilm,heat passing through the boundary of the particles is more frequently the main cause of the phonon scattering.The diffuse boundary scattering due to the short wavelength in comparison to interface roughness of dominant phonon heat carriers not only reduces the phonon mean free path,but can also destroy the coherence of the phonons[19].Thermal resistance at particle junctions known as thermal boundary resistance or Kapitza resistance is one of the primary causes of heat transfer property reduction.In the presence of a heatflux across the boundary,this thermal resistance causes a temperature dis-continuity at the boundary.Due to the differences of the electronic and vibrational properties of various materials,an energy carrier will scatter when attempting to traverse the interface[20–22].It is known that hexagonal BN particles have a plate-like shape withflat surfaces corresponding to the basal planes of the hexagonal crystal structure.The basal plane of BN is molecularly smooth and has no surface functional groups available for chemical bonding or interactions.In contrast,the edge planes of the platelets have functional groups such as hydroxyl and amino groups.These functional groups allow the BNfiller to disperse in an organic solvent and chemically bond with other rge BN particles are significantly decreased in the edge plane areas,resulting in difficulty obtaining uniform dispersion and chemical bonding.To this end,Sato et al.employed0.7μm BN particles as a thermal conductivefiller on polyimide resin[23,24].For the effective use of micro-scale BN as afiller,another surface treatment is necessary to make the reaction site of the particle surface.In this study,a polymer matrix,dimethyl siloxane-basedepoxy,was employed to fabricate a thermally conductivecomposite and a12μm BN particle was adopted as acompositefiller to reduce phonon scattering and improve thethermal conductivity.To increase the affinity and dispersibilityof thefiller in the epoxy matrix,which is expected to provide agood thermal conductivity,two types of surface curing agentswere employed.The resulting surface curing agent-coated BNpossessed electrical insulating properties in addition toenhanced thermal conductivity due to reduced thermal resis-tance at the junction.The mechanical properties of thefabricated composites were measured and the data demon-strates that a small amount of surface curing agent enhancesthe thermal and mechanical properties.2.Experimental2.1.Synthesis of ETDSThe epoxy-terminated dimethysiloxane(ETDS)oligomerwas obtained from Shin-Etsu silicon(KF-105,equivalentweight(E.E.W)=490g/eq,density=0.99g/cm3).In ourprevious study,the weight ratio of the epoxy to the curingagent was determined to provide efficientflexibility of thematrix.In this study,the equivalent weight ratio of ETDS toDDM(4.4′-diamino diphenylmethane)was1:2.1.9g of DDMwas placed in a four-neck roundflask equipped with a refluxcondenser and was preheated to363K.9.5g of the ETDSresin was added and heated in an oil bath at363K for1hunder a N2atmosphere.The bubbles in the mixture wereremoved by placing the mixture in a vacuum oven for30minat room temperature.The mixture was then placed in an oilbath at323K for10min in a N2atmosphere.Thefinaldegassing was performed in a vacuum oven for1h at roomtemperature to remove air bubbles[25].2.2.Surface modification of BNThe detailed synthesis procedure is shown in Fig.1.First,micro-BN particles were suspended in a5M sodium hydro-xide solution at1101C for18h to attach more hydroxide ionsonto the surfaces.Because micro-BN particles have fewfunctional groups,surface treatment is necessary to facilitatechemical bonding with the surface curing agent.After basesolution dipping,the particles were rinsed with D.I.water and filtered several times to adjust the pH from basic to neutral. The micro-BN hydroxide particles were left in the furnace at801C for5h,cooled to room temperature,and then stored indesiccators.The BN particles were modified with two surface curingagents,KBM-403and KBM-703,obtained from Shin-EtsuSilicon by a sol-gel reaction.An appropriate amount of3-glycidoxypropyltrimethoxysilane(KBM-403;3–5%based onthe weight of the micro-BN particles)and3-chlorop-ropyltrimethoxysilane(KBM-703)were added to D.I.waterand stirred at501C for30min to achieve hydrolysis.Themicro-BN hydroxide particles were then dipped into theK.Kim et al./Ceramics International40(2014)2047–2056 2048resulting solution and stirred at 701C for 1h,followed by rinsing with D.I.water and filtering three times.The particles were then vacuum dried at 801C for 5h to remove the solvent.The amount of the coating solution necessary is preferably 0.05–10%by weight,based on the weight of the particles.When the amount of the coating solution is less than 0.05%by weight,there is a tendency for insuf ficient and non-uniform particle coating to occur.When the amount of the coating solution exceeds 10%by weight,the obtained particles may possess excessive thermal resistance,thereby causing a decrease of the thermal conductivity of the composite films [26].2.3.Preparation of the BN/epoxy compositesThe composites were prepared by solution blending and a casting method consisting of (a)adding surface curing agent-coated micro-BN to the ETDS epoxy resin (50,60,70wt%)for approximately 3h in N,N-dimethylformamide (DMF)until the synthesized materials were completely mixed,(b)fabricat-ing the composite films to a uniform thickness via a doctor blade on the Te flon mold,(c)pre-curing the films at 1501C for 3h until no air bubbles appeared on the surface followed by post-curing at 1801C for 5h,and (d)cooling to room temperature.2.4.CharacterizationFourier transform infrared (FT-IR;Parkin-Elmer Spectrum One)spectroscopy and X-ray photoelectron spectroscopy (XPS;VG-Microtech,ESCA2000)were employed to analyze the surface curing agent-coated BN.For FT-IR spectroscopy,the ATR mode was used to avoid the in fluences of moisture adsorbed on the potassium bromide (KBr)particles and the scans were performed using radiation in the frequency range of 400–4000cm À1.In the XPS analysis,a monochromatic Mg K αX-ray source was used at 1253.6eV and the Gaussian peak widths obtained by curve fitting were constant in each spectrum.Thermogravimetric analysis (TGA;TGA-2050,TAinstrument)of the samples was carried out to examine the thermal degradation of BN,BN-403,and BN-703.4mg of the samples were heated to 8001C at a heating rate of 101C/min under a nitrogen atmosphere.Field emission scanning electron microscopy (FE-SEM;Sigma,Carl Zeiss)was carried out to con firm the cross-sections of the component films before and after the silane treatment.The samples were sputtered with a thin layer of platinum to avoid the accumulation of charge before the FE-SEM observations.The thermal diffusivity (δ,mm 2s À1)at room temperature was measured on disk samples using a laser flash method (Netzsch Instruments Co.,Nano flash LFA 447System).The speci fic heat (C ,J g À1K À1)at room temperature was measured on disk samples via differential scanning calorimetry (DSC;Perkin-Elmer Co.,DSC-7System)and the bulk density (ρcomp ,g cm À3)of the specimens was measured using the water displacement method.The thermal conductivity (Ф,W mK À1)was calcu-lated using the following equation:Ф¼δC ρcompTo study the mechanical properties of the composite materials,mechanical analysis (DMA;Triton Instrument,Triton DMTA)was carried out.The storage modulus of the solid films was measured at a frequency of 1Hz.The temperature range was À180to 1801C with cooling and heating rates of 101C/min.3.Results and discussion3.1.Structure analysisThe chemical structures of the surface-modi fied BN were determined using Fourier transform infrared spectroscopy (FT-IR),thermogravimetric analysis (TGA),and X-ray photo-electron spectroscopy (XPS).Fig.2(a –c)shows the FT-IR spectra of pristine BN,BN-403,and BN-703,respectively.For pristine BN,the bands at 1400and 800cm À1indicate stretching vibration in the hexagonal BN.The absorption band of pristine BN at 2300–2380cm À1represents absorbed CO 2.Fig.1.Reaction scheme for the preparation of surface curing agent treated BN particle (BN-403,BN-703).K.Kim et al./Ceramics International 40(2014)2047–20562049Comparing the pristine BN and the surface curing agent-treated BN (BN-403and BN-703),the new band at 1100cm À1corresponds to stretching of the Si –O bonds,which existed in the pure surface curing agent.Detailed surface information of pristine BN,BN –OH,BN-403,and BN-703was collected by X-ray photoelectron spectroscopy (XPS)and the corresponding results are pre-sented in Fig.3.In the spectrum of pristine BN,there are only two elements of B and N.However,the O 1s signal emerges in the spectrum of BN –OH.This result implies that the hydroxyl groups were effectively introduced on the BN surfaces and edges via the sodium hydroxide treatment.These hydroxyl groups,acting as anchor sites,enabled attachment between the BN particles and surface curing agent.Moreover,the new peaks of C 1s and Si 2p can be assigned in the spectra of both BN-403and BN-703,indicating that both surface curing agents,403and 703,were successfully attached to the surface and edges of pristine BN particles.The detailed chemical bonding of fabricated,surface-treated BN particles was con firmed from the de-convoluted B 1s,Si 2p,and C 1s spectra,the results of which are shown in Fig.4.Fig.4(a and b)show the de-convoluted B 1s spectra of BN-403and BN-703,respectively.The B 1s spectra of both BN-403and BN-703showed a strong binding energy peak for the B –N bond and a weak binding energy peak for the B –OH bond at 190.4eV and 192eV,respectively [27,28].The B –OH peak resulted from the introduction of a hydroxyl group by the base treatment.In order to provide clearer evidence of chemical bonding between the BN particles and the silane curing agent,the Si 2p peak of these synthesized materials can be fitted by a curve with several component peaks.Fig.4(c and d)shows the de-convoluted Si 2p spectra of BN-403and BN-703,respectively.In the spectra of both BN-403and BN-703,the strong peak at the binding energy of 102.1eV represents the bond between silicon and oxygen originating from the BN particles (B –O –Si),indicating that the surface curing agent and BN particles are connected through the hydroxyl groups.The peak at 103.3eV is attributed to siloxane (Si –O –Si)resulting from the partial hydrolysis of the silane curing agent molecules during the silanization reaction.Moreover,the peak at 100.8eV is attributed to Si –C bonding in the silane curing agent molecules.These results are in agreement with the reaction mechanism of silane,including the hydrolysis of –OCH 3,condensation to oligomers,hydrogen bonds between oligomer and hydroxyl groups on the substrate,and the formation of the covalent linkage between silane and the substrate.The peak at 102.5eV is attributed to Si –OH bonding,indicating that some hydroxyl groups did not hydro-lyze and a small amount of hydroxyl group remained [29,30].This implies that the amount of hydroxyl groups on the BN surface was not suf ficient to make a uniform siloxane network and some hydroxyl groups in the surface curing agent were not hydrolyzed.This is due to the basal plane of the boron nitride particle surface having no functional groups.In addition,the silane coupling agent does not coat the surface uniformly such that the hydroxyl groups of the surface curing agent remained.The C 1s spectra of both BN-403and BN-703were de-convoluted to compare the structural differences of the two silane curing agents and the results are shown in Fig.4(e and f),respectively.In the spectra of both BN-403and BN-703,the strong peak at a binding energy of 284.7eV indicates the C –C bond and the weak peak at the binding energy of 283.44eV represents the C –Si bond,which exists in the surface curing agent structure.The primary difference between KBM-403and KBM-703is that KBM-403has ether and epoxide groups,whereas KBM-703has a chloride atom at the end of the carbon chain.In the C 1s spectrum of BN-403,C –O bonding is observed at a binding energy of 286.2eV,which originates from the ether and epoxide groups.However,in the case of BN-703,the peak at 285.9eV is attributed to C –Cl bonding,which can be explained by the existence of a chloride atom at the end of the carbon chain [31].Based on these results,it can be concluded that the silane treatment can effectively introduce the surface curing agent onto the surface ofBN.Fig.2.FT-IR spectra of (a)raw BN,(b)BN-403and (c)BN-703.Fig.3.X-ray photoelectron spectroscopy survey scans of (1)raw BN,(b)BN-OH,(c)BN-403,and (d)BN-703.K.Kim et al./Ceramics International 40(2014)2047–20562050Fig.4.XPS spectra of BN-403and BN-703.(a)XPS B 1s spectrum of BN-403:(b)XPS B 1s spectrum of BN-703:(c)XPS Si 2p spectrum of BN-403:(d)XPS Si 2p spectrum of BN-703;(e)XPS C 1s spectrum of BN-403:(f)XPS C 1s spectrum of BN-703.K.Kim et al./Ceramics International 40(2014)2047–20562051The compositions of the as-prepared BN,BN-403,and BN-703composites were further investigated via TGA (Fig.5).The experiments were performed up to 8001C in air at a heating rate of 101C min À1.Under these conditions,weight loss was not observed up to 8001C for pristine BN,whereas weight losses of about 4%and 3.6%were observed for BN-403and BN-703,respectively,due to thermal decomposition of the surface curing agents attached to the BN.The mass ratios of KBM-403/BN and KBM-703/BN for BN-403and BN-703were calculated to be 0.042/1and 0.037/1,respec-tively.Moreover,these ratios between BN and the surface curing agent are optimal to mix the surface curing agent-treated BN as a filler and the silane-based epoxy as a matrix [32].As reported by Itoh et al.,the surface curing agent is poorly dispersed in the particles when too little is added and the desired effect of improved crack formation resistance in the cured resin composition cannot be achieved [33].An excess of surface curing agent in the resin composition leads to a decreased thermal conductivity.This is because the redundant coupling agent causes phonon scattering and gives rise to a decreased thermal conductivity of the composites,resulting in low thermal conductivity materials.3.2.Thermal propertiesThe thermal conductivity of the composites is controlled by the intrinsic conductivities of the filler and matrix as well asthe shape,size,and loading level of the filler.Table 1shows the variations of the thermal conductivity of the BN/ETDS composites with nano-BN ($1μm),micro-BN (8μm,12μm),and a filler content ranging from 50to 70wt%.The thermal conductivity of pristine ETDS is approximately 0.2W/mK.It can be seen that as the weight fraction of these fillers increased,the thermal conductivity also increased consider-ably.With 12μm particles at loadings of 50wt%,60wt%,and 70wt%,the thermal conductivity increased by factors of 11.1,13.35,and 14.58,respectively,compared to the pure resin ($0.2W/mK).As shown for the three types of particles,the thermal conductivity is also a function of the particle size,where the results parallel the effect of the particle type.The highest thermal conductivity values were obtained from the 12μm particle-filled composites at all filler loading levels.This result can be explained by the thermal interface resistance caused by phonon boundary scattering.In theory,the scatter-ing of phonons in composite materials is primarily due to the existence of an interfacial thermal barrier from acoustic mismatch or damage of the surface layer between the filler and the rge particles tend to form fewer thermally resistant polymer-layer junctions than small particles at the same filler rge particles are therefore used as a thermal conducting filler because of their negligible phonon scattering effect and excellent thermal conductivity [34,35].In this paper,the use of a micro-filler to improve the thermal conductivity of composites was studied.The in fluence of the BN concentration and surface treatment on the thermal conductivity of BN/ETDS composites is presented in Fig.6.It can be seen that as the weight fraction of these synthesized materials increased,the calculated thermal conductivity of all of the investigated composites increased considerably.The use of surface curing agents clearly improved the thermal con-ductivities of the composites.At 12μm BN particle loadings of 50,60,and 70wt%,the thermal conductivities of the KBM-403-and KBM-703-treated BN/ETDS composites increased by factors of 1.17,1.23,and 1.41and 1.15,1.19,and 1.33compared to the untreated BN/ETDS composite,respectively.This effect could be explained by the enhanced dispersibility of particles in the composite caused by the surface curing agent.The two surface curing agents used contain an epoxide group and chloride functional groups that interact with the active groups of the epoxy matrix.Thus,the organic active groups or long molecular chains on the surface of the modi fied BN either react or entangle with the reactive groups of the epoxy matrix.The addition of surface curing agents totheFig.5.TGA thermograms of pristine BN,BN-403and BN-703.Table 1Thermal conductivity of various particle size and filler contents (W/mK).Size of BN particlesThermal conductivity at various filler concentration [W/mK]50wt%60wt%70wt%$1m m 1.49 1.67 2.158m m 2.16 2.35 2.7712m m2.322.732.92K.Kim et al./Ceramics International 40(2014)2047–20562052epoxy matrix therefore improves the interface bonding between the BN particles and matrix,leading to an enhanced thermal conductivity.In addition,this result could beexplained by the reduction of the phonon diffuse boundary scattering that constitutes a signi ficant part of the thermal resistance accompanying an imposed temperature gradient.The phonon scattering at interfaces,both for free surfaces and those bonded to other materials,observed for most real interfaces has yet to be quantitatively explained.The boundary resistance between two carefully bonded solids appears to be satisfactorily described by the acoustic impedance mismatch between the two media.The silane coupling agents acted as phonon transfer bridges between the polymer and the ceramic filler,which reduced the phonon boundary scattering and improved the thermal conductivity at low concentrations.As demonstrated in this study,the KBM-403treatment was more effective than KBM-703in enhancing the thermal conductivity.This can be explained by the ETDS/DDM polymerization mechanism.When the composite curing was performed at high temperature,epoxide groups in the ETDS react with DDM,and the ring opening and polymerization reactions proceed continuously.Similarly,epoxide groups in KBM-403react with DDM and are polymerized with ETDS.As a result,the boron nitride filler linked with the matrix through covalent bonding.However,KBM-703has a chloride group that instead forms non-covalent bonding,a dipole-dipole interaction,with the ETDS matrix.Therefore,KBM-403-Fig.6.Effect of surface treatment of BN particles on the thermal conductivity of BN/ETDS composites at various fillerconcentration.Fig.7.SEM cross section image of (a)–(b)BN/ETDS,(c)–(d)BN-403/ETDS and (e)–(f)BN-703/ETDS composites with 50wt%filler concentration.K.Kim et al./Ceramics International 40(2014)2047–20562053treated BN has a stronger interaction with the ETDS matrix along with good dispersibility and a higher thermal conduc-tivity than the KBM-703-treated BN composite.The differences in the cross-sectional images of each composite can be correlated to the existence of a silane coupling agent.Fig.7shows FE-SEM images of the cross-sections of50wt%BN/ETDS and two kinds of surface coupling agent-treated BN/ETDS compositefilms.As observed in Fig.7(a,c and e),all of the compositefilms appear to be homogeneously distributed.However,when the BN/epoxy compositefilm is observed at higher magnification (Fig.7(b)),it can be seen that the BNfiller settled to the bottom and a non-uniform distribution can be observed in the top of thefilm.This phenomenon is due to sedimentation of thefiller,which is an endemic problem of the casting method. BNfillers were well mixed for a sufficient time with the epoxy resin,maintaining goodfluidity at the high temperature,but sedimentation of thefiller progressed in the post curing step. On the other hand,the images in Fig.7(d and e)show a uniform cross-section of the silane coupling agent-treated BN, which was dispersed more uniformly and embedded in theepoxy,creating superior interface adhesion with the BN in the epoxy matrix.Uniform distribution of BN particles develops in the conduction carrier path.Moreover,BN has an idiopathic high surface energy,indicating that the phase interaction force between the epoxy and BN particles is very weak and suggesting that a low energy is needed to pull BN particles out from the matrix[36].The images in Fig.7(d and f)show an enhanced homogeneous distribution of BN particles throughout and a decrease of cracks and voids between the BN particles.This is further evidence that the surface curing agent enhanced the BN particle affinity with the matrix. Fig.7shows that the use of surface coupling agents effectively improves the homogeneous dispersion of BN particles in the epoxy,eliminates the agglomeration offiller, and decreases the void content and defects in the composites, resulting in an increased thermal conductivity.3.3.Mechanical propertiesThe mechanical properties of the composites with enhanced thermal conductivities were also measured by dynamic mechanical analysis(DMA).This was carried out to determine the improvement of the mechanical properties after the surface modification of the boron nitride particles in the polymer matrix.Since the operation temperature of the electronic package is generally about1501C,the stability of the composites was examined up to this temperature.The storage modulus of compositefilms with afiller content of70wt%is displayed in Fig.8as a function of temperature.As expected, the slopes of the curves tended to decrease near the glass temperature(T g).It can be clearly seen that the storage modulus of the composites increased withfiller surface modification,which is due to the mechanical reinforcement resulting from the strong interactions between BN and the ETDS matrix.As mentioned above,silane coupling agents improved the adhesive property between thefiller and matrix, as the stress is not well transferred when the same force is applied to the composite.The KBM-403in the composites prevented efficient treeing of the propagation of stress and,as a result,the storage modulus could be improved where the modulus of the KBM-403treated with the BN composite was higher than that of the KBM-703-treated BN composite. The tanδpeak position,which is a measure of the glass transition temperature(T g),shifted to higher temperatures with surface modification.The peak height was reduced when compared to that of the surface-untreated BN composite because the well dispersedfiller and sufficient incorporation of epoxy restricted the mobility of the epoxy chains,resulting in the higher mechanical properties observed for the surface-treated BN composites.4.ConclusionBN/epoxy compositefilms with different BN particle sizes and contents were successfully fabricated with a surface curing agent using a solvent casting method.The thermal conductiv-ities of polymer compositesfilled with various types of particles were evaluated and the thermal interface resistance theory was applied.Various particle tofiller ratios were tested and the12μmfiller demonstrated a higher performance,in the range of136–149%,than the nano-sizefiller($1μm). Furthermore,by applying micro-sized particles,the formation of conductive networks was maximized while minimizing the thermal interface resistance along the heatflow path.This thermal interface resistance is caused by phonon scattering in the interface of materials,which is the primary cause of decreased thermalconductivity.Fig.8.Storage modulus of ETDS and ETDS composites with70wt%filler concentration.K.Kim et al./Ceramics International40(2014)2047–2056 2054。

1.To access the description of a composite material, it will be necessary to specify the nature of components and their properties, the geometry of the reinforcement, its distribution, and the nature of the reinforcement–matrix interface.2. However, most of them are not chemically compatible with polymers3. That’s why for many years, studies have been conducted on particles functionalization to modulate the physical and/or chemical properties and to improve the compatibility between the filler and the matrix [7].4. Silica is used in a wide range of products including tires, scratch-resistant coatings, toothpaste,medicine, microelectronics components or in the building5. Fracture surface of test specimens were observed by scanning electron microscopy6.Test specimens were prepared by the following method from a mixture composed with 40 wt% UPE, 60 wt% silica Millisil C6 and components of ‘‘Giral.’7.Grafted or adsorbed component amounts on modified silica samples were assessed by thermogravimetric analysis (TGA) using a TGA METTLER-TOLEDO 851e thermal system. For the analysis, about 10–20 mg of samples were taken and heated at a constant rate of 10 C/min under air (purge rate 50 mL/min) from 30 to 1,100 C.8.Nanocomposites with different concentrations of nanofibers wereproduced and tested, and their properties were compared with those of the neat resin.9.Basically, six different percentages were chosen, namely 0.1, 0.3, 0.5, 1, 2, 3 wt %.10.TEM images of cured blends were obtained with a Philips CM120 microscope applying an acceleration voltage of 80 kV.Percolation threshold of carbon nanotubes filled unsaturated polyesters 11.For further verification, the same experiment was carried out for the unmodified UP resin, and the results showed that there were no endothermic peaks12.The MUP resin was checked with d.s.c, scanning runs at a heating rate of 10°C min 1. Figure 4a shows that an endothermic peak appeared from 88 to 133°C, which indicates bond breaking in that temperature range.13.On the basis of these results, it is concluded that a thermally breakable bond has been introduced into the MUP resin and that the decomposition temperature is around I lO°C.14.The structures of the UP before and after modification were also checked with FTi.r. Figure 5 shows a comparison of the i.r. spectra of the unmodified and modified UP resins.15This is probably a result of the covalent bonding ofthe urethane linkage being stronger than the ionic bondingof MgO.16.These examples show that different viscosity profiles can be designed with different combinations of the resins and thickeners according to the needs of the applications.17. A small secondary reaction peak occurred at higher temperatures, probably owing to thermally induced polymerization. 18.Fiber-reinforced composite materials consist of fibers of high strength and modulus embedded in or bonded to a matrix with a distinct interfaces between them.19.In this form, both fibers and ma-trix retain their physical and chemical identities,yet they provide a combination of properties that cannot be achieved with either of the constituents acting alone.20.In general, fibers are the principal load-bearing materials, while the surrounding matrix keep them in the desired location, and orientation acts as a load transfer medium between them and protects them from environmental damage.21.Moreover, both the properties, that is,strength and stiffness can be altered according to our requirement by altering the composition of a single fiber–resin combination.22.Again, fiber-filled composites find uses in innumerable applied ar- eas by judicious selection of both fiber and resin.23.In recent years, greater emphasis has been rendered in the development of fiber-filled composites based on natural fibers with a view to replace glass fibers either solely or in part for various applications. 24.The main reasons of the failure are poor wettability and adhesion characteristics of the jute fiber towards many commercial synthetic resins, resulting in poor strength and stiffness of the composite as well as poor environmental resistance.25.Therefore, an attempt has been made to overcome the limitations of the jute fiber through its chemical modification.26.Dynamic mechanical tests, in general, give more information about a composite material than other tests. Dynamic tests, over a wide range of temperature and frequency, are especially sensitive to all kinds of transitions and relaxation process of matrix resin and also to the morphology of the composites.27.Dynamic mechanical analysis (DMA) is a sensitive and versatile thermal analysis technique, which measures the modulus (stiffness) and damping properties (energy dissipation) of materials as the materials are deformed under periodic stress.28.he object of the present article is to study the effect of chemical modification (cyanoethylation)of the jute fiber for improving its suitability as a reinforcing material in the unsaturated polyesterres in based composite by using a dynamic mechanical thermal analyzer.30.General purpose unsaturated polyester resin(USP) was obtained from M/S Ruia Chemicals Pvt. Ltd., which was based on orthophthalic anhydride, maleic anhydride, 1,2-propylene glycol,and styrene.The styrene content was about 35%.Laboratory reagentgrade acrylonitrile of S.D.Fine Chemicals was used in this study without further purification. 31.Tensile and flexural strength of the fibers an d the cured resin were measured by Instron Universal Testing Machine (Model No. 4303).32.Test samples (60 3 11 3 3.2 mm) were cut from jute–polyester laminated sheets and were postcured at 110°C for 1 h and conditionedat 65% relative humidity (RH) at 25°C for 15 days.33.In DMA, the test specimen was clamped between the ends of two parallel arms, which are mounted on low-force flexure pivots allowing motion only in the horizontal plane. The samples in a nitrogen atmosphere were measured in the fixed frequency mode, at an operating frequency 1.0 HZ (oscillation amplitude of 0.2 mm) and a heating rate of 4°C per min. The samples were evaluated in the temperature range from 40 to 200°C.34.In the creep mode of DMA, the samples were stressed for 30 min at an initial temperature of 40°C and allowed to relax for 30 min. The tem- perature was then increased in the increments of 40°C, followed by an equilibrium period of 10min before the initiation of the next stress relax cycle. This program was continued until it reached the temperature of160°C. All the creep experiments were performed at stress level of20 KPa (approximate).35.The tensile fracture surfaces of the composite samples were studied with a scanning electron microscope (Hitachi Scanning electron Microscope, Model S-415 A) operated at 25 keV.36.The much im proved moduli of the five chemically modified jute–polyester composites might be due to the greater interfacial bond strength between the ma trix resin and the fiber.37.The hydrophilic nature of jute induces poor wettability and adhesion characteristics with USP resin, and the presence of moisture at the jute–resin interface promotes the formation of voids at the interface. 38.On the other hand, owing to cyanoethylation, the moisture regain capacity of the jute fiber is much reduced; also, the compatibility with unsaturated polyester resin has been improved and produces a strong interfacial bond with matrix resin and produces a much stiffer composite.39.Graphite nanosheets(GN), nanoscale conductive filler has attracted significant attention, due to its abundance in resource and advantage in forming conducting network in polymer matrix40.The percolation threshold is greatly affected by the properties of the fillers and the polymer matrices,processing met hods, temperature, and other related factors41.Preweighted unsaturated polyester resin and GN were mixed togetherand sonicated for 20 min to randomly disperse the inclusions.42.Their processing involves a radical polymerisation between a prepolymer that contains unsaturated groups and styrene that acts both asa diluent for the prepolymer and as a cross-linking agent.43.They are used, alone or in fibre-reinforced composites, in naval constructions, offshore applications,water pipes, chemical containers, buildings construction, automotive, etc.44.Owing to the high aspect ratio of the fillers, the mechanical, thermal, flame retardant and barrier properties of polymers may be enhanced without a significant loss of clarity, toughness or impact strength.45.The peak at 1724 cm-1was used as an internal reference, while the degree of conversion for C=C double bonds in the UP chain was determined from the peak at 1642 cm-1and the degree of conversion for styrene was calculated through the variation of the 992 cm-1peak46. Paramount to this scientific analysis is an understanding of the chemorheology of thermosets.47．Although UPR are used as organic coatings, they suffer from rigidity, low acid and alkali resistances and low adhesion with steel when cured with c onventional ‘‘small molecule’’ reagents.48．Improvements of resin flexibility can be obtained by incorporating long chain aliphatic com-pounds into the chemical structure of UPR. 47．In this study, both UPR and hardeners were based on aliphatic andcycloaliphatic systems to produce cured UPR, which have good durability with excellent mechan-ical properties.50．UPR is one of the widely used thermoset polymers in polymeric composites, due to their good mechanical properties and relatively inexpensive prices.51．[文档可能无法思考全面，请浏览后下载，另外祝您生活愉快，工作顺利，万事如意!]。

doi:10.3969/j.issn.1009-881X.2020.03.004经皮椎间孔镜与改良PLIF手术治疗老年性腰椎管狭窄症的疗效比较黄群，朱现玮，严飞，徐炜，徐沁，周志平（苏州大学附属张家港医院，江苏张家港 215600）摘要：目的比较经皮椎间孔镜下减压术与改良后路减压融合内固定术在治疗老年性腰椎管狭窄症的临床疗效。

方法回顾分析78 例获得完整随访的老年性腰椎管狭窄症患者的治疗情况。

根据手术方法患者分为2组，开放手术组：40 例行改良后路减压融合内固定术（改良PLIF），微创手术组：38 例行经皮椎间孔镜下减压术。

记录两组患者围手术期观察指标、视觉疼痛模拟评分（visual analogue scale, V AS）、Oswestry功能障碍指数（Oswestry disability index, ODI）和改良Macnab 疗效评定标准对手术疗效进行评估。

结果微创手术组患者手术时间、切口长度、术中出血量、住院时间及术后并发症发生率明显优于开放手术组，差异具有统计学意义（P＜0.05）。

微创手术组手术优良率（89.47%）明显优于开放手术组（80.00%），差异具有统计学意义（P＜0.05）。

随访结果显示微创手术组术后各时间段V AS评分、ODI评分均优于开放手术组，差异具有统计学意义（P＜0.05）。

术后1 年两组患者VAS评分、ODI评分差异无统计学意义（P＞0.05）。

结论对于老年性腰椎管狭窄症患者，经皮椎间孔镜技术能够取得与改良PLIF手术相似的临床效果，但经皮椎间孔镜技术在手术时间、切口长度、术中出血量、住院时间、术后并发症等方面具有明显优势，并且对脊柱稳定性影响较小，症状改善明显，术后恢复较快，疗效确切。

但在临床应用上，需要严格把握手术适应证。

关键词：腰椎管狭窄症；经皮椎间孔镜；后路减压融合内固定；老年中图分类号：R687.3 文献标识码：A 文章编号：1009-881X(2020)03-0287-06 Comparison of the Efficacy of Percutaneous Interforamoscopy and Modified PLIF in the Treatment of Senile Lumbar Spinal StenosisHUANG Qun, ZHU Xian-wei, YAN Fei, XU Wei, XU Qin, ZHOU Zhi-ping(Zhangjiagang Hospital Affiliated to Soochow University, Zhangjiagang, Jiangsu, 215600, China) Abstract：Objective To compare the clinical efficacy of percutaneous endoscopic discectomy and posterior decompression fusion internal fixation in the treatment of senile lumbar spinal stenosis. Methods A retrospective analysis was made on the treatment of 78 cases of senile lumbar spinal stenosis with complete follow-up. The patients were divided into 2 groups according to the surgical method. In open surgery group, 40 patients underwent the posterior decompression fusion internal fixation (improved PLIF); in minimally invasive surgery group, 38 patients underwent percutaneous endoscopic discectomy. Perioperative observation indicators, visual analogue scale (V AS), Oswestry disability index (ODI) and modified Macnab efficacy evaluation criteria were recorded to evaluate the surgical efficacy of the two groups. Results The operative time, incision length, intraoperative blood loss, length of stay and incidence of postoperative complications in the minimally invasive surgery group were significantly better than those in the open surgery group, with statistically significant differences (P＜0.05). The 基金项目：国家自然科学基金资助项目(81874008)收稿日期：2020-04-25 作者简介：黄群(1988—),男,江苏南通人,硕士,主治医师,研究方向:慢性脊柱退行性疾病。

八年级英语议论文论证方法单选题40题1. In the essay, the author mentions a story about a famous scientist to support his idea. This is an example of _____.A.analogyB.exampleparisonD.metaphor答案：B。

本题主要考查论证方法的辨析。

选项A“analogy”是类比；选项B“example”是举例；选项C“comparison”是比较；选项D“metaphor”是隐喻。

文中提到一个关于著名科学家的故事来支持观点，这是举例论证。

2. The writer uses the experience of his own life to prove his point. This kind of method is called _____.A.personal storyB.example givingC.case studyD.reference答案：B。

选项A“personal story”个人故事范围较窄；选项B“example giving”举例；选项C“case study”案例分析；选项D“reference”参考。

作者用自己的生活经历来证明观点，这是举例论证。

3. The author cites several historical events to strengthen his argument. What is this method?A.citing factsB.giving examplesC.making comparisonsing analogies答案：B。

选项A“citing facts”引用事实，历史事件可以作为例子，所以是举例论证；选项B“giving examples”举例；选项C“making comparisons”比较；选项D“using analogies”使用类比。

Bull Earthquake Eng(2008)6:645–675DOI10.1007/s10518-008-9078-1ORIGINAL RESEARCH PAPERNumerical analyses of fault–foundation interactionI.Anastasopoulos·A.Callerio·M.F.Bransby·M.C.R.Davies·A.El Nahas·E.Faccioli·G.Gazetas·A.Masella·R.Paolucci·A.Pecker·E.RossignolReceived:22October2007/Accepted:14July2008/Published online:17September2008©Springer Science+Business Media B.V.2008Abstract Field evidence from recent earthquakes has shown that structures can be designed to survive major surface dislocations.This paper:(i)Describes three differentfinite element(FE)methods of analysis,that were developed to simulate dip slip fault rupture propagation through soil and its interaction with foundation–structure systems;(ii)Validates the developed FE methodologies against centrifuge model tests that were conducted at the University of Dundee,Scotland;and(iii)Utilises one of these analysis methods to conduct a short parametric study on the interaction of idealised2-and5-story residential structures lying on slab foundations subjected to normal fault rupture.The comparison between nume-rical and centrifuge model test results shows that reliable predictions can be achieved with reasonably sophisticated constitutive soil models that take account of soil softening after failure.A prerequisite is an adequately refined FE mesh,combined with interface elements with tension cut-off between the soil and the structure.The results of the parametric study reveal that the increase of the surcharge load q of the structure leads to larger fault rupture diversion and“smoothing”of the settlement profile,allowing reduction of its stressing.Soil compliance is shown to be beneficial to the stressing of a structure.For a given soil depthH and imposed dislocation h,the rotation θof the structure is shown to be a function of:I.Anastasopoulos(B)·G.GazetasNational Technical University,Athens,Greecee-mail:ianast@civil.ntua.grA.Callerio·E.Faccioli·A.Masella·R.PaolucciStudio Geotecnico Italiano,Milan,ItalyM.F.BransbyUniversity of Auckland,Auckland,New ZealandM.C.R.Davies·A.El NahasUniversity of Dundee,Dundee,UKA.Pecker·E.RossignolGeodynamique et Structure,Paris,France123(a)its location relative to the fault rupture;(b)the surcharge load q;and(c)soil compliance.Keywords Fault rupture propagation·Soil–structure-interaction·Centrifuge model tests·Strip foundation1IntroductionNumerous cases of devastating effects of earthquake surface fault rupture on structures were observed in the1999earthquakes of Kocaeli,Düzce,and Chi-Chi.However,examples of satisfactory,even spectacular,performance of a variety of structures also emerged(Youd et al.2000;Erdik2001;Bray2001;Ural2001;Ulusay et al.2002;Pamuk et al.2005).In some cases the foundation and structure were quite strong and thus either forced the rupture to deviate or withstood the tectonic movements with some rigid-body rotation and translation but without damage(Anastasopoulos and Gazetas2007a,b;Faccioli et al.2008).In other cases structures were quite ductile and deformed without failing.Thus,the idea(Duncan and Lefebvre1973;Niccum et al.1976;Youd1989;Berill1983)that a structure can be designed to survive with minimal damage a surface fault rupture re-emerged.The work presented herein was motivated by the need to develop quantitative understan-ding of the interaction between a rupturing dip-slip(normal or reverse)fault and a variety of foundation types.In the framework of the QUAKER research project,an integrated approach was employed,comprising three interrelated steps:•Field studies(Anastasopoulos and Gazetas2007a;Faccioli et al.2008)of documented case histories motivated our investigation and offered material for calibration of the theoretical methods and analyses,•Carefully controlled geotechnical centrifuge model tests(Bransby et al.2008a,b)hel-ped in developing an improved understanding of mechanisms and in acquiring a reliable experimental data base for validating the theoretical simulations,and•Analytical numerical methods calibrated against the abovefield and experimental data offered additional insight into the nature of the interaction,and were used in developing parametric results and design aids.This paper summarises the methods and the results of the third step.More specifically: (i)Three differentfinite element(FE)analysis methods are presented and calibratedthrough available soil data.(ii)The three FE analysis methods are validated against four centrifuge experiments con-ducted at the University of Dundee,Scotland.Two experiments are used as a benchmark for the“free-field”part of the problem,and two more for the interaction of the outcrop-ping dislocation with rigid strip foundations.(iii)One of these analysis methods is utilised in conducting a short parametric study on the interaction of typical residential structures with a normal fault rupture.The problem studied in this paper is portrayed in Fig.1.It refers to a uniform cohesionless soil deposit of thickness H at the base of which a dip-slip fault,dipping at angle a(measured from the horizontal),produces downward or upward displacement,of vertical component h.The offset(i.e.,the differential displacement)is applied to the right part of the model quasi-statically in small consecutive steps.123hx O:“f o c u s ”O ’:“e p i c e n t e r ”Hanging wallFootwallyLW –LW hx O:“fo c u s ”O ’:“e p i c e n t e r ”Hanging wallFootwallyL W –LWq BStrip Foundation s(a )(b)Fig.1Definition and geometry of the studied problem:(a )Propagation of the fault rupture in the free field,and (b )Interaction with strip foundation of width B subjected to uniform load q .The left edge of the foundation is at distance s from the free-field fault outcrop2Centrifuge model testingA series of centrifuge model tests have been conducted in the beam centrifuge of the University of Dundee (Fig.2a)to investigate fault rupture propagation through sand and its in-teraction with strip footings (Bransby et al.2008a ,b ).The tests modelled soil deposits of depth H ranging from 15to 25m.They were conducted at accelerations ranging from 50to 115g.A special apparatus was developed in the University of Dundee to simulate normal and reverse faulting.A central guidance system and three aluminum wedges were installed to impose displacement at the desired dip angle.Two hydraulic actuators were used to push on the side of a split shear box (Fig.2a)up or down,simulating reverse or normal faulting,respectively.The apparatus was installed in one of the University of Dundee’s centrifuge strongboxes (Fig.2b).The strongbox contains a front and a back transparent Perspex plate,through which the models are monitored in flight.More details on the experimental setup can be found in Bransby et al.(2008a ).Displacements (vertical and horizontal)at different123Fig.2(a)The geotechnicalcentrifuge of the University ofDundee;(b)the apparatus for theexperimental simulation of faultrupture propagation through sandpositions within the soil specimen were computed through the analysis of a series of digital images captured as faulting progressed using the Geo-PIV software(White et al.2003).Soil specimens were prepared within the split box apparatus by pluviating dry Fontainebleau sand from a specific height with controllable massflow rate.Dry sand samples were prepared at relative densities of60%.Fontainebleau sand was used so that previously published laboratory element test data(e.g Gaudin2002)could be used to select drained soil parameters for thefinite element analyses.The experimental simulation was conducted in two steps.First,fault rupture propagation though soil was modelled in the absence of a structure(Fig.1a),representing the free-field part of the problem.Then,strip foundations were placed at a pre-specified distance s from the free-field fault outcrop(Fig.1b),and new tests were conducted to simulate the interaction of the fault rupture with strip foundations.3Methods of numerical analysisThree different numerical analysis approaches were developed,calibrated,and tested.Three different numerical codes were used,in combination with soil constitutive models ranging from simplified to more sophisticated.This way,three methods were developed,each one corresponding to a different level of sophistication:(a)Method1,using the commercial FE code PLAXIS(2006),in combination with a simplenon-associated elastic-perfectly plastic Mohr-Coulomb constitutive model for soil; 123Foundation : 2-D Elastic Solid Elements Elastic BeamElementsInterfaceElements hFig.3Method 1(Plaxis)finite element diecretisation(b)Method 2,utilising the commercial FE code ABAQUS (2004),combined with a modifiedMohr-Coulomb constitutive soil model taking account of strain softening;and(c)Method 3,making use of the FE code DYNAFLOW (Prevost 1981),along with thesophisticated multi-yield constitutive model of Prevost (1989,1993).Centrifuge model tests that were conducted in the University of Dundee were used to validate the effectiveness of the three different numerical methodologies.The main features,the soil constitutive models,and the calibration procedure for each one of the three analysis methodologies are discussed in the following sections.3.1Method 13.1.1Finite element modeling approachThe first method uses PLAXIS (2006),a commercial geotechnical FE code,capable of 2D plane strain,plane stress,or axisymmetric analyses.As shown in Fig.3,the finite element mesh consists of 6-node triangular plane strain elements.The characteristic length of the elements was reduced below the footing and in the region where the fault rapture is expected to propagate.Since a remeshing technique (probably the best approach when dealing with large deformation problems)is not available in PLAXIS ,at the base of the model and near the fault starting point,larger elements were introduced to avoid numerical inaccuracies and instability caused by ill conditioning of the element geometry during the displacement application (i.e.node overlapping and element distortion).The foundation system was modeled using a two-layer compound system,consisting of (see Fig.3):•The footing itself,discretised by very stiff 2D elements with linear elastic behaviour.The pressure applied by the overlying building structure has been imposed to the models through the self weight of the foundation elements.123Fig.4Method1:Calibration of constitutive model parameters utilising the FE code Tochnog;(a)oedometer test;(b)Triaxial test,p=90kPa•Beam elements attached to the nodes at the bottom of the foundation,with stiffness para-meters lower than those of the footing to avoid a major stiffness discontinuity between the underlying soil and the foundation structure.•The beam elements are connected to soil elements through an interface with a purely frictional behaviour and the same friction angleϕwith the soil.The interface has a tension cut-off,which causes a gap to develop between soil and foundation in case of detachment. Due to the large imposed displacement reached during the centrifuge tests(more than3m in several cases),with a relative displacement of the order of10%of the modeled soil height, the large displacement Lagrangian description was adopted.After an initial phase in which the geostatic stresses were allowed to develop,the fault displacement has been monotonically imposed both on the right side and the right bottom boundaries,while the remaining boundaries of the model have beenfixed in the direction perpendicular to the side(Fig.3),so as to reproduce the centrifuge test boundary conditions.3.1.2Soil constitutive model and calibrationThe constitutive model adopted for all of the analyses is the standard Mohr-Coulomb for-mulation implemented in PLAXIS.The calibration of the elastic and strength parameters of the soil had been conducted during the earlier phases of the project by means of the FEM code Tochnog(see the developer’s home page ),adopting a rather refined and user-defined constitutive model for sand.This model was calibrated with a set of experimental data available on Fontainebleau sand(Gaudin2002).Oedometer tests (Fig.4a)and drained triaxial compression tests(Fig.4b)have been simulated,and sand model parameters were calibrated to reproduce the experimental results.The user-defined model implemented in Tochnog included a yielding function at the critical state,which corresponds to the Mohr-Coulomb failure criterion.A subset of those parameters was then utilised in the analysis conducted using the simpler Mohr-Coulomb model of PLAXIS:•Angle of frictionϕ=37◦•Young’s Modulus E=675MPa•Poisson’s ratioν=0.35•Angle of Dilationψ=0◦123hFoundation : Elastic Beam ElementsGap Elements Fig.5Method 2(Abaqus)finite element diecretisationThe assumption of ψ=0and ν=0.35,although not intuitively reasonable,was proven to provide the best fit to experimental data,both for normal and reverse faulting.3.2Method 23.2.1Finite element modeling approachThe FE mesh used for the analyses is depicted in Fig.5(for the reverse fault case).The soil is now modelled with quadrilateral plane strain elements of width d FE =1m.The foun-dation,of width B ,is modelled with beam elements.It is placed on top of the soil model and connected through special contact (gap)elements.Such elements are infinitely stiff in compression,but offer no resistance in tension.In shear,their behaviour follows Coulomb’s friction law.3.2.2Soil constitutive modelEarlier studies have shown that soil behaviour after failure plays a major role in problems related to shear-band formation (Bray 1990;Bray et al.1994a ,b ).Relatively simple elasto-plastic constitutive models,with Mohr-Coulomb failure criterion,in combination with strain softening have been shown to be effective in the simulation of fault rupture propagation through soil (Roth et al.1981,1982;Loukidis 1999;Erickson et al.2001),as well as for modelling the failure of embankments and slopes (Potts et al.1990,1997).In this study,we apply a similar elastoplastic constitutive model with Mohr-Coulomb failure criterion and isotropic strain softening (Anastasopoulos 2005).Softening is introduced by reducing the mobilised friction angle ϕmob and the mobilised dilation angle ψmob with the increase of plastic octahedral shear strain:123ϕmob=ϕp−ϕp−ϕresγP fγP oct,for0≤γP oct<γP fϕres,forγP oct≥γP f(1)ψmob=⎧⎨⎩ψp1−γP octγP f,for0≤γP oct<γP fψres,forγP oct≥γP f⎫⎬⎭(2)whereϕp andϕres the ultimate mobilised friction angle and its residual value;ψp the ultimate dilation angle;γP f the plastic octahedral shear strain at the end of softening.3.2.3Constitutive model calibrationConstitutive model parameters are calibrated through the results of direct shear tests.Soil response can be divided in four characteristic phases(Anastasopoulos et al.2007):(a)Quasi-elastic behavior:The soil deforms quasi-elastically(Jewell and Roth1987),upto a horizontal displacementδx y.(b)Plastic behavior:The soil enters the plastic region and dilates,reaching peak conditionsat horizontal displacementδx p.(c)Softening behavior:Right after the peak,a single horizontal shear band develops(Jewelland Roth1987;Gerolymos et al.2007).(d)Residual behavior:Softening is completed at horizontal displacementδx f(δy/δx≈0).Then,deformation is accumulated along the developed shear band.Quasi-elastic behaviour is modelled as linear elastic,with secant modulus G S linearly incre-asing with depth:G S=τyγy(3)whereτy andγy:the shear stress and strain atfirst yield,directly measured from test data.After peak conditions are reached,it is assumed that plastic shear deformation takes placewithin the shear band,while the rest of the specimen remains elastic(Shibuya et al.1997).Scale effects have been shown to play a major role in shear localisation problems(Stone andMuir Wood1992;Muir Wood and Stone1994;Muir Wood2002).Given the unavoidableshortcomings of the FE method,an approximate simplified scaling method(Anastasopouloset al.2007)is employed.The constitutive model was encoded in the FE code ABAQUS(2004).Its capability toreproduce soil behaviour has been validated through a series of FE simulations of the directshear test(Anastasopoulos2005).Figure6depicts the results of such a simulation of denseFontainebleau sand(D r≈80%),and its comparison with experimental data by Gaudin (2002).Despite its simplicity and(perhaps)lack of generality,the employed constitutivemodel captures the predominant mode of deformation of the problem studied herein,provi-ding a reasonable simplification of complex soil behaviour.3.3Method33.3.1Finite element modeling approachThefinite element model used for the analyses is shown for the normal fault case in Fig.7.The soil is modeled with square,quadrilateral,plane strain elements,of width d FE=0.5m. 123Fig.6Method 2:Calibration ofconstitutive model—comparisonbetween laboratory direct sheartests on Fontainebleau sand(Gaudin 2002)and the results ofthe constitutive modelx D v3.3.2Soil constitutive ModelThe constitutive model is the multi-yield constitutive model developed by Prevost (1989,1993).It is a kinematic hardening model,based on a relatively simple plasticity theory (Prevost 1985)and is applicable to both cohesive and cohesionless soils.The concept of a “field of work-hardening moduli”(Iwan 1967;Mróz 1967;Prevost 1977),is used by defining a collection f 0,f 1,...,f n of nested yield surfaces in the stress space.V on Mises type surfaces are employed for cohesive materials,and Drucker-Prager/Mohr-Coulomb type surfaces are employed for frictional materials (sands).The yield surfaces define regions of constant shear moduli in the stress space,and in this manner the model discretises the smooth elastic-plastic stress–strain curve into n linear segments.The outermost surface f n represents a failure surface.In addition,accounting for experimental evidence from tests on frictional materials (de 1987),a non-associative plastic flow rule is used for the dilatational component of the plastic potential.Finally,the material hysteretic behavior and shear stress-induced anisotropic effects are simulated by a kinematic rule .Upon contact,the yield surfaces are translated in the stress space by the stress point,and the direction of translation is selected such that the yield surfaces do not overlap,but remain tangent to each other at the stress point.3.3.3Constitutive model parametersThe required constitutive parameters of the multi-yield constitutive soil model are summari-sed as follows (Popescu and Prevost 1995):a.Initial state parameters :mass density of the solid phase ρs ,and for the case of porous saturated media,porosity n w and permeability k .b.Low strain elastic parameters :low strain moduli G 0and B 0.The dependence of the moduli on the mean effective normal stress p ,is assumed to be of the following form:G =G 0 p p 0 n B =B 0 p p 0n (4)and is accounted for,by introducing two more parameters:the power exponent n and the reference effective mean normal stress p 0.c.Yield and failure parameters :these parameters describe the position a i ,size M i and plastic modulus H i ,corresponding to each yield surface f i ,i =0,1,...n .For the case of pressure sensitive materials,a modified hyperbolic expression proposed by Prevost (1989)and Griffiths and Prévost (1990)is used to simulate soil stress–strain relations.The necessary parameters are:(i)the initial gradient,given by the small strain shear modulus G 0,and (ii)the stress (function of the friction angle at failure ϕand the stress path)and strain,εmax de v ,levels at failure.Hayashi et al.(1992)improved the modified hyperbolic model by introducing a new parameter—a —depending on the maximum grain size D max and uniformity coefficient C u .Finally,the coefficient of lateral stress K 0is necessary to evaluate the initial positions a i of the yield surfaces.d.Dilation parameters :these are used to evaluate the volumetric part of the plastic potentialand consist of:(i)the dilation (or phase transformation)angle ¯ϕ,and (ii)the dilation parameter X pp ,which is the scale parameter for the plastic dilation,and depends basically on relative density and sand type (fabric,grain size).With the exception of the dilation parameter,all the required constitutive model parameters are traditional soil properties,and can be derived from the results of conventional laboratory 123Table1Constitutive model parameters used in method3Number of yield surfaces20Power exponent n0.5Shear modulus G at stress p1 (kPa)75,000Bulk modulus at stress p1(kPa)200,000Unit massρ(t.m−3) 1.63Cohesion0 Reference mean normal stressp1(kPa)100Lateral stress coefficient(K0)0.5Dilation angle in compression (◦)31Dilation angle in extension(◦)31Ultimate friction angle in compression(◦)41.8Ultimate friction angle inextension(◦)41.8Dilation parameter X pp 1.65Max shear strain incompression0.08Max shear strain in extension0.08Generation coefficient in compressionαc 0.098Generation coefficient inextensionαe0.095Generation coefficient in compressionαlc 0.66Generation coefficient inextensionαle0.66Generation coefficient in compressionαuc 1.16Generation coefficient inextensionαue1.16(e.g.triaxial,simple shear)and in situ(e.g.cone penetration,standard penetration,wave velocity)soil tests.The dilational parameter can be evaluated on the basis of results of liquefaction strength analysis,when available;further details can be found in Popescu and Prevost(1995)and Popescu(1995).Since in the present study the sand material is dry,the cohesionless material was modeled as a one-phase material.Therefore neither the soil porosity,n w,nor the permeability,k,are needed.For the shear stress–strain curve generation,given the maximum shear modulus G1,the maximum shear stressτmax and the maximum shear strainγmax,the following functional relationship has been chosen:For y=τ/τmax and x=γ/γr,withγr=τmax/G1,then:y=exp(−ax)f(x,x l)+(1−exp(−ax))f(x,x u)where:f(x,x i)=(2x/x i+1)x i−1/(2x/x i+1)x i+1(5)where a,x l and x u are material parameters.For further details,the reader is referred to Hayashi et al.(1992).The constitutive model is implemented in the computer code DYNAFLOW(Prevost1981) that has been used for the numerical analyses.3.3.4Calibration of model constitutive parametersTo calibrate the values of the constitutive parameters,numerical triaxial tests were simulated with DYNAFLOW at three different confining pressures(30,60,90kPa)and compared with the results of available physical tests conducted on the same material at the same confining pressures.The parameters are defined based on the shear stress versus axial strain curve and volumetric strain versus axial strain curve.Figure8illustrates the comparisons between numerical simulations and physical tests in terms of volumetric strain and shear stress versus123Table2Summary of main attributes of the centrifuge model testsTest Faulting B(m)q(kPa)s(m)g-Level a D r(%)H(m)L(m)W(m)h max(m) 12Normal Free—field11560.224.775.723.53.1528Reverse Free—field11560.815.175.723.52.5914Normal10912.911562.524.675.723.52.4929Reverse10919.211564.115.175.723.53.30a Centrifugal accelerationFig.9Test12—Free-field faultD r=60%Fontainebleau sand(α=60◦):Comparison ofnumerical with experimentalvertical displacement of thesurface for bedrock dislocationh=3.0m(Method1)and2.5m(Method2)[all displacements aregiven in prototype scale]Structure Interaction(FR-SFSI):(i)Test14,normal faulting at60◦;and(ii)Test29,reverse faulting at60◦.In this case,the comparison is conducted for all of the developed numerical analysis approaches.The main attributes of the four centrifuge model tests used for the comparisons are syn-opsised in Table2,while more details can be found in Bransby et al.(2008a,b).4.1Free-field fault rupture propagation4.1.1Test12—normal60◦This test was conducted at115g on medium-loose(D r=60%)Fontainebleau sand,simu-lating normal fault rupture propagation through an H=25m soil deposit.The comparison between analytical predictions and experimental data is depicted in Fig.9in terms of vertical displacement y at the ground surface.All displacements are given in prototype scale.While the analytical prediction of Method1is compared with test data for h=3.0m,in the case of Method2the comparison is conducted at slightly lower imposed bedrock displacement: h=2.5m.This is due to the fact that the numerical analysis with Method2was conducted without knowing the test results,and at that time it had been agreed to set the maximum displacement equal to h max=2.5m.However,when test results were publicised,the actually attained maximum displacement was larger,something that was taken into account in the analyses with Method1.As illustrated in Fig.9,Method2predicts almost correctly the location of fault out-cropping,at about—10m from the“epicenter”,with discrepancies limited to1or2m.The deformation can be seen to be slightly more localised in the centrifuge test,but the comparison between analytical and experimental shear zone thickness is quite satisfactory.The vertical displacement profile predicted by Method1is also qualitatively acceptable.However,the123Method 2Centrifuge Model TestR1S1Method 1(a )(b)(c)Fig.10Test 12—-Normal free-field fault rupture propagation through H =25m D r =60%Fontainebleau sand:Comparison of (a )Centrifuge model test image,compared to FE deformed mesh with shear strain contours of Method 1(b ),and Method 2(c ),for h =2.5mlocation of fault rupture emergence is a few meters to the left compared with the experimen-tal:at about 15m from the “epicenter”(instead of about 10m).In addition,the deformation predicted by Method 1at the ground surface computed using method 1is widespread,instead of localised at a narrow band.FE deformed meshes with superimposed shear strain contours are compared with an image from the experiment in Fig.10,for h =2.5m.In the case of Method 2,the comparison can be seen to be quite satisfactory.However,it is noted that the secondary rupture (S 1)that forms in the experiment to the right of the main shear plane (R 1)is not predicted by Method 2.Also,experimental shear strain contours (not shown herein)are a little more diffuse than the FE prediction.Overall,the comparison is quite satisfactory.In the case of Method 1,the quantitative details are not in satisfactory agreement,but the calculation reveals a secondary rupture to the right of the main shear zone,consistent with the experimental image.4.1.2Test 28—reverse 60◦This test was also conducted at 115g and the sand was of practically the same relative density (D r =61%).Given that reverse fault ruptures require larger normalised bedrock123Fig.11Test28—Reversepropagation through H=15mD r=60%Fontainebleau sand:Comparison of numerical withexperimental verticaldisplacement of the surface forbedrock dislocation h=2.0m(all displacements are given inprototype scale)displacement h/H to propagate all the way to the surface(e.g.Cole and Lade1984;Lade et al.1984;Anastasopoulos et al.2007;Bransby et al.2008b),the soil depth was set at H=15m.This way,a larger h/H could be achieved with the same actuator.Figure11compares the vertical displacement y at the ground surface predicted by the numerical analysis to experimental data,for h=2.0m.This time,both models predict correctly the location of fault outcropping(defined as the point where the steepest gradient is observed).In particular,Method1achieves a slightly better prediction of the outcropping location:−10m from the epicentre(i.e.,a difference of1m only,to the other direction). Method2predicts the fault outbreak at about−7m from the“epicenter”,as opposed to about −9m of the centrifuge model test(i.e.,a discrepancy of about2m).Figure12compares FE deformed meshes with superimposed shear strain contours with an image from the experiment,for h=2.5m.In the case of Method2,the numerical analysis seems to predict a distinct fault scarp,with most of the deformation localised within it.In contrast,the localisation in the experiment is clearly more intense,but the fault scarp at the surface is much less pronounced:the deformation is widespread over a larger area.The analysis with Method1is successful in terms of the outcropping location.However,instead of a single rupture,it predicts the development of two main ruptures(R1and R2),accompanied by a third shear plane in between.Although such soil response has also been demonstrated by other researchers(e.g.Loukidis and Bouckovalas2001),in this case the predicted multiple rupture planes are not consistent with experimental results.4.2Interaction with strip footingsHaving validated the effectiveness of the developed numerical analysis methodologies in simulating fault rupture propagation in the free-field,we proceed to the comparisons of experiments with strip foundations:one for normal(Test14),and one for reverse(Test29) faulting.This time,the comparison is extended to all three methods.4.2.1Test14—normal60◦This test is practically the same with the free-field Test12,with the only difference being the presence of a B=10m strip foundation subjected to a bearing pressure q=90kPa.The foundation is positioned so that the free-field fault rupture would emerge at distance s=2.9m from the left edge of the foundation.123。

Comparative Research Report Template AbstractThe purpose of this comparative research report template is to provide researchers with a clear structure for creating a comprehensive and effective research report. The template includes sections for the introduction, background, methodology, results, analysis, and conclusion. By following this template, researchers can ensure that their reports are both well-organized and easy to read.IntroductionThe introduction should provide a brief overview of the topic being studied and emphasize why the research is important. It should also include research questions and objectives, as well as a clear statement of the hypothesis being tested. In this section, it is paramount to provide context and significance of the research problem.BackgroundIn this section, the researcher must provide a comprehensive and thorough review of the literature on the study topic. The literature review should summarize previous research studies, theories, and notable works in the field. The literature review should be an overview of the background information relevant to the research, which may include historical background, current contexts, phenomena or theories related to the research. The literature review is crucial in establishing the need for and importance of the research, as well as highlight gaps in knowledge presenting the opportunity for further research.MethodologyThe methodology section should detail how the research was conducted, including participants, data collection instruments, and procedures. This section should be clear and concise to ensure the reproducibility of the study. It should also include a discussion of the reliability and validity of the data and the analysis methods employed in the research. In addition, this section should also include a statement of ethics, including the protection of human subjects in research.ResultsIn this section, the researcher presents the findings of the research. This may include qualitative or quantitative data analysis. The presentation of the results should be clear, concise and make effective use of tables, graphs and charts. The statistical analysis used to analyze data should be clearly explained to ensure readers can understand how the data were analyzed. The interpretation of theresults should be unbiased, and a discussion of any limitations of the research should also be presented.AnalysisIn this section, the researcher analyzes the results and discusses how they relate to the research questions and objectives. The researcher should consider the study’s implications, identify significant points, patterns in the data, and compare results with previous research in the field. This section should include a discussion of the implications of the research and the conclusions that can be drawn.ConclusionThe conclusion is a brief summary of the main findings of the research study. It should include a statement of the study’s contributions to the field and present recommendations for future research. Also, the researcher must draw inferences, consolidate observations and offer a firm conclusion to the research problem discussed in the introduction.ReferencesFinally, it is essential to provide the sources that were used to inform the report. The references should follow in the selected citation style. The references should be comprehensive and should include all the sources that were cited in the report.。

秩和比综合评价法和topsis的区别秩和比综合评价法（Rank and Ratio Comprehensive Evaluation Method）和Topsis（Technique for Order of Preference by Similarity to Ideal Solution）都是常用的综合评价方法，用于对多个方案或对象进行评估和排序。

我们来了解秩和比综合评价法。

这种方法主要包括以下几个步骤：数据归一化、权重确定、求得秩值、计算加权秩和比值、综合排序。

在这个方法中，首先需要对原始数据进行归一化处理，将不同量纲的指标转化为无量纲的相对指标。

然后，根据实际情况确定各个指标的权重，以体现不同指标的重要性。

接下来，通过对各个指标的相对大小进行排序，得到每个指标的秩值。

然后，根据指标的权重和秩值，计算加权秩和比值。

最后，根据加权秩和比值的大小对方案或对象进行综合排序。

而Topsis方法则是另一种常用的综合评价方法。

它的步骤包括：数据标准化、确定理想解和负理想解、计算离理想解的距离和负理想解的距离、计算综合评价指数、排序。

在这个方法中，首先需要对原始数据进行标准化处理，将其转化为无量纲的相对指标。

然后，根据具体问题确定理想解和负理想解，理想解是指在各个指标上取最大值，负理想解是指在各个指标上取最小值。

接下来，计算每个方案或对象与理想解的距离和负理想解的距离。

然后，根据距离的大小计算综合评价指数。

最后，根据综合评价指数的大小对方案或对象进行排序。

从上面的步骤可以看出，秩和比综合评价法和Topsis方法在处理数据的方式上有一些区别。

秩和比综合评价法将原始数据进行归一化处理，并通过对指标的排序和加权来得到综合评价结果。

而Topsis 方法则是将原始数据进行标准化处理，通过计算与理想解和负理想解的距离来得到综合评价结果。

两种方法在权重的确定上也有所不同。

秩和比综合评价法需要根据实际情况确定各个指标的权重，以体现其重要性。

RESEARCH LETTEREffect of orlistat on weight loss,hormonal and metabolic profiles in women with polycystic ovarian syndrome:a randomized double-blind placebo-controlled trialAshraf Moini •Mahia Kanani •Ladan Kashani •Reihaneh Hosseini •Ladan HosseiniReceived:25April 2014/Accepted:5September 2014/Published online:8October 2014ÓSpringer Science+Business Media New York 2014IntroductionPolycystic ovary syndrome (PCOS)is characterized by hyperandrogenism and chronic anovulation.This disorder is estimated to affect 5–10%of women of reproductive age [1].PCOS is strongly associated with obesity and metabolic syndrome components.It is believed that PCOS and obesity exacerbate one another in a number of ways [2].Insulin resistance caused by obesity is one reason for hyperinsulinemia which can subsequently stimulate ovarian androgen synthesis [3–7].Additionally,vaspin,an insulin-sensitizing adipokine vis-ceral adipose tissue-derived serine protease inhibitor has been shown to cause an increase in PCOS and play a role in androgen excess,abdominal adiposity,and insulin resis-tance [8].Therefore,many of these women face weight loss challenges that are attributed to long-term disturbances in hormonal patterns and inappropriate nutritional habits [9].Orlistat is a potent,irreversible inhibitor of carboxylester lipase.This medication inhibits the digestion of dietary tri-glycerides and decreases the absorption of lipids [10].The aims of this study were to determine the effect of combined orlistat and conventional hypo caloric diet compared to diet alone in overweight and obese women with PCOS.Materials and methodsThis was a randomized double-blind,placebo-controlled clinical trial.We recruited 100patients from our clinic at Arash Hospital between May 2010and May 2012.After obtaining informed consents,we used the randomization table method to divide the patients into two groups.All patients were diagnosed with PCOS according to Rotter-dam Criteria (2004).Patients’primary complaints included abnormal menses (oligomenorrhea and menometrorrhagia).All patients were of reproductive age (19–38years)and had a body mass index (BMI)[25.Study participants had no histories of taking hormonal medications in last six months,no current dietary modifications or dietary modi-fications for the preceding six months prior to study entry.The exclusion criteria were as follows:a history of cho-lestasis,liver disease,renal disease,malabsorbtion,or hypothyroidism.All patients received a hypocaloric diet that consisted of 55%carbohydrates,30%fat,and 15%protein.Each serving of this diet provided approximately 1,200–1,800kilocalories per day according to each indi-vidual’s primary BMI.This is monounsaturated fatty acid (MUFA)diet—one of the diet protocols which is used in PCOS [11–13].The patients had normal physical activity and were encouraged to walk for 30min daily.Participants completed weekly exercise diaries to monitor forElectronic supplementary material The online version of this article (doi:10.1007/s12020-014-0426-4)contains supplementary material,which is available to authorized users.A.Moini ÁM.Kanani ÁL.Kashani ÁR.Hosseini (&)Department of Gynecology and Obstetrics,Arash Women’s Hospital,Tehran University of Medical Sciences,Tehran,Iran e-mail:rayh_h@A.MoiniDepartment of Endocrinology and Female Infertility,Royan Institute ACECR,Tehran,IranL.HosseiniResearch Development Center,Arash Women’s Hospital,Tehran University of Medical Sciences,Tehran,IranEndocrine (2015)49:286–289DOI 10.1007/s12020-014-0426-4compliance.The consistency of exercise was77%in the control group and74.8%in the intervention group.The intervention group received orlistat(120mg)three times per day.The control group received a placebo.Both the placebo and orlistat were manufactured by Aburaihan Pharmaceutical Company and were identical in shape.The duration of treatment was3months.A member of the study team who was blinded to both groups visited each participant monthly.Weight,BMI[weight(kg)/height(m2)],and waist cir-cumference were measured at the beginning and at the end of the three-month period.Insulin(2.0–25.0l u/ml)and total testosterone during the follicular phase(0.14–0.9ng/ml) were measured using ELISA(Monobid,USA).Fasting glucose(B100mg/dl),triglycerides(B150mg/dl),and high density lipoprotein(HDL[40mg/dl)were determined by photometry(Parsazmoon,Iran).Ourfindings showed an inter-assay variation of\5%and intra-assay variation of \8%for testosterone and insulin.We used the homeostatic model assessment of insulin resistance(HOMA-IR)to evaluate insulin resistance based on the following formula: fasting plasma glucose(mg/dl)9fasting plasma insulin (l U/ml)divided by405.All participants were advised to use a non-hormonal contraception method.The effect of treatment was evalu-ated by comparing the changes in variables before and after treatment in both groups.We used a mixed design(between and within groups) analysis of variance(ANOVA)in order to provide both inter-and intra-group comparisons.Relationships between different values of the variables were subsequently explored using simple comparison between the obtained measurement and baseline by the t test or Mann–Whitney test according to the variables’distributions.We consid-ered a p value\0.05as significant.The analysis was per-formed using the Statistical Package for Social Sciences (SPSS)version16(SPSS Inc.,Chicago,IL,USA). ResultsIn the intervention(n=50)and control groups(n=50),the same numbers of participants completed the study(n=43for both groups).Participants’mean age was27.42±3.31years in the control group and26.80±5.16years in the interven-tion group.Participants were excluded from the study for the following reasons:lack of compliance for follow-up visits(4 in the control group and3in the intervention group);partici-pants expressed concerns about treatment/side effects(one in the control group and2in the intervention group);the pre-sence of medical conditions(one in the intervention group); and use of different medical treatments(2in the control group and one in the intervention group).A comparison between before and after treatment showed a significant decline in BMI(p\0.01)and testosterone level (p\0.01)in the intervention group compared with BMI (p=0.43)and testosterone level(p=0.39)in the control group.Although participants had a significant mean weight loss in the control group from80.91kg at the beginning of the study to79.15kg after treatment(p=0.01),the reduction in BMI was not significant.There was a6.37%weight loss in the intervention group and2.27%weight loss in the control group.After3months of treatment,the BMI was 27.16±1.93in the intervention group and28.50±1.9in the control group,which its difference was significant (p\0.001).The changes in parameters are shown in Table1.The control group comprised31individuals with oligo-menorrhea,10with menometrorrhagia,and2with normal menses.In the intervention group,there were28patients with oligomenorrhea,12with menometrorrhagia,and3who had normal menses.After treatment,there were a total of4indi-viduals with normal menses in the control group and6in the intervention group,which was not significantly different both before and after treatment and between the two groups.The mean triglyceride levels were103.61±13.2mg/dL for the intervention group and159.97±11.93mg/dL for the control group,which showed a substantial decrease in the intervention group(p\0.01).We observed the same decrease in plasma low-density lipoprotein(LDL)levels with a mean of71.18±2.34mg/dL in the intervention group and 102.83±6.90mg/dL in the control group(p\0.01). Additionally,an increase in HDL level in the intervention group(54.13±2.32mg/dL)was observed compared to the control group(49.23±1.47mg/dL;p\0.01).Even after controlling for the effect of weight loss by regression analysis,it was noted that orlistat significantly decreased LDL and triglyceride levels,increased HDL levels,and showed no significant changes in insulin and fasting glucose levels.Also inter-and intra-group com-parisons of HOMA-IR showed no significant changes in the control and intervention groups(Table1).Approximately50%of intervention group patients complained of adverse effects that included an urgent need to go to the bathroom(54%),oily spotting in undergar-ments(30%),oily or fatty stools(22%),and headaches (3%).In the control group13(22%)patients reported the following side effects of headaches(2patients),dizziness (4patients),and defecation problems(diarrhea or consti-pation in7patients).There was no case of drug discon-tinuation due to any reported adverse effects. DiscussionIt has been shown that treatment with orlistat is effective for weight loss in obese d weight loss(5%ofinitial body weight)has been shown to increase the fre-quency of ovulation and fecundity and improve testoster-one and lipid profiles in women with PCOS[3–7].In this study we aimed to compare the effect of orlistat,an anti-obesity drug,in combination with conventional hypocalo-ric diet to diet alone in terms of weight loss.We sought to determine the hormonal and metabolic consequences in PCOS women.Our data demonstrated that orlistat combined with a mild low-calorie diet was associated with a reduction in body weight in obese PCOS patients.Ourfinding(6.3% weight loss)is consistent with Heymsfield et al.study (6.8%weight loss)in1year treatment[14]and Jayagopal et al.(4.69%in3months)[15].Although in the control group we observed a reduction in weight,the reduction in BMI was not significant.Of note,BMI changes take longer than weight changes.Following a restricted diet and an exercise program for an extended period of time is difficult for many obese patients.According to a review article by Bray et al.,although diet and lifestyle improvement are thefirst lines of any weight-loss strategy in obese patients,in many cases additional interventions may be necessary[16].In the current study,the intervention group showed a significant reduction in testosterone levels which was consistent with other reports for PCOS patients[17,18]. The androgen excess has two main pathways in PCOS: First,increased level of LH and Insulin stimulated P450c17 and its androgen production.Second,the level of sex hormone binding globulin(SHBG)is lower in PCOS patients[19].In our study,the testosterone levels decreased without any major changes in insulin levels,which might be attributed to the changes SHBG levels or a modification in secretion pattern following treatment.Both groups experienced significant decreases in lipid profiles,which were consistent with the results of a study by Ghandi on PCOS women[20].An increase in HDL level was also observed.However,these changes were more significant in the intervention group.Cho et al.reported an effect of orlistat on insulin resis-tance in PCOS women[21];however,in the current study, there was no substantial effect of orlistat on glucose and insulin levels and also HOMA-IR.Sahin et al.[22].and Jayagopal et al.[15]have also reported the same results in non-diabetic obese women.Of note,the balance in glucose profiles is related to constant weight loss and reduction of blood lipids which is expected during long-term follow-up. The difference amongfindings may be attributed to a longer follow-up,for example,in Heymsfield et al.study(one-year treatment)[14]or larger sample size in Jacob et al.study [23].Also in the last study,the cases had diabetes and the duration of treatment was different in cases.The same conclusion can be applied for the current study’s control group as they showed improvements in lipid profile and weight;however,BMI and glucose/insulin levels failed to be influenced by the low-caloric diet during this short-term follow-up.Possibly,long-term treatment might change thesefindings as has been shown in a study by Mehrabani et al.[24]on PCOS obesity.If the treatment period were longer,it was possible that additional adverse effects might disturb the patients as has been reported by Johansson et al.[25].According to this study and those by Ghandi et al.[20], Diaz and Folgueras[26],and Smith et al.[27],it seems thatTable1Comparison between characteristics of two groups before and after treatmentParameters Treatment groupMean±SD Control groupMean±SDComparisonbetween twogroups beforeComparisonbetween twogroups afterBefore After p Before After p p pWeight(kg)81.5±4.0476.25±4.3\0.0180.91±4.2379.15±4.510.010.14\0.01 BMI(kg/m2)29.01±2.0927.16±1.93\0.0128.60±4.228.57±1.900.430.54\0.01 WHR(cm)0.88±0.040.76±0.03\0.010.87±0.030.86±0.030.680.78\0.01 Testosterone(ng/ml)83.46±5.0863.95±1.63\0.0182.56±4.8581.60±4.640.390.390.01Fasting insulin(l u/ml)17.24±6.4917.20±6.720.2117.49±6.8317.34±7.270.520.390.97Fasting bloodglucose(mg/dl)107.61±4.44107.05±4.240.06106.70±4.40106.35±4.240.160.850.62HOMA-IR 3.46±1.99 3.43±1.110.43 3.43±1.70 3.41±1.420.610.080.21 Triglyceride(mg/dl)157.09±11.70128.34±16.52\0.01159.97.02±11.52158.98±11.93\0.010.45\0.01 LDL(mg/dl)96.47±5.1171.18±2.34\0.01102.83±6.9099.63±5.80\0.010.25\0.01 HDL(mg/dl)48.75±2.3754.13±2.32\0.0148.30±2.3649.23±1.47\0.010.08\0.01orlistat is a reasonable drug for obese patients diagnosed with PCOS and those without PCOS.On the other hand, adverse effects and the need for long-term treatment limit its use.This study has a relatively appropriate sample size,a PCOS control group,and a randomized double-blind design, which can reduce the bias risk compare with previous stud-ies.However,more studies that have a longer duration of treatment are needed to evaluate the effects of this drug. Acknowledgments This study wasfinancially supported by Tehran University of Medical Sciences.We express our appreciation to Fariborz Sadeghi Shahrestani for his kind cooperation.Conflict of interest The authors report no conflict of interest.References1.S.Franks,Polycystic ovary syndrome.N.Engl.J.Med.13,853–861(1995)2.S.E.Kedikova,M.M.Sirakov,M.V.Boyadzhieva,Leptin levelsand adipose tissue percentage in adolescents with polycystico vary syndrome.Gynecol.Endocrinol.29,384–387(2013)3.R.S.Legro,Obesity and PCOS:implications for diagnosis andtreatment.Semin.Reprod.Med.30,496–506(2012)4.A.K.Schro¨der,S.Tauchert,O.Ortmann,K.Diedrich,J.M.Weiss,Insulin resistance in patients with polycystic ovary syn-drome.Ann.Med.36,426–439(2004)5.R.S.Legro,A.R.Kunselman,W.C.Dodson,A.Dunaif,Preva-lence and predictors of risk for type2diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome:a prospective,controlled study in254affected 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December2003:397–412 Lead Review ArticleEvaluation of Insulin Sensitivity in Clinical Practice and in Research SettingsLais U.Monzillo,M.D.,and Osama Hamdy,M.D.,Ph.D.Insulin resistance is the core metabolic abnormal-ity in type2diabetes.Its high prevalence and its association with dyslipidemia,hypertension,hy-perinsulinemia,and high coronary and cerebro-vascular mortality put it in the forefront as the plausible target for aggressive intervention.Mea-surements of insulin sensitivity provide clinicians and clinical researchers with invaluable instru-ments to objectively evaluate the efficiency of both current and potentially useful interventional tools.Although several methods had been devel-oped and validated to evaluate insulin sensitivity, none of these methods can be universally used in all patients.Nonetheless,a method suitable for use in clinical or basic research may not neces-sarily be a practical method for use in clinical practice or for epidemiologic research.We re-viewed the currently used methods for assess-ment of insulin sensitivity.For each method,we summarized its procedure,normal value,cut-off value for defining insulin resistance,advantages and limitations,validity,accuracy for each patient population,and suitability for use in clinical prac-tice and in research settings.The methods re-viewed include fasting plasma insulin,homeo-static model assessment,quantitative insulin sensitivity check index,glucose-to-insulin ratio, continuous infusion of glucose with model as-sessment,indices based on oral glucose toler-ance test,insulin tolerance test,and the so called “gold standard”methods,the hyperinsulinemic euglycemic clamp and the frequently sampled–intravenous glucose tolerance test.Key words:insulin resistance,insulin sensitivity, clinical practice©2003International Life Sciences Institutedoi:10.1301/nr.2003.dec.397–412IntroductionInsulin resistance is a state in which physiologic concen-trations of insulin produce a subnormal biologic re-sponse.1It underlies abnormalities of glucose,lipid,and blood pressure homeostasis.2This cluster of metabolic abnormalities is referred to as the insulin resistance syndrome,syndrome X,or the metabolic syndrome,and is related to type2diabetes,obesity,hypertension,and dyslipidemia.3–5In fact,insulin resistance is present long before the clinical manifestations of the individual com-ponents of the syndrome.6–8Epidemiologic evidence indicates that insulin resistance is directly related to the risk of developing atherosclerosis and cardiovascular disease.9–11To clinically identify patients with the metabolic syndrome,the National Cholesterol Education Program Expert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III,ATP III)suggested that individuals having three or more of the following criteria are defined as having the metabolic syndrome:121.Abdominal obesity:waist circumferenceϾ40inchesin men andϾ35inches in women;2.Hypertriglyceridemia:Ͼ150mg/dL(1.69mmol/L);3.Low high-density lipoprotein(HDL)cholesterol:Ͻ40mg/dL(1.04mmol/L)in men andϽ50mg/dL(1.29mmol/L)in women;4.High blood pressure:Ն130/85mmHg;5.High fasting plasma glucose:Ն110mg/dL(Ն6.1mmol/L).A recent epidemiologic study among adults above age20 showed that the age-adjusted prevalence of the metabolic syndrome in the United States is23.7%,with a higher prevalence among minority populations.13Several clinical trials have shown that lifestyle mod-ification delays the progression to type2diabetes among individuals with impaired glucose tolerance;14–17how-ever,none of these studies included quantitative evalu-ation of insulin sensitivity as an integral component of the study design.It is possible that an improvement in insulin sensitivity can be achieved either through life-style modification18–21or pharmacologically with met-Drs.Monzillo and Hamdy are with the Clinical Research Center,Joslin Diabetes Center;Department of Medicine,Harvard Medical School,Boston,MA 02215,USA.formin22,23or thiazolidinediones.24–26The Food and Drug Association(FDA)has not approved either of these pharmacologic compounds for treatment of insulin resis-tance in nondiabetic individuals;however,the diagnosis of type2diabetes,hypertension,and dyslipidemia man-dates aggressive appropriate treatment with antidiabetic, blood pressure–lowering,and lipid-lowering agents aimed at reducing cardiovascular morbidity and mortal-ity.The rapidly growing epidemic of obesity and con-sequent insulin resistance has increased the interest in finding quantitative,accurate,and easy methods to eval-uate insulin sensitivity in both clinical research and clinical practice.Such a tool is not only useful for early identification of insulin resistance but also to assess the degree of success in treating this syndrome and its consequences.This review will summarize our current knowledge of the available methods used to evaluate insulin sensitivity in humans.The components of each method,its indications,and its limitations are discussed. Fasting Plasma Insulin ConcentrationOne of the most practical ways to estimate insulin resis-tance from the clinical perspective is to measure plasma insulin concentration after an overnight fast.As it is inexpensive and easy to do,it has been used in several population-based studies.27–30Very high plasma insulin values reflect the presence of insulin resistance.Despite the relatively good correlation between fasting plasma insulin and insulin sensitivity derived from the hyperin-sulinemic euglycemic clamp,measures of fasting plasma insulin explain no more than5to50%of the variability in insulin action seen in nondiabetic subjects.31,32This is because plasma insulin levels depend not only on insulin sensitivity,but also on insulin secretion,distribution,and degradation.33Moreover,with the development of diabetes,fasting plasma insulin levels tend to decrease owing to beta cell dysfunction.Therefore,plasma insulin levels in diabetic patients are valid reflection of both target tissue insulin resistance and diminishing insulin production.34This explains why fasting plasma insulin levels may accu-rately predict insulin sensitivity among normoglycemic patients than among those with impaired glucose toler-ance(IGT)or type2diabetes.32,35,36Another limitation to using fasting plasma insulin to predict insulin resis-tance is cross-reactivity between insulin and proinsulin. Proinsulin levels are high among insulin-resistant sub-jects with type2diabetes and IGT,37,38but not in people who are insulin resistant and normoglycemic.39 The commonly used radioimmunoassay(RIA) method has a lower specificity and sensitivity,and a higher interassay coefficient of variation,when com-pared with the two-site monoclonal antibody-based in-sulin assay methods(immuno-radiometric[IRMA],im-muno-enzymometric[IEMA],and immuno-fluorimetric [IFMA])methods.40,41The presence of anti-insulin an-tibodies in type1and type2diabetic patients,who are treated with human or animal insulin,can interfere with both the RIA and two-site monoclonal assay,unless removal of anti-insulin antibodies and antibody-bound insulin is performed.41,42The normal range for insulin levels using RIA is3to 32mU/L.43,44However,there is no defined cut-off value indicating insulin resistance.This lack of consensus stems partly from the various means used to define abnormal.In a population-based study examining the association between insulin levels and cardiovascular risk,Lindahl et al.8defined insulin resistance as a plasma insulin levelϾ7.2mU/ing the hyperinsulinemic euglycemic clamp as the reference standard,McAuley et al.45found that a fasting insulinϾ12.2mU/L predicted insulin resistance among normoglycemic adults. Laakso,32also using the hyperinsulinemic clamp in nor-moglycemic adults,arrived at a cut-off of18mU/L. Finally,defining the abnormal range as the upper10% percentile,Ascaso et al.46defined insulin resistance in nondiabetic individuals when plasma insulin levels were equal or greater than16.7mU/l(Table1).While these variations illustrate how study designs influences what insulin level is determined to represent insulin resistance, the lack of established standards for insulin assay proce-dures further complicates the issue.47Another limitation for measurement of fasting plasma insulin is the pulsatile mode of insulin secretion (pulses with a periodicity of10–15minutes,and ultra-dian oscillations periods of1to3hours).The periodicity, amplitude,and ultradian oscillations of insulin pulsesparison of Fasting Plasma Insulin Values and Insulin Assays Used to Assess Insulin Sensitivity in Different StudiesStudy Year Population Insulin Assay Insulin Resist Value Lindahl et al.81993General population RIAϾ7.2mU/L McAuley et al.452001General population RIAϾ12.2mU/L Laakso et al.321992Normoglycemic RIAϾ18mU/L Ascaso et al.462001Normoglycemic RIAՆ16.7mU/L RIAϭradioimmunoassay.vary in the fasting state,and are altered in IGT and in type2diabetes.41Because of these limitations,fasting plasma insulin levels are of limited value for clinical purposes,but have some utility as a research tool in population-based studies.The Homeostasis Model Assessment(HOMA)Because fasting insulin per se does not provide an accu-rate measure of insulin sensitivity in diabetic patients, efforts have been made to incorporate fasting plasma glucose in a formula to arrive at a better estimate of insulin-sensitivity.HOMA was developed by Matthews et al.48as a method for estimating insulin sensitivity from fasting serum insulin(FI)and fasting plasma glu-cose(FG)using the following mathematic formula: HOMA Insulin Resistance(HOMA IR)ϭFIϫFG/22.5FI is measured in␮U/mL and FG is measured in mmol/L.Low HOMA IR indicates high insulin sensitiv-ity,whereas high HOMA IR indicates low insulin sensi-tivity.In their original report,Matthews et al.found HOMA IR ranges between1.21and1.45in normal sub-jects and between 2.61and 2.89in insulin-resistant diabetic subjects.48However,further epidemiologic studies performed in the general population reported higher HOMA IR values of2.1,442.7,31and3.8.46 Because fasting insulin is a major component of the HOMA IR calculation,all previously mentioned limita-tions should apply to this formula.Three samples for fasting plasma insulin should be drawn5minutes apart to avoid errors that may arise owing to the pulsatile nature of insulin secretion.However,most studies use only one basal insulin measurement to calculate HOMA IR.HOMA IR correlates well with the glucose disposal rate derived from the hyperinsulinemic euglycemic clamp.49–53In addition,two authors found a good cor-relation between the HOMA IR and the insulin sensitivity index(S i)derived from the frequently sampled intrave-nous glucose tolerance test(FSIVGT).54,55By contrast, Anderson et al.35failed to demonstrate a good correla-tion between the two.Furthermore,some of the studies that initially demonstrated significant correlation be-tween the HOMA IR and the clamp-derived insulin sen-sitivity used a low insulin infusion rate of20 mU⅐m2Ϫ1⅐minuteϪ1during the clamp,which might not have completely suppressed the hepatic glucose pro-duction and may have created an error in calculating theglucose uptake by peripheral tissues.51,52One of the limitations of HOMA IR is the model assumption that insulin sensitivity in the liver and pe-ripheral tissues are equivalent,whereas it is known that they can differ considerably in the same individual.50 Furthermore,some data suggest that the accuracy of HOMA IR is limited by hyperglycemia.Those studies that demonstrated good correlations between HOMA IR and the clamp-derived insulin sensitivity in diabetic patients tended to enroll patients without significant hyperglyce-mia.48–50,52,53Mari et al.56failed to show a significant correlation between HOMA IR and clamp in type2dia-betic patients with higher glucose levels(mean basal plasma glucose of205mg/dL).In addition,Anderson et al.35and Brun et al.57found that the correlation between HOMA IR and S i derived from the FSIVGT weakened as glycemia increased.These results suggest a non-linear relationship between S i and HOMA IR.The coefficient of variation(CV)for HOMA IR is as high as31%,48which limits its use in clinical practice and clinical research.47Optimizing sample size and in-sulin assay method reduceHOMA IR CV to8to12%.49,51 In conclusion,HOMA IR is mostly useful for the evaluation of insulin sensitivity in euglycemic individu-als and in persons with mild diabetes;however,this index appears to offer little or no advantage over the fasting insulin concentration alone.31,45,58In patients with severe hyperglycemia or in lean diabetic patients with beta cell dysfunction,the HOMA IR may not be accurate.Its usefulness should therefore be restricted to large population-based studies that require a simple method to assess insulin sensitivity.Quantitative Insulin Sensitivity Check Index (QUICKI)QUICKI is another mathematic model available to esti-mate insulin sensitivity.59QUICKIϭ1/[log(I0)ϩlog(G0)],where I0is the fasting plasma insulin level in␮U/mL, and G0is the fasting plasma glucose level in mg/dL.The mean QUICKI for lean,obese,and obese-diabetic sub-jects are0.382,0.331,and0.304,respectively.59Al-though other studies have found a similar range for a normal healthy population of0.372and0.366,60,61one study showed a wider range between0.265and0.518.62 The mathematic difference between the QUICKI and the HOMA IR is that the former uses the reciprocal of the logarithm of both glucose and insulin to account for the skewed distribution of fasting insulin values.As expected,there is very good correlation between QUICKI and HOMA IR,63especially when the HOMA IR is log-transformed.59,62,64,65Although two studies failed to demonstrate any real advantage of QUICKI when compared with log HOMA IR,62,65other studies argue that QUICKI has the advantage of being applied to wider ranges of insulin sensitivity.61,63,64QUICKI was also shown to correlate well with the FSIVGT66and the hyperinsulinemic eu-glycemic clamp.58However,the correlation is weakerwhen insulin levels were low,as seen in non-obese insulin-sensitive subjects and diabetic patients with di-minished insulin production;59,60,62,65,67,68this is be-cause low insulin levels lead to variability in determined insulin concentrations and because of the oscillatory pattern of insulin secretion in healthy individuals.Other limitations to this mathematic method include its limited applicability for type1diabetic patients owing to lack of endogenous insulin secretion,59and its inaccuracy if conducted following exercise training.67In conclusion,the QUICKI may be a useful and simple tool for assessing insulin sensitivity in epidemi-ologic settings;it may offer some advantage over the HOMA IR,especially in obese and diabetic individuals with relatively preserved beta cell function.However, the model needs validation in a wider range of subjects with different glucose tolerance patterns in order to confirm its reliability for use in clinical practice and in research settings.Fasting Plasma Glucose-to-Insulin Ratio(G/I)G/I is another mathematic method that uses fasting plasma insulin and fasting plasma glucose to estimate insulin sensitivity.The higher the ratio,the more insulin-resistant an individual is.The index generally correlates well with other indi-ces of insulin sensitivity.1,45,69–75It correlated with in-sulin sensitivity indices derived from the oral glucose tolerance test(OGTT,rϭ0.82,PϽ0.05),1,71and FSIVGT(rϭ0,76,PϽ0.001).1,69,72Vuguin et al.72 found that a fasting G/I ratioϽ7provided87%sensitiv-ity and89%specificity for identifying low insulin sen-sitivity in young girls with premature adrenarche.In another study of white nondiabetic women with polycys-tic ovarian syndrome(PCOS),Legro et al.69found the G/I ratio to be the best screening test for insulin resis-tance.The authors showed that a cut-offϽ4.5provided an87%positive predictive value and94%negative predictive value in screening for insulin resistance in PCOS.G/I ratio was found to correlate well with HOMA IR(rϭ0.83,PϽ0.01),fasting insulin(rϭ0.95, PϽ0.001),73and QUICKI(rϭ0.91,PϽ0.0001)74in healthy individuals.Data on the correlation between G/I ratio and insulin sensitivity derived from the euglycemic clamp procedure are inconsistent;whereas two studies found a significant correlation,1,45another did not.50 Adding to the previously mentioned problems that in-clude precision of insulin assay,pulsatile pattern of insulin secretion,and cross reactivity with proinsulin,the major problem with using the G/I ratio is its inaccuracy in diabetic patients owing to defects in insulin secretion and high plasma fasting glucose.1,50,70,76In subjects with normoglycemia,G/I ratio offered little advantage over the1/insulin measure76or fasting insulin.45Moreover,it provides indirect information on whole-body sensitivitybut not on the effect of insulin in peripheral tissues.1Inconclusion,this index,like the previously describedindices,should be limited to the nondiabetic population.For research purposes,its superiority over the fastinginsulin is questionable.Continuous Infusion of Glucose with Model Assessment(CIGMA)Because of the inaccuracy that may result from low basalinsulin concentrations,an alternative mathematic methodwas proposed.This method assesses insulin sensitivitythrough the evaluation of the near–steady state glucoseand insulin concentrations after a continuous infusion ofglucose with model assessment.77This procedure mim-ics postprandial glucose and insulin concentrations.CIGMA not only provides information about glucosetolerance and insulin sensitivity,but also about beta celling a mathematic model of glucose ho-meostasis,glucose and insulin values are compared withknown physiologic data of glucose and insulin kinetics inresponse to glucose infusion that are derived fromhealthy lean subjects with no family history of diabetes.The glucose and insulin values used for CIGMA areobtained during the last15minutes of the60-minutecontinuous glucose infusion(5mg glucose⅐kg idealbody weightϪ1⅐minuteϪ1).Samples are collected at five-minute intervals,to avoid the oscillatory variation ininsulin concentration.The average is then compared withpredicted values from the computer model.The medianvalue for normal subjects is1.35and for diabetic patientswith mild hyperglycemia is4.0.77Although CIGMA has been used in several studiesto evaluate insulin resistance,78–83few studies havecompared CIGMA with other insulin sensitivity indices.In elderly normoglycemic patients,CIGMA significantlycorrelated with mean fasting plasma insulin concentra-tions.84Hermans et al.55compared CIGMA,HOMA IR,FSIVGT,and the insulin tolerance test(ITT),in subjectswith glucose tolerance ranging from normal to frankdiabetes.They found that CIGMA and HOMA IR wereable to discriminate differences in insulin sensitivityamong subjects as well as the FSIVGT and better thanthe ITT.Among the four methods,CIGMA was the bestdiscriminatory test in precision analysis.It is worthmentioning that CIGMA in this study derived from a2-hour test(compared with the original1-hour CIGMA).Other studies have also reported data from2-hourCIGMA.85,86Data aiming to validate CIGMA against the clamp-derived insulin sensitivity index are scarce.In the orig-inal article,CIGMA was shown to correlate well with theeuglycemic hyperinsulinemic clamp(rϭ0.87,P Ͻ0.0001)77in normal subjects and in diabetic patientswith mild hyperglycemia.However,the relationship be-tween CIGMA and the clamp was nonlinear for diabetic patients with severe insulin resistance.Nijpels et al.70 studied90subjects,most of them with normal or im-paired glucose tolerance,and found a modest correlation between CIGMA and the clamp-derived insulin sensitiv-ity(rϭ0.66;PϽ0.05).The CV of CIGMA ranges between17%84and20%.77There are two main advantages of CIGMA over HOMA IR.First,the insulin values that are measured in CIGMA are much higher than those in HOMA IR owing to the glucose stimulus;therefore,the high insulin inter-assay CV(10–15%)41,47that is problematic at low insu-lin a concentration is avoided.55Second,higher insulin concentration in CIGMA stimulates peripheral glucose uptake producing a steady-state glucose concentration, which is a better reflection of the peripheral insulin sensitivity.Although CIGMA is more physiologic,practical, cheaper,and less invasive than the FSIVGT and clamp procedure,the model incorrectly assumes that levels of insulin resistance at the liver and peripheral tissues are equal.Furthermore,in insulin-deficient subjects,where the insulin response is insufficient to stimulate glucose uptake,the interpretation of CIGMA is difficult.33As CIGMA is a procedure and not a simple test such as fasting insulin or the HOMA IR,its use in clinical practice is limited.Moreover,due to insufficient data comparing CIGMA against the“gold standard”euglycemic hyper-insulinemic clamp,its use in research settings should also be viewed with caution.The Oral Glucose Tolerance Test(OGTT) Because oral glucose tolerance is in part determined by sensitivity of peripheral tissues to insulin,the OGTT has been used to evaluate insulin release and the sensitivity of the peripheral tissue to the insulin action.Being a less costly and less labor-intensive procedure compared with the FSIVGT and the euglycemic clamp,the OGTT has been considered a practical method for epidemiologic studies,58for population screening,and for large-scale intervention trials.50,63,87Several indices to estimate in-sulin sensitivity have been derived from the four samples of insulin and glucose(0,30,60,and120minutes)taken after ingestion of75grams of glucose(Table2). Insulin Sensitivity Indices Based on the OGTT Levine et al.88was one of thefirst authors to use the product of the area under the curve for glucose(AUC G) and the area under the curve for insulin(AUC I)during the OGTT to derive an estimate of insulin sensitivity. Later,AUC I was used alone as an estimate.31,36,89Cederholm and Wibell Index90SIϭM/G⅐log I,where Mϭglucose load/120ϩ(0-h plasma glucose concentration–2-h plasma glucose concentration)ϫ1.15ϫ180ϫ0.19ϫbody weight/120;where Gϭmean plasma glucose concentration,and Iϭmean serum insulin.A normal reference value is79Ϯ14.Gutt et al.Index91ISI0,120ϭMCR/log MSI(mean serum insulin),uses the fasting(0min)and120min post-load insulin and glucose concentrations,where MCR(metabolic clear-ance rate)is m/MPG(mean plasma glucose),where mϭ(75000mgϩ[0min glucose–120min glucose]ϫ0.19ϫbody weight)/120min.The reference range for lean controls was89Ϯ39,for obese58Ϯ23,for IGT 46Ϯ12,and for diabetic patients23Ϯ19.Avignon et al.Index92Sibϭ108/(IϫGϫVD)⅐(normal rangeϭ11.99Ϯ1.43)Si2hϭ108/(I2hϫG2hϫVD)⅐(normal rangeϭ1.79Ϯ0.33), where Iϭfasting insulin,Gϭfasting plasma glucose, G2h and I2hϭplasma glucose and insulin at the second hour of the OGTT,and VDϭvolume distribution(150 mL/kg of body weight).An additional insulin sensitivity index(S i M)was derived by the average of the2,after multiplying S i b by a correcting factor:SiMϭ[(0.137ϫSib)ϩSi2h]/2(normal rangeϭ1.71Ϯ0.24). Matsuda et al.Index50ISI(composite)ϭ10,000/͙(FPGϫFPI)ϫ(GϫI), where FPGϭfasting plasma glucose,FPIϭfasting plasma insulin,and Gϭmean plasma glucose,and Iϭmean plasma insulin concentration.Belfiore et al.Index93ISIϭ2/(INSpϫGLYp)ϩ1,where INSp and GLYp are the insulinemic and glycemic areas of the person under study recorded during OGTT. Reference value in normal controls was around1,butmarkedly reduced in the obese and obese-diabetic sub-groups.Stumvoll et al.Index94MCR est(OGTT)ϭ18.8Ϫ0.271BMIϪ0.0052ϫI120Ϫ0.27ϫG90, where MCR est stands for metabolic clearance rate estimate derived from the OGTT,BMIϭbody mass index,I120ϭplasma insulin at120minutes OGTT,and G90ϭplasma glucose at90minutes OGTT.Mari et al.Index56OGIS180ϭ[637106(G(120)Ϫ90)ϩ1]Cl ogtt, where OGIS180ϭoral glucose insulin sensitivity,G120ϭplasma glucose at2h OGTT,andCl ogttϭ289DoϪ104[G(180)ϪG(120)/60]G(120)ϩ14.0103G(0)440I(120)ϪI(0)ϩ270, where Clϭglucose clearance in mL⅐minϪ1⅐mϪ2, Doϭoral glucose dose in g/m2,G(120)ϭplasmaTable2.OGTT-derived Indices to Estimate Insulin Sensitivity and their Correlation with the Euglycemic Hyperinsulinemic Clamp or Frequently Sampled Intravenous Glucose Tolerance Test(FSIVGT)in Various PopulationsFormulae Subjects Correlation with 1.AUC I NGT Euglycemic clamp89rϭ0.61,Pϭ0.001IST31rϭ0.79,PϽ0.001AUC II30min I2hrG30min G2hr NGT,IGT ITT36rϭϪ0.51,PϽ0.001rϭϪ0.43,PϽ0.001rϭϪ0.39,PϽ0.001rϭϪ0.28,Pϭ0.01rϭϪ0.38,PϽ0.0012.SIϭMGϫlog INGT,IGT,DMEuglycemic clamp90rϭ0.62,PϽ0.00013.ISI0,120ϭMCR/log MSI NGT,IGT,DM Euglycemic clamp91rϭ0.63,PϽ0.001 4.Sibϭ108/(f Iϫf GϫVD)NGT,IGT,DM FSIVGT92Si2hϭ108(I2hϫG2hϫVD)rϭ0.90,PϽ0.0001 SiMϭ[(0.137ϫSib)ϩSi2h]/25.ISI(Comp)ϭ10,000͙(FPGϫFPI)ϫ(GϫI)NGT,IGT,DMEuglycemic clamp50rϭ0.73,PϽ0.00016.ISIϭ2(INSpϫGLYp)ϩ1NGT,O,ODMEuglycemic clamp93rϭ0.96,PϽ0.0017.MCRestϭ18.8Ϫ0.271BMIϪ0.0052ϫI120Ϫ0.27ϫG90NGT,IGT Euglycemic clamp94rϭ0.80;PϽ0.000058.OGIS180ϭ[637106(G{120}Ϫ90)ϩ1]Cl ogtt L,O,IGT,DM Euglycemic clamp56rϭ0.73;PϽ0.0001 AUC Iϭarea under the insulin curve,NGTϭnormal glucose tolerance,IGTϭimpaired glucose tolerance,I30minϭ30minutes post-load insulin,I2hrϭ2hours post-load insulin,G30minϭ30minutes post-load glucose,G2hrϭ2hour post-load glucose, ITTϭinsulin tolerance test,SIϭinsulin sensitivity,Mϭglucose uptake rate in mg⅐minϪ1,Gϭmean glucose concentration,Iϭmean insulin concentration,DMϭtype2diabetes,ISI0,120ϭindex of insulin sensitivity from fasting and120minutes post OGTT insulin and glucose concentrations,MCRϭmetabolic clearance rate,MSIϭmean serum insulin,Sibϭinsulin sensitivity in the basal state,Si2hϭinsulin sensitivity at the second hour,f Iϭfasting insulin concentration,f Gϭfasting glucose concentration,VDϭ150mL/kg of body weight,SiMϭinsulin sensitivity index,ISI(Comp)ϭcomposite whole-body insulin sensitivity index,FPGϭfasting plasma g glucose,FPIϭfasting plasma insulin,Gϭglucose,Iϭinsulin,ISIϭinsulin sensitivity index,INSpϭinsulinemic area,GLYpϭglycemic area,MCRestϭmetabolic clearance rate estimate,OGISϭoral glucose insulin sensitivity,Doϭoral dose glucose,Cl ogttϭglucose clearance.glucose at120minutes OGTT,G(180)ϭplasma glucose at180minutes OGTT,G(0)ϭfasting plasma glucose, I(120)ϭinsulin levels at120minutes,and I(0)ϭfasting insulin.Reference values in lean controls ranged300–600mL⅐minϪ1⅐mϪ2.As shown in Table2,the insulin sensitivity mea-sures derived from these formulas correlate well with insulin sensitivity determined by the euglycemic clamp50,89,90,93and FSIVGT.93However,the correlation was weaker in type2diabetic patients50,92,94and in the IGT group.36,58Belfiore et al.93advocate that their for-mula should not be used in type2diabetic patients with significant insulin deficiency.On the other hand,Mari et al.formula(OGIS),56showed a positive correlation with the clamp data in type2diabetic patients(rϭ0.49,P Ͻ0.002).In addition to the inadequacy of this method in insulin deficient states,other problems should be consid-ered.First,during the oral glucose tolerance test suppres-sion of hepatic glucose production is minimal,confound-ing interpretation of the plasma glucose level.Thus,it is impossible to differentiate among whole-body,periph-eral,or hepatic insulin sensitivity separately using data from the OGTT.49Second,the insulin level achieved in response to an oral glucose load involves gut hormones, neural stimulation,and of course the integrity of the pancreatic beta cells.68For example it has been shown that after75grams of glucose,obese subjects exhibit insulin hypersecretion,95while type2diabetes patients show a blunted response.96Third,glucose homeostasis in the postprandial state depends partly on the suppression of glucagon secretion and partly on the rate of entry of ingested glucose into the circulation.This rate is deter-mined by the rate of gastric emptying and splanchnic glucose uptake.60,61Fourth,the OGTT is poorly repro-ducible.Several studies show only about50to65% reproducibility of the results of an OGTT.63,97,98 Despite these limitations,the OGTT may be used in clinical settings to assess insulin action and in large-scale clinical and epidemiologic studies.However,the glucose and insulin excursions in the OGTT should be inter-preted with caution in populations with varying glucose tolerance.The Insulin Tolerance Test(ITT)ITT was one of thefirst methods developed to assess insulin sensitivity in vivo.99In this method,afixed bolus of regular insulin(0.1U/kg body weight)is given intra-venously after an8-to10-hour fast.The plasma glucose decrement over60minutes is then measured.The faster the decline in glucose concentration,the more insulin sensitive the subject is.The slope of the linear decline in plasma glucose(K ITT)can be calculated by dividing 0.693by the plasma glucose half-time(50%from base-line,Figure1).100K ITTϭ0.693/t1/2ϫ100,where t1/2represents the half-life of plasma glucose decrease.Normal K ITT isϾ2.0%/minute and values Ͻ1.5are considered abnormal.This method gives an indirect estimate of overall insulin sensitivity.It has been shown to correlate with the euglycemic clamp(rϭ0.811,PϽ0.001)101in several studies.101–104Some of the drawbacks of this method include the supraphysi-ologic insulin dose used,102and also the fact that the test does not differentiate peripheral versus hepatic insulin resistance.A major limitation of this test is the risk of hypo-glycemia,particularly in normoglycemic subjects and in elderly diabetic patients.Moreover,hypoglycemia trig-gers counterregulatory hormonal responses,which may interfere with insulin sensitivity.A lower insulin dose method of0.05units/kg,or shortening the test to15 minutes was suggested as an attempt to decrease the risk of hypoglycemia.105–107The lower dose ITT has also been shown to correlate well with the clamp.105How-ever,some studies failed to demonstrate reduction of the risk of hypoglycemia in insulin sensitive sub-jects.55,108,109They also showed a higher CV(16and 31%)in comparison to the conventional dose ITT(6–9% CV).101,103,104,110The shorter version101,103evolved from the notion that the counterregulatory hormone re-sponse occurs only after20minutes of the insulin infu-sion.111–113The short ITT yielded a good correlation with the euglycemic clamp101,103,105and has been used in most of the recent studies.114–117In conclusion,the ITT should be used with great caution in insulin sensitive individuals because of the increased risk of hypoglycemia,even when thesmallerFigure1.Calculation of the KITT(percentage decline in plasma glucose concentration per minute)in nondiabetic subjects.100 The time(t1⁄2)required for the plasma glucose concentration to decline by50%(i.e.,from90to45mg/dL)was25minutes.From the equation,KITTϭ0.693/t1⁄2ϫ100,the K rate was determined to be2.77%.。

Package‘MPCI’October12,2022Type PackageTitle Multivariate Process Capability Indices(MPCI)Version1.0.7Date2015-10-23Depends R(>=3.1.0),graphics,stats,utilsAuthor Edgar Santos-Fernandez,Michele Scagliarini.Maintainer Edgar Santos-Fernandez<**************************>Description It performs the followings Multivariate Process Capability Indices:Shahri-ari et al.(1995)Multivariate Capability Vector,Taam et al.(1993)Multivariate Capability In-dex(MCpm),Pan and Lee(2010)proposal(NMCpm)and the followings based on Princi-pal Component Analysis(PCA):Wang and Chen(1998),Xekalaki and Per-akis(2002)and Wang(2005).Two datasets are included.License GPL-2LazyLoad yesNeedsCompilation noRepository CRANDate/Publication2015-10-2517:36:24R topics documented:MPCI-package (2)dataset1 (3)dataset2 (4)mpci (5)Index1012MPCI-package MPCI-package Multivariate Process Capability Indices(MPCI)DescriptionIt allows the computation of the following Multivariate Process Capability Indices(MPCI):Shahriari et al.(1995)Multivariate Capability Vector.Taam et al.(1993)Multivariate CapabilityIndex(MCpm).Pan and Lee(2010)correction of the Taam et al.(1993)(NMCpm).and thefollowings based on Principal Component Analysis(PCA):Wang and Chen(1998)MultivariateProcess Capability Indices(MPCI),Xekalaki and Perakis(2002)MPCI.Wang(2005)MPCIAuthor(s)Edgar Santos-Fernandez,Michele Scagliarini.Maintainer:Edgar Santos-Fernandez<**************************>ReferencesAnderson,T W(1963)."Asymptotic theory for principal component analysis".The Annals ofMathematical Statistics,34,122-148.Chen H(1994)."A multivariate process Capability index over a rectangular solid zone."StatisticaSinica,4,749-758.Hubele N,Shahriari H,Cheng C(1991)."A bivariate process Capability vector".In JB.Keats andDC.Montgomery(Eds.)"Statistical Process Control in Manufacturing".Marcel Dekker,New York.Jackson,J E(1991)."A user’s guide to principal components".John Wiley&Sons.New York.Pan J N,Lee C Y(2010)."New capability indices for evaluating the performance of multivariatemanufacturing processes".Quality and Reliability Engineering International26(1)Rencher,A C(2002)"Methods of Multivariate Analysis".2nd Ed.John Wiley&Sons.New York.Santos-Fernandez E,Scagliarini M(2012)."MPCI:An R Package for Computing Multivariate Pro-cess Capability Indices".Journal of Statistical Software,47(7),1-15,URL /v47/i07/.Scagliarini M(2011)."Multivariate process capability using principal component analysis in thepresence of measurement errors."AStA Advances in Statistical Analysis,95,346-357.Shahriari H,Hubele N,Lawrence F(1995)."A multivariate process capability vector."Proceedingsof the4th Industrial Engineering Research Conference,1,304-309.Taam W,Subbaiah P,Liddy W(1993)."A note on multivariate capability indices."Journal ofApplied Statistics,20,339-351.Wang,C(2005)"Constructing multivariate process capability indices for short-run production."The International Journal of Advanced Manufacturing Technology,26,1306-1311.Wang F,Chen J(1998)."Capability index using principal components analysis."Quality Engineer-ing,11,21-27.Wang F,Hubele N,Lawrence F,Miskulin J,Shahriari H(2000)."Comparison of three multivariateprocess capability indices."Journal of Quality Technology,32,263-275.Xekalaki E,Perakis M(2002)."The Use of principal component analysis in the assessment of process capability indices."Proceedings of the Joint Statistical Meetings of the American Statistical Association,The Institute of Mathematical Statistics,The Canadian Statistical Society.New York. See AlsoMSQC packageExamplesalpha<-0.0027Target<-c(2.2,304.8,304.8)LSL<-c(2.1,304.5,304.5)USL<-c(2.3,305.1,305.1)x<-matrix(c(2.196,2.184,2.135,2.140,2.119,2.163,2.145,2.209,2.227,2.277,304.728,304.704,304.713,304.721,304.724,304.670,304.699,304.791,304.737,304.859,304.798,304.746,304.680,304.719,304.767,304.792,304.753,304.816,304.754,304.822),nrow=10)#Matrix with three columns(quality#characteristics)and ten rows(number observations)#Computing the Shahriari et al.(1995)Multivariate Capability Vectormpci(index="shah",x,LSL,USL,Target,alpha)#Performing the Taam et al.(1993)Multivariate Capability Index(MCpm)mpci(index="taam",x,LSL,USL,Target,alpha)#Performing the Pan and Lee.(2010)correction of the Multivariate Capability Index(NMCpm) mpci(index="pan",x,LSL,USL,Target,alpha)#Computing the Wang and Chen(1998)Multivariate Process Capability Indices(MPCI)alpha=0.05mpci(index="wang",x,LSL,USL,Target)#Performing the Xekalaki and Perakis(2002)MPCI.mpci(index="xeke",x,LSL,USL,Target,Method=2)#Computing the Wang(2005)MPCImpci(index="wangw",x,LSL,USL,Target,Method=1,alpha=0.05)dataset1Simulated data setDescriptionThis is a dataset used in the examples.Usagedata(dataset1)FormatA data frame with180observations on the following5variables.X1a numeric vectorX2a numeric vectorX3a numeric vectorX4a numeric vectorX5a numeric vectorExamplesdata("dataset1")##maybe str(dataset1);plot(dataset1)...dataset2Real bivariate data setDescriptionThis example represents the measurements on the brinell hardness(X_1)and tensile strength(X_2) discussed by Wang and Chen(1998).Usagedata(dataset2)FormatA data frame with25observations on the following2variables.X1brinell hardnessX2tensile strengthReferencesWang F,Chen J(1998)."Capability index using principal components analysis."Quality Engineer-ing,11,21-27.Examplesdata("dataset2")##maybe str(dataset2);plot(dataset2)...mpci5 mpci Multivariate Process Capability IndexDescriptionIt performs capability indices for multivariate processes using the following approaches:Shahri-ari et al.(1995)Multivariate Capability Vector.Taam et al.(1993)Multivariate Capability Index (MCpm).Pan and Lee(2010)correction of the Taam et al.(1993)(NMCpm).and the follow-ings based on Principal Component Analysis(PCA):Wang and Chen(1998)Multivariate Process Capability Indices(MPCI),Xekalaki and Perakis(2002)MPCI.Wang(2005)MPCIUsagempci(index,x,LSL,USL,Target,npc,alpha,Method,perc,graphic,xlab,ylab,...)Argumentsindex is the name of the type of index to use.For instance:index="shah"or in-dex="taam"x matrix of the quality characteristics.LSL is the vector of the Lower Specification Limits.USL is the vector of the Upper Specification Limits.Target is the vector of the target of the process.npc is the number of principal component to use.Only for indices based on PCA.alpha for the Shahriari et al.(1995)and Taam et al.(1993)indices,alpha is the proportion of nonconforming products(conventionally=0.0027)In the case of the indices based on Principal Component Analysis(PCA)(Wangand Chen(1998),Xekalaki and Perakis(2002),Wang(2005)),alpha is the thesignificance level.Method is the Method used to decide how many Principal Components(works only with PCA indices).perc is the percent of Cumulative Proportion of explained variance specified by the user in Method1(only for PCA indices).graphic allows in bivariate case the graphical representation.xlab x axis label.ylab y axis label....others parameters6mpci DetailsWhen the parameter Target is not specified,then it will be estimated as Target=LSL+(USL-LSL) /2.If alpha is missing the function assume alpha=0.0027for thefirst two indices and0.05for the others.A priori,the user can choose the number of Principal Components using:summary(princomp(x))In order to work with the number of Principal Components(npc),the user can:Specify the value of npc.Else,choose betweenfive methods described below(without introduce a value of npc).If npc and Method is not specified the function works uses Method1(default Method=1).In this case,the user could specify a desired percentage other than the default80On the other hand,if npc and Method are both specified the function computes the MPCI using the number of principal components.It can be used one of thefive methods(modified of Rencher(2002)):Method1or Percentage:guarantees at least the80percent of Cumulative Proportion of explained variance.(or other percent specified by the user with the argument perc)Method2or Average:works with the principal components whose eigenvalues are greater than the average of the eigenvalues.Method3or Scree:using the Scree Graph(plot Eigenvalue number vs.Eigenvalue size)user can choose the principal components to retain.Method4or Bartlett.test:It implements the Bartlett’s test to ignore the principal components not significantly different to the rest.Method5or Anderson.test:it computes the Anderson’s test to ignore the principal components not significantly different to the each other.ValueUsing the index="shah"the function return a vector composed by of three components(CpM;PV;LI).The First(CpM)is a ratio of the areas or the volumes.A value of CpM higher than one indicate that the modified process region is smaller than the engineering tolerance region.The second component of the vector is defined as the significance level of a Hotelling T^2statistic computed under the assumption that the center of the engineering specifications is considered to be the true underlying mean of the process.Values of PV close to zero indicate that the center of the process is far from the engineering target value.The third component of the vector summarizesa comparison of the location of the modified process region and the tolerance region.It indicateswhether any part of the modified process region falls outside the engineering specifications.When index="taam"or"pan"the function return the value of MCpm or NMCpm.When the process mean vector equals the target vector,and the index has the value1,then99.73percent of the process values lie within the modified tolerance region.For values of index="wang","xeke"or"wangw"function return the followings indices:Mcp, MCpk,MCpm and MCpmk.When all indices are greater than1,the process is capable.mpci7NoteThe results can be different according to the Methods to compute the npc.The value of alphaused in Indices based on PCA(usually0.05)is different of the value in index="shah"or"taam"(conventionally=0.0027).Author(s)Edgar Santos-Fernandez,Michele Scagliarini.ReferencesAnderson,T W(1963)."Asymptotic theory for principal component analysis".The Annals ofMathematical Statistics,34,122-148.Chen H(1994)."A multivariate process Capability index over a rectangular solid zone."StatisticaSinica,4,749-758.Hubele N,Shahriari H,Cheng C(1991)."A bivariate process Capability vector".In JB.Keats andDC.Montgomery(Eds.)"Statistical Process Control in Manufacturing".Marcel Dekker,New York.Jackson,J E(1991)."A user’s guide to principal components".John Wiley&Sons.New York.Pan J N,Lee C Y(2010)."New capability indices for evaluating the performance of multivariatemanufacturing processes".Quality and Reliability Engineering International26(1)Rencher,A C(2002)"Methods of Multivariate Analysis".2nd Ed.John Wiley&Sons.New York.Santos-Fernandez E,Scagliarini M(2012)."MPCI:An R Package for Computing Multivariate Pro-cess Capability Indices".Journal of Statistical Software,47(7),1-15,URL /v47/i07/.Scagliarini M(2011)."Multivariate process capability using principal component analysis in thepresence of measurement errors."AStA Advances in Statistical Analysis,95,346-357.Shahriari H,Hubele N,Lawrence F(1995)."A multivariate process capability vector."Proceedingsof the4th Industrial Engineering Research Conference,1,304-309.Taam W,Subbaiah P,Liddy W(1993)."A note on multivariate capability indices."Journal ofApplied Statistics,20,339-351.Wang,C(2005)"Constructing multivariate process capability indices for short-run production."The International Journal of Advanced Manufacturing Technology,26,1306-1311.Wang F,Chen J(1998)."Capability index using principal components analysis."Quality Engineer-ing,11,21-27.Wang F,Hubele N,Lawrence F,Miskulin J,Shahriari H(2000)."Comparison of three multivariateprocess capability indices."Journal of Quality Technology,32,263-275.Xekalaki E,Perakis M(2002)."The Use of principal component analysis in the assessment ofprocess capability indices."Proceedings of the Joint Statistical Meetings of the American StatisticalAssociation,The Institute of Mathematical Statistics,The Canadian Statistical Society.New York.See AlsoFor other alternatives to select npc,see nFactors package or Jolliffe,I.T.(2002).Principal Compo-nent Analysis.Second edition.Springer Series in Statistics.8mpci Examplesalpha<-0.0027Target<-c(2.2,304.8,304.8)LSL<-c(2.1,304.5,304.5)USL<-c(2.3,305.1,305.1)x<-matrix(c(2.196,2.184,2.135,2.140,2.119,2.163,2.145,2.209,2.227,2.277,304.728,304.704,304.713,304.721,304.724,304.670,304.699,304.791,304.737,304.859,304.798,304.746,304.680,304.719,304.767,304.792,304.753,304.816,304.754,304.822),nrow=10)#Matrix with three columns(quality#characteristics)and ten rows(number observations)#Computing the Shahriari et al.(1995)Multivariate Capability Vectormpci(index="shah",x,LSL,USL,Target,alpha)#Computing the Shahriari et al.(1995)index using only x and the#specification limits(LSL and USL).#The function estimate the Target and assume alpha=0.0027rm(Target);rm(alpha)#Removing the parameters Target and alpha#previously defined.mpci(index="shah",x,LSL,USL)#Computing the Taam el al.(1993)Multivariate Capability Vectoralpha<-0.0027Target<-c(2.2,304.8,304.8)a<-mpci(index="taam",x,LSL,USL,Target,alpha)#Performing the Pan and Lee.(2010)correction of the Multivariate Capability Index(NMCpm) mpci(index="pan",x,LSL,USL,Target,alpha)#Using the indices based on based on PCAdata("dataset1")x<-dataset1Target<-c(30,70,15,12,120)LSL<-c(24,60,10,8,100)USL<-c(36,80,20,16,140)alpha<-0.05#Computing the Wang and Chen(1998)Multivariate Process Capability Indices(MPCI) #using the Bartlett s test to select how many principal components.mpci(index="wang",x,LSL,USL,Target,alpha=alpha,Method=4)#Wang and Chen(1998)index using the default method(Method1or#Percentage)and value of alphampci(index="wang",x,LSL,USL)#Xekalaki and Perakis(2002)Multivariate Process Capability Indices(MPCI)mpci9 #using the Bartlett s test to select how many principal components.mpci(index="xeke",x,LSL,USL,Target,alpha=alpha,Method=4)#Xekalaki and Perakis(2002)using the default method(Method1or#Percentage)and value of alphampci(index="xeke",x,LSL,USL,Target)#Wang(2005)Multivariate Process Capability Indices#using the Anderson s test to select how many principal components.mpci(index="wangw",x,LSL,USL,Target,alpha=alpha,Method=5)#Computing the Wang(2005)using the Method2(Average)mpci(index="wangw",x,LSL,USL,Target,alpha=alpha,Method=2)Index∗datasetsdataset1,3dataset2,4∗mpcimpci,5∗packageMPCI-package,2dataset1,3dataset2,4MPCI(MPCI-package),2mpci,5MPCI-package,210。

盐酸安罗替尼胶囊联合康莱特注射液在晚期非鳞非小细胞1.3.4.5江西省赣州市兴国县人民医院内科3424001.江西省赣州市兴国县人民医院普外科3424002.摘要：目的观察分析康莱特注射液联用安罗替尼是否能对晚期驱动基因阴性、非鳞非小细胞肺癌患者起到更好的治疗作用，为提高基层医院恶性肿瘤治疗水平提供理论基础，为肿瘤患者寻求实用、安全、有效的治疗方法。

方法将2018年9月-2019年3月我院40例晚期非鳞非小细胞肺癌三线治疗患者采用单双号的方式随机分为两组，分别命名为对照组与研究组，两组患者均为20例，予以对照组患者盐酸安罗替尼胶囊进行治疗，研究组患者在此基础上联合康莱特注射液进行治疗；观察比较两组患者不良反应发生情况以及客观疗效并进行统计。

结果研究组患者不良反应发生情况均明显低于对照组患者，同时，研究组客观疗效高于对照组，两组各项指标比较存在明显差异，具有统计学意义（P＜0.05）。

结论给予服用安罗替尼的患者联用康莱特注射液安全性更高，治疗效果更好，还能进一步减少安罗替尼尼的副作用。

关键词：盐酸安罗替尼胶囊；康莱特注射液；晚期非鳞非小细胞肺癌三线Clinical study of anlotinib hydrochloride capsule combined with Kanglaite injection in the third-line treatment of advanced non-squamous non-small cell lung cancerZhong Hui1 Zhong Zhenwu2 Liu Yan3 Liu Dan4 Wang Suhua51.3.4.5 Department of Internal Medicine, People's Hospital of Xingguo County, Ganzhou City, Jiangxi Province 3424002. General Surgery, People's Hospital of Xingguo County, Ganzhou City, Jiangxi Province 342400Abstract: Objective To observe and analyze whether Kanglaite injection combined with anlotinib can play a better role in treating patients with advanced driver gene negative, non-squamous non-small cell lung cancer, and provide a theoretical basis for improving the treatment level of malignant tumors in primary hospitals. Find practical, safe and effective treatments for cancer patients. Methods From September 2018 to March 2019, 40 patients with advanced non-squamous non-small cell lung cancer third-line treatment in our hospital were randomly pided into two groups using the single and double numbers, and were named the control group and the study group. Twenty patients were treated with anlotinib hydrochloride capsules in the control group. Patients in the study group were treated with Kanglaite injection on the basis of this. Observation and comparison of adverse reactions and objective curative effects were compared between the two groups of patients. Results The incidence of adverse reactions in the study group was significantly lower than that in the control group. At the same time, the objective curative effect in the study group was higher than that in the control group. There was a significant difference between the two groups in terms of indicators (P <0.05). Conclusion Patients taking anlotinib combined with Kanglaite injection have higher safety, better treatment effect, and can further reduce the side effects of anlotinib.Key words: anlotinib hydrochloride capsule; Kanglaite injection; advanced non-squamous non-small cell lung cancer third-line随着肿瘤治疗的迅速发展和不断完善，人类在征服肿瘤的进程中取得了很大成绩，但仍然需要不断地探索、不断地进步[1-3]。

Direct measurement of the melting temperature of supported DNA by electrochemical methodRita Meunier-Prest*,Suzanne Raveau,Eric Finot 1,Guillaume Legay 1,Mustapha Cherkaoui-Malki 2and Norbert Latruffe 2Laboratoire de SyntheÁse et d'Electrosynthe Áse Organome Âtalliques,UMR CNRS 5188,Universite Âde Bourgogne,6Bd.Gabriel,21000Dijon,France,1Laboratoire de Physique,UMR CNRS 5027,F-21011Dijon,France and 2Laboratoire de Biologie MoleÂculaire et Cellulaire,GDR CNRS 2583,Universite Âde Bourgogne,F-21000Dijon,FranceReceived July 18,2003;Revised September 29,2003;Accepted October 7,2003ABSTRACTThe development of biosensors based on DNA hybridization requires a more precise knowledge of the thermodynamics of the hybridization at a solid interface.In particular,the selectivity of hybridiza-tion can be affected by a lot of parameters such as the single-strand (ss)DNA density,the pH,the ionic strength or the temperature.The melting tempera-ture,T m ,is in part a function of the ionic strength and of the temperature and therefore provides a useful variable in the control of the selectivity and sensitivity of a DNA chip.The electrochemical tech-nique has been used to determine the T m values when the probe is tethered by a DNA self-assembled monolayer (SAM).We have built a special thin layer cell,which allows the recording of the cyclic voltam-mogram under controlled temperature conditions.T m has been determined by recording the thermo-gram (current versus temperature)of a redox indica-tor on a double-stranded hybrid (dsDNA)modi®ed electrode and comparison with the corresponding ssDNA response.T m of supported DNA varies linearly with the ionic strength.The stability of the SAMs has been considered and comparison between T m in solution and on a solid support has been discussed.INTRODUCTIONThe knowledge of the melting temperature,T m ,is of technological interest to understand the hybridization mech-anism involved in a DNA chip.T m is generally used as a parameter to adjust the properties of the cell in a DNA chip.The number of bases of DNA is modi®ed so that T m is maintained constant for each cell.The T m value used is that measured in liquid medium.T m in solution is well determined by spectroscopy and many empirical formulas were developed to account for both the ionic strength and the mole fraction ofG-C base pairs (1,2).More precise T m values can be obtained through on-line T m calculators (/)(3).However,the environment of oligomers can differ between a solid interface and the bulk solution due to difference between ionic strengths.The change in surface charge density induced by the hybridization is expected to in¯uence the T m value.There is rather scarce information on T m when DNA strands are immobilized on to a surface.The dif®culty is to measure the true surface temperature of the substrate and therefore ®nd the more appropriate method to heat the DNA support.The nature of the substrate onto which the DNA is immobilized is generally governed by the choice of the signal transduction.For example,in classical tests involving ¯uorescent or radiolabeled arrays,DNA probes are attached mostly to silica or glass surfaces (4±7)whereas piezoelectric,surface plasmon resonance or electrochemical detection involve nucleic acids immobilized on gold elec-trodes (4,8,9).For DNA on silica,the `supported'T m values have been determined by using ¯uorescence (10)and impedance meas-urements (11).The thermodynamic stability of immobilized double-stranded (ds)DNA is different from that of dsDNA in bulk solution and depends on the DNA density,namely the nearest-neighbor interactions (10).Concerning the DNA attached to gold via an alkanethiol anchor,T m has been measured by two-color surface plasmon resonance spectroscopy (12).As the substrate is deposited on a prism,the immobilized DNA is heated indirectly by means of the solution.These three techniques give T m values close to those in solution,varying by <10°C.Nevertheless,some key issues are still unclear:the thermal stability of SAMs is of crucial importance in the determination of T m ;aliphatic alkanethiols have been reported to thermally desorb (13±16).The desorption temperature ranges from 37°C to >100°C depend-ing on the aliphatic chain length and on the surface state.We propose a new approach that can provide an alternative and easy way to both measure the T m of supported DNA ®lm and verify the stability of the immobilization.The electro-chemistry has the advantage of combining the analytical power of electrochemical methods with the speci®city of the biological recognition process.The present work aims to*To whom correspondence should be addressed.Tel/Fax:+33380396086;Email:rita.meunier-prest@u-bourgogne.frNucleic Acids Research,2003,Vol.31,No.23e150DOI:10.1093/nar/gng150at Istanbul University Central Library on December 14, 2010 Downloaded frominvestigate the capability of the electrochemical methods to determine the T m of supported DNA.We have adapted the electrochemical cell for heating the substrate within0.1°C accuracy and measuring the electrical signal of a redox indicator.Different redox indicators have been tested to select the best candidates for thermal studies.The high packing density of the DNA monolayer is controlled using permeabil-ity experiments.In such experiments,the stability of self-assembled monolayer(SAM)versus the applied potential is very important.SAMs have been shown to be stable to potentials between approximately+0.8and±1.4V versus saturated calomel electrode(SCE)depending on the type of thiol derivative and on the properties of the metallic surface(17±22).Within these limits,thiol SAMs do retain structural order and high packing density especially in aqueous medium. Therefore,the indicators used in this study are electroactive within this potential window.Discussion focuses on the comparison between T m in solution and on the electrochemical probe to correlate the T m with the ionic strength.MATERIALS AND METHODSMaterialsMethylene blue(MB)(Aldrich),potassium ferricyanide (Aldrich)and hexaammineruthenium(III)chloride(Aldrich) were used as received at a concentration of5Q10±5,10±4and 10±4M,respectively.HPSFâpuri®ed5¢-TTT TTT TTT TTT TTT-(CH2)6-SH-3¢and underivatized complement were purchased from MWG Biotech(Evry,France).Mercaptohexyloligonucleotides were stored frozen to prevent oxidation of the thiol. HybridizationMercapto-and underivatized oligonucleotides(0.1mM)were hybridized in5mM phosphate/50mM NaCl by heating to 90°C for10min followed by slow cooling to room tempera-ture.In all experiments,hybridization is performed before the immobilization on to the gold electrode. Derivatization of gold electrodesAu(III)surfaces were prepared by thermal evaporation at a pressure of10±6Pa(0.1nm/s)of a thick gold layer(175nm)on to glass plated with4nm of chromium.Freshly evaporated gold electrodes were then modi®ed by incubation in0.1mM solutions of derivatized DNA duplexes in5mM phosphate/ 50mM NaCl(pH7.4)for18±48h at ambient temperature. Modi®ed electrodes were rinsed in phosphate buffer prior to use.The DNA density was previously quanti®ed by 32P-radiolabeling(23).We obtained a surface coverage of 8Q1011strands/cm2.ElectrochemistryAll the electrochemical experiments were carried out in a deoxygenated buffer made of5mM phosphate/x mM NaCl (x=35,50,100,200)Millipore water(pH7.4).The electrochemical instrumentation used for these experiments includes an EG&G283potentiostat connected to a PC.Data collection and analysis were performed using a Princeton Applied Research Software Model270.The DNA modi®ed electrodes were used as working electrodes.Potentials were measured relative to the Ag|AgCl|NaCl xmM reference elec-trode and then recalculated with respect to the SCE.The electrochemical techniques used are cyclic voltammetry and square-wave voltammetry.We have shown previously(23) that the electrochemical response and in particular the signal-to-noise ratio is greatly improved by using square-wave voltammetry.Square-wave voltammetry(24)is a dynamic method in which a train of pulses is applied at a stationary electrode.A rather large amplitude symmetrical square-wave perturbation is applied,each cycle of the square-wave coinciding with one cycle of an underlying staircase (Fig.1A).The waveform is characterized by D E S,the step height of the staircase,E SW,the half-peak-to-peak amplitude of the square-wave and t,the period of the square-wave excitation.The time parameters may be described alterna-tively by the frequency,f=t±1,or the pulse width,t p=t/2.The pulse width is the characteristic time of the experiment. Current is sampled over sampling interval t s.The current sampled on the forward-going or®rst half-cycle is referred to as the forward current(i f).The reverse current(i r)corresponds to the second half-cycle.Generally the net peak current (D i=i f±i r)is used because it is greater than i f since i r for a reversible system is opposite in sign to i f near the peak.W1/2is de®ned as the net peak half-height width.After optimization of the different parameters,the best results have been obtained with f=100Hz,D E S=1mV and E SW=50mV.All the square-wave voltammograms have been carried out under these conditions.Measurement cellA special cell was developed to control the temperature of the DNA modi®ed electrode(Fig.1B),as described previously (23).The main characteristic of the cell is its small internal volume(3Q1.5Q9mm)thereby permitting us to handle only a few microliters of solution using a microsyringe.Inlets and outlets of liquid of110m m in diameter are located in the cell base.The tightness of the cell is ensured by pressing all elements using four screws.All solutions passing through the cell are deoxygenated prior to experiments.Due to the small size of the cell,deoxygenation is not necessary during experiments.The electrode support constitutes the upper part of the cell.Located in the lower part,the auxiliary electrode is a platinum disk of2mm in diameter and the reference is a thermodynamic Ag|AgCl|NaCl xmM electrode, which relies on chloride concentration in the¯ow stream.The temperature is controlled within0.1°C accuracy from20up to 80°C using a Peltier heating plate in contact with the electrode support.To ensure a good equilibrium in temperature, electrochemical measurements are performed10min after the increase in temperature.RESULTS AND DISCUSSIONSurface controlThe negative anion Fe(CN)64±was chosen since it does not bind to the DNA,a poly-anionic molecule,due to repulsive effects(25)and is electro-inactive even at over-potentials as high as+1V.Fe(CN)64±becomes particularly interesting toe150Nucleic Acids Research,2003,Vol.31,No.23P AGE2OF8at Istanbul University Central Library on December 14, Downloaded fromestimate the DNA coverage on the electrode.Therefore,when the electrode is covered with a densely built-up monolayer,the cyclic voltammogram presents a lack of signal.Alternatively,when the gold electrode is partially uncovered,Fe(CN)64±is oxidized on the gold surface leading to a characteristic electrochemical response of ferrocyanide at 0.18V whose intensity is proportional to the amount of desorbed DNA.Cyclic voltammetry of Fe(CN)64±is used then as a routine method to guarantee a good derivatization of the probe.Choice of the redox indicatorFigure 2shows the square-wave voltammograms of three redox species at a DNA modi®ed electrode:ferrocyanide Fe(CN)64±,hexaammineruthenium(III)Ru(NH 3)63+and MB.The second redox indicator,Ru(NH 3)63+,is a groove binding agent (26).Its reduction proceeds through the facilitated diffusion of the ruthenium complex along the grooves of the DNA helix (25).Recording the electrochemical response of Ru(NH 3)63+as a function of temperature does not yield measurable differences.This may be due to the binding modeof Ru(NH 3)63+,which remains rather far from the stacked bases responsible for the electron transfer.The best results have been obtained with MB.The intensity of the square-wave voltammogram is 12t-fold higher than that of Ru(NH 3)63+.MB behaves as an adsorbed molecule:in cyclic voltammetry,the peak current varies like v and the shape of the peak corresponds to a strong adsorbed system (27).MB intercalates into the DNA base stack and therefore participates in electron transfer mediated by the stacked bases.This is the reason why MB has been chosen as the electrochemical intercalator in the following.At ambient temperature,the peak intensity is nearly the same whether the DNA is hybridized or not.The DNA duplex helices are tightly packed on the gold surface necessitating that MB binds at sites close to the DNA/solvent interface.In contrast,diffusion of MB into the single strand (ssDNA)monolayer becomes facilitated (28,29).This phenomenon counterbalances the rapid electron transfer observed with hybridized DNA (30,31)and therefore provides approximately the same signal inten-sity for both modi®ed electrodes.It is worth noting that the electrochemical study of Ozsoz et al .(28,29),which presents a diminution of the peak height after hybridization,involves DNA strands lying on the surface of the electrode,therefore ET through the p -stacks of the double helical DNA does not occur;in dsDNA,the bases are less accessible than in the ssDNA so the signal of dsDNA is reduced.In our case,the DNA strands form a densely packed monolayer upright oriented with respect to the gold electrode,favorable to ET.The monolayer thickness has been estimated by AFM between 4and 6nm for a 15mer oligonucleotide.This corresponds to upright or slightly bent strands.The same observations,obtained by ellipsometry measurements,have also been reported by Kelley and Barton (32).Desorption phenomenaFigure 3shows the variation of the maximum net peak current of MB in square-wave voltammetry as a function of the electrode temperature varying between 20up to 80°C bystepsFigure 2.Square-wave voltammetry of:(black line)10±4M Fe(CN)64±;(red line)10±4M Ru(NH 3)63+and (blue line)5Q 10±5M MB at a gold electrode modi®ed with 5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢hybridized to its complement in 5mM phosphate/50mM NaCl.Voltammograms were obtained with f =100Hz,D E S =1mV and E SW =50mV.Figure 1.(A )Potential time waveform for square-wave voltammetry and de®nition of the different parameters:E sw is the square-wave amplitude,D E s the staircase step height,t p =t /2the pulse width.(B )The cell design.P AGE 3OF 8Nucleic Acids Research,2003,Vol.31,No.23e150at Istanbul University Central Library on December 14, 2010 Downloaded fromof 0.5°C.When the temperature increases,the signal of MB with both ssDNA and dsDNA grows until a temperature of 28.5°C for ssDNA and 32°C for dsDNA,then falls down until a value of D i/W 1/2=1.8m A.mV ±1.Such a bell-shaped curve has been observed with alkanethiol SAMs and imputed to dynamic movements of the SAMs (13,33).Molecular dynamic simulations predict that at a low temperature the chains are orientationally ordered.When increasing the temperature,chain-disordering processes occur passing from a crystalline-like to a melted state.Partial desorption and surface migration of thiolates have also been observed.The experiment has been repeated with other 15mer DNA duplexes containing guanine bases.The thermograms present the same aspect,namely a maximum of the curve coupled with a limiting value D i/W 1/2=1.8m A.mV ±1at temperatures >70°C.The maximum intensity 20%higher with a 15mer DNA containing seven guanines indicates a greater af®nity of MB to guanine and cytosine bases (34,35).The current decrease does not depend on the DNA sequence reaching the same limiting value at high temperatures (T >70°C).Lets ®nd the possible origin explaining such a current decrease.It is well known that in square-wave voltammetry,moderately slow quasi-reversible redox reactions give responses larger than much fasterreversible reactions (36±38).It has been shown theoretically (36)that in the quasi-reversible region,the contributions of the forward and reverse currents to the net current are approxi-mately equal near the maximum net peak height,then the net peak splits into two.Experimentally,when the net intensity decreases,a split has never been observed and both contribu-tions of the forward and reverse currents remain of the same order.Moreover,the forward and reverse peaks were found to be symmetrical even at high temperatures.These results suggest that the increase in the reaction rate induced by the temperature increase cannot explain the current fall.Alternatively,some authors have suggested that a thermal desorption of alkanethiols SAMs can occur (14±16).This can be considered as the ultimate stage of the SAMs dynamic movements'process.The electrochemical response of MB on a bare gold electrode has been recorded as a function of the temperature (Fig.3).MB presents the characteristics of an adsorbed system;in particular,the cyclic voltammogram has a shape corresponding to an electrochemical reaction occurring on the electrode surface and the current is proportional to the scan rate (27,39,40).The low current value at the initial temperature reveals a smaller amount of MB adsorbed on the bare electrode compared with the DNA modi®ed electrode.From 20to 35°C the net peak decreases due to the apparition of a pre-peak (39,41)close to the other peak on the forward current.This induces a broadening of the net peak and a decrease of its height.When increasing the temperature,the two peaks merge.The current of MB at the gold electrode increases as expected for an activated process (42)until D i/W 1/2=1.8m A.mV ±1is reached at T =70°C,which matches with the minimum of the DNA modi®ed electrode signal at high temperature.Moreover,cyclic voltammograms have been carried out with Fe(CN)64±on a gold electrode tethered with 5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢hybridized with its complementary strand.A study in function of the temperature shows a lack of electrochemical signal until 60°C (Fig.4A and B).Then,the electrochemical response of Fe(CN)64±merges progressively with increasing the tempera-ture and reaches nearly the same intensity as that observed on a bare gold electrode at T =80°C (Fig.4A).Note that Fe(CN)64±is not oxidized on a well covered electrode due to repulsion of the DNA.The electrochemical signal at high temperatures reveals a partial destruction of the DNA monolayer and a strip of the gold surface where oxidation of Fe(CN)64±can occur.The thermal desorption of thiol SAMs has already been reported for aliphatic alkanethiol SAMs (13±16).Let us de®ne by T 1/2the temperature corresponding to desorption of half of the monolayer.Figure 4C represents the variation of T 1/2with the logarithm of the salt concentration.The thermal desorption of the SAMs is dramatically emphasized by an increase of the ionic strength.The sensibility of DNA SAMs to temperatures is of great importance in the practical use of such DNA probes.In particular,it has been shown that hybridization of an ssDNA immobilized by a thiol anchor has to be realized under mild temperature conditions and at rather low ionic strength.T m determination and effect of ionic strengthWe have reported in Figure 5B the literature `supported'T m values (solid lines)and compared them to the corresponding T m in solution (dotted lines).For the 25mer DNA (12)aFigure 3.Variation of the ratio of the square-wave peak current on the half-height width (D i/W 1/2)as a function of the temperature for 5Q 10±5M MB in 5mM phosphate/35mM NaCl (black solid circle)at a bare gold electrode and at a gold electrode modi®ed with:(red open circle)the single strand 5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢and (blue open circle)the duplex 5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢hybridized to its complement.(Blue solid line)Fitted curve obtained by calculation of a 6order polynomial regression on the whole experimental curve after elimination of the points that form the bulge.e150Nucleic Acids Research,2003,Vol.31,No.23P AGE 4OF 8at Istanbul University Central Library on December 14, 2010 Downloaded fromdecrease of ~10°C between the DNA in solution and the supported DNA has been observed.Different results have been obtained for the dA20:dT20duplex:the solution T m values calculated with an empirical formula (/)(3)are of the same order as those for DNA on silica (10).In that case,the slope d T m /dlog(c NaCl )is little different.An easy way to determine the T m is to compare the electrochemical responses given by both an electrode tethered with an ssDNA,i.e.5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢and a second electrode tethered with the corresponding hybridized strands (dsDNA).The signal obtained for both ssDNA and dsDNA increases with increasing temperature up to 28.5°C for ssDNA and 32°C for dsDNA (Fig.3).Contrary to the rise of the current that is regular for the ssDNA,the one obtained with the dsDNA presents a bulge at 24°C (for a salt concentration of c NaCl =35mM).A ®ne procedure has been developed to determine precisely the temperature related to the peak maxima.The ®tted curve has been obtained by calculating a high order polynomial ®t on the whole experimental curve after elimin-ation of the experimental points that form the bulge.For example,the curve corresponding to dsDNA with a salt concentration of c NaCl =35mM (blue circles in Fig.3)can be ®tted by a polynomial equation of order 6or more (blue solid line in Fig.3).Figure 5A shows the difference between the experimental measurements and the `regular'®t (blue solid line in Fig.3).As the temperature approaches T m ,the progressive separation of the two strands of the helicalDNAFigure 4.(A )Cyclic voltammetry of 10±4M Fe(CN)64±in 5mM phosphate/50mM NaCl (black dotted line)at a bare gold electrode at T =80°C and at a gold electrode modi®ed with 5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢hybridized to its complement at different temperatures:(red solid line)T =21°C;(green solid line)T =60°C and (blue solid line)T =80°C.(B )Peak current height of 10±4M Fe(CN)64±in 5mM phosphate/50mM NaCl as a function of the temperature (same DNA as A).(C )Variation of the half desorption temperature (T 1/2)with the logarithm of the ionic strength (log c NaCl )for the 15mer duplex 5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢hybridized to its complement and tethered on a gold electrode.P AGE 5OF 8Nucleic Acids Research,2003,Vol.31,No.23e150at Istanbul University Central Library on December 14, 2010 Downloaded fromfacilitates the diffusion of MB into the DNA monolayer,leading to an increase in the electrochemical response.Then,the complement strand is completely dehybridized and the signal falls down.To make sure that this temperature can be attributed to T m ,which is known to vary as a function of ionic strength,the experiment has been repeated at different salt concentrations (35mM `c NaCl `200mM)and theelectrochemical thermograms (current versus temperature)have been drawn.For ssDNA a regular curve is obtained while for dsDNA a bulge is observed.The same procedure as described previously has been performed and the results presented in Figure 5.When increasing the ionic strength,T m is shifted towards higher temperatures,indicating stabilization by greater Na +concentrations.To compare our results with those in solution,we have determined the T m of the DNA±MB complex in solution by UV spectroscopy.The equivalent oligonucleotide concentration has been calculated as follows:the electrode area is 0.15Q 0.9=0.135cm 2on which the DNA density is 8Q 1011strands/cm 2.This corresponds to 1.79Q 10±13mol in a cell volume of 4.05Q 10±5l,i.e.a concentration of 4Q 10±9M.The absorbance for l =260nm has been reported as a function of the temperature carefully measured with a thermocouple plunged into the solution.This melting curve has been repeated with different ionic strengths.The straight line obtained is presented in Figure 5B (blue dotted line).The T m of the DNA±MB complex in solution is lowed by 10°C with respect to the DNA without MB in solution.MB intercalates between the bases and therefore provides a deformation of the DNA,which induces a lower stability of the DNA and facilitates pletely different results have been observed with major groove binding agents (43,44),which contribute to increase the DNA cohesion:it has been shown that DNA is stabilized by iridium or ruthenium complexes and T m increases with nearly 5±10°C (43,44).When the DNA±MB complex is tethered on a support,the stability increases.The `supported'T m varies linearly as a function of log(c NaCl )with approxi-mately the same slope as that obtained in solution but shifted by >12°C compared with the solution.The T m increase observed for supported DNA can be interpreted as an increase of the salt concentration in the monolayer.Moreover,it appears that high packing density facilitates some destabiliza-tion of hybridized immobilized oligonucleotides and therefore diminished the T m (45).Figure 5B regroups our results together with the literature results obtained with a 20base (10)and a 25base tethered DNA (12).The melting temperature rises as the DNA length increases and the slope [d T m /d(log c NaCl )]is of the same order of magnitude whatever the DNA sequence,indicating an identical sensitivity of T m to the ionic strength.In the study of Peterlinz et al.(12),comparison between T m in solution and tethered on the gold electrode shows a decrease of 5°C for immobilized oligonucleotides.These results seem to be under estimated values due to thermal gradients in the SPR apparatus between the modi®ed prism surface and the thermal regulator as noticed by the authors.In our case,the temperature measurement corresponds well to the temperature of the DNA probe because the Peltier element is directly in contact with the electrode.CONCLUSIONSA more precise knowledge of the hybridization occurring at a solid interface is important in the development of DNA chip.Our work provides a comparison between tethered and untethered DNA.We have shown that the melting tempera-ture,T m ,of immobilized DNA can be obtained via the square-wave voltammetric response of MB as a function of the temperature probe.The supported melting temperaturesvaryFigure 5.(A )Current difference obtained by subtraction of the experimental points with the `regular'®t (blue solid line in the inset of Fig.3)as a function of the temperature for 5Q 10±5M MB in 5mM phosphate/x mM NaCl at a gold electrode modi®ed with the duplex 5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢hybridized to its complement.Magenta open diamond,x =35mM;green open up triangle,x =50mM;blue open circle,x =100mM and red open square,x =200mM.(B )Variation of the T m with the logarithm of the ionic strength (log c NaCl ).Solid lines correspond to DNA tethered on solid support,dotted lines to the corresponding DNA in solution.Experimental results for (blue solid square)the 15mer duplex 5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢hybridized to its complement and tethered onto a gold electrode in presence of MB,(blue solid circle)the 15mer duplex 5¢-TTT TTT TTT TTT TTT-(CH 2)6-SH-3¢hybridized to its complement in presence of MB in solution and literature results obtained with:(red open up triangle)silica coated with dA20:dT20(10);(green cross)5¢-HS-(CH 2)6-CAC GAC GTT GTA AAA GCA CGG CCA G-3¢hybridized to its complement (12).e150Nucleic Acids Research,2003,Vol.31,No.23P AGE 6OF 8at Istanbul University Central Library on December 14, 2010 Downloaded from。

Unit 01 > Textbook Study > Key t o Book ExercisesListening and S peaking1.1) The master said, “To learn without thinking is unavailing. To think without learning is dangerous.”2) The master said, “The superior man is modest in his speech, but exceeds in his actions.”3) The master said, “The wise take joy in water; the humane take joy in mountains. The wise are active; the humane are tranquil. The wise enjoy; the humane endure.”4) The master said, “Walking along with three people, my teacher is sure to be among them. I choose what is good in them andfollow it and what is not good and change it.”5) The master said, “They who know the truth are not equal to those who love it, and they who love it are not equal to those who delight in it.”Text AReading Comprehension1.(Paras. 1–2) Becoming a(n) good and responsible person(Paras. 3–4) Finding the sacred in the relationships of ordinary life(Paras. 5–8) Leaning toward harmony as life’s ultimate value(Paras. 9–10) Helping people all over the world grow in the arts of becoming good people2.A.b) in harmonious and respectful relations in the workplacec) in being a gracious and hospitable host to guestse) in having a sense of inner self-discipline and restraintf) in being polite and respectful to old peopleg) in being willing to give yourself to the n eeds of your familyB.b) seen in the variety of foods on a dinner tablec) felt in mutually respectful relations with other peopleAccording to the author, harmony includes healthy disagreements and has a democratic spirit.According to Whitehead, the ultimate form of harmony is love.Language in Use4.1) harmonious2) enrich3) adopted4) intense5) restraint6) dynamic7) flexible8) collapsed9) exemplified10) diversify5.1) equate with2) at the expense of3) at issue4) is compatible with5) speak of6) is embodied in7) be subordinate to8) in a ction6.1) are … consistent w ith2) be familiar with3) was confronted with4) annoyed with5) be identified with6) are … satisfied w ith7) is popular with8) are patient with7.1) a) persistb) stick2) a) consciousb) conscious; aware3) a) capableb) competentc) able4) a) liveb) livingc) alive5) a) keepb) reservec) preserve6) a) valueb) costc) worth8.1) 美国人最大的愿望就是过上一种更像儒家式的生活：更重视教育，更尊敬老人，个人需求更能服从集体利益，对家人更尽责，在生活中更有礼貌，在工作中更努力。

et al.Early identification of peripheral neuropathy based on sudomo-tor dysfunction in Mexican patients with type 2diabetes [J].BMC Neurol,2019,19(1):109-111.[13]Hui Y ,Yan YX,Yin D,et al.Study on the correlation between serumomentin-1level and insulin resistance in patients with type 2diabetes peripheral neuropathy [J].Chinese Journal of Diabetes,2021,29(6):453-456.惠媛,闫永鑫,尹冬,等.2型糖尿病周围神经病变患者血清网膜素1水平与胰岛素抵抗相关性的研究[J].中国糖尿病杂志,2021,29(6):453-456.[14]Celiker H,Erekul G,Turhan SA,et al.Early detection of neuropathyin patients with type 2diabetes with or without microalbuminuria in the absence of peripheral neuropathy and retinopathy [J].J Fr Ophtal-mol,2021,44(4):485-493.[15]Reynès C,Beaume JB,Latil-Plat F,et al.Concomitant peripheral neu-ropathy and type 2diabetes impairs postexercise cutaneous perfusion and flowmotion [J].J Clin Endocrinol Metab,2021,106(10):e3979-e3989.[16]Yang XR,Xiang Q,Qiu Y ,et al.Correlation between serum 25hy-droxyvitamin D and peripheral neuropathy in type 2diabetes [J].Journal of Kunming Medical University,2021,42(7):88-93.杨晓瑞,向茜,邱娅,等.血清25羟维生素D 与2型糖尿病周围神经病变的相关性[J].昆明医科大学学报,2021,42(7):88-93.[17]Sampath Kumar A,Arun Maiya G,Shastry BA,et al.Correlation be-tween basal metabolic rate,visceral fat and insulin resistance among type 2diabetes mellitus with peripheral neuropathy [J].Diabetes Metab Syndr,2019,13(1):344-348.(收稿日期：2022-11-16)氩氦刀冷冻消融联合PD1抑制剂+化疗治疗Ⅲb~Ⅳ期非小细胞肺癌的疗效评价娄小飞1，杜可朴2，王猛2，李亚丹2，高飞2，高梦宇2，杜雅冰3郑州大学第一附属医院药学部1、放射科2、脑瘤内科3，河南郑州450052【摘要】目的评估氩氦刀冷冻消融联合抗程序性死亡蛋白1(PD1)抑制剂+化疗治疗Ⅲb~Ⅳ期非小细胞肺癌(NSCLC)的临床疗效。

Journal of Chromatography A,1217(2010)858–880Contents lists available at ScienceDirectJournal of ChromatographyAj o u r n a l h o m e p a g e :w w w.e l s e v i e r.c o m /l o c a t e /c h r o maReviewThe challenges of the analysis of basic compounds by high performance liquid chromatography:Some possible approaches for improved separationsDavid V.McCalley ∗Centre for Research in Biomedicine,University of the West of England,Frenchay,Bristol BS161QY,UKa r t i c l e i n f o Article history:Available online 3December 2009Keywords:HPLCBasic compounds Stationary phases Reversed-phase HILICa b s t r a c tThis review considers some of the difficulties encountered with the analysis of ionised bases using reversed-phase chromatography,such as detrimental interaction with column silanol groups,and over-loading which both lead to poor peak shapes.Methods of overcoming these problems in reversed-phase (RP)separations,by judicious selection of the column and mobile phase conditions,are discussed.Hydrophilic interaction chromatography is considered as an alternative method for the separation of some basic compounds.©2009Elsevier B.V.All rights reserved.Contents 1.Introduction.........................................................................................................................................8592.Choice of column....................................................................................................................................8592.1.Column testing procedures..................................................................................................................8592.2.The Tanaka test and the Snyder hydrophobic subtraction parison of results with direct peak shape measurements...8602.3.Monolithic silica columns ...................................................................................................................8632.4.Slow column equilibration.Anion-exchange behaviour of alkylsilica RP columns e of column materials other than silica...................................................................................................8653.Choice of mobile phase..............................................................................................................................8663.1.Choice of modifier ...........................................................................................................................8663.2.Choice of mobile phase pH.Problem of reduced retention of bases at low pH.............................................................8664.Overloading .........................................................................................................................................8674.1.Overview of the problem....................................................................................................................8674.2.Possible causes of overloading ..............................................................................................................8684.3.Effect of buffer anion on overload...........................................................................................................8704.4.Overloading on mixed-mode reversed-phase/cation-exchange columns..................................................................8714.5.Effect of buffer pH on overloading ..........................................................................................................8715.Temperature effects.................................................................................................................................8736.Hydrophilic interaction chromatography (HILIC)..................................................................................................8747.Concluding remarks.................................................................................................................................8787.1.Overloading..................................................................................................................................8787.2.Selection of mobile phase pH................................................................................................................8787.3.Quality and choice of column ...............................................................................................................8797.4.Temperature.................................................................................................................................8797.5.Alternative separation mechanisms—e.g.HILIC.............................................................................................879References...........................................................................................................................................879DOI of original article:10.1016/j.chroma.2009.11.067.∗Tel.:+441173282469;fax:+441173282904.E-mail address:david.mccalley@0021-9673/$–see front matter ©2009Elsevier B.V.All rights reserved.doi:10.1016/j.chroma.2009.11.068D.V.McCalley/J.Chromatogr.A1217(2010)858–8808591.IntroductionThe analysis of basic compounds by high performance liquid chromatography(HPLC)continues to be of interest,as over70% of pharmaceuticals are bases(with about20%being acids)[1–3].A large number of compounds of biomedical and biological signifi-cance are also bases.Reversed-phase(RP)separations are by far the most common in liquid chromatography(LC),due to advantages that include ease of use with gradient elution,compatibility with aqueous samples,versatility of the retention mechanism allowing changes in the separation to be brought about by changes in pH, organic modifier or additives,and long experience with the tech-nique,allowing the rapid establishment of suitable experimental conditions for the analysis of a given sample[4].Nevertheless,it has been recognised for a long time that the analysis of basic com-pounds poses particular difficulties in RP separations.Many of these problems are associated with the complex structure of the surface in silica-based RP packings,shown in Fig.1.The surface concentra-tion of silanols on bare silica is reported to be about8.0␮mol m−2 [5].C18ligands are too bulky to react completely with all silanols; thus,a maximum coverage of4–4.5␮mol m−2can be achieved.A further number of reactive silanols can be“endcapped”by reac-tion with smaller silylating agents such as trimethylchlorosilane, but as many as50%of the original silanol groups remain unreacted on a typical RP column.The average p K a of these silanol groups is around7.1,but their acidity can be enhanced by the presence of metal impurities in the silica.Some groups appear to be suffi-ciently acidic that their ionisation cannot be entirely suppressed using acidic mobile phases with a pH within the stability limit of typical RP columns(2.5–7.5).Over this range of operational pH values,basic compounds are likely to be ionised,leading to ionic interactions with ionised silanol groups.BH++SiO−M+→SiO−BH++M+(1) where BH+represents the protonated base,and M+the mobile phase buffer cation.The problem of poor column efficiency(N)and exponentially tailing peaks shown by small quantities of bases is often attributed to this mixed mechanism process of hydropho-bic interaction and ion-exchange with the silanols.The slower sorption–desorption kinetics of silanol ion-exchange sites(kinetic tailing)with sample ions may be responsible[6],which will occur regardless of sample size.The simple existence of two retention processes cannot per se be the sole cause of tailing,as mixed-mode phases with carboxylic acid functions embedded within a hydrophobic chain can show excellent peak symmetry for bases[7]. However,the kinetics of interaction of such embedded groups,and the stereochemistry around the active site,could be completely dif-ferent from that of ionised silanols,which may be buried beneath the hydrophobic chains on classical C18phases.Instead of sim-ple ion-exchange sites,Neue et al.[8]have proposed the existence of strong synergistic sites with combined RP and ion-exchange properties.The overall retention for bases was described by the equation:k=k RP+k IX+k∗RP k∗IX(2) where k is the total retention,k RP is the hydrophobic contribu-tion,k IX is the ion-exchange contribution from surface silanols,and k∗RP k∗IX is a multiplicative contribution of both processes.These syn-ergistic sites could correspond to the subset of very high-energy sites with slow kinetics which have been long suspected to be the cause of exponential tailing for bases,as they appear to be domi-nant in the retention process.It was shown that this type of tailing is not responsive to small changes in sample load in RP–LC at low pH[6].This result might indicate that exponential tailing is not caused by overload of a small number of strong sites on the column. In contrast,overload often gives rise to right-angled triangle peak shapes when ionisation of silanols is suppressed in RP–LC when working at low pH.Overload tailing still occurs even for the most modern columns operated under conditions where there are no or a negligible number of ionised silanols on the column surface.It was recognised more than20years ago that bonded phases synthesised from pure silica(Type B phases)made from the hydrol-ysis of metal-free tetraalkoxysilanes resulted in reduced silanol acidity,and their use has considerably improved the analysis of bases[9].Only small contamination of such materials occurs dur-ing the processing of such packings,or from the water used in the hydrolysis.Nevertheless,some other features of the analysis of these solutes(such as overloading)remain problematic,and these issues have not been resolved by the use of high-purity silica.Already in1988,Snyder and co-workers[10]had reviewed the problems of analysis of basic solutes and had proposed some pos-sible solutions.The following recommendations were made: (a)Judicious selection of the column to reduce the number of avail-able acidic sites.(b)Reduction of the mobile phase pH to suppress ionisation of thesilanols.(c)Increasing the mobile phase pH above the analyte p K a,such thatthe analyte is unprotonated.(d)Addition of a silanol blocker such as triethylamine to the mobilephase to interact preferentially with ionised silanols.(e)Reduction of the sample concentration to alleviate the satura-tion of the acidic sites.Most of the arguments in this paper remain true more than20 years later,and these conclusions can be used as a simple guide for the chromatographer aiming to achieve the best separations for basic solutes.Perhaps only the use of silanol blocking agents has fallen somewhat out of favour,as these are less necessary with modern high-purity silica phases,and can also have some undesirable effects.Such effects include the generation of addi-tional background in HPLC–MS,the difficulty of removal from the stationary phase after use leading to permanent alteration of its properties,and even chemical reaction with some solute types.This topic,and some other well-known aspects of the chromatography of bases have been covered adequately in earlier reviews[11–13]. However,other features of the chromatography of these“difficult”compounds are still extensively debated in the literature,for exam-ple,the problem of their ready overloading in RP separations.This review will concentrate on the latest research in these topics,while attempting to summarise briefly previousfindings.Thus,it will con-sider RP column choice by use of evaluation data obtained from the Tanaka and the Snyder“hydrophobic subtraction”tests;current theories and the effect of overload for ionised solutes;the use of high pH to improve peak shape;whether temperature is a useful parameter in improving peak shape;andfinally whether other sep-aration mechanisms such as HILIC can provide a viable alternative to RP–LC for the analysis of bases.2.Choice of column2.1.Column testing proceduresThe selection of an appropriate RP column for the analysis of bases can be a daunting task,as now many hundreds are com-mercially available,with a considerable number recommended especially by their manufacturers for the analysis of basic solutes. Nevertheless,several databases are now available where a large number of different columns have been subjected to the same test procedure by the same group of workers on the same or similar instruments,allowing a useful and objective comparison of perfor-860 D.V.McCalley /J.Chromatogr.A 1217(2010)858–880Fig.1.Structures present on a typical RP monomeric-bonded silica (C8)endcapped with trimethylsilyl groups.After U.D.Neue,“Silica Gel and its derivatization for Liquid Chromatography”,in “Encyclopedia of Analytical Chemistry”,R.A.Meyers,Ed.,John Wiley &Sons,Ltd.,Chichester (2000)11450–11472.mance to be made.A question arises as to the validity of databases constructed by evaluation of only a few or even a single column of a given type,as to whether the results obtained may be truly repre-sentative of the performance of this brand,due to column to column and batch to batch variations.However,a careful study [14,15]has suggested that columns from major manufacturers actually show a rather high degree of reproducibility,probably resulting from the use of stringent quality control procedures.Indeed,the industry is likely to be self-regulating to a degree,as dissatisfied customers would switch to the use of more reproducible brands.Tight reten-tion specifications exist in the HPLC user environment,especially in the pharmaceutical industry,and changes in the column can jeop-ardise product release.However,it is possible that a manufacturer could be forced to change the sourcing of a production raw mate-rial,which might occur for example,if the column manufacturer does not make their own silica.Thus,under some circumstances,a recently purchased column may not behave in the same way as one tested several years beforehand.Nevertheless,we believe that such situations are rare,and in most cases,manufacturers strive to main-tain the reproducibility of their products over a long period of time,as many customers have established methods on a given brand of phase.It appears more common to introduce a new name or name variant of an existing phase to mark definitively such changes or improvements to the production process.Taking this factor,and the reasonable reproducibility of commercial columns into account,it seems that the results of tests on a particular brand of column would generally reflect the performance of that brand throughout the product lifetime.Both of the column evaluation methods described in detail below incorporate strongly basic compounds as test probes.In each test,their retention is monitored at low and intermediate pH val-ues.Columns which give relatively low retention of basic probes are also likely to give higher efficiency for basic solutes,as shown by correlation studies for at least one of the procedures (see below).2.2.The Tanaka test and the Snyder hydrophobic subtraction parison of results with direct peak shape measurementsWhile many different column testing methods have been devel-oped,two have become prominent and have the distinct advantage that databases of results for many hundreds,rather than just a few columns,are available.The Tanaka method [16]and the hydropho-bic subtraction procedure developed by Snyder et al.[17]both incorporate tests which allow a user to select phases that are likely to be suitable for the separation of basic compounds.We will consider here the Tanaka method as adapted and applied by Euerby and Petersson [18]to the evaluation of over 200commercial columns that can be compared on a freely available program from Advanced Chemistry Development [19].These databases appear to be updated periodically;for instance,the ACD database contains evaluations of recently introduced sub-2␮m phases.An alternative adaptation of the Tanaka procedure and its application to a large number of different stationary phases has also been made [20],and data are again freely available [21].A fourth testing scheme is that published by the US Pharmacopeia.This protocol is an adaptation of the work of Sander and Wise [22].For activity towards bases,this method uses the tailing factor of amitriptyline (the same probe as used in the Snyder–Dolan procedure).At the time of writing,the database contained fewer columns than the two major proce-dures (∼100)and will not be considered further here.However,data for both this procedure and the Snyder–Dolan (S–D)method are available on the USP website [23].In the Tanaka–Euerby (T–E)procedure,columns are tested by measurement of k for pentylbenzene as a measure of sur-face area and surface coverage;hydrophobic selectivity from the ratio of k (pentylbenzene)/k (butylbenzene);shape selectivity from k (triphenylene)/k (o-terphenyl);hydrogen bonding capac-ity from k (caffeine)/k (phenol)in unbuffered methanol–water;total ion-exchange capacity from k (benzylamine)/k (phenol in methanol–phosphate buffer pH 7.6;and acidic ion-exchange capacity from k (benzylamine)/k (phenol)in methanol–phosphate buffer pH 2.7.The latter three tests are of particular interest for the analysis of basic solutes.The program [19]allows the comparison of the similarities and differences between various columns,and per-mits the separate weighting of the various factors—for example,columns can be ranked according solely to their total ion capacity at pH 7.6if so desired.The S–D model recognises that hydrophobic retention is the dominant process in RP chromatography,and in the absence of other retention mechanisms,plots of log k for one column versus another should be a straight line.However,these other mechanisms give rise to scatter in the plots.Clearly,ion-exchange and hydrogen bonding are important contributors to the retention of basic solutes.The general equation for retention in theD.V.McCalley/J.Chromatogr.A1217(2010)858–880861Table1Evaluation of some selected RP columns by two different procedures.For details on the procedure,see text.Column name k pentylbz k(pentbz)/k(butbz)k(triphen)/k(terph)k(caff)/k(phen)k(bzm)/k(phen)2.7k(bzm)/k(phen)7.6Tanaka–Euerby procedureChromolith 4.22 1.24 1.310.480.120.63Discovery Amide 1.65 1.35 1.810.490.190.44Discovery C18 3.32 1.48 1.510.390.100.28Inertsil ODS-37.74 1.45 1.290.480.010.29Resolve C18 2.40 1.46 1.59 1.29 1.23 4.06Spherisorb ODS-2 3.00 1.51 1.560.590.230.76Symmetry C18 6.51 1.46 1.490.410.010.68Symmetry Shield RP18 4.66 1.41 2.220.270.040.20Xterra MS C18 3.52 1.42 1.260.420.100.35Xterra RP18 2.38 1.29 1.830.330.070.20H S A B C(2.8)C(7.0)Snyder procedureChromolith 1.0030.0290.008−0.0140.1030.187 Discovery Amide0.7200.013−0.6250.218−0.092−0.025 Discovery C180.9840.027−0.1280.0040.1760.153 Inertsil ODS-30.9900.022−0.146−0.023−0.474−0.334 Resolve C180.968−0.1270.335−0.046 1.921 2.144 Spherisorb ODS-20.962−0.0760.070.0340.908 1.263 Symmetry C18 1.0520.0630.018−0.021−0.3020.123 Symmetry Shield RP180.8500.027−0.4110.093−0.7280.136 Xterra MS C180.9840.012−0.143−0.0150.1330.051 Xterra RP180.757−0.043−0.4830.097−0.170−0.173model is:log˛=log k/log k(ethylbenzene)=Á Hhydrophobic − S∗steric resistance(to bulky interactions)+ˇ Acolumn H-bond acidity(non-ionised silanols)+˛ BH-bond basicity(from sorbed water)+Ä Cion interaction(ionised silanols)(3)Ethylbenzene is used as a non-polar reference solute.Greek letters represent empirical,eluent-and temperature-dependent proper-ties of the solute,which are relative to the values for ethylbenzene, for which all solute parameters are identically zero.The selection of the optimum probes for evaluation of each retention mode has been made from detailed studies.Bold capitals represent eluent-and temperature-independent properties of the column;these val-ues are relative to a hypothetical average Type B C18column.Any column which behaves identically to this hypothetical reference column will have H=1and all other values S*,A,B,C=0.The dataset of columns evaluated by this procedure is even larger than that for the T–E procedure and presently extends to at least400columns.In some versions of the program,different weightings can be assigned to each evaluation parameter,as in the Euerby procedure.Results for some RP columns selected from each database are shown in Table1.The T–E data show clearly that the older Type A bonded phases(Resolve C18and Spherisorb ODS-2)give higher retention of benzylamine relative to phenol at pH7.6(alpha values 4.06and0.76,respectively)compared with newer Type B phases based on highly pure silica(Discovery C18and Inertsil ODS-3, alpha values0.28and0.29,respectively).Similarly with the S–D method,values of C(7.0)for Resolve C18and Spherisorb ODS-2 are high(2.144and1.263,respectively)compared with Discov-ery C18and Inertsil ODS-3(0.153and−0.334,respectively.Values of alpha(benzylamine/phenol)at pH2.7and values of C(2.8)are also higher for the Type A compared with the Type B phases using both procedures,indicating general agreement between them. Snyder and co-workers[24]have correlated a published dataset of“silanol activity”for a number of RP columns(measured by the average plate number for amitriptyline and pyridine with methanol-phosphate buffer pH6.0)with values of C at pH6.0,inter-polated from C(2.8)and C(7.0).Columns with a highvalue of C(6.0) correlated with columns of high silanol activity,and those with low values of C(6.0)with low silanol activity.In a later study[6]95%of Type B columns(designated either on the basis of manufacturer claims,or on the date a column wasfirst sold)were shown to have C(2.8)≤0.25,while only11%of Type A columns satisfied this crite-rion.Tailing of basic solutes(as measured by the asymmetry factor A s)was minimal for columns with C(2.8)<0.25(i.e.Type B columns) and tended to increase for larger values of C(2.8).From Table1,the Type A phases Resolve C18and Spherisob-ODS-2,now identified as such due to values of C(2.8)≥0.25,also give the highest values of hydrogen bonding acidity(parameter A,0.335and0.07,respec-tively,determined from the retention of amide probe compounds). Similarly,these phases also gave the highest relative retention of caffeine/phenol in the Tanaka procedure(1.29and0.59,respec-tively).The data can also be used to compare the effect of other features,e.g.the performance of embedded polar group phases (EPG)and the equivalent conventional C18phase,manufactured on the same silica.EPG phases include columns with embedded amide groups within the hydrocarbon chain:or carbamate groups:EPG phases have been proposed to give better peak shapes for the analysis of bases[24,27].The incorporation of an EPG in XTerra RP18reduces somewhat the Tanaka alpha(benzylamine/phenol) 7.6parameter to0.20,compared with0.35for the XTerra MS C18 column.Similarly,the S–D C(7.0)parameter is reduced to−0.173 for the EPG compared with0.051for the conventional phase.It is862 D.V.McCalley /J.Chromatogr.A 1217(2010)858–880possible that the reduced retention of benzylamine and other bases may be caused by a layer of water that is adsorbed close to the surface of EPG phases,providing some deactivating effect for the silanol groups [25,26].Other authors have compared conventional and EPG phases bonded on the same type of silica,on the basis of peak shape measurements.It was found that on average,peak shapes were indeed improved on the latter phases [27].Neverthe-less,it appears that the EPG technology gives more improvement in performance with phases bonded on older impure silicas,rather than the modern Type B silicas [27].This result seems to be reflected in the somewhat inconclusive data from Table 1concerning the rel-ative retention of bases on conventional and EPG phases.Thus the Discovery EPG phase (amide)has a slightly larger value of the T–E alpha (benzylamine/phenol)7.6parameter (0.44)compared with the regular C18phase (0.28).In contrast,the S–D C (7.0)parameter is smaller on Discovery Amide (−0.025)compared with Discovery C18(0.153).Similarly,while the T–E procedure indicates a con-siderable lower value of alpha (benzylamine/phenol)at pH 7.6for Symmetry Shield (0.2)compared with Symmetry C18(0.68),the S–D C (7.0)parameter for the EPG phases is slightly greater (0.136)compared with the regular phase (0.123).Euerby and Petersson pointed out that the extra retentiveness of phenols on EPG phases might invalidate the results of tests for silanophilic activity which involve the use of such solutes.They therefore suggested substitut-ing benzyl alcohol for phenol in the Tanaka test.Benzyl alcohol has retention properties similar to those of phenol but does not show excess retention on EPG phases [28].These particular comparisons point to some possible differences in the compatibility of column evaluations from either method.The Hoogmartens group looked more generally at the compati-bility of results from the S–D method and their own adaptation of the Tanaka procedure [29],finding a rather poor overall correlation between the two approaches.In a previous paper,this group had demonstrated a good correlation between their own method and the Euerby results.This latter finding is perhaps not surprising,as both are based on the Tanaka method.The problem of compatibility of the S–D and Tanaka methods may well be in the different mobile phase conditions and different probe solutes used in these tests.The S–D procedure uses the retention of the strong bases amitriptyline and nortriptyline in acetonitrile–phosphate buffer to calculate the cation-exchange term C (2.8)and derives the value of C (7.0)from the C (2.8)results by multiplying by the ratio of the retention fac-tors of the quaternary amine berberine at pH 7.0and 2.8;the T–E benzylamine tests use methanol as the organic modifier.Indeed the use of these different modifiers may explain the somewhat differ-ent evaluations of the EPG phases by either method.Even using the same mobile phase conditions,McCalley and Brereton [27,30–32]showed that peak shape data was not consistent between different basic probes.Thus,for example there was little correlation between A s for codeine and nortriptyline when using methanol–phosphate buffers at pH 3.0,whereas either of these solutes has been used as a single test compound to evaluate the relative silanol activity of different phases.One phase (Waters Symmetry Shield)gave,of 9highly inert RP columns,the highest N and lowest A s for nico-tine using acetonitrile–phosphate buffer at pH 7.0but the lowest efficiency for analysis of pyridine.Fig.2shows a principal compo-nents analysis (PCA)loadings plot for analysis of nine basic solutes on eight different RP columns using a mixture of methanol with a pH 3.0buffer.Lines can be drawn from the centre of the plot to each data point.Parameters that are opposed (i.e.appear at 180◦)measure equivalent but opposite trends.Thus N and A s values are opposed,with efficiency increasing as asymmetry decreases,as expected.Parameters that are at 90◦,like the asymmetry factors of pyridine and quinine,measure unrelated trends,and thus may be evaluating relatively different aspects of the detrimental inter-action of bases with the column surface.Conversely,the asymmetry parameters of nortriptyline and diphenhydramine have a smaller angle between them,and may be measuring more related proper-ties.It might therefore not be necessary to include both substances in a test mix for these particular mobile phase conditions.For over-all evaluation of column properties exploring different aspects of detrimental interactions,a test mix could include five compounds:codeine,quinine,amphetamine,nortriptyline and pyridine.The ranking of columns at pH 7using methanol was different from that at pH 7using acetonitrile;note that these correspond to the differ-ent modifiers of the T–E and S–D evaluation schemes,respectively.Snyder and co-workers [6]also observed that the tailing of basic (cationic)solutes on a given column appeared to be solute specific,finding that values of A s for the bases amitriptyline,nortriptyline,the quaternary compound berberine,and 4-n -hexylaniline corre-lated extremely poorly (r 2=0.01–0.19).The use of multiple basic test solutes and different mobile phase modifiers at different pH values would be a considerable task for the construction of these column evaluation databases.However,inclusion of a range of test compounds would undoubtedly improve the performance of these databases.It seems certain that these differences in test solutes and conditions contribute to the lack of correlation between the S–D and T–Etests.Fig.2.PCA loadings plots based on retention factor (k ),column efficiency (N ),Dorsey–Foley column efficiency (N df )and asymmetry factor (A s ).Data for eight different Type B reversed-phase columns and nine different probe compounds with methanol–phosphate buffer pH 3.0as mobile phase.See [30].。