To improve the safety of ammonium nitrate explosives, the melamine urea-formaldehyde resin (MUF resin) was selected for the preparation of three typical nitramine explosives  based green polymer-bonded explosives (GPBXs) via interfacial polymerization. Meanwhile, the corresponding composite particles prepared by physical mixing and drying bath methods were studied and compared. The particle morphology, crystal structure, thermal stability, and safety performance of the resultant composite particles were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectra, differential scanning calorimeter (DSC), and impact sensitivity test, respectively. SEM results showed that MUF was successfully coated on the surface of the three explosives, and different composite particles prepared by the same method have their own unique characteristics. Such effect is attributed to the resin’s ability to isolate and buffer external stimuli. It is obvious that the interfacial polymerization is an effective desensitization technique to prepare core-shell composite particles for explosives.The online version of this article (10.1186/s11671-018-2803-z) contains supplementary material, which is available to authorized users. As technology and weapon systems continue to evolve, ammunition is required not only to have high precision, high power, and long range for the weapon firepower system, but also to maintain relatively high safety in other environments. However, conventional explosives like hexahydro-1,3,5-trinitro-1,3,5-trizine (RDX), 1,3,5,7-teranitro-1,3,5,7-tetrazocane (HMX), and 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaiso-wurtzitane (CL-20) are difficult to meet these requirements  was from Tianjin Sailboat Chemical Reagent Technology Co., Ltd. Urea, formaldehyde, hydrochloric acid , and resorcinol (R-80) were provided by Tianjin Tianli Chemical Reagent Co., Ltd. Ammonium chloride was purchased from Tianjin Guangfu Technology Development Co., Ltd. Polyvinyl alcohol 2488 (PVA) was supplied by Qingdao Yousuo Chemical Technology Co., Ltd. Pure water was obtained from pure water supply of Taiyuan Iron and Steel Co., Ltd.HMX, RDX, and CL-20 were provided by Gansu Yinguang Chemical Industry Group Co. In our study, the raw materials were selected in drying bath process. When preparing explosive/MUF composites by physical mixing and interfacial polymerization methods, the raw materials were recrystallized according to the reference . DimethyThe MUF binder with excellent comprehensive properties was prepared by a two-step process. Firstly, preparation of urea-formaldehyde resin prepolymer. 0.62 g of urea and 1.87 g of formaldehyde solution (the concentration is 37%) were mixed, and then the urea was sufficiently dissolved with a magnetic stirrer. The pH value of the mixture was tuned to 8.5~9.5 with triethanolamine. The solution was placed in a water bath at 65 °C and stirred for 1 h until a transparent and viscous urea-formaldehyde resin prepolymer was obtained. After cooling, HCl was added dropwise until the pH value of the solution was adjusted to about 3.5, and set it aside. Secondly, preparation of MUF. 1.87 g of prepolymer was added to 35 ml of deionized water to form an emulsion under uniform stirring. Subsequently, 8% PVA, 0.01 g of melamine, 0.125 g of resorcinol, and 0.06 g of ammonium chloride were successively added, and the pH value was adjusted to about 3.5 with dilute hydrochloric acid. Then the three-necked flask was placed in the water bath at 65 °C and reacted for 3~4 h, followed by standing, natural cooling and vacuum filtration. The solution was washed with deionized water, finally affording high-quality MUF resin. After drying, approximately 0.3 g of MUF was weighed.The preparation of explosive/MUF composite particles by interfacial polymerization and drying bath methods is completely consistent with the preparation of urea-formaldehyde resin prepolymer in the two-step synthesis of MUF binder. However, the second step is obviously different.In the fabrication of explosive/MUF composite particles by interfacial polymerization, 6 g of explosives was added to 35 ml of deionized water, and 0.01 g of span-80 was dropwise added as an emulsifier. Subsequently, the system was emulsified and sheared at a rate of 7000 rad/min for 30 min until a stable explosive emulsion was formed. The explosive emulsion replaced the deionized water in the two-step synthesis of MUF resin. The synthesis diagram is shown in B in Fig. In the preparation of explosive/MUF composite particles by the drying bath method, 6 g of explosive was dissolved in 35 ml of DMSO at 65 °C to form an explosive solution. The explosive solution replaced the deionized water in the two-step synthesis of MUF resin. After 3 to 4 h of reaction, a stable explosive/MUF milky mixture was formed. Then, the emulsion was placed in an oven and dried at 70 °C for 48 h, finally affording explosive/MUF composite particles. The synthesis diagram is shown in C in Fig. In order to compare with the explosive/MUF particles prepared by the first two methods, we also prepared explosive/MUF particles by using a simple physical mixing method. The MUF binder, prepared by the two-step synthesis, was mixed with 6 g of explosive in 35 ml of deionized water, and then, the mixed solution was stirred in the water bath at 65 °C for 2 h. After that, the mixture was let to stand, followed by filtration and drying; explosive/MUF composite particles were obtained. The preparation sketch is shown in A in Fig. We labeled the samples prepared by interfacial polymerization method, drying bath method, and physical mixing method, as sample 1, sample 2, and sample 3, respectively.λ = 1.5418 Å. All samples were scanned from 5° to 50° with steps 0.03 and 6 s counting time; Fourier transform infrared (FT-IR) spectra were characterized by a Nicolet FT-IR 8700 Thermo  with a wave number resolution of 4 cm−1 and a single average of 32 scans at number temperature; thermal analysis was performed on a differential scanning calorimeter  at heating rate of 10 °C/min. The drop hammer apparatus; the special height (H50) represents the height from which 2.500 ± 0.002 kg drop-hammer will result in an explosive event in 50% of the trials. In each determination, 25 drop tests were made to calculate the H50. And the mass of sample is 30 mg. The friction sensitivity of the samples was tested with a WM-1 friction instrument. In each determination, 25 samples were tested, and an explosion probability  was obtained. And the mass of sample is 20 mg. The particle size tested by QICPIC dynamic particle analyzer , and its working environment is 5~35 °C; relative humidity is less than 85%; light source type is He-Ne laser; power is 2.0 mW; and wavelength is 0.6328 μm.Field-emission scanning electron microscopy (FESEM) images were taken on a MIRA3 LMH SEM (Tescan) at 10 k; X-ray diffraction (XRD) patterns were obtained using a DX-2700  X-ray diffractometer with Cu-Kα  radiation at The morphology and structure of the raw RDX, HMX, and CL-20; the synthesized MUF binder , and one hydrate phase (γ-HMX). And β-HMX is generally considered as the most stable phase with high explosive energy, large density, and low sensitivity, which is of course related to the spatial structure of its monoclinic P21/c . In the periment .Probing the thermal decomposition process is very important for energetic materials . In our For HMX, the DSC curve shows an endothermic peak at 279.2 °C, subsequently an exothermic peak at 284.54 °C Fig. , attribuH50 increased from 21.6 cm, 31.8 cm, and 15.3 cm to 73.4 cm, 85.6 cm, and 64.03 cm, respectively


Rhizoma chuanxiong. Pot experiments were conducted with six amendments . The results showed that soil pH, biological activities  and R. chuanxiong biomass were greatly improved with the addition of amendments in all treatments, especially in T3 and T6. Also, amendments effectively decreased the concentration of malondialdehyde and H2O2 in R. chuanxiong. In the T3 treatment, the bio-available Cd and Cu in soil were significantly decreased by 0.53 and 0.41 mg kg−1, respectively. Meanwhile, the amendment in T3 reduced Cd and Cu accumulation in R. chuanxiong about 45.83 and 39.37%, respectively, compared to T0. Moreover, the Fourier transform infrared spectroscopy spectra showed the surface functional groups of every amendment. To conclude, this study offers an effective and environmental method to reduce metal accumulation in R. chuanxiong on heavy metal co-contaminated soil.An improved method was applied for remediating cadmium and copper co-contaminated soil and reducing the metal concentration in  Heavy metals such as aluminium (Al), copper (Cu), lead (Pb), cadmium (Cd) and chromium (Cr) are easy to transfer into soil and water, which will pose extreme toxicity to plants and aquatic organisms ,2. For eet al.  found thet al. . MoreoveRhizoma chuanxiong , the dried rhizome of the Umbelliferae plant species R. chuanxiong Ligusticum chuanxiong Hort, is one of the most popular and oldest herbal medicines in the world [Rhizoma chuanxiong has been used for thousands years in traditional Chinese, Japanese and Korean folk medicine [. In addition, R. chuanxiong has attracted many researchers' attention owing to the ability of accumulating heavy metals. For example, Li et al. [R. chuanxiong to Cd and Cu was more remarkable, especially to Cd, compared to Pb and Hg. Up to now, there are only few reports about the methods of reducing metal uptake by R. chuanxiong. Therefore, to ensure the safe use of R. chuanxiong, it is of key significance to reduce heavy metal concentration in R. chuanxiong.he world . Rhizomamedicine , and appmedicine , hypertemedicine , ischaemmedicine , etc. Ini et al.  found thMany methods have been applied to reduce the availability of heavy metal in soil and plants, including physical, chemical and biological methods. Chemical immobilization is to decrease the concentration of dissolved contaminants by sorption , which w2PO4, CaH2PO4 and H3PO4), one of the most common amendments [Bentonite clays is a cost-effective amendment for stabilization of heavy metals in soil owing to its isomorphic substitution, permanent negative charges at surfaces as well as its environmental compatibility and ready availability –17. Phosendments , could rendments . Hence, endments . Humic aendments . Siliconendments . Biologiendments .R. chuanxiong by applying different amendments; (ii) evaluate remediation efficiency of amendments by estimating malondialdehyde (MDA), hydrogen peroxide (H2O2) and metal accumulation in R. chuanxiong coupled with the variety of soil quality ; and (iii) explore the correlation between soil pH, the content of available heavy metals in soil and accumulation of heavy metals in R. chuanxiong.The main objectives of this experiment were to: (i) investigate reduction in metal concentration in 2.2.1.−1, relatively. The components of amendments were bought from Tianjing Environmental Protection Monitoring Station, China.In this study, soils were collected from the campus of Sichuan University, Chengdu, China, where a remotely experimental site has been applied for scientific research about heavy metals for many years. The collected soil samples were air-dried and passed through a 2 mm sieve, then homogenized adequately for uniform distribution of heavy metals and other substrates. The soil basic prosperities are given in R. chuanxiong  were planted in each pot, then cultivated from August to November with an average temperature of 25°C indoors.Plastic pots (height 13 cm and diameter 20 cm) were used for this experiment. After air-drying, soil samples (2 kg) were mixed with 1.5% of amendments (w/w). The amendments mostly consisted of bentonite and phosphate, and the experiment set seven experimental groups with three replicates, including six groups (T1–T6) added amendments and a group with (T0) non-addition as a control . Two plaR. chuanxiong were harvested successively and washed with deionized water, then wet weights were recorded. Rhizoma chuanxiong were dried at 60°C for 3 days in an oven.Approximately three months later, 2.2.2 [One gram of air-dried soil was weighed in a 5 ml breaker, and added to 2.5 ml of deionized water without CO2 . The sol2.3.R. chuanxiong was harvested to estimate soil enzyme activities and bacteria counts. The measurement of dehydrogenase was through a spectrophotometer as described by Zhou et al. [−1). The activity of urease was spectrophotometrically determined at 578 nm and presented as mg NH4+ g−1 soil. The activity of invertase was determined spectrophotometrically at 508 nm and presented as milligram glucose per gram soil per 24 h. Bacterial counts in soil were counted on LB agar medium through the spread-plate method as described by Liu et al. [Soil samples were collected from each pot after u et al.  with minu et al. , Yan [27u et al.  and Gu [u et al. , respectu et al. .2.4.R. chuanxiong and soil samples was detected by atomic absorption spectroscopy  as described by Wu et al. [4 .Heavy metals in u et al. . Dried p2 extraction [−1 HAc at pH 2.88 ± 0.05 and shaken for 18 h. Then the solution was filtered with a 0.45 µm filter membrane for Cd and Cu analysis. At room temperature (about 25°C), 2.5 g of air-dried soil samples were incubated for 3 h in a shaker at 250 rpm with 12.5 ml of 0.1 mol l−1 CaCl2. Then the solution was centrifuged at 3000 rpm for 10 min and filtered with a 0.45 µm filter membrane. All the extraction was determined by flame atomic absorption spectrometry.The soil samples were collected to measure metal bioavailability by a toxicity characteristic leaching procedure (TCLP) and 0.01 M CaCltraction ,33. Two 2.5.et al. [R. chuanxiong tissues (1 g) were ground with 2 ml of 10% trichloroacetic acid (TCA) and quartz sand, then homogenized with 8 ml of 10% TCA. The absorbance was determined at 450, 532 and 600 nm. MDA was quantified with equation (2.1):According to the method of Liu et al.  with som2.6.2O2 determination was conducted following the steps of the hydrogen peroxide reagent kit from Nanjing Jiancheng Bioengineering Institute, China, and the absorbance was measured at 450 nm with spectrophotometry.H2.7.−1 at a resolution of 2 cm−1.The Fourier transform infrared spectroscopy (FTIR) spectra of amendments prepared as KBr discs were recorded in a Perkin-Elmer Spectrum 100 Model Infrared Spectrophotometer to examine functional groups of amendments . FTIR sp2.8.p < 0.05. All figures were performed by using Origin 8.5 software. Also, SPSS version 21.0 for Win was used to reflect the multivariate linear relationship among contaminated soil physicochemical characteristic, microbial abundance and metal fractions.The mean and standard deviation of the three replicates were calculated in this study. Statistical significance was performed through using one-way ANOVA in SPSS 17.0, and the mean values were compared using the least significant difference calculated at a significant level of 3.3.1.p > 0.05) among T0, T3 and T6. T2 presented the highest increase in soil pH. Bentonite which was the same component in all amendments had a positive effect on soil pH [The pH values of soil with different treatments at the end of the experiment are shown in  soil pH , therefo3.2.2 extraction can remove metals by ion exchange with Ca2+ and/or complexation with the chloride species [2 extraction methods. It could be observed that the available metals  decreased compared with T0, especially for Cd extraction by CaCl2 . Bacterial counts in T3 (log6.89 CFU g−1 soil) increased most, followed by T4 (log 6.72 CFU g−1 soil) compared to T0. Also, the highest and lowest fungi number were presented in T3 (log 5.50 CFU g−1 soil) and T0 (log5.11 CFU g−1 soil), respectively. On the whole, the number of microbes increased after the immobilization process, indicating that the addition of amendments contributed to soil micro-environment improvement.The microbial counts including bacteria and fungi counts and soil respiration are shown in figure 3b. It was clear that the respiration intensity in T6 (0.45 CO2mg g−1 dried soil 24 h−1) was around three times that of T0 (0.14 CO2mg g−1 dried soil 24 h−1); meanwhile, the respiration intensity of T3 (0.28 CO2mg g−1 dried soil 24 h−1) and T4 (0.22 CO2mg g−1 dried soil 24 h−1) were both almost two times more than in T0. Besides, the respiration intensity in other treatments also increased more or less.The respiration intensity of soil is shown in figure 32) diffusion, thereby stimulating aerobic activity in soil [The available heavy metals decreased, which reduced the environmental stress to microbes. Thus, the microbial counts and respiration intensity increased. Soil bacterial and fungal population were significantly and positively correlated with soil organic matter . Amendme in soil .3.4.a. Dehydrogenase activity showed different degrees of increase in all treatments compared to T0 (262.46 mg TPF g−1). It indicated that a light fluctuation happened in T2 (326.69 mg TPF g−1) and T4 (278.65 mg TPF g−1). Also, T3 and T6 presented the largest activities of dehydrogenase, about 472.86 and 461.90 mg TPF g−1, respectively.The activity of dehydrogenase in soil is shown in figure 4p < 0.05) among all treatments with comparison to T0. But higher activity presented in T3, T4 and T6  compared to T2 (just about 190 mg NH4–N g−1) (a).For urease activity, there was no significant difference (4–N g−1) a.b). The highest activity of invertase presented in T3 and T6, in specifically, about 108 and 112 mg glucose g−1, respectively, both of which were four times than that of T0 (27 mg glucose g−1). Compared to T0, invertase activity increased to approximately 50 glucose g−1 in T1, and nearly 70 mg glucose g−1 in T4. The activities of invertase in T2 and T5 increased slightly, compared to the control.Invertase activity is by far less sensitive to heavy metals than dehydrogenase and urease . Yet, itfigure 4b). More concretely, higher FDA activity presented in T3, T4 and T6 treatments, which were around two times greater than the activity in T0. Besides, the FDA activity showed a slight increase in T1, T2 and T5 in comparison to the control.The activity of FDA presented increased trends with the addition of amendments compared to T0 b. More cThe increase in soil enzymatic activities cooperated with the increase in soil microbes ,43. With3.5.R. chuanxiong in metal-contaminated soil, biomass of R. chuanxiong was recorded  the reduction in available heavy metals made it difficult for metals to enter the plant; (ii) amendments used in this experiment were full of organic matter which played an important role in retaining soil Cd and in decreasing its availability to plants through cation exchange capacity (CEC) [et al. researched [et al. [R. chuanxiong in T3 might indicate the biological matrix and compost was better for bentonite and phosphate on immobilizing metals.The phenomena about the reduction in heavy metal concentrations in ty (CEC) . As Marcsearched , soil or [et al. , bentoni [et al. ; and  and increase the activities of catalase (CAT) and peroxidase (POD) –60. Becad by CAT . So, the3.8.−1 might detect the inner hydroxyl groups [−1 are ascribed to stretching vibration of methylene (−CH2) groups in antisymmetric and asymmetric [−1 expressed the C–H bend from CH2 and C–O bend from carboxylate ions, and the P = O from phosphate, C–O–P and P–O–P were absorbed at 1241, 1197 and 1148 cm−1 [−1 represent the Ca = Ca torsion, C–OH3 torsion of the methoxy group and ring torsion of phenyl [−1 might indicate that –OH, –NH2, –CH2 and phosphate were related to the immobilization and complexation progress of Cd and Cu. Moreover, compared to T6, the vibration of 1241, 1197, 1148, 1074 cm−1 and below 500 cm−1 might imply that P=O, C–O–P, P–O–P, the Ca=Ca torsion, C–OH3 torsion of the methoxy group and ring torsion of phenyl were involved in metals  uptake by R. chuanxiong.The results of FTIR are shown in l groups , and it ymmetric , which a148 cm−1 –65. The f phenyl . The vib4.R. chuanxiong. Also, the amendments slightly improved soil pH, and soil biological activities . In all kinds of treatments, T3 and T6 showed a better effect on reducing metal availability in soils, which indicated that the recipes of amendment in T3 and T6 are more suitable to immobilizing Cd and Cu, compared to other treatments; whereas, amendment of T1 and T3 appeared to work better to reduce metal concentration in R. chuanxiong. In summary, results from this experiment declared that the amendment in T3 was the best treatment to reduce soil metal toxicity and concentration in R. chuanxiong. This experiment provided an effective and environmentally friendly pathway to remediate heavy metal-contaminated soil in situ.In the present study, the addition of amendments reduced the bioavailability of heavy metals and concentration in


The matrix effects and extraction recoveries of sirolimus ranged from 144% to 152% and from 80% to 96%, respectively. The inter- and intraday relative standard deviations were both <10%. The stability investigation showed that the blood samples were stable for 30-day-storage at −20°C, for 8 h storage at room temperature, for 24 h storage in the auto-sampler at 4°C, and for three freeze-thaw cycle process. The pharmacokinetic results demonstrated that the Cmax, AUC, and AUMC of sirolimus in rats  were increased after beincoadministration with Tanreqing Injection at 2.5, 5.0, and 7.5 mL/kg (i.v.), respectively, or at 5 min, 2 h, and 4 h  after SRL dosing, respectively. For the first time, the results proved the herb-drug interaction between Tanreqing Injection and sirolimus and accordingly suggested avoiding concurrent reception of those two drugs for patients.To evaluate the effect of Tanreqing injection on the pharmacokinetics of sirolimus in rats, a high performance liquid chromatography tandem mass spectrometry method was developed for sirolimus assay in whole blood. Calibration curve of sirolimus was acquired over a concentration ranging from 2.5 to 100 ng/mL with r For sirolimus , a common immunosuppressant, its efficacy came from inhibition on the serine/threonine kinase mammalian target (mTOR) by forming a complex with the immunophilin FK-506-binding protein (FKBP)-12. As an eTanreqing Injection (TRQ), a classical TCM formulation, is produced from five herb raw material: Scutellariae Radix, Fel selenarcti, Cornu naemorhedi, Lonicerae japonicae Flos, and Forsythiae fructus. In China , 6, it iLately, the safety of SRL application was concerned in combined drug administration treatment, in which case drug/herb-drug interactions (DDI/HDI) may result in some adverse effects (AEs). For example, an article described that a drug-drug interaction between azole antifungals or macrolide antibiotics and SRL in five patients led to an increase of SRL exposure , while aImmunoassay was reported as a reliable and convenient method for SRL blood concentration detection. However, it was also known that immunoassay might lead to overestimation of SRL concentration as a result of cross-reactivity with metabolites . TherefoAs above mentioned, no literatures were reported about the herb-drug interactions between SRL and TRQ. In order to investigate the potential HDI between SRL and TRQ, a LC-MS/MS method was established to evaluate the effect on the pharmacokinetics of SRL in rats after its co-administration with TRQ (1) on three different doses and (2) at three different times.SRL and cyclosporin D   with anaStock solutions (1 mg/mL) of SRL and IS were prepared in methanol, respectively. SRL stock solution was diluted in methanol-water (50:50) to obtain a series of working solutions, at concentrations of 25, 50, 100, 200, 400, 500, 800, and 1000 ng/mL. Calibration standards were prepared by dilutions of the above working solutions with appropriate blank rat blood to attain concentrations of 2.5, 5, 10, 20, 40, 50, 80, and 100 ng/mL. QC samples were obtained with concentrations of 5, 40, and 80 ng/mL. All solutions were stored at −20°C.μm, 2.1 mm × 75 mm, I.D. Agilent, USA) was kept at 55°C and a flow rate of 0.5 mL/min. Mobile phases consisted of methanol with 0.2% formic acid and 10 mM ammonium acetate (A) and 0.2% aqueous formic acid solution with 10 mM ammonium acetate (B). Gradient elution program was used for analysis: 0–3 min, 60% A; 3–5 min, 60–95% A; 5–8 min, 95%A. Injection volume was set at 10 μL.Analysis was carried out on an Agilent 1290 series HPLC coupled with an Agilent 6460 triple-quadrupole mass spectrometer that was equipped with jet stream electrospray ionization (ESI). Data acquisition and processing was performed on Agilent 6460 Quantitative Analysis version B.01.02 analyst data processing software . A Poroshell 120 SB-C18 (2.7  m/z 931.6⟶864.5 and fragmentation/collision energy 170 V/13 eV for SRL and m/z 1233.9⟶1216.9 and fragmentation/collision energy 190 V/17 eV for IS.Nitrogen (purity 99.9999%) was applied as the collision gas (0.1 MPa). The detector was operated in the positive mode. The conditions of the source parameters were: capillary voltage 4.0 kV, nebulizer 35 psi, drying gas temperature 225°C, drying gas flow 10 L/min, sheath gas temperature 325°C and sheath gas flow 12 L/min. The optimized multiple reaction monitoring (MRM) conditions of the analytes wereμL blood was added with 200 μL 0.4 M zinc sulfate aqueous solution: methanol precipitating solution , followed by vortex-mixing (2 min) and centrifugation . The sample supernatant (200 μL) was obtained and then loaded to LC-MS/MS system for analysis.100 x2) least squares linear regression analysis. The lower limit of quantification (LLOQ) was defined as the lowest SRL concentration with a signal-to-noise ratio of 10:1 and evaluated by analyzing spiked blood samples prepared in six replicates. The intra- and interday precisions and accuracies were obtained by analyzing five replicates of QC samples in three levels. The precision was defined as the relative standard deviation (RSD) and accuracy was expressed as relative error (RE). Matrix effect was determined by comparing the peak areas of SRL and IS spiked in extracted QC samples with those of analytes in standard solutions at equivalent concentrations. Extraction recovery was evaluated by comparing the peak areas of SRL and IS spiked in extracted QC samples with those of un-extracted standard solutions containing the equivalent amount of SRL. Stability evaluation was performed in the following conditions. Long-term stability was tested for the samples that were kept at −20°C for 30 days before analysis. Short-term stability was tested for the samples that were kept at room temperature for 8 h before analysis. Post-preparative stability was tested when the samples were kept in an auto-sampler at 4°C for 24 h before analysis. Freeze and thaw stability was tested for three freeze-thaw cycles when the samples were stored at −20°C for 24 h and thawed at room temperature.Method validation was performed according to US FDA guidance . SelectiAll animal protocols were approved by Animal Ethics Committee of Second Military Medical University. Sprague-Dawley rats  were obtained from Shanghai SLAC laboratory animal Co. Ltd. . Rats were quarantined for one week prior to study, and were housed in well ventilated cages at 20 ± 1°C and 50 ± 10% air humidity while on a 12-h light-dark cycle. All rats were fasted with free access to water for 12 h before experiment.In order to investigate the effect of different dose levels and dosing time of TRQ on the pharmacokinetics of SRL analysis, SD rats were divided into 6 groups of 6 animals each: control group-SRL  alone, group A1-coadministration of SRL  with TRQ , group A2-co-administration of SRL  with TRQ , and group A3-co-administration of SRL  with TRQ . TRQ were given to all rats at 5 min after SRL dosing in groups A1–A3.In order to investigate the effect of different dosing time of TRQ on the pharmacokinetics of SRL analysis, SD rats were divided into 4 groups of 6 animals each: control group-SRL  alone, and the rest rats in groups B1–B3 were treated with SRL  and TRQ . TRQ were given to rats at 5 min, 2 h and 4 h after SRL dosing in groups B1–B3, respectively. See the experimental protocol in supplementary Cmax, Tmax, t1/2, AUC, AUMC, and MRT) were calculated on Drug and Statistics DAS 3.2.6 , using noncompartmental pharmacokinetic analysis. The differences between groups were evaluated by Student's t test and were considered to be significant at ∗P<0.05 and ∗∗P<0.01.Blood samples (0.5 mL) were collected into heparinized tubes via retro-orbital plexus at pre-dose (0), 20, 40 min, 1, 2, 4, 6, 8, 12, 24, 36, and 48 h post-dose. Blood samples were stored at −20°C prior to analysis. Pharmacokinetic parameters (including LC-MS/MS condition”.Cyclosporine D was served as IS as the previous report . As MRM 2= 0.9955) over a range of 2.5–100 ng/mL, with LLOQ of 2.5 ng/mL. In detail, inter- and intraday precisions and accuracies for SRL had RSD values less than 10%. The extraction recovery was between 80% and 96%. The matrix effect of SRL was between 144% and 152%. Stability investigation showed that the RE values for SRL were less than 15% in rat blood for 30-day-storage at −20°C, below 8% for 8-h-storage at room temperature, less than 10% for 24-h-storage in the auto-sampler at 4°C, and below 20% for three freeze-thaw cycle process, which indicated that the blood samples were stable during the entire experiment. All the above results were within the ranges requested by the FDA for bioanalytical method validation and could be applied to the SRL pharmacokinetic study in rat.Calibration curve of SRL (y=0.0024x -0.0026) exhibited effective linearity , 28% , and 70% , respectively. In parallel, the AUC0→t of A1, A2, and A3 groups were significantly increased by 59% , 39% , and 92% , respectively, when compared to control group (219.673±32.306 ng·h/mL). As for AUMC, it was significantly increased by 60% , 44% , and 104% , respectively, when compared to control group (4122.178±593.331 ng·h/mL). It revealed that coadministration of SRL with single-dose TRQ could markedly increase the blood concentration of SRL. In the lowest dose of TRQ group (2.5 mL/kg), the three parameters of SRL mentioned above were increased by approximately 1-fold, suggesting that the HDI might appear even with lowest dose of TRQ coadministration. However, no change in Tmax was observed with or without TRQ coadministration. Also, values of t1/2 and MRT were similar with or without TRQ co-administration. The above observations suggested a potential HDI between SRL and TRQ.To evaluate the effect of different dose levels of TRQ on the pharmacokinetics of SRL, SRL pharmacokinetic data of control group and group A1–A3 were demonstrated in AUC0→t showed significant difference (P< 0.01) in groups B1–B3 when compared with those in control group, and AUC0→t in group B3 was smaller than that in groups B1 and B2. Tmax and AUMC presented in a similar trend with AUC0→t (without significance). In detail, compared with that of control group (219.673±32.306 ng·h/mL), the AUC0→t of B1, B2, and B3 groups were significantly increased by 39% , 37% , and 35% , respectively. As for AUMC, it was significantly increased by 44% , 49% , and 37% , respectively, when compared to control group (4122.178±593.331 ng·h/mL). Therefore, it could be concluded that the TRQ significantly enhanced the AUC of SRL when TRQ was administrated at the same time with SRL or 2 hours after SRL administration. This effect was not obvious when TRQ was administrated 4 hours after SRL administration. Besides, the pharmacokinetic profiles of SRL also showed the similar curves in the groups B1–B3. Based on the effect of different dose levels and different dosing time of TRQ, it could be found that the AUCs in groups A1-A3 and groups B1–B3 were higher than those in control groups, which indicated that TRQ might cause overexposure of SRL in patients receiving SRL along with TRQ.To evaluate the effect of different dosing time of TRQ on the pharmacokinetics of SRL, SRL pharmacokinetic data of control group and groups B1–B3 were listed in SRL is a substrate for CYP3A and P-gp. It is not sure that the five TCMs from TRQ or its main components inhibit the hepatic and intestinal CYP3A/P-gp system. However, it have been reported by some literatures that baicalin, a main component from Scutellariae Radix in TRQ, could inhibit hepatic CYP3A activity as well as P-glycoprotein efflux pump in the small intestine –22. TherActually, like the pharmacokinetic profile of the mean value of SRL in the stable renal transplant patients , the con∗1 carriers), he might need more SRL to reach target concentrations when compared with those with CYP3A5∗3/∗3 carriers [It was reported that SRL pharmacokinetics was associated with CYP3A and MDR1 genetic polymorphisms, but we failed to determine the relevant genetic information of the patient in the introduction. If the patient expressed the CYP3A5 enzyme (CYP3A5carriers . It mighA simple and accurate LC-MS/MS method was developed and validated for SRL assay in rat blood following a quick PPT procedure, which demonstrated good selectivity, linearity, precision and accuracy, matrix effect and recovery, and stability. This assay was successfully applied to evaluate the pharmacokinetics of SRL, when it was administrated alone and coadministrated with TRQ in rat. The results showed that different dose levels and different dosing time of TRQ would increase SRL blood concentration and exposure, indicating a potential HDI between TRQ and SRL. The study provided valuable information for SRL treatment: from the pharmacokinetic point of view, coadministration with TRQ or baicalin-derived products was not recommended in clinic. A systematical TDM for SRL was greatly encouraged for safety and would help to discover a possible DDI/HDI.


Chemical exchange saturation transfer (CEST) exploits the chemical exchange of labile protons of an endogenous or exogenous compound with water to image the former indirectly through the water signal. Z-spectra of the brain have traditionally been analyzed for two most common saturation phenomena: downfield amide proton transfer (APT) and upfield nuclear Overhauser enhancement (NOE). However, a great body of brain metabolites, many of interest in neurology and oncology, contributes to the downfield saturation in Z-spectra. The extraction of these “hidden” metabolites from Z-spectra requires careful design of CEST sequences and data processing models, which is only possible by first obtaining CEST signatures of the brain metabolites possessing labile protons. In this work, we measured exchange rates of all major-for-CEST brain metabolites in the physiological pH range at 37 °C. Analysis of their contributions to Z-spectra revealed that regardless of the main magnetic field strength and pH, five main contributors, i.e. myo-inositol, creatine, phosphocreatine, glutamate, and mobile (poly)peptides, account for ca. 90% of downfield CEST effect. The fundamental CEST parameters presented in this study can be exploited in the design of novel CEST sequences and Z-spectra processing models, which will enable simultaneous and quantitative CEST imaging of multiple metabolites: multicolor CEST. The large voxel size of MRS, however, is a limitation when it comes to metabolic profiling of highly heterogeneous diseased tissues such as tumorous tissue.Proton -magnetic resonance imaging (MRI). CEST is an imaging technique, which exploits chemical exchange of labile protons of a particular (endogenous or exogenous) CEST agent with water to detect the former indirectly with high sensitivity through the water signal1. In CEST, a Z-spectrum, which is a plot of the water signal attenuation versus off-resonance saturation frequency , is normally acquired. The labile protons of endogenous tissue metabolites contribute to the water signal attenuation downfield (Δω = 0–5 ppm) from the water resonance. CEST has been exploited in metabolite-weighted imaging of glutamate2, glucose4, glycogen5, creatine6, myo-inositol7, glycosaminoglycans8, and mobile proteins and peptides rich in amide protons (these metabolites are abbreviated in this work as “mobile amides”)9. Thus far, the measurement efforts have mainly resulted in single metabolite-weighted (<75% purity) contrast, e.g. for glutamate2. Still, contamination of the contrast with other metabolites (other 25% or more) may result in misinterpretation of glutamate-CEST contrast in pathology. Ideally, one would like to use optimized CEST sequences for simultaneous imaging of multiple metabolites and decompose the frequency-dependent metabolite-weighted contrast in the Z-spectra into corresponding (multicolor) metabolic maps. However, the design of multicolor CEST sequences and advanced data processing models requires a precise knowledge of metabolic CEST signatures in the tissue of interest.Complementary to 13, two dominant saturation effects in brain Z-spectra14. The extraction of other clinically relevant “hidden” metabolites, such as those mentioned above, from brain Z-spectra is a major challenge, as it is still unknown in which proportions the exchangeable protons of the different brain metabolites contribute to the Z-spectra and how their contribution depends on field strength, pH and sequence parameters.Multiple methods have been implemented for the extraction of downfield amide proton transfer (APT) and upfield nuclear Overhauser enhancement (NOE)15 simulations to find the main contributors to brain Z-spectra at different field strengths and pH as a function of saturation frequency offset. This in turn was used to optimize CEST-prepulse parameters for metabolic imaging at different field strengths.The aim of this work was to analyze CEST contributions from brain metabolites to the Z-spectra at different field strengths and pH. To this end, the exchange rate, arguably the most important parameter for CEST experiments, of major brain metabolites was measured at 14.1T in the physiological pH range at 37 °C. Subsequently, the CEST signatures of those metabolites were used in Bloch-McConnell equation (BME)16.The information on CEST-relevant metabolic parameters and CEST-prepulse parameters provided in this study, can be exploited in the design of novel CEST sequences and advanced Z-spectra processing models, which is the first step towards simultaneous and quantitative CEST imaging of multiple metabolites on par with MRS: multicolor CEST17 taking into account their in vivo concentrations, and type and number of exchangeable protons. Metabolic solutions in 10 mM phosphate-buffered saline with different pH values  were prepared for all of the identified metabolites. For each metabolite at each pH value, Z-spectra were acquired at multiple B1 saturation levels of the CEST-prepulse on a 600 MHz NMR spectrometer at 37 °C. To determine the resonance frequencies, exchange rates and T2 relaxation times of labile protons, full Bloch-McConnell equations (BME) were fitted to the Z-spectra of the in vitro metabolic solutions. Those experimental results at a pH of 7.0  are summarized in Table in vivo metabolic concentrations in the brain. It is interesting to note that the error in the fitted resonance frequencies was less than 0.01 ppm . Considering that a single resonance frequency was fitted at all pH levels, such a small error suggests that pH dependence of the frequency offsets (metabolites with respect to the water resonance) in the studied pH range of 6.4–7.3 is negligible. The Z-spectra with BME fits  has a faster exchange rate than that of the Glc α-isomer . All six hydroxyl protons of MI have an average resonance frequency of 1.00 ppm. The exchange rates of the hydroxyl protons of Glc are higher compared to those of MI, except for the Glc hydroxyl proton at position 5 resonating at 0.74 ppm.The hydroxyl protons of both glucose (Glc) and myo-inositol (MI) have their resonance frequencies close to water (Δω up to 1.40 ppm downfield from the bulk water resonance) with an exception for the α- and β-protons of Glc  and 2.64 .The four magnetically equivalent guanidinium protons of creatine (Cr) resonate at 2.00 ppm and have an exchange rate of 810 Hz, whereas the resonance frequencies of the guanidinium protons of phosphocreatine are 1.93 ppm , taurine (Tau), glutamate (Glu) and glutamine (Gln) have their resonance frequencies around 3.00 ppm and are characterized with fast exchange rates, i.e., k = 17 Hz and k = 49 Hz, respectively. The single amide proton of N-acetyl-L-aspartate (NAA) resonating at ca. 3.33 ppm was measured to have a very slow exchange rate k ≈ 0 Hz. Based on the literature, the amide protons originating from mobile proteins and peptides (mAmides) resonate at 3.5 ppm and have an exchange rate k = 22 Hz20.The amide protons of Gln resonate at 2.15 ppm and 2.87 ppm and are characterized with a slow exchange, Figure Figure In Fig. Figure The aim of this work was to identify the major brain metabolites that contribute to downfield CEST phenomena in brain Z-spectra at different field strengths and pH. To address this, we quantified exchange rate constants of major brain metabolites and used the signatures of these metabolites in BME at different field strengths and pH. We show that, regardless of field strengths and pH levels, five metabolites, i.e. myo-inositol, creatine, phosphocreatine, glutamate and mobile amides, account for ca. 90% of CEST contras in Z-spectra downfield from the bulk water resonance.k) is arguably the single most important parameter for optimizing detection of metabolites in CEST experiments. This parameter governs the labeling efficiency of labile protons10 and determines the optimum parameter settings for the CEST-prepulse21 for in-vivo imaging of the metabolites. Multiple BME simplified approaches have been suggested for exchange rate measurements of labile protons24. However, these simplified methods are not valid for fast exchanging protons25. Previously, resonance frequencies and exchange rates (line broadening in 1H-NMR) for many metabolites with a single exchanging site were determined at 11.7T at 25 °C26. Others studied metabolic variations with CEST  in human breast cancer cell lines at 11.7T at 37 °C27. In a recent review, simulations for four downfield CEST effects, i.e. for myo-inositol, creatine, glutamate and amides, were performed at the field strengths of 3T, 7T and 11.7T28. However, comprehensive measurements of metabolic exchange rates at 37 °C and an extensive analysis of pH-dependent metabolic contributions to Z-spectra in the brain for multiple field strengths are not yet available in the literature.The exchange rate constant  and exchange rate. To increase precision and reduce parameter correlation, which is especially important for the metabolites with multiple exchanging sites, BME were fitted simultaneously to metabolic Z-spectra  obtained at multiple B1 saturation levels of the CEST prepulse. Once metabolic CEST parameters are known, BME can be used to yield metabolic CEST signatures at any field strength and at any pH. In this work, we used metabolic CEST signatures to study metabolic contributions to brain Z-spectra over a variety of main field strengths, i.e. 3T, 4.7T, 7 T, 9.4T, 11.7T, and 14.1T, in the physiological pH range.Therefore, in this work, we chose to quantify exchange rates by fitting full BME to metabolic Z-spectra obtained at an ultra-high field strength of 14.1T at an 29, three resonances from four protons (from 0.7 ppm to 1.4 ppm) are suitable for in vivo imaging of Glc due to favorable exchange rates. The relatively low in vivo concentration of Glc, however, necessitates its exogenous administration for a detectable CEST effect, which has been exploited for imaging of the blood brain barrier disruption in brain tumors31.Out of the five hydroxyl proton resonances identified for Glc32 and MI mapping may help in diagnosis and treatment monitoring of many neuropsychiatric conditions. In the first publication on MI CEST in human brain at 7T7, a resonance frequency of 0.6 ppm and exchange rate of 600 Hz (pH = 7.4) were reported for MI hydroxyl protons. These results are different from those of our study (Δω = 1.00 ppm and k = 2090 Hz), which we attribute to the fact that authors used a simplified equation for exchange rate measurement and an asymmetry analysis (MTRasym) for determining the resonance frequency, both of which are not accurate for fast exchanging protons. The peak CEST effect in MTRasym for fast exchanging protons (k > Δω) appears to be shifted closer to the bulk water resonance, which can be mistaken for its real resonance frequency. Glu is a nice example of this effect, with the resonance of its amino protons being at Δω = 3.20 ppm, whereas the peak CEST effect in MTRasym at 7T (pH = 7) appears at ca. Δω = 1.20 ppm2. The resonance frequency of MI hydroxyl protons (Δω = 1.00 ppm) lies in the frequency range used for Glc imaging. However, the endogenous concentration of MI is much higher than for Glc. This, combined with six protons in MI resonating at the same frequency, makes MI a stronger contributor to CEST contrast at 1.00 ppm than Glc7. Rather than quantifying the MI CEST effect at a single frequency, an increase in sensitivity can be achieved if an area from ca. 0.2–1.1 ppm is used.MI is one of the osmolytes in the central nervous system33. Cr is converted by the enzyme creatine kinase (CK) to PCr, which acts as a temporal energy buffer in brain and muscles, according to the reaction34:The results of our measurements of resonance frequency and exchange rate for the guanidinium protons of Cr and PCr are close to the literature values17 yields the following ratios of their CEST effects (Cr/PCr at pH = 7) at Δω = 2.00 ppm (with the saturation scheme yielding the largest CEST effect for Cr): 2.5 (3T), 3.2 (4.7T), 3.3 (7T), 3.5 (9.4T), 3.8 (11.7T) and 3.8 (14.1T); and at Δω = 2.64 ppm (with the saturation scheme yielding the largest CEST effect for PCr): 1.1 (3T), 1.4 (4.7T), 1.6 (7T), 1.8 (9.4T), 1.9 (11.7T) and 1.9 (14.1T). In skeletal muscle, where at least 70% of total Cr exists in its phosphorylated form, i.e. PCr36, the ratios of their CEST effects (Cr/PCr at pH = 7) at Δω = 2.00 ppm (with the saturation scheme yielding the largest CEST effect for Cr) become: 1.1 (3T), 1.4 (4.7T), 1.4 (7T), 1.5 (9.4T), 1.6 (11.7T) and 1.6 (14.1T); and at Δω = 2.64 ppm (with the saturation scheme yielding the largest CEST effect for PCr): 0.5 (3T), 0.6 (4.7T), 0.7 (7T), 0.8 (9.4T), 0.8 (11.7T) and 0.8 (14.1T). Total Cr has recently been measured experimentally in mouse brain with 1H-MRS at 11.7T and the CEST effect at 2.00 ppm at 11.7T (2 µT B1 amplitude and 2 s saturation) was estimated to consist of ca. 20% protein and 80% total creatine, of which 83% Cr and 17% PCr37. From our estimates, CEST effect in the brain at 2.00 ppm at 11.7T (2.3 µT B1 amplitude and 2.6s saturation) consists of 79% Cr and 21% PCr, which is in line with the recent study37. Cr and PCr constitute a coupled cellular energy transport system38 and the possibility of simultaneous and independent detection of Cr and PCr by CEST could open up a new way of studying cellular energy transport system in vivo, which is currently limited to in vitro experiments in mitochondrial extracts, in vivo1H/31P MRS, or using 13C enriched labeling39.Our results suggest that the guanidinium proton of PCr should also give a detectable CEST effect further downfield from water (Δω = 2.64 ppm). An assumption of a Cr/PCr ratio of 1 in the brain40. A method for in vivo Glu mapping at 7T was published before and a 75% Glu-weighted CEST-MRI contrast was reported. However, in the present study, the exchange rates of major brain metabolites were measured by fitting full BME to their Z-spectra, and the purity of Glu CEST contrast was found to be only 57%.Glu is the major excitatory neurotransmitter in the brain, the abnormal variation of which is associated with many diseases of the central nervous systemThe findings of this study can be exploited in the design of novel CEST sequences and advanced Z-spectra processing algorithms, which is the initial step towards quantitative metabolic CEST imaging. Even though, the focus of this work was the brain tissue, the results can be reanalyzed for other tissues as well.Low specificity due to overlapping CEST effects from multiple metabolites is one of the challenges towards quantitative CEST. In this work, we found CEST saturation schemes yielding the maximum CEST effects for many brain metabolites. However, it is important to realize that even these saturation schemes never generate a pure contrast for any particular metabolite. Therefore, we analyzed metabolic contributions to Z-spectra as a function of frequency offset.13.Neither magnetization transfer (MT) nor upfield nuclear Overhauser enhancement (NOE) phenomena were included in the BME model, as there are multiple approaches to remove those effects from the Z-spectra41. As such, mobile proteins in vivo may have other downfield CEST effects in the range 0–4 ppm. For instance, the CEST effect at 2 ppm in mouse brain at 11.7T (2 µT B1 amplitude and 2 s saturation) was estimated to consist of ca. 20% protein and 80% total creatine37. To make matters worse, protein CEST effects in vivo may be dependent on protein conformational changes42, which is difficult to take into account in simulations. Therefore, all metabolic ratios presented in this work should be considered with the above information in mind.In this study, we analyzed downfield CEST effects from low molecular weight metabolites with an exception for the CEST effect at 3.5 ppm originating from the amide protons of mobile proteins and peptides. However, mobile proteins have other types of exchangeable protons, although in a lower concentration compared to the abundant amide protons43. Ideally, the composition of in vitro metabolic solutions should reflect the relevant in vivo chemical environment. Unfortunately, that is difficult to achieve as the precise cellular composition is unknown and is highly variable. Free phosphate and its derivatives with similar acid dissociation constant, i.e. adenosine triphosphate and phosphate monoesters, which are known to be predominant exchange catalysts in intracellular fluid43, amount to a concentration of 8.5 mM in brain and 13.0 mM in muscle tissue43. Therefore, in this work, we chose to use a 10 mM phosphate-buffered saline (PBS) as a medium for metabolic solutions.The exchange rate constant of labile protons depends, among other factors, on their chemical environment, which can be highly catalyticAll metabolites were purchased from Sigma-Aldrich and used as received without further purification.®) were used for measurements: D2O and sample were put in outer and inner tube, respectively. Metabolic Z-spectra were acquired with a 5 s rectangular pulse for magnetization preparation with a post-readout T1 recovery of 25 s. Water T1 relaxation times (T1water) in phantoms were measured by inversion recovery (IR) at the following inversion times (IT): 4 ms, 30 ms, 100 ms, 200 ms, 500 ms, 1 s, 2 s, 4 s, 8 s, 12 s, 16 s, 20 s, and 25 s. For both CEST and T1 measurements, a flip angle of 10° was used. B1 saturation levels of the prepulse were optimized for a particular metabolite. To decouple correlated parameters, which is especially important for the metabolites with multiple exchanging sites, multi-pool BME were fitted to metabolic Z-spectra , obtained at multiple B1 levels, simultaneously , myo-inositol (MI), creatine (Cr), phosphocreatine (PCr), gamma-aminobutyric acid (GABA), glutamine (Gln), N-acetyl-aspartate (NAA), taurine (Tau), and glutamate (Glu), were performed in 25 mM or 50 mM phantoms  at 37 °C on a 600 MHz NMR-spectrometer (Bruker). Coaxial inserts , and so k0 may contain a contribution from the kc term. The rate constants k0 and kb for the exchangeable protons of each metabolite were obtained by fitting Equation ka = 0, kc = 0) to the experimentally determined plot of the exchange rate  versus pH.The exchange rate measurements were done in metabolic solutions with a pH ≥ 6.4, therefore we assumed that 44 using the following bulk water relaxation times49: T1/T2 = 0.9 s/70 ms (at 3T), T1/T2 = 1.07 s/60 ms (at 4.7T), T1/T2 = 1.2 s/40 ms (at 7T), T1/T2 = 1.66 s/37 ms (at 9.4T), and T1/T2 = 1.74 s/27 ms (at 11.7T) for white matter (WM); T1/T2 = 1.45 s/90 ms (at 3T), T1/T2 = 1.47 s/73 ms (at 4.7T), T1/T2 = 1.8 s/55 ms (at 7T), T1/T2 = 2.1 s/42 ms (at 9.4T), and T1/T2 = 2.11 s/37 ms (at 11.7T) for grey matter (GM). The water relaxation times at 14.1T were obtained by fitting and extrapolating the above literature values , for imaging of MI, Cr, PCr, Glu and mAmides was done in BME at the field strengths of 3T, 4.7T, 7T, 9.4T, 11.7T, and 14.1T. Multi-pool  BME were solved numericallyS is the simulated signal in the z-spectrum at the resonance frequency Δω, and Ma is the simulated amplitude of CEST effect.The exchange rates used in BME were obtained by using the experimentally determined exchange rate constants and Equation CESTi is the CEST effect size for a particular metabolite at a specific frequency, is the sum of CEST effects for all metabolites at the same frequency.Normalized CEST contribution for a particular metabolite in stacked bar plots was calculated as follows:Supplementary material


ZT value of 0.6, together with a power factor of 29 μW cm−1 K−2 at 873 K, were achieved for the nonstoichiometric sample V0.9CoSb. This proved that moderate V vacancy could improve the thermoelectric (TE) properties of VCoSb. The noticeable improvements are mainly owing to the incremental Seebeck coefficient, which may benefit from the optimized carrier concentration. However, too much V vacancy will result in more CoSb impurity and deteriorate the TE performances of VCoSb owing to the increased thermal conductivity.The effects of V vacancy on the thermoelectric performance of the half-Heusler compound VCoSb have been investigated in this study. A certain amount of CoSb secondary phase is generated in the VCoSb matrix when the content of V vacancy is more than 0.1 at%. According to the results, a  ZT = S2σT/(κe + Lκ), where S is the Seebeck coefficient, σ is the electrical conductivity, T is the absolute temperature, and κe and Lκ are the electronic and lattice contributions to the total thermal conductivity κ, respectively [S, σ, and κ) are correlated with each other by carrier concentration. An effective way to enhance ZT is by optimizing carrier concentration.Thermoelectric (TE) materials are a type of functional material that can be used to directly convert thermal energy into electrical energy through the motion of internal carriers in solids. The conversion efficiency of TE materials is characterized by the dimensionless figure of merit ectively . ParticuZT, there are two strategies for ZT enhancement: One strategy is increasing the TE power factor (S2σ) via band engineering, for example, modifying electron states by resonant levels [Lκ, e.g., alloying to induce point defects [According to the definition of  factor Sσ via bant levels , low bant levels , or weakt levels . The oth defects , increas defects , or usin defects  and low  defects .INiSn, MICoSb , MIIFeSb , and their alloys have been extensively investigated as promising TE materials applicated at medium-high temperature [Over the last few decades, half-Heusler (HH) compounds, a type of thermoelectric material, have been given a lot of attention for their desirable characteristics, such as excellent mechanical robustness, good TE performance, high-temperature stability, and low toxicity, all of which are of great significance for TE materials’ practical applications ,11,12. Tperature ,20,21,22ZT value of about 0.4 and 0.5 at 973 K [0.8CoSb with 18-electron and Nb vacancies was pointed out to be a more stable semiconductor [0.8CoSb is a stable HH compound, and the carrier concentration can be improved by the content of Nb vacancy. A peak ZT of about 0.9 at 1123 K was achieved for Nb0.83CoSb [Unconventionally, experiments have confirmed that NbCoSb and VCoSb, with a cubic HH structure and 19 valence electrons per unit cell, exhibit moderate n-type TE properties and achieve a at 973 K ,24. Howeat 973 K ,26,27. Monductor . More re0.83CoSb .x1−CoSb compounds with different contents of V vacancies , and investigated the effects of V vacancy on the TE properties. According to our experiment results, too much V vacancy will generate more impurity phase (CoSb), leading to a reduction in the TE performance. It is noteworthy that a certain amount of V vacancy in VCoSb will enhance the power factor and increase ZT of VCoSb. A peak ZT value of about 0.6 was achieved for V0.9CoSb at 973 K. The present work again demonstrates that nonstoichiometric 19-valence electron HH compounds are hopeful TE materials.In this work, we focus on another HH compound, the thermoelectric material VCoSb with nominal VEC = 19 . Inspired by previous research on NbCoSb, we have synthesized Vx1−CoSb samples with different contents of V vacancies  were synthesized by powder sintering, ball milling, and hot pressing. The raw powder materials were loaded into a stainless-steel jar, mixed for 0.5 h without grinding balls, and then consolidated into disks by cold pressing at room temperature for 20 min. The pre-compression disks were sealed in a quartz tube, sintered at 1073 K for 18 h, and then air cooled to room temperature. The sintered disks were sealed inside a jar in a glove box with argon gas protection, and then ball milled for 5 h by a high-energy SPEX 8000M Mixer/Mill  to yield the powder. The obtained powder was transferred and loaded into a graphite die, then hot-pressed at 1023 K for 2 min under 75 MPa by a direct current hot press to obtain a disk sample. The dense samples obtained were about 12.7 mm in diameter and 2 mm in thickness.A series of Vκ = dDCp was calculated using the measured density (d) using the Archimedes method, thermal diffusivity (D) using the laser flash method , and specific heat capacity (Cp) using differential scanning calorimetry . Bar-shaped samples of about 2 mm × 2 mm × 11 mm were used for measuring the electrical conductivity and Seebeck coefficient simultaneously from 300 to 973 K .The thermal conductivity α radiation. The microstructures were observed using a field emission scanning electron microscope .The phase characterizations were measured by X-ray diffraction  with Cu Kx1−CoSb (x = 0–0.25) samples. As we can see, the main phase is the HH phase of the VCoSb with a cubic MgAgAs-type crystal structure. Although extremely weak impurity peaks of CoSb phase can be found in the V0.9CoSb sample, the stoichiometric VCoSb sample and the nonstoichiometric V0.95CoSb sample were found to be pure in phase. Obvious peaks of impurity phase of CoSb are observed when the content of V vacancy is more than 0.1, and the amount of the impurity phase of CoSb increases with the increasing content of V vacancy. Although there is a certain amount of V vacancies in our samples, the cubic HH phase crystal structure still remains. x1−CoSb samples are shown in dcal = ∑niMi/(a3AN), where ni is the number of atoms of V, Co, and Sb per unit cell, Mi is the corresponding atomic mass of each element, a is the lattice constant, and AN is the Avogadro constant (6.023 × 1023 mol−1). The relative densities of all of the hot-pressed samples were more than 93%.The lattice parameter, and the theoretical, experimental, and relative densities of the V0.9CoSb sample indicates dense and compact hot-pressed bulk samples, and the grainsize of the sample is in a range from hundreds of nanometers to one micrometer. The back-scattering electron (BSE) image of V0.9CoSb in 0.9CoSb sample.As shown in D monotonically decreased over the whole measured temperature range. Additionally, the thermal diffusivity clearly increased when the V vacancy content is more than 0.15, which may be due to the increasing amount of CoSb secondary phase in the sample. As shown in pC. κtotal for Vx1−CoSb samples as the temperature changes. κtotal of V0.9CoSb decreased with increasing temperature from 3.84 W m−1 K−1 at 300 K to 3.58 W m−1 K−1 at 873 K, almost close to that of VCoSb. Typically, the total thermal conductivity contains two parts, the electronic thermal conductivity and the lattice thermal conductivity, namely, κtotal = eκ + Lκ. The electronic thermal conductivity eκ can be estimated by the Wiedemann–Franz relation, e = LσTκ, where L is the Lorentz number. Usually, the Lorentz number is between two limiting values. For metals and highly degenerate semiconductors, it is 2.45 × 10−8 Ω W K−2, whereas, for a non-degenerate semiconductor, it is 1.49 × 10−8 Ω W K−2. Herein, the Lorentz number is estimated by fitting the measured Seebeck coefficient using a single parabolic band (SPB) model, as shown in −8 Ω W K−2 [nF(η) is the nth order Fermi integral, η is the reduced Fermi energy, r is the scattering factor, h is Plank’s constant, kB is Boltzmann’s constant, x is the variable of integration, and e is the electron charge.The temperature-dependent thermal properties are shown in Lκ and eκ are plotted in Lκ exhibits significant enhancement with increasing V vacancy, i.e., increasing amounts of CoSb impurity. For example, Lκ at room temperature increased from 2.32 W m−1 K−1 for the V0.95CoSb sample to 3.41 W m−1 K−1 for the V0.8CoSb sample. As shown in the inset of eκ of VCoSb showed an increasing trend over the whole temperature range; however, it decreased with the increasing temperature for V-deficient samples Vx1−CoSb (x > 0). Furthermore, eκ at room temperature distinctly increased from 1.75 W m−1 K−1 for VCoSb to 2.64 W m−1 K−1 for V0.75CoSb upon the increasing V vacancy content, which can be ascribed to the high electrical conductivity of the CoSb impurity.The obtained x1−CoSb samples. The electrical conductivity decreased at the beginning with the increasing temperature due to the strong electron scattering, displaying metal or degenerate semiconductor transport behavior. However, after 873 K the electrical conductivity started to increase, which may be due to the intrinsic carrier thermal excitation. We calculated the temperature-dependence-exponent of the conductivity (σ vs. αT) before thermal excitation and found that the carrier scattering mechanism may change after inducing V vacancy. The conductivity of VCoSb showed a temperature exponent of −0.65 (green dotted line), indicative of alloy and phonon scattering of the carriers, although alloy scattering is stronger. However, the temperature exponent of −0.9 for V0.9CoSb (blue dotted line) and −0.93 for V0.75CoSb (red dotted line) implies that phonon scattering has a stronger effect  [ttering) ,32.3, and a room temperature conductivity of 37.5 × 105 S/m. Based on its conductivity dependence on temperature (σ vs. T−1.5), which implies that acoustic phonon scattering is predominant during the carrier transport, the carrier concentration here is considered to be nearly temperature-irrelevant due to the metallic nature of carriers. Therefore, too much CoSb impurity in the matrix will degrade the TE performance of VCoSb, compared with other secondary phases, such as ZnO and SiC [We also prepared pure phase CoSb, and characterized its electrical properties, as shown in  and SiC ,34. CoSb0.75CoSb. The V0.9CoSb sample has the highest peak Seebeck coefficient of –153 μV/K at 873 K, which should benefit from the improved carrier concentration.As shown in S2σ) increased during the whole temperature range and the V0.9CoSb sample had an improved peak value of 29 μW cm−1 K−2; greater than VCoSb (21 μW cm−1 K−2) at 973 K  were prepared by powder sintering, ball milling, and hot pressing. The influences of V vacancy on the thermoelectric properties of the HH compound VCoSb were studied. A certain amount of CoSb secondary phase was generated in the VCoSb matrix when x was more than 0.1. Too much V vacancy yields more CoSb impurity, and deteriorated the TE performance, owing to the increased thermal conductivity; while moderate V vacancy could improve the TE property, which may benefit from the optimized carrier concentration. Finally, a maximum ZT of about 0.6 was obtained at 873 K for V0.9CoSb, mainly because of the increased Seebeck coefficient compared with VCoSb.A set of V vacancy V


Results: Maximal muscular strength was similar between international- and national-level water polo players, but it was higher in centers than in peripherals . IL players showed higher V4, V5, and V10 compared to NL players , , and V10 (IL: 1.50 ± 0.31 vs. NL: 1.35 ± 0.06 m·s−1) (p < 0.01)). However, no significant differences were detected between centers and peripherals inV4, V5, and V10. Conclusions: We suggest that V4, V5, and V10 distinguish playing level in water polo, whereas they are comparable between playing positions. Although maximal strength is similar between playing levels, it is different between playing positions.Background: We aimed to investigate whether water polo players of different playing levels and positions differ in fitness parameters . Methods: Twenty-four water polo players were assigned to international- (IL) and national-level (NL) groups or to centers and peripherals. At the beginning of preseason training, maximal bench press strength was measured and a speed–lactate test (5 × 200m) was performed to determine the speed corresponding to lactate concentrations of 4.0 (V4), 5.0 (V5), and 10.0 (V10) mmol·L Therefo players . AlthougMoreover, the demands of water polo are role dependent and mainly linked to the required individual skills . A numbeBased on the abovementioned analysis, the recording of both muscular strength level and fitness indices of elite male water polo players appears to be of great scientific and practical interest for two main reasons. First, it provides a scientific picture of the upper limits of the adaptations derived from long-term water polo training. Second, because it provides scientific evidence to coaches regarding the strength level and fitness profile of modern water polo players, thus offering evidence regarding water polo players’ selection and profiling.Therefore, the purpose of the present study was to examine whether international-level (IL) and national-level (NL) players as well as players of different positional roles  differ in muscular strength and in important indicators of aerobic and anaerobic potential, such as V4, V5, V10, and V10–V5. It was hypothesized that IL players would present higher strength and aerobic and anaerobic potential compared to the NL players. It was further hypothesized that centers and peripherals would demonstrate similar fitness levels due to the similar overall physiological load applied on the players during competition. Nonetheless, it was expected that centers would exhibit greater muscular strength compared to peripherals.Twenty-four male water polo players participating in three different clubs in the top-level division of the Greek Championship took part in the study and were assigned to international-level  and national-level  players. Accordingly, they were assigned to two groups of different playing positions . All players were at the top level and trained on a daily basis. From the selected IL players, 10 of them were regular members of the Greek National Team which competed in Olympic Games of London and Rio , whereas the other two were members of the Spanish and Croatian National Teams competing in the same Olympic Games. NL players were elite players participating in the Greek top-level division with more than five years of training and playing experience. Informed consent was obtained from all players before testing. The experimental protocol was approved by the faculty review board of the University of Athens and conformed to the Declaration of Helsinki.−1  were calculated from the speed–lactate curve by interpolation of a second-order polynomial function. The lactate tolerance ability was defined as the differential velocity between blood lactate concentrations of 5.0 and 10.0 mmol·L−1 (V10–V5) [At the beginning of preseason training, players’ fitness level was evaluated through an incremental swimming test (5 × 200 m) . After at-test was also employed to detect differences between groups in anthropometric characteristics. As a measure of effect size, Cohen’s d was computed by calculating the mean difference for the groups and then dividing the result by the pooled standard deviation. The magnitude of each effect size was classified as trivial (d < 0.2), small (d = 0.2–0.6), moderate (d = 0.6–1.2), large (d = 1.2–2.0), very large (d = 2.0–4.0), and extremely large (d > 4.0) [p < 0.05.Before using parametric statistical test procedures, the normality of the data was verified by the Shapiro–Wilk test. Analysis of variance for repeated measures on independent samples  was used to detect differences in strength level, V4, V5, V10, and V10–V5. Tukey’s test was employed to allocate post-hoc specific differences. A d > 4.0) . Data arp = 0.87) and body mass (p = 0.29), but they were taller compared to NL players . Maximal muscular strength was similar between IL and NL water polo players . The speed–lactate curve of IL and NL players is presented in −1 vs. 1.17 ± 0.06 m·s−1, p < 0.01, d = 1.75), V5 , and V10  than NL players. Nonetheless, V10–V5 was similar between groups of different playing levels .IL water polo players had similar age (p = 0.00 and d = 2.0) and taller (p = 0.00 and d = 1.4) than peripherals, while both groups had a similar age . Maximal muscular strength was greater in centers than in peripherals . The mean speed–lactate curve for centers and peripherals is depicted in −1 vs. 1.22 ± 0.06 m·s−1, V5 1.28 m·s−1 ± 0.08 vs. 1.28 ± 0.06 m·s−1, V10 1.42 ± 0.10 m·s−1 vs. 1.42 ± 0.08 m·s−1, p > 0.05).Regarding playing position, centers were heavier  muscular strength is similar between IL and NL water polo players, but IL players demonstrate higher aerobic (V4) and anaerobic (V5 and V10) potential compared to NL players, and (b) centers demonstrate a higher strength level but similar aerobic and anaerobic potential compared to peripherals.Due to the high presence of dynamic actions that occur in water polo match-play , an adequate strength level is essential for water polo players . Accordi−1) [Moreover, the total duration of the game along with the high frequency of high-intensity bouts separated by efforts of short duration imply that both aerobic and anaerobic potential are crucial for in-game water polo performance. According to our first hypothesis, we expected that V4, V5, V10, as well as the index of lactate tolerance (V10–V5) would be different between IL and NL players and our findings partially confirmed our assertions. Indeed, we observed that the aerobic and anaerobic potential of IL players was higher by 8–10% compared to the NL players. Interestingly, the V4 values presently observed are similar to those observed in a previous study (1.29–1.35 m·s−1)  concerni−1) , and as We also found that centers are heavier and taller compared to peripherals. This finding is in accordance with previous observations regarding the anthropometrical differences between playing positions  and indiThe present study has practical importance because it demonstrates that (a) absolute strength level, as measured by the bench press, is not a distinguishing factor between playing levels in men’s water polo, (b) aerobic and anaerobic potential is considerably different between playing level, and (c) centers show higher absolute strength but similar V4, V5, and V10 compared to peripherals. These results provide information regarding the fitness requirements of top-class water polo players and can contribute to talent selection and identification.In summary, our study suggests considerable differences in aerobic and anaerobic potential between IL and NL water polo players, whereas the respective fitness indices are comparable for centers and peripherals. More research is needed to identify to role of different strength measures in discriminating water polo players of different playing level.


While caudal block has been widely used during pediatric lower limbs and lower abdominal surgeries, few studies to date have evaluated the perioperative effects of caudal block on pediatric patients in laparoscopic upper urinary tract surgery.Ninety-six pediatric patients, aged 6 months to 7 years, ASA grade I-II, scheduled to undergo laparoscopic upper urinary tract surgery, were randomized to a non-block group , an ROP1.0 group (patients received 1.0 mL/kg of 0.15% ropivacaine) and an ROP1.3 group (patients received 1.3 mL/kg of 0.15% ropivacaine). The primary outcome variable was perioperative fentanyl use. The secondary outcome variables were pain score, hemodynamic fluctuation, the number of patients needing rescue fentanyl and side effects.P < 0.01; ROP 1.3 vs. ROP 1.0, P < 0.05). Moreover, patients in the ROP1.3 group, compared to those without, displayed more stable hemodynamics, lower pain score in the PACU and 8 h after operation, less demand for rescue fentanyl, shorter time of PACU stay.Caudal block with 1.3 mL/kg of 0.15% ropivacaine significantly decreased perioperative fentanyl usage (ROP 1.3 vs. non-caudal block, Caudal block with 1.3 mL/kg of 0.15% ropivacaine reduced perioperative fentanyl use during laparoscopic upper urinary tract surgery on pediatric patients and produced good postoperative analgesia when compared with no caudal block and caudal block with 1.0 mL/kg of 0.15% ropivacaine.ChiCTR1800015549, chictr.org.cn.Clinical trial number:  It is well known that pediatric laparoscopic surgery has many advantages, such as minimal injury, invisible scar, fast recovery, and shortened hospital stay , 2. HoweCaudal block, a well-established technique in pediatric surgeries such as lower limb surgery and lower abdominal surgery, can produce good analgesic effects and maintain stable hemodynamics –13. SeveThe study was approved by the China Medical University’s Institutional Review Board and written informed consent was obtained from all subjects participating in the trial. After receiving written consent from each patient’s guardian, we enrolled 96 pediatric patients  grade I or II) who were scheduled to undergo elective laparoscopic upper urinary tract surgery. The upper urinary tract surgery includes pyeloplasty, nephrectomy, heminephrectomy, ureteroureterostomy, pyeloureterostomy and ureteral reimplantation. Pediatric patients who were allergic to local anesthetics and not suitable for caudal block  were excluded from this study. This study was conducted from May, 2018 to October, 2018 and adhered to CONSORT guidelines.n = 32). Information regarding the patient’s age, gender, body weight, ASA grade, diagnosis and types of surgery was collected. All patients were from Shengjing hospital of China Medical University.A total of 96 patients were equally randomized to a non-block group , a ROP1.0 group , and anROP1.3 group  by stratified blocked randomization. Each group had the same number of patients (2) was performed throughout the procedure. All patients received the standard general anesthesia induction procedure: fentanyl 1μg/kg, etomidate 0.3 mg/kg, succinylcholine 1.5 mg/kg and endotracheal intubation. Cisatracurium 0.05 mg/kg was used to provide continuous muscle relaxation. Sevoflurane of 1.0–1.3 minimal alveolar concentration (MAC) with 50% nitrous oxide was used to maintain anesthesia during the surgery. The tide volume was set to 6–10 mL/kg to guarantee that the end-tidal CO2 (ETCO2) was between 35 and 45 mmHg.After the patients were transferred to the operating room, standard monitoring such as non-invasive blood pressure (NIBP), heart rate (HR), electrocardiography and pulse oximetry including pulse oxygen saturation  HR increasing or decreasing by more than 30% of the baseline and lasting for more than 2 min. If HR decreased by more than 30% of the baseline, atropine 0.01 mg/kg was given intravenously. If NIBP or HR increased by more than 30% of the baseline, an extra of 0.5 μg/kg fentanyl was given intravenously according to the anesthesiologist’s experience in hemodynamics fluctuation. The total amount of fentanyl used during surgery and the times of hemodynamic fluctuation were also recorded.The site of laparoscopic port was decided by the surgeon for a successful procedure. Usually there needs to be three ports, one very close to the umbilicus (T10 dermatome), one at the intersection between arcus costarum and midclavicular line (T8 dermatome), and the last one near the iliac fossa (T12 dermatome). The pressure for laparoscopy was 8 mmHg, and the flow of carbon dioxide was 8 L/min.Thirty minutes before the end of the surgery, patients were intravenously given ondansetron 100 μg/kg (to a maximum of 4 mg) and ketorolac 0.5 mg/kg (to a maximum of 15 mg). At the end of the surgery, patients received infiltrated anesthesia of ropivacaine around the laparoscopic port. After waking up naturally, patients were extubated when the extubation criteria were met and were transferred to the Post Anesthesia Care Unit (PACU).In PACU, pain evaluation was performed by using the FLACC (Face Legs Activity Cry Consolability) score described by previous studies , 17, 18.After the PACU stay, patients were transferred to the ward, and the FLACC score of every 8 h in ward was also investigated. If the patients suffered from acute pain, oral paracetamol 15 mg/kg was prescribed. The number of patients needing NSAIDs, time to the first NSAIDs use in ward and side effects were also evaluated.P value of less than 0.05 was considered statistically significant.Continuous variables such as fentanyl usage, the FLACC score and the time of PACU stay were presented as mean ± standard deviation (SD) or median with interquartile range. Categorical variables such as the frequency of hemodynamic fluctuation and the number of patients needing rescue fentanyl were presented as absolute numbers. Before comparing the differences in continuous variables, D’Agostino-Pearson omnibus normality test was performed to investigate data distribution. Since fentanyl usage, the FLACC score and the time of PACU stay were normally distributed among groups, one-way ANOVA and Bonferroni correction were used one after another to investigate the difference between groups. Differences in categorical variables were analyzed by a Chi-square test or a Fisher’s exact test. For all statistical analysis, a In order to calculate the sample size needed for this study, a pilot study was performed. The pilot data showed that the perioperative fentanyl use (the primary outcome variable of this study) of the non-block group, the ROP1.0 group and the ROP 1.3 group were1.87 ± 0.35 μg/kg, 1.57 ± 0.32 μg/kg and 1.29 ± 0.29 μg/kg respectively. Since we assumed that the type I error was 0.05 and the power was 0.9, the sample size calculated based on the non-block group and the ROP1.0 group was 24, while the sample size calculated based on the ROP1.3 group and the ROP1.0 group was 27. Considering the 10% dropout rate, we increased the sample size by 20% and the final result was 32 per group.A total of 96 pediatric patients were enrolled in this study, 32 in each group. Four patients withdrew from the non-block group because of the change of surgery method and incomplete data. Two patients in the ROP1.0 group and two patients in the ROP1.3 group were left out because of incomplete data and refusal of participation. The final numbers of patients in the non-block group, the ROP1.0 group and the ROP 1.3 group were 28, 30 and 30 respectively. There was no significant difference between these three groups regarding age, body weight, gender, ASA grade and operating time . Compared to the ROP1.0 group, patients in ROP1.3 group needed less fentanyl . The frequency of hemodynamic fluctuation during operation was also recorded. As shown in Fig. P < 0.001), and patients in the ROP1.3 group showed more stable hemodynamics than patients in the ROP1.0 group .First we investigated the perioperative fentanyl usage (fentanyl use in the operation and in PACU), which is the primary outcome of this study. As depicted in Fig. P = 0.032; and ROP1.3 vs. non-block: 2.70 ± 1.64 vs. 5.00 ± 1.67 times, P < 0.001). In accordance with the FLACC score, more patients in the non-block group needed rescue fentanyl in the PACU when compared with patients in the ROP1.0 and the ROP1.3 groups . Patients with no caudal block needed NSAIDs earlier, and more patients needed postoperative NSAIDs when compared with patients in the ROP1.0 and the ROP 1.3 groups . We simply attached a sterile sticker to cover the same site of caudal block groups. We believed that a placebo injection was an invasive injection that could be harmful to the patient. 2. In previous studies, the maximal level of cranial spread was about T10, while in this study, when the surgeon performed an incision at the T8 level, most of the patients in the ROP1.3 group showed stable hemodynamics. That said, we cannot directly conclude that the maximal level of cranial spread was T8, and further investigation needs to be done to confirm that. 3. Previous studies showed that the maximal level of cranial spread in elder patients was lower than that in younger patients, while in our study we did not observe a significant difference between younger and older patients due to the small sample size. Further study with a larger sample size needs to be done to investigate the relationship between age and caudal block effect.Caudal block with 1.3 mL/kg of 0.15% ropivacaine reduced fentanyl use during laparoscopic upper urinary tract surgery on pediatric patients and produced good postoperative analgesia when compared with no caudal block and caudal block with 1.0 mL/kg of 0.15% ropivacaine usage.


Several studies on the growth rates of abdominal aortic aneurysm (AAA) in Chinese population have been conducted; however, this issue remains unclear. The aim of this study is to systematically review published data of the AAA growth rates among people in China.We conducted a comprehensive search of multiple databases to identify all studies of AAA growth in the Chinese population from inception until June 2017. AAA growth rates were combined to yield the growth rates at specified aneurysm diameter ranges, with using a random-effects model or fixed-effects model according to heterogeneity.A total of 8257 studies were initially identified and only 4 studies were eventually included. A random-effects analysis showed that the growth rates of AAA in Chinses population is ranging from 0.18 cm/year to 0.75 cm/year. The pooled mean growth rates among individuals with aneurysm measuring 3.0–3.9 cm, 4.0–5.9 cm and ≧ 6.0 cm in diameter were 0.21 cm/year (95% CI: 0.19 cm/year to 0.23 cm/year), 0.38 cm/year (95% CI: 0.33 cm/year to 0.43 cm/year), and 0.71 cm/year (95% CI: 0.64 cm/year to 0.77 cm/year) respectively. Further analysis found that the pooled mean growth rates for individuals with small AAA (diameters measuring 3.0–4.9 cm) was 0.28 cm/year (95% CI: − 0.06 cm/year to 0.61 cm/year)`and for individuals with large AAA (diameters ≥5.0 cm) was 0.75 cm/year (95% CI: 0.20 cm/year to 1.3 cm/year). Finally, meta-regression showed a strong trend of linear relationship between AAA growth rate and aneurysm diameter.The growth rates of AAA in the Chinese population increase with AAA enlargement and appear to range from 0.18 cm/year in the smallest AAAs to 0.75 cm/year when the diameter exceeds 6 cm. However, based on current studies, it is difficult to estimate the accurate average AAA growth rate in Chinese patients. More large-scale, high-quality studies are required to achieve that. Overall, AAA growth rate increase with increased aneurysm diameter.The online version of this article (10.1186/s12872-019-1160-x) contains supplementary material, which is available to authorized users. Abdominal aortic aneurysm (AAA) refers to an abdominal aortic dilation, with an aortic diameter greater than 3.0 cm or 1.5 times the expected normal diameter . The risThe management plan of AAA has been established on the basis of data for estimated growth rate, estimated rupture rate, and estimated risk of a surgical procedure, nearly all of which have been acquired from European and American populations , 20–22. This systematic review followed the quality reporting guideline set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group . EnglishStudies were identified using the abovementioned search strategies. Data extraction was performed by two independent reviewers. Where there was any disagreement, a third reviewer was consulted. The following information/data were extracted from studies that met the inclusion criteria: year of publication, study design, method of follow-up , frequency of follow-up, participant information , length of follow-up, inclusion criteria, recruitment period, trial using a particular drug, outcomes , and analysis.Quality assessment was performed by two reviewers independently and a third reviewer was consulted in cases of any disagreement. There is no widely recognized quality assessment tools for single-group observational studies, and we had to relax the eligibility criteria for studies because related studies are very limited, so we only performed a basic quality assessment. The criteria for quality control included: type of study, standardization of imaging, description of outcomes, and reporting methods . Quality assessment of the included studies is shown in Table N1M1 + N2M2)/(N1 + N2) and Reported overall mean growth rates (mm/year) and its standard deviation (SD) were extracted from each study. If growth was reported by size bands, growth rates in size bands were also extracted. If growth rates were reported in size bands only without reporting of the overall growth rate, the size band estimates were pooled, using formulas M= .All analyses were based on previous published studies; therefore, no ethics approval or patient consent was required.A study flow diagram is shown in Fig. The characteristics of the four included studies are summarized in Table 2 =97.7, 95% confidence interval (CI): 96 to 99%), with growth rates ranging from 0.18 cm/year to 0.75 cm/year. Because one study included aortic diameters greater than 2.1 cm whereas the remaining three studies reported diameters greater than 3.0 cm, meta-analysis was performed after excluding data acquired from patients with aneurysm diameter less than 3.0 cm. The heterogeneity  remained substantial (figure not shown), and the random-effects meta-analysis estimate of the average AAA growth rate was 0.43 cm/year (95% CI: 0.23 cm/year to 0.64 cm/year).A forest plot summarizing overall average growth rate estimates is shown in Fig. 2 ranging from 94.2 to 98.5%) did not change markedly with the exclusion of individual studies, indicating that the meta-analysis was relatively reliable.We performed a sensitivity analysis of the influence of each study on the pooled estimate for aneurysm growth rate (figure not shown). The pooled AAA growth rates (0.32 cm/year to 0.51 cm/year) and heterogeneity  than the overall estimates; hence, a fixed-effects model was applied. Growth rate increased with increased aneurysm diameter. The pooled mean growth rates for individuals with baseline diameters measuring 3.0–3.9 cm, 4.0–5.9 cm and ≥ 6.0 cm were 0.21 cm/year (95% CI: 0.19 cm/year to 0.23 cm/year), 0.38 cm/year (95% CI: 0.33 cm/year to 0.43 cm/year), and 0.71 cm/year (95% CI: 0.64 cm/year to 0.77 cm/year), respectively. AAA diameters at baseline were divided into 2.1–2.9 cm, 3.0–4.9 cm, and ≥ 5.0 cm in a study by Li et al. [2 ranging from 97.4 to 98.2%). The pooled mean growth rates for individuals with baseline AAA diameters measuring 3.0–4.9 cm and ≥ 5.0 cm were 0.28 cm/year (95% CI: − 0.06 cm/year to 0.61 cm/year) and 0.75 cm/year (95% CI: 0.20 cm/year to 1.3 cm/year), respectively.In two studies , 37, AAAi et al.  and intoi et al. . EstimatMeta-regression showed no statistically significant linear relationship between AAA growth rate and the covariates of age and female proportion, indicating that these might not be the sources of heterogeneity. The mid-point of the reported size range and the corresponding growth rate were used to perform meta-regression Fig. , which sThis is the first systemic review of AAA growth rate in the Chinese population. In the review, the eligibility criteria for studies had to be somewhat flexible because relevant studies were very limited. We found the growth rates of AAA in Chinses population is ranging from 0.18 cm/year to 0.75 cm/year and that the growth rate increased with increased aneurysm diameter. Aneurysm diameter was one of the major sources of heterogeneity between studies.Methods of growth rate estimation have been reported to influence aneurysm growth rate ; however2 =96.3%) and 0.21 cm/year , respectively. For aneurysm measuring 3.0–4.9 cm, the growth rates in western population and in Chinese population are 0.21 cm/year  and 0.28 cm/year , respectively. Nevertheless, in order to match aneurysm diameters, only two studies can be used to estimate pooled aneurysm growth rates in Chinese patients, and one of the results has a wide range of 95% CI (− 0.06 to 0.61 cm/year) and hence is not statistically significant. Besides, in Tompson’s study, about half of patients are smokers, whereas in our study, in two of the four studies included, there are higher proportions of smokers while in the others two studies, patients’ smoking status was not described. Also, most patients in our study are with hypertension whereas only about one third patients in Tompson’s study are with hypertension. The difference of these risk factors in two population may also contribute to different growth rates. However, the information available is not sufficient for us to compare the AAA growth rates after matching risk factors. So this results do not necessarily mean that aneurysm growth rate is higher in Chinese patients than in western patients. More studies are required to elucidate the influence of race on aneurysm growth rate.Thompson et al. reported that the overall AAA growth rate among Europeans and Americans was 0.232 cm/year , whereasFrom the results of meta-regression, sex and age were not sources of heterogeneity. Normally, at least 10 studies are required to perform meta-regression. Therefore, the result of meta-regression of sex and age on AAA growth rate was unreliable, which means sex and age do not necessarily exert no influence on AAA growth rate. Although the meta-regression showed a strong trend of linear relationship between AAA growth rate and aneurysm diameter, none of the four included studies was specific to sAAA, and the sizes in these studies were less than 100. Hence, the findings of the current study are insufficient to put forward appropriate surveillance intervals for sAAA.There is much work that remains to be done to help improve understanding of the epidemiological features of AAA in the Chinese population. There is no large-scale population screening of AAA at present in China; therefore, the prevalence rate of AAA in Chinese people is unclear. Multicenter studies investigating the growth and rupture rates of AAA, especially sAAA, are needed, to provide a basis for establishing a surveillance scheme and choosing suitable intervention times for Chinese patients. Currently, most of the related studies are retrospective. More prospective studies are needed that include standardized imaging processes, imaging performed independently by different people, and controlled follow-up frequency, to improve the quality of studies.In summary, we found that the growth rates of AAA in the Chinese population increase with AAA enlargement and appear to range from 0.18 cm/year in the smallest AAAs to 0.75 cm/year when the diameter exceeds 6 cm. However, based on current studies, it is difficult to estimate the accurate average AAA growth rate in Chinese patients. More large-scale, high-quality studies are required to achieve that. Overall, AAA growth rate increase with increased aneurysm diameter.Additional file 1:Table S1. Excluded full-text articles with reasons for exclusion. (DOCX 13 kb)