Vedolizumab serum trough concentrations with and without thiopurines in ulcerative colitis: The prospective VIEWS pharmacokinetics study

BACKGROUND Ulcerative colitis(UC)is a chronic inflammatory condition requiring continuous treatment and monitoring.There is limited pharmacokinetic data on vedolizumab during maintenance therapy and the effect of thiopurines on vedolizumab trough concentrations is unknown.AIM To investigate the exposure-response relationship of vedolizumab and the impact of thiopurine withdrawal in UC patients who have achieved sustained clinical and endoscopic remission during maintenance therapy.METHODS This is a post-hoc analysis of prospective randomized clinical trial(VIEWS)involving UC patients across 8 centers in Australia from 2018 to 2022.Patients in clinical and endoscopic remission were randomized to continue or withdraw thiopurine while receiving vedolizumab.We evaluated vedolizumab serum trough concentrations,presence of anti-vedolizumab antibodies,and clinical outcomes over 48 weeks to assess exposure-response asso-ciation and impact of thiopurine withdrawal.RESULTS There were 62 UC participants with mean age of 43.4 years and 42%were females.All participants received vedolizumab as maintenance therapy with 67.7%withdrew thiopurine.Vedolizumab serum trough concentrations remained stable over 48 weeks regardless of thiopurine use,with no anti-vedolizumab antibodies detected.Pa-tients with clinical remission had higher trough concentrations at week 48.In quartile analysis,a threshold of>11.3μg/mL was associated with sustained clinical remission,showing a sensitivity of 82.4%,specificity of 60.0%,and an area of receiver operating characteristic of 0.71(95%CI:0.49-0.93).Patients discontinuing thiopurine required higher vedolizumab concentrations for achieving remission.CONCLUSION A positive exposure-response relationship between vedolizumab trough concentrations and UC outcomes suggests that monitoring drug levels may be beneficial.While thiopurine did not influence vedolizumab levels,its with-drawal may necessitate higher vedolizumab trough concentrations to maintain remission.

Impact of Pollutant Concentration and Particle Deposition on the Radiative Flow of Casson-Micropolar Fluid between Parallel Plates

Assessing the behaviour and concentration of waste pollutants deposited between two parallel plates is essential for effective environmental management.Determining the effectiveness of treatment methods in reducing pollution scales is made easier by analysing waste discharge concentrations.The waste discharge concentration analysis is useful for assessing how effectively wastewater treatment techniques reduce pollution levels.This study aims to explore the Casson micropolar fluid flow through two parallel plates with the influence of pollutant concentration and thermophoretic particle deposition.To explore the mass and heat transport features,thermophoretic particle deposition and thermal radiation are considered.The governing equations are transformed into ordinary differential equations with the help of suitable similarity transformations.The Runge-Kutta-Fehlberg’s fourthfifth order technique and shooting procedure are used to solve the reduced set of equations and boundary conditions.The integration of a neural network model based on the Levenberg-Marquardt algorithm serves to improve the accuracy of predictions and optimize the analysis of parameters.Graphical outcomes are displayed to analyze the characteristics of the relevant dimensionless parameters in the current problem.Results reveal that concentration upsurges as the micropolar parameter increases.The concentration reduces with an upsurge in the thermophoretic parameter.An upsurge in the external pollutant source variation and the local pollutant external source parameters enhances mass transport.The surface drag force declines for improved values of porosity and micropolar parameters.

Strain concentration factor of heterogeneous materials and analytical influence functions based on Eshelby tensor

In this manuscript,Eshelby tensor is employed to assess the strain concentration that arises in the matrix phase at the interface,offering precise values and locations of maximum strain under specific loading conditions for both spherical and cylindrical inclusions.When compared to numerical simulation results,the analytical predictions grounded in the Eshelby tensor exhibit satisfactory accuracy.Then an analytical calculation method based on Eshelby tensor for the elastic strain influence functions of reduced-order homogenization(ROH)method is developed and adopted on particle-reinforced and fibrous composites,presenting its feasibility and advantage on off-line stage calculation of ROH method.The error analyses between analytical and numerical results are conducted.The numerical results also exhibit the necessity of finer interface partitioning to obtain the response on micro-scale with higher resolution.

A Facile Li_(2)TiO_(3) Surface Modification to Improve the Structure Stability and Electrochemical Performance of Full Concentration Gradient Li-Rich Oxides

Full concentration gradient lithium-rich layered oxides are catching lots of interest as the next generation cathode for lithium-ion batteries due to their high discharge voltage,reduced voltage decay and enhanced rate performance,whereas the high lithium residues on its surface impairs the structure stability and long-term cycle performance.Herein,a facile multifunctional surface modification method is implemented to eliminate surface lithium residues of full concentration gradient lithium-rich layered oxides by a wet chemistry reaction with tetrabutyl titanate and the post-annealing process.It realizes not only a stable Li_(2)TiO_(3)coating layer with 3D diffusion channels for fast Li^(+)ions transfer,but also dopes partial Ti^(4+)ions into the sub-surface region of full concentration gradient lithium-rich layered oxides to further strengthen its crystal structure.Consequently,the modified full concentration gradient lithium-rich layered oxides exhibit improved structure stability,elevated thermal stability with decomposition temperature from 289.57℃to 321.72℃,and enhanced cycle performance(205.1 mAh g^(-1)after 150 cycles)with slowed voltage drop(1.67 mV per cycle).This work proposes a facile and integrated modification method to enhance the comprehensive performance of full concentration gradient lithium-rich layered oxides,which can facilitate its practical application for developing higher energy density lithium-ion batteries.

Analysis of PM2.5 concentrations in Heilongjiang Province associated with forest cover and other factors

Atmospheric particulate matter(PM2.5) seriously influences air quality. It is considered one of the main environmental triggers for lung and heart diseases. Air pollutants can be adsorbed by forest. In this study we investigated the effect of forest cover on urban PM2.5 concentrations in 12 cities in Heilongjiang Province,China. The forest cover in each city was constant throughout the study period. The average daily concentration of PM2.5 in 12 cities was below 75 lg/m^3 during the non-heating period but exceeded this level during heating period. Furthermore, there were more moderate pollution days in six cities. This indicated that forests had the ability to reduce the concentration of PM2.5 but the main cause of air pollution was excessive human interference and artificial heating in winter. We classified the 12 cities according to the average PM2.5 concentrations. The relationship between PM2.5 concentrations and forest cover was obtained by integrating forest cover, land area,heated areas and number of vehicles in cities. Finally,considering the complexity of PM2.5 formation and based on the theory of random forestry, we selected six cities and analyzed their meteorological and air pollutant data. The main factors affecting PM2.5 concentrations were PM10,NO_2, CO and SO_2 in air pollutants while meteorological factors were secondary.

Rheological properties and concentration evolution of thickened tailings under the coupling effect of compression and shear

Cemented paste backfill(CPB)is a key technology for green mining in metal mines,in which tailings thickening comprises the primary link of CPB technology.However,difficult flocculation and substandard concentrations of thickened tailings often occur.The rheological properties and concentration evolution in the thickened tailings remain unclear.Moreover,traditional indoor thickening experiments have yet to quantitatively characterize their rheological properties.An experiment of flocculation condition optimization based on the Box-Behnken design(BBD)was performed in the study,and the two response values were investigated:concentration and the mean weighted chord length(MWCL)of flocs.Thus,optimal flocculation conditions were obtained.In addition,the rheological properties and concentration evolution of different flocculant dosages and ultrafine tailing contents under shear,compression,and compression-shear coupling experimental conditions were tested and compared.The results show that the shear yield stress under compression and compression-shear coupling increases with the growth of compressive yield stress,while the shear yield stress increases slightly under shear.The order of shear yield stress from low to high under different thickening conditions is shear,compression,and compression-shear coupling.Under compression and compression-shear coupling,the concentration first rapidly increases with the growth of compressive yield stress and then slowly increases,while concentration increases slightly under shear.The order of concentration from low to high under different thickening conditions is shear,compression,and compression-shear coupling.Finally,the evolution mechanism of the flocs and drainage channels during the thickening of the thickened tailings under different experimental conditions was revealed.

Dynamics and genetic regulation of macronutrient concentrations during grain development in maize

Nitrogen(N), phosphorus(P), and potassium(K) are essential macronutrients that are crucial not only for maize growth and development, but also for crop yield and quality. The genetic basis of macronutrient dynamics and accumulation during grain filling in maize remains largely unknown. In this study, we evaluated grain N, P, and K concentrations in 206 recombinant inbred lines generated from a cross of DH1M and T877 at six time points after pollination. We then calculated conditional phenotypic values at different time intervals to explore the dynamic characteristics of the N, P, and K concentrations. Abundant phenotypic variations were observed in the concentrations and net changes of these nutrients. Unconditional quantitative trait locus(QTL) mapping revealed 41 non-redundant QTLs, including 17, 16, and 14 for the N, P, and K concentrations, respectively. Conditional QTL mapping uncovered 39 non-redundant QTLs related to net changes in the N, P, and K concentrations. By combining QTL, gene expression, co-expression analysis, and comparative genomic data, we identified 44, 36, and 44 candidate genes for the N, P, and K concentrations, respectively, including GRMZM2G371058 encoding a Doftype zinc finger DNA-binding family protein, which was associated with the N concentration, and GRMZM2G113967encoding a CBL-interacting protein kinase, which was related to the K concentration. The results deepen our understanding of the genetic factors controlling N, P, and K accumulation during maize grain development and provide valuable genes for the genetic improvement of nutrient concentrations in maize.

Trends of surface ozone based on hourly concentrations in the Beijing–Tianjin–Hebei region during 2017–2021

As a typical secondary air pollutant,surface ozone has been monitored routinely since 2013 in China.Most studies on the spatiotemporal variation of ozone have been centered around the daily maximum 8-h average,with little attention paid to the trends of hourly ozone,especially hourly ozone exceedances.Focusing on hourly ozone exceedances and peak values,the spatiotemporal trends of hourly ozone at 77 sites in 13 cities of the Beijing-Tianjin-Hebei(BTH)region during 2017-2021 were analyzed in this study.The number of hours with exceedances(N_(H200))in 2019 was nearly three times that of 2021.On a five-year average,the percentage of cumulative NH200 in June accounted for up to 40.5%of all hourly exceedances.Cities in central Hebei Province had the highest cumulative annual N_(H200).June had the highest average hourly ozone exceeded multiples of 0.158.The top two cities with the highest average exceeded multiple were Tangshan(0.166)and Beijing(0.158).Tangshan and Xingtai ranked as the top two in terms of the mean of the 10 highest daily maximum ozone concentrations(MTDM),with 286.74 and 285.37μg m^(−3),respectively.The gap between the MTDM and the daily maximum of hourly ozone averaged over all sites had narrowed to 97.88μg m^(−3) in 2021,much lower than that in other years,which indicated that the stability and convergence of ozone pollution in BTH region had been enhanced in 2021 to some extent.

Seasonal dynamics and impact factors of urban forest CO2 concentration in Harbin,China

CO2 concentrations in different plant communities （larch, birch, lilac, and grassland） were measured during the growing season in the Heilongjiang Forest Botanical Garden to study diurnal variation, seasonal and annual dynamics and factors that impact CO2 concentration in different spaces. CO2 concentration in different communities in green lands had an obvious diurnal variation, chronically decreasing, and temperature influenced the lilac area and the grassland. Seasonally, CO2 was lowest in the larch green land （344.03 ±23.03 μmol/mol） and highest in the grassland （360.13 ± 22.43 μmol/mol）. The overall trend in CO2 concentration was autumn 〉 spring 〉 summer; temperature is the main factor controlling variation in CO2 concentrations during the growing season; the CO2 concentration at the larch, birch, lilac, and grassland types of sites was negatively correlated with land surface temperature and air temperature, and the CO2 concentration at the larch and birch sites was positively correlated with atmospheric pressure. Without any obvious annual change law, further study and observation are needed.

Influence of Soft Filler on Stress Concentration Factor of Elliptic Holes in a Rectangular Plate

Finite element models were established to analyze the influence of soft filler on stress concentration for a rectangular plate with an elliptic hole in the center. The influence was quantified by means of stress concentration factor (SCF). Seven shape factors of the elliptic hole and three levels of elasticity modulus of the soft filler were considered. The reduction coefficient and sensitivity index of SCF are the two indicators in evaluating the influence of soft filler. It was found that the reduction coefficient of SCF increases significantly as the shape factor and the elasticity modulus of the filler increase, indicating that soft filler can reduce the concentrated stress effectively, especially when the shape factor is great. Analysis for the sensitivity index of SCF indicates that SCF is more sensitive to materials with small elasticity modulus than to materials with large one.

Effect of Surface Topography on Stress Concentration Factor

Neuber rule and Arola-Ramulu model are widely used to predict the stress concentration factor of rough specimens. However, the height parameters and effective valley radius used in these two models depend strongly on the resolution of the roughness-measuring instruments and are easily introduce measuring errors. Besides, it is difficult to find a suitable parameter to characterize surface topography to quantitatively describe its effect on stress concentration factor. In order to overcome these disadvantages, profile moments are carried out to characterize surface topography, surface topography is simulated by superposing series of cosine components, the stress concentration factors of different micro cosine-shaped surface topographies are investigated by finite element analysis. In terms of micro cosine-shaped surface topography, an equation using the second profile moment to estimate the stress concentration factor is proposed, predictions for the stress concentration factor using the proposed expression are within 10% error compared with the results of finite element analysis, which are more accurate than other models. Moreover, the proposed equation is applied to the real surface topography machined by turning. Predictions for the stress concentration factor using the proposed expression are within 10% of the maximum stress concentration factors and about 5% of the effective stress concentration factors estimated from the finite element analysis for three levels of turning surface topographies under different simulated scales. The proposed model is feasible in predicting the stress concentration factors of real machined surface topographies.

Linear QSAR Regression Models for the Prediction of Bioconcentration Factors of Chloroanilines in Fish by Density Functional Theory

Density functional theory（DFT）-B3LYP level with the 6-311G＊＊（d,p） basis set was used to calculate a set of molecular quantum chemical descriptors of 12 chloroanilines. Quantitative structure-activity relationship（QSAR） models of the bioconcentration factors（BCF） of the anilines in fish were established using some of the following calculated descriptors： EHOMO, ENHOMO, ELUMO, ENLUMO, ΔE1（= ELUMO- EHOMO）, ΔE2（= ENLUMO- ENHOMO）, dipole moment（μ）, molecular volume（V）, vibrational energy of 0 K（Ev）, thermodynamic energy（E）, heat capacity（Cv）, entropy（Sm） and the charge of benzene ring（Qph）. Using the variable selection and leaps-and-bounds regression, the quantum chemical descriptors derived directly from the molecular structures were employed to develop a linear QSAR model between the bioconcentration factors（BCF） and two descriptors（Sm, ENHOMO） of 12 chloroanilines. Statistically, the most significant one is a two-parameter linear equation with the correlation coefficient（R^2） of 0.981 and cross-validated correlation coefficient（Rcv^2） of 0.967. The established QSAR model has good stability and predictability based on the results from Rcv2 of leave-one-out cross-validation, AIC, FIT and tα/2. The quantum chemical analyses were performed from two aspects of frontier molecular orbital and entropy. The results show that two structural describers are crucial to the bioconcentration activity of chloroanilines.

Parametric Equation of Stress Concentration Factor for Circular X-Joints Under Axial Loads

In engineering practice, tubular X-joints have been widely used in offshore structures. The fatigue failure of tubular X-joints in offshore engineering is mainly caused by axial tensile stress. In this study, the stress concentration factor distribution along the weld toe in the hot spot stress region for tubular X-joints subject to axial loads have been analyzed by use of finite element method. Through numerical analysis, it has been found that the peak stress concentration factor is located at the saddle position. Thereafter, 80 models have been analyzed, and the effect of the geometric parameters of a tubular X-joint on the stress concentration factor has been investigated. Based on the experimental values of the numerical stress concentration factor, a parametric equation to calculate the stress concentration factor of tubular X-joints has been proposed. The accuracy of this equation has been verified against the requirement of the Fatigue Guidance Review Panel, and the proposed equation is found capable of producing reasonably accurate stress concentration factor values for tubular X-joints subject to axial loads.

Stress concentration factor expression for tension strip with eccentric elliptical hole

Two explicit expressions of the stress concentration factor for a tension finite-width strip with a central elliptical hole and an eccentric elliptical hole, respectively, are formulated by using a semi-analytical and semi-empiricai method. Accuracy of the results obtained from these expressions is better, and application scope is wider, than the results of Durelli＇s photo-elastic experiment and Isida＇s formula. When eccentricity of the elliptical hole is within a certain range, the error is less than 8%. Based on the relation between the stress concentration factor and the stress intensity factor, a stress intensity factor expression for tension strips with a center or an eccentric crack is derived with the obtained stress concentration factor expressions. Compared with the existing formulae and the finite element analysis, this stress intensity factor expression also has sufficient accuracy.

Estimation and Prediction of Bioconcentration Factors of Nonionic Organic Chemicals in Fish by Electrotopological State Indices and Structural Parameter

Based on the characteristics of atom types, Hall＇s electrotopological state indices （En） are calculated for 165 nonionic organic compounds. On the basis of the characteristics of substituent and conjugated matrix, a novel molecular structure parameter （G） is defined and calculated for 165 molecules in this paper. En and G show good structural selectivity for organic molecules. G, a satisfactory relationship between bioconcentration factor （BCF） and En, is expressed as： 1gBCF = -0.283 ＋ 1.246G ＋ 0.079E42 ＋ 0.351E9- 0.063E17 （n＇ = 122, R = 0.967, F = 425.636, s = 0.394）, which could provide estimation and prediction for the lgBCF of nonionic organic chemicals. Furthermore, the model is examined to validate overall robustness with Jackknife tests, and the independent variables in model do not exist cross correlation with VIF. All these regression results show that the new parameter G and electrotopological state index have good rationality and efficiency. It is concluded that the En and G will be used widely in quantitative structure-property/activity relationship （QSPR/QSAR） research.

Analysis of mass concentration of atmospheric particulate matter in a sandstorm course and its affecting factors in the Taklimakan Desert

During the course of a major sandstorm from April 17 to April 23, 2008 in the Taklimakan Desert, data pertaining to the mass concentrations of different-sized atmospheric particulate matter were observed continuously with Grimm 1.108, Thermo RP 1400a, TSP, and CAWS-600 instruments. The results showed that： （1） during the entire sandstorm process there were some dif- ferences between the daily mean particle concentration peaks and the hourly mean particle concentration peaks because the actual sandstorm lasted for only about 4 hr, whereas more particles were accumulated in the floating dust days before and after the actual sandstorm; （2） the intensity of the sandstorm was enhanced with the increase of wind speed, and this was related to the peak mass concentrations of atmospheric particulate matter; the wind speed directly affected the concentration of atmospheric particulate matter： the higher the wind speed, the higher the mass concentration （〉0.23 μm was 39,496.5 μg/m^3, and 〉20.0 μm was 5,390.7μg/m^3）; （3） the concentration changes of PM10 and TSP were also related to the course and intensity of the sandstorm; and （4） the mass concentration of atmospheric particulate matter had the following sequence during the dust weather： clear day 〈 floating dust 〈 floating and blowing dust 〈 sandstorm. Temperature, relative humidity, and barometric pressure are important factors affecting the strength of storms, which could also indirectly affect the concentration change of atmospheric particulate matter.

ANALYTICAL VARIATIONAL METHOD OF SOLUTION FOR STRESS CONCENTRATION FACTORS OF FINITE PLATES WITH A PIN HOLE

First of all, Laurent series expansions of stress and displacement fields satisfying all the governing equations of plane problems in theory of elasticity are derived. Next, the variational method is applied to satisfy the boundary conditions of a plate with a pin hole. Then, the coefficients in Laurent series and the stress concentration factor can be determined. Finally, the convergency tests and systematical results are given for engineering applications.

Factors influencing the concentration of negative air ions during the year in forests and urban green spaces of the Dapeng Peninsula in Shenzhen, China

Negative air ions(NAIs)benefit the mental and physical health of humans,but rapid urbanization can decrease the abundance of NAIs.Quantifying the spatial and seasonal distribution of NAIs and determining the factors that infl uence the concentration during urbanization is thus essential.In the present study of a typical developing urban district in southern China,negative air ion concentrations(NAICs)in 60 forests sites and 30 urban green spaces were quantifi ed on seven consecutive days in each of the four seasons.Large seasonal variations in NAIC were revealed in forests and urban green spaces with trough values in summer.NAIC progressively decreased from forests to urban green spaces and was infl uenced by local land morphology,vegetation characteristics,and climatic factors.The vast,heavily vegetated northeastern region was the richest area for NAIs,whereas the narrow central region(urbanized area)was the poorest,implying dramatic impacts of urbanization on the spatial distribution of NAIs.The relationship between air temperature and NAIC was better fi tted with a quadratic equation than a linear equation.Moreover,the NAIC was more sensitive to local morphology in urban green spaces than in urban forests,indicating the vulnerability of NAIs in urbanized areas.Therefore,the appropriate design of local urban morphology is critical.

Influence of geometric parameters on stress concentration factors of undermatched butt joint with single V-groove under three-point bending load

In order to improve the bending load-carrying capacity （BLCC） of undermatched butt joint under three-point bending load, the influence of joint geometric parameters on stress concentration factors （SCF） at the weld bottom center and the weld toe of uudermatched butt joint with single V-groove are studied respectively based on the finite element method in this paper. Results show that the reinforcement height and the cover pass width play decisive role in the BLCC for undermatched butt joint. BLCC of undermatched butt joint can be improved by choosing the appropriate joint geometric parameters.

Effect of Different Concentrations of Neogenin on Proliferation,Apoptosis and Related Proliferative Factors in Human Trophoblasts

The underlying effect of different concentrations of neogenin on proliferation, apoptosis and the related proliferative factors in human trophoblasts was explored in order to understand the function of neogenin during placentation. TEV-1 cell line was cultured and the expression of netrin-1 was detected by using indirect cellular immunofluorescence. Exponentially growing TEV-1 cells were treated by different concentrations of neogenin (0, 1, 5, 10, 50 ng/mL) for 24 h. Cell viability was measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. TEV-1 cell apoptosis was assessed by flow cytometry (FCM). The expression of netrin-1 mRNA and protein in TEV-1 cells was examined by using real-time PCR and Western blot, respectively. It was found that immunoreactivity for netrin-1 was observed in cytoplasm of the trophoblasts. Immediately after treatment with different concentrations of neogenin for 24 h, the netrin-1 expression began to increase. Real-time PCR revealed that the expression level of netrin-1 mRNA was 37.59±10.25 times higher than control group when TEV-1 cells were exposed to 50 ng/mL neogenin (P<0.01), and the same tendency was seen by using Western blot. MTT results showed that proliferation of TEV-1 cells was independent of neogenin. Meanwhile, apoptosis was significantly increased to (22.15±6.15)% at 50 ng/mL neogenin and (6.55±0.25)% without neogenin (P<0.01). It is suggested that neogenin regulates proliferation and apoptosis of TEV-1 cells. And it can enhance the ability of TEV-1 cells to express netrin-1 in a dose-dependent manner. Neogenin may play an important biological role in the normal human pregnancy and contribute to the physiological pregnancy process.