In contrast to traditional approaches to simulating fresh concrete, the model applied here allows issues such as liquid phase and the motion of sub-scale particles to be considered. The rheological behavior of fresh concrete materials was investigated, and the slump test and pumping process of fresh concrete were simulated by combining the smooth particle hydrodynamics coupled with discrete element method. Based on Bi-viscosity model and Bingham model, linear and nonlinear fitting of rheometer data and the derivation equations were educing. Bi-viscosity model and the Bingham model were compared in slump test. The results show that the Bi-viscosity model is more accurate in simulation, and the error percentage is less than 10%. The Bi-viscosity model was used to simulate and predict the results of slump experiment, and the influence of rheological parameters on the slump velocity and shape was obtained. The simulation analysis model of concrete single-cylinder pumping is established, and the experimental and simulation analysis models are compared. The results show that the SPH-DEM pumping pressure prediction is very close to the experimental results. Due to the complex composition of concrete, the experimental process is difficult to analyse and control more accurately the specific influencing factors9 for the changes in pumpable performance.Despite the development of computational science and simulation technology, some physical phenomena, can be reasonably characterized and analysed by computer technology. However, for the transport11 argued that fresh concrete can be used to show the properties of concrete with Bingham fluid, which is a non-Newtonian fluid with a certain yield stress, and irreversible flow and deformation will occur only when the fluid is subjected to a shear stress greater than the yield stress. As the research progresses, and the fitness ratio of concrete changes, the shear rate of fresh concrete is not linearly related to the shear stress similar to the Bingham model, but will exhibit shear thinning and shear thickening properties12. Checking the pumpability of concrete, in engineering applications, is generally predicted by slump tests. Chidiac et al.13 showed in their study that the slumping process of concrete occurs only when the gravity of the bottom material exceeds the effect of yield stress, while no shear flow occurs in the upper region, and the bottom concrete keeps flowing downward, resulting in a continuous increase in experimental slump and eventually The flow stops when the shear stress from the gravity of the top concrete is equal to the yield. However, the experimental procedure for concrete cannot quantify its characteristics such as viscosity, velocity, and yield, and it is difficult to analyze the factors affecting the concrete pumping process.Roussel et al.14, which is 15, i.e., 16. Robin De Schryver et al.17 used OpenFOAM  single-phase flow to calculate the pressure of the concrete pumping process, the results are one pressure value higher than the experimental values, which is explained by the fact that concrete undergoes compositional changes during transport in the pumping pipeline, which results in much smaller rheological parameters near the walls than the actual concrete.Secrieru et al.18 and others, using the commercial software Fluent (Ansys Ltd), divided the concrete into two phases, using the rheological parameters of the lubrication layer near the wall and the internal plunger flow using the rheological parameters of the concrete itself for pumping pressure analysis, and the simulation results were very close to the experimental numerical results.Bingham model is commonly used to express the rheological properties of concrete19, discrete concrete large scale particles and continuous fluid, analyzed the concrete coarse aggregate shape for concrete test L box clogging factors were explored. Krenzer et al.20 divided concrete into wet and dry particles, and applied particle replacement method to form a new material particle after wet and dry collision to simulate the aggregation of slurry and aggregates during concrete mixing, and conducted an analytical comparison between slump experiments and simulation to verify the feasibility of DEM method to study concrete materials. However, no systematic industrial application of the DEM method in and pipeline conveying has been seen.The phenomenon of formation and analysis out of the pumping process can also be used Discrete element method (DEM), which discrete the concrete into two phases of aggregate, slurry, and fitted with different material friction and recovery coefficients, respectively. Cui et al.21 analyzed the trajectory of the particle motion in the pumping pipe and its exploration of the easy clogging parts of the pipe, and the results showed that the particles at the bends are prone to aggregation, and this result is consistent with the results analyzed by Jiang et al.22 Considering the large grid size (large particle size), it is difficult to capture the action and characteristics of the boundary layer, which affects the final pressure calculation results.Another analysis method is to use CFD-DEM . For example, Zhan et al.In summary, the former research method of DEM is more for concrete materials and cannot characterize the fluid properties of concrete, so it is rarely involved in pumping aspects. The classical CFD method, which esteemed the concrete components as single-phase fluid, is far from the actual complex concrete composition. It is impossible to characterize the movement of large-grained aggregates in concrete. In addition, the interaction between aggregate and slurry cannot be characterized, and the causes of aggregate precipitation, settlement and blockage in the pumping process cannot be analyzed. It is necessary to couple the movement of slurry and aggregate. Therefore, the SPH-DEM coupling analysis method is selected here, which can consider the particle motion and the large rigid body motion of the concrete cylinder.24 compared to the classical computational fluid dynamics (CFD) method. The SPH-DEM method is used to establish a concrete model for the pumping rheological behavior of concrete, and the pumping experiments are used to test the applicability of the method and provide evaluation, prediction and improvement of analysis methods for pumping experimental results.The smoothed particle hydrodynamics coupled with discrete elements method(SPH-DEM) is a sub-particle scale (SPS) analysis method, which can simulate large-scale particle motion (particle size larger than the grid)27 is used to solve the fluid phase, which is a computational fluid dynamics method under the Lagrangian framework. In SPH, ‘particles’ represent the fluid space domain. The solution of SPH is solved by the integral and differential of the flow field variables  and the kernel function. The Navier–Stokes (N–S) equations of computational fluid dynamics, which continuity and momentum equations are written as Eqs.  as Eqs.  and 2)1127 is us31. The integral of the function is transformed into the integral of the kernel function written asThe solution of the Eqs.  and 2)  2) consiWhere mentclass2pt{minim26 is written asTherefore, the N-S equation in SPH schemea and a. where, 31. To solve this problem the Dynamic boundary condition(DBC) is chosen for the work of this paper, while DBC is used in the study of Newtonian and non-Newtonian fluids33.Considering that when the fluid is in contact with a solid or a boundary, the integration region of the kernel function is not the whole region that the fluid can contain at this time, the range of action of the kernel function will be truncated by the boundary, which will lead to the loss of accuracy of the kernel function of the SPH36 is used to solve computational fluid dynamics. The Project Chrono engine (open-source DEM code) is coupled for collisions and interactions between solid large particles and bottom area, rigid bodies, and other particles.DualSPHysics (open-source CFD code based on SPH method) v5.0.51There are a large number of coarse aggregate particles inside the fresh concrete material. The motion process of large particles is generally solved by DEM method, and then the velocity and displacement are solved by Newton’s law of motion. The solution process of the DEM method is shown in Fig. In Fig. where, It is also possible to derive the movement of an object by considering its interaction with fluid particles and using these forces to drive its motion. This can be achieved by summing the force contributions for an entire body. By assuming that the body is rigid, the net force on each boundary particle is computed according to the sum of the contributions of all surrounding fluid particles according to the designated kernel function and smoothing length. Each boundary particle k therefore experiences a force per unit mass given by Eq. 15\documeFor the motion of the moving body, the basic equations of rigid body dynamics can then be used37 and H-B model isBingham and H-B models were used to study the rheological properties of fresh concrete. Both of them consider the initial flow state of concrete, and the shear stress In Eqs.  and 15)15), the 38, and make a reasonable correction to convert the H-B model from a discontinuous process to a continuous HBP process, such asWhen the shear rate is small, the viscosity tends to infinity at this time, which will bring convergence problems to the simulation process. Therefore, it is necessary to improve the Eq.  reasonabThe viscosity of the motion process at this time isTherefore, the rheological model under the HBP model shows continuity, and as the management parameter m increases, it will become more and more close to the ideal Bingham model, and its mapping relationship and image are shown in Fig. The Bi-viscosity model is based on the HBP model, which enlarges the viscosity coefficient in the small shear rate region, making the Bi-viscosity model closer to the ideal Bingham model. The image is shown in Fig. The force diagram of the concrete rheometer during the sampling process is shown in Fig. The torque of the rotary process of the rheometer isSince the tangential velocity of the rotation axis is zero, the tangential velocities of the blades AC and BD are The torque of the blade AB and CD is41 have shown that no shear behavior occurs in the ABCD region when the blade is rotating. When the blade rotates, the surface of the blade exerts a tangential force along the surface direction on the concrete in the ABCD region. The centrifugal force generated by the rotating fluid in the ABDC region is completely balanced by the fluid outside the ABDC region, and there is no radial displacement. After the rotational speed of the rheometer shaft is stable, the rotational speed of the fluid in the ABDC region is consistent with the rotational speed of the blade, and the fluid and the blade have no relative movement trend in the radial and tangential directions. Therefore, the fluid in the ABDC region does not apply shear stress to the blade, that is, the required torque Previous studiesThis region can be simplified as an annular flow, and the speed of the blade is AC/BD. The speed of the blade is the boundary speed This area can be simplified into two rotating plates, and the upper part of the plate rotates unilaterally, for the occurrence of concrete shear. The velocity The torque integral The force analysis of the torque in this region is similar to that of Considering that the velocity of any height z in this region isThe corresponding shear rate is defined by the shear rate asThe torque contribute in this region isThe analysis process of this region is similar to Therefore, the overall torque Eq. , becausento Eqs. , 27), \documentWhen d of Eq.  correspo42, which indirectly proves the correctness of the derivation form. In the actual measurement process of the rheometer, it is not a linear relationship similar to the Bingham form, but a nonlinear Bi-viscosity form Eq. (The calculation result of Eq.  is the sform Eq.  is writtSubstituting the geometric parameters of the rheometer blade m to Eq. , the corThe shear strain corresponding to rotation isSimilarly, the shear rate of the Bingham model isThe materials used in the four groups of concrete experiments for this test are ordinary Portland cement PO42.5, with a density of 3050 In order to comprehensively study the influence of the rheological properties of concrete on the flow process, different proportions of concrete were prepared in this paper to prevent contingencies during the experiment. The specific match is shown in Table Considering that the material used in the experimental process is less, it is necessary to accurately control the quality of the material, especially the control of the water content has a great influence on the experimental results. In addition, in order to simulate the movement of large aggregate in concrete, the size and gradation distribution of aggregate in concrete are screened as shown in Fig. The slump test is to detect the pumpability of concrete. Generally, the fluidity of concrete with slump greater than 180 mm is higher. The specific structure of the slump instrument is a cone with a top diameter of 100 mm, a bottom diameter of 200 mm, and a height of 300 mm, as shown in Fig. In order to ensure the relative stability of the data obtained during the collapse process, the above four experimental groups were stirred and tested as shown in Fig. entclass1pt{minimaThe torque of the rheometer blade during rotation is calculated to convert the rheological properties of the concrete. ICAR Rheometer is used, as shown in Fig. The rheometer in Fig. Considering that during the operation of the rheometer, if the blade stirs to a larger aggregate, a certain fluctuation will occur, which will affect the final calculation results and thus affect the analysis results. Therefore, it is necessary to process the data of the rheometer. The original data of the rheometer is shown in Fig. Obviously, the data in Fig. The rheological test data of the concrete in the experimental group are shown in Table The data in Table Similarly, the Bingham model fitting can be obtained as shown in Table The solver used for this work is the explicit integration solver Symplectic. The fluid–solid interaction part uses Inlet/outlet boundaries with an initial time step of 1e−6. The computation time step is automatically adjusted based on the CFL number. The GPU of the computer is NVIDIA RTX A60000, and the CPU has 96 cores.In order to obtain the accuracy of the fluid force on the solid during the SPH-DEM coupling process, a simple cylindrical flow model is established. As shown in Fig. 43. The data are shown in Fig. At different conditions of Reynolds number The data in Fig. The simulation model of concrete slump is composed of two phases, which are slurry, generated by fluid particles of Bi-viscosity model, and large aggregate DEM solid. The aggregate file is scanned into stl format and converted into SPH particles to form rigid large particle Vtk format, as shown in Fig. The concrete slump instrument is filled with slurry and coarse aggregate, and the proportion of slurry and aggregate is calculated by the results given in Fig. After the concrete slump model is established, the rheological parameters and aggregate friction coefficient of the experimental group are substituted for simulation analysis. The simulation and experimental results are compared. The first set of simulation analysis is shown in Fig. It can be seen from Fig. The results of the third 44, n takes 1 here for comparative analysis. Considering that the yield stress is related to the anti-deformation ability of the fluid, the greater the yield stress, the stronger the anti-deformation ability, and the slower the flow. The simulation analysis results are shown in Fig. There are three main parameters in the Bi-Viscosity model, which will affect the simulation results. Based on the Bi-viscosity rheological parameters of the experimental group Comparing the simulation results with the empirical formula, it can be obtained that the simulated slumps with yield stress of 400, 200 and 100 are 230 mm, 231 mm and 237 mm, respectively, while the empirical formula results are 246 mm, 237 mm and 220 mm. Therefore, the error percentages of simulation analysis and empirical formula are 6.6%, 2.8% and 7.5%, respectively. The overall error percentage is less than 10%.The comparison between spherical coarse aggregate and non-spherical coarse aggregate is mainly to consider the interaction between aggregate shape and bottom and aggregate. Because the contact and action range of spherical coarse aggregate is less than that of non-spherical coarse aggregate. Therefore, the expansion range of spherical coarse aggregate should be larger than that of non-spherical aggregate. The simulation results are shown in Fig. The power law coefficient in the Bi-viscosity model is changed to explore the influence of its change trend on the concrete slump experiment, as shown in Fig. Changing the fluid density for slump simulation analysis, the most intuitive change brought by density is the difference in gravity, which leads to the difference in shear stress corresponding to the motion process. The greater the density, the greater the shear stress, and vice versa. Therefore, the slump and expansion of the fluid with higher density will increase, and the slump of the fluid with lower density is relatively small. The simulation results are shown in Fig. The industrial application of fresh concrete is mainly concrete pumping. In order to explore the applicability of the model in industrial application, a simple pumping platform is established, as shown in Fig. In the initial pumping process of the concrete cylinder, in order to reduce the influence of friction resistance on the pumping pressure collection, the concrete cylinder wall is smeared with grease, and the no-load pressure after smearing grease is collected. The total pressure minus the no-load pressure of the concrete cylinder is the pressure required for the concrete pumping process. The pumping speed of the concrete cylinder hydraulic system is set to 73.6 mm/s, and the piston motion stroke is 1.04 m, as shown in Fig. Under the above conditions, the rheological parameters are simulated and analyzed. The Bi-viscosity model The simulation results of group E1 are shown in Figs. The pressure drop trend of the motion process is higher than that of the simulation, but Fig. SPH-DEM fluid–solid coupling force analysis model is established, and the drag coefficient under different Reynolds numbers is calculated. The simulation results are very close to the experimental results.SPH-DEM method was used to simulate the rheological behavior of fresh concrete with large particle size. The Bi-viscosity model and Bingham model of concrete were established. The slump simulation analysis model was compared with the experiment. The results show that the Bi-viscosity model has higher fitting accuracy than the Bingham model and the experiment, and the overall error is less than 10%. The fitting error of the Bingham model for the experiment is about 20%.Influence of different rheological parameters of Bi-viscosity model on the simulation process of concrete slump is analyzed. The results show that the greater the critical yield stress, the stronger the anti-deformation ability of concrete, and the smaller the slump movement process under gravity. The error between the simulation analysis of the slump of the yield stress and the empirical formula is less than 10%. The effect of density on slump is converted between relative gravity and yield stress. Under the same yield stress, the smaller the density is, the smaller the gravity is. Therefore, the larger the density is, the larger the expansion and slump are. The influence of power law index on slump simulation is to affect the initial motion state. At this time, the acceleration is the largest, the shear rate is the largest, and the corresponding shear stress changes the most. With the extension of the simulation time, the movement is gradually gentle, and the shear stress fluctuates up and down at the yield stress. The influence of the final slump and the expansion degree is close to each other. The slump simulation analysis process of spherical coarse aggregate and non-spherical coarse aggregate is compared. The results show that the slump and expansion of spherical coarse aggregate are larger than those of non-spherical particles.Concrete pumping model is established and the pumping pressure test is carried out. The simulation analysis results are compared with the experimental results. The consistency of the simulation initial value and the trend of the intermediate process is obtained. Considering that the rheological parameters of the boundary layer will change during the pumping process, the boundary layer characteristics can be added in the follow-up study to more accurately simulate the rheological properties of the concrete during the pumping process.This paper intends to use a new method to describe the rheological behavior and particle movement of concrete during pumping. The following conclusions are obtained by combining simulation and experimental results.


The incorporation of rubber can enhance concrete’s durability and effectively reduce the damage caused by freeze-thaw cycling (FTC). Still, there has been only limited research on the damage mechanism of RC at the fine view level. To gain insight into the expansion process of uniaxial compression damage cracks in rubber concrete (RC) and summarize the internal temperature field distribution law during FTC, a fine RC thermodynamic model containing mortar, aggregate, rubber, water, and interfacial transition zone (ITZ) is established in this paper, and the cohesive element is selected for the ITZ part. The model can be used to study the mechanical properties of concrete before and after FTC. The validity of the calculation method was verified by comparing the calculated results of the compressive strength of concrete before and after FTC with the experimental results. On this basis, this study analyzed the compressive crack extension and internal temperature distribution of RC at 0, 5, 10, and 15% replacement rates before and after 0, 50, 100, and 150 cycles of FTC. The results showed that the fine-scale numerical simulation method can effectively reflect the mechanical properties of RC before and after FTC, and the computational results verify the applicability of the method to rubber concrete. The model can effectively reflect the uniaxial compression cracking pattern of RC before and after FTC. Incorporating rubber can impede temperature transfer and reduce the compressive strength loss caused by FTC in concrete. The FTC damage to RC can be reduced to a greater extent when the rubber incorporation is 10%. With accelerating urbanization, the center of gravity of China’s development has shifted from the original coastal cities to the alpine regions in the northwest. Influenced by environmental factors, such as high altitudes and large temperature differences between day and night, many infrastructures in these areas are subjected to freeze-thaw damage . Freeze-In the 1990s, Eldin and Senouci conducted preliminary research on rubber concrete (RC) as a new material. They found that adding rubber to concrete can, on the one hand, reduce the pressure caused by the environmental damage caused by discarded tires; on the other hand, adding rubber improves concrete’s durability to a certain extent . Based oNumerical simulations can gradually replace complex FTC experiments due to the rapid development of computer simulation technology and the in-depth study of the coupling theory of fracture mechanics and thermodynamics. This phenomenon has greatly reduced the experimental time and has alleviated the environmental damage caused by the extraction of raw materials. Numerical simulation of FTCs is the process of simulating computer models of concrete using the relevant theories of fracture mechanics and size effects. By calculating the temperature distribution inside concrete and the crack development after mechanical experiments, it is possible to derive how the variable factors affect the mechanical properties of concrete after FTCs. To improve the realism of numerical simulations, related scholars have established multi-scale computational models using the relevant principles of pore mechanics and thermodynamics and have compiled the laws of the damage evolution process of FTCs. Duan  establisHowever, many scholars have studied the numerical simulation of FTCs without considering the effect of water or ice effect, and the numerical simulation of FTCs of RC is still in the early stage. In this paper, we analyzed the FTC models of many scholars, established a two-dimensional mesoscopic calculation model of multiphase concrete, and added a cohesive force element as the interface transition zone to investigate the effect of rubber admixture on the FTC of concrete. The analytical results were compared with relevant experimental data to determine the relationship between the rubber content and the rate of compressive strength loss after FTCs, verifying the numerical simulation’s feasibility. The model also provides a relevant theoretical study for the use of RC in alpine regions.This study used a stochastic aggregate model for numerical simulation calculations. In the mesoscale model, RC is usually considered a multiphase material consisting of mortar matrix, coarse aggregate, mortar-coarse aggregate ITZ, rubber particles, mortar-rubber ITZ, and water, and each aggregate is considered an isotropic material in the model design. Aggregate diameter was chosen from 5–10 mm, 10–15 mm, and 15–20 mm, following the random aggregate placement principle and using Fuller’s gradation to achieve the best performance of the generated RC model .(1)P=10P—Percentage of aggregate passing through sieve diameter The Ravavin formulation is a three-dimensional concrete computational model transformed into a two-dimensional planar model for relevant research calculations , ensurinAggregate generation code was written in the Python language. Before the aggregates are generated, it is necessary to determine the model boundary range first, the maximum and minimum particle sizes of the generated aggregates, and rubber, The flow chart of aggregate generation is as follows:The use of Equation (2) to find the area of each aggregate is shown in Through the above steps, the distribution of the generated aggregates is calculated as follows:The two-dimensional random aggregate RC model is a composite model composed of multiple materials. The model mainly explores the effect of the rubber substitution rate on the FTC of RC and simulates the overall thermodynamic damage state of concrete using the thermodynamic properties of each phase material. The mortar matrix plays a crucial role in the mechanical properties of rubber concrete. Since the mortar matrix is considered concrete with a lower strength, it is regarded as a homogeneous and continuous elastic-plastic material during the modeling process, and a concrete plastic damage (CDP) model is used as the constitutive law of the mortar. It was shown  that conAggregate shape can also have a large effect on the numerical simulation results. Finite element analysis and experimental data by Kim et al.  and HuanIn this study, the model was designed with reference to the thermodynamic models of Yu  and Peng−15, and a maximum value of 0.05. In this case, the model convergence is good. The direct vertical displacement load is applied to the upper nodes, which can avoid the load inertia factor affecting the compressive strength. The bottom restrains the movement in the y-axis direction, and the middle node is fixed by hinging, thereby restoring the pressurization of the real load-bearing machine. The loading process of single-axis compressive numerical simulation is shown in The numerical analysis of this model selected a 150 × 150 mm calculation model. The static uniaxial compression process was simulated in the Abaqus2021 standard analysis program. Geometric nonlinearity was chosen for the analysis step setting, with initial incremental steps of 0.01, a minimum value of 1 × 10Many numerical simulation experiments have shown that the model’s mesh size and maximum particle size are relevant factors that must be considered during the calculation phase ,36. AfteDetermining the ITZ in concrete computational models can accurately simulate micro-mechanical damage within the concrete, so it is especially important to accurately grasp the ITZ working mechanism and damage in mesoscale calculations. The current experiments on the ITZ mainly include macroscopic experiments to measure mechanical parameters or use micro-CT and nanoindentation . Still, The model of this study uses cohesive elements as a zero-thickness ITZ, mainly including a mortar-coarse aggregate ITZ, a mortar-rubber ITZ, and a water-mortar contact zone. The thermal analysis is calculated using the viscous heat transfer element COH2D4T to analyze the temperature field distribution during each FTC and to restore the actual situation to a greater extent.The traction separation theory of cohesive elements is used to define failure and progressive damage in the cohesive layer , using aTo accurately explore the failure and damage processes of various phase materials in the calculation process, the model introduces an initial damage criterion: the degradation of material point response. When a specific value or higher is reached, the damage starts. When the nominal stress ratio of the quadratic interaction function is 1, it is expressed as:A nominal strain ratio of 1 for the secondary interaction function is expressed as:The rapidity of the stiffness rate is described using damage evolution, which consists of two main parts. The first part consists of three factors: the initial effective displacement of damage The fracture energy criterion of Benzeggagh–Kenane was used for the damage evolution.When Damage variable D is:The relevant ITZ parameters are shown in To better investigate the effect of FTC damage on the mortar part, the model treats the intrinsic relationship of the mortar part as a plastic damage intrinsic relationship and simulates the nonlinear response of the concrete material more realistically by calculating the damage accumulation in compression and tension of the model. The uniaxial tensile and compressive stress–strain responses are shown in The mortar stress–strain relationship is as follows:The isotropic damage K is the ratio of the tensile and compressive radial first and stress invariants.The focus of this study is to investigate the effect of FTC on RC in uniaxial compression using the change in compressive strength values before and after FTC. Lee et al. obtained the stress–strain conditions for concrete in uniaxial tension or compression based on the relevant equations to modify the intrinsic yield function :(10)F=11The equation of the stress–strain curve under pressure is:The basic parameters of the relevant mortars are shown in Different materials have different heat transfer rates, which can cause uneven temperature distribution inside the RC, resulting in differences in internal temperature stresses and crack expansion. The cohesive element is selected for the transition zone of the concrete model interface, the cohesive heat transfer effect is considered in the temperature transfer, and the temperature-displacement coupling solution is selected for the thermal sequence coupling solution of the model. Using ABAQUS for FTCs, the temperature solution mode needs to be set first, and this paper adopts a transient solution. After determining the single cycle time, the total FTC time is calculated for the setting. Subsequently, the boundary conditions are set, and the fixed method is a hinge support constraint at one end and a displacement constraint in the Y-axis direction at the other end; this constraint method cannot affect the temperature expansion and contraction of concrete. The temperature conditions are then set to apply a temperature load of 20 °C to the model boundary, and the load is set to cyclic using an amplitude table; i.e., the external temperature is applied at ±20 °C, with an initial temperature of 0 °C and an absolute zero of −273.15 °C. After determining the above settings and modifying the cell type, the COH2D4T heat transfer element was used to represent the ITZ. The calculated temperatures of each node were imported into the uniaxial compression experiment to obtain the compressive load capacity after the FTC.In the temperature calculation of finite elements, the set external heat source continuously transfers heat to the model interior through the heat transfer medium. Different element material properties can cause inconsistencies in temperature transfer rates, as well as storage temperatures, resulting in differences in the linear expansion of the concrete model. During the FTC, the set mortar elements shrink when the temperature decreases. The ice property elements expand, and the expansion is converted into a stress field by ABAQUS calculations. When this temperature stress gradually increases and reaches the maximum fracture energy of the ITZ, the ITZ is damaged, and the stress is transferred to the mortar around the ice property element. After reaching the set plastic stage of the mortar element, the element begins to fail; i.e., ice expansion leads to concrete damage and cracking.The experimental data in this subsection were obtained from Wang , who stuThe properties of the experimental cement are shown in Uniaxial compression experiments were conducted on plain concrete and RC, respectively, to compare the strength of RC with different admixtures and to obtain the relationship between the rubber replacement rate and compressive strength. Then, the fast freezing experiments were conducted on RC, and the strength of each experimental specimen was measured after 50, 100, and 150 cycles so that the addition of rubber to concrete and FTCs brought about by the damage could be modeled.Based on the above simulation test method, the generated ordinary concrete model and RC model were calculated and analyzed to obtain the compressive strength under each admixture, which is shown in 0% replacement rate RCBy analyzing the compressive strength of ordinary concrete before and after FTCs, the compressive strength of concrete did not decrease significantly after 50 FTCs, and it conformed to the bearing capacity strength of C35 concrete. When the number of FTCs increased to 100, the compressive strength decreased significantly. The trend of strength change in the simulation was basically consistent with the experimental results. The calculated compressive strength deviated from the experimental values, with a maximum deviation of 5.24%. The maximum deviation of strength damage value was 3.39%, but it was within the error range of numerical simulation calculations. Therefore, this model can effectively simulate the strength change process of ordinary concrete after FTCs.5% replacement rate RCAfter adding 5% rubber, the FTC damage of concrete was reduced compared to concrete without rubber, and the changing trend was consistent with the previous simulation. What is different is that the damage increased sharply after 50 cycles of ordinary concrete. In contrast, the strength damage percentage curve’s 5% replacement rate RC slope showed a significant upward trend after 100 FTCs. This phenomenon means that, after 100 FTCs, 5% of RCS suffered more severe freeze-thaw damage. Comparing the numerical simulation strength and experimental strength, the maximum deviation between the two was 2.4%, and the maximum deviation of strength damage was 2.7%, within the acceptable error range.10% replacement rate RCConcrete with 10% rubber further enhances the resistance of concrete to freeze-thaw damage, and the damage is more obvious after 100 FTCs. The simulation results are consistent with the experimental results, with a maximum compressive strength deviation of 4.19% and a strength damage deviation of 1.69%. The conclusion drawn is that the frost resistance of RC increases with increasing content when the rubber content does not exceed 10%.15% replacement rate RCThe slope of strength loss in the By comparing the above experimental results with the numerical simulation results, the maximum error between them is 5.24%, which is within the acceptable range. The results show that the thermal model established in this study can better simulate the changes in the increases and decreases in the compressive strength of rubber concrete before and after FTZ, verifying the feasibility of the model. It also provides data support for the analysis, which can better study the subsequent uniaxial compressive crack expansion and temperature field distribution at the fine view level.The ABAQUS damage cloud diagram uses the SEDG indicator to determine the degree of RC damage, and the value of SEDG ranges from 0 to 1. When it reaches 1, it indicates that the element is completely damaged there. The compressive damage cloud for each mix of rubber concrete is shown in During the loading process of the 5% low substitution rate RC model, the water-mortar ITZ was the first to be damaged, followed by the mortar-rubber ITZ, which was damaged and extended to the surrounding mortar. The reason for this outcome is that the Poisson’s ratio of the rubber material is much larger than that of the mortar. The Poisson effect generated by the compression deformation of the rubber is directly transferred to the weak mortar-rubber ITZ, causing the small cracks in the RC to start here. The stress concentration generated destroys the mortar around the rubber particles. As the compressive load increases, the cracks unfold in the oblique vertical direction, and the mortar-aggregate ITZ also begins to break down, mainly in the direction of the line between the center of the rubber particles and the surrounding near-aggregate. The cracks located between the aggregate and the rubber extend into the damaged aggregate and rubber ITZ, as can be seen from the stress cloud diagram, showing that the cracks mainly occur near the dense area of large diameter aggregate and rubber. Low substitution rate rubber distribution is more dispersed, with cracks initially unfolding in part of the rubber above and below, and a small amount of rubber above and below both produce cracks, while very little rubber near did not appear cracks. When the loading reached two-thirds of the maximum strain, the rubber at the beginning of the cracks was produced by the extension of the oblique vertical direction, and the presence of a relatively small number of rubber particles only occurred in the ITZ damage. When the maximum strain was reached during loading, cracks extending toward nearby rubber particles occurred at the ITZ of the mortar aggregate. More initial cracks at the rubber appeared with the initial cracks of another section of rubber to produce joint enlargement cracks. Some cracks in the mortar appeared to extend along the tangential direction of the rubber-aggregate ITZ unfolding. When the residual strain was reached, the RC was completely crushed, and the crack damage form showed minor conical damage according to the typical concrete damage type under compression. Still, the incorporation of rubber led to no obvious major cracks, which guarantees the integrity of the RC after being compressed.Compared with the 5% substitution rate, the 10% substitution rate resulted in reduced internal spacing and good distribution, and the stressed regions showed more substantial integrity. When loaded to two-thirds of the maximum strain, the damage of the model was similar to that of the 5% substitution rate, with the initiating cracks appearing at both ends of the rubber and multiple mortar-rubber ITZs produced by cracks connected in the direction of the line connecting the center of the damaged rubber transition zone with the center of the nearby damaged rubber ITZ. Compared to the 5% replacement rate rubber, the 10% damage occurred much later, with significantly more unconnected microscopic cracks, rapidly expanding cracks at maximum strain, a wider distribution of cracks and extension into the dense rubber zone, and a significantly greater number than with 5% RC. The residual strain was reached, no large penetration cracks were evident, microscopic cracking increased, and resistance to damage improved, indicating that adding the rubber material resulted in the RC having better integrity after compressive stress.The initial crack unfolding of 15% high-substitution RC was similar to that of low-substitution RC, with cracks appearing in the mortar-rubber ITZ and the mortar region near the rubber in sequence, followed by the extension of the mortar-aggregate ITZ to the mortar region around the aggregate. When loading reached two-thirds of the maximum strain, more joint cracks and dispersed cracks formed in the internal areas of the concrete than in the RC with low replacement rates. When reaching the maximum strain, most of the rubber had a linkage effect with the surrounding rubber, the mortar-aggregate ITZ was destroyed, more long cracks were produced in the internal mortar region, and the crack direction was the same as the tangent direction of the already destroyed rubber and aggregate ITZ. After reaching the final damage, the number and width of cracks were significantly greater than those of the low substitution rate rubber, and the integrity was well maintained, with more cracks distributed around the large grain size aggregate and more uniform distribution of conical cracks at the bottom.To analyze the distribution of the internal temperature field of RC, the RC with 0% substitution and 10% substitution were taken for comparison and exploration. Each admixture’s RC after different FTCs was subjected to uniaxial compression, and the final damage clouds are shown in After 50 FTCs of RC with a 0% substitution rate, the crack on the left side occurred and extended toward the top center; after 100 cycles, the concrete material was severely damaged, the lower crack penetrated and joined with the middle and upper cracks, and the specimen formed two major conical damage cracks; after 150 cycles, the damage did not change much, and the crack width increased. After 50 FTCs of RC with a 5% substitution rate, a crack appeared on the right side. After 150 cycles, the material damage was more serious, and the main crack was obvious after pressure, which means that the FTC of RC with 5% substitution rate was greater than 100 times, the frost resistance was weakened, and the damage was greater. After 50 cycles, some of the cracks widened, causing a small number of crack extensions; with 100 FTCs, the upper right side of the crack extended more, creating more tiny cracks; when the FTC reached 150 times, the upper part also showed the formation of many scattered cracks and downward extension, but still for the formation of the main crack, it was maintained better overall. In RC with a 15% substitution rate after 50 FTCs, some cracks continued to extend, and a small amount of crack damage was aggravated; after 100 cycles, the damage was significantly aggravated due to more micro-crack extension, resulting in the formation of the main crack during compression; after 150 cycles, there were more 100 times more undamaged cracks, with a large number of cracks obviously extending, consistent with the results for compressive strength in In the uniaxial compressive damage cloud, shown in The uniaxial compressive stress–strain curves  were anaThe random distribution of materials inside the concrete model makes the formation of microscopic cracks stochastic in nature, coupled with the complexity of external temperature variations, which requires a special mathematical and statistical approach to solve the functional relationship between freeze–thaw damage and rubber admixture. The three-parameter Weibull distribution is widely used in predicting the probability of failure, and according to the three-parameter Weibull probability model, the expression of the density function for the service life of concrete in the FTC state is obtained as follows:Then its distribution function is:To predict the residual strength of RC after temperature damage, this article establishes the relationship between strength loss value and FTCs to determine the fatigue degree of RC. A least-squares fit was performed using the Weibull probability model. After considering the damage threshold, the empirical formula is a nonlinear quadratic correlation between the strength loss value and the number of FTCs, so it is assumed that it fits the following formula :(17)ϑ=AN2 meets the requirements. It is found that the fitted curve is closer to the trend the FTC strength loss of RC, which has some reference significance for the subsequent load-bearing strength damage of RC.The fitted equations are shown in This study establishes a thermally coupled RC model, which contains rubber, mortar, pore water, and aggregate multiphase materials inside it, which is a more novel numerical simulation model. The study analyzed the effect of temperature on the compressive strength of RC. It verified the reducibility and feasibility of the model by analyzing the strength loss and damage cloud diagram of uniaxial compression. The model can also be used to analyze the thermodynamics of concrete with other admixture materials by changing the internal material composition, the size of admixture materials, and the thermodynamic properties, providing diversified ideas for related studies.In this study, voids are defined as pore water for thermal analysis. Still, it is found that the introduction of cohesive elements as ITZs and the generation of a small number of voids in uniaxial compression simulations will reflect the actual damage form better than the traditional uniaxial compression model, rendering the simulated damage process closer to the test and improving the accuracy of the simulation.In this study, a two-dimensional calculation model was used. With the improvement of computer performance and analytical capability, the research and development of a three-dimensional calculation model can better study the freeze-thaw damage of RC and achieve a higher level of accuracy.A thermodynamic calculation model of RC was established using the ABAQUS analysis platform. The effect of the rubber admixture on frost resistance was analyzed by the changes in the increases and decreases in uniaxial compressive strength before and after FTC, and the accuracy of the model was verified by comparing the calculated results of the compressive strength of concrete before and after FTCs with the experimental results. The results of this study are as follows.The RC model established in this paper adopts a relatively novel research method in uniaxial compression and temperature transfer and effectively compensates for the defects of the traditional uniaxial compression model through the use of pore and cohesive elements, providing a reference basis for the numerical simulation of other types of polymer concrete. Adding rubber to concrete can impede temperature transfer and effectively improve the damage caused by FTCs. After FTCs of RC with 0%, 5%, 10%, and 15% admixtures, the strength loss rates are 40.62%, 35.76%, 31.91%, and 37.49%, respectively, and the rubber admixture at 10% has a better ability to resist damage by FTCs. The addition of rubber to concrete causes the original compressive strength of concrete to decrease, and the larger the rubber admixture, the lower the compressive strength. RC is subjected to external compressive loads to produce more micro-cracks than ordinary concrete, mainly concentrated in large aggregate and rubber-dense areas. However, adding rubber will destroy the concrete’s integrity and is less likely to form main cracks.


In correctional facilities, due to the high incidence of bacterial infections, antibiotics are widely prescribed. As a result, it may occur a massive and improper use of antibiotics, which promotes the development of antibiotic-resistant bacteria. However, in literature, specific experiences, interventions or guidelines aimed to optimize their prescription within prisons are sporadic.In an Italian hospital where belong patients from four penitentiary institutions, a multidisciplinary team has implemented an antimicrobial stewardship project. The aim of the project was to reduce the incidence of antibiotic resistance in penitentiary institutions by optimizing and rationalizing antibiotic prescribing.Following the analysis of microbiological prevalence and antibiotic consumption data within correctional facilities, the Antimicrobial Stewardship Team developed operational tools to support prison healthcare staff to manage properly antibiotic therapies.The analysis showed a gradual increase in antibiotic resistance: in 2021 the prevalence of resistant microorganisms was 1.75%, four times higher than in 2019. In contrast, between 2019 and 2021, antibiotic consumption decreased by 24%. Based on consumption data, pharmacy has drafted an antibiotic formulary for correctional facilities, supplemented with guidelines and data sheets, and also developed a prescription form for critical antibiotics.Results showed an increasing incidence of antibiotic resistance within prisons, highlighting the need to establish a dedicated antimicrobial stewardship program. This project may impact positively not only on prisoners, but also for the entire community, as prisons can be considered as places of health education and promotion. The significant incidence of bacterial infections in prison facilities is currently one of the main critical issues plaguing prison health care. HIV infection and viral hepatitis are the most common infectious diseases affecting people living in prison (PLP) , althougIn order to counteract the spread of this phenomenon, a multidisciplinary team from an Italian hospital to which the four Milan penitentiary institutions belong, has implemented an antimicrobial stewardship project. The project aimed to provide operational tools to optimize prescription, rationalize the use of antibiotics and promote the safety of drug therapies by reducing the risk of prescription mistakes and antibiotic-related toxicity in prison, with the aim of decreasing the incidence of antibiotic resistance in this particular setting. Furthermore, this work aimed to analyze the microbiological prevalence and local consumption of antibiotics in Milan penitentiary setting between 2019 and 2021, describing all the interventions implemented for the development of a prison-specific antimicrobial stewardship program.The project has been developed through two steps and it has been addressed to the four penitentiary institutions in Milan . A multicenter retrospective epidemiological survey of the four penitentiary institutions has been carried out, to analyze microbiological prevalence and local antibiotic consumption data. Sample included prison population at Milan penitentiary facilities between 2019 (3665 PLP), 2020 (3346 PLP), and 2021 (3316 PLP). Data have been compared over this period, to assess trends in antibiotic consumption and in bacterial resistance. Based on results of the previous analysis, an antimicrobial stewardship program has been implemented. The program involved several health care professionals and provided for the development of operational tools aimed to support antibiotics prescription. Actions undertaken were addressed to a sample consisting of the population detained in Milan prisons since the beginning of the project. In particular, sample included 3540 adults, of which 192 women, 40 young male juveniles and 5 mothers with their 5 children. 40.5% of PLP were foreigners . The aveThe microbiology unit shared microbiological prevalence data, which have been obtained through the collection and analysis of microbiological sample reports from correctional facilities, referring to the years 2019, 2020, and 2021.Antibiotic consumption data have been provided by the hospital pharmacy. In particular, the analysis focused on data for the years 2019, 2020, and 2021, which have been extracted from the hospital’s management software. The data have been entered into a database containing the list of antibiotic drugs used in prisons, classified by Anatomical Therapeutic Chemical classification system (ATC) and marketing authorization code (MA code), dosage and pharmaceutical form. In addition, for each drug the database reported the Defined Daily Dose (DDD) value and the annual consumption, defined as the amount of antibiotic, expressed by the number of dosage units, used in penitentiary facilities in the period analyzed. According to the National Plan to Face Antimicrobial Resistance, approved in Italy in 2022, which assesses trends in territorial antibiotic consumption in DDD/1000 population per day , the folThe project included the development of an Antimicrobial Stewardship Team, including the following professional figures: infectious diseases specialist, pharmacist, nurse, microbiologist and health management physician. Team members attended a series of multidisciplinary meetings to analyze local epidemiological data, to identify the main purposes and working methods, and to periodically assess the advancement of the project.After the collection and the review of microbiological prevalence and antibiotic consumption data, the Antimicrobial Stewardship Team addressed the following actions:based on antibiotic consumption data, the identification of active agents used in prisons, in order to draft a specific formulary for antibiotic therapies;the development of data sheets for each antibiotic included in the formulary, to guide physicians in prescribing and supporting nurses in the proper management of antibiotic therapies;the identification of critical antibiotics, which require approval by an infectious diseases specialist before their administration, and the development of a specific request form for their prescription;the drawing up of guidelines for the treatment of the most common infections in penitentiary institutions.Proteus mirabilis with a multiresistance profile to penicillins, cephalosporins, ciprofloxacin, colistin, fosfomycin, tigecycline, and to the trimethoprim-sulfamethoxazole association, has been identified. The bacteria infected a prisoner at the San Vittore penitentiary. In 2020, two microorganisms have been isolated in two people living in San Vittore prison: a β-lactamase-producing Enterobacter hormaechei resistant to penicillins and cephalosporins, and an extended-spectrum β-lactamase (ESBL)-producing Escherichia coli strain.In 2019, 2020, and 2021 the microbiology unit analyzed a total of 742 microbiological samples coming from Milan prisons: 251 samples have been analyzed in 2019, 232 and 229 in 2020 and 2021, respectively. Most of them were respiratory or urinary samples. The results showed the presence of 7 antibiotic-resistant bacteria. In 2019, only a strain of In 2021, the following microorganisms have been isolated in four PLP detained in Bollate and San Vittore prisons:Escherichia coli resistant to penicillins, cephalosporins, fluoroquinolones, and to the trimethoprim-sulfamethoxazole association;an ESBL-producing Klebsiella pneumoniae;an ESBL-producing Morganella morganii strain, specifically resistant to amikacin, penicillins, cephalosporins, ciprofloxacin, ertapenem and fosfomycin;a multiresistant Escherichia coli strain.an ESBL-producing All microorganisms have been detected in PLP’s urine and processed by urinoculture.Antibiotic-resistant bacteria accounted for 0.94% of all microbiological isolates coming from Milan prisons, from 2019 to 2021. The analysis showed a progressive increase in antibiotic resistance: in 2019 and 2020 the prevalence was 0.39 and 0.86%, respectively, whereas in 2021 there was an increase of the prevalence up to 1.75% .The analysis conducted by the hospital pharmacy showed a gradual decrease in antibiotic consumption within correctional facilities. In 2019, a total antibiotic consumption of 20600 DDD has been found. In 2020, this figure decreased by 12%, going to 18041 DDD. In 2021, the total consumption of antibiotics decreased further, settling around the value of 15670 DDD, 13% less than the previous year . ConsistAnalyzing the consumption trend of the most widely used systemic antibiotics in Milan prisons, in 2021, compared with 2019, a lower use of the associations of penicillins and β-lactamase inhibitors has been observed. In particular, the consumption of amoxicillin-clavulanic acid tablets at the dosage of 875 mg + 125 mg decreased by 21%, going from 9914 DDD in 2019 to 7791 DDD in 2021. However, amoxicillin-clavulanic acid was still the most widely used antibiotic. Macrolides, such as clarithromycin and azithromycin, were also widely prescribed. In this case, the analysis showed a 23% reduction in consumption between 2019 and 2021, although there has been a sudden increase in 2020, especially for azithromycin . This significant increase in 2020 was likely due to the fact that azithromycin was initially recommended for the treatment of COVID-19 in non-hospitalized patients , the required antibiotic, its dosage, duration of treatment, whether it was prescribed as monotherapy or in combination with other medicines, its clinical indication, specifying whether the treatment was empiric or targeted and the name of the isolated microorganism, any previous antibiotic therapies. Eventually, the last section of the form required specifying whether the prescribed medication had been approved by an infectious diseases specialist. After verifying the request’s appropriateness, according to antimicrobial prescribing criteria, the pharmacist can authorize it. The hospital pharmacy also prepared data sheets for each antibiotic included in the formulary, to provide support to healthcare professionals in prescribing and managing antibiotic therapies. Each data sheet contained information about pharmacokinetics, dosage, interactions, major side effects, methods of preparation and storage. The formulary has been supplemented with specific guidelines for the treatment of the most recurrent infections in prisons: skin and soft tissue infections, STIs, urinary tract infections, otorhinolaryngological infections and pulmonary infections. The guidelines have been developed by the pharmacy, in cooperation with the infectious diseases specialists working in prisons. They referred to both community and nosocomial infections, as PLP could develop infections before and/or during the incarceration. Moreover, they could also contract care-related infections during any hospitalization and, once discharged, they could continue their care within correctional facilities. They focused on antibiotic therapies, distinguishing between empiric therapies and following treatment lines, and indicating which active agents must be chosen once detected antibiotic resistance, specifying any particular contraindication or recommendation for allergic patients or pregnant women who live in prison.From a social perspective, prison communities are largely represented by individuals with great difficulties, such as homeless or people with mental disorders or drug addictions , 11. TheThe results of this study show that in Milan prisons, in recent years there has been a high number of empirical prescriptions, as well as a massive use of broad-spectrum antibiotics. This led to an increasing trend in the development of antibiotic-resistant bacteria. Therefore, it is crucial to establish an antibiotic stewardship program within correctional institutions, which provides supportive operational tools and defines a shared pathway aimed at improving the prescriptive appropriateness of antimicrobial therapies. In addition, the implementation of an antimicrobial stewardship project could be a significant initiative not only to improve PLP health conditions, but also to positively impact on the whole community. In fact, detention represents a health risk factor due to several determinants, such as social and cultural marginalization of penitentiary population, overcrowding, poor hygienic conditions and high turnover. However, prison often represents a contact point with the National Health System and an environment to prevent, diagnose, and treat infectious diseases.The original contributions presented in the study are included in the article/supplementary files. Further inquiries can be directed to the corresponding author.LM, CD’A, and RR: conceptualization. LM, AZ, and CD’A: methodology. LM, CB, NC, and CD’A: investigation. LM, AZ, and RR: writing – original draft preparation. CD’A, CB, NC, and RL: writing – review and editing. CD’A, CB, NC, RL, and RR: visualization. All authors contributed to the article and approved the submitted version.


Metformin-induced lactic acidosis with acute kidney injury is rare but well known. Here we report a case of a Japanese patient taking metformin who experienced severe acute renal failure accompanied with significantly elevated metformin plasma concentrations and signs of lactic acidosis.N-acetyl-β-d-glucosaminidase level, and β2-microglobulin level, the patient was further diagnosed with AKI . A renal biopsy performed on day 3 after admission revealed renal tubular epithelium necrosis, supporting this diagnosis. The patient underwent intermittent hemodialysis until he was discharged on day 13. The metformin concentrations on days 3, 5, and 7 were 8.95, 2.58, and 0.16 μg/mL, respectively, which is significantly higher than the maximal steady-state concentration of metformin at the recommended dosage (approximately 1 μg/mL). The calculated pharmacokinetic parameters of metformin suggested poor renal excretion and a low distribution volume at higher metformin levels. Other possible acute kidney injury-causing factors included dehydration, alcohol consumption, and the use of an angiotensin receptor blocker or SGLT2 inhibitor.A 60-year-old Japanese man with type II diabetes, who was taking metformin (500 mg three times a day) along with several other medications, visited the emergency department with dizziness, malaise, and oliguria. The initial laboratory test results showed elevated levels of serum creatinine and blood urea nitrogen, although his renal function was normal approximately 2 weeks earlier. His lactate level was raised (4.27 mmol/L), and he was diagnosed with lactic acidosis. Considering the low creatinine clearance and elevated urinary albumin/serum creatinine ratio, urinary This is the first reported case of acute kidney injury possibly caused by high levels of metformin with lactic acidosis in a patient treated with the recommended metformin dose. Thus, the development of metformin-induced acute kidney injury should be considered for patients with several acute kidney injury risk factors who are taking metformin. Metformin (Met) is a biguanide used to treat type II diabetes mellitus T2DM). It inhibits gluconeogenesis in the liver, decreases glucose absorption from the intestine, and promotes the utilization of glucose in the peripheral tissues by activating adenosine monophosphate (AMP)-activated protein kinase . Met is DM. It inA 60-year-old Japanese man with a 9-year history of T2DM presented at the emergency department of Kariya Toyota General Hospital with anuria and severe general fatigue. On admission, the patient was transported by ambulance due to his difficulty in moving. On evaluation, the patient reported fatigue, malaise, weight loss, and intermittent nausea and vomiting. He reported no headaches, joint, or muscle pain. He denied having a fever or contact with another sick individual.Apart from T2DM, his past medical history included hypertension and lumbar disc herniation. He had no history of psychiatric disease and no known drug allergies. He had no family history of diabetes mellitus, lived alone, and his educational status was not obtained. The patient had smoked 1 pack of cigarettes per day for 45 years and consumed approximately 540 mL of Japanese sake daily. His medications included Met (500 mg three times daily), sitagliptin (50 mg once daily), pioglitazone (15 mg once daily), dapagliflozin (5 mg once daily), amlodipine (5 mg once daily), azilsartan/amlodipine (20 mg/5 mg once daily), rosuvastatin (2.5 mg once daily), and a hydrogel patch containing loxoprofen sodium.Renal function was normal before admission and the Met dosage used to treat T2DM was suitable for this patient. No abnormality was found in the patient’s blood tests (data not shown) when he had visited his doctor 13 days before admission. Notably, 12 days before admission, his work had changed from office to physical work . He had noted a gradual decrease in urinary output for several days before admission, but had no other symptoms. Two days before admission, he developed anuria, dizziness, and nausea.The initial laboratory findings are shown in Table The physical examination at admission indicated the following: height of 172.3 cm, weight of 69.3 kg, blood pressure of 159/94 mmHg, regular pulse of 96 beats per minute, body temperature of 36.3 °C, and oxygen saturation of 99% breathing ambient air. There was no sign of hypoglycemia since blood glucose was 129 mg/dL  showed slight cortical atrophy in the bilateral kidneys; however, no kidney stone or hydronephrosis was observed. There was irregular thickening of the small bowel wall without adjacent fat stranding and no sign of inferior vena cava collapse.N-acetyl-β-d-glucosaminidase (420.3 U/g Cre), and β2-microglobulin/creatinine ratio (149 µg/g Cre)   or Pinnafine® PN-140   (at day 5 and 7 with Nafamostat Mesilate)] with blood and dialysate  flow rates of 150 and 500 mL/min, respectively, for 3 hours per session. During the HD session, the patient’s condition was stable. The eGFR was calculated from serum creatinine levels on days 0, 3, 5, 7, 10, and 19 were 5.1, 4.5, 10.8, 31.9, 61.2, and 59.9 mL/min/1.73 m2, respectively , he was hospitalized and hemodialysis (HD) was introduced to remove Met and improve acid–base disruption and anuria. In detail, HD was performed with a polysulfone dialyzer [Pinnafine® PN-100  of 0.04 hours−1 and calculated t1/2 (day 3–7) of 16.5 hours. Moreover, the t1/2 (day 3–5) was 26.7 hours, and t1/2 (day 5–7) was 11.9 hours.The plasma concentrations of Met were measured using high-performance liquid chromatography (HPLC)–ultraviolet (UV) as per a previous report , with slThis is a case where a patient was being treated with the recommended Met dose and presented at the emergency unit and was diagnosed with AKI. PK analysis revealed that AKI might be caused by high plasma Met levels, consistent with previous reports that have demonstrated that Met overdose causes AKI –9. Possit1/2 of Met was 16.5 hours. This t1/2 is comparable to that of patients with severe renal failure (creatine clearance rate: 10–30 mL/minute) [t1/2 (day 3–5) and t1/2 (day 5–7) were 26.7 and 11.9 hours, respectively. Considering that the patient underwent 5 hours of HD between days 0 and 3, 3 hours between days 3 and 5, and 4 hours between days 5 and 7, the actual t1/2 would have been far worse. However, slight renal function recovery occurred after day 5, which is consistent with the eGFR recovery.The patient had severe renal failure with oliguria on the day of hospitalization (day 0), although laboratory data obtained 13 days earlier indicated normal renal function. Based on three data points of Met plasma concentration up to 7 days after hospitalization, the /minute) . Howevert1/2 (day 3–5), the one-compartment analysis yielded an estimated plasma Met concentration on the day of hospitalization (C0) of 58 µg/mL. This value is notably higher since healthy volunteers receiving the recommended Met daily dose (500 mg three times a day) had a Met Cmax at a steady-state  of approximately 1.0 µg/mL [Regarding the value of .0 µg/mL . This hi.0 µg/mL . In the .0 µg/mL . These rt1/2 = 17.2 hours) who received a single 850 mg Met dose had an estimated Cmax of 3.93 µg/mL [Cmax, we extrapolated the Cmax of our patient who had taken 500 mg of Met three times a day before admission, when the symptoms started to appear. Using the equation Css,max of 8.4 µg/mL. This value is lower than our estimated C0 of 58 µg/mL. This data suggests that other PK parameters elevated the C0.Up to day 19, the patient showed moderate renal failure (eGFR: 59.9–61.2 mL/minute). A previous report indicated that patients with severe and moderate renal failure had similar Met PK parameters . In that93 µg/mL . From thC0 is the volume of distribution (Vd). That is, a decreased Vd can increase the Met plasma concentration levels. Considering the patient’s background, dehydration probably caused by working outside in high temperatures, decreased Vd [Considering the following PK formulas, eased Vd . Moreoveeased Vd . Therefo+ ratio in the patient, which inhibited the gluconeogenesis from lactate [Furthermore, in this case, the other possible AKI causes were alcohol consumption and the use of other prescribed medication, such as angiotensin receptor blockers (ARBs) , 14. Alc lactate . Thus, a lactate . Further lactate . NonsterThe limitations of this study included the scarce Met concentration data and the absence of the quantification of other drugs possibly related to AKI, such as ARBs or azilsartan. Further analyses of the Met concentration in the dialyzed fluid samples can increase our understanding of Met distribution. Moreover, it is difficult to rule out the alternate possibility to increase plasma Met concentration that acute tubular necrosis caused the accumulation of Met in tubular epithelium. For example, multidrug and toxin extrusion proteins (MATEs) are transporters located on the apical side of tubular epithelium , 22, invVd. Other factors, including prescription medication use, might also play a part in the development of AKI. Taken together, patients with several AKI risk factors should be aware that even the daily recommended Met dose could induce AKI.To the best of our knowledge, this is the first report of AKI caused by high plasma Met concentration levels with mild lactic acidosis in a patient treated with the recommended Met dose. PK analysis unveiled the importance of dehydration and alcohol consumption to cause high plasma Met by decreasing


Oral ulcers are a lesion in the oral mucosa that impacts chewing or drinking. Epoxyeicosatrienoic Acids (EETs) have enhanced angiogenic, regenerative, anti-inflammatory, and analgesic effects. The present study aims to evaluate the effects of 1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea (TPPU), a soluble epoxide hydrolase inhibitor for increasing EETs level, on the healing of oral ulcers.The chemically-induced oral ulcers were established in Sprague Dawley rats. The ulcer area was treated with TPPU to evaluate the healing time and pain threshold of ulcers. The expression of angiogenesis and cell proliferation-related protein in the ulcer area was detected using immunohistochemical staining. The effects of TPPU on migration and angiogenesis capability were measured with scratch assay and tube formation.in vitro.Compared with the control group, TPPU promoted wound healing of oral ulcers with a shorter healing time, and raised pain thresholds. Immunohistochemical staining showed that TPPU increased the expression of angiogenesis and cell proliferation-related protein with reduced inflammatory cell infiltration in the ulcer area. TPPU enhanced cell migration and tube-forming potential The present results support the potential of TPPU with multiple biological effects for the treatment of oral ulcers by targeting soluble epoxide hydrolase. Oral ulcers are a common and frequently-occurring ailment in the mouth characterized by a loss of epithelium and underlying connective tissue, resulting in a crateriform appearance, which can occur on the lips, cheeks, tongue and gums.Although the pain and discomfort caused by oral ulcers will lessen in a few days and disappear in about two weeks without treatment, oral ulcers may also risk developing halitosis, chronic pharyngitis, irritable mood, headache, or other symptoms, causing great trouble to their daily life. However, since the pathogenesis hasn't been elucidated, there aren't effective measures to cure oral ulcers.in vivo, rapidly hydrolyzed by soluble Epoxide Hydrolase (sEH) into Dihydroxyeicosatrienoic Acids (DHETs).Epoxyeicosatrienoic Acids (EETs) are a lipid medium produced by arachidonic acid metabolism. However, EETs are highly unstable The EETs or using sEHi to increase EETs levels have been shown to reduce the inflammatory response and adhesion molecules expression, promote proliferation and the migration of endothelial cells for angiogenesis, and accelerate tissue growth, organ regeneration, and wound healing.Relieving pain to ease uncomfortable symptoms is one of the general measures for oral ulcer treatment. EETs or using sEHi to increase EETs levels have shown a peripheral anti-nociceptive effect that can block the Lipopolysaccharide (LPS)-induced inflammatory pain in rats, reduce neuropathic pain in a murine diabetic neuropathy model, reverse pain behavior in a mouse model of osteoarthritis.in vitro, and confirmed that TPPU contributed to the healing of chemically-induced oral ulcers in rats by angiogenesis, reducing inflammation, relief of pain and reduction of oral ulcer duration.In this study, the authors evaluated the effects of TPPU on cell migration and tube-forming potential In Vivo Experiments (ARRIVE) guidelines to minimize pain and suffering and to reduce the number of animals used.Sprague Dawley (SD) rats  were obtained from the Animal Experimental Center of Dalian Medical University. Rats were kept at room temperature 22°C, humidity 50%‒60%, and 12h light-dark cycle. All the experiments were approved by the Institutional Animal Care and Use Committee of Dalian Medical University (L2014035). This study compiled the Animal Research: Reporting Oral ulcers were induced in rats using previously described methods.TPPU  stock solutions were prepared by dissolving TPPU in DMSO at the concentration of 12.5 mg/mL. The SD rats subjected to chemically-induced oral ulcers were randomly assigned into two groups: TPPU-treated groups (n = 5) and PBS-treated groups . The oral ulcer area was treated with a circular filter paper (3 mm diameter) soaked with TPPU (10 μM in PBS) or PBS for 3 days . The days from the appearance of the ulcer to healing are defined as healing time. The wound bed appearance was recorded and photographed every day until the ulcer healing. The oral ulcer wound surface area was calculated using standardized digital imaging and the Image J software  on days 3, 5, 7 and 9 after acetic acid treatment. Given that the oral ulcer may affect the diet of rats, the daily weight of SD rats was measured after acetic acid treatment, as a criterion for evaluating the effectiveness of treatment.Pain sensitivity of the oral ulcer area was assessed using the manual Von Frey test every day until the ulcer healed. In brief, the threshold of mechanically evoked hyperalgesia-like behaviors was measured using von Frey filaments of varying forces (in grams) by an investigator blinded to the treatment group. Each filament was applied three times with a maximal duration of 2‒3s, and a 5s interval between each test. The pain threshold of normal SD rats without oral ulcers (NS group) served as a baseline.All examinations and evaluations of the ulcers were performed by two experienced dentists. The Kappa test for data from two evaluators is carried out to ensure consistency .Human Gingival Epithelial Cells (HGECs) were obtained for cell proliferation and wound healing assay, which were isolated and cultured as described previously.2.Human umbilical vein endothelial cells  were used for tube formation assay. HUVECs were cultured in endothelial cell medium  with 5% fetal bovine serum , 1% penicillin-streptomycin, and 1% endothelial cell growth supplement  at 37°C with 5% COThe tissue on day-5 after 50% acetic acid treatment was isolated from the oral ulcer area in rats and was fixed in 4% Paraformaldehyde (PFA), and embedded in paraffin. 5 µm sections were prepared. The sections were stained with Hematoxylin and Eosin (H&E) to evaluate oral mucosal morphology and inflammatory cell infiltration. For immunohistochemistry, sections were incubated overnight with primary antibodies  at 4°C, then were incubated with secondary antibody for 30 minutes and horseradish labeled chain ovalbumin for 15 minutes  at room temperature. Finally, sections were visualized using 3, 3-diaminobenzidine , and counterstained with hematoxylin.5/well) and treated with 10 μM TPPU (TPPU+ group) or without TPPU (TPPU- group) for 3 days, then the cells were fixed with 4% PFA and blocked in blocking buffer, and incubated with primary antibody (anti-Ki-67) in 4°C for overnight. Cells were then incubated with fluorescent secondary antibodies followed by nuclear DAPI staining.To detect the effect of TPPU on HGECs proliferation, HGECs were cultured in 96-well plates  and evaluated using Image-Pro Plus software.HUVECs were pretreated with TPPU (TPPU+ group) or without TPPU (TPPU- group) for 3d, The HUVECs cells were seeded into 96-well plates precoated with Matrigel  and incubated for 3h at 37°C. The formed capillary-like structures were fixed and observed under a light microscope (Olympus Corporation).5 HGECs per well were plated in 12-well plates overnight and treated with 10 μM TPPU (TPPU+ group) or without TPPU (TPPU- group) for 3 days. A single linear scratch was made with a 200 μL pipette tip. After gently washing the well twice, cells were cultured for 24h with TPPU or DMSO, then photographed. The width of the wound area was quantitatively evaluated using Image-Pro Plus software.A total of 3×10t-test was used for comparison between different groups. Significance was defined as p < 0.05.Data are presented as the mean ± SEM and were analyzed with SPSS13.0 software. An unpaired Student's TPPU-treated mice showed less weight loss and faster recovery than the PBS-treated group (data not shown). After 48 hours of acetic acid treatment, the appearance of the mucosa changed from pink to white. A uniform, shallow circular ulcer in the labial mucosa was clinically visible in each group. The oral ulcer bed was covered with a yellowish-gray pseudomembrane with a central depression and surrounding hyperemia swelling, and intense pain response to irritation A.Fig. 2Wrd day after acetic acid treatment, the area of oral ulcers decreased gradually until they disappeared completely. While the appearance of wounds over time in the TPPU-treated group was significantly better than that in the PBS-treated group  and were remarkably reduced in TPPU-treated group (p < 0.01) compared with the NS group . Ki-67, a proliferating cell-associated nuclear antigen expressed throughout the active cell cycle, was detected using immunohistochemistry. The present results showed there were more Ki-67+ cells in the TPPU-treated group (< 0.01). Next, the authors evaluated the effect of TPPU on the migration and proliferation ability of HGECs. A scratch healing assay showed that TPPU accelerated wound closure (< 0.0001). Cell proliferation assay demonstrated that the cells treated with TPPU (TPPU+) expressed higher cell proliferation marker Ki-67 than the cells treated without TPPU (TPPU-) (< 0.0001).During the wound healing process, cell apoptosis and proliferation is the key to repair. To evaluate the effects of TPPU on wound healing, the authors examined the tissue from the oral ulcer area on day-5 using TUNEL staining and Ki-67 cell proliferation assays. TUNEL staining identified that TUNEL+ apoptosis cells were primarily represented in the center of oral ulcers in the PBS-treated group Fig. 5A). Quantitative analysis showed that the apoptosis levels were significantly upregulated in the PBS-treated group , inflammatory cytokines, and Cyclooxygenase-2 (COX-2) gene. Studies based on animal models have also confirmed that EETs/sEHi are effective in treating inflammatory diseases. The elevation of EETs could alleviate intestinal mucosal damage in ulcerative colitis.It has been confirmed that the gray area in the ventral aspect of the midbrain treated with 14, 15-EET in the thermal-induced painful tail-war model can produce a potent analgesic effect.Due to the limitations of this experiment, the authors did not set up other treatment alternatives. It is necessary to further confirm the potential of TPPU in the treatment of oral ulcers through an in-depth comparison of TPPU and other alternatives such as topical corticosteroids or low-intensity lasers.The present results suggest that TPPU topical administration targeting sEH can be considered a potential therapeutic strategy for oral ulcers by exerting multiple biological effects of EETs, including shortening healing time, reducing inflammatory cell infiltration, promoting angiogenesis, enhancing cell migration and proliferation, which provides new ideas for the treatment and prevention of clinical oral ulcers. However, the medication method and mechanism need further exploration.Fu Wang and Xiaojie Li designed the project. Juanjuan Li, and Zihan Wen performed animal experiments. Yue Lou and Jili Chen performed cytology experiments, data statistics and analysis. Lu Gao and Xiaojie Li kindly provided support during animal experiments. Juanjuan Li, Fu Wang wrote the manuscript. All the authors read and approved the final manuscript.This work was supported by the National Natural Science Foundation of China (nº 81771032); and the Natural Science Foundation of Liaoning Province (nº 2021-MS-293).The authors declare no conflicts of interest.