Jumping is a key movement developing in the preschool period, but limited studies have reported the determinants of jumping performance and its relationship with gross motor development. This study aimed to determine the correlations among jumping performance, quantitative parameters of jumping, and gross motor development in preschool children. Twenty-one preschool children were recruited from one kindergarten, and fifteen of them with complete data were further analyzed. The quantitative parameters of standing long jump (SLJ) and standing vertical jump (SVJ) were measured using a video-based motion capture system. The gross motor development was measured using the Preschooler Gross Motor Quality Scale (PGMQ). The Spearman’s rho value and a linear regression model were used to determine the relationships among the jumping performance, the quantitative measures, and the total PGMQ scores. The results indicate that the jumping performances were significantly correlated with the takeoff velocity, which was predicted by trunk inclination before takeoff in SLJ and by the ranges of trunk inclination during jumping in SVJ. Regression analysis showed that the preschool children with higher normalized jump height had better gross motor development, and that the jump performance and the gross motor development were directly or indirectly predicted by the slope of the hip-to-ankle angle plot during pre-takeoff. In conclusion, this study identifies key components of jumping in jumping performance and gross motor development in preschool children for physical education. Preschool is a crucial period for young children to develop many fundamental movements and to learn and gradually master various motor skills. Several studies have indicated the importance of motor skills in physical activity, and this relationship could present early in children ,2,3. MotTypically developed preschool children possess the abilities of walking, running, jumping, and hopping, and these performances are commonly tested during this period . JumpingThe major difference between SVJ and SLJ is the direction of projection. SVJ projects mainly in the upward direction, while SLJ projects in both the forward and upward directions . PreviouAs well as using biomechanical determinants, the development of jumping skills can also be evaluated using qualitative scales. Two qualitative scales of gross motor development in preschool children have been reported in recent years: the Preschooler Gross Motor Quality Scale (PGMQ)  and the Both quantitative and qualitative measures have been reported to be references for jumping performance and general development. Few studies have reported quantitative descriptions of the developing and controlling processes for jumping skills during the preschool period ,30. MostTypically developed children aged 4 to 6 years old were recruited from a kindergarten in Taichung, Taiwan, using convenience sampling. The Preschool Child Development Checklist screening test developed by Taipei City Government was used to exclude children with developmental delay problems. Children with any neuromuscular or musculoskeletal problems that may have affected their motor performances were also excluded. The purpose and experimental procedures of this study were explained to the teachers and parents, and informed consent was obtained before the data collection started. This study was approved by the Institutional Review Board of the China Medical University Hospital (DMR99-IRB-335-1).The quantitative analysis of the jumping performances was obtained using a video-based motion capture system  with four Basler monochrome cameras at four corners. The child wore athletics clothes but had bare feet. Twenty-seven reflective markers were first attached to specific bony landmarks, including the midpoint of the posterior superior iliac spine, both sides of the anterior superior iliac spine, the midpoint of the lateral thigh, the femoral lateral epicondyle, the femoral medial condyle, the tibial tuberosity, the lateral malleolus, the medial malleolus, the heel, the 2nd metatarsal head, the 5th metatarsal head, the acromion process of the scapula, the humeral lateral epicondyle, and the dorsal midpoint between the ulnar styloid process and the radial styloid process. The jumping task was demonstrated by a researcher first, and then the child repeated the jump three times. The integrity of the collected data was confirmed, and then the data were included for further data processing. The video data from each camera were first digitized in the MaxTRAQ 2D environment, and then reconstructed in MaxTRAQ 3D to obtain the movement trajectories of the bony landmarks in space. Afterwards, the coordinate system of each segment was defined and used to calculate several quantitative measures using the MATLAB program . The calculated variables included the jump distance, jump height, takeoff velocity, takeoff angle, trunk inclination, and slope of the angle–angle plots for the lower extremities before takeoff. The jump distance and jump height were considered the outcome measures of the jumping performance in SLJ and SVJ, respectively. They were calculated using the recorded trajectories of the body’s center of mass (COM), represented by the center of the pelvis ,34, and The angle–angle plot is the angular time series of two joints , and it The total PGMQ score  was used to examine the general level of gross motor development , althougThe correlations between jump height/distance, all the quantitative variables, and the total PGMQ score were analyzed using nonparametric correlation analysis in SPSS software, to obtain the Spearman’s rho. For those variables with significant correlations, linear regression analysis was used to further establish the relationships among the jump performance, the quantitative measures, and the total PGMQ score. The stepwise method was selected to control the sequences of the variable entering the regression equation. The statistical significance was set at 0.05 in this study.Twenty-one preschool children (7 boys and 14 girls) aged 4 to 6 years were enrolled in this study, but six of them were excluded due to incomplete data. Therefore, fifteen children (4 boys and 11 girls) were included in the analysis. Their basic anthropometric characteristics, jump performances, and qualitative scores are summarized in The nonparametric correlations of the jump performance and PGMQ-Total score with the quantitative variables in SLJ are shown in The nonparametric correlations of the jump performance and PGMQ-Total score with the quantitative variables in SVJ are shown in The stepwise regression results for SLJ and SVJ are shown in This study aimed to determine the correlations among jumping performance, the quantitative parameters of jumping, and gross motor development in preschool children. The results of this study show that TOV had a strong correlation with jumping performance in preschool children. Other quantitative variables, including TkBTO, TOA, TkROM, THA, dTHA, and KA in SLJ, as well as dHA, dKA, TkROM, TkBTO, and HA in SVJ, were also correlated with jumping performance. The gross motor development, evaluated using PGMQ, was correlated strongly with TkBTO, TkROM, TOV, and dHA, and moderately with dHA, KA, HA, and jump height in SVJ. Nevertheless, the total PGMQ score was only correlated strongly with ndHA and HA, and moderately with ndKA in SLJ.The mean jump distance before normalization with leg length was 0.91 m in our 4 to 6-year-old preschool children. The performance matched the mean jump distance of 0.91 m in the middle class of kindergarten in Liu’s study on preschool boys in Taiwan , and alsIn this study, the TOV, TOA (assessed only in SLJ), TkBTO and TkROM were correlated with jump performance. According to the principles of projectile motion, the horizontal distance of jumping can be maximized when takeoff angle is 45 degrees. However, Wakai and Linthorne suggested that the calculated optimum takeoff angle was 19–27 degrees in their study. This is because takeoff speed declines with an enhanced takeoff angle for overcoming one’s body weight . ConsistSeveral studies have showed the involvement of trunk movement during jumping activities. The study of Vanrenterghem et al.  showed tIn this study, the movement pattern of the dominant leg before takeoff in SVJ showed moderate associations with jump performance and gross motor development. A previous study investigated the landing kinematics of single-leg hopping between the dominant and non-dominant leg, showing that hip extension in the dominant leg was smaller than in the non-dominant leg, but the dominant leg had a longer hopping distance . In thisThe relationships between the quantitative variables of jumping and the gross motor development in preschool children have not previously been extensively investigated in the literature. The results of the present study demonstrate moderate correlations between the total PGMQ score and jumping performance only in SVJ, which indicates that SVJ would be more appropriate to differentiate gross motor development in preschool children. Jumping performance in SLJ did not have a significant correlation with the total PGMQ score, which might be due to the complex techniques in SLJ, making it hard to achieve a specific level of SLJ in the preschool period.In this study, correlations between the PGMQ-Total score and quantitative parameters of jumping in SLJ were found only in the specific slopes of angle–angle plots, including ndHA, HA, and ndKA. A previous study investigated the landing movement of a drop jump, showing a larger dynamic knee valgus angle in the dominant leg than in the non-dominant leg during unilateral landing, and showing more stability in the non-dominant leg . AnotherCorrelations between the PGMQ-Total score and quantitative parameters in SVJ were found in TOV, trunk movement, including TkBTO and TkROM, and the specific slopes of angle–angle plots, including dHA, HA, dKA, and KA. The gross motor development displayed the same features as the jump performance regarding the correlations with the trunk movement during SVJ in preschoolers. Both HA and KA in SVJ were negatively correlated with the PGMQ-Total score, which indicated that, with a higher gross motor level, preschoolers use more movements at the hip and knee joints rather than at the ankle joint during the pushing phase before takeoff. In addition, HA in SLJ was also negatively correlated with the PGMQ-Total score, indicating the importance of the hip joint movement control in gross motor development. This agreed with the study of Mana et al., which also identified the hip flexion angle before takeoff as a predictor for jumping distance in preschoolers. Although the hip flexion angle was defined by the trunk segment and thigh segment in Mana’s study, the results still showed the importance of the trunk and hip movement in SLJ . Zhao etA major limitation of this study was the use of convenience sampling to recruit our participants and the small sample size. Though the gender distribution of these children was uneven, the PGMQ-Total score demonstrated no significant differences during normal development . AdditioThis study found that several quantitative parameters were correlated with the performance in two types of jumping, including TOV, TkBTO, and TkROM. Most of these parameters were found to be correlated with the gross motor development only in SVJ. Regression analysis further showed that the preschool children with higher normalized jump height had better gross motor development. Regarding the movement pattern, the regression analysis showed that the jump performance and the gross motor development could be directly or indirectly predicted from the slope of the hip-to-ankle angle plot during pre-takeoff.Despite the small sample size, the results of this study indicate that SVJ is an appropriate activity to include in physical education in the preschool period because the practice of SVJ might assist gross motor development. When instructing preschoolers to perform SVJ, the emphasis should be placed on hip movement before takeoff as well as the range of trunk motion from inclination to extension. In contrast, when instructing them to perform SLJ, the focus should be placed on knee movement before takeoff as well as trunk inclination before takeoff, in order to enhance the performance. This study has established the relationships between jumping performances, quantitative variables, and gross motor development. In future studies, a similar analysis could also be used for children with developmental delay, to further understand their motor abilities.


The machinery behind bacterial flagellar motility is an astounding example of natural nanotechnology. The bacterial flagellar motor (BFM) is the end point of chemotaxis, a sensory pathway that helps bacteria to navigate their surroundings in search of an optimally hospitable niche. The BFM, which coordinates the rotation of an extracellular filament to drive motility is sensitive to the electrochemical and mechanical nature of its environment, dynamically tuning its structural composition and power output on the fly. For example, the BFM recruits torque-producing stator units to increase its power output in response to increased mechanical loads. Thus, the motor not only generates force and torque, but is also involved in surface sensing and mechanosensing. Bacterial motility underlies the virulence of pathogens, especially those which infect areas under high flow, as well as the linkage between force sensing, quorum sensing, and biofilm formation. Bacterial motility and surface interactions are a key area of study in the face of rising antimicrobial resistance, which is one of the dominant public health issues of this century. This Research Topic sought to highlight the similarities and diversities of the BFM and chemotaxis systems across species, to understand their evolutionary origins, and to reveal how the BFM's dynamic structure and activity can be modulated by, and in response to changes in its environment.Zhou and Roujeinikova review the structure and composition of the proteinaceous periplasmic stator scaffolds found in many polar flagellar motors, imaged via electron cryotomography, which are instrumental for sustaining the abnormally high speeds and torques of monotrichous bacteria (as compared to peritrichous bacteria). Arroyo-Pérez and Ringgaard asked how Vibrio parahaemolyticus ensures proper positioning of its single flagellum at the old cell pole after cell division. They investigated the subcellular spatiotemporal localization of the polar flagellar determinants FlhF and FlhG, revealing their cell cycle-dependent intracellular coordination, which depends upon the cell pole determinant protein HubP and another still unidentified factor. Xu et al. investigated the mechanism by which the hook penetrates the peptidoglycan (PG) sacculus in spirochetes, providing evidence that FlgJ and BB0259, a previously uncharacterized cell wall-degrading enzyme, coordinate PG penetration in the Lyme disease spirochete Borrelia burgdorferi. Ferriera et al. shed light upon how different flagella evolved in closely related lineages. By contrasting data from protein phylogenetics and structural data from electron cryo-tomography and subtomogram averaging, they posit that Enterobacteriaceae flagella were horizontally acquired from an ancestral β-proteobacterium, giving them a ”general-purpose” BFM which is able to adjust to a wide range of conditions.Many of the articles in this special issue highlight the diversity in both structure and assembly through investigations of traditionally less well-characterized flagellar motors. Kenney reviews the ways in which histidine kinases funnel diverse environmental stimuli, including mechanical stress and changes in membrane tension, into changes in gene expression, underscoring that many of the molecular mechanisms underlying mechanical force sensing in bacteria remain to be unraveled. The activity of the BFM is also modulated by external cues, via a growing list of proteins and regulators, including the chemotaxis response regulator CheY and c-di-GMP-binding proteins that act as molecular brakes or clutches. In Shewanella putrefaciens, Pecina et al. identify MotL as a novel stand-alone PilZ-domain protein which regulates the lateral flagellar system in response to intracellular levels of the secondary messenger c-di-GMP. Exceptionally, MotL does not act upon the polar motor, thus demonstrating differential regulation of two flagellar systems in a single species. The soil motile Azospirillum brasilense has a complex chemotaxis system, with two distinct chemotaxis pathways and four CheY homolog response regulators. Ganusova et al. show that, in addition to fine-tuning the rotational bias of the polar flagellum, each of the four CheY homologs plays a distinct role in swimming (planktonic movement), swarming (collective movement across a surface), attachment to abiotic and biotic surfaces, and biofilm formation.Other articles in this series spotlight the diverse ways in which bacteria adapt their behavior in response to external cues. Bacteria sense and adapt to physical forces in their environment, such as shear-induced or surface-induced forces on the membrane. Islam et al. turn to the longstanding open question of the mechanism of stator ion selectivity and which ion holds energetic primacy for the BFM. They reconstructed and engineered ancestral sequences of the MotB stator sub-unit, and by assessing motor functionality as a function of the ionic power source, they add to our understanding of the contributions of specific residues within the ion channel. Biquet-Bisquert et al. sprovide a comprehensive review of the complex relationship between the ion motive force across the cell membrane, motor activity, and the dynamic assembly of stator units. Lin et al. use a fast perfusion microfluidic system to reveal that stator assembly dynamics in sodium-driven chimeric BFMs show a complex dependence upon the extracellular sodium concentration. Their results call into question current models of stator unit assembly and underline the extent to which the mechanisms of stator unit exchange remain unclear. These works reinforce the versatility of the BFM, as both a functional motor and as a bellwether of the bacterial environment, coordinating signals and response, to drive survival and spread.Finally, the emergence of the stator unit as a crucial component in sensing and motor modulation is underlined by three articles here. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This process is governed by a combination of environmental factors, selective pressures, and the constraints imposed by the genetic architecture of metabolic networks. In addition, many independent results hint that the process of niche construction, by which organisms actively modify their own and each other’s niches and selective pressures, could play a major role in microbial innovation and diversification. Yet, the general principles by which niche construction shapes microbial macroevolutionary patterns remain largely unexplored. Here, we discuss several new hypotheses and directions, and suggest metabolic modeling methods that could allow us to explore large-scale empirical genotype-phenotype-(G-P)-environment spaces in order to study the macroevolutionary effects of niche construction. We hope that this short piece will further stimulate a systematic and quantitative characterization of macroevolutionary patterns and processes in microbial metabolism.Microorganisms display a stunning metabolic diversity. Understanding the origin of this diversity requires understanding how macroevolutionary processes such as innovation and diversification play out in the microbial world. Metabolic networks, which govern microbial resource use, can evolve through different mechanisms, e.g., horizontal gene transfer or  Prokaryotes exhibit by far the most diverse collection of metabolisms on earth. Disentangling the mechanisms by which such diversity arises is paramount for understanding both the emergence of complex life and the structure and function of modern microbial ecosystems.Our knowledge about the history of life on earth contains numerous examples suggesting that the process of niche construction might play a central role in diversification. An obvious one is the early appearance of autotrophic metabolism, which profoundly transformed the biosphere by generating complex, energy-rich carbon molecules and releasing oxygen to the atmosphere, creating new ecological opportunities . Many adThe short-term, microevolutionary consequences of niche construction have been extensively characterized, both theoretically and empirically . The mosEscherichia coli in the Long Term Evolution Experiment (LTEE). Recent findings have shown that the two main mutations leading to this innovation, the aerobic expression of dctA and citT, were intimately linked to an eco-evolutionary interaction mediated by the release of metabolites to the environment (gltA), likely achieved fixation because of its beneficial effect on acetate, a constructed niche . This illustrates that innovation and exploration of untapped ecological opportunities still depends on historically contingent, and thus rare, combinations of mutations -fitness maps. Genome-scale metabolic models have been already successfully applied, for instance, to gain insight into long-term phenotypic evolution in microbes , by a Packard Fellowship from the David and Lucile Packard foundation, and by the National Institutes of Health through grant 1R35 GM133467-01 to AS, and by a Templeton Foundation Grant (61866) to MM. MR-G acknowledges support from the Donnelly Fellowship from Yale University.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The fluid flow over a rotating disk is critically important due to its application in a broad spectrum of industries and engineering and scientific fields. In this article, the traditional swirling flow of Von Karman is optimized for Maxwell fluid over a porous spinning disc with a consistent suction/injection effect. Buongiorno’s model, which incorporates the effect of both thermophoresis and Brownian motion, describes the Maxwell nanofluid nature. The dimensionless system of ordinary differential equations (ODEs) has been diminished from the system of modeled equations through a proper transformation framework. Which is numerically computed with the bvp4c method and for validity purposes, the results are compared with the RK4 technique. The effect of mathematical abstractions on velocity, energy, concentration, and magnetic power is sketched and debated. It is perceived that the mass transmission significantly rises with the thermophoresis parameter, while the velocities in angular and radial directions are reducing with enlarging of the viscosity parameter. Further, the influences of thermal radiation  The researchers have been interested in Maxwell nanofluid flow over a porous spinning disc because of its many uses in engineering and innovation. Non-Newtonian fluids are important in a variety of manufactured liquids, including plastics, polymers, pulps, toothpaste and fossil fluids. To simulate the analysis of these liquids, a variety of models have been suggested. Shear stress and shear rate are linked in non-Newtonian liquids because of their nonlinear existence. The momentum equation in these fluids involves dynamic nonlinear terms, making it difficult to solve. A variety of mathematical models exist in the literature to simulate the performance of these fluids.In the present era, the role of nanotechnology to fulfill the increasing demand for energy and face energy challenges is remarkable. The usage of nanoparticles in ordinary base fluid  effectively enhances the heat transfer and improves their thermal properties. The applications of nanoparticles in certain fields of engineering and industry are in the cooling systems of electronic devices and in cancer therapy, heat exchangers, transformer cooling, nuclear reactors, and space cooling systems. Due to the ability of oil wetting and dispersing, they are also used for cleaning purposes, in power generation, microfabrication, hyperthermia, and metallurgical purposes.The rotating disk phenomena are widely used in centrifugal filtration, turbomachines, the braking system of vehicles, jet motors, sewing machines, turbine systems, heat exchangers and computer disk drives, etc. Von Karman  for the 2O3 nanoparticles to study heat and flow transfer in the microchannel. Hatami et al. [The people of the modern world are facing many challenges due to the increasing demand for energy by the latest technologies. Firstly Choi  presentei et al.  reportedi et al. . Aziz ani et al.  have usei et al.  studied The study of a Newtonian fluid, due to its wide applicability in different fields of science and engineering, attracted the attention of scientists and researchers during the last few decades. Its major role is in geophysics, polymer solution, paper production, cosmetic processes, exotic lubricants, paints, suspensions, colloidal solutions, nuclear and chemical industries, pharmaceuticals, oil reservoirs, bioengineering, etc. . Xiao etDarcy’s law is a mathematical equation that explains how fluid flows through a porous medium. Henry Darcy developed the law based on the effects of studies on the flow of water across sand beds, laying the groundwork for hydrogeology, a branch of earth sciences . FourierViscoelastic fluids are a subclass of Newtonian fluid having memory effects. The intensity of energy discharged by these fluids is mainly accountable for recovery after the stress is removed. The Maxwell flow regime is the most basic viscoelastic fluid model, expressing memory effects by fluid relaxation time . The attc and w are the spinning and extending rates, respectively. The disk temperature is represented by Consider an unsteady hybrid nanoliquid flow over a stretching porous spinning disc. The magnetic force Under the presuppositions stated above, the flow equations are as observes :(1)∇.V=0The temperature difference within a flow is assumed to be small, therefore higher-order in Taylor series and ignored at s follow : (14)qr=The boundary conditions are: Considering the following transformation, to reduce the system of PDEs to the system of ODEs: The following system of ODEs is obtained by using Equation (17) in Equations (7)–(13) and (15) and (16): fined as : (25)Ws=The skin friction itten as ,33:(26)CThe skin friction, Sherwood and Nusselt numbers have a non-dimensional structure as:Here The higher-order model equation is brought down to first order by choosing variables: The boundary conditions are:The discussion section is devoted to understanding better the graphical and physical description. The system of non-linear Equations (18)–(23) along with their boundary conditions, Equation (24), are solved through numerical method bvp4c. The configuration of the problem is described in The implications of the suction factor The radial, azimuthal, tangential velocity profile and temperature distribution variation are illustrated in Pr and the thermal radiation factor change. The thermal dispersion of a strong Prandtl fluid is low, while the thermal diffusivity of a low Prandtl fluid is high. Nt, the nanofluid concentration field raises while with Nb, the concentration profile drops. The suction parameter Sc effect are illustrated in Bt and injection parameter Ws positively effect the magnetic strength profile along axial and radial direction.Rd and Brownian motion parameter Nb, respectively. Because of the improving effect of radiation, the fluid temperature also rises, which enhances the heat transmission rate. In the present mathematical model, the Maxwell nanoliquid flow over a porous spinning disk with suction/injection effects has been examined. The flow is studied in the context of magnetization and radiation. The numerical results are found through bvp4c, while for comparison purposes, the computation is carried out via the RK4 technique. From the above studies the following conclusions have been drawn:The centrifugal force is more effective and dominant near the disk surface, so causes the maximum velocity in the neighborhood of the surface of the disk.The fluid velocity reduces by the action of suction effects. Because the suction effect gripping the fluid particles towards the pores of the disk, which causes the momentum boundary layer reduction.The axial, radial and tangential velocities are boosts with the increases of injection parameter. The enhancement in rotation parameter also boosts the azimuthal and radial flows. Nb. The Brownian motion produces random movement between fluid particles, which generate more heat, as a result, the fluid temperature increases.The thermal energy profile enhances by the consequence of Brownian motion parameter The fluid temperature decline with Prandtl number The nanofluid concentration field enhances with


This study examined the week of a 6-session integrated dementia p program on dementia knowledge, attitude toward dementia, fear of dementia, and dementia prevention behaviors among community dwelling elders. Using a nonequivalent control group, pre-posttest design, study participants were recruited from a senior center in Seoul, Korea. A total of 40 participants completed the study while half of them were in the experimental group and another half were in the control group. They completed survey questionnaires before and after the program. The findings showed that the program was effective only to decrease the fear of dementia of the older adults. Knowledge, attitude toward dementia, and healthy behaviors may be difficult to change in a short period of time. However, the integrated dementia prevention program may be effective to decrease negative emotions, particularly, fear toward dementia among older adults. The fear of dementia needs to be further assessed individually in order to identify particular causes and triggers and provide tailored interventions.


R-square on the other hand. This study demonstrated the viability of UV-visible fingerprinting (routine approach) coupled with chemometric tools for the classification and quantification of chemotherapeutic drugs during clinical preparation.In clinical treatment, the analytical quality assessment of the delivery of chemotherapeutic preparations is required to guarantee the patient's safety regarding the dose and most importantly the appropriate anticancer drug. On its own, the development of rapid analytical methods allowing both qualitative and quantitative control of the formulation of prepared solutions could significantly enhance the hospital's workflow, reducing costs, and potentially providing optimal patient care. UV-visible spectroscopy is a nondestructive, fast, and economical technique for molecular characterization of samples. A discrimination and quantification study of three chemotherapeutic drugs doxorubicin, daunorubicin, and epirubicin was conducted, using clinically relevant concentration ranges prepared in 0.9% NaCl solutions. The application of the partial least square discriminant analysis PLS-DA method on the UV-visible spectral data shows a perfect discrimination of the three drugs with a sensitivity and specificity of 100%. The use of partial least square regression PLS shows high quantification performance of these molecules in solution represented by the low value of root mean square error of calibration (RMSEC) and root mean square error of cross validation (RMSCECV) on the one hand and the high value of  Currently, oncology treatment studies have become very important. Unfortunately, the number and cost of new anticancer drugs are still higher than ever before. This constitutes an economic challenge for countries with limited resources .Daunorubicin, doxorubicin, and epirubicin belong to the family of anthracyclines used primarily as first-line drugs in combination with other chemotherapeutic drugs for a wide range of cancers, including breast cancer, bladder cancer, soft tissue and bone sarcomas, malignant lymphomas, and acute lymphocytic leukemia . HoweverThe preparation of these anticancer drugs represents an important step in oncological treatment. Generally, this preparation has to comply with several rules and objectives; the safety of all personnel involved in terms of exposure, patient safety, and good production practices . This prIn order to guarantee the pharmaceutical and chemical quality of the preparation, several strategies of quality control have been elaborated to make sure that the right drug is delivered at the right concentration .High-perHigh-performance liquid chromatography coupled with spectrometry is a well-established approach for monitoring hospital chemotherapy preparations . GeneralToday, UV-visible spectroscopy combined with chemometric classification algorithms is widely used to develop rapid methods for drug quality control  and wellThis study focused on three chemotherapeutic drugs that are very similar in physicochemical properties and are difficult to discriminate: epirubicin, doxorubicin, and daunorubicin. These drugs are anthracyclines and antitumor antibiotics consisting of a planar anthraquinone ring attached to a carbohydrate containing an amino group. Doxorubicin is a natural product obtained from Streptomyces galilaeus while epirubicin is its semisynthetic analogue which differs only in its stereochemistry. These molecules function by intercalating DNA strands and leading to the formation of complexes that inhibit DNA and RNA synthesis. Daunorubicin is an anticancer drug used in the treatment of acute myeloblastic leukemia and acute lymphoblastic leukemia. Daunorubicin (DNR) derived from the fermentation of Streptomyces strains and was the first anthracycline used in clinical practice , 21. It The aim of this study was to confirm the ability of UV-visible spectroscopy combined with multivariate data analysis such as PCA, PLS-DA, and PLS to monitor three anthracycline drugs at different concentrations, in order to examine the ability of this technology to discriminate and quantify these three drugs, which are considered among the most crucial to distinguish between them due to their similar chemical structures and their low concentrations.Several commonly used anthracyclines  have been diluted at different concentrations with 0.9% sodium chloride which are usually used for this type of reconstitutions. Subsequently, they were analyzed directly using a double-beam spectrophotometer UV-visible Perkin-Elmer Lambda 12, at a wavelength ranging from 350 to 800 nm.The study was performed at different concentrations corresponding to . A calibration model was developed by PLS-DA, and then crossvalidation was used to validate these models. For the construction of the PLS-DA and PLS regression model, a database of 52 samples has been used .Chemometrics, also known as multivariate data analysis, is the science that implements optimal mathematical and statistical approaches to process chemical data. Chemometrics involves experiment design upstream and data processing to obtain valuable information once measurements have been taken. The growing need for chemometric tools comes especially through the development of analytical equipment that provides big amounts of complex data .This scientific field comprises a wide variety of statistical methods, aimed at analyzing numerous data sets especially spectral data such as infrared spectroscopy, fluorescence, and UV-visible spectroscopy to achieve several objectives.Partial least squares (PLS) regression is a chemometric technique often used for data modeling. PLS allows the reduction of predictors to a smaller set of noncorrelated components called latent variables (LVs) and performs the least squares regression on these main principal components (LV). The PLS feature is especially useful when the initial variables (predictors) are strongly correlated, or when the number of predictors exceeds the number of observations. PLS regression can be summarized in two related steps:X  and Y (response matrix) matrix into latent variables using score projections. Then, the incorporation of a vector, known as weight (w), relates to the two latent variable matrices and providing the covariance between the X and Y scores as an optimization criterion.Dimensionality reduction of the The partial least squares (PLS) algorithm was initially implemented for the regression task and subsequently evolved into a well-known classification method known as PLS discriminant analysis (PLS-DA). PLS-DA integrates dimensionality reduction and discriminant analysis into a unique algorithm and is especially applicable to high-dimensional data modeling .Traditionally, PLS has been proposed to deal with continuous variables  in regression. But in the cluster task, the output variables will be always categorical. Hence, the first step in PLS-DA modeling is to recode the categorical variables  into continuous  variables , 24.Two principal algorithms can be applied to perform PLS regression: an iterative procedure is known as the NIPALS algorithm  , or a diAll data analysis of UV-visible spectra and chemometric applications, PCA, PLS-DA, and PLS regression, were performed using Unscrambler software, version 10.4 camo analytic.According to the UV-visible spectrum of the molecule, we notice that these three molecules absorb in a similar wavelength region with maximum absorption in 480 nm as shown in Due to the similarity shown in the molecular structure of the three molecules belonging to the anthracycline family, it is very difficult to discriminate between these three molecules during the pharmaceutical preparation using UV-Visible spectroscopy.In PCA analysis revealed that the variability distribution was mainly given by the first principal component PC1, which represents 100% of total variability. The use of the score plot  demonstrPCA analysis shows that the first component gives useful information about the concentration of these drugs, and samples of high concentration contribute substantially and positively with the PC1 axis while samples of low concentration contribute negatively with the PC1 axis.In order to successfully develop classification models capable of determining the class of the three drugs, chemometric classification tools have been applied to the spectral data. In this study, PLS-DA was used to discriminate the three chemotherapeutic drugs. The correct classification rate % CCR, sensitivity, and specificity are the main parameters used to assess the discriminatory power of an analytical method.R-square and the low value of root mean square of calibration RMSEC and crossvalidation RMSECV.The observation of the 3D score plot generated by PLS-DA  shows a Assessment of the performed models reveals that the correlation coefficient is between 99% and 98% for the calibration results and between 98% and 96% for the crossvalidation results, whereas the root mean square error of the calibration is between 0.04 and 0.07 and for crossvalidation ranges between 0.06 and 0.08 .Eventually, the results were displayed in the form of confusion matrices, enabling the estimation of the correct classification rate, specificity, and sensitivity of the discrimination achieved across the test set.According to the confusion matrix , it can The combination of UV-visible spectral data with the PLS-DA method provides powerful results for the discrimination of the three drugs regarding specificity, sensitivity, and CCR. These results are generally consistent with other studies that have used factorial discriminant analysis (PCA-FDA) in combination with RAMAN and infrared spectroscopy . Other sR-square.In order to optimize the quantification models of the three drugs of the anthracycline family, a PLS regression method was applied to the UV-visible results. Numerous pretreatments were applied for the construction of the PLS models. The best quantification models were chosen on the basis of statistical parameters, and the best patterns are those having the lowest root mean square error of calibration (RMSEC), the lowest root mean square error of crossvalidation (RMSECV), and the highest R2) for calibration and crossvalidation and errors (RMSECV) (RMSEC).This table presents the performance parameters of the PLS quantification models and the number of latent variables (LVs) used to build the PLS models. It provides also information on the predictive performance results, including the coefficient of determination (R-square (R-square indicates strong linearity between the reference and predicted values as shown in The results found by PLS regression show high performance for the quantification of the three drugs using the first latent variable that represents 100% of the total variability of the data set. This performance is explained by the low value of RMSECV and RMSEC and the high value of R-square . TherefoR-square of 0.99 and RMSECV ranging between 0.0127 and 0.0220 [These results found are adequate with the results found by Makki et al., which shows an This study confirms the qualitative and quantitative capability of the combination of UV-visible spectroscopy and chemometric models to identify and verify cytotoxic drug preparations. Total discrimination was observed over the entire range of therapeutic concentrations, even for low concentrations, and no samples were misclassified. Strong linearity was observed for the quantification models over the entire concentration range. In light of these results, the use of UV-visible spectroscopy using chemometric methods is an excellent approach to ensure the nature of the drug prior to administration to patients.Besides the analytical performance, the robustness of the instrument and its simplicity of use constitute favorable arguments for implementing the UV-visible portable scanner. With regard to the expected results, it will be valuable to expand this trial to additional drugs and containers used to deliver drug therapy in order to enhance safety management in the clinical drug preparation.In this study, a rapid qualitative and quantitative approach has been developed for the discrimination and quantification of the content of three drugs used in oncology. The combination of UV-visible spectroscopy and chemometric methods shows high performance for the discrimination between the three drugs with a sensitivity and specificity of 100%.R-square.The application of PLS regression also shows a high capacity in the quantification of these three drugs, and this capacity is explained by the low values of RMSECV and RMSEC as well as the high value of As a general conclusion, the coupling of UV-visible spectra and suitable chemometric analysis tools, in particular PLS regression and PLS-DA, has demonstrated their efficiency for the discrimination and quantification of doxorubicin, daunorubicin, and epirubicin.Similar multivariate models are strongly recommended as a clean, rapid, and reliable means of assessing the quality control of clinical chemotherapeutic preparations.


Coronary computed tomography angiography (CCTA) is a comprehensive, non-invasive and cost-effective imaging assessment approach, which can provide the ability to identify the characteristics and morphology of high-risk atherosclerotic plaques associated with acute coronary syndrome (ACS). The development of CCTA and latest advances in emerging technologies, such as computational fluid dynamics (CFD), have made it possible not only to identify the morphological characteristics of high-risk plaques non-invasively, but also to assess the hemodynamic parameters, the environment surrounding coronaries and so on, which may help to predict the risk of ACS. In this review, we present how CCTA was used to characterize the composition and morphology of high-risk plaques prone to ACS and the current role of CCTA, including emerging CCTA technologies, advanced analysis, and characterization techniques in prognosticating the occurrence of ACS. Acute coronary syndrome (ACS) may be the first manifestation of coronary artery disease (CAD), mainly caused by the rupture or erosion of unstable plaques –4, whichHowever, these invasive diagnostic approaches with low positive predictive value and unclear cost-effectiveness have not been widely used in clinical practice . CoronarIn this review, we delineate the current understanding of the pathology of the atherosclerotic plaques associated with ACS and corresponding manifestations on CCTA in clinical practice. The application of CCTA in characterizing the composition and morphology of high-risk plaques prone to ACS and prognosticating the occurrence of ACS are further described. Finally, the progress in emerging CCTA technologies, advanced analysis and characterization techniques are also reviewed. The new techniques can provide the comprehensive assessment of high-risk plaques and surrounding environment, and may provide personalized risk assessment of future ACS events and further guide clinical decision-making.The detection and characterization of plaque by CCTA is based on histopathology, therefore, and therefore it is vital to grasp the histopathological characteristics and evolution process of high-risk atherosclerotic plaque.Atherosclerosis, most often observed at the branch points and low shear stress areas of blood vessels, is a multifactorial systemic disease and has a chronic and progressive process . About tThe characteristics of high-risk plaques are related to the vulnerability of plaques . Based oThe percentage of stenosis is important information on CCTA. When coronary heart disease cannot be ruled out clinically, the percentage of stenosis on CCTA can help to rule out patients in stable condition and with low possibility of coronary heart disease –27. Howein vivo detection of coronary artery, IVUS examination confirmed that the cross-sectional area of the vessel at the atherosclerotic site was significantly larger than that at the proximal reference segment, then the concept of positive remodeling was proposed which refers to the compensatory increase of vessel wall when atherosclerotic plaque volume increases continuously, thus maintaining the effective area in the lumen , which is defined as mean attenuation <30 Hounsfield units (HU) of at least three regions of interest (ROIs) in general , 45 Figb. HoweveSpotty calcification is the initial state of calcification. Since calcification is one of the consequences of local inflammation, spotty calcification may indicate active local inflammation. Mechanical stimulation on fibrous cap caused by spotty calcification and local inflammation may lead to the plaque with spotty calcification easy to rupture, thereby accelerating disease progression –48. Ther2)   correspo rupture . The den rupture , 14.Although the risk of plaque instability increases with the degree of coronary stenosis, most of the culprit lesions found in ACS are considered non-obstructive before rupture. Previous studies indicated that the characteristics of high-risk plaques identified by CCTA have a prognostic value independent of stenosis and atherosclerotic burden  see Tab.In 2007, Motoyama et al. found that compared with SA lesions, the frequency of positive remodeling, non-calcified plaques or low-attenuation plaques (<30 HU) and spotty calcification on CCTA was higher in ACS culprit lesions, and these three characteristics could independently predict the occurrence of ACS. Moreover, among the three plaque features, positive remodeling has the highest accuracy in ACS prediction . In addiP = 0.01)  . These r = 0.01) , 54, 55. = 0.01) .In a number of cross-sectional studies, investigators found that spotty calcification was associated with culprit lesions in ACS –52, 55. P < 0.001], which indicated napkin ring sign was an independent predictor of ACS  of ACS in patients with the napkin ring sign was 5.55 [95% confidence interval (CI), 2.0–14.70; r of ACS . In a lor of ACS .post-hoc analysis of the SCOT-HEART study, the adverse plaque was defined as a plaque with one or more of the features above observed. The results revealed that patients with adverse plaques had three times higher risk of myocardial infarction than patients without adverse plaques, and the prediction effect was stronger when combined with the presence of stenosis  has used advanced fluid dynamics analysis method which combines the advantages of CCTA and traditional FFR  is the ratio of the pressure at the distal end of the stenosis to the pressure at the proximal end of the normal vessel in a state of maximum hyperemic condition. In recent years, FFR derived from CCTA , wall shear stress (WSS) and axial plaque stress are important hemodynamic parameters, which has been reported to be associated with the occurrence of adverse clinical events   . These sVascular inflammation can promote the progression of coronary atherosclerosis and vulnerable plaque rupture, leading to the occurrence of ACS . EpicardInflammation of adipose tissue around the plaque will directly affect the formation and stability of coronary plaque. Therefore, PCAT attenuation measured by CCTA is a promising indicator for identifying high-risk plaques. In patients with ACS, cases of PCAT stranding have been reported around culprit lesions . GoellerAlthough FAI can detect the changes of PCAT composition caused by coronary artery inflammation, it can only measure the average density of the ROI and cannot fully reflect the fine structural characteristics of the ROI. Inflammation, fibrosis, and angiogenesis are three main causes of adipose tissue dysfunction . AdvanceModern CCTA assessment provides a series of advantages by combining the coronary anatomy, plaque morphology, atherosclerotic plaque load and coronary blood flow, which allows for the evaluation of morphological and functional characteristics of high-risk plaques, and the individual risk of ACS.In addition to CCTA, positron emission tomography (PET), magnetic resonance coronary angiography (MRCA), IVUS, OCT, and other imaging modalities are also effective methods to assess coronary atherosclerotic plaques –98. Notain vivo, offering prognostic implication of patients at higher risk of ACS . Furthermore, combining multi-dimensional methods can comprehensively evaluate the anatomy and biology of the coronary artery, and further integrate CCTA into clinical practice. However, the identification of high-risk plaque characteristics based on CCTA and emerging technologies such as FAI have not been verified in randomized controlled trials with definite results, which requires verification of the clinical benefits of CCTA applications in the future.GL substantially planned, wrote, and revised the manuscript and made illustrates and the table. WY polished and revised the manuscript. JO and XL contributed to the collection of CT images. ZT and TL contributed to linguistic revision of the manuscript. HL substantially contributed to instruction of the writing and revision of the manuscript. All authors read and approved the final manuscript.The work was supported by the Key R&D Program of Guangdong Province of China (No. 2018B030339001 to HL), the National Natural Science Foundation of China (No. 81974262 to HL), Guangdong Basic and Applied Basic Research Foundation (No. 2020A1515010650 to HL), and Guangdong Nurses Association Research Foundation (No. gdshsxh2021b077 to XL).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The COVID-19 pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions. World-Wide FINGERS international network convened a forum for researchers to discuss statistical design and analysis issues they faced during the pandemic. We report experiences of three trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials. The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessments protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within site stratification, interim power projections, and sensitivity analyses. Robust approaches to study design and analysis are critical to negotiate issues related to the intervention.


Ischemic stroke is a common cause of death and disability worldwide, which leads to serious neurological and physical dysfunction and results in heavy economic and social burdens. For now, timely and effective dissolution of thrombus, and ultimately improvement in the recovery of neurological functions, is the treatment strategy focus. Recently, many studies have reported that transcranial ultrasound stimulation (TUS), as a non-invasive method, can dissolve thrombus, improve cerebral blood circulation, and exert a neuroprotective effect post-stroke. TUS can promote functional recovery and improve rehabilitation efficacy among patients with ischemic stroke. This mini-review summarizes the potential mechanism and limitation of TUS in stroke aims to provide a new strategy for the future treatment of patients with ischemic stroke. Ischemic stroke is the most common type of cerebrovascular disease. According to the data of the global burden of disease (GBD) study, stroke is the most common cause of death among Chinese residents . From 20Statistical data have shown that only 16% of patients with acute ischemic stroke in China are admitted to the hospital within 3 h of symptom onset, and only 1.3% of these patients receive thrombolytic therapy ,b. TransThe neuroprotective effect of TUS has become a hot topic in recent years, especially in the field of stroke. TUS mainly exerts a neuroprotective effect through the following mechanisms.The earlier the restoration of cerebral blood supplies after acute cerebral infarction, the better the recovery of neurological function . Therefovia near-infrared spectroscopy. The system was also applied to stroke rehabilitation after temporal middle cerebral artery occlusion (MCAO) in rats. The stimulation was found to induce hemodynamic changes in the sonicated area, whereas open-field tests showed that ultrasound applied to the ipsilateral hemisphere for 5 consecutive days after stroke facilitated recovery. Another study conducted by Transcranial ultrasound stimulation has also been shown to improve the vascular recanalization rate, which is an important index to evaluate the treatment effect in acute ischemic stroke. Evgenii et al.  reportedInflammatory mediators can cause further damage to neurons in the ischemic penumbra. A recent study applied low-intensity TUS to the ischemic cortex after distal MCAO and found that ultrasound may activate coagulation factors through certain signal transduction pathways and reduce neutrophils in the ischemic region, thus reducing the inflammatory response and facilitating neuronal recovery in the ischemic penumbra . SimilarAs ischemic stroke induces cellular apoptosis, especially neuronal apoptosis, which leads to neurological dysfunction, determining a means to alleviate neuronal apoptosis has become an important issue for researchers while evaluating the outcome of patients with ischemic stroke. A study conducted in 2021  found thNeurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), are considered to be involved in the regulation of key nerve functions and neuroplasticity in stroke . A previUltrasound has direct and indirect thrombolytic effects. Indirect thrombolytic effects of TUS mainly enhance the effectiveness of thrombolytic drugs. In addition, ultrasound can directly dissolve the thrombus through its special physical and chemical properties . The maiCavitation is the generation of a large number of small bubbles when ultrasound is applied to a liquid . These bThe mechanical action is the main mechanism of ultrasound thrombolysis. The mechanical vibration of ultrasound can destroy blood clots, decompose thrombi, increase the contact between enzyme and fibrin, and promote the dissolution of thrombi. Ultrasound can also enhance the vitality of the brain cells and promote the repair of nerve cells after cerebral ischemia .The microflow effect is caused by the cavitation effect. Here, the pressure generated by the burst microbubble causes the liquid to form microflow, which can accelerate drugs to the ischemic region .Treatment with TUS lacks clinical trials, as there are great differences between animal models and clinical patients, many problems remain to be solved in the clinical application of TUS. Although some clinical studies have proved that TUS can improve the clinical efficacy in ischemic strokes, these evaluation methods cannot reflect the improvement in a patient’s ability during the rehabilitation process. More detailed and specific assessment scales should be used for evaluating the effect of TUS, such as assessment of cognitive, speech, sensory, motor, and other aspects. Moreover, most of the current clinical studies are about a combination of TUS and thrombolytic drugs to improve the thrombolytic effect. Clinical research in the future may explore TUS and other rehabilitation treatment methods, such as physical therapy, speech therapy, and low-frequency neuromuscular electrical stimulation, to improve the effectiveness of rehabilitation therapy in patients with ischemic stroke. For example, anodal transcranial direct current stimulation combined with constraint-induced movement therapy resulted in the improvement of functional ability of the paretic upper limb compared with constraint-induced movement therapy alone, indicating that TUS may enhance the effect of rehabilitation in patients with chronic stroke . In addiUltrasound thrombolysis has already been used widely; low-frequency TUS can exert its effect based on the mechanical vibration, cavitation, or microflow, consequently dissolving the thrombus, reducing the infarct size in patients, promoting cerebral circulation, rescuing the ischemic penumbra, and improving the prognosis of patients with stroke. Low-frequency TUS is mostly used clinically at present. Numerous studies have explored the mechanism of low-frequency TUS and confirmed that low-frequency TUS has certain neuroregulatory effects, which have both excitatory and inhibitory effects on the human cerebral cortex .In summary, although there are still many issues that need to be explored and solved in terms of clinical application, numerous studies have shown that TUS can promote thrombolysis, increase cerebral blood circulation, and improve neurological recovery. Thus, after ischemic stroke onset, timely and proper TUS intervention may improve the neurological function and quality of life of post-stroke patients.QL participated in the design of the review. SZ, BM, JJ, XW, NLu, and NLi drafted the manuscript. HS and LW critically revised the text and figure. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In contrast to motor symptoms, non-motor symptoms in Parkinson’s disease (PD) are often poorly recognized and inadequately treated. Fatigue is one of the most common non-motor symptoms in PD and affects a broad range of everyday activities, causes disability, and substantially reduces the quality of life. It occurs at every stage of PD, and once present, it often persists and worsens over time. PD patients attending the 2013 World Parkinson Congress voted fatigue as the leading symptom in need of further research. However, despite its clinical significance, little progress has been made in understanding the causes of Parkinson’s disease-related fatigue (PDRF) and developing effective treatment options, which argues strongly for a greater effort. Transcranial direct current stimulation (tDCS) is a technique to non-invasively modulate cortical excitability by delivering low electrical currents to the cerebral cortex. In the past, it has been consistently evidenced that tDCS has the ability to induce neuromodulatory changes in the motor, sensory, and cognitive domains. Importantly, recent data present tDCS over the frontal cortex as an effective therapeutic option to treat fatigue in patients suffering from multiple sclerosis (MS). The current opinion paper reviews recent data on PDRF and the application of tDCS for the treatment of fatigue in neuropsychiatric disorders to further develop an idea of using frontal anodal tDCS as a potential therapeutic strategy to alleviate one of the most common and severe non-motor symptoms of PD. Fatigue is a complex symptom and a multifaceted construct that leads to a general feeling of exhaustion, loss of motivation, and behavioral performance problems . It is aIn patients with PD, fatigue is one of the most common non-motor symptoms affecting a wide range of daily activities, leading to disability, and significantly reducing the quality of life . DespiteWhile transcranial direct current stimulation (tDCS) has recently been shown to alleviate fatigue in multiple sclerosis (MS) effectively ,7,8, datIn the current opinion paper, I will propose that NIBS approaches can contribute to a better understanding of the fatigue syndrome and stimulate the development of efficient treatments based on rational hypotheses about the underlying pathophysiology, and, finally, argue for frontal anodal tDCS as a potential therapeutic option in Parkinson’s disease-related fatigue (PDRF).Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting approximately 1% of the population over 50 years of age . PD is tfatigare, fatigue describes an overwhelming feeling of tiredness, weakness, lack of energy, and exhaustion unrelated to physical activity [In general, from the Latin activity . In variactivity ,18. Nowadays, patients suffering from PD are usually appropriately treated for their motor symptoms, whereas a significant proportion of NMS still remains unrecognized or unreported . HoweverAlthough fatigue is a common and debilitating symptom in PD, the exact etiology and underlying pathophysiology of fatigue in PD remain unclear , and—accThis lack of a consistent fatigue taxonomy complicates its understanding, measurement, and consequently its treatment . To dateAnalogous to the assessment in patients with MS, an objective fatigue diagnosis appears to be a prerequisite for information and education in the early disease management of patients with PD ,32 and uThe inconsistencies in fatigue definitions also negatively affected the understanding of the pathophysiology of PDRF . DespitePreviously, PDRF was often assumed to be a reactive phenomenon . In factRecent hypotheses on pathophysiological mechanisms suggested that specific dysfunctions in the frontal cortex may play a significant role in fatigue. Evidence for the involvement of frontal lobe dysfunctions came from observations of fatigue-related executive impairment in patients with PD ,45. AccoAccording to the 2018 review of the International Parkinson and Movement Disorder Society (MDS) Evidence-Based Medicine (EBM) committee, which regularly publishes recommendations on treating Parkinson’s disease nonmotor symptoms, only the monoamine oxidase (MAO)-B inhibitor rasagiline was considered possibly useful for the management of PDRF when other secondary causes of fatigue were excluded . The effAs PDRF drastically affects the patients’ quality of life, the development of efficient therapeutic methods for fatigue treatment is of high clinical relevance. Furthermore, for a systematic treatment evaluation and optimization, a reliable and valid assessment of the individual fatigue level by objective parameters is essential. Transcranial direct current stimulation (tDCS) may offer a unique opportunity to manipulate the maladaptive neuronal activity underlying PD-associated fatigue. The neuromodulatory potential of tDCS was widely demonstrated for cognitive, perceptual, and motor processes . In a clTDCS can generally be considered safe and well-tolerated. The safety of this technique was studied and tested by several researchers who concluded that tDCS, when used and monitored in accordance with international safety guidelines, was a safe and well-tolerated intervention . Due to In general, tDCS delivers small electrical currents to the cerebral cortex. The current flows between an active electrode and a reference electrode. While the scalp shunts some of this current, the majority enters the brain tissue , modulaThe majority of the stimulation studies, designed to counteract the development of fatigue, applied anodal tDCS over the dorsolateral prefrontal cortex (DLPFC), as this area had proven to be most affected by fatigue ,77,78,79In healthy participants, positive effects of anodal tDCS over the left DLPFC were consistently demonstrated. A single dose of anodal tDCS was able to reduce fatigue-related vigilance performance decrements over time ,80, evenFor MS-related fatigue, positive stimulation effects on subjective fatigue assessed with self-report scales were also reported after five consecutive days of anodal tDCS over the bilateral motor cortex or somatosensory cortex ,82, overIn PD, applications of tDCS showed to be able to produce transient beneficial effects, both in the motor  as well 2 in 12 patients in an active treatment group and 11 patients in a placebo group. The data showed that anodal tDCS reduced fatigue immediately after treatment and also after a 3-month follow-up. As a further development of this approach, Dobbs and colleagues [Nowadays, however, reports of positive effects of tDCS on PDRF are only very sparse. In a first experiment, Forogh and colleagues  investiglleagues  proposedlleagues . Howeverlleagues  and deprlleagues . In summary, PDRF is one of the most common non-motor symptoms occurring in the majority of patients and affecting a wide range of daily activities. PDRF results in a significant disability and markedly reduces the quality of life. The underlying pathophysiological mechanism in fatigue includes specific dysfunctions of the frontal cortex. However, despite its clinical importance, progress in developing an effective treatment for PDRF is still remarkably limited. Frontal anodal tDCS has proven to be effective for treating fatigue in both healthy participants and patients with neurological disorders such as multiple sclerosis. Moreover, anodal tDCS has been shown to raise hypofunctionality within stimulated cortical areas, including the DLPFC. Accordingly, the use of frontal anodal tDCS holds the promise of a potential therapeutic option for the treatment of PDRF. Further research is needed to determine the parameters of an optimal stimulation as well as to complement the purely subjective measures of fatigue with ones that provide an objective and valid assessment of fatigue and its potential reduction during treatment to make it useful in clinical settings. The concurrent use of neuroimaging methods such as EEG/MEG and fMRI in combination with tDCS is warranted and may be helpful in both target identification and outcome assessment for future tDCS trials for the treatment of PDRF. To conclude that frontal anodal tDCS can be an effective approach for the treatment of PDRF in a clinical setting, further data are needed that convincingly demonstrate (I) that a single session of anodal tDCS over the left DLPFC positively affects PDRF (transient effects), (II) that multisession tDCS can stabilize and/or enhance this effect, (III) that theses stimulation regimens lead to long-term effects of adequate duration, (IV) the specific conditions for a pronounced effect on the patient’s subjective as well as objective fatigue, and, finally, (IV) the specific parameters of a successful home-application.


This Research Topic, which consists of 8 articles by a total of >40 authors, addresses different aspects of metaplasticity in acquired neurological and psychiatric disorders. Metaplasticity refers to the activity-dependent modulation of synaptic plasticity. This pivotal determinant of learning, memory, and other functions represents a higher order of synaptic plasticity that acts on the threshold for modifying synaptic strength . HoweverThomson and Sack reviewed studies utilizing transcranial magnetic stimulation  to study and modulate metaplasticity, with specific interest in clinical applications. In particular, they focused on the use of repetitive TMS (rTMS) with intermittent theta burst stimulation (iTBS) and continuous TBS, as these are two of the most known and applied stimulation paradigms within research and clinical settings. After reviewing the relevant literature, the authors concluded that there is indeed a great potential to develop metaplasticity-based treatments to induce or restore a desired level of synaptic plasticity. They further identified accelerated iTBS at longer intervals (60 min) as being of particular interest, as it seems to maximize metaplasticity effects and clinical outcomes.Given its role in regulating synaptic plasticity, alterations to metaplastic mechanisms are likely to represent an important element of many neurological disorders. Until relatively recently, though, investigation of these processes was limited to invasive techniques in animal models. However, the development of non-invasive brain stimulation techniques (NIBS) has meant that it is now possible to induce and modulate metaplasticity in human subjects. Excitingly, there is a rapidly growing constellation of novel interventions that have been developed using NIBS, many of which are showing promise as therapeutic tools for treating neurological and neuropsychiatric disorders, despite our still limited understanding of the contribution made by metaplasticity. In support of this, the study by Korai et al., the neurobiological mechanisms underlying the after-effects of tDCS and tACS was therefore reviewed. The authors discuss that, in contrast to TMS, these forms of NIBS do not produce action potentials in affected tissues. Instead, they modulate membrane potential within a sub-threshold range, and this leads to consequent changes in synaptic transmission. The role of meta-plasticity in mediating these effects is further discussed by the authors. In particular, the way in which synaptic efficacy is effectively modulated only when concurrent neuronal discharge take place  and alternating (tACS) current stimulation, both of which involve low intensity electrical stimulation to the scalp, have also become widely applied within this field. In the study by ke place , 7. ThisHamaguchi et al. instead aimed to identify if it is possible to predict participants that will benefit from a combination of NIBS and occupational therapy (OT)  based on pre-treatment functional scores. In 1,254 patients with upper extremity post-stroke paralysis, the authors therefore assessed if the response to low frequency  rTMS applied to the contralesional primary motor cortex (M1) immediately prior to OT could be predicted by pretreatment Fugl-Meyer Motor Assessment (FMA) scores of the upper limb. The intervention showed a facilitation of muscle movements by the rTMS-modulation of M1 excitability. Moreover, the probability of being non-responders was 59.2% when the initial FMA score was 48.9, whereas when the initial score was 38.8 the incidence of responders and hyper-responders was 45.5 and 16.0%, respectively. Notably, ~45% of the patients with FMA scores from 30 to 40 before treatment improved, and even >25% of those with more severe initial values. Overall, these results suggest that pretreatment assessment can estimate the possibility of a patient's recovery in the chronic phase, with relevant implications for therapists and patient's compliance and cooperation.Although applied broadly across many clinical domains, there has been a preponderance of NIBS-based research in the area of stroke. In particular, the development of interventions able to promote functionally beneficial patterns of brain activity in stroke patients has been common, and this approach likely involves metaplastic mechanisms. In an alternative take on this goal, the study by Zhong et al. tested how the site of stimulation influences recovery from dysphagia in subacute stroke patients. Specifically, the benefit of 5 Hz-rTMS combined with standard sensory-motor rehabilitation of dysphagia was compared when applying stimulation to the M1 and cerebellum of both affected and unaffected hemispheres. They reported that, relative to a non-stimulated control group, 2-weeks of combined stimulation and training resulted in improved recovery, and this was consistent across all sites of stimulation. This implies that rTMS may have stimulated the training-induced plasticity involved in swallowing control, possibly by acting on different circuits, although the specific pathomechanisms need to be clarified.Using a slightly different approach that nonetheless highlights the utility of combining NIBS with functional interventions in stroke patients, the study by Fray et al. instead evaluated the use of intense rTMS to treat post-stroke depression (PSD). In six subacute stroke patients, high-frequency (20 Hz) rTMS was applied over the left dorsolateral prefrontal cortex (DLPFC) during five sessions per day and over 4 consecutive days . At the end of the procedure and after 3 months, scores of depression significantly decreased, without any procedure-related adverse event. The authors concluded that, despite the small sample size of this pilot study, intense rTMS may be a safe and effective alternative or adjunctive therapy for PSD patients.While a large amount of the literature utilizing NIBS in stroke has been focused on improving motor symptoms, the interesting study by Sumiyoshi et al. determined whether tDCS improves semantic memory in schizophrenia patients, assessed using text-mining analyses of category fluency data. Indeed, semantic memory deficits have been previously reported in schizophrenia and associated with negative symptoms and quality of life. In 28 schizophrenia patients, cognitive assessment was carried out at baseline and 1 month after tDCS, which was performed twice per day for five consecutive days, with the anode electrode over the left DLPFC and cathode electrode over the right supraorbital area. After multi-session tDCS, the authors observed a normalization of semantic associations. The left prefrontal region is assumed to be related to the ability of tDCS to improve the organization of information and retrieval of clustered words, thus supporting the role of neuromodulation in improving cognitive functions in psychiatric disorders.In further support of the cognitive benefits that are achievable when applying NIBS in the clinic, the elegant study by Suarez-Garcia et al. sought to characterize the current evidence supporting the use of tDCS for treating cognitive impairment in Parkinson's disease (PD). A systematic review was used to identify 8 studies, the data from which was subsequently entered in to a meta-analysis. Although the results of this analysis were limited by the low number of studies and the heterogeneity of stimulation protocols and clinical features, they nonetheless identified strong benefits to executive functions in patients. In particular, anodal tDCS appears to improve problem solving and planning, verbal fluency, and cognitive flexibility.The third review within this edition also serves to demonstrate the cognitive benefits that can be derived from utilizing NIBS as an adjunctive therapy within a clinical population. Accordingly, the mini-review by Serrano-Castro et al. Despite an invasive neurostimulation approach, they opened the way to a customized neuroplastic-guided rehabilitation protocol, which allowed a previously inoperable tumor to be successfully removed and subsequently help treat the patient's refractory epilepsy.Finally, an example of metaplastic modulation in clinical practice has been described in the case reported by In conclusion, this Research Topic includes a number of remarkable advances that further our understanding of the complex phenomena underlying metaplasticity, demonstrate how aberrant metaplasticity can contribute to pathophysiology, and show that modifying metaplasticity with NIBS can be an effective avenue for treating network disorders of the brain. Translationally, this will encourage future clinical and neurophysiological studies and open novel therapeutic perspectives in this fascinating topic.MC, FR, and CT draft the manuscript. MC, GL, and CT conduct the analysis of data. GL and GO revise the manuscript critically for important intellectual content. All the authors approve the version of the manuscript to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


It is well known that exercise produces analgesic effects ) in animal models and chronic pain patients, but the brain mechanisms underlying these EIH effects, especially concerning the emotional aspects of pain, are not yet fully understood. In this review, we describe drastic changes in the mesocorticolimbic system of the brain which permit the induction of EIH effects. The amygdala (Amyg) is a critical node for the regulation of emotions, such as fear and anxiety, which are closely associated with chronic pain. In our recent studies using neuropathic pain (NPP) model mice, we extensively examined the association between the Amyg and EIH effects. We found that voluntary exercise (VE) activated glutamate (Glu) neurons in the medial basal Amyg projecting to the nucleus accumbens (NAc) lateral shell, while it almost completely suppressed NPP-induced activation of GABA neurons in the central nucleus of the Amyg (CeA). Furthermore, VE significantly inhibited activation of pyramidal neurons in the ventral hippocampus-CA1 region, which play important roles in contextual fear conditioning and the retrieval of fear memory. This review describes novel information concerning the brain mechanisms underlying EIH effects as a result of overcoming the fear-avoidance belief of chronic pain. The biopsychosocial model of pain chronification emphasizes the importance of psychosocial factors in addition to biological factors in the development and maintenance of pain . Among tThe research findings of human brain imaging studies have indicated that chronification of pain is produced via plastic changes in brain regions closely associated with the emotional aspects of pain, such as anxiety and fear. These findings suggest that the intensity of noxious stimulation is not the only cause of chronic pain. In particular, the mesocorticolimbic system of the brain, consisting of the medial prefrontal cortex (mPFC), amygdala (Amyg), nucleus accumbens (NAc), hippocampus (HIP), and ventral tegmental area (VTA), plays an essential role in the chronification of pain because these regions are closely associated with cognitive and emotional aspects of pain ,9,10 FiB. Our fiThe mammalian mPFC is divided into the prelimbic cortex (PL) and the infralimbic cortex (IL). The mPFC is strongly innervated by the Amyg and HIP and acts as a node for cognitive functions, such as working memories and decision-making, in addition to its role as a top-down controller of pain through robust projections to the NAc, Amyg, and periaqueductal gray (PAG). Pain-induced activation of glutamatergic (Glu) neurons in the basolateral amygdala (BLA) can activate parvalbumin (PV)-expressing GABA-positive interneurons in the mPFC , and the central nucleus of the amygdala (CeA). The CeA is further subdivided into the CeL , the CeM , and the CeC (capsular division). Noxious information that was modified by past painful experiences and mood states via the central nervous system is received into the CeA via the BLA (BLA–CeA pathway). On the other hand, noxious information derived from peripheral tissues and organs is directly received into the lateral parabrachial nucleus (lPBN) via the spinal dorsal horn, from where it is sent onwards to the CeC of the CeA (lPBN–CeA pathway). It has been demonstrated that Amyg neurons are overactivated in experimental animals suffering from various pain states, including visceral pain, formalin-induced inflammatory pain, acid-induced muscle pain, arthritic pain, and neuropathic pain . HyperexThe HIP (hippocampus) is divided into the dorsal and ventral HIP (vHIP), which play important roles in several cognitive and emotional functions, including spatial memory, learning, fear, and anxiety. The vHIP is strongly innervated by the mPFC and the BLA and sends projections to the mPFC, the BLA, and the CeA that contribute to the expression of fear memories and anxiety . NeurogeThe brain’s reward system consists of a projection pathway of dopamine (DA) neurons from the lateral VTA (latVTA) to the NAc lateral shell (NAc lat shell), and activation of this pathway can promote positive behaviors and reinforce learning and desire. The NAc is a core brain region of the reward system that controls valence  and allows us to adapt to our external environment. Production of DA in the latVTA is inhibited in chronic pain patients, and this inhibition can contribute to the development of depression . In addiMeta-analyses and experimental animal studies over the past 30 years have demonstrated that exercise, such as running or swimming, can promote analgesic effects (EIH) and that the ability of exercise to improve chronic pain is well established in humans and animals ,27,28. IWhen inflammatory pain model mice were kept in an enriched environment with a running wheel, significant improvements in perceptual, emotional, and cognitive brain functions were observed in active mice compared to sedentary mice . It has The role of endogenous opioids in producing EIH effects has been reported by Stagg et al. . They inWakaizumi et al.  examinedOur previous studies ,34 and pChronic pain patients show anxiety, depression, and learning and memory deficits, which may be partially induced via atrophy and dysfunction of the HIP. Complex regional pain syndrome (CRPS) patients and chronic lower back pain patients showed significant decreases in HIP volume . It has Brellenthin et al. reported that positive family environments predict attenuated pain sensitivity and greater EIH, whereas negative and chronic pain-present family environments predict worse pain and EIH outcomes. These findings indicate that psychosocial variables, such as the family environment and mood states, can affect both pain sensitivity and the ability to modulate pain through EIH . Further


In this research, reinforced concrete (RC) and strain-hardening cementitious composite (SHCC) columns subjected to lateral loads combined with a constant load were investigated, both by experiments and predictions, with two distributed inelastic finite element models established by the stiffness and flexibility formulations. SHCC applied in the column plastic hinge region could not only enhance the lateral load and displacement capacities of columns but also offer effective advantages in the control of bending and shear cracks induced by multiple microcracks, the prevention of the spalling of cover concrete, and the resistance to buckling of steel bars. With the layered cross-sectional approach using constitutive laws of SHCC considering a proposed model of the post-cracked high-ductile tensile characteristics, as well as concrete and reinforcing steel bars, an inelastic beam-column finite element model was presented with a distributed flexibility formulation. In comparison with experiments concerning the RC and reinforced strain-hardening cementitious composite (R-SHCC) columns, the current flexibility method showed relatively accurate estimations in the lateral load and displacement responses of column systems as well as in localized nonlinear responses of cross-section as estimated in axial strains of longitudinal reinforcing steel bars. In comparison with the stiffness method, the current flexibility method gave more accurate solutions at both element and structural levels, as manifested in the experiments and analysis solutions. Sometimes reinforced concrete (RC) columns at the lower stories of a building, under medium or strong earthquake loads, can experience severe damages caused by the progress of bending and shear cracks, the spalling of cover concrete, and the yielding and buckling of longitudinal reinforcing steel bars, and the damage to the the column, especially, were localized to concentrate in the column plastic hinge region ,2,3.The nonlinear solution of RC beam-column finite element (FE) model is important in applications of performance-based evaluation, design, and retrofit of concrete structures in medium or strong earthquake zones. The inelastic analyses of RC frames were initially concentrated at the ends of beams and columns by means of nonlinear springs located at the member ends ,5. An imConcrete or cementitious binders mixed with steel, metal, or synthetic fibers could be innovated as their mechanical characteristic from a brittle material weakened by tensile cracks to a post-cracked high ductile material induced by multiple microcracks. Many researchers, for this purpose, have developed several types of fiber cementitious composites, such as engineered cementitious composites (ECC), high-performance fiber-reinforced cementitious composites (HPFRCC), and strain-hardening cementitious composites (SHCC) ,12,13,14In the current study, SHCC was applied as an attempt to improve structural performances of conventional RC structural columns and the applications were evaluated by a series experiments and finite element predictions on cantilever columns subjected to lateral loads combined with a constant load. As for the novelties of this research: first, the efficiency of SHCC instead of concrete at column plastic hinge regions was evaluated with cases of tied and non-tied steel bars. Second, in order to ensure more accurate solutions both in global load and displacement responses and in local damages and local nonlinear responses at critical column plastic hinge regions, an inelastic flexibility beam-column finite element analysis model was newly developed for the analysis of R-SHCC applied concrete composite columns. Moreover, the cross-sectional force and deformation relation was newly established with constitutive laws of SHCC as a proposed model of the post-cracked high-ductile tensile characteristic, and the sectional nonlinear responses were solved with integrations of the layered approach. Therefore, the element formulation was cast in a distributed inelastic beam-column finite element method in which the element state was determined by the convergence of a nonlinear solution in an element in order to satisfy equilibrium within the element. The following sections of this article consist of the manufacture and mechanical characteristics of SHCC, the formulation and modeling of the flexibility beam-column finite element for R-SHCC and concrete composite columns, manufactures and loading setups of column specimens, experiments and finite element predictions of columns, and finally conclusions are presented.In order to improve tensile brittle characteristics of concrete, as shown in For the compressive test on hardened SHCC, three specimens of SHCC from cubic molds were manufactured and the compressive strength of SHCC at 28 days was measured as an average of 39.2 MPa. To evaluate the tensile characteristic of hardened SHCC, on the other hand, a direct uniaxial tensile test was carried out using a 10 kN capacity universal testing machine (UTM) by controlling the displacement of 0.2 m/min, as shown in The specimens had a dimension with a 30 mm × 30 mm cross-section and a length of 330 mm ,10,11,18Three column specimens were manufactured with representing the first-storey column between the footing and the inflection point. As shown in Three column specimens were presented with design variables as shown in Reinforcing steel bars produced in Korea had the yielding stresses for the main steel bar, D13, and the tied steel bar, D10, as 385 MPa and 383 MPa, respectively. Concrete was mixed with ordinary Portland cement, crushed stones with a maximum aggregate size of 20 mm, sand and admixtures, and the uniaxial compressive strength of hardened concrete in cylinder test was recorded as the average of 29 MPa after curing at 28 days.Each column specimen was installed on the reaction base and the reaction wall as illustrated in In order to predict inelastic responses of RC and R-SHCC columns, an inelastic distributed frame finite element model was applied using an isoparametric finite element formulation combined with a layered cross-sectional approach.The current R-SHCC column element was formulated using a flexibility beam-column finite element, which was basically an extended version of a RC beam-column element model originally presented by Spacone et al. . In the The element formulation discussed here was established in the local coordinate system without rigid body modes, as shown in Denoting with increments of the corresponding quantities, the section deformation The element relation between force increments and corresponding deformation increments could be obtained from the principle of virtual forces, Upon rearrangement of above equations, the element flexibility equation could be derived as, Equation (5):The selection of the interpolation functions The element stiffness matrix To model the beam-column finite element for RC and R-SHCC beam or column members, the element formulation relied on the layered cross-sectional discretization in order to compute the section force vector and section flexibility matrix, which were corresponding to the section deformation, as shown in As uniaxial laws, concrete and reinforcing steel bars were adopted as well-known stress and strain models ,21, but Based on the description in this manuscript, a program of Matlab code was developed to analyze RC and R-SHCC beams, columns, and frames. Inelastic nonlinear finite element modeling and analysis of the RC and R-SHCC cantilever columns was also performed, corresponding with a series of experiments on three columns, as mentioned in the previous chapter. The cantilever column subjected to lateral load, H, combined with a constant axial load, P, was modeled as a distributed inelastic beam-column finite element formulation with a layered cross-sectional approach, as shown in From the experiments and the analysis of three column specimens, the lateral load and top displacement envelope curves of the columns are presented as shown in The damages and failure patterns of three columns are shown in The predicted lateral load and displacement curves by the two elements and beam-column finite element models were compared with experiments, as shown in For three column specimens, local nonlinear responses of cross-sections within the critical plastic hinge region were evaluated by measurements of axial strains in longitudinal steel bars, both at initial yielding of main steel bars and at the ultimate yielding, and the measured axial strains were plotted from the column base along the height of column, being compared with the predicted axial strains both by the stiffness model and flexibility model, respectively, as shown in In comparison with the predicted axial strain distributions of longitudinal steel bars, the stiffness finite element method gave a constant distribution within an element along the height so that the predicted nonlinear responses in cross-sections didn’t provide accurate estimations. On the other hand, the flexibility finite element method gave a linear distribution of the axial strains between the integration points so that the predicted nonlinear responses in the cross-sections were able to be provided more accurately.Laterally loaded columns, such as the columns in the current experiments, as well as lower story columns in buildings commonly reach failure by localized damages concentrated in the column plastic hinge zone. The accuracy of nonlinear problems in inelastic beam-column finite element models, therefore, mainly depends upon the estimation of nonlinear responses in local levels of cross-sections. The stiffness method could not satisfy equilibrium in an element, but the current flexibility method could satisfy equilibrium in an element because the element force and deformation fields were adjusted until the section’s constitutive relations were satisfied, while always satisfying equilibrium in an element. For the reason, the current flexibility method gave more accurate solution at both the element and structural levels, as manifested in the experiments and analysis solutions, as shown in In the current research, RC and R-SHCC columns subjected to lateral loads combined with a constant load were investigated by experiments and distributed inelastic beam-column finite element predictions, and the following conclusions were presented.Instead of concrete, SHCC was applied in the column plastic hinge region as a scheme of minimizing damages in the region and the experiments showed that the use of SHCC could enhance the lateral load and displacement capacities of columns. Within the column plastic hinge region, SHCC could offer some effective advantages in the control of bending and shear cracks induced by multiple microcracks, the prevention of the spalling of cover, and the resistance of buckling of steel bars, so as to minimize damage localizations concentrated in the region.Based on constitutive laws of SHCC considered with a proposed model of the post-cracked high-ductile tensile characteristic as well as concrete and reinforcing steel bars, the inelastic beam-column flexibility finite element model for the analysis of RC and R-SHCC columns was presented. In comparison with the well-known stiffness finite element method, the current flexibility method could give more accurate predictions of the lateral load and displacement responses of the column systems as well as of localized nonlinear responses of cross-sections as estimated in axial strains of longitudinal reinforcing steel bars.


Molecular cloning and the conventional sequencing of SCCmec have been adopted to verify the presence and structure of a novel SCCmec type, while convenient PCR-based SCCmec identification methods have been used in practical settings for many years. In addition, whole-genome sequencing has been widely used, and various SCCmec and similar structures have been recently identified in various species. The current status of the SCCmec types, SCCmec subtypes, rules for nomenclature, and multiple methods for identifying SCCmec types and subtypes were summarized in this review, according to the perspective of the International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements.Staphylococcal cassette chromosome  Staphylococcus aureus (MRSA) was identified ”, which has already been adopted for non-aureus staphylococci. Discussions should be continued on the appropriate way of differentiating and naming the SCCmec structures present in both S. aureus and other species using whole-genome sequencing data and/or in silico investigations from public genome databases.To date, complete structures of SCCmec was based on the findings from multiple researchers about MRSA in the 20th century, and its importance in the fields of molecular epidemiology, infection control and prevention, and investigation of the evolution of MRSA has been developed along with the evolution of molecular analysis technologies. The implementation of whole-genome sequencing will contribute to reveal the entire relatedness of the SCCmec elements found not only in MRSA but also in other Staphylococcus species and Gram-positive bacteria. Importance as a tool of molecular typing might be declined if whole-genome sequencing is more widely used in clinical settings, but PCR-based methods will continue to be used as easy and costless tools for molecular epidemiology, infection control, and prevention. Therefore, the nomenclature rule of SCCmec should be followed, and the IWG-SCC should continue to update the most appropriate policy to designate SCCmec elements, especially for isolates other than S. aureus, or MRSA isolated from animals or the environment.The discovery of SCC