Robot-assisted training is a promising tool under development for improving walking function based on repetitive goal-oriented task practice. The challenges in developing the controllers for gait training devices that promote desired changes in gait is complicated by the limited understanding of the human response to robotic input. A possible method of controller formulation can be based on the principle of bio-inspiration, where a robot is controlled to apply the change in joint moment applied by human subjects when they achieve a gait feature of interest. However, it is currently unclear how lower extremity joint moments are modulated by even basic gait spatio-temporal parameters. In this study, we investigated how sagittal plane joint moments are affected by a factorial modulation of two important gait parameters: gait speed and stride length. We present the findings obtained from 20 healthy control subjects walking at various treadmill-imposed speeds and instructed to modulate stride length utilizing real-time visual feedback. Implementing a continuum analysis of inverse-dynamics derived joint moment profiles, we extracted the effects of gait speed and stride length on joint moment throughout the gait cycle. Moreover, we utilized a torque pulse approximation analysis to determine the timing and amplitude of torque pulses that approximate the difference in joint moment profiles between stride length conditions, at all gait speed conditions. Our results show that gait speed has a significant effect on the moment profiles in all joints considered, while stride length has more localized effects, with the main effect observed on the knee moment during stance, and smaller effects observed for the hip joint moment during swing and ankle moment during the loading response. Moreover, our study demonstrated that trailing limb angle, a parameter of interest in programs targeting propulsion at push-off, was significantly correlated with stride length. As such, our study has generated assistance strategies based on pulses of torque suitable for implementation via a wearable exoskeleton with the objective of modulating stride length, and other correlated variables such as trailing limb angle. Robot-assisted training is a promising tool under development for improving walking function , 2. A prOur research group is exploring the use of robot-assisted gait training to directly target and modulate TLA, thus allowing subjects to modulate GS. A possible controller could be composed of torque pulses applied at specific instants during the gait cycle, with the advantage of not constraining gait to follow prescribed trajectories . This apThe joint kinetics associated with GS modulation in healthy control subjects have been thoroughly elucidated in the literature, where an increase in GS is generally associated with increase in magnitude of peak joint moments. A very early investigation examining knee kinetics found increasing GS to be strongly correlated with an increase in peak knee extension moment . FurtherHowever, fewer investigations have focused on the joint kinetics associated with the modulation of spatiotemporal parameters such as SL or TLA, and studied this effect at multiple GS values. Summed joint work has been observed to be strongly correlated with SL in both young and old adults, where young adults primarily utilized swing phase hip work to modulate SL and old adults utilized ankle and knee joint work . An earlThus far, the factorial modulation of both GS and SL and resulting hip, knee, and ankle kinetics has not been investigated; as such it is unclear how lower extremity joint moments are modulated by both gait parameters. Addressing this gap of knowledge, we designed an experimental study to establish the effects of GS and SL on the resulting hip, knee, and ankle joint moments. The findings are intended to inform the design of a robotic controller that delivers pulses of torque to the lower extremity joints with optimal timing and amplitude to induce desirable modulations of GS and SL, and of associated spatiotemporal parameters.20 healthy adults  were recruited to participate in this study . Subjects—age (mean ± std) 21.55 ± 2.50 yrs, height 1.73 ± 0.08 m, body mass 69.20 ± 8.73 kg—were naive to the purpose of the study, and free of orthopedic or neurological disorders affecting walking function. Subjects were required to wear their own comfortable athletic shoes and lightweight clothing for the walking experiment.k was defined based on the right heel strike time t and anteroposterior coordinate in the laboratory frame x and constant velocity of the treadmill v:Subjects walked on an instrumented dual-belt treadmill , as shown in k) GS, with five levels, and ii) SL, with three levels. Factor levels were defined in terms of percent change relative to subject self-selected (ss) values to accommodate inter-subject variability in gait parameters. Moreover, to account for the correlation between GS and SL  in a randomized order. For each GS, ss-SL was calculated as the mean SL measured at that treadmill speed and utilized for the definition of subsequent desired SL values at each GS.After determination of ss-SL for all five GS conditions, ten additional walking trials were conducted consisting of ninety seconds of data acquisition, two for each treadmill speed value, using biofeedback to cue a desired SL. For each GS, the desired SL was set to be either 17% greater or 17% smaller than the ss-SL at that GS, in a random order. The range of change in SL values was specified based on previous studies showing feasibility of achieving distinguishable gait kinetics when SL was modulated by 17% of the ss value . The invi) noise gating of measured force with a 25 N threshold ii) low-pass filtering of marker and force/torque data , iii) interpolation of missing marker data with a third order polynomial fit for a maximum gap size of five samples, iv) application of the subject mass, height, and standing calibration marker positions to an anatomical template to derive a 7 segment  link-segment subject model, and v) use of an optimization algorithm applied to inverse kinetics and kinematics equations to obtain joint angles and net moments.Raw marker trajectories were labeled offline. Marker position and force/torque data were fed into a standard Visual3D processing pipeline, which included nd order low-pass zero-shift Butterworth filter with a cut-off frequency of 15 Hz. Gait cycles were segmented between subsequent heel strike events, defined as the instants at which the vertical ground reaction force changed in value from zero to positive, and remained positive for a minimum of 400ms. Due to events such as marker occlusion or subjects’ foot stepping on the contralateral force plate, acquired data were manually screened and some gait cycles were excluded from the analysis. A minimum of 25 segmented gait cycles were linearly resampled in the  % gait cycle domain In a custom MATLAB  script, hip, knee, and ankle joint angles and moments for the right leg in the sagittal plane were extracted and filtered with a 2W is body weight in N, and Ll is leg length in m, measured as the distance between the hip joint center and the floor during straight-leg standing.Prior to obtaining average group moment profiles, joint moment profiles were non-dimensionalized. In agreement with , the nong is the acceleration of gravity. Although several other factors such as body mass and athletic fitness condition account for the variability in ss-GS across individuals [A non-dimensional GS was defined as the Froude number ividuals , the Froividuals . As such0 value for each of the 15 conditions for all subjects and conducted a linear correlation analysis using these two measurements as factors to assess the statistical association between normalized stride length and TLA.Two gait parameters were also calculated; SL was measured using We sought to determine if the two factors GS and SL had any significant effect on the sagittal plane moment profiles for the hip, knee, and ankle joint anova2rm [α = 0.05 based on SPM1D’s correction based on random field theory (RFT) to estimate the smoothness in the input data.Since the dependent variable e series . We usede series , to contanova2rm . Inferenncomp = 30 pairwise comparisons. Pairwise comparisons were conducted using two-tailed paired t-tests using SPM1D function ttest_paired, and defining thresholds t-scores for significance at α = 0.05 using a Bonferroni correction (n = ncomp) on the paired difference thresholds calculated by SPM1D.After the main effect analysis, we conducted pairwise comparisons to establish the specific effect of SL on the measured joint moment profiles, testing for the null hypothesis that the mean profiles measured at the same speed for nominal and bio-feedback modulated SL conditions were not different from one another at any time point. This resulted in two comparisons  per speed, per joint, for a total of j were extracted as:We then conducted a second analysis with the specific purpose of composing a controller based on the application of pulses of torque at select phases of the gait cycle. As such, we sought to approximate the effect of SL modulation on joint moment profiles with a series of rectangular pulses of torque. First, the normalized difference αl, and amplitude Al as in the equation:The rectangular torque pulses N = 1, 2) approximation of the function fmincon—to find the values of parameters A and α that minimize the norm of residuals αl was defined as the set of integers between 5% and 95%, providing a quantization in the time of application of torque pulses equal to 1% of a gait cycle duration. For each joint, we divided the estimated pulses into two different groups depending on whether their amplitude was in the positive, or negative direction .For this specific work, we examined the one and two pulse . For the purposes of our analysis, pulse magnitude is the absolute value of pulse amplitude. Four separate linear mixed effects models  were performed on the one and two pulse approximations for both the pulse magnitude and location data sets to test the null hypothesis that no independent variable had an effect on the outcome measures. The models included fixed effects for each of the independent variables as well as all two-way and one three-way interaction between them. Heterogeneity due to trials completed under different gait speed conditions, and multiple pulses in the case of the two pulse approximation were accounted for by the inclusion of random effects. Correlation between multiple measurements taken on the same subject were accounted for by the inclusion of a repeated measure effect. Upon comparing nested model Akaike information criterion (AIC) values, the lowest AIC value came from the unstructured covariance structure and was therefore selected for the final models.α < 0.05 level, effects and interactions were further investigated through post hoc Tukey-Kramer tests (α = 0.05). The Tukey-Kramer post hoc test for the joint and SL modulation interaction was used to establish the presence of significant differences in pulse magnitude means between joints for SL modulation conditions, separately. The three-way interaction between joint, SL modulation, and pulse sign was broken down using the Tukey-Kramer post hoc test to find the significant differences between torque pulse location, for a given joint, under different combinations of factors SL modulation and torque pulse sign. We were especially interested in testing whether there were specific instants of time where the application of a positive torque pulse would modulate SL in a certain direction, and, simultaneously, where the application of a negative torque pulse would modulate SL in the opposite direction. As such, for each joint, we conducted two pairwise comparisons: one to compare the location variables measured for positive pulse torque sign and positive SL modulation with the variables measured for negative pulse torque sign and negative SL modulation, and a second one to compare the location variables measured for positive pulse torque sign and negative SL modulation with the variables measured for negative pulse torque sign and positive SL modulation.In case of effects statistically significant at the To visually illustrate the distributions of torque pulses in gait cycle, location histograms were generated. All pulses were combined across the twenty subjects and five gait speed conditions and grouped by joint and SL modulation condition for the one and two pulse approximations, separately. For representation purposes, within each histogram, the pulses are divided into positive and negative groups according to the sign of pulse amplitude CVFr = 0.106, slightly greater than CVss-GS = 0.104, and both smaller than 0 values for all five non-feedback conditions, averaged across all subjects, was relatively small (σmax = 3.86%). Based on these measures, we conclude that the protocol significantly modulated values of SL and GS, such that statistical analysis may be performed.The mean Froude numbers with 95% confidence intervals, across gait speed conditions, are shown in the left of 0 and TLA, which indicates that subjects also modulated TLA while achieving biofeedback cued SL modulation. The group analysis of joint moments in the three SL conditions across five GS conditions is depicted in As seen in the right side of The continuum analysis showed an effect of GS on the normalized joint moment profiles, where a significant effect of GS was detected for a total 82.4%, 80.4% and 64.7% of the gait cycle for the hip, knee, and ankle joint respectively, as shown in Pairwise comparisons for the hip joint show that during increased SL conditions , right, For the knee, during increased SL conditions , right, For the ankle, during increased SL conditions , right, Figs The results of the linear mixed effects model analyses for torque pulse magnitude are shown in Tables Figs The linear mixed effects model results for torque pulse location in gait cycle are shown in Tables All of the pairwise comparisons conducted to assess the symmetry of the effect for a reversal of SL conditions are reported in Tables CVss-GS = 0.103. Based on these measures, it is apparent that our protocol significantly modulated both SL and GS, such that statistical analysis may be performed to assess changes in joint kinetics arising from exposure to these conditions. Our analysis showed a strong correlation (r = 0.87) between SL and TLA, indicating that TLA was indirectly modulated through the explicit cueing of SL modulation. Our data analyses focused primarily on the effects on joint kinetics introduced by modulation of SL at various GSs and secondarily on the effects introduced by GS.We exposed subjects to a factorial modulation of gait speed (GS) and stride length (SL) and utilized inverse dynamics to estimate the lower extremity joint moments in the sagittal plane. With our protocol, we modulated SL of individuals significantly between conditions, with a mean change in SL equal to ±15% of the self-selected value, close to the target ±17%. Furthermore, inter-individual variability in self-selected gait speed (ss-GS) was reasonably small, with a coefficient of variation p < 0.001) with Tukey-Kramer post hoc tests indicating the knee having the greatest normalized pulse magnitude  for increases in SL, in nine of the ten pairwise comparisons at all speeds, shown in 0 and TLA, pulse torque approximation patterns associated with SL modulation are also associated with TLA modulation. These findings suggest that a possible joint moment assistance strategy based on pulses of torque applied primarily at the hip and the knee joint could induce modulations in both SL and TLA. According to our analysis, the application of an extension pulse of torque in early stance and a flexion pulse in late stance to the knee appear to be suitable assistance strategies to support an increase of SL and TLA during walking. If pulse torque assistance is to be applied at an additional joint, pulse torque assistance could be applied at the hip with a flexion pulse applied during late swing.Our study has measured the effects of stride length (SL) on the lower extremity joint moment profiles at different speeds, demonstrating several consistent effects in our population. The main effects of increasing SL at the knee include an increase in knee extension moment at early stance and an increase in flexion moment at late stance. At the hip, the main effects of increasing SL are a decrease in flexion moment during early swing and a decrease in extension moment during late swing. For an increase in SL, the ankle primarily exhibits an increase in dorsiflexion moment during loading response. Given the observed linear relationship between SLThis study has some limitations. The methods pursued in this paper are based on a group analysis of joint moment profiles measured via inverse-dynamics. As such, it is possible that the most successful assistance strategies may significantly change between different individuals. Therefore, the group analysis based assistance strategy candidate could be best utilized as an initial estimate and assistance strategies could be iteratively optimized for each subject using human-in-the-loop optimization, like it has been done for single-joint assistance schemes .Moreover, the proposed assistance strategy is based on the assumption that human contribution will not change when an assistive torque is applied via a wearable exoskeleton, such that the combination of torques applied by the two agents would result in a simple summation. However, it is well known that the human neuromuscular system is non-linear  and invo


Based on the base force element method (BFEM), the dynamic mechanical behavior of concrete under uniaxial compression loading at different strain rates is investigated. The concrete can be considered as a three-phase composite material composed of aggregate, cement mortar, and interfacial transition zone (ITZ) on the meso-level. A two-dimensional random aggregate model is generated by the Monte Carlo method. A multi-linear two-dimensional damage model is applied to describe the damage properties of each phase in the concrete. The strain-softening behavior, strain-rate effect, and failure patterns of the concrete are studied. The numerical results find that the peaks of compressive stress and compressive strain of concrete show the rate-sensitivity in various degrees under different strain rates. The calculated results of the dynamic enhancement factors are in a good agreement with the formula given by the Comité Euro-International du Béton (CEB) and other experimental results. The failure diagram of the specimen clearly describes the compressive failure process of the concrete specimen. This failure’s characteristics are similar to the experimental results. In practice, the concrete used in infrastructure is usually subjected to dynamic loading, including impact loading and sustained loading. The previous obtained results show that the mechanical properties and damage characteristics of concrete under dynamic loading are very different from those under static loading ,2. ThereHitherto, much research based on the traditional experimental test has been conducted. Abram  was the In recent years, numerical analysis with computer modeling has become an efficient method to study the properties of concrete. On the basis of a damage parameter, Simo and Ju ,22 propoGeorgin et al.  exploiteTo date, the relationship between the failure mechanism of concrete and the stress distribution at high strain rate is not clear; however, the mesoscopic components remarkably affect the macroscopic mechanical properties of plain concrete. Therefore, on the meso-level, it is important to know the dynamic behavior of the concrete. In this paper, according to the investigations of concrete-like materials, under static loading with the base force element method (BFEM) proposed by Peng et al. ,44,45, aGenerally, the behavior of real physical structures subjected to loadings or displacements is almost dynamic. According to the D’Alembert’s principle, considering the actions of inertial force and damping force, the balance equation of a single-degree-of-freedom system can be obtained as follows:Furthermore, the full variable form of the Newmark-β method is adopted to solve the dynamic equilibrium equation in the study.According to the BFEM, which is based on the potential energy principle, a plane triangular element matrix KIJ , expressx and y represent Cartesian coordinate system, and the element matrix For plane strain problems, In the finite element dynamic analysis, lumped mass matrix, one of the most common forms of the element mass matrix, is applied to simplify the calculation and reduce the storage space. According to the equivalent static principle, the mass of the element can be evenly distributed among three vertexes of a triangular element, according to the hypothesis that there is no interaction between the inertial forces of each vertex. In dynamic response problems it is generally assumed that the viscous damping force is proportional to the velocity of particle motion. Therefore, the effect of damping in the dynamic structural analysis at a high loading rate cannot be ignored. As a widely used orthogonal damping model, the Rayleigh damping model can be expressed as follows:It should be noted that, in the process of the meso-mechanical failure of concrete, there are few research works on damping models. The damping theory is a methodology which aims to describe the microscopic mechanism of damping in a macroscopic way. For the general structural analysis, Rayleigh damping is usually used to approximately describe the damping characteristics. Normally, the damping ratio of the engineering structure ranges from 0.01 to 0.1. The average value 0.05 is applied in this paper.In this paper, to simplify the model, the influence of damage development on damping matrices is not considered. Consequently, the initial stiffness matrix of the specimen is adopted in the present dynamic analysis and the damping ratio is regarded as a constant. It is assumed that the mass matrix is independent from the damage state due to the conservation of mass.It is well known that concrete is a multi-phase heterogeneous brittle material. The mechanical properties of concrete are determined by components in its mixture. In this paper, concrete is described as a three-phase composite material at the meso-level, composed of coarse aggregates, cement mortar, and an ITZ between both phases. With the spherical aggregate applied, the microstructure in concrete can be depicted as in In this paper, in order to simulate the real distribution of aggregate as possible, the Monte Carlo method is used to establish the two-dimensional random aggregate model. Based on the Fuller three-dimensional aggregate gradation curve, Walraven  developeThe number of aggregate particles meeting the requirement of According to the theory of Fuller’s maximum density curve, three representative diameters  of aggregates are selected to calculate number of aggregate particles. The numbers are, respectively, 66, 11, and 3, as obtained from Equation (20). The aggregates calculated are put into the two-dimensional region, the same size as concrete specimen, by using the Monte Carlo method with three sets of different random numbers. Each aggregate should be in line with the boundary conditions and not overlap with the other aggregates before it is put on. The modeled aggregates are shown in In the finite element analysis, two common methods are adopted to deal with the thickness of ITZ in order to simplify the calculation. One considers the thickness of the ITZ from 0.5 mm to 2 mm ,49, and The finite element mesh is shadowed on the random aggregate model. The different mechanical properties are assigned to the corresponding elements. A linear elastic triangular finite element grid is applied in the paper, shown in As known, the mechanical properties of microscopic components have a great influence on the fracture damage behavior of concrete. Therefore, the heterogeneity of concrete should be taken into account in this numerical simulation. In this paper, concrete can be treated as a three-phase composite material composed of coarse aggregate, cement mortar, and the ITZ. Each phase material in concrete is assumed to be homogeneous and isotropic. The constitutive relation is presented in In In practice, damage patterns and mechanical properties of concrete under dynamic loading present different forms, which is called the strain-rate effect and is characterized by the dynamic increase factor (DIF). The dynamic increase factor for the compressive strength is recommended by Comité Euro-International du Béton  as the fconcrete .y-direction; other surfaces of the specimen are free in all directions. The influence of friction between the specimen and the loaded end on the compressive strength of concrete is ignored.In this section, the dynamic test of concrete subjected to uniaxial compressive loads is simulated with the BFEM. A standard concrete specimen, with the dimensions 150 mm × 150 mm, is chosen to conduct the test. The particle diameter of the coarse aggregates ranges from 5 mm to 40 mm. The boundary conditions are shown in y-axis. Dynamic displacement step-load is applied in this study and the velocity of displacement loading is well controlled by the duration of each load-step. Vertical strain rate Continuous and uniform vertical displacement loading is used on the specimens. The direction of vertical displacement loading is parallel to the Based on the meso-mechanical numerical simulation proposed in the present study, the specimen can be subdivided into triangular finite element meshes where the mesh size is 1 mm. With eight groups with different loading rates applied, dynamic uniaxial compression tests are carried out on the concrete specimens. The corresponding macroscopic nominal strain rates are The stress–strain curves of concrete specimens are shown in The stress–strain curves are similar to the static at low strain rates from The meso-cracks first occur and spread in the ITZ, or the weak link, in cement mortar. Finally, a region is formed, filled with a concentrative zonal crack, which results in the destruction of concrete. At the high strain rates from In The BFEM for dynamic analysis of concrete introduced in the present study verifies an efficient numerical simulation method to investigate the damage mechanism of concrete. The strain-rate effect and the failure characteristics are explored using two-dimensional models. Several conclusions can be obtained as follows:(1) The present results prove that the failure process of concrete under dynamic compression is simulated well. With the increase of stress, the material enters the nonlinear stage and the stress–strain curves show a nonlinear increase relationship, simultaneously.(2) The variation tendency of the DIF of concrete at different strain rates is consistent with the available experimental test data and the CEB empirical formula.(3) At high strain rates, cracks increase and, in a diffusion state, some of the elements present fracture damage and more energy is released, which could enhance the dynamic strength of the concrete.(4) The strain peaks of concrete present rate-sensitivity under different strain rates similar to stress peaks.For future work, a three-dimensional model of dynamic problems could be addressed by the BFEM and other conditions could be considered; for instance, considering the shape of aggregates, complicated boundary constraints, and so on, so as to simulate real concrete as much as possible.


Statistical learning (SL) is a method of learning based on the transitional probabilities embedded in sequential phenomena such as music and language. It has been considered an implicit and domain-general mechanism that is innate in the human brain and that functions independently of intention to learn and awareness of what has been learned. SL is an interdisciplinary notion that incorporates information technology, artificial intelligence, musicology, and linguistics, as well as psychology and neuroscience. A body of recent study has suggested that SL can be reflected in neurophysiological responses based on the framework of information theory. This paper reviews a range of work on SL in adults and children that suggests overlapping and independent neural correlations in music and language, and that indicates disability of SL. Furthermore, this article discusses the relationships between the order of transitional probabilities (TPs)  and entropy  regarding SL strategies in human’s brains; claims importance of information-theoretical approaches to understand domain-general, higher-order, and global SL covering both real-world music and language; and proposes promising approaches for the application of therapy and pedagogy from various perspectives of psychology, neuroscience, computational studies, musicology, and linguistics. The brain is a learning system that adapts to multiple external phenomena existing in its living environment, including various types of input such as auditory, visual, and somatosensory stimuli, and various learning domains such as music and language. By means of this wide-ranging system, humans can comprehend structured information, express their own emotions, and communicate with other people . AccordiThe SL phenomenon can partially be supported by a unified brain theory . This thSL is considered an implicit and ubiquitous process that is innate in humans, yet not unique to humans, as it is also found in monkeys ,25, songAs a result of the implicit nature of SL, however, humans cannot verbalize exactly what they statistically learn. Nonetheless, a body of evidence indicates that neurophysiological and behavioural responses can unveil musical and linguistic SL effects ,42,43,44nth-order Markov models [n-gram models [n-gram models has frequently been used in natural language processing, it has also recently been used in music models [nth-order Markov and (n + 1)-gram models is the conditional probability of an event ne+1, given the preceding n events based on Bayes’ theorem:According to SL theory, the brain automatically computes TP distributions in sequential phenomena  , grasps v models  or n-gram models   can be calculated from information contents:H(iX+1|iX) is the Markov entropy; P(iX) is the probability of event xi occurring; and P(iX+1|iX) is the probability of iX+1, given that iX occurs previously. Previous articles have suggested that the degree of Markov entropy modulates human predictability in SL [SL models are sometimes evaluated in terms of entropy ,73,74,75ty in SL ,81. The nth-order Markov model has been applied to develop artificial intelligence that gives computers learning and decision-making abilities similar to those of the human brain, thus generating systems for automatic music composition [nth-order Markov models, may be useful in understanding the domain-general SL, as it functions in response to real-world learning phenomena in the interdisciplinary realms of brain and computational sciences.The word segmentation paradigm is frequently used to examine the neural basis underlying SL  modalities directly measure brain activity during SL and represent a more sensitive method than the observation of behavioral effects ,41,104. It has been suggested that SL could also be reflected in oscillatory responses in the theta band ,116. MorNeuroimaging studies have indicated that both cortical and subcortical areas play an important role in SL. For instance, the auditory association cortex, including the superior temporal sulcus (STS)  and supeSome studies have suggested that the sensory type of each stimulus modulates the neural basis underlying SL. For instance, some previous studies have suggested that the right hemisphere contributes to visual SL . ParaskePerceptive mechanisms of summary structure  are considered to be independent of the prediction of each stimulus with different TPs  ,61. ReceAlthough SL is a domain-general system, some studies have reported that SL is impaired in domain-specific disabilities such as dyslexia ,52,53 anBecause of the acoustic similarity , corticaMusical training could also facilitate the effects of SL on N400 , which iThe SL of word segmentation plays an important role in various speech abilities. Recent studies have revealed a strong link between SL of word segmentation and more general linguistic proficiency such as expressive vocabulary  and foreRecent neural studies have demonstrated that SL of speech, pitch, timbre, and chord sequences can be performed and reflected in ERP/ERF ,37,40,46Previous studies have demonstrated that auditory SL can be performed even by sleeping neonates ,86,162. nth-order Markov and n-gram models based on information theory have frequently been used in natural language processing [nth-order Markov models [SL is a domain-general and interdisciplinary notion in psychology, neuroscience, musicology, linguistics, information technology, and artificial intelligence. To generate SL models that are applicable to all of these various realms, the ocessing ,71 and iocessing ,68,69. Sv models ,61,81, cv models ,73,74,75v models ,76. Prevv models  and activ models . Hasson v models  proposedv models  investigAccording to recent studies, acquired statistical knowledge contributes to the comprehension and production of complex structural information, such as music and language , intuitiPrevious studies suggest that neurophysiological correlations of SL can disclose subtle individual differences that might be underestimated by behavioral levels ,89,187, Although SL is generally considered domain-general, many studies also report that comprehension of language and music, which have domain-specific structures including universal grammar, tonal pitch spaces, and hierarchical tension ,3,4,5, mThis paper reviews a body of recent neural studies on SL in music and language, and discusses the possibility of therapeutic and pedagogical application. Because of a certain degree of acoustic similarity, neural overlap, and domain generality of SL between speech and music, musical training positively affects language skills in SL. Recent studies also suggested that SL strategies in the brain depend on the hierarchy, order ,35,58,59


MET p.Y1234C mutation to be responsible for arthrogryposis in this pedigree. MET p.Y1234C mutation caused the failure of activation of MET tyrosine kinase. A Met p.Y1232C mutant mouse model was established. The phenotypes of homozygous mice included embryonic lethality and complete loss of muscles that originated from migratory precursors. Heterozygous mice were born alive and showed reduction of the number of myofibers in both appendicular and axial muscles. Defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were proven to be responsible for the skeletal muscle dysplasia of mutant mice. Overall, our study shows MET to be a causative gene of arthrogryposis and MET mutation could cause skeletal muscle dysplasia in human beings.Arthrogryposis is a group of phenotypically and genetically heterogeneous disorders characterized by congenital contractures of two or more parts of the body; the pathogenesis and the causative genes of arthrogryposis remain undetermined. We examined a four‐generation arthrogryposis pedigree characterized by camptodactyly, limited forearm supination, and loss of myofibers in the forearms and hands. By using whole‐exome sequencing, we confirmed  The biological effects exerted by MET are triggered by the stimulation of its only ligand, hepatocyte growth factor  mutation to be responsible for the pathogenesis of arthrogryposis in this pedigree. MET p.Y1234C mutation was shown to cause the dysfunction of phosphorylation and tyrosine kinase activity of MET in vitro. We established a Met c.A3695G  mutant mouse model, and the defective migration of myogenic progenitor cells and impaired proliferation of secondary myoblasts were demonstrated to be responsible for the disturbed muscle development.Herein, we recruited a rare four‐generation Chinese arthrogryposis pedigree with only upper limb involvement, and we found the A four‐generation Chinese family presented with completely penetrant, autosomal dominant arthrogryposis characterized mainly by camptodactyly Fig A. All paSubject IV:7 is a patient with unilateral camptodactyly, absent flexion crease, and limited forearm supination. Severe pronator quadratus aplasia of affected forearm was observed through magnetic resonance imaging MRI; Fig C. For thet al, MET; c.G2074A (Refseq NM_006019) in TCIRG1 (MIM:604592). By using Sanger sequencing, we excluded the SNV on TCIRG1 because MET c.A3701G turned out to be the only one which co‐segregated with disease phenotypes in this family  mutant mouse model was constructed. No homozygous newborns were found. The ratio of homozygous embryos started to decline since E14.5, and E16.5 was the latest time that homozygous embryos could survive, which was consistent with Met null mutants  and Met was assessed in embryonic limbs and dermomyotome at the end of migration (E10.5). In dermomyotome, heterozygous and homozygous embryos showed more Pax3‐positive (Pax3+) and Met‐positive (Met+) cells than wild types  homozygous embryos were lower than that of wild types  were studied. The body size and weight of E16.5 embryos decreased in heterozygotes and homozygotes  in European and North American populations . Sequences were generated on a HiSeq PE150 (Illumina). Base calling was performed, and raw sequencing read files were generated in FASTQ format. Subsequently, the sequenced reads were aligned to the reference human genome . SeattleSeq Annotation 150 (version 9.10) was used to perform the annotation. Various databases, including dbSNP database, 1000 genomes, Mutation Taster, Polyphen‐2, and SIFT, were used to predict and filter mutations. Data analysis was performed as given below: Exome capture was performed using an Agilent SureSelect Human All Exon Kit and sequences were generated on HiSeq PE150. After mapping to the human reference genome , an average of 99.3% of reads were mapped and a sequencing depth per target base of 168 times on average was provided, with at least 20 times for 99% of bases. More than 154,876 SNVs per individual were identified. We first chose variants that were shared by the four affected individuals but not present in the unaffected individual. We found 5,350 such variants. Next, to identify potentially pathogenic variants, we annotated those variants and filtered out synonymous variants, non‐coding variants, intergenic variants, and variants located in introns, retaining those affecting splice sites. We then parsed a total of 1,441 variants and kept only those that were novel in dbSNP.Mut), and Vector plasmids were expressed in a 293T cell expression system. Forty‐eight hours post‐transfection, cells were treated with 10 ng/ml recombinant human HGF  for 1 h. As previously reported . Lysates were incubated with 20 μl anti‐Flag affinity agarose  overnight at 4°C. Beads containing affinity‐bound proteins were washed seven times with 5 ml wash buffer  and collected by centrifugation. Samples were subjected to SDS–PAGE and immunoblotting analysis after the addition of 30 μl of sample buffer  and denaturation. The following antibodies were used: 1:1,000 dilution of anti‐Phospho‐Met (Tyr1234/1235) antibody , 1:1,000 dilution of anti‐Phospho‐Met (Tyr1349) antibody , 1:500 dilution of anti‐Phospho‐Met (Tyr1356) antibody , 1:2,000 dilution of anti‐GAPDH antibody , and 1:1,000 dilution of anti‐FLAG antibody .Flag‐tagged MET, p.Y1234C mutant MET .Flag‐tagged MET/METMet gene  is located on mouse chromosome 6, and human MET c. A3701G is identical to Met c.A3695G in mouse gene. Twenty‐two exons have been identified, with the ATG start codon in exon 3 and TGA stop codon in exon 22. The Tyr1232 is located on exon 20. Exon 20 was selected as a target site. MET gRNA targeting sequencing 5′‐GCTTGGCACCCGTCTTGTTGTGG‐3′ and donor oligo were designed. The Tyr1232Cys (TAC to TGC) mutation sites in donor oligo were introduced into exon 20 using homology‐directed repair. A silent mutation (GTC to GTA or ACG to ACT) was also introduced to prevent the binding and recutting of the sequence by gRNA after homology‐directed repair. Cas9 mRNA, gRNA generated by in vitro transcription, and donor oligo were co‐injected into fertilized eggs for KI mouse production.The mouse Tissues from E14.5, E16.5, and P0 mice were dissected and fixed in 4% paraformaldehyde overnight, dehydrated, and embedded in paraffin. Sections for histological analysis were rehydrated and stained with hematoxylin‐eosin. Immunofluorescence was performed with Histostain‐Plus Kit . Primary antibodies included: 1:400 dilution of anti‐myosin antibody ; 1:200 dilution of anti‐Ki67 antibody . Detection was conducted using 1:1,000 dilution of anti‐mouse IgG fragment, Alexa Fluor 555 conjugate , and 1:1,000 dilution of anti‐rabbit fragment, Alexa Fluor 555 conjugate . Nucleus was stained by DAPI in a final concentration of 0.1 μg/ml . TUNEL assay was performed according to the manufacturer's instructions . Quantification of Ki67‐positive rate and TUNEL‐positive rate was conducted using ImageJ (version 1.51) software.Transmission electron microscope analysis was performed on the gastrocnemius in standard fashion. Ultra‐thin sections were stained with uranyl acetate and lead citrate, and then examined using a Tecnai transmission electron microscope (FEI) operated at 80 kV.In situ hybridization using RNAscope probes was performed on E10.5 mouse embryos. Embryos were fixed with 4% paraformaldehyde for 24 h at 4°C, dehydrated, and embedded in paraffin. Tissue sections were washed twice with PBS for 5 min, followed by incubation in hydrogen peroxide  for 10 min at room temperature, boiling in target retrieval  for 15 min. After target retrieval, slides were briefly washed with distilled water and incubated for 30 min at 40°C with Protease Plus . Following all pretreatments, the manufacturer's protocol for RNAscope 2.5 HD Detection Kit‐Brown  was followed to hybridize probes and detect the signals. The following probes were used: RNAscope Probe‐Mm‐Pax3 ; RNAscope Probe‐Mm‐Met ; RNAscope Negative Control Probe‐DapB ; and RNAscope Positive Control Probe‐Mm‐Ppib .post hoc test for multiple comparisons. The positive rates of Ki67‐ and TUNEL‐labeled cells were analyzed using the chi‐square test (χ2 test). All statistical analyses were conducted with the SPSS (version 19.0) statistical software. The level of statistical significance was set at P < 0.05. See P‐value in each experiment.All quantitative data are here presented as mean ± standard deviation (SD). Statistical analysis of body weight of transgenic mice was performed using one‐way ANOVA followed by Dunnett's Written informed consent was obtained from all subjects or, in the case of children under 16 years of age, their parents. Collection and usage of patient samples for this study were approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat‐sen University. All procedures in studies involving human participants were performed in accordance with the principles set out in the WMA Declaration of Helsinki and the Department of Health and Human Services Belmont Report. Transgenic mice were raised in the laboratory animal center of Sun Yat‐sen University, and all animal experiments, housing, and husbandry followed the operating procedures approved by the Institutional Animal Care and Use Committee of Sun Yat‐sen University.PS designed the experiments. HZ, CL, XY, SZ, ZL, TZ, CX, and XH conducted the experiments. TW, DS, XQ, XW, YL, BG, and YC raised transgenic mice. HZ and CL analyzed the data and wrote the manuscript. DH, GY, QF, and CG helped with the replication studies.The authors declare that they have no conflict of interest.Arthrogryposis is a group of disorders characterized by congenital contractures of two or more joints, and it affects about 1/3,000 newborns. As a group of phenotypically and genetically heterogeneous disorders, the underlying molecular etiology and mechanism remain unknown in a large number of cases of arthrogryposis.MET p.Y1234C mutation was found to be responsible for arthrogryposis in a four‐generation pedigree. In vitro study showed that MET p.Y1234C mutation caused dysfunction of the phosphorylation and tyrosine kinase activity of MET protein. A Met p.Y1232C mutant (corresponding to MET p.Y1234C mutation in human beings) mouse model was constructed, and the phenotype of homozygotes was identical to Met null mutant mice, including embryonic lethality and complete loss of muscles that originate from migratory precursors. Heterozygous mice were born alive and showed reduction of myofibers in both appendicular and axial muscles. Further study demonstrated that the defective migration of muscle progenitor cells and impaired proliferation of secondary myoblasts were responsible for the muscular dysplasia in mutant mice.In the present study, MET mutation and skeletal muscle dysplasia in human beings.This is the first study to report MET to be a disease‐causing gene of arthrogryposis. We showed that arthrogryposis could be caused by the reduction of myofibers around the affected joints. Our study is also first to demonstrate a direct relationship between The URLs for data presented in this article are as follows:(i)http://www.omim.org/OMIM, (ii)http://www.ncbi.nlm.nih.gov/projects/SNP/dbSNP, (iii)http://snp.gs.washington.edu/SeattleSeq Annotation 150, (iv)http://genome.ucsc.edu/NCBI Build 37, hg19, (v)http://www.1000genomes.org/1000 genomes, (vi)http://www.mutationtaster.orgMutation Taster, (vii)http://genetics.bwh.harvard.edu/pph2Polyphen‐2, (viii)http://sift.jcvi.org.SIFT, (ix)https://www.ncbi.nlm.nih.gov/clinvar/Clinvar dataset, AppendixClick here for additional data file.Expanded View Figures PDFClick here for additional data file.Table EV1Click here for additional data file.Source Data for Expanded ViewClick here for additional data file.Review Process FileClick here for additional data file.Source Data for Figure 1JClick here for additional data file.


A composite concrete column with encased fiber reinforced polymer (FRP) confined concrete cores (EFCCC) is proposed in this paper. The cross-sectional form of the EFCCC column is composed of several orderly arranged FRP confined concrete cores (FCCCs) surrounding a filled core concrete. This novel composite column has several advantages, such as higher compressive capacity, stronger FRP confinement, and ductile response. The compressive experiment is employed to investigate the compressive behavior of the EFCCC column with deferent parameters, such as outside concrete and stirrups. Test results show that the main failure mode of the EFCCC column with and without an outside concrete or stirrups is tensile fracture of the glass fiber reinforced polymer (GFRP) tubes. Compared to a reinforced concrete (RC) column, the strength and ductility of the EFCCC column was obviously improved by 20% and 500%, respectively. A finite element model (FEM) based on the Drucker–Prager (D-P) was developed that can accurately predict the axial compression behavior of the composite column with FRP confined concrete core. The predicted results obtained by using this FEM have excellent agreement with the experimental results. Currently, in regard to modern engineering structures, carrying capacity and deformation properties are in great demand . In the Nowadays, FRP composites are often used to reinforce existing concrete members, such as beams and columns for building structures, and many researchers investigated the performance of reinforced concrete beams and columns with FRP ,5,6,7,8.More recently, researchers have focused on the concrete-filled FRP tube (CFFT) with circular section for new structures in civil engineering construction. A number of investigation show that FRP confinement is very effective for circular columns ,12. The In fact, square and rectangular columns have a wide range of applications in building structure construction. It is now well recognized that square and rectangular tubes provide less effective confinement than circular tubes . TherefoIn this paper, a novel hybrid column shown in  named en(1).The FCCCs were poured in the factory and transported to the laboratory;(2).The stirrups were tied into a skeleton (for specimen T8) or the position of the prefabricated steel end-plate was fixed (for specimen T8N);(3).The FCCCs were placed into the skeleton of the rebar (for specimen T8) or steel end-plates (for specimen T8N);(4).b×h), height (H) and tube quantity, are shown in The concrete was poured into the specified location. The detailed parameters, including the size , according to the code for the design of concrete structures GB50010-2010 ; the exp−3 were installed at the top-height facing the load header to measure the axial deformation , which can be obtained using the method presented in uN), initial stiffness (k1), and hardening stiffness (k2), are shown in γ (uN/yN) and μ (ue/ye), are also summarized using the methods presented in γ and μ represent the ratio of the peak load to the yielding load and the ratio of the corresponding displacements, respectively. Thus, ye and ue are the corresponding axial displacements. The axial stiffness of a column is defined as the slope of the load-displacement curve. The axial stiffness k1 is given by Equation (1), while k2 is given by Equation (2) through the method proposed by Feng [The test results of all the columns, including the yielding load ( by Feng .(1)k1=NyN = 2600 kN and uN = 2990 kN), the yN and uN of specimen T8 increased by 7.7% and 20.1%, respectively. yN increased by only 7.7% because the yielding load of a column is mainly determined by the cracking of the concrete. Due to the presence of eight internal FCCCs, the bearing capacity of specimen T8 was greatly improved.Compared to specimen T0, which was manufactured by one-time monolithic pouring (yf and uf are introduced in this paper. The parameter yf is defined by Equation (3), and the parameter uf is given by Equation (4). The calculation results are shown The cross-sectional areas of the T8N specimens are different from the cross-sectional areas of specimen T0 and specimen T8. Therefore, to effectively compare the T8N specimens with specimen T0 and specimen T8, parameters yf and uf are the yielding stress and peak stress of a column, respectively; yN and uN are the yielding load and peak load of a column, respectively;A is the cross-sectional area of a column .yf = 36.49 MPa and uf = 46.79 MPa), the yf values of specimens T8N-1 and T8N-2 increased by 42.89% and 45.82%, respectively, and the uf values of specimens T8N-1 and T8N-2 increased by 44.56% and 48.72%, respectively. The yf values of T8 and T0 are almost the same due to invalid stress redistribution caused by the outside concrete while the effective stress redistribution induced larger yf values in T8N-1 and T8N-2. Compared to specimen T8 (k1 = 21.88 GPa and k2 = 0.7 GPa), the k1 values of specimens T8N-1 and T8N-2 decreased by 14.0% and 13.4%, respectively, and the k2 values of specimens T8N-1 and T8N-2 decreased by 2.9% and 10.0%, respectively. Compared to specimen T8 , which indicates the ratio of the peak load uN to the yielding load y.N This ratio is calculated by Equation (5).To evaluate the increase in load during the hardening stage, the ratio γ for different specimens are shown in The results of μ is the ductility ratio, ue corresponds to the maximum displacement, and ye represents the yielding displacement.Ductility is an important characteristic of evaluating structural deformability. In this study, the method of ductility calculation that was defined in  was usedue of the EFCCC column is based on the displacement corresponding to the peak load. The ductility coefficient of each specimen is derived from Equation (6) and is listed in The maximum displacement fl and ultimate strength of FCCC φ=0.0After using the calculation methods for the strengths of unconfined concrete, confined concrete, FRP tube, and steel , the strThe following variable definitions were used in the equations above:ybN and ycN represent the yielding strength of specimen T8 and the T8N specimens, respectively;ubN and ucN represent the ultimate strength of specimen T8 and the T8N specimens, respectively;Ac1, Ac2 and Ac3 represent the cross-sectional areas of concrete “Core concrete”, concrete “Filled concrete” and concrete “Outside concrete”, respectively, in fA and sA represent the cross-sectional areas of the FRP tube and longitudinal bars, respectively;σfa and sf represent the cross-sectional stress of the FRP tube and longitudinal bars, respectively.yN and Nu are the experimental results and yNT and NuT are the theoretical results. Note that “Avg” indicates the average value.The simulations of all the experimental tests all performed by using ANSYS, which is a commercial finite element program. Four-node shell41 elements, which are 3-D elements that have membrane (in-plane) stiffness but no bending (out-of-plane) stiffness, were used for the GFRP tubes, two-node link180 elements were used for the rebar, and eight-node solid65 elements that are capable of cracking , crushing, plastic deformation, and creep were used for the concrete.Direct tests of the concrete, rebar, and GFRP tubes were conducted before the study. To accurately predict the behavior of the concrete, the actual stress–strain relationships of unconfined concrete and rebar were used in the finite element model. Moreover, a constitutive model that adaptively considers the surrounding pressure provided from the tubes is essential for the FEM. A critical review and assessment shows that the Drucker–Prager (D-P) plasticity model can successfully predict the behaviors of FRP-confined and other passively confined concrete ,33,34. Tk1 is the confined effectiveness factor, which Teng suggested should be set as 3.3 [The cohesion and angle of the internal friction for concrete can be calculated by Equations (17) and (18).t as 3.3 . The estThe comparison of the failure modes of the tube obtained from experiments and finite element (FE) analysis is shown in yN) and ultimate axial compressive load (uN) were computed by the model proposed above. The load-displacement curves of EFCCC columns obtained from the FE analysis have good agreement with that obtained from experiments and is shown in ue) values of specimens T8 and T8N, which the model calculated to be 7.2 mm and 9.7 mm respectively; this inaccurate prediction was caused by the non-convergence of the outside unconfined concrete. The predicted results of the specimens are presented in yN by the proposed FEM was 6.0%. The mismatch between the marked blue circular area in uN was 222.5 kN, which occurred in specimen T8. No average error existed between simulated and experimental results in uN. The predicted yield load .The reduced bearing capacity of the EFCCC column is dominated by the fractures of corner tubes, and the sequential failures of the other tubes. The mechanical behavior of the EFCCC column consists of three distinct stages, namely, the first linear stage, the yielding stage, and the hardening stage.(2).yf) values of the T8N specimens increased by 42.89%, and the average peak stress (uf) values increased by 44.56%. These findings can be interpreted as the stress level of the unconfined outside concrete is much lower than that of the filled concrete and the core concrete. Compared to RC column, the ductility of the EFCCC column is increased by a factor of 5, and the ratio of the peak load to the yield load is also increased by a factor of 1.28–1.31, due to the effective stress redistribution caused by the built-in FCCCs.Compared to specimen T8, the average yielding stress ((3).An analytical model that considers the effect of the slenderness ratio on the internal FCCCs of the column was developed to predict the axial behavior of the EFCCC column. The analytical predictions were generally in good agreement with the experimental results.(4).A finite element model based on the D-P model was developed that considers nonrelated flow and hardening rules and has a satisfactory degree of agreement with the experimentally determined peak load, yielding load, and the peak load to yielding load ratio; however, the model did not accurately predict the yielding load and peak load of specimen T8N because the D-P model, which is the ideal plastic model, does not consider the cracking and damage of concrete. In future studies, many experiments with variable parameters should be conducted for the purpose of more meaningful results regarding EFCCC column.A new type of composite column, which is referred to as a composite concrete column with encased FRP confined concrete cores (EFCCC), was introduced and tested under compressive loading. The failure modes, axial load-displacement relationships, and axial stress–strain responses were determined. The failure modes and mechanical characteristics were investigated. To determine the overall mechanical behavior of the novel composite columns, finite element models based on the D-P model were proposed. The corresponding major conclusions are summarized as follows:To further understand the mechanical performance of EFCCC column and promote the utility of EFCCC column in building structure construction, the eccentric behaviors of EFCCC column should be investigated. The theoretical analyses and FEM based on the D-P model in this paper could be a reference to investigate the mechanical characteristics of EFCCC column under eccentric load.


The nature of abstract and concrete semantics and differences between them have remained a debated issue in psycholinguistic and cognitive studies for decades. Most of the available behavioral and neuroimaging studies reveal distinctions between these two types of semantics, typically associated with a so-called “concreteness effect.” Many attempts have been made to explain these differences using various approaches, from purely theoretical linguistic and cognitive frameworks to neuroimaging experiments. In this brief overview, we will try to provide a snapshot of these diverse views and relationships between them and highlight the crucial issues preventing this problem from being solved. We will argue that one potentially beneficial way forward is to identify the neural mechanisms underpinning acquisition of the different types of semantics , which may help explain the distinctions found between the processing of concrete and abstract semantics. HoweverResearch of concrete and abstract concepts has a long history; a landmark event in its modern period was Paivio’s seminal article “Abstractness, imagery, and meaningfulness in paired-associate learning” . NumerouNotably, some investigations showed that concrete words elicit faster responses in lexical decision task only when there is no context information helping to understand the meaning; when context is available, the concreteness effect is reduced or absent . These oA similar view on the distinctions between concrete and abstract words suggests that they are represented in mind in qualitatively different ways . This hyOther cognitive frameworks, rather than stressing the differences between abstract and concrete processing mechanisms, focus on searching for their similarities. For instance, the embodied cognition view on language grounds semantic representations in bodily functions  and proposes that abstract word processing, in the same way as that of concrete words, relies, at least in part, on sensorimotor systems . This, hIn cognitive linguistics, a somewhat similar approach is offered by the so-called conceptual metaphor theory (CMT), an influential theoretical framework, according to which abstract concepts may be understood in reference to more concrete words by using metaphors . Howeverlove, joy, fear) as a kind of abstract concepts ; further, this may depend on a person’s individual experience. To put it differently, it is uncertain why, in the win or jeopardy were included into the group of abstract words while daughter and dentist were treated as concrete words, even though their meaning clearly carries emotional aspects.One theoretically contentious issue in accounting for concrete and abstract features of word semantics is that of a relationship between “concreteness” and “emotionality”. Many authors consider words connected to emotions , or, to address causality, using neurostimulation techniques  and/or brain-damaged patients. Neuropsychological data indicate that concrete words are more resistant to different brain injuries than abstract ones , suggestHowever, there are still multiple contradictions across available neuroimaging studies , which hThere are virtually no studies of concrete vs. abstract semantics using brain stimulation techniques , with only a handful of TMS papers that suggested prefrontal and motor areas to take part in abstract word comprehension e.g., . One wayClinical data distinguishing between abstract and concrete concepts are extremely rare. While there are some cases (“case studies”) of specific impairments in abstract or concrete concept comprehension, separately, they are based on very limited observations ranging from one to four patients at most . FurtherWhereas cognitive accounts of semantic representations, abstract semantics in particular, have gone a long way in recent decades, their neural counterparts so far suffer from the lack of studies and contradictions in the available data. The reasons for these contradictions could be many and include different properties of stimulus materials used, stimulation parameters, imaging modalities, and experimental tasks. One key difficulty lies with balancing basic psycholinguistic and physical properties of abstract and concrete words under investigations in a particular study; the lack of such balance confounds any differential results. A related issue that appears important is that most studies deal with pre-existing representations that are confounded by their surface properties, previous learning trajectories, daily use, and existing associations, all of which may obscure the results. In addition, the concrete-abstract dichotomy may not be complete and more fine-grain distinctions have been suggested: for example, action-related and object-/visually related concrete words, mental state-, emotion-, and mathematics-related abstract words . Furtherprocess of acquisition of novel concrete and abstract semantics in laboratory settings, using stimuli with fully controlled and systematically modulated semantic, physical and psycholinguistic parameters. By observing the learning process behaviorally and its counterparts in the brain, it may be possible to elucidate the systems that take part in building up novel representations and the degree to which they differ between semantic types. To avoid confounds related to different modes of acquisition of abstract and concrete semantics, the learning regime should be maximally matched between semantic conditions, using, for instance, context-based inference or direct instruction   or unfamper se . This, ign words .There is still a predominance of studies dedicated to investigation of learning mechanisms of concrete rather than abstract semantics; they are targeted more often owing to their more obvious link with sensorimotor experience  that lenOn another note, most available studies use correlational measures, e.g., showing distinct activation patterns accompanying perception. Clearly, causal evidence is also needed to demonstrate functional relevance of such distinctions. Outside of limited patient studies, such evidence is presently lacking. The use of neurostimulation techniques (such as TMS or tDCS) to influence both comprehension and acquisition of concrete and abstract semantics may provide the much-needed evidence for the involvement of particular brain areas in representing specific semantic types. For example, To conclude, the literature suggests cognitively and neurophysiologically distinct systems that support abstract and concrete representations in mind and brain. Yet, the data available to date, particularly with respect to abstract semantics, do not allow for clear delineation of the underlying brain systems and thus explaining the effects found behaviorally. To fill these gaps in the field, future studies should use a combination of rigorously matched behavioral regimes, controlled modes of presentation, a comprehensive set of tasks to assess behavioral outcomes at different times, and different neuroimaging tools able to assess both the complex dynamics of word comprehension and the causal relationships between brain structures and representation types. One way to help disentangle the mechanisms underpinning different semantic representations is to focus on their acquisition in controlled experimental settings.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.


Qualitative work has described the differences in prescribing practice across medical and surgical specialties. This study aimed to understand if specialty impacts quantitative measures of prescribing practice.We prospectively analysed the antibiotic prescribing across general medical and surgical teams for acutely admitted patients. Over a 12-month period (June 2016 – May 2017) 659 patients  were followed for the duration of their hospital stay. Antibiotic prescribing across these cohorts was assessed using Chi-squared or Wilcoxon rank-sum, depending on normality of data. The t-test was used to compare age and length of stay. A logistic regression model was used to predict escalation of antibiotic therapy.p < 0.001) with lower Charlson Comorbidity Index scores (p < 0.001). Antibiotics were prescribed for 45% (162/362) medical and 55% (164/297) surgical patients. Microbiological results were available for 26% (42/164) medical and 29% (48/162) surgical patients, of which 55% (23/42) and 48% (23/48) were positive respectively. There was no difference in the spectrum of antibiotics prescribed between surgery and medicine (p = 0.507). In surgery antibiotics were 1) prescribed more frequently (p = 0.001); 2) for longer (p = 0.016); 3) more likely to be escalated (p = 0.004); 4) less likely to be compliant with local policy (p < 0.001) than medicine.Surgical patients were younger  between general surgical and medical teams. Antibiotic stewardship interventions targeting surgical specialties need to go beyond surgical prophylaxis. It is critical to focus on of review the patients initiated on therapeutic antibiotics in surgical specialties to ensure that escalation and continuation of therapy is justified. Evidence suggests that a large proportion of antibiotic prescribing in hospitals may be inappropriate –3. OptimThis study was conducted across general medical and general surgical teams in one of the five hospitals of a university affiliated Healthcare NHS Organisation, in London. The hospital selected had the largest Emergency Department (ED) and the highest annual turnover of patients. The hospitals have an established, multidisciplinary antimicrobial stewardship programme (ASP). Studies across the hospitals have previously demonstrated a 10% difference in compliance to the local antibiotic policy between medical and surgical teams, with medical teams demonstrating a higher rate of concordance [A power calculation for two independent study groups with a dichotomous primary endpoint was carried out . Using pBetween June 2016 – May 2017 adult patients (aged ≥18 years) admitted to the medical and surgical teams and prescribed empiric antibiotics other than for prophylaxis were eligible to be included in the study. Data were collected from each ward on alternate weeks. Patients were prospectively identified on qualitative observations of acute ward rounds as part of a mixed methods study [This study had a prospective cohort design. The reference group were the medical cohort and the comparison group were the surgical cohort. An accurate assessment of the appropriateness of the prescribed antibiotics requires real-time infectious diseases consultations in parallel to the care provided by the respective teams. In the absence of being able to measure appropriateness, the primary outcome measures selected in this study were compliance to the local antibiotic policy, and changes to antibiotic prescriptions . The secondary outcome measures were, duration of antibiotic prescriptions, length of hospital stay, use of microbiology and radiology to guide therapy, and 30-day readmission. Patient demographics, antibiotic prescriptions and corresponding indications, and inflammatory marker results were obtained from the patient notes. One researcher (EC) collected all the data. A single reading of white cell count, C-reactive protein, and temperature, closest to the time of initiating antibiotic therapy were recorded. Procalcitonin is not routinely tested for patients in this hospital. The International Classification of Diseases, tenth revision (ICD-10) coding was used to calculate the age-adjusted Charlson comorbidity index (ACCI) for subjects . ComorbiClostridium difficile infection.The antibiotic exposure days were measured as the number of days that a patient received one or more systemic antibiotics. The cumulative antibiotics days, where multiple antibiotics prescribed on the same day were counted as multiple antibiotic days, was also measured. Cumulative antibiotic exposure days has been used previously , regardiAntibiotics were ranked in ascending order according to their relative activity against drug-resistant organisms Table 1)1).TableChanges made to prescribed antibiotics were classified, using published criteria . EscalatWas the indication documented on the electronic chart or the medical notes?Did the indication have a matching recommendation in the policy?If there was no recommendation in the policy, was there any infection team input?The following criteria were used to assess whether the antibiotics prescribed were compliant with local empiric policy:For cases where the indication was missing or vague e.g. ‘for infection’, this variable was labelled as unclear. The reason for having an unclear category as opposed to missing data was to identify cases where the antibiotic prescription had been prescribed and no indication recorded in the notes or the medication chart. One of the requirements of the policy is that for all therapeutic courses of antibiotics, there should be an indication recorded. If antibiotic therapy did not match the recommendation in the policy for the recorded indication, and there was no infection team input, it was labelled as non-compliant.p ≤ 0.05. The length of stay and ACCI were tested in the regression model as both continuous and categorical variables. In both cases, the scaling (i.e. variable) type with the best fit was categorical. In the final analysis, these two variables were fitted as categorical.The analysis was carried out using Stata,  version 13.1. Variation in the descriptive variables between the cohorts was assessed using Chi- squared or Wilcoxon rank-sum, depending on normality of data. An independent t-test was used to determine if there were statistical differences in the age and length of stay of patients in the cohorts. We created a logistic regression model to understand the predictors of antibiotic prescribing  and see whether there were differences between the two groups after adjusting for these. Escalation was the measure used in the model as deviations from policy can often have a legitimate reason, and hence compliance to policy was not deemed an appropriate measure of the quality of antibiotic prescribing. The variables specialty, length of stay, ACCI, positive chest X-ray and microbiological results were selected as predictors based on existing literature and discussions with the clinicians . The lenAll subjects had complete data for the variables included in this study. The teams admitted 659 patients (362 in medicine and 297 in surgery) during the study period Fig. . One surAt the time of initiating antibiotics, a normal white cell count was present in 76/162 (47%) of medical, and 52/164 (32%) of surgical patients (Table p = 0.507) in the spectrum and rank of antibiotics that the medical and surgical patients were exposed to during their stay.There were 395 antibiotic prescriptions in medicine and 461 in surgery. These included the same antibiotic given by a different route or on different occasions to the same patient in the same admission spell. Of the prescribed antibiotic courses, 200/395 (51%) of medical, and 395/461 (86%) surgical were intravenous. Over half, 90/162 (56%) of medical patients were initiated on antibiotics for a respiratory infection (Table p = 0.0553 (Table p < 0.001). Thirty-day readmission to hospital was significantly higher in medicine versus surgery (p < 0.001). There was no difference (p = 0.977) in mortality during the admission episode in the two groups. Monotherapy, was more likely (p < 0.001) in medicine than surgery, with 36/162 (22%) vs. 12/164 (7%), of patients being treated with one course of antibiotics during their stay, respectively (Table 4). Surgical patients had 50/164 (30%) cumulative antibiotics days equal to or greater than 15, compared with 22/162 (15%) medical patients (p = 0.016). Escalation of the initial antibiotic therapy was more likely in the surgical patients than in medical patients, with 49/164 (30%) therapy escalations in surgery compared with 31/162 (19%) in medicine (p = 0.0037).The mean length of stay was 11 days (±1.21) in medicine, 16 days (±1.87) in surgery, t 324), 24, p = 0p < 0.001) in compliance to policy between medicine  and surgery  (Table The lack of a documented indication for prescribed antibiotics made it difficult to assess the compliance to policy for 21/164 (13%) patients in surgery. When included as a three-category variable (Yes/No/Unclear) there was a statistically significant difference  of patients underwent an operation during their stay. Having an operation (reference set as not having an operation) was associated with increased odds of escalation of antibiotic therapy  in the surgical cohort, although this was not statistically significant. In the fully adjusted logistic regression model the odds ratio of antibiotic therapy escalation in surgical patients remained significantly higher compared to medicine . Comorbidity, culture and sensitivity results and signs of infection on chest X-ray did not significantly affect the odds of therapy escalation in the regression model. There was a statistically significant association between length of stay and escalation of therapy  were prescribed antibiotics in the absence of raised white cell count or a fever. There is no difference in the spectrum of antibiotics prescribed between medicine and surgery. Surgical patients are significantly more likely to a) receive a greater number of courses of antibiotics; b) have their initial therapy escalated; and c) be on a course not in line with local policy. There are opportunities to widen the reach of ASP and focus on perioperative care, focusing on the review of antibiotic prescriptions in the post-operative phase.


Limitations of optical devices for motion sensing such as small coverage, sensitivity to obstacles, and privacy exposure result in the need for improvement. As motion sensing based on radio frequency signals is not constrained by the limitation above, channel state information (CSI) from Wi-Fi devices could be used to improve sensing performance under the above circumstances. Unfortunately, CSI phase cannot be practically obtained due to the temporal phase rotation generated from Wi-Fi chips. Therefore, it would be rather complicated to realize motion analysis, especially the direction of motion. To mitigate the issue, this paper proposes a CSI calibration method that employs a back-to-back channel between Wi-Fi transceivers for phase rotation removal while preserving the original CSI phase. Through experiment, calibrated CSI showed a high similarity to the channel without phase rotation measured using a Vector Network Analyzer (VNA). Another experiment was conducted to observe Doppler frequency due to simple hand gestures using the Wavelet transform. A visual analysis revealed that the Doppler frequency of calibrated CSI could correctly capture the motion pattern. To the best of the authors’ knowledge, this is the first calibration method that maintains the original CSI and is applicable for in-depth motion analysis. Currently, technology in human-computer interaction (HCI) is moving toward the contactless interface where users could communicate with any computing devices by merely performing a particular gesture in the air. Some vision-based motion sensing systems have already been commercialized such as Kinect, Leap Motion, and Orbbec. Although these systems promise high tracking accuracy and precision, it unavoidably has to deal with the physical limitation of the optical device. For example, it has small active sensing area which highly depends on the focal length of the lens, operates only in the presence of line-of-sight (LoS) between device and user, and might raise a concern in privacy exposure issue ,2,3. TheWith respect to recent works in the extraction of channel state information (CSI) from the physical layer of commodity Wi-Fi network interface cards (NIC) ,13, whicAs a consequence, performing any motion analysis is infeasible without separation of the phase rotation from the CSI. Besides, spatial mapping (SM) and cyclic shift diversity (CSD) modulated in the transmitter may remain attached to the extracted CSI when operating in multiple transmit streams configuration ,24. HencIn order to effectively suppress the phase rotation without contaminating the CSI, we introduce a calibration method by using a back-to-back (b2b) channel in this paper. Furthermore, this technique also can remove SM and CSD matrices without requiring their knowledge in the process and thus returning the channel matrix without distortion. For validation, the experiment was performed to compare between the calibrated CSI with the channel measured using a Vector Network Analyzer (VNA) as ground truth. The results have successfully shown a similarity of the CSI phase component relative to the ground truth albeit with the constant residual phase offset. After removing the constant residual offset, the CSI phase closely resembled the result from the ground truth with a root-mean-square error (RMSE) of approximately 0.117 radians. Another experiment was conducted to observe the Doppler frequency of hand-waving gesture using the calibrated CSI. A bell-shaped profile due to the gesture was observed as the higher power spectrum in the time-Doppler domain. Furthermore, the relative motion direction was also correctly detected from the sign of Doppler frequency according to the bistatic Doppler model . We beliThe rest of the paper is organized as follows: the basic concept of channel state information and the time-varying phase rotation model are addressed in t. The wireless channel at each subcarrier frequency k represents subcarrier frequency index ranging from Z. In a nutshell, the CSI is physically a collection of Wi-Fi OFDM signals getting attenuated, faded, and scattered by interacting objects (IOs) during propagation which can be modeled as, L are wavelength at subcarrier frequency index k, complex attenuation for l-th path, and a set of paths which signal propagate with the length of l-th path signal only interacts with stationary IOs. However, the interaction with the moving IOs will cause the variation of complex attenuation Multiple-input multiple-output (MIMO) transmission and beamforming have been introduced in many wireless communication systems in order to improve data transmission rate and reliability. They require a knowledge of real-time CSI to perform spatial multiplexing and diversity techniques. Therefore, a CSI frame has been included in the physical layer (PHY) of Wi-Fi systems since the IEEE 802.11n standard, specifically training symbols in the high throughput long training field (HT-LTF) preamble format . Wi-Fi ucy shift  which wi−jϕ  as shownThe dynamic component consists of a set of signals propagated via In the case of MIMO configuration, each OFDM symbol standard  as shownRegarding the IEEE 802.11n standard, there are two methods to obtain CSI depending on where CSI estimation is calculated. Considering a scenario where transmission is initiated at ST1 Wi-Fi transmitter which sends a signal tive CSI ,24, (4)HFor instance, an open-source Linux 802.11n CSI tool developed by  used theThe phase component of CSI is the most significant feature for motion detection analysis. This is because when there is any motion, the set of signal that interact with these dynamic IOs will physically experience change in their propagation paths. Specifically, Equation  keeps chThe sources of phase rotation have been widely discussed throughout CSI phase related literature. There are at least four sources listed below that contribute to CSI phase information.Carrier frequency offset (CFO) [et (CFO) ,37,38,39Sampling frequency offset (SFO) [k.et (SFO) ,38,39,40Packet boundary delay (PBD) [ay (PBD) ,37,39,40Phase-locked loop offset (PLO) [et (PLO) ,36,37 phThe time-varying phase rotation entirely ,36. As cThe goal of our CSI calibration method is to virtually subdue phase rotation and maintain original CSI in both the amplitude and phase components. The calibration should be able to analytically explain the effect of movement in a target CSI which is assumed to be the measured channel This calibration, however, does not consider the effect of SM and CSD, so Equation . In factRegarding the practical reference CSI for the implementation of our calibration method, the previous works of using CSI amplitude and the phase difference approaches also use the concept of reference CSI where the target CSI itself and the CSI measured from different antenna port are treated as the reference respectively. As it was mentioned in Equation . MoreoveEquation  can be sIt is now clearly seen from the equation above that the calibration preserves CSI and removes the phase rotation term though with a constant scaling in amplitude and phase shifting by Equation  was condv within a short period To understand clearly how the presence of moving IOs influences signal propagation paths geometrically, this motion effect is explained in terms of the bistatic Doppler radar system. This radar system is commonly used for speed and position estimation of moving objects from the reflected RF signal between a transmitter and receiver separated by the length of baseline rding to ,41, the This equation evidently explains the effect of motion perceived by the reflected RF signal which depends not only the object’s speed and RF frequency but also the relative position with respect to the transmitter and receiver. The sign of Doppler frequency mostly depends on t from Bistatic Doppler model in Equation  could beu with scale a which is inversely proportional to the center frequency of Although using the Fourier transform allows the analysis of overall Doppler spectrum in rinciple ,44. As aanalysis ,46,47.This section explains the details of the experimental setting and phase rotation mitigation performance of the CSI calibration method explained in A testbed was implemented on commercial equipment. Two laptops equipped with Intel 5300 802.11n MIMO Wi-Fi NICs were used as Wi-Fi stations. Commercial Wi-Fi 6dBi-omnidirectional antennas operating in both 2.4 GHz and 5 GHz bands were externally connected to the Wi-Fi NICs through a coaxial cable with 0.77 velocity factor and U.FL-to-SMA adapter cables. A Mini-Circuits ZFSC-2-10G 2-way RF power splitter/combiner was applied at the first transmit antenna for dividing the signal into the b2b channel where a 40dB-attenuator was inserted at the cable connected to the second receive antenna. For comparison, an E5071B VNA developed by Keysight Technologies (formerly known as Agilent’s Electronic Measurement), Santa Rosa, California, USA, was used as the standard for evaluating the performance of CSI after calibrating phase rotation. The The performance of our calibration method is determined based on how close the calibrated CSI to channel measured using the VNA which represented the CSI without phase rotations. Although there is virtually no phase rotation in VNA, the calibration method was also applied on the channel measured from the VNA for a fair comparison. In this experiment, measurement was conducted in the room without people (static environment) using both instruments within a 10-s period, and was repeated three times for reproducibility of the calibration. As it can be clearly observed in  methods ,22,29,30As it seems phase rotations are almost convincingly removed except for the residual PLO, it would be possible to compare the power delay profiles (PDP) of CSI which is simply the magnitude squared of channel impulse response. The Hanning window was multiplied with the channel before transformation to suppress the effect of the distorted subcarriers as well as the side lobes. As depicted in In this experiment, simple hand gestures were used for motion detection analysis performed at three marked points depicted in The measurement was repeated six times at each marked point for reproducibility. Since the results at the same point are similar, one of the measurements at positions A, B, and C were illustrated at the left side of model in  was condThis result could qualitatively confirm that the use of bistatic Doppler for motion analysis can be successfully achieved with calibrated CSI. Moreover, fine-grained or micro-motion detection may use this calibration model as a basis for further investigation. Although calibrated CSI does not remove the constant phase offsets from the residual PLO, it should not have any impact for motion analysis because any constant value will be added to zero Doppler frequency component during transformation. By comparison with related works, it would be difficult to produce correctly the Doppler frequency profiles as depicted in This paper first described how WI-Fi channel state information is estimated and the significance of spatial mapping and cyclic shift diversity to the additional shift of CSI phase which needs to be removed before further analysis. Secondly, a CSI calibration method was introduced to virtually remove time-varying phase rotation while preserving original phase information. The proposed technique uses a so-called reference CSI, a time-invariant channel that experiences the same phase rotation as the target CSI. Practically, a back-to-back channel representing a wired channel in the cable between transmit and receive antenna ports was selected as the reference CSI. Bistatic Doppler radar model was employed to describe the effect of motion as Doppler frequency in CSI.An experiment was conducted to validate the performance of our method by comparison with a channel measured by a VNA. The result showed that phase rotation was mitigated according to our propose CSI calibration model and portrayed a similar pattern but with a higher phase variation than the channel from the VNA. Although a constant phase offset possibly due to the residual of the PLO still existed after calibration, it should have small significant for CSI-based motion analysis as any constant would result in zero Doppler frequency. For a fair validation, we statistically removed the constant phase offset from the calibrated CSI. Promisingly, the data produced high correlation to the result measured using the VNA with approximately 0.117 radians RMSE phase error. Another experiment was carried out to observe the effect of hand waving on the calibrated CSI at three different locations. The movement profile was visualized in the time-Doppler domain after the CSI was Wavelet transformed. A bell-shaped pattern of Doppler frequency caused by the hand gesture was observed where the sign of Doppler which indicates the motion direction was correctly predicted according to the bistatic Doppler model and also agreed with the simulation result. To the best of our knowledge, this CSI calibration model is the solution to practically obtain Wi-Fi CSI without phase offset and thus allowing full use of the Wi-Fi channel for further in-depth CSI-based motion analysis.


IgG4-related disease (IgG4-RD) is an emerging immune-mediated disease characterized by multi-organ involvement and variable clinical behavior.We describe the case of a 50-year-old woman affected by a rare variant of IgG4-RD, characterized by eyelid xanthelasmas, adult-onset asthma and salivary and lacrimal glands enlargement. Multiple lymphadenopathies and a pulmonary mass were present at initial evaluation.After a single course of rituximab (2g in 2 refracted doses), an almost complete clinical remission was achieved without chronic steroid administration.Magnetic resonance imaging (MRI), high-resolution computed tomography (HRCT) of the thorax, and positron emission tomography (18FDG-PET-CT) confirmed good response to treatment. Circulating plasmablasts dropped to undetectable levels as well. Xanthelasmas only remained unchanged. Remission persisted at 1-year follow-up.Steroid therapy is still considered standard first-line therapy in IgG4-RD. However, high doses are generally required and relapses are common during the tapering phase. Rituximab is a well described steroid-sparing strategy, so far reserved to refractory cases only. In our experience, rituximab has been used as first-line monotherapy, showing great and sustained efficacy and optimal tolerability. The peculiar variant of IgG4-RD affecting our patient, the relatively low baseline plasmablast concentration, and the early placement of rituximab therapy may have facilitated the good response. From 2003 to nowadays, a common pathogenetic basis has been recognized for dozens of conditions previously considered as unique entities, changing their management. Recently, a syndrome known as adult-onset asthma and periocular xanthogranulomas (AAPOX), originally described as case series of 6 patients with asthma and xanthogranulomas, characterized by giant cells, lymphocytic, and plasma cells infiltration, has been included under the umbrella of IgG4-RD.–6IgG4-related disease can involve almost every tissue, leading to enlargements, fibrosis, and organ dysfunction.,8 Current approach is based on relevant doses of steroids (0.6 mg/kg/d) for 2 to 4 weeks, followed by a slow tapering. This protocol exposes patients to significant risk of relapses and side effects. Steroid-sparing agents, as synthetic immunosuppressive agents  or rituximab proved to be of benefit in not randomized studies.–12Despite accumulating evidence of effectiveness of therapeutic target molecules, corticosteroids remain the first-line treatment of IgG4-RD and AAPOX syndrome.However, monotherapy with rituximab as first-line treatment, in order to totally avoid steroid exposure and reduce relapses, has been attempted in very few cases with specific contraindication .We report the first case of a patient with IgG4-related AAPOX syndrome treated with rituximab as first-line therapy, without steroid, showing an excellent and sustained clinical and laboratory response.http://www.equator-network.org/reporting-guidelines/care).The article has been written according to the International Guideline for case-reporting CARE  and hydroxychloroquine 200 mg/d were ineffective. Therapy had been stopped 6 months before our observation due to inefficacy. In her past medical history a moderate asthma for few years, requiring treatment with long acting beta2 agents and inhaled steroids, was noteworthy. Physical examination revealed evident swelling of salivary and lacrimal glands and bilateral yellow eyelids xanthelasmas . Complete laboratory features are summarized in Table  After microbiological screening and informed consent, 1 cycle of 2 g rituximab (RTX) (1000 mg each 15 days apart together with methylprednisolone 100 mg single shot premedication) was administered. No chronic therapy was prescribed and no adverse effects were observed. Patient referred a rapid and complete improvement of exocrine glands swelling, and resolution of asthma, allowing bronchodilator therapy discontinuation, whereas xanthelasmas were still visible and unchanged. Remission persisted at the 12-months follow-up visit and was confirmed by MRI. Furthermore, neither the pulmonary lesion was visible at HRCT  stepped down from 14 to 6, serum IgG4 levels roughly halved and plasmablasts concentration became undetectable , where this pleiotropic disease was recognized as a systemic entity. complete response to the treatment, absence of neutrophils, and microorganisms in the bronchoalveolar lavage are elements of suspicion.Pulmonary lesions have not been described in AAPOX population so far. The lack of histological demonstration of tissue infiltration by IgG4 plasmacells makes attribution of observed lung nodule to the IgG4-RD uncertain. However, radiological appearance as solid nodular lesion, that is the most frequent pattern described in IgG4-RD,,6According to the standard therapeutic approach, all previously described AAPOX patients were treated with corticosteroids, mostly at high doses (1 mg/kg/d); in 3/5 cases low-dose methotrexate (2 cases) or rituximab was added due to relapse during steroid tapering.In our patient, in order to avoid potentially relevant steroid related side effects in a post-menopausal woman, we administered a RTX monotherapy. Remission of clinical signs and symptoms , disappearance of lung nodule, clear attenuation of 18-FDG uptake in lymph nodes followed the 2 g RTX single course. Only xanthelasmas remained unchanged. Remission persisted at the latest follow-up evaluation (>1 year).RTX for IgG4-RD showed evidence of efficacy in observational cohorts, when used in second-line regimens after steroid failure or to maintain remission. Two interventional clinical trials investigating RTX-steroid association are actually under way . These cells are responsible for inducing the differentiation of B cells into plasmablasts producing IgG or IgG4 both in the germinative center of lymph nodes and in follicular aggregates in affected tissues. Oligoclonal expansion of CD19+ CD20- CD38bright plasmablasts characterizes peripheral blood of these patients and correlates with serum IgG4 levels. Moreover the proportion of circulating plasmablasts, as well follicular helper T-cells, decreases when clinical remission can be achieved, re-increasing during relapse.,22 Therefore, flow cytometry may represent a useful tool for disease activity monitoring. Although CD20 negative, plasmablasts concentration is clearly affected by RTX treatment, maybe through depletion of CD20+ progenitors pool.RTX mechanism of action in IG4-RD is still under investigation, despite progresses achieved in understanding disease pathophysiology. Recent data highlight the pivotal role played by follicular helper T-cells (Tfh) infiltrating target tissues and lymph nodes.,21 However, in comparison to available data from IgG4-RD case series, plasmablasts concentration was located in the lower part of the range, reflecting the limited extension of systemic involvement. This finding may contribute to explain the surprisingly deep and persistent response to treatment, as seen in other immune-mediated diseases, where plasmablasts baseline level predicts response to rituximab.In our patient circulating number of plasmablasts was higher than usually measured in healthy population.IgG4-RD is a complex disease with high variability in clinical and biological behavior. A better understanding of underlying molecular mechanisms may contribute to improve risk stratification and could lead to a tailored treatment selection and monitoring.The authors warmy thank Dr Luca Butini for performing flow-cytometric analysis, Dr Giuseppe Garraffa, and Dr Fabio Fringuelli for their support to CT-PET scan interpretation and analysis.Conceptualization: Giovanni Pomponio, Diletta Olivari, Massimo Mattioli, Alessia Angeletti, Giulia Rossetti, Gaia Goteri, Armando Gabrielli.Data curation: Giovanni Pomponio, Diletta Olivari, Massimo Mattioli, Alessia Angeletti, Gaia Goteri, Armando Gabrielli.Formal analysis: Giovanni Pomponio, Diletta Olivari, Massimo Mattioli, Gaia Goteri, Armando Gabrielli.Funding acquisition: Armando Gabrielli.Investigation: Giovanni Pomponio, Massimo Mattioli, Gaia Goteri, Armando Gabrielli.Methodology: Giovanni Pomponio.Writing – original draft: Giovanni Pomponio, Diletta Olivari, Massimo Mattioli, Gaia Goteri, Armando Gabrielli.