Dynamics in complexes of porphyrin cage compounds and viologen‐derived guest molecules are investigated by selective exchange NMR spectroscopy (1D EXSY). Exchange rates were found to be independent of excess guest concentration, revealing a dissociative exchange mechanism, which is accompanied by negative activation entropies, indicating significant reorganization of the host–guest complex during dissociation. Nonsymmetric viologen guests with bulky head groups had more unidirectional binding and slower exchange rates than guests with less‐bulky head groups. Thermodynamic and kinetic studies revealed that the exchange process is primarily driven by the thermodynamics of binding and that guest binding can be influenced by introducing steric and electronic groups on the host . Exchange studies with guests bearing a polymer chain revealed that both slippage and full dissociation takes place and the rate constants for both processes were determined. The slippage rate constant revealed that for smaller guests exchange takes place nearly exclusively under thermodynamic control. Dynamics in complexes of porphyrin cage compounds and viologen‐derived guest molecules are investigated by selective exchange NMR spectroscopy (1D EXSY). These studies explore the mechanism of host–guest exchange, how steric and electronic properties influence the rate of exchange, and whether the exchange process is governed by kinetic or thermodynamic factors. Ka≈104–106 M−1). was kept constant at 2 mM.We studied the exchange of the complex between the unsubstituted, symmetric host V1]) plot  versus log. The lower binding constant for the minor complex coincides with the lower activation enthalpy for the dissociation of the minor complex , compared to that of the major counterpart . This indicates that thermodynamic factors play a role in the chemical exchange in these systems.When a solution of a porphyrin cage compound is irradiated at a wavelength of 419 nm, the porphyrin gives rise to two fluorescence bands at 650 and 716 nm. These bands are subsequently quenched when a viologen‐derived guest binds inside the host, and through titration, the binding constants and the related Δ21H‐25H, Figure V1. All studied hosts were racemic mixtures of enantiomers. Similar to 22H, when V1 is bound inside the cavity of 24H or 25H, two different host‐guest complexes are formed in different abundances due to the nonsymmetrical nature of both the host and guest. NMR studies showed that for each of these host‐guest systems the major complex is the one in which the C5‐linker connected to the blocking group is located at the nitro‐ or amine‐substituted cavity portal. After having determined the rate constants of exchange at different temperatures, the activation Gibbs free energies (ΔG≠) could be extracted from the Eyring plots. These energies are visualized in Figure V1 with the bis‐nitrated host compounds comprise both the lowest and the highest activation free Gibbs energy barriers, viz. ΔG≠=16.97±0.46 kcal mol−1 for the anti‐facial bis‐nitrated host 23H and ΔG≠=20.24±0.38 kcal mol−1 for the syn‐facial bis‐nitrated host 24H. Remarkably, the highest degree of unidirectional binding of the guest (ratio of major to minor=4:1) was observed for the complex between 24H and V1. All determined activation free energies are well within the ranges reported for other supramolecular systems in which small guests exchange.[23H and V1 has the lowest energy barrier for exchange  of all complexes may be explained by the required passage of a cation across an additional nitro‐plane. Since 23H has two nitro functionalities in an anti‐facial manner, both sides of the host destabilize the binding of V1, resulting in the weakest binding of the guest inside the cavity of the measured systems , which coincides with a smaller energy barrier for dissociation and exchange.Ongoing studies in our group to enantioselectively epoxidize polymer chains utilize porphyrin cages that are nonsymmetrically functionalized at their sidewalls. For this reason, we expanded the scope of host‐guest complexes and investigated the influence of unsubstituted, mono‐ and di‐substituted side walls of the porphyrin cage compounds , and the activation Gibbs free energy is significantly higher . The exchange of V1 in mono‐nitrated host 22H shows activation barriers  that are in between the values observed for guest exchange in 23H and 21H. This observation suggests that the steric and electronic effects imposed by the nitro groups influence the ΔG≠ of exchange. The syn‐facial bis‐nitrated host 24H showed the highest activation Gibbs free energy barrier for exchange with V1. In this host, the two nitro groups are located at one of the cavity portals, which likely complicates dissociation of the guest via that side of the cavity. The two nitro‐groups may “pinch” the guest while it is bound and therefore increase the activation energy for exchange. Preliminary molecular modeling calculations using the Spartan program  supports this hypothesis.For comparison, the unsubstituted host 24H and V1 is significantly larger than the activation enthalpies for the other nitro‐containing hosts, which is in line with the hypothesis of 24H pinching the guest, resulting in an increase of the activation barrier for its dissociation. Interestingly, despite displaying the highest activation enthalpies, the activation entropies for this host‐guest system  are significantly lower than the activation entropies for the other systems. We explain this observation by a gain in flexibility of the guest during its dissociation, in particular of the C5‐linker, which is close to the nitro groups.For further comparison, differences in the activation enthalpy and entropy values were investigated and compiled Table . The act25/V1H the activation Gibbs free energy values are slightly higher than those of 22/V1H. We explain this increase by the electron‐donating nature of the amino‐group, which can strengthen the π‐π stacking interactions between the more electron‐rich cavity sidewall and the electron‐poor 4,4′‐bipyridinium moiety of V1, thereby increasing the energy barriers for exchange.Remarkably, for complex V1–V5, see Figure 22H indicate that shortening the linker between the blocking group and the viologen moiety leads to a significant decrease in unidirectionality of the binding, compare Kmaj/min=1.2 for V2 (n=3) with Kmaj/min=2 for V1 (n=5) ; V1: Kbind,maj=1.24×106±4.22×104 M−1, Kbind,min=6.42×105±2.18×104 M−1 (see Table SI4). This also coincided with lower Gibbs free energies of activation of V2 exchanging in 22H  compared to the Gibbs free energy of activation for the exchange of V1 in 22H . In contrast, V5, which contains a C11‐linker displays overall similar energy barriers for dissociation as V1 (n=5), indicating that after a linker length of C5 there is no significant impact on the dissociation process. Furthermore, fluorescence binding studies show that the thermodynamics of binding of V5 and V1 in 22H do not differ significantly  than that for the reverse conversion . This trend is also present in the systems 24/V1H and 25/V1H. We attribute this difference to the lower ground state energy of the major species, as opposed to the minor species, which will be further discussed below (vide infra). We also investigated a guest with a methyl instead of a methylcyclohexyl group . However, the Gibbs free energy difference between major and minor species (ΔΔG≠maj‐min) showed no significant difference for 22/V1H and 22/V3H, which shows that a higher energy barrier for the major to the minor species can be found than vice versa.For the combination V3 in 22H is significantly lower than that of the guest with the methylcyclohexyl end‐group (V1). Going from methylcyclohexyl to methyl significantly decreases the bulkiness of the guest, which provides it with more flexibility to dissociate from the cavity of the host. The system might have gained more flexibility as indicated by the small difference in entropy cost for the exchange of V3  compared to that of V1 . A big difference between the dissociation processes of V3 and V1 is the lower activation enthalpy measured for V3  compared to that of V1 . We attribute this difference to the differences in the van der Waals interactions between host and guest that need to be broken and formed during the exchange process. The question whether this effect results from a lower activation barrier or a higher ground state energy will be discussed in the next section. The difference in population between the major and minor species for the complex between 22H and V3 is 2:1, which is the same value as observed for the complex between 22H and V1. These results demonstrate that the degree of unidirectionality in the bound viologen guest is determined by the length of the linker between the blocking group and the viologen moiety, which increases the bulkiness of the guest close to the cavity of the host if this linker is short. Guest V4 contains a 2‐ethylbutyl group as head group and was expected to be less sterically encumbering than V1, but bulkier than V3. The 1D EXSY studies confirm this hypothesis as the activation Gibbs free energies for 22/V4H  are higher than those for 22/V3H, containing a methyl group, but lower than those for 22/V1H, containing a methylcyclohexyl group.The energy barrier for the exchange of 22H and V1 were repeated, but this time using an excess of host to follow the exchange of free to bound host and vice versa. In the top spectrum in Figure In order to obtain more insight in the individual steps of the exchange reaction, the 1D EXSY studies of the complex between 21H and V1 is stronger than that between the minor abundant complex between 24H and V1 , while in contrast the activation barrier for binding a guest in the free host is significantly lower for the complex between 24H and V1  compared to that for the minor abundant complex between 21H and V1 . This means that slow exchange between the components of the host‐guest complex does not necessarily indicate stronger host‐guest binding, and vice versa. The activation barriers going from a bound to a free complex decrease in energy upon an increase in the number of nitro‐groups on the xylylene sidewalls of the host, with the exception of 24H. To investigate whether only steric interactions play a role in the decrease of the activation barrier or also electronic ones, we investigated with 1D EXSY the properties of 25H, in which the strongly electron‐withdrawing nitro‐group is replaced by the strongly electron‐donating amino‐group. Remarkably, the activation barriers going from a bound to free complex in the case of 25H and V1 are in the same range as that for the complex between 22H and V1. This result suggests that mostly steric interactions affect the kinetics of guest binding. However, the ground state energy difference between the free and the bound state is significantly larger for the complex of 25H than for any of the other complexes with V1. This difference suggests that electronic effects determine the thermodynamics of binding. The latter effect is explained by the occurrence of more favorable π‐π interactions between the electron‐poor viologen and the electron‐rich sidewall of 25H compared to the interaction of this guest with the unsubstituted host 21H. With regard to the structure of the guest, the complexes between 22H and V1 and between 22H and V2 display similar energy barriers for exchange. Despite this similarity, the degree of unidirectionality (Kmaj/min) of guest binding is significantly different, viz. 2 for 22/V1H and 1.2 for 22/V2H. This difference suggests that the longer linker between the blocking group and the viologen moiety of V1 reduces the steric interactions between this blocking group and the nitro‐group of the host enough to direct the group at the open end to the unsubstituted face of the host, resulting in a higher degree of unidirectionality. 1D EXSY measurements on the complex between 22H and V3 under the conditions of excess host were unsuccessful due to excessive broadening of the proton signals as a result of a too fast exchange of the components. Even at lower temperatures (down to −30 °C) the signals could not be accurately selected.From these diagrams it is clear that there are significant differences between the kinetic and thermodynamic factors of exchange. For example, the binding between 22H and a poly‐(THF)49‐substituted viologen, capped with a blocking group  showed observable exchange of the polymer in the 2D ROESY spectrum after a mix time of 400 ms  compared to the orientation change which requires full dissociation (kor: 0.374±0.028 s−1). This means that both slippage and full dissociation occurs in this host/guest system and that at the measured temperature of 60 °C the slippage rate constant is kb→f−kor=1.625±0.094 s−1. This rate constant is in the same range of magnitude as the rate constants we found for the porphyrin host with the small guest 22/V1H at 60 °C (kmin=2.525±0.077 s−1 and kmaj=1.337±0.058 s−1), which means that exchange with small guest molecules (V1–V5) is almost fully under thermodynamic control.After having performed host‐guest exchange studies with low molecular weight viologen guests, we decided to investigate whether we could apply 1D EXSY to follow the exchange process of a viologen guest with a polymeric side chain. An NMR sample containing mono‐nitrated porphyrin cage s Figure . The int22/VPH (compared to 2 to 1 for 22/V1H), which indicates that the system shows less unidirectionality when the chain at the open end of the viologen is elongated. To investigate whether a thermodynamic equilibrium had already been reached for the host‐polymer guest complex and whether the major to minor ratio is purely a result of the thermodynamic equilibrium, a week after sample preparation the Kmaj/min ratio was determined again; it had remained constant . A duplicate experiment was performed later using the same conditions, which resulted within experimental error in the same major to minor ratio (1.23 to 1).Focusing on the extent of unidirectionality, the ratio of the major to the minor abundant host‐guest complex was 1.18 to 1 for syn‐dinitro compound 24H, increases the population difference of the major and minor occurring complex significantly, that is, in the direction of a higher degree of unidirectional binding. Increasing the steric hindrance in the guest by shortening the linker between the blocking group and the viologen moiety resulted in a smaller degree of unidirectional binding, although it increased the overall energy barrier for exchange. Decreasing the steric bulk at the open end of the viologen moiety from a methylcyclohexyl to a methyl group did not affect the degree of unidirectional binding, but resulted in an overall decrease in activation energy of exchange. By comparing the host‐guest binding behavior of the syn‐dinitro‐substituted host 24H with that of the other hosts, it appears that steric factors of the substituents have a larger impact on the activation energy barriers of host‐guest exchange than electronic factors. The results obtained with the amino‐and nitro‐substituted hosts suggest that electronic effects of the host substituents have a larger impact on the energies of the ground states of the complexes than steric effects. Taking all previous observations together, we can conclude that more unidirectional binding can be achieved if bulkier groups are introduced to one face of the porphyrin cage compound. For instance, one nitro‐group on one side of the porphyrin cage compound leads to a selectivity of 67 % major product and 33 % minor product, whereas two nitro‐groups on the same side of the host already increases this selectivity to 80 % major and 20 % minor product. Lastly, we have shown that the EXSY studies are also applicable to exchange studies with guests containing a polymer chain (22/VPH). Furthermore, we determined that full dissociation as well as slippage takes place and that the slippage‐rate constant was in the same range of magnitude as the rate constant for exchange with a smaller guest (22/V1H), which confirms the statement that exchange of small guests (V1–V5) takes place almost fully under thermodynamic control.From our studies it is evident that selective exchange spectroscopy (1D EXSY) NMR is a suitable method to monitor the exchange kinetics of host‐guest systems involving porphyrin cage compounds and viologen guest molecules, including polymeric ones. By measuring exchange rates at different guest concentrations, we were able to demonstrate that the host‐guest exchange mechanism follows a dissociative process. This mechanism was corroborated by the observation that the overall energy involved in going to different bound states is not different from the energies linked to individual dissociation and re‐association steps in the process of going from a free to a bound host, and vice versa. The introduction of sterically bulky groups on one side of the host, as in the The authors declare no conflict of interest.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


The goal of the condition assessment of concrete structures is to gain an insight into current condition of concrete and the existence of defects, which decrease durability and usability of the structure. Defects are quite difficult to detect using infrared thermography when concrete elements cannot be thermally excited with the Sun, together with unfavorable thermophysical properties of concrete structures. In this paper, principal component thermography (PCT) is applied as a post-processing method to a sequence of thermograms in order to enhance defect detectability in concrete structures. Defects are detected by analyzing a set of empirical orthogonal functions (EOFs), which were acquired by applying principal component analysis to a sequence of thermograms. The research was performed using concrete samples containing known defects, which were tested using a step heating thermography setup. The results of presented research show that PCT is an effective post-processing method to improve defect detection in concrete structures. By effectively improving the defect detection, PCT has a potential to improve the non-destructive testing (NDT) accuracy of using infrared thermography (IRT) on concrete structures, especially in shaded areas of such structures. The research also shows the defect detectability depending on concrete type thermal excitation setup and defect geometry. Today concrete is understood to be one of the most widely used materials in civil engineering structures around the world ,2. ConcrThe goal of the condition assessment of concrete structures is to gain an insight into current condition of the concrete, the existence of voids, delamination and other defects. Detection and characterization of different defects in concrete structures is often performed using one or (more often) several different reliable and efficient NDT methods, which have been developed over the last 30 years. These methods serve different purposes, from corrosion detection methods, methods used to determine mechanical properties and permeability of concrete, up to a vast range of methods and techniques used for detection and characterization of defects and damaged areas in new and existing concrete structures ,6,7,8.To date, the biggest advantage of using infrared thermography (IRT) for defect detection in concrete structures was its ability to perform an assessment of large surfaces in relatively short period of time , and to Passive IRT as a method used for defect detection in concrete structures is based on quite simple principles and are fairly straightforward to carry out if the concrete structure to be tested is under natural, solar excitation . Passive IRT is being used for concrete bridge deck testing since the late 1970 s ,12 and iOn the other hand, active IRT is done by utilizing some sort of thermal excitation of the object under examination and by simultaneous monitoring of object’s surface temperature evolution in time, especially when the object is in transient state. In solids, thermal energy is diffused in a form of thermal wave, while the IR camera is used to monitor the temporal change of temperature field on the object’s surface . DefectsDefect quantification  in concrete structures using IRT was performed by only a few research groups ,18,19,20If one considers real conditions in-situ, detection of defects using IRT is hindered by the solar irradiance variations, shading caused by clouds or the surrounding objects, as well as the condition of the concrete’s surface  ,26,27. TCommon conclusion from the review of the literature dealing with active thermography in concrete structures is that in case of artificial thermal excitation, defects are quite difficult to detect. This is due to thermal inertia of concrete structures owing to specific heat capacity and density of concrete as well as considerable dimensions of concrete structures, while at the same time, concrete has relatively low thermal conductivity. It means that significant amount of energy is needed to influence the temperature change and to initiate a thermal wave propagation in concrete structures. Additionally, when using artificial thermal excitation sources, the problem with non-uniform heating occurs. This means that often, defects are masked by the temperature field caused by focused thermal excitation source, which can lead to false positive IRT inspection results. When all these surface and subsurface effects are combined with the surroundings affecting the IRT thermograms, straightforward interpretation of thermograms turns out to be challenging, if not even impossible in some cases. Thus, in order to be able to enhance defect detectability in concrete by using active IRT, complex post-processing methods are required for thermogram analysis. One of the post-processing methods that could be used for defect detectability enhancement is principal component analysis (PCA), which is not studied enough when it comes to defect detection in concrete structures. Even though it has a mature background in enhancing thermal pattern in metals and fibre-reinforced composite materials ,31,32, rThe aim of the presented research was to determine whether the post-processing method of PCT could be applied to data obtained with step heating thermography to enhance the defect detectability in concrete structures. Additionally, the paper explores more deeply the possibilities and limitations of the PCT and gives insight in defect detectability depending on the defect dimensions, properties of concrete and thermal excitation distance. This would then serve to broaden the current knowledge on the defect detection possibilities in concrete using IRT.PCA is a statistical tool used for identification of specific patterns in data sets, and analyzing data sets in a way which enables depicting similarities and differences of specific patterns occurring in the data using statistical modes acquired by decomposing data to singular values . The uset thermograms, each thermogram consists of u horizontal elements (pixels)—Nu and v vertical elements (pixels)—Nv —Nv . u∙Nv dimensional vector X (Equation (1)):i are the individual pixels of the thermogram arranged one behind the other thus forming a 1D vector.In order to apply PCT to a thermogram sequence, it is necessary to convert the 3D matrix to a 2D matrix, which is achieved by the following procedure: Each thermogram in the sequence can be represented by a Nt thermograms in the sequence, it is possible to generate a 2D matrix in which each row represents one thermogram of the sequence, and the column retains the Nt vectors of the individual thermograms. The resulting matrix is called a raster-like matrix.If an analogous procedure is followed with all NCov is calculated according to Equation (2):X matrix is obtained after normalization, and the covariance matrix is of the dimension Nu·Nv × Nu·Nv.For the collected data set, the 2D raster matrix, it is necessary to first calculate the mean value, which is then subtracted from the initial data set in order to normalize the data. For the matrix of normalized data, the covariance matrix DCov is a diagonalized matrix with eigenvalues on the diagonal, and P is a matrix with eigenvectors as columns, in total it has Nu·Nv eigenvectors.Eigenvalues and eigenvectors are calculated by matrix diagonalization (Equation (3)):DCov matrix needs to be rearranged in such a way that the eigenvectors are organized in descending order of magnitude. A similar change of order has to be made also in the matrix of eigenvectors P. For the observed data set, the eigenvector with the largest eigenvalue is the main component. In most instances, the first three to five main components contain in excess of 95% of the variance. Utilizing the main components, the data set is reconstructed, which now indicates the similarities and differences in the data set.The The main difficulty of PCT is very intense computation of diagonal matrix and eigenvalues of the 2D raster matrix. Thus, singular value decomposition (SVD) performs identical procedure as described in the equations above, but with less computation intensity. SVD is applied to normalized data to compute the decomposed matrices A is a 2D raster matrix consisting of Nt rows and Nu Nv columns, A is arranged in such a way that the columns represent temporal variations while the rows represent spatial variations. In the described structure, the columns of the matrix U represent a set of orthogonal statistical modes known as the empirical orthogonal functions (EOFs). The matrix Γ is a diagonal matrix with singular values on the diagonals. These singular values in matrix Γ are the eigenvalues for the corresponding eigenvectors in the matrix V. Columns in the matrix V represent the principal components or eigenvectors of the data set, and are arranged in descending order of magnitude.TV. The principal components and empirical orthogonal functions (EOF) acquired by using PCA have all non-zero matrix elements. Principal components, which represent time variations, have been rearranged into rows of matrix 1) corresponds to the first most characteristic data variability, the second EOF (EOF2) corresponds to the second most characteristic variability, etc. The first mode is characterized by a spatially uniform field with exponential decay, which is reminiscent of the behavior of the sample without damage, from which it is not possible to determine the existence of defects, while the second mode is characterized by a non-uniform field where spatial distribution can be correlated with contrast signal, which occurs due to the defect in the sample.If EOF images are depicted, the first EOF  that PCT can successfully isolate different information levels .TM Researcher Pro 2.9 software and MatLab), where a series of 2D thermograms (720 thermograms), was converted into a 3D matrix, where rows and columns are rows and columns of the thermograms and the third dimension gives the pixel’s temporal temperature change. The experimental setup a consist3). Also, XPS does not absorb water, which means that the properties will remain the same after concreting and conditioning of samples. Furthermore, XPS is a rigid material, which ensures that after concrete casting the defect thickness would remain as designed, and also enables easier positioning of the defects in the desired location within the specimens (having in mind the disruptive process of concreting).The presented research was performed using the concrete specimens with known defects, which were prepared by embedding the defect mockups using the extruded polystyrene (XPS) foam b,c. XPS Defect thickness, size and installation depth were varied so that the influence of defect’s geometry and depth could be investigated. The size and depth of the simulated defects in concrete samples tested in this research was determined with intention to simulate voids and compaction defects occurring up to the depth of concrete cover, which is critical for durability of concrete structures. The XPS foam defects simulation have been affixed and fresh concrete was casted with caution into the molds in order to obtain the planned defect depth. All the specimens were tested from both sides (top side and bottom side), in order to obtain data for as much as possible defect depths. The size of the samples was determined by the requirement that they should be relocated for storage and testing in the laboratory facilities, while on the other had they were sized to be a good representation of a real concrete structure with a representation of real defects, avoiding the influence of sample’s edges and/or interfering temperature field. Concrete properties were also varied in order to determine its influence on te defect detectability, and for the purpose of this research, three concrete mixtures with the properties listed in max = 16 mm. Three concrete types were used in order to replicate the three most used concrete types in real structures. Due to their different mix composition, these three concrete types vary in density, compressive strength and thermal conductivity, thermal diffusivity (due to different density and conductivity). Different thermal properties are mostly due to the different air content in concrete, since the same aggregate was used for all three mixtures, dolomite aggregate DThe samples were heated using a step heating (SH) thermography (60 min long excitation period) during which a sequence of thermograms was collected a. After The cooling period was kept at 60 min even though cooling process is slower than heating in natural conditions because preliminary tests showed that the surface temperature of the defected and sound area of concrete samples are equal and with the same rate of cooling. SNR was used to describe the contrast between the area of defects and neighboring sound area. SNR values were calculated for the defects in all test configurations . This allowed authors to quantify the goodness of PCT applied for defect detection in concrete compared to optimal thermograms (raw data). Additionally, SNR allowed us to quantify the impact of concrete type as well as the excitation distance on defect detectability. It will be shown later in the paper that defect detectability depends on the analyzed EOF and thus also SNR varies depending on the specific EOF. Due to paper length limitation, SNR is presented only for respective EOFs presented in this paper, while others can be made available if needed. S represents average values of the “signal” area on the defect, while N represents average values of the “noise” area around the respective defect. Equation (5) was used to calculate the SNR:noiseσ is the standard deviation of the noise area around the defect. Here signal area was always selected to include the whole area of the defect, while the noise area encircles the defect and includes an area of half the distance to the neighboring defect , it can be seen that with increasing the distance of thermal excitation from the sample’s surface , the possibility of detecting defects in concrete decreases . 2 representations are given, because there is a slight influence of uneven heating of the samples, but nevertheless, it is evident that majority of defects was detected by using PCT post-processing method. Higher SNR values  as a post-processing method , the supIn general, it can be concluded that in case of small diameter defects, PCT analysis applied on the cooling sequence or only part of the cooling sequence proved to be a better methodology compared to an analysis of thermogram sequence acquired from heating or both heating and cooling period. There is a visible difference in the results obtained by PCT analysis  as well In addition to being able to detect a smaller number of defects (those of lower thickness or those deeper in concrete), there is a serious problem with the effect of reflection and uneven heating of the samples, which particularly affects the results of PCT analysis.In the case of large defects at a relatively shallow depth, it can be concluded that there is no difference between the possibility of detecting defects by analyzing thermograms acquired during the entire sequence or only the cooling sequence.Defect detectability using optimal thermograms with no post processing is shown in It is evident from the thermograms shown in Direct comparison of SNR ratios obtained from thermograms  and EOFsLarge defects (100 mm in diameter) can be detected at a depth of 40 mm using PCT in case of all concrete qualities and excitation distances used in this research. Defects of 50 and 70 mm in diameter and up to 40 mm in depth are also detectable with high certainty if they are at least 20 mm thick and if there is enough energy transferred into the specimen (at 1.5 m and 2 m distance). This is encouraging since, honeycombs and voids in concrete structures occur mainly up to concrete cover depth and are of large diameter and thickness. Thicker defects are also more likely to be detected compared to lower thickness defects even though defects are of the same diameter . It is eSome defects, which were not visible in the sample with lower quality concrete BM 1-y, became visible for BM 2-y and BM 3-y concretes, especially those of lower thickness (i.e. 10 mm) and those embedded deeper into samples . The detIt can be concluded from the presented research that PCT is an effective post-processing method to improve defect detection in concrete structures. This paper showed that PCT applied to a sequence of thermograms can increase the SNR of defects compared to optimal thermograms in the case of the presented testing methodology. Even though a majority of defects were detected (even those with relatively low thickness), the results are still to be considered with care since the effects like reflection and noise can have an influence.It was shown in the presented research that for all concrete types analyzed, the results acquired using PCT post-processing method revealed defects of different thicknesses (10–40 mm) and defects located at different depths (up to 40 mm) with 1000 W halogen lamp as a thermal excitation at maximum 3 m distance.PCT proved to be quite valuable for detecting small defects in concrete samples (50 mm in diameter), but interpretation of EOFs has to be performed with care due to the possible influence of reflection in certain EOFs. The reflection can be identified by analyzing several EOFs where defects pattern will change slightly while reflection pattern will change significantly. It has to be highlighted here that the main difficulty of PCT is very intense computation, which means quite powerful computers are needed, especially when one uses high resolution IR camera.It was confirmed in this research that excitation source  distance from the samples influences the detectability of defects since less energy is entering the samples with greater distance making defects harder to detect, but at the same time samples are heated more uniform which is beneficial for defect detection. SNRs obtained for excitation distance of 2 m were lower than those obtained for 1.5 m distance, but never the less 2 m distance enabled more uniform heating of samples and would also enable heating of larger surface area while testing in-situ.The quality of concrete also affects the possibility of defect detection, with the obvious difference in the possibility of detecting defects in samples marked BM 1-y (compressive strength 18.93 MPa), compared to samples BM 2-y and BM 3-y strengths of 40.99 MPa and 89.05 MPa), for which it is generally possible to detect a larger number of defects in this way. These defects are also more pronounced (have better contrast and larger SNR) compared to the undamaged part of the sample. In the case of a better quality concrete, it is possible to detect defects at greater depths, as well as defects of smaller thickness compared to concrete of poor quality. The reason for better defect detectability in BM 2-y and BM 3-y samples is higher thermal conductivity of concrete out of which the mentioned samples are made. This higher thermal conductivity allows faster thermal wave propagation to the defect, compared to lateral heat propagation which to some extent masks the existence of the defect. Although concrete’s thermophysical properties affect the test results, it was shown in this research that detection of defects is nevertheless feasible if the measurement setup is adapted accordingly.SNRs obtained from EOFs were generally a bit higher than those obtained from phasegrams and ampligrams for the same test configurations, which means that for defect detection in concrete, PCT has comparable results to PPT, even though it has some limitations in defect quantification potential, computation intensity and the influence of reflections. It is noted that the results and conclusions of this research are only valid for the environmental conditions and the test conditions discussed.Additional research needs to be performed in order to implement the proposed methods for inspection of real reinforced concrete structures. These could include the variation of thermal excitation periods  or using more powerful halogen lamps to achieve shorter excitation periods making the method more viable for in-situ testing. One could investigate the existence of optimum combination of excitation source energy input and the excitation period. There is also a possibility to explore improved PCA techniques developed in the field of carbon fiber reinforced polymers and metals and their applicability for defect detection in concrete structures. These techniques include Stable principal component pursuit (SPCP), Weighted PCT, Sparse PCT, Generative PCT, etc.


The shortage of natural aggregates has recently emerged as a serious problem owing to the tremendous growth of the concrete industry. Consequently, the social interest in identifying aggregate materials as alternatives to natural aggregates has increased. In South Korea’s growing steel industry, a large amount of steel slag is generated and discarded every year, thereby causing environmental pollution. In previous studies, steel slag, such as blast furnace slag (BFS), has been used as substitutes for concrete aggregates; however, few studies have been conducted on concrete containing both BFS and Ferronickel slag (FNS) as the fine aggregate. In this study, the compressive strength, chloride ion penetrability, and carbonation characteristic of concrete with both FNS and BFS were investigated. The mixed slag fine aggregate (MSFA) was used to replace 0, 25%, 50%, 75%, and 100% of the natural fine aggregate volume. From the test results, the highest compressive strength after 56 days was observed for the B/F100 sample. The 56 days chloride ion penetrability of the B/F75, and B/F100 samples with the MSFA contents of 75% and 100% were low level, approximately 34%, and 54% lower than that of the plain sample, respectively. In addition, the carbonation depth of the samples decreased with the increase in replacement ratio of MSFA. Owing to the immense growth of the global concrete industry, the shortage of natural aggregates has emerged as a serious problem. In Korea, the lack of aggregates has often led to construction problems. Therefore, a considerable amount of social and research interest has been focused on finding alternative aggregate materials to replace natural aggregates ,4,5,6,7.Saha et al.  studied Choi et al.  investigLee et al.  investig2 reduction, and energy savings [Blast furnace slag (BFS) is also another steel industry byproduct that is obtained from blast furnaces used in the manufacturing of pig iron. The annual amount of produced BFS in Korea is approximately 15 million tons. The BFS has been extensively used as a successful replacement material for Portland cement in concrete materials to improve the durability and in the production of high-strength concrete, with environmental and economic benefits, such as resource conservation, CO savings ,9,10,11. savings ,13, BFS In this study, the slump, air content, compressive strength, resistance to chloride ions, and carbonation characteristic of concrete with both FNS and BFS as the fine aggregate were investigated to effectively utilize the mixed slag fine aggregate (MSFA) as a substitute material for the natural aggregate in the concrete industry.max 25 mm) with a density of 2.65 and fineness modulus of 6.49 was used.An ASTM type I ordinary Portland cement manufactured by Asia Cement Co. , BFS powder obtained from Daehan Slag Co., Ltd. , and fly ash obtained from the Honam power plant in Korea were used as cementitious materials in this study. In addition, a crushed coarse aggregate , 25%, 50%, 75%, and 100% of the volume of the NS. A constant water-to-binder ratio of 0.518 was used. In all mixtures, the BFS powder and fly ash were used to replace 20% and 10% (weight) of the cement, respectively. The mixing proportions of the concrete samples are summarized in The slump and air content tests of the concrete samples were carried out in accordance with Korean Standards (KS) F 2402  and KS FChloride ion penetration tests were carried out after 7, 14, 28, and 56 days, according to ASTM 1202 C . Specime2 concentration of 5 ± 0.2%. During the testing period, the samples were split into two halves and the carbonation depth was measured by spraying an approximately 1% phenolphthalein solution on the broken surface of the sample, after the dust was removed.Accelerated-carbonation test  of the cS F 2584 , by usin(1)The slumps of all mixtures were similar (200 to 210 mm), regardless of the replacement ratio of MSFA. The WRA dosage decreased with the increase in replacement ratio of MSFA.(2)The compressive strength of the plain sample was approximately 23.9 MPa, while those of the samples with the MSFAs were in the range of 21.2 to 23.5 MPa after seven days. After 56 days, the highest compressive strength (approximately 38.8 MPa) was observed for the B/F100 sample. The increase in compressive strength could be explained as the particle size distribution of the MSFA was similar to that of the NS and the formation of the secondary CSH gel was initiated.(3)After seven days, the charge passed through B/F100 was the smallest, approximately 37% smaller than that through the plain sample. After 28 days of curing, the chloride ion penetrabilities of all samples were moderate level according to ASTM C 1202. After 56 days, the chloride ion penetrabilities of B/F50, B/F75, and B/F100 were low level, approximately 17%, 34%, and 54% lower than that of the plain sample, respectively.(4)The resistances to penetration of chloride ions of the samples with the MSFAs were better than that of the plain sample. The tendency that the concrete with BFS has a good resistance to chloride ions is similar to those in previous reports.(5)The chloride ion penetrability decreased with the increase in compressive strength. In addition, the chloride ion penetrabilities of the samples with the MSFAs were lower than that of the plain sample at the same compressive strength.(6)The higher replacement ratio of MSFA led to a smaller carbonation depth. The carbonation depth (0.79 mm) of B/F100 was the smallest after 56 days. The results show that the use of the MSFA in the mortar or concrete can be effective for the improvement in carbonation resistance.The conclusions of this study can be summarized as follows.However, further studies are needed to establish the strength development mechanism and respective relationships between the strength properties of mortar containing various slag aggregate and water-binder ratio, density, alkali content, and durability, etc.


Compared with ordinary concrete, ultra-high performance concrete (UHPC) has excellent toughness and better impact resistance. Under high temperatures, the microstructure and mechanical properties of UHPC may seriously deteriorate. As such, we first explored the properties of UHPC with a designed 28-day compressive strength of 120 MPa or higher in the fresh mix phase, and measured its hardened mechanical properties at seven days. The test variables included: the type of cementing material and the mixing ratio , the type of fiber , and the fiber content (volume percentage). In addition to the UHPC of the experimental group, pure concrete was used as the control group in the experiment; no fiber or supplementary cementitious materials  were added to enable comparison and discussion and analysis. Then, the UHPC-1 specimens of the experimental group were selected for further compressive, flexural, and splitting strength tests and SEM observations after exposure to different target temperatures in an electric furnace. The test results show that at room temperature, the 56-day compressive strength of the UHPC-1 mix was 155.8 MPa, which is higher than the >150 MPa general compressive strength requirement for ultra-high-performance concrete. The residual compressive strength, flexural strength, and splitting strength of the UHPC-1 specimen after exposure to 300, 400, and 500 °C did not decrease significantly, and even increased due to the drying effect of heating. However, when the temperature was 600 °C, spalling occurred, so the residual mechanical strength rapidly declined. SEM observations confirmed that polypropylene fibers melted at high temperatures, thereby forming other channels that helped to reduce the internal vapor pressure of the UHPC and maintain a certain residual strength. Ultra-high performance concrete (UHPC) is a cementitious composite characterized by high compressive strength, typically greater than 120 MPa, specific durability, tensile ductility, and toughness ,4,5. In Basically, the overall cost of a structure is directly related to the cross-sectional dimensions of the structural members. The use of UHPC structural members reduces the cross-sectional dimensions and provides additional useful space in the building . UHPC blUnder the action of high temperature, the microstructure and properties of cement hydration products change, which directly or indirectly changes the macroscopic properties of the substrate, and affects the overall behavior of hardened concrete ,20. Due As mentioned above, UHPC is a more a sustainable material due to its improved durability, ecological factors, economic benefits, and recycling capabilities for a variety of applications. As a result, the use of UHPC in infrastructure projects has increased in recent years. Fire damage is a special characteristic failure mode of concrete structures because it has a considerable impact on the overall safety of the structure. Basically, the failure of structural concrete in a fire varies depending on the nature of the fire, the loading system, and the type of structure. The behavior of concrete during a fire mainly depends on its mix proportions and constituents and is determined by complex physicochemical transformations occurring in heating . When ex2/g was used. The silica fume was produced locally, with a specific gravity of 2.1 and a silicon dioxide content of 92.4%. The ultra-fine silica powder was purchased from Dawei Stone Industry Co. . It had a specific gravity of 2.73 and an average particle diameter of 0.075 to 0.225 μm. The fine aggregate contained two different sizes of quartz sand (Type I and Type II). The physical properties and chemical composition of the fine particles are shown in The materials used in the tests included cement, silica fume, ultra-fine silica powder, fine aggregate, superplasticizer, viscous agent, steel fiber, and polypropylene fiber. A locally produced Type I Portland cement with a specific gravity of 3.15 and a fineness of 3400 cm(1)Before mixing, the fine aggregates were treated in a dry state because their water absorption rate approached zero.(2)We placed the cementitious materials, aggregates, and fibers (steel fiber and polypropylene fiber) into a mixing tank, and then dry blended uniformly for 5 min.(3)We poured the water into the mixer. After mixing for about 1 min, we poured all the superplasticizer and viscous agent into the mixture and mixed for another 4 min to produce fresh concrete.The concrete test proportions of each group were mixed using a forced single-shaft mixer, and the mixing procedure was as follows:After the concrete mixture was uniformly mixed, the fresh properties of each mixture were measured and recorded. Afterward, concrete specimens required for each test were cast and compacted using an external vibrator to ensure that the specimens were sufficiently compacted. The compressive strength and elastic modulus tests were conducted with cylindrical specimens with a diameter of 100 mm and a height of 200 mm. For the splitting strength test, we used a cylindrical specimen with a diameter of 150 mm and a height of 300 mm. For the flexural strength test, a prism sample 360 mm long, 100 mm wide, and 100 mm thick was used. After casting, all the specimens were covered with polyethylene sheets for 24 h overnight. The demolding operation was then conducted and each specimen was placed in a laboratory water bath until the day before the mechanical test.The UHPC tests of unit weight, slump, slump flow, compressive strength, elastic modulus, splitting tensile strength, and flexural strength were conducted according to the ASTM specifications listed in 3. For the experimental group, the unit weight ranged from 2274 to 2316 kg/m3. Overall, the unit weight ratio between the experimental group and the control group ranged from 0.981 to 0.999, with no significant differences between each other.The fresh properties of each concrete mixture are listed in The seven-day results of the hardened properties of the control group and the experimental group, including the compressive strength, elastic modulus, flexural strength, and splitting strength, are shown in The use of pozzolanic material has a significant impact on the development of UHPC’s early compressive strength, mainly depending on its type, addition amount, mineral composition, particle shape and fineness, and pozzolanic activity. The load versus midspan deflection curves for each group of concrete specimens are shown in Regarding the splitting strength of concrete, the test results were between 4.4 and 10.8 MPa. The HPC-1 mix had the lowest splitting strength (4.4 MPa) and UHPC-5 mix had the highest (10.8 MPa). Overall, the splitting strength of the experimental group was 1.66 to 2.45 times that of the control group. This shows that the steel fiber content is an important factor affecting the splitting strength of concrete. To understand the influence of high temperature on the mechanical properties of UHPC, the UHPC-1 specimens of the experimental group were selected for further compressive, flexural, and splitting strength tests after exposure to high temperatures in an electric furnace. Generally, in the fire test, the heating rate of the electric furnace had a strong influence. In this study, we first tried to reach the target temperature (600 °C) with heating rates of 15, 10, 5, and 2 °C/min, and maintained the furnace temperature for an additional hour. However, for all of the above cases, this resulted in specimen spalling, as shown in When the internal temperature of the electric furnace reached the target temperature, the internal temperature of the concrete specimen gradually increased due to heat conduction. In this study, two thermocouples were embedded in a concrete cylindrical specimen with a diameter of 10 cm and a height of 20 cm. One of the thermocouples located at half the height was 3 cm from the surface of the concrete specimen and the other at the core of the specimen was 5 cm from the surface of the concrete specimen to measure the actual temperature inside the specimen. Based on these data, the relationship between the internal temperature of the UHPC-1 specimen and the heating and cooling times of the electric furnace was plotted. After reaching the maximum fire temperature, its holding time was 0.5 h, and then the electric furnace was turned off. When the target temperatures were 300, 400, and 500 °C, the relationship curves between the internal temperature of the concrete specimen and the heating as well as cooling time of the electric furnace were plotted, as shown in The results of the 56-day compressive strength of the UHPC-1 specimen are shown in At room temperature, the 56-day flexural strength of the UHPC-1 specimen was 13 MPa, which was significantly higher than that of ordinary concrete . Table 1The results of the 56-day splitting strength of the UHPC-1 specimen are shown in 2O3–Fe2O3–tri) and silicate was detected in the pores present. After exposure to high temperatures, the microstructure and properties of the UHPC matrix changed with increasing temperature, as shown in 2O3 or Fe2O3 was lost; about 20% of the bound water of C–S–H gels was also lost [In general, when the temperature inside concrete reaches 105–200 °C, C–S–H gels begin to lose bound water and undergo chemical changes ,20. Whenlso lost ,20. At tlso lost , Hager elso lost , and Wu lso lost . HoweverIn this study, we explored the mechanical properties of UHPC before and after exposure to high temperatures. Based on the analysis and discussion of the test results, the results obtained are summarized as follows. At room temperature, the 56-day compressive strength of the UHPC-1 mix was 155.8 MPa, which is higher than the general compressive strength requirement of 150 MPa for UHPC. After the UHPC-1 specimen was exposed to 300, 400, and 500 °C, the residual compressive strength did not decrease significantly, and even increased. The strength of the specimen increased slightly due to the drying effect of temperature rise. When the target temperatures were 300, 400, and 500 °C, the maximum internal temperature of the concrete specimen was about 120, 180, and 250 °C, respectively. Therefore, the fire damage did not cause the decay of the concrete matrix. However, when the fire damage was 600 °C, the internal temperature of the concrete specimen had caused the concrete matrix to decay and spall. In terms of flexural strength, the 56-day strength of the UHPC-1 mix at room temperature was 13 MPa, which was significantly higher than that of ordinary concrete. After the UHPC-1 specimen was exposed to 300, 400, and 500 °C, the residual flexural strength did not decrease significantly, and even increased slightly due to the drying effect of heating. The relative residual flexural strength ratios after fire damage at 300 and 400 °C were both greater than one. However, as the target temperature of the fire damage reached 500 °C, the residual flexural strength of the UHPC-1 specimen decreased significantly, and its residual flexural strength ratio after fire damage was 0.79. For the splitting strength, the 56-day splitting strength of the UHPC-1 mix at normal temperature was 9.8 MPa, which is also significantly higher than that of ordinary concrete. After the UHPC-1 specimen was exposed to 300, 400, and 500 °C, the residual splitting strength did not decline significantly, and even increased slightly due to the drying effect of heating. The relative residual splitting strength ratio after fire damage at 300 °C was greater than one. However, as the fire damage temperature reached 400 and 500 °C, the residual splitting strength declined, and the residual splitting strength ratio after fire damage was 0.94. SEM observations confirmed that polypropylene fibers melted at high temperatures, forming other channels that helped to reduce the internal vapor pressure of UHPC and maintain a certain residual strength. However, the optimal amount of polypropylene fiber needs to be further explored.


Delivery by cesarean section (C-section) is associated with adverse short-term and long-term infant outcomes. Given that antibiotics during early life are prescribed for infant outcomes that are more likely among c-section deliveries, we hypothesized that postnatal antibiotic exposure will be greater among c-section infants compared to vaginally delivered infants.The aim of this paper was to evaluate if mode of infant delivery was associated with patterns of systemic antibiotic exposure in children during their first three years.Pediatric electronic health records from UFHealth, 2011 to 2017 were reviewed. We included singleton, term infants (37–42 weeks gestation) with a birth weight ≥ 2500 grams, with documented mode of delivery and well visits on record. Infants with a neonatal intensive care unit stay were excluded. Both oral and intravenous antibiotics for a 10-day duration were classified as a single episode. The primary outcome was antibiotic episodes in the first three years of life, and a sub-analysis was performed to compare broad-spectrum versus narrow-spectrum antibiotic exposures.The mean number of antibiotic episodes in 4,024 full-term infants was 0.34 (SD = 0.79) and 24.1% of infants had at least one antibiotic episode. Penicillins were the most prescribed antibiotic in children 0–1 years (66.9%) and cephalosporins were the most common antibiotic prescribed for children 1–3 years (56.2%). We did not detect a meaningful or significant rate ratio (RR) between mode of delivery and overall antibiotic episodes 1.14 , broad-spectrum episodes 1.19 .Our results do not support the hypothesis that postnatal antibiotic exposure was greater among infants delivered by cesarean section compare to infants delivered vaginally during the first three years of life. Cesarean section (CS) is the most common surgical procedure in the United States and accoAntibiotics are among the most common drug class prescribed to children  with theDe-identified linked maternal-infant electronic health records (EHRs) were collected from UFHealth Shands Hospital and UFHealth Jacksonville between June 1, 2011 and April 30, 2017. Briefly, an honest broker within UF Health Integrated Data Repository (IDR) used fully identified data to perform the linkage, then removed identifiers from the linked data set before releasing the de-identified data to the research team. Demographic information such as insurance type at delivery, age, race, and ethnicity were extracted from the maternal chart and infant demographics including sex, race and ethnicity were extracted from the infant chart. Notably, all infants delivered with the UF Health system are linked to maternal records as a standard of care. The inclusion criteria for maternal-infant pairs included in the analysis is presented in The primary outcome of interest was systemic antibiotic episodes in the first 36 months of life. We extracted antibiotic prescription information from all clinical encounters, including inpatient, emergency or ambulatory visits at ≤36 months of age. All antibiotics were categorized according to the Anatomic Theraputic Chemical (ATC) index, a hierarchical classification system for the purposes of drug statistics that was developed by the World Health Organization. Systemiα = 05 using SAS software version 9.4 .We evaluated the association between mode of delivery and the rate of antibiotic episodes over the first three years via negative binomial regression, which accounted for differential follow-up time per child . We alsop < .0001) and had smaller birthweight  compared to children in the cesarean section group. Mothers who delivered either by cesarean section or vaginally had similar race/ethnicity and health insurance profiles. Those who gave birth by cesarean section were older .We obtained data on 16,684 infants born between June 1, 2011 and April 30, 2017. Of these, 4,024 (24.1%) children with at least one well visit met inclusion criteria . Mother Of 1,375 antibiotic prescriptions in 970 infants, penicillins, which includes Ampicillin, (66.9%) were the most prescribed antibiotic class in children 0–1 years . We alsoWe evaluated the association between mode of delivery and pediatric postnatal antibiotic exposure in the first three years among term infants using linked mom-baby EHRs. Our analysis revealed that nearly 1 in 4 infants in our study had at least one postnatal antibiotic episode within the first three years of life. Penicillins  were the most prescribed antibiotic in children 0–1 years and cephalosporins were the most common antibiotic for children 1–3 years . The primary finding of this study demonstrates that there was no statistical difference in the rate of prescribed antibiotics in children delivered via CS compared to children delivered vaginally in the first three years of life. Although we adjusted for potential confounding factors, the possibility that residual confounding exists within our results is plausible. Nevertheless, the precision of the effect estimates and confidence intervals from our analysis indicates that even if the association between mode of delivery and postnatal pediatric antibiotics at age three were significant, it would not represent a clinically meaningful association, as the 95% CI’s did not contain values that one would consider to represent clinically meaningful differences between the modes of delivery . Taken tThe prevalence of pediatric antibiotic episodes in our study are generally consistent with population-based estimates. Holstiege et al 2014, demonstrated that among five European countries, the rates of prescriptions were highest in young children (≤4 years) in all countries, predominantly due to high use of broad spectrum penicillins . In a coThe impact of antibiotic exposure and child-maternal health outcomes has largely focused on intrapartum antibiotic prophylaxis (IAP) to reduce neonatal early-onset sepsis (EOS) . As a stCesarean sections delivery and pediatric antibiotic exposure have each independently been associated with changes in pediatric outcomes such as obesity  and asthOur study has several strengths. It is the largest population-based study to examine this question with more than 4,000 children followed for up to three years. We also adjusted for potential confounding factors that have not been previously examined including method of delivery and the presence of birth complications. In addition, our birth cohort was large enough to adequately examine multiple courses of antibiotics and the impact of mode of delivery on broad and narrow-spectrum antibiotics. This study indicates that mode of delivery in healthy full term infants should not be influenced by concern for future antibiotic use of infant. Although providers should continue to strive for lower cesarean section rates in the United States ; our resS1 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Numerous studies have indicated that abnormal activation of the HGF/c-Met signaling pathway can lead to cell proliferation, invasiveness, and metastasis of cancers of the digestive system. Moreover, overexpression of c-Met has been implicated in poor prognosis of patients with these forms of cancer, suggesting the possibility for HGF/c-Met axis as a potential therapeutic target. Despite the large number of clinical and preclinical trials worldwide, no significant positive success in the use of anti-HGF/c-Met treatments on cancers of the digestive system has been achieved. In this review, we summarize advanced development of clinical research on HGF/c-Met antibody and small-molecule c-Met inhibitors of cancers of the digestive system and provide a possible direction for future research. Cancers of the digestive system comprise hepatocellular carcinoma (HCC), gastric, pancreatic, esophageal, and colorectal cancers (CRCs) and have been reported to result in high morbidity and mortality all over the world . A numbe-β heterodimer linked by disulfide bond. The α-chain (69 kDa) comprises an N-terminal (N) hairpin-loop and 4 kringle domains (K1–K4) while the β-chain (32–34 kDa) has a serine proteinase homology (SPH) domain  domain . It has ) domain . The aut) domain . Activat) domain .In vivo studies have provided direct evidence that the effect of autocrine HGF/c-Met signaling is very important for proliferation and growth of lung adenocarcinoma cells  curative effect was recorded  (p < 0.001) and objective response rate (ORR)  also improved significantly. The main adverse events were erythrodysesthesia, hypertension, increased aspartate aminotransferase level, fatigue, and diarrhea.Cabozantinib is a novel small-molecule multi-target tyrosine kinase inhibitor of c-Met, VEGFRs, RET, KIT, and AXL . In mice= 0.005) . The proForetinib is a multi-target inhibitor for c-Met, AXL, RON, VEGFR2, and TIE-2 . A phaseTepotinib is an effective and highly selective c-Met inhibitor, and its c-Met selectivity exceeds that of most kinase inhibitors with a cell-based 50% inhibitory concentration (IC50) of 1.7 nM . In contCapmatinib (INC280) is a highly selective c-Met inhibitor who has an IC50 of 0.13 nM for c-Met . A phaseSeveral other similar c-Met inhibitors, such as golvatinib (E7050) and SU11274 have also been reported to have antitumor activity against HCC . HoweverPancreatic cancer (PC) is a highly malignant disease with the worst prognosis due to its strong invasion and metastasis ability. The disease’s 5-year survival rate is approximately 9%, the lowest of any cancer . Pancreain vitro experiment showed that crizotinib can be used to treat peritoneal spread of pancreatic cancer based on inhibition of cell proliferation and metastasis mediated by phosphorylation of the c-Met pathway , a monoclonal antibody of the human IgG2 targeting HGF, can block binding of HGF to c-Met. A randomized phase II clinical trial showed that this antibody in combination with epirubicin, cisplatin, and capecitabine (ECX) could prolong PFS in advanced gastric cancer patients relative to the control group, especially in patients with high c-Met expression . Based oEscherichia coli  is a humanized immunoglobulin G4 monoclonal anti-Met antibody. The drug inhibits the activation of HGF/c-Met pathway by preventing HGF from binding to its receptor, c-Met, and by degrading c-Met . A phaseTelisotuzumab (ABT-700) is a novel anti-c-Met antibody that binds c-Met with high affinity and inhibits c-Met signaling. Unlike most other c-Met antibodies, it destroys the productive dimerization and activation induced by HGF or c-Met on the cell surface independent of ligand . A phaseSavolitinib is a novel and highly selective c-Met inhibitor, which has shown encouraging results in the phase III randomized clinical trial of papillary renal cell carcinoma (PRCC) . In a prTivantinib, foretinib, and other c-Met tyrosine kinase inhibitors (TKIs), have previously resulted in no clear antitumor activity in gastric cancer patients . AlthougColorectal cancer is the third most common cancer in the world, although a decline in CRC mortality has been observed in the recent past . VariousFiclatuzumab (AV-299) is a humanized, high-affinity monoclonal antibody that can block HGF/c-Met binding and mediate downstream phosphorylation of the signaling pathway . A studyThe therapeutic effect of rilotumumab in CRC has also been evaluated in a randomized phase Ib/II research where panitumumab  was combined with rilotumumab or placebo in patients with kirsten rat sarcoma (KRAS) wild-type metastatic CRC who met the prespecified criterion for improvement in ORR . AlthougIn vivo experiments showed that daily administration of SU11274 in mice resulted in inhibition of tumor growth in xenografts. It was also found that SU11274 could significantly inhibit survival and growth of colon cancer cells , providing a lot of reliable experience for the treatment of digestive system cancers .n = 33) and group sunitinib (n = 27). The primary end point was PFS; group savolitinib and group sunitinib were 7.0 and 5.8 months, respectively. Tivantinib and tepotinib have demonstrated significant antitumor activity in NSCLC. In a phase III study of tivantinib in patients with NSCLC, tivantinib combined with erlotinib led to a significant prolongation of PFS (13.0 vs. 7.5 months) and OS (25.5 vs. 20.3 months) compared to erlotinib monotherapy (n = 66) and the tissue-biopsy group (n = 60) were 48% and 50%, respectively. Median duration of response was 11.1 months. In a phase III clinical trial, 330 patients with progressive metastatic MTC were randomly assigned to the cabozantinib group (n = 220) or the placebo group (n = 110)  . Median Previous clinical trials have indicated that that high expression of c-Met gene is involved in poor prognosis and high risk of many types of cancer. Consequently, scientists have extensively studied the relationship between overexpression of the c-Met gene and prognosis of a single tumor, mainly focusing on CRC, gastric cancer, breast cancer, and lung cancer . A meta-in vitro experiment of NSCLC (A large number of clinical trials have proved that the safety of HGF or c-Met inhibitors is reliable; however, there is no significant clinical benefit for patients. A variety of potential factors contribute to the regrettable result. The pathway of c-Met signal transduction is extremely complex, and there is extensive crosstalk between c-Met and other carcinogenic pathways, which may lead to the treatment of targeting HGF, or c-Met cannot fully block the downstream signal transduction. In addition, the inhibition of c-Met promotes the stability of PDL1 and makes tumor cells escape from immune surveillance. A study found that the expression of PDL1 is up-regulated in the HCC cells of mice treated with c-Met inhibitors, which induces the functional inactivation of T-cells and enables HCC cells to escape from the killing of T-cells . Similarof NSCLC . Therefoin vitro study showed that simultaneous inhibition of c-Met and EGFR pathways inhibits HCC tumor growth (A study has shown that inhibiting the c-Met signaling pathway compensatively activates the EGFR pathway . In addir growth . Similarr growth . A phaser growth . OverallA study has indicated that the anti-tumor effect of the single drug of tivantinib or anti-PD1 is not as good as the combination of tivantinib and anti-PD1, and the combined treatment is more effective in inhibiting the growth of liver tumor . SimilarAn imbalance in HGF/c-Met signal transduction is a driving factor for cancers of the digestive system, and this promotes tumor growth, as well as its invasiveness and dissemination. Numerous studies have shown the wide application of c-Met in digestive system cancers with related clinical and preclinical evidences supporting the anti-HGF/c-Met signaling pathway as a reliable treatment for HCC, gastric, pancreatic, and CRC among others. In particular, c-Met-positive patients showed encouraging results in the phase II study, suggesting that finding the most appropriate subgroup of patients may make the most of HGF inhibitors. A crosstalk between c-Met and other signaling channels holds the key to future therapies. Particularly, single targets for inhibition of HGF/c-Met may not be the most ideal method for developing treatment against this condition. It will also be important for future research works to target other key signaling pathways during development of therapies.In general, the HGF/c-Met axis is an excellent therapeutic target, but it needs a more in-depth and guided research approach. The key challenges for future research include the selection of patients who may benefit from the treatment, development of optimal therapeutic combinations, and identification of highly sensitive biomarkers for monitoring disease prognosis.ZS, HP, ST, and JZ drafted the manuscript. AS and SY reviewed and modified the manuscript. All authors contributed to the article and approved the submitted version.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.


Reconstruction of the scapho-lunate (SL) ligament is still challenging. Many different techniques, such as capsulodesis, tendon graft and bone-ligament-bone graft have been described to stabilize reducible SL dissociation. If primary ligament repair alone is not possible, an additional stabilizer is needed to achieve scapho-lunate stability. A new local bone-ligament transfer using half of the radio-luno-triquetral ligament is performed. The direction of traction of the transposed ligament is very similar to the original ligament. Ideal tension can be attained by fixation of the bone block at the dorsal ridge of the scaphoid. The biomechanical stability of this bone-ligament transfer shall be examined biomechanically.Computed tomography imaging was performed using eight cadaveric forearms with a defined position of the wrist. Axial load was accomplished with tension springs attached to the extensor and flexor tendons. Three series  after reconstruction with bone-ligament transfer] were reconstructed three-dimensionally to determine the angles between radius, scaphoid and lunate. The radial distal part including a bone fragment of the radio-luno-triquetral ligament was transferred from its insertion at the distal edge of the radius to be attached to the dorsal ridge of the scaphoid.SL gap was widened after its transection. Average SL distance was 6.6 ± 1.6 mm. After ligament reconstruction, the gap could be narrowed significantly to 4.2 mm (± 0.7 mm). The movement of the scaphoid and lunate showed significant changes, especially in wrist flexion, fist closure and radial deviation. These deviations could be corrected by the bone ligament transfer.Reconstruction of a transected SL ligament with a bone-ligament transfer from the radio-luno-triquetral ligament reduces SL dissociation under axial load. The described surgical technique causes low donor-side morbidity and can be considered in addition to improve stability if SL ligament suture alone does not appear sufficient.Level II, therapeutic investigating experimental study. The scapho-lunate (SL) ligament is part of the intrinsic ligaments of the wrist and forms a crescent-shaped interosseous connection between the proximal pole of the scaphoid bone and the lunate. According to Tottermann , it is tEight fresh frozen cadaveric upper extremities  have been prepared as described below after thawing them at room temperature. Donors had voluntarily donated their bodies for scientific purposes after their demise.According to a similar experimental setup from Pollock, we decided to use the same weights to simulate wrist movement . Tensionp < 0.05. Power analysis of the SL interval difference before and after dissection with a type-I-error value of 0.05 and type-II-error value of 0.1 indicated that a sample size of 8 allows a power of 90%, assuming a standard deviation of the SL interval size of 1 mm , the extensor retinaculum was incised over the third and fourth dorsal wrist compartment through a dorsal approach and a radiocarpal arthrotomy was performed by splitting the radiolunotriquetral ligament (RLT) in two halves in direction of its fibers. This exposed the SL ligament, which was then completely transected sharply with a scalpel followed by division of the volar radioscaphocapitate ligament and scapho-trapezial ligament to create SL dissociation , 18. AccFor the third series [c], the previously split radio-luno-triquetral ligament was detached proximally at the margin of the distal radius with a connecting bone block 3 × 5 mm in size using a chisel. A corresponding bone window was removed from the dorsal ridge of the scaphoid and the bone-ligament transfer was fitted ), radial deviation ), and ulnar deviation . The lunate extends after destabilization of the scapho-lunate interval significantly at clenched fist position ) and wrist flexion ).Sagittal movement means flexion and extension of the carpal bones. In the lateral view, the scaphoid shows significant flexion after separation of the SL ligament, but only in wrist flexion ) and radial deviation ). However, no difference can be seen during other wrist positions. The lunate does not rotate in the coronal plane after SL dissection.Coronal movement means radial and ulnar deviation of the carpal bones. After separation of the SL ligament, the scaphoid experiences radial deviation during wrist flexion  and radial deviation (p = 0.002).After reconstruction, rotation of the scaphoid is restored both, in flexion (p < 0.05)) but less obvious in other wrist positions. Whereas the lunate performs a slight supination movement after the SL ligament has been divided. This rotation can only be detected in flexion ) and ulnar deviation ).Axial movement means pronation and supination of the carpal bones. Scaphoid bone experiences pronation after cutting the SL-Ligament. This rotation can be seen best in radial deviation  and ulnar deviation (p < 0.05).These slight rotations in pronation and supination are corrected after ligament reconstruction, especially in radial  in the native group [a]. After dissection of the SL ligament and its secondary stabilizers [b], a SL distance of 6.6 mm (SD 1.6) was measured. This difference is statistically significant (p < 0.001). After reconstruction with the bone-ligament transfer of the RLT ligament [c], the distance was reduced to 4.2 (SD 0.7 mm) (p < 0.001). The mean values in the native group and reconstruction group correlate exactly and show the same range (see Fig.  in the nMany surgical procedures have been described to reconstruct SL dissociation. Garcia-Elias et al. advice, how to stage SL dissociation and how to treat it adequately . At stagMany biomechanical studies have investigated different methods of SL ligament repair , 24, 25.Our results show that after dissecting the SL ligament, the scaphoid follows its natural movement into flexion, especially during wrist flexion, radial, and ulnar deviation. Simultaneously, the lunate follows a dorsal extension movement, again during flexion of the wrist, but particularly during fist closure. It's worth mentioning that these are relative motions to each other. We could demonstrate that the ligament reconstruction neutralizes this abnormal movement after a divided SL interval. During wrist flexion and radial deviation, the scaphoid itself undergoes radial inclination, while the lunate does not perform any particular movement in the coronary plane. This pathological deviation could also be corrected by bone-ligament reconstruction described above. When looking at the scaphoid and the lunate from the axial view, one will be able to recognize a pronation of the scaphoid and a slight supination of the lunate after an SL dissociation has been created. Again, this effect is not observed in all wrist positions.On the other hand, we could show that the separation of the SL ligament and its secondary stabilizers result in a significant increase of the SL distance in all wrist positions. Interestingly, the SL distance increases more during fist closure, flexion, and radial deviation. With the radio-luno-triquetral reconstruction, the SL distance could be restored in its original position.Comparing other techniques like Blatt capsulodesis , which cThe modified Brunelli technique as described by Talwalkar, Van den Abbeele, and Garcia-Elias –31, trieOther authors suggest a bone-ligament-bone reconstruction to restore SL instability , 23. DonLimitations of our study include those inherent in cadaver-based studies. Cadaver specimens do not allow tissue healing to assess reconstruction durability accurately. The age of the deceased and their degenerative changes on the wrist may have an influence on the results, particularly since this injury must be treated surgically, principally in younger patients. Although we could show that the SL distance can be reconstructed very well with this technique, the evidence for anatomical carpal alignment is more difficult to realize. For certain wrist positions, this seems to be possible, but for others not at all. This is probably due to the fact that the bone ligament graft does not address the secondary stabilizers, which is not the aim of this technique.In conclusion, this study showed a more detailed analysis of the pathological movement that occurs in the carpal structure after SL dissociation. Especially during wrist flexion, clenched fist, and radial deviation, an increased aberration of scaphoid and lunate from the native position is apparent. It can be assumed that the stress of the SL interval is greatest in these positions. We also demonstrated that the described radio-luno-triquetral bone-ligament transfer restores the pathological deviations in the corresponding wrist positions. In particular, the widened SL gap could be significantly reduced by the bone-ligament reconstruction.Since the described surgical technique causes low donor-side morbidity, this surgical procedure can be considered in addition to the primary suture, if the quality of the SL ligament is doubtful. So far, we have little experience in the clinical use of this new bone-ligament transfer. It will have to be demonstrated, whether SL dissociation can be corrected in the long-term follow-up using this method. The biomechanical results are very promising.