It is shown that the use of composite materials in strengthening structures increases the bearing capacity up to 41%, and the stiffness of the sections increases up to 30%. Based on the results of the study, recommendations are proposed for improving the calculation method for inflexible columns reinforced in the transverse direction, which take the work of concrete under the conditions of a three-dimensional stress state into consideration.Currently, many studies are devoted to the use of polymer composite materials to increase the strength and stability of concrete elements. In compressed reinforced concrete elements, the bearing capacity depends on the eccentricity of the external application of the external force and the corresponding stress-strain state, as well as the location and number of composite materials glued to the surface of the structure. The choice of a scheme for placing composite materials depending on the stress state of the structure is an urgent scientific problem. At the same time, the issue of central compression and the compression of columns with large eccentricities has been well studied. However, studies conducted in the range of average eccentricities often have conflicting results, which is the problem area of this study. The primary aim of this study was to increase the strength and stiffness of compressed reinforced concrete elements reinforced with composite materials, as well as a comparative analysis of the bearing capacity of ten different combinations of external longitudinal, transverse, and combined reinforcement. The results of testing 16 compressed columns under the action of various eccentricities of external load application ( An analysis of the modern construction market indicates that, along with the growth in capital construction, the volume of investments in the repair, restoration, and strengthening of building structures will certainly grow. In some cases, the volume of such investments is compared with the volume for new construction. In practice, the use of composite materials is increasing ,2,3. In Polymer composite materials are used in modern construction in various versions and technological forms. The use of polymer fibers as dispersed reinforcement is widely known ,10,11,12Reinforcement with polymer composite rods, which are used instead of steel reinforcement, is widely used ,14,15,16In recent years, polymer composite materials have been widely used as external reinforcement ,22,23,24An experimental approach to bending reinforcement of reinforced concrete beams with reinforcement on the outer side using carbon fiber fabrics is presented in . The resExternal reinforcement of the beams due to the attachment of a polymer plate in the lower tension zone  leads toBridge structures operating under conditions of cyclic dynamic loads were the object of study in . StrengtAn important structural element is the beam-to-column junction area, which experiences stress concentration. In , severalThe long-term performance of the laminate in the joint area was investigated in  and assoIn , the autThe considered variants for strengthening structures are mainly aimed at increasing the tensile strength in the lower chord. At the same time, shear failure of reinforced concrete structures is a common phenomenon, and the use of polymer reinforcement, in this case, is not sufficiently described in the literature. In , the autIn recent years, the use of reinforced concrete columns in the construction of high-rise buildings and unique structures has expanded. Axial and eccentric loads lead to lateral deflections, which can critically affect the performance of the structure. In , the behThe behavior of reinforced concrete columns made of plain concrete and fiber-reinforced concrete wrapped with CFRP sheets and load eccentricity factors d tested  under ecThe choice of the optimal scheme for strengthening the structure during repair and restoration is a scientific problem, especially with an eccentrically applied load . Twenty-In , the resThe review shows that, with many studies, the issue and main gap of the effective use of longitudinal and transverse methods of strengthening compressed reinforced concrete elements remains unexplored, considering the actual stress-strain state, which depends on the eccentricity of the load application.Thus, the purpose of this work was to study the numerical parameters of the efficiency of composite reinforcement variants depending on the variable parameters and to develop a methodology for their calculation.The scientific novelty of the work lies in the experimental and analytical study of the assessment of the strength of compressed elements reinforced with composite materials at various eccentricity coefficients.To study the features of the work of compressed reinforced concrete elements reinforced with composite materials, as well as to obtain data on their strength, a series of experiments was carried out.h) mm and a length of 1200 mm.At the first stage of the research program, 16 reinforced concrete columns were made. All samples had sections of 250 × 125 . The percentage of reinforcement, in this case, was 1.44% to identify the maximum effect of concrete reinforcement with composite materials. The main transverse reinforcement is knitted in the form of closed collars with a diameter of 6 mm with a tensile strength of 500 MPa (class B500). Stirrups were installed in increments of 180 mm. In addition to the main transverse reinforcement, 6 structural meshes are installed at the ends of the columns§ with a step of 50 mm. Their purpose is to increase the strength of concrete within the length of the anchoring zone of the longitudinal working reinforcement of the columns. The grids are made with a mesh size of 50 × 40 mm from wire reinforcement with a diameter of 3 mm with a tensile strength of 500 MPa. The strength characteristics of the working reinforcement and stirrups were obtained from the results of tensile tests of 5 samples of each type. The tests were carried out on a GRM-20 universal tensile testing machine No. 1837  in accordance with GOST 12004-81. A strain gauge station measured longitudinal deformations based on 100 mm with a scale division of the indicators equal to 0.01 mm. The average test results of rod reinforcement of class A500 and B500 and wire with a diameter of 6.0 mm (used in meshes and clamps) are given in All columns were designed according to the recommendations . The desA general view of the sample prepared to reinforce the columns with transverse stirrups is shown in To ensure three types of stress-strain state of the compressed elements, the load on the prototypes was transferred with a clearly fixed eccentricity through a specially designed steel head, which was bolted to the ends of the columns before testing. The design of the head is shown in Three slots were made on the end plates of the indicated heads, located along the geometric axes of the prototypes and at distances of 2.0 and 4.0 cm from them. The load from the press was transferred to the columns through trihedral steel knives with a leg of 70 mm installed in these slots, thereby creating three types of stress-strain state. This is conditionally central compression at a value of 2, carbon laminates (strips) that were 1.2 mm thick and 50 mm wide, and round rods Ø8 mm. All materials, including primer, putty, and adhesives, were provided by the Moscow branch of MBRACE–BASF BUILDING SYSTEMS LLC. Specifically, carbon laminates (MBRACE®LAM CF210/2400.50 × 1.4.100 m) were used as elements of the longitudinal composite reinforcement, and carbon fabric (MBRACE FIB CF 300/4900.300 g/5.100 m) was used as transverse reinforcement. The strength characteristics of carbon fabric are taken from the results of tests of three-layer samples. Average value of temporary resistance Three types of carbon fiber composite materials were used to reinforce the columns, namely carbon fabric, the density of which was 300 g/mUsing these materials, 13 different reinforcement variants were developed: 5 variants for reinforcing samples of series A, 5 for series B, and 3 for series C. The reinforcement variants were divided into 3 types—external transverse, longitudinal, and combined reinforcement. The variants of reinforcements are shown in The first three capital letters of the alphabet—A; B; C—designate reference samples without reinforcement that were prepared for a constructive version of reinforcement with stirrups, which will be tested, respectively, with an axial eccentricity of the load application The capital letter U, located next to the first three capital letters, indicates the presence of a reinforced prototype.The capital letter X indicates the presence of one of the variants for external transverse reinforcement—a stirrup, and the number next to this letter is a variant of transverse reinforcement: (1)—stirrups with a width of L indicates the presence of external longitudinal reinforcement with laminates (strips) 50 mm wide and 1.2 mm thick.The capital letter R indicates reinforcement with carbon-fiber rods Ø8 mm, glued symmetrically on both sides along the uprights into strips (grooves) cut in the protective layer with a depth of 20 mm.The capital letter L or R means that flat or round composite reinforcements are glued symmetrically on both sides of the elements.The lowercase letters (c) and (r) indicate the presence of external longitudinal reinforcement, which is glued, respectively, from the side of the compressed (less compressed) face of the uprights, or the stretched one. The absence of lowercase letters (c) and (r) next to 2 did not provide adequate rigidity and were torn at the rounded corners of the prototypes.With external transverse reinforcement, the widths of the stirrups and the gaps between the transverse stirrups were varied. With external longitudinal reinforcement, the cross-sectional areas of composite materials and the variants for gluing reinforcement elements changed—symmetrically from two sides, or from one side, respectively, on a compressed (less compressed) or stretched face. All stirrups and a solid clip were made of three layers to ensure their sufficient rigidity, because according to studies , two-layRound longitudinal rods according to the AU-X1R variant were glued into longitudinal grooves—gaps, 20 mm deep, cut in the protective layer of concrete with a diamond saw along the reinforced elements. With combined reinforcement, the longitudinal reinforcement elements were glued first, followed by the transverse ones.For all reinforcement variants, the prototypes, regardless of the presence of longitudinal reinforcement elements, had three-layer stirrups 100 mm wide, located next to the metal heads. They are called anchor stirrups—clips—and are designed to provide anchoring of the longitudinal elements of the composite reinforcement, i.e., putting them into work. The design of the reinforcement of the columns with external transverse composite reinforcement and the load application scheme are shown in A general view of the prototype reinforced according to the AU-X5 variant is shown in -Surface marking according to reinforcement variants;-Removal of cement-sand milk in the places of installation of reinforcement elements until large filler is exposed and corners are rounded with a radius of curvature 20 mm in places where stirrups or clips are glued;-Dedusting the surface and applying a primer, if necessary—leveling the surface with an epoxy-based putty;-Reinforcement of the structure according to the reinforcement variant.The technique for strengthening prototypes was based on recommendations from the manufacturer of composite materials and algorithms for strengthening reinforced concrete structures, which are given in the annexes of regulatory documents of various countries on strengthening reinforced concrete structures with composite materials. The work sequence was adopted as follows:After strengthening, the prototypes were kept until the moment of testing for 7 days until the adhesive composition was completely cured.The strength characteristics of concrete for prototypes according to their reinforcement variants are shown in Testing of prototypes was carried out on a specially equipped stand. N = 2000 kN. The load on the columns was transmitted by two multidirectional forces through the blades of triangular isosceles knives. The latter were installed on a jack and under the top plate of the press. The force from the knives to the column was transmitted through steel heads with three slots to fix the eccentricities. Considering the thickness of the end plates of the heads, the estimated length of the columns was 1250 mm.Loading of prototypes was carried out using a DG-200 jack, developing a force of The loading of prototypes during the test was carried out with a step-increasing load with an intensity of 1/20 of the theoretical breaking load at levels up to In accordance with the program of experimental studies, all 16 samples were tested by short-term load to failure. Six columns were tested for central compression, six for relative eccentricity The data obtained show that the effectiveness of external composite reinforcement is affected not only by the design of reinforcement variants but also by the stiffness of the reinforcement elements, as well as the value of the axial eccentricity of the load application e0 = 0; The nature of the destruction of the samples , as wellThe influence of various reinforcement variants on the strength of reinforced samples is presented in With eccentricity The second largest coefficient Column (6), in which 4 carbon rods with a diameter of 8 mm were glued on both sides within the depth of the protective layer of concrete, showed an increase in strength of 20%.Column (5), in which, simultaneously with the transverse clamps, two strips of carbon laminate were glued on opposite sides, also did not increase its strength . This isColumn (10), loaded with an eccentricity Column (8), which was reinforced according to the X1 variant, as well as column (9) with X2 stirrups with a gap of 95 mm, and column (11), with a similar X2 clamp but in combination with two laminate strips glued to a more compressed edge, showed close strengths, which are 32–35% higher than the strength of the reference column (7).Column (12) with X1 stirrups in combination with two strips only on the tension face showed a strength increment of 18%.The prototypes loaded with an eccentricity Columns (15) and (16), which were reinforced with external longitudinal composite reinforcement in combination with transverse stirrups, increased their strength compared to the reference (13) by 25 and 44%. It can be seen from In For compressed elements, with axial load application  and especially at The variant of reinforcing the columns with wide stirrups at With an eccentricity of The stirrups according to the X3 and X4 variants, which were used to strengthen the columns, were equal in width to one third of the length of the prototypes. They showed the effect of reinforcement only with complex reinforcement together with external longitudinal composite reinforcement. At the same time, with an increase in the width of the clamp, the influence of the clip effect decreased.Finishing the assessment of the influence of external transverse reinforcement, it is also important to note that the effectiveness of the influence of transverse clamps glued to the longitudinal elements of external reinforcement decreases.The longitudinal external reinforcement of the columns, using laminate at A clearer picture of the influence of reinforcement variants on the bearing capacity of prototypes can be traced when analyzing the experimental values of the composite reinforcement coefficient, which are obtained by dividing the reduced strength of the reinforced columns by the average strength of the reference samples. Their values are given in column 9 of the The influence of the eccentricity of the load application on the change in the eccentricity of the load application on the change in the coefficient The maximum bearing capacity was shown by columns reinforced with a solid three-layer casing according to the X5 variant, tested with an eccentricity The second most effective variant was the X1R variant, in which the reinforcement was made by round rods with a diameter of 8 mm, glued into a groove cut in the protective layer of concrete. A similar picture was obtained in studies  where, iAt an eccentricity of The longitudinal external reinforcement of short studs using laminate at ained in .With an eccentricity of sions of ,12.b is the width of the section of the column; x is the height of the compressed zone of concrete in the section, determined by formulas (4) and (5); a’ is the distance from the extreme compressed concrete fiber to the center of gravity of the reinforcement located at the most compressed edge of the section; e is the eccentricity of the external force application relative to the center of gravity of the least compressed or tensioned reinforcement in the section, determined by formula (2).The theoretical bearing capacity of columns under eccentric compression was determined by the following formula (1):Depending on the eccentricity of the application of the external force, two cases of column failure were observed. In the first case, the stresses in the tensile reinforcement reached the yield point, and in the second case, the root cause of the destruction of the column was the achievement of stresses in the concrete of the compressed zone of the limit values. The calculation of the height of the compressed zone was carried out according to the following dependencies:In the first case of calculation, when In the second case of calculation, when RS;In both cases, the value of the boundary value of the height of the compressed zone N is the bearing capacity of the column; D is section stiffness.The calculated eccentricity of the application of the external force was determined by the formula (8)ke calculated by the formula indicated in the block diagram, the numerical value of the coefficient kf2 is determined, which is presented in the form of expression (9).Using the flexibility of the element, the value of the relative eccentricity, as well as the value of deflections, depending on the value of the coefficient kf2, which takes into account the effect of transverse reinforcement on the rigidity of structures. The calculation results are presented in Using the proposed algorithm, the theoretical bearing capacity of transversely reinforced posts was calculated, considering the proposed coefficients kf1, which corrects the ultimate relative deformation of concrete, and the coefficient The analysis of the obtained results showed that the introduction of the proposed coefficients kf1 and kf2 into the calculation ensures good convergence of the experimental and theoretical strength of the samples. The standard deviation of the experimental from the theoretical bearing capacity is 0.06.The final calculation formula for determining the strength of concrete under conditions of volumetric stress state is:Comparison of the experimental and theoretical values of the strength of the posts when calculating the bearing capacity of reinforced specimens using the formulas (1)–(11) proposed by the authors makes it possible to improve the convergence of the results of calculation and experiments, which positively affects the reliability of the proposed recommendations.In centrally compressed columns, the maximum effect of increasing the bearing capacity is achieved with continuous wrapping with composite materials (41%). The use of external linear reinforcement elements located along the axis of action of the force does not give a positive result, since at a load level of about 80% of the limit, the laminates were destroyed due to local buckling of the strips and their fracture. The use of carbon-fiber rod reinforcement, glued symmetrically into the cut longitudinal grooves, gives the effect of increasing the bearing capacity up to 20% due to the guaranteed inclusion in work before the application of the breaking load.0 = 0.16 h, under conditions of nonuniform compression of the section, all options for strengthening in the transverse direction had a positive effect (from 30% to 40%). The use of external linear reinforcement elements located along the axis of action of the force from the side of the most compressed concrete fibers does not increase the bearing capacity, and the sticking of longitudinal laminates on the least compressed edge gives a minimal increase in strength due to the redistribution of forces in the cross-section through the transverse clamps.In columns with an eccentricity value of e0 = 0.32 h, reinforcement in the transverse direction gives a minimal effect of increasing the bearing capacity (15%), and the use of longitudinal laminates on the side of tensioned concrete in combination with transverse clamps increases the strength up to 25%. Under the condition of the use of a wide collar in the middle part, which ensures guaranteed transmission of tensile stresses to the composite material, the strength increases up to 44%.In columns with an eccentricity of application of the external force eTests of compressed reinforced concrete elements reinforced with various types of transverse, longitudinal, and combined composite reinforcement and tests at three values of the stress-strain state made it possible to obtain new data on the strength, deformability, and stiffness of reinforced samples, which indicate the high efficiency of composite strengthening of reinforced concrete structures. Based on the test results presented in this article, the following conclusions are drawn:This study identified cases of possible effective use of longitudinally located reinforcing elements made of composite materials in compressed columns. The amount of FRP reinforcement and the configuration of the reinforcement, depending on the flexibility of the columns (the ratio of the length to the height of the section), requires further study.


In 2020, Afghanistan supplied around 85% of the world's heroin. The recent Taliban takeover and political upheaval seems highly likely to impact the supply chain, but how? This literature review aims to explore the background of heroin production and possible consequences of the recent conflict, both for suppliers and for end users.In addition to recent mainstream media news articles on the Afghanistan conflict, PubMed search terms “heroin adulteration” were used to find 202 results. Only results published from the year 2000 onwards were examined for relevance, leaving 160 results. These were reviewed for relevance and led to suggestions of similar PubMed articles to arrive at the final 23 sources used.Studies of previous heroin shortages in Australia and the UK are discussed to gain insight into the potential effects of a future shortage. A reduction in heroin exports from Afghanistan would cut down the supply to most nations excluding North and South America. Sources of evidence for our current understanding of the supply chain are examined. Specific US and UK policy failure which led to the current situation is also provided for context.Methods of production in Afghanistan and smuggling routes are also examined to help predict impending changes.Given the number of factors involved it is difficult to anticipate with much certainty how the Taliban takeover of Afghanistan will affect the global heroin trade, but based on the available literature it seems more likely that this will cause shortages rather than an increased supply.Clinicians should be aware that in line with previous shortages, this may cause a shift towards increased rates of polysubstance use in regular heroin users. We may also see a rise in incidents of harm from heroin adulteration with substances other than the currently widespread paracetamol and caffeine.


This study was performed to quantify research development, patterns, and trends in the use of SN in the field of HIV/AIDS, and used Global publications extracted from the Web of Science Core Collection database. Networks of countries, research disciplines, and most frequently used terms were visualized. The Latent Dirichlet Allocation method was used for topic modeling. A linear regression model was utilized to identify the trend of research development. During the period 1991–2019, in a total of 5,698 publications, topics with the highest volume of publications consisted of (1) mental disorders (16.1%); (2) HIV/sexually transmitted infections prevalence in key populations (9.9%); and (3) HIV-related stigma (9.3%). Discrepancies in the geographical distribution of publications were also observed. This study highlighted (1) the rapid growth of publications on a wide range of topics regarding SN in the field of HIV/AIDS, and (2) the importance of SN in HIV prevention, treatment, and care. The findings of this study suggest the need for interventions using SN and the improvement of research capacity  MoreThe importance of SN has attracted scholars around the world to investigate its application in mitigating the burden of HIV/AIDS. There has been substantial growth in the body of publications about this topic over decades, and many systematic reviews have been performed to measure the effects of SN and SNIs on different key populations , 35–38. In our study, the Web of Science (WoS) Core Collection database was chosen for the searching process because it includes more information for our analysis than other databases including publications' contents  and metrics  , 40. TheWe developed the search query aiming to retrieve the articles about social networks application in HIV research. We divided the search process into two stages. First, we used the search terms “HIV,” “AIDS,” “Human Immunodeficiency Virus,” and “Acquired Immune Deficiency Syndrome” for the topic search. Then, after achieving the HIV/AIDS dataset, we searched the following terms in the title/abstract to filter the social network-related studies: “social network(s),” “social network analysis,” “network analysis,” “network analyses,” “friendship network(s),” “peer network(s),” “sociometric(s),” “sociogram(s),” “sociomap(s),” “egonetwork(s),” “respondent driven,” “respondent-driven,” “social support,” “interpersonal,” “cliques,” “community support,” and “social capital.” We also searched for terms regarding popular software for social network analysis such as “UCINET,” “NetDraw,” and “Pajek.”Only articles were (1) original or review articles, (2) published in peer-reviewed journals in the English language, and (3) used or discussed the social networks in HIV-related topics were included. We excluded gray literature, book/book chapter, conference abstract/proceeding, or other types of documents that did not meet the inclusion criteria. Finally, a total of 5,698 articles were used for bibliometric analysis .We applied the bibliometric approach to evaluate the selected articles. For bibliometric analysis, we used Stata version 15.0For visualizing the co-occurrence of the most frequent terms, the VOSviewerp-value < 0.05 to detect statistical significance.We used Latent Dirichlet Allocation (LDA), a type of machine learning method, to exploit the latent topics and figure out the research tendency over the years. LDA is one of the most used techniques in this area for further analysis. In order to understand the structure of research development, current trends, and multidisciplinary landscapes of research in HIV/AIDS and social networks, it was useful to group articles into subjects that were comparable to one another. Each component in a random vector represents the likelihood of drawing the words or texts connected with that component. We utilized LDA to classify the text in each abstract to a topic where Dirichlet is employed as a distribution over discrete distribution –43. The The general characteristics of selected articles are presented in Results of twenty papers with the highest number of citations   –56, whicIn this study, we also observed that the geographical distribution of articles was not equal. Although the result recorded that authors from ninety countries participated in the SN-related studies, most of the publications were produced by researchers from the United States, England, South Africa, Canada, China, and Australia. Meanwhile, there were a limited number of publications in other countries in African  or Asian  countries with a high burden of HIV. Additionally, among approximately 6,000 selected publications, we only found more than 400 papers with intervention design, and most of them were performed in high-income countries. This finding suggested that the application of SN in developing HIV-related interventions is still limited. Moreover, it should be noted that behavioral change interventions rely on the behaviors and cultures of target populations, in other words, must be contextualized in order to obtain the highest effectiveness . The limBy using the LDA, we could uncover the fifteen latent topics of selected publications. The findings of this study indicated a diversity of topics regarding SN use, including risk behaviors, HIV/STIs prevalence, mental disorders, HIV care and treatment, stigma, reproductive health service use, and online social media interventions. Mental health was the dominant topic, followed by HIV/STI prevalence and HIV-related stigma. This result could be justified by the characteristics of SN that SN reflects how one person can socially interact with another. Social support serves as a functional characteristic of SN, and people with stronger social support can mitigate the negative influence of mental problems such as depression or anxiety . Meanwhivia titles/abstracts of publications instead of using full texts.Study strengths included the analysis of global literature as well as the application of advanced techniques namely the LDA for content analysis. Nonetheless, some limitations should be noted. First, we only searched literature through only the WoS, which might cover publications in peer-reviewed journals not indexed in this database. Second, gray and non-English literature was excluded from this study. Third, we only performed content analysis via regional collaborations to reduce the HIV burden in low- and middle-income countries.This study highlighted the rapid growth of publications in a wide range of topics regarding SN in the field of HIV/AIDS, underlining the importance of SN in HIV prevention, treatment, and care. The findings of this study suggested the need for interventions using SN and the improvement of research capacity The original contributions presented in the study are included in the article/Conceptualization: LPD, LB, CAL, and BJH. Data curation: LHN, HTN, GTV, and CSHH. Formal analysis: PA, HTN, and BJH. Investigation: PA, CAL, and CSHH. Methodology: PA, GTV, BJH, and RCMH. Supervision: HTN, CAL, and BJH. Writing—original draft: LPD, LHN, LB, GTV, and RCMH. Writing—review and editing: LPD, LHN, LB, CSHH, and RCMH. All authors have read and agreed to the published version of the manuscript.The article process charge of this paper is supported by NUS Department of Psychological Medicine (R-177-000-100-001/R-177-000-003-001) and NUS iHeathtech Other Operating Expenses (R-722-000-004-731).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To study the effect of the bonding area on the dynamic failure process of a reinforced concrete beam with the same reinforcement ratio, the experimental and numerical researches on the impact response of notched reinforced concrete beams in the low-velocity regime (≤2.5 m/s) are presented. The tests are carried out with a drop hammer impact testing machine and then the structural responses under different impact velocities are analyzed. Additionally, the dynamic three-point bending simulation for specimens with different bonding areas, but the same reinforcement ratio is conducted. In this numerical model, the parameters of a cohesive model verified from a steel bar pullout test are applied to the bonding layer to simulate the bond-slip behavior of steel bars. Then, the energy dissipation for each component  are compared and discussed. The dynamic experimental results suggest that the energy absorbed during the impact process increases with the growth of the impact velocity, while the effect of the impact velocity on the reaction force can be ignored. The numerical results indicate that the failure pattern changes from a bending failure to shear failure with the increase in the bonding area and impact velocity. With the growth of the bonding area, the steel bars reach the plastic stage easily and the internal energy dissipation of the bonding layer decreases, which protects the bonding effect between the steel bar and concrete effectively. During the service life of reinforced concrete structures, they may be subjected to various types of dynamic loading in the form of blasts or impacts ,2,3. TheThe failure behaviors of complete reinforced concrete beams under varying impact velocities have been investigated by many experimental and numerical studies ,7. Drop-Except for the dynamic bearing capacity, the energy absorbed during the dynamic failure process is also important to evaluate the impact resistance of reinforced concrete beams. Actually, part of the impact energy is used to the failure beams, yet the other part is applied to accelerate the specimen. In order to evaluate the absorbed energy for destroying the beam, the equivalent static method is proposed . After cUnder impact loads, the effect of the reinforcement ratio on the dynamic failure behavior of reinforced concrete beams cannot be ignored. Some researchers have studied the influence of the reinforcement ratio on the impact response for reinforced concrete beams, whereas the effect of the bonding area on the dynamic failure behavior is hard to find. Fujikaka et al.  carried In this paper, the steel bar pullout simulation is established, where the cohesive elements with 0 thickness are inserted between the concrete and steel bars to simulate the bond-slip behavior for steel bars. After comparing with the pullout experimental result, the cohesive parameters are obtained. Subsequently, the finite element model for the drop hammer impact system is established and verified with the drop hammer three-point bending experimental results for notched reinforced concrete beams. Based on this numerical model, the influences of the impact velocity and the bonding area on the dynamic failure process and energy dissipation for each of the components are investigated. In addition, the dynamic three-point bending tests for notched reinforced concrete beams are carried out and the failure pattern and the structural response are discussed.b) of 150 mm, a depth (H) of 150 mm, and a clear span length (S) of 0.6 m. A schematic of these specimens is presented in 3, and the average compressive strength was 67.39 MPa. Hotrolled Ribbed Bars (HRB) with a yield strength of 335 MPa  by weight was 1: 0.35: 2.62: 1.55. Cement with a strength grade of P.O 42.5 was applied in the preparation process. All the specimens have rectangular cross sections with a width (H) were 50, 150, and 250 mm, and the specimens were indicated as S1-50, S1-150, and S1-250. According to the 2 mm/s, 1.71 × 103 mm/s, and 2.21 × 103 mm/s, respectively, where g is the acceleration of gravity (g = 9.8 m/s2). In this paper, the maximum impact energy is just enough to make the crack run through the specimen. Before starting the impact test, two steel supports were fasted on the rigid base symmetrically. As presented in All the impact tests were conducted with the drop hammer impact device designed and constructed in the Qinghai Provincial Key Laboratory of Energy-saving Building Materials and Engineering Safety, as shown in Finite element analysis was conducted to simulate the dynamic response of the reinforced concrete beams subjected to impact loading using a commercial Finite Element Model (FEM) software  . In this−1. The strain effect of concrete has not been considered in this study.Many scholars have analyzed the constitutive relationship of concrete under uniaxial tension and compression. Assuming that concrete is a kind of uniform, homogeneous, elastic, and brittle material. In this paper, the CDP model is applied to describe the nonlinear behavior of concrete in ABAQUS. This constitutive model considers the tensile/compressive damage and has been used to analyze the failure process of concrete under static/dynamic loads, cyclic loads, and monotonic loads ,35,36,37The damage factors in the damage plastic model can describe the stiffness degradation and failure process of concrete. The stress–strain curves of concrete materials under uniaxial tensile and compressive loads are shown in Under a uniaxial tensile load, the peak stress of concrete is The uniaxial compressive stress of concrete can be obtained from Equation (2), where According to the research results from other scholars , the calThe constitutive model of concrete under a uniaxial tensile load is expressed in the form of Similar to the compressive damage parameters, the tensile damage parameters of concrete can be calculated as Equation (7).cb = 0.7 and tb = 0.1 were obtained by fitting the stress–strain curves of plain concrete subjected to repeated loads. The parameters of the concrete model are listed in In the reference , bc = 0.5 MPa. The yield strength and ultimate strength of steel increase with the increase in the strain rate, and the constitutive equation can be expressed as Equations (8) and (9), respectively.−1 is used for the static strain rate. Additionally, −1 are selected, as shown in In this model, a three-fold model is applied to the reinforcing bar. The test results show that , the elaely. Lin  conducte4–109 MPa/mm [6 MPa/mm, and the constitutive equations in normal and tangential directions are as follows:The cohesive model can reflect the mechanical properties, such as the strength and elastic modulus of the interface layer between the two materials by setting appropriate parameters. When the stress of the interface layer element reaches a certain strength, the bonding between the two materials starts to fail and the separation between the two materials is presented. In this numerical model, the cohesive model is used to simulate the bond-slip behavior of a steel bar. Thus far, the cohesive behavior between the steel bars and concrete can be described with different traction-displacement curves, such as trapezoidal, bilinear, exponential, and polynomial curves ,45. Amon9 MPa/mm ,48. In tAs illustrated in In order to obtain the material parameters of the bonding layer between the steel bar and concrete, the pull-out test of reinforcement was conducted with the YAW4306 electro-hydraulic servo testing machine. Before the test, a steel bar 400 mm in length and 12 mm in diameter embedded in the concrete block was applied. The bonding length of steel bar was set to 60 mm , the bond-slip curve is plotted. The comparison result is presented in 3) was applied for the hammer. Two supports were assumed as rigid bodies, which could slide only in a horizontal direction. After analyzing the sensitivity of the mesh, 2 mm and 15 mm were adopted for the steel bar and concrete, respectively. Additionally, the three-dimensional 8-node reduced integral element (C3D8R) was adopted for the concrete and steel element types.In order to simulate the dynamic failure process of notched reinforced concrete beams, the finite element model for the drop hammer impact system was established with the bond-slip constitutive model mentioned before, as shown in 3 mm/s. As presented in For brevity, a representative comparison is shown only for structural response when the impact velocity was 1.71 × 102, 0.04 m2, and 0.06 m2, respectively.The reinforcement ratio is an important material parameter to describe reinforced concrete structures. However, under the same reinforcement ratio, significant differences are found in the bonding area of concrete specimens with steel bars of different diameters. In the experiment, the diameter of the steel bar was 12 mm, and the reinforcement ratio was 0.5%. By keeping the reinforcement ratio, depth, and width of the notch, the distance between the reinforcement and the bottom of the specimen unchanged, and by inserting steel bars with different diameters into the concrete matrix, the effect of the reinforcement configuration on the dynamic failure process of the reinforced notched beams can be studied. As illustrated in Exx) under different impact loading, as presented in Considering the low reinforcement ratio and low impact velocity, the crack at the mid-span of the beam initiates from the notch root and then propagates upwardly to the loading point. Thus, a spray-painted speckle pattern is applied onto the mid-span surface of the specimens to monitor the crack propagation process. Additionally, then Digital Image Correction (DIC) technology is conducted to measure the displacement field. Subsequently, the strain field is given from the displacement field with the Euler–Lagrange algorithm in MATCH-ID 2021.2, MATCH-ID NV . Finally, the crack path is obtained from the change in the strain field in the horizontal direction , the maximum value of the steel strain is about 1000 Apart from the dynamic bearing capacity, the absorbed energy is another important parameter in evaluating the structural safety. The area enclosed by the reaction force-mid-span deflection curve can be taken as the energy absorbed in the failure process of the beam . The reaBased on the numerical model mentioned before, three impact velocities for 0.5 m/s, 1.5 m/s, and 2.5 m/s are assigned to the hammer reference points in a vertical direction to study the failure pattern for specimens with different amounts of steel bars. The dynamic failure process is shown in The reaction force and mid-span deflection from numerical results are obtained to evaluate the absorbed energy. Based on the method used in the previous tests, the energy consumed by the specimens during the impact process is calculated by integrating the reaction force-mid-span deflection curves. The impact energy during the impact process is the kinetic energy of the hammer, which can be calculated according to According to the static simulation results, the static bearing capacity of the specimens increases with the growth in the bonding area. To evaluate the effect of the bonding area on the dynamic bearing capacity, the ratio of the maximum reaction force (In the numerical simulation, the maximum mid-span deflections of concrete specimens with different reinforcement conditions are extracted, as presented in The effect of the bonding area on the deflection can be ignored when the impact velocity is 0.5 m/s and 1.5 m/s. When the impact velocity is 2.5 m/s, the maximum mid-span deflection decreases more obviously as the bonding area increases. Under the same impact energy, the steel bars with a small radius reach the plastic stage easily, which leads to the deformation resistance for the increases in the reinforced concrete beam.As presented in For the purpose of investigating the dynamic failure process, the energy dissipation for concrete, steel bars, and the bonding layer are analyzed. The damage energy dissipation of concrete under different velocities are compared, as shown in In the numerical model, the bonding layer between the steel bar and the concrete is modeled with cohesive elements of a zero thickness, whose plastic deformation is not found. Therefore, only the plastic energy dissipation for steel bars and concrete are analyzed, as shown in The internal energy dissipation for each component is compared and analyzed, as shown in Although the specimens with different bonding areas have the same failure pattern when the impact velocity is less than 2.5 m/s, a difference in the stress distribution is found, as shown in In conclusion, when the reinforcement ratio is a constant value, the increase in the bonding area leads to the decrease in the maximum stress of the bonding layer, which reduces the failure of the bonding layer and protects the integrity of the specimen.When the reinforcement ratio remains constant, with the growth of the impact velocity and bonding area, the failure pattern for the notched reinforced concrete beam changes from bending failure into shear failure.As the bonding area increases, the damage energy dissipation for concrete decreases when shear failure occurs, which is opposite to that in the bending failure pattern.The larger the bonding area is, the higher the plastic energy dissipation for steel bars is and the smaller the mid-span deflection is. This indicates that the impact resistance enhanced with the growth of the bonding area.Under different impact velocities, the internal energy dissipation of the bonding layer decreases with the growth of the bonding area. Therefore, the increase in the bonding area can protect the bonding effect between steel bars and concrete.For the purpose of investigating the effect of the bonding area on the dynamic fracture behavior for notched reinforced concrete beams with the same reinforcement ratio, dynamic three-point bending tests and a numerical simulation are carried out. Additionally, the effects of the bonding area on the energy dissipation for each component are discussed. The main findings are summarized as follows:


MET exon 14 skipping mutation (METex14). Savolitinib was developed as a monotherapy for NSCLC with MET alterations, and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who developed resistance to EGFR–TKIs because of MET alterations. Savolitinib showed anti-tumor activity in preclinical models. The early phase I trial established the recommended phase II dose to be 600 mg once-daily. Savolitinib plus osimertinib showed beneficial efficacy and safety in EGFR mutant patients with acquired resistance due to MET amplification and/or c-MET overexpression. Benefits were noted with savolitinib in Chinese patients with pulmonary sarcomatoid carcinoma and other NSCLC subtypes positive for METex14 mutation. Results from phase III trials are awaited to further confirm the beneficial effects from early phase trials.In this article, we outline updates on the clinical development of savolitinib, a novel, reversible c-MET kinase inhibitor conditionally approved in China for treatment of advanced non-small cell lung cancer (NSCLC) patients harboring ®) is highly selective mesenchymal epithelial transition (MET)–tyrosine kinase inhibitor (TKI), which is conditionally approved in China for advanced NSCLC with MET exon 14 skipping mutations (METex14). This article summarizes the clinical development of savolitinib, as a monotherapy in NSCLC with METex14 mutation and in combination with epidermal growth factor receptor (EGFR) inhibitor in post EGFR–TKI resistance NSCLC due to MET-based acquired resistance. Preclinical models demonstrated anti-tumor activities in MET-driven cancer cell line and xenograft tumor models. The Phase Ia/Ib study established an optimized, recommended phase II dose in Chinese NSCLC patients, while TATTON study of savolitinib plus osimertinib in patients with EGFR mutant, MET-amplified and TKI-progressed NSCLC showed beneficial efficacy with acceptable safety profile. In a pivotal phase II study, Chinese patients with pulmonary sarcomatoid carcinoma, brain metastasis and other NSCLC subtype positive for METex14 mutation showed notable responses and acceptable safety profile with savolitinib. Currently, results from ongoing clinical trials are eagerly anticipated to confirm the efficacious and safety benefits of savolitinib as monotherapy and in combination with EGFR–TKI in acquired resistance setting in advanced NSCLC and its subtypes with MET alterations.Non-small cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Savolitinib (Orpathys EGFR), anaplastic lymphoma kinase (ALK) and c–ros oncogene 1 (ROS1), is considered as standard-of care to select the most appropriate up-front treatment  as well as 34%—at the high threshold [IHC90+ and/or FISH10+] subgroups. MET amplified and/or c-MET overexpressed in this study suggesting amplification and/or overexpression is the most common osimertinib resistance mechanism. The baseline characteristics are provided in n = 193) with high MET amplification and/or high threshold c-MET overexpression level show a trend toward better efficacy benefit, emphasizing the necessity of patients’ selection according to appropriate MET detection criteria in this population. Among the overall population, ORR was 32%; median DoR was 8.3 months; and median PFS was 5.3 months, while among 108 patients who met the threshold for high MET amplification and/or high threshold c-MET overexpression level (IHC90+ and/or FISH10+), ORR was 49%; median DoR was 9.3 months; and median PFS was 7.1 months  continues to explore the sequence of savolitinib plus osimertinib with previous osimertinib monotherapy resistance. It is a phase II, single-arm study evaluating the efficacy of osimertinib in combination with savolitinib in 259 patients with 1 months . The saf1 months . The incMET amplified and/or c-MET overexpressed, EGFR-mutant advanced NSCLC. In SOUND trial (NCT05374603), an open-label, interventional, multi-center, exploratory trial, savolitinib combined with durvalumab will be evaluated in Chinese EGFR wild-type locally advanced or metastatic NSCLC patients with MET alterations. NSCLC patients from China with MET amplification (n = 30) and METex14 mutation (n = 30) will be treated with 1500 mg durvalumab and 300 to 600 mg savolitinib (OD) for 28-day/cycle till disease progression, death or toxicity. Efficacy endpoints will be PFS, ORR, DoR, DCR, 12 m OS rate and safety endpoints will be AEs and AEs of special interest (AESI) [EGFR mutated, c-MET overexpressed and/or MET gene amplified) who have progressed on osimertinib treatment.In addition, the FLOWERS trial (NCT05163249) explores the efficacy and safety of osimertinib with or without savolitinib in patients with de novo t (AESI) . FurtherMETex14 mutation in China; patients of one cohort are with disease progression or toxicity intolerance after previous platinum-based chemotherapy regimens, and patients of another cohort are with no prior systemic antineoplastic therapy for advanced disease. The patients were treated until disease progression or intolerable toxicity. Phase III SACHI trial (CTR20211441) is a randomized, two-arm, open-label, multi-center study evaluating the efficacy and safety of savolitinib plus osimertinib versus chemotherapy in NSCLC patients from China with MET amplification who has progressed after first- to third-generation EGFR–TKI therapy and has already begun its recruitment in multiple centers. Another similar phase III trial SAFFRON is designed to evaluate the efficacy and safety of the same combined therapy as SACHI versus chemotherapy, but focus on global advanced NSCLC patients with MET amplification/c-MET overexpression that progressed after osimertinib treatment. SANOVO Phase III study is evaluating the efficacy and safety of savolitinib in combination with osimertinib in treatment-naïve patients with EGFR mutant positive and c-MET overexpression advanced NSCLC (NCT05009836).Currently, four phase III trials evaluating savolitinib as a monotherapy and in combination with EGFR-TKIs are underway. The confirmatory phase IIIb clinical study (CTR20211151) is evaluating efficacy and safety of savolitinib in two cohorts from patients with locally advanced or metastatic NSCLC with MET-dependent cancer cell line growth and MET-driven tumor growth in xenograft models. Following which, data from a phase I clinical trial established recommended phase II dose in patients with METex14-mutated NSCLC. Further, the TATTON study established utility of savolitinib with osimertinib in advanced NSCLC with MET-mediated acquired resistance to EGFR-TKIs. Final results of the phase II study (NCT02897479) further confirmed the benefit of savolitinib in patients with METex14-mutated NSCLC across all predefined subgroups. In addition, phase IIIb clinical study CTR20211151 is confirming the result of phase II study on METex14-mutated NSCLC, while three ongoing phase II trials, SAVANNAH, SOUND and FLOWERS, as well as three phase IIIB trials, SAFFRON, SACHI and SANOVO, are actively exploring solutions for different types of savolitinib combination regimens against EGFR resistance mechanisms. Preliminary results of the SAVANNAH trial have demonstrated the beneficial efficacy of osimertinib plus savolitinib in EGFRm NSCLC patients with MET amplified and/or c-MET overexpressed, supporting the results of TATTON study and paving the way for phase III SACHI and SAFFRON study.Savolitinib, an investigational MET highly selective agent, has shown pronounced efficacy in preclinical and clinical studies. Savolitinib demonstrated preclinical anti-tumor activity against METex14-altered advanced NSCLC, with mOS reaching 12.5 months. The effect of savolitinib was rapid, substantiated by time to response (TTR) of 1.4 months. Promising results with PFS of 5.5 months and OS of 10.6 months were also seen in the PSC subtype, which does not respond well to chemotherapy and has limited effective treatments. By now, savolitinib is the only MET inhibitor with data related to PSC associated with METex14 mutation and is becoming the first approved agent in this setting. For patients of treatment naïve population, the PFS and OS of savolitinib were 6.9 months and 10.9 months, respectively, while PFS and OS of prior treatment patients reached 6.9 months and 19.4 months, respectively. In the current scenario, the reported ORR of savolitinib is the highest in the prior treatment population compared to other treatments  [METex14-altered NSCLC after systemic treatment resistance or unable to receive chemotherapy. Post-marketing phase IIIb trial is now undergoing (HutchMed) in larger population of NSCLC patients and is expected to provide more clinical evidences for savolitinib in first-line therapy. Furthermore, latest post hoc analysis based on ctDNA detection suggests undetectable baseline METex14 or post-treatment clearance in ctDNA being relevant to favourable clinical outcomes, including better PFS and OS results, while secondary MET mutations and other acquired gene alterations after treatment  may explain resistance mechanism to savolitinib [In the hallmark phase II registry trial, savolitinib displayed promising efficacy and tolerability in patients with antamab) ,62,63,64antamab) ,48. Baseolitinib .METex14-altered advanced NSCLC population as well as subtypes [subtypes ,71,72,73subtypes . Tumor rsubtypes ,71,72,73MET signaling pathway is one of the important mechanisms leading to EGFR–TKI resistance. MET-driven resistance can be manifested as gene-level amplification or protein-level overexpression with previous treatment regimens such as chemotherapy, immunotherapy and targeted therapies including EGFR, BRAF and MEK [MET amplification and/or c-MET overexpression after first/second-generation EGFR–TKI resistance is limited, with a mPFS of only 4.9 months [MET amplification and/or c-MET overexpression subgroup data. Nivolumab monotherapy has limited efficacy after EGFR–TKI resistance, with a mPFS of only 1.5–1.7 months [MET amplification and/or c-MET overexpression was reported; meanwhile, safety of the combination therapy regimen needs attention [MET-amplified and/or c-MET overexpressed advanced NSCLC patients with EGFR–TKI resistance have limited therapeutic effect with MET inhibitor monotherapy. Only 1 of 12 evaluable patients on inhibitor monotherapy reported an objective response [EGFR and MET pathways may bring synergistic therapeutic benefit in MET-driven EGFR–TKI-resistant advanced NSCLC patients [EGFR wild-type NSCLC with MET alterations is also under exploration in SOUND trial, as previously described.Bypass activation mediated by the  and MEK ,75. The 9 months ,77. The 7 months ,79. In Ittention ,81. MET-response . Dual-tapatients . MeanwhiMET-driven resistance to EGFR–TKIs. Acquired resistance to first- and second-generation EGFR–TKIs is often caused by the acquisition of the T790M mutation, which accounts for approximately 60% of resistant cases and has been overcome by third-generation EGFR–TKIs such as osimertinib. For first- and second-generation EGFR–TKIs, acquired resistance for MET-amplification is at least 5% , while up to 25% of acquired resistance is observed with third generation EGFR–TKI  [MET amplification associated with EGFR–TKI resistance offered explicit benefit with savolitinib in NSCLC patients without prior third-generation EGFR–TKI, while those who were administered with a prior third-generation EGFR–TKI had a relatively lower rate of response regardless of T790 status, possibly related to larger proportion of patients with ≥3 lines of treatment comprising the prior third-generation EGFR–TKI group (56.5% vs. 22.6% in partB2 + partD). Nonetheless, TATTON program demonstrated beneficial efficacy of savolitinib plus osimertinib combination in the MET-amplified, EGFR mutation–positive setting with acceptable safety profile which is a first in this setting [MET amplification or c-MET overexpression due to osimertinib-acquired resistance. Initial results from the SAVANNAH trial show a trend toward improved response rates, with increasing level of MET amplified and/or c-MET overexpressed. Across all patients in this analysis, ORR was 32%; mDoR was 8.3 months; and mPFS was 5.3 months, while in high level MET amplification and/or c-MET overexpression subgroup, ORR was 49%; mDoR was 9.3 months; and mPFS was 7.1 months [MET alterations treated with combination therapies available so far is provided in The combination of EGFR inhibitor and MET-highly selective TKI possesses the potential to prevent or overcome ertinib) . TATTON  setting . FurtherMET amplification can be detected by using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). With MET amplification, MET/CEP7 ratio is as follows: low: ≥1.8 to ≤2.2; intermediate: >2.2 to <5; or high: ≥5 will be applied in clinical settings when treating patients with MET inhibitors [MET amplification in NSCLC ranges from 3% to 10% depending on the cut-off of MET copies per cell [MET positive [MET detection method and the dual-target efficacy after third-generation EGFR–TKI resistance: Based on FISH detection, the ORR value of MET local amplification was higher than that of MET polysomy patients although polysomy patients benefited from the treatment. In the MET-amplified population, patients with higher gene copy numbers detected by FISH had a better treatment benefit [MET amplification and/or high threshold c-MET overexpression level (IHC 90+ and/or FISH 10+) with an ORR 49%, mDoR of 9.3 months, and mPFS of 7.1 months was observed. The safety profile was acceptable, similar to that of TATTON study [hibitors . The freper cell . c-MET opositive . The TAT benefit . FurtherON study . FurtherMETex14-mutated NSCLC is based on encouraging results from phase 2 trial conducted in China including patients with the more aggressive PSC subtype and brain metastasis. Savolitinib is a potent, highly selective MET inhibitor with robust response in advanced NSCLC. Preclinical and clinical data have shown savolitinib as effective and tolerable treatment in advanced NSCLC patients with METex14 skipping mutations. When used in combination with EGFR-TKIs, savolitinib has the potential to overcome resistance to these treatments driven through MET amplifications and/or c-MET overexpression, with future clinical trials verification needed. In conclusion, savolitinib offer another promising targeted treatment in the paradigm of metastatic NSCLC.The conditional approval of savolitinib for the treatment of metastatic


Antibiotic stewardship programs optimize antibiotic use in hospitalized children, but most do not routinely review antibiotic prescriptions at discharge. Up to 30% of discharged children receive additional days of antibiotics, and one single-center study found that 27% of discharge prescriptions were suboptimal.We conducted a retrospective cohort study to evaluate duration of therapy (DOT) and antibiotic choice for children < 18 years admitted to 4 children’s hospitals from January 1, 2019 - December 31, 2019 and prescribed antibiotics at discharge for uncomplicated community-acquired pneumonia (CAP), skin and soft tissue infection (SSTI), or urinary tract infection (UTI). We excluded children with complex medical conditions, > 1 infection requiring antibiotics, > 7 day hospital stay, or intensive care unit stay. The primary outcomes were the percentage of subjects prescribed optimal (1) total (inpatient plus outpatient) DOT , and (2) antibiotic choice ; UTI: cephalexin, amoxicillin, amoxicillin-clavulanate, TMP/SMX, or nitrofurantoin) based on current national guidelines and available evidence.2105 encounters were included: 783 CAP, 916 SSTI, and 406 UTI. Median age was 4 years and 49% were female. DOT for each condition are shown in Figure 1 and antibiotic choice in Figure 2. Antibiotic choice was optimal for 66% with CAP, 98% with SSTI, and 88% with UTI. DOT was optimal for 11% with CAP, 4% with SSTI, and 21% with UTI. Both DOT and choice were optimal for 2% with CAP, 4% with SSTI, and 19% with UTI. For all indications, antibiotic choice was optimal for 84% and DOT was optimal for 10%, while only 6% of antibiotic courses included both optimal DOT and antibiotic choice.Total duration of therapy for 2105 children discharged with antibiotics for community-acquired pneumonia, urinary tract infection, and skin and soft tissue infection.Discharge antibiotic choices for 2105 children with community-acquired pneumonia, urinary tract infection, and skin and soft tissue infection.At 4 children’s hospitals with established antimicrobial stewardship programs, 94% of discharge antibiotic courses for CAP, UTI, and SSTI were suboptimal either by choice of antibiotic or duration of therapy. Discharge antibiotic prescribing represents a significant opportunity to improve antibiotic use in children.Jason Newland, MD, AHRQ: Grant/Research Support|Merck: Grant/Research Support|NIH: Grant/Research Support|PEW Charitable Trust: Grant/Research Support|Pfizer: Grant/Research Support.


Hybrid hydrogels composed of chitosan (CS) have shown great potential in bone tissue engineering and regeneration. The introduction of polyhedral oligomeric silsesquioxanes (POSS) in the biopolymeric matrix has been demonstrated to improve the rheological and biological properties of the hybrid composites. In this work, we have integrated the favourable features of chitosan (CS) and POSS nanoparticles to design new nanocomposites for bone tissue regeneration, focusing our attention on the effect of POSS concentration within the CS matrix  on the chemical, physical, rheological, and in vitro biological properties of the final composites. The drug release ability of the synthesized hydrogel scaffolds were also investigated using, as the model drug, ketoprofen, that was included in the scaffold during the gelling procedure, showing a more controlled release for the hybrids with respect to CS (86–91% of drug released after two weeks). The results of the in vitro biological tests performed on human fetal osteoblastic cells (hFOB 1.19) culture demonstrated the great biocompatibility of the hybrid materials. The hybrids, at the different POSS concentrations, showed values of cell mortality superimposable with control cells (11.1 vs. 9.8%), thus revealing the CS/POSS hydrogels as possible candidates for bone tissue engineering applications. Bone tioperties ,26,27,28operties ,26. Biocoperties . The incoperties ,29. Moreoperties .2 group of chitosan to the double bond present in the POSS structure was performed using POSS amounts of 0.5, 1, and 1.5 wt%, with respect to chitosan, thus allowing the formation of CS-POSS hybrid materials with different POSS contents  characterizations were performed using a TAQ500 instrument  from 20 °C to 600 °C, at a rate of 20 °C/min, under inert atmosphere. Rheological measurements were accomplished using a rotational rheometer  at 37 °C, with parallel-plate geometry. UV analyses were carried out with a Thermo Nicolet mod. Evolution 500 spectrophotometer, by measuring the absorbance of the drug at 260 nm. Fluorimetric analyses were performed using a microtiter plate reader ; for the morphological analyses, a TCS SP2 instrument  equipped with an Ar/Kr laser and coupled with a microscope (Leica DM IRB) was employed.The reagents chitosan , acetic acid (99.9%), and ketoprofen (>99%), ninhydrin, were purchased from Sigma Aldrich ; acryloxypropyl-heptaisobutyl-POSS  was purchased from Hybrid Plastics (USA); genipin (>98%) was acquired from Carbosynth . All chemicals and solvents were used without further purification. Cell line hFOB 1.19 was purchased from ATCC-, while fluorophores and cell culture media were purchased from Sigma-Aldrich. The infrared spectra were obtained using a Two FT-IR Spectrometer (PerkinElmer Inc.), by the ATR method in the range of 4000–500 cm1 (ratio CS/POSS = 1:0.5), CS-POSS 2 (ratio CS/POSS = 1:1), and CS-POSS 3 (ratio CS/POSS = 1:1.5), were treated with a saturated solution of NaHCO3 until neutral pH was reached, and subsequently, purified through dialysis bags  for two days. Finally, the samples were lyophilized by freeze-drying at −80 °C for 72 h and used for subsequent characterizations. The amount of free amino groups present in the CS and in the CS-POSS hybrids were evaluated by UV–vis absorption spectra, after reaction with ninhydrin, following a method reported in the literature [CS-POSS hybrids were synthesized by Michael type reaction . Brieflyterature . Briefly1, CS-POSS 2, and CS-POSS 3 hydrogels, respectively.Chitosan powder (200 mg) or CS-POSS hybrid samples (200 mg) were dispersed in a 2% aqueous acetic acid solution for 30 min, at 45 °C. Then, 20 mg (0.1 mmol) of genipin was slowly added to the mixture leading to the formation of a 3D gel. The hydrogels were then rinsed with deionized water and then stored at 15 °C in a hermetic sealed pan with a constant relative humidity. The amount of water content, measured by drying the hydrogels in a beaker for 24 h at 37 °C and at a vacuum drying pressure of 65 mbar until constant weight, was found to be of 94 wt%, 82 wt%, 78 wt%, and 73 wt% for CS, CS-POSS Ketoprofen-doped CS and CS-POSS hydrogels were prepared and stored, following the procedure described in The drug release behavior was evaluated from ketoprofen-doped CS and CS-POSS hydrogels in order to study the effect of the presence of the silica cage on the drug release properties of chitosan-based matrices. The study was conducted at a temperature of 37 °C, in phosphate buffer solution (pH 7.4) using the dialysis bag diffusion technique. The amount of drug released was evaluated by UV-Vis absorption analyses, measuring the absorbance of the drug at 260 nm, referring to a calibration curve recorded under the same conditions. The Linearity Standard calibration curve was found to be linear at concentrations ranging from 0.25 to 250 ng/mL (y = 0.0854x + 0.0357) with a correlation coefficient of 0.9772.Rheological analyses were carried out on cylindrical samples (diameter of 25 mm and height of 1 mm) by means of a rotational rheometer. Measurements were carried out in a controlled humidity environment by filling the specimen holding system with deionized water and sealed with an insulating cover to avoid drying of the samples during the tests . The dyn2, in order to mimic the natural living tissue environment. The samples (100 μL) were gelified at room temperature in 6-well cell culture plates, to which the cell suspension (5 × 104 cells/mL) was added while cells, cultured in their specific medium and grown in wells without the gelified sample, were used as negative controls. In each well, the area covered by the hydrogels was calculated using ImageJ software  in order to use only wells with a sample area equal to 35% (±5) of the entire well area. Cells were grown on the formed hydrogels for 48 h. The biocompatibility of the tested materials with increasing amounts of POSS concentrations  was evaluated by fluorimetric analysis (λ exc 493–λ em 636 nm) using a DNA intercalating probe propidium iodine (PI 20 μg/mL) for 15 min at −20 °C. The analyses were performed at least in triplicate both on the cell medium to detect the detached cells (death cells) and, after cell permeabilization by methanol, on the adherent cells to assess the viable cells. The data were presented as the mean ± standard deviation (SD) and were analysed by one-way analysis of variance (ANOVA) to assess possible significant differences, which were accepted at p < 0.05 (GraphPad Prism 8). To evaluate any morphological alterations due to the effects of the hydrogels, confocal microscope observations were performed by a CLSM equipped with a 40× 1.0 NA immersion objective and a TCS SP2 instrument . The cell-permeable metachromatic fluorophore acrydine orange (AO) was used. AO allows you to clearly visualize both the cytoplasmic compartment where, thanks to the presence of the acid compartment, the organelles that emit red fluorescence can be seen, and the nuclear ones with green fluorescence, due to the bond between AO in monomeric form and DNA double helix.Human fetal osteoblastic cells  were used as in vitro models to assess the biocompatibility of the synthesized CS- and CS-POSS-based hydrogels. The cells were grown in a 1:1 mixture of Ham’s F12 and DMEM medium without phenol red and with the addition of 2.5 mM L-glutamine, 0.3 mg/mL G418, and 10% of fetal bovine serum, at 34 °C in an atmosphere of 5% CO1, 53% to CS-POSS 2, and to 39% to CS-POSS 3.The first step to obtain CS-POSS-based hydrogels was to perform the Michael addition reaction between the amino group of chitosan and the terminal double bond present in the POSS molecule. In order to investigate how a different amount of POSS can tune the chemical-physical, mechanical, morphological, and biological behaviour of the composites, we used 0.5, 1, and 1.5 equivalents in weight of POSS with respect to the used weight of CS. The reaction, performed in water solution and at a mild temperature (50 °C) afforded the conjugated compounds, which were purified through a dialysis bag able to retain compounds with MW of 12,000 or higher. The subsequent reaction with the cross-linking agent genipin allows the binding of two amine groups between the neighbouring chains of the CS polymer, leading to the formation of the corresponding hydrogels . The amo−1 due to the stretching of N–H and O–H bonds, a band at 1580 cm−1 attributable to N–H bending, and a peak at 1028 cm−1 corresponding to the stretching of the C–O group; in addition, the presence of the peak at 1650 cm−1, corresponding to C=O stretching of the primary amide, confirms the existence of residual N-acetyl groups in the chitosan structure. The POSS sample shows the diagnostic signals at 1111 cm−1 attributable to Si-O-Si stretching of the silica cage, and the peak at 1735 cm−1 corresponding to C=O stretching of the ester group. In the spectra of the three CS-POSS conjugate samples, namely CS-POSS 1, CS-POSS 2, and CS-POSS 3, containing 0.5, 1, and 1.5 equivalents of POSS in weight, respectively, the stretching frequency of the C=O ester groups occurred at lower frequencies (~1640 cm−1) than that observed for the starting POSS (1735 cm−1). The observed blue shift is attributable to the weakening of the C=O ester bond strength, since the double bond of the α,β-unsaturated ester is no longer present in the hybrid systems [The effectiveness of Michael type reactions in affording new hybrid materials after covalent binding was investigated by FTIR spectroscopy and TGA analyses for all the synthesized samples, before the gelation procedures. FTIR spectra demonstrated the presence of a covalent bond between CS and POSS, at the different concentrations . The FTI systems , thus co1, CS-POSS 2, and CS-POSS 3, are indicative of their different chemical composition with respect to CS and POSS precursors after the conjugation reactions, differing only in the amount of POSS molecules inside the hybrids, as also reported in the literature for similar systems [The conjugation between chitosan with POSS leading to CS-POSS samples was confirmed also by TGA, performed under inert atmosphere . All the systems ,27. Thes3 sample, the values drop three orders of magnitude . A similar trend is repeated at a frequency of 10 rad/sec. The rheological results are in agreement with the data obtained from the UV-vis quantification of the free amino groups. In fact, the progressive decrease of these groups needed for the cross-linking reaction with genipin, from CS to CS-POSS 1, CS-POSS 2, and CS-POSS 3 samples, leads to a progressive reduction of the reticulation degree. This decrease, together with the steric hindrance induced by the increasing POSS concentrations, also reduces the overall degree of cross-linking of the polymer matrix. Consequently, there is a decrease in stiffness (as suggested by the lowering in the G′ modulus) and in structural complexity (as suggested by the reduction in viscosity). Thus, the presence of the three different concentrations of POSS in the hydrogel changes the rheological response; the steric hindrance of POSS decreases the overall degree of cross-linking of the polymer matrix, decreasing its structural complexity. Thus, the stiffness (and viscosity) of CS-POSS-based samples progressively decreases by increasing the POSS content inside the polymeric matrix, resulting in materials that are more ductile, even more so than pure CS.All the hybrid samples and CS were then treated with genipin which, after cross-linking reaction with the free amino groups present in the CS, gave the corresponding hydrogels. The rheological properties of the so synthesized hydrogels were evaluated in dynamic stress and frequency scan modes to verify the linear viscoelastic region (LVR) and to evaluate the main rheological features , as described in The drug release behavior was investigated for the hydrogels obtained from CS and CS-POSS at different POSS concentrations, in order to study the effect of the presence of the silica cage on the drug release properties of CS-based matrices. The study was performed at the temperature of 37 °C, in phosphate buffer solution (pH 7.4) using the dialysis bag diffusion technique. The amount of drug released, evaluated in triplicate, was quantified by UV-Vis absorption spectra by measuring the absorbance of the drug at 260 nm, referring to a calibration curve recorded under the same conditions .1, CS-POSS 2, and CS-POSS 3 percentages of drug release of 91%, 89%, and 86%, respectively, after 2 weeks. The results of this study suggest the presence of specific intermolecular interactions between the POSS silica cage and ketoprofen molecule, as also observed in a previous study [The hydrogel obtained from CS shows a release of approximately 48% of the drug in 1 h, and reaches 100% of the released drug in 1 day. For the CS-POSS-based hydrogels, the release curves also show a rapid drug release (about 37%) in the first hour (see inset in us study . In factp ns). As shown in Human fetal osteoblastic cells (hFOB 1.19) were utilized as in vitro models to evaluate the cytotoxicity and biocompatibility of the synthesized CS-POSS-based hybrids. All samples highlighted a negligible cytotoxicity and, at the highest concentration of POSS (1.5 wt% with respect to CS), the percentage of dead cells was 13.3 vs. 9.8 detected in the control cells  culture demonstrated their great biocompatibility at different POSS concentrations.The combination of CS and POSS, by exploiting different conjugation procedures and different CS/POSS ratios, will represent, of course, a future research topic for the development of biocompatible and biomimetic engineered scaffolds for drug delivery, and to guide the regeneration of bone tissues.


Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease that typically manifests as mass lesions affecting almost any organ including the pancreas, lacrimal and salivary glands, liver, lung and kidney. However, IgG4-RD with urethra involvement is scarce. We describe a rare case of IgG4-RD involving the urethra mimicking urethral carcinoma and review the published literature. A 64-years-old female presented with progressive dysuria for more than 2 months. Pelvic gadolinium-enhanced magnetic resonance imaging revealed a huge mass encasing the urethra which showed obvious enhancement in the arterial phase. And contrast-enhanced ultrasound showed that the entire mass was heterogeneously enhanced and displayed a fast-forward and fast-out pattern, which was highly suggestive of malignant tumor. The diagnosis of IgG4-RD was finally established by ultrasound-guided transvaginal mass needle biopsy. The patient was treated with methylprednisolone and cyclophosphamide and dysuria disappeared in the first week of therapy. She has been followed up in our clinic for 1 year without recurrence. The diagnosis of IgG4-RD should be considered in the differential diagnosis of a periurethral mass. Ultrasound-guided transvaginal mass needle biopsy is a safe and well-established tissue sampling method and should be performed in order to avoid unnecessary surgery. Immunoglobulin G4-related disease (IgG4-RD) is a chronic, systemic, immune-mediated fibroinflammatory disease that is characterized by swelling or mass formation in various organs with abundant tissue infiltration of IgG4-positive plasma cells. It was first described in the pancreas in 1961 by Sarles H et al. in a patient with hypergammaglobulinemia and chronic pancreatitis . Since tIgG4-RD involvement of the urinary tract is relatively uncommon and the majority of the reported cases were located in the kidney, ureter and prostate  done at the local institution revealed 3.5×3.3×3.7 cm sized periurethral mass which extended from the distal urethra to the bladder neck  while serum complement component C3 and C4 were both normal, measuring 0.88 g/L and 0.11 g/L respectively. Erythrocyte sedimentation rate (ESR) was elevated to 64 mm/h and C-reactive protein level was within the normal range. Her serum rheumatoid factor level was elevated to 142 IU/mL (cut-off <15.9 IU/mL) and antinuclear antibody (ANA) was detected at a titration of 1:160 but extractable nuclear antigens (ENAs), including anti-ribonucleoprotein, anti-smith antibody, anti-double stranded DNA, anti-Ro, and anti-La antibodies were all negative. Other tests  were all normal and urine analysis results were not remarkable.At admission, the patient was afebrile with mild, painless bilateral lacrimal and submandibular glands swelling. Physical examination revealed a fixed, hard mass bulging from the anterior vaginal wall, which was palpated through the vagina. Laboratory tests showed that peripheral eosinophil cell count was 0.15×10Then, the patient underwent transvaginal ultrasonography which revealed a large well-defined heterogeneous hypoechoic mass in front of the anterior vaginal wall, measuring 3.7×3.1×3.5 cm . The results of submandibular glands ultrasound showed that the echoes were uneven and there were numerous patchy hypoechoic regions inside the glandular parenchyma . The patvia histopathology revealing significant lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis as its three key pathologic features. In addition, other histological characteristics of IgG4-RD include eosinophil infiltration and phlebitis without obliteration (IgG4-RD is a complex multi-system disorder with distinct pathological, serological, and clinical manifestations. The clinical manifestations of IgG4-RD are widely diverse and can occur in multiple organs simultaneously or metachronically over months to years. Most patients with IgG4-RD have subacute or chronic symptoms, which depends on the organ location and usually originate from the mass effect of involved organs. It can manifest in a variety of ways, ranging from mild localized symptoms to severe tissue damage and subsequent organ failure . And dueteration . In 2019teration . Our patNotably, the patient had urethral involvement with dysuria as the predominant symptom, which was uncommon and easily missed. In 2012, Yamamoto H et al. firstly reported a case of urethral IgG4-RD in an elderly woman, which resembled, at first glance, an enlarged prostate in man on MRI images . Lately,Additionally, the patient had a history of asthma and increased serum IgE levels. It should be noted that a high percentage of IgG4-RD patients report an allergic background, such as asthma, chronic sinusitis, eczema and peripheral eosinophilia –18. SomeTo date, data on imaging manifestations of IgG4-RD of the urethra are limited and unspecific. Typical imaging finding of urethral IgG4-RD reported in the literature was a solitary well-defined mass around the urethra while Zhang Z et al. reported a case of IgG4-RD affecting bladder wall and urethra at the same time . MRI wasIt is remarkable that all previously recorded patients, with the exception of one who had surgery due to a clinical suspicion of bladder cancer, underwent ultrasound-guided transvaginal urethral biopsy, just as our patient did. Among them, five specimens revealed an IgG4/IgG ratio of more than 40% and one even higher than 70%. Thus, ultrasound-guided transvaginal urethral biopsy is highly effective and safe and should be considered as a crucial tissue sampling method for a definitive diagnosis of a periurethral mass.In terms of treatment, except for one asymptomatic patient, all documented cases utilized glucocorticoids as the initial treatment and only one patient received azathioprine as a supplementary steroid‐sparing medication. Glucocorticoids are the first‐line agents to induce remission in patients with IgG4‐RD. Although almost all IgG4-RD patients respond excellently to glucocorticoids, disease flares are prevalent during tapering, and nearly 40% of patients fail to achieve remission after 1 year , 26. TheIn conclusion, we present a rare case of IgG4-RD with multi-organ involvement including a periurethral mass which mimics malignant periurethral tumor. IgG4-RD is a systemic disorder potentially involving urethra, and is often ignored due to its rarity. It should be considered in the differential diagnosis especially when typical morphologic traits involving several organs or anatomical sites are present. The application of ultrasound-guided transvaginal biopsy and early engagement of pathologists and rheumatologists may help to diagnose the disease to avoid unnecessary surgery.Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.ZZ participated in the management of the patient and wrote the manuscript. XL designed the study, treated the patient and revised the manuscript. SG participated in the management and follow-up of the patient. All authors contributed to the article and approved the submitted version.


Background: Provider-specific prescribing metrics can be used for benchmarking and feedback to reduce unnecessary antibiotic use; however, metrics must be credible. To improve credibility of a recently described risk-adjusted antibiotic prescribing metric for hospital medicine service (HMS) providers, we assessed whether providers who initially prescribed excess antibiotics continued to prescribe antibiotics excessively. Methods: We linked administration and billing data among patients at 4 acute-care hospitals  to calculate days of therapy (DOT) ordered by individual hospitalists for each of 3 NHSN antibiotic groupings: broad-spectrum hospital onset (BS-HO), broad-spectrum community-onset (BS-CO), or anti-MRSA for each patient day billed from January 2020 to June 2021. To incorporate repeated measures by provider, mixed models adjusted for patient-mix characteristics  were used to calculate serial, bimonthly, provider-specific, observed-to-expected ratios (OERs). An OER of 1.25 indicates that the prescribing rate observed was 25% higher than predicted, adjusting for patient mix. We then used log binomial generalized estimating equations to assess whether a high prescribing rate (defined as an OER ≥ 1.25) for an individual provider in an earlier bimonthly period was associated with a persistent high rate for that provider in the following period. Results: Overall, 975 bimonthly periods were evaluated from 136 hospitalists. Most (58%) contributed data the entire 18-month study period. Median OERs were similar between hospitals: 0.94  for BS-HO antibiotic use, 0.99  for BS-CO antibiotic use, and 0.95  for anti-MRSA antibiotic use. At the individual prescriber level, roughly one-quarter of bimonthly OERs  were categorized as high. At 3 of the 4 hospitals, a provider with a high OER for either BS-HO or BS-CO antibiotic use in any bimonthly period was more likely to have a high OER in the subsequent period (Fig. Conclusions: Our findings suggest that hospitalists with a higher than expected 2-month period of antibiotic prescribing are likely to continue to have elevated prescribing rates in the following period, particularly for BS-HO antibiotics. These findings increase the credibility of using a 2-month prescribing metric for BS-HO antibiotic stewardship efforts; further work is needed to evaluate utility for other antibiotic groupings.ospitals ,571 bedsFunding: NoneDisclosures: None