This paper focuses on the investigation of the material properties of FC500 foam concrete. Innovation is very important for the solution of cast-in-place concrete forms in practice today. Part of its innovative construction application is the possibility of using foam concrete in a composite structure and the use of its mechanical properties in the load-bearing parts of civil engineering structures. The method of detecting the mechanical properties of foam concrete by using non-standard cantilever test is also innovative. Here, an advanced approach of modelling specimens using powerful computational systems based on the finite element method is used. This modern material is researched especially for its use in transportation structures. For its application, it is necessary to define its resistance to mechanical loads. The main content of the research consists of correlations between experimental measurements and analytical and numerical results. This is the principle of quasi-linear identification of the non-linear behavior of polymeric cementitious porous material during tests on specimens. The focus of the research is an extensive experiment: measurements of the deformation of the specimens until failure. The following methods were chosen to investigate the material properties: small cantilever test, standard tensile test and compression test. The cantilever test was performed for the individual components of the FC500 composite and cement concrete, but also as a compact composite. Numerical simulation models were developed to correlate the individual results in order to validate the uniaxial test results. The conclusions of the research led to the definition of standardized stress–strain diagrams of the FC500 material for compression and especially tension. This is a definition of the behavior of this polymer composite, usable for the development of numerical models of full-scale structures. The results of the research will be applied in the development of national standards for the use of advanced materials in transportation structures . The first foam concrete (FC) appeared with the Romans, who discovered that adding animal blood to a mixture of small stones, sand and hot lime made the mixture easier to work with, more durable and more porous. Nevertheless, the first concrete composed of a mixture of Portland cement and foam was not patented until 1923 by Axel Eriksson. An initial comprehensive survey was further carried out by Valore 1954) [ [4]. Com3 and 1600 kg/m3  is the material’s compliance matrix  and its form isThe inverse matrix to the compliance matrix is the material stiffness matrix [The stiffness matrix is based on the basic Hooke’s law as a one-element matrix of the formb} is the vector of volumetric forces on the element and the vector {p} is the vector of surface forcesThe vector {∂] used in the relations of the geometric and physical equationsn] of the external normal x, ny, nzn to the surface S in the relations of static boundary conditions and kinematic boundary conditions have an arrangement similar to the operator matrixFrom the bulk forces and stress balance conditions on the differential element of a solid, it is possible to obtain the operator matrix  in general form, while also allowing for the non-linear behavior of the material in different directions. Displacement of points on deformed one-dimensional element is presented on When changing the position of a specific point of an element, this movement affects the points that are connected to it. The influence depends on the stiffness of the element, which is expressed by stiffness constants that depend on the material and cross-sectional characteristics of the element and its boundary conditions; this is the aforementioned material stiffness matrix [E—modulus of elasticity, I—quadratic moment of section area, L—length. It is possible to create a stiffness matrix and evaluate forces and moments accordingly (39) for the element.The deformed element has directly defined border conditions. The element’s material and cross-section parameters are known: Connected elements can be solved the same way. Their resulting forces and moments are defined by a global stiffness matrix and a global deformation vector, which depends on the geometric positions of the elements, their interconnection and the boundary conditions of the system.However, when solving such problems in practice, it is not always possible to define the deformation vector in advance; rather, the external influences are defined by the load vector, or forces and moments. Additionally, the real calculated unknown is the deformations of the nodes.This problem can be solved analytically, but the disadvantage remains that with the large number of elements used in solving practical problems, it is time consuming and, in most cases, impossible. Therefore, the numerical methods mentioned above are chosen to approximate the result. This is where modern computing comes to help.The well-known method of solving this numerical model, assuming an approximation to the result, is the variational method, which works with a so-called functional that represents the total energy of the system . If the u(x) such that it minimizes the functional, which is written as [δ is the first variation of the functional in the variation model [For the solution, it is necessary to find a function itten as .(44)δIxon model .Finite element geometry selection:For the foam concrete specimens, based on experimental measurements, three-dimensional elements were selected for the finite element method model development. The elements were chosen because of a more accurate response and greater agreement with the experiment itself.The use of one-dimensional elements is not directly suitable for this particular type of material as it has different mechanical properties in compression and tension and the member element does not accurately represent the behavior that takes place in the cross-section as it does not have a sufficient number of elements in the vertical direction where the variable stresses are located.However, the use of two-dimensional elements would already be possible, since it is in this plane that the element is loaded, and the most important progression of internal forces and stresses can be captured.However, three-dimensional elements were used . Mainly,Deformation vector of a three-dimensional element:The rotation of the nodes is defined by the spatial rotation of the whole element, therefore there is no component of the rotation of the nodes in the deformation vector.Two computational models were created. Of these, one computational model was based on the theoretical basis of a unilaterally embedded beam, as it was representative of the experiment itself.Many authors use four-point bending to determine the flexural properties of foam concrete, which detects the failure of the material in pure bending, since no shear force enters the internal forces. However, this is not true in a cantilever test  and the The second computational model, from which the material model or stress–strain diagram of the foam concrete was later defined in an iterative manner, is based on numerical finite element methods. Specifically, the original Ansys numerical system with its original subsystems was used in combination with the modern Ansys workbench. The model was based on three-dimensional elements, mainly because of the way the specimens were loaded to simulate the experiment more accurately.In the experimental investigation, the special numerical signs for all tested specimens were created. In this numerical identification sign is implemented the date of specimen manufacture unit mass after 28 days and the type of series. All presented specimens’ results were selected as representative examples from the median evaluated of the series.The experimental setup was calibrated using a calibration steel rod and tested using multiple cement concrete specimens, which were loaded till collapse and then evaluated . The resFor the presentation of the results, several representative specimens were selected and further used for the evaluation of the material model of foam concrete in software based on the finite element method. These specimens were also used for comparison with the predicted linear mechanical properties of foam concrete in the following chapters. Other specimens were excluded from the work due to incorrect fitting in the measuring line and thus their failure mode or measured nonrepresentative values. All tested series were performed and evaluated until collapse .From the evaluated specimen data, it is possible to observe a nonlinear deformation progression depending on the specimen loading, which is observed in many studies of international as well as Slovak authors. Since the work is also concerned with the development of a material model of foam concrete, this particular specimen is chosen together with its deformation curve. The material model will represent an increase in deformation similar to this particular curve. This is justified by the use of FEA software and its ability to simulate a non-linear material model, which is represented by specifying specific values for the stress–strain diagram. However, the values that the FEM model will output may be influenced by the actual behavior of the mathematical model, which will overlay the curve for the model to work properly.Materials and Design, under the title “Experimental and numerical investigation of influence of air-voids on the compressive behavior of foamed concrete”. However, this statement needs to be further verified by experiments that will focus directly on this type of deformation. It should also be pointed out that this is an element subjected to bending and not to compression, as is the case in the literature referred to above. Thus, it is very likely that the specimens or the measuring device may be subject to slip deformation.It is a fact that at loads ranging from 90 N to 120 N, which is approximately 0.14 MPa to 0.19 MPa for this type of specimen, a large number of specimens slip. It is quite probable that this may represent the aforementioned pore shrinkage observed by the authors of the articles in the journal The deformation, deflection and load force data were recorded from the individual specimens. Measurement errors were systematically removed from these data along with the specimens that were determined to be non-conforming for the evaluation of the experiment. From the suitable specimens, these data were entered into a table and their flexural strength was evaluated; however, it should be noted that this is not a pure bending test, but a bending accompanied by shear, since it is a cantilever bending test. The elastic modulus of the specimens themselves was also evaluated, which was determined mainly from their linearly behaving part. The average of these values was also evaluated to unify the results. It should be noted that these are experimentally measured values. Below, The analytical model that was used to evaluate the specimens varies depending on the specimen parameters. Each specimen has its own dimensional parameters from which its quadratic moment of cross-section area is derived as follows:E mentioned in E = 520 MPa is used for comparison.Another parameter in the analytical calculation model is the modulus of elasticity of foam concrete. In this case, the modulus of elasticity Additionally, of course, the boundary conditions of the cantilever model, such as load and support at the point of insertion are correctly modeled.y” axis, denoted by “w” in millimeters, and an increasing force “F” in Newtons. The progression of these values will be indicated by the green dashed line in captures 3.4.2 and 3.4.3.The result is a linear deflection in the direction of the “To compare the average values, a material model of foam concrete was constructed iteratively in Ansys Mechanical APDL 2022 R1 using tensile and compressive parameters.The tensile parameters for the model were taken from the work of Matej Prišč , who perUsing a number of scientific articles, a number of diagrams of the material under pressure have been compiled ,27,28,29x-axis shows the axial stresses in the x-axis direction, either tensile or compressive, and the y-axis shows the axial compressive strengths in the y-axis direction. Thus, at a forty-five-degree angle in the first quadrant and in the third quadrant, we are talking about biaxial tensile and compressive stresses, respectively, and in the second and fourth quadrants, the model represents tensile stresses in one axis and compressive stresses in the other axis.The material characteristics thus created were entered into Ansys via a non-linear material model called “Cast-Iron” , which aHowever, the input values implemented to the material model did not accurately represent the behavior of the specimen. The tensile stress–strain diagram was relatively unchanged, except for minor modifications. It should be noted, however, that the original stress–strain dependence in compression prior to the iterative changes was made from specimens that were loaded in pure compression. Already, as Coulomb-Mohr theory shows, the material has a higher resistance in compression than in tension. A cantilever test experiment was realized in which tensile failure of the specimen is assumed. Thus, it was necessary to refine the details of the stress–strain in compression to tensile failure. The stress–strains taken from different authors were inaccurate or considered as linear in such low stresses.Since it is still a non-linear material, it is not possible to assume a linear distribution of stresses across the cross section, which was observed when the stress–strain was iterated . This isThis behavior caused the cross-sectional failure due to compression in the case where the working diagram of the foam concrete in compression was completed at the same stress as in tension. In order to increase the load, it was necessary to add values for the resistance of the material in compression above the stress of 0.3 MPa, at which collapse is considered in the case of tensile loading. This simulates the aforementioned non-linear stress distribution across the cross section. It should also be noted that stresses above 0.3 MPa in compression should not be considered as correct, since this is a region that is defined when the specimen collapses in tension and cannot be assumed to be consistent.It should be noted that this graph  is experThe experimental stress–strain diagram of the foam concrete FC500 was created and iterated, an algorithm was developed to compose a finite element numerical model that was loaded in a very similar to identical manner to the experiment itself. The deflections of the modelled specimen were measured at the same point as in the experiment and the analytical model, respectively. Subsequently, the numerical model produced in Ansys Mechanical APDL  was compared with the predicted analytical model of foam concrete, using the linear assumptions of the theories already mentioned.It can be observed from For the comparison of experimental measurements and analytical models, two sets of data were selected, which are divided into two parts, namely those suitable for the determination of material properties, and data that are not suitable for further use as a demonstration.The aforementioned double integration method was used to demonstrate the comparison between experimental measurements and analytical models on individual specimens. It is clear from the type of stress on the specimens that boundary conditions would be determined to establish the relevance of the results. The upper boundary condition is prompted by a compressive modulus of elasticity of 1.2 MPa, while the lower boundary is bounded by a tensile modulus of 0.3 MPa, which is based on the experimental data of the cited papers mentioned in chapter three. It is evident that most of the specimens selected as presentable fall within the zone bounded by these conditions. The third linear model used in the graph  under thFrom these results, it is noticeable that the experimental data behave in a non-linear manner, and it is not possible to accurately capture their behavior in a real situation. Therefore, under this assumption, material models were further constructed using numerical methods.The next graph  depicts 1 redistribution on the central plane is presented in Since the material model was based on the assumption that there is pore shearing or weakening of the material in compression by increasing stress, the deflection behavior of the numerical model is highly nonlinear. The example of normal stress σThe stresses observed in the FEM model represent the non-linear behavior of the material where plasticization occurs in the tensile area. This behavior leads to an increase in stresses at the lower compressive area above the theoretical linear limit considered and, hence, it is necessary to use a stress–strain diagram that achieves bearing stresses up to 0.47 MPa; however, above this limit, the stress–strain diagram cannot be iterated in this case. This is represented by the dashed line in the diagram .Since this specimen (a) from Generally, this type of material can be used in road construction, but it can also find its application in building construction. It should be noted, however, that we know of materials which have a far higher tensile strength than cement concrete, and it is possible to use these together in combination with cement concrete.Since cement concrete has better tensile properties than foam concrete, it is possible to load the overall cross-section more, since without the added composite the foam concrete itself collapses due to tensile overload. The following several observed facts can be discussed in further research:Several specimens collapsed without delamination .Since the clamps in some of the observed experiments were designed without surface correction, delamination of the two layers due to shear, which is present in this type of bending test, were observed .When the cement concrete cross-section is overloaded in tension in the upper surface, the element plasticizes and redistributes tensile stresses into the foam concrete layer below, which subsequently collapses. Shear delamination is probably observed not only at the point of failure but throughout the cross-section. This fact needs to be investigated further.It can be clearly seen that the cement concrete is subjected to much greater tensile stresses than when the cross-section was purely composed of foam concrete . This isIt shows the evolution of different stresses across the cross-section at the point of contact of two different materials with different material characteristics. The magnitude of the stresses varies with increasing force. In this case, it is the condition at a load of 300 N, as in the case of a no composite system.ctkf,0.05 = 1.5 MPa, it is possible to load a cross-section with a force value of 250 N in the simulation, considering 50 mm of foam concrete and 20 mm of cement concrete rigidly connected. The cement concrete in tension reaches stresses of up to 1.1 MPa, while the foam concrete only takes part of the stress.Considering a 5% tensile strength fraction of cement concrete of class C20/25 The FC500 polymer foam concrete material is investigated by authors in Slovak institutions by researchers at the University of Zilina ,31,32. T


Varieties of Inner Speech Questionnaire-Revised (VISQ-R) is a self-report questionnaire designed to measure characteristics of inner speech. In the current study, we adapted and validated a Hebrew version of VISQ-R. Our first hypothesis was that Confirmatory Factor Analysis (CFA) of the Hebrew VISQ-R would confirm the five subscales replicating the factor structure of the original questionnaire. In addition, building on previous findings that inner speech is involved in tasks that require the executive functions we examined the relationship between VISQ-R and self-reported executive functions questionnaire (BRIEF-A). We hypothesized that correlations between subscales of the Hebrew VISQ-R would reveal covariance between BRIEF-A and some but not all inner speech subscales.The 406 participants completed the Hebrew VISQ-R and 280 of them also completed the BRIEF-A.As hypothesized, CFA confirmed the factor structure revealing the same 5 subscales reported in the original English version, with acceptable internal reliability. Partial support was found for the hypothesized correlations between VISQ-R and BRIEF-A, with covariance of executive functions with some subscales of inner speech , and distinct variance with others (Condensed and Positive).These results indicate that the Hebrew version of the VISQ-R has good psychometric properties and that it can be used in future research. The implications concerning the contribution of inner speech for people with difficulties in executive functions are discussed. Such self-report questionnaires may use an open-format e.g., , or a liThe VISQ-R’s subscales have convergent validity with other self-report scales measuring various aspects of inner speech. For example, More recently, The VISQ-R has been adapted to Spanish in a process of translation and independent backtranslation , and fouInner speech has been linked to executive functions . ExecutiThe Behavior Rating Inventory of Executive Function-Adult BRIEF-A;  is a selThe purpose of this study was to assess the validity of the Hebrew version of the VISQ-R. We hypothesized that:Confirmatory Factor Analysis of the Hebrew version of the VISQ-R would reveal five subscales similar to those of the original questionnaire.The correlations between subscales of the Hebrew VISQ-R and self-reported executive functions would reveal covariance between executive functions and some aspects of inner speech but not with all of them. Specifically, we expect that scores on the BRIEF-A will be correlated with VISQ-R subscales related to representation of other people  and regulation . By contrast, the Condensed subscale which is more associated with the form of inner speech is not expected to correlate with executive functions.2.2.1.via publication on social media for volunteers from the general public (305) or from an undergraduate program of behavioral sciences (101) in an Israeli college. As in the original VISQ-R questionnaire, only participants who completed 80% or more of the items in the VISQ-R were included in the sample. Of the 406 participants that were included, 337 (83.0%) were women, with age ranging between 18 and 66 . 280 (68.96%) participants of the sample also completed the executive functions questionnaire (BRIEF-A).Participants were recruited either 2.2.2.2.1.The Varieties of Inner Speech Questionnaire-Revised VISQ-R;  resulted2.2.2.Behavior Rating Inventory of Executive Function-Adult . The questionnaires were administered online 3.The results consist of two analyses. First, we present CFA and the reliabilities and inter-correlations of the subscales. These analyses were designed to examine the consistency of constructs structured according to their theoretical or empirical conceptualization, based on the 5 factors reported in 3.1.n = 406) and was conducted using AMOS 23.0. We chose the following values for acceptance: Comparative Fit Index (CFI) > 0.90 . All the items loaded sufficiently onto the appropriate factors, except for item number 21 that loaded in the opposite direction than expected.This analysis is based on all participants  > 0.90 , and roo) > 0.90 . The mod) > 0.90  showed g3.2.p < 0.01 (two-tailed).The internal reliability of the subscales in the Hebrew version was acceptable, though somewhat lower than the reliabilities reported for the English version: Dialogic inner speech had an internal reliability of Cronbach’s α = 0.71; Evaluative/Critical inner speech had Cronbach’s α = 0.82; Condensed inner speech had Cronbach’s α = 0.68; Other-People in inner speech had Cronbach’s α = 0.86, and Positive/Regulatory inner speech had Cronbach’s α = 0.73. Inter-correlations of VISQ-R subscales are presented in 3.3.Pearson’s correlations were calculated between VISQ-R subscales scores and the Hebrew version of the Behavior Rating Inventory of Executive Functions-Adult (BRIEF-A). The results based on 280 participants are shown in 4.The main objective of this study was to examine the psychometric properties of the Hebrew version of the VISQ-R . CFA conThe second objective of the current study was to examine the convergent and divergent validity of the Hebrew version of VISQ-R, by analyzing its relationship with the self-report questionnaire of executive functions BRIEF-A . The corBeyond contributing to the validity of the VISQ-R in Hebrew, the pattern of correlations with the BRIEF-A is of interest as it sheds light on the functions of inner speech. Three VISQ-R subscales—Dialogic, Evaluative, and Other-people—correlated significantly with more difficulties on all aspects of executive function. This finding suggests that among individuals with difficulties in executive functions, the use of some aspects of inner speech is enhanced, possibly as a strategic compensation mechanism. This interpretation is consistent with previous findings, indicating that participants who used motivational and evaluative inner speech had reduced conflict effects and switch-effects compared to those who used inner speech less, even when controlling for intelligence and working memory abilities . SimilarAnother perspective on the correlations of these subscales of inner speech and executive functions is proposed by Two of the inner-speech subscales did not correlate with the executive function’s subscales—the Condensed and the Positive. The Condensed subscale is associated with the form of inner speech rather than its function. It reflects the use of syntactic, acoustic, and phonological language qualities besides semantics . As suchThe finding that the Positive subscale did not correlate with executive function  is inconsistent with our hypothesis. This finding may be explained by the differences between the Positive subscale and the other VISQ-R subscales associated with functions of evaluation and self-regulating. For example, 4.1.In conclusion, the results of the current study indicate that the factor structure of the Hebrew version of the VISQ-R  is consiThe results of this study should be considered in light of its limitations. This was a cross-sectional correlational study, with a single measurement. The participants were a convenience sample, rather than a random population sample. Importantly, we used self-report rating questionnaires for convergent and divergent validity. The limitation of such questionnaires is that the participants’ responses are constrained and less ecologically valid. Future research that will use open-format questionnaires e.g.,  may be mThe aim of the current study was to adapt the VISQ-R questionnaire to Hebrew. Future research might translate the VISQ-R to other languages and cultures, to allow cross-cultural examination of its applicability, structural validity, and predictive validity. It would also be informative to further examine the distinction between the Evaluative, Dialogic, and Other People subscales and the Condensed and Positive subscales of the VISQ-R; The first three subscales are most often found to be correlated with various pathologies  of the Ruppin Academic Center. The patients/participants provided their written informed consent to participate in this study.DR contributed to the data curation. LL-A contributed to the formal analysis, methodology, and implementation. AZ, HK, and TS contributed to data analyses and interpretation. TS drafted the first version of the manuscript. All authors contributed to the article and approved the submitted version.This project was funded by the Israeli Science Foundation (grant number 216/21 to HK) and Ruppin Academic Center Research Authority Grant (grant number 33802 to HK and 33502 to AZ).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.


MET expression. The European Organization for Research and Treatment of Cancer (EORTC) 90101 “CREATE” phase II trial evaluated the MET inhibitor crizotinib in ASPS patients, achieving only limited antitumor activity. We performed a comprehensive molecular analysis of ASPS tissue samples collected in this trial to identify potential biomarkers correlating with treatment outcome. A tissue microarray containing 47 ASPS cases was used for the characterization of the tumor microenvironment using multiplex immunofluorescence. DNA isolated from 34 available tumor samples was analyzed to detect recurrent gene copy number alterations (CNAs) and mutations by low-coverage whole-genome sequencing and whole-exome sequencing. Pathway enrichment analysis was used to identify diseased-associated pathways in ASPS sarcomagenesis. Kaplan–Meier estimates, Cox regression, and the Fisher’s exact test were used to correlate histopathological and molecular findings with clinical data related to crizotinib treatment, aiming to identify potential factors associated with patient outcome. Tumor microenvironment characterization showed the presence of PD-L1 and CTLA-4 in 10 and 2 tumors, respectively, and the absence of PD-1 in all specimens. Apart from CD68, other immunological markers were rarely expressed, suggesting a low level of tumor-infiltrating lymphocytes in ASPS. By CNA analysis, we detected a number of broad and focal alterations. The most common alteration was the loss of chromosomal region 1p36.32 in 44% of cases. The loss of chromosomal regions 1p36.32, 1p33, 1p22.2, and 8p was associated with shorter progression-free survival. Using whole-exome sequencing, 13 cancer-associated genes were found to be mutated in at least three cases. Pathway enrichment analysis identified genetic alterations in NOTCH signaling, chromatin organization, and SUMOylation pathways. NOTCH4 intracellular domain dysregulation was associated with poor outcome, while inactivation of the beta-catenin/TCF complex correlated with improved outcome in patients receiving crizotinib. ASPS is characterized by molecular heterogeneity. We identify genetic aberrations potentially predictive of treatment outcome during crizotinib therapy and provide additional insights into the biology of ASPS, paving the way to improve treatment approaches for this extremely rare malignancy.Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma characterized by an unbalanced translocation, resulting in ASPSCR1-TFE3 fusion that transcriptionally upregulates  Chemothpulation . This tupulation . ASPS isreceptor . MET inhTFE3 rearrangement by fluorescence in situ hybridization (FISH). Even though the vast majority of ASPS treated in the CREATE trial were classified as MET-positive, MET inhibition with the oral tyrosine kinase inhibitor was only associated with very sporadic responses. Nevertheless, the long duration of treatment (median number of three-weekly cycles: 12.5) and the very high disease control rate (90%) observed in patients with TFE3-rearranged tumors suggested some activity of crizotinib in this trial [TFE3 rearrangement in ASPS development. Previous studies in MET-driven non-small cell lung cancer (NSCLC) linked MET exon 14-alterations with crizotinib sensitivity, while phosphoinositide 3-kinase (PI3K) pathway alterations correlated with a worse response to MET inhibition [EGFR) mutated NSCLC patients, receiving an EGFR inhibitor [In the European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90,101 “CREATE,” the MET inhibitor crizotinib was evaluated in patients with MET-positive and MET-negative ASPS. MET status was defined by the presence or absence of is trial . Intereshibition ,8. In adInterestingly, in contrast with the majority of other soft tissue sarcomas, ASPS is believed to be sensitive to immune checkpoint inhibitors (ICIs), as presented in several case reports and in a phase II trial of atezolizumab, in which 8 out of the 19 patients had durable responses ,11. HoweArchival tumor material was available from 47 centrally confirmed ASPS patients. These samples included 43 MET-positive, three MET-negative, and one MET-unevaluable tumor according to the criteria of the original trial protocol. Biological material was composed of 37 primary tumors and 10 metastatic lesions. The male-to-female ratio was 1.24 and the median age at enrollment of the trial was 32 years (range: 16–69). Among 43 clinically evaluable patients, two had a partial response (PR), and 35 had stable disease (SD) as the best response to crizotinib. Progressive disease (PD) was the best response in 6 cases. Median progression-free survival (PFS) and overall survival (OS) were 6 and 27.1 months, respectively, for the evaluable patient populations. For subsequent analyses, 47 cases were included in the tissue microarray (TMA) and therefore, were available for histopathological evaluation. DNA samples were isolated from 34 cases and subjected to an extensive molecular genetic analysis . Clinicopathological variables for all individual patients are summarized in n = 2). As for the assessment of TILs, CD3 (T cells), CD4 (helper T cells), CD8 (cytotoxic T cells), CD14 (monocytes), CD56 (NK cells), CD68 (macrophages), and FOXP3 (regulatory T cells) were found in 17.8% (n = 8), 11.1% (n = 5), 4.4% (n = 2), 4.4% (n = 2), 0% (n = 0), 71.1% (n = 32), and 4.4% (n = 2) of evaluable cases, respectively. We detected MHC I and MHC II in 73.3% and 57.8% of cases, respectively, suggesting effective antigen presentation ability in ASPS. In 51.1% of cases (n = 23), we found co-expression of MHC I and II, whereas 22.2% (n = 10) of cases were double negative. We observed a higher percentage of cases with a T cell infiltration having a shorter PFS  and a trend towards MHC II absence in the MHC I-negative cases; however, this correlation was not statistically significant. To investigate the composition of the TME in ASPS with a focus on immunocompetent cells, we performed Multiple Iterative Labeling by Antibody Neodeposition (MILAN) using TMAs containing 47 ASPS cases. Sequential staining against TFE3, programmed cell death 1/ligand 1(PD-1/L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD3, CD4, CD8, CD14, CD56, CD68, forkhead box protein P3 (FOXP3), and major histocompatibility complex class I/II (MHC I/II) was successfully performed in 7 cycles, and at least 45 cases were evaluable in each cycle. PD-L1 expression was seen in 10 cases (21.7%), while we observed no expression of PD-1 and only sporadic expression of CTLA-4 , of which two were negative for a TFE3 rearrangement, as determined by FISH . These two MET-negative cases were analyzed post hoc with an Archer fusion panel, and in one of these MET-negative specimens, we detected a typical ASPSCR1-TFE3 fusion, with an unusual breakpoint in exon 6 of TFE3. Interestingly, this patient had a remarkable response (PR) to crizotinib. No fusion was identified in the second case immunopositive for TFE3, but with a negative MET status. Next, we also evaluated MET expression using immunohistochemistry .The ASPS-specific marker TFE3 was detected by immunohistochemistry in 93.3% of cases (hemistry  and comphemistry A. We obsp < 0.001), while losses of 8p (p = 0.01), 1p36.32 (p = 0.01), 1p33 (p = 0.03), and 1p22.2 (p = 0.02) were associated with shorter PFS in patients receiving crizotinib treatment  analysis to reveal the copy number alteration (CNA) profile of ASPS in 34 assessable samples. Recurrent regions affected by broad  and focal (region level) CNAs were detected. The most common broad CNA was a gain of chromosome 12q, observed in 14 out of 34 (41%) ASPS cases. Other broad CNA events were gains of chromosomal arm 12p (38%), 15q (24%), 20p (24%), 5q (21%), and 20q (21%), while losses mainly affected chromosome 1p (32%), 22q (32%), 9p (29%), 21q (29%), 8p (24%), 10p (21%), 10q (21%), and 18q (21%) A. Furthereatment B. No sigAR (androgen receptor) mutations were found in 7 out of 34 cases as the most common alteration, and 13 were found to be mutated in at least three specimens , FBXO11, KMT2D, NCOR2, ATM, BRCA1, CLTC, FAT4, NRG1, RECQL4, SETD2, and TRRAP  in MET-positive ASPS tumors from patients who achieved PR or SD as the best response to crizotinib. The ALK p.F921C mutation was reported in squamous cell carcinoma and adenocarcinoma and were predicted as pathogenic, while the ALK p.P1139L mutation was a novel variant with uncertain clinical significance [ALK substitutions were located in the glycine-rich region and tyrosine kinase domain, respectively . Excluding synonymous mutations, we identified 4795 missense mutations, 123 nonsense mutations, and 772 insertions and deletions (indels). For further analysis, we focused on genes that were previously documented as CGCs. A total of 256 mutations that affected 175 CGCs were identified, with an average of 8 range 2–14) per case. Of these, pecimens A. Becausnd TRRAP A. Of notc events B. Furthe per caseectively C. To datactivity . Among gTFE3 rearrangement. The molecular landscape is summarized in Next, we combined the molecular findings from the CNA and mutational analysis, aiming to explore the disease biology beyond ASPSCR1-TFE3 fusion, resulting in MET overexpression. In the prospective phase II trial EORTC 90,101 “CREATE”, the activity of the MET inhibitor crizotinib was assessed in patients with this rare disease. Clinical results suggested the presence of factors other than TFE3 rearrangement that might predict treatment outcome [n = 47) originating from the CREATE trial, we were able to characterize the composition of the TME and genomic alterations in the tumor tissue and further correlate these findings with the patient outcome on crizotinib treatment, aiming to identify potential biomarkers and additional therapeutic targets. ASPS is an ultra-rare subtype of STS that is characterized by the  outcome . Moreove outcome . Using on = 2) and FOXP3-negative (n = 41) groups, we cannot overestimate the predictive power. Apart from the sparse presence of TILs (0–8%), macrophages (CD68-positive cells) were observed in 71% of cases, which was in line with a recent study showing that CD68-positive macrophages outnumbered TILs in various sarcomas [Since PD-L1 and immunocompetent cells in the TME have been suggested as potential predictors for patient outcomes on both tyrosine kinase inhibition (TKI) treatment and immunotherapy in various cancers ,16,17,18sarcomas . On the sarcomas . Among 8sarcomas ,22. In sASPSCR1-TFE3 fusion with an unusual TFE3 breakpoint (exon 6). Although ASPSR1 is more often fused to TFE3 at either exon 3 or 4, ASPSCR1-TFE3 can also involve the fusion of exons 1–7 of ASPSCR1 to exon 5 or 6 of TFE3 [TFE3/Xp11.2 gene in this case, highlighting the importance of an additional methodology to identify TFE3-rearranged ASPS. In another MET-negative case with TFE3 expression, no fusion was identified, suggesting an alternative mechanism inducing TFE3 expression in the absence of TFE3 rearrangement. For instance, cellular stressors such as DNA damage and oxidative stress have been implicated in activating TFE3 [TFE3 rearrangement were negative for MET expression. Likewise, two cases without TFE3 expression or TFE3 rearrangement expressed MET. These suggested the presence of other factors that may result in MET down-/upregulation. For instance, DAXX  binding to the MET promoter can result in the transcriptional repression of MET [Interestingly, a MET-negative case that had a remarkable response to crizotinib was positive for TFE3 expression. We therefore performed additional Archer analysis and identified an  of TFE3 ,24. Our ing TFE3 . Moreoven of MET , while An of MET . NeverthCDK4 and MDM2) were frequently seen in patients with soft tissue and bone tumors [GLI1 amplification may serve as an alternative mechanism of oncogenic activation akin to GLI1 fusions, which was reported to contribute to the development of STS [AJAP1) encoding an integral membrane protein has been considered as a tumor suppressor. The loss of AJAP1 expression (caused by deletion or methylation) was associated with poor clinical outcome in patients with malignant gliomas [By low-coverage whole-genome sequencing, we aimed to identify significant CNAs in ASPS. The most common CNAs observed were gains of chromosome 12q (41%) and losses of 1p36.32 (44%) as broad and focal alterations, respectively. Similar to our observation, the gain of the 12q amplicon was previously found in individual ASPS cases ,29, and e tumors ,31. Thist of STS ,34. With gliomas . TherefoPDE4DIP, a gene transcribing myomegalin that is important for the engagement of 4D phosphodiesterase to the Golgi complex [PDE4DIP was identified as a putative susceptibility gene in ASPS. A recent study has also characterized the molecular alterations in ASPS, derived from the American Association for Cancer Research GENIE database, revealing 40 cancer-associated mutations detected in 20 ASPS tumors [KMT2D (lysine methyltransferase 2D), ATM (ATM serine/threonine kinase), and RECQL4 (ATP-dependent DNA helicase Q4) were also found in our cohort of 34 cases. The proteins encoded by KMT2D, ATM, and RECQL4 are implicated in epigenetic modification, DNA damage repair, and genome caretaking, respectively [ALK mutations located at the glycine-rich region (p.F921C) and the tyrosine kinase domain (p.P1139L) in two TFE3-positive cases that achieved a PR and SD on crizotinib treatment, respectively. These alterations were either predictively pathogenic or located in the catalytic region, suggesting a potential impact of ALK mutations on the sensitivity to crizotinib, as previously described in various tumor types  [ALK, MET, and other alterations has been observed in a series of cases with lung cancer [ALK mutations.Next, we investigated the ASPS mutational profile using WES and focused on recurrent mutations identified in our cohort. The most frequently mutated gene was  complex . Mutatio complex ,38. ThisS tumors . Of thesectively ,42. Thisc tumor) ,44,45. Hg cancer  and is rWe combined genomic alterations identified in this study, revealing the molecular heterogeneity in ASPS. To further investigate the overrepresented dysregulations in molecular pathways, we further analyzed the mutational dataset to identify pre-defined pathways enriched with mutated CGCs. Our findings showed that disease-associated alterations might be actively involved in NOTCH signaling, chromatin organization, and SUMOylation . Notably, SUMOylation has already been related to the functionality of TFE3, which possesses a SUMOylation site and can be post-transcriptionally modified to regulate the transcriptional activity . The mutThis study has some limitations. First of all, because of the unavailability of matching germline samples, we used computational strategies with restricted criteria to exclude common single nucleotide polymorphism. However, it is still possible to have a small proportion of germline polymorphisms included in our dataset. Secondly, although the public databases  and Reactome) we used to study genomic alterations are extensive and well-annotated, novel alterations and their functionality are still being documented over time. Emerging genomic data and new annotations should be implemented for better clinical interpretation, and further investigation is still required to validate the observations in this study. Furthermore, we only focused on cancer-related genes (CGCs), which might overlook rare or uninterpreted alterations in the process of variant identification. Nevertheless, to the best of our knowledge, this study is one of the largest ASPS study cohorts, in which we present a comprehensive molecular analysis of this rare disease.A total of 47 archived formalin-fixed, paraffin-embedded (FFPE) tissue samples from patients with ASPS were collected in the context of the clinical trial and were used for the construction of an ASPS-specific TMA with 1.5 mm triplicate cores per case . To detehttp://www.eortc.be/services/doc/protocols/90101v10.0.pdf). A tumor was considered MET-positive if it showed TFE3 rearrangement in at least 15% of cells by FISH (home-made break-apart TFE3 probe set RP11-344N17 and RP11-552J9) [post hoc targeted next-generation sequencing-based Archer FusionPlex CTL Panel , to evaluate the presence of specific fusions in MET-negative ASPS specimens. MET expression was evaluated using immunohistochemistry with anti-MET monoclonal antibody .In the CREATE trial, MET status was indirectly assessed centrally by FISH, as described in the study protocol (accessed on 17 December 2021 1-552J9) . We also® HiSeq4000  was used for sequencing at low coverage (± 0.1×). Raw sequencing reads (50 bp) were mapped to the human reference genome (GRCh37/hg19 version) using Burrows-Wheeler Aligner  and sorted with SAMtools . Picard tools were used to remove duplicates. QDNASeq and ASCAT were used to count and segment aligned reads in bins of 50k [We isolated DNA from FFPE tumor samples, and 34 out of 47 samples were available , with quality that was acceptable for DNA libraries preparation. Illuminas of 50k ,55. The s of 50k , and sigLibraries prepared for low-coverage whole-genome sequencing were enriched for exomic sequences using the SeqCapV3 exome enrichment kit  following the manufacturer’s instructions. They were sequenced on HiSeq4000 using a V3 flow cell, resulting in 2 × 150 bp paired-end reads that were further mapped and sorted as described above. Duplicate reads were removed using Picard tools , followed by base recalibration, local realignment, and single nucleotide variant calling performed with the Genome Analysis Tool Kit . Low-quality mutations were excluded if the coverage for calling substitutions, insertions, and deletions (indels) was less than 10×. Furthermore, Dindel was used for calling insertions and deletions (indels), with criteria of a quality score of more than 50 and at least 10x coverage. Since no germline samples were available, a strict filtering strategy was applied based on publicly available databases to exclude the common single nucleotide polymorphisms. Mutations occurring in large databases  with an allelic frequency > 0.001, as well as mutations occurring in smaller, appropriate databases  were removed if they occurred in more than one individual. The CGC set developed by the COSMIC v89  was then applied to include genes that have been implied in cancer for further analysis . The visTo identify affected pathways that are mutation-mediated in ASPS, pathway enrichment analysis was performed using g:Profiler , a tool integrating bioinformatic and statistic approaches to call pathways whose genes are significantly enriched or overrepresented in a list of genes, as compared to all genes in the genome . We allop values < 0.05 were considered significant. The response to crizotinib in the clinical trial was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST v1.1), as previously reported . In the We characterized the composition of the TME and genomic alterations in ASPS, revealing molecular heterogeneity. The correlation of molecular findings with patient outcome revealed potential biomarkers with predictive value for crizotinib treatment. Our study provides insights into the biology of this complex and clinically challenging ultra-rare malignancy, which may pave the way for the development of better therapeutic strategies for ASPS patients.


The ability to use bio‐inspired building blocks in the assembly of novel supramolecular frameworks is at the forefront of an exciting research field. Herein, we present the first polyproline helix to self‐assemble into a reversibly porous, crystalline, supramolecular peptide framework (SPF). This framework is assembled from a short oligoproline, adopting the polyproline II conformation, driven by hydrogen‐bonding and dispersion interactions. Thermal activation, guest‐induced dynamic porosity and enantioselective guest inclusion have been demonstrated for this novel system. The principles of the self‐assembly associated with this SPF will be used as a blueprint allowing for the further development of helical peptide linkers in the rational design of SPFs and metal‐peptide frameworks. The ability to use bio‐inspired building‐blocks in the assembly of novel supramolecular frameworks is at the forefront of an exciting research field. Herein, we present the first polyproline helix to self‐assemble into a reversibly porous, crystalline, supramolecular peptide framework (SPF). Thermal activation, guest‐induced dynamic porosity and enantioselective guest inclusion have been demonstrated for this novel system. This interconversion can be controlled as a function of the environment it is exposed to  and can be monitored by circular dichroism (CD) spectroscopy. on an Fmoc‐associated pair . Subsequently, simultaneous thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) of PP4‐SPF showed a crystalline melting point with an endothermic peak .Due to the porosity of the framework, it has the potential for “activation” by removal of the solvent from the pores, thereby allowing the introduction of other guests into the activated pores. To investigate the ability for thermal release of ethanol from the framework channels, Powder X‐ray diffraction (PD‐XRD) analyses revealed a change in phase upon de‐solvation, with significant differences to the original sample . To rule out the possibility of partial recrystallization causing the phase change, a sample of PP4‐SPFact was soaked in hexane and showed no change in phase on the powder pattern, as such hexane was used as the diluent for other guest molecules. The framework was soaked in a 5 % solution of various guests . After soaking the SPF was washed thoroughly with fresh hexane to remove excess guest. PDXRD analysis was then carried out to determine whether a change in phase had occurred  for each guest (Supporting Information 13.4). The mol % of guest retained within the pores was analysed by 1H NMR, after dissolving the framework in [D4]methanol .Due to the framework exhibiting dynamic porosity, attempts were made to see if this behaviour would apply with other guests. PP1H NMR data showed significantly higher proportions of hexane than for the SPF soaked alone in hexane , which suggests that once porosity is recovered hexane is adsorbed into the framework. However, the proportion of guest alters significantly , favouring adsorption of guest molecules over the hexane diluent (Supporting Information 13).All the guests analysed  1‐phenylethanol, and iodine), elicited a change in phase from the de‐solvated structure, after analysis of the solid SPF after soaking, suggesting they all act to reinflate the structure (Supporting Information 13.4). However, differences in the powder patterns of the samples suggests either a degree adaptation of the framework to accommodate different guests when compared to the original ethanol guest or ordering of the new guest molecules resulting in new diffraction peaks. Although, differences in peak intensities and loss of some low angle peaks are likely attributable to both loss of crystal quality through the processes of activation and guest inclusion. It should be noted that the activated material loses crystallinity when mechanically ground , and so the measured diffraction patterns for the (unground) materials also exhibit some preferred orientation effects. Analysis of the 4‐SPF ‐1‐phenylethanol)  1‐phenylethanol (PhEtOH) within the framework , chiral HPLC was utilized to investigate whether any enantioselectivity was exhibited (Supporting Information 13.5). These results showed a clear shift in the enantiomeric ratio from the reference racemic (±) PhEtOH after exposure to PP4‐SPF@I2 was performed which showed that the SPF readopted the initial solvated structural geometry and was able to adsorb iodine with a chemical occupancy for I2 of ≈12 % , thus demonstrating the potential of the PP4‐SPF to perform thermally responsive guest release.Activated single crystals were then exposed to a solution of iodine in hexane to allow visualization of a guest within the reinflated pores through single‐crystal diffraction, even at lower guest loadings, due to the high electron density of iodine. A colour change was evident with the crystals taking on a yellow‐orange hue. SC‐XRD analysis of PP% Figure . To inve4‐SPF) using the resilience and rigidity of the polyproline II helix in a short oligoproline is reported. This SPF shows remarkable reversible porosity and the ability to reversibly host chemical guests in its channels with exhibited enantioselectivity of this adsorption process. The self‐assembling principles associated with this SPF can be used as a blueprint in the synthesis of novel helical SPFs and have exciting potential for the rational design of functionalized cavities, offering an exceptional level of positional control of easily incorporated new functionalities. These materials have clear applications in chemical separation and potential chiral catalysis.In conclusion, the first supramolecular peptide framework formed by the self‐assembly of a polyproline helix  should be addressed to the authors.Supporting InformationClick here for additional data file.


The effectiveness of concrete confinement by fiber-reinforced polymer (FRP) materials is highly influenced by the orientation of fibers in the FRP laminates. In general, acceptable deviation limit from the intended direction is given as 5° in most design guidelines, without solid bases and reasoning. In this paper, a numerical study using finite element modeling was conducted to assess the effects of small deviations in fiber orientation from the hoop direction on compressive behavior of concrete cylinders confined with FRP. Different fiber angles of 0°, 2°, 5°, 8°, 10° and 15° with respect to hoop direction, unconfined concrete compressive strengths of 20, 35 and 50 MPa, FRP thicknesses of 0.2, 0.5 and 1.0 mm and FRP moduli of elasticity of 50 and 200 GPa were considered. The results showed that total dissipated energy ( The need for rapid, safe and efficient repair of concrete structures has grown in recent years ,2,3. RepMost studies on FRP-confined concrete columns have focused on the use of fibers in the hoop direction due to the anticipated effect of increasing axial capacity and simplicity. A number of studies reported their findings on FRP-confined concrete specimens with fibers in inclined directions. These studies are mainly focused on the effect of different stacking sequences of cross-ply FRP wraps , or different winding angles in the case of concrete-filled FRP tubes (CFFTs), with fiber orientations of more than 15°  with respect to hoop direction ,29,30,31Numerous research studies experimentally investigated the axial compressive behavior of fiber-reinforced polymer tube-confined concrete cylinders in the past two decades . Only a As discussed before, the majority of existing studies tested a variety of cross-ply wraps with inclined fibers in different stacking sequence configurations and types of mixes. However, in practice, most columns are confined with unidirectional wraps in the hoop direction, and that is where the effects of deviations in fiber orientation and evaluating the current deviation limit of 5° in design codes become important. Moreover, only a comprehensive study of all significant parameters  results in a complete understanding of the effects of deviation in fiber orientation. No study to date has thoroughly investigated the influence of small deviations in fiber orientation, combined with three other significant parameters, on the axial behavior of concrete columns confined with FRP.Studies were also carried out on FRP strengthening reinforced concrete beams, including those with complex T-beams ,35. The As described above, it is rare to analyze the parameters of the FRP composite depending on small deviations of the fiber inclination angle, moreover, the analysis of stress–strain models to predict the strength and strain enhancement ratio of fiber-reinforced polymer tube-confined concrete cylinders under axial compression is also very rare . TherefoA particularly important issue can be found in the research of Seffo M. et al. . Their eThe key parameters affecting the performance of FRP-confined concrete columns are concrete compressive strength, modulus of elasticity, thickness and fiber orientation of FRP laminates. To date, however, less attention has been paid to fiber orientation. Mechanical properties of FRP materials are highly influenced by fiber orientation, and even small variations in fiber angle will result in major reductions in expected property enhancements. In the current ACI 440.2 design guidelines, the acceptable limit for the deviation from the intended direction of fiber alignment is given as 5°, without any reported reasoning. No study to date has thoroughly investigated the influence of small deviations in fiber orientation, combined with three other key parameters, on the axial behavior of FRP-confined concrete columns. The current study tries to provide a better understanding by systematically investigating the influence of deviation in fiber orientation on the behavior of FRP-confined concrete columns under axial loading.This paper reports on a numerical study aimed at investigating the effects of small deviations in fiber orientation on important compressive characteristics of concrete columns confined with FRP using finite element analysis (FEA). Firstly, a summary of the finite element (FE) modeling is provided. Then, a validation of the FE modeling by comparing the results with available experimental data is presented. Following this, the results of the parametric study are offered, in which the effects of deviation in fiber orientation with respect to hoop direction on stress–strain behavior, compressive capacity, ultimate deformation and energy dissipation of FRP-confined concrete are discussed. In addition, the loss of ultimate concrete compressive stress and strain along with the reduction in the total dissipated energy corresponding to 5° deviations  are presented. Finally, allowable values of deviation in fiber orientation with practical confidences (95% and 99%) for a range of declines in the mentioned properties are suggested.®-Standard  was employed to generate numerical models and simulate the structural response of the concrete columns strengthened with FRP. The output of the generated models was validated against available experimental results.General purpose FEA software AbaqusThe geometry and boundary conditions of the columns are described in this section. Fully wrapped concrete cylinders had dimensions of 152 × 305 mm. Given the geometry of the model, a cylindrical coordinate system was defined and assigned to the specimens. Since the complete stress–strain behavior of the columns was determined, the loading was applied under a displacement control regimen from the top of the samples. In order to apply the axial displacement as loading, the columns were fixed at the top and bottom in all directions, except for the longitudinal direction at the top. Two rigid plates were defined and attached to both ends in order to uniformly distribute the applied displacement. To define the friction between contacting surfaces of the concrete and rigid plates, the Coulomb friction model was used. This model requires the coefficient of friction. For dry interfaces of concrete and steel, the value is suggested as 0.57 ,39. It iThe unidirectional FRP laminate was defined as a deformable shell material with a linear elastic behavior. Shell element “S4R” was selected for FRP laminates. In order to obtain accurate results from the FE modeling, the element size of the FRP wrap and outer surface of the concrete cylinder were assigned as equal to ensure both materials shared the same nodes. Under a plane stress condition, which is the case in a shell element, only the values of Concrete was considered as an isotropic elastic body and was defined as a deformable material with both elastic and plastic behaviors. Solid element “C3D8R” was selected for concrete. The elastic behavior of concrete is defined by its elastic modulus, tion (1) :(1)Ec=47tion (2) , if not K) and dilation angle (The plastic behavior of FRP-confined concrete is defined by the linear extended Drucker–Prager (DP) plasticity model. This model has been shown to perform well in modeling the stress–strain behavior of confined concrete ,47,48. TK should lie between 0.78 and 1.00 [K was assumed to be 1.00 for confined concrete. The plastic dilation angle is the major parameter governing the DP flow rule. Jiang et al. [D are FRP modulus of elasticity in hoop direction, FRP thickness and diameter of concrete cylinder, respectively. ®, material properties can be made dependent on the so-called “solution-dependent field variables” (SDFV) using the user-defined subroutine USDFLD. The SDFV is a field variable that varies throughout the solution process. In this study, the plastic dilation angle relationship was calculated using the stated equations and entered into the model as tabular data through the SDFV option.The yield criterion in the linear DP model is defined by the angle of friction, which is assumed to be 54° based on previous studies ,48. To eand 1.00 . In thisFinally, to define the DP hardening law in the program, the relationship between axial plastic strain  mesh size. Therefore, to reduce the computation time and have uniform stress contours, the optimum mesh size of 20 mm was chosen. In the next step, the accuracy of the proposed FE model was validated by numerical simulation of existing experimental results reported in the literature ,43,50. TIn this study, the validated FE model was implemented to assess the compressive characteristics of FRP-confined concrete columns, with deviation in fiber orientation from the hoop direction as the primary parameter. As mentioned before, unconfined concrete strength, FRP modulus of elasticity in hoop (0°) direction and thickness of FRP wrap were also considered as variables. The combined effects of these variables with deviation in fiber orientation were investigated. The geometry and boundary conditions of the models were kept constant during the study. Important compressive characteristics investigated in this study were stress–strain behavior, ultimate axial stress and strain and total dissipated energy. Details of parametric study models are presented in the following sections. Comprehensive numerical results were shown in As previously mentioned, following parameters were considered: deviation in fiber orientation with respect to hoop direction  are given in ordingly ,52 by usIt should be noted that In order to understand the behavior of FRP-confined concrete when using fibers in hoop direction, a total of 18 configurations were modeled and the results are tabulated in In As observed in  studies . Table 4As explained previously, 2E) of the wrap. Additionally, for 5° deviation in In The lateral strain of concrete in As the fiber angle increased, the fiber orientation strain decreased remarkably and differed noticeably from the ultimate hoop tensile strain of the FRP wrap. A closer look at the trend of change in the response from 5° to 15° reveals that for higher In this section, the effect of deviation in It is clear from Since the primary objective of rehabilitation projects was enhancing the strength and load-carrying capacity, it was beneficial to study the variations of Based on The overall reduction in As shown in Based on 2 = 0.988. The equation obtained from regression analysis gives the value of As shown in Based on ed to E1 .It is shown in ncreased , and theBased on  of fco′ . As a reThe effect of deviation in The variations of the strain enhancement ratio, As tabulated in 2 = 0.99.Finally, In this part, the results presented in previous sections will be compared. The crucial issue was to find out which compressive characteristic among strength improvement ratio, strain improvement ratio or total dissipated energy were the most sensitive to deviations in ,95 from  for eachIt could be observed from that the The findings confirmed the acceptable deviation from the intended direction of fiber alignment (5°) given by the current ACI 440.2 design guidelines. Based on the results, simple stiffness or deformation models that take into account the fiber orientation as a variable could be developed, so designers could quickly generate stiffness or deformation values based on the prescribed material system.For 5° deviation in fiber orientation, the average reduction in strength improvement ratio, strain improvement ratio and total dissipated energy was 2.4%, 2.8% and 4.5%, respectively. These numbers confirm the acceptable deviation from the intended direction of fiber alignment (5°) given by the current ACI 440.2 Design Guidelines.The calculated allowable limit of deviation in fiber orientation for a 2.5% reduction in strength improvement ratio, strain improvement ratio, and total dissipated energy was 6°, 3° and 2°, respectively, with a 95% confidence. In other words, with 6° deviations in fiber orientation, the strength improvement ratio would reduce by 2.5%, with a 95% confidence. Or, to limit the reduction in total dissipated energy to 2.5%, the deviation in fiber orientation should be less than 2°, with a 95% confidence.The total dissipated energy reduced the most with deviation in fiber orientation, followed by the strain improvement ratio and strength improvement ratio.The adverse effects of deviation in fiber orientation were positively associated with For the numerical specimens analyzed, the CFRP wrap was more sensitive than GFRP to deviation in fiber orientation, considering the strength improvement ratio.The reduction in the strength improvement ratio, strain improvement ratio, and total dissipated energy followed a similar trend to that of the FRP hoop modulus of elasticity (The reduction in the strength improvement ratio, strain improvement ratio and total dissipated energy with deviation in fiber orientation was more sensitive to the FRP modulus of elasticity than the FRP wrap thickness or concrete compressive strength.This paper reported the results of a numerical investigation into the effects of small deviations in fiber orientation from the hoop direction (


Currently, the production of sustainable concrete with high strength, durability, and fewer environmental problems has become a priority of concrete industries worldwide. Based on this fact, the effective microorganism (EM) solution was included in the concrete mixtures to modify the engineering properties. Concrete specimens prepared with 50% fly ash (FA) as an ordinary Portland cement (OPC) replacement were considered as the control sample. The influence of EM solution inclusion  in the cement matrix as water replacement was examined to determine the optimum ratio that can enhance the early and late strength of the proposed bio-concrete. The compressive strength, porosity, carbonation depth, resistance to sulphuric acid attack, and the environmental benefits of the prepared bio-concrete were evaluated. The results showed that the mechanical properties and durability performance of the bio-concrete were improved due to the addition of EM and FA. Furthermore, the inclusion of 10% EM could increase the compressive strength of the bio-concrete at 3 (early) and 28 days by 42.5% and 14.6%, respectively. The durability performance revealed a similar trend wherein the addition of 50% FA and 10% EM into the bio-concrete could improve its resistance against acid attack by 35.1% compared to the control specimen. The concrete mix designed with 10% EM was discerned to be optimum, with approximately 49.3% lower carbon dioxide emission compared to traditional cement. In recent years, various types of effective microorganisms (EMs) have been used to produce some innovative bio-concretes for construction applications ,2,3. ForIsa et al.  found th2 emissions.Looking at the immense advantages of the EM solution-incorporated modified bio-concretes, we proposed some eco-friendly high-performance concrete mixes containing EM solution and FA that can withstand aggressive environments, including sulphuric acid attacks. The optimum content of EM solution that can improve the early and late strength performance of the FA-cement-modified bio-concrete was determined. The CS values of the modified bio-concrete mixes were measured at various curing ages . The benefits of FA/EM solution incorporation into the bio-concrete for enhancing their durability properties in terms of the resistance against sulphuric acid attack, porosity, and carbonation depth were analyzed. In addition, the environmental benefits of the proposed eco-friendly sustainable bio-concretes containing FA/EM were evaluated to demonstrate the reduction in CO2) and aluminum oxide (Al2O3), contributing more than 86% of the total weight. OPC was obtained from a local supplier and used as the main resource for calcium oxide (CaO), which was mainly composed of CaO and SiO2 (82%). In the bio-concrete mixes, 50% of OPC was replaced by FA to reduce the CaO and increase the Al2O3 contents, thus improving the ratio of SiO2 to Al2O3 and CaO to Al2O3.In this study, the EM solution (as a tap water replacement) activated bio-concretes were prepared using high volume FA as OPC replacement. FA class F  was obtained from a local power plant  and used without further chemical or physical treatment. The chemical composition of FA  was analBacillus subtilis and lactic acid bacteria. The activated solution was made (with a pH of less than 4) using fermentation for 7–10 days without an oxygen supply. The existence of the EM in the solution and its solubility in water were examined before implementation into the concrete mixes. The color appearance of the produced bio-concrete (fresh and hardened phases) was analyzed. Initially, EM showed a dark brown hue, then transformed to dark yellowish after substituting with 10% of water, and finally became homogeneous light brown after substituting with 25% of water. Similar findings regarding the EM solution colors were reported elsewhere [In this study, 5 kg of type 1 EM (EM-1) was procured in a closed vessel , and 5% of it was activated using 90% water and 5% blackstrap molasses as the primary food source. As shown in lsewhere .2SO4 solution (10% concentration), and the pH of the acid solution was maintained for 2 months. The immersed specimens were tested after 180 and 365 days to measure their strength loss, weight loss, internal cracks, ultrasonic pulse velocity (UPV) readings, visual appearance, and surface morphologies. Several tests were adopted to evaluate the sustainability performance of the suggested bio-concrete, including the CS, porosity, carbonation depth (CD), resistance against sulphuric acid attack, and carbon dioxide emission. For the CS evaluation, cubic specimens with size (100 mm × 100 mm × 100 mm) were made and recorded at various curing ages . For each age, three specimens were tested to find the statistical average. The CS test was conducted following the ASTM C109 and ASTM C150 stipulations. Following the ASTM C642 standard, the porosity and total voids of the disc-shaped specimens (100 mm diameter and 50 mm depth) were obtained. The BS 1881 standard was followed to measure the CD of the cylindrical specimens (100 mm diameter and 200 mm depth). Regarding the durability performance in an aggressive environment, modified bio-concretes were immersed in H2 emission levels. For this assessment, each material  was considered over the entire life cycle, including the production, transport cost, and other chemical treatments in the laboratory. The distance of transportation for FA and OPC was 35 km and 5 km, respectively. Regarding the life cycle of each constituent of the bio-concrete, the net CO2 release was calculated depending on the production, transport distance, and fuel consumption to procure each component. For each ton of OPC, FA, and EM, the corresponding net CO2 release was 0.904, 0.012, and 0.00001 ton/ton. For every cubic meter of the constituent material, the net CO2 emission was calculated via:GY is the net CO2 release (ton/ton), xi is the mass of constituent i (ton/m3), di is the transportation distance (km), fi is the diesel usage (liter/km), zi is the CO2 release (ton) for 1 L diesel burning.The environmental benefits of the FA and EM-incorporated bio-concretes were evaluated in terms of CO2S) and Tricalcium Silicate (C3S). The non-crystalline silicate minerals in FA reacted with Ca(OH)2 to create the cement hydration products such as calcium silicate hydrate (C-S-H) gels. The reduction in Ca(OH)2 and increase in C-S-H gel led to the enhanced strength performance and durability of the bio-concrete. The SEM image analyses , belite (Ca2SiO4), and tricalcium aluminate (Ca3Al2O4) [2 that existed in the cement. However, the increased curing time enhanced the CS value of the specimens; this increase was mainly due to the pozzolanic reactions that enabled the C-S-H gel formation in contrast to the control specimen at 7 days [analyses ,34. Meana3Al2O4) ,36. The a3Al2O4) , togethea3Al2O4) ,39. Convt 7 days ,41,42.The effect of the EM solution on the early and late CS development of the cement-FA concretes was evaluated . The inc2 and hydrated C–S–H gels, restricting their expansion in the concrete network. Similar results were obtained by Ali et al. [The early-age CS values of the modified concrete were directly influenced by the pH of the solution. It was shown  that thei et al. , who shoThe acceleration of the hydration process enabled efficient pore filling by C-(A)-S-H gels, thus achieving a better strength performance in the bio-concrete made with 5 and 10% EM than the control specimen. Moreover, the low value of the surface tension of the mixed water was responsible for the better performance of the bio-concrete, wherein very tiny pores were formed by the water when mixed in the concrete. It was inferred that the interaction amid the capillary walls could be controlled by lowering the solution surface tension because the capillary pores’ diameter is reduced to micro-scale during drying . In addi3SiO4 from the hydration reaction, which is vital for the CS development of the bio-concrete. However, at higher molasses contents, the ettringite formation was accelerated, averting the second hydration of the aluminates phase and delaying the hydration of the Ca3SiO4 [The inclusion of EM at high amounts could reduce the solution surface tension, thus reducing the CS values of the bio-concretes . The flo Ca3SiO4 .2, CaCO3, and C-(A)-S-H gels. The results show that the increasing content of FA resulted in more non-reacted silica, as displayed by the peaks at 20.1, 39.8, 50, and 60.4°. These consisted of sharp crystalline peaks corresponding to the quartz (SiO2), portlandite (CaOH)2, calcite (CaCO3), ettringite (Ca6Al2(SO4)3(OH)12·26H2O), and gypsum (CaSiO4) phases that resulted from the binary blends (OPC and FA). It was found the intensity of the quartz peaks trend to increase with the increasing FA level from 0 to 50% as an OPC replacement, wherein more quartz became nonreactive at 50% of FA (MC2-50-0) compared to the control sample (MC1-0-0), which resulted in lower strength. These products were generated from the reaction between the amorphous SiO2 and Al2O3 from FA with highly crystalline C3S, C2S, and C3A from OPC phases. Conversely, the concrete made without OPC showed portlandite and calcite peaks around 18-65°. However, by replacing OPC with 50% FA, the portlandite peaks in the range of 18–50° became lower. Unlike with the inclusion of 10% of EM in the OPC-FA matrix modified concrete specimens (MC4-50-10), the quartz peak intensity was decreased at the expense of the portlandite peak intensity as more silica dissolved and created the C-(A)-S-H gels in the hydration process  and CS was ascertained 2 reacted with the SO4−2 ion and produced CaSO4.2H2O. Consequently, the concrete networks were expanded and contained more inner cracks. This observation was consistent with the other findings [2 and gypsum (Ca2SO4·2H2O) levels. The recorded loss in concrete mass and strength can be ascribed to acid molecule diffusion into the cement network matrix and subsequent gel damage. In addition, the soft and soluble gypsum strongly reacted with Ca(OH)2 and generated ettringite (3CaO·Al2O3·3CaSO4·32H2O). Nevertheless, the existence of FA and EM in the concrete matrix led to a reduction in unstable calcium, restricting the formation of gypsum and thus lowering the concrete spalling and deterioration [findings ,55,56,57ioration ,58,59.2SO4 solution exposure. The resistance of the modified concrete to sulphuric acid attack was enhanced, as shown by the reduced external cracks, edges, and surface deterioration. The specimen devoid of FA and EM (control sample) showed the formation of larger cracks compared to the bio-concrete containing both FA (50%) and EM solution (10%). The bio-concrete corrosion was significantly decreased with the increased FA and EM levels of 50% and 10%, respectively. The inclusion of FA and EM into the concrete mixes could reduce the gypsum formulation as well as enabling the generation of more stable gels, improving the bio-concrete resistance and preventing deterioration.2SO4 solution exposure for one year. Specimens containing FA or FA and EM solution showed a decreased quantity of gypsum and presented with a lower deterioration compared to the cement-based concrete (control sample). The concrete specimens prepared with cement only  [2 level in the bio-concrete was responsible for the improved acid attack resistance and enhanced durability.ent only a displayent only b,c. The ent only a reveale(gypsum) ,61. Gene2 emissions of the modified concrete. 2 emissions, achieving substantial environmental benefits. The inclusion of FA and EM solution into the cement matrix was found to reduce the CO2 emissions from 0.4068 kg/m3 to 0.2067 kg/m3. The proposed concrete achieved much lower carbon emissions (above 49.3%) compared to the pure OPC-based control specimen. Conversely, the inclusion of 50% FA as a cement replacement in the high-performance bio-concrete was shown to reduce the demand for natural resources as well landfill problems related to the disposal of hazardous waste materials.The environmental benefits of the FA and EM solution-incorporated bio-concrete were evaluated in terms of the predicted lowering of carbon dioxide emissions. i.The replacement of tap water with the EM solution led to a reduced pH and surface tension. However, the viscosity of EM solution was increased with the increase in the EM level. The fresh and hardened properties of bio-concrete were significantly influenced by the inclusion of the EM solution.ii.The inclusion of 50% FA as an OPC replacement could directly affect the early and late strength development of the proposed bio-concrete.iii.The inclusion of 5% and 10% EM in the cement-FA matrix improved the CS at early and late ages.iv.The highest CS was achieved for the bio-concrete prepared with 10% EM. The EM solution improved the hydration process and led to the formulation of denser gels, thus yielding a better performance compared to other dosages of EMs.v.The SEM results showed that the replacement of tap water with 10% EM solution could improve the surface morphology of the bio-concrete and reduce the number of pores. This, in turn, increased the strength and reduced the porosity of the bio-concrete. An inverse relationship was observed between strength and porosity of modified concretes.vi.The reduction in the porosity and total number of pores in the modified concrete prepared with 10% EM could contribute to the improvement of their durability by reducing the carbonation depth.vii.The inclusion of FA and EM in the cement matrix led to an increase in the concrete resistance during sulphuric acid attack in terms of the reduced strength loss, weight loss, internal cracks, and deterioration of both the surface and edges.viii.Overall, the FA and EM solution-incorporated concrete showed a great potential for construction applications. It is asserted that such bio-concretes may offer a possible solution to reduce the reliance on standard OPC-based concretes that contribute appreciably to pollution, promoting the development of materials of greater sustainability and thus minimizing the negative effect on the environment.In this work, the possibility of producing sustainable bio-concrete using FA and EM with improved strength and durability performance was explored. From the obtained results, the following conclusions were derived:


BackgroundOveruse or misuse of broad-spectrum antibiotics appeared to be a major cause of increased antibiotic resistance. This study aimed to explore awareness and knowledge of antibiotic prescribing and resistance among hospital physicians in Medina, Saudi Arabia.MethodologyA cross-sectional study was conducted among 223 physicians in seven public hospitals in Medina, Saudi Arabia. A validated self-administered questionnaire was used, including questions on sociodemographics, awareness about the current scope of antibiotic resistance, knowledge and frequency of antibiotic prescribing, confidence and input seeking, factors influencing antibiotic prescribing, and attitude toward antibiotic use. t-Test and analysis of variance (ANOVA) tests were used to compare total knowledge scores across the sociodemographic variables. The level of significance was set at 0.05.Resultssometimes) colleagues before prescribing. Factors associated with knowledge were age (P = 0.001), educational level (P = 0.002), working years (P = 0.004), current position (P = 0.003), specialty (P = 0.023), duration since graduation from medical school (P = 0.002), and duration since the last qualification (P = 0.022).Most participants were aware that antibiotic resistance is a problem in Saudi Arabia (87.4%) and worldwide (93.3%). The majority of physicians (77.6%) were classified as having moderate knowledge, the mean knowledge score on antibiotics was 4.41, and 26.5% of the respondents prescribed antibiotics more than once daily. Most physicians (91.4%) were confident in antibiotic prescribing, and 94.1% of them consulted (at least ConclusionsThe majority of physicians had a moderate knowledge level of antibiotics, and most of them were prescribing antibiotics more than two times per week. Most respondents agreed that antimicrobial resistance is a worldwide concern and that it is a problem in Saudi Arabia. This study recommends training and courses on the fact that appropriate antibiotic prescribing should be ensured to have the best practice in antibiotic prescription among physicians. Globally, antibiotic resistance is one of the greatest public health threats of the twenty-first century as a result of antibiotic overuse -2. In 20The consequences of antibiotic resistance affect both the economic sector such as increased treatment costs and lack of resources and the health of the population such as increased morbidity and mortality and decreased quality of life ,7. An efMost of the previous surveys were conducted in Saudi Arabia to assess the general population's knowledge, attitude, and practice of antibiotic use and misuse, especially in upper respiratory tract infections ,10. PhysThis cross-sectional study was conducted in seven governmental hospitals in Medina . All are teaching hospitals, with a total capacity of all hospitals around 1,000 beds . The samWe included general practitioners, residents, specialists, consultants, and fellow physicians from five specialties: medicine, pediatrics, surgery, emergency, obstetrics, and gynecology. Physicians working in other specialties were excluded as they do not routinely prescribe an antibiotic. A validated self-administered questionnaire was distributed on-site during working hours. The questionnaire was adopted from previous studies in the United States, Malaysia, Peru, Egypt, and Pakistan -16. BefoThe 30-item questionnaire addressed the demographic and professional profile of the participants (eight questions), frequency of antimicrobial prescription (one question), basic knowledge (seven questions), awareness about the current scope of antimicrobial resistance (three questions), sources of information and continuing education about antimicrobial (one question), confidence and seeking inputs (two questions), factors influencing decisions around antimicrobial prescription (three questions), attitude toward antibiotic use (three questions), and the acceptability and appropriateness of potential interventions (one question).strongly disagree to strongly agree or never to always or useful to not useful. The basic knowledge questions of the clinical indications, spectrum, administration, and pharmacology of antibiotics were as follows: three case-based questions that addressed the choice of antibiotics for treating acute diarrhea, upper respiratory tract infection, and sepsis in a patient with impaired renal function; one question addressed the safety of antibiotics during pregnancy; and three questions addressed the spectrum of antibiotics and ability to cross the blood-brain barrier [Most of the questions used a five-point Likert scale, with answers ranging from  barrier -16. Ethilow representing two or fewer correct answers, moderate representing three to five correct answers, and high representing six or more correct answers. The t-test and ANOVA tests were used to compare the total knowledge scores across the sociodemographic variables. The level of significance was set at 0.05.Analysis was performed by using the Statistical Package for the Social Sciences . Descriptive statistics were used to obtain the frequency and percentage for categorical variables and mean and standard deviation (SD) for continuous variables. For knowledge assessment, each correct response was scored 1, while a wrong response was scored 0 and then the sum of the scores was added to obtain the total knowledge score. Then the total knowledge score was categorized into three types , with A total of 223 out of 246 physicians completed the questionnaire with a 91% response rate. The majority were males (60.5%), aged 25-35 years (63.7%), and practiced for six years or more (46.2%). More than half (52.5%) were general practitioners or residents, 28.2% were specialists, and 19.3% were consultants (Table The mean (±SD) knowledge score was 4.41 (±1.1) with a range of 4-7. According to the knowledge level score, the majority of physicians (77.6%) were classified as moderate knowledge, 16.1% were classified as high knowledge, and 6.3% were classified as low knowledge.P = 0.001), educational level (P = 0.002), working experience (P = 0.004), current position (P = 0.003), department (P = 0.023), time since graduation from medical school (P = 0.002), and duration since the highest qualification (P = 0.022)  of the respondents agreed that antimicrobial resistance is a worldwide concern and 87.4% agreed that antimicrobial resistance is a problem in Saudi Arabia, while 62.3% agreed that it is a problem in their daily practice. The majority agreed upon the perception of overuse of antibiotics in both Saudi Arabia hospitals (86.1%) and the community (85.6%) (Table very confident (43%) or at least somewhat confident (48.4%) about optimal antibiotic prescribing. Only 19 (8.5%) physicians felt hesitant about optimal antibiotic prescribing. The majority (94.1%) discuss their decision to prescribe antibiotics with their senior colleagues at least sometimes, while the remaining (5.8%) never seek any opinion from senior colleagues. Regarding the acceptability and appropriateness of potential intervention, most of the participants strongly agreed or just agreed with the development of antimicrobial prescribing educational programs (91.5%) and agreed that a local antimicrobial guideline would be more useful than an international one (78.2%).Regarding confidence and input seeking, most respondents (91.4%) felt either Table more than once a day, 53 (23.8%) prescribed antibiotics three to five times per week, 46 (20.6%) prescribed antibiotics one to two times per week, 45 (20.2%) prescribed it less than once a week, and 20 (9%) prescribe it once a day.A total of 59 (26.4%) participants prescribed antibiotics Overall, the most useful source of information reported by the participants was the internet (57%) followed by information from a senior colleague or fellow (47.5%) and information from the Ministry of Health Drug Formulary (37.2%). Hospital pharmacy and British National Formulary (BNF) were reported as useful sources of information by 35% and 29.1%, respectively, among participants. The least useful source of information was the Sanford Antimicrobial Guide (21.1%) Table .strongly agree or agree that patients’ demand for antimicrobial therapy contributes to their overuse in the community, whereas only half (50.3%) did so in a hospital setting. More than third (36.8%) agreed with the statement that the antimicrobial available in their hospitals are of poor quality and are not effective. Nearly half of them (44.9%) agreed that the choice of antibiotic was affected by its availability in their setting more than by the cause of infection  of the participants 0.4% of tThis study aimed to explore awareness and knowledge of antibiotic prescribing and resistance among hospital physicians. In this study, the mean knowledge score was 4.41 ± 1.11, which was lower than two previous studies from Malaysia (5.31 ± 1.19) and Peru (6.0 ± 1.3), whereas higher than the study reported from Pakistan (3.66 ± 1.1) ,14,15. IOur finding indicated that a longer duration of practice ensures good knowledge of antibiotic prescribing. Overall, the basic knowledge about the clinical indications, spectrum, administration, and pharmacology of antibiotics ranged from moderate to high. Despite this surprising score, it should be noted that more than half of the participants recommended using antibiotics for upper respiratory tract infections. Therefore, we highly encourage raising the study recommendation for a focused educational activity to higher authority at the Ministry of Health.Regarding the confidence level, this study showed that only 43% of the respondents were very confident in choosing the right antibiotics, which is lower than the study reported from Peru among residents (47%) and attending physicians (82%), whereas it is higher than reported studies from the United States (21%), DR Congo (11.4%), and Malaysia (4%) -17.sometimes compared to Pakistan (80%), DR Congo (79.4%), and Malaysia (77%) [ In this study, there was a significant association between years of working and confidence level scores. A similar finding was reported by a previous study from Peru . Howeveria (77%) ,14,17.In our study, the respondents were very receptive to intervention in prescribing antibiotics. Most of the respondents would prefer national antibiotic guidelines more than international guidelines because they felt that the local data would be more useful for their practices. Therefore, national guidelines will certainly be more focused and useful for doctors who practice locally. The awareness of participants about antibiotic resistance is a worldwide as well as a national problem that was very high among the respondents in this study, which is consistent with the previous studies ,15. Mostmore than once a day in the last week, which is lower than previous studies from Pakistan (66%), Egypt (60%), Malaysia (52%), DR Congo, and Peru (49%) [two times or less in the last week [In this study, 26.5% of the participants have prescribed antibiotics ru (49%) -15,17. Iast week . Regardisenior colleagues [In this study, the most common source of information on antibiotics was the internet. Similar results were found in Malaysia and Peru ,15. Howelleagues ,16. In tlleagues ,19. In tlleagues ,15.A potential limitation could be some of the participants may tend to answer with socially desirable responses. This potential bias is minimized by ensuring complete confidentiality regarding the finding of the survey. Another limitation of this study is that not all physicians in Medina have been included in the study; therefore, the results cannot be generalized to all the physicians in Medina.The majority of physicians had a moderate knowledge level of antibiotics, and most of them were prescribing antibiotics more than two times per week. Most respondents agreed that antimicrobial resistance is a worldwide concern, and it is a problem in Saudi Arabia. This study recommends that training and courses on appropriate antibiotic prescribing should be ensured to have the best practice in antibiotic prescription among physicians.