MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are components of many signaling pathways associated with tumor aggressiveness and cancer metastasis. Some lncRNAs are classified as competitive endogenous RNAs (ceRNAs) that bind to specific miRNAs to prevent interaction with target mRNAs. Studies have shown that the hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/c-Met) pathway is involved in physiological and pathological processes such as cell growth, angiogenesis, and embryogenesis. Overexpression of c-Met can lead to sustained activation of downstream signals, resulting in carcinogenesis, metastasis, and resistance to targeted therapies. In this review, we evaluated the effects of anti-oncogenic and oncogenic non-coding RNAs (ncRNAs) on c-Met, and the interactions among lncRNAs, miRNAs, and c-Met in cancer using clinical and tissue chromatin immunoprecipition (ChIP) analysis data. We summarized current knowledge of the mechanisms and effects of the lncRNAs/miR-34a/c-Met axis in various tumor types, and evaluated the potential therapeutic value of lncRNAs and/or miRNAs targeted to c-Met on drug-resistance. Furthermore, we discussed the functions of lncRNAs and miRNAs in c-Met-related carcinogenesis and potential therapeutic strategies. MET gene, located on chromosome 7 (bands q21–q31)  is a receptor tyrosine kinase that belongs to the MET (MNNG HOS transforming gene) family Salgia, . C-Met i31) Liu, . As a ki31) Liu, . Binding31) Liu, , to indu31) Liu,   Liu, . The HGF31) Liu, . The onc31) Liu, . Amplifi31) Liu, . FurtherEarly studies have proved that besides proteins, there are lots of unique RNAs encoded by the genome are functional. Subsequent researches discovered a variety of non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)  and the HGF/c-Met axis. In addition, we showed through this literature review that miRNAs and lncRNAs are critical regulators of c-Met in multiple cancers. Furthermore, the lncRNAs/miRNAs/c-Met axis may have potential as a target for treatment of cancer.Studies have shown that c-Met is a target gene of multiple miRNAs , 2 that MET promoter , metastasis, and stemness, and was shown to promote apoptosis, which resulted in suppression of tumor growth and carcinogenesis  for miR-34a as well. XIST may compete with c-Met for miR-34a binding, which promotes thyroid cancer cell proliferation and tumor growth (Liu et al., in vivo and in vitro studies have shown the potential treatments for sorafenib resistance in HCC (Chen and Xia, NEAT1, a highly abundant lncRNA in the nucleus, was found to be present at higher levels in glioma than in non-cancerous brain tissues. NEAT1 acts as a molecular sponge for miR-449b-5p, which leads to upregulation of c-Met, resulting in glioma pathogenesis (Zhen et al., Other oncogenic lncRNAs include lnc-TALC in glioblastoma (Wu et al., YBX1, MET, and p21, which resulted in reduced cell survival and increased cell death signaling in human primary lung tumors (Su et al., In addition to most lncRNAs act as miRNAs sponges to upregulate the expression of c-Met, there are also some lncRNAs suppress the cancer progression by targeting c-Met through other pathways . ReducedAs mentioned above, miRNA-34 is crucial in HGF/c-Met signaling. Many studies have focused on lncRNAs, including lnc-XIST, lnc-MALAT1, lnc-GAPLINC, lnc-HOTAIR, and lnc-ARSR, as ceRNAs targeting to miR-34 . RecentlIn this section, resistance to current anticancer strategies used for treatment of lung, kidney, and pancreatic cancer is discussed . Lnc-ARSin vivo studies have been performed. Preclinical models and successful clinical trials are of critical importance. MiR-34a has been extensively studied and is a promising miRNA therapeutic candidate (in vivo, which is a promising therapeutic technology (Hansmeier et al., Events such as c-Met gene mutation, overexpression, and amplification may be closely related to aberrant activation of HGF/c-Met signaling in human cancers (Barrow-Mcgee et al., andidate . Like miandidate . Moreoveandidate , and proandidate . Among nandidate . To solvandidate . Besidesandidate . The firandidate . Howeverandidate , synthetandidate , dendrimandidate , cyclodeandidate , chitosaandidate , N-acetyandidate . Furtherandidate . Rnase Handidate  and CRISandidate . LncRNA-MET gene. The relationships among lncRNAs, miRNAs, and c-Met in cancer require further characterization. Studies that evaluate the effect of specific lncRNAs or miRNAs on c-Met in different types of cancer are required to determine the therapeutic potential of targeting this signaling pathway.Studies have shown that c-Met is associated with tumor formation, progression, and metastasis. Recent studies have highlighted the HGF/c-Met axis as a promising therapeutic target for treatment of metastatic tumors. Metastatic dissemination represents a critical problem in the treatment of malignancy, and results in poor prognosis and increased mortality in patients with cancer. The metastatic process includes growth and proliferation of the primary tumor, and migration, adhesion, invasion, and survival at distal sites. A number of lncRNAs and miRNAs that target c-Met may play different roles in carcinogenesis through various molecular mechanisms, including up-regulation or mutation of the Studies have shown that ncRNAs/HGF/c-Met signaling is involved in many physiological and pathological processes, and most miRNAs are anti-oncogenic and most lncRNAs are oncogenic. LncRNAs act as ceRNA, decoys, or sponges and bind to specific miRNAs, to prevent interactions with c-Met, which results in malignancy. Studies have shown that c-Met may drive oncogenesis and promote resistance to targeted therapies such as EGFR, VEGFR, HER2, and BRAF inhibitors (Engelman et al., In conclusion, overexpression of c-Met can be induced by upstream lncRNAs and/or miRNAs in various types of tumors . ClinicaHZ and ST drafted the manuscript. FZ revised the manuscript. AS and JL reviewed and modified the manuscript. All authors agreed on the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor and the authors are affiliated with Zhejiang University, Hangzhou, but do not have any collaborations.


Background: While subtyping of the majority of malignant chromophobe renal cell carcinoma (cRCC) and benign renal oncocytoma (rO) is possible on morphology alone, additional histochemical, immunohistochemical or molecular investigations are required in a subset of cases. As currently used histochemical and immunohistological stains as well as genetic aberrations show considerable overlap in both tumors, additional techniques are required for differential diagnostics. Mass spectrometry imaging (MSI) combining the detection of multiple peptides with information about their localization in tissue may be a suitable technology to overcome this diagnostic challenge.Patients and Methods: Formalin-fixed paraffin embedded (FFPE) tissue specimens from cRCC (n=71) and rO (n=64) were analyzed by MSI. Data were classified by linear discriminant analysis (LDA), classification and regression trees (CART), k-nearest neighbors (KNN), support vector machine (SVM), and random forest (RF) algorithm with internal cross validation and visualized by t-distributed stochastic neighbor embedding (t-SNE). Most important variables for classification were identified and the classification algorithm was optimized.Results: Applying different machine learning algorithms on all m/z peaks, classification accuracy between cRCC and rO was 85%, 82%, 84%, 77% and 64% for RF, SVM, KNN, CART and LDA. Under the assumption that a reduction of m/z peaks would lead to improved classification accuracy, m/z peaks were ranked based on their variable importance. Reduction to six most important m/z peaks resulted in improved accuracy of 89%, 85%, 85% and 85% for RF, SVM, KNN, and LDA and remained at the level of 77% for CART. t-SNE showed clear separation of cRCC and rO after algorithm improvement.Conclusion: In summary, we acquired MSI data on FFPE tissue specimens of cRCC and rO, performed classification and detected most relevant biomarkers for the differential diagnosis of both diseases. MSI data might be a useful adjunct method in the differential diagnosis of cRCC and rO. Classification of primary renal tumors is a common task in routine histopathological diagnostics. While the differentiation of most renal tumors is possible on morphology alone, some require additional histochemical, immunohistochemical (IHC) or molecular investigations. A frequent scenario where additional studies are recommended is in the differential diagnosis of oncocytic renal tumors While tumor cells in both tumors generally show a nested or broad trabecular unencapsulated growth and eosinophilic finely granular cytoplasm, typical morphological features of cRCC are distinct cell borders, raisinoid, irregular, wrinkled and angulated nuclei, bi- or multinucleation, perinuclear halos and fibrovascular stroma. Typical morphological characteristics of rO include more closely arranged tumor cells at the periphery of the lesion, presence of oncoblasts, uniform small, round centrally located nuclei, and myxoid or hyalinized stroma . One should be aware that rO may exhibit perinephric or renal sinus fat invasion, venous invasion, degenerative atypia with bizarre pleomorphic nuclei and mitosis A helpful histochemical stain in the differential diagnosis is the colloidal iron stain . While cRCC frequently exhibit intense reticular staining, rO show less intense fine dust-like reactivity Figure 1).A survey among urologic pathologists reported cytokeratin (CK) 7 (94%) as most frequently used and most helpful adjunct IHC stain in the differential diagnosis of cRCC and rO With regard to genetic changes, losses of multiple chromosomes by karyotyping was regarded supportive of cRCC by most (65%), and chromosomal gains only by some (18%) in the same study In an attempt to better characterize the proteomic landscape of renal tumors, mass spectrometric methods have been applied Figure 1). Tissue blocks were extracted from the archive of the Institute of Pathology Erlangen, with the support of the local tissue bank according to standards defined by the local ethics committee . Tissue microarray (TMA) construction was performed as previously described Supplementary Table 1).The cohort consisted of formalin-fixed paraffin embedded (FFPE) specimens from patients with diagnosed with either cRCC (n=71) or with rO (n=64). Diagnosis was made according to the recommendations of the 2016 World Health Organization classification of renal Three micrometer thick sections of the TMA were cut and mounted onto conductive indium tin oxide-coated glass slides . Sample slides were processed for dewaxing with xylene , rehydrated through graded ethanol washes (Fischer Scientific), and subjected to heat induced antigen retrieval in 10 mM tris buffer at pH 9.0 at 95 °C for 20 min, as previously described MSI was performed using an Autoflex Speed matrix-assisted laser desorption/ionization time-of-flight (TOF)/TOF mass spectrometer  operated in reflectron mode with positive polarity and equipped with a smartbeam laser. MSI runs were programmed using flexControl and flexImaging software . Each spectrum was automatically generated at a spatial resolution of 150 µm  in the mass range of m/z 500-5000. 1600 laser shots were acquired for each spectrum with 2 kHz repetition rates. A peptide calibration standard mix including bradykinin, angiotensin II, angiotensin I, substance P, bombesin, ACTH clip 1-17, ACTH clip 18-39, and somatostatin 28  was used for external calibration. Following MSI measurements, matrix was removed by two washes in 100% methanol (Fischer Scientific) for 5 min each followed by hematoxylin and eosin (HE) staining.Tissue sections analyzed by MSI and stained by HE were scanned by a slide scanner  and the tumor regions were annotated using SCiLS Cloud . MSI data were processed using SCiLS Lab (SCiLS GmbH) for peak- and image visualization. Annotations were imported into SCiLS Lab software and spectra were corrected to baseline using the algorithm TopHat and normalized by total ion count. After manual peak picking, the mean intensity of reprocessed spectral peaks of each patient was exported for further statistical analysis.All statistical analyses were performed in R-Statistical Software  and R-Studio .t-distributed stochastic neighbor embedding (t-SNE) was performed to visualize the separation of cRCC and rO samples based on the high-dimensional m/z peak intensities data set Different linear, nonlinear and more advanced machine learning algorithms  with internal cross validation were applied to calculate the accuracy and variable importance of tissue type prediction based on all and selected m/z values Figure 2 shows the sum spectra obtained in the MSI analysis.Proteomic MSI analysis was successfully performed on cRCC (n=71) and rO (n=64) FFPE tissues. 159 peptide peaks in the m/z range from 515.1 and 4953.4 were detected and selected for further statistical analysis. The mean MSI peak intensity of all peaks ranged between 0.05 and 1.59 regardless of tissue type. Aiming future classification of unknown tissue samples a t-SNE analysis and five different machine classification algorithms have been applied. An internal cross validation approach was performed to calculate the prediction accuracy of each machine classification algorithm.Figure ). Similarly, applying different machine learning algorithms under consideration of all m/z peaks classification accuracy between cRCC and rO of 85%, 82%, 84%, 77%, and 64% was reached for RF, SVM, KNN, CART and LDA .The first differentiation approach including all available m/z peaks (n=159) resulted in low visual separation accuracy with t-SNE . Representative mass spectrometry images of cRCC and rO are displayed in Under the assumption that a reduction of variables (i.e. m/z peaks) would lead to a higher classification accuracy m/z peaks were ranked based on their variable importance contributing most to the differentiation between cRCC and rO in the RF algorithm. The six most important m/z values for cRCC and rO classification in descending order starting from the most important were: m/z 1377.6, m/z 1906.9, m/z 1786.8, m/z 1692.8, m/z 1629.8 and m/z 1495.7 , which can also be seen in unsupervised cluster analysis . Moreover, the median classification accuracy of the machine learning algorithms improved to 89%, 85%, 85%, and 85% for RF, SVM, KNN, and LDA and remained at the level of 77% in CART algorithm . Having the highest classification accuracy RF high be the most suitable classification algorithm between cRCC and rO based on proteomic MSI data. The sensitivity and specificity of the final tuned RF model was 89% and 81% respectively.Reduction of variables (i.e. m/z peaks) to six most important resulted in an improvement of visual separation between cRCC and rO in t-SNE .The peaks m/z 1377.6, m/z 1906.9, m/z 1786.8, m/z 1692.8, m/z 1629.8 and m/z 1495.7 were identified as most important peaks in contributing to differentiation between cRCC and rO by RF. All but m/z peak 1906.9  showed a higher median peak intensity in rO compared to cRCC: m/z 1377.6 - cRCC 0.29 (range 0.24-0.54), rO 0.45 (0.25-1.25); m/z 1786.8 - cRCC 0.23 (range 0.18-0.50); rO 0.37 (0.20-0.78); m/z 1692.8 - cRCC 0.25 (range 0.21-0.29); rO 0.33 (0.25-0.53); m/z 1629.8 - cRCC 0.27 (range 0.21-0.71); rO 0.44 (0.22-1.23) and m/z 1495.7 - cRCC 0.30 (range 0.22-2.83); rO 0.39 (0.26-1.03),  typical of cRCC and rO Of note, the MSI data were acquired on a mass spectrometer of the former generation. In our experience, even more peptide peaks can be detected on the newer compared to the older instrumentation; however it is not clear whether classification results might be improved by analysis on the most recent generation of mass spectrometers In summary, we acquired MSI data on FFPE tissue specimens of cRCC and rO, performed classification and detected most relevant biomarkers for the differential diagnosis of both diseases.Supplementary figures and tables.Click here for additional data file.


Sir,Many dialysis patients rely on tunneled central venous catheters for long-term vascular access. Hemodialysis catheter dysfunction (HCD) caused by intraluminal thrombosis is a common problem often necessitating replacement. We have noticed increasing prescription of thrombolytic therapy for HCD across our health service in recent years. Thrombolytic agents are relatively costly and evidence for their use and cost-effectiveness in treating HCD is sparse. Given budgetary considerations in our health service, we sought to examine this subject by auditing our hospital records. We intended to observe local practices regarding HCD and evaluate whether adherence to standard guidelines improves the efficacy of thrombolysis.We performed a retrospective chart review of all patients receiving intra-catheter thrombolysis for tunneled HCD over 12 months in our hospital network from August 2018. Although HCD is variably defined, we defined it for this audit as documented extracorporeal blood flow less than 300 mL/min despite an arterial line pressure exceeding negative 200 mmHg. We considered successful treatment to be improvement in catheter function to below that threshold during the next dialysis session. This quality improvement project was permitted by our local research committee.Thrombolysis was administered on 66 occasions to 30 different patients in the 12-month period, at a cumulative cost of AU$12,795.42. Intravenous alteplase is the only agent used for this purpose in our renal unit, dosed in vials of 2.5 mg/2.5 mL at a price of AU$193.87 per vial. Agents available at other centers may include urokinase, streptokinase, and tenecteplase. Thrombolysis successfully reversed HCD in 56% (36/64) of cases. The median catheter survival after administration of intraluminal thrombolysis was 40 days and censored 3-month catheter survival was 31%. Although some machine and flow parameters were documented on most occasions, objective measurements satisfying the criteria for HCD were present in only 44% (29/66) of patients, indicating that thrombolysis may have been prescribed inappropriately in a number of cases. In patients who met the criteria, based on documented readings, thrombolysis efficacy increased to 64% (18/28).In addition to intra-catheter thrombolysis, other basic interventions for HCD can include evaluating fluid status to avoid hypovolaemia and obtaining a chest radiograph to confirm catheter tip position . There iWe presented our findings to our local renal unit and described an unofficial protocol  includinIntraluminal thrombosis accounts for approximately two thirds of catheter replacements . Most tuMost of the interventions reviewed in our audit, to the author’s knowledge, have not been previously examined in the literature. The results of this chart review are encouraging and generate the hypothesis that the utility and cost-effectiveness of thrombolysis for HCD can be improved with judicious use. This is an important subject for nephrologists and warrants further high quality clinical research.


This paper presents a method for modeling the dynamic properties of steel–polymer concrete beams, the basic structural components of machine tools, assembly lines, vibratory machines, and other structures subjected to time-varying loads during operation. The presented method of modeling steel–polymer concrete beams was developed using the finite element method. Three models of beams differing in cross-sectional dimensions showed high agreement with experimental data: relative error in the case of natural frequencies did not exceed 5% (2.2% on average), the models were characterized by the full agreement of mode shapes and high agreement of frequency response functions with the results of experimental tests. Additionally, the developed beam models supported the reliable description of complex structures, as demonstrated on a spatial frame, obtaining a relative error for natural frequencies of less than 3% (on average 1.7%). Full agreement with the mode shapes and high agreement with the frequency response functions were achieved in the analyzed frequency range. Successful diagnosis of the static and dynamic properties of composite structural elements requires the development of a reliable model as a tool to assist engineers in making design decisions. One such composite structural element is the steel–concrete or steel–polymer-concrete beam. Despite the extensive literature on the modeling of the static properties of such structures ,6,7,8,9,In , the autIn , the autIn , the autIn , a hybriIn , the autThe aforementioned works indicate that accurate computational analysis is crucial in designing composite machine components. However, the literature barely mentions the experimental verification of frequency response functions to describe the dynamic properties across wider frequency ranges. The agreement of individual natural frequencies between the model and experiment is just one and not even the most important aspect of validating modeling results. The more important factors are the agreement of the mode shapes for individual natural frequencies  with the frequency response functions in a given frequency range.This paper presents a method for the finite element modeling (FEM) of the dynamic properties  of composite structural components consisting of a hollow steel profile filled with a highly heterogenous polymer concrete. The process of modeling the dynamic properties of the described beams required appropriate simplifying assumptions. These assumptions determined the structure of the model, the methods of determining its parameters, and the choice of an appropriate validation method . Assumptions made during modeling resulted from a study on the modeled object based on a series of experiments. The experiments were carried out in two stages: the first aimed at determining the material properties of the steel and polymer concrete, and the second aimed at providing information about the dynamic properties of the object. The presented method was verified for beams with a variety of cross-sectional dimensions, as well as a composite frame composed of such beams. In this paper, it has been proven in experimental, analytical and numerical studies that highly heterogeneous polymer concrete can be modeled using a linear isotropic model of the material, provided that it is present in the composite steel–polymer concrete structure.The structure of the paper is as follows: in The concept of the presented beam is based on the synergic use of steel (ensuring the assumed stiffness of the structure) and polymer concrete (increasing its ability to dissipate vibration energy). When properly arranged and appropriately filled with polymer concrete, the beams allow the shaping of the dynamic properties of larger structures ,16. PolySelected polymer concrete consisted of an epoxy resin mixed with different grades of mineral filling. Taking the grain size as the dividing criteria, mineral fillings can be categorized as follows: ash, a fine fraction (consisting mainly of sand) of grain size 0.25–2 mm, a medium fraction of grain size 2–10 mm and a coarse fraction of grain size 8–16 mm. The coarse and medium fractions comprised mainly irregular shaped gravel. The proportion of the mass (percentage) of the individual fractions in the polymer concrete are presented in The presented polymer concrete was poured into the steel profiles and fully vibrated. In this research, 1 m lengths of three different square cross-sectional steel profiles filled with polymer concrete were used: (i) 140 mm × 140 mm, 6 mm wall, (ii) 70 mm × 70 mm, 3 mm wall, and (iii) 50 mm × 50 mm, 2 mm wall. All the specimens were cured in the room conditions (at 23 °C and 50% relative humidity) for 72 h. The steel–polymer concrete beam is presented in In the first stage of the experiment, the material parameters  of the steel and polymer concrete were determined. Cuboidal samples of steel (50 mm × 50 mm × 110 mm) and polymer concrete (45 mm × 45 mm × 110 mm) were subject to compression tests using an Instron 8850 press  operating in an air-conditioned laboratory at 23 °C and 50% relative humidity. The press was equipped with a class 0.5 measuring head with a range up to 250 kN and a class 0.2 Instron 2620-603  tactile extensometer with a 25 mm and 12.5 mm measuring range (±1 mm). The samples were conditioned in the laboratory for 72 h prior to testing . The tesThe second stage of the experimental investigations consisted of a modal analysis. An impact test was carried out for the 1 m long 70 mm × 70 mm × 3 mm steel–polymer concrete beam. The tested beam was suspended at each end using steel ropes to minimize the influence of the stand. A diagram of the test stand is shown in The basic assumptions of the modal analysis , are summarized in The parameters of the modal model in the form of natural frequencies and corresponding frequencies of modal damping are presented in The steel–polymer concrete beam fulfilled the basic assumptions of the modal analysis, which validates its use in the assessment of its dynamic properties;The steel–polymer concrete beam is characterized by the close identity between the complex and real mode shapes, which indicates the proportional damping of the beam;Despite the fact that the steel–polymer concrete beam was made of materials with significantly different properties, the experimental mode shapes were similar to those of a beam made of homogeneous material, which indicates a lack of mutual displacements between the steel profile and polymer concrete filling.The results of the experimental study showed that:Based on the experimental study, certain simplifications were used in order to build the FEM model. A schematic representation of the adopted simplifications of the model is shown in It was assumed that the suspension method of the tested beam during the experimental studies would have a negligible influence on the dynamic properties. It was therefore assumed that the calculations could be carried out as if for an unconstrained (free–free) model.Another assumption was made for the model of the material used to describe the dynamic properties of the polymer concrete. Despite its heterogeneous structure, it was assumed that in the studied frequency range and in the case of displacements not exceeding 0.5 mm , theIn the next step, a mathematical model of damping was selected to describe the ability of the steel–polymer concrete beam to dissipate the vibration energy. Analysis concerned Rayleigh damping ,27 and tIt was then assumed that the contact between the steel profile and the polymer concrete filling occurs over the entire internal surface of the steel profile. In addition, the adhesion forces prevent tangential displacement within the contact area of the materials. Hence, the contact of the steel profile with the composite filling was modeled via the coincidence of nodes. The application of this model was dictated by the analogy between the analyzed beam and concrete filled steel tubes (CFST) used in civil engineering. Research on CFST ,35,36,37Based on the assumptions made, the geometric model was discretized using a Midas NFX 2018 R1 preprocessor  . The calThen, the natural frequencies and corresponding mode shapes were determined for the unconstrained model of the beam. This task was realized by solving the eigenproblem in the following way:In order to compare the accuracy of the established discrete FEM model, a continuous mathematical model (used to model this type of structure in most of the research works presented in the introduction) was defined. The model is based on the Timoshenko beam theory for bending and shear deformation and Saint-Venant’s theory for torsional vibration. In order to determine the coefficients of the steel–polymer concrete beam equations, Hamilton’s principle was applied. Assuming that the Timoshenko model takes into account flexural, shear and longitudinal deformations, the equation for a beam with free vibrations can be determined as:The elements of this equation may be expressed as λ1j, ±λ2. The general solution for natural vibration analysis takes the following form:The elements of this equation may be expressed as ±After separating the variables, taking into account boundary conditions appropriate for a free–free beam resulting from the fact that the bending moments and shear forces at both ends of the beam equal zero and substituting the boundary conditions at both ends of the beam  50 mm × 50 mm, 2 mm wall thickness, and (2) 140 mm × 140 mm, 6 mm wall thickness, were modeled. Then, the results of the model analyses were compared with the results of the experimental tests.In order to show the usefulness of the established model of a steel–polymer concrete beam, a model was built of a frame consisting of 50 mm × 50 mm steel–polymer concrete beams .The developed unconstrained FEM model of the steel–polymer concrete structure consisted of 60,584 finite elements (CHEXA and CPENTA) and 225,384 degrees of freedom . The eigThe obtained results were then experimentally verified. Experimental tests of the real object were carried out using an impact test and the stand is presented in Selected mode shapes determined in the studied frequency range are shown in The analysed beam meets the Maxwell’s Reciprocal Theorem, which indicates its linearity;The identity of the complex and real mode shapes were close, which indicates the proportional damping of the beam;The similar values of natural frequencies for forms 1 and 2, 3 and 4, and 6 and 7 may indicate the isotropicity of the polymer concrete;That, despite the highly heterogenous character of the polymer concrete used, the experimental mode shapes were similar to those of an isotropic homogenous beam, which may indicate the lack of mutual displacements between the steel profile and polymer concrete filling and that it can be modeled using a linear isotropic model of the material that is present in the composite structure.Summarizing the research presented in this article, the experimental studies show:The derived Hamiltonian Equation (3) indicates that it is possible to build a reliable analytical model of a composite steel–polymer concrete beam using an homogeneous beam model with equivalent bending stiffness The analytical model could accurately represent mode shapes and natural frequencies of the analyzed beams: 50 mm × 50 mm , 70 mm × 70 mm  and 140 mm × 140 mm .Analytical studies showed that:The proposed FEM model of a steel–polymer concrete beam ensured agreement of the mode shapes with the experimentally determined mode shapes;The agreement of the mode shapes for torsional and flexural vibrations show the correctness of adopting the linear elastic isotropic model for polymer concrete; it confirms conclusions (i), (iii) and (iv);The application of the structural damping model, expressed as a complex stiffness model, enables a good representation of the damping properties of steel–polymer concrete beams, which is shown in the high compliance of frequency response functions (FRFs) calculated and experimentally determined; this also confirms conclusion (ii);The developed procedure and the determined model parameters allow for the development of reliable models for steel–polymer concrete beams with sizes: 50 mm × 50 mm , 70 mm × 70 mm  and 140 mm × 140 mm  for natural frequencies;The developed FEM model is a good alternative to continuous models, showing only slightly larger discrepancies compared to the results of experimental tests.The presented results of tests and analyses indicate that the proposed methodology of modeling the dynamic properties of steel–polymer concrete beams facilitates obtaining the results of calculations with high reliability, both in terms of quality and quantity, also for complex structures.FEM studies showed that:Agreement of the mode shape was obtained for the model of a complex steel–polymer concrete structure;Relative errors obtained by comparing the calculated and experimentally determined values did not exceed 3%, on average they were 1.7%, which proves good quantitative agreement of the model with the real structure;The calculated frequency response functions obtained for the complex model of a structure consisting of steel–polymer concrete beams showed good agreement with experimental data, which showed that the model reliably reproduced the dynamic properties of the structure in the studied frequency range;A reliable description of the dynamic properties of a complex steel–polymer concrete structure was obtained without additional  model updating.In particular:The modeling method presented in this article has a large application potential in constituting a tool supporting the design of complex steel–polymer concrete structures. The conducted comprehensive research, i.e., experimental tests complemented with analysis of a mathematical models, helps us to understand the phenomena occurring in a complex steel–polymer concrete structure. Based on this understanding, it is possible to adopt simplifications that allow the building of a reliable, relatively simple finite element model which competes with the continuous models  presented in the literature.One of the key simplifications adopted is the use of a linear elastic isotropic material to model the highly heterogenous polymer concrete. This simplification reduced the model’s complexity by eliminating the necessity of modeling the polymer concrete as fine and coarse aggregates bound with an epoxy resin, and at the same time obtaining reliable results—the models presented in this paper are characterized by the agreement of the mode shapes, and relative errors in the case of natural frequencies below 5%, in relation to the results of experimental tests.Another important feature of the presented model, distinguishing it from others presented in the literature review, is the high compliance of FRFs with the experimental data. The obtained FRFs enable the reliable assessment of dynamic properties of the analyzed structures across a wide frequency range, taking into account their damping properties. This is a key aspect in the process of designing mechanical structures, as it enables the determination of the real displacements occurring in the structure under the influence of external loads.However, the presented method may have some limitations resulting from the adopted model assumptions. The first of these may be the use of polymer concrete, in which the binder is a resin with high shrinkage. It can cause contact loss on the steel–polymer concrete contact surface, contradicting one of the presented model assumptions. Another limitation may be the application of the presented method for modeling beams with a cross-section smaller than 50 mm × 50 mm, for a composition similar to the polymer concrete presented in the article. This limitation is due to the dimensions of the coarse fraction elements of the mineral filling (8–16 mm), and the associated possible poor mixing of the mineral filling, leading to a disruption of the structure of polymer concrete . In thisIn summary, the modeling methodology presented in this paper facilitates obtaining a reliable description of the dynamic properties of both steel–polymer concrete beams and the complex structures constructed from them.


For the efficient and durable design of concrete, the role of fiber-reinforcements with mineral admixtures needs to be properly investigated considering various factors such as contents of fibers and potential supplementary cementitious material. Interactive effects of fibers and mineral admixtures are also needed to be appropriately studied. In this paper, properties of concrete were investigated with individual and combined incorporation of steel fiber (SF) and micro-silica (MS). SF was used at six different levels i.e., low fiber volume (0.05% and 0.1%), medium fiber volume (0.25% and 0.5%) and high fiber volume (1% and 2%). Each volume fraction of SF was investigated with 0%, 5% and 10% MS as by volume of binder. All concrete mixtures were assessed based on the results of important mechanical and permeability tests. The results revealed that varying fiber dosage showed mixed effects on the compressive (compressive strength and elastic modulus) and permeability (water absorption and chloride ion penetration) properties of concrete. Generally, low to medium volume fractions of fibers were useful in advancing the compressive strength and elastic modulus of concrete, whereas high fiber fractions showed detrimental effects on compressive strength and permeability resistance. The addition of MS with SF is not only beneficial to boost the strength properties, but it also improves the interaction between fibers and binder matrix. MS minimizes the negative effects of high fiber doses on the properties of concrete. Plain cement concrete (PCC) is the most versatile construction material owing to its multiple benefits i.e., high compressive strength, cost-efficient, in-situ formability, thermal and electrical insulation, imperviousness, etc. Ingredients and mix design of PCC can be changed to obtain different types of concrete that suit different structural loadings and environments. To further raise the importance of conventional concrete, several performance-related issues need to be resolved. PCC generally performs weakly under tensile loadings. Its splitting tensile strength (STS) is very low compared to its compressive strength (CS). According to Ali and Qureshi ,2 and KoNowadays, fibers are being used as a discrete 3-dimensional reinforcement to overcome the deficiency of PCC in tensile strength. With the addition of proper fiber-type in concrete, initiation and proliferation cracks under both tensile and compressive loads can be controlled or delayed. Many types of reinforcements are available commercially that own their application-specific characteristics e.g., carbon fiber, steel fiber (SF), glass fiber, polypropylene fiber  organic There are several issues relevant to the underutilization of SF in fiber-reinforced concrete that must be addressed. According to Lee et al. , the priThe effect of SF on the properties of the fibrous composite also depends on the dosage of fiber. There is a consensus among researchers that the tensile and bending capacity of concrete improves the increasing fiber dosage (0 to 2% by volume fraction) ,21,22,23There are some issues related to application of SFRC that are vital to be understood and resolved. The reasons behind the mixed effects  of SF dose on compressive strength of concrete are still needed to be understood for the effective use of fibers under compression loadings. Moreover, poor bond strength between fiber and binder matrix reduces the utilization of full potential of SF. It is essential to investigate the influence of such materials  on SFRC that help in strengthening binder matrix and improve the dispersion of fibers ,10. ThisConventional and supplementary materials used for the production of concrete mixtures are explained in this section. Type I general purpose cement  was used as the main binder as per specifications of ASTM C150 . Micro-s3. It was sourced from Dramix© . SF has a length of 30 mm and a diameter of 0.38 mm. Its overview is shown in Hooked steel fiber (SF) was studied as a discrete reinforcement in concrete. It has tensile strength of 750 MPa and a density of 7750 kg/mA total of 21 concrete mixes were studied in this research. Six different doses  of SF were used to produce fiber-reinforced concretes. SF volumes were selected to observe the effects of a wide range of fiber doses on the properties of concrete. Fibers were used as by volume fraction of concrete . Each fiber dosage is investigated with 0%, 5% and 10% micro-silica (MS). MS serves as the matrix-strengthening agent by producing calcium silicate hydrate gels from the free portlandite-CH a by-product from the hydration of cement. Plain concretes were also produced with and without MS and served as reference mixes. Composition and mix proportioning of all concrete mixtures are provided in Mixing of all concretes was done in a mechanical mixer having adjustable rotation speed. In the first stage, aggregates and binder were dry mixed for 3 min at speed of 40 rpm. In the second stage, half of the mixer and water reducer were added to the mix and blending continued for 3 min at speed of 40 rpm. In the third stage, the remaining water was added to the mix, and mixing was done a high speed of 80 rpm for 2 min. In the last stage, SF was added to the concrete mix, and blending continued for the next 4 min at 80 rpm. After mixing, a slump test was performed to check the desired workability of mixes . Mixer continued to run at a slower speed of 20 rpm until the casting of specimens was completed.3 solution to observe the depth of CIP. The further detailed procedure for CIP testing can be assessed from studies [All specimens were cast in standard steel molds and protected with a waterproof membrane for 24 h setting immediately after casting. After setting, specimens were cured in tap water for 28-days at room temperature conditions. All mixes were tested for three important mechanical parameters i.e., compressive strength (CS), modulus of elasticity (MOE), and splitting tensile strength (STS). For CS, 100 φ mm × 200 mm cylindrical specimens were tested as per ASTM C39 . To dete studies . All theIn From the results of CS and MOE, it is quite clear that both of these mechanical properties show a similar response to varying SF and MS contents. Therefore, both parameters can predict each with great accuracy. Since MOE is difficult to determine in the laboratory; therefore, it is predicted usually from CS. The relationship between MOE and half power of CS is shown in STS in an estimate of true tensile strength of concrete. Due to the complexity of measuring the true tensile strength under the direct tension test, STS provides a simpler measurement of the tensile strength of cementitious materials. MS addition provides a little advancement in the tensile strength, see For plain concrete, STS can be fairly correlated with CS or MOE. But for fibrous concrete STS cannot be correlated with CS or MOE, see WA capacity of concrete represents its water-permeable volume of voids. High WA generally indicates high porosity. The effect of SF on the WA capacity of each mix is shown in By constricting the microchannels across the ITZs at fibers, MS can efficiently minimize the degrading effect of fibers on CIP. Almost all engineering properties of concrete depend on the growth and density of microstructure i.e., strength and permeability characteristics. CS, CIP, and WA are correlated with each other in (1)Fibers have mixed effects on compressive strength (CS). The positive effect of SF on CS is observed only at small doses. A high-volume dose of SF negatively affects CS. MS improves the utilization of SF in advancing the CS of concrete.(2)Similar to CS results, modulus of elasticity (MOE) also shows mixed behavior with varying fiber dose. Low volumes (0.05–0.5%) of SF are beneficial to MOE, whereas high volumes (1–2%) are detrimental to MOE. MS shows synergistic effects with SF on MOE. SF doses of 0.5% produce optimum MOE and CS. The addition of MS is highly useful compared to SF addition if the increment in CS or MOE is desired.(3)Splitting-tensile strength (STS) increases up to 36% with the rising dose of SF (0 to 2%). There is no significant achievement in STS when SF doses increased beyond 1%. STS experience more gain than CS and MOE at all doses of SF. MS improves the net gain in STS due to SF addition. The combined addition of 10%MS and 1%SF produces concrete with 60% more STS than plain concrete.(4)Considering the combined behavior of CS, MOE, and STS, 1%SF can be taken as the optimum dose for high strength concrete.(5)At low to medium fiber doses (0.05–0.25%), the WA of concrete was slightly lower than that of the plain concrete. Whereas high fiber doses (0.5–1%) are determinantal to the imperviousness of concrete. The positive effect of low fiber volumes is very negligible compared to that of the MS. MS can play a key role in downing the WA capacity of high fiber volume concretes.(6)Similar to WA, chloride-ion penetration (CIP) experiences a small reduction of 0.05–0.25% SF. The detrimental effect of high fiber dose can be minimized by MS addition. With the help of 10%MS, 2%SF concrete shows a significant 25% lower CIP compared to plain concrete.This study evaluates the influence of a wide range of SF doses on the basic engineering characteristics of high strength concrete. It also explores the modifications of SF-reinforced concrete properties with micro-silica (MS). Following important conclusions can be taken from this research:Effect of micro-silica on the interfacial zones of fibers should be studied using scanning electron microscopy. Moreover, combined effect of MS and SF on different strength classes of concrete should also be investigated and compared. Effect of different MS contents on the freeze-thaw and corrosion resistance of SFRC can also be studied.


P/gfcA′ < 0.3, P/gfcA′ = 0.3, and P/gfcA′ > 0.3 for the considered columns, the yielding of reinforcement, yielding of reinforcement and/or concrete crushing, and concrete crushing governed the yield conditions, respectively. It can be noted that the cross-section dimension and axial load level became the primary parameters. Even though the independent effects with regard to particular parameters remained at minimal levels, the combined effects of them with the axial load became important in terms of the equivalent yield curvature.In this study, the response quantities affecting the equivalent yield curvature, which is important in the deformation-based seismic design and assessment of structural systems, are investigated for reinforced concrete columns with a square cross-section. In this context, the equivalent yield curvatures were determined by conducting moment–curvature analyses on various column models, in which the axial load level, cross-section dimension, longitudinal reinforcement ratio, and concrete compression strength were changed parametrically, and the independent and/or combined effects of the relevant parameters were discussed. Depending on the axial load levels of  One of the most important problems in force-based design is the selection of an appropriate stiffness, especially for reinforced concrete building and bridge-type construction systems. The stiffnesses used when determining the natural vibration period of structures and linked to the equivalent lateral earthquake loads are not known at the beginning of design. The gross-section stiffness and reduced effective stiffness considering the cracking of concrete in some situations are based on structural members . Many design codes stipulate coefficients for reducing the bending stiffness of different types of members ,2,3,4,5.y) obtained from bi-linearization of the moment–curvature response is almost constant in very large regions of the axial load level and longitudinal reinforcement ratio [This approach, with regard to the bending stiffness, points out not only that the effective stiffness is constant, regardless of the strength, but also that the stiffness does not change with the increasing bending capacity of the member. Therefore, the yield displacement becomes directly proportional to the strength, as shown in nt ratio ,7,10.P/gfcA′ = 0–0.4) and reinforcement ratios (lρ = 0.5%–4.0%) under a constant dimension, thickness of concrete cover, concrete compressive strength, and yield strength of reinforcement. The results showed that both parameters had a significant influence on the moment carrying capacity, as would be expected (yhϕ/yε) were slightly affected by the changes in relation to these parameters, and the mean value of 2.10 was recommended for the rectangular column sections. Therefore, the equivalent yield curvatures may be determined within a band of ±10% .Sheikh et al.  evaluateThe results of numerical investigations related to reinforced concrete columns in the literature ,20,21,22In the present study, different response quantities affecting the equivalent yield curvature were numerically investigated for square reinforced concrete columns. In this context, over 1500 column models were generated by parametrically changing the dimensions, axial load level, longitudinal reinforcement ratio, and concrete compressive strength. The changes with respect to the yield strength of reinforcement were not taken into consideration since the yield curvature was directly influenced by it. The independent and/or combined effects of these parameters on the equivalent yield curvature were discussed after conducting moment–curvature analyses.bxh) and eight longitudinal reinforcement ratios (lρ) were systematically changed, were generated to investigate the response quantities that have an influence on the equivalent yield curvature. Thereafter, these column models were diversified by changing the axial load levels (in the P/gfcA′ range of 0 to 0.5) and concrete compressive strengths (ranged from 20 to 60 MPa). In this manner, a total of 1680 analysis models were developed. The geometries of analyzed column sections are given in yf) and the cover thickness ratio has a notable influence, these parameters were kept constant to sensitively consider the independent and/or combined effects of variations in other parameters  between the yield and ultimate conditions; and to determine the force-deformation-ductility relationships of members. However, moment–curvature analysis is also a useful tool for checking whether or not tension reinforcements are ruptured, compression reinforcements are bucked, compression concrete block is crushed, and the member’s shear capacity is exceeded for the stipulated limit state .yϕ′, yM′). Later on, the equivalent yield curvature (yϕ) related to the idealized response can be determined by extrapolating the line up to the nominal moment capacity (point C). Therefore, the plastic branch of the response comes into view when combining the equivalent yield point  and ultimate point   with respect to the bi-linearized moment–curvature response can be calculated by means of Equation (1)–(3), respectively [For the ductility calculation at a cross-section level, the moment–curvature response can be idealized by two linear branches comprised of the elastic and plastic sections. As shown in  . The equectively .(1)ϕy=MP/gfcA′, cross-section dimension—bxh, longitudinal reinforcement ratio—ρl, and concrete compressive strength—cf′), which may directly or indirectly affect the equivalent yield curvature, were numerically investigated for various column sections. In this context, moment–curvature analyses were conducted on the constituted column models, and the equivalent yield curvatures were calculated based on the approach indicated above. The variations of yield curvatures from the point of the considered parameters, as well as how and in what proportion these parameters change the curvatures, were discussed comprehensively. The moment–curvature analyses were conducted by means of the CUMBIA computer program [CUMBIA, which was coded through the Matlab platform, can perform nonlinear cross-section analyses of rectangular and circular reinforced concrete column sections separately considering the cover and core layers. In this sense, constitutive models for un-confined and confined concrete, as well as reinforced steel bars, can be specified by the user or default models in CUMBIA. While the default models used for the un-confined and confined concrete are those of Mander et al. [In this section of the study, the particular response quantities  and/or the outermost cover concrete layer crushed (cε = coε). Therefore, the following cases, in general, came into existence in the formation of yield curvatures, depending on the axial load level:In the determination of the yield condition relation to the investigated column cross-sections, the axial load levels governed the behavior, irrespective of whether the yield of reinforcement yielded  were investigated, and are given in After conducting moment–curvature analyses for the column cross-sections, the variations of equivalent yield curvatures with the axial load levels , in which the concrete crushing governed the yield condition, conversely, the curvatures decreased up to ≈20% in comparison to the case without an axial load. It can be noted that despite the relative changes in the yield curvature for P/gfcA′ ≤ 0.3 having similar ratios for each column dimension, the differences showed a decreasing trend as the cross-section dimension increased, as shown in When the influence of the axial load level on the equivalent yield curvature was investigated a in termP/gfcA′ levels. It can be noted that an increase in the axial load level results in a more pronounced influence for low reinforcement ratios, and the curvature can decrease by up to 22% in comparison to the case without an axial load.For different reinforcement ratios ranging from 0.5% to 4.0%, as shown in P/gfcA′ ≤ 0.3, they exhibited a decreasing trend for axial load levels preceding the concrete crushing, depending on the compressive strength. In this region, while the relative changes were limited by −1.2% in comparison to the non-axial load cases, the differences calculated could reach up to −22% for the case of cf′ = 60 MPa. This outcome means that the combined effect of the axial load and concrete compressive strength on the equivalent yield curvature is important.When the analysis results were taken into consideration in terms of the concrete compressive strength, as shown in bxh = 25 × 25 to 200 × 200 cm, the variations of the equivalent yield curvature with the cross-sectional height (h) are given in For the square column sections ranging from h = 25–50 cm) relatively decreased by nearly 51%, these changes among h = 50–75, 75–100, 100–125, and 125–150 cm were roughly determined to be 33%, 26%, 20%, and 18%, respectively. It can be noted that the relative changes calculated for the equivalent yield curvature had similar ratios for all axial load levels.Considering the variations of equivalent yield curvatures determined for the particular cross-sectional heights in each axial load level, although the equivalent curvatures rapidly decreased up to the section height of 125 cm, the changes remained limited for further dimensions a. Here, Regardless of the yield of reinforcement and/or concrete crushing regarding the yield condition, an increase or decrease in the reinforcement ratio for different sectional heights did not affect the characteristics of curvature behavior, as shown in cf′ = 20 and 60 MPa.Similar to the response obtained from the reinforcement ratio, the direct effect of the concrete compressive strength on the yield curvature response was determined to be very small, as shown in lρ = 0.5% and 4%, the variations of equivalent yield curvatures with the reinforcement ratios were investigate and are given in lρ = 0.5%, relative changes up to 31% were determined, depending on the axial load level.Based on the particular longitudinal reinforcement ratios between the range of P/gfcA′ level showed significant differences. Here, the equivalent curvatures corresponding to P/gfcA′ = 0, 0.1, 0.2, and 0.3 could relatively increase by up to 28%, 21%, 16%, and 10%, respectively, depending on the reinforcement ratio. For the further axial load levels, the related differences reached up to 31% in comparison to the results calculated for lρ = 0.5%.It can be noted that the general characteristic corresponding to the equivalent yield curvature–reinforcement ratio responses did not change for different column sections b. HoweveP/gfcA′ ≤ 0.3), where the reinforcement yield governed the yield condition, as shown in P/gfcA′ > 0.3), the yield curvatures decreased as the concrete compressive strength increased for each reinforcement ratio. It can be noted here that the general characteristic relation to the curvature responses did not have a significant influence. However, the equivalent curvatures exhibited an increasing trend as the reinforcement ratio increased for each compressive strength (lρ = 0.5% and 4%), depending on the concrete compressive strength. Here, the combined effect of the axial load ratio and compressive strength became evident for the each reinforcement ratio.For lower axial load ratios , where the concrete crushing governed the yield condition. In this region, the differences between the yield curvatures calculated for cf′ = 20 and 60 MPa may reach up to 28%. For the column sections with different concrete compressive strengths ranging from P/gfcA′ < 0.3. In contrast to this behavior, the combined effect of the axial load and concrete strength on the equivalent yield curvature was important for the further axial load levels. In this sense, the differences between the yield curvatures for the column models with cf′ = 20 and 60 MPa were roughly determined to be max. −14%, −24%, and −29% at P/gfcA′ = 0.3, 0.4, and 0.5, respectively. It can also be noted that these differences were nearly the same for each column dimension. When the graphs related to the concrete compressive strength–yield curvature responses were investigated for different reinforcement ratios  and concrete compressive strengths (ranged from 20 to 60 MPa). In this manner, a total of 1680 moment–curvature analysis models were developed with all possible combinations. All results with respect to the parameters influencing the equivalent yield curvature are summarized in a single graph in In this study, the independent and/or combined effects of different response quantities affecting the equivalent yield curvature were numerically investigated for reinforced concrete columns with a square cross-section. A total of 56 reinforced concrete column models, of which seven cross-sectional dimensions and eight longitudinal reinforcement ratios were systematically changed, were generated to discuss how and in what proportion these parameters change the yield curvature. Thereafter, these column models were parametrically diversified by changing the axial load levels  up to y others ,32,33. Hy others ,12,33,34P/gfcA′ level showed significant differences. In addition, the yield curvatures exhibited an increasing trend as the reinforcement ratio increased for the compressive strengths considered (For each considered axial load ratio, the equivalent yield curvature showed an increasing trend as the reinforcement ratio increased. Relative changes of up to 31% were determined, depending on the axial load level. It should be noted that despite the combined effect of the reinforcement ratio and cross-section diameter on the curvature response not being notable, the relative changes calculated for each nsidered . P/gfcA′ < 0.3. In contrast to this behavior, the combined effect of the axial load and concrete strength on the equivalent curvature was important for the further axial load levels and thus the equivalent curvatures rapidly decreased (The direct effect of the concrete compressive strength on the curvature response was determined to be less than 10% up to ecreased . This reAs a consequence of the moment–curvature analyses, it was deduced that the cross-section height and axial load level were the primary parameters influencing the equivalent yield curvature, as also indicated in references ,15,21,22Even though the proposed simple equations may give reasonable results for low axial load levels, it is recommended that the curvature response be evaluated by moment–curvature analysis since the combined effects activated other responses at higher axial load levels, where the compressive concrete governed the yielding condition.


Clinicians who work in primary care are potentially the most influential healthcare professionals to address the problem of antibiotic resistance because this is where most antibiotics are prescribed. Despite a number of evidence based interventions targeting the management of community infections, the inappropriate antibiotic prescribing rates remain high.Core Elements of Outpatient Antibiotic Stewardship, supported by resources to fund the implementation of AMS interventions that are connected to quality improvement initiatives. This article debates how this can be achieved.The question is how can appropriate prescribing of antibiotics through the use of Antimicrobial Stewardship (AMS) programs be successfully implemented in primary care. We discuss that a top-down approach utilising a combination of strategies to ensure the sustainable implementation and uptake of AMS interventions in the community is necessary to support clinicians and ensure a robust implementation of AMS in primary care. Specifically, we recommend a national accreditation standard linked to the framework of The paper highlights that in order to support the sustainable uptake of AMS programs in primary care, an approach similar to the hospital and post-acute care settings needs to be adopted, utilising a combination of behavioural and regulatory processes supported by sustainable funding. Without these strategies the problem of inappropriate antibiotic prescribing will not be adequately addressed in the community and the successful implementation and uptake of AMS programs will remain a dream. Clostridioides difficile infection and community-acquired fluoroquinolone-resistant E.coli urinary tract infections [The majority of antibiotics are prescribed outside of hospitals and the most common indication is acute respiratory tract infections (ARIs) , 2. ARIsfections , 6. Therfections .Core Elements of Outpatient Antibiotic Stewardship for outpatient facilities [Studies have shown that it is possible to reduce inappropriate antibiotic prescribing through behavioural interventions. Although initial findings are promising, limited information is available to determine whether they can be implemented and effective across a range of contexts in real world settings . It is icilities .This paper argues that in order to improve the appropriate use of antibiotics in the community there is a need to support a bottom-up approach, i.e. the implementation and uptake of AMS interventions, by a top-down strategy, namely the application of a national accreditation standard linked to the Framework. Many evidence-based interventions have been trialled in research settings Table . Howevercore elements of outpatient antibiotic stewardship (Table We identified relevant literature through PubMed searches (limited to English-language publications) and author libraries. We included original and review articles and systematic reviews published between 2004 and 2020 to formulate an evidence-based narrative review focusing on interventions that have resulted in a decrease in antibiotic prescribing at the point of care in primary care and reflect the ip Table . Search Strategies from the framework should focus not only on appropriate use, but also on sustainability of behavioural change for both clinicians and patients . ImproviCommitment as defined by the framework is the demonstration of dedication to and accountability for optimising antibiotic prescribing and patient safety. It is recommended to appoint a clinical leader who is accountable to senior facility leaders to promote appropriate antibiotic prescribing . For an An example of clinicians’ demonstration of commitment to appropriate antibiotic prescribing is by displaying a public statement in support of AMS in the clinic , which wMany interventions at the point of care have shown to be effective in decreasing antibiotic prescribing in primary care. These include a variety of strategies aimed at the clinician and/or patients. Using evidence-based diagnostic criteria and treatment recommendations such as clinical decision support, back-up (delayed or ‘wait and see’) prescribing and point of care tests are key strategies to change clinician behaviour. The debate is how these interventions can be implemented in a sustainable manner in the primary care setting.Many clinical decision support tools have been developed and incorporated into clinical practice. These tools come in either printed materials or can be incorporated into electronic prescribing systems. Most of these interventions have been developed for the management of respiratory tract infections with variable effectiveness Table .Table 2A number of these clinical decision support tools have been integrated into electronic prescribing with the support of an Electronic Health Record platform. These tools have been associated with reduced inappropriate antibiotic prescribing –18; howeWhen there is clinical uncertainty about whether a condition is self-limiting or is likely to deteriorate, back-up prescribing (delayed prescribing) offers clinicians an alternative to immediate antimicrobial prescribing. It involves giving patients a prescription but suggesting that they not fill it unless they begin to feel worse or develop specific symptoms . The firTherapeutic Guidelines: antibiotic in the management of acute otitis media and sinusitis [An alternative strategy to delayed antibiotic prescribing is the watchful waiting approach which involves providing symptomatic relief with a clear plan for follow-up if symptoms worsen or do not improve. It has been shown to safely decrease antibiotic use when used in accordance with clinical practice guidelines . This stinusitis –51.Two types of point of care (POC) tests exist to support clinical decision making in infections; 1) tests measuring the level of non-specific inflammatory markers in the blood (such as CRP) and 2) tests assessing the presence of a pathogen  .The CRP test is widely used in primary care in some European countries . A CochrFor nearly 30 years, the rapid antigen detection test (RADT) has been available for detection of Lancefield group A β-hemolytic streptococci (GABHS) in patients with a sore throat. In Europe, there is a lack of consensus for the use of RADT. A European trial has demonstrated there is no additive effect of utilising RADT in patients with a sore throat either for symptomatic or antibiotic management as compared to a clinical score alone to guide antibiotic prescribing . The UniPoint of care tests have the potential to decrease diagnostic uncertainty, support non-prescription decisions, and to reassure patients . HoweverTracking and reporting, which is reviewing clinician antibiotic prescribing and providing direct feedback to the prescriber, has been shown to reduce antibiotic prescribing –34, 53. Public reporting of antibiotic usage data across medical practices and individual providers to enable national benchmarking and possibly reimbursement modification is another strategy that is being explored in some countries in order to promote appropriate use of antibiotics .It is important to note that uptake of AMS interventions does not happen spontaneously; rather an active implementation approach over the long term is required . Gerber Although a number of benefits have been demonstrated with audit and feedback to prescribers it is not without its challenges. The auditing process relies on practices having an Electronic Health Record system in place in order for the data to be extracted. If more in depth audits are being conducted, such as evaluating adherence to guidelines, then an important factor is the accurate documentation of patient information, for instance an indication for the antibiotic is readily accessible in the medical records. The auditing process is also time consuming and requires additional resources. In addition, the auditors need to be trained and have the expertise to validate and interpret the data.Providing educational resources on antibiotic prescribing to clinicians and patients, and ensuring access to relevant expertise on optimising antibiotic prescribing is a core element of the CDC framework . It is iIt is important to be aware that outpatient antibiotic prescribing is also driven by psycho-social factors, including lack of self-awareness, fear of complications and perceived patient expectations . PatientStrategies such as shared decision making, have been utilized to educate patients about when antibiotics are and are not needed. Shared decision making tools have been shown to reduce antibiotic prescribing for ARIs from 47 to 29% as compared to standard management (RR 0.61 95% CI 0.55 to 0.68) without an increase of patient-initiated re-consultations  and also without impacting on patient satisfaction  .There are a number of education activities targeting clinicians. Didactic training for clinicians is only marginally effective whereas the greatest effect has been shown when it is accompanied by communication skills training and support , 38–40. Core Elements of Outpatient Antibiotic Stewardship. This should be complemented by a bottom-up approach utilising practice level AMS interventions that can be scalable to a national level. The question is how this can be achieved in the community where in many cases care is delivered in small scale clinics. We propose a tiered approach to support the implementation of AMS strategies in the clinical practice setting [This paper proposes that in order to facilitate the change management process for appropriate use of antibiotics in the primary care setting, a top-down approach is needed with a combination of regulatory and policy decision making processes in place at a national level supported by the framework addressing the  setting  which inCore Elements of Outpatient Antibiotic Stewardship into national accreditation standards should also be explored [Implementation of AMS models requires both the leadership and culture change supported by policy development. External motivators such as embedding AMS frameworks such as the explored . Accrediexplored ; howeverexplored . In the explored .This paper highlights that the interventions described above have mainly being conducted in a research setting with limited length of observations. Interventions utilised at the point of care such as those focusing on patient doctor interactions and knowledge of antibiotics have been associated with increased adherence and acceptance of treatment and often led to lower rates of antibiotics . In ordeIncentives that have been identified for implementing AMS strategies in primary care include the need for a funding model and reimbursement strategy that supports AMS activities and penalises clinicians and practices that fail to adopt AMS. These facilitators likely require governmental policy change, although they could also be considered by third party payers . CountriA few countries have implemented AMS strategies in primary care with various degrees of success. For instance the successful Swedish strategy known as Strama (Swedish strategic program against antibiotic resistance) was created in 1995 and started off with a bottom-up approach of coordinating activities for the containment of antibiotic resistance in the community. In order to support clinicians in the community, a top-down strategy was added including setting a national target for the number of prescriptions in outpatient care and defining quality indicators based on treatment recommendations, as well as providing local feedback to prescribers. It is important to note that sustainable funding was allocated for these strategies at both a national and local level . In JanuSuccessful AMS adoption models in European countries showed a distinct pattern: a slow and long early adoption phase at the practice level followed by policy changes that eventually trigger large-scale adoption. In addition, a few opinion leaders became early adopters, recognising the importance of using AMS strategies to support their decision-making in antibiotic prescriptions .Core Elements of Outpatient Antibiotic Stewardship provides the ideal platform to support the successful implementation and uptake of AMS programs in primary care because it utilises the combination of education, guidance, interventions and a supportive policy environment. It is also important to remember that for an AMS program to be effective it requires the commitment of all staff at a practice level in order to ensure the uptake of these interventions. Clinicians at the point of care are well placed to be effective stewards of antimicrobials and every clinician is ultimately responsible for appropriate use of antibiotics.The framework Core Elements of Outpatient Antibiotic Stewardship. Sufficient resources should support such a strategy in order to ensure the implementation of interventions connected to quality improvement initiatives. Without these strategies the problem of inappropriate antibiotic prescribing in the community will not be adequately addressed and the successful implementation and uptake of AMS programs will remain a dream.In summary, in order to ensure the sustainable implementation and uptake of AMS interventions in the community a top down approach complementing a bottom-up commitment and utilising a combination of strategies is warranted. National accreditation standards are essential and could be linked to the framework


Model list of essential medicines for children.To compare dosing guidance in the paediatric formularies of high- and middle-income countries for 32 commonly prescribed antibiotics on the World Health Organization’s (WHO’s) 2017 We identified paediatric antibiotic guidelines that were either widely used internationally or originated from countries in which antibiotic use has increased markedly in recent years .Manual of childhood infections: the blue book; (ii) the BNF  for children; (iii) the ®: 2018–2021 report of the committee on infectious diseasesRed book; (iv) WHO’s Pocket book of hospital care for children; and (v) Indian National treatment guidelines for antimicrobial use in infectious diseases. There was marked heterogeneity in the recommended dosing  for most commonly used antibiotics. The rationale for dosing recommendations was generally unclear.The study analysis considered five leading antibiotic guidelines: (i) the Model list of essential medicines antibiotic working group to develop an evidence-based consensus and identify research priorities.The pharmacokinetic, pharmacodynamic and clinical evidence supporting paediatric antibiotic dosing, particularly on total doses and on age or weight dosing bands, needs to be improved. Future research should consider whether the variations in guidance identified stem from different clinical disease patterns, varying levels of antibiotic resistance or drug availability rather than historical preferences. Interested global parties could collaborate with WHO’s  WHO Model list of essential medicines has undergone substantial revision.,–,,Global antibiotic consumption increased markedly between 2000 and 2010, with Brazil, China, India, the Russian Federation and South Africa accounting for 76% of the increase.–,,Clinicians’ prescribing practices are often informed by formularies, which recommend antibiotic doses that balance efficacy, toxicity and drivers of antimicrobial resistance. However, recommendations are frequently based on historical practice rather than evidence.WHO Model list of essential medicines for children.Although previous efforts have been made to compare local paediatric antibiotic guidelines, to the best of our knowledge there has been no detailed comparison of guidance from leading paediatric antibiotic formularies globally.Manual of childhood infections: the blue book, 4th edition, 2016, which is endorsed by the Royal College of Paediatrics and Child Health in the United Kingdom and the European Society of Paediatric Infectious Diseases and is a leading handbook used in Europe;BNF  for children, 2017, which is a commonly used paediatric reference for prescribing in the United Kingdom;®: 2018–2021 report of the committee on infectious diseases, 31st editionRed book, which is endorsed by the American Academy of Pediatrics Committee on Infectious Diseases;Pocket book of hospital care for children, second edition, 2013, from WHO, which is part of a series of documents and tools that support the integrated management of childhood illness;National treatment guidelines for antimicrobial use in infectious diseases, 2016, which were developed by the Indian National Centre for Disease Control.Indian Although we consulted national experts, we were unable to find paediatric antibiotic guidelines from Brazil, China, the Russian Federation or South Africa that were clearly endorsed nationally.We identified antibiotic guidelines that were either widely used internationally or originated in countries in which antibiotic use has increased markedly in recent years .WHO Model list of essential medicines for children, with the exception of: (i) benzathine benzylpenicillin; (ii) procaine benzylpenicillin; (iii) cefixime; (iv) tigecycline; (v) fosfomycin; (vi) daptomycin; (vii) polymyxins (e.g. colistin); (viii) fourth-generation cephalosporins, with or without a β-lactamase inhibitor (e.g. cefepime); and (ix) fifth-generation cephalosporins, with or without a β-lactamase inhibitor (e.g. ceftaroline). We included levofloxacin in our analysis even though it was not listed in the 2017 model list. We grouped the final selection of 32 antibiotics into the three AWaRe categories and compared dosing recommendations made by the different guidelines.From each publication, we obtained the recommended dosage of all antibiotics listed in section: 6.2  of the 2017 BNF for children, in general, arranges guidance by route of administration and then by age band. The Blue book provides guidance by drug, giving the dose in milligrams per kilogram and the dosing frequency per day. The Red book® presents separate tables for neonates and children, with neonatal doses stratified by gestational age and then by postnatal age (where applicable): paediatric recommendations are given as a total daily dose per kilogram with a frequency of administration. The Pocket book of hospital care for children presents separate summary tables for neonates and children; guidance on neonatal dosing is given by route of administration and stratified by age into the first week of life and a postnatal age of 2 to 4 weeks. The Indian National Centre for Disease Control guidelines present two dosing summary tables: (i) a dosing guide for commonly used antimicrobial agents; and (ii) drug doses in the paediatric age group. We primarily used information from the first table, as the second table was less complete. However, we consulted the second table and the text to resolve inconsistencies. The Indian guidance did not present a separate table for neonates. The Where possible, we present doses in mg/kg per day or mg/day along with dosing frequency to enable guidelines to be compared. When dosing guidance was given for specific syndromes or suspected causative organisms, we included those for priority syndromes  and for severe infection, especially meningitis. We excluded prophylactic doses, loading doses and doses for nonpriority syndromes and for low- or very-low-birthweight infants. In all cases where the guidance provide in summary tables was unclear, we consulted the primary text.http://www.who.int/bulletin/volumes/98/6/19-234310). Of all the guidelines, the Pocket book gave dosing guidance for the fewest antibiotics reviewed (i.e. 12 of 32); it did not give recommendations for some commonly used Access  and Watch  antibiotics. In fact, it included guidance on only one antibiotic in the Watch group (i.e. erythromycin) and none in the Reserve group. For all 32 antibiotics studied, there were differences in recommended dosages across the five guidelines . Moreover, the five guidelines all proposed different age ranges for dosing and the suggested dosing interval was 6, 8 or 12 hours.There was a considerable variation in recommended doses for each antibiotic. For example, ,We found marked differences between the guidelines reviewed on paediatric dosing recommendations for 32 commonly prescribed antibiotics. There were differences in the age basis for dosing , the frequency of administration and the total daily dose. Although some of this heterogeneity may reflect differences between settings in epidemiology, risk factors, causative organisms (e.g. due to different vaccination policies) or patterns of antibiotic resistance and may therefore be appropriate, other variations (e.g. the use of different age or weight dosing bands) can create confusion. In many instances, it is difficult to discern the rationale behind the dosing recommendations, whether they are derived from the accompanying summary of product characteristics, academic publications or expert consensus. Several national paediatric formularies, such as the Dutch, Italian and Spanish formularies, have been developed, but have been criticized for not presenting the underlying evidence or for referring to outdated paediatric dosing handbooks.,Blue book alone indicated the strength of the recommendations for each individual dose but did not present the supporting evidence. Moreover, the pharmacokinetic data underpinning many older off-patent antibiotics are very limited and were based on studies that were not conducted in accordance with recent standards.Variations between guidelines may partly be due to a lack of robust evidence on the best treatment. In addition, defining optimal drug dosing is more complex for children than adults: antibiotic doses must be adapted to maturational changes in pharmacokinetics and consider changes in pharmacodynamics, yet still be simple and pragmatic. However, few studies on antibiotic pharmacokinetics or effectiveness have been performed in children.A few strategic trials in children have examined high- and low-dose strategies and have reported efficacy and toxicity outcomes. However, these studies have used widely varying inclusion and exclusion criteria and end-points, which makes data synthesis between trials difficult. In addition, the absence of formal regulatory guidance on the design and conduct of antibiotic clinical trials in neonates and children has also hampered studies of clinical effectiveness. Our ability to compare therapies and treatment strategies would be improved by international collaboration to agree case definitions and outcome measures, similar to the collaboration that was effective in developing harmonized guidance for paediatric prescribing of antiretroviral drugs.The different age and weight dosing bands in leading global guidelines have been influenced by both practical considerations and historical usage. Although the most accurate method is to select the dose by weighing the child, this is not always possible. Simulations of orally administered amoxicillin in children show that the use of weight bands, rather than the exact weight, can often result in the administration of drug doses outside the therapeutic range.We identified several important omissions in global guidelines. First, we were unable to identify nationally endorsed, comprehensive treatment and dosing guidelines from Brazil, China, the Russian Federation or South Africa, although some individual institutions had their own local guidance. A unified approach within and, where appropriate, between countries would increase treatment standardization and make it easier to integrate the evidence. It is likely that many other countries, particularly low- and middle-income countries, also lack country-specific guidance and may have adopted recommendations developed elsewhere. In fact, published evidence often focuses on high-income settings, with little representation of low- or middle-income countries.The wide variation in paediatric antibiotic dosing recommendations we found between leading formularies could be rectified by: (i) carrying out a systematic review of the pharmacokinetic and clinical evidence underpinning current global guidance on the most commonly used antibiotics in children; (ii) producing an evidence-based, transparent, consensus, guidance document on the optimal dosing of Access antibiotics based on current knowledge; and (iii) identifying antibiotics that should be a priority for future research because more evidence is needed to optimize paediatric dosing, the nature of the evidence needed should be clear. Interested global parties could be brought together under the auspices of WHO’s antibiotic working group on the Model List of Essential Medicines for Children to develop an evidence-based consensus and identify research priorities.