In general, plastic waste has been growing remarkably. Numerous waste plastic products are generated by manufacturing processes, service industries, and municipal solid waste (MSW). The increase in plastic waste increases concern about the environment and how to dispose of the generated waste. Thus, recycling plastic waste becomes an alternative technique to the disposal of plastic waste in a limited landfill. One of the solutions is to use plastic waste as recycled material in concrete construction to produce what is called green concrete. This research illustrates a summary of studies that utilized polyethylene terephthalate (PET) in concrete as a volume ratio or concrete aggregate replacement. It presents data with regard to mixing design and concrete behavior when PET is used. Moreover, using PET in concrete industries may reduce environmental pollution such as the emission of carbon dioxide and plastic waste disposal problems. Nowadays, plastic plays a significant role in nearly every aspect of our lives. This led to an increase in the need for proper disposal management due to the huge quantity of plastic waste. The highest percentage of plastic waste is found in containers and packaging such as bottles, product packaging, cups, etc. It can also be found in building materials, furniture, etc. . Since 1There are two kinds of plastic. The first is thermoplastic, which can be melted and recycled in the plastic industry. Examples of thermoplastics are high-density polyethylene (HDPE), low-density polyethylene (LDPE), polyethylene terephthalate (PET), polyethylene (PE), polyethylene polystyrene (PS), polypropylene (PP), polyamide, polyoxymethylene (POM), and polytetrafluorethylene (PTFE) ,8,9 Fig. The sect), thermal conductivity (k), and Young’s modulus of elasticity (E) of regularly used polymers are illustrated in Properties such as tensile strength  test is considered a nondestructive in-situ test that is usually used to evaluate the quality of concrete . The ASTPET aggregate replacement leads to a noticeable ultrasonic pulse velocity loss ,51,73,87A researcher studied the effects of PET fibers on pulse velocity. Different waste PET fiber ratios were used: 0.25, 0.50, 0.75, 1.0, 1.25, and 1.50%. The result showed that as the PET ratio increased, pulse velocity decreased . The samσ2 is the stress that corresponds to 40% of the maximum load; σ1 is the stress that corresponds to the longitudinal strain (50 × 10−6); and e2 is the longitudinal strain produced by σ2.The stiffness of concrete is measured by its modulus of elasticity, which is an excellent indicator of its strength. The concrete can withstand more stress and becomes brittle as the modulus of elasticity increases. The elastic modulus of concrete is generally between 30 and 50 GPa . Based oThe modulus of elasticity of concrete is reduced in the presence of waste PET. It is a reverse relation; when the ratio of the substituted or added PET is increased, it accompanies a reduction in the modulus of elasticity ,45,53,67To investigate the microstructure of concrete, a scanning electron microscope (SEM) is usually used. Concrete containing PET shows a relatively irregular form that leads to the formation of pores of about 2–4 µm. Multiple bright inclusions (cement formations) encircled by hydrating agents could be observed on the surface, which improves the bonding between the PET fibers and the matrix . ConcretOn the other hand, Faraj 2020  claimed In concrete structures, compressive strength is considered one of the most essential mechanical properties, and it usually indicates the quality of the concrete ,100. ASTBelmokaddem et al., 2016  conducteThe reduction in concrete strength is due to the fact that PET particle usage causes some deficiencies in the inner structure of the concrete, resulting in a reduction in tensile strength and stiffness. This behavior could be advantageous when ductility is required . Table 3Tensile strength is an important property of concrete because structural loads expose it to tensile cracking. In general, concrete’s tensile strength is significantly lower than its compressive strength. Concrete’s tensile strength is estimated to be around 10% of its compressive strength. Due to the difficulty of the direct method, indirect methods are used to determine tensile strength. It is worth noting that the results from these methods are higher than the results from the uniaxial tensile test. The split cylinder test and the flexural test are two indirect techniques .The concrete tensile efficiency was shown to be influenced by the synergistic effect between the fiber volume and fiber length. A study conducted by Pereira et al., 2017  shows thFlexural strength, also known as modulus of rupture, is defined as the material stress prior to yielding in a flexure test. Flexural strength is considered one of the significant properties of concrete to determine tensile strength based on bottom fiber maximum stress. The flexural strength of concrete is affected when PET is added or replaced. When replacing fine aggregate with only 5% PET with a w/c ratio between 0.5 and 0.6.5, it can increase flexural strength by 6–8%. In contrast, replacing fine aggregate with 15% PET can reduce flexural strength by 6–14%, depending on the w/c ratio . AnotherLoad-carrying capacity is improved when PET is used in the concrete mix. A 10–20% enhancement is observed when 0.5–1.25% PET is added as a fiber addition . The parIn terms of deflection, adding PET increases deflection by 20–80% when 0.25–2% is added to the mix, which results in a growth in the member ductility . Some otResearchers started utilizing recycled plastic waste as green, light-weight aggregates to replace, in part or in full, the natural aggregates of concrete. Using PET in concrete structures has led to savings in concrete and steel quantities of up to 7.23% and 7.18%, respectively, depending on the structural configuration of the building . Using PPET can be utilized successfully and effectively to replace traditional fine or coarse aggregate.As the volume ratio of the utilized PET increased, concrete workability decreased.If a concrete mixture with a high ratio of PET is used, water-reducing admixtures are required.The fresh density of concrete containing PET is reduced if PET is added to the mixture. This is due to the low specific gravity of PET compared to the specific gravity of natural fine or coarse aggregate.The permeability of concrete is reduced when a low ratio of PET is used, up to 5%.Compressive strength is increased by about 5% when 0.2–0.4% PET is added to the concrete mixture. Beyond this ratio, compressive strength is gradually reduced.PET polyester fiber can increase compressive strength by 10% to 20% when 0.2 to 0.3% is added.For concrete compressive strength, the optimum PET ratio as a natural aggregate replacement is 1%.The split tensile strength of concrete using PET is remarkably increased by 10–20% when a 0.4–1% PET ratio is used. In the case of using PET as a replacement material, adding 1–8% would increase split tensile strength by 1–20%. On the other hand, if PET is used as a coarse aggregate replacement, that would negatively affect the split tensile strength.In the case of adding PET polyester to the concrete, this leads to a reduction in split tensile strength.Adding PET as an addition material to the concrete mix has no observed enhancement, apart from several authors who claimed different points of view.Adding PET as a replacement for fine aggregate would increase flexural strength by 40% when a 0.5–6% ratio is used. In the case of PET being used as a coarse aggregate replacement, that would negatively affect the flexural strength.Load-carrying capacity is improved when PET is used in the concrete mix. A 10–20% enhancement is observed when 0.5–1.25% is added.Adding 0.25% PET polyester leads to a slight increase in flexure strength of about 6 to 15%.Adding PET increases deflection by 20–40% when 0.25–2% is added to the mix, resulting in growth in member ductility. A reduction in deflection and ductility is observed when PET is used as a partial aggregate replacement, and the ratio goes beyond 10% with a non-remarkable enhancement in load-carrying capacity.Using PET on several floors of a building could reduce the quantity of concrete by about 5%.PET presence enhances cracking performance.The increase in plastic waste increases concern about its recycling, its effects on the environment, and its disposal. Hence, researchers conducted studies on utilizing PET in concrete mixtures as an addition or recycling PET as an aggregate replacement. PET affects the mechanical properties of concrete as well as the structural behavior of reinforced concrete beams. The effectiveness increases depending on whether PET is utilized as an additional material or as a replacement material for fine or coarse aggregate. Secondly, it also depends on the ratio of PET. Below are some points that summarize the findings and conclusions:Although many studies have investigated the effects of PET length on concrete behavior, the aspect ratio effect is rarely studied.One of the drawbacks of utilizing PET is a reduction in slump test measurement. Therefore, it is recommended to study the effects of different mix designs and additives on increasing workability in PET concrete.Further study is needed on the effects of PET ratio on concrete thermal conductivity and its result on the construction of energy-efficient buildings as environmental concerns.Many studies investigated the effects of different PET ratios on post-cracking without considering the effects of different PET geometry on post-cracking.Further study is needed on the effects of different PET lengths and geometry on split tensile strength.Further study is needed on utilizing a higher PET percentage as a partial fine aggregate replacement without affecting the overall mechanical properties of concrete; the current optimum replacement ratio is 1–5%.Durability is an important aspect and needs further studies looking at abrasion resistance, long-term shrinkage, and creep.The economic evaluation of utilizing PET in concrete needs to be investigated, considering the savings generated by the incorporation of PET as well as the advantages of saving time in the disposal of plastic waste.There has been little consideration for a recycling analysis comparison between traditional plastic waste and recycling PET in concrete.There was a lack of research on modeling concrete using PET.Further study is needed on the effects of using nanomaterials in concrete containing PET.Examine the effects of the PET ratio on water permeability, gas permeability, chloride resistance, and freeze-thaw resistance.Demonstrate the effects of elevated temperatures on concrete containing PET.An experimental study is required to investigate the fatigue and toughness resistance of concrete containing PET.Utilizing PET in concrete is considered an environmentally friendly method for the disposal of plastic waste. It could also increase the mechanical properties of concrete in some circumstances, and it could affect the mechanical behavior of concrete negatively as well depending on some factors such as the shape of the PET, length, aspect ratio, adding ratio, and concrete strength. Below are some recommendations and future directions for research:Through this article, it was possible to demonstrate the main studies that investigated PET as a partial aggregate replacement or used PET as fibers in concrete. Advantages and disadvantages were discussed, in addition to future research directions.


The utilization of ultra-high-molecular-weight polyethylene fibers (UHMWPEFs) to enhance recycled-brick-aggregate concrete represents an efficacious approach for ameliorating the concrete’s performance. This investigation addresses the influences of recycled-brick aggregates (RAs) and UHMWPEFs on the concrete’s slump, shrinkage, flexural strength, resistance to chloride-ion ingress, and freeze–thaw durability. The mechanisms through which UHMWPEFs ameliorate the performance of the recycled-brick-aggregate concrete were elucidated at both the micro and macroscopic levels. The findings underscore that the three-dimensional network structure established by the UHMWPEFs, while resulting in a reduction in the concrete slump, substantially enhances the concrete’s mechanical properties and durability. A regression model for the multifaceted performance of the UHMWPEF-reinforced recycled-brick-aggregate concrete (F-RAC) was formulated by employing response-surface methodology, and the model’s reliability was confirmed through variance analysis. The interactive effects of the RA and UHMWPEFs on the concrete were analyzed through a combined approach involving response-surface analysis and contour plots. Subsequently, a multiobjective optimization was conducted for the F-RAC performance, yielding the optimal proportions of RA and UHMWPEFs. It was determined that the optimal performance across the dimensions of the shrinkage resistance, flexural strength, chloride-ion resistance, and freeze–thaw durability of the F-RAC could be simultaneously achieved when the substitution rate of the RA was 14.02% and the admixture of the UHMWPEFs was 1.13%. Concrete presently stands as one of the most widely employed and abundantly consumed construction materials. Recent statistics have indicated a global annual consumption of approximately 200 billion metric tons of concrete . Within Crushed bricks were first extensively employed as aggregates in concrete in the post-World War II reconstruction era . Rashid To mitigate these shortcomings of recycled-brick-aggregate concrete, researchers have sought improvements through adjustments in the water-to-cement ratio, the utilization of CFRP wrapping, and the incorporation of fibers. Among these approaches, the addition of fibers has emerged as a highly effective and operationally feasible method. Islam et al. employed steel fibers measuring 50 mm in length and possessing a length-to-diameter ratio of 55.6 as the reinforcing material for recycled concrete . The res4 g/mol  MPa,  × 10−4 mol/L, and , respectively. By examining the response-surface plots, it can be ascertained that the order of surface curvature from high to low is as follows: The response-surface plot visually demonstrates the degree to which the interaction of the two factors affects the response variable. A more pronounced surface curvature indicates a more substantial influence of the factor interaction on the response variable. Conversely, a flatter surface suggests a weaker influence. The response-surface plots for the impact of the RA replacement rate and UHMWPEF content on concrete properties, as determined based on the regression model established in −4, and the flexural strength is 7.43 MPa. The substitution rate of RA is 12.57%, and the volume fraction of UHMWPEF is 1.24%. The second optimization objective, building upon the first optimization, aims to maximize concrete’s resistance to chloride ion erosion as much as possible. Optimization based on this criterion reveals that the optimization objective can be achieved when the substitution rate of RA and the volume fraction of UHMWPEF are 12% and 1.15%, respectively. Under these conditions, the F-RAC exhibits a 28-day shrinkage of 14.82 × 10−4, a flexural strength of 7.43 MPa, and a 90 d chloride ion concentration of 36.24 × 10−4 mol/L.Various relationships exist between the different properties of F-RAC, the substitution rates of RA, and the addition of UHMWPEF, with some correlations being completely opposite. Therefore, the optimization of the regression models using the desirability function is employed to prepare an F-RAC that can simultaneously meet various performance requirements. Three optimization objectives were established in the research, and the results are presented in −4, 7.4 MPa, and 36.24 × 10−4 mol/L, respectively. At this point, the fitted value for the relative dynamic modulus of F-RAC after 100 freeze–thaw cycles is 75.19.The third optimization objective considers the frequent occurrence of concrete structural damage due to freeze–thaw cycles in high-latitude regions. Therefore, the F-RAC design should prioritize maximizing freeze–thaw resistance while meeting relevant mechanical performance indicators. In this scenario, the optimization objective is to simultaneously achieve low shrinkage, high flexural strength, outstanding resistance to chloride ion erosion, and freeze–thaw durability, all while considering the prerequisite of mechanical performance. This optimization objective can be achieved when the RA replacement rate is 14.02% and the UHMWPEF content is 1.13%. The results indicate that the 28-day shrinkage, flexural strength, and 90 d chloride ion concentration are 14.73 × 10−4, which was 4.41% higher than the predicted value. The average actual flexural strength and chloride ion concentration were 7.26 MPa and 38.58 × 10−4 mol/L, respectively, falling within the confidence intervals of  and , respectively. After 100 cycles of freeze–thaw testing, the measured relative dynamic modulus of elasticity for F-RAC was 71.61, which was 3.58 lower than the predicted value. While the experimental value was close to the lower limit of the 95% confidence interval, it remained within an acceptable range.Experiments corresponding to the RA replacement rate and UHMWPEF volume fraction for the third optimization scenario were conducted. The experimental results and fitted values are presented in The root mean square error (RMSE) is a statistical metric to quantify the disparities between model-predicted and actual observed values. A smaller RMSE indicates more accurate predictions, while a larger RMSE suggests more significant prediction errors in the model . Table 1This research investigated the influence of the recycled-brick-aggregates (RA) replacement ratio for natural aggregates and the ultra-high molecular weight polyethylene fiber (UHMWPEF) content on concrete. The research objectives encompass shrinkage, flexural strength, resistance to chloride ion penetration, and freeze–thaw resistance. The impact mechanisms of RA and UHMWPEF on concrete were explored by analyzing both macroscopic properties and microscopic structure. The interactions between RA and UHMWPEF on concrete were analyzed using response-surface methodology. Simultaneously, utilizing regression models, a multi-objective optimization of concrete was conducted to determine the optimal combination of RA and UHMWPEF. In conclusion, the following findings are derived:(1) Both RA and UHMWPEF have a detrimental impact on the concrete slump, with the effect of UHMWPEF being pronounced. The coarse surface of RA and its high water absorption rate reduce the actual water–cement ratio of concrete. Furthermore, the formation of a three-dimensional network structure by UHMWPEF in concrete hinders the relative displacement between aggregates and other particles.(2) Excessive RA significantly diminishes the concrete’s resistance to shrinkage, flexural strength, and resistance to chloride ion erosion. However, this effect is modulated by UHMWPEF. The ultra-high molecular weight of UHMWPEF provides it with an exceptionally high elastic modulus, enabling it to share a portion of the stress within the concrete effectively. With a fixed RA replacement rate, UHMWPEF has a dual impact on concrete performance. Within a specific range of volume fractions, the addition of UHMWPEF enhances concrete performance. However, the beneficial effects decrease rapidly beyond a certain threshold and may even hurt concrete.(3) The bridging effect of UHMWPEF and the porous structure of RA play pivotal roles in the freeze–thaw resistance of concrete. RA provides additional space to accommodate the increase in volume when water transforms into ice. The bridging effect of UHMWPEF contributes to sharing temperature-induced stress and resisting crack propagation, thereby preserving the overall integrity of the concrete.(4) The impact of the interaction between RA and UHMWPEF on concrete performance was analyzed using response-surface methodology. It was determined that the order of influence on concrete properties due to the interaction between RA and UHMWPEF, from high to low, is as follows: freeze–thaw resistance > resistance to chloride ion erosion > flexural strength > shrinkage resistance.(5) Three optimization objectives were proposed to determine the optimal proportions of RA and UHMWPEF. When the replacement rate of RA is 14.02%, and the content of UHMWPEF is 1.13%, the concrete achieves the best shrinkage resistance, flexural strength, chloride ion erosion resistance, and freeze–thaw resistance. Experimental results demonstrate a high level of agreement between predicted values and actual measurements, indicating the reliability of the optimization results for F-RAC based on the response-surface methodology.


FRP bars are used in concrete structures as an alternative to steel bars as they have many advantages such as high tensile strength, high strength-to-weight ratio, electromagnetic neutrality, lightweight and no corrosion. There is a perceived lack of standard regulations for the design of concrete columns with FRP reinforcement, e.g., in Eurocode 2. This paper describes a procedure for predicting the bearing capacity of concrete columns with FRP reinforcement based on the interaction of axial force and bending moment, which was developed on the basis of existing design recommendations and standards. It was shown that the bearing capacity of eccentrically loaded RC sections depends on two parameters, which are the mechanical reinforcement ratio ω and the location of the reinforcement in the cross-section expressed by the β factor. The analyses carried out showed the existence of a singularity in the n–m interaction curve indicating the fact that in a certain loaded range, the curve is concave, and more it was shown that the balance failure point for sections with FRP reinforcement takes place for eccentric tension. A simple procedure for calculating the required reinforcement from any FRP bars in concrete columns was also proposed. Nomograms developed from n–m interaction curves provide for the accurate and rational design of FRP reinforcement in columns. Reinforced concrete structures are often exposed to destructive environmental influences such as the effects of moisture, salt, frost, acid and frequent changes in temperature and loads. These are factors that cause accelerated corrosion of the steel reinforcement in RC elements. For this reason, non-metallic reinforcement made of FRP (Fibre Reinforced Polymer) bars is increasingly used in concrete structures. The market offers a wide range of FRP bars made from different materials with very different mechanical properties. Composite bars have a very high tensile strength, and, in most cases, a low modulus of elasticity compared to steel bars. The tensile properties of FRP bars have linear elastic characteristics up to rupture. Due to the lack of plastic deformation, the failure occurs suddenly. Therefore, the behaviour of concrete columns reinforced with FRP bars is different from that of columns reinforced with steel bars.A complete overview of the approach and design philosophy of concrete structures reinforced with FRP composites is presented in Fib Bulletin . In the However, due to the very conservative provisions of some standards ,4 and thNumerous formulas for calculating the capacity of axially compressed columns can be found in the literature , but theRecommendations ,2 only cFRP bars are made of continuous fibres of various high-strength materials and a matrix, which is a polymer resin. The strength characteristics of composite bars depend, among other things, on the type of fibre used, the type of matrix and the fibre saturation of the matrix. Rods made from FRP are characterized by, among other things, high tensile strength, corrosion resistance and a lack of magnetic properties. The most commonly used materials for non-metallic bars are glass fibre (GFRP), carbon fibre (CFRP), basalt fibre (BFRP) and aramid fibre (AFRP).ff, ultimate strain fuε and elastic modulus fE. These parameters vary widely and depend primarily on the type of fibre. Thus, for CFRP bars: ff = 600–3000 MPa, fuε = 0.5–1.8%, fE = 80–500 GPa, for GFRP bars: ff = 400–1600 MPa, fuε = 1.2–3.7%, fE = 30–60 GPa, for AFRP bars: ff = 600–2500 MPa, fuε = 1.8–4.0%, fE = 30–125 GPa [ff = 1100–1450 MPa, fuε = 2.2%, fE = 55–78 GPa. In order to improve the mechanical properties of FRP bars and reduce their manufacturing costs, research is being conducted on bars made of Hybrid Fibre-Reinforced Polymer (HFRP), in which carbon and basalt fibres and various resins are applied [The mechanical properties of FRP reinforcement are characterized by three parameters: tensile strength  applied .The nature of FRP bars confers them orthotropic properties. Therefore, their compressive strength is different from their tensile strength, where the compressive strength is much lower. For GFRP and CFRP bars, the compressive strength is between 30% and 60% of the tensile strength, depending on the diameter of the bars . HoweverNumerous experimental studies on the behaviour of mainly short concrete columns reinforced with GFRP, CFRP and BFRP bars under axial and eccentric forces have been carried out ,23,24,25Experimental results  show thaIn order to improve the effectiveness of FRP reinforcement, there are also studies of concrete columns with hybrid reinforcement, e.g., steel bars and GFRP bars , as wellThe experimental results of columns with FRP reinforcement presented above correspond to the results of FEM analyses , which ff = min  and ff = min , respectively [To avoid over deformation of elements reinforced with FRP bars, the limit strains and limit stresses in tension bars are reduced to εectively , and theectively . Standarectively ,4 prescrectively ,36 indicectively , the conIn summary, it can be concluded that the experimental results to date and some numerical and analytical analyses indicate some discrepancies with the standards in estimating the resistance of columns with FRP bars. Therefore, further research is needed. In order to make the right choice for the type of FRP reinforcement, a method of predicting and evaluating the behaviour of columns reinforced with such bars over the entire load range is needed. This can be achieved by analysing the axial force-bending moment interaction curves for different FRP reinforcements.According to the standards ,4, for eu and the ultimate bending moment Mu for a specified state of stress are determined from the relation:c is the cross-sectional area of the compressed zone of the concrete, σc is the compressive stress distribution in the concrete, σf1 and σf2 are the stresses in the tension and compression bars, respectively, Af1 and Af2 are cross-sectional area of the tension and compression bars, respectively, Sf1 and Sf2 are the static moments of the cross-sectional area of the tension and compression bars, respectively, related to the centre of gravity of the section.The strength of an eccentrically loaded RC section is equal to the values of the axial force N and the bending moment M lying on the interaction curve N–M  determinThe bearing capacity of a reinforced concrete column depends primarily on its slenderness . If the There are often many load combinations in columns, with three static equilibrium paths possible , as illuu, Nu) from the interaction curve.For the design of a column to be considered adequate (safe), the combination of action effects  must be less than the combination of design strengths  the plane sections remain plane, (b) the concrete strength is neglected, (c) a parabolic–rectangular stress diagram in the compression zone, (d) a linear elastic stress diagram for the tension and compression bars. fu and the strength of the concrete by the limit strain εcu. According to recommendations [fu = 0.01.ndations , the strcu = 0.0035 is assumed to be no greater than 0.002 for axial compression. In the same range, the strain in the compression bars εf2 change.According to EC2 , the limco—compressive strength of concrete, b—width of section and d—effective height of the section.Lines from 1 to 9 in f1 = Af2, a1 = a2). The cross-section is described by two parameters: the mechanical reinforcement ratio ω [f is the modulus of elasticity of the FRP bars.The section is symmetrically reinforced  is the point at which the strains in the concrete and reinforcement simultaneously reach limit values, i.e., in the tension bars at 0.01 and in the extreme compression fibre of the concrete at 0.0035. Then, the height of the compression zone is equal to ξ = 7/27. This means that for a height of the compression zone ξ < 7/27, the tensile reinforcement decides the section load capacity (tension failure), and for a height of the compression zone ξ > 7/27, the concrete in the compression zone decides the section load capacity (compression failure). Point no. 4 is referred to as the balance failure point. The balance failure point for sections with FRP reinforcement takes place for eccentric tension, which is different from that for sections with steel reinforcement. In cu = 0.0035) already takes place for eccentric tension.The fourth point on the interaction line , concrete compressive strength: fco = 44.7 MPa, axial force eccentricities: e/h = 0, 0.5 and 1.0. When the column’s (for e/h = 1.0) load capacity was reached, the measured deformation in the tension bars was equal to εf1 ≅ 0.4%.In order to validate the presented method, the results obtained from the proposed formulae were compared with the results obtained from FEM analyses performed with the XTRACT application from Imbsen Software Systems . Figure As can be seen in The n–m interaction curve between points 4 and 8 see  is concaAccording to the authors, this is a concavity of the n–m curve resulting from the adopted strain hypothesis of strength and the use of a linear elastic material of high strength-FRP bars and an elastic plastic material-concrete. The concavity of the curve can be proved by the existence of an inflection point on this curve.cu = 0.0035 and the section height ξ varying from 7/27 to (1 + β). The interaction curve equations in this strain range are as follows:The strain state of the section, for the pivot point B , is limiAn inflection point on the curve exists when the second derivative of the parametric function is equal to zero:The solution of Equation (9) can be reduced to a third-degree polynomial:The analytical solution of Equation (10) is elaborate. As a result of the numerical solutions, the heights of the compressed zone ξo can be determined, and from this, the coordinates of the inflection point on the interaction curve (n(ξo); m(ξo)) can be calculated.For example, for ω = 0.2 and β = 0.1, the height of the compression zone is ξo = 0.439, and the coordinates of the inflection point are n(0.439) = 0.320; m(0.439) = 0.195. The inflection point on the interaction curves occurs when ω ≥ 0.027. The concavity in the interaction curve is visible in As mentioned earlier, the compressive strength of composite bars is much lower than their tensile strength . Therefosy = 400 MPa, ω = 0.2).If the eccentricity of the axial force is e/d < 0.3, then the amount of reinforcement has no effect on the bearing capacity of the eccentrically compressed section. The neglect of the forces transmitted by the compression bars in the analysis of the bearing capacity of an eccentrically compressed section makes the use of FRP reinforcement in ‘heavily’ loaded columns problematic.1) and the choice of concrete class (fco) have been determined, the values of the sectional forces  from the actions can be plotted on the nomograms, as shown in f), the cross-sectional area of reinforcement required in the section can be calculated using the formula:After determining the section dimensions , the position of the reinforcement in the section (af. The diagrams were constructed for FRP bars with different fibre (Ef = 20–200 GPa) and reinforcement ratio ρ from minimum (0.2%) to maximum (4%), as recommended by EC2 [f). Then, using the readout of the reinforcement ratio ρ from the nomogram, the cross-sectional area of the reinforcement Af1 and Af2 can be determined using the formula:d by EC2 . These cf = 180 GPa) and GFRP bars (Ef = 60 GPa) in a column with cross-sectional dimensions h = 40 cm, b = 40 cm, a1 = 3.5 cm, d = 36.5 cm made of concrete with a compressive strength of fco = 30 MPa for a combination of action effects (including or neglecting geometric imperfections and second order effects) where N = 1500 kN and M = 315 kNm (e = M/N = 21 cm). The calculation should be carried out for two cases: with and without the presence of compression bars.We design a reinforcement with CFRP bars (Ef1 + Af2) is calculated from (12). The results of the calculations are given in For this purpose, the normalised bending moment m and axial force n from the considered load combination  is found using Equations (3) and (4). Then, the mechanical reinforcement ratio ω is read from Non-metallic reinforcement made of FRP bars based on various types of fibre, usually glass and carbon fibre, is increasingly used in concrete structures. FRP reinforcement is used primarily in structures exposed to unfavourable environmental conditions. At present, only a few standards and recommendations allow the design of structures with this type of reinforcement. Numerous experimental studies are still being carried out and calculation methods are being developed with the aim of introducing rules for the design of concrete structures with FRP reinforcement into standards, including Eurocode 2 .The behaviour of RC sections with FRP reinforcement is different from sections with steel reinforcement. Sections reinforced with FRP bars have a significantly higher eccentric tension carrying capacity than eccentric compression. The balance failure point for sections with FRP reinforcement takes place for eccentric tension. The interaction curves for the sections with FRP bars are concave at a certain segment.In the design of reinforced concrete columns, axial force–bending moment interaction curves are very effective, as they allow the most unfavourable combination of loads and bearing capacity reserves to be easily determined. This paper presents n–m interaction curves for eccentrically loaded sections with FRP reinforcement based on current guidelines and standard recommendations. Interaction curves were developed for two cases: with and without compression reinforcement bars. The bearing capacity of sections where compression bars are not included is considerably lower especially for compression at low eccentricity since only the concrete part of the section carries the axial force. In this case, the FRP reinforcement only acts as a minimum structural reinforcement due to cracking, as the section’s load capacity is determined only by the concrete. Therefore, further experimental research and analysis are needed on the effect of FRP bars in compression on the load carrying capacity of concrete columns.The bearing capacity of sections with FRP reinforcement depends on two parameters: the mechanical reinforcement ratio ω and the position of the reinforcement in the section expressed by the coefficient β.The proposed method of designing the reinforcement is universal. Based on this procedure, any of the possible types of FRP bars and others with linear elastic characteristics can be designed. This procedure can be used in the design of column reinforcement, but then the design values of loads and material strengths considering partial safety factors and environmental reduction factor have to be introduced.The analysis of the reinforced concrete section follows the provisions of the strength design method and the unified design rules, with all strength conditions satisfying the applicable equilibrium and deformation compatibility conditions. The presented analytical method and the developed nomogram allow a rational choice for the type of FRP bars and their amount in the section.


Around 3% of patients with Non-Small-Cell Lung Cancer (NSCLC) harbour a MET exon 14 skipping mutation (METex14). Early mutation identification is important for accurate treatment of these patients because they receive more benefit from chemotherapy than from immune checkpoint inhibitors (ICIs). Moreover, the treatment landscape of this disease has radically changed in recent years thanks to the introduction of new selective and potent MET inhibitors (MET-Is). The aim of our review was to summarize the historical milestones since the discovery of the MET pathway through studies investigating the role of MET in the prognosis of NSCLC patients harbouring MET alterations to the discovery of MET exon 14 skipping mutation, the real target of this pathway in NSCLC. Moreover, we focused on the results from pivotal clinical trials of MET inhibitors and on mechanisms of resistance to these drugs. The last section of this review is dedicated to future developments.Non-Small-Cell Lung Cancer (NSCLC) can harbour different MET alterations, such as MET overexpression (MET OE), MET gene amplification (MET AMP), or MET gene mutations. Retrospective studies of surgical series of patients with MET-dysregulated NSCLC have shown worse clinical outcomes irrespective of the type of specific MET gene alteration. On the other hand, earlier attempts failed to identify the ‘druggable’ molecular gene driver until the discovery of MET exon 14 skipping mutations (METex14). METex14 are rare and amount to around 3% of all NSCLCs. Patients with METex14 NSCLC attain modest results when they are treated with immune checkpoint inhibitors (ICIs). New selective MET inhibitors (MET-Is) showed a long-lasting clinical benefit in patients with METex14 NSCLC and modest activity in patients with MET AMP NSCLC. Ongoing clinical trials are investigating new small molecule tyrosine kinase inhibitors, bispecific antibodies, or antibodies drug conjugate (ADCs). This review focuses on the prognostic role of MET, the summary of pivotal clinical trials of selective MET-Is with a focus on resistance mechanisms. The last section is addressed to future developments and challenges. MET  is a proto-oncogene situated on chromosome 7q21-q31 that encodes for transmembrane receptor tyrosine kinase normally expressed on epithelial cells. The Hepatocyte Growth Factor (HGF)/c-Met pathway is well characterized and recognized for its essential role in several cell vital processes in embryonic development, in the repair of injured tissues, as well as in carcinogenesis and tumour progression ,5. The HSeveral landmark papers have demonstrated that NSCLC can harbour different MET alterations (MET+), such as MET overexpression (MET OE), MET phosphorylation (its activated form), MET amplification (MET AMP), or MET gene mutations and that these alterations can negatively affect the patients’ clinical outcomes ,28,29,30This review will focus on the first reports that have demonstrated that MET alterations are significant prognostic factors for NSCLC patients ,28,29,30Some retrospective studies of surgical series have reported the prognostic role of MET dysregulation in NSCLC, which is summarized in HGF and MET OE have been studied in four retrospective studies that found that these factors could be associated with aggressive disease phenotype (high ki-67 score), more extensive pathological disease (pT and pN), and worse overall survival (OS) ,19,20,21Three independent studies have shown that MET mRNA levels were associated with more extensive disease (pN) and worse disease-free survival (DFS) ,23,24.Three studies reported that the MET gene copy number (GCN) in MET AMP, whatever the cut-off used, has an impact on survival ,26,27. BOnly two Asian studies included all three MET parameters, MET OE, MET AMP, and MET exon 14 skipping mutations (METex14), in their analyses, stating that METex14 are extremely rare (less than 5%) and can be associated with worse OS ,30.MET exon 14 encodes part of an important regulatory region and a binding site for cBL E3-ubiquitin ligase in the juxtamembrane domain of the MET receptor. Loss of this binding site leads to decreased ubiquitination, thereby reducing MET receptor internalization and degradation, resulting in increased MET levels ,32,33. MFrampton et al. analyzed tumour samples from 38,028 patients and found 221 (0.6%) cases with METex14: 3.0% in lung adenocarcinoma and 2.3% in non-adenocarcinoma lung cancers . Awad etAn important issue is the diagnostic of METex14 mutations due to their relative rarity and complexity, as not all of them lead to an exon 14 deletion. Next-generation sequencing (NGS) is the best choice as a testing platform because it has the advantage of detecting other oncogenic drivers concurrently using one test performed on a single sample. Given the complexity of the MET exon 14 skipping mutations, different tools to target enrichment for NGS vary dramatically in their ability to detect these events . DNA-basESMO guidelines strongly recommend testing for METex14 skipping through an NGS panel. When using an RNA-based assay, it is mandatory that adequate internal validation and quality control measures are in place to ensure that rare gene mutations are not missing, and liquid biopsies can be used to test for molecular drivers. However, all patients with a negative blood test still require tissue biopsy .The MET amplification (MET AMP) is due to an increase in the copy number of the MET gene (GCN), resulting in protein overexpression. True gene amplification results from gene duplication should not be confused with increased MET copy number due to high polysomy where there is complete chromosome duplication leading to multiple copies of chromosome 7 in tumour cells. Distinguishing between these two mechanisms is critical as true MET amplification is thought to drive oncogenesis, whereas polysomy usually does not  Figure . MET amplification (MET AMP) as a ‘druggable driver’ has a longer and more complex history because, in this circumstance, we need to select the real gene-addicted tumours to avoid the ‘dilution effect’ that consists of including a heterogeneity patient population that comprises polysomy and low gene amplification.In fact, the frequency of MET GCN in NSCLC ranges from 0.7% to 21%, depending on the technique used and the cut-off point for positivity . FluoresOne of the first cut-offs used was the University of Colorado Cancer Center (CCC) criteria, which established the gene amplification on the basis of GCNs and the ratio between GCN and centromere of chromosome 7 (MET/CEP7). It also distinguishes low polysomy (≥4 copies in 10–40% of cells), high polysomy (≥4 copies in ≥40% of cells), and gene amplification (presence of tight gene clusters and a MET/CEP7 ratio of ≥2 or 15≥ copies of MET per cell in ≥10% of cells) . The nexp = 0.04). This rigorous cut-off (ratio > 5) helped to identify extremely rare true amplificated cases (less than 1%) without other concomitant gene alterations [Noonan et al. analyzed 1164 patients with adenocarcinoma with information on MET/CEP7 ratio and 686 with information on mean MET per cell value from two separate cohorts, and the GCN was reported by two methods: mean MET copy number per cell value  and the ratio MET/CEP7  . Out of erations . HoweverIt should be noted that MET AMP has been described in patients with NSCLC not previously exposed to tyrosine kinase inhibitors (TKIs) (de novo MET amplification) or as a mechanism of resistance to TKIs, mainly to EGFR (acquired MET amplification).MET protein overexpression ranges from 15 to 70% in NSCLC . The METIn the past, two randomized phase III trials with onartuzumab  and tivantinib (a selective MET TKI inhibitor) in the second/third line were conducted in an unselected NSCLC patient population, and these trials failed to meet their primary endpoint in improving the OS ,54 Tabl. Additionally, several MET-Is have been developed despite the failure of these first approaches ,54. MET-Crizotinib is a type Ia MET-I through G1163 residue interaction and inhibits the ATP-binding pocket of active kinase . Table SThe AcSé was a French phase II trial in heavily pretreated patients with MET+ or ROS1+ NSCLC . They scThe METROS was an Italian multi-center phase II trial of patients with MET+ or ROS1+ NSCLC . They scThe expansion cohort of the phase I trial PROFILE-1001 included 69 patients with METex14 who had previously been treated for NSCLC . Among tAs for the cohort of 38 pretreated patients with MET AMP (cut-off MET/CEP7 ratio ≥ 1.8) NSCLC in the PROFILE-1001 study, 21 pts had high, 14 pts had medium, and 3 pts had low MET AMP . ConcurrSong et al. reported a retrospective series of 15 patients with MET AMP NSCLC (cut-off MET/CEP7 ≥ 1.8) collected from five Chinese hospitals from 2014 to 2016 and treated with crizotinib . They reCapmatinib is a type Ib selective MET-I. Preclinical data have shown that capmatinib is active in MET+ cancer models both in vitro and in vivo ,72.The phase I trial enrolled 55 patients with MET+ NSCLC (MET IHC 2+ or 3+/MET GCN ≥ 6 or MET/CEP7 ratio ≥ 2) treated with capmatinib and attained an ORR of 20%, 47%, and 100% among all the patients, 15 patients with MET GCN ≥ 6 and 4 patients with METex14, respectively .GEOMETRY-mono 1 was an international, multi-center, phase II trial in 364 patients with MET+ NSCLC treated with capmatinib and distributed in several cohorts based on MET-type alteration and prior treatments . In thisGEOMETRY mono-1 also included patients with MET AMP NSCLC regardless of GCN cut-off . All cohThe median duration of exposure to capmatinib varied across the cohorts, ranging from 6.6 weeks to 48.2 weeks, and the most common AEs were oedema 51% (G ≥ 3= 9%), nausea 45% (2%), vomiting 28% (2%), and creatinine 24% (0%). Of note, the ILD was 4.5% of them, and one patient died. The G3/4 rate was 67%, AEs leading to dose reductions were 23%, and drug discontinuation was 11%. Importantly, a lower incidence of gastrointestinal AEs was observed in cohorts 6 and 7 (capmatinib administered without fasting restrictions) .Tepotinib is a highly selective type of Ib MET-I . A phaseVISION was an international, multi-center, multicohort, phase 2 trial to evaluate the efficacy and safety profile of tepotinib in 337 MET+ NSCLC patients . This trA total of 313 patients with METex14 NSCLC were enrolled: 152 (cohort A) and 161 (confirmatory cohort C). Patients with brain metastases were 20% in cohort A and 15% in cohort C ,86,87. TTwenty-four patients with NSCLC harbouring MET AMP have been enrolled in cohort B of the VISION trial . The METThe most common AEs with tepotinib were oedema 66.5% , nausea 23.3% (0.6%), hypoalbuminemia 23% (3.2%), diarrhea 22.4% (0.3%), and creatinine level increase 21.7% (0.6%). The TRAEs G3-4 was 34.8%, and the AEs leading to dose interruptions, dose modifications, or drug discontinuation were 42.5%, 33.5%, and 14.7%, respectively ,86,87.Savolitinib is a type Ib MET-I. Preclinical studies have demonstrated its activity towards MET AMP gastric cancer patient-derived tumour xenograft models ,92.A single-arm phase 2 study of savolitinib in 70 patients with METex14 NSCLC pretreated with one or more standard treatments or unfit for standard treatment across 32 hospitals in China . This trCurrently, the clinical efficacy of savolitinib is being investigated in several tumours and EGFR+ NSCLC that progress to osimertinib and develop MET OE/MET AMP .It refers to primary resistance and, to our knowledge, is a phenomenon poorly described for MET+ NSCLC treated with MET-I. Moreover, there are currently no translational studies that have investigated epigenetic alterations that could have helped us better understand the mechanisms of resistance to inhibitory METs. Type I MET inhibitors’ activity does not seem to be negatively influenced by the different types or localizations of the METex14 mutations ,74,84,93In METex14 or MET AMP NSCLC, patients treated with MET-Is acquired mutations in the tyrosine kinase domain (TKD) and can sustain resistance to these inhibitors. Importantly, D1228 and Y1230 seem to mediate resistance to type I inhibitors by disrupting drug binding, while L1195 and F1200 mutations seem to confer resistance to type II inhibitors ,103,104.In a retrospective study, Recondo et al. reported 20 patients with METex14 NSCLC treated with MET-Is . They foA second Chinese retrospective study has been conducted with 86 patients with NSCLC harbouring MET TKD mutations . ImportaFrom a small phase II trial of capmatinib in 20 patients with METex14 NSCLC after crizotinib treatment, among the sixteen patients with detectable ctDNA, five (31%) had acquired MET mutations, three (19%) had MAPK pathway alterations, and two (13%) had ERBB pathway alterations . From thAs for MET AMP NSCLC, nine evaluable patients out of twenty-four patients enrolled in cohort B (MET amplification) of the VISION trial have had liquid biopsy profiles at disease progression: two (22.2%) of them had acquired MET resistance mutations; one patient had D1228H/N/Y, Y1230C/H, and D1231N; and another had D1228N/H, Y1230H, and D1231N (90). Pivotal clinical trials of ICI have excluded or not included patients with known MET alterations NSCLC; therefore, our knowledge of efficacy in this target patient population can only be derived from translational research and retrospective trials . MET OE MET AMP NSCLC correlated with higher PD-L1 score, CD8+ T-cell infiltration, higher incidence of concomitant gene mutations and worse OS . PatientInstead, there are conflicting results regarding patients with METex14 NSCLC and PD-L1 expression: one study showed that they are associated with higher PD-L1 score , anotherSabari et al. reported 24 patients with METex14 NSCLC treated with ICI; the ORR was 17%, and the mPFS was 1.9 months. Responses were not enriched in tumours with PD-L1 ≥ 50% nor high TMB .Dudnik et al. reported 14 patients with METex14 NSCLC and 5 patients with MET AMP (cut-off not specified) NSCLC . The actThe IMMUNOTARGET registry was a large European multi-center retrospective trial also involving EGFR and KRAS and enrolled 551 patients with gene-addicted NSCLC . ICI wasThe GFPC01-2018 study has enrolled 30 patients with METex14 NSCLC (enriched for PDL-1 positive and ever smokers) treated with nivolumab or pembrolizumab and showed an ORR of 36%, an mPFS of 4.9 months, and an OS of 13.4 months .This was recently reported in two retrospective studies. In the first study of 87 patients with METex14, NSCLC in the mPFS of ICI-based regimens was numerically low (2.4 months in patients with high PD-L1) . In the Post hoc analyses from GEOMETRY-mono1 and VISION trials have demonstrated that the activity of the MET inhibitor (capmatinib or tepotinib) was irrespective of prior therapies (including ICI); however, the median time to treatment of ICI in the VISION trial was less than 4.5 months, and the OS of patients treated with ICI alone was inferior respect to patients treated with chemotherapy +/− ICI (15.8 vs. 20 months) ,119.Currently, there are new agents targeting MET that are at an advanced stage of clinical research (completed phase I/II) and are summarized in Amivantamab is a new bifunctional monoclonal antibody against EFGR and MET ,121. ChrTelisotuzumab vedotin  is a cleavable antibody–drug conjugate (ADC) of a recombinant MET–targeting humanized monoclonal antibody (ABT-700) and monomethyl auristatin E (MMAE), a potent inhibitor of microtubule polymerization . The phaTPX-002, or elzovantinib, is a new type I TKI directed against MET, SRC, and CSF1R. SHIELD-1 TRIAL is an ongoing phase I trial investigating the safety and activity of elzovantinib in 52 patients with advanced solid tumours harbouring MET alterations. Fifty-two patients have been enrolled across seven dose levels, including thirty NSCLC patients . Among 11 TKI-naïve NSCLC patients, the ORR was 36% among all the doses (43% among the 7 patients treated at the RP2D) .Sym015 is a mixture of two humanized antibodies and triggers MET degradation . The SymREGN5093 is a new biparatopic MET antibody in which each arm of the antibody recognizes a distinct epitope of MET, which induces MET internalization and degradation. The phase I study enrolled in the dose expansion cohort 44 patients with METex14, MET AMP , or OE (3+ or H score ≥ 200) . In cohoIn the early-stage setting, a perioperative usage of capmatinib is investigated in the GEOMETRY-N (NCT04926831) and the neoadjuvant chemo-immunotherapy  is explored in 30 patients with rare molecular driver NSCLC (NCT05800340).In the advanced setting, MOMENT (NCT05376891) is a registry of patients with METex14 NSCLC on active treatment. NCT05567055 and NCT04739358 are clinical trials of capmatinib and tepotinib in 35 and 65 patients with active brain metastases, respectively.As far as the new drugs against MET are concerned, they are in different stages of clinical research; this is summarized in Additionally, other clinical trials are ongoing with combinations of drugs to augment their efficacy (TKI plus MEK-I or ICI plus amivantamab).The MET pathway was discovered in 1984 . Since tDespite the growing awareness of the MET role in NSCLC, many years had to pass before the identification of the real molecular driver(s) in this disease. METex14 mutations were first described and then characterized around 2004–2006 ,32,34. IFurthermore, several MET-Is have been developed after the failure of the first approaches (onartuzumab and tivantinib) ,54,146. Despite the initial paramount results, most of the patients develop resistance to MET-Is through on- and/or off-target mechanisms . SimilarThere are higher expectations of relying on new drugs with different structures and functions. They consist of novel selective and potent small molecules MET-Is, bispecific/trispecific antibodies and ADCs. Thus far, no clinical trial of these drugs has been designed to investigate overcoming resistance to prior MET-Is. In fact, in all of these trials, prior MET-Is were allowed without a dedicated sub-cohort for patient refractory to prior MET-Is. So far, amivantamab is the sole drug with proven efficacy in 28 patients with METex14 NSCLC and previously pretreated with MET-Is (the ORR was 17% with an mPFS of 4.2 months) . TherefoMETex14 can be considered a real entity in NSCLC among the other molecular drivers. Selective MET-Is (capmatinib and tepotinib) have been approved worldwide in patients with METex14 NSCLC. Given the great results obtained in non-pretreated patients, we think that the optimal place for MET-Is could have been the first line. However, in European countries, in the absence of controlled randomized trials, capmatinib and tepotinib have been approved for ICI +/− CT previously treated METex14 NSCLC patients. Great efforts in translation research and new drugs active towards MET+ NSCLC will allow us to improve these encouraging results further. The road still seems to be long but now with a favourable wind.


Legionella pneumophila, Mycoplasma pneumoniae, and Clamydophila pneumoniae (LMC).Many factors determine empirical antibiotic treatment of community-acquired pneumonia (CAP). We aimed to describe the empirical antibiotic treatment CAP patients with an acute hospital visit and to determine if the current treatment algorithm provided specific and sufficient coverage against A descriptive cross-sectional, multicenter study of all adults with an acute hospital visit in the Region of Southern Denmark between January 2016 and March 2018 was performed. Using medical records, we retrospectively identified the empirical antibiotic treatment and the microbiological etiology for CAP patients. CAP patients who were prescribed antibiotics within 24 h of admission and with an identified bacterial pathogen were included. The prescribed empirical antibiotic treatment and its ability to provide specific and sufficient coverage against LMC pneumonia were determined.Of the 19,133 patients diagnosed with CAP, 1590 (8.3%) patients were included in this study. Piperacillin-tazobactam and Beta-lactamase sensitive penicillins were the most commonly prescribed empirical treatments, 515 (32%) and 388 (24%), respectively. Our analysis showed that 42  of 113 patients with LMC pneumonia were prescribed antibiotics with LMC coverage, and 42  of 364 patients prescribed antibiotics with LMC coverage had LMC pneumonia.Piperacillin-tazobactam, a broad-spectrum antibiotic recommended for uncertain infectious focus, was the most frequent CAP treatment and prescribed to every third patient. In addition, the current empirical antibiotic treatment accuracy was low for LMC pneumonia. Therefore, future research should focus on faster diagnostic tools for identifying the infection focus and precise microbiological testing.The online version contains supplementary material available at 10.1186/s12879-023-08565-6. Community-acquired pneumonia (CAP) is one of the most common infections among patients in the emergency department and carries high mortality worldwide , 2. GlobStreptococcus pneumoniae and Haemophilus influenzae, typically respond to narrow-spectrum beta-lactam antibiotics like benzylpenicillin in countries with low penicillin resistance [Legionella pneumophila, Mycoplasma pneumoniae, and Clamydophila pneumoniae (LMC) are uncommon, seldom cause severe pneumonia and can be treated with macrolides or quinolones [The most frequent CAP pathogens, sistance , 5. Otheinolones .Clostridium difficile infection, cardiotoxicity and teratogenicity [Indiscriminate use of antibiotics like macrolides and quinolones is problematic. Firstly, they are drivers of the increasing worldwide problem of antimicrobial resistance (AMR) , 8. WHO genicity –12.The microbiological etiology is rarely known when a patient is treated for suspected CAP, and empirical antibiotic treatment should be adjusted to local epidemiology and AMR patterns . GuideliIn addition to the guidelines, factors such as comorbidities, previous antibiotic treatment, community outbreaks of specific pathogens, treatment sites, antibiotic supplies, and the treating physicians’ knowledge and compliance with guidelines all impact the choice of empirical antibiotic treatment –21. DespTherefore, our aim was 1) to describe the type of empirical antibiotic treatment prescribed to CAP patients on arrival and 2) to determine if the current treatment algorithm provided specific and sufficient coverage against LMC pneumonia.This study was conducted in the Region of Southern Denmark, the third largest region in Denmark, with a population of 1.2 million. The region has four hospital units: Odense University Hospital, Lillebaelt Hospital, Hospital South West Jutland, and Hospital Sønderjylland.We conducted a descriptive cross-sectional study based on the Southern Denmark Antibiotic Stewardship (SODAS) database. The database was established to evaluate the impact of the implementation of the Region of Southern Denmark’s antibiotic stewardship (RSDAS) in 2017 on individual antibiotic treatment . SODAS cRSDAS was implemented through campaigns and mandatory educational training , 25. In Our study adheres to the STROBE guidelines for reporting observational studies in epidemiology .th edition (ICD-10): DJ100, DJ111, DJ158, DJ159, DJ180, DJ189) were eligible  was calculated from the last ten years' discharge diagnoses prior to admission and grouped into three groups; 0, 1, ≥ 2 points . CURB-65The last prescribed antibiotic treatment within 24 h of admission was regarded as the empirical treatment. Antibiotic guidelines for CAP are listed in Table Information on penicillin allergy was not available.For our second aim, prescribed macrolide or fluoroquinolone was assumed to reflect the application of treatment guidelines to ensure antibiotic coverage against LMC pneumonia. Tetracyclines are not recommended in Danish guidelines and are rarely used for CAP in Denmark.The microbiological identified etiology of CAP was determined from standard clinical, microbiological testing. Guidelines for microbiological testing are described in appendix More extensive microbiological testing, Polymerase chain reaction (PCR) for LMC pathogens and treatment targeting LMC pathogens, were recommended for patients with CURB-65 score > 2, and a source of potential detection bias.Patients' characteristics were reported with mean or proportion when relevant. Empirical antibiotic treatment and microbiological etiology were reported as quantity and percentage of the total. Empirical antibiotic treatment accuracy for LMC pneumonia was expressed as 1) quantity and proportion of LMC pneumonia prescribed antibiotic covering LMC pneumonia. 2) Quantity and proportion of patients prescribed antibiotics covering LMC with LMC pneumonia. 3) Number of prescribed antibiotics covering LMC pneumonia needed to correctly treat one LMC pneumonia. 95% confidence interval was calculated for proportions when appropriate.Cases with missing microbiological etiology or empirical antibiotic treatment were excluded from the main analysis.The sample size was determined by the number of cases in the SODAS cohort. Data analysis was done using STATA 17 .The study was performed in accordance with the Helsinki declaration. According to the Danish Act on scientific ethical treatment of health science research projects, register based studies do not require ethics committee approval . The neeDuring the study period, a total of 443,953 contacts were included in the SODAS database, of which 21,624 had a discharge diagnosis of pneumonia  and 388 (24%), respectively (Table % and 388Antibiotics with LMC coverage were prescribed to 364 (23%) totally, among these to 42  of 113 LMC pneumonia patients and 42  with prescribed LMC antibiotics had LMC pneumonia  and 388 (24%), respectively. Additionally, our analysis showed that only 42  of patients with LMC pneumonia were covered by the empirical antibiotic treatment, while only 71  of patients treated with antibiotics with LMC coverage actually had LMC pneumonia.The majority, 515 (32%) of all antibiotics prescribed were monotherapy Piperacillin-tazobactam. This was notwithstanding a shortage of Piperacillin-tazobactam from May to September 2017 . PiperacIn a Danish study, 45% of CAP patients were treated with Beta-lactamase sensitive penicillins, compared to only 24% in our study . The higWe found that the empirical treatment guided by severity scores covering LMC pneumonia to be non-specific and insufficient. This result is not surprising, as studies assessing the ability of severity scores to predict the etiology of CAP reported a decreased frequency of LMC pneumonia in patients with high severity scores , 38. In All these factors may explain our results: the prescription of antibiotics with LMC pneumonia coverage in 23% of patients despite LMC only being identified in 7% of patients, only 37% of patients with LMC pneumonia were prescribed antibiotics with LMC coverage, and only 12% (95% CI: 8–15) of patients prescribed antibiotic covering LMC had an LMC-pneumonia. This indicates a considerable potential for improvement in use of antibiotics with more accurate and faster microbiological testing in the future.In our setting, PCR analysis for LMC pathogens was only recommended in patients with a CURB-65 score of 3–5. Therefore, we were less likely to identify LMC-pneumonias in the group prescribed antibiotics without LMC coverage and likely overestimated the proportion of LMC-pneumonias prescribed antibiotics covering LMC pneumonia. To PCR test all CAP patients or all patients prescribed antibiotics with LMC coverage  may leadStreptococcus pneumoniae compared to other European countries but a similar frequency compared to USA and Canada [The relative frequency of each pathogen in our study was consistent with other studies from Denmark and Norway , 42. We Denmark and other Scandinavian countries have a low level of LMC frequency and antibiotic resistance, and guidelines usually recommend narrow-spectrum penicillin, in contrast to non-Scandinavian countries where broad-spectrum antibiotics are often used as first-line empirical treatment , 42–44. A limitation of this study was that the population was selective and only included 8% of patients with CAP, as it was only possible to identify microbiological etiology in 13% of patients. Sputum culture and PCR are the primary microbiological tests for CAP. However, studies have shown a tendency for a low sputum culture yield of 14–17% in CAP patients because of an inability to obtain sputum samples and a low positive rate of sputum culture , 46. In Some, limitations stem from our population-based design, which relies on discharge diagnoses for pneumonia, potentially skewing results due to less robust patient selection. Furthermore, the overrepresentation of patients from Odense University Hospital, with its unique patient demographic and extensive microbiological testing, could have biased our results, specifically in antibiotic prescription patterns. The impact of these factors is challenging to quantify or account for.In conclusion, piperacillin-tazobactam was the most frequent empirical antibiotic treatment for CAP with later established clear etiology. The accuracy of empirical antibiotic treatment covering LMC pneumonia was low. We found that there was potential for improvement of empirical antibiotic treatment of CAP and that diagnostic uncertainty regarding focus and cause of infection may be major factors for unnecessary use of broad-spectrum antibiotics.Additional file 1: Appendix 1. List of ICD-10 codes and n included in the study. Appendix 2. Guidelines for microbiological testing. Appendix 3. Potential CAP pathogens by microbiological tests. Appendix 4. Extended list of empirical antibiotic treatment. Appendix 6. Frequency of microbiological testing in all CAP patients and frequency of positive test for a CAP pathogen.


Streptococcus (Strep A).Antibiotic consumption can lead to antimicrobial resistance and microbiome imbalance. We sought to estimate global antibiotic consumption for sore throat, and the potential reduction in consumption due to effective vaccination against group A We reviewed and analysed articles published between January 2000 and February 2022, identified though Clarivate Analytics’ Web of Science search platform, with reference to antibiotic prescribing or consumption, sore throat, pharyngitis, or tonsillitis. We then used those analyses, combined with assumptions for the effectiveness, duration of protection, and coverage of a vaccine, to calculate the estimated reduction in antibiotic prescribing due to the introduction of Strep A vaccines.We identified 101 studies covering 38 countries. The mean prescribing rate for sore throat was approximately 5 courses per 100 population per year, accounting for approximately 5% of all antibiotic consumption. Based on 2020 population estimates for countries with empiric prescribing rates, antibiotic consumption for sore throat was estimated to exceed 37 million courses annually, of which half could be attributable to treatment for Strep A. A vaccine that reduces rates of Strep A infection by 80%, with 80% coverage and 10 year’s duration of protection, could avert 2.8 million courses of antibiotics prescribed for sore throat treatment among 5-14 year-olds in countries with observed prescribing rates, increasing to an estimated 7.5 million averted if an effective vaccination program also reduced precautionary prescribing.A vaccine that prevents Strep A throat infections in children may reduce antibiotic prescribing for sore throat by 32–87% depending on changes to prescribing and consumption behaviours.The Wellcome Trust, grant agreement number 215490/Z/19/Z. Streptococcus (Strep A), and the distribution of antibiotic classes prescribed for sore throat. We used Clarivate Analytics’ Web of Science (WoS) search platform, which includes the WoS Core Collection and Medline, to search for articles published between January 2000 and February 2022. Search terms included tonsillopharyngitis, pharyngitis, sore throat, throat infection, and antibiotics. No restrictions on language were applied.We conducted a global systematic review of the worldwide literature to identify data on the rate of antibiotic prescribing or consumption to treat sore throat among the general population, the proportion with known aetiology of group A To our knowledge, this is the first study to compile worldwide data from peer-reviewed and grey literature on the rate, and class, of antibiotics prescribed to treat sore throat and the proportion of prescribed antibiotic courses that can be attributed to Strep A. There was limited data from low- and middle-income countries. We used available data to model the potential impact of Strep A vaccines based on assumptions for their direct impact on infection rates and their potential impact on precautionary prescribing practices. Our analyses suggest that the latter assumption has as much, if not more, importance on overall reductions in antibiotic prescribing as differences in vaccine efficacy, coverage, and duration of protection.Our study found limited empirical data to estimate the global consumption of antibiotics due to sore throat, and more specifically for Strep A infection. These data are crucial to understanding the broader impact of Strep A vaccination—impact beyond a direct reduction in infections–and, therefore, its wider economic and societal value.Streptococcus pyogenes, also known as group A Streptococcus (Strep A), is the most common bacterial case of sore throat , collectively causing more than 600 million cases per year globally.Infection by Accurate diagnosis and antibiotic treatment of Strep A sore throat is known to reduce the risk of developing ARF and may reduce the risk of other severe sequelae.The frequent occurrence of sore throat infections combined with difficulties in discriminating Strep A infections from viral aetiology results in sore throat being one of the most common reasons for antibiotic prescription globally. For example, analysis of the most recent Eurobar data on antimicrobial resistance (AMR) shows that sore throat was the second most common reason for antibiotic prescription in Europe, responsible for 14% of all antibiotics consumed by adults.,,Inappropriate and excessive antibiotic consumption is a major contributor to AMR.Understanding the full scope of antibiotic consumption for sore throat is a key part of understanding the potential value of Strep A vaccination. Therefore, for countries with observational data, this study aimed to: (1) estimate the mean rate and total number of antibiotic courses prescribed to treat sore throat; (2) estimate the proportion of prescriptions for sore throat that is attributable to treatment of sore throat caused by Strep A; (3) summarise the distribution of antibiotic classes prescribed for sore throat, and (4) explore the potential reduction in antibiotic prescribing for sore throat due to implementation of prospective Strep A vaccines.We conducted a systematic review to identify, collate, and analyse data related to aims one through three. We then used those analyses, combined with assumptions for the effectiveness, duration of protection, and coverage of a vaccine, to calculate the estimated reduction in antibiotic prescribing due to the introduction of Strep A vaccines.We conducted a systematic review for aims 1–3 in accordance with PRISMA guidelines.Studies were considered for inclusion in one or more of our analyses if they evaluated one of three outcomes of interest: (1) rate of antibiotic prescription for sore throat among the general population, (2) distribution of antibiotic prescription for sore throat by laboratory or point-of-care diagnosis, or (3) distribution of antibiotic prescriptions for sore throat by antibiotic class. We included observational studies and control arms of randomized control trials of treatment regimens. We restricted studies to those among primary care patients, but we included studies conducted in primary care settings that also involved outpatient and emergency departments. We excluded studies conducted solely in hospital-based outpatient or emergency departments as treatment of sore throat in those settings is relatively rare compared to primary care and likely reflect prescribing rates among severe cases. Studies of attitudes towards antibiotic consumption with no primary data on prescribing or consumption were also excluded, as were studies in which participants who were surveyed on antibiotic consumption that were recruited from pharmacies, to limit biases towards treatment. Studies on post-operative sore throat were considered inappropriate for this review and were excluded. Search results were uploaded to Endnote X9 for deduplication and cataloguing. Two authors (JWC and KM) independently screened and reviewed the titles and abstracts of potential studies against the eligibility criteria. Papers meeting the inclusion criteria were sourced in full text for final review for inclusion. Google Translate was used to translate non-English language papers; however, the search was conducted in English. Differences in opinion between the two reviewers were resolved by discussion to achieve consensus.Following full text review, two reviewers  independently extracted data from each of the eligible studies using a standardised proforma. Variables included: authors; year of publication; study period; study location ; study setting; number of participants; participant age range, sex, and population group; diagnosis ; and outcome measures .The primary outcome tracked (or “monitored”) was sore throat, including pharyngitis and tonsillitis. A secondary outcome tracked was sore throat caused by Strep A. A case of sore throat was defined as any illness in a participant who reported symptoms consistent with a sore throat or who was clinically diagnosed with pharyngitis or tonsillitis, regardless of other clinical symptoms. A case of Strep A sore throat was defined as illness in a participant who complained of sore throat or who had clinical signs of pharyngitis or tonsillitis combined with microbiologic confirmation of Strep A in the oropharynx by a positive throat culture, rapid antigen detection test (RADT), nucleic acid amplification test, or another appropriate molecular test.The appropriateness of antibiotic prescribing was assessed based on adherence to recommended antibiotics as listed in current country or regional specific guidelines. Antibiotic classes were categorised according to the Anatomical Therapeutic Chemical Classification System, controlled by the WHO Collaborating Centre for Drug Statistics Methodology.We defined outcomes to be among children and young adults when study participants were predominately <20 years old and among adults when participants were predominately ≥20 years old. However, we estimated the numbers of antibiotics prescribed and potentially averted by vaccination for children aged 5–14 years as that age range aligned with our assumed vaccination parameters .Checklist for Prevalence Studies”.Articles eligible for inclusion in our meta-analysis for the proportion of prescriptions attributable to Strep A were independently assessed for quality by two reviewers (KM and JWC) using the Joanna Briggs Institute (JBI) “All statistical analyses and plotting were performed using R (version 4.1.0) statistical software.We summarised the rates of antibiotic prescribing for sore throat by study country and by age group at the time of treatment. Prescribing rates were defined as the number of courses to treat sore throat per 100 population per year, which were acquired directly from the study or calculated using the data reported by the study. Some studies reported prescribing rates stratified by several age groups, in which case we combined age-specific rates to match our definitions of children and young adults and adults as closely as possible. Demographic data from the United Nations World Population Prospects were used for nationally representative data  when population denominators were not reported.Using the country- and age-specific prescribing rates, we calculated the arithmetic mean prescribing rate and the population-weighted mean prescribing rate of all countries for each age group. For countries with more than one study among a particular age-group, we used the most recent or nationally representative prescribing rate because most within-country studies were updated analyses of the same or similar data sources.We also used the most recent or nationally representative prescribing rate to estimate the number of antibiotic courses prescribed to treat sore throat in 2020 among each country analysed in our review. Here, we estimate the number of courses prescribed to treat sore throat among children aged 5–14 years and among the total population  by multiplying country-specific prescribing rates for children and young adults and for all ages by, respectively, the estimated 2020 population aged 5–14 years and total population.Additionally, we estimated the percent of total antibiotic prescription for any health conditions or infections that was due to sore throat treatment for each county. We estimated the number of defined daily doses (DDDs) per 1000 inhabitants per day (DID) using the method described elsewhere2 and Cochran’s Q tests.We conducted a random-effects meta-analysis of the proportion of all prescriptions for sore throat that were diagnostically confirmed as Strep A sore throat . We conducted sub-group meta-analyses by age group (children and young adults and adults) at time of treatment and by study country. Between-study heterogeneity was assessed using the IAn effective Strep A vaccination strategy would reduce the incidence of Strep A infection and may influence antibiotic prescribing practices for sore throat. Over the last decade, the benefit of antibiotic treatment for sore throat of any aetiology in populations where ARF, rheumatic heart disease, and other severe complications of Strep A pharyngitis are rare has been debated.Scenario 1 (no change in prescribing practices) assumed that there would be no change in prescribing practices but that the proportion of prescriptions for sore throat that are attributable to Strep A  would be averted by vaccination; the modelled effect of vaccination against Strep A infection is described at the end of this section. While an effective vaccine would prevent infection among cases that may not traditionally be prescribed antibiotics, our analysis aimed to explore only the reductions in antibiotic prescriptions rates and not in both treated and untreated infection rates.Scenario 2 (reduced prescribing rates in HICs) assumed that there would be a change in prescribing practices among children in HICs presenting with sore throat in conjunction with a decrease in Strep A infection rates. In HICs, prescribing rates were assumed to match, based on this review, the country with the lowest prescribing rate among children, while in low- and middle-income countries (LMICs), prescribing practices were assumed to be unchanged. Given the revised  antibiotic prescribing rates, we then assumed, as in Scenario 1, that a proportion of prescriptions attributable to Strep A would be averted by vaccination.In both scenarios, the proportion of prescriptions attributable to Strep A that could be prevented by vaccination were based on the following assumptions: vaccination at age five years; vaccine effectiveness (for prevention of Strep A pharyngitis) of 80%, based on the WHO’s Preferred Product Characteristics for Strep A vaccinesAdditionally, we conducted sensitivity analyses to explore the impact of uncertainty in vaccine coverage (70–90%), efficacy against Strep A pharyngitis (70–90%), and duration of protection (5 and 10 years) on the potential numbers of antibiotics averted by Strep A vaccination. The effect of a reduced duration of protection to 5 years was mirrored in a reduced age-range for changes in prescribing practices under Scenario 2; the minimum rate was applied only to 5-9 year-olds, while prescribing among 10-14 year-olds was modelled as observed. Further details for these calculations are provided in the Descriptive statistics were used to describe the distribution of prescriptions by antibiotic class and calculate the rate of appropriate antibiotic prescriptions. To estimate levels of appropriate antibiotic prescribing, we compared antibiotics prescribed with the antibiotics recommended in relevant national or regional treatment guidelines. Data was excluded for studies conducted in countries where guidelines were not available. We calculated the average distribution of classes prescribed across studies with equal weighting.The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Authors were not precluded from accessing data in the study, and all authors had final responsibility for the decision to submit for publication.We identified 5051 studies, of which 561 studies were retained for full text review after title and abstract screening. Subsequently, 101 studies covering 38 countries were included in one or more analyses .Fig. 1PR,,,,,,,,,,,n = 11), UK (n = 7), the Netherlands (n = 6), and Sweden (n = 5). Studies from low- and middle-income countries were underrepresented . Twenty-seven studies from 12 countries included rates for all ages ,5,20, 21Based on data from the most recent year(s) or nationally representative studies among all age groups (n = 12), the mean and population-weighted mean rates of antibiotic courses prescribed for sore throat were 5.0 and 5.2 per 100 population per year, respectively . At a coAmong studies with rates for children and young adults , the mean and population-weighted mean rates of antibiotic courses prescribed for sore throat were 13.4 and 10.7 per 100 population per year, respectively . For aduFor 2020, we estimate that 8.6 million antibiotic courses were prescribed for sore throat among children aged 5–14 years (8.0 million among the HICs reviewed) and 37.4 million antibiotic courses for all ages.,,Nineteen studies across nine countries reported prescriptions for diagnostically confirmed Strep A pharyngitis .26,40,63Of all antibiotic prescriptions for sore throat, 50% (95% CI 41–59%) were for Strep A positive patients, and the remaining proportion were for Strep A negative patients or those not tested  and 6% of the global population aged 5–14 years (53% of children from HICs and 1% of children from middle income countries). There were no studies from low-income countries.Based on our meta-analyses, we assumed that 50% of all prescriptions for sore throat are due to Strep A and that this estimate did not differ by age group or country; the latter assumption was due to the limited number of studies from each country and the significant statistical heterogeneity among studies within the US. Thus, estimates for the potential reduction in antibiotic courses prescribed to treat sore through due to vaccination are shown in The sensitivity analyses indicate that, with lower vaccine efficacy (70%) and coverage (70%), more than 2.1 million antibiotic courses may be averted among children under Scenario 1 (24.5% reduction in prescribed courses), increasing to approximately 3.5 million courses averted (40.5% reduction) with higher vaccine efficacy (90%) and coverage 90%; . The corFor the sensitivity analyses of Scenario 2, the difference in averted courses for changes in vaccine efficacy, coverage, and duration of protection, are outweighed by the impact from the assumed change in prescribing practices. In this scenario, over 7 million and over 3 million antibiotic courses are averted for vaccines with durations of 10 years and 5 years, respectively . For vac,,,,59,,,,,,,,,,,,,,,n = 50; 82%), seven were from four upper-middle income countries , and four were from three lower-middle income countries, . No studies from low-income countries were available for inclusion. The most commonly prescribed antibiotics for sore throat across studies were ‘penicillin beta-lactam antibacterials’ (JO1C) (70.1%), of which penicillins with extended spectrum  were most commonly prescribed  and to children aged 5–14 years in the reviewed countries. The implementation of a Strep A vaccine, if administered to 5-year-old children, could avert over 2.7 million courses of antibiotics prescribed for Strep A pharyngitis by directly preventing infection, which is a 32% reduction in prescriptions among 5-14 year-olds. If, in addition to directly preventing Strep A infection, vaccination reduces the rate of precautionary prescribing in HICs, then we estimate that almost 7.5 million courses of antibiotics prescribed for sore throat among children could be averted. As indicated by the results of our sensitivity analyses, the assumed impact of a vaccine on prescribing practices has as much, if not more, importance as differences in vaccine efficacy, coverage, and duration of protection. Under Scenario 1 (no changes in prescribing practices), the relative difference in averted prescriptions increased 1.65 fold when vaccine efficacy and coverage increased from 70% to 90%; this relative difference was the same for either duration of protection assumption. The relative difference in averted prescribing under Scenario 2 (changes in prescribing practices among HICs) was just a 1.04 fold increase when vaccine efficacy and coverage rates increased. Further research could explore the impact that those vaccination parameters have on effecting changes in prescribing practices.,Our estimated reductions in antibiotic prescribing to treat sore throat do not include the potential reduction in Strep A sore throat due to herd protection among non-vaccinated children and adults, nor does it account for the potential to alleviate the need for antibiotic use for sore throat globally.Lewnard et al.,To our knowledge, we present the first meta-analysis for the proportion of antibiotic prescriptions to treat sore throat that are attributable to Strep A based on diagnostic outcomes among patients receiving an antibiotic prescription. Our results, which indicated that 50% of all prescriptions for sore throat were microbiologic test-confirmed Strep A infections, suggest that there is room for improved antimicrobial stewardship. It is possible that some proportion of prescriptions that were for sore throat infections not due to Strep A were not dispensed or consumed, particularly in populations practicing delayed consumption pending testing results. However, a proportion  to reduce inappropriate antibiotic prescribing. Large-scale studies reviewing rates of antibiotic prescribing over time would be useful to evaluate the impact of antimicrobial stewardship programs globally. Studies from the US reported that the antibiotic prescribing decreased from 76% of sore throat visits among adults (in 1989–1992)Overall, our findings indicated that there is little empirical data to estimate the global consumption of antibiotics due to sore throat, nor the proportion attributable to Strep A infection. The available data comes largely from HICs with electronic medical records that facilitate a linkage or connection between diagnosis or symptoms and treatment. Such data infrastructure is less prevalent in LMICs, so traditional community-based surveys may be required to better understand consumption rates and practices. These data are crucial to understanding the broader impact of Strep A vaccination—impact beyond a direct reduction in infections–and, therefore, its economic and societal value.KM and JWC conducted the literature review and analyses and prepared the first draft manuscript. JWC conceptualised the study, and KM, TB, DC, DB, and JRC provided constructive feedback and suggestions to the study design. All authors contributed to reviewing and editing the final manuscript.The data that support the findings of this study are within the The authors have no conflicts of interest to disclose.