In this paper, the recycled fine aggregates and powders produced from crushing old basaltic concrete and natural basalt were used to produce new concrete. The sand was partially replaced by two types of recycled wastes at five percentages: 0%, 20%, 40%, 60%, and 80%. The cement was partially replaced by recycled powders and silica fume (SF) at four percentages: 0, 5%, 10%, and 20%. The concrete strengths and water absorption were obtained at several curing ages. The obtained results emphasized the positive effects of increasing the curing time on enhancing the concrete properties, regardless of the types or the waste sources. Moreover, the recycled powders retarded the hydration reaction. In addition, the recycled fine aggregates and powders could achieve about 99.5% and 99.3% of the ordinary concrete strength and enhance the tensile strength. Furthermore, the mix containing 40% of recycled fine concrete aggregate diffused the highest contents of both calcium and silicate, which led to enhancing the interfacial transition zone (ITZ) and concrete properties, compared to the other tested mixes. Finally, the water absorption of all tested concrete mixes decreased with an increase in the curing age, while the mixes integrating 10% and 20% of SF experienced the lowest values of water absorption. Construction industry growth has become significant worldwide and its environmental impacts have increased rapidly due to the high demand for extracted raw materials. Concrete aggregates (sand and gravel) and water are the main materials used around the world, although their renewal rates are less than their usage. In 2017, about 45 billion tons of natural aggregates were extracted, while in 2025, the estimated extracted amount is predicted to rise to 66 billion tons. Moreover, the cement industries consume aggregates at a rate of about 40 billion tons/year worldwide . To redu2, CO, and NOx). Using equipment with low fuel combustion or alternative materials instead of cement and natural aggregates  are two alternatives for reducing hazardous gas emissions. To reduce the EI of cement and aggregate production, fly ash was used as a replacement material  [Ameliorating the environmental impact (EI) of concrete production became essential some time ago. Cement production and natural aggregate-extracting processes are one of the main hazardous gas sources  ,16. Addi cement) ,18,19. F cement) ,20. In a cement) , when RC cement) ,23, maxiSeveral researchers have previously studied the influence of recycled fine concrete aggregate (RFCA) on the mechanical behavior and durability of concrete ,27,28,29Several supplementary cement-based materials (SCM), such as metakaolin, rice husk ash, waste glass, GGBFS, and silica fume have been implemented during the last decade as a cement replacement ,39,40,41In a previous study , the macThe basalt aggregates and powder improved the concrete’s properties, while silica fume (SF), basalt powder, and ordinary Portland cement (OPC) had nearly the same composition ,56,57. TThe above review reports the limited research that has studied the incorporation of recycled basaltic concrete . Moreover, the waste fines produced during the production of coarse basalt aggregate were usually used for leveling the roads. The incorporation of the previous fines was slightly used in concrete. In this study, the fines produced from the crushing of old basaltic concrete or those produced from the production stations of the basalt aggregates were used to replace the fine NA and cement. All the obtained results were compared, to discuss the effects of curing time and the sources of recycled fine aggregates and powders on the strengths, microstructure, and WA of concrete.The fines from old basaltic concrete were sieved to form recycled fine concrete aggregate and fine basaltic concrete powder (RFCA and RCP), respectively. Subsequently, the waste fines produced from the production station of basalt aggregate were sieved to form recycled fine natural aggregate and aggregate micro-fines (RFNA and AMF), respectively. The RFCA and RFNA were used to substitute the natural sand at five percentages . Then, the cement was partially replaced by RCP, AMF, and SF at four percentages . Finally, the effects of RFCA, FRCP, RCP, AMF, and SF on the microstructure properties, mechanical properties, and water absorption of the resulting concretes were studied.Crushed basalt with a maximum nominal size (MNS) of 12.5 mm was used as a coarse aggregate. The basalt grading curve was adopted to comply with ASTM C33 regulations  Figure a. The na2, Fe2O3, and Al2O3 should be greater than 70% for the pozzolanic materials (ASTM C618). For RCP and AMF, the sum of the three components  was 87.68% and 90.59%, respectively, which met the requirements for natural pozzolana (ASTM C618). Moreover, the main chemical component of RCP and AMF was silica (SiO2). The SF as a well-known industrial pozzolanic material , along with energy dispersive spectroscopy (EDS). The EDS analysis of the RCP, AMF, and SF are shown in cuf,28) was 35 MPa; the slump was 50–80 mm, while the W/C was 0.5. To study the source effect of recycled fine aggregates (RFCA and RFNA) and powders (RCP and AMF) on the concrete strength and WA, all other components of the concrete mix were kept constant. Although most of the previous researchers [In this paper, the control mix (M0), cast with NA and cement, was designated according to the model in . The tarearchers ,51,53,653 cubes were cast from each mix, de-molded after one day, and submerged in water until testing. Three cubes were directly tested in compression , 28 days , and 56 days . The other three cubes were diagonally tested in compression  [b and d are the cube width and diagonal length, respectively, while P is the failure load and β = 0.15. The cubes were loaded using a concrete-testing machine (capacity = 2000 tons) with loading rates of 4 and 3 kN/s for the compression and diagonal tests, respectively.The authors tried to keep all factors constant except the replacement material, so no water reducers were added when the cement or NA was replaced by recycled materials or SF. The aggregates  were dry-mixed using a mechanical concrete mixer for 1 min. Subsequently, cement and other pozzolanic materials (if any) were added to the mixer; then, all components were dry-mixed for an additional 1 min. Afterward, the calculated water amount was steadily added to the mixer and a further 2 min of mixing was conducted. Twenty-one 100 × 100 × 100 mmpression a at eachpression b at 28 dtion (1) :(1)σmax=3, approx = 800 g). In this study, the specimens were dried at 100–110 °C (time ≥ 24 h) then the oven-dry mass (A) was measured. Afterward, the specimens were immersed in water (time ≥ 28 h and temperature ≈ 21 °C), then the surface-dried samples’ weights (B) were measured . The WA was calculated for all mixes at 28 and 56 days, using Equation (2) [There are a limited number of standard methods used to measure the WA of concrete in laboratory situations. The most rigorous standard approaches are ASTM C1585 and ASTM C642 . Moreovetion (2) :(2)WA % µ7), 28 days (µ7), and 56 days (µ56) is also summarized in µ28/7% = cuf,28/cuf,7 × 100 and µ56/28% = cuf,56/cuf,28 × 100 for all mixes are also listed in cu,ageµ%) was also measured (see Equation (3)).The measured compressive strengths at 7, 28, and 56 days are classified in fcu,age (RAC) and fcu,age (M0) are the cuf values for the mix containing recycled materials and the control mix, respectively.Here, cT increased, the RAC strength improved for all mixes , compared to that of M0. Moreover, at Tc = 28 days, the concrete strength was reduced by 4.6–9.45% (µ = 7.68% and µσ = ±1.58%), compared to that of M0, when the RFCA replaced sand by 20–80%. Furthermore, at Tc = 56 days, the strength reduction was about 0.50–11.0% (µ = 5.75% and µσ = ±4.22%), compared to that of M0, when the RFCA replaced sand by 20–80%. The lowest reduction in strength values was obtained for M7, when tested at 7 and 28 days (µ7 = 1.0% and µ28 = 4.6%), and for M6, when tested at 56 days (µ56 = 0.50%). These lowest strength reductions support the use of RFCA as a good replacement for natural sand.The influence of fine recycled materials on concrete strength was studied . As the ll mixes . Moreove8 values . This emcT on the strength of concrete integrating RFNA was nearly the same as that integrating RFCA  for mixes integrating RFNA was 13.1–37.1%. Conversely, the µ28 for M8-M11 mixes was 5.5–10.8%, while the µ56 for M8-M11 mixes was 6.7–13.5%. The two mixes (M10 and M11) integrating high RFNA percentages experienced the lowest values of µ56 . The mixes integrating RFCA showed better compressive strength results than those integrating RFNA  by the same percentages as the RFCA 0–80%, . The effing RFCA . At Tc =ing RFNA . The higµ = 77.6% and µσ = ±3.03%) when the RFCA replaced sand by 0–80%. Consequently, the Rc56 values were 108.8–126.0% (µ = 114.7% and µσ = ±5.95%) when RFCA replaced sand by 0–80%. The highest values of Rc7 and Rc56 were obtained for M3 and M2, respectively (µ = 66.8% and µσ = ±7.15%) when the RFNA replaced sand by 0–80%. In addition, the Rc56 percentages were 110.1–120.0% (µ = 114.24% and µσ = ±3.24%) when the RFNA replaced sand by 0.0–80%. Comparing Rc7 and Rc56, in mixes integrating RFNA (except M9), with that of mix M0 emphasized the low effect of the RFNA percentage on the Rc7 and Rc56 values. From all the above tests, owing to the concrete strength results, basaltic RFCA and RFNA could be considered good replacement materials for the fine NA used to produce sustainable concrete, integrating high RFCA and RFNA contents and reducing the environmental impact and concrete production costs.ectively . Compariectively . From thµ56 were 4.8–15.2%, 7.1–27.1%, and 5.7–12.5% when the OPC was partially replaced by RCA, AMF, and SF, respectively. The low values of µ28 and µ56 compared to µ7 ensured the late hydration of RCP, AMF, and SF. Moreover, mixes M6 (10% RCP), M16 (5% AMF), and M19 (5% SF) showed the lowest values of µ28 . Furthermore, mixes M6 (10% RCP), M17 (10% AMF) and M20 (10% SF) showed the lowest values of µ56 . At 28 days, the mixes integrating RCP, AMF, and SF exhibited about 99.3% (M6), 89.7% (M16), and 86.4% (M19) of that of M0, respectively. Consequently, at 56 days, the mixes integrating RCP, AMF, and SF exhibited about 95.2% (M6), 92.9% (M17), and 94.3% (M20) of that of M0, respectively. The previous findings demonstrated the pozzolanic effects of RCP, AMF, and SF.To produce green concrete, RCP, AMF, and SF were used to partially replace the OPC. The OPC was partially substituted by RCP, AMF, and SF at four percentages . From The effects of RCP, AMF, and SF on the achieved strength at 7 and 56 days, relative to that at 28 days, were calculated  for all concrete mixes. The tensile strengths at 28 and 56 days of curing  are reported in tµ,28, and at 56 days = tµ,56) due to the partial substitution of sand and cement with recycled materials is also presented in tµ56/28) on the diagonal concrete strength for all mixes was also calculated  and at 56 days  were also evaluated  at each curing time was determined using Equation (4):The cubic diagonal test was used to evaluate the concrete tensile strength  and ftu,age(M0) are the tuf values for the mixes containing recycled materials and the control mix, respectively. The RFCA and RFNA replaced the natural sand at five percentages . The cubic diagonal strength depended on the type and percentage of the recycled materials, as well as curing time . Moreover, at the same curing age, the mixes cast with RFCA and RFNA had higher diagonal strengths than M0, except for M5, M6, and M13 at 28 days . Addinggiven in ; similargiven in . In contto 22.6% ; it was For mixes integrating RFCA and RFNA, the diagonal tensile strength and compressive strength were slightly reduced, due to the pores in the ITZ. Conversely, in the mixes integrating basaltic RCP and AMF, the amount of cement was reduced; then, the compressive strength and tensile strength were initially reduced. The pozzolanic effect of the recycled materials may have enhanced the bond between the concrete particles and increased their tensile strength, while the voids existing in the recycled materials had a greater effect on decreasing the concrete’s strength. When the basaltic RCP and AMF partially replaced the cement, the amount of cement was reduced and the amount of C-S-H in the ITZ was reduced. Afterward, the C-S-H amount increased with time, and the ITZ densified with time. As the cement hydration was faster than that of the basaltic powders ,79, the 2 = 0.995). Consequently, at 56 days, the relationship between the tensile and compressive strengths was also linear , where y, x, and R are the compressive strength, the diagonal tensile strength, and the correlation between the tensile and compressive strengths, respectively. From the previous relationships, it was obvious that the diagonal cubic strength was linearly raised as the compressive strength was enhanced with the high correlation, depending on the replacement recycled materials.The relationship between the diagonal tensile strength and compressive strength of the tested cubes at 28 and 56 days is shown in To study the effects of RFCA, RFNA, RCP, AMF, and SF on the concrete durability, the WA for all mixes was found at 28 and 56 days . All mixThe SEM images of mixes incorporating 40% RFCA, 40% RFNA, 10% RCP, 10% AMF, and 10% SF were evaluated . The figThe EDS analyses of the RFCA, RFNA, RCP, AMF, and SF mixes are shown in Increasing the curing time (Tc) augmented the compressive and tensile strengths regardless of the concrete components. The concrete strength increased at a high rate until 28 days had passed, then the rate decreased afterward because the cement was highly hydrated during the first 28 days.The source, type, and content of the recycled fine basaltic aggregate and powders had a great effect on the concrete’s properties. Consequently, as RFCA replaced sand by 40%, the RFCA achieved about 99.5% of the M0 compressive strength at 56 days as RFCA may integrate more basaltic and cement powders than RFNA.As RCP, AMF, and SF were partially replaced with cement, the compressive strength was reduced by dissimilar percentages, depending on the additional amount of C-S-H gel produced in the mix. At 28 days, for the 10% RCP mix, the compressive strength was about 99.3% that of the M0 sample strength.The tensile strength greatly depended on the source, type, and percentage of the fine recycled aggregates and powders, apart from the curing ages. As the RFCA and RFNA replaced the sand, the tensile strength was augmented. Conversely, as the RCP, AMF, and SF replaced the cement, the tensile strength was enhanced.The WA diminished with the increased curing time or testing ages. The WA of the AMF mixes decreased as the RFNA percentage increased, while the RFCA mixes showed the opposite trend. Moreover, compared to M0, the mixes integrating RCP, AMF, and SF generally showed small WA differences. Furthermore, mixes integrating 10% and 20% SF experienced the lowest values of WA.The SEM analysis showed that the C-S-H did not completely cover the basalt particle surface for all mixes. The mixes integrating RFCA had the densest nature, in terms of the ITZ.2 and produce additional C-S-H gel.The RCP and AMF had the same potential pozzolanic reactivity as SF, but they retarded the hydration reaction. The basaltic RCP and AMF contents could consume Ca(OH)Comparing the magnesium, calcium, and silicate contents in the tested mixes showed that the 40% RFCA mixes diffused the highest contents of both calcium and silicate. The high calcium and silicate contents enhanced the ITZ and enhanced the concrete properties, compared to the other tested mixes.2 emissions that result from OPC production. Therefore, using recycled materials to replace both natural aggregate and cement is an effective way to lessen construction costs and their environmental impact.As the concrete properties obtained from both recycled and natural aggregates are nearly the same, the use of recycled aggregate to partially replace the natural ones reduces the extraction energy needed. Conversely, using concrete micro fines to partially replace OPC lessens the CO


Precast beam–column connections act as vital elements of precast concrete frames. To enhance the resistance to the earthquake-induced damage and environment-induced deterioration of precast beam–column connections, an innovative precast concrete beam-to-column connection locally enhanced by prefabricated ultra-high-performance concrete (UHPC) shells was proposed. For studying the seismic behaviors of these novel connections and the influence caused by the prefabricated UHPC shell length, full-scale precast specimens were experimentally investigated using low-cyclic reversed loading tests. The obtained results were analyzed and discussed, including hysteresis curves, skeleton curves, strength and deformability, performance degradation, energy dissipation capacities, and plastic hinge length. The results reveal that the novel precast concrete beam–column connections with UHPC shells behaved satisfactorily under seismic loadings. The damage in the concrete near the lower part of the beam end is reduced by the prefabricated UHPC shells. The longer prefabricated UHPC shells were more useful for decreasing the damage to the precast concrete components and improved the structural performance. The precast specimen with 600-mm long UHPC shells can achieve a ductility of 4.87 and 4.0% higher strength than the monolithic reference specimen. Buildings constructed with prefabricated concrete elements have been deemed a basic construction method since the invention of normal concrete and they remain increasingly popular in the construction industries of the current world. In China, as the construction industry expands and green development is being promoted, structures with prefabricated concrete components have become the necessary choice for new concrete buildings in many areas due to their inherent advantages, such as high production efficiency, short construction period, good quality, and low environmental pollution . SeismicIn precast concrete structures, the connections between different prefabricated elements are the inherent positions where the stiffness of components changes. Under earthquake attacks, the seismic loading-induced damage in precast concrete structures is prone to concentrate at the connection zones locally ,5,6,7, lBeginning development in the early 1960s, ultra-high-performance concrete (UHPC) is a new cementitious material generally consisting of high-content binder, fine aggregates, superplasticizers, and low water–binder ratio (0.2–0.3). Compared with conventional concrete, UHPC demonstrates ultra-high-performance, including strength , workability (>260 mm), superior durability, etc. . TherefoIn this investigation, an innovative beam-to-column connection in an emulative prefabricated concrete frame—which is locally reinforced by U-shaped prefabricated UHPC shells—was proposed to enhance the resistance to the earthquake-induced damage and environment-induced deterioration without increasing the construction costs and difficulties at sites. The UHPC shell is prefabricated at factories together with the precast concrete beams, the reinforcing rebars and construction process remain identical to that of conventional precast concrete structures that are familiar to contractors. An experimental study was conducted on full-scaled specimens to investigate the seismic behaviors of this innovative connection.Precast beam ends connected to columns of emulative precast concrete frames in China are usually designed to bear the so-called negative moments, putting the upper fiber of beam ends in tension and the bottom fiber in compression. Therefore, the ratio of the upper longitudinal reinforcing bars at the beam end becomes commonly higher than that of the lower rebars. When cyclic loadings induced by earthquakes occur, the lower concrete at the beam ends is often severely damaged, which is prone to become the controlling factor determining the overall seismic behaviors of the beam-to-column connection following the structural design philosophy of a “strong column–weak beam”. This is proved by numerous investigations ,8,11. SiIn this study, based on the widely used precast configurations, a prefabricated UHPC shell is added to make U-shaped hollow sections at the beam end in a manufacturing factory, strengthening the bottom portion at the precast concrete beam ends, as shown in A high-rise building comprised of precast frames and monolithic shear walls in China was selected as prototype structure, based on which the test specimens were designed. 3 [A local commercial company in Jiangsu, China offered the proprietary UHPC material used for these specimens. The raw materials for the UHPC consisted of reactive powder, sand, water, steel fibers, and admixtures, of which the proportions are listed in 3 . MoreoveNormal concrete of Grade C40 and reinforcements of Grade HRB400 were adopted to make the test specimens. The control cubes of two different sizes were cast to obtain the compressive strength of UHPC and normal concrete ,26, respTo simulate the deformation mode of an idealized frame in which the moment at the midspan of the column and the beams approached zero, the test setup illustrated in Based on the load-bearing conditions of the high-rise prototype structure, the vertical column axial load ratio remained equal to 0.22. As shown in As presented in By picking up the peak points in the hysteresis curves at different loading amplitudes, the actual skeleton curves were obtained, as shown in The strength and deformability are important indices to compare the seismic performance of the monolithic and precast specimens. The turning points of the skeleton curves were considered the yield points of the specimens, of which the corresponding moment and loading drift were adopted as the yield moment and yield drift. The critical strength of the three specimens is shown in Ductility was utilized to evaluate deformability, which was calculated by dividing the ultimate drift by the yield drift. The ultimate drift was gained as the corresponding loading drift when the applied load fell to 80% of the maximum load. As listed in i-th loading cycle at the j-drift loading level and i equals 2 or 3. The average values of the strength coefficients in the positive and negative directions are compared in Due to the accumulation of damage, the structural performance of the specimens deteriorates with increasing applied cyclic loadings. Strength and stiffness degradation are always utilized to evaluate seismic performance degradation. As defined in Equation (1), the coefficient of strength, employed for strength deterioration, is calculated as the result dividing the peak load in the second or third loading cycle at a certain loading level by the corresponding first peak load.374.1-05 .j-drift loading level, normk, was calculated as the ratio of the secant stiffness to the values corresponding to the 0.5% loading drift. The normalized stiffness curves are presented in Regarding the stiffness deterioration, the secant stiffness—defined in Equation (2)—of the first loading cycle at certain loading level is utilized to characterize the stiffness degradation of the specimens.eqζ) and cumulative dissipated energy. As the test specimens in this paper were manufactured at different times, the values of eqζ were calculated and utilized in this investigation, which equaled the result of dividing the dissipated energy in one hysteresis loop by the product of the dissipated energy in an equivalent linear system and a constant, 2π [eqζ values of the three specimens and the number of loading cycles. The variation characteristics of the presented curves of the three specimens were relatively close, showing a similar developing process of the energy dissipation capacity as the loading process. Except for the failure stage, the equivalent viscous damping ratio of Specimen S1, due to the better integrity, was marginally higher than those of Specimens PU1 and PU2, showing a relatively better capacity of energy dissipation. In the failure stage, the eqζ values of Specimens PU1 and PU2 became comparable with that of Specimen S1, and the total number of loading cycles was also larger than that of Specimen S1. This revealed that the prefabricated UHPC shells were able to increase the energy dissipation capacity of the precast specimens at the failure stage. The eqζ values of Specimen PU2 remained greater than those of Specimen PU1 in the main loading stage, indicating that the longer UHPC shell was more helpful for improving the energy dissipation capacity.As one of the most important indicators of seismic performance, the capacity of energy dissipation of structures or components is usually evaluated by two different indices, the equivalent viscous damping ratio . As summarized in For a reinforced concrete member, the plastic hinge not only affects the plastic deformation capacity but also influences the damaged regions of the member under reversed cyclic loadings. There are two concepts of plastic hinge length, of which one is that the length of a plastic hinge is an assumed value related to the calculation of a concrete member deformation. The other concept proposed by investigators is that the length of a plastic hinge is a real physical parameter related to concrete damage ,31, and (1)The precast concrete beam–column connections, locally reinforced by U-shaped UHPC shells, exhibited good seismic performance with comparable hysteresis behaviors that were close to the ones of the monolithic reference specimen.(2)The failure mode of the beam sideway mechanism was achieved by the novel connections; thus, the principle of a “strong column–weak beam” could be used to design the proposed connection.(3)In comparison with the monolithic reference specimen, the prefabricated UHPC shells could reduce the damage in the concrete near the lower parts of the beam ends. They could also enhance the seismic behaviors of the precast concrete specimens under large loading drifts and maintained better capacity of load-bearing and energy dissipation when the precast specimens approached failure.(4)The longer precast UHPC shell was more conducive to reducing the concrete damage of the precast specimens and improving the strength, ultimate deformation capacity, and capacity of energy dissipation. The precast specimen with 600-mm long UHPC shells can achieve a ductility of 4.87 and 4.0% higher strength than the monolithic reference specimen.An innovative beam-to-column connection in an emulative precast concrete frame was put forward, which was locally enhanced by U-shaped UHPC shells. The seismic behaviors of the innovative beam–column connections were studied by reversal cyclic loading tests on the cruciform full-sized specimens. Conclusions can be reached based on the experimental investigations, as follows:Note: The analysis and conclusions presented in this paper are restricted to the specimens designed according to the principle of “strong column–weak beam”.


A steel fiber-reinforced recycled concrete (SFRRC) is a porous material, and its macromechanical properties are affected by its microstructure. To elucidate the change rules and internal mechanisms of the mechanical properties of SFRRCs, the mechanical properties and failure modes of SFRRCs were studied at different water–cement ratio, replacement rate of recycled concrete aggregate (RCA), and steel fiber content. Moreover, the microstructures of the interface transition zones (ITZ) of the SFRRC specimens were tested by scanning electron microscopy and mercury intrusion, and the effect of the microscopic pore structure on the macromechanical properties of SFRRC was analyzed. The research results showed that an appropriate amount of steel fibers could reduce the size and number of cracks in the ITZ and improve the pore structure of an SFRRC. Based on the fractal dimension, porosity and other factors, the quantitative relationship between the macromechanical properties and microscopic pore structure parameters of SFRRCs was established. In urban construction, the demolition of old buildings produces a large amount of construction and demolition waste, which causes environmental pollution [Since the beginning of the 21st century, concrete has been the most important material basis for urban construction, and its demand has also been increasing. Currently, the annual output of concrete globally is approximately 4 billion mResearch results show that RCAs are damaged during the production process, which produces numerous microcracks inside them . SimultaIn engineering practice, commonly used fibers are steel fiber (SF) , polyproTherefore, the main purpose of this study is to explore the relationship between the macromechanical properties of SFRRC and the microscopic pore structure. This work tested the macromechanical properties and microstructure of nine sets of SFRRC specimens with different water–cement ratios, RCAs replacement rates, and SFs content. Finally, a modified formula for the calculation of the strength of SFRRCs based on natural concrete is proposed, and the reasons for the variation of macromechanical properties of SFRRCs from the perspective of microstructure were revealed, and a quantitative relationship between the strength of SFRRCs and microscopic pore structure parameters was proposed.The coarse aggregates (RCAs and NCAs) used in this study were purchased from Shaanxi Hong Wei Ecological Environmental Protection Technology Co., Ltd. , and the fine aggregates were natural river sand from Xi’an, Shaanxi Province. Among them, RCAs mainly come from the waste concrete blocks generated from the demolition of old buildings (20–30 years old) in Xi’an city, the strength of these concrete blocks is about C20 to C40, and the adhered mortar content of RCAs is in the range of 40–45%. The size ranges of the coarse and fine aggregates were 5–20 mm and 0–5 mm, respectively, and the particle dimension distributions of the aggregates are shown in lf) of the SFs is 38.0 mm, the equivalent diameter (df) is 0.6 mm, the aspect ratio (lf/df) is 63.3, and the tensile strength is 1000 MPa. The cementitious materials used in all the mixtures were cement (P.O42.5), whose physical and chemical properties are listed in The shear-cut type of the SFs used in this study, which are wavy overall, is shown in w/c), replacement rate of the RCAs (ar), and SF volume content (vsf) on the mechanical properties of SFRRCs were studied. To effectively analyze the influence of various factors on the mechanical properties of SFRRCs, orthogonal experiments were conducted, as summarized in 3 and 0.44, respectively. The mixture proportions for the SFRRC specimens are listed in In this research, the effects of the water–cement ratio , splitting tensile strength (fts), axial compressive strength (fc), and elastic modulus (Ec) of the SFRRCs. Their dimensions were 100 mm × 100 mm × 100 mm and 150 mm × 150 mm × 300 mm, respectively.For each mixture, six cubic and prismatic specimens were prepared for testing the cubic compressive strength .F is the ultimate load and A is the splitting surface area. Because the cube test block was a nonstandard test block, fts was multiplied by a conversion factor of 0.85 [A TYE-2000E machine was used for all tests, which is shown in  of 0.85 .F0) is applied, which is followed by a constant load for 60 s. Subsequently, a load equal to the stress of fc/3 load (aF) is applied, followed again by a constant load for 60 s to ensure that the deformation difference between the two sides is less than 20%. This loop is repeated thrice, following which the preloading ends. After unloading the load, the load is increased from 0 to F0, the deformation value, L0, is recorded; subsequently a load from F0 to aF is added, and the deformation value, aL, is recorded. Finally, the deformation measuring instrument is removed, and the specimen is loaded to failure. The difference between the failure load and the previously measured axial compressive strength should not exceed 20%. The elastic modulus is calculated using Equation (2).Ec is the elastic modulus, aF is taken as fc/3, F0 is taken as 0.5 MPa, A is the pressure-bearing area of the specimen, L is the test distance of the specimen, and aL and L0 are the average deformation values on the two sides when the loads are aF and F0, respectively.The specimen needs to be preloaded to ensure axial loading. First, loading from 0 to 0.5 MPa  is frequently used to analyze the microscopic pore structure of materials. A scanning electron microscope has a high resolution, magnification, and large depth of field, and it can analyze the characteristics of a material at the nanometer level. Thus, the microscopic morphologies of the SFRRC specimens were analyzed using scanning electron microscopy (SEM), and their pore structures were analyzed via MIP. In this research, the SEM experiments employed a Gemini SEM300 scanning electron microscope  with a resolution of 0.8 nm and an acceleration voltage of 30 KV. The MIP experiments were conducted using an American AutoPore IV 9500 , and the pressure range was 0.003–300 MPa. The test instruments are shown in Before the tests, the specimens are placed in a curing chamber for 28 days. The temperature and relative humidity of the curing chamber are, respectively, 20 ± 2 °C and not less than 95%.In the cubic compressive tests, a specimen without SFs undergoes compression deformation and transverse elongation deformation during compression. At the initial stages of loading, microcracks appear on the surface of the concrete and gradually develop into edges and corners. With an increase in the load, the rapid development of microcracks occurs, expanding both the concrete inside and the surface of the specimen, with the latter severely falling off. Finally, the concrete is crushed, and the failure mode exhibits a wedge shape on the surface of the specimen, which is understandably brittle failure. During the compressive failure process, cracks appear later in the specimens mixed with SFs than in the specimens without SFs. The cracks are significantly small in the early stages, and the microcracks gradually develop and become larger in the later stages, with reduced peeling of the surface of the test specimen. Until the end of the loading of a specimen with SFs, the specimen does not undergo wedge failure and maintains good integrity, showing remarkable plastic failure. A large amount of SFs implies fewer cracks, less shedding, and good integrity. It is found that the addition of SFs improves the failure mode of the concrete and transforms it from brittle failure to plastic failure. The failure modes in the axial compressive strength tests are basically the same as those in the cubic compressive strength tests. The typical failure modes in the cubic and prismatic axial compressive tests of the SFRRC specimens are shown in In the splitting tensile tests, a specimen without SFs starts to show microcracks along the shims as the load is first increased. When the ultimate splitting strength is reached, the cracks rapidly penetrate the bottom and top surfaces of the specimen, at which time the load drops sharply, and the specimen is split into two parts. The damage is heard with a notable ringing sound, which belongs to brittle failure. The failure surface of the specimen shows that the fracture occurs mainly at the intersection of the aggregates and the cement mortar, and the aggregates themselves are not pulled off. The failure mode of a specimen changes significantly after the addition of SFs. As the load is increased, the cracks on the surface of the concrete gradually increase, a part of the concrete begins to fall off, and cracks develop through the bottom and top surfaces. However, the specimen is not split into two parts owing to the connection of the SFs between the cracks. The SFRRC has good integrity, and its failure mode belongs to plastic failure. The results show that the admixture of SFs effectively inhibits the development of cracks. The SFs consumes a large part of the energy, and cracks are produced mainly on the surface of the specimen during the failure process and the concrete is not severely peeled off and broken, and these phenomena become more significant with the increase in the SF admixture. The typical failure modes of the SFRRC specimens in the splitting tensile tests are shown in fcu, fts, fc, and Ec of each group of specimens are obtained, as summarized in Loads are applied to the specimens by a pressure-testing machine, and the fcu and fc, with the ratio fluctuating at approximately 0.73, which is similar to that of natural concrete. The ratio of fts to fc significantly fluctuates, which is mainly due to the large influence of the SFs on the splitting tensile behavior of the concrete. fcu and fts are the main mechanical properties of concrete. The results in It can be found that there is a significant linear relationship between fcu decreases with the increase in w/c and ar, which is consistent with the research results of [fcu and fts of the SFRRCs only decreased by 6.38% and 1.06% when ar increased from 50% to 100%, so it is recommended that ar be increased to achieve more consumption of recycled aggregates in actual engineering. The SFs had a particularly significant influence on fts, when the SFs volume content is 1% and 2%, the fts increases by 28.66% and 49.51%. At the same time, the fcu increased by 5.55% and 2.45%, indicating that too much SFs dosing will instead reduce the fcu of SFRRC, after considering fcu simultaneously, it is recommended that the amount of SFs should not be extremely large. Since SFs have a significant impact on the mechanical properties of recycled concrete, the microstructure of SFRRC will be analyzed in detail in the follow-up, and the reasons for the change in macromechanical properties will be explained through the microstructure.It was found that sults of . The fcuEc) reflects the relationship between the stress and deformation of a material in elastic state, and it is a necessary parameter for calculating deformation in concrete structure design [fts, Ec, and fcu of concrete [fts and Ec are evaluated according to Chinese code GB50010-2010 [Tensile strength is an important property for reflecting the cracking resistance of concrete, and most scholars advocate the use of splitting tensile tests of cylinders or cubes to indirectly determine the tensile strength of concrete . Elastice design . The resconcrete ,30. In t010-2010  as folloSimilar formulas are available in the code, ACI318-14 , as exprfts, Ec, and fcu are drawn as scatter points in fts are larger than the standard calculated values, mainly because of the significant enhancement in fts caused by the SFs. In general, SFs enhance the Ec of concrete, whereas the RAC shows a suppressive effect, and a combined effect of the two factors in a test value of Ec is a large deviation from the standard calculated values. Therefore, the calculation formula for natural concrete is unsuitable for the SFRRCs.The calculation results of the above formula are compared with the test results of this study, and the connections between fts and Ec are still calculated from fcu. Considering the influence of different factors in the orthogonal tests on the fcu of the SFRRCs, multiple parameters need to be defined to predict fcu. Assuming that there are linear relationships between the fcu of SFRRCs and the water–cement ratio, replacement rate of the RCAs, and SF volume content, a calculation model for SFRRCs based on the following formula is proposed:ib (I = 1–4) are the regression coefficients of the compressive strength, w/c is the water–cement ratio, ar is the replacement rate of the RCAs, mλ is the product of the SF volume content and the aspect ratio of the SFs, ic (I = 1–4) are the regression coefficients of the splitting tensile strength, and id  are the regression coefficients of the elastic modulus.According to the formula in the standard, fcu, fts, and Ec of SFRRCs were established by regression analysis. As expected, fcu and fts is approximately 20%, the average error is approximately 5%, the maximum error of Ec is approximately 10%, and the average error is approximately 2%. Consequently, the modified formulas can be applied to predict the fcu, fts, and Ec of SFRRCs with satisfactory accuracy.The formulas for the Concrete is a composite material consisting of three parts: aggregates, mortar, and aggregate–mortar ITZ, where the ITZ is the weakest region in concrete and has a significant impact on the strength of concrete. From + > K+ > SO42− > Al3+ > Ca2+ > Si4+, and the first products to be formed in the water film are hexagonal-shaped calcium hydroxide (CH) and needle-shaped ettringite (AFt). Compared to the cement matrix, the water–cement ratio in the ITZ is higher, and its ion saturation is lower. Thus, CH and AFt can grow freely and oriented on the aggregate surface without restriction. This prevents the calcium silicate hydrate (CSH) gel from contacting the aggregates and increases the porosity close to the ITZ. As the ion concentration in the ITZ decreases, the amount of the CSH gel is reduced, which eventually leads to the formation of a loose network structure in the ITZ. Therefore, the weakest position in the ITZ of the aggregates is that close to the surface of the aggregates. Similarly, the mechanical properties of an SFRRC also strongly depend on the microstructure of the ITZ, i.e., the area where the SFs are in contact with the cement matrix. Results of the SEM with energy-dispersive X-ray analysis (SEM-EDXA) for an SF-cement matrix-based ITZ are shown in For the aggregate ITZ, when cement is dissolved in water, the dissolved ions diffuse and enter the water film. The active order of ions is Na2+ ions first decreases and subsequently increases. At 25–35 µm from the surfaces of the SFs, the Fe2+ ion concentration is close to the lowest value. After 40 µm, the Fe2+ ion concentration begins to level off, and at 100 µm, it is the inherent Fe2+ ion concentration of the cement itself. The results show that a part of the Fe2+ ions can be dissolved from the surfaces of the SFs, which is different from an ordinary aggregate interface. This part of the Fe2+ ions enters the water film, and the superposition of the ions dissolved in the cement and the ions dissolved from the SFs makes the concentration of ions in the interface higher than that in the ordinary aggregate interface. Fe2+ ions can reduce some of the adverse effects of the water film, and more CSH is formed close to the SFs. This increases the probability of the CSH contacting the SFs and causes it to fill the porous structure close to the surface of the SFs, therefore enhancing the compactness of the structure. The Fe2+ ion concentration is lower in the A area slightly further from the fiber surface, and the needle-shaped AFt and hexagonal-shaped CH mainly accumulated in the area. Owing to the influence of solid particle shape, the sparse accumulation of particles around the side wall produces numerous pores, resulting in the formation of a loose structure in the ITZ around the aggregates, which can be considered to be a weaker area in the SF–matrix. However, excessive SFs can have a detrimental effect on the concrete, which requires a more detailed analysis of the microscopic pore structure parameters.It can be seen that, as the distance from the surfaces of the SFs increases, the concentration of FeThe microscopic pore structures of the SFRRCs were determined using the MIP method, and the pore structure parameters of each specimen are listed in fcu of an SFRRC mainly depends on the compactness of its matrix, and the fts of an SFRRC mainly depends on the bonding strength of the SF–matrix interface. The SFs can bond with the matrix well and have the effect of strengthening and toughening the concrete; therefore, the fts of the concrete is significantly improved with the increase in the SFs. However, excessive addition of the SFs adversely affects the pore structure of the concrete, resulting in a decrease in fcu.From R is equally divided into m parts, following which m3-small cube elements are obtained and n small cube elements are randomly eliminated. After k times, the number of remaining cubes is (m3 − n)k and the side length of the smallest cube unit is kr = R/km. The fractal dimension, Dm, of the sponge model is calculated using the box-counting method, as expressed below:The static pore structure of concrete as a porous medium is generally analyzed using the Menger sponge model, and this method has been recognized by many researchers . As showVs, of the sponge model has a power relationship with the length, rk, of the smallest cube elements, and their derivatives can be obtained as follows:According to the fractal theory, the remaining cube volume, The remaining cube volume of the sponge model is:pV, is:The pore volume of the remaining cube, Based on Equations (12) and (13), the following formula is obtained:pdV/kdr and kr have a linear relationship, and the fractal dimension, mD, can be obtained by fitting of the curve, and the result is shown in It can be seen from Equation (14) that the logarithm of −It can be seen from fcu and fts are the most basic mechanical indicators of the macroscopic properties of concrete, and the magnitude of the strength is closely related to the microscopic pore structure. Research results show that the mechanical strength of concrete is related to its porosity [porosity , pore sif is the SFRRC strength, ie (I = 1–8) are the regression coefficients of strength, mD is the fractal dimension, mλ is the product of the SF volume content and the aspect ratio of the SFs, and ar is the replacement rate of the RCAs.It can be found that the fitting between the concrete strength and the porosity or the fractal dimension needs to be improved. To obtain a higher precision calculation model, it is necessary to consider the effects of both the porosity and fractal dimension, and the influence coefficients of the SF volume content and the replacement rate of the RCAs should be added. Based on the above analysis results, a calculation model of SFRRC strength based on the following formula is proposed:fcu and fts are calculated as shown in fcu and fts are 0.89 and 0.97, respectively. Moreover, the maximum errors of the compressive strength and splitting tensile strength do not exceed 10% and 5%, respectively, indicating that the regression effect is significant. Therefore, the calculation model results are in good agreement with the experimental results and can accurately describe the quantitative relationships between the macromechanical properties of SFRRCs and the microscopic pore structure parameters.Based on Equation (15), the relationships between the concrete strength and the pore structure parameters, SF volume content, and RCA ratio were obtained by multiple regression analysis, and The SFs can inhibit the development of SFRRC cracks, increase the strength and ductility of the SFRRC, and significantly improve the failure mode of the SFRRC, changing it from brittle failure to plastic failure.fts of the SFRRCs increase significantly. When the SFs volume content is 1% and 2%, the fts increases by 28.66% and 49.51%. At the same time, the fcu increased by 5.55% and 2.45%, indicating that too much SFs dosing will instead reduce the fcu of SFRRC, which is related to the microscopic pore structure of SFRRCs.With the increase in the SF volume content, the The formula for calculating concrete strength in the code is not applicable to SFRRCs. By a multifactor analysis, a mechanical calculation model for SFRRCs is obtained using Equations (7)–(9), and the calculation and test results have a high degree of fit.2+ ions dissolved on the surface of the SFs can improve the structure of the ITZ and increase the bonding strength of the interface. The weak region of the SF–matrix ITZ is approximately 25–35 µm from the SF surfaces, which is related to the concentration of Fe2+ ions.The FeWhen the SF volume content is 1%, the total porosity and average pore diameter of the SFRRCs are 18.33% and 51.42% lower than those of the specimens without SFs. Compared to the SFRRC with 1% SF volume content, the total porosity and pore size of SFRRCs increased by 17.41% and 78.64%, respectively, when the SF content was 2%. This phenomenon is because adding the appropriate amount of SFs reduces the size and number of cracks in the ITZ and makes the pore structure distributions of the SFRRCs more reasonable. An excessive amount of SFs causes an uneven distribution of the pore structure, increasing the total pore space and the pore size, therefore reducing the compressive strength of the SFRRCs.It is inaccurate to use the porosity or the fractal dimension alone to calculate the strength of an SFRRC. The regression of a multifactor strength calculation model using the fractal dimension, porosity, SF volume content, and RCA replacement rate is significant, and the model can accurately describe the quantitative relationships between the strength of the SFRRCs and the pore structure parameters.This study investigated the mechanical properties of SFRRCs with different water–cement ratios, RCA replacement rates, and SF volume contents by orthogonal tests. Combined with an SFRRC microstructure analysis, the following conclusions were drawn:


URIs are the most common indication for outpatient antibiotic prescribing. Given high rates of unnecessary prescribing, these indications have been identified as a high-priority target for outpatient antimicrobial stewardship programs (ASP). Our primary objective was to evaluate the impact of a system-wide, multifaceted, outpatient ASP intervention bundle on unnecessary antibiotic prescribing for URI.This quasi-experimental study was conducted from 2019 to 2021. ICD-10 codes for URIs were grouped into 3 tiers . Encounters from 5 care specialties  with a tier III URI primary ICD-10 code but without a secondary tier I or tier II code were included. COVID-19 ICD-10 codes were excluded. Interventions included construction of a prescribing data model, dissemination of clinician prescribing data and education, promotion of symptom management strategies, a patient-facing commitment poster, and a pre-populated URI order panel. Tools were designed at a system level and implemented by regional champions beginning in the 3rd quarter of 2020. The primary outcome was the rate of antibiotic prescribing, and the secondary outcome and counterbalance measure was the rate of repeat URI-related healthcare contact within 14 days. Outcomes were analyzed with chi-square with an α level of 0.05.A total of 147403 encounters were included. The overall antibiotic prescribing rate decreased from 24.1% to 12.3% between 2019 and 2021 (p< 0.01). Significant reductions in tier III antibiotic prescribing were demonstrated for each region, care specialty, and syndrome evaluated (Table 1). A reduction in repeat healthcare contact was seen across the total cohort ; decreases in repeat contact rates were observed in those not initially receiving an antibiotic , but not in those who initially received an antibiotic .Tier III URI encounter level antimicrobial prescribing rates by region, care specialty, and syndromeA multifaceted, outpatient ASP intervention bundle decreased rates of unnecessary antimicrobial prescribing without increasing rates of 14-day repeat URI-related healthcare contact.Paschalis Vergidis, MD, AbbVie: DSMB|Cidara: Grant/Research Support|Scynexis: Grant/Research Support Evan Draper, PharmD, Gilead Foundation: Grant/Research Support Sara Ausman, PharmD, Gilead: Honoraria Christina G. Rivera, PharmD, Gilead: Grant/Research Support|Gilead: Honoraria|Insmed: Honoraria.


Research has demonstrated that antibiotic prescribing and use are social processes. Despite the availability of guidelines and policies for optimized use, many challenges remain. Whilst much of the research in antimicrobial resistance is focused on new drugs, the socio-cultural and socio-economic drivers for infections and antibiotic use are also important considerations. Context-specific solutions that are co-developed with end users are needed if we are to optimize the use of existing and new antibiotics. The threat of antimicrobial resistance is not subject to geographical boundaries, and to truly be effective, interventions need to have the potential to be scaled to different settings. The inequities in funding, knowledge generation, ownership and transfer between the global North and South must be acknowledged and eradicated. Striking a balance in funding and equity requires in-country capacity building for: (i) delivering sustainable research; (ii) assuring equitable representation in research outputs; and (iii) supporting career progression of researchers through further funding, to support the generation of locally owned knowledge that contributes to optimized healthcare systems and translation into clinical practice. Antibiotic prescribing and use are complex processes under the influence of socio-economic and socio-cultural drivers. Human beings have a dynamic and evolving relationship with antibiotics at the biological and sociological level. Biologically, the emergence of antibiotic resistance is potentiated by exposure to antibiotics, through their consumption by humans and animals, and through the environment . In the last 30 years, there have been increasing efforts to optimize antibiotic use in human populations and also, as part of a One Health approach, in farming, fisheries, agriculture and the environment. Following WHO guidelines, every country is encouraged to have a National Action Plan that identifies specific objectives for optimizing antibiotic use in humans, and across a One Health agenda. These efforts are supported by a growing body of evidence indicating where gains have been made and where further work is needed. Despite these efforts, suboptimal antibiotic use remains a major concern.Discovered in 1928 and mass-produced during the Second World War, antibiotics were touted as wonder drugs that were going to cure heretofore incurable and deadly diseases. Though resistance to them developed very rapidly, the original aura of these ‘wonder drugs’ has not been tarnished in the collective psyche. The overreliance on and false confidence in antibiotics to always save the day remains. Despite the growing evidence and the efforts of scientists, clinicians, and campaigners, the overarching sentiment is that there will be more antibiotics developed and the risk of using existing antibiotics to treat the present patient is lower than any future harm associated with their use. This is a fallacy, as the antibiotic pipeline is not as free-flowing as anticipated, with little incentive for big pharma to invest in antibiotic drug discovery and development. Despite this, the call for more research and development of new drugs is the loudest voice in the antibiotic resistance research field, with much of the initial drug discovery research conducted using public funding through research grants. Though a necessary investment, this alone will not solve the problem of antibiotic resistance. Unless we understand the sociocultural and behavioural drivers for antibiotic use and develop contextually fit, equitable and sustainable strategies to address them, no amount of new antibiotics will cut the tide of emerging antibiotic resistance and its spread through populations.Human beings operate within social norms and rules that moderate behaviours. Healthcare is a microcosm of human cultures and behaviours, complete with its own tribes, social norms, and microcultures. Research has demonstrated that hierarchies exist within healthcare across professional divides, specialism, and levels of seniority, and they influence antibiotic use and prescribing, despite evidence-based recommendations. One of the failures of our work to date has been to not recognize this when developing strategies to influence antibiotic-prescribing practices. Successful strategies will only work if we understand who the opinion leaders are within specialities, professions, and organizations. Furthermore, we need to understand that clinicians like to practice autonomously and value their own expertise and experience and that of colleagues they consider to be their peers. To influence behaviours, diplomacy is as critical as having a robust evidence base to support one’s arguments. We need to co-develop strategies with peers from the specialities, organizations and professions whose antibiotic-prescribing behaviours we want to change and or optimize. We need to understand the language of risk that will resonate with the target audience. It may not always be sufficient (or even appropriate) to talk about the threat of antibiotic resistance, which is a negative message. First, we must identify what risks and outcomes matter to our colleagues and how the threat of antibiotic resistance would influence these risks and outcomes. That is where the conversation about antibiotic resistance should always start.When developing solutions to tackle antibiotic resistance, we often overlook the contextual needs, behavioural drivers, and the stakeholders who need to be involved. This is critical, particularly in collaborations between high-income countries (HICs) and low- and middle-income countries (LMICs). The threat of antibiotic resistance is greatest where there are fewest resources. Solutions invented with research funding in HICs cannot be ‘airlifted’ and applied in LMICs. What is needed is a thorough and thoughtful consideration of the resource limitations and needs in each setting. This means fostering more-equitable research partnerships between HICs and LMICs, built on mutual trust and respect, to enable bilateral learning and knowledge exchange. Infectious disease and antibiotic resistance do not recognize or respect cultural or geographic boundaries. To truly have a chance of stemming the tide of antibiotic resistance, we also need to break through the cultural and geographic boundaries that are influencing the flow of resources and knowledge between the global North and the global South.Internationally, policymakers, funders and organizations with a stake in global health need to develop expectations and targets for change that reflect the resource limitations of different countries. Funders need to identify strategies for more equitable distribution of research money between HICs and LMICs – currently, over 70% of global health research funding remains in HICs. This requires a shift not only in platitudes and pledging to greater diversity and equity reports, but a seismic change in how we fund research. Equity in funding means giving more resources to LMICs to be able to match what is available in HICs. Achieving the needed balance in funding and equity is dependent on building capacity and supporting in-country researchers to: (i) deliver sustainable research; (ii) have equitable representation in research outputs; (iii) track follow-on career progression through further funding, setting up research teams and emerging leaders. These are measurable targets, which funders can build into a framework for evaluating equity. The above indicators can facilitate the development of a framework for equitable partnerships in global health and antibiotic resistance research. Furthermore, we as clinicians, researchers, and advocates in global health and antibiotic research should advocate for funders to commit to investing at least 50% of all publicly funded research over the next 5 years to equitable research partnerships. To champion this approach there needs to be greater representation of global South scientists, experts, and researchers in (i) identifying research priorities and gaps in global health and (ii) co-developing and leading funding calls and panels. This is where every one of us has a role to play, by speaking up for those not currently represented and making room for them by sharing our platform.


MET (MET protocol oncogene) play a significant role in the development of resistance to targeted drugs in advanced non-small cell lung cancer (NSCLC). In this review, we aim to clarify the biological mechanisms of MET amplification-mediated resistance to tyrosine kinase inhibitors, discuss the challenges of commonly used assays for the identification of MET amplifications. We also summarize the latest findings on combined strategies to overcome acquired MET amplification-mediated resistance, especially the combinatory regimens with EGFR-TKIs and MET-TKIs.Secondary amplifications/copy number changes of the gene MET amplification has been proven to be a driver of resistance to tyrosine kinase inhibitor (TKI)-treated advanced NSCLC with its activation of EGFR, ALK, RET, and ROS-1 alterations. The combined therapy of MET-TKIs and EGFR-TKIs has shown outstanding clinical efficacy in EGFR-mutated NSCLC with secondary MET amplification-mediated resistance in a series of clinical trials. In this review, we aimed to clarify the underlying mechanisms of MET amplification-mediated resistance to tyrosine kinase inhibitors, discuss the ways and challenges in the detection and diagnosis of MET amplifications in patients with metastatic NSCLC, and summarize the recently published clinical data as well as ongoing trials of new combination strategies to overcome MET amplification-mediated TKI resistance.Targeted therapy has emerged as an important pillar for the standard of care in oncogene-driven non-small cell lung cancer (NSCLC), which significantly improved outcomes of patients whose tumors harbor oncogenic driver mutations. However, tumors eventually develop resistance to targeted drugs, and mechanisms of resistance can be diverse.  EGFR, KRAS, and BRAF mutations; ALK, RET, and ROS1 gene rearrangements; MET alterations including MET exon 14 skipping mutations and MET amplifications; ERBB2 (HER2) mutations; and NTRK 1/2/3 gene fusions , with duration of response not reached   .MET alterations, are summarized in Other studies investigating the clinical evidence of dual inhibition of EGFR and MET with small molecule inhibitors or monoclonal antibodies, such as capmatinib plus geftinib, telisotuzumab plus erlotinib, savolitinib plus geftinib, onartuzumab plus erlotinib, capmatinib plus erlotinib, and emibetuzumab plus erlotinib within patients with NSCLC with EGFR-mutant and MET amplification functions as a mechanism of resistance to targeted therapies in NSCLC, and now has been proven to be a pharmaceutical target to overcome this resistance. Although evidence was most abundant and convincing for MET amplification mediated resistance to EGFR TKIs, its role in mediating resistance to other targeted therapies, such as ALK, ROS1, or RET TKIs, is being recognized. Case reports and case series have indicated that dual inhibition of MET and the initial oncogene driver pathway may be a valid clinical approach to overcome resistance. With MET amplification serving as a general resistance mechanism to targeted therapies in lung cancer, it is crucial to be able to detect MET amplification in a reliable manner, in order to identify the appropriate patients who can benefit from MET-targeting therapy.Acquired MET amplification or MET overexpression could be detected by multiple clinical pathology laboratory tests, including FISH, NGS, and IHC. However, clinically meaningful cut-offs need to be standardized for continuous variables, including the copy number gain of MET amplification and MET overexpression. As clinical diagnostic methods migrate towards more comprehensive and technically sophisticated NGS assays, further understanding of NGS assays for the detection of MET amplification is needed, both in tumors and plasma, and ideally both in DNA and RNA. The effective detection of MET-dependent cancers is critical, given that MET-directed targeted therapy is active in many of these cancers. Importantly, the level of activity of MET-targeted therapies is associated with the degree of oncogenic addiction to MET pathway signaling.MET amplification-mediated acquired resistance to TKIs, combination therapies to inhibit both MET and the primary driver oncogene are necessary. EGFR-MET TKI combination therapy has shown promising clinical efficacy in this setting. While awaiting the maturation of the large clinical trial results and regulatory approval of this approach, further studies are necessary that aim to standardize the MET amplification detection assay and the cut-off values.To overcome


Pseudomonas aeruginosa (PA) is an opportunistic human pathogen, which is involved in a wide range of dangerous infections. It develops alarming resistances toward antibiotic treatment. Therefore, alternative strategies, which suppress pathogenicity or synergize with antibiotic treatments are in great need to combat these infections more effectively. One promising approach is to disarm the bacteria by interfering with their quorum sensing (QS) system, which regulates the release of various virulence factors as well as biofilm formation. Herein, this work reports the rational design, optimization, and in‐depth profiling of a new class of Pseudomonas quinolone signaling receptor (PqsR) inverse agonists. The resulting frontrunner compound features a pyrimidine‐based scaffold, high in vitro and in vivo efficacy, favorable pharmacokinetics as well as clean safety pharmacology characteristics, which provide the basis for potential pulmonary as well as systemic routes of administration. An X‐ray crystal structure in complex with PqsR facilitated further structure‐guided lead optimization. The compound demonstrates potent pyocyanin suppression, synergizes with aminoglycoside antibiotic tobramycin against PA biofilms, and is active against a panel of clinical isolates from bronchiectasis patients. Importantly, this in vitro effect translated into in vivo efficacy in a neutropenic thigh infection model in mice providing a proof‐of‐principle for adjunctive treatment scenarios. Pseudomonas aeruginosa lung infections. The described quorum sensing inhibitor (QSI) acts with high anti‐virulence efficacy, favorable DMPK, and no overt safety pharmacology. Notably, this compound synergizes with antibiotic tobramycin in vitro and in vivo providing a compelling in vivo proof‐of‐concept.This work presents a drug discovery campaign from an optimized hit until a potential candidate compound for adjunctive treatment of chronic  It is well‐known that the bacteriostatic or bactericidal action of antibiotics intrinsically leads to development of resistance resulting in the emergence of multi‐ or even pan‐resistant PA strains. In order to cope with this problem, there is a pressing need for new nontraditional and innovative therapy options beside the continuous search for “traditional” antibiotics. Also enhancing or rescuing the efficacy of antibiotics in clinical use is of interest, helping to circumvent or reduce resistance. One strategy, which could help to tackle PA infections via new modes‐of‐action while synergizing with antibiotics, is the so‐called pathoblocker approach, which aims to disrupt the virulence of the bacteria without killing them. Working either as stand‐alone anti‐infective agents or via adjunctive treatment together with a backbone antibiotic, this strategy would also help to decrease the development of resistance. To be more precise, the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the clinical response to standard‐of‐care (SoC) aminoglycosides in patients is typically characterized by the ratio of exposure  to in vitro efficacy . Hence, boosting the antibacterial effect through potentiating agents has the potential to improve an efficient clinical response. In chronic infections, PA forms hard‐to‐eradicate biofilms, tremendously impairing antibiotic efficacy. Here, instead of the MIC value, which is measured against planktonic bacteria, the minimal biofilm‐eradicating concentration (MBEC) should rather be considered as a critical efficacy parameter. In short, enhancing the antibiotic‐mediated biofilm eradication should directly improve clinical response and, hence, most likely reduce the risk of resistance development.Figure A promising target for QS inhibitors (QSI) in PA is Pseudomonas quinolone signaling receptor (PqsR), also called multiple virulence factor regulator (MvfR). PqsR is a transcriptional regulator that controls the Pseudomonas quinolone signaling (PQS) system and is considered as one of the master regulators of PA virulence. We and others have demonstrated the utility of PqsR as an attractive antivirulence target.Our strategy to disrupt bacterial virulence is based on the interfere with quorum sensing (QS)—a cell‐to‐cell communication system, which coordinates the release of the various virulence factors and co‐regulates biofilm formation Figure1.—more info in the manuscript.Supporting InformationClick here for additional data file.