Due to the strong interface effect of continuous steel–concrete composite beams with conventional shear connectors, the efficiency of applying pre-stress in the negative moment zone is greatly reduced, which leads to a difficulty of anti-cracking design in the negative moment zone of pre-stressed steel–concrete composite box girder. In order to study the feasibility and the working mechanism of improving the crack resistance of continuous steel–concrete composite bridges by releasing the interfacial slip effect within the negative bending moment region, two groups of model tests were carried out in the paper. Two steel–concrete composite beams were used for model test, one of them using the conventional stud shear connectors, another one using the new shear connectors, named uplift-restricted and slip-permitted shear connectors. The results show that, compared with the composite beam with conventional shear studs, the composite beams with uplift-restricted and slip-permitted shear connectors have a higher pre-stress application efficiency, and the new connector could release the interface slip, which can make the tensile stress distribution in concrete slab more uniform within the negative moment zone, thus increasing the cracking load of concrete slab and reducing the subsequent crack width effectively. This study is helpful to understand the relationship between the interface slip and the anti-crack characteristics in negative moment zones, and a new anti-crack design method is proposed for the design of continuous composite girder. The steel–concrete continuous composite girders have many obvious structural advantages over the simply supported composite beams, but they are confronted with the design problem of anti-cracking of concrete bridge deck in negative moment zones. Because the concrete bridge deck is under the tensile state, it is easy to crack. Furthermore, the rainwater may infiltrate into concrete to corrode the shear connectors; thus, the durability of the composite structure is reduced.Previous research showed that there are two kinds of crack-resisting design methods for steel–concrete composite continuous beams, especially focusing on the hogging bending moment zone. One is to allow for the cracking of concrete bridge decks, but the crack width could be limited, based on the numerical simulation to the crack development process ,2, such At present, there are two conventional types of shear connectors, named the stud connector and perfobond strip connector, that are widely used in simply supported steel–concrete composite girders . BecauseThere are many literatures showing that the interfacial slip is not conducive to the mechanical performance of the simply supported composite structure, which will lead to the reduction of the structure stiffness, the increase of deformation, and the reduction of the structure bearing capacity ,15,16,17It is well-known that the combination of the steel portion at the bottom layer and concrete slab at the upper layer can be said to perfectly meet the structural stress requirements, giving full play to the respective characteristics of the two types of materials in the positive bending moment region of continuous composite girders. However, the concrete slab in the region of negative bending moment is under tensile mechanical states, and a high level of anti-crack resistance becomes a key issue for the design of a continuous composite girder. Therefore, the focus of structural design in the negative moment zone is obviously different from that in the positive moment zone, and there should be different design concepts, so as to effectively solve the problem that the concrete slab in the negative moment zone is easy to crack.Based on the above preliminary understanding to the combination of steel and concrete, the authors of the paper consider that, since the shear action of the shear connectors leads to the transferring of prestress from the concrete bridge deck to the steel portion, then the available effective way to improve the efficiency of prestressing is to produce enough interface slip, rather than limit it. The method mentioned above may be an effective method to enhance the crack resistance of concrete slab in the region of the negative bending moment.The effective way to reduce tensile stress in concrete is to release the shearing force between the steel and concrete, instead of restricting it. However, there is little literature on enhancing the crack resistance of bridge deck in the region of negative bending moment by reducing interfacial shear action. A flexible shear member for a composite girder bridge was proposed by Abe and Hosaka  Figure a, hereinIn order to further eliminate the adverse effect of shear connectors mentioned above, a new novel shear connector was put forward by covering foam material not only on both sides of the shear element but also on the flange plate at the top of the shear element, so as to increase the sliding deformation between the shear element and concrete thoroughly ,10,26. TThe feasibility of the new connectors to improve the crack resistance in the region of a negative moment has been confirmed by the existing experimental studies ,19,29,30Based on the model test of two steel–concrete composite box girders with vertical webs, the stress characteristics near the middle support of continuous girder are simulated, including one ordinary experimental beam with stud connectors  and another experimental beam with URSP connectors .Specimen SRB and specimen SPB have the same dimensions and structure frames, but some differences in connectors. The shear connectors of two test specimens were different, and the detail sizes of them are shown in The size detail of the model test beam is referred to in the relevant literature , and theBased on the structural design mentioned above, the concrete slab of composite girder is equipped with unbonded prestressed steel bars, the cross-section of concrete slab has a width of 550 mm and a height of 100 mm. The top and bottom concrete slabs are, respectively, equipped with eight ordinary steel bars along the longitudinal direction, each steel bar has a diameter of 8 mm, and with a number of ordinary steel bars along the transverse direction, each has a diameter of 6 mm. In addition to the ordinary steel bars mentioned above, the upper concrete slab is also equipped with a stirrup with a diameter of 6 mm and with a longitudinal spacing of 10 cm. The concrete slab has a reinforcement ratio of 1.462% along the longitudinal direction. In addition to ordinary reinforcement, the upper concrete slab is also equipped with prestressed reinforcement, 14 N·mm2 at the intermediate support section, while the bending stiffness EI of the upper concrete slab is 1.58 × 1012 N·mm2. The flexural stiffness ratio of steel portion-to-upper concrete slab is 90.60.Based on the above structure states, it can be calculated that the bending stiffness EI of the steel portion (including bottom concrete contribution) is 1.43 × 10The difference between the two experimental beams lies in the different forms of shear connectors. In the specimen SRB, the stud connectors with a diameter of 16 mm are welded on the upper flange plate of the steel portion, with a spacing of 10 cm, but encrypted at both ends, as shown in In the specimen SPB, the EVA (Ethylene-vinyl acetate) foam is wrapped around the traditional studs, which are welded on the upper flange of the steel portion to form an uplift-restricted and slip-permitted connector (named URSP connectors) , as showThe material performance is listed in The loading devices of two specimens SRB are shown in The loading process was divided into two loading conditions, as follows.(1)Tensioning prestress bars of the upper concrete slabThe two experimental beams were placed on the temporary supports, the prestressed reinforcements were pretensioned before loading, and the perforated pressure sensors were used to monitor the preload value. After the completion of prestress tensioning, the effective preload obtained through monitoring was 150 kN. At the same time, the structural strains of test beam and the interface slip of key sections along the longitudinal direction were all measured.(2)Loading upward in the mid-span section of test beamAfter the prestress was applied, an upward load was exerted by a jack, and the two ends of the experimental specimens were restrained by the roller support. In order to test the applicability of the test system, the specimen was preloaded to about 60 kN. Step loading was adopted during the loading processing. The loading value of each step of the jack was 20 kN, which was stopped when the loading value reached 980 kN. After 5–10 min, when the loading value was unchanged, the value of load, load deformation, the interface slip, structural strain, and tension of the prestressed steel bar was recorded for each step.The arrangements of strain gauges and displacement gauges of each specimen are consistent, and the strain gauges position is shown in Three dial gauges for displacement meters were employed in three key sections to measure the relative interface slip. The specific layout and fixing method are shown in (1)Specimen SRBThe specimen behaved in an elastic state at the beginning of loading. When the load reached 300 kN, applied by the jack, some short cracks occurred in the upper slab near the mid-span section of the test beam. When the load was up to 420 kN, a long main fracture appeared near the mid-span section of the test beam. When the load reached 490 kN, the main fracture crossed through the section of concrete slab and the crack width reached 0.1 mm. With the increase of load, there were more and more cracks near the mid-span section of the test beam. At last, eight main concrete cracks occurred, as shown in (2)Specimen SPBAt the beginning stage of loading, the specimen SPB behaves well in an elastic state. When the load reached 620 kN, some short concrete cracks occurred near the mid-span section of test beam. When the loading value reached 800 kN, the previous short crack developed slightly. With the increase of load, a number of short cracks appeared again in the concrete slab. The maximum value of crack width was up to 0.02 mm, when the loading up to 900 to kN. When the load reached 980 kN, the density of short cracks increased, distributed within a wide length range of 1800 mm, and the maximum value of crack width for most concrete cracks was 0.02 mm. As shown in (3)Comparison of crack property on two experimental beamsThe crack property of the concrete slab of the experimental beams is shown in In light of The initial cracking load of specimen SPB was 107% higher than that of specimen SRB, indicating that the interface slip effect between steel and concrete of specimen SPB was more pronounced, due to the use of URSP connectors, which improves crack resistance.SPB specimens had a slower fracture follow-up rate than SRB specimens. When the loading value of specimen SRB reached 490 kN, the first main fracture ran through the concrete slab, and a total of 8 main fractures were generated, with a maximum fracture width of 0.2 mm. However, as a result of loading, specimen SPB did not show any obvious main cracks and had a maximum crack width of 0.02 mm. This indicates that the interface slip effect can slow down the crack development speed of concrete slab and effectively reduce the crack width under the same loading conditions.In terms of fracture distribution, specimen SPB had a wider fracture distribution range. It indicates that the tensile stress distribution of specimen SPB is more uniform than that of specimen SRB.(1)Comparative analysis of stiffnessThe mid-span section with the most obvious deflection variation was selected as the observation point to analyze the influence of structural stiffness on structural deformation, so as to reflect the stiffness differences between the two types of experimental beams.According to (2)Comparative analysis of interface slipThe setting of three measuring points of interface slip in the negative moment zone is shown in After prestressing, each measuring point’s slip value was set as the initial slip value. The slip value of specimen SRB with the traditional connector was small, and with the loading increases, the relative slip of the measuring point 1 also occurred in the opposite direction. It shows that the direction of the relative displacement between the concrete and steel turned to the right, instead of to the left, when the concrete cracked at the mid-span section.The uplift-restricted and slip-permitted connectors were used in specimen SPB, and the initial slip value and subsequent slip value were larger, which achieved the design purpose of “uplift-restricted and slip-permitted connecting” by new shear connectors. The slip value of measuring point 1 at the mid-span section was always small, and the initial slip value of measuring point 2 was less than that of measuring point 3. However, the slip value of measuring point 2 increased faster during the loading process. After the loading value reached 780 kN, the slip value of measuring point 2 slightly exceeded that of measuring point 3. Because both ends of the experimental beam were constrained by two roller supports, a large normal stress was generated between the steel–concrete interface, which increased the sliding friction at both ends of the experimental beam. Therefore, in the late loading stage, the interface slip value of measuring point 3 was slightly lower than that of measuring point 2, due to the effect of interface friction. However, in general, except for the mid-span section, the mechanical effect of interfacial slip in other regions was still obvious.(3)Comparative analysis of prestress efficiencyThe experimental beam was configured with strain gauges in seven cross-sections. The specific arrangements of strain gauges are shown in As can be seen from As can be seen from According to the strain monitoring data corresponding to the SPB beam in The results indicate that the SPB beam had significant interface slip, resulting in almost no prestress transferring to the upper flange of the steel beam, so that most prestress was borne by the concrete slab. The prestress efficiency of the specimen SPB was significantly improved, and the crack resistance of the concrete slab of the composite girder was also improved. The mechanical properties mentioned above are consistent with the design objective of applying prestress, and it is evident that increasing the interface slip improves the crack resistance of concrete slab within the negative moment region of continuous composite beams.(4)Comparative analysis of longitudinal strain distribution at the mid-span sectionThe layout of strain gauge at the mid-span section is shown in In each loading stage, the longitudinal strains of the bottom surface of the concrete slab and the upper flange plate of the steel portion of specimen SRB were basically the same, indicating that the concrete slab and the steel portion formed a combined section to work together. However, the longitudinal strain of concrete slab and steel portion of SPB was much different from that of SRB, and both had specific strain distribution characteristics, respectively. This shows that two portions in the negative bending moment region of specimen SPB formed an ideal laminated beam, and the steel structure and concrete slab bore the load, respectively.In the subsequent loading stages, the compressive strain of the concrete slab in specimen SRB was smaller than that of concrete slab in specimen SPB, and the tensile strain of the steel portion in specimen SRB was smaller than that in the specimen SPB steel portion. The above facts show that most of the negative bending moment is borne by the steel beam due to the interface slip effect, thus reducing the tensile stress borne by the concrete slab.It is obvious that the increase in tensile strain on the top surface of concrete slabs in specimen SPB was smaller than that in specimen SRB as applied load increases, so the interface slip effect caused specimen SPB have a better crack resistance.According to the data analysis in (5)Analysis on strain on top surface of concrete slab at mid-span sectionAs can be seen from (6)Comparative analysis of the longitudinal distribution of strain on the top surface of concrete slabA concrete slab with seven longitudinal sections is taken as the object in In order to study the feasibility and the working mechanism of improving the crack resistance of continuous steel–concrete composite bridge by releasing the interfacial slip effect within the negative bending moment region, two group of model tests were carried out in the paper. The main conclusions are as follows.(1)The model tests show that the crack resistance of continuous composite beams in the negative moment region can be improved significantly by releasing the interface slip. The cracking load of composite structure rises by 107% when the continuous composite structure uses the uplift-restricted and slip-permitted connectors in the negative moment zone, due to releasing its interface slip. Moreover, the interface slip can make the tensile stress distribution more uniform on the concrete slab within the negative bending moment region and avoid the concentration of tensile stress in the mediate support, resulting in a wider distribution of cracks in the bridge deck within the negative bending moment region and a slower development rate of cracks.(2)Compared with the composite beam with conventional shear studs, the composite beam with Uplift-Restricted and Slip-Permitted shear connectors has a higher pre-stress application efficiency, due to an important fact the new connector could release the interface slip. As the interface slip is released, the applied prestress can be effectively retained in the concrete slab, preventing the prestress from being transferred to the steel structure through the shear connectors.(3)Another working mechanism in which the releasing interface slip improves the crack resistance of the structure is that, during the loading stage, specimen SPB behaves with lower values of both tensile strain and tensile strain growth curvature than specimen SRB, and the tensile strain distribution in the concrete slab of specimen SPB is more uniform along the longitudinal direction. This indicates that releasing the interface slip can effectively slow down the increase of the tensile strain of the concrete slab during the loading process after cracking.(4)Despite the application of uplift-restricted and slip-permitted connectors in the hogging moment zone, the structural stiffness of the SPB beam was not significantly different from that of the continuous composite structure with traditional stud connectors, indicating that, in the negative moment zone of the continuous composite box girder, the releasing interface slip had no significant effect on structural stiffness.


A main global challenge is finding an alternative material for cement, which is a major source of pollution to the environment because it emits greenhouse gases. Investigators play a significant role in global waste disposal by developing appropriate methods for its effective utilization. Geopolymers are one of the best options for reusing all industrial wastes containing aluminosilicate and the best alternative materials for concrete applications. Waste wood ash (WWA) is used with other waste materials in geopolymer production and is found in pulp and paper, wood-burning industrial facilities, and wood-fired plants. On the other hand, the WWA manufacturing industry necessitates the acquisition of large tracts of land in rural areas, while some industries use incinerators to burn wood waste, which contributes to air pollution, a significant environmental problem. This review paper offers a comprehensive review of the current utilization of WWA with the partial replacement with other mineral materials, such as fly ash, as a base for geopolymer concrete and mortar production. A review of the usage of waste wood ash in the construction sector is offered, and development tendencies are assessed about mechanical, durability, and microstructural characteristics. The impacts of waste wood ash as a pozzolanic base for eco-concreting usages are summarized. According to the findings, incorporating WWA into concrete is useful to sustainable progress and waste reduction as the WWA mostly behaves as a filler in filling action and moderate amounts of WWA offer a fairly higher compressive strength to concrete. A detail study on the source of WWA on concrete mineralogy and properties must be performed to fill the potential research gap. One of these innovations is the production of geopolymers to be used as alternative materials to replace all or part of the ordinary Portland cement used in construction, which is obtained either from metakaolin or from industrial, forestry, and agricultural waste with a high aluminosilicates content [2 production by up to 90%, while preserving or even improving their mechanical properties  [Globally, 0.74 kg of solid waste is generated per capita per day, with national rates varying between 0.11 and 4.54 kg per capita per day depending on urbanization rates and income levels ,3. The Er person ,10,11. B content ,13,14,15 content ,17,18,19 content . Additio content . The useability) ,23.2/Al2O3 ratios positively influences the mechanical compressive strength of geopolymers [Several researchers have devoted themselves to using different raw materials for the production of concrete, for example, agricultural residues such as rice husk ash and palm oil ash , sugar cpolymers , and it polymers . Researcpolymers  used as polymers . Currentpolymers . Other tpolymers  producedpolymers .Cement consumption in the world currently amounts to approximately 3 billion tons, which translates into 1.5 billion tons of carbon dioxide emitted into the environment . AccordiEnergy extracted from burning the wood results in the formation of WWA. WWA is very fine, which results in the ease of pollution causing respiratory problems for human beings and animals around the site of WWA production . Loose aWWA is problematic if spread regularly and requires slow delivery rates from spreaders . BecauseThe topsoil of the system is affected by pH differences and its blocks the crop or tree to obtain enough amount of nutrition from the soil. The delivery rate of calcium to soils is reliant on the primary shape of the ash, with loose ash such as WWA possibly instigating a temporary quick increase in pH in the soil . For theApproximately 2.5 kilo-tons of WWA are annually discarded in lands, as of 2006 , but it When WWA is in contact with water, the pH solution becomes higher as the hydroxides and oxides in the WWA are dissolved and hydroxide ions are developed. WWA has a liming impact when introduced into soils and could be utilized to neutralize acidity. Three tons of WWA have a liming effect equal to one ton of quicklime. The solubility of different nutrition elements in the WWA varies considerably. Generally, the solubility of the nutrients elements are in the order of potassium > magnesium > calcium oxide > phosphorus .pH, organic material content, and hydrous oxide play the main roles in the adsorption of heavy metals from the soil . When WWWilliams et al. (1996)  observedAs per Grau et al. , the WWA50 (mm) is 0.223, bulk density (kg/m3) is 663–997, and specific surface area (m2/kg) is 4200–100,600  [As per the report from Etiegni and Campbell et al. , 80% of ., 2015) . An incrWood combustion produces highly alkaline ash (pH varies from 9 to 12) . Ash yieThe alkalinity of WWA depends on the carbonate, bicarbonate, and hydroxide content in it. WWA composition also varies during storage and under different environmental conditions as carbon dioxide and moisture react with WWA to form carbonates, bicarbonates, and hydroxides . An incrZajac et al.  divided Szakova et al.  determinThe following compound composition limits were also reported: titanium dioxide (0% to 1.5%), sulfur trioxide (0.1% to 15%), silica (4% to 60%), aluminum oxide (5% to 20%), ferric oxide (10% to 90%), magnesium oxide (0.7% to 5%), potassium oxide (0.4% to 14%), calcium oxide (2% to 37%), loss of ignition (0.1% to 33%), moisture content (0.1% to 22%), and available alkalis (0.4% to 20%). WWA is usually very low in nitrogen because it evaporates during incineration. Trace elements such as boron (B), molybdenum (Mo), copper (Cu), and zinc (Zn) have been observed in WWA, which are called micronutrients .Waste wood ash is an easily available agricultural discarded material that enhances the workability, quality of microstructure, and improves the strength characteristics of concrete samples. The key characteristics of concrete can be enhanced, and most importantly, the time for hydration is reduced due to the pozzolanic effect . The disThe properties of various mixes have been studied with different water to binder ratios. The optimal dose was 20% WWA with rice husk ash, which improved the compression strength significantly and also showed enhanced durability . BecauseDashibil and Udoeyo (2002)  examined2SO4, as shown in Ejeh and Elinwa (2004)  investigEjeh and Elinwa (2004)  inspecteUdoeyo et al. (2006)  studied Wang et al. (2008)  examinedHorsakulthai et al. (2010)  investigBaxter and Wang (2007)  studied Naik et al. (2003)  examinedGarcia et al.  studied Awolusi et al.  investigIt can be observed from the SEM image shown in Chowdhury et al.  studied WWA consists of particles sizes that vary between 10 µm and 200 µm, as is observed in WWA can have a positive influence in developing cement from an environmental standpoint . The minGorpade et al.  assessedWaste wood ash seems to be an auspicious pozzolanic material for the partial replacement of binder, with no reduction in concrete strength, with enhanced durability of sample, and contributing significantly to the sustainability of the construction industry . Waste wThe quality and quantity of waste wood ash are dependent on different features, specifically, the temperature of the burning of waste wood and the type of burning technique utilized for waste wood. Thus, the appropriate classification of WWA is obligatory before its usage as an ingredient material in the development of geopolymer concrete mixes.The distribution of wood ash particles is usually grainier as compared to cement. However, the specific surface of WWA is moderately smoother than that of Portland cement because of the higher irregularity in wood particles and their permeable behavior.2 elements.The chemical arrangement of WWA differs considerably within types of trees from which the biomass of wood is obtained, but it is usually rich in CaO and SiOBinders blended with WWA as a fractional substitute have higher initial and final times and high standard consistency. Geopolymer mixes having WWA are inclined to have a low heat of hydration.A considerable amount of ettringite crystals is shaped within a paste of binder upon the hydration of OPC–WWA geopolymer samples, specifically at high doses of binder replacement with WWA.Geopolymer mixes of mortar and concrete comprising WWA as a fractional substitution of the binder have more water requirements to obtain a desirable level of slump value in comparison to similar geopolymer mixtures with no WWA.The addition of WWA as fractional binder substitution in mixes of mortar and concrete at a high dose of binder substitution could lead to a steady decrease in the bulk density of hard mixes of geopolymer mortar and concrete.Usually, the inclusion of WWA as fractional binder substitution in the preparation of geopolymer concrete blend decreases the compression, flexural, and split tensile strength of geopolymer concrete. However, there are hopeful outcomes as the addition of WWA at a low dosage level of binder substitution truly assisted in the improvement of the compression strength of the developed mixes of geopolymer concrete. WWA as a fractional substitute for binder at a substitution level of 10% by binder weight can make geopolymer mortar or concrete, which can be produced and utilized in building applications with suitable strength and durability characteristics.Metakaolin can be utilized as an activator for making geopolymer concrete or mortar with WWA as a fractional substitute of binder to improve the mechanical strength of geopolymer concrete or mortar.Geopolymer concrete blends comprising WWA as fractional binder substitute display more resistance against rusting when exposed to strong acids in comparison to mixes with no WWA.Geopolymer concrete blends having more quantity of WWA as a partial substitute of binder can have a high degree of water absorption.The utilization of WWA as fractional replacement of binder in geopolymer concrete blends at substitution levels of up to 25% by binder weight does not have detrimental impacts on the resistance of the geopolymer concrete against chloride ion diffusion. Furthermore, the utilization of 80% fly ash and 20% WWA in geopolymer concrete considerably improves the sample’s capability to resist chloride ions diffusion.The advantage of present study is that the addition of very fine size WWA, made from burning of rice husk, wood, bagasse, assists considerably in enhancing the durability characteristics of the geopolymer sample in terms of ASR and resistance against chloride ions. The existence of WWA in geopolymer concrete had a considerable role, as it reduced the extent of the geopolymer sample’s drying shrinkage considerably.The disadvantage of present study is that, to make WWA, it needs a considerable higher degree of fire to burn the waste wood, which will need a lot of energy and resources, and finding naturally burnt WWA is highly difficult.Waste wood ash has the possibility of being a substitute construction material for sustainability purposes, as a fractional substitute of binder and aggregates. The usage of waste wood ash in large volumes is conceivable. Some research has been conducted on this and some hopeful outcomes have been observed, as WWA can be utilized as an eco-efficient material with little to no compromise on the properties of geopolymer concrete samples. However, for now, WWA has been utilized in a limited amount in the development of samples. This extensive review study of WWA on geopolymer concrete as a fractional substitute of binder showed that the shape, size, source, method of making WWA, and chemical and physical composition of WWA have a significant impact on the strength and durability properties of the sample in which WWA is utilized. Thus, waste wood ash is suitable as a binder replacement, and if it is used in construction as a building material, it will reduce the demand for cement, which will reduce the outflow of greenhouse gases from the production of cement and also preserve the natural reserves of limestone used in the making of cement, thus helping the environment and assisting the construction industry by increasing its sustainability.


In the second scenario, an acceptable and reasonable low permeability (less than 2.7 × 10−11 m/s) and water absorption (less than 6.7%) were also obtained when the replacement percentage increased up to 60%. In contrast, the high content coconut shell, such as 90% and 100%, developed concrete with a high permeability and water absorption and was defined in the third scenario. It was also inferred that both the experimental and mathematical models  have consistent and accurate results. The correlation statistics indicators (R2) were greater than 0.94 and the error was less than 0.3, indicating a strong correlation and minimum error. In conclusion, coconut shell could act as a good alternative material to produce cleaner concrete with an optimum value of 50% as a fine aggregate replacement.The concern about coconut shell disposal and natural fine aggregate depletion has prompted researchers to utilize coconut shell as aggregate in recent years. However, the majority of the present literature has focused on utilizing coconut shell as a coarse aggregate replacement in concrete via the traditional method. In this study, concrete incorporating coconut shell as a fine aggregate replacement (10–100%) was evaluated using permeability and water absorption tests in a systematic way. The response surface methodology (RSM) was first used to design the experimental works. In addition, an artificial neural network (ANN) and genetic expression programming (GEP) were also taken into account to mathematically predict the permeability and water absorption. Based on both experimental and theoretical modeling, three scenarios were observed. In the first scenario, high quality concrete was achieved when the replacement percentage of sand by coconut shell ranged from 0% to 10%. This is because both the permeability and water absorption were less than 1.5 × 10 Similarnd Nehme ,29. In cnd Nehme . In the nd Nehme . Similarnd Nehme ,33,34.R) and a low root-mean-square error (RMSE) were achieved indicating that the model was reliable and efficient [From another perspective, the majority of the existing literature relies on the traditional lab work, while the mathematical and systematic experimental work of concrete containing coconut shell is still in its infancy. In this spirit, extensive theoretical research was carried out to predict and optimize the concrete durability using response surface methodology (RSM), artificial neural networks (ANN), and genetic expression programing (GEP) in the existing literature ,36,37,38fficient . It can be inferred that very limited experimental research was conducted to examine the permeability and water absorption of concrete containing coconut shell as fine aggregates. Accounting for that in this present study, and to fill the gap of the existing literature, both experimental and mathematical modeling were considered to predict and obtain the optimum content of coconut shell as the replacement of fine aggregate using genetic expression programming (GEP), artificial neural networks (ANN), and response surface methodology (RSM). In addition, ANOVA, error and correlation statistical validation methods were considered to evaluate the performance of the proposed models.As shown in n axial points and 2n factorial points where n is the number of independent variables. Q) was found to be thirteen using Equation (1) where m represented the number of center points [Z and Zc are the real value of the independent value and real value of independent variables at the center point, respectively [L denoted the coded value of the independent variable. Experiment design is an optimization algorithm that involves both mathematical and statistical procedures to analyze the interaction and relationship between the output or, namely, the responses (dependent variables) and input or influential factors (independent variables) . In addir points . Moreoveectively . Furtherβii is the quadratic coefficients, oβ corresponds to intercept of the model, and βi denotes to the linear coefficients. Furthermore, X1 and X2 represent the input data involving CA content and time, while Y is the response (permeability and water absorption). For the purpose of verification of the proposed equation, analysis of variance (ANOVA) was taken into account. In particular, R2 was calculated to evaluate the closeness between the response and real results as shown in Equation (4) where TSS represents the total sum of square error, ESS is the sum of square error based on the predicted results, and PY and AY are the predicted and real values. In the same context, DF is the degree of freedom and RSS represents the sum square of differences error between the actual and predicted values. The predicted W refers to the estimated residual sum of square without the ith. Meanwhile, the signal-to-noise ratio was evaluated using the adequate precision (SN) as shown in Equation (7) in which its value should be greater than 4 [2 denote to the residual mean square. In addition, the p-value and F-value were also taken into account to validate the significance of the proposed equation. The achievement of the high F-value and p-value less than 0.005 led to the equation being considered as significant [A second order polynomial equation was considered to represent the permeability of CA-based concrete. The general form of the second order polynomial equation is presented in Equation (3)  where βition (5)  where DFtion (6) . The difore data  where W r than 4  where σ2nificant .(3)Y=βo3 and 536 kg/m3, respectively. It is interesting to note that the CA was added as a partial replacement of fine aggregate according to the suggested array experiment design of CCD as shown in Prior to obtaining the ingredients of the concrete mixture, the materials are first collected and prepared to satisfy the specification. For example, the crushed granite was exploited as coarse aggregate, while the fine aggregate was collected for the natural sand. Both the coarse and fine aggregate met the requirement of international standard EN 933-1:2012. Meanwhile, the ordinary Portland cement is produced (OPC). Another crucial element in the mixing of concrete is water. Water helps to bind the cement and aggregates to produce concrete. BS EN 1008: 2002 defines sources of water and provides requirements as well as testing frequencies for qualifying individual or combined water sources. Apart from that, the pH value of water is also taken into consideration. In this research, the source of water was tap water used for water absorption and permeability tests. Regarding coconut shell, it was collected from a local supplier in Malaysia. After that, the CA is exposed to grinding via an impact pulverizer to achieve the suitable target size a. The siWA) test was carried out in compliance with BS 1881-122:2011. Three concrete cubes with the dimension of (100 × 100 × 100) mm were considered for each experiment run as shown in W2 and W1 represent the wet weight of the concrete cube and the dry weight of the concrete cube, respectively. It is also interesting to note that the correction factor (CF) was taken into account to tackle the sample length variation, which was in line with the study reported by Kwan and Ramli [Aiming to explore the impact and extent to which coconut shell could affect the capillary and concrete voids, a water absorption (nd Ramli . (8)WA=WKw) were obtained to evaluate the performance of concrete incorporating CA as shown in Equation (9) where d is the depth of water penetration, T refers to time under pressure, and h represent the hydraulic head. In addition, the porosity (v) is the function of the area of the cubes (A), water density (d), and the differences of mass sample (m) as shown in Equation (10). To implement the test, the concrete cubes in the dimension of (100 × 100 × 100) mm were tested after 28 days for each experiment run. After the test arrangement was pressurized with 5 bars for 3 days as shown in To further analyze the evolution of water transport in concrete with and without coconut shell, a water permeability test was conducted in accordance with BS EN-12390-8:2009. In particular, water permeability coefficients  and (13), respectively.In recent years, extensive theoretical research was adopted to quickly analyze the behavior of concrete properties under different influential parameters. Herein, a data-driven model using an artificial neural network was utilized to provide a predictive mathematical equation that is able to examine and evaluate the effect of coconut shell on permeability as well as the absorption of concrete. R and R2 were calculated to assess the relationship between the real and predicted results as descried in Equations (14) and (15). The closer the R to one, the strength and closeness results could be achieved. For the error statistic indicators, four methods were taken into account involving the mean absolute error (MAE), mean root relative squared error (RRSE), relative absolute error (RAE), and root mean square error (RMSE) as show in Equations (14)–(19).The theoretical framework of concrete properties has become a hot trend in the scientific community, specifically for civil structural engineers. Moreover, many researchers have recognized the GEP model as a reliable and robust model. In this study, two mathematical equations were developed to simulate the permeability and water absorption of CA-based concrete. As shown in The evolution of water absorption and permeability of concrete under different replacements of fine aggregate by coconut shell were also investigated and evaluated using both experiments and modeling involving RSM, ANN, and GEP models.WA) of concrete is one way to assess its durability and it is related to the movement of liquid such as water into the concrete matrix owing to surface tension acting in the capillaries. BS 1881-122:1983 defined the WA as the weight’s increment by absorbed water that might be occurred compared to that of the dry concrete samples. This increment is attributed to the high pressure inside the pores when the dry concrete samples are exposed to and submerged in water. Therefore, a high percentage of pore volume and interconnectivity pores inside the concrete could be indicated by the value of the water absorption of concrete samples. Less water absorption refers to dense and high-quality concrete, while high absorption could be considered as a concern of concrete deterioration. An excellent water absorption of concrete could be achieved when its value is lower than 5% according to ASTM C 642-06 [As is well known, the water absorption  was obtained when the replacement of fine aggregate by coconut shell was 10% compared to the normal concrete as shown in d Nomeli  defined Despite both the permeability and absorption of concrete being experimental indicators to assess the quality of concrete in terms of water penetration, absorption tests differ from concrete permeability tests and do not necessarily fully relate the absorption to the permeability . As is w−11 m/s at 28 days, which is in a good agreement with the present literature. For example, Cuadrado-Rica and Sebaibi [−11 m/s to 5.0 × 10−11 m/s. In addition, according to ACI standard 301-89, a high-quality concrete is obtained when the water permeability is lower than 1.5 × 10−11 m/s. In our study, the water permeability of concrete containing 10% of the coconut shell as a replacement of the fine aggregate was found to be 1.2 × 10−11 m/s confirming that the concrete quality is still high when it met the specifications. In the same context, with the increase in the coconut shell up to 60%, the water permeability of the concrete slightly increased up to 2.7 × 10−11 m/s, which also can be considered a low and reasonable permeability. This fact is in line with Amriou and Bencheikh [−12 m/s and 3.2 × 10−11 m/s. This result was consistent with all the data sets obtained from the RSM, ANN, and GEP models as shown in −11 m/s in indicating that the concrete quality is good. After that, the slop of water permeability increased with the increases in coconut shell content, specifically, 90% and 100%. This result is also presented using a counter plot as shown in In the present study, the water permeability of control concrete without the coconut shell was 1.1 × 10 Sebaibi  concludeencheikh , who defp-values were 0.0026 and 0.0033, respectively. This is consistent with the previous studies that determined that the model could be considered as significant if the p-value is lesser than 0.005 and F-value is high [RMSE. It was found that the value of the RMSE is minimum, specifically the RMSE value of WA and WP were 0.1492 and 8.2 × 10−13, indicating that the model was able to estimate accurate results. This fact is in line with Algaifi and Alqarni [R2 proved the closeness and correlation between the predicted and actual results in which the value of R2 was high. According to Huseien and Sam [R2 is greater than 0.7. Herein, the R2 value of WA and WP were 0.9993 and 0.9995, thus highlighting that the predicted results were acceptable. In addition, the capability of these quadratic equations to accurately predict further data was also proved using The evolution of the water permeability and absorption of CA-based concrete were estimated and evaluated using quadratic equations as shown in  is high . The acc Alqarni  who used and Sam , a good and Khed  developep-value of the coconut shell content was 0.0007 and 0.0006 based on the water absorption and permeability, respectively, while the F-value of CA was 1352.83 and 1787.27. For the same regards, the significance of each parameter involving time and coconut shell on the permeability and water absorption of concrete was investigated and evaluated. It can be inferred that the coconut shell content has three scenarios in terms of slop gradient as shown in 3. This fact is line with Khoshkenari and Shafigh [3, while the density of ordinary or normal concrete is in the range between 2240 and 2400 kg/m3. Herein, the concrete density is divided into two zones as shown in Moreover, the desirability functions were also used to optimize the optimum value of coconut shell content in CA-based concrete. Equation (19) represents the general mathematical form for the optimization purpose using RSM. Herein, the optimization equation is a function of two independent variables involving time and CA content. It was found that 78 solutions were obtained using the optimization equation. In addition, the optimal content of the CA content was considered as 53% in the present study as shown in  Shafigh  and Nowa Shafigh , who demo)). The structural tree was later converted into a mathematical expression using the Karva language.The evolution of water absorption and permeability were also theoretically predicted using GEP. As shown in R2 values of 0.991 and 0 and 9878 for training and validation. This outcome was similar to the present findings. In particular, the value of R2 of the proposed water permeability equation using GEP and ANN were 0.9519 and 0.9719 for training, while its value was higher than 0.967 for validation. These positive results are almost in line with the findings from the predicted equation of water absorption using ANN and GEP. In particular, the R2 were higher than 0.856 for both training and validations. As such, it can be inferred that both GEP and ANN models showed its ability to predict with high correlation and minimum error. The accuracy and reliability of the predicted GEP equations were also examined and assessed using both correlation and error statistics validations methods. It was found that the differences between actual and estimated results were found to be minimum and acceptable. According to Ali Khan and Zafar , the accIn recent years, the utilization of waste agricultural material as an alternative of aggregate in concrete was rapidly increased in order to address the environmental problems. In the present study, coconut shell was taken into account as a replacement of fine aggregate. Both the permeability and water absorption of CA-based concrete tests were assessed in a systematic way using RSM, ANN and GEP models. It can be concluded that utilizing coconut shell as a fine aggregate is helpful to address environmental problems, however, our work was focused on conventional concrete. Pozzolanic-based material such as fly ash could be very useful to enhance and produce CA-concrete. In addition, further study is encouraged to assess the thermal conductivity of concrete using coconut shell. All mathematical models of RSM, ANN, and GEP proved their ability to evaluate the behavior of CA-based concrete, in which the predicted data and the actual data were consistent.−11 m/s and 5%, receptively.Based on ANN, GEP, and RSM models, the replacement percentage of fine aggregate by coconut shell up to 50% produce a good quality concrete in which the permeability and water absorption were less than 2.7 × 10−11 m/s) and high water absorption (greater than 10%).The ANN, RSM, and GEP also revealed that the high replacement of fine aggregate by coconut shell produced a concrete with high permeability (greater than 4.5 × 10In the same context, based on the experimental and predicted results, it can be concluded that:


MET is a proto-oncogene and plays an important role on tumor cell survival, proliferation, metastasis, and drug resistance. Patient with MET amplification has shown an inferior outcome comparing to patients without MET amplification. Fluorescence in situ hybridization (FISH) is often used to detect MET amplification, and immunohistochemistry (IHC) is often used to assess MET expression level. Though some institutions provide both tests, IHC is more readily available in most pathology laboratories and is cheaper than FISH. This study evaluated the correlation of MET expression level with MET copy number gain/amplification, and the MET overexpression with patient’s outcome. By studying 446 patients with lung adenocarcinoma, we found that the concordance of MET expression and MET copy number gain/amplification was low; high-level of MET expression was associated with inferior outcome, but it was not an independent poor prognostic factor. These findings indicate that IHC for MET expression can’t substitute FISH analysis for MET amplification.MET amplification has been associated with shorter survival in cancer patients, however, the potential correlation of MET overexpression with either MET amplification or patient outcome is controversial. The aim of this study was to address these questions by correlating MET expression level with MET copy number and patient outcome in a cohort of 446 patients who had a lung adenocarcinoma: 88 with MET amplification, 118 with polysomy 7, and 240 with negative results by fluorescence in situ hybridization. MET expression assessed by immunohistochemistry was semi-quantified by expression level: absent (0+), weak (1+), moderate (2+) and strong (3+); or by H-score: 0–99, 100–199, and ≥200. MET expression level or H-score was positively but weakly correlated with MET copy number or MET/CEP7 ratio. Strong expression of MET (3+ or H-score ≥ 200) was associated with a shorter overall survival, but it was not an independent hazard for survival by multivariant analysis. We conclude that MET expression is loosely correlated with MET copy number gain/amplification. Strong expression of MET does not independently predict patient outcome. MET, located on chromosome 7q31, is an oncogenic receptor tyrosine kinase for hepatocyte growth factor. Activation of MET pathway, either by MET amplification or a splice site alteration in exon 14, plays important roles on tumor cell survival, proliferation, metastasis, and drug resistance [EGFR-mutant [ALK-positive patients [MET exon 14 mutation or MET amplification can benefit from MET inhibitors [sistance ,3. Evidehibitors ,6,7.MET copy number change or MET amplification. MET amplification often exhibits a high copy number of MET  and/or a MET/CEP7 (centromere of chromosome 7) ratio ≥ 1.8 [MET amplification has been detected in 1% to 5.8% of treatment-naïve NSCLC patients [EGFR-mutant NSCLC who develop resistant to EGFR inhibitors [MET amplification has been associated with an inferior outcome [MET amplification or MET exon 14 mutation in lung cancer [Fluorescence in situ hybridization (FISH) has been commonly used to detect io ≥ 1.8  or ≥2.0 io ≥ 1.8 ,11 by FIpatients ,15,16,17hibitors ,19,20. M outcome ,22,23,24 outcome ,29,30,31 outcome ,33. On t outcome ,27,28,29g cancer . PreviouMET copy number gain /amplification (by FISH) and MET expression level (by IHC). We also evaluated whether overexpression of MET can predict patient outcome.In this retrospective study, we included 446 patients with lung adenocarcinoma, we evaluated the correlations between MET copy number/amplification by FISH and MET expression by IHC. Patient follow-up and outcomes were obtained by electronic chart review. This study was approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center and was conducted in accord with the Declaration of Helsinki.The study group included patients who were diagnosed with lung adenocarcinoma at our institution during a six-year period (January 2014 to December 2019), and who had been evaluated for MET/CEP7  was performed on formalin-fixed paraffin-embedded (FFPE) tissue sections as a part of clinical workup for all newly diagnosed NSCLC at our institution as described previously [MET and CEP7 and calculated the MET/CEP7 ratio for each specimen. For cells with clusters of MET signals, the copy number of MET was recorded as 20 for calculation purpose. MET amplification (MET-amp) was considered when one or more of these criteria were met: the MET/CEP7 ratio was ≥1.8; >10% of cells showed clusters of MET signals; or MET copy ≥ 15. Polysomy 7 was considered if MET/CEP7 ratio < 1.8 and MET copy ≥ 5 but <15. The remaining cases were designated as MET negative (MET-neg) [FISH analysis for eviously . After hMET-neg)  . MET expression intensity (level) and percentage of cells were evaluated and recorded by two pathologists independently. In tumors that exhibited intra-tumor heterogeneous staining intensity, the predominant (≥50% of tumor cells) staining pattern was recorded. The intensity was classified as absent (IHC0+), weak (IHC1+), moderate (IHC2+) and strong (IHC3+) , ×20. InMET copy number (or MET/CEP7 ratio). Chi-square was used to compare categorical variables. Overall survival (OS) was estimated by Kaplan-Meier method from the date of diagnosis of lung adenocarcinoma to the date of death from any cause or censored at time of last follow-up for living patients. Multivariate cox proportional hazard regression analysis was used to assess the relationship between survival and age, tumor stage, MET FISH groups and MET overexpression (IHC3+ or H-score ≥ 200). The difference was considered as significant when p < 0.05.Spearman correlation analysis was used to analyze the correlation coefficient (r) between MET expression level (IHC or H-score) and MET/CEP7 tested on the first diagnostic specimen of lung adenocarcinoma in our institution, including 112 (5.6%) patients with MET/CEP ratio ≥ 1.8 (MET-amp), 146 (7.3%) with polysomy 7, and 1729 (87%) with a MET-neg FISH results.9 Among the 258 patients with MET-amp or polysomy 7, 206 (88 with MET-amp and 118 with polysomy 7) had materials available for IHC. In addition, we included a comparable number (n = 240) of patients from MET-neg group who had IHC available and who showed similar distribution of age, gender, tumor stage, and diagnostic year compared to the groups of MET-amp and polysomy 7.During this study period, there were 1987 patients who had FISH for Among the 446 patients included in this study cohort, 95 (21.3%) patients with stage I/II and 351 (78.7%) patients with stage III/IV disease. The sex and age distribution are shown in MET IHC exhibits membranous and cytoplasmic reactivity, and the IHC pattern was relatively homogenous in most cases. The expression level was determined on the basis of the stain intensity and fraction of positive cells by two pathologists. In most cases  observations by both pathologists were concordant. Discordance occurred in 54 patients: 18 with 1+ or 2+ and 36 with 2+ or 3+. The discordant cases were reviewed by the third pathologist. After consensus, 41 (9.2%) neoplasms were negative for MET (0+), 55 (12.3%) were weakly positive (1+), 231 (51.8%) were moderately positive (2+), and 119 (26.7%) were strongly positive (3+). H-score fell into 0–99 in 96 (21.5%) cases; 100–199 in 205 (46%) and ≥200 in 145 (32.5%) patients .MET copy number (p < 0.0001) or MET/CEP7 ratio (p < 0.0001), with a correlation coefficient (r) ranged from 0.4298 to 0.4431 (p < 0.0001) among patients with MET-amp, polysomy 7 or MET-neg (MET expression level (IHC 0–3) and MET H-score were loosely and positively correlated with o 0.4431 . MET exp MET-neg . High prp < 0.0001). Similarly, H-score ≥ 200 was also associated with advanced tumor stage (p = 0.0021).MET expression level and tumor stage are summarized in p = 0.0005, p = 0.0966). Although these data show a trend that patients with a higher level of MET expression (1+~3+) had a shorter survival comparing to the patients without MET expression (0+), but the differences were not significant   B.p = 0.0463, p = 0.6630)  could predict patient’s survival. As shown in  0.6630) .p = 0.0110, p = 0.2950)  could predict patient’s outcome. As shown in  0.2950) .MET FISH, age (≥65 years), tumor stage (III/IV), and MET expression (either with a IHC3+ or with b H-score ≥ 200) were co-analyzed for OS (p < 0.0001). High-level MET expression (either IHC3+ or H-score ≥ 200) was not a significant hazard to survival.Though MET-amp, IHC3+ and H-score ≥ 200 were significantly associated with inferior survival in the univariate analysis, only MET-amp remained (in addition to older age and advanced stage) to be prognostically significant by multivariate analysis when d for OS . When agMET is an oncogenic receptor tyrosine kinase. In vitro and in mice, overexpression of MET alone is sufficient to induce oncogenic transformation [MET amplification, MET exon 14 mutation, or the response to MET kinase inhibitors. To date, the results of these studies have been contradictory  and patient outcome.The design of this study is slightly different from the studies published previously. First, this study cohort included a large number of patients with MET-amp (n = 88) and polysomy 7 (n = 118), in contrast with most published studies in which a smaller number of patients with MET-amp and polysomy 7 were included . This higher proportion of cases with MET-amp and polysomy 7 enabled us to do a better comparison of MET expression and MET copy number gain/amplification. Second, we analyzed the association of high-level expression of MET (IHC3+ or H-score ≥ 200) with survival by both univariate and multivariate analysis, though high-level of MET expression was associated with inferior survival by univariate analysis, it was not a significant hazard to survival by multivariate analysis when age and tumor stage were included in analysis. Third, we also analyzed the association of spectrum of stain intensities (0+~3+) with FISH results , which was in line with other studies [We compared the association of  studies ,27,28,29 studies . Among tMET expression and MET gene copy number (GCN). Biologically, MET expression is not only controlled by MET GCN, but also by transcriptional and/or translational regulation. Besides, intratumoral heterogeneity [Multiple factors could contribute to the low concordance rate between ogeneity ,37, sampMET amplification, IHC3+ or H-score ≥ 200 was significantly associated with inferior survival by univariate analysis, however, IHC3+ or H-score ≥ 200 was not an independent hazard to survival by multivariate analysis when age and stage were included (with or without MET FISH groups). This could be due to the fact that high expression of MET (IHC3+ or H-score ≥ 200) was highly associated with advanced tumor stage [or stage . Thus, oor stage ,27,28,29MET GCN/amplification is low. Unlike MET amplification highly associates with a short survival, MET expression level is not significant hazard to survival. MET expression level by IHC can’t substitute FISH analysis for MET copy gain/amplification.In summary, the concordance between MET expression and MET copy or MET/CEP7 ratio. High-level MET expression (IHC3+ or H-score ≥ 200), though seemed to be associated with an inferior survival, was not an independent hazard to survival.Apart from previous studies, this study cohort included much higher proportion of cases showing MET-amp  and polysomy 7 , in addition to 240 (54%) cases with MET-neg. We found that MET expression was weakly and positively associated with


Worsening of the overdose crisis in the USA has been linked to the continuing proliferation of non-pharmaceutical fentanyl (NPF). The recent wave of NPF spread in the USA has been fueled by an increased presence of counterfeit pills that contain NPF. This qualitative study aims to characterize the motivation and practices of counterfeit NPF pill initiation and use among individuals using illicit opioids in Arizona.Between October 2020 and May 2021, semi-structured interviews were conducted with 22 individuals meeting the following eligibility criteria: (1) 18 years or older; (2) residence in Arizona; and (3) use of illicit opioids in the past 30 days and/or opioid use disorder treatment in the past 12 months. Participants were recruited through referrals by a harm reduction organization, craigslist ads, and referrals by other participants. Interviews were conducted virtually via Zoom. Qualitative interviews were transcribed and analyzed thematically using NVivo.Out of 22 participants, 64% were male, and 45% were ethnic minorities. Age ranged between 25 and 51 years old. Participants noted significant recent increases in the availability of counterfeit NPF pills  that were most commonly used by smoking. The majority indicated first trying NPF pills in the past year, and the first use often occurred in situations of reduced access to heroin or pharmaceutical opioids. Participant decisions to switch over to more frequent NPF pill use or to maintain some levels of heroin use were shaped by local drug availability trends and personal experiences with NPF effects. They were also influenced by conflicting views of social acceptability of pharmaceutical-like drugs, perceived harms of NPF in terms of overdose risks and increased difficulty of quitting, and perceived benefits of switching to the non-injection route of opioid administration .Our findings highlight the need for the implementation of novel policy, treatment, and harm reduction approaches to address the growing unpredictability of drug supply and NPF pill-specific risks, attitudes, and behaviors. Provisional data from the US Centers for Disease Control and Prevention (CDC) indicate that there were over 100,000 drug overdose deaths in the USA during the 12 months ending in April 2021, almost a 30% increase compared to the year before . The conThe new wave of NPF spread is linked to the increased presence of counterfeit pills , 9. CounIncreases in counterfeit pill presence have been especially dramatic in Arizona. Located on important drug trafficking routes, Arizona is considered to be the “ground zero” of the evolving NPF epidemic . AccordiDespite the substantial uptick in the opioid overdose mortality in the Southwest, most prior studies on the NPF-related experiences among people who use illicit opioids (PWUO) were conducted in the eastern or midwestern states , 17–25. Individuals who use illicit opioids were recruited via social media posts, craigslist ads, referrals by a local harm reduction organization, and from other participants. To qualify, individuals had to meet the following criteria: (1) at least 18 years of age; (2) currently residing in Arizona; and (3) use of illicit opioids in the past 30 days and/or participation in substance use treatment for OUD in the past 12 months. Phone-based eligibility assessment was conducted first before scheduling an interview. Due to COVID-19 restrictions, all interviews were conducted using the Zoom platform. The study was approved by the Arizona State University Institutional Review Board.n = 2), were in long-term recovery from opioid use (n = 1), or did not reside in Arizona (n = 3). Out of a total number of 30 who were scheduled for an interview, seven did not keep their interview appointments. One respondent who passed phone-based eligibility and completed the interview was removed from the final sample because of inconsistencies that were identified in the interview responses. There was a final sample of 22 completed interviews between December 2020 and May 2021.A total of 36 individuals contacted the research team and participated in a phone-based eligibility assessment. Out of a total of 36 callers, 30 met eligibility requirements and were scheduled for a zoom-based meeting. Six individuals were not eligible because they did not use opioids  and eight were female (36%). In terms of ethnic/racial background, 12 were non-Hispanic White, seven were of Hispanic/Latinx ethnic background, one was of Native American, one African-American, and one of mixed white and Asian ethnic background. Age ranged from 25 to 51 years old, with a mean of 33.9 years. The majority of participants  resided in Maricopa County (Phoenix area), four individuals were from Pima County (Tucson), and others were from Mohave, Yuma, Pinal, and Yavapai Counties  reporting use of NPF pills. In terms of frequency of use, 14 individuals indicated that they used NPF more frequently than heroin, seven used heroin more frequently, and one person indicated only using non-prescribed pharmaceutical opioids. At the time of the interview, eight individuals were enrolled in opioid use disorder treatment .Nearly all participants described recent dramatic increases in the availability of non-pharmaceutical fentanyl (NPF) in the form of pressed pills mimicking 30 mg oxycodone, most commonly referred to as “blues,” “dirty oxys,” or fentanyl pills. Amy, a 31-year-old woman from Phoenix, who had a history of illicit pharmaceutical opioid use before transitioning to heroin at the age of 21 and then eventually to NPF pills at the age of 30, explained: “Well, they say it’s fentanyl, but they honestly look like Perc 30 s because…when I was doing Perc 30 s they looked exactly the same. And it says 30 on it.” Alex, a 43-year-old man who recently moved from Phoenix to his hometown in the northwestern part of Arizona to attend a methadone treatment center, also described the increased presence of NPF pills: “Okay, so, yeah, it was just an ingenious thing to make money that they did, making those counterfeit Perc 30 s. In Phoenix, they are absolutely everywhere.”There’s a mass amount [of “blues”]. The fact that when I first bought my first pills, it was $8. The way that it is now, it’s $5, shows you that the supply is flooding and outdoing the demand. They’re flooding the market so much that the pills are getting cheaper to buy.The increasing availability of NPF pills was associated with sharp declines in the prices of these pills. Ricky, a 42-year-old man from Phoenix, who started using NPF pills amid the COVID-19 pandemic and in the context of personal losses and turmoil in his life, explained the changes in prices between the summer 2020 and spring 2021:Similarly, Kai, a 31-year-old man from the Tucson area (Pima County), explained his experiences: “Cause before, in the beginning, it would be like $10 for one pill, but now I would never wanna pay that much for one pill. It’s more like $5 a pill or $6.”Increased street availability of NPF pills was often compared to the declining availability of heroin. Sofia, a 28-year-old woman from Tucson, noted, “It [heroin]’s been very difficult to find, and blues are everywhere. In the city I live in, they’re everywhere. That’s all anybody wants to do anymore is fentanyl.” Similarly, Jeff, a 40-year-old man from Phoenix who used illicit opioids to manage his pain issues, described his experiences: “Like my roommate, he's got to drive like eight miles to buy heroin when I could literally walk out in the apartment courtyard and find three or four people selling blues because the only reason I started doing it because it [blues] was cheaper and more accessible.”Most participants noted that unlike the easy availability of counterfeit pills, access to genuine pharmaceutical opioids has declined sharply. Johnny, a 31-year-old man from Phoenix who used “blues” daily, characterized genuine pain pill availability: “The real ones [pain pills] are extremely, extremely hard to get. You have to get those prescribed, and I think only car accident and cancer patients can get prescribed real Percocet, you know what I mean, especially 30 mg.”I've had heroin like that [mixed with NPF]. You can usually taste it. A lot of dealers will let you know, “Hey, this has been laced with fentanyl because it gives you a better high…” I stay away from that. I have one particular dealer that I use that I have had for quite some time now. He's pretty honest with me with what he knows is going into it, and I stay away from it for the most part.Several participants discussed the increasing presence of NPF in the local heroin supply. Powder-type heroin was viewed as being more prone to contamination with NPF. However, some individuals also noted the increasing presence of NPF in black tar heroin, which is the most common form of heroin available in the region. Lucas, a 26-year-old man from Mohave County described his experiences: “I mean, any time I get powdered heroin, then I know it’s fentanyl…. Even black tar heroin will have fentanyl in it, but it’s not as much. If it’s powdered heroin, then it’s pretty much just fentanyl.” Beth, a 40-year-old woman from Phoenix, also described prior experiences of obtaining heroin that was laced with fentanyl. She avoided it, though, by limiting her dealings to established and trusted sources:No, it's not [very available in Arizona]. It's really expensive. Most of my people that sell the pills don't also have access to the pure. But I've come across it quite several times and on it and then it is just kind of weird because some of the powder is white, some is pink, some is purple, and you're not really sure what you're getting. I guess, or why it's different colors. But it's great when you do find it. Some you can smoke it or shoot up and it's just really strong.A few participants mentioned sporadic availability of powder-type NPF in Arizona, although it was viewed as far less common than NPF in counterfeit pill form. Jasmine, a 26-year-old woman from Phoenix, described her experiences of obtaining powder-form fentanyl, referred to as “pure”:Antonio, a 25-year-old man from Yuma who had a prior history of selling NPF and other drugs, explained why local availability of NPF pills was greater than that of powder-form NPF, “Here […] for the most part the cartels are just pushing the pills. They don’t wanna sell the pure thing, or obviously, they’ll be killin’ the client base. For the most part, you only find pills out here…”.Nearly all individuals reported the first use of pressed NPF pills in the past year, and all of them had prior experiences of using other illicit opioids. A few individuals noted that they first tried NPF pills because of the social circumstances that facilitate their access to the drug and sparked their curiosity about its effects. Maria, a 47-year-old woman from Mohave County, transitioned to heroin use three years ago after many years of using prescribed and illicit pain pills. She indicated that she first smoked NPF pills just a few months prior to the interview: “Unfortunately, I had a family member that was, um, is probably still currently involved in the trade of it, and like that through them. Socially, you know, ‘Here, you want to try it?’”.I live in Tucson now, but I actually ended up going back home—back to Scottsdale [city northeast of Phoenix] where I grew up—where my parents live. I went back for Christmas with my girlfriend at the time. We both did heroin. I got back to Scottsdale. We actually ran out of “black”—out of heroin—and we were trying to get more. I, actually, couldn’t find heroin. The people… that I’d known from growing up, didn’t have heroin. They had, actually, these pills. These fentanyl pills. They were actually the only thing I was able to get at that time. I ended up getting them. I wasn’t very happy about it. I didn’t really know about them. I knew about them, but in my opinion, I didn’t really care because I did heroin. I didn’t care to try anything else or try something different. Heroin worked for me. I didn’t really have a choice in the matter ‘cause I was gonna get sick. I actually ended up buying the fentanyl pills.More commonly, the first use of NPF pills occurred in the context of reduced access to heroin. In most situations, these initiation decisions were driven not by consumer preferences but by shifting market situations and circumstances. For example, Scott, a 30-year-old man, described his first use of NPF pills:All the pain management places that you go to, now they're so afraid because of the opiate epidemic that they don't want to put you on what you need to be on… […] I think after being out of the nursing home for a few months, and they cut my pain pills down again, and [it] just wasn't enough. And I couldn't function, I couldn't walk when you have two shattered legs. And I think somebody ended up giving me one of those fentanyl pain pills, and you know it helped… it was way better than what I was getting from my pain management.For a few individuals, the first use of NPF pills occurred through a pathway of reduced access to pharmaceutical opioids. Jeff, a 40-year-old man from Phoenix, explained how he was first introduced to NPF pills in the context of reduced access to legitimate pain pills that were prescribed to him after a serious work-related injury:Although nearly all individuals had tried NPF pills, participants noted distinct patterns and trajectories of switching over to NPF pills and/or maintaining some levels of heroin use. Some individuals transitioned to NPF use nearly immediately after trying them for the first time. For example, Scott explained, “Basically, from that moment on, is when I started seeking out the fentanyl pills and doing those on a daily. Then, basically, within a week I phased out heroin and was not shooting up anymore. I was just smoking these pills.”In contrast, others made a slower transition by initially supplementing and then eventually replacing heroin with NPF pills over the course of several weeks or months. Johnny, a 31-year-old man, who was smoking about 10 NPF pills per day, explained: “Gradually, I started picking a couple of them up along with some heroin here at a time, and then after a while, I just started to like the pills better.” Others have maintained a varying pattern of dual-use, relying on NPF pills intermittently when heroin was more difficult to find, while still using heroin when available. Some individuals had tried using NPF pills but attempted to avoid them altogether and maintained a more or less consistent pattern of heroin use. For instance, Beth, a 40-year-old woman, who used heroin daily to help her with chronic pain, noted: “The pills I won't even touch honestly unless I haven't been able to find the heroin or I'm somehow in some type of withdrawal state is the only time that I'll actually smoke one of those pills. It's really just to get better until I can find the heroin.”Participant decisions and processes of switching over to NPF pills or maintaining some levels of heroin use were shaped by a range of personal and contextual factors including availability trends, personal experiences with NPF effects, views about the social acceptability, as well as perceived benefits and risks of NPF versus heroin use.I didn’t really start using [NPF pills] until last year [2020] and just because it was cheaper. I know a lotta people that never would’ve touched it [NPF pills], touched it last year. That’s just because we were locked in and couldn’t go anywhere. The drugs got frozen pretty much south of the border, and the only thing coming in were [NPF] pills.For most participants, their personal experiences with the availability and prices of NPF pills relative to heroin  were among the most important factors that determined their transition trajectories and patterns of NPF pill use. For example, Antonio noted that the COVID-19 pandemic “shorted the market on a lotta drugs and opened up the way for fentanyl.” As a result, these changes pushed many into NPF pill use:Kai, a 31-year-old man from Pinal County who smoked NPF pills every day and heroin on about seven days in the past month, also noted that drug availability was one of the key factors in his transition to more frequent use of NPF pills: “Then the pills, they started just becoming more available. There was more of them than there was of the heroin, and they were cheaper.”In contrast, Alex, a 43-year-old man, explained that he did try using NPF pills on several occasions, but maintained more frequent heroin use before starting methadone treatment. One of the underlying reasons for his continued more frequent use of heroin: “I actually met somebody that would sell it [heroin] to me fairly reasonable, and I could afford to be a heroin addict in Phoenix. I was doing it for $20 a gram there in Phoenix.” Similarly, Lucas, a 26-year-old man from Mohave County, had tried smoking NPF pills but considered heroin his drug of choice and injected it daily in the past 30 days. He reflected on the potential for him to eventually switch over to NPF pill use: “If I can’t find heroin, then I definitely will switch to blues, you know what I mean? I’ll probably end up doing that.”For many individuals, subjective experiences of fentanyl high were often discussed as another key factor that influenced their decisions and preferences concerning more or less frequent NPF pill use. Scott, a 31-year-old man, explained that in addition to the shifting availability trends, greater potency of NPF pills was one of the key motivators for his rapid transition from heroin to NPF pills: “Me and my girlfriend at the time, we smoked them, and they worked amazing. They got me higher than heroin did.” Antonio, a 25-year-old man, shared similar experiences: “Fentanyl was just more powerful to me. It calmed me down faster, got me in a high zone a lot faster than heroin did.”The fentanyl is to me, I really didn't get a whole lot out of it personally. Then again, I didn't do a lot of it… It was once or twice in a probably a 4-5-day span and then that was it… I'm not continuing to use it at all, because I really didn't get a lot out of it.In contrast, Maria, a 47-year-old woman, smoked NPF pills on a few occasions but was not impressed with their euphoric properties. She preferred to inject heroin and continued to use it more frequently:Everyone is doing blues. It makes people nod out. It puts people asleep—look like they’re sleeping all the time… I don’t enjoy spending my entire day with my head sunk between my legs, nodded out. That’s what fentanyl does to everybody, at least that I see. I don’t enjoy that. I believe that heroin is better for me to do if I’m gonna do it because I don’t nod out on heroin.Some individuals disliked the effects of NPF pills even as they were gravitating toward more frequent use because of easier accessibility. In comparison with heroin, fentanyl was viewed as more overpowering and disruptive to their daily functioning and routines. Sofia, a 28-year-old woman, who preferred heroin and, to the extent possible, sought to use it more frequently than NPF pills, explained her hesitancy to make a complete switch from heroin to NPF pills:Well, because you only gotta do one-shot [of heroin] in the morning and you’re good all day. Fentanyl is one of them things. It’s like coke, man […] when you do smoke a fentanyl pill and you’re good for a little while, and then you gotta smoke another one. You’re good for a little while, and then the times get shorter and shorter...Similarly, Francisco, a 51-year-old man, used NPF pills more frequently than heroin because of easier access. However, he found fentanyl effects less attractive in comparison with heroin because of the shorter duration of action and the need to engage in more frequent use:Well, fentanyl was just a weird thing how that whole thing happened. I told you I was familiar with Perc 30. I took a lot of those pills from my pain management doctor. When the cartels decided they were gonna start making bootleg Perc 30s using fentanyl, I liked it initially.Some individuals felt that NPF pill resemblance to well-known pharmaceutical drugs contributed to the increased social acceptability and a sense of familiarity which made the transition easier and more likely. Alex, a 43-year-old man, described his initial reactions and experiences with increased NPF pill availability:Naturally, [since] the fentanyl is introduced as a Percocet, Percocet 30 milligram, of course people who already were keen with liking those kinda drugs took a keen interest to fake 30s… [They] were already comfortable with the idea of taking it ’cause it was familiar to them.Similarly, Antonio, a 31-year-old man, explained how he and his peers viewed the introduction of NPF pills to the illicit drug market:NPF pills in the form of pressed 30 mg oxycodone tablets were generally administered by smoking. Jaime, a 31-year-old man, explained his first experiences with NPF pills: “I remember, thinking it was weird that you put this pill on some tin foil and you smoke…. I didn't really care for the smell. I was still kind of all about heroin, but it did [work]…”.It was like my saving grace from a worse evil I guess you could say. Surprisingly, just one day… I put the needle and the heroin down, and I just started smoking [NPF pills]. I guess I could say it’s a matter of opinion, but I say it’s the lesser of the two evils when it comes to how you’re doing it as I think smoking is obviously a lot better than injecting.For individuals who had been using heroin by injection, switching to NPF pills also meant a transition from the injection route of opioid administration to smoking. As a result, some felt that their switch to NPF pills was “a saving grace” because smoking was viewed as a less stigmatized and overall safer and more convenient alternative to the injection route of opioid administration. Johnny described his transition to NPF pills:Lucas had been using black tar heroin more frequently than NPF pills, but considered that switching the route of administration was one of the attractive aspects regarding his potential future switch to NPF pills: “You know, actually, I’ve heard that a lot of people got off shootin’ heroin by doin’ blues. They stopped shootin’ heroin by doing that, so I don’t know. Maybe it’s something I’ll get into… It’d be nice to not have to shoot up heroin anymore…”.Others have also felt that the smoking route of NPF pill administration could help moderate their overdose risks, although in some situations these risk perceptions were difficult to reconcile with the observed NPF-related overdose experiences in the community. Scott reflected, “From my heroin addiction, people didn’t overdose when they smoked it. The only way to overdose was to do a huge shot of heroin. […] But now I’ve seen people overdose from smoking this fentanyl… I don’t really know how to weigh the risk.”Most of those pills are stronger than a regular pharmaceutical Perc 30, and I liked that. I tended to stay more towards heroin. I did smoke my share of those pills. A lotta people die from 'em. That’s why it scared me.Several participants expressed their concerns about the increased overdose risks associated with NPF use, and these fears deterred some individuals from making a complete switch over to NPF pills. As Alex, who used heroin more frequently than NPF pills, explained:It’s very addictive. It’s a lot stronger than heroin so it’s a lot harder to get off of than heroin and that’s another thing that I’ve noticed. I’ve had a lot of people tell me that it’s almost impossible to get off of. That’s what I heard.Others were also concerned that NPF was more difficult to quit because of greater potency and more severe withdrawal symptomatology. Tahlia, a 26-year-old woman from Phoenix, discussed her concerns:This is one of the first studies to describe PWUO experiences with increased availability and use of counterfeit NPF pills in the USA. Similar to prior studies on the initiation of NPF in powder form and/or mixed with heroin , 29, couImportantly, our participants emphasized that counterfeit NPF pills in Arizona were generally used by a smoking route of administration, and for many, changes in the route of administration (from injecting heroin to smoking NPF pills) were viewed as a positive aspect of NPF transitions. No prior studies on heroin to NPF transitions conducted in the eastern part of the country have identified changes in the route of opioid administration that were described by our study participants. A recent study conducted in San Francisco, California,  was the Participant views and experiences with the transition to the non-injection route of drug administration have significant implications for the development of harm reduction services. Prior research has established that the injection route of drug use is linked to greater drug-related harms  than other routes of drug administration –35. MostWe acknowledge that these findings are based on the data derived from a small qualitative sample. Although we were able to recruit participants from distinct regions of the state Fig. , and difOur findings indicate the rapid proliferation of NPF in Arizona, primarily in counterfeit pill form, and are consistent with the law enforcement statistics  and overFrom a community and clinical practice standpoint, there is an urgent need to address the structural and attitudinal barriers for patient access to life-saving medications for opioid use disorder . Our intFrom a research standpoint, it is imperative to continue examining the confounding influence of the COVID-19 pandemic on individuals who are at risks resulting from NPF as the combined crisis could lead to increased health disparities over time  especial


Oryza sativa L.) is one of the most important food crops, feeding half of the world’s population. Its yield relies on its agronomy traits, such as the number of panicles , the number of grains per panicle, and the grain weight. Uncovering and elucidating the mechanism which could influence or regulate rice tiller developments is thus interesting, because it would provide a theoretical foundation for yield promotion.Rice  are activated to grow and form new leaf primordia and finally develop as tillers bearing panicles, whereas other tiller buds are found to stop growing after formation, without elongation, but in dormancy . Recentl3−) and ammonium (NH4+) mostly (Nitrogen (N) is one of the essential macronutrients needed by all plant species, and N deficiency hinders plant growth, thus decreasing yield . A study) mostly .Although SL plays the key role in regulating tiller formation, little is known whether its biosynthesis and signaling genes are involved in N-dependent tiller formation. Therefore, in this opinion paper, we highlighted the emerging evidence to support a potential role of SL in mediating tiller formation in response to N availability. It further allows expanding the knowledge of the molecular mechanisms underlying tiller formation in response to environmental signals.via modulating nitrogen absorption and transport  biosynthesis (asparagine synthetase 1 (ASN1) in rice reduces the concentration of asparagine and inhibits tiller bud outgrowth, hence restraining the number of tillers. It indicates that ASN1 is involved in the bioprocess regulating rice tiller development (4+ and promotes the growth of tiller buds by regulating N-dependent biosynthesis of phytohormone cytokinin (Studies on amino acid transporters (AATs/AAPs) have also suggested that they are involved in the regulation of tiller development. Knocking out ler buds . OsAAP5 ynthesis . The amielopment . Glutamiytokinin .GRF4 ngr2 can largely increase tiller number and thus result in high NUE in the current high-yielding rice .In addition to cytokinin, other phytohormones and several TFs are also involved into the process of which N regulates tiller outgrowth deeply. For instance, the gibberellin (GA) signaling pathway was identified to be essential for N regulation on tiller number . GA can ing rice . Meanwhiing rice . Most repression . The nitDWARF17 (D17) and D10, respectively  by β-carotene isomerases CAROTINOID CLEAVAGE DEOXYGENASE 7 (CCD7) and CCD8, encoded by ectively . CL is fectively . Finallyectively . ImportaD14 , which encodes a SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) family TF SPL14, plays a significant role regulating rice plant architecture  and biosynthesis mutant (d10). It indicates that SL signaling is involved in the coordination of tiller development and P metabolism , a core regulator of the circadian clock, to repress the tiller number, whereas PSEUDORESPONSE REGULATOR1 (PPR1), the suppressor of the circadian clock, causes the opposite effects on D14 expression and tiller development.Under phosphorus (P) deficiency conditions, endogenous SL content is elevated in wild-type seedlings, leading to attenuated tiller bud outgrowth. However, this inhibition does not occur in the SL signaling mutant (tabolism . A recentabolism . The D14Trifolium pretense L.) was elevated in response to various nutrients  and, in sorghum, the major SL 5-deoxystrigol was much higher under low P and also N  were significantly suppressed in SL biosynthetic and signaling mutants , and d3 .d3 and d10 mutants. However, the reduction was much severe in WT, which indicated that the responses to the N level was insensitive in the SL mutant compared with WT (d mutants (Because N is also an important restriction factor for the tiller outgrowth, its regulation on SL was also investigated. Under nitrogen-deficient conditions, the tiller number reduced in both WT and  with WT . To some mutants . The resTiller number is one of the important parameters and agronomy traits determining rice NUE and yield. Understanding the mechanism of its response to N availability is thus necessary and indispensable for high-efficiency agriculture in future. As the core regulator of tiller development, the SL signal is essential in mediating tiller development responses to various endogenous and environmental signals. This is based on promising evidence that several regulators, such as GA signal and TCP transcription factors, which mediate N-dependent tiller development, also interact with SL signaling components. Thus, we proposed a potential role of SL signals in regulating tiller development in response to the available N concentration underground, probably through the activation of the complex signaling cascades Figure 1The author contributed to the writing of the manuscript, to designing the figure, and to its approval for publication.


Savolitinib is a tyrosine kinase inhibitor being developed for the treatment of metastatic non–small cell lung cancer (NSCLC) with mesenchymal–epithelial transition (MET) factor exon 14 skipping alterations. However, the role of savolitinib in neoadjuvant therapy for lung cancer remains unclear. Here, we present a case of a 65-year-old woman diagnosed with stage IIIA  upper right lung adenocarcinoma harboring MET exon 14 skipping alterations. After 4 weeks of therapy, a partial response was achieved with neoadjuvant savolitinib, and significant shrinkage in tumor and lymph nodes was observed. We also measured the immune microenvironment of the primary tumor pre- and posttreatment with savolitinib. Mesenchymal–epithelial transition (MET) exon 14 (METex14) skipping mutations occur in approximately 3% of lung adenocarcinoma patients and 1%–2% of patients with other lung cancer subtypes  scan revealed a mass of 43-mm diameter in the right upper lung and enlarged mediastinal lymph nodes . Bronchoscopic biopsy confirmed the diagnosis of adenocarcinoma of clinical stage IIIA (cT2bN2M0) with a Ki-67 score of 40%. Further testing using a real-time PCR  detected only METex14 skipping mutation. Multidisciplinary team (MDT) recommended neoadjuvant therapy followed by surgical resection. Savolitinib at a dosage of 250 mg twice daily was prescribed after obtaining informed consent from the patient.+ tumor-infiltrating lymphocytes (TILs), and the level of PD-1 expression was increased significantly after neoadjuvant treatment, whereas PD-L1 amount remain unchanged. No CD57+ lymphocytes were detected before and after neoadjuvant therapy.After 4 weeks of treatment, a chest CT scan showed 60% tumor shrinkage and a partial decrease of mediastinal lymph nodes 2. The pNeoadjuvant therapy is recommended to improve the survival rate of stage IIIA NSCLC patients. Previous reports have shown that neoadjuvant-targeted therapies are feasible for oncogene-positive NSCLC patients –8. We reIn the present case, savolitinib exhibited a significant response in an NSCLC patient with METex14 skipping. The Ki-67 proliferation index decreased, and the tumor showed significant shrinkage after the savolitinib therapy, which was followed by successful lobectomy and systemic lymphadenectomy. Although radiological evaluation of most lymph nodes showed significant reduction after savolitinib neoadjuvant therapy, surgical pathology confirmed micrometastasis in lymph nodes [station 2 (2/8)]. Previous studies have reported that the response rate of CTONG 1103 (EMERGING) with a 42-day erlotinib neoadjuvant in EGFR-positive patients decreased, with a major pathologic response (MPR) of 9.7% and a lymph node downstaging rate of 10.8%  treatment, had prolonged responses . Chen etIn conclusion, our study showed that savolitinib neoadjuvant therapy is feasible for NSCLC patients with METex14 skipping mutation. Currently, an ongoing phase II trial of neoadjuvant and adjuvant capmatinib in NSCLC with METex14 skipping mutation is underway (NCT04926831). For NSCLC patients with METex14 skipping mutation, savolitinib as neoadjuvant treatment might provide a better option to replace chemotherapy. Further clinical trials are needed to evaluate the outcome and long-term prognosis of savolitinib in neoadjuvant therapy.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.HZ: Data curation, Formal analysis, Writing Original draft preparation. YZ: Formal analysis, Resources Writing Original draft preparation. HQ: Data curation, Writing- Original draft preparation. JT: Resources. BZ: Visualization. NZ: Formal analysis. LL: Resources. ZQ: Conceptualization, Methodology, Supervision, Writing- Reviewing and Editing. CL: Resources, Conceptualization, Supervision, Validation. SX: Conceptualization, Validation, Visualization. Writing- Reviewing and Editing. All authors contributed to the article and approved the submitted version.The present study was funded by the National Natural Science Foundation of China (82172776), Tianjin Science and Technology Plan Project (19ZXDBSY00060), Tianjin Key Medical Discipline  Construction Project, and Tianjin University training Program for Young and Middle‐Aged Backbone Innovative Talents (303078100412).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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