Geopolymer cement (GPC) is a sustainable alternative to ordinary Portland cement (OPC) that considerably cuts the emission of carbon dioxide linked to the building of concrete structures. Over the last few decades, while a large number of papers have been written concerning the use of GPC with natural aggregates and OPC with recycled aggregates, few papers have been devoted to investigating the use of Geopolymer Recycled Aggregate Concrete (GRAC) in structural members. Most of them show more interest in the mechanical strength of the material, rather than the structural behavior of RC members. This review critically compiles the present and past research on the behavior of structural members cast with different types and compositions of GRAC. The focus is on the few research studies investigating the structural behavior of GRAC elements, with an analysis of the load-bearing capacity, the load-deflection mechanism, shear behavior, tensile and flexural strength, and ductility of GRAC structural members. This review aims to indicate the research and experimental tests needed in the future for characterizing the behavior of structural members made up of GRAC. Six different cylindrical samples with a 100 mm diameter and 200 mm height were prepared. Three of the samples had 100% limestone  and three samples had 100% RA. The mechanical properties of GRAC prepared with FA (19% By Weight (BW)), sodium silicate (6.9% BW), and sodium hydroxide 8 M, 12 M, and 16 M (4.5% BW) were investigated.The results showed that RA can be used in GPC with high calcium fly ash content. In the case of 8 M NaOH, the compressive strength of GRAC was found to be approximately 76.93% of GPC with NA, and 93% and 91% for 12 M NaOH and 16 M NaOH, respectively. In the case of 8 M NaOH, the flexural strength of GRAC was found to be approximately 95% of GPC with NA, while an increment of 4% and 7% was observed for 12 M NaOH and 16 M NaOH, respectively. Finally, 12 M NaOH was found to be most appropriate for GPC with high calcium fly ash content .Wongsa et al. (2020) conducted comparative research to discover the physical properties of Pressed Geopolymer Concrete (PGC) made with GPC. The GPC was prepared with lignite coal fly ash, a sodium hydroxide solution (NaOH), and a sodium silicate solution. The GPC was mixed with RA obtained from demolition waste, Recycled Concrete Block Aggregate (RB), and limestone dust to obtain concrete to be used for concrete blocks. The RA and RB meshed into fine aggregates having a 4.75 mm diameter.The results showed that: (a) pressed geopolymer concrete made up of limestone dust exhibited more compressive strength, less porosity, and water absorption than concrete made up of RB and RA; (b) the compressive strength of pressed GPC made up of RA and RB was nearly equal to the strength of moderate strength lightweight concrete prepared according to ACI 213 ; and (c)Le and Bui (2021) studied the use of GRAC and the effect of the ratio between alkaline activated solution (AAS) and FA and the use of the lignosulfonate superplasticizer. AAS was taken as a combination of NaOH and a sodium silicate solution. Three different AAS/FA values  were used for testing. An alkali-activated binder (geopolymer binder) was made using low calcium FA, a sodium silicate solution, a sodium hydroxide solution, and a lignosulfonate superplasticizer. Specimens were cured both at 60 °C and environmental temperature.The results showed encouraging behavior of the GRAC specimen when the use of low calcium fly ash was joined with curing at 60 °C, even if a 100% replacement NA with RA was made, as a much lower decrease in strength was observed .The use of GGBS, in addition to FA, increases the amount of aluminosilicate content, increasing the compressive strength and modulus of elasticity, and making them less dependent on the Water to Binder ratio (W/B). Moreover, it decreases the negative effect of weak ITZ that affects RA strength, resulting in a higher compressive strength.3 were prepared and tested under a three-point loading test.Hu et al. (2019) performed an experimental study to find the flexural strength of GRAC members using different percentages of Ground Granulated Blast Furnace Slag (GGBS) and recycled aggregates. Twelve different mixtures were prepared. NA replacement was prepared at ratios of 0%, 50%, and 100% by weight. Specimens of size 100 × 100 × 400 mmIt was found that the use of GGBS provides an increment of compressive strength irrespective of the replacement ratio of RA, up to 100% when 30% of GGBS was used. This was due to the increase in high calcium content after GGBFS addition, which ultimately resulted in the formation of a gel phase that reduced the porosity.The flexural strengths of the mixtures with recycled aggregate were found to be lower than that of the corresponding mixtures with natural aggregate. A further decrease in strength was observed with an increase in the RA percentage. The reason for the lower flexural strength was the poor quality of the recycled aggregate and the low bonding strength between the RA and the GPC. However, the flexural strength tended to increase with the addition of GGBS. After the inclusion of 10%, 20%, and 30% GGBS, the flexural strengths increased by 54%, 78%, and 92%, respectively, for the mixtures with 100% RA, and 51%, 60%, and 64%, respectively, for the mixtures with 50% RA , stressiXie et al. (2019) conducted an experimental investigation to find the combined effects of FA and GGBS and considered the effect of W/B on the fresh and hardened properties of GRAC. A total of 100% RA was used for the preparation of GRAC, with different percentages of GGBS, FA, and the W/B ratio. The results revealed that the combination of GGBS and FA provides encouraging results regarding workability and the mechanical performance of GRAC.Replacing the OPC matrix with FA/GGBS-based geopolymer improved the strength of recycled aggregate concretes. The compressive strength of GRAC was found to increase with a decrease in the W/B ratio, and with the inclusion of more GGBS content, the compressive strength increased. The compressive strength of GRAC with 50% and 75% GGBS content was found to be 50% and 180% higher than that of normal concrete .Srinivas and Abhignya (2020) observed that by using FA and GGBS as a replacement for cement and RA as a replacement for NA, GRAC beams, and columns, performed much better than conventional reinforced concrete beams and columns referring to compressive and flexural strength. The optimum replacement percentage of RA was found to be 30% because with this replacement the ductile nature of both geopolymer and conventional concrete beams was almost the same .Moulya and Chandrashekhar (2022) performed an experimental study to find the effect of the recycled aggregate replacement ratio on the strength of GRAC. The geopolymer concrete was made with a fixed ratio of GGBS to FA (50:50), and a sodium hydroxide concentration of 8 M was used. NA was replaced with RA at percentages of 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, and 100%, and tests were performed after 3, 7, 14, and 28 days.The results indicated that as the percentage substitution of RA increased, the compressive strength of the GRAC was reduced, but it was also found that the strength of GRAC increased with age/casting days. The maximum compressive strength of GRAC was found to be 60.02 MPa after 28 days with 70% RA replacement, which was very close to 100% natural aggregate geopolymer concrete. Hence, in this experimental analysis, it was recommended that a combination of FA and GGBS be used, with 8 M NaOH and 70% RA replacement for precast construction with environmental curing .Recently, the use of MK as a binder in GPC has been growing, since it is characterized by a high alumina and silica content and high reactivity due to its pozzolanic nature. Its high reaction speed with calcium hydroxide produces calcium aluminates hydrates and silicon aluminates that reduce the percentage of voids in concrete, improving its mechanical behavior.In (2018) Nuaklong et al. (2018) modified the former mixture for GPC using MK with fly ash-based geopolymer concrete and performed a comparative assessment of the use of NA and 100% RA concrete. Two different schemes were adopted using: (1) Limestone as the natural aggregate in geopolymer concrete; (2) 100% recycled aggregate in geopolymer concrete. It was found that when the metakaolin amount was increased, the compressive strengths of GRAC with metakaolin  were 32.9, 40.4, 45.0, and 47.2 MPa, respectively. GRAC mixtures with metakaolin achieved approximately 15–34% higher compressive strength than concrete without metakaolin. This enhancement of compressive strength was due to increased geo-polymerization and denseness of the microstructure. Increasing metakaolin from 10% to 30% also led to an increase in the splitting tensile strength from 2.9 to 5.4 MPa for GPC with NA and from 2.7 to 3.5 MPa for GRAC. The strength of geopolymer concrete also increased in both types (1 and 2) since the compressive strength of (1) was almost 7–19% higher than (2). Moreover, the researchers stressed that usually, the formation of geopolymer occurs by casting geopolymer slurry in the mold with a significant amount of alkali solution, increasing the chances of high porosity. These pores can act as a point of stress concentration and mechanical failure. In this context, the application of pressure reduces porosity .3 were prepared with different percentages of MK and RA. Flexural strength tests were performed 28 days after casting. It was found that the sample without RA and MK had a flexural strength of 4.59 MPa, which decreased to 4.22 MPa and 3.9 MPa with the addition of 50% and 100% RA, respectively, in the concrete mix. The reason for the reduction was found to be poor bonding between RA and GPC and the presence of loose residual mortar attached to RA. MK proved to be efficient for the increase in flexural strength. For members having 50% RA, flexural strength gains of 2.8%, 8.1%, 9%, and 4.7% were observed with the incorporation of 5%, 10%, 15%, and 20% metakaolin, while 4.6%, 11.3%, 13.8% and 10% flexural strength gains were detected for concrete with 100% RA [Muduli and Mukharjee (2019) conducted an experimental study on the flexural strength of members made of GRAC. A total of 15 samples of size 100 × 100 × 500 mm 100% RA . These rLee et al. (2020) stressed that superplasticizers can be used to improve the workability of concrete, but when they are applied to calcium-rich, alkali-activated materials, they give inconsistent results; by contrast, the use of Methyl Isobutyl Carbinol (MIBC) and polycarboxylate superplasticizers is found to be effective in improving the workability and strength of MK-based geopolymers, especially after 7 days .Berhanul et al. (2021) examined the effect of metakaolin as a cement replacement on the properties of fresh and hardened recycled aggregate concrete and natural aggregate concrete. The recycled aggregates were obtained from first-hand cast laboratory cubes whose compressive strength was already known.Different concrete mixtures were prepared and tested with different percentages of recycled aggregates and MK. Namely, 0%, 6%, 12%, 18%, and 24% replacement of OPC with MK, and 0%, 25%, 50%, 75%, and 100% replacement of NA with RA was made. The results showed that the use of metakaolin as a cement replacement improved the strength of GRAC. In the case of GRAC with 100% replacement with RA, the optimum content for OPC replacement with MK was found to be 6% .Xu et al. (2021) reviewed the current research on the mechanical properties of GRAC, confirming that GPC in GRAC is an ideal substitute for cement and, similarly, RA is also an ideal substitute for NA because of its environment-friendly effects. The strength of GRAC depends on many factors such as the type of geopolymer, the casting temperature, the type of aggregates, etc. But these strength-influencing factors are similar to those for GPC, and there is a lack of research on the use of GRAC so the focus must be on the practical use of GRAC .Treatments of RA to reduce the unfavorable influence on GRAC mechanical properties lie beyond the scope of this review. Here, we will just mention that to mitigate the risk of failure due to the ITZ of recycled aggregates, Liang et al. (2013) previously proposed two different mixing procedures, named the Mortar Mixing Approach (MMA) and the Sand-Enveloped Mixing Approach (SEMA).The schematic diagrams of both methods are given in . In the Recently, Alqarni et al. (2021) proposed a new two-stage mixing approach with silica fume and cement. In this treatment process, a cement-silica fume slurry solution was prepared by mixing the cement and silica fume in different percentages with water by weight. RA was dried in an oven for a day and then cooled. After that, the RA was mixed with a cement-silica fume slurry solution for about 30 min; this treatment was found to increase the compressive strength of concrete .This trend is not reflected in most of the other research in the literature. A more comprehensive comparison of the different approaches to compensating the strength reduction due to the incorporation of significant amounts of recycled aggregates is reported in This section focuses on the structural behavior of GRAC members, reviewing recent research developments on flexural strength, the load-bearing capacity, the load-displacement relationship, and the shear behavior of GRAC structural members. The results are discussed on the basis of the results reviewed in the previous section. Most of the research is devoted to investigating the flexural behavior of GRAC-reinforced beams with fixed concrete properties and the RA replacement ratio being varied, while only one paper investigated the behavior of a shear critical beam , and ano3, longitudinal and hanger reinforcement #2 with ⌀ = 10 mm, stirrups of ⌀ = 6 mm with a pitch of 100 mm, and tested in flexure. Three beams were prepared with conventional concrete mixes having a 0%, 10%, and 30% replacement of RA (1). Six beams had varying proportions of FA (12.6–8.33% BW), GGBS (4.2–8.5% BW), and recycled coarse aggregates  (2). A four-point loading scheme was used in the test. It was found that the average ultimate loads for GRAC beams ranged from 65 kN to 103.55 kN, while for (1) it ranged from 38.1 kN to 55.6 kN. Moreover, the cracking load of GRAC beams was found on average to be 30% more than that of conventional reinforced concrete beams. The load-carrying capacity of all the beams decreased when a larger quantity of recycled aggregates was incorporated. The same load-deflection characteristics were obtained for ordinary reinforced cement concrete beams and geopolymer concrete with 10% replacement of RA. The deflection for (2) ranged between 5.28 mm and 7.04 mm and for (1) it ranged between 3.35 mm and 4.54 mm. The failure behavior of geopolymer concrete beams was found to be similar to that of cement concrete beams, as both types of beams failed initially due to the yielding of the tensile steel; then concrete crushing occurred [Thangamanibindhu and Murthy (2015) carried out research on the behavior of environment-cured GRAC beams. The GPC was prepared using GGBS, FA, and sodium silicate solution. Sodium hydroxide was used as an alkali activator, and a superplasticizer was used to improve the mechanical characteristics. A total of nine beams were cast having a dimension of 100 × 200 × 1200 mmoccurred .Kathirvel and Kaliyaperumal (2016) conducted an experimental study to investigate the influence of RA obtained from demolished construction waste on the flexural behavior of GRAC beams. The casting of GRAC occurred at room temperature. GGBS (19.71% BW), NaOH (3.28% BW), sodium silicate (6.5% BW), and superplasticizers were used to achieve high strength. A total of six beams with dimensions of 1.5 m × 0.1 m × 0.15 m, having #2 @ 12 mm ⌀ longitudinal bars, #2 @ 8 mm ⌀ hanger bars, and stirrups of 6 mm @100 mm c/c were cast. Five beams were of geopolymer concrete having 0%, 25%, 50%, 75%, and 100% replacement of RA, and one beam was normal concrete. All beams were tested under a four-point flexure load scheme similar to that indicated by ASTM C1161 . RA was The results revealed that with an increase in RA content, there was a slight decrease in initial stiffness. Due to pre-wetting and the inclusion of plasticizers up to 50% RA replacement, the compressive strength and water absorption characteristics improved a, while Deepa and Jithin (2017) performed an experimental study to find the strength and behavior of GRAC beams. RA taken from demolition waste were used as coarse aggregate.The ingredients of GPC were low-calcium FA (Class F), sodium silicate alkaline solutions, and a sodium hydroxide solution. Coarse aggregate, fine aggregate, and superplasticizer were used with GPC to prepare GRAC. NA were replaced with RA with the following percentages: 20%, 30%, 40%, 50%, and 60%. The optimum replacement ratio was found to be 40% on the basis of workability. Beams were cast of dimensions 175 mm × 150 mm × 1200 mm, having #2 @ 10 mm ⌀ and #1 @ 6 mm ⌀ longitudinal bars, #2 @ 6 mm ⌀ hanger bars, and stirrups of 6 mm @100 mm c/c. The beams were then subjected to a bending test. From the experimental study, it was concluded that there was a slight reduction in strength and deformability with the addition of RA b. The flThe main aim of the experimental study performed by Srinivas and Anhignya (2021) was to determine the optimum percentage of RA for GRAC and to study the behavior of structural members (beams and columns) when subjected to axial compression or bending. Recycled aggregates were obtained from demolition waste and mixed with geopolymer cement to produce GRAC. In the production of GRAC, GPC was prepared using fly ash (13.68% BW), GGBS (2.41% BW), and an alkaline solution (sodium silicate and sodium hydroxide). Naphthalene sulphonate formaldehyde and superplasticizers were used for better strength of GPC. In this experimental study, 20%, 30%, 40%, 50%, and 60% replacement of recycled aggregates was made. Three beams and three columns of dimensions 150 mm × 150 mm × 1200 mm were prepared. The beams were tested under a four-point loading test and the columns were tested under axial loading.The results revealed that based on mechanical properties and workability, the optimum replacement percentage of RA was 40%. The crack pattern and failure mode of GRAC beams and geopolymer concrete beams were the same. GRAC columns with 40% of RA in axial compression behaved in the same way as geopolymer concrete beams. Due to the inclusion of naphthalene sulphonate formaldehyde, it was also found that almost 8% more ultimate load strength was obtained for GRAC as compared to geopolymer concrete beams; it was thus suggested that GRAC is a practical and eco-friendly solution .Zhang et al. (2021) conducted a comparative study on GRAC and ordinary recycled aggregate concrete beams (OPC with RA). Static loading tests were conducted on three ordinary recycled aggregate concrete beams and seven GRAC beams. Metakaolin-based fly ash geopolymer and alkaline solution were used in the preparation of GPC. MK was used at 5.65% BW, while fly ash and potassium silicate were used at 5.65% BW. The test variables included the RA replacement ratio, the replacement pattern, and the reinforcement ratio. Three replacement ratios  of RA were taken. The conventional aggregate replacement pattern was to replace the same percentage of all particle sizes but in a new, larger replacement pattern; (up to 19 mm) NA particles were replaced with RA, and a 70% replacement ratio was used/set in both replacement patterns. Ten reinforced concrete beams with dimensions (1800 mm (L) × 100 mm (W) × 250 mm (H)) having the same geometry but different concrete types and replacement ratios were made. The bottom longitudinal reinforcement of eight beams was #2 @ 14 mm ⌀, one beam was #2 @ 10 mm ⌀, and one was #2 @ 18 mm ⌀. For all beams, the hanging bars were #2 @ 10 mm ⌀ and stirrups were 6 mm ⌀ @ 100 mm spacing.The tests revealed that the geopolymer concrete has the same compressive strength as ordinary concrete but with a smaller elastic modulus  because Young’s modulus of geopolymer concrete is affected by a microstructure based on speciation of the alkali silicate activating solutions as well as the properties of the aggregates. Because of this, GRAC beams have a lower height of the neutral axis and more deflection than ordinary recycled aggregate concrete beams at the same loading a, depend3 were cast for each shear span-to-effective depth ratio and each concrete mix type. Then, 4-point bending tests were performed to determine the shear behavior of the beams. Parameters including load-deflection curves, moment curves, and crack propagation were used to assess the mechanical performance of the beams. It was also found that the compressive strength of the members made of this GRAC was 3% higher than that of conventional concrete members. The results indicated that the beams made up of geopolymer concrete exhibited a similar performance to normal concrete beams of the same grade. However, when recycled aggregates were used, then the failure mechanism shifted from flexure-dominated to shear-dominated. This shift was more common in the beams with a larger span to an effective depth ratio [Aldemir et al. (2022) were the only researchers who investigated the shear behavior and structural performance of GRAC beams in detail. A new type of geopolymer concrete was prepared from demolition wastes. Roof tiles, red clay, hollow bricks, and concrete rubble were used as wastes along with slag, fly ash, sodium hydroxide, and sodium silicate. In this study, four different mixes were prepared: (1) GRAC, (2) geopolymer natural aggregate concrete, (3) ordinary recycled aggregate concrete, and (4) normal concrete. In previous studies, the authors found that with the addition of RA both in ordinary concrete and in GPC, workability and compressive strength decreased but, in this study, it was assessed that, when the same Water Cement Ratio (W/C) ratio is used, in GRAC the porosity of the concrete decreased because part of the water is absorbed by the RA, thus increasing the strength of the concrete. Three shear span-to-effective depth ratios  were used to examine the different failure modes. Four beams of dimension 150 × 250 × 1100 mmth ratio .Raza et al. (2021) performed an experimental study on the structural performance of GRAC columns with glass fiber-reinforced composite bars and hooks subjected to a compressive axial load. Nine mid-scale circular columns of dimensions 250 mm × 1150 mm, having six, eight, or ten longitudinal reinforcing bars , and pitch hooks at 75 mm, 150 mm, and 250 mm  were tested. The mix design of GPC was chosen with the following proportion by weight: RA 50.13%, sand 21.18%, water 5.20%, sodium hydroxide solution (14 M) 1.65%, FA 10.236%, GGBS 6.89%, superplasticizer Sika ViscoCrete-3425 0.16%, and sodium silicate 4.44%.GRAC was prepared with the 100% replacement of NA. The axial force-displacement curves in The bond strength between the concrete and steel reinforcement is essential for the ultimate strength of the structural members. Romanazzi et al. (2022) performed an experimental investigation to examine the bond behavior of GPC with steel bars and sand-coated Glass Fiber Reinforced Polymer (GFRP) bars using a pull-out test. The test results revealed that the adhesion bond characterizing the behavior of GPC is stronger than that shown with OPC, both for sand-coated GFRP bars and deformed steel. However, the ultimate bond strength of GPC with steel bars was two to three times higher than that of sand-coated GFRP bars. This is due to the fact that there is adequate mechanical interlocking and a good bond strength between the GPC and steel bars, irrespective of the bar diameter. Thus, in the case of GFRP bars, the predominant mechanisms are those of adhesion and friction, while between concrete and steel bars, the predominant contribution is that of mechanical interlocking .The use of geopolymer concrete with recycled aggregate is a complex topic. The efficiency of GRAC depends on several factors: the type and composition of GPC, the molarity of the alkaline solutions, the mixing procedure, the curing temperature and environmental conditions, and the mechanical and chemical characteristics of the RA and ITZ; how these factors relate to the amount and characteristics of the attached mortar; the extraction process from the demolition construction waste; and, lastly, the replacement percentage of RA with NA, etc.The type of geopolymer cement created is one of the most important aspects, as different amounts and types of chemicals are used in the production of GPC. In older studies, GPC was prepared with fly ash and the results were not very encouraging (the recycled aggregate replacement ratio was limited to 30–40%).In recent research, it was found that when metakaolin and GGBS-based GPC were used, larger values of replacement ratios (up to 100%) can occur without a significant reduction in the flexural strength of the structural member. The tensile strength of GPC concrete can increase the cracking strength of the beam, which decreases with an increase in the RA replacement ratio; however, OPC with NA-reinforced beams and GRAC-reinforced beams usually exhibit a similar failure mode and cracking pattern. Only a shear-critical beam can exhibit premature failure when GRAC with a large RA replacement ratio is used.A large amount of RA can cause workability issues, but from the latest research, it was also found that the use of polycarboxylate superplasticizers and methyl isobutyl carbinol (MIBC) can improve workability, allowing for a reduction in the W/B ratio and increasing the strength of metakaolin-based geopolymers.In this regard, it must be pointed out that most of the research was performed using RA in a saturated surface condition which reduces the compressive strength and elastic modulus of the concrete.The excessive use of alkali activators reduces the elastic modulus of concrete, causing an increase in beam deflection. Hence, a precise quantity of alkali activators in relation to other materials should be used in GPC production. There is not yet a unanimous consensus on the exact quantity and type of material; therefore, the quantity and type of GPC should be chosen depending on the characteristics of available RA.An Interfacial Transition Zone (ITZ) develops between the attached mortar and the new cement paste. This is one of the weakest zones, so proper chemical and mechanical treatment is advised before using RA. It was found in the latest research that the addition of fillers and fly ash is helpful to fill the pores of RA, thus reducing the vulnerability of failure along the ITZ; to this aim, the Two Stage Mixing Technique (TSMA) can also be adopted, in which a cement coating forms on the surface of the recycled aggregate, thus filling up the cracks before actual mixing of concrete.From the literature review, it is seen that there are no general limits to the use of coarse RA in a concrete mixture. Some of the former researchers recommended a maximum 30% replacement of NA with RA, while recent researchers suggest that the RA replacement can be up to 50% or 100% if the mix design, batching methodology, and moisture condition of the RA are properly handled. In most of the research, the use of a 70% RA replacement ratio does not significantly affect the load capacity and only slightly affects the deformability of the GRAC beam loaded in flexure.In general, much research is still needed to identify the optimal mix design and to optimize the production methods and rules for setting the geopolymer concrete and its mechanical properties, particle size distributions, and aggregate processing for the production of GRAC. However, current knowledge already makes it possible to produce GRAC with a predetermined class of compressive strength, while its tensile strength and related characteristics, such as the bond between GRAC and reinforcement, related cracking phenomena, and ductility that can be conferred through confinement, are more uncertain.Particular attention must be paid when GRAC is to be used in conjunction with GFRP bars, since the confinement of the transverse reinforcement, which is able to provide an increase in compressive strength, is not always effective in increasing the deformation at the decay of resistance to 85% of the maximum value, and, more generally, ductility and toughness, a condition which can only be achieved in the presence of an adequate number of longitudinal bars capable of transferring the confinement action exerted by the transverse reinforcement more uniformly.Regarding the bond between GRAC and reinforcement, GRAC has exhibited promising behavior when used in conjunction with steel cold-form reinforcement, while bond strength is reduced up to 33% when used with sand-coated GFRP bars. This is because the predominant influence ensuring the bond between concrete and steel bars is mechanical interlocking, while in the case of GFRP bars, the predominant mechanisms are those of adhesion and friction.It is also found that no research has been conducted on the beam-to-column joint made up of GRAC. The beam-column joint is one of the most vulnerable structural members belonging to moment-resisting frames made of cast-in-situ concrete. Thus, in order to prove the effectiveness of GRAC, this aspect should also be analyzed.Similarly, a research gap has been found regarding the seismic behavior of GRAC structural members. The seismic assessment of GRAC structural members should be carried out in order to evaluate the ductility and energy dissipation capacity of reinforced GRAC for construction in seismic areas.Therefore, from the above literature review, it can be concluded that there is still a need for experimental tests that study the behavior of structural members made up of GRAC, characterizing the phenomenon of bond, the strength and ductility of members subjected to bending with or without axial load, and the shear strength of members with and without transverse reinforcement. Moreover, there is a need for studies focusing on the influence of the casting and curing conditions on the mechanical strengths of the structural member.


Rugby union is a popular and continuously growing sport globally. With the advance of technology, practices have been implemented to quantify the match running demands of rugby union players. The aim of this study was to analyse the match loads of rugby union players between the 2016 and 2018 Varsity Cup competitions.The sample consisted of 562 match observations of male university rugby union players competing in the Varsity Cup tournaments.p = 0.001; ES = 0.49); have greater high-speed running , very high-speed running  and sprint distances  than forward players. Backline players also accumulated a high number of metres per minute , total Player Load , RHIE  and number of accelerations .The backline players ran significantly longer total distances (5105 m; These findings may assist coaches to develop player position specific training programmes to meet the physical demands of rugby. In rugby union, players experience an extensive amount of high-intensity running, with bouts of low intensities which occur throughout matches. The game of rugby requires players to be well-conditioned with respect to endurance, speed, agility, power, flexibility and game-specific skills.,4 The use of microtechnology, such as Global Positioning System (GPS) devices, has enabled practitioners to quantify the match loads of rugby union players.,6 The knowledge gained from this technology allows for detailed position speciﬁc movement proﬁles that could help facilitate optimal player training programmes in match-play preparation. ,6,7Rugby union has become one of the most exciting and a continuously growing sport around the world. Total distance has been reported to be dependent on playing position, with backline players covering greater distance (6471 m) than forwards (5853 m) during matches. In a related study, a detailed analysis of physical demands among professional rugby union players at university level in England was carried out by Read et al. . Findings showed that forwards and backline players covered total distances of 4683 m and 5889 m, respectively.  It was further reported that forwards typically accumulated greater Player Load and Player Load (slow) measures than backs.  The high volume of these metrics could be due to short burst of directional changes associated with backline players during match-play.The characteristics of the in-game demands have been explored generally between the forward and backline players in rugby union. A systematic review by Glassbrook et al.  found that backline players covered the greatest relative distance at high speed; however, it was not significantly different to the forwards in the professional rugby league. In contrast, forwards covered significantly less slow-speed distance than the backs. The authors further reported that forwards completed the greatest number of repeated high-intensity efforts (RHIE) over a full match than backs. Previous studies have found that backline players covered a higher number of sprints and accelerations than forward players.,13Differences between positions have also been noted in relation to high-intensity activities during match-play. , 11 there is a paucity of information on university players in South Africa. With the game of rugby union evolving, it is important for coaches to better understand the physical demands of the modern game to implement more specific training programmes. Understanding the physical demands of rugby players during match-play is essential for sports scientists and coaches to develop game-specific conditioning programmes. , 14 The aim of this study was to analyse the match loads of rugby union players between the 2016 and 2018 Varsity Cup competitions.Despite the physical demands of rugby union players in professional leagues, This study used a longitudinal retrospective quantitative design utilising secondary data.The sample consisted of 562 match observations of male university rugby union players from 25 matches in the 2016–2018 Varsity Cup tournaments. The players were grouped according to the following playing positions: forwards and backs. Ethical clearance was obtained from the university ethics committee (REC-01-159-2018). The distances examined are total distances, as well as distances covered in four key velocity bands. These were moderate speed running (7–16 km/h), high-speed running (16–20 km/h), very high-speed running (20–25 km/h) and sprinting distance (>25 km/h). Player Load expresses arbitrary units of the square root of the sum of the squared instantaneous rates of change in acceleration in each of the three planes of motion and further divided by 100.  The difference between Player Load and Player Load (slow) is that in the latter, the velocities achieved by the players are less than 2 m.s−1.  Another metric unit which is widely accepted as a critical variable to consider is RHIE. These efforts take place, with minimal recovery (~6 s), during and after tasks such as tackles, rucks, and accelerations during match-play.  After every match, the data were exported to a Microsoft Excel spreadsheet.Data were collected by a strength and conditioning coach who used the Catapult Optimeye X4 microtechnology device which was worn by each player in a tight vest during the matches. The microtechnology device has shown levels of accuracy and reliability for distance and speed measurements during intermittent exercise bouts involving high-intensity actions.t-test was used to compare differences on match loads between back and forward players. Two-way analysis of variance was used to examine the interaction between the year and playing position (backs and forwards) on match running distances of rugby union players. A significance level was set at p<0.05. Effect size (ES) was also used to assess the magnitude of the differences in the mean scores of variables. ES values were interpreted as follows: trivial (<0.20); small (0.20–0.59); moderate (0.60–1.19); large (1.20–2.00); and very large (>2.00). All analyses were conducted using the IBM SPSS Version 25.Data were reported as means ± standard deviations. An independent p = 0.001; ES = 0.49, small effect), high-speed running , very high-speed running , sprinting distance , metre per minute , total Player Load , RHIE  and number of accelerations . In contrast, forwards had higher Player Load (slow)  than backline players. who reported that backline players and forwards covered total distances of 6392 m and 5731 m, respectively. The low total distances observed in the current study may be attributed to the fact that the sample consisted of semi-professional rugby union players from the university competition, while that of Yamamoto et al.  included professional players from the Japanese domestic league teams. This supports Gabbett et al., who highlighted that the professional rugby league places considerable physical demands on the aerobic energy system. Therefore, the level of competitiveness may differ within teams of elite and less elite players, as well as teams playing in different countries.–8, 14 The greater physical demands on backline players in the present study demonstrates that conditioning drills can then be tailored to the specific playing position match demands. The aim of this study was to analyse the match loads of rugby union players between the 2016 and 2018 Varsity Cup competitions. The findings showed that backline players covered total distances of 5105 m while forwards ran 4097 m during rugby matches. The reason why forwards covered less distance is because of the game dynamics as they are more involved in set pieces and collisions. However, the present results are lower than those of Yamamoto et al.  and Lacome et al.  respectively who reported that forwards run significantly lower total distances during a match. A plausible reason for this finding could be that backline players cover larger distances in matches because they generally run from a deeper position in field than their forward counterparts, thus creating more space for the backline players to gain speed for their runs with the ball in hand.  Consistent with previous research,  the present study suggests that forwards should be prescribed more low intensity activities than backline players but should complete prescribed high speed and sprinting distances.Backline players covered longer distances at very high-speed levels and with sprinting than forwards, by a large proportion. These findings are in line with those of Austin et al.  It should be noted, however, that the magnitude of the difference in total Player Load was small between backline players and forwards, demonstrating that there are minor variations in the physical demands of rugby matches at university level. The current study also indicated that forwards had greater Player Load (slow) than backline players. Therefore, it seems that both backline players and forwards accumulate similar loads from low velocity activities such as tackles and physical collisions.  This result contrasts with previous research which found that backline players achieved a higher Player Load (slow) than forwards in New Zealand.  Such discrepancies could be due to different playing tactics or strategies and the physical capacities of players across countries.This study also found that backline players had a significantly higher total Player Load than forwards. A possible explanation for this may be that backs are attributable to both being tackled and having short bursts of changes of direction during matches. indicated that backline players are more likely to perform intense accelerations than their forward counterparts during the game. It has been previously reported by McLellan, that backline players are found in more space on the outer edges of the field. As a result, they need to accelerate to reach the opposition when carrying the ball, as well as having to sprint when performing kicks and chases. In view of the importance of acceleration in rugby union, the training programmes should consider the differences in the playing positions. Sprint training programmes for rugby players should focus on developing acceleration qualities for all playing positions, with the greater emphasis on backline players. Preferably, forwards should emphasise acceleration from a standing start, while backline players are needed to effectively change between jogging and sprinting.Backline players recorded a significantly higher number of accelerations than the forwards. Yamamoto et al.  A variation in this law occurred in 2017, which may have influenced the team to change their in-game tactics to use this variation to their benefit. This law was aimed at promoting attacking rugby and ball retention, and therefore players may have had increased possession and opportunities to run further during matches.In the 2016 Varsity Cup, forwards ran their highest total distance, while running less in the 2017 and 2018 Varsity Cups respectively. When the Point of Origin law was introduced in 2016, the teams may have been uncertain how to fully utilise this law to their advantage and therefore this may be a reason as to why the forwards ran their highest distance during matches in 2016.Although this study provided novel information on match running demands of university rugby union players, certain limitations should be noted. The current study consisted of players from one team, which limits the generalisation of findings to the whole population. Furthermore, this study did not consider a specific playing position , locomotive characteristics (accelerations and decelerations) and situational variables . Future studies should also combine GPS to match physical demands and technical indicators using video-based performance to provide a comprehensive reflection of the more specific running position profiles of university rugby players.This study found that backline players significantly covered greater total distances, high-speed running, very high-speed running and sprinting distance than forwards. The backline players also had higher averages on RHIE, total Player Load and number of accelerations than forwards. These results have practical implications for rugby coaches in the development and implementation of individualised training sessions according to playing position. Therefore, it is recommended that training for backline players should focus on developing aerobic capacity and sprint training sessions in a match scenario. Similarly, low speed running exercises should be recommended for forwards while completing the prescribed high-speed and sprinting distances.


Antibiotic resistance is a global health challenge that threatens human and animal lives, especially among low-income and vulnerable populations in less-developed countries. Its multi-factorial nature requires integrated studies on antibiotics and resistant bacteria in humans, animals, and the environment. To achieve a comprehensive understanding of the situation and management of antibiotic use and environmental transmission, this paper describes a study protocol to document human exposure to antibiotics from major direct and indirect sources, and its potential health outcomes. Our mixed-methods approach addresses both microbiological and pathogen genomics, and epidemiological, geospatial, anthropological, and sociological aspects. Implemented in two rural residential areas in two provinces in Eastern China, linked sub-studies assess antibiotic exposure in population cohorts through household surveys, medicine diaries, and biological sampling; identify the types and frequencies of antibiotic resistance genes in humans and food-stock animals; quantify the presence of antibiotic residues and antibiotic resistance genes in the aquatic environment, including wastewater; investigate the drivers and behaviours associated with human and livestock antibiotic use; and analyse the national and local policy context, to propose strategies and systematic measurements for optimising and monitoring antibiotic use. As a multidisciplinary collaboration between institutions in the UK and China, this study will provide an in-depth understanding of the influencing factors and allow comprehensive awareness of the complexity of AMR and antibiotic use in rural Eastern China. Since the mass production and clinical application of effective antimicrobials in the 1940s, their effectiveness in treating bacterial infection has been challenged by a gradual increase in antimicrobial resistance (AMR) worldwide . The eveThere is a high burden of AMR in China ,11, withPopulation exposure to antibiotics is not limited to clinical use, as antibiotic residues can be transmitted through the living environment. While the biological drivers of antibiotic resistance are well explored, human–microbial interactions are less well understood. Although microbial ecosystems among human, animal, and environmental components differ, the environment acts as a bridge in the accumulation and transmission of antibiotic-resistant bacteria (ARBs) and ARGs between humans and animals, particularly through food sources and excrement. The widespread use of antibiotics does not only put pressure on both humans and animals, but also affects the environment, which, in turn, may result in further selection and circulation of ABRs among different microbial ecosystems. Researchers have investigated resistance genes in humans, animals, and the aquatic environment, but only a few studies have explored transmission across different environmental compartments .Policy interventions and surveillance of antibiotic use and ABRs mainly focus on pharmaceutical prescribing within the healthcare system and in retail outlets. National policies and regulations, together with the national surveillance system, provide generic guidance on antibiotic use; meanwhile, in practice, multiple departments at provincial and lower levels may design or specify detailed and context-related policies or guidelines in accordance with the local situation across healthcare, food and drug administration, the environment, and agriculture. Thus, although several studies have demonstrated reductions in the overall use of antibiotics following national interventions on antibiotic use and healthcare reforms, their effects on local patterns of antibiotic prescription and use have been little-documented, particularly in rural settings, outside the public healthcare system, and in relation to food safety and industry.To achieve a comprehensive understanding of the situation and management of antibiotic use and environmental transmission in Eastern China, this protocol describes a study to document human exposure to antibiotics from major direct and indirect sources, as well as its potential health outcomes. Our mixed-methods approach addresses both microbiological, pathogen genomics, epidemiological, geospatial, anthropological, and sociological aspects. Implemented in two rural residential areas in two provinces in eastern China, linked sub-studies will assess antibiotic exposure in population cohorts through household surveys, medicine diaries and biological sampling; identify the types and frequencies of ABR genes in humans and food-stock animals; quantify the presence of antibiotic residues and ABR genes in the aquatic environment, including wastewater; investigate the drivers and behaviours associated with human and livestock antibiotic use; and analyse the national and local policy context, to propose strategies and systematic measurements for optimising and monitoring antibiotic use.This study aims to investigate direct and indirect human exposure to antibiotics and the subsequent potential health effects; the transmission of ABR in the aquatic environment, animals and humans; and current policy provision and implementation relating to ABR through a set of linked sub-studies, in order to provide the evidence needed to facilitate effective antibiotic stewardship and identify ways to monitor and control potential health hazards.To comprehensively assess the exposure levels of humans to antibiotics from clinical and environmental sources.To investigate the types and abundance of ARGs; assess the effects of antibiotic exposure on resistance genes; and explore possible pathways of transmission of ABR genes among livestock, the environment, and the population.To describe the spectrum of antibiotics and usage patterns in representative Chinese populations, and explore the relationship between the use of antibiotics and exposure levels of humans to antibiotic residues and antibiotic-resistant genes.To assess comprehensive spatiotemporal community-wide public exposure to antibiotics  and the resulting ABR using wastewater-based epidemiology (WBE).To understand the current policy context relating to antibiotic usage and systems for monitoring ABR; to explore the implementation of policies to limit antibiotic use in the health, agricultural, and environmental sectors; and to identify strategies to improve monitoring and optimise antibiotic use.The study objectives are:Due to its dense population, intensive livestock breeding industry, and high antibiotic use, East China is a well-recognised hotspot of antibiotic consumption and ABR. This study focuses on two economically and epidemiologically distinct rural residential areas in Eastern China—Village A of Zhejiang Province and Village B of Jiangsu Province. Both sides are economically comparable, but the former is a relatively remote setting, whereas the latter is located near a large city with convenient access to its healthcare system. Differences between settings, antibiotic use, local regulations, water environment, and poultry and aquaculture practices in the two communities provide opportunities for comparison. The study sites were selected to facilitate the use of existing epidemiology study cohorts to explore the potential long-term effects of antibiotic use and exposure to environmental antibiotic residues and resistance genes.Study site A has a total population of 2071. The local topography is high in the west and low in the east; the source of surface runoff in the dry season is via a lake system, and during the rainy season, it is mainly via a mountain water system. Water in the local community is supplied by a centralised water plant. Residents’ drinking water is mostly via tap water, but wells and ponds are used for washing and laundry. The treatment of rural domestic water discharge is “one pipe connected to the end”, as bathroom sewage, kitchen sewage, washing sewage, and bathing sewage are all collected by the same pipe system and delivered to the sewage-treatment terminal. Aquaculture farming is the main local business, and the total scale of ponds is around 1.33 million square metres. Specialised ecological channels surrounding the farm ponds are used to transfer fishery farming discharge/wastewater to the specialised treatment facility. Although residents cultivate small-scale crops and poultry for self-consumption, their main source of food for daily consumption is the grocery store and supermarket.Study site B is a community with around 1978 residents in an area that traditionally has a high incidence of liver cancers. Local housing follows a linear pattern alongside irrigation canals, and the housing and canals are interlaced within the residential area. Water in the irrigation canals is stagnant, filled with precipitation and residential domestic water discharge as the two main water sources; excrement from poultry from local households is directly discharged into the open irrigation canals. The local population has high exposure to irrigation canal water, as it is used by the surrounding residents for their small-scale poultry and aquatic farming, the products of which are consumed by the residents directly; it is also used during food preparation. Even though tap water and well water are the main sources of drinking and cooking water, the groundwater level is less than three metres deep.Wastewater Treatment Plants (WWTPs) located adjacent to study sites A and B will be included to explore public exposure to antibiotics in larger communities using the wastewater-based epidemiology (WBE) approach. Due to the complexity of local economic structure, sources of antibiotics in WWs include hospitals, residential areas, animal farming and industrial districts. A total of 6 WWTPs representing different scales will be selected, which serve population sizes ranging from 12,000 to 634,000 in the local area.To measure local population exposure to antibiotics, all adults living in the study areas for no less than three months and able to give consent to participate in the study will be eligible for recruitment. All participants will be invited to complete the survey and record daily medicine intake in the household for a one-year period.All village clinics, township health centres/hospitals, and county hospitals that serve the two areas will be included in the formal research. At each study site, physicians and health professionals from different departments of county-level and community-level health institutes, especially professionals overseeing the management of clinical antibiotic use, will be invited for interview. In-depth interviews will be conducted with relevant experts, including officers in hospital or pharmacy management departments, managers from the local health committees, medical product administration, and managers from county-level hospitals and township health centres. Technicians and related personnel in county hospital labs will also be included in the formal research. Local farmers, workers from retail pharmacies and veterinary pharmacies and veterinary technicians will also be interviewed.Microbiology and genomics analysis will include collection of human , animal , and environmental (water and wastewater) samples from local residential and occupational populations, livestock, and aquatic products. ARG detection will be used to explore the distribution of ABR genes in the environment and animals, as well as the potential transmission from environmental and animal sources to the residents.Environmental assessment will focus on sampling different types of water, which includes household drinking water such as tap water, well water, and bottled water, and wastewater from treatment plants, farms, irrigation canals, and the water surface surrounding the residential areas. The objective is to assess potential environmental exposure to antibiotic residues and ABR genes in the water and its association with local population exposures—which will be measured via urine samples from households in the two study areas.To describe the spectrum and patterns of antibiotic use in the population and livestock, and explore the relationship between antibiotic use, ABRs, and human health in the daily living context, village doctors, patients, and residents from the two study sites will be recruited for semi-structured interviews. Information on residents’ antibiotic use will be collected both inside and outside the healthcare system. Clinical prescription data will be obtained through electronic patient records from hospitals, but the records do not contain comprehensive information on antibiotic use at lower-level health facilities or where antibiotics are purchased over the counter from retail pharmacies.A survey questionnaire and a medicine diary  and biochemical tests (urine creatinine) will be performed at the time of the annual health check and household survey. Spot urine samples will be collected from each participant during the investigation and stored at −20 °C at the local health service centre. All samples will be transported to the lab within one month after collection and then stored at −80 °C for future analysis of antibiotics. Two-hundred and twenty-five (225) flesh samples of fish will be collected from local fish farms and households. A total of 115 food samples from meat, market produce, and abattoirs will be collected and analysed for antibiotics.In all study areas, we will conduct geospatial mapping of observed surface water using a GPS-enabled drone. Two detailed maps of the selected study sites will be drawn and measured to depict the geographic distribution of municipal sewage discharge, main rivers, and cultivation industry (including aquaculture farms and chicken farms). The mapping area will also include local resident households, from which 20 households per site will be selected randomly. Drinking water samples, cooking/well water samples, and surface water samples from the nearest location will be collected from each household. For water samples collected from the river, the sampling location will be at both ends of the river, and also at each site of given distance along the river. The collection of water samples will be repeated during different seasons (dry and wet) with two parallel samples collected at each site. GPS coordinates will ensure the repeatability of geographic location of sites. By connecting the wastewater sample with medicine diary, this will enable us to explore the connections between residents’ antibiotic use and ABR residues in the wastewater sample.Wastewater sampling will be conducted during different seasons, along with the above-mentioned environmental sampling in the villages. Influent samples will be collected over 7 consecutive days for each campaign. In order to obtain a representative influent sample, a flow-proportional composite sampling strategy will be adopted by using an auto-sampler to collect influents at regular time intervals for 24 h. The method used for the quantification of antibiotics in wastewater will follow a previous study . A totalThe genomic DNA of the samples from wastewater will be extracted and sequenced ,24. ExtrIn addition to metagenomic sequencing, representative ABR genes will be selected for quantitative PCR (qPCR) analysis. The selection of ABR genes should correspond to the antibiotic groups analysed. The ABR gene spectrum of microbiome in the population, animals, and the environment will be analysed and integrated with the characteristic of antibiotic exposure.Solid-phase extraction (SPE) will be conducted using a sample preparation protocol developed by Holton et al. . BrieflyRaw data originally generated from the instrument will be integrated using MassLynx software packages , and results will be presented as concentration levels (ng/L or μg/L) in wastewater influents. Daily mass loads of antibiotics will be calculated by multiplying the concentrations of the analytes by the daily flow rate (L/day) and then normalised by the population size of the served communities . Human metabolism and sewer loss will be incorporated into the calculation to correct the antibiotic consumption levels in the community. Final data will be presented as (mg/day/1000 people) and will further be compared with the medicine diary data to fully understand the spatiotemporal public exposure vs. the environmental burden of antibiotics.TM system coupled with a Xevo TQD-ESI Mass Spectrometer. Mobile phase and matrix quality controls will be used to monitor analyte calibration and physical–chemical behaviour between the varying sample compositions. Physical sample duplicates will be prepared and analysed to improve overall confidence.After the sample collections are completed, samples will be stored on ice until transferred to the laboratory. Deuterated (stable isotope-labelled) standards will be spiked on-site and samples will subject to solid-phase extraction. The analytical method for antibiotic quantification will be performed using a Waters ACQUITY UPLCHousehold registration records from two sites will be used as the overall sampling frame, in which all long-term residents (living in the area for at least three months at the time of survey) will be recruited. Residents who were not documented in registration records but meet this criterion will also be recruited in the study. Survey will be carried out during the local annual health examination—a free health service funded by NRCMS medical insurance scheme and provided by the local community to all residents. If residents were absent from the health check-up, they will be contacted afterwards by the researcher, assisted by local practitioners and community workers.A trained survey team will administer the questionnaire to those residents who consent to being recruited following their physical examination and collection of urine samples. Representatives of the research team will be present to ensure quality control. The structured questionnaire will collect detailed information from respondents, including demographic information, medical history, personal lifestyle, physical activity, dietary preference, self-evaluated health status (using EQ5D-5L questions), and attitude and knowledge on antibiotic use (adapted version based on WHO ABR awareness survey). Those residents who do not attend the annual health examinations will be contacted subsequently by the village doctor on their regular household visits. Doctors and researchers will seek non-attendees’ consent to be recruited to complete the survey and provide relevant samples.Statistical tests will be performed in SAS or SPSS software. The dietary exposure to antibiotics will be estimated by combing data on antibiotic contamination in foods and drinking water, along with the information on dietary consumption. Multiple statistical models, including the logistic regression model and linear regression model, will be used to explore the potential effects of exposure to antibiotics from multiple sources on obesity, diabetes mellitus, asthma, and IBD in the cohort, by examining the associations between their occurrence and antibiotics in urine, after adjustment for potential confounders.During initial recruitment, all participants will be asked to provide consent to being followed up for the data collection of their medicine diaries. Data collection will continue for 12 months to capture possible seasonal variations. A structured and self-reported form has been developed to collect information on demographic backgrounds, chronic disease, and daily use of medicine of all members in the household.Those who consent will receive training on how to complete the medicine diary from local village doctors. Data on medicine use for each household member are recorded weekly by participants using the structured form to capture the types, reasons, sources , frequencies, doses, side effects, and other details of both antibiotic use and use of medicines for long-term conditions. Considering the length of the data collection period, accessibility of the sites, and dialects, local village doctors will be trained to provide consultation to the participants and assist with data collection. Medicine diaries will be collected by the village doctor from households, while researchers will collect each batch of medicine diaries, carry out onsite quality control, and analyse the data monthly. Village doctors will also contact participants regularly through telephone calls as a reminder of the monthly diary collection. During the period of data collection, all pharmaceutical packages of the medicine consumed by the participants will be collected side-by-side. Modest remuneration in kind will be provided at the time of diary collection to acknowledge participants’ time and effort.All data will be double-entered into EpiData software . Qualitative data will be coded and analysed using the inductive method. The results will be correlated to the consumption mode of antibiotics based on the medicine diary. To ensure data quality, all data will be recoded and double-entered by a special team of graduates. The investigators will provide a detailed interview manual and undertake onsite quality control.One year of medicine records, including pilot and pandemic period, in local healthcare facilities  will be collected. Completed medicine diaries will then be used to compare with individual patient records from the local village clinic every three months in the following year. The research team will review all entries in the electronic records, and the records will be matched with participants using their medical insurance number and ID number. This data will be anonymised and utilised to compare with self-reported medicine diaries and calculate the rates of antibiotic prescription and self-medication.Qualitative data will be collected using standardized and semi-structured topic guides across study sites. Interviews will be audio recorded with pre-consent. Data collection will stop once data saturation has been reached. Participants will include farmers, patients, doctors, administrators, and managing staff  and doctors (20 per study area) will take place in the recruitment village clinic, township health centre, private clinics, andprivate hospitals. Two topic guides will be used to investigate their experience of consultation and diagnosis; knowledge and attitudes on antibiotics; and understanding of resistance and regulation. In addition, a series of COVID-related questions will be used to investigate the influence of the pandemic on the prescription and use of antibiotics.The administrator and managing staff from local government will be recruited to explore the detailed regulation and surveillance of antibiotic use, residue, and resistance. All administrators and pharmacists whose main responsibility relates to stewardship in local regulation departments and recruited hospitals will be interviewed to understand the accessing of antibiotics, possible economic drivers, and institutional regulation of antibiotic use. Based on a pilot study and the local staffing structure, 10–15 interviews will be conducted per study area. Pharmacy and veterinary pharmacy workers located within the areas of study will also be recruited. Relevant managing staff (5 per study area) and poultry and aquatic workers (10 to 15 per study area) will be interviewed to collect their knowledge and practice of antibiotics in farming activities.In each study site, based on the population age and gender structure, 2 to 3 focus groups of 20 to 30 residents who have completed the household survey and medicine diary, with different socioeconomic statuses, will be recruited. The topic guide will cover recent experience of illness, experience of healthcare services, accessing drugs, attitudes and knowledge on antibiotic use, perceptions of resistance, and proper use.For qualitative data, coding will be undertaken independently by at least two researchers for each sub-group of informants in NVivo v.12 and a common coding framework developed. Following the identification of emergent themes, further coding across groups will be undertaken to generate generalizable findings. Interview data will be used to characterize antibiotic use and systems for ABR monitoring in our study regions, including the allocation of incentive, human resources, technologies, and information, and the building of supervision systems. The implementation processes and outcomes of these policies and regulations, including how health and agricultural sectors aim to reduce the use of antibiotics, supervision tools, incentives for changing behaviour, and outcomes, will be assessed. Recommendations and strategies for optimizing antibiotic use and ABR monitoring systems in lower-level hospitals and rural health facilities will be informed by the key findings and international comparisons.Data gathered during focus group discussions will be analysed using systematic thematic coding in NVivo to explore experiences of treatment-seeking and antibiotic use, including self-medication; drivers and practices regarding antibiotic use; and ABR in communities and livestock.Considering the documented types, frequencies, and doses of antibiotics consumed, total antibiotic consumption will be calculated and compared between different subgroups by using nonparametric tests methods. The qualitative and quantitative social science and microbiological datasets will be linked in order to perform more complex analyses. Consumption levels of antibiotics from medicine diaries and household survey data, as well as from electronic patient records, where available, will be correlated with environmental sample analyses to triangulate evidence on antibiotic exposure (see above). The analysed data will be used to develop a hierarchical risk-based framework for structured decision-making and to identify key hazard sites and pathways for the development of future interventions.A total of 1520 urine samples were collected in July to August 2020 at the time of the household survey. One-hundred and sixty-two fresh samples of food, including vegetables, meat, fish, and eggs were collected from local households.With a GPS-enabled drone, detailed maps of the two selected study sites were drawn and 10 households were selected randomly in each site. A total of 822 water samples, including drinking water, well water, pond water, and surface water, were collected. The collection of water samples was repeated during different seasons  with two parallel samples collected at each site. Moreover, 84 wastewater samples were collected during different seasons, along with the above-mentioned environmental sampling in the villages.The genomic DNA of the water samples has been extracted and sequenced, but the analysis of ABR genes is still ongoing. Selected typical MDR bacteria, e.g., MRSA, have been isolated, and their genomes are also under analysis.Using UPLC-Q/TOF MS, 25 antibiotics and two of their metabolites have been detected in the above-mentioned water samples. However, the detection of antibiotics in food samples has not been completed yet.Household registration records from two sites were used as the overall sampling frame. A field investigation was carried out from July to August 2020, and 1521 subjects were recruited into this study.From July 2020 to June 2021, 783 subjects provided the medicine diary, monthly, from two sites. All data were double entered into the EpiData software . One year of medicine records in local healthcare facilities  were collected and are being matched with participants using their medical insurance number and ID number.Qualitative data were collected using standardised and semi-structured topic guides. In total, 103 individuals were interviewed deeply, and 13 focus groups of 67 subjects have been conducted since 2019. For qualitative data, coding was undertaken independently by at least two researchers for each sub-group of informants in NVivo v.12 with a common coding framework.Using two villages in Eastern China as an example, this proposal plans to study the diverse and complex problem of antibiotic use and resistance. It proposes the utilisation of a ‘One health’ approach to provide better evidence and a broader understanding of the environmental, community, economic, and healthcare drivers and burdens of ABR based on a systems perspective that recognises that interactions between these areas is urgently needed, as are evaluation tools to measure the effectiveness of different ABR-reducing intervention strategies. Due to a dense population, an intensive livestock-breeding industry, and massive antibiotic use, Eastern China is a key region for controlling antibiotic use and ABR. Our research aims to bridge these key evidence gaps and strengthen disciplinary and methodological research skills, through a set of closely linked projects that will generate the holistic knowledge which is needed to design, deliver, and monitor targeted strategies to limit ABR in China and comparable settings.New knowledge and robust evidence will be gained regarding the transmission pathways of antibiotic resistance between aquatic environments, animal food sources, and workers who are professionally exposed to these sources. The monitoring approach that will be developed through sampling in the aquatic environment will provide a potential tool for use in the research and monitoring of ABR transmission elsewhere. The utilisation of sophisticated assays to detect antibiotic residues in population cohorts with well-documented antibiotic use will produce rich data on the relationship between direct and indirect antibiotic exposure and the associated long-term health risks. Analysis of wastewater from these populations will contribute to appraising the potential of this novel approach in monitoring community public health. Our research findings on antibiotic use from this project will also produce a uniquely detailed, representative data set on when, why, and where antibiotics are prescribed and purchased in low- and middle-income countries’ community settings. This will be valuable for health systems researchers and social scientists  working in global health, while our work on policy implementation will provide insights into the anticipated and unplanned consequences of policy and regulatory changes that aim to limit the prescription and consumption of antibiotics and other medicines.Local stakeholders are invited for meetings to discuss the preliminary study results. There is a possibility of community meetings to share/provide feedback on the study results with local residents and stakeholders. The findings from the study will be disseminated in peer-reviewed journals and will also be presented at scientific conferences.This multidisciplinary collaboration between institutions in the UK and China will provide an in-depth understanding of the influencing factors and allow comprehensive awareness of the complexity of AMR and antibiotic use in rural Eastern China.


What is the association between antimicrobial stewardship programs (ASPs) implemented across multiple health care settings and antibiotic use?In this systematic review and meta-analysis of 52 studies with more than 1.7 million patients conducted in different health care and income settings, ASPs were associated with reduced consumption of antibiotics overall as well as of antibiotics in the World Health Organization Watch group.The findings of this study support the use of ASPs to reduce antibiotic use in both hospital and nonhospital settings. This systematic review and meta-analysis synthesizes current evidence regarding the association between antimicrobial stewardship programs and the consumption of antibiotics globally. Antimicrobial resistance continues to spread rapidly at a global scale. Little evidence exists on the association of antimicrobial stewardship programs (ASPs) with the consumption of antibiotics across health care and income settings.To synthesize current evidence regarding the association between antimicrobial stewardship programs and the consumption of antibiotics globally.PubMed, Web of Science, and Scopus databases were searched from August 1, 2010, to Aug 1, 2020. Additional studies from the bibliography sections of previous systematic reviews were included.Original studies of the association of ASPs with antimicrobial consumption across health care and income settings. Animal and environmental studies were excluded.Following the Preferred Reporting Items in Systematic Reviews and Meta-Analyses guideline, the pooled association of targeted ASPs with antimicrobial consumption was measured using multilevel random-effects models. The Effective Public Health Practice Project quality assessment tool was used to assess study quality.The main outcome measures were proportion of patients receiving an antibiotic prescription and defined daily doses per 100 patient-days.Overall, 52 studies (with 1 794 889 participants) measured the association between ASPs and antimicrobial consumption and were included, with 40 studies conducted in high-income countries and 12 in low- and middle-income countries (LMICs). ASPs were associated with a 10%  reduction in antibiotic prescriptions and a 28% reduction in antibiotic consumption . ASPs were also associated with a 21%  reduction in antibiotic consumption in pediatric hospitals and a 28% reduction in World Health Organization watch groups antibiotics .In this systematic review and meta-analysis, ASPs appeared to be effective in reducing antibiotic consumption in both hospital and nonhospital settings. Impact assessment of ASPs in resource-limited settings remains scarce; further research is needed on how to best achieve reductions in antibiotic use in LMICs. The main objectives of the present review are (1) to provide up-to-date pooled estimates of the association of ASPs with antibiotic consumption and (2) to estimate the differential association of ASPs with the use of different antibiotic classes and across health care and income settings.Moreover, little evidence exists on how targeted interventions can improve the rational use of specific antibiotic classes in different health care contexts. Existing research on ASPs has been mostly restricted to limited comparisons in hospital and intensive care settings.PRISMA) reporting guideline.17 The protocol was registered with PROSPERO (CRD42020206479). We searched PubMed, Web of Science, and Scopus databases from August 1, 2010, to August 1, 2020, for articles on the association of ASPs with antimicrobial consumption  assessed the eligibility of each full-text article; a third reviewer (M.L.) decided cases without consensus. Two of us (K.Z.Y. and P.T.N.W.) reviewed identified articles and the data extraction process as suggested by the PRISMA checklist. P.T.N.W. conducted the quality assessment of all eligible studies. A third author (M.L.) reviewed the articles in doubt, additional references, and data extraction items.18 EPHPP is a widely used assessment tool for quantitative studies designed for systematic literature reviews of effectiveness studies.19 The aim of the quality assessment was to evaluate the overall quality of evidence and the risk of bias.19 Two independent reviewers rated all articles as strong, moderate, or weak in each domain  quality assessment tool to assess 6 domains of quality: (1) selection bias, (2) design, (3) confounders, (4) blinding, (5) data collection methods, and (6) withdrawal and dropouts.We extracted the following information from all studies: the aim of the study, country, study design, type of health care facility, study populations, number of health care workers and facilities, pathogens, antibiotic studied, timeline, duration of the interventions, intervention components, and quantitative measure of antibiotic consumption before and after intervention whenever possible. Two separate outcome measures were extracted for preintervention vs postintervention study designs; 4 outcome measures were extracted for randomized trials with clearly defined control and treatment groups. When a study reported both antibiotic-specific consumption measures and an average over all antibiotics, we extracted detailed antibiotic-specific measures. ASPs were defined broadly to include both single-component and multicomponent interventions .20 DOT is the number of days of antibiotic therapy administered to a patient, regardless of the number of doses administered or dosage strength.20 Since DDD and DOT are conceptually similar, we pooled them in the meta-analysis. We standardized all DDD and DOT measures to 100 PDs. The second outcome often used is the proportion of patients receiving an antibiotic prescription—a separate measure that does not measure drug consumption directly. For each study we calculated 1 of 2 outcomes: (1) the change in antibiotic prescriptions after the intervention compared with before or (2) the rate ratio (RR) of antibiotic consumption after intervention measured in DDD or DOT per 100 PDs compared with the preintervention period. To calculate standard errors of the rate ratios, we calculated log rate ratios as an intermediate step.21 Given that these yield asymmetric confidence intervals, we truncated the upper bounds of the intervals at a value of 20.The current literature uses 2 distinct types of outcome measures. First, actual drug consumption is typically measured either as defined daily dose (DDD) per 100 or 1000 patient-days (PDs) or as days of therapy (DOT) per 100 or 1000 PDs. DDD measures drugs administered as multiples of the assumed average maintenance dose per day for a specific patient .22 In contrast to the standard random effects meta-analytical model that accounts for study-level sampling error and between-study heterogeneity, a 3-level model can account for within-study heterogeneity.22 With this approach, all reported effect sizes from a single study can be included in the analysis, but multiple effect sizes from the same study contribute less to the overall estimates than single effect sizes from other studies.23 The specific weight assigned to each study depends inversely on how strong the correlations are between all effect sizes derived from the same study. Two strongly correlated effect sizes from the same study will both receive lower weights than two weakly correlated effect sizes since they will add little independent information to the pooled effect size. This will then be reflected in a lower study-specific weight. Restricted maximum likelihood models with nested 3-level random-effects were estimated, and Cochran’s Q as well as I2 were computed to assess heterogeneity. R version 4.1.2  was used to conduct statistical analysis. Statistical significance was set at P < .05.We estimated 3-level meta-analytical models to get pooled average effectiveness estimates.24; study settings ; patient settings ; antibiotic restriction ; and World Health Organization Access, Watch, and Reserve (AWaRe) classification antibiotics 2019.25 Finally, we stratified results by individual ASP components when it was possible to obtain their individual associations with antibiotic consumption.We stratified results based on the following subgroups: HICs and LMICs based on the World Bank income group classification72 were included in qualitative synthesis, while 34 studies72 had sufficient data to be included in the quantitative meta-analysis .61 The remaining studies were conducted in general practitioner medical practices (n = 3),56 ICUs (n = 3),72 and nursing homes (n = 3).57 Participants were typically inpatients, including ICU patients (n = 32),76 followed by outpatients (n = 10),61 pediatric inpatients (n = 7),60 and nursing home residents (n = 3).57 Most studies analyzed ASPs comprising multiple components. It was therefore not possible to estimate the associations between most individual components of ASPs and antibiotic consumption, except for 2 components: (1) training and guidelines and (2) decision support tools . The Egger test suggested possible publication bias (P = .007). Five different antibiotic classes from 10 studies reported RRs of antibiotic consumption after intervention measured in DDD per 100 PD compared with the preintervention period. Pooled analysis suggested that, on average, ASPs were associated with a 28% reduction in antibiotic consumption  . Stratifying results by broad-spectrum antibiotic classes revealed nonstatistically significant pooled differences between ASPs and consumption. However, these associations were based on a small number of studies, resulting in large confidence intervals, and the direction of the effect sizes was systematic: 33 of 34 RRs suggested a reduction in consumption. All class-specific pooled RRs consistently suggested large reductions in consumption, although the results were not statistically significant: fluoroquinolones (42% reduction), penicillin and β-lactamase inhibitor combinations (39% reduction), carbapenems (31% reduction), macrolides (26% reduction), and cephalosporins (15% reduction)     decrease in antibiotic prescriptions overall based on 17 estimates ,3,7,28,2timates) A.5,27,38duction) A.5,27,38timates) B.27,64,6timates) .5,27,36,55 or inpatients and nursing home residents ,61 although reductions cannot be ruled out due to the small sample size. Similar nonsignificant results were found across different settings, including public hospitals  and pediatric hospitals   . Antibiot sizes) . Decisiot sizes) D. Detail65 ASPs were also associated with reduced consumption of antibiotics on the WHO Watch list, with particularly high risk of selection of bacterial resistance.73 In light of concerning increased use of Watch antibiotics globally, this is good news, as it suggests that protecting these drugs through appropriate ASPs is possible.73The results of our meta-analysis presented here suggest that ASPs were associated with a 10% reduction in antibiotic prescriptions and a 28% reduction in antibiotic consumption rates. Reductions in consumption were observed across all antibiotic classes, including penicillin and β-lactamase inhibitor combinations, macrolides, fluoroquinolones, cephalosporins, and carbapenems. The only exceptions were penicillins, which is not surprising giving that these are not targeted by all interventions and in some cases even encouraged.74 Prescriptions for other inpatient, outpatient, and nursing home patients were generally smaller and often not significant.Subgroup analysis suggests that ASPs were associated with reductions in antibiotic prescriptions in pediatric care, where antibiotic use is particularly high.14 For the meta-analysis, we only identified 4 studies in LMICs, 3 of which were from China29 and 1 from Iran.41 While ASPs were associated with relatively large reductions in prescriptions in LMICs, this must be interpreted with caution due to the small number of studies currently available from LMICs. Uncertainty still remains about the outcomes of ASP in resource-limited settings. One study conducted in a pediatric tertiary hospital in China56 suggested that a multicomponent ASP package combining prior authorization, audit and feedback, and pay for performance was more effective than a single strategy. A study in multiple primary care institutions in China61 found that physicians’ prescribing behavior did not affect the rate of antibiotic prescriptions, but a computer network-based feedback intervention was associated with significant reductions in antibiotic prescriptions.Moreover, our pooled analysis suggests that ASPs implemented in HICs were associated with reduced antibiotic prescriptions by 6%, echoing findings from previous studies.63 did not report quantitative estimates of consumption, but it found that introducing pharmacist expertise in a setting with limited infectious disease resources had substantial consequences for antibiotic use and consumption. Overall, the evidence from LMICs remains mixed. Given the challenges involved with the implementation of ASP in LMICs, including often limited availability and access to antibiotics, unavailable diagnostics, and weak adherence to treatment, further research on how to best implement ASPs without compromising the quality of care provided to patients in LMICs is urgently needed.78 While the present study tried to also analyze the outcome of specific ASP components, the currently available data are not sufficient to assess the relative effectiveness of each component.A study conducted in 47 small hospitals in South AfricaThis study has limitations. First, the pooled effect sizes cannot be directly interpreted as the causal effect of ASPs on antibiotic prescription or consumption rates since few of the included studies were designed as randomized clinical trials. A control group followed up through the baseline and intervention periods could provide important information on time trends, seasonality, or other factors, including trends in pathogen prevalence or changes in infection control measures that could affect antibiotic consumption. Moreover, as already mentioned, we found very few studies from LMICs. While we may expect the marginal impact of a well-implemented ASP to be larger in an LMIC than in an HIC, the currently available data are not sufficient to assess these differences systematically. Furthermore, our review also did not assess the impacts of stewardship programs on animals and the environment, which are 2 areas that are likely affected and important from one health approach.In this systematic review and meta-analysis of the association of ASPs with antimicrobial consumption, ASPs were associated with reduced antibiotic consumption in both hospital and nonhospital settings. Our results show that ASPs can reduce the consumption of WHO Watch group antibiotics with high resistance potential and can potentially contribute to major reductions in antimicrobial consumption in pediatric patients. Overuse and misuse of antibiotics are the main drivers of AMR; reducing antimicrobial consumption through ASPs should thus contribute toward reducing the risk of AMR. This study is limited by the availability of assessments of ASPs in resource-limited settings. Pragmatic randomized clinical trials of ASPs explicitly linking appropriateness of antibiotic utilization to resistant bacterial prevalence as an outcome should therefore be a key research priority. Performance of ASPs might vary considerably in different income settings, and this warrants a particular focus on LMICs where implementation of ASPs could face operational, behavioral, and financial challenges.