Insulated sandwich concrete panel (ISCP) is widely used because of its high thermal insulation efficiency and low construction cost. Aiming at improving traditional ISCP, a new cast-in-situ concrete wall structure made of ISCP is proposed, which is composed of thin-walled cold-formed steels, slant steel wire connectors, steel wire meshes, concrete layers, expanded polystyrene sheets and reinforced concrete embedded columns. In order to assess the hysteretic properties of the new insulated sandwich concrete wall and the influence of various parameters, low-frequency horizontal cyclic load tests were carried out on seven full-scale specimens of new type cast-in-situ insulated sandwich concrete wall. The specimens were compared and analyzed with respect to failure mode, bearing capacity, ductility, degradation characteristics and energy dissipation capacity. The results show that the final failure pattern of the specimen is two main diagonal cracks intersecting each other; the bearing capacity is greatly affected by concrete thickness and axial compression ratio, regardless of concrete strength. Brittle failure is typically observed when the steel wire spacing is large, while ductility is pronounced when the concrete layer thickness is small and the concrete strength is low; the smaller the thickness of concrete layer, the faster the stiffness degrades. The wall structure shows a better energy dissipation performance with a smaller steel wire spacing, lower concrete strength and smaller axial compression ratio. Nowadays, environmental protection and sustainable development are hot issues of global concern. In the architectural field, more and more scholars focus on the study of energy-saving buildings. Insulated sandwich concrete panel (ISCP) is representative of an energy-saving building, which is typically composed of concrete layers on both sides, insulation layers in between, and shear connectors. The main advantages of this panel are: (i) ease of erection at reasonable costs, (ii) high efficiency of thermal and sound insulation, and (iii) flexibility in utility, either as enveloping elements or as load-bearing components.To date, research on ISCP mainly focuses on efficiency of thermal insulation, composite action, materials and constructions and structural performance.In terms of insulation efficiency, how to reduce the influence of cold bridge effect is mainly considered. Currently, the most popular method is to make shear connectors with materials with low thermal efficiency. For instance, a new type of hybrid connector wrapped with nylon was proposed to improve the thermal performance of ISCP wall . Other cIn terms of composite action, ISCP are usually categorized into non-composite (NC), partially composite (PC) and fully composite (FC) according to the degree of composite action . It is generally believed that the composite action of ISCP is mainly provided via shear connectors, and studies indicate that connectors’ dimension and spacing greatly affect composite action, and that connectors inserted at an angle other than 90° are considerably stronger than those inserted perpendicularly . Most stIn terms of materials and constructions, many researchers proposed different forms of materials and constructions. The changes of materials and constructions for better mechanical performance, higher insulation efficiency and easier construction, but they often restrict each other in practice. In order to make the construction operation easier, the sandwich concrete panel without shear connector was proposed ,8, and tExisting insulated sandwich concrete structure systems often lead to the cold bridge effect due to the discontinuity of the insulation layer at the joints of walls, and most of the joints are complex in composition and inconvenient in construction. Although the thermal efficiency problem can be solved by using FRP connectors, FRP connectors are prone to brittle fracture and be pulled-out, and the cost is high ,12. In oAll the walls are sandwich walls, composed of three-dimensional steel wire skeletons, expanded polystyrene sheets, concrete and thin-walled cold-formed steels.The two concrete layers of the wall are connected by slant steel wires used as shear connectors. The angle between the slant steel wire and the wall is 72°, and the layout spacing is 50 mm. The wall belongs to partially composite sandwich structure.The thickness of concrete layers on both sides is identical, as is the ratio of horizontal and vertical reinforcement.In the openings, centers and edges of the sandwich walls, closed frames are formed by horizontally and vertically welding thin-walled cold-formed steels with rectangular sections.The walls are connected by reinforced concrete embedded columns and additional reinforcements.Seven full-scale specimens of the wall were made and tested under horizontal cyclic load in-plane, to investigate the potential effect of four variables , and to evaluate the seismic performance of the new structure.The remainder of this paper is organized as follows: Section 2 introduces the construction of this new-style structure, Section 3 describes the key points of the cyclic loading experiment, and Section 4 presents the failure patterns and mechanisms. In Section 5, the hysteretic curve, load-bearing capacity, ductility, stiffness degradation and energy dissipating capacity are analyzed based on the experimental results. The anti-seismic performance and influence of the main parameters are discussed in Section 6.A cast-in-situ insulated sandwich concrete wall is composed of an expanded polystyrene sheet, steel wires, rectangular steel tubes, additional reinforcements and concrete layers, as shown in 3.A polystyrene sheet used as an insulation layer has a thickness of 80 mm and density of 20.4 kg/mThe steel wires are made of low carbon galvanized steel wires, including horizontal steel wires, vertical steel wires and slant steel wires, usually with a diameter of 2.5 mm. The horizontal steel wires and vertical steel wires are spot welded together at the intersection, with a steel wire spacing of 50 mm. The slant steel wires travel through the polystyrene sheet and the two ends are spot welded on the steel wire meshes composed of horizontal steel wires and vertical steel wires on both sides of the wall; the adjacent two columns of slant steel wires have opposite directions, and the angle between the slant steel wire and the polystyrene sheet is 72°, the spacing of slant steel wires is 50 mm, as shown in Thin-walled cold-formed steel tubes are adopted with rectangular sections (70 mm×40 mm×1.5 mm), which are arranged in the openings of doors and windows, the center and edges of the wall, and welded on the steel tubes additional reinforcements that extend into the wall. Additional reinforcements are plain bars with a diameter of 6 mm and a spacing of 300 mm, as shown in The thickness of concrete layers on both sides is identical (50 mm), as shown in The walls mainly bear vertical load and horizontal load. In order to ensure the complete transfer of horizontal load at the wall joint, the joint may bear bending, shearing and axial force. Therefore, different connection patterns are proposed for different joint forms. Four types of joint are used in this study: continuous joint of two walls (‘–’ shape), orthogonal joints of two walls (‘L’ shape), connecting joints of three walls (‘T’ shape) and orthogonal joints of four walls (‘+’ shape). Each type of joint targets at an overall performance regarding mechanical behavior of structure, thermal efficiency, feasibility of construction and economic feature.The continuous joints of two walls (‘–’ shape) are constructed by setting formed steel and additional reinforcements at the joint, as shown in The orthogonal joints of two walls (‘L’ shape) are constructed by setting reinforced concrete special-shaped columns and additional reinforcements at the junction of the two walls, as shown in The connecting joints of three walls (‘T’ shape) and orthogonal joints of four walls (‘+’ shape) are constructed by setting reinforced concrete columns with additional reinforcements extended into each wall at the joint, as shown in The main purpose of the experiment is to observe the pseudo-static behavior of the single cast-in-situ insulated sandwich concrete walls under low-frequency horizontal cyclic load, to reveal how various parameters influence the mechanical properties and deformation of the wall, and to evaluate the seismic performance of the structure. With this aim, a full-scale test of quasi-static force is carried out.t, steel wire spacing s, concrete strength fc and axial compression ratio λ. Accordingly, a total of seven specimens were made for experimental research. Parameters of each specimen is shown in Four parameters were varied: thickness of concrete layer Low frequency horizontal cyclic load and constant vertical load are applied to each specimen. The horizontal cyclic load is controlled by displacement, and the displacement of each level circulates twice until the horizontal load value drops to 85% of the peak load, so as to observe the pattern of strength degradation, stiffness degradation and damage development induced by repeated loading and unloading. The magnitude of vertical load is determined by the axial compression ratio. Two axial compression ratios are adopted, respectively representing different upper wall loads, to assess the influence of axial force.Throughout the test, the relationship curve between load and displacement and failure mode are documented, which will be used to evaluate the mechanical properties of the wall and the influence of various research parameters.All seven specimens measure 1900 mm in height and 1000 mm in width. All specimens have a total wall thickness of 230 mm (75+80+75) except for CWS-2 (210 = 65+85+65 mm) and CWS-3 (250 = 85+80+85 mm), as shown in The specimens are fabricated in the following procedures.Firstly, expanded polystyrene sheet (EPS) with steel wire arranged according to design is obtained through automatic processing machine: the spacing between horizontal steel wire and vertical steel wire is 50 mm, the horizontal and vertical spacing of the slant steel wire is also 50 mm, the angle between the slant steel wire and EPS plate is 72°. The thickness of expanded polystyrene is 80 mm, as shown in Then, the reinforcements of the foundation beam and additional reinforcements are installed and tied. As shown in Finally, concrete layers on both sides of EPS insulation layer are cast with three different thicknesses of concrete layers: 65 mm, 75 mm and 85 mm. Typically, there are three cast-in-situ methods adopted in practice, such as manually plastered concrete, sprayed concrete and cast-in-place concrete with supporting formwork. The cast-in-situ concrete with supporting formwork is adopted in this experiment, as shown in The materials used in the specimens are typically used in construction sites. Three kinds of concrete  were tested for axial compression strength and splitting tensile strength, as shown in The test device consists of a reaction frame, a hydraulic actuator, and a sliding device. The holding device is installed on the top of the specimen. The horizontal cyclic load is applied by a double-acting hydraulic actuator through the holding device. The vertical load is applied by the vertical actuator through a load-bearing steel beam on the top of the specimen. The near end of the vertical actuator is a spherical hinge, and the root is fixed on the reaction frame by sliding device. The vertical actuator can slide freely along the loading direction of the horizontal actuator. The specimen foundation beam is fixed on the reaction frame with a high-strength bolt. In order to prevent rigid body slip-off of the specimen along the loading direction, a hydraulic jack is set at the southern end of the foundation beam along the horizontal loading direction to tighten the foundation, as shown in Four digital indicators each with a range of 50 mm and one draw-wire displacement sensor (both are manufactured by Beijing Jinghaiquan Sensor Technology Co. LTD) are applied to each specimen to measure its displacement, as shown in Absolute horizontal displacement is measured by digital indicator No. 1 and No. 3 and the draw-wire displacement sensor.The horizontal rigid body displacement of the foundation beam is measured by digital indicator No. 2 and No. 4.During the loading process, the vertical load, horizontal load, and horizontal displacement are automatically collected by the DONGHUA-DH3821 data collection system, while the wall cracking and damage phenomena are observed by the naked eye.This section presents the cracking and final failure patterns of the single cast-in-place sandwich concrete panel specimens during loading.At the initial stage of loading, all the specimens show horizontal bending cracks at the edges of wall, and they gradually develop as diagonal shear cracks with the displacement growth. Each specimen is damaged together with the diagonal shear cracks penetration in the lower part of the wall. Finally, the cracks develop to the bottom of the wall, forming a main crack with a considerable width and length in both directions. The two main cracks intersected in an “X” shape, determining the failure mode of the wall. Observations will be presented in groups according to different research parameters, wherein the panel CWS-1 is a reference specimen.t = 65 mm), CWS-1 (t = 75 mm), CWS-3 (t = 85 mm), the wire spacing is 50 mm, the reinforcement ratio is 0.13%, the axial compression ratio is 0.06, and the failure modalities of them are similar. Taking the CWS-1 as an example: the axial force applied to CWS-1 is 340 kN, and the ultimate displacement is 0.9% (15 mm). The first crack, nearly horizontal, is a bending crack generated at a height of approximately 630 mm (1/3 of specimen height) above the lower edge of the specimen at the negative cyclic displacement of -0.18% . When loaded to -0.24% , the crack extends diagonally as a shear crack. When loaded to -0.72% , the crack reaches the bottom of the specimen. When the load was increased to +0.5%  and +0.72% , a crack is created in the other direction, intersecting the existing crack. It is worth noting that CWS-1 and CWS-2 only produce one main crack in the positive and negative loading direction respectively, and the branch cracks are few; in contrast, the crack distribution of CWS-3 is denser, as shown in For the specimens with the thickness of the concrete layer as the variable: CWS-2 (F = -151 kN), a horizontal crack of 0.1 mm wide is produced at the bottom of the south side of the panel, which is a bending crack. A 0.1 mm wide horizontal crack is generated at the bottom of the north side of the panel when the positive cyclic displacement is +0.7% , and the two cracks are connected to each other. When the displacement gradually increases to -1.0% , the edge of the panel cracks suddenly with a loud burst and the cracks quickly penetrate to the bottom of the wall. The maximum width of the cracks is 4.5 mm. The cracks start horizontally, and then proceed diagonally. Finally, the specimens are damaged without omen. The reason for this may be the lower reinforcement ratio of CWS-4. In contrast, although the damage of CWS-1 also shows brittleness, it is not sudden, but rather gradual and manageable. See For CWS-4 with the wire spacing as the variable, the concrete layer thickness is 75 mm, the vertical axial force applied is 340 kN, the axial compression ratio is 0.06, the wire spacing is 100 mm, the reinforcement ratio is 0.07%, and the ultimate displacement is 1.0% (17 mm). When the negative cyclic displacement is -0.5% , which is a bending crack. When the positive cyclic displacement is +0.36% , the crack develops diagonally as a shear crack. On the other hand, when the negative cyclic displacement is -0.36% , a shear crack is also generated along the diagonal direction, and the two cracks intersect with each other and stretch to the bottom of the specimen. Compared with CWS-1, the failure patterns of the three are similar, but the cracks in CWS-5 are slightly denser, indicating that the strength of concrete has little effect on the failure pattern of single cast-in-situ insulated concrete wall, as shown in For the specimens CWS-5 and CWS-6 with concrete strength as the variable, the concrete layer thickness is 75 mm, the wire spacing is 50 mm, the reinforcement ratio is 0.13%, the vertical axial force applied are 220 kN and 400 kN respectively, the axial compression ratio is 0.06, the ultimate displacements are 1.7% (28 mm) and 1.0% (18 mm), the concrete strength grades of specimens CWS-5 and CWS-6 are C20 and C40 respectively, and the cracking patterns of them are similar. The CWS-5 specimen is taken as an example for description. For CWS-5, a horizontal crack is generated in the center and lower part of the north side of the panel at a positive cyclic displacement of +0.24% . When the negative cyclic displacement is -0.45% , another crack is formed in the lower middle part of the south side of the specimen. Both cracks are horizontal. When the displacement reaches 0.8% , the cracks develop diagonally, and as the displacement gradually increases, cracks continue to occur until the specimen is destroyed. Compared with CWS-1, the crack position of CWS-7 is higher. Although the number of cracks is comparable between the two specimens, CWS-7 has a larger width of cracks, a number of branch cracks, a denser distribution of cracks, more serious damages and spalling. This is seen in For the specimen CWS-7 with the axial compression ratio as the variable, the concrete layer thickness is 75 mm, the wire spacing is 50 mm, the reinforcement ratio is 0.13%, the vertical axial force applied is 600 kN, the axial compression ratio is 0.12, and the ultimate displacement is 1.9% (32 mm). The first crack is observed in the center of the north side of the specimen when the positive cyclic displacement is +0.45%  in specimens CWS-1 and CWS-4 are 50 mm and 100 mm. There is no descending branch in the hysteresis curve of CWS-4. There is almost no residual deformation and the specimen CWS-4 breaks suddenly. This tells CWS-4 experiences brittle failure. The reinforcement ratio of CWS-4 is low (0.07%). For CWS-4 the steel wire is broken at the same time of the concrete crushing, while for CSW-1 the strength degradation occurs and structural behavior is more ductile, as shown in The concrete grades of specimens CWS-1, CWS-5 and CWS-6 are C30, C20 and C40. The hysteresis curves of these three are very similar. There is no obvious yielding and the peak loads are close to each other . The hysteresis curve of CWS-5 is slightly plumper because CWS-5 has a better deformation capacity. The ultimate displacement of CWS-5 is 1.6% comparing with 0.9% of CWS-1 and 1.0% of CWS-6 See . In addiF = +196 kN). This major crack causes severe pinching effect in the hysteresis curve of CWS-7 in positive direction, while more cracks are generated in the negative direction as the increase of displacement, as shown in The axial compression ratios of specimens CWS-1 and CSW-7 are 0.06 and 0.12, respectively, corresponding to axial forces of 340 kN and 600 kN. The other parameters for these two specimens are the same. It is seen in Figs Fp is taken as the ultimate load, and the corresponding displacement is defined as the ultimate displacement. However, for some specimens (e.g. CSW-5), the failure occurs before the load drops to 85% of the peak load. In this case, the last stage of the cyclic load is taken as the limit state. The load and displacement at the limit state are taken as the ultimate load and ultimate displacement for these specimens.The most common methods to determine the yielding point are the energy equivalent method, the geometric mapping method and the R. Park method . The R. μ is defined as the ratio of the ultimate displacement Δu to the yield displacement Δy [Fy, peak load Fp, ultimate load Fu, the corresponding displacements and displacement ductility factor μ of all specimens are listed in The displacement ductility factor ement Δy . The yieFrom The concrete layer thickness t has an evident correlation with the horizontal bearing capacity. The horizontal peak load increases by 25% (from 132 to 165 kN) when the concrete layer thickness is increased by 30% (from 65 to 85 mm). In addition, the displacement ductility factor ratios of CWS-1, CWS-2 and CWS-3  indicate that the specimen has a better deformation ability and ductility with less concrete layer thickness.Steel wire spacing s has little influence on the bearing capacity, but significant influence on the ductility of the specimens. The displacement ductility factor μ significantly decreases (from 1.0 to 0.75) when the steel wire spacing is increased (from 50 mm to 100 mm). The smaller the wire spacing is, the greater the ductility is.fc has little effect on the lateral bearing capacity. This is due to a low reinforcement ratio which can’t make the full use of concrete strength. The crack develops in the specimens at a low load level, and the lateral bearing capacity is controlled by concrete tensile strength, which fails to give full play to the good compressive strength of concrete. Based on the displacement ductility factor ratios of CWS-1, CWS-5 and CWS-6 , the lower the concrete strength, the better the ductility.The concrete strength The axial compression ratio has a significant effect on the lateral bearing capacity. Greater axial compression ratio gives higher bearing capacity. As the axial compression ratio increases from 0.06 to 0.12, the bearing capacity is increased by 58% (from 138 to 219 kN). Meanwhile, the ductility decreases from 1.0 to 0.88.Ki, which is defined by Fi is the peak load at the i-th cycle; i is the corresponding displacement, ‘+’ and ‘-’ signs indicate the direction of loading.The stiffness of a specimen is expressed by secant stiffness Ki of the i-th cycle to the secant stiffness K1 of the first cycle).Under in-plane lateral cyclic load, the stiffness degradation of the wall depends on the degree of damage during the cyclic response. t = 75 mm), CWS-2(t = 65 mm) and CWS-3 (t = 85 mm) (For CWS-1(= 85 mm) , CWS-2 es = 50 mm) and CWS-4 (s = 100 mm) (For CWS-1( 100 mm) , at the fcp = 34.36 MPa), CWS-5(fcp = 24.39 MPa) and CWS-6 (fcp = 44.69 MPa) (For CWS-1 (.69 MPa) , at the λ = 0.06) and CWS-7 (λ = 0.12) (For CWS-1 ( = 0.12) , at the E is often used to measure the energy dissipation capacity of the structure. It is defined by S(ABC+CDA) is the enclosed area by hysteretic loops (the shaded part), S(OBE+ODF) is the total area of two triangles bounded by dotted lines  above the lower edge of the specimen, and the two main cracks intersected in an ‘X’ shape. These two cracks predominated and defined the final failure pattern of the wall.When all the specimens failed, the concrete layers on either side are not detached from the polystyrene layer in between, which indicates that the slant steel wire shear connector can guarantee the overall working performance of the insulated sandwich concrete cast-in-situ wall.The hysteretic curve of the specimens with larger concrete layer thickness is plumper, showing better energy dissipation capacities. The hysteretic curves of specimen with large steel wire spacing show serious pinching phenomenon, small plastic deformation, sudden destruction and poor energy dissipation performance.The horizontal bearing capacity is significantly affected by concrete layer thickness and axial compression ratio, but less affected by concrete strength. In addition, a better ductility can be achieved by lowering concrete strength, thickness concrete layer or axial compression ratio.When secant stiffness is used as an indicator of stiffness degradation, it is found that the rate of stiffness degradation is gentler when the concrete layer is thicker. It is also found that the strength of concrete has little effect on the rate of stiffness degradation.Energy dissipation ratio is used to represent energy dissipation performance. The results show that the concrete layer is thicker, the energy dissipation performance is better when the steel wire spacing is smaller, the concrete strength is lower, and the axial compression is smaller.According to the research results of this paper, the following suggestions are given to make the insulated sandwich concrete panel structure used more efficiently in actual construction.For the concrete layer thickness, 50~60mm is a reasonable range.Improving the reinforcement ratio and adding the lateral constraint members such as RC or profile steel columns can effectively improve the seismic performance.Prefabricated ISCP is a good way to simplify and accelerate the construction of this structure.To improve the non-continuity of insulation layer in traditional structure, the new joint construction is proposed in this paper, which are shown in To improving the insulation of steel shear connectors, the hybrid connectors, i.e., covering the surface of steel elements by using the insulating material, have been proposed.In non-load-bearing components, it is a good way to improve the thermal efficiency by using foamed concrete layer as two side plates.S1 Data(RAR)Click here for additional data file. 4 Sep 2019PONE-D-19-21558Cyclic loading test study on a new cast-in-situ insulated sandwich concrete wallPLOS ONEDear Dr. Qiao,Thank you for submitting your manuscript to PLOS ONE. 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This is in line with our reproducibility publication criterion, see  Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: PartlyReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/AReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: This study performed cyclic loading test on 7 sandwich concrete walls for better insulation performance. In the first part, the authors explained the method to improve insulation performance and connection joint details. But, in the tests, the authors evaluated the cyclic behavior of single wall. Thus, the paper writing flow needs to be modified for better clearness. Following comments are recommended for better quality of this paper.1. Introduction is too long. Particularly, reviewing of existing studies needs to be briefly written.2. The authors introduced connection methods of walls, but the structural performance of only single wall was evaluated. Thus, the chapter “Connecting joints of walls” can cause misunderstanding to the readers.3. In general, cylinder strength is used to evaluate the structural performance. Please provide the cylinder strength also.4. In Fig. 6(a), cracks are observed in footing slab, which affects the test results.5. Cyclic curve shape is completely different from conventional wall test results. Particularly, in unloading part. Maybe this is because of test setup problem . The authors need to explain such problem and the reason of strange unloading curve, and it is difficult to compare the structural performance based on test error.6. How to define yield load? From nominal strength or rebar strain?7. For direct evaluation of test results, nominal strength of flexure and shear should be provided, and those should be compared with the cyclic curve.8. High-strength concrete improves shear strength, which reduces or delays shear damage. On the other hand, the authors’ test results exhibited the same performance regardless of concrete strength. It needs to be explained more clearly.9. The authors used this wall system to improve insulation performance. According to test parameters, insulation performance is also affected. Thus, design recommendation addressing both the structural performance and insulation performance needs to be provided.Reviewer #2: Paper is very interesting. It is in detail in technical parts and easy to read and understand. Information presented in this paper will be very useful for engineers and researchers.I have just two comments: 1. Title specified that it is new type of panel (expanded polystyrene sheets embedded into two layer of wire meshes) while this type of panels are not new and it was practiced in construction industry for more than 10 years. However, tests presented in this paper are new. If the authors insisted to claim that it is new it should be further explored and justified.2. As a results and main conclusion, it is expected that the authors give their recommendation to choose the best system for a real construction work.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  22 Oct 2019Authors' Replies to Reviewer #1:1. The introduction of this paper has been modified according to your suggestion. See Manuscript or Revised Manuscript with Track Changes.2. The section "the structure system" of this paper aims to introduce a complete structure system of insulated sandwich concrete wall, which includes wall composition and the construction of connection joints. Considering the limitation of article length, we design the article content reasonably and the main research content of this paper focuses on the structural performance of single wall under cyclic load. In fact, we have carried out cyclic load tests on both the single wall specimens and the wall-wall junction specimens. As for the mechanical properties of the wall-wall junctions under cyclic load, the research conclusions will be published separately in another paper.3. So far, the shape and size of concrete specimens have not been completely unified in terms of compressive strength. At present, there are two main shapes of concrete specimens:●Standard specimen of cylinder: 150mm in diameter and 300mm in height, adopted by the United States, Japan, France, Canada, Australia and other countries.●Standard cube specimen: 150mm in side length, used in China, Britain, Germany and other countries.According to the value given by UNESCO's Handbook of Reinforced Concrete, the ratio of the compressive strength of the cylinder fcy to the compressive strength of the cube fcu is 0.80. According to the A. M. Neville formula,Where P is the compressive strength; P6 is the compressive strength of cube with 150mm side length; v is the volume of specimen; h is height of specimen; d is maximum transverse size of specimen.After conversion, the ratio of the compressive strength of the cylinder fcy to the compressive strength of the cube fcu is 0.81.In this paper, prismatic concrete specimens are adopted in accordance with Chinese specifications. According to Principle and Analysis of Reinforced Concrete, the ratio of prismatic compression strength fpr to cubic compression strength fcu is 0.76, so it can be seen that prismatic compression strength fpr is very close to cylinder compression strength fcy. Therefore, it is reasonable to use prismatic compression strength fpr to evaluate the structural performance.4. As for figure 6 (a), there may be a misunderstanding. After careful checking, no damage traces were found in the footing slab. This misunderstanding may be due to the electric wires and projections of the digital indicators, the uncleared steel wires used to fix the formwork and projections on the bottom of the specimen. The original photograph is provided below for verification.5. The reason why the curve is different from the hysteresis curve of the conventional wall is that the construction and material are different from that of the conventional RC wall but not the small sized footing. To be specific, the reinforcement ratio (0.13%) of the specimens is lower than that of the conventional RC wall, and the steel wires have no obvious yield point.Taking specimen 2 as example, after the specimen cracks, the width and length of the crack increase with the increasing of displacement, and then the stiffness decreases sharply. When the cracks spread to the bottom of the wall, the horizontal displacement applied to the specimen is mainly resisted by cracks’ opening or closing, so the displacement increases significantly but the load increases a little. As the tensile fracture happens to the steel wires gradually, that the cracks in the compression zone contact will generate friction under the action of axial pressure, so the load continues to keep rising. When unloading in the opposite direction, the existing cracks continue to open or close, the friction between cracks and the new cracks still play a role, the bearing capacity no longer increases until the cracks completely penetrate the whole specimen. All of these factors cause the difference of the curve shape.6. The definition of the yield load has been made in the section "Bearing capacity and ductility" in this paper. It is defined from nominal strength by R. Park method.7. The description in this paper has been modified according to your suggestion, and the description of strength value has been added to the manuscript. See in Revised Manuscript with Track Changes.8. The specimens in this paper is not equipped with lateral constraint members, and the reinforcement ratio of the specimens is low, which can’t make the full use of concrete strength. The crack develops in the specimens at a low load level, and the lateral bearing capacity is controlled by concrete tensile strength, which fails to give full play to the good compressive strength of concrete. Therefore, specimens 1, 5 and 6 showed similar performance despite different concrete grades.This explanation has been added to the section ‘Bearing capacity and ductility’. See Revised Manuscript with Track Changes.9. In terms of the structural performance, the following suggestions are given:●For the concrete layer thickness, 50~60mm is a reasonable range.●Improving the reinforcement ratio and adding the lateral constraint members such as RC or profile steel columns can effectively improve the seismic performance.●Prefabricated ISCP is a good way to simplify and accelerate the construction of this structure.About the thermal performance, some suggestions are listed as follows:●To improve the non-continuity of insulation layer in traditional structure, the new joint construction is proposed in this paper, which are shown in figure 2.●To improving the insulation of steel shear connectors, the hybrid connectors, i.e., covering the surface of steel elements by using the insulating material have been proposed.●In non-load-bearing components, it is a good way to improve the thermal efficiency by using foamed concrete layer as two side plates.These suggestions have been added to the manuscript in section "Suggestion". See Revised Manuscript with Track Changes.Authors' Replies to Reviewer #2:Many thanks to the positive comments.1. ISCP (Insulated Sandwich Concrete Panel) structures have indeed been used in the construction industry for more than a decade. A typical ISCP consists of concrete layers, insulation layer and shear connectors. The concrete layers locate on both sides of the insulation layer, which are connected by shear connectors. However, the traditional ISCP is improved by adding steel tubes and additional reinforcements in this paper. In addition, special constructions of special-shaped columns and additional reinforcements are adopted as well to ensure both the continuity of the insulation layer and strength of wall-wall junction.2. According to the research results of this paper, the following suggestions are given to make the insulated sandwich concrete panel structure used more efficiently in actual construction.In terms of the structural performance, the following suggestions are given:●For the concrete layer thickness, 50~60mm is a reasonable range.●Improving the reinforcement ratio and adding the lateral constraint members such as RC or profile steel columns can effectively improve the seismic performance.●Prefabricated ISCP is a good way to simplify and accelerate the construction of this structure.About the thermal performance, some suggestions are listed as follows:●To improve the non-continuity of insulation layer in traditional structure, the new joint construction is proposed in this paper, which are shown in figure 2.●To improving the insulation of steel shear connectors, the hybrid connectors, i.e., covering the surface of steel elements by using the insulating material have been proposed.●In non-load-bearing components, it is a good way to improve the thermal efficiency by using foamed concrete layer as two side plates.These suggestions have been added to the manuscript in section "Suggestion". See Revised Manuscript with Track Changes.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 29 Oct 2019Cyclic loading test study on a new cast-in-situ insulated sandwich concrete wallPONE-D-19-21558R1Dear Dr. Qiao,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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Reviewer #1: N/AReviewer #2: Yes**********4. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: The sandwich concrete walls may be useful in practice. The authors addressed well the reviewer's comments. It is acceptable.Reviewer #2: (No Response)**********what does this mean?). If published, this will include your full peer review and any attached files.7. 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To fully appreciate the importance of antibiotics to everyday life, we must step back to the edge of the pre-antibiotic era when these lifesaving drugs were first introduced into clinical use. In the pre-antibiotic era skin and soft tissue infections such as cellulitis and erysipelas (frequently confused) were often deadly. These serious infections of the subcutaneous fascia could involve the lymphatics and spread systemically. In the pre-antibiotic era, bacteremia was common and mortality reached as high as 15%. The introduction of sulfonamides into clinical use in the 1930s changed that and the resulting mortality was reduced to 2% , sa, sa92], Transferable exclusivity vouchers could be a powerful incentive . In thisS. pneumoniae and N. gonorrhoeae and in nosocomial Gram-negative pathogens such as P. aeruginosa and A. baumannii. This resistance forces us to use more and more of our “last line” antibiotics which, in turn, selects for resistance to those agents. At the same time, the broken antibiotic marketplace has left us in a situation where our pipeline of new antibiotics is precarious at best. To address this threat, we need to preserve the activity of the antibiotics we have today by controlling their use both for human disease and in the agricultural sector. Our most pressing need, though, is to fix the broken antibiotics market. Without addressing this critical problem, we can expect companies to continue to abandon antibiotic research. This, combined with continued consolidation within the industry, will further deplete our resource of antibiotic discovery researchers. This, in turn, will lead to a further deterioration in our already meager pipeline of new and desperately needed antibiotics. To fix the market, we need to assure a return on investment for those companies pursuing antibiotic discovery and development. “Push” incentives, those that reduce costs of research, have already been well established in the United States and Europe and are helpful. But these will not be sufficient because they do not take into account the capital costs of research failures. To address this problem and ultimately to assure a return on investment, “pull” incentives will be required. A number of models have been proposed for such incentives and, in our opinion, could perform as predicted. None have yet been adopted by any national or regional authority.Antibiotics are “miracle drugs.” They can cure disease in just a few days and, more importantly, save lives. Resistance to these drugs by pathogenic bacteria now threatens this miracle. Resistance is found in community-based pathogens such as


Hepatocellular carcinoma (HCC) is a devastating and highly metastatic cancer worldwide. Metformin (MET) is the priority drug for treatment of type 2 diabetes; however, it possesses multiple biological effects like anticancer and hepatoprotective activity. Herein, we examined the effects of aloin  and MET as well as combination treatment in HCC cell line in vitro and in vivo. As a result, aloin and MET alone exhibited inhibitory effects on proliferation and invasion of HepG2 and Bel‐7402 cells. Specially, combination treatment of aloin and MET showed enhanced inhibitory effects in vitro. Aloin and MET alone induced apoptosis and autophagy in vitro. Similarly, aloin and MET cooperated to promote apoptosis and autophagy in HepG2 and Bel‐7402 cells. In the HepG2 xenograft models, aloin in combination with MET confine tumor growth and facilitate apoptosis and autophagy. Both the in vitro and in vivo results showed that aloin and MET alone as well as combination treatment activated the PI3K/AKT/mTOR pathway. Overall, our research demonstrated that the concomitant treatment with aloin and MET enhances the antitumor effect by inhibiting the growth and invasion as well as inducing apoptosis and autophagy in HCC through PI3K/AKT/mTOR pathway. Our research demonstrated that the concomitant treatment with aloin and MET enhances the antitumor effect by inhibiting the growth and invasion as well as inducing apoptosis and autophagy in HCC through PI3K/AKT/mTOR pathway. The HCC incidence continues to increase rapidly, ranking third with more than 600 000 deaths per year.Metformin (MET) is the first‐line antidiabetogenic drug for treatment of type 2 diabetes.Aloin  was proved to possess anticancer role in different kinds of cancer cells: Ehrlich ascites carcinoma cell, myeloid leukemia, and acute lymphocytes leukemia cancerous cells.22.12 at 37°C. Aloin was obtained from Selleck and dissolved in DMSO (concentration: 1 mg/ml). MET HCl was obtained from Selleck and dissolved in ddH2O (concentration: 1 mg/ml).The HepG2 cells (American Type Culture Collection) and Bel‐7402 cells were cultured in ATCC‐formulated Eagle's Minimum Essential Medium . To make the complete growth medium, 10% fetal bovine serum , penicillin , and streptomycin  were supplemented. The cell lines were placed in an incubator with 5% CO2.2HepG2 cells were treated with PBS  (control), aloin 50 μmol/L, MET 40, and aloBel‐7402 cells were treated with PBS (control), aloin (50 μmol/L), MET (400 μmol/L), and aloin (50 μmol/L)+ MET (400 μmol/L). The cells in all groups were harvested after 48 hours of treatment to measure the expression of corresponding cellular markers.6 HepG2 cells into the right flank near the hind leg of each nude mouse. The experiments began when the mice bore palpable tumors (the tumor volume was ~100 mm3), and they were randomly divided into four groups (n = 7) with treatment of (a) control , (b) aloin , whereas HepG2 xenografts were established by inoculating 2.0 × 10 40 mg/kg, (c) MET 40 mg/kg or (d) a2.33 cells in 200‐μl complete growth medium/well. Then, the 96‐well plates were cultivated in incubator at 37°C with 5% CO2. CCK‐8 experiment was performed according to the manufacturer's instructions. Absorbance at 490 nm was obtained by a microplate reader .Cell proliferation was determined by Cell Counting Kit‐8 (CCK‐8) assay. HepG2 and Bel‐7402 cells were pretreated with PBS, 50 μmol/L aloin, 400 μmol/L MET, and aloin (50 μmol/L) + MET (400 μmol/L) for 0, 24, 48, 72, and 96 hours, then cells were detached and seeded into 96‐well plates at a density of 1.5 × 102.4HepG2 and Bel‐7402 cells were pretreated with PBS, 50 μmol/L aloin, 400 μmol/L MET, and aloin (50 μmol/L) + MET (400 μmol/L); cells were cultured in drug‐free medium for approximate 14 days. The cells were fixed with cold methanol‐glacial acetic acid and stained with crystal violet.2.54/200 µL) into the upper transwell chambers with serum‐free DMEM. The lower chambers were filled with 500‐µL 10% FBS EMEM. Simultaneously, PBS (control), 50 μmol/L aloin, 400 μmol/L MET, and aloin (50 μmol/L) + MET (400 μmol/L) were added into upper chamber. After 24‐hours incubation, cells in lower chambers were fixed in 95% ethanol, and then stained with hematoxylin. The invasive number of cells was calculated and imaged under an inverted microscope.Transwell experiment was performed to detect cell invasion of HepG2 cells. HepG2 cells were seeded  + MET (400 μmol/L) for 24 hours; cell images in the scratch area were captured under the inverted microscope at 100 × magnification .2.75, stained with Annexin V‐FITC and PI, respectively. Finally, flow cytometric analysis was performed according to the manufacturers' instructions .Flow cytometry was performed to detect cell apoptosis. As previously described,2.8Cell autophagy was detected by analyzing the protein expression of Beclin‐1, ATG8, P62, and LC3 as well as the location of LC3. Protein expressions were determined by western blotting. The location of LC3 was detected by immunofluorescence staining. The experiment was performed as described by H. Tong et al.2.9Forty microgram proteins extracted from cells and tumors were resolved on (6%‐12%) SDS‐PAGE, then the proteins on gel were transferred to PVDF membranes (Millipore). Next, PVDF membranes were probed with primary antibodies. Antibodies were as follows: anti‐PI3K, AKT and mTOR (Abcam), anti‐GAPDH (Abcam), anti‐Ki67 (Abcam), anti‐Caspase‐3 (Abcam), anti‐VEGF (Abcam), and anti‐MMP‐9 (Abcam). After removing the primary antibody, membranes were incubated with horseradish peroxidase (HRP)‐conjugated secondary antibody (Santa Cruz Biotechnology). The target proteins were visualized using the Amersham ECL Prime Western Blotting Detection Reagent (Amersham Pharmacia Biotech). Finally, protein images were obtained by a ChemiDocxRS imaging system and analyzed by Quantity One analysis software (Bio‐Rad Laboratories).2.10The orthotopic xenograft models were established according to the study by M.A. Hossain et al.2.11The paraffin‐embedded tumor sections were incubated with anti‐Ki67 and anti‐VEGF (Abcam). The immunohistochemistry assay was performed as previously described by N. D et al.2.12P < .05.SPSS software (version 19.0) was used for all the statistical analyses. The data were shown as mean ± SD. Statistical comparisons were analyzed by one‐way analysis of variance (ANOVA) followed by the least significant difference (LSD) test. The difference was considered statistically significant when values of 33.1P < .05). In addition, the combination treatment of aloin and MET showed that the proliferation‐inhibiting effects were stronger in HepG2 and Bel‐7402 cells compared with the MET alone group (P < .05). The proliferation result was verified by protein expression of Ki67 and PCNA exhibited in Figure P < .05). Similarly, combination of aloin and MET showed that the expression of Ki67 and PCNA was less than MET alone (P < .05).As shown in Figure 3.2P < .05). Expectedly, the combination treatment of aloin and MET reduced the invasive cells in HepG2 and Bel‐7402 compared with the MET alone (P < .05). The relative expressions of MMP‐9 and VEGF were significantly reduced in HepG2 and Bel‐7402 cells by both aloin and MET alone treatment (P < .05). Also, the expressions of MMP‐9 and VEGF were reduced in combination therapy than MET alone (P < .05).As shown in Figure 3.3P < .05); meanwhile, the combination of aloin and MET significantly increased the apoptotic cell compared with the MET alone (P < .05). The expression of cleaved caspase‐3 and caspase‐9 was significantly increased in HepG2 and Bel‐7402 cells by both aloin and MET alone treatment (P < .05); interestingly, the expression of cleaved caspase‐3 and caspase‐9 was high in combination therapy than MET alone .As shown in Figure 3.4P < .05). Interestingly, combination therapy showed the expression level of P62 was less but the expression of Beclin‐1, LC3II, and ATG8 was high in HepG2 and Bel‐7402 cells than MET alone (P < .05). As shown in Figure P < .05).As shown in Figure 3.5P < .05); meanwhile, combination treatment of aloin and MET showed stronger inhibition of the phosphorylation levels of PI3K, AKT, and mTOR compared with MET alone (P < .05).As shown in Figure 3.6As shown in Figure 4HCC is an aggressive tumor characterized by highly proliferative and invasive capability.Aloin, a natural bioactive anthracycline, is extracted from Aloe barbadensis Miller leaves.PI3K/Akt pathway is associated with cell proliferation, apoptosis, autophagy, and inflammation.Autophagy, an intracellular lysosomal pathway, is involved in protein degradation and organelle degradation. Autophagy is closely connected to a variety of human disease and physiology, including HCC.Autophagy is a mechanism by which the cells try to survive while apoptosis is a mechanism of cell death. Autophagy and apoptosis are two distinct processes which play seemingly opposite biological roles in response to genotoxic or pharmacological stresses. However, both autophagy and apoptosis may be triggered by common upstream signals, resulting in the activation of combined autophagy and apoptosis. Specially, the p38 and JNK MAPK pathways in regulating the balance of autophagy and apoptosis will hopefully provide prospective strategies for cancer therapy.In summary, aloin was demonstrated to enhance the anticancer effect of MET via attenuating the proliferation and invasion, and facilitating apoptosis and autophagy in vitro and in vivo. Therefore, aloin is promising to be a novel medication for HCC therapy when combined with MET.Ruijie Sun conceived and designed the experiments; Ruijie Sun and RuirenZhai performed the experiments; Changlin Ma analyzed the data; Wei Miao drafted or revised the manuscript.


This study analyzes the trajectories of antibiotic consumption using different indicators of patients’ socioeconomic status, category and age-group of physicians.This study uses a pooled, cross-sectional, time series analysis. The data focus on 22 European countries from 2000 to 2014 and were obtained from the European Center for Disease and Control, Organization for Economic Co-operation and Development, Eurostat and Global Economic Monitor.There are large variations in community and hospital use of antibiotics in European countries, and the consumption of antibiotics has remained stable over the years. This applies to the community  as well as the hospital sector . Some socioeconomic variables, such as level of education, income, Gini index and unemployment, are not related to the rate of antibiotic use. The age-group of physicians and general practitioners is associated with the use of antibiotics in the hospital. An increase in the proportion of young doctors (<45 years old) leads to a significant increase in antibiotics consumption, and as the percentage of generalist practitioners increases, there use of antibiotics in hospitals decreases by 0.04 DDD/1000 inhabitants.Understanding that age-groups and categories  of physicians may predict antibiotic consumption is potentially useful in defining more effective health care policies to reduce the inappropriate antibiotic use while promoting rational use. Antibiotic resistance is a major public-health problem of global importance because it is related to treatment failure, increased use of health care services and increased mortality ,2. ConsuIn response to this problem, the European Union put in place over time community strategies and action plans supporting, as pillar, antimicrobial stewardship, defined as a coherent set of actions which promote using antimicrobials responsibly. Antimicrobial stewardship aimed to provide evidence-based data on possible links between consumption of antimicrobial agents and the occurrence of antimicrobial resistance in humans and food-producing animals and, then, to develop EU guidelines for the prudent use of antimicrobials in human medicine and to assist Member States implement EU guidelines for the prudent use of antimicrobials in veterinary medicine . At natiSince late 2005, the understanding and the measurement of inequalities in health and health-care use has been identified as a priority by the WHO Commission on Social Determinants of Health. SeveralSeveral studies measure particular aspects of socioeconomic parameters, such as educational level, rather than investigate a set of two or more determinants.This study analyzes the trajectories of antibiotic use across 22 EU countries and it assesses: (i) how the antibiotic consumption has changed in the community and hospital sectors over a 15-year period; (ii) the correlations between antibiotic use and a variety of socioeconomic determinants; (iii) the correlations between antibiotic use and categories of prescribing physicians or age of physician, which is used as a proxy for experience, and the background of the prescribing physician.This study used a pooled cross-sectional time series analysis of secondary data for 22 European countries between 2000 to 2014. These countries and years were chosen based on the availability of data. The unit of analysis was each country in each year (country-year). The countries included in the study were the following: Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Netherlands, Norway, Slovakia, Slovenia, Spain, Sweden and the United Kingdom.Official data were obtained from the European Center for Disease and Control (ECDC), Organization for Economic Co-operation and Development (OECD), Eurostat and Global Economic Monitor (GEM). The indicators considered are related to: the consumption of antibiotics in two different sectors, that are primary care and hospital; the prescribing physicians stratified in five age groups, which are 35–44, 45–54, 55–64, 65–74; the physician categories, that are generalist, specialist and not further defined medical doctors; and related to socio-economic determinants such as the GINI coefficient, household income and education level of the population aged 25–64, stratified into three classes.These indicators are shown in To assess the relationship between dependent and independent variables over the 15-year study period, the study adopted a pooled, cross-sectional, time series design. Specifically, this design involved observing the variables for different cross-sections over a given timespan . The depA fixed-effects linear regression was done by performing a Hausman test with Sigmamore option  because To avoid model overfitting, indicators 3 to 16 were halved by collapsing age groups, while secondary and tertiary education levels (6 and 7) were merged because they gave similar results. Additionally, no results were reported for indicators 9 and 16 because they complement the 100 indicators shown in the Results section. The relationship between all the remaining dependent and independent variables were separately examined, resulting in 12 distinct fixed-effects models. This choice was driven primarily by concerns about model over-fitting and multicollinearity.p < 0.05, and listwise deletion was used. The significance of each independent variable was assessed using robust standard errors due to results obtained from performing a modified Wald test for group-wise heteroskedasticity in the regression residuals [For all the analyses, the significance level was set at esiduals . All datThe antibiotic use patterns in hospital and community settings is shown in The figure reveals considerable variability among the countries regarding the consumption in primary care sector in 2014. The consumption pattern in the Netherlands was approximately 10 DDD, while in Belgium, France, Italy and Luxembourg, the pattern was approximately 30 DDD at the end of the observation period. Five countries  had DDD values above 24 in 2014. However, the DDD values were already high for these countries in 2000.The results show that hospital use of antibiotics, which is poorly reported in the ECDC database, is very low. Eight countries  had DDD values above 2 in 2014. In the hospital sector, the variability was very high, indeed 3 of the countries  started with a higher value, 2 of the countries  had a constant DDD and 3 of the countries  started with a lower value.The fixed effects regression model confirmed the evidence of this first graphic analysis. Linear and quadratic terms were not significant and these apply to the community  as well as the hospital sector .According to the results, some socioeconomic variables, such as level of education, income, Gini index and unemployment, were not related to the rate of antibiotic consumption both in hospital and in the community . SimilarThe only significant findings relate to the association between the consumption of antibiotics in the hospital and some prescribing physicians’ characteristics, age and category. Our results highlight that an increase of a percentage-point of doctors between 35 and 44 years of age led to an average increase of 0.08 in daily doses per 1000 inhabitants, while a one percent increase in doctors between 45 and 54 years old led to a consumption decrease by an average of 0.10 doses. The results of older age classes  were not significant, but the results confirm the trend observed in the 45-54-year-old group. Additionally, as the percentage of GPs increases, there is an average decrease of 0.04 DDD per 1000 inhabitants in hospitalization consumption of antibiotics.It is difficult to compare the antibiotic consumption in the community and the hospital sector among the EU countries due the heterogeneous methodologies used to collect data and due to poor availability of data over the years under consideration. Nevertheless, it is clear that there are large variations in community and hospital use of antibiotics in European countries and that the consumption of antibiotics has remained stable over the years. The Netherlands shows the lowest total consumption of antibiotics (11.55 DDD) whereas Belgium, France and Italy had the highest consumption (>30 DDD) in 2014. There was a three-fold difference between countries with the highest and the lowest use of antibiotics. This difference was already present in 2000.This variability among countries may be affected by antimicrobial stewardship programmes performed in the different European countries. Netherland, which has the lowest levels of antibiotic use, was one of the first countries to adopt a universal, national strategy for AMS in all settings. The Netherland programme started by a Working Party on Antibiotic Policies founded in 1996, supported by the government since 1999. It aimed to provide educational tools in the form of national antibiotic use tests, and in the publication of a national blueprint for an antibiotic policy that can help fellow physicians and pharmacists involved in making such policies at the local level in hospitals and other stations where antibiotics are dispensed .Italy, instead, adopted its first National Action Plan on Antimicrobial Resistance (PNCAR) 2017–2020 in November 2017. The PNCAR represents the tool for implementing the Italian strategy. In order to face the increasing resistance and spread of antibiotic-resistant microorganisms, the PNCAR provides for national coordination, specific objectives and actions through the synergy between national, regional and local levels, the different key stakeholders involved and a governance, in which the roles of the institutions are clearly defined .In Belgium, the Belgian Antibiotic Policy Coordination Committee (BAPCOC) was officially established in 1999 by royal decree. The overall objective of BAPCOC was to promote judicious use of antibiotics and to promote infection control and hospital hygiene, reducing antibiotic resistance and optimizing care. To address these specific tasks BAPCOC founded five multidisciplinary working groups, wich included ambulatory care, hospital care, awareness campaigns, infection control. Specifically, BAPCOC focused on hospital setting through funding of dedicated staff and technical support to antibiotic stewardship (ABS) teams in all Belgian hospitals, the training of over 500 healthcare professionals in ABS, integration of surveillance programs on antibiotic use in hospital ,18.It is not easy to explain the reason for high level of antibiotic use in France. Over the last decade, France implemented three national plans to reduce antibiotic prescriptions. As part of the plans, the French government initiated a long-term nationwide campaign to reduce antibiotic overuse and control the dissemination of resistant bacteria in the community. The national program, named “Keep Antibiotics Working,” was launched in 2001, targeting both the general public and health care professionals, to encourage surveillance of antibiotic use and resistance and to promote better-targeted antibiotic use. Since 2002, a public service campaign is launched each winter with the primary goal of decreasing prescriptions. Unfortunately, the impact of these policies has levelled of the antibiotic use, illustrating again the need for an effective antimicrobial stewardship .Antibiotics consumption in the community continues to account for between 85% and 95% of total consumption in 2014. The highest use in the community was in Belgium, France, and Italy (≥28 DDD9) and in the hospital sector in Finland and the UK. The Netherlands had the lowest use in both of the settings .These findings of substantial stability may explain the behavior of patients and doctors as underlined by the extant literature. A recent review  concludeAccording to the results, some socioeconomic variables, such as level of education, income, Gini index and unemployment, are not related to antibiotics consumption in both settings. However, some other extrapolations may be made. Although the impact is not significant, it seems that increasing inequality (Gini index) and unemployment rates reduce the consumption of antibiotics in the community. There are no studies that investigate the correlation between income inequality, unemployment and consumption of antibiotics. A study conducted in Switzerland reported a weak association between income inequality and antimicrobial consumption, but no causal link has been established . To justThe results also show that increasing the average income reduces antibiotic consumption. Filippini’s study on socioeconomic determinants of regional differences in outpatient antibiotic consumption supports this finding, highlighting the notion that income is negatively related to antibiotics use . In addiAnother important finding in this study is that an increase in the proportion of young doctors (<45 years old) may lead to a significant increase in antibiotics prescription and consumption, while an increase in the percentage of older physicians  reduces the consumption of antibiotics.One possible hypothesis is that practitioners’ experience and professional development activities influence physicians practice, and these factors are responsible for the differences in antibiotics prescribing patterns. This suggestion is supported by some literature ,30, wherAnother important but unexpected result is that as the number of general practitioner increases, the antibiotics consumption is reduced both in the hospital and community sectors. It is difficult to find an explanation for this phenomenon. A previous study has shown some relationship between ambulatory antibiotic use and hospital use. It highlighted the idea that when the use of antibiotics in one country is high in the community context, it is also likely to be high in the hospital context and vice versa. Assuming that there is a causal link between the percentage of general practitioners and antibiotics consumption in the hospital, the mediating factor that may be most important is the antibiotics consumption pattern in the community.The reduced use of antibiotic may be attributed to the fact that by increasing the number of general practitioners in the area, they are able to visit patients, establish a relationship of trust and prescribe antibiotic therapy more appropriately.The main weakness of this study is that the analysis of the trend of use was conducted for all antimicrobials without studying the trajectory of individual antibiotic groups. A focus on individual typologies would help to better understand what may justify the stability of the trend and the typologies with a divergent behavior. A second weakness lies in the fact that the epidemiology of the population of the European areas has not been analyzed. A study of the prevalent pathologies would allow a further explanation of this trend in antibiotics use.Using different indicators of socioeconomic status and different categories of prescribing physicians and insights from extant literature ,33, thisAlthough it is a known fact that antibiotics consumption varies between countries, the current study confirms this link through analyzing a 15-year period and 22 EU countries as well as shows that the consumption of antibiotics has remained stable over the years. These results may promote and help to define more effective health care policies to reduce the inappropriate use of antibiotics.S1 Dataset(XLS)Click here for additional data file.


The application of artificial intelligence techniques for processing electronic health records data plays increasingly significant role in advancing clinical decision support. This study conducts a quantitative comparison on the research of utilizing artificial intelligence on electronic health records between the USA and China to discovery their research similarities and differences.Publications from both Web of Science and PubMed are retrieved to explore the research status and academic performances of the two countries quantitatively. Bibliometrics, geographic visualization, collaboration degree calculation, social network analysis, latent dirichlet allocation, and affinity propagation clustering are applied to analyze research quantity, collaboration relations, and hot research topics.JAMIA with 135 publications and JBI with 13 publications are the top prolific journals for the USA and China, respectively. Harvard University with 101 publications and Zhejiang University with 12 publications are the top prolific affiliations for the USA and China, respectively. Massachusetts is the most prolific region with 211 publications for the USA, while for China, Taiwan is the top 1 with 47 publications. China has relatively higher institutional and international collaborations. Nine main research areas for the USA are identified, differentiating 7 for China.There are 1031 publications from the USA and 173 publications from China during 2008–2017 period. The annual numbers of publications from the USA and China increase polynomially. There is a steadily growing presence and increasing visibility of utilizing artificial intelligence on electronic health records for the USA and China over the years. The results of the study demonstrate the research similarities and differences, as well as strengths and weaknesses of the two countries. With the expanding use and increasing possibility of including information relating to patient outcomes and functionality such as clinical decision support, Electronic Health Records (EHRs) becomes increasingly valuable information about patient health conditions and responses to treatment over time . The fieResearch publication plays an important role in providing key linkage between knowledge generation, uptake and use in the scientific process . BibliomTo that end, relevant publications in the field were retrieved from both WoS and PubMed to quantitatively explore the academic performances of the two countries in terms of current research status, research intellectual structures, and research focuses. Analyzing techniques include bibliometrics, geographic visualization, collaboration degree calculation, social network analysis, latent dirichlet allocation, and affinity propagation clustering.Specifically, the following comparisons are conducted: 1) studying the quantitative distributions and growth characteristics of the publications, 2) identifying prolific publication sources, authors, and affiliations, 3) exploring publication geographical distributions, 4) investigating collaboration degrees and collaboration patterns, 5) visualizing scientific collaboration relations, and 6) discovering hot research topics and topic evolutions.The publications in the research field during 2008–2017 from WoS and PubMed databases were preferred. With a list of search keywords determined by domain experts, as shown in Table In addition to basic bibliometric analysis, the techniques used in this paper include: geographic visualization, co-authorship index and collaboration degree calculation, social network analysis, and topic modelling analysis.Geographic visualization  refers tCo-authorship index shown as Eq. , was firNij is the publication count co-authored by j authors in the ith country, Nio is the publication count in the ith country, Noj is the publication count co-authored by j authors in all countries, Noo is the publication count in all countries. CAI = 100 represents the average level. CAI > 100 indicates higher than the average, while CAI < 100 reflects lower than the average.In the equation, As a measure of scientific research’s connective relation to the level of author, affiliation, or country, the collaboration degree can be calculated as Eq.  14, 15], 1514, 1CAi indicates the collaboration degree of the i year in the author, affiliation or country level. αj donates the count of author, affiliation or country for each publication. N is the annual publication count.In the equation, In this study, co-authorship index is used to study collaboration patterns of authors, and collaboration degree is applied to measure the scientific research’s connective relation to the three levels.Social network analysis (SNA) focuses on the structure of ties within, e.g., persons, organizations, or the products of human activity or cognition such as web sites . SNA worword is defined as an item from a vocabulary indexed by {1, …, V}, a document is a sequence of N words denoted by d = , and a corpus is a collection of M documents denoted by D = {d1, …, dM}. The generation process is as follows: 1) The term distribution β indicating the probability of a word occurring in a given topic is as β~Dirichlet(δ); 2) The proportions θ of the topic distribution for a document d are determined by θ~Dirichlet(α); 3) A topic is chosen by the distribution zi~Multinomial(θ) for each word wi in the document d, and a word is chosen from a multinomial probability distribution conditioned on the topic zi : p. As for variational expectation-maximization, the log-likelihood for one document d ∈ D is given by Eq.  is an improved three-layer Bayesian model developed by Blei et al. . In LDA,s as Eq. .Further, Affinity Propagation (AP) clustering is used for the cluster analysis of the topics identified by LDA. AP was proposed by Frey and Dueck  with a br and the “availability” a, shown as Eqs.  is the suitableness of k as an exemplar for i, while a is the evidence that i should choose k as an exemplar.AP calculates the “responsibility”  as Eqs.  and 6)  r s is the similarity between two nodes i and k. When a good set of exemplars emerges, Eqs.  + r. If i = k, then i is an exemplar. Numerical oscillations is controlled using a damping factor between 0 and 1.In the equations, es, Eqs.  and 6)  s In this study, words from author keywords and Keywords Plus/PubMed MeSH, publication title, as well as abstract with weights 0.4, 0.4, and 0.2 determined by our former study  are used. The publication counts for both two countries are overall showing increasing trends in fluctuation. The average publications during the study period are 103.1 and 17.3 articles per year. The highest productivity is observed in 2017 with a total of 205 (19.88%) articles for the USA and 44 (25.43%) articles for China. The annual growth rates reach 26.18 and 40.54% on average for the USA and China, respectively. The trend of publications for the USA is similar with the polynomial curve  expressed as y = 1.113636x2 − 4463.762x + 4473014, while the publication trend for China is similar with the polynomial curve  expressed as z = 0.3674242x2 − 1475.01x + 1480346. With the simulation curves, the future productivity can be predicted. The predictive values for year 2018 for the USA and China are 230 and 47, respectively.The distributions of total publications by year for the USA and China are shown in Fig. 1Journal of the American Medical Informatics Association, Journal of Biomedical Informatics, and AMIA Annual Symposium Proceedings. As for China, the top 3 prolific ones are Journal of Biomedical Informatics, Journal of Biomedical Engineering, and Studies in Health Technology and Informatics.The 1031 records from the USA are published in 347 unique journal or conference proceeding sources, and 92 publication sources contribute to China’s 173 publications. The top 16 publication sources for the USA in Table Joshua C. Denny (53 publications), Hongfang Liu (36 publications), Guergana Savova (34 publications), Hua Xu (32 publications), and Christopher G. Chute (28 publications) as the top 5 for the USA. As for China, Buzhou Tang (7 publications) and Jianbo Lei (6 publications) are the top 2. Table Harvard University with 101 publications is ranked at 1st for the USA. Other prolific affiliations include Vanderbilt University with 96 publications and Mayo Clinic with 93 publications. As for China, the top 3 are Zhejiang University, National Taiwan University, and China Academy of Chinese Medical Sciences.Three thousand three hundred fifty authors and 542 affiliations from the USA contribute to the 1031 publications, and 635 authors and 208 affiliations from China for the 173 publications. Table We study the concentration of researches in the USA and China at regional levels. The spatial characteristics of the publications from the two countries are explored. 46 states in the USA involve in the 1031 publications and 25 regions in China contribute to the 173 publications. The geographical distributions are shown as Figs. CAI for the USA and China have been illustrated in Fig. CAIs of multi- and mega-author publications in the research filed in China are slightly higher than the average. However, the CAIs of multi- and mega-author publications in the USA are lower than the average. Figure The profiles of The collaboration among countries/regions for the USA’s publications is then visualized as Fig. Drug (483), Medication (411), Cancer (370), Adverse (362), and Phenotype (275), while the top terms for China are Risk (195), Medicine (125), Drug (107), Cancer (76), and Diabetes (71). Figures α is then set to 0.01339416 for the USA and 0.008163102 for China. We estimate the LDA models using Gibbs sampling with the parameters. Potential themes are assigned to each topic through semantics analysis of representative terms and text intention reviewing. Table Drug adverse event, Vaccine, Diabetes mellitus, Health data confidentiality, and Health data analysis technique, while the top 5 for China are Named entity recognition, Drug adverse event, Smoking, Prescription & drug, and Risk event. The AP clustering results based on term-topic posterior probability matrix are shown in Figs. By setting TF-IDF value threshold as 0.1, top used terms in the author keywords, Keywords Plus/PubMed MeSH, title, and abstract of the publications are ranked by frequency. The top 5 terms and their frequencies for the USA are  Cancer 30, AdversDrug 43, MedicaAdverse 32, and Phre Risk 15, Medici5), Drug 7, Cancerication 4, Cancer Medicine 5, Drug (AMIA Annual Symposium Proceedings, indicating a wide influence of journal in the research field. From the publication distributions in region levels, it is obvious that for both the USA and China, most top prolific regions are also of economic prosperity.In this study, a comparative quantitative analysis of literature of utilizing artificial intelligence on electronic health records in the USA and China are conducted. This study identifies 1031 publications from the USA and 173 publications from China for the comparative analysis. Significant and polynomial increases in publication counts for both two countries can be found. This reflects a growing interest in the research field. However, the publication count of China is not at par with that of the USA, this can also be reflected by Tables From the authorship pattern analysis, it is found that publications published by scientists in the research field in China prefer to work in larger collaboration groups. This is consistent with the finding of Guan and Ma  that resThrombosis, Health data privacy & confidentiality, Drug adverse event & vaccine, Imaging, Disease, Audio-visual function, Application of Bayesian, Clinical data analysis technique, and Nursing. Meanwhile, the 35 identified topics for China’s research are classified into 7 areas including Cancer, Imaging, Clinical decision support, Drug & risk event, Chinese medicine, Gestational diabetes mellitus, and Clinical data analysis techniques. The results demonstrate the similarities and differences of the research between the two countries. From Figs. Diabetes mellitus, Heart failure, Health data privacy & confidentiality, and etc., present statistically significant increasing trends at the two-sided p = 0.05 level. The same is for 6 topics for China, including Named entity recognition, Risk event, Chinese medicine, Brain imaging, Drug adverse event, and Cancer. As an emerging focus in drug and cancer research topics, drug resistance has currently been one of the biggest obstacles in the treatment of cancers in clinical practice [Through topic modelling and clustering analysis, the 35 identified topics for the USA’s research are categorized into 9 areas including practice . Some expractice  proposedpractice  conducteIn this study, there are some limitations that are inherent to the database used and to search query developed by the authors. Such limitations were also encountered in the existing bibliometric studies, e.g., , 33. FirUtilizing artificial intelligence techniques on EHRs research is an emerging and promising field. This research provides a most up-to-date quantitative analysis for exploring and comparing the research performance and development trends of the research field from the USA and China during the period 2008–2017. Results of this exploration present a comprehensive overview and an intellectual structure of the research, especially, research topics, for the two countries in the last decade.