In the late 1990s using robotic technology to assist children with Autistic Spectrum Condition (ASD) emerged as a potentially useful area of research. Since then the field of assistive robotics for children with ASD has grown considerably with many academics trialling different robots and approaches. One such robot is the humanoid robot Kaspar that was originally developed in 2005 and has continually been built upon since, taking advantage of technological developments along the way. A key principle in the development of Kaspar since its creation has been to ensure that all of the advances to the platform are driven by the requirements of the users. In this paper we discuss the development of Kaspar’s design and explain the rationale behind each change to the platform. Designing and building a humanoid robot to interact with and help children with ASD is a multidisciplinary challenge that requires knowledge of the mechanical engineering, electrical engineering, Human–Computer Interaction (HCI), Child–Robot Interaction (CRI) and knowledge of ASD. The Kaspar robot has benefited from the wealth of knowledge accrued over years of experience in robot-assisted therapy for children with ASD. By showing the journey of how the Kaspar robot has developed we aim to assist others in the field develop such technologies further. Investigating how robots could potentially be used as assistive tools for children with Autistic Spectrum Disorder (ASD) emerged as a field of research in the late 1990s with Dautenhahn and Werry  conductiThe Kaspar robot was originally developed in 2005 by Blow et al.  as a HumSince the initial creation of Kaspar there have been numerous technological advances and the accessibility of sophisticated manufacturing has increased due in part to the expiration of major 3D printing patents in recent years , 11. TheThe following sections provide a detailed explanation of the developmental journey of the Kaspar robot since 2005 and how this has been influenced by user requirements, technological advances and accessibility of modern manufacturing techniques.The first Kaspar robot K1, Fig.  designedThe K1 robot was very successful in its ability to attract and maintain the attention and interest of many children with ASD who had interacted with the robot. It provided more advanced interaction possibilities than the previously used Robota robot. Thus, a second implementation of Kaspar K2, Fig.  was deveDriven by a European project called ROBOSKIN, in 2009 the third version of the Kaspar robot was constructed by M. Walters K3, Fig. . IdenticBased on the positive results of the previous studies with the Kaspar robots since 2005, indicating that robots such as Kaspar could assist in helping children with ASD e.g. develop their turn taking skills, collaborative skills and tactile social interaction skills , the firServos—The K5 robot possesses 22 DOF with 3 DOF in each eye/eyelid, 2 DOF in the mouth, 3 DOF in the neck, 5 DOF in each arm and 1 DOF in the torso. The DOF in the eyes/eyelids of the robot used the Hitec HS-82MG servos whilst the more substantial joints in the robot used the Dongbu Robot Herkulex drs-0101 and drs-0201 servos. The Herkulex drs servos were chosen because of their small form and compliance feature. The servos could be programmed to provide an elastic response to external force, meaning that if a child moved the arm of the robot manually and forced it, the servo would not break as they would have on previous models. Using these servos made the robot much more reliable and suitable to tactile interaction.Sensors—The K5 uses 15 FSR sensors to facilitate tactile interaction which are placed as follows: 2 in each hand with one on the palm and another on the back of the hand, 1 on each of the arms, 1 on each of the legs, 1 on each of the feet, 1 on the chest and 4 in the face of the robot.Connectivity—This version of Kaspar was the first to utilise Wi-Fi connectivity and was therefore no longer required to be physically tethered to a computer—an important feature to remove the hazard of users tripping over wires.Power—The robot is powered by two 12 v 7Ah Lithium Iron Phosphate batteries which can last for up to 7 h. The recharge time of these batteries is 6 h, but has the capacity to be much faster with a 7 amp charger.Speaker—The speaker of the robot was mounted in the head to help create the illusion that the sound is coming from Kaspar’s mouth.Concealment—Because this version of Kaspar was to be used directly by parents and teachers it was essential to ensure all wires, servos and metal parts were concealed, as they were not in previous iterations of Kaspar. The design of the K5 concealed as many parts of the robot as possible to eliminate the potential for small fingers getting caught in gaps and to make the robot more robust. An example of this is the construction of the hands. The FSR sensors were placed on the 3D printed core then covered by a silicon skin which protected the sensors and provided the hands with a pleasant feel. The arm and neck joints of the K5 were shielded with bellows (flexible covers) that were designed in CAD and 3D printed using NinjaFlex a thermoplastic polyurethane (TPU) material. Note, in order to maintain the introduction of Kaspar as a robot, not a ‘small child’, we covered e.g. the robot’s neck with transparent flexible, 3D printed covers, so that the robotic nature of the robot was clearly visible to the children and adults present.Since 2014 a number of hardware and software upgrades have been made to the K5 platform to improve the functionality and usability of the robot constituting the K5.5 robot  skills of children with ASD , 42. VPTSince the latest application area puts a particularly high cognitive load on the human operator it is important to develop methods of making the robot easier to control and allow the adult operator to focus on the child and not the robot. Very often in robot-assisted therapy for children with ASD the robot has to be partially or fully controlled remotely by an adult operator, whether this is a researcher, therapist, teacher or parent. Whilst using this method enables the adult operator to administer a highly personalised intervention focusing on high-level objectives such as developing the child’s social skills, it does require the operator to divide their attention between the child and the robot to ensure that the robot is responding appropriately to the child’s behaviour. Although this method is highly robust and does not require a complex control system for the robot, it is an unsustainable model for long-term interactions as the cognitive workload on the adult operator is very high . In ordeTo integrate some semi-autonomous features into the most recent generation of the Kaspar robot (K5.5) , Zaraki The Sense-Think-Act architecture on Kaspar is a network-based platform independent architecture that has been implemented in a number of different programming languages (C sharp .Net and Java) and is capable of being distributed over a number of different processors in order to reduce the total computational cost. Since we have created the architecture on the basis of the IrisTK toolkit, the architecture has the capacity to operate on a number of different machines. In this instance, several IrisSystems are connected to a central broker (IrisBroker), which relays events to all connected systems. In each machine the events are serialised in standard JSON data packets and sent over TCP/IP. Using this method, it is also possible to connect modules that are implemented in other programming languages Fig. . The arcThe sense layer includes a number of sensors which sense the environment and the associated perception modules that we have developed to interpret the sensory information in order to extract “events” occurring in the CRIs. We have chosen the sensors and developed the associated perception modules based on the requirements of the VPT games that we have been developing for the Kaspar robot. The core technical requirements to facilitate these games are object recognition and 3D orientation tracking.Since the core objective of the robot in the application area is to teach the children about VPT, it is essential that the robot has the capacity to robustly recognise an object if a useful level of autonomy is to be achieved. The perception module developed for Kaspar has been implemented using an image processing library (Aforge .Net) which receives the image from the embedded camera in Kaspar’s eyes and tracks and recognizes multiple toys based on their colours and the size of the colour regions Fig. . In ordeBecause some of the VPT games require an accurate representation of the objects orientation, Inertial Measurement Unit (IMU) sensors were used in some of the objects Fig.  to estimThe Think layer is functioning as the brain of the architecture and as such receives all of the event streams from the Sense and Act layers via the network (IrisTK Broker) in real time and decides how to handle this information in order to make an appropriate decision for the robot’s action. In the decision-making process it considers the game modality (which game the robot is currently in), the status of the game (the progress of the child in the game), and the previous action shown by Kaspar. Figure The final layer of the architecture is a reactive (act) system which has been developed to provide Kaspar’s control signals in order to display different behaviours on the robot. to the IrisTK Broker and receives all the events however we have subscribed only to the Think layer which means that the reactive system only listens to the events that streamed from the Think layer. Similar to other layers, the reactive layer is also connected. The Kaspar reactive system Fig.  has seveThe semi-autonomous architecture implemented on Kaspar was tested at a school with children with ASD. Testing the system in this setting allowed us to evaluate the real-time performance of the architecture in controlling Kaspar in a real-world setting. It also allowed us to establish if the architecture is capable of controlling the robot’s behaviour in an autonomous and acceptable way in both dyadic and triadic interactions with children. We installed the three layers (“sense-think-act”) of the architecture on a single laptop  for the compatibility test as well as to check the overall performance.Bringing the animal themed toys into the robot’s FOVShowing Kaspar animal pictures on different sides of a cubePhysically manipulating Kaspar’s head to look at animal toys placed around the roomControlling the robot’s head orientation together via two joysticks  as a pair to make Kaspar look at animal toys placed around the room.During these sessions the data of 11 child–robot interactions were collected (Fig. Four children with ASD that have different levels of ability took part in the study where they played 4 different games, one of which was a joint game for pairs of children. The games focused on VPT and included:ted Fig. . The triWhilst our work with Kaspar has focused on developing both the hardware and software aspects of a robot with realistic humanlike features for children with ASD, many other projects have used other robotic platforms such as NAO , PROBO , 54 and User focused—Although technology can greatly assist in the development of robotic systems, it should not be the primary focus. The primary consideration should be the therapeutic and educational objectives rather than technology. Technology is merely a facilitator and should be used to fulfil the needs of the users.Usability—To ensure that technology has a genuinely useful impact on its target users it must be sufficiently usable, otherwise it will likely never be used and could even be seen as a burden by its users.Reliability—Instilling user confidence in a system is critical in getting users to want to use and embrace a system. Although this is particularly challenging in the field of assistive robotics for children with ASD, the Kaspar robot has been able to achieve good levels of reliability by considering how the users will use the system and what could and has gone wrong in the past. Developing any robotic system is an iterative process in order to make it reliable and thus embraced by users.Safety—Ensuring that any robotic system is safe is a top priority regardless of the user group. As such the Kaspar robot was developed to ensure that it was safe to use with children. This means ensuring that there were no pinch points, no chance of electrical shock, no sharp edges and numerous other considerations. The K5.5 robot was installed with extensive safety features to ensure it was suitable to be placed into a home or school environment.Affordability—In order for robotic systems to become accessible to users they must be produced at an accessible price. Ensuring that the Kaspar robot would potentially be affordable if it was to go into mass production has always been a key pillar of the platform and as such the latest K5.5 version of the robot has been produced with less than As can be seen from the iterative development of the Kaspar robot over the last 12 years, technological advancements are enabling more useful and complex scenarios and systems to be developed. The advancements are not only facilitating new games that can assist children learn new skills, but are also making therapeutic robots such as Kaspar more robust. When Kaspar was first developed the ability to track users without attaching devices to them and with reasonable accuracy was not even a possibility. However, new sensing technologies such as the Kinect are not enough on their own. More work and research needs to be conducted in order to fully utilise the benefits of such technologies.Since 2005 the Kaspar robot has continually been developed both in terms of hardware and software, during this time many lessons have been learnt about developing humanoid robots for children with ASD. The primary considerations that need to be observed when developing robots for this user group are as follows:


Axial compression tests were carried out on 72 FRP (fiber reinforced polymer)–stirrup composite-confined concrete columns. Stirrups ensure the residual bearing capacity and ductility after the FRP fractures. To reduce the effect of stress concentration at the corners of the confined square-section concrete columns and improve the restraint effect, an FRP–stirrup composite-confined concrete structure with rounded corners is proposed. Different corner radii of the stirrup and outer FRP were designed, and the corner radius of the stirrup was adjusted accurately to meet the designed corner radius of the outer FRP. The cross-section of the specimens gradually changed from square to circular as the corner radius increased. The influence of the cross-sectional shape and corner radius on the compressive behaviour of FRP–stirrup composite-confined concrete was analysed. An increase in the corner radius can cause the strain distribution of the FRP to be more uniform and strengthen the restraint effect. The larger the corner radius of the specimen, the better the improvement of mechanical properties. The strength of the circular section specimen was greatly improved. In addition, the test parameters also included the FRP layers, FRP types and stirrup spacing. With the same corner radius, increasing the number of FRP layers or densifying the stirrup spacing effectively improved the mechanical properties of the specimens. Finally, a database of FRP–stirrup composite-confined concrete column test results with different corner radii was established. The general calculation models were proposed, respectively, for the peak points, ultimate points and stress–strain models that are applicable to FRP-, stirrup- and FRP–stirrup-confined concrete columns with different cross-sectional shapes under axial compression. Confined concrete is a classical structural subject. At present, stirrups and fibre-reinforced polymers (FRPs) are two types of common binding materials in engineering. Closely spaced stirrups or spiral stirrups are often used to provide a higher lateral binding force to core concrete, but their effect of improving the concrete bearing capacity in actual engineering is still limited ,2. FRPs In the axial compression tests of FRP-only, stirrup-only or FRP–stirrup composite-confined concrete columns, test variables usually include FRP thickness, FRP type, steel tube thickness, stirrup spacing and other common variables. Liao et al.  and Li eIn addition, in the research on the axial compression performance of confined concrete, the section forms of the specimens are mainly circular or square, of which the most common is circular ,37,38,39ρ of the specimen as 0~1 and showed that when the cross-section of confined concrete was close to circular (ρ = 1), the strength of the confined concrete column increased the most. Ceccato et al. [To reduce the effect of stress concentration at the corners of the confined square section concrete column and improve the restraint effect, rounding the square section’s corners is an effective technical measure. The axial compression characteristics of confined concrete columns with different corner radii are also very different. Gao et al.  and Li eo et al. , using ao et al. ,45. In ao et al. ,49,50.Based on the current situation that there are many studies on the mechanical properties of confined concrete columns with circular sections, and relatively few studies on the mechanical properties of rectangular section specimens, the axial compression properties of FRP–stirrup composite specimens with different section shapes under compression are studied in this paper. The square specimens are the main research object. In order to improve the stress concentration at the corners of square section specimens, different corner radii of the stirrups and outer FRP were designed, and now, the research on the influence of different corner radii on the axial compression performance of FRP–stirrup composite-confined concrete specimens is limited. Thus, the corner radii are used as a test variable in this test. The cross-sections of the specimens were gradually changed from square to circular as the corner radii increased. Therefore, in addition to studying the influences of common test variables  on the axial compression properties of FRP–stirrup composite-confined concrete specimens, this test focused more on the influence of different corner radii and cross-sectional shapes.At present, there are few theoretical calculation models for the load-carrying capacity of rectangular FRP–stirrup composite-confined concrete columns, and there are fewer calculation models suitable for quantitatively describing the mechanical properties of rectangular FRP–stirrup composite concrete columns with different cross-section characteristics under axial compression. Therefore, a database considering the effects of corner radii, FRP type, FRP layer number, stirrup spacing, etc., on the mechanical properties of FRP and stirrup-confined concrete is established, which ensures the parameter diversity of the newly proposed model fitting data. Then, we use the data in the database to evaluate the models of FRP–stirrup composite-confined circular concrete. Based on the constraint mechanism and test results, the effective restraint coefficient of the stirrup and the cross-sectional shape coefficient of the FRP were introduced to modify the calculation model of FRP–stirrup composite-confined circular concrete while further considering the reduction in the restraint effect of a small corner radius on the core concrete. Therefore, the peak points, ultimate points and stress–strain curve models considering the restraint effect of stirrups and suitable for FRP-only, stirrup-only and FRP–stirrup composite-confined concrete specimens with small corner radii and large corner radii are proposed. The proposed models provide a reference for the follow-up study of composite-confined concrete columns. Moreover, the FRP stirrup composite-confined concrete structure proposed in this paper also has certain practical significance. The composite restraint of FRP and stirrup on the concrete column makes it have a higher bearing capacity and better deformation capacity, which is of great significance to the development of various civil buildings, highways, bridges and underground structures. Due to the corrosion resistance of FRP, this structure can also be used in marine engineering to block the corrosion of chloride ions in seawater and sea sand.Seventy-two FRP–stirrup composite-confined concrete columns with heights of 300 mm were designed and tested under axial compression. Taking into account the stress concentration phenomenon of the square columns, the corners of the stirrups and outer FRP of all specimens were rounded. The corner radii of the outer FRP (R) are 5 mm, 25 mm, 40 mm and 75 mm. Because when stirrups are used to restrain concrete columns, the shape design of stirrups is usually consistent with the cross-sectional shape of specimens, so the corner radii of the stirrups (r) are adjusted accurately to meet the corner radius of the outer FRP. Due to the limitations of stirrup bending, the minimum corner radius of the stirrups could only be 15 mm. The cross-sections of the specimens gradually changed from square to circular as the corner radii increased. The length (b) and width (d) of the specimens with square sections are equal, both of which are 150 mm, and the diameter of the circular section was 150 mm. The main function of FRPs and stirrups in the structure is to serve as the external restraint material of core concrete, limit the transverse deformation of concrete under axial compression and make the concrete under three-dimensional compression so as to improve its bearing capacity and deformation capacity. Therefore, twelve unreinforced concrete specimens were constructed, consisting of six unreinforced circular columns a (φ150 mm × 300 mm (PC-C series)) and six unreinforced square columns (150 mm × 150 mm × 300 mm (PC-S series)). According to the type of external FRP (CFRP or BFRP), the specimens were divided into two batches. Each batch included seven groups of concrete specimens. The specimens were coded according to their cross-sectional shape (S: square), corner radius , stirrup spacing , FRP type  and the number of FRP layers . Two identical specimens with the same parameters were produced. The S20 restrained concrete specimens were divided into four groups according to the corner radius of the specimens , and only two S40groups of specimens with corner radii  were produced. To ensure the accuracy of the test, two specimens with the same parameters were prepared. The corner radii, number of FRP layers, stirrup spacing and FRP type of different specimens are shown in 3, respectively. At the same time, six concrete cubes of 150 mm × 150 mm × 150 mm were prepared for both batches. According to the standard for test methods of mechanical properties on ordinary concrete (GB/T50081-2016) [y,f yield strain yε and modulus of elasticity yE were 325.5 MPa, 0.0024, and 201.0 GPa, respectively. The BFRP and CFRP both had the same nominal thickness of 0.167 mm. The CFRP used is produced by Nanjing mankat Technology Co., Ltd. , the BFRP is produced by Zhejiang Shijin Basalt Fiber Co., Ltd. . According to the test method for tensile properties of orientation fibre reinforced polymer matrix composite materials (GB/T 3354-2014) [fuf, ultimate tensile strain fuε and elastic modulus fE were 4113 MPa, 0.0222 and 74.04 GPa for the BFRP sheets and 4334.64 MPa, 0.0175 and 249.71 GPa for the CFRP sheets, respectively. The average tensile strength, modulus of elasticity and ultimate tensile strain of the epoxy resin adhesives (L-500 AS/L-500 BS) provided by Sanyu Resin Co., Ltd. .were 67.7 MPa, 2.9 GPa and 0.029, respectively. These properties were taken from the specifications of the manufacturer.The concrete columns confined by BFRP and CFRP were cast in two batches with a 0.46 water-cement ratio. The cement, water, sand and gravel in the concrete were 402, 185, 598 and 1215 kg/m81-2016) , the ave81-2016) , the ave54-2014) , the mecThe tests were carried out on a high-stiffness testing machine with a capacity of 3000 kN provided by Popwil Electromechanical Control Engineering Co., Ltd. . The displacement control loading mode was adopted in the experiment. The initial loading rate was 0.3 mm/min. After FRP fracture, the loading rate increased to 0.5 mm/min. The axial loads of concrete specimens were measured by load sensors attached to the testing machine. The displacements in the whole range of specimens were measured by two common displacement meters (D) arranged symmetrically, and the displacements in the 250 mm range in the middle of the specimens were measured by two laser displacement meters (JD) arranged symmetrically. Meanwhile, the axial and longitudinal strains of the concrete specimens were measured by 5 mm × 3 mm axial strain gauges (AFs) and 100 mm × 2 mm longitudinal strain gauges (LFs) bonded onto the surfaces of the specimens. The strain data was acquired from a TDS-530 strain gauge. The instrumentation configuration and test setup for FRP–stirrup composite-confined concrete columns are shown in The typical failure modes of concrete column specimens are shown in For the concrete columns confined only by stirrups, the corner radii of the stirrups were 15 mm, 25 mm, 40 mm and 75 mm, the cross-section gradually changed from square (R = 5 mm) to circular (R = 75 mm), and the cross-section with a corner radius of 75 mm was circular. The final failure mode of concrete columns confined only by stirrups was that almost all the concrete on the surface of the specimen fell off, and the internal stirrup was exposed. The specific failure process is as follows: when the axial load increased, small cracks appeared on the surface of the concrete, especially at the corners. When approaching the ultimate load, the external concrete was severely fragmented, and more small pieces of concrete peeled off. When the concrete column specimens were finally destroyed, nearly all the concrete on the surface fell off, and the inner stirrups were exposed. Different corner radii and stirrup spacing have a greater impact on the failure mode of concrete specimens confined only by stirrups. The increase in corner radius reduced the extent of the damage to concrete. For specimens with larger corner radii (R = 40 mm and 75 mm), the crushed concrete block was small, and the exposed area of the stirrups was less than those of specimens with smaller corner radii (R = 5 mm and 25 mm), which reflects the excellent bearing capacity of the specimens with larger corner radii. In addition, for specimens with a smaller stirrup spacing (S = 20 mm), the concrete on the surface of the specimens almost completely fell off, the core concrete still retained a good bearing capacity in the later stage of the test, showing a high ductility of the column; for specimens with a larger stirrup spacing (S = 40 mm), the concrete on the surface of the specimen will fell off completely, and the concrete between the transverse stirrups peeled off extensively, resulting in taper-shaped damage.For the concrete columns confined by stirrups and FRP, the corner radii of the outer FRP were 5, 25, 40 and 75 mm, and the corner radii of the stirrups were adjusted accurately to meet the designed corner radius of the outer FRP. Different corner radii had obvious effects on the failure mode of FRP–stirrup composite-confined concrete columns under axial compression. At the beginning of loading, the surface of the specimen had no obvious change, and with the increase in axial load, the FRP–stirrup composite concrete columns appeared local buckling in the middle area, accompanied by a slight sound of epoxy resin glue cracking. For specimens with small corner radii, the local buckling in the middle of this specimen was more serious. Near the ultimate load, the FRP fractured. Due to the stress concentration, FRP tensile fracture mainly occurred at the corners of the concrete columns firstly. Then, with the increase in load, the fracture of FRP spread to the column body along the crack at the corner. Especially for specimens with smaller corner radii , the fracture of FRP at the corner was very obvious , the peak stress, peak strain, ultimate stress and ultimate strain of specimens confined by two layers of CFRP increased by 1.57 to 2.41 times, 6.13 to 7.68 times, 2.42 to 4.34 times and 19.15 to 22.65 times, respectively; the peak stress, peak strain, ultimate stress and ultimate strain of specimens confined by one layer of BFRP increased by 1.13 to 1.76 times, 1.75 to 4.42 times, 1.31 to 2.52 times and 7.28 to 15.94 times, respectively. When the stirrup spacing was 40 mm, compared with the ultimate stress and the ultimate strain of plain concrete columns, and when the corner radius of the test piece increases from 25 mm to 40 mm, the peak stress, peak strain and ultimate stress of specimens confined by two layers of CFRP increased by 13.7%, 22.9% and 9.5%, respectively; the peak stress, peak strain, ultimate stress and ultimate strain of specimens confined by two layers of BFRP increased by 20.6%, 25.6%, 25.4% and 5.3%, respectively. In particular, when the radius of the corner was very small (5 mm), the confinement effect of FRP was the worst, and the slope of the stress–strain relationship curve was very small in the strengthening stage. At this time, the confinement pressure of FRP was small. Since FRP does not easily fracture, the ultimate strain of the specimen under compression will be the largest, as presented in With the same corner radius and FRP layers, the smaller the stirrup spacing, the better the achievable bearing capacity and deformation capacity, as presented in lf is an important factor affecting the mechanical properties of confined concrete. It refers to the lateral restraint of the confining material on the core concrete columns, which directly determines the restraint efficiency of confined concrete structures. lf of FRP and stirrups on circular concrete columns is shown in Equation (1), in which gA is the total section area of restrained concrete specimens , lff is the effective lateral restraint force of the FRP and lsf is the effective lateral restraint force of the spiral stirrups. The area distribution of each component of the specimen is shown in The lateral restraint strength For FRP–stirrup composite-confined rectangular concrete columns, the confinement forces at the corners of the section are larger than that at the middle of the side of the confined concrete columns. Considering the influence of a nonuniform confinement force in the calculation and analysis of rectangular concrete columns confined by FRP and stirrups is difficult. The concept of an effective lateral confinement force has been widely used in the study of confined concrete.lsf of rectangular spiral stirrups on the core concrete by introducing the effective restraint coefficient ek of the stirrups on the basis of experiments and considering the influence of rectangular section characteristics on core restraint concrete.ccρ is the volume ratio of the longitudinal reinforcement; iw is the distance between adjacent longitudinal bars; n is the number of longitudinal bars; cb and cd are the length and width of the core concrete, respectively (cd ≥ cb); s is the spacing between adjacent stirrups; s’ is the vertical distance in the concrete between adjacent stirrups; sA is the cross-sectional area of the stirrup; and yf is the average stirrup yield stress.Mander et al.  calculatsk of FRP-confined rectangular concrete columns with different cross-sectional shapes and calculated the effective lateral restraint force lff of FRP:frpE is the elastic modulus of the FRP; frpε is the ultimate tensile strain of the FRP; t is the thickness of the FRP; D is the equivalent cylinder diameter; b and d are the length and width of the rectangular section, respectively; and R is the corner radii of the outer FRP.Lam and Teng  defined cof and coε are the peak stress and corresponding strain of plain concrete, respectively; b, d and R are the length, width and corner radius of the cross-section, respectively; fρ, fε and fE are the content, ultimate strain and elastic modulus of FRPs, respectively; sΡ and sE are volume ratio and elastic modulus of stirrup, respectively; lf,ef, ls,ef and l,ef are the effective lateral restraint strength of the FRP, stirrup and the whole structure, respectively. Most of the models are suitable for circular or rectangular cross-sections, and a few are suitable for both common rectangular and circular sections and rectangular sections with rounded corners.The existing stress–strain relationship models of FRP–stirrup composite-confined concrete columns have been summarised, as presented in To establish a widely applicable model of FRP–stirrup composite-confined concrete columns with different corner radii, a database including the test results of FRP–stirrup composite-confined concrete columns with different corner radii by Harajli et al. , Ilki etb and c on the basis of Popovics et al. [f(x) for the stress of confined concrete (cf) and the peak stress of confined concrete (ccf) is shown in Equation (9):secE is the secant modulus at the peak point; cE is the elastic modulus of the concrete; cof and coε are the peak stress and corresponding strain of plain concrete, respectively; cf and cε are the stress and strain of specimen, respectively; ccf and ccε are the peak stress and peak strain of the specimen, respectively; and cuf and cuε are the ultimate stress and ultimate strain of the specimen, respectively. For FRP- or FRP–stirrup-confined concrete columns, b and δ are −0.1 and 0.01, respectively. For stirrup-only confined concrete columns, both b and δ are 0.Most of the existing stress–strain models of FRP–stirrup composite-confined concrete columns only consider the change in the stress–strain relationship curve before the concrete column structure reaches its ultimate bearing capacity, and only a few stress–strain models can be used for predicting the descending curve after FRP fracture. In order to study the constitutive model of FRP stirrup composite-confined rectangular concrete column under axial compression under multi-parameter conditions, Wu and Wei  innovatis et al.  model toa. The stress–strain relationship curve can be determined by the peak stress ccf and peak strain ccε of the specimen. In the FRP-only confined concrete model (right branch in the flowchart), the curve before the peak point is determined by parameter a, while parameter c controls the strengthening or softening of the curve after the peak point. The stress–strain relationship curve can be determined by the peak stress ccf, peak strain ccε, ultimate stress cuf and ultimate strain cuε of the confined concrete column. For the FRP–stirrup composite-confined concrete columns , before FRP fracture, the stress–strain relationship curve of FRP–stirrup composite-confined concrete columns is similar to the stress–strain relationship curve of FRP-only confined concrete column. After the FRP fracture, the concrete is confined only by the stirrups, and the stress–strain relationship curve is similar to that of the stirrup-only confined concrete column.cuf and cuε of FRP–stirrup composite-confined circular concrete columns have been established [The formulas for calculating ablished :(13)fcufek of the stirrups is introduced for the ultimate stress model of columns with noncircular sections. Considering the different cross-sectional shapes of the specimens, the section shape factor sk of FRP, the equivalent circular diameter D of the rectangular section and the core equivalent circular diameter cD of rectangular concrete in the core area are introduced. As shown in D is the equivalent circle diameter of the square section; b and d are the length and width of the square section, respectively; the blue circle represents the equivalent circle of square core concrete; cD is the equivalent circle radius of square core concrete; cb and cd are divided into length and width of square core concrete; D = b = d, cD = cb = cd. Then, the effective lateral confinement force of FRP–stirrup-confined concrete columns is calculated. Furthermore, considering the reduction in the confinement effect of the core concrete due to the smaller corner radius of the specimen section, it is suggested that the bearing capacity calculation model of FRP–stirrup composite-confined concrete columns with different corner radii  is as follows:R is the corner radius of the outer FRP, r is the corner radius of the stirrups, lff is the effective lateral restraint force of the FRP, lsf is the effective lateral restraint force of the spiral stirrups, gA is the total section area of the restrained concrete specimens and ccA is the core area of the restrained concrete with a stirrup.The influence of the cross-section shape has not been considered in the above models, so the models for FRP–stirrup composite-confined concrete columns with different cross-section shapes should be further studied. Because the specimens studied are confined not only by the FRP but also by the stirrups, the effective confinement factor α is added into the above formula. Through the regression analysis of the database data, it is suggested that the value of α is 0.76.To make the formula universal to specimens with different corner radii, the influence factor of the corner radius of section To evaluate the accuracy and versatility of each model listed below, three major indicators  were used as verification indicators to evaluate each model.The ultimate stress model takes full account of the influence of the cross-sectional shapes and corner radius of the specimens. The comparison of the prediction results and test results of the ultimate stress model is shown in In addition, it was found that the ultimate strain model of FRP–stirrup composite-confined circular concrete columns performed well in predicting the data in this paper and in the database. As presented in ccf, ccε) of the stress–strain relationship curve of FRP–stirrup composite-confined concrete columns under axial compression are the turning points of the rising branch of the curves, which are between the linear elastic rising stage and the strengthening stage. The specific method of determining a peak point is to temporarily select a peak point on the actual test stress–strain relationship curve of FRP–stirrup composite-confined concrete columns and use the formula to determine the values of parameters a and c to obtain the theoretical stress–strain relationship curve. We then adjust the position of the peak point until the error between the theoretical stress–strain relationship curve and the test curve is minimised.The peak points  is as follows:A comparison of the prediction results and test results of the peak stress and strain models is shown in ccf, peak strain ccε, ultimate stress cuf and ultimate strain cuε of confined concrete columns into Equations (10) and (11) to determine the values of parameters a and c, thus obtaining the predicted stress–strain relationship curves of confined concrete column specimens in this database. The general model proposed in this paper can predict the stress–strain relationship curves of concrete columns with different corner radii  confined by stirrups, FRP and combinations of the two. The accuracy of the stress–strain model can be judged by comparing the predicted curves with the test curves. The specific operation is to substitute the theoretical values of peak stress The stress–strain relationship curve model of FRP–stirrup-confined concrete columns with different corner radii was analysed and evaluated by comparing test specimens and other research specimens in the database. The section shapes of these specimens include circular, square and square with rounded corners. The comparison between the model predicted curves and the test curves are shown in The predicted curves of the general model of confined concrete columns with different cross-sectional shapes  not only coincide very well with the curves of the specimens tested in this paper, but they can also fully predict the specimens reported by others that are in the database. The model has a wide range of applicability, and its accuracy can provide a reference for the research of confined concrete structures with circular, square and square structures with rounded corner cross-sections. According to this, the foundation for practical engineering applications is laid.(1)The cross-sectional shape directly affects the confinement efficiency of confined concrete columns. Compared with the circular section, the lateral confinement forces of confined rectangular section concrete columns are unevenly distributed around the section. The confinement efficiency of rectangular concrete columns is worse than that of circular concrete columns.(2)For the FRP–stirrup composite-confined concrete columns with a small corner radius, FRP tensile fractures occur at the corners of the columns. For the specimens with a large corner radius, the FRP exhibited tensile failure or delamination; tensile failure occurred not only at the corners but also at the sides of the concrete columns.(3)The larger the corner radius is, the closer the section approaches the circular section, the more uniform the lateral expansion deformation of concrete is and the more effective the lateral restraint provided by the FRP.(4)The larger the corner radius is, the greater the slope and stiffness of the specimen in the strengthening stage; the more backwards the peak points and the ultimate points on the curves are; the stronger the ultimate bearing capacity and deformation capacity values of the specimens, especially for the specimens with a corner radius of 75 mm (a circular section).(5)By introducing the effective confinement coefficient and cross-sectional shape coefficient of FRP and further considering the effect of a smaller corner radius on the confinement of core concrete columns, the peak points, ultimate points and stress–strain curve models are applicable to FRP, stirrup and FRP–stirrup-confined concrete columns with different cross-sectional shapes proposed, which was verified by a large number of confined concrete columns.Monotonic axial compression tests of 72 FRP–stirrup composite-confined concrete columns with different cross-sectional shapes  were carried out. The test data of FRP-only and stirrup-only confined concrete columns are also summarised, the existing models of FRP–stirrup composite-confined concrete are contrasted, and the following conclusions are drawn:


This study aimed to determine the correlation between intraoperative 5-ALA-induced fluorescence and preoperative MET-PET signals of gliomas. We quantitatively measured the fluorescence intensity from tumor samples and calculated the MET-PET uptake by the tumor. Our study showed that strong tumor fluorescence correlated with high MET-PET uptake and cellular proliferation. Our findings might be valuable to rapidly provide information on tumor biology at the time of surgery in circumstances where MET-PET is inaccessible.In malignant brain tumor surgery, precise identification of the tumor is essential. 5-Aminolevulinic acid (5-ALA) labels tumor cells with red fluorescence to facilitate tumor resection. On the other hand, the nuclear medicine imaging technique, positron emission tomography with 11C-methionine (MET-PET) represents the activity of brain tumors with precise boundaries but is not readily available. We hypothesized that quantitative 5-ALA-induced fluorescence intensity might correlate with MET-PET uptake in gliomas. Methods: Adult patients with supratentorial astrocytic gliomas who underwent preoperative MET-PET and surgical tumor resection using 5-ALA were enrolled in this prospective study. The regional tumor uptake of MET-PET was expressed as the ratio of standardized uptake volume max to that of the normal contralateral frontal lobe. A spectrometric fluorescence detection system measured tumor specimens’ ex vivo fluorescence intensity at 635 nm. Ki-67 index and IDH mutation status were assessed by histopathological analysis. Use of an antiepileptic drug (AED) and contrast enhancement pattern on MRI were also investigated. Results: Thirty-two patients, mostly with Glioblastoma IDH wild type (46.9%) and anaplastic astrocytoma IDH mutant (21.9%), were analyzed. When the fluorescence intensity was ranked into four groups, the strongest fluorescence group exhibited the highest mean MET-PET uptake and Ki-67 index values. When rearranged into fluorescence Visible or Non-visible groups, the Visible group had significantly higher MET-PET uptake and Ki-67 index compared to the Non-visible group. Contrast enhancement on MRI and IDH wild type tumors were more frequent among the Visible group. AED use did not correlate with 5-ALA-induced fluorescence intensity. Conclusions: In astrocytic glioma surgery, visible 5-ALA-induced fluorescence correlated with high MET-PET uptake, along with a high Ki-67 index.Background: 5-Aminolevulinic acid (5-ALA) is widely employed to assist fluorescence-guided surgery for malignant brain tumors. Positron emission tomography with  The most common primary malignant brain tumor in adults is glioblastoma (GBM). This cancer, along with other tumor types of the same lineage , has a dismal prognosis despite the current intensive treatment strategies ,2. GBM, To facilitate maximal safe reduction of the tumor, fluorescence-guided surgery (FGS) has become a widely employed technique to identify the presence of tumor cells intraoperatively ,6,7. In 11C-methionine (MET), has been reported to delineate brain tumors with better sensitivity [Preoperatively, tumor localization and its boundary must be vigorously investigated predominantly by imaging studies to assist brain tumor surgery. Magnetic resonance imaging (MRI) with gadolinium contrast enhancement is the most accepted technique for diagnosing this actively proliferating tumor. In general, GBM exhibits solid enhancement on the rim and minor or no enhancement in the necrotic tissue core (ring enhancement) due to the BBB breakdown in and around the tumor. More recently, positron emission tomography (PET) imaging with metabolic tracers, especially amino acid tracers such as sitivity  in the psitivity . Furthersitivity  and reflsitivity , MET-PETsitivity  with morsitivity . Despitesitivity .Given these backgrounds, we hypothesized that quantitative 5-ALA-induced fluorescence intensity might correlate with MET-PET uptake as both parameters reflect the tumor cell malignancy. Thus, the purpose of this study is to elucidate the relationship between preoperative MET-PET uptake and intraoperative 5-ALA-induced fluorescence intensity quantified from ex vivo tumor specimens, adding a new axis to the 5-ALA-induced fluorescence in glioma surgery.The patients were enrolled in this prospective study at the Department of Neurosurgery, Tokyo Medical and Dental University, from May 2016 to August 2019. The inclusion criteria were age >20, a diagnosis of supratentorial malignant glioma (newly diagnosed or recurrent), eligibility for surgical resection of the tumor using 5-ALA, and availability of the MET-PET data taken prior to the surgery. Biopsy cases were excluded. Because oligodendrogliomas are known to have higher MET-PET uptake relative to astrocytomas , only asPositron emission tomography measurements were determined using a PET scanner  and presented as the equilibrated radioactivity 20 min after intravenous injection of MET (250–350 MBq), as described previously . The traThe patients received an oral administration of 5-ALA  at 20 mg/kg body weight three hours before elective craniotomy as part of the routine procedures for fluorescence-guided resection of gliomas. Tumor removal was conducted using standard neurosurgical procedures. Tumor samples were obtained from a MET uptake-high region of the tumor according to the image-navigation system using the preoperative images, including Gd-enhanced MRI and MET-PET . PreoperThe ex vivo fluorescence intensity from the tumor specimens was measured immediately after collecting the sample in the operating room. As previously described , we usedAll tumor specimens were subject to histopathological analysis by neuropathologists who were blinded to the presence of the fluorescence. Hematoxylin and eosin (H&E) staining and immunohistochemistry  were used as part of routine procedures to make final diagnosis according to 2016 WHO Classification of Tumors of the Central Nervous System. t test and one way ANOVA test compared two and multiple groups, respectively. In addition, the Pearson Chi-square test was used to test the frequency of the two variables. All p-values were two-sided, and p-values less than 0.05 were considered statistically significant. All statistical analyses were conducted using JMP version 14.2.0 .Fluorescence intensity was compared by non-parametric analysis. The Unpaired A total of 52 adult patients with supratentorial tumors suspected of malignant glioma underwent surgical resection using 5-ALA, and 32 patients were included in the final analysis after excluding those without adequate MET-PET data or those diagnosed other than astrocytic tumors . Fresh surgical specimens from the tumor indicated by the navigation system were collected and subject to fluorescence measurement in the operating room. Samples were cut into pieces approximately 10 mm in diameter before scanning the fluorescence spectrum. A quantitative spectroscopic fluorescence excitation and detection system was used as previously described , with a Two illustrative cases are shown in We next compared the four tumor groups of varying intraoperatively measured fluorescence intensities for the levels of preoperative MET-PET uptake a. We alsp < 0.001 for MET-PET uptake and p = 0.0091 for Ki-67 index, Unpaired t tests). We next rearranged the tumors into two groups: Visible  or not: Non-visible , because we noted that the fluorescence from ex vivo tumors was obviously visible when the intensity is above 5000 a.u. Our further analysis of the relationship between the MET-PET uptake or Ki-67 index and fluorescence intensity showed that the Visible group had significantly higher MET-PET uptake c and Ki-p = 0.0007). IDH wild type tumors were more common in the subjects with strong fluorescence than non-fluorescent tumors; conversely, IDH-mutant tumors were more frequent in the non-fluorescent tumors than fluorescent tumors (p = 0.0434). In contrast, AED use did not correlate with the intensity of 5-ALA-induced fluorescence (p = 0.6996).Lastly, we investigated the association between other parameters  and tumor 5-ALA fluorescence using mosaic plots and Pearson Chi-square test . Ring orThere are only a few reports regarding combining 5-ALA and MET-PET. 5-ALA-induced fluorescence and MET-PET correlated to cell density or Ki-67 index but did not correlate with each other ,38. MET-11C-methionine and 5-ALA  has not been understood. The expression of L-Type amino acid transporter 1 (LAT1: SLC7A5) in human glioma correlates with MET uptake [+- and Cl−-dependent taurine transporter (TAUT: SLC6A6) [The mechanism behind the correlation between T uptake . On the  SLC6A6) ,46,47. T SLC6A6) . AlthougA limitation of this study is that the location of the tumor specimen might not have been precisely matched with the preoperative MET-PET images due to the brain shift that occurred during surgery. Therefore, when available, we utilized the specimen exhibiting the strongest fluorescence to correlate with the SUVmax of the MET-PET. Secondly, because of the limited dynamic range of the spectrometer relative to the marked brightness of 5-ALA-induced fluorescence in some cases, our fluorescence intensity data could not be used as a continuous value. Consequently, the data points were distributed somewhat unevenly among the fluorescence intensity groups, making statistical analysis challenging. On another note, the MET-PET uptake was calculated as the SUV max of the lesion over the SUV max of the normal region. Accordingly, the calculated values may look smaller compared with reports in which the SUV max of the lesion is divided by the SUV mean of the normal region . NeverthTogether, the present study demonstrated a correlation between the preoperative MET-PET uptake and Ki-67 index versus intraoperative ex vivo fluorescence intensity in astrocytic glioma surgery. The visible 5-ALA-induced fluorescence may suggest the locus of high MET-PET high uptake. Given the broad clinical availability of the 5-ALA technique, our findings might be valuable to provide information on tumor biology rapidly  at the time of surgery in circumstances where MET-PET is inaccessible. Additionally, intraoperative quantitative measurement of excised tumors can inform the surgeon of the presence of viable tumors cells at the resection margins and assist a decision-making process towards maximizing the extent of resection during astrocytic brain tumor surgery.In astrocytic glioma surgery, visible 5-ALA-induced fluorescence correlates with high MET-PET uptake, along with a high Ki-67 index. This quantitative, biological insight might add a new axis to the utilities of fluorescence-guided brain tumor surgery using 5-ALA.


Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized systemic, immune-mediated, and fibro-inflammatory disease. Hypocomplementemia was found in part of IgG4-RD patients especially in the setting of active disease.This study aimed to clarify the clinical features, treatment efficacy, and outcome in IgG4-RD patients with hypocomplementemia.312 IgG4-RD patients were recruited in our prospective cohort conducted in Peking Union Medical College Hospital. Patients were divided into hypocomplementemia group and normal complement group according to serum C3 and C4 levels measured at baseline before treatment. Low serum C3 levels (< 0.73 g/L) and/or C4 levels (< 0.10 g/L) were defined as hypocomplementemia. Demographic data, clinical characteristics, laboratory parameters, treatment, and outcome of two groups were analyzed and compared.p < 0.05). Serum C3 and C4 showed a significant positively correlation with each other. Both C3 and C4 were negatively correlated with the number of involved organs, IgG, IgG3, IgG4, and IgG4-RD RI, as well as positively correlated with IgA and hypersensitive C reactive protein (hsCRP). 64 (98.5%) patients responded quickly to initial therapy at a 3-month follow-up. Fifteen (23.1%) patients relapsed during follow-up with mean recurrence time of 14.2 ± 13.8 months. Compared with normal complement group, there was no significant difference of relapse rate in two groups (P = 0.401).Hypocomplementemia was identified in 65 (20.8%) cases of untreated IgG4-RD patients at baseline. The average age of hypocomplementemia group was 55.85 ± 10.89 years, with male predominance (72.3%). Compared with normal complement group, patients with hypocomplementemia were likely to have more involved organs, higher IgG4-RD responder index (IgG4-RD RI), and higher laboratory parameters such as counts of eosinophils, inflammatory markers, immunoglobulin G (IgG), IgG1, IgG3, IgG4, and IgE. In addition, lymph nodes, lacrimal gland, submandibular gland, parotid gland, paranasal sinus, bile ducts, and prostate gland were more commonly affected (Clinical characteristics of IgG4-related disease with hypocomplementemia differ from normal complement group. Serum C3 and C4 at baseline before treatment could be biological markers for disease activity. IgG4-RD with hypocomplementemia responded well to treatment and had no significant difference of relapse rate in IgG4-RD with normal complement. Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized multi-organ, immune-mediated, and fibro-inflammatory disease with pathologically characterized by IgG4-positive lymphoplasmacytic infiltration, storiform-fibrosis, and obliterative phlebitis. IgG4-RD affects nearly every organ, particularly the lacrimal glands, salivary glands, pancreas, bile ducts, lungs, kidneys, retroperitoneum, artery, thyroid gland, meninges, and orbits. Approximately, a quarter to a third of patients with active IgG4-RD have hypocomplementemia defined by the low level of complement component C3 or C4 , 2.Complement is one of the first lines of defense against infections by promoting inflammation and orchestrating opsonization of pathological material, and other critical roles including disposal of immune complexes and apoptotic cellular debris . In addiExcessive and uncontrolled activation of the complement has been implicated in a series of autoimmune diseases with different pathway and mechanism such as systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). In SLE, the predominant role of the classical pathway in initiation of complement activation, while alternative pathway amplification loop caused complement-mediated damage , 6, 7. IIn this study, we focus on clinical features, serum markers, treatment response, and outcome in IgG4-RD with hypocomplementemia; meanwhile, we are trying to investigate whether complement C3 and C4 levels at disease onset could be a biological marker for disease activity and prognosis.ClinicalTrials.gov ID: NCT01670695), 312 newly diagnosed patients were enrolled from January 2014 to January 2019, who fulfilled the 2011 comprehensive diagnostic criteria [In our prospective cohort of IgG4-RD carried out in the Peking Union Medical College Hospital  (2018 version) at baseline and each follow-up was evaluated  LaboratoDisease response was defined as the decline of the IgG4-RD RI ≥2 points compared with baseline . ClinicaTo compare therapeutic outcomes of hypocomplementemia group and normal complement group, patients who were initially treated with initial GCs alone or GCs plus IMs, with initial GC doses of 0.5–1.0 mg/kg/day (30–60 mg/day) of prednisone equivalent, and followed-up more than 24 months were included.t tests. Non-normally distributed data were analyzed with Mann–Whitney U test. Categorical data were analyzed using the chi-square test. The correlation between serum complement level and laboratory parameters was analyzed with Pearson correlation coefficient in hypocomplementemia group at baseline. Kaplan-Meier survival curves and log-rank tests were used to compare relapse-free survival. Univariate and multivariate Cox regression analysis was performed to estimate the hazard ratio (HR) of relapse for each potential risk factor. P values < 0.05 were considered to represent significant differences between two groups.Statistical analyses were performed using the IBM SPSS Statistics version 24.0 software , the Prism software version 6.1 . Data were reported as means ± standard deviation or median and interquartile range (IQR). Normally distributed data between two groups were analyzed using independent-samples P < 0.001) and higher IgG4-RD RI  significantly at baseline.In this study, we prospectively enrolled 312 newly diagnosed IgG4-RD patients without treatment, 65 (20.8%) patients had hypocomplementemia (hypocomplementemia group), 244 (78.2%) patients had normal complement , and 3 (1.0%) patients had elevated complement. Of the hypocomplementemia group, 45 (69.2%) cases had both complement C3 and C4 reduction, 14 (21.5%) cases with only C3 reduction, and 6 (9.2%) cases with only C4 reduction. As the number of cases with elevated complement was very small, we mainly compared and discussed hypocomplementemia group and normal complement group. Demographic features of such two groups were shown in Table P < 0.001), lacrimal gland , submandibular gland , pancreas , lung , paranasal sinus (41.5% vs 27.9% P = 0.029), parotid gland , bile duct , and prostate gland  , ESR , IgG , total-IgE , IgG1 , IgG3 , IgG4 , ratio of IgG4/IgG, whereas significantly lower count of platelet  and IgA .The average level of serum C3 in hypocomplementemia was 0.54 ± 0.17 g/L  and C4 was 0.061 ± 0.047 g/L ). We further compared the laboratory tests between two groups . The level of serum C3 was negatively correlated with number of involved organs , IgG , IgG3 , and IgG4 , whereas positively correlated with IgA . Similarly, serum C4 level was negatively correlated with number of involved organs , laboratory parameters such as IgG , IgG1 , IgG3 , and IgG4 . In addition, serum C3 was weakly correlated with the age , IgG4-RD RI , IgG1 , and hsCRP . Serum C4 was weakly correlated with IgG4-RD RI , hsCRP , and IgA .We performed Pearson correlation coefficient analysis to investigate the association between serum complement level and age of onset, duration of disease, number of involved organs, IgG4-RD RI, and laboratory parameters including C3/C4, count of eosinophil, ESR, hsCRP, IgG, IgA, IgM, IgE, IgG1, IgG2, IgG3, and IgG4, in total patients at baseline. As shown in Fig. n = 22, 33.8%), mycophenolate mofetil (MMF) , methotrexate (MTX) , iguratimod 5 , and leflunomide .All patients with hypocomplementemia were treated with glucocorticoids (GCs), GCs combined with immunosuppressant agents (GCs plus IM) or GCs combined with rituximab (RTX). The standard induction dosage of oral prednisone was 0.5–1.0 mg/kg/day in the first month and tapered per 1 or 2 weeks to the maintenance dosage. 18 (27.7%) patients received GC monotherapy. One (1.5%) patient received GCs plus RTX. Others were treated with GCs plus IM, including cyclophosphamide (CYC)  . Higher IgG4-RI and more organs involved in hypocomplementemia group, indicating that the different treatment regimens between the two groups.We compared the first-line treatment between the two groups. The initial doses of GCs in hypocomplementemia group were higher than the normal complement group , there was no significant difference between two groups at 12, 24, 36, and 48 months after therapy  , hypocomplementemia patients treated with combined therapy group (n = 23), normal complement GCs treated with monotherapy group (n = 42), and normal complement treated with combined therapy group (n = 63). The relapse rates of four subgroups within 24 months were 40.0%, 21.7%, 21.4%, and 27%, respectively. The relapse rate of hypocomplementemia GC monotherapy group was higher than hypocomplementemia combination therapy group (P = 0.225) without statistical difference, as well as normal complement GC monotherapy group (P = 0.161)  of prednisone equivalent, and followed-up more than 24 months were included. The results showed that although IgG4-RD RI score was higher in hypocomplementemia group at baseline and 6th month follow-up (As far as we know, this is the first study to elaborate the clinical and laboratory characteristics, treatment response, and prognosis of IgG4-RD with hypocomplementemia. Further, we investigated serum C3 and C4 would be biomarkers for disease activity.In our prospective cohort, complements C3 and/or C4 were decreased in one fifth of the IgG4-RD patients. Compared with normal complement group, IgG4-RD with hypocomplementemia was a distinct clinical phenotype, which with higher number of involved organs, higher disease activity, and disparities of involved organs. John Stone suggested that IgG4-RD consisted of two overlapping subsets: a proliferative type and fibrotic type. Patients with the proliferative subset of IgG4-RD tend to have disease affecting the glandular and epithelial tissues and have high serum concentrations of IgG4, IgG1, and IgE; a higher likelihood of hypocomplementemia . Our stuAs we known, hypocomplementemia is one important inclusion criteria associated with kidney involvement in 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD .  KawanoWe compared treatment outcomes between two groups. After 1-month treatment, the average level of serums C3 and C4 in hypocomplementemia group recovered swiftly. Hypocomplementemia at baseline would not be the predictor for prognosis as there was no significant difference of relapse rate within 72 months in two groups after treatment. However, considering that patients with hypocomplementemia were given more aggressive treatment because of the higher disease activity, the predictive value of hypocomplementemia for prognosis of IgG4-RD in this study may be biased. We compared relapse rates in four subgroups after matching treatment. The relapse rate of hypocomplementemia with GC monotherapy group was 40.0% higher than other groups, while there was no statistics difference possible due to the small sample size. Prospective cohort study with larger sample size is needed.Mechanism of complement activation in IgG4-RD remains not clear. It was reported that anti-galectin-3 , anti-anIn conclusion, IgG4-RD patients with hypocomplementemia compared to normal complement patients had higher disease activity, higher number of affected organs and proliferative subtype features. The levels of serum C3 and C4 were negatively correlated with indicators of disease activity number of involved organs and laboratory parameters such as IgG, IgG3, and IgG4, and implicated serums C3 and C4 could be the biomarkers for disease activity. The low level of serums C3 and C4 could be recovered quickly after immunosuppressive therapy. IgG4-RD patients with hypocomplementemia respond well to treatment and have no significant difference of relapse rate in IgG4-RD patients with normal complement.


Moreover, the statistical check and k-fold cross validation methods were also applied for the performance confirmation of the model. The mean absolute error (MAE), mean square error (MSE), and root mean square error (RMSE) were evaluated to confirm the model’s precision.In a fast-growing population of the world and regarding meeting consumer’s requirements, solid waste landfills will continue receiving a substantial amount of waste. The utilization of solid waste materials in concrete has gained the attention of the researchers. Ceramic waste powder (CWP) is considered to be one of the most harmful wastes for the environment, which may cause water, soil, and air pollution. The aim of this study was comprised of two phases. Phase one was based on the characterization of CWP with respect to its composition, material testing  and evaluation of concrete properties both in fresh and hardened states . Concrete mixes were prepared in order to evaluate the compressive strength (CS) of the control mix, with partial replacement of the cement with CWP of 10 and 20% by mass of cement and 60 prepared mixes. However, phase two was based on the application of the artificial neural network (ANN) and decision tree (DT) approaches, which were used to predict the CS of concrete. The linear coefficient correlation (R One of the challenging tasks for the world is to utilize the waste materials obtained from various industries, such as ceramic waste powder (CWP) . It has 2 [Concrete is one of the most famous and high-demand materials all over the world . The use2 . This in2 . The pro2 . The dif2 ,19. Earl2 . The rep2 ,22. The 2 ,24,25.The application of various waste material in concrete not only showed satisfactory results for concrete’s properties, but also made a positive impression on environmental conditions. Siddique et al.  conducte2 value was about 80%, indicating a high accuracy level of the model. Feng et al. [2 value of 0.51. Ahmadi et al. [2 equals 0.91 as opposed to individual approaches. The main objective of this study is to incorporate the waste material (ceramic waste powder) in concrete to replace the cement by 10 and 20% to analyze the compressive strength and for comparison with that of normal concrete. The novelty of this study is not only relying solely on the experimental results, but also the application of (ML) approaches, ANN, and DT to forecast the compressive strength of ceramic powder-based concrete. The comparison was also made among the actual results obtained from the experimental work at the laboratory and the results from the ML algorithms, for better understanding. Statistical checks and the k-fold cross validation were applied to check the accuracy level between the actual and predicted outcomes. The ANN showed high accuracy with less variance as compared to DT when opting for the available data. The findings of this study are anticipated to promote knowledge and guidance on utilizing CWP as a waste material in concrete to reduce its negative impact on the environment and help to produce the environmentally friendly concrete. In addition, it is also important to investigate the supervised ML approaches for the prediction of the strength property in advance for comparison with the actual result, which would help researchers to investigate the outcomes from the input parameters without consuming time in the practical work.The most important parameter of concrete is its compressive strength (CS), which cannot be ignored in any type of construction work . To obtag et al.  represeng et al.  worked oi et al.  conductei et al.  present i et al.  present i et al.  present i et al.  employedi et al.  also prei et al.  put forwi et al.  comparedThis research consists of two phases. Phase one includes the laboratory tests on the material used in order to determine the compressive strength of concrete containing CWP. Phase 2 concerns the application of DT and ANN approaches for the prediction of the compressive strength of CWP-based concrete. Spyder (python 3.8) from the anaconda navigator software was used to run the models using python coding from the sklearn (Scikit-learn) library.In this phase, the properties of the materials used in the experimental program were evaluated, and the compressive strength of normal concrete as well as that containing CWP at certain percentages (10 and 20%) were observed at the age of 28 days. The effect of CWP on concrete mixtures was investigated by performing various tests to determine both fresh and hardened properties of concrete. The workability of fresh concrete was measured by a standard slump test as per ASTM C143 . The har2) values. The model performance was also investigated through statistical checks as well as other metrics and the k-fold cross-validation method. The error distribution was also evaluated in this phase to confirm the accuracy level of the model.This phase focused on ANN and DT-based modeling for forecasting the compressive strength of concrete developed during the experimental work at the laboratory. The CS was predicted via ANN and DT models and the accuracy level was compared between the actual and predicted outcomes through coefficient correlation  as a principal binder. The OPC gives confirmation to the ASTM C150 . Type I 3 and the water absorption was 1.2%. The grading analysis for the fine aggregate  and coarse aggregate are listed in 3 and water absorption was noted as 2.2%. The physical properties of the cement used are illustrated in The coarse aggregate employed in this experimental program was natural crushed stone  with a nominal size of 10 and 20.5 mm. The specific gravity for the coarse aggregate was noted as 2650 kg/mThe materials in this study have been used for two different processes, for the experimental work performed in the laboratory and as an input parameter used to run the model for the predicted outcome. The data in the arranged form used to run the model can be seen in annexure A. Python coding was used via the anaconda software to run the model. The six parameters  were used as inputs and one parameter (compressive strength) was used as the output for the ANN model. The descriptive analysis with the mathematical indication of the variables used to run the models, along with their ranges, are listed in A total of 60 mix designs were prepared with different water cement ratios, from which 20 mix designs were based on the control mixes. A total of two minutes were given for the mixing of plain concrete in the concrete mixing machine, while three minutes were given for concrete containing ceramic waste. A replacement of ordinary Portland cement was carried out by 10 and 20% of ceramic waste powder, from which the 20 mix designs were prepared for each percentage. Six cubes were cast from each batch of mix design. The details of all the mix designs are listed in The compressive strength of all the concrete samples (cubes) prepared with and without waste material were tested after 28 days of curing. These specimens were tested according to the standard of ASTMC129. The average value of three specimens were taken as the compressive strength of the said mix. Moreover, fresh properties like slump tests were also carried out for each mix as per the ASTM standard.Artificial intelligence (AI) with innovative advances gives a clear indication that artificial neural networks (ANNs) learn to solve multiplex problems in a limited time . ANNs arThe slump tests were carried out for all mixes at a room temperature of 25 °C ± 1 °C as per ASTM C143 . The slu3 as per ASTM C138 [3, respectively. Specimens with 10% ceramic waste gave the maximum and minimum values for dry densities of 2178 and 2002 kg/m3; similarly, these values for the specimen with 20% ceramic waste were 2103 and 2002 kg/m3, respectively, as depicted in The densities of the specimens were also evaluated in kg/mSTM C138 . The denThe compressive strength test for all concrete specimens was conducted in compliance with the guidelines of ASTM C39 . The com2 equal to 0.67 between the actual and predicted output, as well as with less variance, as presented in 2 value equal to 0.63, and the error distribution for the DT model is presented in The general distribution of the actual, predicted, and constant mean results of the model can be seen in the An analysis was done to check the actual performance of the model through the k-fold cross validation method. This method is normally adopted to evaluate the execution level of the employed models. K-fold cross validation involves splitting the randomly set data into k-groups. In this study, 10 groups were prepared from the data and out of these ten, nine groups were utilized for training purposes, and one was employed for the validation of the model. This process was rerun ten times to obtain the average of these iterations. There is a possibility of observing high performance of the model with the application of the k-fold cross validation method. In addition, the employment of the statistical check provides the response of the model towards the prediction as shown in the form of Equations (1)–(5).n = number of samples.2), mean square error (MSE), mean absolute error (MAE), and root mean square error (RMSE) were applied to assess the obtained result of the cross-validation for both ANN and DT as shown in 2 value, equal to 0.67, indicating high accuracy of the predicted result, while DT gives the R2 value of 0.63 and seems close to the ANN result with a smaller margin. The average value of the correlation coefficient (R2) for the ANN model was equal to 0.44 with the maximum and minimum values of 0.80 and 0.12, respectively. The result of the MAE was also reported with average, maximum, and minimum values of 12.03, 16.49, and 5.67 MPa, respectively. These values of the same order for MSE were 15.69, 21.37, and 11.34 MPa. Similarly, the RMSE gives maximum and minimum values of 4.62 and 3.37 MPa, respectively, as depicted in 2 for DT was 0.10, with maximum and minimum values equal to 0.96 and 0.60, respectively. While the average, maximum, and minimum values of the MAE were 19.37, 7.53, and 3.33 MPa, these values for MSE were 28.48, 9.63, and 5.35 MPa, respectively, as shown in The parameters correlation coefficient (R2) value, which was equal to 0.67 in this study, indicating the strong relation between the actual and predicted outcomes, as depicted in This research describes the application of ceramic waste powder in concrete at 10 and 20% replacement of the ordinary Portland cement (OPC) and analyzes the effect on the compressive strength (CS) of concrete and the prediction of CS through the ANN model. The supervised machine learning algorithm (ANN) model outcome for CS was compared with the actual result. The replacement of OPC with ceramic waste in concrete affects the strength properties with less variance and was utilized successfully with appreciable results. In addition, the ANN model also shows an impressive result in terms of forecasting the compressive strength of the concrete containing ceramic waste. The indication of a better response of the ANN model can be visualized from the coefficient correlation (R2) and low values of the parameters describing the errors of the forecasting. The following conclusions can be drawn from the study.This study explains the behavior of concrete’s compressive strength when ceramic waste is used as a partial replacement of ordinary Portland cement at certain percentages (10 and 20%), as well as the predicted outcome of the CS from the ANN model. The results from the experimental work, compared with the outcomes from the supervised machine learning algorithm (ANN), shows innovation for research work. The ANN model shows a strong relation through the linear correlation coefficient .This waste can be utilized in concrete where the normal strength of concrete is recommended.ANN and DT are very useful supervised machine learning (ML) approached for the prediction of compressive strength of any type of concrete and can be favorably used for this purpose.2 value equal to 0.67, as opposed to DT, which gives a value of R2 equal to 0.63.In comparison, the ANN model shows better accuracy with less variance between the actual and predicted result by indication of the RThe K-fold cross validation method also proved the high performance of the ANN model.The two positive aspects of this research are the utilization of waste material in concrete minimizing the environmental risks, and the other is the prediction of CS at an initially high accuracy. To obtain a desired CS, it normally takes 28 days by employing the hit and trial method, which is a time-consuming task. ML algorithms can be successfully used without investing money and consuming significant time. However, more research is still required for the evaluation of the best-performing ML approach.Other various types of ceramic waste (white paste for twice-fired ceramic and white paste for sanitary ware) can be used in concrete as a partial replacement of OPC to check the other mechanical properties of concrete .The data points can be increased with the practical work to obtain a better response from the models.More checks and analysis can be applied to evaluate the model’s performance .


BRAF fusions are rare driver oncogenes in non-small cell lung cancer (NSCLC). Similar with BRAF V600E mutation, it could also activate the MAPK signaling pathway. There are a few case reports which had indicated the potential response to BRAF inhibitors and its important role as de novo driver mutation. In addition, the co-occurring MET amplification has been defined as a poor prognostic factor in patients with epidermal growth factor receptor (EGFR) mutant NSCLC. Currently, there are ongoing clinical trials which investigate the MET amplification as a therapeutic target in patients with EGFR mutant NSCLC and acquired resistance to osimertinib, which imply that the MET amplification also had a therapeutic significance. However, the co-occurring MET amplification had not been studied in patients with BRAF fusion before. A 67-year-old man was diagnosed with metastatic poorly-differentiated adenocarcinoma. He received first-line therapy with the combination of pembrolizumab and chemotherapy because the genomic test revealed wild-type EGFR, and negativity of ALK and ROS1 by immunohistochemical stain. Upon disease progression, the next-generation sequencing revealed co-occurring KIAA1549-BRAF fusion and MET amplification. Subsequent dabrafenib, trametinib, and capmatinib combination therapy showed a remarkable treatment effect. The combination therapy targeting the co-occurring driver mutations is a potential effective treatment for NSCLC patients. Further prospective study is still warranted to investigate the role of co-occurring driver mutations and the relevant treatment strategy. BRAF fusions are mostly detected in melanoma, thyroid cancer, and astrocytoma and are rare driver oncogenes in non-small cell lung cancer (NSCLC)  . They prutations . The KIAe domain . Currentametinib , 4, whicMET amplification had been widely studied in patients with epidermal growth factor receptor (EGFR) mutant NSCLC and was defined as a poor prognostic factor  staining for anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1) were both negative. The IHC staining of programmed death-ligand 1 was 3%. The next generation sequencing (NGS) could not be performed due to insufficient tissue. Thus, the combination of cisplatin, pemetrexed, and pembrolizumab was administered. After 12 months, the patient demonstrated disease progression with an enlarged right middle lung mass. The NGS was suggested in order to optimize subsequent therapy. To obtain sufficient tissue for NGS, video-assisted thoracoscopic surgery (VATS) biopsy was performed due to previous experience of insufficient tissue from computed tomography-guided biopsy.In December 2018, a 67-year-old man was diagnosed with stage IV pulmonary poorly differentiated adenocarcinoma with negativity of TTF-1 and P40 expression  signaling pathway and respond to MEK inhibitor in a case with melanoma  (MET amplification.Combination therapy targeting co-occurring utations . In a xesistance . In the bination . CurrentNAH NCT0378229 (7)BRAF mutation and MET amplification, the inhibition of MEK expression induces dose-responsive MET activation , elevated liver enzyme (11%), hypertension (11%), and vomiting (8%) (Previous study regarding the adverse events in the combination therapy of different targeted therapies remains limited. According to the phase 2 study investigating the treatment efficacy of dabrafenib and trametinib in patients with ing (8%) . Meanwhiing (8%) . In thisKIAA1549-BRAF fusion and MET amplification in a patient with a durable response and tolerant adverse event to combination therapy with dabrafenib, trametinib, and capmatinib. Future prospective studies are warranted to validate the efficacy of combination therapy in patients with multiple driver oncogenes.We report a case of advanced NSCLC harboring co-occurring The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by The Review Board and Ethics Committee of National Cheng Kung University Hospital. The patients/participants provided their written informed consent to participate in this study.Y-TC and P-LS had full access to data in this case report and takes responsibility for the integrity and accuracy of data analysis. Y-TC and P-LS contributed to pleuroscopic examination. C-CL, DP, and P-LS contributed to the scientific review and final approval of this manuscript. All authors read and approved the final manuscript.The present study was funded by grant no. MOST 110-2314-B-006-102 from the Ministry of Science and Technology, Taiwan.DP is an employee of Foundation Medicine Inc. (FMI) and has equity interest in F. Hoffmann-La Roche AG, of which FMI is a wholly owned subsidiary.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.