The confinement of reinforced concrete (RC) compression members by fiber-reinforced polymers (FRPs) is an effective measure for the strengthening and retrofitting of existing structures. Thus far, extensive research on the stress–strain behavior and ultimate limit state design of FRP-confined concrete has been conducted, leading to various design models. However, these models are significantly different when compared to one another. In particular, the use of certain empirical efficiency and reduction factors results in various predictions of load-bearing behavior. Furthermore, most experimental programs solely focus on plain concrete specimens or demonstrate insufficient variation in the material properties. Therefore, this paper presents a comprehensive experimental study on plain and reinforced FRP-confined concrete, limited to circular cross sections. The program included 63 carbon FRP (CFRP)-confined plain and 60 CFRP-confined RC specimens with a variation in the geometries and in the applied materials. The analysis showed a significant influence of the compressive strength of the confined concrete on the confinement efficiency in the design methodology, as well as the importance of the proper determination of individual reduction values for different FRP composites. Finally, applicable experimental test results from the literature were included, enabling the development of a modified stress–strain and ultimate condition design model. Regarding circular cross sections, the transverse pressure distributes evenly along the FRP jacket, as shown in σj in the hoop direction. Exceeding the initial compressive strength, an effective confinement leads to a multidimensional stress state of the concrete. Thereby, it is possible to increase its maximum bearing capacity and its ultimate strains without significantly affecting the dead loads. The confinement of axially loaded concrete members is an effective measure for improving load-bearing capacity and ductility. Apart from conventional transverse tie reinforcing steel in combination with shotcrete, fiber-reinforced polymers (FRPs) are becoming increasingly considered for the strengthening and rehabilitation of reinforced concrete (RC) structures. The composite material most commonly combines synthetic fibers  and an epoxy-based resin matrix. In the application of confinement, the linear elastic FRP jacket resists the concrete’s lateral expansion, leading to a steadily increasing transverse pressure, The load-bearing behavior of short, plain concrete members confined with FRP composites has been extensively researched in the last two decades, leading to various experimental programs and design models, see, e.g., in ,21,22,23fcc and the accompanying axial strain εccu are derived by Equations (1) and (2):fc0 is the mean value of the unconfined concrete strength, εc0 is the peak strain of the unconfined concrete, flj is the confinement pressure provided by the FRP jacket, εju is the rupture strain of the FRP jacket in the application of confinement, and k1–k4 are factors affecting the impact of flj on fcc and εccu. In general, the ultimate confined concrete strength flj provided by the FRP jacket. The commonly used form for the calculation of the confining pressure is given by Equation (3):ρj is the confinement ratio, Ejl is the confinement modulus, Ej is the modulus of the composite material, tj is the FRP thickness, and D is the diameter of the circular cross section. The prediction of the ultimate condition of the confined concrete is directly dependent on the confining pressure εju, has a significant impact on the confinement pressure, flj. According to the current state-of-the-art, εju is defined as the actual hoop rupture strain measured in the FRP jacket, as, in most cases, it is considerably smaller than the ultimate tensile strain found from flat coupon tensile tests εFRP. Therefore, Lam and Teng [kε, defined byThe rupture strain of the carbon FRP (CFRP) jacket in the application of confinement, and Teng  establisAlthough most approaches are derived by the same basic functions, the design models show significant differences. c)–strain (εc) curves with a parabolic first portion and a straight line second portion (second modulus). An example is given by the stress–strain model of Lam and Teng [E2 is the second modulus, Ec is the modulus of elasticity, and εt is the strain value at the transition between the parabolic curve and the straight-line second portion. A graphical representation of Lam and Teng’s stress–strain model is given in Most design models are used to determine the ultimate stress and strain conditions of a column under concentric compression or with comparatively small eccentricities. However, proper confinement can also provide significant strength enhancement for members subjected to combined compression and flexure. For the design of eccentrically loaded, FRP-confined columns, proper material models are essential. In general, these models use stress (σand Teng :(5)σc = k1 (ultimate stress) and k2–k4 (ultimate strain). In the majority of cases, k1 and k2–k4 are defined as constant values or are solely dependent on the maximum confining pressure flj. These concepts lead to considerable discrepancies regarding the prediction of confined columns with different initial concrete strengths, fc0. fcc and εccu can be seen. The discrepancies between the predicted results tend to increase significantly alongside the unconfined concrete strength.The empirical approaches for the development of design-oriented models  mostly ffc0 = 30 MPa may be due to the fact that most empirical design models use experimental investigations on normal-strength concrete for the derivation of the confinement effectiveness, k1 and k2–k4 Diameter and volumetric ratio of the transverse steel reinforcementMechanical properties of the transverse steel reinforcementSurface texture of the transverse steel reinforcementVolumetric ratio of the longitudinal steel reinforcementCFRP materialVolumetric ratio of the CFRP jacketTherefore, a test program of CFRP-confined plain and RC cylinders, including the following variation parameters, was conceived:In total, the program included 63 CFRP-confined plain concrete specimens and 60 CFRP-confined RC specimens with circular cross sections.The following materials were used for the production of the test specimens.fc0 between 25 and 40 MPa. The properties of the hardened concrete were determined on cylinders with a diameter of 150 mm according to EN 12390-3:2009 [The concrete specimens were produced using different concrete mixtures. Each series was made of concrete from the same batch. All series used CEM II 32.5 cement according to EN 197-1:2011 , natural0-3:2009 .The variation in the mechanical properties of the transverse steel reinforcement was realized using bars with differing yield strengths  and without ribbing .The confining jackets consisted of unidirectional carbon fiber (CF) sheets and a two-component, thixotropic impregnating epoxy adhesive. To ensure the variation of the material properties, three different sheets from two different manufacturers were used.CF sheets M1 and M2 showed approximately the same material characteristics, as they originated from one manufacturer, but had a different arrangement of the carbon fibers. CF sheet M3 had a considerably higher tensile strength and rupture strain. The exact material properties, as provided by the manufacturer, are shown in Prior to the strengthening process, the concrete surface was ground until aggregates >4 mm could be seen. Additionally, the top and bottom of the cylinders were ground plane and parallel to ensure uniform load distribution. Seven days prior to the compression tests, the CFRP jacket was applied in a dry lay-up process; after the application of a primer coat to the surface of the concrete, the CF sheets were laminated continuously around the cylinders. The overlap length of the CFRPs was 100 mm, as specified by the manufacturers. The application process is shown in The specimens were tested under uni-axial compression through monotonically applied loading using a hydraulic press with a 5000 MPa load-carrying capacity. The testing machine was set to a displacement-controlled mode with a constant rate of 0.01 mm/s. The axial displacements were measured using linear variable differential transformers (LVDTs). Lateral strains of the CFRP jacket were measured using strain gauges bonded to the specimens at mid-height. In cases where the specimens have internal reinforcement, steel strain gauges were applied on the rebar surface of the transverse reinforcement test specimen at mid-height .fc0 on the material behavior of the confined specimens. Furthermore, series D15-P-M2-2L-6 additionally contained a grit aggregate to examine the impact of the aggregate form and type.E2) as well as in the transverse  direction. As an example, E2 and the volumetric ratio of the CFRP jacket. An increase in the applied CFRP layers led to higher second moduli and higher ultimate states of strength (fcc) and strain (εccu).The evaluation focused on the stress–strain behavior of the confined plain and RC specimens. Therefore, the axial stress was determined by the ratio of the applied load to the cross-sectional area of the concrete, disregarding the thickness of the CFPR and its possible axial resistance. Axial and lateral strains were obtained from the applied LVTDs and strain gauges. The stress–strain behavior  of the CFRP-confined specimens was bilinear in general, and consisted of a three-phase behavior like that predicted by the material model illustrated in fcc, and strain, εccu. Typical examples of failed confined plain and RC specimens can be seen in The failure of the CFRP-confined plain or steel reinforced specimens was caused by a sudden and noisy fracture of the CFRP sheets at ultimate strength, k1 (cf. Equation (1)) and the second Poisson’s ratio of the confined member ν2. Typical examples are shown in In addition to the stress–strain relationships, the development in the comparative diagrams showing the axial–transverse strain responses and the axial–confinement stress responses of the CFRP-confined concrete specimens was an important aspect of the evaluation process. These diagrams enable the analysis of the factor ν2. Furthermore, the axial–confinement stress response explains the design factor, k1. Once the axial stress exceeds the unconfined concrete strength, the curves converge to flatter linear relationships compared to that of the initial behavior, expressing the empirical confinement effectiveness coefficient k1.In most cases, the initial slopes of the axial strain and transverse strain relationships matched well the typical initial Poisson’s ratio for concrete of 0.2. As the axial strain increased, the ratio between the transverse and axial strain also increased, indicating the acceleration of the expansion of the concrete. This second linear slope describes the second Poisson’s ratio ρj, Ejl, and flj had to be determined for each series. Set in relation to the unconfined concrete strength, the ratios Ejl/fc0, Ejl/fc02, and flj/fc0 can be defined . As expected, flj had a significant impact on fcc and εccu. Furthermore, the investigations indicated that the unconfined concrete strength, fc0, is a second impact factor. fcc (Δfcc = fcc − fc0) and the ultimate strain, εccu, on the initial concrete strength, fc0.The variation in the diameter of the cylinder, as well as the thickness of the CFRP, led to varying volumetric ratios of the CFRP jackets, fc0 was changed. Only test specimens with equal diameters (150 mm) and properties of the applied CFRP system were used, while the concrete strength, fc0, varied. An impact of fc0 on fcc and εccu can be recognized, but a sufficient correlation is pending. Therefore, the proposal of Xiao and Wu [fl is set in relation to fc0, satisfying regressions for the prediction of fcc and εccu can be found. fcc, and the ultimate strain, εccu.For this comparison, only o and Wu  was applThe high coefficients of determination of the regression curves indicate the reliability of the ratio between confinement pressure and unconfined concrete strength to predict the load-bearing capacity of a CFRP-confined concrete member. Ejl to the divisor fc0 enables the prediction of E2,t, as well as ν2,. E2,t and the second Poisson’s ratio, ν2.Further analysis confirmed that relating the confinement modulus Ejl and the calculated confinement pressure flj are sufficient for the consideration of the varying diameter.The comparison of the variation in the cross-sectional diameter showed no significant size effect on the FRP-confined concrete. The use of the confinement modulus kε < 1.0 should be mandatory. An overview of different approaches to determine kε is given in Regarding the CFRP’s rupture strain reached by the CFRP jacket, the investigations correspond with the findings of Lam and Teng ,23. In akε = 0.49 and kε = 0.70. The use of a mean value kε, as mainly suggested in literature, can, therefore, be uncertain. Due to the large scattering of the test results, the conservative approach introduced by Niedermeier [kεk. In accordance with EN 1990:2002 [kε on the used CFRP material.While most approaches suggest a common, universally valid reduction factor for CFRP systems, the conducted experimental program shows significant differences, even between the used carbon fibers. The average value for the three different CFRP systems differed remarkably between dermeier ,40 was a990:2002 , charactγj for the used CFRP materials. The approach introduced in the fib bulletin 80 [αR is the sensitivity factor (αR = 0.8), Vx is the presumed coefficient of variation of the rupture strain εFRP, β is the reliability factor (β = 3.8), γRd1 is a factor considering model uncertainties, and γRd2 is a factor considering geometrical uncertainties.Furthermore, the findings enabled the derivation of particular partial factors letin 80  was usedVx vary remarkably between the used CFRP materials. Hence, γj should be determined separately for each FRP system—for instance, within a technical approval procedure.As shown in γRd1 was predicted with a value of 1.20 because model uncertainties are comparable to that of models for shear design. In contrast, γRd2 was determined with a value of 1.0. For columns with a circular cross section, the geometrical uncertainties are negligible, as kε persisted at a constant value independent of the column diameter. For the derivation of the displayed partial factors according to Equation (7), γj depends on Vx of the FRP jacket’s hoop strain applied to the column perimeter. The same applies for the characteristic values of the FRP strength and rupture strain.In comparison, the calculated safety factors are significantly higher than those suggested by current recommendations, codes, and guidelines, as listed in ρst is the transverse steel volumetric ratio, fy is the yield stress, ke is the coefficient of lateral and vertical efficiency of the transverse steel reinforcement according to Niedermeier [Dc is the horizontal center distance of the spiral or tie reinforcement, Øw is the diameter of the transverse steel reinforcement, and s is the vertical spacing between the spiral or tie bars.dermeier , Dc is tAsl and the maximum stress carried by the longitudinal reinforcement during the compression test σsl are specified. The strength enhancement Δfcc is defined as Δfcc = fcc − fc0 − σsl.For the following analysis, the provided confinement pressure and confinement stiffness had to be determined for each series. The specific values are shown in fl(j+w) and fc0. As for the results of the sole confined plain concrete specimens, satisfying regressions for the prediction of fcc and εccu can be found.In the diagrams of As observed for the plain concrete, the bearing behavior of the confined RC is defined by a decrease in the specimens’ axial rigidity. However, the transition zone is smoother and prolonged.Ø = 10 mm, s = 55 mm) was compared to a specimen of the same diameter and confinement but without reinforcement (series D30-P-M1-2L-1). As explained by Equation (7), a constant confining pressure of the yielding steel transverse reinforcement can be assumed. The second modulus is similar to E2 observed in confined plain concrete, as further strength enhancement depends on the linear elastic CFRP jacket.Ø = 8 mm, s = 40 mm) was compared to a specimen of series D25-TR-M1-2L-2 with the same diameter and CFRP confinement but with tie reinforcement .In addition to the amount of transverse reinforcement, the reinforcement type was varied by the application of normal ties and heavy spirals. A comparison between both reinforcement types is given in E2, of the spiral reinforced specimen is more extended. Until its yielding strength is reached, the spiral reinforcement can activate a significantly higher confinement pressure, leading to a higher fcc and εccu. However, the E2 reached is almost similar. In addition, εst increased more slowly compared to the CFRP jacket, εj. This behavior is contradictory to the assumptions of most material models, e.g., Hu et al. [εj and εst. The transition zone between the first linear increase and second linear branch, u et al.  or Eid au et al. . These mkε. Niedermeier [kε = 0.50 and a characteristic value kεk = 0.25. This procedure was adopted by the German Guideline for FRP Strengthening of Concrete Structures by DAfStb [Previous investigations on the impact of longitudinal reinforcement on the CFRP jacket’s rupture strain, e.g., by Pellegrino and Modena  and Bai dermeier ,40 folloy DAfStb .Ø = 6 mm, s = 100 mm) with a different number of longitudinal reinforcing bars (Ø = 12 mm) were compared, showing that the number of bars differed between 4, 6, and 8. In all cases, approximately the same maximum axial strain, εccu, was reached. A strong impact of the longitudinal reinforcement on εju should influence the confinement pressure, fl; because of this, the diagram on the left of kε for the three longitudinal bar configurations by using the proposal of Pellegrino and Modena [kε should decrease and, therefore, reduce εccu; however, the tests could not confirm these assumptions.The experimental investigations did not confirm the assumption suggested in . In genekε remains constant independent of the applied longitudinal reinforcement. Low reduction values such as kεk = 0.25 are highly conservative and may provoke an unnecessary loss of load-bearing capacity.In conclusion, the reduction factor The obtained test database was enlarged with the test results of Eid et al. , Xiao anEj), concrete mixtures with variable unconfined concrete strengths (until a high-performance area >100 MPa), and different reinforcement approaches. In The implemented databases enabled the consideration of different FRP materials  and the unconfined concrete strength fc0.Only few references regarding tests with CFRP confined RC specimens offer sufficient and comprehensive data concerning the applied CFRP system, the arrangement and construction of the longitudinal and transverse reinforcement as well as detailed information on the reached fl(j+w)/fc0 covered by the experimental results could be enlarged to values close to fl(j+w)/fc0 = 1.0. In this case, the confinement pressure exceeded the unconfined concrete strength. The correlations in The extent of the tested ratios fcc, and strain, εccu, the results of the CFRP-confined plain concrete specimens, as well as the CFRP-confined RC specimens, were considered in a unified regression analysis. The database and the regression results are presented in fcc and εccu could be determined as the following,For an overall evaluation of the achievable ultimate concrete strength, fcck:fck is the characteristic concrete compressive strength, εjuk is the characteristic rupture strain of the FRP jacket in the application of confinement (εjuk = εFRP · kεk), and fyk is the characteristic yield stress of the steel reinforcement. To allow the implementation of the results in modern limit state design concepts, Equation (10) presents an approach for the calculation of the characteristic strength, The limitations ensure that the calculation is within boundaries of the gathered experimental results. E2,t, the second Poison’s ratio, ν2, and the second modulus in the axial direction, E2. Therefore, the following equations for the prediction of E2 can be proposed,For the design of a stress–strain model, the stress–strain relationships proposed by Lam and Teng   of the CFRP’s hoop strain, εju, and the related partial factor, γj. However, further research efforts are still pending. In particular, the confinement of low-strength concrete, as well as substandard concrete, was not examined in the current study. Furthermore, the effect of particularly high confinement pressures exceeding the unconfined concrete strength has yet not been sufficiently considered.FRP materials are gaining importance in construction. Especially for strengthening purposes, fiber-reinforced polymers show great potential ,52. FRP


Immunoglobulin G4 (IgG4)-related hypophysitis is a rare disorder which often requires invasive pituitary gland biopsy to confirm its diagnosis. We present a case whereby peripheral organ lesion biopsy and imaging findings were sufficient for the diagnosis.A 77-year-old man with diplopia was referred to our department by an opthomologist who had diagnosed the patient with right abducens nerve palsy.Head magnetic resonance imaging revealed enlargement of the pituitary gland and pituitary stalk, while hormonal analysis revealed panhypopituitarism, thereby indicating a diagnosis of hypophysitis. Abdominal computed tomography imaging revealed a solid mass that encompassed the left kidney ureter. Although the patient did not have an increase in serum IgG4, a biopsy of the periureteral mass revealed infiltrating plasma cells that were positive when stained for IgG4.The patient was given corticosteroid pulse therapy (methylprednisolone: 1 g × 3 days), followed by oral corticosteroids .The right abducens nerve palsy improved and the pituitary lesion shrank after the initiation of corticosteroid treatment.Based on the diagnosis of IgG4-related disease in the retroperitoneal organ and response to corticosteroid treatment, this patient was diagnosed with IgG4-related hypophysitis. This hypophysitis caused enlargement of the pituitary gland with resulting nerve compression, causing abducens nerve palsy. When IgG4-related hypophysitis is suspected, a thorough examination of other organ lesions and biopsy should be considered. His symptoms gradually worsened, leading him to consult an ophthalmologist who diagnosed him with right abducens nerve palsy. The patient was subsequently referred to our department and was hospitalized in order to perform detailed investigations.Findings on admission: height 165 cm, body weight 56 kg, body temperature 36.2°C, blood pressure 135/85 mm Hg, and peripheral capillary oxygen saturation 98% (room air). His superficial lymph nodes were not palpable, and there was no rash or mucosal eruption. He was lucid and fully conscious, with no sign of disorientation. His corrected visual acuity was 1.0 and 1.2 in the right and left eyes, respectively, and no abnormalities were observed in his anterior segment or fundus. Both pupils were of equal size and round, and demonstrated rapid light reflexes. The patient showed right esotropia, and right abduction disorder was identified in his eye movements; however, the movement did not exceed the median. His other cranial nerves did not show any abnormal findings, and he had no muscle weakness or sensory disturbance.Laboratory data revealed a white blood cell count of 9.700 cells/μL and a C-reactive protein concentration of 2.43 mg/dL, indicating a mild inflammatory response. There were no notable findings in the biochemistry and coagulation tests. The cerebrospinal fluid was clear, with a cell count of 48 cells/μL , glucose concentration of 84 mg/dL (124 mg/dL blood glucose), protein concentration of 182 mg/dL, and negative oligoclonal bands. Hormonal analysis revealed low levels of free triiodothyronine and free thyroxine, no elevation of thyroid stimulating hormone (TSH), total urinary free cortisol excretion below the level of detection, and low serum cortisol, growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels (Table Contrast-enhanced magnetic resonance imaging (MRI) of the head revealed enlargement of the pituitary gland and pituitary stalk Fig. . AbdominLoad tests were conducted using four hypothalamic hormones: LH-releasing hormone (100 μg), GH-releasing hormone (100 μg), corticotropin-releasing hormone , and thyrotropin-releasing hormone  in order to confirm the diagnosis of panhypopituitarism. During the load tests, TSH and adrenocorticotropic hormone levels were maintained in response to stimulation with TRH and CRH, respectively. In contrast, the response to LH and FSH was low, and there was no increase in GH. The patient's free cortisol levels remained low and did not respond to CRH administration. Based on these findings, he was diagnosed with panhypopituitarism, which, based on the imaging findings of swelling spanning from the pituitary gland to the pituitary stalk, had occurred as a result of hypophysitis.Additionally, since the abdominal CT revealed possible retroperitoneal fibrosis, the prospect of an IgG4-related disease was considered. Thus, a CT-guided needle biopsy was performed of the solid mass surrounding the left ureter. Histological examination revealed lymphocytic infiltration, which included lymphoplasmacytes. Further IgG4 immunostaining confirmed an abundant infiltration of IgG4-positive plasma cells. The IgG4/IgG ratio was 66.9% and the number of IgG4 positive cells was 175/high power field Fig. . AlthougHe was started on levothyroxine sodium (12.5 μg/d) for his hypothyroidism, and was given corticosteroid pulse therapy (methylprednisolone: 1 g × 3 days) because, as hypophysitis had developed, his abducens nerve palsy was also considered to be an IgG4-related disease. In addition, oral corticosteroids  were administered post-therapy, beginning on Day 12 of his admission. He responded well and his right abducens palsy improved. He was discharged on Day 24. Follow-up imaging on Day 35 revealed shrinkage of the pituitary lesions and the retroperitoneal mass pituitary histology with mononuclear infiltrates ;(2)MRI findings with pituitary enlargement;(3)biopsy-proven involvement in other organs;(4)serologic findings of elevated serum IgG4 (>140 mg/dL); and(5)tumor or symptom response to corticosteroids.It has been proposed that (1) alone, (2) + 3), or (2) + (4) + (5), can be considered sufficient to make a diagnosis of IgG4-related hypophysitis  Hypophysitis can be diagnosed if the basal-blood concentration of at least 1 anterior pituitary gland hormone is decreased and its target hormone is likewise decreased, a decreased responsiveness in the anterior pituitary gland hormone secretory stimulation test is seen, diffuse swelling of the pituitary gland, or, hyperplasia of the pituitary stalk are observed in imaging tests, and IgG4-positive plasma cell infiltration is observed in the tissue of lesions present in other organs. In other words, as was the case with our patient, even without confirming the pathology in the pituitary gland or observing elevated serum IgG4, it was possible to diagnose IgG4-related hypophysitis based on pituitary enlargement observed through imaging, and the histology of the retroperitoneal lesion.Five nerves run across the cavernous sinus, the oculomotor, trochlear, the first and second branches of the trigeminal nerve, the ophthalmic and maxillary nerves, and the abducens nerve. Of these, the abducens nerve is located closest to the pituitary gland. As a result, the abducens nerve was the only cranial nerve affected. It was affected as a result of lateral compression which resulted from the hypophysitis and pituitary enlargement.The treatment of IgG4-related hypophysitis similar to the of treatment of other IgG4-related diseases. The recommended initial dose of corticosteroids for IgG4-related diseases is 0.5-0.6 mg/kg/d of prednisolone; however, corticosteroid pulses are considered depending on the disease state.4The possibility of IgG4 related disease should be considered when findings of hypophysitis are observed in head MRIs of patients presenting with external ophthalmoplegia, and assessment of peripheral organ lesions should be performed.Conceptualization: Takeshi Imai. Yasuhiro Hasegawa.Supervision: Yasuhiro Hasegawa.Visualization: Takeshi Imai.Writing – original draft: Takeshi Imai.Writing – review & editing: Takeshi Imai. Yasuhiro Hasegawa.


Gating of positron emission tomography images has been shown to reduce the motion effects, especially when imaging small targets, such as coronary plaques. However, the selection of optimal number of gates for gating remains a challenge. Selecting too high number of gates results in a loss of signal-to-noise ratio, while too low number of gates does remove only part of the motion. Here, we introduce a respiratory-cardiac motion model to determine the optimal number of respiratory and cardiac gates. We evaluate the model using a realistic heart phantom and data from 12 cardiac patients . To demonstrate the benefits of our model, we compared it with an existing respiratory model. Based on our study, the optimal number of gates was determined to be five respiratory and four cardiac gates in the phantom and patient studies. In the phantom study, the diameter of the most active hot spot was reduced by 24% in the dual gated images compared to non-gated images. In the patient study, the thickness of myocardium wall was reduced on average by 21%. In conclusion, the motion model can be used for estimating the optimal number of respiratory and cardiac gates for dual gating. Thus, motion introduces image blurring, resulting to loss of small details and image contrast. In most 18F-FDG patient studies, the respiratory and cardiac motion amplitudes have been determined to be more than 5 mm, which is above the FWHM of modern PET scanners1. The benefit of motion compensation is especially important for imaging of the coronary plaques, as recent studies have shown for 18F-NaF3. Thus, methods to estimate the amount of motion and minimise its effects to detection of small targets, such as coronary plaques are needed.Image quality in cardiac positron emission tomography (PET) is reduced by respiratory and cardiac motions. The resolution and contrast of PET images are reduced when the motion amplitude is above the full-width half maximum (FWHM) of the PET scanner6, where PET raw data is divided into smaller time frames according to a motion. The motion signal can be obtained by tracking the respiration or the heartbeat. For respiratory motion tracking, various methods have been introduced9. A recent summary of the methodologies available can be found from the following reviews by11. For cardiac motion tracking, ECG still remains the most common option.To reduce motion effects, numerous gating methods have been introduced19, where simultaneous respiratory and cardiac gating is applied. Motion correction methods have also been extensively studied24, however they are not yet widely applied in clinical practice.In clinical practice, only respiratory or cardiac gating is usually applied instead of using both simultaneously. Cardiac gating is routinely used for cardiac 18F-FDG imaging. In a single gating study, a respiratory gate will contain residual cardiac motion while a cardiac gate will contain residual respiratory motion. Ideally, the effect of both motions can be minimised. For this purpose, dual gating has been introduced25 and result to a loss of contrast in small targets, such as coronary plaques. To compensate for the reduced SNR, the acquisition time needs to be extended or the number of gates needs to be reduced.In principle, increasing the number of gates enables to capture motion in each gate with increased accuracy, as each gate contains only a small fraction of the total motion seen in non-gated images. However, while this reduces motion effects as a function of the number of gates, the signal-to-noise ratio (SNR) will be reduced as well which might cause variation in quantitative measurements26. The optimal number of gates has been investigated previously in the literature for respiratory gating in oncology27 and cardiology26. However, authors are not aware of any previous studies to determine the optimal number of dual gates, for both cardiac and respiratory gates with motion modelling. Moreover, the number of gates used in dual gated PET studies is much varied. The number of gates used were four respiratory and eight cardiac gates in28, six respiratory and three cardiac gates in29, three respiratory and four cardiac gates in19, eight respiratory and four and six cardiac gates16, four respiratory and four cardiac gates3 and eight respiratory and eight cardiac gates in13.Thus, a balance between optimal image quality and captured motion must be found to determine the optimal number of gates. Moreover, to determine the amount of motion from the gated images, the motion in the gated images needs to be modelled in terms of respiration, cardiac contraction and their combination30. Furthermore, spirometric measurements have been proposed to have potential to guide selection of optimal number of respiratory gates in cardiac PET30. In this study, motion from respiration, cardiac contraction and their combination was modelled and validated with a moving heart phantom to derive the optimal number of respiratory and pulsatile gates. The motion models were applied to an 18F-FDG coronary plaque study to determine the optimal number of dual gates in a group of patients. To the best of our knowledge, this is the first study to implement a dual respiratory-cardiac motion model in cardiac PET.Therefore, there is a dire need to develop modelling approaches which can be applied to define the optimal number of dual gates in patient studies. In this study, we developed and assessed such an approach by motion measurement and modelling to estimate the optimal number of dual gates in a phantom and a patient study. For measurement of respiratory motion, we propose to use the spirometric volume, which has been shown to change linearly in terms of the motion of the myocardium in cardiac PET31. The scanner was equipped with a spirometry device  and the Varian Respiratory Position Monitor (RPM)  for respiratory gating. The patients used an airtight breathing mask that was connected to S/5 anaesthesia monitor to which an airflow signal was stored. An IVY Biomedical 3150-B ECG monitor was used for cardiac gating. The scanner has an effective resolution of 5.2 mm and axial field of view (FOV) of 15.7 cm. More technical details of the scanner can be found in31. The technical details including the set-up and validation of the spirometry device for respiratory gating can be found in the article by Kokki et al.30.Phantom and patient studies were performed on a GE Discovery VCT PET/CT . The study protocol was approved by the Ethics Committee of the Hospital District of Southwest Finland. All methods were carried out in accordance with relevant guidelines and regulations. The detailed performance evaluation of the scanner can be found in19. The phantom32 contains an outer and inner plastic balloon, which are nested and filled with radioactive water. The inner balloon inflates and deflates to simulate pulsatile motion. The diameter of the outer balloon changes 7 mm at maximum. The balloons are also moved mechanically in axial direction, simulating respiration. The resulting respiratory motion is 20 mm. Radioactive point sources were attached to the outer balloon to simulate coronary plaques of 3 mm in size. The phantom is programmed to send both respiratory and cardiac triggers at intervals corresponding to respiration and pulsatile motion to the PET/CT system. Detailed description of the phantom study with figures is given in19.In the phantom study, a realistic heart phantom with respiratory and cardiac motion was used18F-FDG in the myocardium33. The patients where the dieting was not successful (N = 5) to supress the myocardium uptake are also marked in Table In the patient study, the data of 12 cardiac patients was used. The full details of the patient cohort can be found in Table During the PET/CT imaging, two of the scans had technical problems and could not be used in the analysis of image quality, specifically the measurement of SNR. Patient 2 experienced a mismatch between PET and CTAC scans resulting to erroneous attenuation correction. Patient 7 had to be excluded due to overestimation in scatter correction, resulting to large photophenic regions in the lung.18F-FDG PET of one bed position covering the thorax, followed by 4D CT. PET acquisitions were collected in list-mode with acquisition time of 30 min. Respiratory signals were recorded simultaneously with the RPM and the S/5 anaesthesia monitor at sampling frequency of 25 Hz, while ECG signal was recorded with the ECG monitor. Both the RPM and ECG monitors were set to insert respiratory and cardiac triggers to the list-mode data. Before gating, PET list-mode data and the volume signal from the spirometry device were synchronized using trigger time information in RPM and list mode data files and cross correlation spectrum between RPM and volume signals. The synchronisation quality of the signals was confirmed visually. The spirometry signal was qualitatively evaluated on basis of signal quality, breathing irregularities and signal artefacts by an experienced nuclear medicine physicist with nearly 10 years of experience in gated PET studies. As the spirometry is a zero-baseline signal, patient motion was evaluated based only on the RPM signal. In addition, the amount of rejected data based on the spirometry signal was calculated. The signal evaluation is found in Table The imaging protocol was identical for both phantom and patient studies. In the patient study, average dose was less than 12 mSv, with 4 mSv due to 4D CT. PET/CT protocol consisted of a CT-based attenuation correction (CTAC) with 120 kV and max 80 mA, followed by gated 19 whereas the data processing for the spirometry data is described in30. Only the data considered as valid by the spirometry system was used in gating and motion modelling.Gating the data into dual gates was performed with an offline computer using a software package provided by GE Healthcare . The gating method is described in detail in the paper of Kokki et al.26. Phase-based gating for cardiac gating is considered to be a clinical standard34.Amplitude-based respiratory gating and phase-based cardiac gating were used for dual gating. Amplitude-based gating is expected to perform better if the respiratory signal includes cycle variations30. In cardiac gating, the ECG cycle was divided into gates which had equal length according to time. The cardiac gate lengths were determined according to the length of the cardiac cycle and the number of cardiac gates used. After combining respiratory and cardiac gates to dual gates, an equal relative displacement according to lung volume signal and equal time according to R-peak interval is contained in each dual gate.The respiratory signal was divided to gates of equal height according to measured lung volume amplitude. The respiratory gating method is described in more detail inTo determine the optimal number of gates, the phantom study was used with a wide coverage of gates, from no motion capture (single gate) to maximal motion capture (60 gates). The number of respiratory gates used was 1, 2, 3, 4, 5 and 6 while the number of cardiac gates was 1, 4, 6, 8 and 10. The number of gates for the patient study was then determined based on the phantom study, resulting to 1, 3, 4 and 5 respiratory gates and 1, 6 and 8 cardiac gates.Reconstruction software provided by GE Healthcare was used for reconstruction. An iterative three-dimensional ordered subsets expectation maximisation algorithm was used with two iterations, 28 subsets and 6 mm Gaussian post-filtering. The size of the reconstructed images was 36. All necessary quantitative corrections for decay, dead-time, scatter, randoms, detector geometry and normalisation were performed.Attenuation correction was performed with 4D CT images, where the corresponding amplitude of respiration in PET and CT was used for attenuation correctionThe general workflow for determining the optimal number of gates is depicted in Fig. 32 and was used to validate the accuracy of the motion model and the modelled motion estimate. True respiratory motion was 20 mm and cardiac motion 7 mm.To derive a motion estimate to be used for model fitting in Section “Respiratory gates corresponding to peak-inspiration and end-expiration were used for to measure the motion between different respiratory states. Similarly, cardiac motion was measured by comparison between systolic, mid-diastolic and diastolic gates, where the start and end of the cardiac cycle was compared to mid-cycle.In the phantom study, the maximal respiratory motion was determined by measuring the location of the hot spots between gated images. A local maximum and a weighted average of local maximum with threshold of 90% were used to locate the centre of hot spots in each gated image. Thereafter, the motion could be measured in mm by determining the difference of the centres of the hot spots between subsequent motion states.22 and used by 37. The difference of CMA between different cardiac and respiratory states was then used to determine the motion in mm between motion states.In patient studies, a similar approach was applied. The respiratory and cardiac motion was determined from the motion of the centre of mass of the myocardium (CMA). The method involves automatic extraction of the myocardium activity and the calculation of the centre of mass, as described originally byDue to the low quality of the dual gated PET images, respiratory- and cardiac-averaged images were used for motion determination. Respiratory-averaged images were created by averaging all gated images in a gating scheme over all respiratory phases. In a similar manner, cardiac-averaged images were created by averaging all gated images in a gating scheme over all cardiac phases. Thereafter, respiratory motion was defined by comparing the motion of CMA in cardiac-averaged images. Cardiac motion was determined by comparing the motion of CMA in respiratory-averaged images. While this approach introduces a small amount of blurring to the images, it allows to reduce the effect of residual noise to the CMA. As a quality control, the location of CMA was confirmed by investigating a fusion image of the location of the calculated CMA and the extracted myocardium.26. The derived model can then be used to deliver a general motion estimate for determining the optimal number of gates as a function of motion amplitude. We also improve on the model of26 which allows to estimate respiratory motion only, while the models presented in this paper can be used for respiratory, cardiac and dual gating. For detailed comparison with the model in paper of Dawood et al.26 and the analytical model presented in this paper, please see section “The final motion amplitude was estimated by motion modelling and fitting to motion data measured in Section “h. Thus, if the data is gated into n gates, then two sequential gates can be assumed to detect motion of approximately n gates form n-1 intervals between midpoints of the gates, the total motion detected by n gates is n. In practice, this would require that each respiratory or cardiac gate would be divided in such a way that each gate would contain an equal amount of motion for the assumption to be valid.Here, we propose a simple analytical model which can be used for both respiratory and cardiac motion modelling. The model is based on the assumption that both cardiac and respiratory motions are cyclic motions with average amplitude of However, in practice, the motion cannot be divided into perfect intervals which contain equal amount of motion. This is due to changes in respiratory and cardiac patterns during the study and inherent inaccuracies in motion signal measurements and gating. In practice, only the total motion r is the number of respiratory, and p is the number of cardiac gates and parameter c is obtained from the fitting, describing the motion amplitude for either respiratory and cardiac motion.The proposed model is thus based on the assumption that using a number of respiratory or cardiac gates r) and pulsatile (p) components separately with individual number of gates defined as r and p. The total motion c = a + b can be described as individual components of respiratory motion a and cardiac motion b.Since respiratory and cardiac motions occur independently, a model for dual gating can be obtained from (1) modelling both the respiratory  and (2) were attained by using the curve fitting toolbox in MATLAB 7.7.0 .As in Eq. , we assuentclass1pt{minima22. However, increasing the number of gates decreases the number of events per gate leading to increase of noise. Thus, the optimal number of gates is determined by motion minimisation and increase of noise. We first determine the optimal number of gates for motion minimisation and later we consider the optimal number of gates in terms of noise increase.Increasing the number of gates allows to reduce the motion more effectively in each gate and to increase the motion amplitude measurable from gated imagesThe model for optimal number of gates in terms of total motion amplitude for respiratory and cardiac gating can be derived from Eqs.  and 2)  2) by usr, then the total amplitude of motion is determined by The total estimated motion of model (1) can be obtained by letting the number of gates to increase limitless. If 26, to be such that the total motion The total estimated motion mentclass2pt{minims is the scanner resolution.For dual gating, model (2) needs to be applied to include both cardiac and respiratory motion for estimation of the optimal number of gates. Thus, in dual gating we obtain:mest. The method to determine the optimal number of gates for the phantom and patient study is described in detail in Section “Equation  has multThe motion was measured from dual gated PET images and was compared to the motion estimated by the models (1) and (2). The motion estimation accuracy of the models was first validated by using phantom data, which served as a reference standard for model performance. Thereafter, the models were applied to the patient data by using the measured patient motion as input.To compare the results, mean difference (MD):We report MD and RMSE to evaluate the difference between measured motion and motion estimated by the models (1) and (2) in phantom and patient studies.After the validation of the motion estimation accuracy with the phantom, we used the motion estimates from model (1) and (2) as input to (3) and (4) determine the optimum number of gates needed to minimise the motion in the phantom and in each individual subject. Thereafter, a generalised model for the optimum number of gates was derived.mest = 12.7 mm by using a respiratory motion of 14.1 mm and a cardiac motion of 3.8 mm  and scanner resolution of 5.2 mm, as 14.1 mm − 2.6 mm + 3.8 mm − 2.6 mm = 12.7 mm. For the phantom study, we report the total motion amplitude as function respiratory and cardiac gates from model (2) and the optimal number of gates given by model (4).For the phantom study, the optimum number of gates was determined as combination of gates, which produces the highest motion minimisation with the minimum number of gates as For the patient study, the motion derived from models (1) and (2) was used as input for (3) and (4), and the optimal number of gates for each patient was determined. For determining the respiratory and pulsatile motion separately, model (1) was used. For dual gating, model (2) was used to estimate the total motion. It should be noted that model (3) estimates the number of respiratory and cardiac gates separately for each motion while model (4) gives the total number of dual gates directly based on total motion, which can be used to determine the optimal number of respiratory and cardiac gates.Thereafter, the estimated motion from models (1) and (2) were plotted against the optimal number of gates estimated with (3) and (4). For model (1), respiratory and cardiac motions were plotted against the optimum number of respiratory and cardiac gates from (3). For model (2), the total motion given by the model was plotted against the number of dual gates estimated with (4). Finally, a generalised model for the optimal number of gates for respiratory, cardiac and dual gating was derived by fitting to the data by linear regression.For the patient study, we report the optimal number of respiratory and cardiac gates given by model (3) and the total number of gates given by model (4) and the resulting optimal combination of respiratory and cardiac gates specific for motion amplitude of each patient.In addition, we report the general models for respiratory, cardiac and dual gating as derived by fitting of the data. Finally, we report the goodness-of-fit for the general models for cardiac, respiratory and dual gating to estimate the number of gates.In addition to motion minimisation, the second limiting condition for optimal number of gates is the image quality. For an image quality metric, the global SNR inside a gating scheme was used as a function of the total number of dual gates derived from (4). SNR is used to monitor the image quality as the number of gates is increased and to evaluate that the value does not decrease on average more than 3 dB from non-gated image to the optimally gated images.26. In short, the SNR is defined from a VOI in a background region where the PET signal is assumed to be quite homogeneous. In the patient study, the lung region was used as the background region whereas the inner balloon was used in the phantom study. An ellipsoid-shaped VOI was placed inside the inner balloon in the phantom study. In the patient study, a cuboid VOI was placed inside the right lung similarly to38. Sizes of the VOIs were: The SNR measurements were performed using the method applied in previous studiesThe SNR was defined as the mean of voxels divided by standard deviation of the voxels in a homogeneous volume of interest (VOI):26 was fitted to the SNR data, where To verify the dependency of SNR on the number of gates, a SNR curve  gating scheme, containing the most optimal gate in terms of counting statistics saved with the best motion minimisation qualities.To evaluate the image quality with optimal number of gates, manually selected profiles for non-gated and gated images were extracted from a single plane of a single gate. In the phantom study, the profile was drawn over the most active hot spot. In the patient study, the profile was drawn so that it overlaps with both the septal and lateral wall of the myocardium. The gates selected for both the phantom and patient analysis were the last gates of each individual gating schema e.g. gate 20 of the 5,4 The peak of the profiles was used to calculate the full width at half maximum (FWHM). The relative difference of FWHM between gated and non-gated images was used as measurement for image quality and improvement in motion minimisation. The relative difference was calculated as follows:26. The model can be used for respiratory motion estimation for determining the optimal number of gates. As this model is only appropriate for estimation of respiratory motion, no comparison with the cardiac model or dual cardiac-respiratory motion model could be made. The analytical derivation of the models is given in Supplementary Data.Finally, the performance of the proposed models was compared to a previously introduced empirical respiratory motion model.26 proposed the following empirical model for estimating the motion amplitude of the heart due to respiratory motion only:r is the number of respiratory gates and parameters a, b and c are obtained from the fitting. The elementary problem with the model in (9) is the behaviour when r is close to 1. When Dawood et alFor the comparison, we report the model fitting results from the estimated motion in (9) and compare it to the estimated motion by (1) in the phantom study. We also report the number of gates as given by (9) and compare the generalised model from (9) to the respiratory motion model in (10).The results from the motion estimation by models 1) and (2) are represented in Table  and (2) In estimation of the total motion from respiration and pulsation for dual gating, model (2) gave an RMSE of 0.93 mm and MD of 1.70 mm. In all cases estimation of the largest hot spot gave more accurate results than estimating all hot spots on average  and 4) is represented in Table  is repreThe results of motion estimation with different models compared to motion measured from PET images in the patient study are presented in Table For the patient data, respiratory motion varied between 2.5 mm and 17.8 mm. Cardiac motion varied between 5.5 mm and 13.0 mm (Supplementary Data The RMSE between the measured and the estimated respiratory motion on average was 0.27 mm for model (1). The average MD between the measured and the estimated respiratory motion 0.20 mm for model (1). For cardiac motion estimation, model (1) gave an RMSE of 0.20 mm and MD of 0.16 mm.Model (2) showed similar behaviour in the patient study as in the phantom study. The average RMSE between the measured and the estimated total motion for model (2) was 0.97 mm, while the average MD was 0.77 mm.The results for the optimal number of dual gates estimated based on models (1) and (2) and models (3) and (4) are presented in Table 26 we choose a linear function to be fitted for the data.The results from the fitting to derive a general model for respiratory, cardiac and dual gates are shown in Fig. From the fitting, we obtained for optimal number of respiratory gates the following general model from models (1) and (3):2 = 0.978, for (11) is R2 = 0.926 and for (12) is R2 = 0.951. To determine the optimal number of dual gates, any of the models in (10), (11) and (12) can be used. Based on the R2 values the preferable method is to use (10) and (12).The correlation coefficient of the data and the fitted line for (10) is RBased on estimated motion in the patient study  to (12):m is the respiratory motion in millimetres. For our data the corresponding linear fit is:Using (1) and (9), a general model can be derived where the number of gates can be obtained as function of estimated respiratory motion. Based on (1), (9) and their data, Dawood et alThe behaviour of the linear functions for the model in (14) and our proposed model for respiratory gating (10) are illustrated in Fig. In this study, two motion models for motion estimation were presented, validated and applied to respiratory, cardiac and dual gating in PET/CT imaging of the vulnerable plaque. Models were built using phantom and patient studies and the motion estimation accuracy was determined against the known motion in the phantom and the motion measured from patient images. The models were then used to define optimal number of dual gates. The effect of the optimal number of gates to image quality was quantified using automated SNR computation and profiles drawn in manually selected regions. While research of dual gated cardiac PET imaging continues to be active, this study is the first attempt to define optimal number of dual gates using two new motion models. To the best knowledge to the authors, no similar attempt has been made previously to derive a dual respiratory-cardiac motion model.We introduced a model for respiratory and cardiac motion (1), and a model for dual motion (2). In terms of motion estimation performance, the generalised model (2) for dual gating gave very similar results to the model (1) both in respiratory and cardiac motion. The differences in estimated motion versus true motion with both models was minimal in the phantom study Table  and in t25. For example, Daou1 reported respiratory motion of 10.5 mm with 41 patients, while Dawood et al. (2009) reported motion of 11.5 mm in nine patients. Finally, coronary motions of 8 to 23 mm on have been reported in MRI imaging39. It can be seen that patients 8, 9 and 10 with low myocardium activity, the motion estimation accuracy is reduced in model (2). However, at maximum this difference is less than 3.5 mm, which is smaller than the resolution of the PET system used in this study.Based on estimated motion in the patient study  and model 4) gave very similar results, with maximum difference of one gate Table . Whereas and mode gave verThe largest difference in the number of gates was seen with patient 10, where using model (4) resulted in a larger number of total gates. As the estimated motion was also largest with this patient with model 2), it seems that errors in motion estimation might propagate to model (4) when estimating the number of gates. However, it should be noted that while in model (3) the number of respiratory and cardiac gates needs to be determined separately, model (4) gives the total number of dual gates directly. Whereas these models could be used directly to optimise the number of gates on patient-to-patient basis for individual motion amplitudes, the optimal number of gates versus motion needs to be generalised for further application. This was determined based on deriving general models (10) to (12) from Fig. , it seemIn deriving a general model to be applicable on this patient group and to other patient studies outside this group, we used motion models (1) and (2) to define estimated motion and the optimal number of gates from (3) and 4) in the patient study for each subject. This information was then used to build general models (10), (11) and (12) for number of gates as function of motion amplitude using linear regression. The results of Section “ in the p26. There are small variations in the accuracy of the fit over individual patients, as shown in Table The image quality was assessed by SNR calculations, visual analysis and measurement of FWHM. A dual gated image with optimal number of dual gates was compared with the non-gated image. The SNR analysis clearly shows that increasing the number of gates further from the optimal will not be beneficial for additional motion capture and will only result in decreased SNR Figs.  and 4. TThe optimal dual gating resulted in improved definition of the hot target in the phantom images and clearer definition of the myocardium in the patient images Fig. . In both., the model (1) is also mathematically simpler and can also be applied to cardiac motion. As there are no respiratory-cardiac motion models introduced previously, we could perform the comparison with respiratory motion modelling only.In comparison to a previously introduced respiratory-only model, the proposed model (1) had equal performance Fig. . The motFirst, our intent was to define the optimal number of gates which could be applied directly in clinical practice without further motion modelling or gating. Thus, applying the gates defined in this study should be applicable to various patient groups, given the fact that in most cases 5 respiratory gates and 4 cardiac gates are sufficient to minimise respiratory motion up to 12 mm and cardiac motion up 10 mm, corresponding to total motion of 22 mm. This amount should be enough to capture the motion accurately in most routine patients. In cases of unusually large motion this number might be increased as required. As the motion amplitude also varies between patients depending on the breathing and cardiac pattern, it is always better to fix the number of gates across a patient group in a way that it offers the optimal motion minimisation in majority of cases in regard to the loss in image quality.m to Eqs.  and apply the motion  to Eqs.  to 12)..m to Eqs30 that you could potentially use the spirometry signal in this study to derive a motion estimate based on the signal alone, as there is a linear dependence between the volume change in the spirometry signal and CMA motion. This would allow to determine the optimal number of gates based on the respiratory signal alone, using a simple linear equation to estimate the motion m, according to Kokki et al.30.Without image reconstruction, the amount of motion could be measured with a quantifiable respiratory signal, which has been determined to correspond to a particular amount of motion. For example, our group has previously shownThe proposed models in Eqs.  to 4) a a4) are In terms of model accuracy, any error in the data which affects the measurement of the total motion in the images will have an effect to the number of gates derived with the model. Regular breathing irregularities will tend to be averaged within the gated images and should not have a large effect to the model accuracy. Since the total motion is also measured between the motion extremes, the model is not very sensitive to small changes in the respiratory or cardiac cycles.However, a large gross motion of the patient might change the total motion and currently the model does not account for that. This might result in over- or underestimation of the number of gates with the patients with large gross motion depending on the direction and magnitude of the repositioning event. With patients 2, 6 and 7 gross motion on the RPM signal was seen. However, on patients 2 and 6 there were no ill effects on the estimated number of gates. On patient 7, the atypical accumulation and a large fraction of lost signal (> 40%) were determined to be the main factors affecting motion estimation as opposed to gross motion..19 used four cardiac gates and the longest gate contained half of the data. As there are numerous ways in determining the division of both respiratory and cardiac gates, it would be of interest to study the optimal division of the gates. Thus, by dividing the amount of data differently, more data could be preserved in the most optimal gate. However, it should be noted that this only concerns the division of gate lengths, not the model itself. Any gating scheme will allow to derive the model as long as motion between two motion extremes in respiratory or cardiac states can be measured and given as input to the model.Our study has a limitation which concern the application of different gating methods. The current study did not compare the effect different gating methods to the preserved amount of data in each gate. For example, in cardiac gating, phase-based cardiac gating is the clinical standard, but with different gate durations. Kokki et al30. Ideally, it would be beneficial to estimate the number of gates also from external signals30, although this method has limitations as well, discussed in40. While CMA is limited in accuracy by resolution of the PET images, it so far offers a viable solution for image-based motion determination for defining the optimal number of gates when number of images to analyse is large (over 1000 in this study) and has been used previously in several studies40. As we used respiratory- or cardiac-averaged images to derive motion estimates, small differences in the uptake are averaged out for accurate motion measurements. The method is limited as it only detects displacement, not rotation or deformation and depending on the segmentation quality, only a part of the heart might be detected. However, since we measure motion between the two motion extremes, this method is also in a sense, robust to changes in also atypical uptake in the myocardium. Potentially, MRI might be used in a future study as an alternative, non-invasive option for as a ground truth measurement for motion41. However, none of the patients in this study cohort undergone MRI.Second, the ground truth motion estimates from the patient studies could only be derived based on patient PET images. The motion was determined by using the motion of CMA measured from PET images42, TOF improves the SNR in the images, whereas using PSF would give also a better definition of the small targets in the image43. Using the number of gates specified in this paper with a more recent PET/CT system would result in improved image quality if TOF and PSF would be included. Thus, further studies for assessing recent reconstruction methods for optimal gating are encouraged.In addition, this study was conducted on the Discovery VCT system which does not incorporate TOF imaging or PSF modelling. Addition of TOF and PSF would result in improved image quality and hence, a higher number of dual gates might be used to achieve the same image quality. On the other hand, the same number of gates could be directly used with PSF and TOF to achieve the same motion minimisation but improved image quality in each gate. According tom to Eqs.  and apply the measured motion  to Eqs.  to 12)..m to EqsFurther assessment of the methodology described in this paper should be performed with larger patient population in regard to optimal coronary plaque detection. To adopt the study materials in practice, patients with larger motion amplitude should also be included. Thus, further studies are encouraged on potential application of the simple models to motion tracking, optimisation of the number of gates and motion correction in PET imaging.We introduced and validated two motion models which can be used for accurately estimating respiratory and cardiac motion in dual gating using spirometry data. The motion estimates from the models can be applied for determining the optimal number of gates for respiratory, cardiac and dual gating. Based on the models, the optimal number of dual gates for minimising both respiratory and cardiac motion effects was derived, consisting of five respiratory and four cardiac gates. This number of gates can be applied to minimise respiratory motion up to 12 mm and cardiac motion of 10 mm, corresponding to total motion of 22 mm across various patient groups.Supplementary Information 1.Supplementary Information 2.Supplementary Information 3.Supplementary Information 4.


The electromagnetic pulse (EMP) is a destructive phenomenon which harms the building, telecommunication, and IT based infrastructure. Thus, it is required to reduce the effect of EMP using shielding materials. In the present study, we have used different thickness of concrete walls by incorporating 1 and 5 wt% of carbon black, as well as 100 µm thick Zn–Al coating using the arc thermal metal spraying method (ATMSM). The EMP was evaluated using waveguide measurement fixture for shielding performance of the concrete wall in the range of 0.85 to 1 GHz frequency. The results reveal that the maximum value, i.e., 41.60 dB is shown by the 5-300-N specimen before application of Zn–Al coating where the thickness of concrete wall was 300 mm and 5% carbon black. However, once the 100 µm thick Zn–Al coating was applied on concrete specimen, this value was increased up to 89.75 dB. The increase in shielding values around 48 dB after using the Zn–Al coating is attributed to the reflection loss of the metal thermal spray coating. Thus, the Zn–Al coating can be used for EMP application instead of metallic plate. Electromagnetic pulse (EMP) typically refers to high power electromagnetic (HPEM) waves ranging from 100 kHz–100 MHz which damages the building structures and military equipment . EMPs haTherefore, the development of technology for shielding electromagnetic waves has been actively conducted with an emphasis on EMP protection facilities ,7,8. In However, when EMP is applied in the field, deterioration of the electromagnetic shielding occurs owing to using defective metal plates, error in joint regions, and problem in connection of the welding and bolts. Moreover, inefficient utilization of space due to the distance from the wall is also a potential problem ,10.The electromagnetic shielding generally consists of three principles: Reflection loss, absorption loss, and multireflection loss. Reflection loss is caused by the impedance difference between the air layer and the shielding material, which is known as the main shielding principle in electromagnetic wave shielding. The second is the absorption loss, which occurs in low density, thin matching thickness, high complex permittivity values along with high conductivity, as well as magnetic materials where the electromagnetic waves pass through the shielding material and are converted into heat via ohmic loss. The third is multireflection loss, caused by electromagnetic waves propagating in a completely different direction through the materials that cannot be penetrated due to the retro-reflection or electromagnetic scattering into the shielding materials ,12.In general, the overall shielding effect of a metal can be expressed by the sum of the absorption loss (A), reflection loss (R), and multiple reflection loss (B), as described in Equation (1):t is the thickness (meter), f is the frequency (Hz), rµ is relative permeability with respect to free space, and rσ is the relative conductivity of the shielding materials with respect to copper. As shown in Equation (2), the absorption loss is proportional to the thickness of the shielding materials, and then the reflection loss in the metal can be expressed by Equation (3):In this equation, all terms are expressed in dB and the multireflection loss (B) can be ignored if the absorption loss (A) is greater than 9 dB. Due to the conducting nature of metals, the absorption of shielding materials is greater and the chances to bounce back the waves are less. Thus, the multireflection loss (B) between two surfaces of the metal materials is very low and can be neglected ,12. Absoconcrete ,14,15,16Existing studies on electromagnetic wave shielding performance  can be classified into either a construction aspect (reflection loss), or a material aspect (absorption loss and multireflection loss). Lee et al. have considered and derived the construction aspect using the metallic coating by the thermal spray method that is effective for the shielding of electromagnetic waves by comparing with iron and copper plates . They haTherefore, it is our prudent thought to study the effect of electromagnetic shielding performance of different thickness of concrete, concrete with 1 and 5 wt% carbon black and 100 µm thick Zn–Al metallic coating deposited by arc thermal spraying process onto the concrete in the range of 0.85–1 GHz frequency using the E8356A network analyzer waveguide for the protection of national security building, military base camp, hospital, etc. from the effect of EMP. Generally, the Zn–Al coating is being used for corrosion protection of smart cities infrastructure using thermal spray techniques ,28 but wIn this study, the experimental variables used to evaluate the electromagnetic shielding performance of a concrete wall are shown in The arc thermal metal spraying method (ATMSM) was used to address the problem of metal plate in construction for existing shielding facilities owing to the cost effectiveness. In the arc thermal metal spraying method, a metal wire rod is coming out from the nozzle of a spray gun that blows compressed air, and is dispersed and cooled on the surface of the specimen to be coated ,35,36,37The Zn and Al (purity 99.95%) twin wires of 1.6 mm diameter were used to deposit the coating onto the concrete surface. The Zn–Al coating was applied onto the concrete surface and the thickness of deposited coating was measured with a nondestructive Elcometer456 . The coating thickness was measured at three different locations on the specimen and the average was taken. The coating thickness was found to be 100 µm (±5 µm). The coating contains 68.50% Zn and 31.50% Al after the deposition which forms the pseudo alloy coating instead of pure metal.The thickness of the concrete wall was varied from 100–300 mm with carbon black  as the conductive material and filled the porosity of the concrete. The Zn–Al coating onto the concrete surface was deposited to evaluate the electromagnetic shielding performance. We have performed the experiment in triplicate for each set. The compressive strength of concrete specimens was performed according to the KS F 2405 standard after 28 days of curing . In the 3 density of ordinary Portland cement [2/g specific surface area. The dibutyl phthalate (DBP) oil was used for proper dispersion of carbon particles. The chemical composition of the binder for the present study is shown in According to the KS L 5201 standard, we have used 3.15 g/cmd cement . The aveA rectangular specimen of 100 × 200 mm was prepared in accordance with KS F 2403 [The details of the experiment design and methodology is shown in The surface morphology and cross-sectional image of the coatings was carried out by scanning electron microscopy  operated at 15 kV. The cross-sectional image of the sample was taken by mounting the sample in a holder, polishing and fixing it.The phase identification of the coating was performed by X-ray diffraction  using Cu Kα radiation (λ = 1.54059 Å) generated at 40 kV and 100 mA from 2θ = 10–90° at a 4°/min scan rate.The electromagnetic shielding performance evaluation methods for EMP protection facilities are typically known as MIL-STD-188-125-1 and IEEE-STD-299 . HoweverIn this study, we have selected the E8356A network analyzer (Agilent) and a customized WR-975 waveguide having 247.65 × 123.83 mm dimension to evaluate the EMP shielding performance of the concrete wall. This wave guide is easy to set the antenna, amplifier, and the distance between the antenna and the test body. The experimental outline is shown in The source of EMP was alternative current (AC) with cutoff frequency in the range of 0.85 to 1.0 GHz ,10. The The electromagnetic shielding performance is the signal transmitted from Port 1 and received at Port 2, which represents the intensity of the signal transmitted through the specimen, located between the waveguides. This can be expressed in Equation (4), where P1 is the power with the material and P2 is the power without the material ,44,45. IThe minimum requirement for electromagnetic shielding in EMP protection facilities should be at least 80 dB in the target frequency band and the transmission coefficient should be measured at 80 dB or more in the network analyzer .The compressive strength of the concrete specimen with inclusion of carbon black was measured three times after 28-days of curing. The measured values of the slump and compressive strength are shown in The compressive strength tended to decrease with an increasing amount of carbon black, which is related to the properties of this material. The carbon black in the cement affects the hydration reaction by blocking the contact between water and cement. Particularly for carbon black with a large surface area, they absorb a considerable amount of water during the mixing process. As a result of these factors, the compressive strength and slump of concrete containing carbon black is reduced as the incorporation rate of carbon black increased .The SEM result of the Zn–Al coating is shown in The presence of phases was determined by XRD and results are shown in The electromagnetic shielding performance of the concrete specimens with different amounts of carbon black at a particular thickness is shown in From When the thickness of the concrete specimens is increased by incorporating carbon black from 0, 1, and 5 wt%, the electromagnetic shielding performance increased by 107.10% to 153.44% without carbon black, 120.70% to 182.02% with 1% carbon black, and 128.71% to 231.74% with 5% carbon black for 200 to 300 mm, respectively compared to 100 mm thickness of concrete b. For thBy comparing Therefore, to achieve acceptable performance of the concrete while considering factors such as cost and workability in addition to the thickness of the concrete, additional elements such as high-strength concrete with a dense structure or the incorporation of conductive materials should be considered. When the conductive material is mixed, it is considered to be effective in improving the electromagnetic shielding performance.In this study, the 5-300-N specimen exhibits the highest shielding performance, i.e., 41.60 dB. However, the possibility of using carbon black mixed concrete in EMP protection facilities is low. Thus, referring to CISPR 16-2-3 and IEC 61000-4-20, in terms of the standards for electromagnetic compatibility of household appliances and lighting equipment, an average of 40 dB is defined as the allowable standard. Therefore, 5-300-N is suitable for commercial electromagnetic shielding facilities instead of EMP protection facilities ,49.The shielding effectiveness of the concrete specimen is increased with thickness and addition of carbon black from 0.85 to 1 GHz studied frequency range . HoweverThe electromagnetic shielding performance of 5-300-N (5 wt% carbon black + 300 mm thick concrete + without Zn–Al coating) specimen with the highest shielding value before the metal thermal spray application was 41.60 dB, which is around 48 dB lower than after the application of Zn–Al metal coating, i.e., 89.75 dB. The Zn–Al coating was applied on the top surface of concrete where it allows to absorb the waves but due to incident of waves through the atmosphere, there would be an impedance between coating and air layer which causes the reflection loss. This result indicates that the reflection loss is mainly used for shielding of electromagnetic waves. Thus, it is suggested that the combination of reflection and absorption loss should be appropriately used to satisfy the target shielding performance of 80 dB.As such, when a Zn–Al metal thermal spray coating is applied on 5-200-A, 1-300-A, and 5-300-A concrete specimen, a shielding value more than 80 dB was obtained. Therefore, to achieve an electromagnetic shielding performance of 80 dB, as required for an EMP protection facility, the use of a concrete containing a conductive material is necessary.As shown in In The shielding effectiveness of the concrete specimen at different studied frequency after application of the Zn–Al coating is shown in From the above results and discussion, it is found that as the carbon content and thickness of concrete wall increased, the shielding performance increased without application of Zn–Al metal coating. Thus, the 5-300-N specimen, i.e., 5 wt% carbon black + 300 mm concrete wall thickness without Zn–Al coating exhibits 41.60 dB shielding value. Moreover, it can be only considered for application to commercial electromagnetic wave shielding facilities. However, once the Zn–Al metal thermal spray coating was applied onto the concrete surface, the shielding performance increased by 89.75 dB for 5-300-A, which is attributed owing to the reflection loss of the Zn–Al metal thermal spray coating. Thus, this process can be recommended for application of EMP. From the results, it is expected that a better shielding performance will be achieved if a hybrid system such as conductive concrete including carbon nanotubes, graphene, and steel fibers can be used by thermal spray technology.


Most patients with an acute bacterial infection have immune defense mechanisms to respond to the pathogen and destroy both resistant and non-resistant bacterial cells, facilitating the elimination of the pathogen. However, a growing population of patients–those with an immune deficiency—may lack some, or many aspects of those defense mechanisms, and thus require effective antibiotic therapy to survive or reduce their time required for recovery. Antibiotic Susceptibility Testing (AST) can help in choosing the most appropriate option. However, misguiding AST results can lead to poor and even fatal outcomes  and the Clinical and Laboratory Standards Institute (CLSI), acknowledge that there are challenges associated with the interpretation of their recommended tests . AST, when performed routinely, determines the E.coli to be sensitive on ciprofloxacin. However, when the same sample is inoculated directly on agar containing 10 microgram/mL of ciprofloxacin, , resistance colonies were clearly detected , and determine the susceptibility result after overnight (16–18 h) incubation. Contrary to this approach, inoculating the original sample directly on antibiotic screening agar plate  reveals 8 CFU/mL)  can measure species-specific growth rates of bacteria in the original sample in response to different antibiotics (Rolain et al., In conclusion, the current evidence suggests that the present methodology of AST should be reconsidered. We must move forward, taking advantage of the new technology available, and abandon inoculum size standardization and the use of pure cultures. This might change the rules both for industry and the public sector but will ultimately benefit patients in need of antibiotic treatment, especially those that are immunocompromised.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In accordance with the integrated results of  In the supramolecular chemistry field, stimuli-responsive molecular host-guest recognition motifs are attracting much attention because of their wide range of applications in the fabrication of various fascinating and important supramolecular systems, such as molecular devices and machines  with good water solubility was prepared by our group  and 2-naphthalenesulfonic acid (2-NA) were selected as guests, owing to their wide uses in rubbers, dyestuffs, insecticides, varnishes, and pharmaceuticals  with p-TSA and 2-NA, respectively. Based on these two molecular recognition motifs, pH-responsive host-guest complexes were demonstrated.Pillararenes  on the guest p-TSA demonstrate significant upfield shifts against free guest p-TSA proton signals . Strong upfield chemical shifts (Δδ) of the aromatic and methyl protons indicate that the p-TSA guest was fully threaded into the host cavity, forming a stable threaded host-guest complex. And the presence of only one set of peaks for the solution of CP6 and p-TSA   of the entrapped 2-NA and the aromatic proton H1 of CP6, which also revealed the interpenetrated geometry.Subsequently, the complexation of e of CP6 , the sig.16 ppm) , suggestESY data  show thep-TSA and 2-NA with host CP6, fluorescence titrations were conducted at 298 K in a PBS of pH 6.0. Job plots  were calculated to be (2.23 ± 0.15) × 104 M−1 and (1.97 ± 0.28) × 104 M−1 for p-TSA and 2-NA, respectively. According to the pKa values of the two aromatic sulfonic acids , it can be concluded that the sulfonic groups of the two aromatic sulfonic acids should be in the deprotonated form at pH 6.0. Thus, we conclude that the interaction mechanism of CP6 with the two aromatic sulfonic acids is that the acidic aromatic sulfonic acids with one sulfonate anion could bind positively charged CP6 bearing 12 –CP6 play a dominant role in formation of the present host-guest complexation. By comparing p-TSA and 2-NA, we can investigate the capability of these guests to form host-guest complexes because of the changed size of the hydrophobic part. The Ka value for p-TSA is almost same as that for 2-NA. Although 2-NA has one more benzene ring than p-TSA and thus the larger π-conjugated system could afford a stronger π-π stacking interaction with the host cavity  between its complexed and decomplexed states. Consequently, the findings of this work enrich the fields of controlled pillararene chemistry. Our further work will focus on expanding these new pH-responsive host-guest binding motifs to construct smart supramolecular materials in the treatment of sulfonated aromatic pollutants in aqueous media.In summary, novel pH-responsive host-guest recognition motifs based on a water-soluble pillar[6]arene dodecyl-ammonium chloride All datasets generated for this study are included in the article/QD, FW, and KL designed the work. QD made contributions to the experiments and collective data. The paper was written by QD. All authors extensively discussed the results, reviewed the manuscript, and approved the final version of the manuscript to be submitted.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Antibiotics are often prescribed inappropriately to patients with upper respiratory infection (URI) in ambulatory care settings; however, the economic burden of such prescription has not been quantitatively assessed. Here, we aimed to evaluate the additional cost of antimicrobial prescription for URI at the population level in Japan.We conducted a retrospective observational survey using longitudinal claims data between 2013 and 2016 obtained from JMDC Claims Database, which contains data from 5·1 million corporate employees and family members under the age of 65 years. Appropriateness of antibiotic prescription was assessed by a panel of six infectious disease physicians according to ICD-10 code in JMDC Claims Database. Total additional cost of antibiotic prescription for URI at the national level was estimated by weighting of age-structured population data.The annual additional cost of inappropriate antibiotic prescription for URI was estimated at 423·6 (95% CI: 416·8–430·5) million USD in 2013, 340·9 (95% CI: 335·7–346·2) million USD in 2014, 349·9 (95% CI: 344·5–355·3) million USD in 2015, and 297·1 (95% CI: 292·4–301·9) million USD in 2016. Three classes of broad-spectrum oral antibiotics  accounted for > 90% of the total additional cost.Although a decreasing trend was observed, annual additional costs of inappropriate antibiotic prescriptions for URI could be a substantial economic burden in Japan. Appropriately prescribing broad-spectrum oral antibiotics might be an important issue to reduce unnecessary medical costs in Japanese ambulatory care. Antibiotic prescription promotes antimicrobial resistance (AMR), which is currently one of the greatest threats to global health . AntibioFollowing the publication of the Global Action Plan on Antimicrobial Resistance in 2015 . AccordiAdditionally, antibiotic prescription for URI might impose a significant burden on our society because although URI is not a severe disease at the individual level, the total cost of antimicrobial use for URI does not seem to be negligible. Furthermore, AMR caused by such antimicrobial use will result in additional AMR infections and these cases will impose significant additional costs.Although there are some previous studies about the additional cost of antimicrobial prescription for URI in ambulatory care settings, these studies focused on more extensive kind of drugs or diseases or specific populations –10. TherWe conducted a retrospective observational survey using longitudinal claims data collected between 2013 and 2016 obtained from JMDC Claims Database, which contains anonymous, de-identified claims data of 5·1 million corporate employees who are covered by the employees’ health insurance plan and their family members under the age of 65 years.We identified the number of claims that included inappropriate antibiotic prescription for URI patients. URI patients were defined by claims with the International Classification of Diseases, 10th Revision (ICD-10) diagnosis code of J00–06 and/or J20–22 without other diagnosis considered as appropriate for antimicrobial treatment.To judge appropriate antibiotic prescribing behaviour for other ICD-10 codes, a panel of six infectious disease doctors at the Japanese Disease Control and Prevention Center, National Center for Global Health and Medicine, assessed the appropriateness of antibiotic prescription for each ICD-10 code. Each physician first independently evaluated whether treatment with antibiotics was optimal. If two or more assessors did not reach an agreement for any diagnosis code, then all six experts reviewed the case at a round table until a consensus was reached. The validity of this approach has been shown in previous studies , 12. DetThe total additional cost of inappropriate antibiotic prescription at the national population level was estimated by the JMDC data, which include the duration and cost of each drug prescribed in each claim. The cost of inappropriate antibiotic prescription in each age group was collected, and each year was weighted according to Japanese age-stratified population structure based on 5-year age group data . We did To reflect uncertainty, we estimated 95% confidence intervals (CIs) of the proportion of population coverage, the proportion of URI cases prescribed antibiotics, and the cost of antibiotics in each case. We conducted the binomial test to estimate 95% CIs of population coverage and the proportion of antibiotic prescription. For the cost of antibiotics, we conducted the t-test to estimate 95% CIs.All analyses were conducted by Stata MP15  . Details of enrollees are described in Table The estimated proportion of inappropriate antibiotic prescription for URI in each year and age group is shown in Table The estimated additional cost of inappropriate antibiotic prescription for URI at the total Japanese population level is shown in Table Figure Annual estimated percentages and additional costs of antibiotic prescription for three broad-spectrum antibiotic classes  are shown in Fig. We also evaluated the share of broad-spectrum antibiotics in the total annual cost of antibiotic prescription. Three antibiotic classes  accounted for over 90% of total additional antibiotic prescription costs for URI (95·3% in 2013 and 94·2% in 2016).We developed a national population level cost estimation about the unnecessary cost of antibiotic prescription for URI. To our knowledge, the present study is the first to assess physicians’ antibiotic prescription behaviour not only in view of the proportion of antibiotic prescriptions but also the associated additional costs. By adding the viewpoint of cost, our findings show novel characteristics of inappropriate antibiotic prescription in ambulatory care settings.First, both the proportion and cost of unnecessary antibiotic prescription for URI have decreased in recent years. The proportion of URI cases to which physicians prescribed antibiotics was 32·41% in 2013 but only 29·36% in 2016. The cost of antibiotic prescriptions for URI cases was 423·6 million USD in 2013 and decreased to 297·1 million USD in 2016. The proportion of URI cases to which physicians prescribed unnecessary antibiotics demonstrated a gradually decreasing trend every year and the total annual cost of antibiotic prescriptions for URI in 2016 was about 30% lower than that in 2013. According to a previous study, Japanese physicians had prescribed antibiotics for 60% of URI cases in 2005 [As mentioned above, the Japanese government established the National Action Plan on AMR in 2016 [Conversely, the proportion of antibiotic prescriptions for URI is difficult to compare with previous studies from foreign countries due to differences in settings and conditions. For example, Barnett and Linder reported that the antibiotic prescribing rate dropped from roughly 80 to 70% around 1993 and decreased again around 2000 to 60% . HoweverFurthermore, we must take the differences in healthcare system between Japan and other countries into consideration. The Japanese healthcare system generally secures ‘free access’ to healthcare services, regardless of facility level, and there is no limitation on the frequency of ambulatory care visit . This imSecond, our results demonstrated the importance of appropriate antibiotic use, especially in paediatric ambulatory care. Despite the comparatively low rate of antibiotic prescription in children and the ratio of children to the total population, the additional cost in children under 15 years accounted for over 30% of total additional costs annually. This finding likely reflects the frequency of healthcare facility visits attributed to URI by children . AdditioThird, it is noteworthy that broad-spectrum oral antibiotics accounted for the majority of additional antibiotic prescription costs for URI. Three antibiotic classes  comprised almost 95% of total additional antibiotic prescription costs for URI in Japan. Our finding of a high prescription rate of third-generation cephalosporins and macrolides is compatible with findings from a previous study . The fluA major strength of the present study is the use of a large number of individual patient-level claims data, which cover both children and adults. Conversely, our data did not include claims of patients 65 years of age or older.While millions of individual claims are included in the dataset, its representativeness is not completely assured because our data are based on information from health insurance purchased by enterprises. Nevertheless, a low proportion of self-employed people (8·48% in 2017) and low unemployment rate (3·1% in 2016) in Japan  enable uIn addition, diagnoses in the dataset are sometimes unreliable. It is often the case that physicians make different diagnosis in the claims on purpose to justify their examinations and prescriptions. Nevertheless, physicians never make a fake diagnosis of “URI” when they would like to prescribe antibiotics, but make a diagnosis of other bacterial infections in order to justify their antibiotic prescriptions. Then therefore unreliable diagnoses might not overemphasize the cost of inappropriate antibiotic prescription.Another strength is that we introduced the concept of cost. Although the rate of antibiotic prescription or defined daily dose  are indiAs we have shown, the present study gives an extensive understanding about the impact of inappropriate antibiotic prescription for URI. Although a decreasing trend was observed, the annual additional cost of antibiotic prescription for URI could be considered a substantial economic burden in Japan. Our study also suggests that appropriate use of broad-spectrum oral antibiotics might be critical to reduce unnecessary medical costs in Japanese ambulatory care.Additional file 1. Supplementary Spreadsheet. Details of the discussion process to judge appropriateness of antibiotic prescription.Additional file 2. Supplementary Table. Appropriateness of antibiotic prescribing for ARTI used in the study.Additional file 3. Table S1. Estimated percentage of third-generation cephalosporin prescriptions for URI in ambulatory care. Table S2. Estimated additional cost of third-generation cephalosporin use for URI in ambulatory care. Table S3. Estimated percentage of macrolide prescriptions for URI in ambulatory care. Table S4. Estimated additional cost of macrolide use for URI in ambulatory care. Table S5. Estimated percentage of fluoroquinolone prescriptions for URI in ambulatory care. Table S6. Estimated additional cost of fluoroquinolone use for URI in ambulatory care.