X, Y, and Z axes) of printed concrete. It evaluates the ratio of flexural strength to the compressive strength of printed concrete along the above three axes. This article explains the influence of variation of printing process parameters on the mechanical properties and discusses reinforcement approaches used for increasing structural performance. The microstructure at the interface of adjacent layers and also at the interface of the reinforcement-cement matrix is discussed. The recent research on the durability performance of printed concrete is critically discussed and future research needs for 3D concrete printing are identified in this paper.This paper provides a state-of-the-art report on the up-to-date research on the emerging 3D concrete printing technology from the concrete materials perspective. It reviews the recent research focused on understanding and characterizing the rheological necessities of the concrete printing process and discusses how the researchers are tailoring compatible mix proportions for the 3D concrete printing process by using eco-friendly binders, waste aggregates, chemical admixtures, and nano-additives. This paper systematically evaluates anisotropic behavior in the mechanical properties of printed concrete and establishes an order for anisotropic behavior in the compressive, flexural, and tensile strengths along three different axes ( Concrete 3D printing is an emerging technique for the construction of buildings and infrastructure. In this method, a 3D model of an object is created in computer-aided design (CAD) software, which is then divided into slices, and a G-code is generated for the movement of the print head to extrude the concrete. The extrusion of concrete through the nozzle and movement of the print head are computer-controlled ,2. ConcrThe application of 3D concrete printing technology in construction is considered a new period for the industry due to its potential to disrupt conventional construction practices ,7. It isThis paper aims to provide a systematic review of the fresh performance and rheological test systems of 3DCP, and the influence of concrete ingredients on the rheology of printable concrete. It can help researchers and engineers to measure the printability performance of their mixes and tune the rheology of the concrete according to their printing requirements. The critical review section of mechanical properties aims to quantify the anisotropic pattern in printed concrete and draw a relationship between flexural and compressive strengths that can be helpful to structural engineers for designing safe, printed concrete structures. The microstructure and durability sections discuss the occurrence of higher porosity and cracks in printed concrete and the expected influence of these strains on the long-term service life of printed concrete. Additionally, future research needs are understanding the early stage, hardened, and long-term performance of extruded concrete are also reflected in this review.This paper has been organized into 10 sections in such a way that it fulfills the needs of beginners as well as advanced researchers in this field. Bingham model has been widely used to characterize the flow of 3D-printable concrete ,31,32,33γ˙ represent shear stress and shear rate, respectively, whereas τ0 and μ represent yield stress and plastic viscosity of concrete, respectively [thix) represents the rate of increase in static yield stress with time [ectively . Three-dectively . As timeectively ,37. The ith time . Dynamicith time . In thisith time ,41, whicith time . Flow cuith time . Thixotrith time ,45, hystith time , and refith time . The strith time ,38.The 3D concrete printing process requires contradicting rheological requirements. It needs high workability during the pumping phase before extrusion, but it needs low workability and high thixotropy after extrusion for better buildability of concrete ,47,48. DThe rheological properties of 3D concrete printing reported in the previous literature have been mostly measured without feeding the concrete in the 3D concrete printer. However, concrete is subjected to excessive shearing when pumped through a pipe to the nozzle of the printer, and this process changes the concrete rheology. In addition, the extrusion through the narrow nozzle alters the composition and rheology of concrete. These changes in concrete are dependent upon the material properties such as plastic viscosity and dynamic yield stress of concrete, plastic viscosity of lubrication layer, and 3D printer associated properties such as pumping rate, pipe radius, and geometry of the nozzle . CharactConcrete used in 3D printing is passed through the stages of pumping, extrusion, and layer-by-layer deposition. These stages require special characteristics from a concrete mix to conform with the sophisticated needs of the printing process, which are discussed in detail in the following subsections.Pumpability is the capability of a mix to be transported through a pipe under pressure. Progressive cavity pumps, positive displacement pumps, and ram extruders have been usually used to transport concrete from the mixing tank or hopper to the extruding nozzles ,81,82,83Mix proportion ;Rheological properties of concrete;3D printer .Extrudability is the capability of concrete to pass under pressure through the contracting nozzle without segregation and produce a continuous filament. Extrusion of concrete through the nozzle is an essential part of the 3D concrete printing process. Le et al.  observedShape retention is the capability of the extruded concrete layer to retain its cross-section equal to the cross-section of the nozzle. The shape retention factor for printed concrete can be measured by dividing the width of the printed layer by the width of the printer nozzle, as given below .(2)S=WffW and nW are the width of the extruded filament and the nozzle, respectively. Chougan et al. [Here, S shows the shape retention factor, and n et al.  tested tn et al.  tested tn et al. ,96,97,98Printing the curved parts of a concrete layer with a rotating circular or rectangular-shaped nozzle extrudes a larger amount of concrete at the corners. This results in increased width of the printed layers at the curves compared to its width at the straight parts. More concrete is deposited on the inner side at the corners compared to the outer side during the rotation of the nozzle. Tearing and cracking of the printed-curved layers can happen on the outer side soon after the deposition, and these cracks can expand due to the weight of the successively deposited layers at earlier ages, which will result in poor surface finishing, as shown in It is the time period after mixing water, cement, aggregate, and other additives during which concrete is extrudable through the nozzle. The printing open time of a candidate concrete mix must be greater than the time required for extruding the concrete during the printing operation. Printing open time is dependent upon mix design ,60, and Buildability is the characteristic of a concrete mix proportion to be successively printed up to a specific height without significant deformation or collapse of the layers. It depends upon the rheological properties of concrete, printing process parameters, and geometry of the target concrete structure. Researchers have presented numerous methods for the evaluation of the buildability of concrete. There is no consensus upon a standardized experimental test method for the measurement of concrete buildability. Le et al.  were theft is critical failure time, τ0,0 is the initial yield stress of concrete, ρ is density, g is the gravitational force, R is the rate of construction, geomα is a geometrical factor and depends on the shape of extruded filament, thixA represents the structuration rate [Here, ion rate . Wolf etion rate  considerion rate . During ion rate . Jayathiion rate  reportedion rate ,104, mayion rate  developeion rate  presenteion rate  presenteion rate  reportedMuthukrishnan et al. ,110 studResearchers have used different concrete ingredients  in their mix designs to understand their effect upon the rheology and consequences upon the printing performance of the concrete. These research efforts have been discussed in the following subsections and summarized in The higher content of cement used in 3D concrete printing raises the sustainability issue of this technology . TherefoResearchers have investigated the influence of aggregate characteristics upon the behavior of printable concrete. Zhang et al.  studied 2CO3), sodium carbonate (Na2CO3), calcium nitrate (Ca(NO3)2), and triethanolamine (TEA). The proper dosage of these accelerators can regulate the setting time within 5–150 min. The above admixtures affect the hydration of the binder and crystallinity of a few hydration products. Khalil et al. [A high dosage of chemical admixtures is used in concrete designed for extrusion and buildability purposes. Dorn et al.  observedl et al.  studied l et al.  used tarl et al.  studied l et al. . Chen etl et al. ,164 measl et al.  observedResearchers have used nanomaterials to modify the fresh behavior of concrete in favor of 3D concrete printing ,167. Cho3D-printed concrete has a layered structure due to the deposition of concrete in the shape of multiple layers to obtain a three-dimensional concrete element. There can be two types of interfaces in printed concrete elements. Extrusion of the succeeding layer over the top of the preceding layer creates a horizontal interface. If the succeeding layer is deposited adjacent to the preceding layer at the same level, then it will create a vertical interface between the two layers. Strength at the core part of the extruded concrete is higher than the strength at the horizontal or vertical interfaces of layers. Printed concrete elements have anisotropic mechanical behavior due to the dependency of performance upon the application of load direction with reference to the printing direction . In the c shows the compressive strength of casted concrete and Cx, Cy, Cz show compressive strength measured along X, Y, and Z axes of printed concrete, respectively. For the measurement of anisotropy, compressive strength values along each axis have been divided by the compressive strength of casted concrete, so Cx/Cc, Cy/Cc, and Cz/Cc represent anisotropy in compressive strength along X, Y, and Z axes, respectively. A comparison of the compressive strength of printed concrete to that of casted concrete  than the compressive strength of the corresponding casted concrete, but these researchers had used fiber-containing concrete for printing. Therefore, the order for anisotropic behavior in compressive strength of printed concrete (without fibers) could be Cx/Cc = Cy/Cc > Cz/Cc. From the structural performance perspective of a printed concrete structure, load applies along the Z-axis if the printed structure is a wall or a column, whereas, for a printed bench or stairs, load applies along the Y-axis. Hence, structural analysis of these printed concrete structures should be conducted while taking into account the application of loads with respect to the direction of printing, anisotropic behavior, and reduction in the compressive strength produced due to the printing process.concrete  shows thm et al.  and Sultm et al.  had repoc shows flexural strength of casted concrete, Fx, Fy, and Fz show flexural strengths measured along the X, Y, and Z axes of printed concrete, respectively. A critical view of the data plotted in X-axis has been reported lower than the flexural strength of casted concrete. Second, the flexural strength measured along the X-axis has also been reported lower than the flexural strength measured along the Y and Z axes [X-axis. The interface is the weakest point of printed concrete; therefore, it could not resist tensile stresses, and hence, flexural strength along the X-axis is lower. Y-axis has been observed to be higher than that of casted concrete [Z-axis. Some studies have reported it to be lower than the flexural strength of casted concrete [Z-axis than the corresponding flexural strength of casted concrete. The increase in flexural performance of fiber-reinforced printable mixes has been associated with the alignment of the fibers along the printing direction at the extruding nozzle [d Z axes ,183,184.concrete ,179,183 concrete ,180,184 concrete ,183,187.concrete ,127 haveg nozzle . Fibers g nozzle ,188. Alig nozzle .x/Fc, Fy/Fc, and Fz/Fc lie within the range of 0.5–0.7, 1.1–1.2, and 1.0–1.1, respectively, which suggests that higher flexural strength would be expected when the flexural load acts along Y-axis as compared to other two axes specifically X-axis. The order for anisotropic behavior in flexural strength of printed concrete (without fibers) could be Fy/Fc > Fz/Fc > Fx/Fc. Flexural strength is an important consideration for the digital construction of structural beams and bridge decks, and these structures should be designed while taking into account the anisotropic behavior in the flexural performance of printed concrete.c shows the tensile strength of casted concrete and Tx, Ty, Tz show the tensile strengths measured along the X, Y, and Z axes, respectively. It is worth mentioning here that most of these studies have used fiber-reinforced concrete for printing [X-axis for printed fiber-reinforced concrete than casted concrete [X-axis than the tensile strength of corresponding casted concrete due to the orientation of fibers along the printing direction. Whereas for printed concrete without fibers, reduced tensile strength is expected due to the imperfections induced due to the printing process. Further research is required to investigate the anisotropic behavior in tensile strength when measured along the Y and Z axes. Furthermore, concrete printing has been used to manufacture formwork for concrete construction and also for aesthetically appealing household items [Contrary to the compressive and flexural strengths of printed concrete, a few research studies have investigated the tensile strength of printed concrete at more than one axis. printing ,127,186 printing . Additioprinting  used splprinting  and Yu aprinting  tested rconcrete ,61,186. concrete . Based old items ,191. TenX, Y, and Z axes) to the corresponding compressive strengths. X-axis lies within the range of 0.05–0.20. High variance is observed for the ratio of flexural strength to the compressive strength along the Y and Z axes, and the tendency of this ratio lies higher than 0.10, which indicates that printing layers act as laminated layers and increase the flexural strength along Y and Z axes.In this review paper, a comparison of flexural strength with compressive strength has been conducted by dividing flexural strength measured along the three orientations  influence the hardened behavior of 3D-printed concrete. The following subsections discuss the effect of these printing process parameters on the mechanical properties of printed concrete in the light of the previously published research papers.There is a unanimous understanding between the researchers that as the time gap between the layers increases, compressive, flexural, and tensile strengths of 3D-printed concrete decrease. Wolf et al.  tested tPanda et al.  associatThe printing time gap affects bond strength between extruded layers significantly. Therefore, various researchers have attempted to compensate for weak interlayer bonds in the concrete printing process by proposing additional materials and treatments. Marchment et al.  applied Van Der Putten et al.  studied Wolf et al.  printed Traditional reinforcing techniques are not compatible with the concrete 3D-printing process ,202. ResThis method introduces a continuous reinforcing cable into the extruding concrete at the nozzle. A reel on which a reinforcing cable is wound is attached to the print head, and the open end of the reinforcing cable is passed into the nozzle through a hole. Simultaneous extrusion of concrete and reinforcing cable through the nozzle winds off reinforcing cable from the reel attached to the print head and introduces it continuously into the concrete filament. Bos et al.  were theAnother approach is to first print a concrete layer and then insert reinforcing elements into the printed concrete with a device attached to the print head. Perrot et al.  reinforcMarchment and Sanjayan  reinforcThis method involves the horizontal placement of reinforcing bars upon freshly printed layers, followed by printing additional layers over them. Baz et al. printed concrete over the conventional reinforcing steel bar (8 mm) and measured the influence of concrete workability upon the bond strength between steel and printed concrete. Results showed that pull-out strength was not affected by the workability of concrete and the direction of printing . HoweverMechtcherine  proposedThe use of fiber-reinforced concrete and engineered cementitious composites (ECC) into 3D concrete printing is considered an alternative to the above reinforcing strategies. Such cementitious mixes do not need any additional automated setup at the extruding nozzle. Extruding of fiber-containing concrete mix aligns fibers parallel to the printing direction and enhances the mechanical performance. Panda et al.  added 0.In this method, the concrete structure is first printed into various designed segments on a flat surface, and then post-processing techniques such as assembling of segments, passing of reinforcement bars through the holes, post-tensioning, and grouting are used to reinforce the printed segments. Salet et al.  construcThree-dimensionally printed concrete consists of numerous extruded layers that are bonded to each other. The core part of layers has a dense microstructure, but the interface between layers has a porous structure . NerellaAnother problem from the microstructural perspective of 3D-printed concrete is the presence of voids and connected porosity at the reinforcement-cement matrix interface ,230. ThiResearchers have focused more on tailoring the rheology, expediting the printing process of 3DCP as well as enhancement of mechanical properties than investigating the durability performance of printed concrete. A few research groups have studied the durability of 3D-printed concrete, and these research attempts are discussed in the subsections given below.3 higher than the inner bulk material due to its rough and porous nature. NT Build 492 test [−12 m2/s. Weger et al. [The connectivity of the pores at the interface increases the susceptibility of printed to the chloride attack . Van Der492 test  showed tr et al.  observedr et al.  also priLe et al.  observedAssaad et al.  studied 2) until the temperature reached 300 °C. The fire resistance performance of printed concrete was similar to the casted concrete except that heating caused spalling in the casted concrete, but it caused the separation of layers at the interface of printed concrete. The better resistance of printed concrete to spalling can be attributed to its connected porosity and higher permeability compared to the casted concrete. D’Hondt et al. [The heating of 3D-printed concrete to elevated temperatures reduces its mechanical and microstructural performance, similar to casted concrete. Cicione et al.  comparedt et al.  exposed t et al.  investigt et al. .Additional in-depth investigations are required for measuring the durability performance of printed concrete in aggressive environmental conditions. The durability behavior of 3D-printed concrete would be different from conventional concrete due to the use of different mix proportions, high dosage of chemical admixtures, and layer-by-layer construction methods. Consensus on a single geometrical model for the measurement of the buildability of a concrete mix should be developed among researchers and industry practitioners. A standard geometrical model with defined layers width and height, number of layers, radius of curves, printing time gap, nozzle standoff distance, and travel speed should be developed so that buildability test measurements of different concrete types as well as different research groups could be easily compared and transmitted;Most of the test methods for the measurement of concrete extrudability and print quality are empirical and manual. These methods rely on human judgment. Inline test methods for calculating shape retention as well as the measurement of print quality in terms of the number of voids per unit length are required. The pumpability of 3D-printable concrete is less discussed in the literature. Lab-scale printers have used small to medium-sized pumps to transport concrete over shorter distances. In commercial projects, concrete would be pumped to larger distances. Investigation of the changes in concrete rheology while pumping it to larger distances and then extruding it through a contracting nozzle needs detailed investigation;Eco-friendly binders , nanoparticles , and chemical additives are very useful for tuning the rheology of concrete according to the requirements of the printing process;x/Cc = Cy/Cc > Cz/Cc. In other words, higher compressive strength is anticipated when load applies along X or Y axes compared to load application along Z-axis. The above order of compressive strength is not valid for fiber-containing concrete mixes;Compressive strength of printed concrete would be lower than the compressive strength of the corresponding casted concrete mix. The expected order for anisotropic behavior in compressive strength of printed concrete with respect to the casted concrete could be CY-axis could be higher than the flexural strength of corresponding casted concrete, but flexural strength along the X-axis is anticipated to be poor than the flexural strength of casted concrete. The order for anisotropic in flexural strength of printed concrete could be Fy/Fc > Fz/Fc > Fx/Fc. Higher flexural strength is expected when load applies along Y-axis, followed by Z and X axes (except fiber-containing mixes);Flexural strength of printed concrete along the X-axis due to the alignment of fibers along the direction of printing;Inferior tensile strength could be exhibited by printed concrete compared to corresponding casted concrete. However, in the case of using fiber-containing mixes, higher tensile strength is expected for printed concrete when tensile load applies parallel to the X-axis of printed concrete could be 5–10% of its compressive strength along the X-axis. For Y-axis, flexural strength would be more than 10% of the corresponding compressive strength. Better performance is expected along the Z-axis, where flexural strength would be more than 15% of corresponding compressive strength. Our literature survey also showed that for casted printable concrete mixes (without fibers), flexural strength mostly lies within the range of 10–15% of its compressive strength;Flexural strength along the Impact resistance and seismic performance of printed concrete have not been studied yet. These properties need to be studied for printed structures intended for military and industrial purposes or for construction at a seismic zone. Printed concrete is expected to exhibit a different seismic response than conventional casted concrete due to its anisotropic mechanical properties, which need detailed scientific investigation;Among the printing process parameters, the time gap is the more influential parameter to influence the mechanical properties of printed concrete especially interlayer bond strength. Variation of concrete rheology affects interlayer bond strength as well as the bond between steel and concrete;Research is needed for integrating reinforcement provision strategies as a part of the automation system. Additionally, reinforcement requirements for resisting shear, flexural, torsional stresses, and impact loads in 3D-printed concrete structures need investigation;Bond strength between printed concrete and reinforcement is reduced as compared to bond strength between casted concrete and reinforcing steel. The porous microstructure can develop at the interface of reinforcements and 3D-printed concrete. Densifying this interface as well as improving the bond strength between printed concrete and reinforcement is required;Porosity is high at the interface of layers, and at the reinforcement-concrete interface, pores at these interfaces can be connected, which can increase the permeability of printed concrete for aggressive ions. Reducing the porosity of printed concrete to improve its impermeability is a research issue. The higher content of binder used in concrete printing and the absence of the proper curing environment can exaggerate the shrinkage cracks, which can negatively affect the durability performance of concrete. The influence of rheology, printing process parameters, porosity, and shrinkage cracks on the durability performance of printed concrete in terms of alkali-silica reaction, delayed ettringite formation, sulfate, chloride, frost attacks, carbonation, and steel corrosion need investigation;Reinforcement attempts such as the introduction of the steel cable into the concrete filament at the printer nozzle and insertion/stapling of steel in printed concrete creates pores around the steel. These reinforcement methods need further development to simultaneously reinforce the concrete and create a dense interface with the printed concrete;Existing durability test methods are designed for casted concrete that has isotropic properties. On the contrary, printed concrete has anisotropic porosity properties. Research is required for the transport mode of aggressive ions into printed concrete and the development of new test methods for the durability behavior of printed concrete. Performance-based standards should be developed to design and print durable 3D-printed concrete structures.This paper critically reviews the latest research on the emerging 3D concrete printing from the standpoint of concrete materials. Unique rheological requirements of the concrete printing method, compatible concrete mix designs for printing, and the effect of eco-friendly binders, aggregates, chemical admixtures, and nanomaterials on the concrete rheology are discussed to help engineers and researchers recognize concrete printing procedures and develop their own mix proportions for this process. This paper gives special attention to the mechanical properties of 3D-printed concrete. It evaluates the anisotropy in compressive, flexural, tensile strengths and the effect of printing process parameters upon mechanical properties. Additionally, this paper also covers the latest research attempts aimed at improving the hardened properties of printed concrete and also discusses the durability performance of 3D-printed concrete in aggressive environments. The following concluding points and research needs are identified from this review work:


Heroin dependency has become a global problem and has caused significant clinical and socioeconomic burdens along with devastating medical consequences. Chronic drug exposure alters the expression and functional activity of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) in the brain. Furthermore, pharmacological blockade of 5-HT2ARs reduces cue-induced cocaine craving behaviors. In this study, we explored the influence of 5-HT2ARs on heroin-withdrawal behaviors in mice. Black C57BL/6J mice were given gradually increasing (10–50 mg/kg over 4.5 days) doses of heroin to induce heroin dependency, after which naloxone was given to precipitate withdrawal symptoms. MDL100907, a selective and potent 5-HT2AR antagonist, attenuated naloxone-precipitated withdrawal symptoms in these mice. In addition, 5-HT2AR protein levels increased significantly in the medial prefrontal cortex (mPFC), while phosphorylation of extracellular signal-regulated kinase (p-ERK) decreased in the mPFC after heroin exposure. In conclusion, these results suggest that 5-HT2ARs might be involved in the development of opioid dependency and that pharmacological blocking of 5-HT2ARs might be a new therapeutic strategy for heroin dependency. Diacetylmorphine (heroin) is one of the most addictive drugs. Heroin use disorders have become a global problem and have caused significant clinical and socioeconomic burdens along with devastating medical consequences. As a morphine derivative, heroin has a high-addictive potency. Once it enters the brain, heroin is rapidly hydrolyzed to 6-acetylmorphine and morphine by serum cholinesterase, which then binds with opioid receptors to activate dopaminergic neurons . Heroin Heroin addiction is increasing, especially in adolescents and young adults . Rehabilq/11, which contributes to inositol 1,4,5-triphosphate and 1,2-diacylglycerol accumulation, intracellular Ca2+ release, and protein kinase C activation  neurotransmitters. The 5-HT receptors modulate drug-addictive behaviors. For example, activation of 5-HT 2C receptors (5-HT2CRs) inhibits behavioral sensitization and drug dependency in heroin-treated mice . 5-Hydrotivation ,b.5-Hydroxytryptamine (serotonin) 2A receptors regulate neuropsychological functions  and haveIn this study, we aimed to investigate the impacts of 5-HT2AR antagonists on heroin-withdrawal symptoms in mice. We showed that the selective 5-HT2AR antagonist, MDL100907 (volinanserin), significantly inhibits heroin-induced abnormal motor activities and withdrawal behavior in male mice.ad libitum access to water and food under a controlled temperature (23 ± 1°C) and 12-h light/dark cycle (dark phase 7:00 p.m. to 7:00 a.m.). Only male mice were used in this study to avoid the effects of the female estrous cycle on behavioral parameters. All animal procedures followed the National Institutes of Health guidelines for the care and use of research rodents, and the Institutional Animal Care and Use Committee reviewed and approved the study protocol.Male C57BL/6J adult mice, aged 8–12 weeks old [license # SCXY (Su) 2011-0003] and weighing 20 ± 2 g, were purchased from Cavion . Mice were housed in groups of four in 29 cm × 18 cm × 12 cm polycarbonate cages with Heroin was provided by the Anhui provincial public security department . MDL100907  was purcNaloxone and saline were purchased from The First Affiliated Hospital of Anhui University of Science and Technology . The time points of MDL100907 treatment were determined based on a previously published report , and dosFor immunoblotting, we used anti-5-HT2AR  and anti-phospho-ERK1/2  primary antibodies and a horseradish peroxidase (HRP)-conjugated anti-rabbit IgG secondary antibody . Protein was quantified using a bicinchoninic acid (BCA) assay kit provided by the Beyotime Institute of Biotechnology .The open-field test was conducted as described elsewhere . Brieflyn = 8–18 per group), which received either placebo , M100907 (0.03 mg/kg), or naloxone (5 mg/kg) at designated time points. Behaviors were monitored for 60 min to evaluate drug-induced behavioral changes. The Noldus PhenoTyper system could accurately calculate the horizontal distance traveled, but not fine behaviors. For example, the system could not distinguish between the head and tail when detecting the direction of movement. Behaviors were monitored with video monitoring  and manual scores .Naïve mice were randomly distributed into three groups  from 10 to 50 mg/kg by day 5. On day 5, mice were injected with saline or MDL100907 at 8:00 a.m. Thirty minutes later, mice were injected with 50 mg/kg of heroin or placebo. After 2 h, naloxone was administered to control withdrawal symptoms, including jumping . The nalg, 10 min). The supernatant containing total protein was transferred to a new Eppendorf tube, and the protein concentration was determined using a BCA protein detection kit. The protein samples were resolved on a 10% SDS-polyacrylamide gel by electrophoresis and transferred to a polyvinylidene fluoride membrane. The membranes were blocked with non-fat-skimmed milk (5% w/v) and washed with Tris-buffered saline with 0.1% v/v Tween-20, then probed with primary antibody (1:100) overnight at 4°C, followed by the HRP-conjugated secondary antibody at 1:10,000 dilution for 1.5 h. Protein bands were displayed with enhanced chemiluminescence substrates (Thermo Fisher Scientific Inc.) and captured using a ChemiDoc™ XRS+ imaging system . The density of the protein bands was quantified  using ImageJ software (NIH). Density measurements for 5-HT2AR were normalized to the internal control β-actin , a post hoc Dunnett’s test or Bonferroni multiple comparison was conducted.Statistical differences in total distance traveled and duration of immobility were analyzed using two-way repeated-measures ANOVA. All data are expressed as mean ± SEM. One-way ANOVA and Student’s F = 5.457, p = 0.0010; F = 6.238, p < 0.001] and also on the 5-min time bin ; however, there was no significant effect on the treatment × time bin interaction  but also on the time × treatment interaction . Injection of 0.3 mg/kg MDL100907 did not affect locomotor activity, so 0.03 mg/kg MDL100907 was administered subcutaneously to heroin-treated mice. We also tested whether MDL100907 affected activity/immobility in the absence of naloxone and found no difference between MDL100907 alone and control (data not shown).Next, we measured the immobility duration for 1 h . The p-ERK/ERK ratio in mPFC tissue  was lower in heroin-treated mice than in saline-treated mice  in the medial prefrontal cortex (mPFC) were quantified by Western blotting. Heroin exposure correlated positively with 5-HT2AR expression [ted mice .People who have experienced heroin dependence are vulnerable to relapses even years into abstinence . ImpulsiWe found that the 5-HT2AR antagonist MDL100907 alleviates naloxone-induced precipitated withdrawal symptoms in heroin-exposed mice. Lower doses of MDL100907 did not affect baseline motor activity, whereas higher doses inhibited heroin-withdrawal symptoms. In line with these findings, another study showed that higher doses of MDL100907 reduce nicotine-withdrawal symptoms in rats . PreviouThe heroin-withdrawal symptoms might be caused by increased long-lasting responses of neurons innervating the nucleus accumbens, dopaminergic neurons in the ventral tegmental area (VTA), and glutamatergic neurons in the PFC and basolateral amygdala . This suImmunoblot analysis revealed that 5-HT2AR expression was upregulated in PFC tissue from heroin-dependent mice. The PFC is a key brain region associated with opioid addictive behavior, so the increased 5-HT2AR expression we observed suggests a crucial link to neural adaptation upon heroin exposure. However, the functional significance of 5-HT2AR overexpression in heroin addiction remains elusive. Elucidating the subcellular distribution and receptor signal transduction of 5-HT2AR will help understand the regulatory mechanisms of heroin dependence. Interestingly, we observed reduced ERK phosphorylation in PFC tissue from heroin-dependent mice, although 5-HT2AR activation upregulates p-ERK1/2 expression. Heroin triggers multiple cellular signaling cascades and, together with its metabolites, can have diverse effects in different brain regions, neural networks, and cell types. This variability might explain the inconsistency between the heroin-mediated increase in 5-HT2AR expression and reduced p-ERK accumulation we observed. It was recently reported that morphine also downregulates p-ERK/ERK. This effect was induced by the D1R–ERK–CREB pathway in the mPFC, and the D1R antagonist SCH-23390 reversed morphine-induced attention dysfunction and morphine-withdrawal symptoms in mice .The 5-HT2AR-mediated heroin withdrawal may involve dopamine neurotransmission. 5-HT2ARs control dopamine outflow to augment dopamine synthesis and excitation . HoweverTaken together, our data have shown that naloxone-induced heroin-withdrawal symptoms can be attenuated by MDL100907. Acute heroin addiction increased 5-HT2AR expression in the PFC, suggesting that 5-HT2AR might be an efficient therapeutic target for treating heroin use disorders.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC).GP and XT conceived and designed the study. BL, JJ, LZ, QS, JL, and YL conducted the experiments, collected the data, and prepared the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In recent years, the use of self-compacting concrete has been a great advantage and garnered undoubted interest in construction. Due to the environmental impact caused by the consumption of natural aggregates in the manufacture of concrete, a more sustainable approach is needed. An approach for more sustainable construction is to use industrial waste such as bottom ash from the combustion of biomass as a replacement for natural aggregates. This research aims to use biomass bottom ash as a replacement for natural sand ; in addition, by utilizing a crushing process of the bottom ash, the ash has been used as a filler replacement . The fresh and hardened properties have been evaluated according to the standard. The results show the feasibility of using biomass bottom ash in self-compacting concrete, providing a sustainable alternative in order to minimise environmental impacts related to the extraction and depletion of natural resources. One of the most significant advances in the construction industry has been the development of self-compacting concrete (SCC), also called high-performance concrete by some authors. This type of concrete is known for its excellent deformability and resistance to segregation. It is a type of fluid concrete that does not need to be vibrated or compacted during the pouring process . Many coConcrete, in general, has undergone great changes in its dosage to achieve better strengths and obtain better durability. To this end, many studies have included materials such as fly ash ,6, fly aAlthough it has been developed with the aim of not needing vibration or compaction, SCC is a recent type of concrete that achieves greater resistance to compression and better durability compared to traditional concrete  mainly dMore and more industries related to concrete manufacturing are trying to apply more efficient technologies by optimising existing resources. For a few years, industrial waste of different types has been used after an exhaustive study of its properties for the manufacture of more sustainable concrete for the environment.Bignozzi and Sandrolini  demonstrMany studies with industrial waste focus on the use of recycled aggregates from construction and demolition waste. González-Taboada et al.  used recHowever, other industrial wastes have not been studied much in the manufacture of SCC, as in the case of ash from biomass combustion. Currently, biomass combustion for electricity generation accounts for 45% of renewable energy in Spain, generating a volume of residue of 120,000 tons/year , of whicIn this context, this research aims to study the mechanical behaviour of self-compacting recycled concrete that incorporates BBA in the replacement of natural sand and crushed BBA as a replacement for natural filler and to determine the effect of its incorporation on its properties in fresh and hardened states. The results obtained can be very significant, both from the point of view of science, which currently does not have much literature, as well as for its practical use due to the reduction in waste, reduction in consumption of natural aggregates and environmental benefits in its application in this type of recycled concrete.The materials that have been used for this type of concrete are those commonly used by companies that produce SCC.Ordinary Portland Cement (OPC) type I with medium-high resistance 42.5 MPa at 28 days with high initial resistance R was used (CEM I 42.5-R) according to ASTM C150. Its high initial resistance performance renders it suitable for the manufacture of SCC. As a cement belonging to the CEM I type, it is ideal for the manufacture of precast and prestressed, obtaining high resistance values. The composition is shown in 3. Its grain size is shown in 2/g.The filler used is a crushed material of a limestone-dolomitic nature supplied by the company “Triturados Puerto Blanco” in Huétor-Santillán , and its density is 2.830 kg/mThe sand is of a limestone-dolomitic nature and is practically free of fines. It comes from the El Rayo quarry, Hermanos Guerrero, Loja .The aggregates used in the manufacture of concrete have a maximum size of 16 mm, the main properties are shown in This is the coarse fraction produced in the primary combustion chamber due to incomplete combustion (decrease in the melting point) and is made up of most of the mineral fraction of the original biomass . The BBAThe fuel supply of the biomass used for the generation of electricity is made up of approximately 40% olive cake and 60% biomass of wood . The BBAs were processed in the laboratory to obtain two different materials used in the manufacture of SCC: BBA (biomass bottom ash kiln-dried for 24 h and sieved with a particle size no larger than 5 mm) and BBA-C . The physical and chemical properties of BBA are presented in The physical and chemical characteristics of BBA depend on the types and the different burned biomass used as fuel, in addition to the technology used in the electricity generation plant by burning biomass ,32.3, respectively). Both parameters are important in the design of mixtures, where the presence of water and the volume of the material are conditioning factors for its manufacture [An important factor in the physical properties of BBAs is their high absorption and low density  of the ash mass. In addition to calcium, BBA is characterised by the relatively high content of potassium (14.06% by weight), the presence of which resulted from the initial content of nutrient ingredients in the olive wood trimmings, in accordance with previous studies .The particle size distribution of the BBA is shown in The most important condition that must be considered in order to carry out the dosing of a self-compacting concrete is to provide a sufficient quantity of the set consisting of “cement + water + fines of less than 0.125 mm content in the aggregates” to achieve self-compacting characteristics.Two series of dosages were carried out. The first series replaced filler with crushed biomass bottom ash (BBA-C) with a replacement of 20%, 40% and 60%, respectively, and the second series replaced natural sand with BBA  without any processing. The additive used was MasterGlenium ACE 325 manufactured by BASF. Dosages are shown in All the mixtures that underwent the tests indicated the current regulations (EHE-08) for the characterisation of self-compatibility: slump flow, according to EN 12350-8; V-funnel according to EN 12350-9; J-Ring according to EN 12350-12; and L-Box test according to EN 12350-10.Slump flow: This is the simplest and most widely used method due to the simplicity of the equipment required. The value of the flow extension (Df) is useful for evaluating the deformation capacity of self-compacting concrete. Df measurements resulting between 60 and 80 cm are recommended, presenting mixtures in that range with good ability or ease for filling, according to EFNARC, 2002 .J-Ring: This determines the ability of self-compacting concrete to flow through narrow openings, including gaps between trusses and other obstructions without segregation or blockage. After flow ceases, the final extension diameter is measured as the mean of two perpendicular diameters.L-Box: This consists of a vertical tank that connects to a horizontal channel through an opening in which reinforcement bars are placed. The test involves filling the reservoir and allowing concrete to flow into the channel through the trusses. The time taken for the concrete to reach a distance of 200 mm (T20) and 400 mm (T40) is determined, and the heights H1 and H2 are reached at both ends of the horizontal part, with the mixture already at rest. The H2/H1 ratio is defined as the blocking coefficient (Cb).V-funnel: This test evaluates the ability of concrete to flow in restricted areas in a vertical direction and under its own weight, qualifying the tendency with respect to segregation and blocking, by observing the variation in flow velocity.The compressive strength was determined on 100 mm × 100 mm cubic samples for ages 7, 28, 90 and 256 days according to EN 12390-3: 2019. The use of industrial by-products as a substitute for the fine fraction directly affects simple compressive strength . Some auIn this work, ranges of 20%, 40% and 60% substitution of limestone filler by BBA-C (Series 1) and 10%, 20% and 30% substitution of natural sand (Series 2) were proposed.The best compressive strength results were shown for Series 1 where lime filler was replaced by BBA-C, which is essential to avoid SCC segregation.The analysis of the 28 day compressive strength showed a reduction in all mixes combined with biomass bottom ash, a result also observed by Mehta and Monteiro and Rosales et al. ,41 HowevThis test was carried out by subjecting a 150 × 300 mm cylindrical specimen cured in a humid chamber for diametric compression for 28 days in accordance with EN 12390-6: 2009. A load was applied evenly along two opposite lines until breakage was achieved. This load causes a relatively uniform tensile stress throughout the diameter of the vertical load plane, and this tension is the one that exhausts the specimen and triggers the break in the diametral plane. The values obtained are shown in The modulus of elasticity of concrete represents the stiffness of this material when faced with a load imposed on it. The test for the determination of the static modulus of elasticity of concrete is carried out by means of the EN 12390-13: 2014 Standard and has as its principle the application of static load and the corresponding produced unit deformation.The first phase (elastic zone) applied a stress of 30% of the compressive strength obtained in the previously described test. In the second phase (curved line), the concrete specimen is submitted to breakage according to the regulations. The results are shown in Regarding the tensile splitting strength, the trend of the experimental data tends to guarantee the existing relationship between compression and traction in concrete. Tensile splitting strength values were observed in the concrete representing approximately 10–15% of the results obtained for compressive strength.In order to observe the relationship between tensile splitting strength and the modulus of elasticity, a trend is proposed which aims to observe the behaviour of these two variables .The modulus of elasticity ranged from 42.01 GPa to 31.77 GPa for Series 1 and between 35.43 GPa and 28.54 GPa for Series 2. These results demonstrate that the manufactured concrete can be suitable for many structural applications, even for structures with demanding limitations regarding serviceability limit states  [The density and absorption percentage were determined in specimens of hardened SCC. Each series was subjected to a cycle of immersion in water for 24 h and subsequently to oven drying between 105 °C and 110 °C for 24 h. With this procedure, the apparent mass in the water, the saturated mass with a dry surface and the dry mass are obtained, and the density and supply are obtained with these data in accordance with the EN 12390-7: 2019 standard (Testing hardened concrete—Part 7: Density of hardened concrete). The test results are shown in The results show how the incorporation of BBA decreases density and increases absorption in all the mixtures . DensityThe depth of water penetration under pressure was determined in 150 × 300 mm cylindrical specimens cured in a humidity chamber for 28 days. The water was applied under pressure of 500 kPa for 72 h. Subsequently, the test piece was divided by breaking it into two halves, and the penetration of the waterfront was recorded in accordance with the EN 12390-8:2019 standard. The results are shown in Structural Concrete Instruction (EHE08) uses the determination of water penetration depth as a verifier that the concrete has sufficient impermeability to ensure durability during the service life of the structure.The limits of the Structural Concrete Instruction are set at 50 mm for maximum depth and 30 mm for the average depth in mass or reinforced concrete.As shown in 2 with concrete portlandite. In order to know the degree of carbonation, the specimens were subjected to a CO2 saturated environment according to UNE 112011:2011 . To carry out the test, a piece of concrete was broken from each of the specimens, then the phenolphthalein solution was applied to the concrete. A colour change (pink) on the application surface will indicate that the concrete is not carbonated. If the colouration does not occur, it means that it is an area that is already carbonated.Carbonation is a process of chemical origin that consists of the combination of CO2 penetrates through the capillary pore network reacting with the moisture present and converting calcium hydroxide (high pH) to carbonates, which are neutral, reducing the alkalinity of the concrete. From a physical point of view, the carbonation of concrete depends directly on the porosity and permeability of the concrete, as well as the environmental conditions to which it is exposed [2 with the Ca(OH)2 formed during cement hydration. From a chemical point of view, the carbonation of concrete produces a decrease in pH, which occurs when CO exposed . Most caThis study has evaluated the properties of biomass bottom ash with different treatments applied and the influence that its use has on the mechanical and durability properties in the manufacture of self-compacting concrete.-3, respectively). Both parameters are important in the design of mixtures where the presence of water and the volume of material is a conditioning factor for its manufacture.An important factor in the physical properties of BBAs is their high absorption and low density (19.83% and 1.73 g/cm-2O in cementitious materials can reduce durability due to deterioration of the microstructure. However, the Si/Ca values of the mixture provide increased mechanical strength due to their pozzolanic character.The presence of K-In relation to the mechanical properties, compressive strength, tensile splitting strength and modulus of elasticity are reduced for all mixes combined with biomass bottom ash. However, the mixtures combined with biomass bottom ash still gain 17–30% in long-term compressive strength compared to the control mixtures.-In terms of durability parameters, water penetration under pressure is higher when biomass bottom ash is incorporated with sand due to the larger particle size and high porosity of the mixture.-The depth of carbonation of concrete depends on many variables, and the most important ones are porosity and permeability. Mixtures with higher porosity and permeability are also those with higher carbonation.The following conclusions were obtained:In conclusion, the use of self-compacting concretes with the substitution of up to 30% of natural sand by screened BBA and up to 60% of filler by crushed BBA is recommended for use in civil infrastructure works. The valorisation of biomass bottom ash instead of exploiting natural or non-renewable resources can eliminate the negative impact associated with indiscriminate disposal of this by-product in landfills.


Major salivary gland  and lacrimal gland (dacryoadenitis) involvement can be a common feature of IgG4-related disease. There can be involvement of lacrimal and parotid gland which was previously called as Mikulicz disease and/or submandibular gland enlargement which was previously called Küttner tumour. These were previously mistakenly considered to be subcategories of Sjogren’s syndrome, but are now classified as IgG4-related disease. Here we discuss a case report of a patient who presented with bilateral dacryoadenitis and unilateral submandibular gland enlargement which initially was thought to be IgG4-related disease but turned out to be low-grade lymphoma.A 15-year-old boy presented with 6-month history of bilateral eyelid swelling. The swelling was more on the lateral side of the eyelids and was painless. It had come on suddenly over a couple of days. No history of weight loss, dry eyes, dry mouth, joint issues or skin rashes or any other symptoms. Physical examination revealed bilateral ptosis, no visual impairment and systemic examination revealed an enlarged right submandibular gland. He had initially been to a local hospital where he had investigations which included autoimmune screen including ANA, ENA, ANCA, dsDNA, serum ace and complement levels which were all negative. C1 esterase inhibitor was normal. Routine bloods including complete blood count, urea and electrolytes, thyroid stimulating hormone and erythrocyte sedimentation rate were within normal limits. Urine albumin to creatinine ratio was not raised. Hepatitis serology including Hepatitis B & C and HIV was negative. Ultrasound abdomen was unremarkable. CT scan of orbits showed bilateral enlarged lacrimal glands with patchy post contrast enhancement and the glands extending up to insertion of lateral rectus muscle. CT chest some enlarged axillary lymph nodes and nodes in lung query infective etiology. CT abdomen and pelvis was unremarkable. Ultrasound neck showed right submandibular node enlargement with colour doppler showing increased vascularity. Fine needle aspirate of the submandibular gland showed reactive lymphoid hyperplasia. He was given two short courses of steroids and each time the swelling rapidly responded to the steroids but recurred on cessation of the steroids. IgG subset analyses revealed elevated IgG4 levels of 1152mg/dl. The differential here was IgG4-related disease but as there was no clear tissue diagnosis a core biopsy of the right submandibular gland was done. This revealed tissue suspicious of low grade  lymphoma and excision biopsy was performed for definitive diagnosis.IgG4-related disease is an immune mediated fibroinflammatory condition which can affect a variety of organs and can present as tumour-like enlargement and/or organ dysfunction. The pathological findings in IgG4-related disease are lymphoplasmocytic infiltrates of IgG4-positive cells along with increased levels of serum IgG4 levels. Salivary and lacrimal glands can be commonly affected and present as enlargement, which is usually painless and bilateral. The combination of lacrimal gland enlargement with both parotid and submandibular gland enlargement is called IgG4-related Mikulicz disease.Apart from salivary glands, another commonly affected organ is the pancreas which can present as a pancreatic mass and painless jaundice, sclerosing cholangitis, retroperitoneal fibrosis, aortitis and periaortitis. Less commonly it can affect thyroid, kidney and lungs.Early recognition, diagnoses and treatment is important due to the fibroinflammatory nature of the disease. Malignancy is always in the differential and should be excluded. Steroids are the mainstay of treatment. If patients experience flare, rituximab can be added.Diagnosis should be confirmed with biopsy but histopathological findings are never alone diagnostic of IgG4-related disease and should be interpreted with clinical, serological and radiological findings.Although this patient had typical presentation of IgG4-related disease with painless enlargement of salivary and lacrimal glands and elevated IgG4 serum levels, biopsy was imperative to get to the diagnoses of low-grade lymphoma and fine needle aspirate was not adequate. As mentioned above, biopsy in IgG4-related disease will confirm the diagnosis provided there are other supporting features . However, it is imperative for excluding other important diseases like lymphoproliferative disorders.


N = 3113). Among antibiotic prescriptions, J01FA Macrolides were the most used . The Watch group constituted 89.0% (N = 2818) of total antibiotic use. Bronchitis  was the most common diagnosis. A total of 292 instances of irrational antibiotic use were identified, with inappropriate prescriptions being the most prevalent subtype . (4) Conclusion: Although APR for children in PHIs in Beijing was relatively low, the pattern of antibiotic use differed from other countries. Further studies are needed to optimize antibiotic use for children in PHIs under different levels of economic development.(1) Background: Few studies have focused on antibiotic use and appropriateness in children in primary health institutions (PHIs). This study aimed to identify the patterns and appropriateness of antibiotic use for children in PHIs in Beijing, China. (2) Methods: Outpatient prescriptions of 327 PHIs from 2017 to 2019 for patients <18 years old were collected. Prescriptions were described using quantity indicators. Antibiotics were categorized according to ATC classification J01 and Access, Watch, Reserve grouping. Appropriateness was reviewed by experts using three subtypes of irrational prescriptions . (3) Results: 20,618 prescriptions were collected in total. The antibiotic prescription rate (APR) was 15.1% ( Escherichia coli in China (CTX/CRO-R ECO) isolated from children and newborns in 2019 were 38.8% and 10.1%, respectively, which were higher than those from adults (28.8%) [The selection pressure of antibiotics, driven by inappropriate antibiotic prescribing, generates antimicrobial resistance ,2. The d (28.8%) . ApproprChina is among the largest consumers of antibiotics worldwide and has taken many measures to strengthen antimicrobials management ,7,8,9. HBeijing is the capital city of China and enjoys a high level of health system management. The Beijing Municipal Health Commission has made great efforts to promote rational antibiotic use in PHIs, including establishing a Prescription Review and Feedback (PRF) system. The PRF, one of the interventions to promote rational antibiotic use, was first introduced in PHIs in Beijing in 2014 . StudiesN = 1,809,616) extracted from 327 reporting PHIs of the Beijing Prescription Reviewing System of Community Healthcare Institutions (BPRSCHI) included in the study, a total of 20,618 prescriptions (1.6%) for children were extracted during the study period, among which 3113 prescriptions (15.1%) contained antibiotics. Among all antibiotic prescriptions, antibiotic combination prescriptions and prescriptions with antibiotic injections accounted for 1.6% (N = 50) and 8.6% (N = 269), respectively. Antibiotic prescriptions that were reviewed and rated as irrational accounted for 9.2% (N = 286) of all antibiotic prescriptions. The antibiotic prescription rate (APR) for children demonstrated a downward trend from 17.9% (N = 995) in 2017 to 13.9% (N = 1447) in 2019. The irrational antibiotic prescription rate showed a more substantial decrease from 14.0% (N = 139) to 4.8% (N = 69) during the study period.The selected indicators of all the sample prescriptions are described in N = 1068, 34.9%), followed by J01DC second-generation cephalosporins , and J01DD third-generation cephalosporins  , followed by the Access group of antibiotics . The Reserve group  and Not Recommend group of antibiotics  were barely prescribed , followed by pharyngitis , bronchitis , and common cold . Bronchitis  was the most common diagnosis among commonly seen infectious conditions, as shown in Among all antibiotic prescriptions for children, J01FA Macrolides was the most commonly prescribed antibiotics  A. When uescribed B. TonsilN = 286) were determined as irrational, amounting to a total of 292 incidences of inappropriate antibiotic use. When divided by types (see N = 233), followed by irregular prescriptions , and no prescriptions were reviewed as abnormal. Among the subtypes of inappropriate prescriptions, prescriptions with inappropriate usage and dosage , inappropriate indication , and inappropriate route of administration  were most commonly mentioned. Among the subtypes of irregular prescriptions, non-conformity with the National Regulations on the Clinical Application of Antibiotics , prescribing without a clinical diagnosis or with an incomplete clinical diagnosis , and unspecified date of birth for infants and newborns  ranked as the top three.As demonstrated in In this cross-sectional observational study, we identified the patterns of antibiotic use and evaluated the appropriateness of antibiotic prescriptions of PHIs in Beijing, China. We found that the pediatric antibiotic prescribing rate in PHIs in Beijing (15.1%) was lower than that in France 26.1%) , Austral.1% , AusJ01FA Macrolides were the most prescribed antibiotics in our study sample. This finding illustrated a difference in antibiotic utilization patterns between communities in Beijing and in other developed countries. In Europe, the most consumed antibiotics in community settings in 2019 were penicillins across all countries but Slovakia, with the proportion ranging from 27% (Slovakia) to 66% (Denmark) of the total antibiotic consumption . In BeijDespite the relatively low APR for children compared with other countries and the decreasing rate of inappropriate antibiotic use, our results suggest that control measures of antibiotic use await further improvements. Our results showed that 28.1% of the prescriptions for bronchitis and 11.2% of the prescriptions for the common cold contained antibiotics. Since antibiotics are not indicated in these two syndromes, and the sample prescriptions were collected based on a reporting mechanism, the inappropriateness may be underestimated. Besides, the Watch group antibiotics were the most prescribed antibiotics for children in our study. There is still a large gap in the utilization of the Access group antibiotics, which is recommended by the WHO to account for at least 60% of total antibiotic use by 2023 . AnotherN = 2057).Our study has several limitations. First, the information of medical history, secondary diagnosis, and pathogenic examination could not be retrieved by the reviewers from the BPRSCHI database, which might introduce bias to the results in the reviewing process. Second, because the prescription-reviewing process was conducted based on prescription per visit instead of per patient, the linkage between prescriptions and patients was not accessible. Nonetheless, the analysis based on prescriptions was accurate enough to reflect the patterns in antibiotic use for children in PHIs. Third, although most of the community healthcare centers (CHCs) were included in the BPRSCHI database, the selection of PHIs could introduce selection bias due to the imbalanced distribution of CHCs and community healthcare stations (CHSs) in the sample PHIs. Fourth, the study sample may not be fully representative of the general child population in Beijing as parents might prefer to seek care at higher-level medical institutions instead of PHIs, potentially leading to overestimated results in this study. Fifth, socioeconomic information on the doctors, which could affect prescribing behaviors , was notWe conducted a cross-sectional observational study to quantify the pattern and appropriateness of antibiotic prescriptions for children in 327 PHIs in Beijing from January 2017 to December 2019.As the capital of China, Beijing had 21.5 million residents (12.6% of whom were aged under 19) and 2075 PHIs (including 345 CHCs and 1730 CHSs) with 68.3 million visits in 2019 . PHIs are designed to be the first level of contact of patients with the national health system. All PHIs in Beijing are outpatient clinics with very little inpatient capacity , providing basic outpatient clinical care and public health services to individuals and families residing in the community.All reported prescriptions from the sample PHIs  were extracted from the Beijing Prescription Reviewing System of Community Healthcare Institutions (BPRSCHI) database. BPRSCHI was established by Beijing Health Commission in 2014 for routine online prescription reviews of the sample prescriptions that are reported to the database. The selection of PHIs in BPRSCHI is based on a convenience sampling method while considering the geographical representativeness of the city. The BPRSCHI database covered 327 PHIs; most of them were community health centers (321 out of 345) during 2017–2019. A sampling software is embedded in the information system of all PHIs. A total of 100 prescriptions were randomly selected from each PHI monthly using a systematic sampling method, with the sampling interval calculated by dividing the number of total prescriptions by 100.N = 1,809,616) from January 2017 to December 2019 were extracted. We selected the prescriptions for children for further analysis. We derived data on prescription code, area text, prescribing date, age, gender, medical insurance status, diagnoses, medication, specification, dosage, administration route, and the result of the reviewing process given by the BPRSCHI review team. Electronic prescriptions were digitally transferred from the database and were double-checked by our researchers. The selection of the antibiotic prescriptions for children is shown in All prescription data in BPRSCHI .In this study, children were defined as patients under 18 years old. A prescription was defined as all the medicines prescribed to a patient during one visit. Antibiotic prescriptions were defined as the prescriptions that contained at least one antibiotic according to Anatomical Therapeutic and Chemical (ATC) classification J01 . Due to The prescriptions for children were described using the following indicators. The percentage of antibiotic-containing prescriptions was calculated by dividing the number of prescriptions that contained at least one antibiotic by the total number of prescriptions. The percentage of antibiotic combination prescriptions was calculated by dividing the number of prescriptions with more than one antibiotic by the total number of antibiotic prescriptions. The percentage of prescriptions with antibiotic injections was calculated by dividing the number of prescriptions that contained at least one antibiotic injection by the total number of antibiotic prescriptions. The percentage of irrational antibiotic prescriptions was calculated by dividing the number of prescriptions reviewed as irrational by the total number of antibiotic prescriptions.We described the patterns of antibiotic use by calculating the proportion of the antibiotic prescriptions, classified according to Anatomical Therapeutic and Chemical (ATC) classification J01 . We alsoWe analyzed the appropriateness of the antibiotic prescriptions by the result of the reviewing process. According to “Regulation Standard for Hospital Prescription Review” issued by the Chinese Ministry of Health in 2010 , the PRFIn light of the “Regulation Standard for Hospital Prescription Review”, an irrational prescription is a prescription with inferior quality in writing or with inappropriate use of medications  compared with relevant law and technical specifications. An irrational prescription could be categorized as one of the following subtypes based on whether the use of antibiotics adheres to standards: irregular prescription, inappropriate prescription, and abnormal prescription based on different types of mistakes or inappropriateness of the prescription. Irregular prescriptions refer to prescriptions with unclear, non-standard, ambiguous, or missing components of a standard prescription. Inappropriate prescriptions refer to prescriptions with unreasonable conditions in drug selection, indications, usage and dosage, drug interaction, etc. Abnormal prescriptions refer to the choice of drug use beyond the general principles of drug therapy or the lack of justification of prescriptions. The detailed criteria of these three subtypes of irrational prescriptions are shown in Descriptive statistics were reported throughout. Statistical analysis was performed using STATA V.15.1  and Excel 2016.Ethics committee approval was obtained from Peking University Institution Review Board (IRB00001052-21048). Patient consent was waived because no contact with patients was conducted and patient anonymity was assured.This study described the patterns in antibiotic use among children in PHIs in Beijing. Although a relatively low level of antibiotic utilization was found, the fact of an extremely high proportion of Watch group prescriptions raises concerns of potential inappropriateness. Besides that, the patterns in PHIs in Beijing differ significantly from settings with comparable levels of economic development. To combat drug resistance and irrational use of antibiotics in children, more research should focus on the use of antibiotics in children in primary care settings and its influencing factors in areas with different economic levels in order to optimize the use of antibiotics in children at the primary level and curb the occurrence of drug resistance in children.


To study antibiotic prescriptions among 0- to 4-year-old children before and after implementing a quality project on prudent prescribing of antibiotics in primary healthcare in the capital region of Iceland.An observational, descriptive, retrospective study using quantitative methodology.Primary healthcare in the Reykjavik area with a total population of approximately 220,000.A total of 6420 children 0–4 years of age presenting at the primary healthcare centres in the metropolitan area over three years from 2016 to 2018.Reduction of antibiotic prescriptions and change in antibiotic profile. Data on antibiotic prescriptions for children 0–4 years of age was obtained from the medical records. Out-of-hours prescriptions were not included in the database.p < 0.0001.The number of prescriptions during the study period ranged from 263.6 to 289.6 prescriptions/1000 inhabitants/year. A reduction of 9% in the total number of prescriptions between 2017–2018 was observed. More than half of all prescriptions were for otitis media, followed by pneumonia and skin infections. Amoxicillin accounted for over half of all prescriptions, increasing between 2016 and 2018 by 51.3%. During this period, the prescribing of co-amoxiclav and macrolides decreased by 52.3% and 40.7%, respectively. These changes were significant in all cases, A substantial proportion of antibiotic prescribing can be considered inappropriate and the antibiotic prescription rate is highest in Iceland of the Nordic countries.After implementing guidance on the treatment of common infections together with feedback on antibiotic prescribing, a decrease in the total number of prescriptions accompanied by a shift in the antibiotic profile was observed.The results show an overall decrease in antibiotic prescribing concurrent with a change in the choice of antibiotics prescribed and in line with the recommendations presented in the prescribing guidelines implemented by the Primary Healthcare of the Capital Area, and consistent with the project’s goals. Antibiotic-resistant bacteria pose a threat to human health, with inappropriate prescribing of antibiotics driving the evolution of resistance .Studies have shown that up to 30 to 50% of antibiotic prescriptions can be considered inappropriate, mainly due to unsuitable prescribing, unfit treatment time or patients not getting clear treatment information . UnnecesIn Iceland, antibiotic resistance is relatively low compared to many other countries regarding multi-resistant bacteria such as MRSA and ESBL-producing bacteria . HoweverThe rate of antibiotic prescribing in Iceland was high during the period 2009–2018 compared to other Nordic countries and somewhat below the midrange in a European context. Besides, broad-spectrum antibiotics are more often prescribed .Most antibiotic prescriptions are issued by general practitioners (GPs) with respiratory infections accounting for more than half of the prescriptions. Acute otitis media (AOM) is the most frequent indication . AOM is Since 2011 pneumococcal vaccination has been a part of routine vaccinations for children in Iceland to prevent invasive infections as well as to counteract the bacterial resistance due to the emergence of multi-resistant strains ,20. AfteThe Primary Health Care of the Capital Area (PHCA) issued guidance to promote rational use of antibiotics among GPs in to contain the overall prescribing of antibiotics, especially broad-spectrum antibiotics, as there is an indication of growing resistance in common bacteria in Iceland. This included implementing new prescribing guidelines in spring 2017  with theThis study aimed to examine changes in antibiotic prescriptions for young children issued by GPs in primary healthcare centres during ordinary hours of work in the Reykjavik area after initiating the quality project in 2017. The PHCA initiated this project in cooperation with the Department of Clinical Microbiology LUH and the Chief Epidemiologist. Out-of-hours on-call services of GPs are beyond the jurisdiction of PHCA.A descriptive retrospective data study was performed using a quantitative methodology involving data collection and statistical analysis. It was a population-based observational study. In May 2017, the PHCA antibiotic stewardship team visited all the healthcare centres under its umbrella and presented the GPs’ prescribing pattern at each healthcare centre. Data on issued prescriptions extracted from the PHCA medical records database was presented and the newly approved prescribing guidelines on antibiotics for common infections in primary care were discussed. The PHCA with 136 GPs comprising the medical staff includes 15 out of 19 primary healthcare centres in the Reykjavik area, with a population of just over 200.000. However, the PHCA does not provide an on-call service outside regular working hours.The study population consisted of all children aged 0–4 years (both years included) who had been prescribed antibiotics from ATC class J01 by the PHCA GPs over three years during opening hours (08-18), from 1st January 2016 to 31st December 2018. Out-of-hours prescribing is not included in the medical records database. The children are included in the study until the age of five. As soon as they reach that age, they are excluded from the study population. Each child could be prescribed antibiotics more than once during the study period so that they could repeatedly appear in the same year as well as in other years.In this study, electronically issued prescriptions from the PHCA medical records database were extracted for all antibiotics in the ATC class J01 for children aged 0–4 years from 1st January 2016 to 31st December 2018. Each person has a unique personal ID number, which is always entered whenever any patient information is recorded in the medical records database. The baseline data collected in the study included age, sex, ICD-10 diagnoses at the time of prescribing, antibiotic class, the number of prescriptions, and the date of the issue.After having extracted the data, it was encrypted and collected in a study database. Thus, each child was assigned a unique encryption ID number, so the personal identity of the child would not be revealed during the processing of the data set.The study’s numerical variables comprised the children’s age, the date of issue of the antibiotic prescriptions and their ID number. The sex of the child, the antibiotic class, and the ICD-10 diagnoses underlying the prescriptions were the categorical variables of the study. The number of antibiotic prescriptions was defined as the response variable that was evaluated for the explanatory variables: sex, age, the date of issue, antibiotic class and ICD-10 diagnoses underlying the prescription.The categorical variables sex and age were assessed regarding; numbers of prescriptions, which antibiotic classes were prescribed and prescription indication.p value < 0,05).Systemic and statistical methods were used in the processing and interpretation of the data in the R-studio. Chi-square test was used to evaluate statistically significant association in the number of antibiotic prescriptions by different categorical variables. Quasi-Poisson distribution was used to evaluate year-on-year antibiotic prescription changes. Significance was defined with 95% confidence (p = 0.98). However, there was a 9% decrease in antibiotic prescriptions between 2017 (289.6) and 2018 (263.6) coinciding with the implementation of the new guidance on treatments of common infections in primary care (p = 1.6*10−7). Thus, the number of prescriptions during the study period ranged from 263.6 to 289.6 prescriptions/1000 inhabitants/year. More than half of the prescriptions were issued for boys or 52.5%, and most of the antibiotic prescriptions were intended for the age group 1-2 years old. Followed by children 2- to 3-year-old, then 0–1- and 3- to 4-year-old children. The fewest antibiotic prescriptions were for the 4-year-old children.The study population consisted of 6420 children in total over these three years. The total number of antibiotic prescriptions over the study period was 11,583. In the three years from 2016 to 2018, 22.6% of the total GP visits in the group of 0–4 years old resulted in an antibiotic prescription. The number of prescriptions increased by 2.3% between the years 2016 and 2017, that is, from 282.9 to 289.6 prescriptions/1000 inhabitants/year, although the difference was not statistically significant (p = 2.2*10−16). Their number increased from 40.0% of the total antibiotic prescriptions in 2016 to 64.0% in 2018 (p = 1.6*10−7) or about 40.7% in 2018, compared to 2017 after the implementation of the new guidance, as well as the prescriptions of co-amoxiclav which decreased by 52.3% (p = 2.2*10−16) at the same time.The children’s antibiotic prescriptions were classified into 11 ATC groups. Extended-spectrum penicillin (J01CA), almost solely amoxicillin, comprised more than half of all the antibiotic prescriptions and increased significantly over the three years  and pneumonia (p = 3.9*10−9).More than half of all the prescriptions were for otitis media, followed by pneumonia . There wp = 9.4*10−9) and streptococcal infections (p = 5.2*10−11) over the study period  was the most common reason for antibiotic prescriptions, as expected , followeto be 0% .Streptococcus pneumoniae strains with intermediate resistance to penicillin, and considerable resistance to erythromycin (39%) and tetracyclines (27%), according to results from routine antimicrobial susceptibility testing at LUH [Streptococcus pneumoniae is one of the most common bacterial causes of AOM, and the connection between the use of antibiotics and resistance is well known [A reduction of 9% in the total prescribing of antibiotics was observed, and at the end of the study period, it amounted to 264 prescription per 1000 inhabitants per year. Our data neither include prescriptions issued during out-of-hours services in primary care in the capital area, primary care outside the capital area nor data from specialists’ clinics. The total sale of antibiotics for children 0–4 years of age in outpatient care in Sweden was 320 prescriptions per 1000 inhabitants per year in 2018 . In the yclines 2%, accordll known . Therefoll known .Although for a long time the Chief Epidemiologist and other official stakeholders have urged doctors to prescribe antibiotics more wisely, it may be that the lack of a structured programme to reduce antimicrobial prescribing and old habits have contributed to keeping the antibiotic prescriptions rate higher in Iceland compared to other Nordic countries. However, we do not have any clear-cut data to substantiate this. In 2020, an application was added to the medical-records software allowing the prescribers to view their prescriptions in comparison with colleagues at the healthcare centre and the prescribing at the PHCA in general. Studies have shown how key issues in educational interventions and individually targeted communication can improve antimicrobial prescribing ,35.During the 25 years of the Swedish STRAMA programme, antibiotic prescriptions have declined dramatically in Sweden, especially for children, and the changes in antibiotic prescriptions for children observed in our study are an encouragement to continue this quality project to urge a more prudent use of antibiotics in the Icelandic health service.This study examined changes in antibiotic prescriptions for young children issued by GPs in primary healthcare centres during ordinary hours of work in the Reykjavik metropolitan area after initiating the quality project on prudent use of antibiotics in 2017. The changes observed should encourage primary care in the whole country to continue with projects on quality improvement in antibiotic prescribing. The first steps have been taken in this respect. Accordingly, the main practical contribution of the present research is that it demonstrates how quality programmes within primary care settings can be an efficient approach for changing the prescribing habits of GPs. In our setting, it was implemented by visiting all the healthcare centres, presenting the GPs with their prescription patterns and promoting the prescribing guidelines as a discussion platform for improvement. Future studies will have to show if similar methods can be used to encourage prudent prescriptions of other drug classes such as opioids and psycholeptics.We observed a marked change in the choice of antibiotics prescribed, in line with the prescribing guidelines’ recommendations. Concurrently, a distinct overall decrease in the prescribing of antibiotics for children 0–4 years of age was observed over the period following the implementation of the guidelines.Click here for additional data file.


This study aimed to evaluate acute toxicities associated with irradiation between the X‐CSI  and P‐CSI  groups in children with brain tumors.Sixty‐two consecutive patients who received initial craniospinal irradiation (CSI) for brain tumors in our center between January 1, 2011 and May 31, 2021, were included in the study. Acute toxicities were retrospectively evaluated during CSI using Common Terminology Criteria for Adverse Events version 5.0. Maximum grades of fatigue, headache, insomnia, nausea, vomiting, dermatitis, constipation, abdominal pain, oropharyngeal mucositis, and hematological toxicities were evaluated.p < 0.001). The P‐CSI group had a lower incidence of more than grade 2 nausea  and vomiting , compared with the X‐CSI group. Multivariate logistic regression analysis with adjustments for potential confounding factors of doses of CSI showed that proton radiation therapy was associated with a marked reduced risk of more than grade 2 nausea and vomiting during CSI .Thirty‐six patients received X‐CSI, and 26 patients received P‐CSI. The median dose of CSI was 18.0 Gy in the X‐CSI group and 23.4 Gy  in the P‐CSI group . This result suggests that proton beam CSI reduces acute gastrointestinal toxicities associated with irradiation. Craniospinal irradiation (CSI) is usually indicated for medulloblastoma (MBL), embryonal tumor with multilayered rosettes, and some germ cell tumors, ependymoma, and atypical teratoid rhabdoid tumors.To reduce the dose to normal tissue at risk keeping the optimal dose for the target coverage, proton radiation therapy (PRT) has used as an alternative technique. Photons emit maximal energy near the body surface; this energy gradually decreases at deeper points in the body. Hence, photon radiation therapy (XRT) is closely related with various acute and late adverse events.PRT can reduce damage to the normal tissue and offers an obvious advantage in reducing dose of organ at risk compared with XRT.Although the number of patients receiving PRT is increased worldwide, there is limited data focused on the comparison of acute toxicities associated with CSI between XRT and PRT in children with brain tumors.This retrospective cohort study aimed to evaluate acute toxicities associated with irradiation between the X‐CSI  and P‐CSI  groups in children with brain tumors.22.1A total of 63 consecutive patients who received initial CSI for brain tumors in Kobe Children's Hospital and Kobe Proton Center between January 1, 2011 and May 31, 2021 were included in the study. The patients treated between January 1, 2011 and September 30, 2019, received CSI as XRT, while the patients treated between February 1, 2019 and May 31, 2021, received CSI as PBT. One patient was excluded because of discontinuation of CSI due to disease progression. Finally, we retrospectively analyzed data of 62 patients from the clinical records. Baseline patients' characteristics were obtained from their medical records.This study was approved by the ethics review committees of Kobe Children's Hospital and Kobe Proton Center.2.2Acute toxicities during CSI were retrospectively evaluated using Common Terminology Criteria for Adverse Events version 5.0. Maximum grade of fatigue, headache, insomnia, nausea, vomiting, dermatitis, constipation, abdominal pain, oropharyngeal mucositis, and hematological toxicities, including white blood cell (WBC) count decreased, anemia, and platelet count decreased, were evaluated. The observational period was from the first day of CSI to the next day after completion of CSI.2.32 on day 1), CDDP (90 mg/m2 on day 2), and CPM , (II) CDDP (90 mg/m2 on day 2), CPM (1000 mg/m2 on day 1), and etoposide (ETP) (100 mg/m2 on days 1–5), and (III) VCR (1.5 mg /m2 on day 1), CDDP (90 mg/m2 on day 2), CPM (1200 mg/m2 on day 1), and pirarubicin (40 mg/m2 on day 1). The second group included weekly VCR: VCR at a dose of 1.5 mg/m2 weekly until the completion of RT. The third group consisted of other regimens: (I) oral ETP (60 mg/m2 daily), (II) temozolomide (150 mg/m2 on days 1–5) and irinotecan (50 mg/m2 on days 1–5), and (III) topotecan (0.75 mg/m2 on days 1–5) and CPM (250 mg/m2 on days 1–5).To evaluate the association of concurrent chemotherapy with acute toxicities during CSI, we divided the regimens of concurrent chemotherapies into three groups due to the heterogeneity of the regimens. The first group consisted of cisplatin (CDDP) and cyclophosphamide (CPM) containing regimen.Methotrexate (MTX)‐containing intrathecal chemotherapy consisted of MTX and dexamethasone (DEX). The dose of these drugs were defined according to age as follows: MTX  and DEX .2.4All patients, other than one patient, received CSI in Kobe Children's Hospital. All patients received anti‐pneumocystis prophylaxis and antifungal therapy using oral sulfamethoxazole/trimethoprim. When the neutrophil count was <500/μL, granulocyte‐colony stimulating factor, and fluconazole were administered.All patients who received concurrent chemotherapy received granisetron (40 μg/kg dose) from day 1 to the last day of each regimen. All patients who received CDDP as concurrent chemotherapy received oral aprepitant or fosaprepitant.During CSI, granisetron, osmotic diuretics, and sodium alginate were administered at the physician's discretion.2.5Dmin (minimum dose) ≥90% of the prescribed dose (PD), and Dmax (maximum dose) <105% of PD; lens, Dmax <10 Gy (RBE). Table The radiation treatments were planned using a computed tomography (CT)‐based three‐dimensional treatment planning system. Each patient was immobilized using a custom‐made thermoplastic cast in the supine position; then, CT was performed. The target volumes and organs at risk were delineated on the CT images basically, and the CT magnetic resonance imaging fusion images were also used, if necessary. The clinical target volume (CTV) included the entire cranial and spinal meninges. The planning target volume was defined as the CTV plus a setup margin , and the vertebral bodies were included if the patient was aged <10 years to prevent scoliosis. The dose constraints were defined only for CTV and the lens: CTV, 2.6t‐test or Mann–Whitney U test was also used to compare continuous variables in patients' characteristics between the X‐CSI and P‐CSI groups. To compare the maximum grade of acute toxicities associated with irradiation, chi‐square test or Fisher's exact test was used. The logistic regression model was used to calculate the adjusted odds ratio (OR) with 95% confidence interval (CI) for the development of more than grade 2 nausea and vomiting associated with the modality of CSI. The multivariate logistic regression model was performed with adjustments for the potential confounding factors of the use of granisetron during CSI, regimens of concurrent chemotherapy, need sedation during CSI, and doses of CSI. For all models, the number of examined covariates was determined by the number of outcome events with 10 events required for one covariate. A p < 0.05 was considered statistically significant. Statistical analyses were performed using EZR , a modified version of R commander .In the present study, the primary outcome was to evaluate acute toxicities associated with irradiation between the X‐CSI and P‐CSI groups. Chi‐square test or Fisher's exact test was used to compare categorical variables in patients' characteristics between the X‐CSI and P‐CSI groups. Unpaired 33.1p = 0.22). There was no significant difference in female/male ratio between the two groups (p = 0.30). In both groups, MBL accounted for the most common as the primary disease (55.6% in the X‐CSI group vs. 73.1% in the P‐CSI group).Table p < 0.001). Eleven (30.5%) patients in the X‐CSI group and all patients in the P‐CSI group received the radiation with daily fractional dose of 1.8 Gy (RBE) (p < 0.001). There was no significant difference between the X‐CSI and P‐CSI groups in the number of patients who received subsequent RT (p = 1.00). Thirty‐five patients (97.2%) in the X‐CSI group and 25 patients (96.2%) in the P‐CSI group received CSI, followed by focal or whole brain irradiation.The median dose of CSI was 18 Gy (12.0–36.0) in the X‐CSI group and 23.4 Gy (RBE) (18.0–36.0) in the P‐CSI group (p = 0.44).In both groups, CDDP and CPM containing regimen was the most common concurrent chemotherapy (65.0% in the X‐CSI group vs. 75.0% in the P‐CSI group). There was no significant difference in the use of intrathecal MTX during CSI between the X‐CSI and P‐CSI groups .Acute toxicity profiles during CSI are summarized in Table p = 0.59). In patients who received irradiation with vertebral body sparing, there were no significant differences in WBC count decreased, anemia, and platelet count decreased between the X‐CSI and P‐CSI groups. There were also no significant differences in neutropenia, episodes of febrile neutropenia, and needs of transfusions between the X‐CSI and P‐CSI groups.Differences in the maximum grade of fatigue, headache, insomnia, constipation, abdominal pain, and oropharyngeal pain were not significant between the X‐CSI and P‐CSI groups Table . Acute hTo identify the risk factor of more than grade 2 nausea and vomiting, multivariate logistic regression analysis was performed with adjustments for the potential confounding factors of use of granisetron during CSI, sedation during CSI, regimens of concurrent chemotherapy, and doses of CSI. Table 4Herein, we compared the acute toxicity profiles between the X‐CSI and P‐CSI groups. In this study, we revealed that the incidence rates of more than grade 2 nausea and vomiting in the P‐CSI group were lower than in the X‐CSI group, although P‐CSI group had higher doses of CSI than the X‐CSI group. Nausea and vomiting are common side effects of RT.A previous study in adults showed that patients who received P‐CSI had significantly lower rates of acute gastrointestinal toxicities, including weight loss, nausea, vomiting, and anorexia compared with patients receiving X‐CSI.p = 0.02, Table In our center, patients who needed sedation during irradiation stopped eating 6 h before irradiation and drinking clear fluids 2 h before irradiation. For this reason, all patients who needed sedation could not eat during CSI. Sedation during CSI reduced the amounts of meals obviously. Hence, the incidence rates of anorexia and weight loss were not examined in the present study. In general, P‐CSI takes longer times to perform than X‐CSI. The number of patients who needed sedation during CSI was higher in the P‐CSI group than in the X‐CSI group,  and CPM (1000–1200 mg/m2 for 1 day or 3 days) and induces greater myelosuppression than other regimens, such as weekly VCR.However, in our study, there were no significant differences in WBC count decreased, anemia, and platelet count decreased between the X‐CSI and P‐CSI groups. This difference could be explained by the intensity of concurrent chemotherapy. In our study, 21 patients (58.3%) in the X‐CSI group, 15 patients (57.7%) in the P‐CSI group received CDDP and CPM containing regimen. This regimen consisted of CDDP . Because of the nature of the retrospective analysis, informed consent, or assent was waived and opt‐out system was presented.Suguru Uemura: Treatment of patients, conceptualization and study design, data collection and interpretation, writing‐original draft, and writing‐review and editing. Yusuke Demizu: Study design and methodology, data analysis and data interpretation, and writing of the manuscript. Daiichiro Hasegawa: Conceptualization, study design, methodology, data analysis, data interpretation, critically revised article. Tomoko Fujikawa: Treatment of patients and data extraction. Shotaro Inoue: Treatment of patients and data extraction. Akihiro Nishimura: Treatment of patients and data extraction. Ryunosuke Tojyo: Treatment of patients and data extraction. Sayaka Nakamura: Treatment of patients and data acquisition. Aiko Kozaki: Treatment of patients and data acquisition. Atsuro Saito: Treatment of patients and data extraction. Kenji Kishimoto: Treatment of patients, data extraction, analysis, and interpretation of the data. Toshiaki Ishida: Treatment of patients and data extraction. Takeshi Mori: Treatment of patients and data extraction. Jyunji Koyama: Treatment of patients, data extraction, and analysis and interpretation of the data. Atsufumi Kawamura: Treatment of patients, data extraction, and analysis and interpretation of the data. Yoshinobu Akasaka: Treatment of patients, data extraction, analysis, and interpretation of the data. Makiko Yoshida: Treatment of patients, data, analysis, interpretation of the data, and critically revised article. Nobuyoshi Fukumitsu: Treatment of patients, data acquisition, formal data analysis, and data interpretation. Toshinori Soejima: formal data analysis and data interpretation, and writing of the manuscript. Yoshiyuki Kosaka: Conceptualization, study design, methodology, formal data analysis, and data interpretation. All authors have approved the final manuscript.