The abnormal increase in serum IgG4 level is an important clinical symptom of IgG4‐related disease (IgG4‐RD), and the detection of serum IgG4 level is a powerful tool for the diagnosis of IgG4‐RD. This study was conducted to establish a simple and rapid immunoassay for the determination of human serum IgG4 levels.3+‐labeled anti‐IgG4 antibody. The immunocomplex was separated and washed in a magnetic field, and the fluorescence counts were measured according to the number of dissociated europium ions.Based on the competition method, a novel immunoassay was established for the determination of human serum IgG4 using a combination of time‐resolved fluoroimmunoassay (TRFIA) and magnetic microspheres. IgG4 was coupled with magnetic microspheres and competed with IgG4 in the samples to bind the EuThe analytical sensitivity of IgG4‐TRFIA based on magnetic microspheres was 0.006 g/L, and the detection range was 0.006–20 g/L under optimal conditions. The precision, recovery, and specificity of this immunoassay were demonstrated to be acceptable. The clinical application of IgG4‐TRFIA based on magnetic microspheres was evaluated and compared with that of immunonephelometry. The results showed that the two detection methods had a good correlation, with a correlation coefficient of .9871.IgG4‐TRFIA based on magnetic microspheres has the advantages of high sensitivity, wide detection range, and short analysis time and has the potential to become a useful tool for the diagnosis of IgG4‐RD. By the combination of time‐resolved fluoroimmunoassay (TRFIA) and magnetic microspheres, we established a simple and rapid immunoassay for the determination of human serum IgG4 levels. IgG4‐TRFIA based on magnetic microspheres has the advantages of high sensitivity, wide detection range, and short analysis time and has the potential to become a useful tool for the diagnosis of IgG4‐related disease (IgG4‐RD). IgG can be divided into four subtypes according to its structure: IgG1, IgG2, IgG3, and IgG4. Different IgG subtypes have different contents and functions in the body. IgG4 accounts for 1%–7% of total IgG, and its content is the lowest among the four subtypes. Abnormal increases in serum IgG4 levels frequently occur in IgG4‐RD such as autoimmune pancreatitis (AIP), Mikulicz disease, and autoimmune hepatitis.IgG4‐RD is an immune‐mediated chronic fibrotic inflammatory disease that has been discovered in recent years. The disease was first proposed by Kamisawa et al.22.13+‐N1‐(p‐isothiocyanatobenzyl)‐diethylenetriamine‐N1, N2, N3, N4‐tetraacetic acid (DTTA), enhancement solution, MES buffer, the Eu3+ labeling kit, and the automatic time‐resolved immunofluorescence analyzer (TRF‐1000) were provided by Zhejiang Boshi Biotechnology Co., Ltd. . The human IgG4 detection kit (immunonephelometry) and BN II fully automated protein analyzer were purchased from Siemens Healthcare Diagnostic Products . All other chemicals were of analytical reagent grade.Human IgG4, anti‐human IgG4 monoclonal antibody, diethylenetriaminepentaacetic acid (DTPA), bovine serum albumin (BSA), Tris base, 1‐(3‐dimethylaminopropyl)‐3‐ethylcarbodiimide hydrochloride (EDC), and N‐hydroxysuccinimide (NHS) were purchased from Sigma‐Aldrich . Carboxyl‐modified magnetic microspheres were purchased from Suzhou Beaver Biomedical Engineering Co., Ltd. . The Sephadex‐G50 column was purchased from Seebio Biotech Co., Ltd. . Eu2.2Serum samples from 27 patients were provided by the Shanghai Tong Ren People's Hospital affiliated with Jiao Tong University. The study protocol was approved by the Medical Ethics Committee of Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine (2020–35).2.33O4 microspheres, which had diameters of 2 μm, and the solution was mixed at 25℃ for 30 min. The mixture was magnetically separated and washed three times with 0.05 mol/L MES buffer (pH = 5.0) and was then suspended with the above buffer solution to make a magnetic particle suspension with a concentration of 100 mg/ml. Then, 1 ml of 0.05 mol/L MES buffer (pH = 5.0) and 50 μg of IgG4 were added to 100 μl of magnetic particle suspension, mixed well, and incubated overnight at 25℃. Then, the supernatant was removed after magnetic separation, and protein concentration was measured. The retained magnetic microspheres were washed three times with 0.05 mol/L Tris‐HCl buffer  and blocked at 25℃ for 30 min. Finally, magnetic microspheres were washed three times with Tris‐HCl buffer , resuspended, aliquoted, and stored at 2–8℃.Thirty microliters of NHS (10 mg/ml) and 50 μl of EDC (10 mg/ml) were added to 10 mg of Fe2.43+ labeling kit. Anti‐IgG4 antibody (1 mg) was dissolved in 50 mmol/L Na2CO3‐NaHCO3 buffer . Then, 0.2 mg of Eu3+‐N2‐[p‐isocyanate‐benzyl]‐DTTA (Eu3+‐DTTA) was added to 1 mg of anti‐IgG4 antibody solution, and the mixture was incubated with shaking at 25℃ for 20 h. The next day, the reaction solution was transferred to a Sephadex‐G50 column pre‐equilibrated with 80 mmol/L Tris‐HCl buffer (pH = 7.8) for purification. The fractions from the first peak containing the highest Eu3+ fluorescence counts were pooled and characterized. The anti‐human IgG4 antibody labeled with Eu3+ was diluted with elution buffer containing 0.2% BSA and stored at −20℃ until use.Anti‐human IgG4 antibody labeling was performed following the instructions of the Eu2.53, pH = 7.8), and assay buffer was used as the zero concentration point.Different concentrations of IgG4 standard solutions  were obtained by the dilution of high‐concentration IgG4 antigen in assay buffer  were added to the reactive wells and incubated at 37℃ for 12 min. At this time, the magnetic particle‐IgG4‐Eu3+‐labeled anti‐human IgG4 antibody complex was formed. The mixture was magnetically separated and washed three times with washing buffer (50 mmol/L Tris‐HCl buffer containing 12.49 g/L NaCl and 1.11 g/L Tween‐20). Finally, 200 μl of the enhancement solution was added and reacted for 5 min at 25℃ with shaking. Fluorescence counts were measured using an automated time‐resolved immunofluorescence analyzer (TRF‐1000). The IgG4 concentration in the serum samples was determined according to the IgG4 standard curve.The levels of IgG4 in serum samples were determined based on the competition method Figure . IgG4 st2.7Each serum sample was tested in duplicate. A commercial human IgG4 detection kit (immunoturbidimetry) was used to verify the clinical reliability of the established method, and the correlation between the two methods was evaluated using Pearson's correlation. ELISA Calc software  was used to perform log‐logit linear fitting for fluorescence counts (Y) and IgG4 standard concentration (X). SPSS version 19  and GraphPad Prism 8.0 software  were used for data analysis.33.13+‐anti‐IgG4 antibody (50 μl) were added to 50 μl of different concentrations of IgG4‐coated magnetic microspheres, and the reaction mixture was incubated. The results showed that the detection range of this method was narrow when the concentration of IgG4‐coated magnetic microspheres was between 0.1 and 0.6 mg/ml, the sensitivity of this method was relatively low when the concentration was 2.0 mg/ml, and high sensitivity and a wide detection range could be obtained at 1.0 mg/ml  was coupled with magnetic microspheres (10 mg). After magnetic separation, the protein content of the supernatant was 2.76 μg, which indicated that 47.24 μg of IgG4 had been coupled to magnetic microspheres, and the coupling rate was 94.48%, with an average of 4.72 μg of IgG4 coated per milligram of magnetic microspheres. IgG4 standard solution (100 μl) and Eu3.23+‐anti‐IgG4 antibody was determined at a high binding rate and low background. The purified Eu3+‐anti‐IgG4 antibody was detected at dilutions of 1:50, 1:100, and 1:200. When the Eu3+‐anti‐IgG4 antibody dilution was 1:100, the slope of the standard curve was the largest, thereby meeting the detection sensitivity and measurement range requirements  twice. Since the assay method in this study was established based on the competition method, linear fitting could be performed using log‐logit . Three quality‐controlled samples with different concentrations  were detected, 10 wells were set for each quality‐controlled sample, and the experiment was repeated three times. The range of intra‐assay CV was 3.70–5.09%. The range of inter‐assay CV was 4.89–6.26%, and the intra‐ and inter‐assay CVs of each quality‐controlled sample were ≤10%. The recovery rate was evaluated by adding a high‐concentration IgG4 standard to samples of known concentration at a ratio of 1:9. The recovery rate was calculated as recovery rate (%) =  × 100%. The range of recovery rates was 99.39–107.90%, indicating that the precision of this method was good. Because this assay method involved a large‐ratio dilution of samples, in order to evaluate the matrix effect of assay buffer on serum, a serum sample containing a high concentration of IgG4 (15.82 g/L) was diluted with assay buffer at different dilution ratios for detection, and the difference between the expected and measured concentrations was within 10.00%, indicating that the matrix effect of assay buffer met the requirements  were used to detect IgG4 in 27 serum samples. The results showed that the two methods were in good agreement, with a correlation coefficient of r1 Figure , indicat4To date, a variety of assay methods have been developed for the detection of serum IgG4 levels, including radio immunodiffusion (RID),3+ chelates, which can reach 290 nm), which makes it easy to separate excitation and emission wavelengths. Moreover, this helps to eliminate interference from non‐specific fluorescence, thereby enhancing the specificity of detection. A delay time can be introduced after the samples are excited by pulsed light, and the fluorescence counts are measured only after the short‐lived background fluorescence caused by serum, solvents, and reaction wells is completely quenched. Thus, the sensitivity of detection is improved, and a high signal‐to‐noise ratio is achieved.TRFIA is an emerging technology that uses lanthanide chelates as a marker. Advantages of TRFIA include zero background, wide linear range, and good stability, and it is widely used in the diagnosis of autoimmune diseases.3+‐labeled anti‐IgG4 antibodies in a short time. This improved the analysis sensitivity, and the reaction time was significantly shortened (to 12 min). As IgG4 is coupled with magnetic microspheres by chemical groups (the coupling rate was 94.48%), the loss of IgG4 due to washing is reduced, and the precision of detection is improved.The excellent analytical performance and reduced reagent costs of TRFIA make it an attractive method for serum IgG4 detection. However, the limitations of the conventional TRFIA remain. For example, antigens or antibodies are usually immobilized, and the contact area with the target substance is small, which increases the reaction time needed (1 h). The magnetic microspheres, an important tool in immunoassays, uniformly and stably distributed in the reaction solution to provide a larger binding surface area and could bind many EuIn conclusion, we established a novel immunoassay method for the detection of human serum IgG4. This method combines the advantages of TRFIA and magnetic microspheres and has the advantages of simple operation, short detection times, wide detection ranges, and high sensitivities. Moreover, the method established has good agreement with immunonephelometry and provides a useful new technique for the detection of human serum IgG4.The authors declare no conflicts of interest.Q.W., C.H., T.L., M.S., P.H., and B.H. designed the experiments; Q.W., C.H., T.L., and R.W. performed most of the experiments; Q.W., C.H., T.L., and R.W. analyzed experimental data; Q.W. and C.H. drafted the manuscript; Y.Q., G.W., M.Z., P.X., M.S., P.H., and B.H. revised the manuscript. All authors contributed to the manuscript revision, read, and approved the submitted version.The study protocol was approved by the Medical Ethics Committee of Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine (2020–35).


Concrete plants accumulate large amounts of concrete wash water. This water, which pH is highly alkaline, has a negative impact on the environment. Its reuse in fresh concrete slightly reduces its mechanical properties. The combination of concrete wash water and zeolitic by-product led to an increase of 4.6% in the compressive strength at 7 days hydration and up to 30% at 28 days hydration. The same combination led to the denser microstructure compared to the samples made with concrete wash water. This could be explained by the pozzolanic reaction of the zeolitic by-product. The complex chemical reactions of cement, zeolitic by-product, and fines presented in the concrete wash water occurred. Therefore, it was suggested the reusing method of concrete wash water together with zeolitic by-product in the fresh concrete mixtures by substituting some amount of tap water with concrete wash water. In this way, the consumption of tap water is possible to reduce in cement systems. In ready-mixed concrete plants, the recycling of wash wastewater is an actual problem. The wash wastewater is accumulated from the washing of concrete mixing trucks and batching plants. In Lithuanian concrete plants, this wastewater is generated in the settling ponds and it could be led to problems of environmental impact. Concrete wash water has high pH values, and it could pollute local water sources or soils . HoweverOne of the environmentally friendly solutions could be the recycling of concrete wash water in the preparation of fresh concrete. Asadollahfardi et al.  stated t2 and Al2O3 in zeolite reacted with Ca(OH)2 which formed during cement hydration. During the pozzolanic reaction, the binding phases such as calcium of silicate hydrate and calcium aluminate hydrate formed. These hydrates have a positive effect on the mechanical properties of cement systems. Markiv et al. [Therefore, the incorporation of concrete wash water in the production of mortar or concrete is related to the decreased strength values in many of the cases studied. Many researchers ,11,12,13v et al.  concludeIn this paper, the effect of concrete wash water with the additive of zeolitic by-product on the main properties of hardened cement paste was investigated. The impact of zeolitic by-product on the hydration temperature, compressive strength, mineral composition, and microstructure was evaluated. The investigated results were compared between the samples with incorporated zeolitic by-product and without it.The chemical compositions of Portland cement and zeolitic by-product were investigated by an X-ray fluorescence spectrometer, a Bruker X-ray S8 Tiger WD , using a rhodium (Rh) tube, an anode voltage Ua up to 60 kV, and an electric current I up to 130 mA. Pressed samples were analyzed in a helium atmosphere. Measurements were performed using the SPECTRA Plus QUANT EXPRESS method .The mineral composition of initial materials such as Portland cement and zeolitic by-product and hardened cement paste were evaluated by using the X-ray diffraction analysis (XRD). This analysis of the materials was performed using the X-ray diffractometer D8 Advance diffractometer . CuKα radiation and Ni filter were used. The power X-ray diffraction patterns were identified with references available in PDF-2 database  .The particle size distribution of the zeolitic by-product was determined by using a laser particle size analyzer . The distribution of solid particles in the air stream was 12–15 wt.%. Compressed air (2500 mbar) was used as the dispersing phase. The measurement time was 15 s . The speThe microstructures of the materials were studied by scanning electron microscope (SEM). A high-resolution scanning electron microscope ZEISS EVO MA10  was used for the research .The hydration temperature measurements of Portland cement paste were performed with 8-channel USB TC-08 Thermocouple Data Logger  (temperature measurements range from −270 to +1820 °C).The pH measurements of concrete wash water were conducted by using a Hanna ISE pH meter . Chlorides were determined according to the method prescribed by LAND 63-2004 ; nitriteTo determine the compressive strength of the hardened cement paste, 2 × 2 × 2 cm cubes were formed from cement paste of normal consistency. The water/solid material ratio of the mixture  was determined according to the standard EN 196-3 . The comThe samples of hardened cement paste were based on Portland cement (OPC) which selected for the CEM I 52.5R type. The chemical composition of OPC and zeolitic by-product was shown in 2/kg) is almost 2.5 times large compared with the surface area of zeolitic by-product (142.1 m2/kg).The surface area of Portland cement  the main peaks reached almost the same time b. The in process .The lowest hydration temperature of the cement pastes 40.2 °C and 40.0 °C was detected for 0TW/100WW and Z0TW/100WW samples respectively. This could be explained by the high content of dissolved solids, compared to the tap water. Due to the common ion effect, the rate of cement hydration slowed down . The higLi et al. stated that  the good2 from concrete wash water leading to a rise in compressive strength [When in the system zeolitic by-product was incorporated then both compressive strength at 7 and 28 days) increased by increasing the amount of concrete wash water b. In thistrength ,6. Laterstrength . Chatveestrength  got the 8 days inThe mineral composition was determined by using XRD patterns . The minθ and slightly higher peaks of ettringite at about 9.1°, 15.9°, and 19.1° 2θ were determined compared with the samples without zeolitic by-product , the peak related to portlandite decomposition was weaker compared to the 50TW/50WW sample b. In thi.68 wt.% a. These The analysis of scanning electron microscopy (SEM) was performed for the evaluation of microstructure . It was These results indicated that concrete wash water could be an alternative and sustainable source of cement systems. The recycling of concrete wash water together with zeolitic by-products in the fresh concrete mixtures could be considered a very promising sustainability key.The high alkalinity of concrete wash water led to the decrease of setting times of cement pastes. Meanwhile, the mixture of concrete wash water and zeolitic by-product almost do not change the times of the main peak.2 from the concrete wash water and cement hydration.The compressive strength of samples with the combination of concrete wash water and zeolitic by-product led to an increase of 30% in the compressive strength at 7 days hydration and up to 4.6% at 28 days hydration compared with Z100TW/0WW samples. This increase could be explained by the reaction of zeolitic by-product and Ca(OH)2 and after that, the larger amount of hydrated products such as calcium silicate hydrate and ettringite was formed.It was determined that concrete wash water with zeolitic by-product did not have a significant impact on the hydration chemistry of Portland cement (OPC). It slightly increased ettringite and decreased the amount of portlandite in hardened cement paste. In this case, the mass loss consisted slightly lower value of 2.54 wt.% compared with the sample without zeolitic by-product (3.60 wt.%). This decrease could be explained by the pozzolanic reactions of the zeolitic by-product: it decomposed and reacted with Ca(OH)So, these results indicated that concrete wash water could be an alternative and sustainable source of cement systems. The recycling of concrete wash water together with zeolitic by-products in the fresh concrete mixtures could be considered a very promising sustainability key.


This study investigates the effect of varying ratios of fly ash as a partial replacement for fine aggregate on the performance of alkali-activated municipal slag composites. The strength and other properties of alkali-activated cementitious material (AACM) composites can be optimized by selecting the appropriate mix proportion. In this study, we used fly ash as a substitute for fine aggregate (FA/S) at varying ratios of 0.0, 5.0, 10.0, 15.0, 20.0, 25.0, and 30.0%, mixed with 50% water (W/SL), and 20% alkali activator (AL/SL) content instead of municipal slag (SL) as a core binder, cured in steam conditions. The effects of these substitutions on the initial mixing temperature, slump flow, compressive and splitting tensile strengths, and microstructure analysis of composites cured in steam conditions were investigated at 1, 7, 28, and 91 days. The evaluation of the experimental results revealed that increasing the ratio of fly ash substitution to fine aggregate by up to 20.0% led to a higher strength attributable to the composites, whereas when the extra substitution ratio of FA/S ranged from 25.0–30.0%, significant decreases in strength were observed. The composites’ strengths were estimated using the ACI 209 and ACI 318 design equations and compared to the measured strengths. The construction sector is one of the main global marketplaces for supplementary cemented materials (SCMs). In the cement system, additional cemented materials (SCMs) can be added as components of concrete. These SCMs may be added to concrete as partial replacements for Portland cement, or they may be supplemented with cement, depending on the characteristics of the materials used and their effects on concrete ,2. SCMs 2, NaOH, NaOH+Na2CO3, KOH, and sodium silicate in various concentrations (water glass). They found that sodium silicate produced the greatest compressive strength. The atomic Si/Al ratio in the reaction products increased in tandem with the increase in sodium silicate SiO2/Na2O mass ratio. Again, the fly ash/slag ratio was the most significant issue in strength development [The advancements in the field of new materials recognized as alkali-activated cementitious materials (AACMs) that can be used as substitutes for Portland cement (PC), and their implications, have been the subject of rigorous study and investigation by the scientific community ,12,13. Felopment ,38,39,40In numerous cases, ground granulated blast furnace slag-Alkali activated cement or fly ash-based polymer cement was examined for making cement-less composites as the core binder. Dai et al.  considerComparatively few investigations have been conducted up to now on the usage of blended slag cement with fly ash activated in alkali as an alternative to Portland cement ,40. M. AM.A. Wafa and K. Fukuzawa  conducteHowever, there are still numerous challenges to be tackled. Therefore, this new study focused on producing slag cement as a new engineering material that could be used as a complete substitute for Portland cement, combined with fly ash as a partial substitution for fine aggregate, to create economically attractive performance mixtures and allow the concrete industry to become more sustainable. The aim of this study was to determine the most favorable mixture design for improving the properties of AACM composites with an acceptable workability and higher strength development, using a microstructure analysis and curing in steam at different ages, as well obtaining more information for determining the correct dosage rate for the composites by achieving the desired effect. Slag cement (SL) and fly ash (FA) have the potential to be used in new, sustainable methods of engineering cementitious materials and to provide the concrete construction industry with an increased capacity to meet more and more demanding requirements for the sustainability of construction materials. Consequently, it is important to develop procedures for designing and manufacturing alkali-activated cementitious materials (AACMs) by using high volumes of fly ash blended with slag cement. The steam curing of concrete has the advantage of accelerating the hydration reactions of cement. Therefore, the material develops compressive strength and reduces its permeability in a shorter time compared with standard curing under ambient conditions. The specific reason for steam-curing concrete is to increase the rate of strength gain and thus the rate of utilization of concrete production by ensuring that the concrete rapidly reaches a sufficient strength to allow early demolding or, in the case of prestressed concrete members, to enable the concrete to be stressed as soon as possible after casting. Furthermore, in the case of precast concrete construction, this is a requirement in some projects that must be completed quickly, especially in urban areas. The ACI 209  and ACI Alkali-activated cementitious materials’ (AACMs) composites are considered among the promising and growing new materials used as cement substitutes. They are currently closely studied and investigated by the scientific community. Municipal slag (SL) and fly ash (FA) blended with alkali-activated (AL) materials are classified as new alkali-activated cementitious material (AACM) composites. Municipal slag (SL) made for municipal activities was used as the main binder for complete replacement of Portland cement. The fly ash (FA) class “F” was produced from coal burning by-products in power plants and was used in this study as a partial substitution to fine aggregate (S). bk) and the hydration module (HM) with standard values of bk ≥ 1.0, HM > 1.4, and 1.3 ≤ CaO/SiO2 (C/S) ≤ 1.4 [HM) be used to exceed 1.4.Equations (1) and (2) define the basicity index for municipal slag (S) ≤ 1.4 ,44,45,46bk) = 1.0, hydration modulus (HM) = 1.8, and CaO/SiO2 (C/S) = 1.33.As a result, the municipal slag basicity index (CaO) content not exceeding 10% of the total mass. White minute metasilicate sodium particles (Na2SiO3) were used as an alkali-activator (AL). The proportion of “SiO2” silicon dioxide to Na2O sodium oxide was 1.0 . Crushed sandstone was used as fine aggregate (S) in this study with a specific gravity of 2.58 and a fineness modulus of 2.83.Fly ash is graded as class “F” by ASTM C618-78 . It exhiThe proportions studied for the mixtures of the alkaline-activated cementitious materials (AACMs) are given in All the composite mixtures of AACM were set at room temperature, around 20 ± 1 °C, with an RH of around 65 ± 5%. All the raw ingredients  were mixed in a 90 s pan mixer. Water (W) was added, and a further 90 s of continuous mixing was performed to create the AACM composites. The AACM composites were investigated by conducting some tests to estimate the most favorable mixture designs for improving the property mixtures with an acceptable workability and higher strength development at different ages and cured in steam conditions, as well as to obtain information for determining the correct dosage rate of the composites by achieving the desired effect. The fresh properties tested included the initial mixing temperature and slump flow to verify the workability of the AACM composites. The initial mixing temperature and slump flow of the AACM composites were recorded directly after mixing. The JIS A 1150 (JSA 2014)  recommenAll the molds were removed one day after casting and maintained at 20 ± 1 °C room temperature with 65 ± 5% RH until the day of testing. In order to explain the typical compressive and splitting tensile strength cured in steam, three samples of individual mixtures were examined at ages 1, 7, 28 and 91 days; hence, the strength development could be observed over time. The microstructure analysis of the AACM composites was conducted by using the technique of scanning electron microscopy (SEM) with ratios of  at 1, 28, and 91 days of steam curing.The initial mixing temperature is one of the main issues that can directly affect the properties of fresh and hardened AACM composites in the form of increased water demand, accelerated slump loss, reduced setting time, improved plastic shrinkage pattern, decreased strength, and reduced durability. The appropriate temperature is therefore an integral factor in any composite quality control scheme. The effect on the initial mixing temperature of the AACM composites of the varying replacement ratios of fly ash to fine aggregate as FA/S is shown in the CaO) content, less than 10%, resulting in decreased heat generation and delayed setting times. Consequently, AACM composites with a high fly ash substitution to fine aggregate (FA/S) ratio are particularly suitable for minimizing autogenous temperature rises directly affecting slump loss, increasing setting time and reducing the strengths of AACMs composites. Therefore, when the higher fly ash substitution to fine aggregate (FA/S) ratio was used, it produced lower initial mixing temperatures. This performance was significant because the impact of the hydration procedure on the setting time of the composite AACMs was delayed.The reduction in the rate of temperature produced and, hence, the initial mixing temperature of the composites of the AACMs, led to the of use fly ash class “F”, which exhibited a pozzolanic reaction, and the silica, alumina, and iron oxide content reached 70% of the total mass with a small percentage of calcium oxide   was usedThe hardened properties of the AACM composites were examined by conducting a compressive strength test to evaluate the most favorable mixture designs for improving the property mixtures with higher compressive strength development cured in steam at different ages, as well as to obtain more information for determining the correct dosage rate of the composites by achieving the desired effect. To define the typical compressive strength of JIS A1108 (JSA 2006a)  cured inHowever, the higher replacement ratios directly delayed the setting time and slowed down the slump loss with reasonable reductions in the compressive strength of the AACM composites, which is suitable in constructions such as dams, bridge piers and abutments, and large concrete footings. The results clearly indicated that the optimum replacement ratios of (FA/S) on the compressive strength of the composite AACMs were about 20.0%. This was directly linked to the enhancement of the microstructure of the matrix by the formation of a denser binder and the higher rate of heat produced and, hence, to the higher initial mixing temperature generated. Consequently, as the substitution ratio (FA/S) rose to 20.0%, the compressive strength of the AACM composites became more beneficial and acceptable for practical use than that obtained with the higher replacement ratios of (FA/S) with reasonable reductions in the compressive strength, which is suitable in some engineering applications, such as dams, bridge piers and abutments, and large concrete footings.The general trend of the growth of the AACM composites’ compressive strength at 1, 7, 28, and 91 days showed a similar pattern with differing replacement ratios of (FA/S) cured in steam. At 1, 7, and 91 days of steam curing, the compressive strength improved to about 82, 88, and 102% of the 28-day compressive strength of the AACM composites, respectively. The compressive strength growth of the AACM composites improved with time, and the strength development trends at 1, 7, and 91 days were identical to those at 28 days. Therefore, the extra replacement ratios of (FA/S) ranging from 25.0–30.0% possibly had an undesirable influence on the AACM composites due to a lack of accessibility for hydration.To define the typical split tensile strength of JIS A1113 (JSA 2006c)  cured inThe results indicated that the replacement ratio of (FA/S) up to 20.0% resulted in the highest split tensile strength. This was because the microstructure of the matrix was affected by the formation of a denser binder and the higher rate of heat produced and, hence, the higher initial mixing temperature generated, which was produced by the chemical reactions. This effect shows that the application of a replacement ratio of (FA/S) up to 20.0% is a more effective way to enhance the splitting tensile strength of the AACM composites than the application of extra replacement ratios of (FA/S) ranging from 25.0–30.0%. The results of the split tensile strength were identical to those of the compressive strength of the AACM composites cured in steam.2SiO3) was used, the N-A-S-H gel did not form alongside the C-S-H gel, and the majority of the urban slag particles were dispersed. Due to the small quantity of silica present in the resin, some incompletely disbanded slag particles did not form the C-S-H gel.Scanning electron microscopy at 1, 28, and 91 days of age studied the microstructure of AACM composites cured in steam with a 20% ratio of fly ash replacement to fine aggregate (FA/S: 20%), 50% water to municipal slag as the core binder (W/SL: 50%), and 20% alkali activator to municipal slag as the core binder (AL/SL: 20%), respectively see a–c. FiguHomogeneously scattered microcracks formed in the exterior surface of the composites. Nevertheless, smaller numbers of microcracks in the denser microstructure were found. This suggested that the C-S-H gel did not contain all the slag particles in the matrix of AACM composites. The microstructure was highly compact, with fewer unreacted slag particles. There were a number of condensed microcracks, but the most extensive cracks formed at the C-S-H boundary.Moreover, the microstructure of the AACM composites featured an extra condensed matrix. The water-to-core-binding ratio affected the hole sizes and the permeability of the composites, which directly controlled the strength of the AACM composites. Upon exposure to steam curing, all the composites demonstrated thick matrices and rough textures, as well as a large amount of micropores see a–c.The initiation of hole formation refers to the Si:Al composite ratio of the AACMs. The Si content in the composites of the AACMs lost the initiation temperature of the production hole as a result of the removal of water hydration when the bubbles were created, resulting in the formation of close bubbled components. In addition, unreacted or even reacted particles remained apparent. The microstructure of the AACM composites therefore revealed a microstructure with dense particles collected with excessive integrated holes, as the test samples with Si:Al percentages were uniform at 1.65, with porosity distributed in tiny holes.An earlier inspection of the microstructure of the AACM composites demonstrated that the growth of the microstructure as the silicon volume increased within the small compositional zone was rapid and incessant. The proportion of Si to Al impacted the hole-size distribution of the AACM composites. The hole-size distributions of the AACM composites tended to be smaller as the Si:Al ratio increased.Thus, the AACM composites cured in steam appeared to be denser and less porous and, explaining their current established strengths. 3—the mean unit weight of the AACMs composites used in this analysis was 2150 kg/m3; and The ACI 209 Code (ACI 1997)  estimate ACI 318  addresseConsequently, the split tensile strength The experimental proportions of the AACM composites cured in steam were equivalent to those of the OPC concrete calculated by ACI 209 and ACI 318. For the 1-day duration, the ratio of the experimental to the predicted proportions was higher than for the 7-, 28-, and 91-day compressive strength of the AACM composites cured in steam.In general, there is little information on the accuracy and validity of using ACI Equations designed for concrete on AACMs to estimate compressive and split tensile strengths. Yang et al.  recordedAs general recommendations, standards such as the ACI code can be applied to AACMs, but the results are conservative. They are, however, sufficient for predicting the properties of AACMs. Based on the results presented in Sustainability and environmental issues are considered as a dual challenge. These were explored by combining municipal slag activated in alkali form with fly ash for the development of new cementitious materials as cement replacements in the core binde. These played a dynamic role in the production of AACM composites and had a major impact on the properties of both fresh and hardened composites.The varying ratio of fly ash substitution to fine aggregate was a significant factor influencing the performance of the AACM composites. Hence, the most favorable mixture design was obtained for improving the properties of composites with an acceptable workability, higher strength development, microstructure analysis, and steam-curing at different ages.The assessment of varying ratios of fly ash substitution to fine aggregate up to 20.0% suggested that the developed strengths were attributed to the AACM composites, which is achievable in order to produce the most favorable mixture designs. The extra replacement ratios of FA/S ranging from 25.0–30.0% were incorporated in the main binder; the strengths decreased significantly, a with potentially adverse influence on the strengths, but with reasonable reductions in the strengths of the AACM composites. This could make the composites suitable for constructions such as dams, bridge piers and abutments, and large concrete footings.The microstructural performance of AACM composites cured in steam conditions had the greatest impact. These composites are applicable in prefabricated concrete construction and other engineering applications requiring greater strength.The ACI 209 and ACI 318 provided appropriate estimations of the compressiveThe mixing effect of alkali-activated municipal slag as a core binder for the full replacement of Portland cement with 50% water content, 20% activator-content-to-binder ratios, and ratios of fly ash substitution to fine aggregate in the binder at 0.0, 5.0, 10.0, 15.0, 20.0, 25.0 and 30.0%, in order to introduce new alkali-activated cementitious material (AACM) composites, cured in steam at ages of 1, 7, 28, and 91 days, were examined experimentally. The effects of different replacement ratios of fly ash to fine aggregate on the initial mixing temperature, slump flow, compressive strength, split tensile strength, and microstructure analysis of AACM composites cured in steam at 1, 7, 28, and 91 days of age were observed. The optimization of the binding mechanism and the properties of the composites of the AACMs were assessed. Predictions of the strengths of the AACMs composites were also performed using ACI design codes. The following conclusions can be drawn from this analysis:


To identify the patterns of antibiotic use and irrational antibiotic prescriptions in primary healthcare institutions (PHIs) in Dongcheng District of Beijing, China.Beijing Prescription Reviewing System of Primary healthcare institutions and analysed retrospectively. The antibiotic prescription rate was calculated and cases of irrational antibiotic prescriptions were identified.All primary healthcare institutions  in Dongcheng District were included in the study. Prescription data from January 2015 to December 2018 was derived from the We extracted 11,166,905 prescriptions from the database. Only 189,962 prescriptions were included in the study, among which 9167 (4.8%) contained antibiotics. The antibiotic prescription rate fell from 5.2% in 2015 to 4.1% in 2018 while irrational antibiotic prescription rate increased from 10.4 to 11.8%. Acute Bronchitis was the most prevalent diagnosis (17.6%) for antibiotic prescriptions, followed by Unspecified Acute Respiratory Tract Infection (14.4%), Acute Tonsillitis (9.9%), and Urinary Tract Infection (6.4%). Around 10% of the prescriptions for the top 7 diagnoses identified were rated as irrational. Cephalosporins, fluoroquinolones, and macrolides were the most prescribed antibiotics, which accounted for 89.3% of all antibiotic prescriptions. Of all the antibiotic prescriptions, 7531 were reviewed, among which 939 (12.5%) were rated as irrational because of antibiotic use. Among all the irrational prescriptions, prescriptions with inappropriate antibiotic use and dosage accounted for the majority (54.4%).Although a relatively low level of antibiotic utilization was found in PHIs in Dongcheng District of Beijing, the utilization patterns differed considerably from developed countries and irrational prescriptions remained. Considering the imbalanced allocation of medical resources between primary healthcare setting and secondary and tertiary hospitals, there need to be more efforts invested in regions with different levels of economic development.The online version contains supplementary material available at 10.1186/s12913-021-06856-9. S. aureus declined to 32.2%, carbapenem-resistant P. aeruginosa to 20.7%, and carbapenem-resistant A. baumannii to 56.1% [Antibiotic use is one of the major drives for antimicrobial resistance (AMR), a significant challenge to public health for all countries alike. China, a large consumer of antibiotics, has long suffered from irrational use of antibiotics and AMR. In the past two decades, the Chinese government has implemented a series of policies and measures to confront AMR, including restricting antibiotic use. The evolution of policy management has been well documented . In 2018to 56.1% –6. TheseMoreover, information on antibiotic use and prescriptions in primary healthcare settings was missing due to issues of data accessibility. We identified one study that investigated patterns of antibiotic use in 48 primary healthcare facilities across China in 2014 . Other tAll PHIs in Dongcheng district of Beijing were included in the study, which consisted of seven community healthcare centres (CHCs) and 59 community healthcare stations (CHSs) during the study period. PHIs were the first point of contact of patients with the national healthcare system. All PHIs in Dongcheng District were outpatient-only clinics, responsible for providing basic outpatient clinical care and services to individuals and families residing in the community. We conducted a retrospective observational study to assess the appropriateness of antibiotic prescriptions in all PHIs covered by the Prescription Review Network in Dongcheng district, Beijing from January 2015 to December 2018.Beijing Prescription Reviewing System of Primary healthcare institutions (BPRSPHI), which was established by the Beijing Health Commission in 2014, collecting routine online prescription review of PHIs.Prescription data was derived from the All outpatient prescriptions in BPRSPHI of the sample PHIs were collected. Data derived included prescribing date, patient age, gender, diagnoses, medications, and the prescription review result. Electronic prescriptions were digitally transferred from the database and double-checked by our researchers.A sampling software was embedded in PHIs’ information systems. No less than 1‰ of the total prescriptions were randomly selected by the sampling software and then reported to BPRSPHI from each PHIs monthly. One hundred prescriptions were randomly selected from each PHIs monthly, using a systematic sampling method, with sampling interval calculated as the number of total prescriptions divided by 100. The selection of antibiotic prescriptions was showed in Supplement Regulation Standard for Hospital Prescription Review” issued by the Chinese Ministry of Health in 2010 [Guideline for the prescription review process of Beijing healthcare institutions, the review should be conducted based on the clinical pathways, medication, and clinical treatment guidelines, as well as the medication manufactory instructions. As quality control measures, the Hospital Medication and Therapeutic Committee was responsible for providing training for the reviewing team before the conduct of reviews, and the Medical Quality Committee was responsible for periodic quality evaluation after reviews.According to “ in 2010 , The preNo patients or members of the public were involved in this study.A prescription in the study referred to all drugs prescribed for one patient during one visit. The antibiotics were classified according to Anatomical Therapeutic and Chemical (ATC) classification J01 , as recommended by the WHO Collaborating Centre for Drug Statistic Methodology .Regulation Standard for Hospital Prescription Review, an irrational prescription is a prescription with writing and/or the clinical use of medication  not conformed to relevant laws and technical specifications. An irrational prescription can be categorized as one of the following sub-types based on whether the use of antibiotics conformed to guidelines: irregular prescription, inappropriate prescription, and abnormal prescription. These sub-types differ by types of mistakes or inappropriateness of the prescription .Of the total 66 community health care institutions included in the study, 189,962 prescriptions (1.7%) out of 11,166,905 prescriptions between January 2015 and December 2018 were extracted from the BPRSPHI. The characteristics of the sample prescriptions were described in Table Table As shown in Table Antibiotics prescriptions, as well as irrational antibiotic prescriptions for the most common conditions, were presented in Fig. Our study identified the patterns in antibiotic use and irrational antibiotic prescriptions in primary health care settings in Dongcheng District, Beijing, using prescription data from a total of 66 Primary Healthcare Institutions. According to the National Health Commission, the outpatient antibiotic prescription rate in Chinese hospitals  declined from 16.2% in 2011 to 7.7% in 2017. Similarly, the inpatient antibiotic prescription rate also declined from 55.2 to 38.0% –15. In oInternationally, the antibiotic prescription rate in primary care settings was relatively high in developing countries and particularly in rural areas, with the rate being over 50% in Malaysia, India, and South Korea –18. ThisThe most commonly seen sub-type of irrational prescriptions was inappropriate prescriptions, among which “inappropriate antibiotic usage and dosage” was the most prevalent issue, accounting for more than 60% of all inappropriate prescriptions Table . When loOur study had several limitations. First, Dongcheng is a unique district in the centre of Beijing with better economic development and medical resources. Thus, the study sample institutions were not fully representative of all PHIs in Beijing. Second, the socio-economic background of the patients was not analysed due to issues in data accessibility, which might introduce bias to the analysis. However, since the elder population accounted for the majority of patients in primary healthcare settings in our study, the impact of patient flow might not be determinant. Third, because the prescription reviewing process was conducted based on prescription per visit instead of each patient, the linkage between prescriptions with patients was not assessible. Nonetheless, the analysis based on prescriptions was accurate enough to reflect the patterns in antibiotic usage in PHIs. Forth, the sample prescriptions in BPRSPHI only accounted for a small proportion of the total prescriptions in all PHIs. Although the sampling process was based on a systematic randomized methodology, we could not avoid the potential selection bias during the reporting process. However, the random selection process could maximize the representativeness of the prescriptions. Fifth, the quality control of the data in BPRSPHI might have varied since its establishment in 2014, with improvements to the database were made every year. Nevertheless, we dropped the data in 2014 to minimize the impact of the discrepancy in data quality.Although a relatively low level of antibiotic utilization was found in the primary healthcare settings in Dongcheng District of Beijing, the utilization patterns differed considerably from developed countries, with a proportion of irrational prescriptions remained. Targeting inappropriate antibiotic use in primary healthcare settings is crucial to attaining the overall goal of rational antibiotic use in China. Considering the disproportionate allocation of medical resources between primary healthcare setting and secondary and tertiary hospitals, there need to be more efforts invested in regions with different levels of economic development.Additional file 1.


Lung cancer is the most fatal and frequently diagnosed malignant tumor. Neoadjuvant therapy is a promising approach for prolonging survival and increasing the chance of cure rates for patients with potentially resectable disease. Currently, many therapeutic alternatives, including chemotherapy, targeted therapy, and immunotherapy, are continually being explored to enrich the content of neoadjuvant therapy. However, neoadjuvant therapy remains to have no unified evaluation standards. Overall survival (OS) is the “gold standard” for evaluating the clinical benefit of cancer treatment, but it needs years for a reliable evaluation. Hence, researchers need to identify surrogate endpoints that can predict OS accurately and reliably without long follow-up periods. In this review, we describe the research progress of different neoadjuvant therapies and explore their response evaluation, aiming to identify stronger predictors of OS. Lung cancer, especially non-small-cell lung cancer (NSCLC), which represents 80–85% of all cases , remainsFor patients with early-stage disease, complete surgical resection is still the most effective initial therapy . NeoadjuFrom a large number of clinical neoadjuvant chemotherapy and targeted therapy, no significant improvement of OS was found. These unsatisfactory results caused our attention and we began to think about how to effectively evaluate the impact of neoadjuvant therapy on survival. Impressed by the great improvement of major pathological response (MPR) rates in neoadjuvant immunotherapy, we reviewed the MPR results from previous neoadjuvant chemotherapy and targeted therapy, and concluded that low MPR may be the reason for unsatisfactory OS. Thus, we compared the radiographic response and pathological response in different neoadjuvant therapy. In this review, we aimed to discuss which indicator has a more predictive value for OS in different neoadjuvant therapies and to explore the most promising treatment for potentially resectable NSCLC.We performed a literature search focusing on outcomes of neoadjuvant therapy in patients with resectable NSCLC. We explored PubMed and Google Scholar with the following search terms: (1) non-small cell lung cancer (NSCLC); (2) neoadjuvant; (3) chemotherapy; (4) targeted therapy; (5) immunotherapy; (6) objective response rate (ORR); and (7) major pathological response (MPR). There was no restriction in article type. We reviewed relevant articles independently and summarized the results of various studies. In this review, we have included the most up-to-date information of neoadjuvant therapy and predictor of OS in resectable NSCLC.Complete resection is an important predictor of OS, but is affected by objective response rate (ORR) and major pathological response (MPR). Preoperative therapy is important because it might downstage the malignancy and make tumors more operable, thereby potentially increasing the chance of performing complete resection. Complete resection is an important factor for predicting OS, which is a widely recognized endpoint and a “gold standard” in determining clinical benefits from any oncology trials. Patients undergoing complete resection can obtain a median OS of 80.1 months and a 5-year survival rate of 58.8% . After nThe tumor ORR is the proportion of patients achieving a complete response (CR) or a partial response (PR) evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. This rate is used for assessing tumor burden after providing chemotherapy treatment to patients with solid tumors. However, with the emergence of immunotherapy, researchers question whether RECIST criteria (the anatomic response criteria reflecting tumor shrinkage mainly for cytotoxic chemotherapy) applies to immunotherapy as well.p = 0.754) and that survival was not significantly different between patients with initial disease progression and those with an initial reduction in tumor size (p = 0.580) [The correlation between ORR and OS. Several studies have already investigated whether changes in tumor volume determined from radiological evaluations are closely associated with survival in patients with NSCLC undergoing neoadjuvant chemotherapy. Birchard et al. reviewed 99 patients and concluded that radiological response had no correlation with survival (= 0.580) .Additionally, a phase III trial by Gilligan et al. explored survival outcomes of 519 patients received surgery alone or platinum-based chemotherapy preoperatively. The neoadjuvant chemotherapy group showed a positive ORR (49%) . HoweverBetter ORR can decrease tumor burden, but not closely associated with OS. Therefore, neoadjuvant-targeted therapy could significantly shrink tumor volume and improve radiological responses, as well as increasing the curative resection rate. However, this impressive tumor shrinkage effect has not been translated into changes in disease stage or pCR rate. Additionally, the insight into whether neoadjuvant-targeted therapy could improve OS compared with neoadjuvant chemotherapy remains unclear. The advent of neoadjuvant immunotherapy has revolutionized the treatment landscape of metastatic and stage III NSCLC. In a phase II pilot single-arm study by Forde, after two preoperative doses of nivolumab, the ORR was only 10%, but with an unexpectedly higher MPR rate of 45% (9 of 20). The rate of recurrence-free survival (RFS) at 18 months was 73%. Considering the relatively short follow-up time, the median OS duration was not reached [As observed in the abovementioned trials, neoadjuvant chemotherapy and neoadjuvant-targeted therapy could sharply increase ORR but could not show significant improvement in OS. In contrast, despite low ORR, the survival outcomes after neoadjuvant immunotherapy were extremely promising. Hence, as the duration of treatment and treatment-related interventions increases, the ORR is not always reliable in predicting corresponding effects in OS, and the ORR assessed by RECIST1.1 is better used only for cytotoxic chemotherapy.p = 0.02) [MPR is tightly correlated with OS. MPR refers to the presence of no >10% viable tumor cells in the resection specimen. The potential of MPR as a surrogate for OS had gained research interest. Junker et al. retrospectively explored the correlation between histopathological regression and survival outcomes through a thorough pathological analysis of 40 patients who underwent neoadjuvant bimodality treatment. The median survival time was statistically significantly longer in the cohort that achieved MPR (36 months) than in all other cohorts with >10% residual tumor (14 months) ( = 0.02) , indicatMoreover, Pataer assessed the capacity of histopathological response to predict a long-term outcome in patients treated with or without neoadjuvant chemotherapy. Results revealed that the proportion of residual viable tumor cells strongly correlated with OS and disease-free survival (DFS) in patients with neoadjuvant chemotherapy regardless of being controlled for pathologic stage. Patients who had <10% viable tumor had significantly longer OS and DFS than those with >10% viable tumor cells  . Hence, Discrepancy between radiographic response and pathological response. Presently, between MPR and ORR, the insight into which is better to appraise the efficacy of neoadjuvant therapy remains controversial. The trend of MPR and ORR was inconsistent among different trails as shown in p = 0.002) than CT-measured tumor response (p = 0.03). In patients who had completed neoadjuvant chemotherapy with >10% remaining viable tumor, the survival outcomes of patients with PR or CR were not significantly different from patients with progressive disease (PD) or stable disease (SD) [A previous study investigated whether or not tumor response based on CT scan findings using the RECIST criteria could predict OS and histopathological response in patients treated with neoadjuvant chemotherapy. The discordance rate was 41% between histopathological response and radiographic response. The histopathological response was proven to be a stronger predictor of OS than radiographic response (ase (SD) . Thus, tAmong various measurements of pathological response, pCR has been preferred for decades. Although pCR is associated with longer survival, it is restricted by its infrequency; the occurrence of pCR in neoadjuvant chemotherapy is generally <10%. The different responses of the primary tumor and mediastinal lymph node metastasis to systemic chemotherapy cause an out-of-sync pathological remission. The nodal response is also associated with long-term survival, but it relies on the accuracy of nodal assessment and is only applicable to patients with lymph node disease confirmed by pathology during diagnosis . ConversThe numerical differences across trials likely reflect differences between histopathological response and radiographic response assessed by RECIST criteria. Knowing the reason for these discrepancies could further help identify significant predictors of OS. The major factor driving this inability of tumor size changes assessed by conventional imaging to predict pathological remission is the composition of NSCLC tumors, which contain a pathologically heterogeneous mixture of cancer cells, stromal tissue, and associated inflammatory cells. Despite that gross necrosis can be identified by CT, its features of stromal, inflammatory, or fibrotic alterations resemble those of viable tumor cells. Consequently, RECIST-assessed radiographic response may only evaluate primary tumor macroscopically because of a high likelihood that the tumor size changes on imaging can be easily confounded by inflammatory or fibrotic changes and difficult to reflect the real remission.This confusion is magnified by a special immune killing process after neoadjuvant immunotherapy. By interrupting the programmed death protein 1 (PD-1)/programmed cell death 1–ligand 1 (PD-L1) regulatory axis, cytotoxic T lymphocyte antigen-4 (CTLA-4), or others, immune checkpoint inhibitors (ICIs) can initiate T cell activation and expansion, increasing the quantity of activated tumor-specific CD8+ T cells. CD8+ T cells could not only kill tumor cells directly but also release more new tumor antigens; subsequently, new antigens released from the collapsed tumor cells are delivered to specific effector T cells at different sites, further amplifying the immune response. Thus, compared with chemotherapy and molecular-targeted therapy, neoadjuvant immunotherapy results in the infiltration of considerably numerous T cells in tumor specimens; hence, the inflammatory reaction is prolonged. The necrotic tumor tissue, which is only surrounded by new connective tissues, is difficult to dissolve and absorb. Progression identified on imaging may be actually a downsized tumor with appropriate infiltration of immune cells, referring to “pseudoprogression” . Taken tMPR can help catch the best timing of surgery. The aforementioned difference between ORR and MPR is crucial in clinical practice. Using only ORR to evaluate tumor shrinkage and antitumor activity may significantly underestimate the benefits derived from neoadjuvant therapy especially immunotherapy, and it may even miss the best timing of surgery. In the NADIM trial, 3 (33%) of 9 patients with SD and 22 (73%) of 30 patients with a PR demonstrated a pCR instead . After oDespite various methods of assessing MPR being used, they have not been defined in detail. In 2020, the International Association for the Study of Lung Cancer (IASLC) has made detailed recommendations on how to assess pathological response of lung cancer resection specimens after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%, which can be used for all systemic therapies . Before surgery and consideration of neoadjuvant therapy, staging with 18F-fluorodeoxyglucose positron-emission tomography (PET) scan is recommended. Different from traditional radiologic imaging technologies, which are based on gross anatomical changes to provide structural information and define disease states, PET imaging provides information on the biochemical processes that may precede gross anatomic change . In the MPR rate was sharply increased in neoadjuvant immunotherapy. As mentioned above, MPR after neoadjuvant therapy could predict the OS of patients with NSCLC. By comparing the rate of MPR among different neoadjuvant approaches, we may determine the most efficient treatment region. Many previous studies used MPR as the primary or secondary endpoint. Results showed that after neoadjuvant chemotherapy, the MPR rates were generally between 7% and 27% ,42,43,44To our satisfaction, since the advent of immunotherapy, particularly ICIs, numerous breakthroughs have been achieved, with new results emerging exponentially. Although vital clinical trials are still ongoing and more data are needed, the completed trials have reported stimulating results. As shown in Overall, MPR plays a more important role in long-term survival, and it could predict OS, serving as a surrogate endpoint. In neoadjuvant immunotherapy, the MPR rates were sharply increased. Although vital clinical trials are still in progress, results obtained from the completed trials were highly encouraging. Evaluating MPR after neoadjuvant immunotherapy with the help of PET is necessary to grasp the best timing of surgery.MPR may be a more decisive factor of long-term OS in patients with NSCLC than ORR. It could act as an effective surrogate endpoint to characterize the activity of neoadjuvant chemotherapy, targeted therapy, and immunotherapy. As discussed above, previous neoadjuvant chemotherapy has dramatically increased ORR, but PFS and OS were not significantly extended; neoadjuvant targeted therapy produced better ORR but poor MPR and survival; neoadjuvant immunotherapy has sharply increased MPR with encouraging interim survival results, and adding chemotherapy would improve ORR as well. Therefore, neoadjuvant immunotherapy is an optimal treatment strategy for potentially resectable NSCLC. The paradigm of NSCLC treatment is expected to be drastically changed by neoadjuvant immunotherapy alone or in combination in the not-too-distant future. Considering that the traditional RECIST criteria cannot appraise the efficacy of immune-related therapy more accurately, accurate evaluation of MPR after neoadjuvant immunotherapy is crucial and staging with PET is recommended. Despite the potential interest of MPR as a surrogate of OS, the specific value has not been established yet, and further studies are needed. A new pathological evaluation standard should be developed, which is applicable to all current treatment methods.


The low swelling property of magnesium oxide concrete is a significant feature that can be used to control the cracking of mass concrete. Based on the characteristics of the chemical reaction, this work proposes a coupled hydro-thermo-mechanical model that can be implemented with the finite element method for predicting the autogenous volumetric deformation of magnesium concrete. By introducing the degree of the hydration reaction of magnesia and the degree of the hydration reaction of cementitious materials as intermediate variables of the chemical reaction system, a prediction model of the concrete temperature and chemical fields is established, and using this model, the effect of the temperature on the reaction rate can be considered in real time. In addition, by combining the relationship between the degree of the hydration reaction of magnesium oxide and the comprehensive expansion of concrete, a mathematical model for calculating the expansion stress of magnesia concrete was established. The algorithms were derived by mathematical equations, and the simulation results were compared to the experimental temperature and autogenous volumetric strain curves, which showed that the hydration model provides a relatively high accuracy. The model was also applied to an arch dam, and the coupled thermo-chemical-mechanical responses of mass concrete during construction were investigated. Simulation results show that the increase in temperature  and expansion volumetric deformation (hydration of MgO) of the concrete on the upstream and downstream surfaces lags obviously behind that of the inner regions. Quantitative analysis for differences of internal and external expansion is worthy of further attention and study on a basis of further experimental data as well as monitored data. For mass concrete structures, thermal stresses that may induce cracking are a major concern, and temperature control measures must be taken during the construction period. For hydraulic mass concrete structures, cracks are mainly caused by temperature deformation shortly after construction . This eaIn the past, to prevent cracks induced by thermal stresses, mass concrete structures were usually poured in layers to artificially increase the construction interval. Moreover, other temperature measures, such as the use of ice to precool aggregates, embedded cooling water pipes, and surface heat preservation, have been used to prevent temperature-induced cracks . HoweverIn research and practice, during the dam concrete preparation process, an appropriate amount of magnesium oxide that has been burned under high temperatures can be added to make the concrete expand, which can compensate for shrinkage deformation ,5 duringThe addition of MgO in mass concrete is a superior technique that can reduce project construction and management costs by simplifying the temperature control measures. However, the expansion mechanism of MgO concrete is very complex , not onlSince the 1970s, MgO concrete has been used in a large number of hydraulic engineering projects in China, and a large amount of deformation data has been collected . B. Zhu The establishment of an expansion and deformation model of magnesium oxide concrete is very important, and many studies that have been carried out can serve as references for practical use and research and are conducive to the establishment of a simulation model and the technical development and popularisation of MgO expansion concrete. However, a unified standard model that considers the chemical reactions of MgO concrete has not yet been developed. Although some models can consider the effect of temperature on the expansion characteristics of magnesium oxide, the calculation methods are controversial because they do not consider the nature of the chemical reaction . Therefore, additional research and relevant projects are needed.In this paper, based on hydration kinetics, a coupled thermo-chemical-mechanical model is proposed for describing the hydration properties of magnesium oxide concrete. In this model, two variables are introduced as the intermediate variables of the chemical reaction system within concrete: the hydration degree of cementitious materials, which determines the hydration heat release, and the hydration degree of magnesium oxide, which determines the autogenous volumetric deformation. In addition, the model is numerically implemented with the finite element method, and the temperature, hydration and stress field within concrete can be simulated. Based on a parameter study, the model is applied in a case study that considers an arch dam to evaluate the coupled thermo-chemical-mechanical responses of mass concrete during construction.The transient heat transfer process of concrete can be described as follows:According to the Arrhenius law, the time-dependent hydration progress can be described as in Equation (2). In the model, the hydration rate is related to the temperature and the chemical affinity dynamics . The fredynamics , a modifdynamics ,20:(4)AξConcrete strain mainly includes elastic strain, creep strain, thermal strain and autogenous volumetric strain:Accordingly, the stress evolution can be described as follows:The expansion of magnesium oxide concrete is essentially due to the hydration of magnesium oxide to form magnesium hydroxide, which follows the general rule of chemical reactions: temperature and concentration are the main factors that influence the reaction process. A higher temperature corresponds to a faster reaction, a higher hydration rate of magnesium oxide and more expansion. Meanwhile, the expansion rate is proportional to the magnesium oxide content involved in the reaction , which conforms to the kinetic chemical reaction equation .t, the hydration rate of magnesium oxide can be expressed as a function of chemical reaction affinity and temperature at that time:mE is the chemical reaction activation energy and R is ideal gas constant.At time B1 and B2 are material constants, mE, B1, B2, T) and water diffusion rate , (3) and (7); to implement the coupled equations in the finite element method, an implicit algorithm of a backward-Euler temporal integration and a Gaussian quadrature spatial integration scheme is adopted. At time Therefore, the hydration equation of the cementitious material can be written asSimilarly, the hydration equation of magnesium oxide can be written asBased on the principle of virtual work, the basic energy balance equation for heat transfer can be written as(1)Input variables: (2)Set a proper temperature increment value and calculate (3)k is the iteration counter, Use a Newton–Raphson iterative method to obtain the values of (4)Calculate the (5)Output variables Combining this equation with (10) and (11) givesThrough the above steps, the temperatures and hydration degrees of the cementitious material and magnesium oxide can be calculated at each moment. Combined with the relationship between the mechanical properties and the hydration degree of concrete, the stress and strain of concrete at each moment can be obtained. In fact, this method can calculate the temperature, stresses and hydration degree synchronously. However, considering that the stress results have little effect on temperature and hydration , a sequential coupling method is essentially the same as a synchronous computation.The relationship between the apparent stress and strain of concrete can be described as follows:E(ξ) is Young’s modulus and μ is Poisson’s ratio.E is the elasticity matrix, which can be written asThe evolution of Young’s modulus can be described as follows:α is the coefficient of linear expansion and I is the unit tensor {1,1,1,0,0,0}T.The thermal strain of concrete can be written asConsidering the influence of magnesium oxide hydration on concrete expansion, the strain produced by the autogenous deformation of concrete can be written asThe creep strain can be calculated by using solidification theory. Therefore, the calculation of volume deformation, strain and the ultimate apparent stress of magnesium oxide concrete during the hydration process can be completed by using the above steps.To scrutinize the deformation characteristics, which are closely related to the hydration properties, necessary experiments should be conducted to obtain the corresponding thermal and mechanical parameters. In this work, the experimental study comes from the engineering field . The usual test indexes of concrete include compressive strength, split tensile strength, bulk density, elastic modulus, ultimate tensile value, linear expansion coefficient, adiabatic temperature rise, thermal conductivity, specific heat and autogenous volume deformation. For MgO concrete, the low expansive characteristic caused by the hydration of magnesium oxide is significant and complicated.The autogenous volume deformation can be monitored by using a digital electric bridge. A strainmeter is placed in the center of a concrete specimen that has been poured in a bottle. The height of the concrete cylinder is 10 cm and the radius is 60 cm. The resistance can be measured by the digital electric bridge, which is connected to the wire of the strainmeter, and then, the autogenous volume deformation can be calculated. Because the ambient temperature has a considerable impact on the test results, a thermostatic water tank is used to adjust the curing temperature of the specimens.Special ordinary Portland cement is used for tests which is produced by Guizhou cement plant in China. The purity of magnesium oxide is greater than 90% and it is produced by Haicheng, Liaoning, China. The fly ash is secondary ash produced by Guizhou Thermal Power Plant.The corresponding adiabatic temperature rise of the two types of MgO concrete at different ages are listed in While the activation energies of the cement hydration of concrete for calculations are plentiful in the literature, they are not easily found for magnesium oxide applications. Moreover, the activation energy of magnesium oxide hydration is closely related to the magnesium oxide production technique; thus, the activation energy values in different studies are quite different. Therefore, in this work, a method that can be used to obtain the activation energy of magnesium oxide hydration within concrete is proposed.According to Equation (7), for an arbitrary degree of hydration of magnesium oxide  can be transformed toBy integrating both sides of this equation,Then, the time required to reach a certain degree of hydration under different temperatures can be described as:mE can be determined:Ultimately, the chemical reaction activation energy of MgO hydration mE.According to Equation (38) and combined with the experimental data of the autogenous volume deformation of oxygen magnesia concrete samples at different ages with varying curing temperatures, the activation energy can be obtained by choosing two different curing ages at which the hydration degrees are equivalent. In practice, the measurement of autogenous volume deformation cannot be conducted at every age of the magnesium oxide concrete; therefore, close values may be chosen, and the interpolation method should be used to obtain appropriate estimates of −1 based on references [As discussed in ferences ,23, and The temperature evolution of the simulations and the adiabatic tests on the concrete samples with fly ash content 30% and 40% are plotted in Based on the data in Once the activation energy is obtained, the other parameters of the model can be calibrated on the basis of the experimental data of autogenous volume deformation. The results of the parameter calibration of the thermo-chemical model that describes the properties of MgO hydration are listed in The autogenous volumetric strain evolution of the simulation values and the experimental data for the concrete samples with fly ash content 30% and 40% are plotted in In Mechanical tests on concrete are typically conducted under isothermal conditions; therefore, the hydration process is simulated under isothermal conditions in this research, and the mechanical characteristics can be linked to the hydration degree rather than to time. The evolution of the Young’s modulus for the isothermal test of the fly ash concrete specimens with fly ash content 30% and 40% are plotted in The Sanjiang Arch Dam, which was constructed with magnesium oxide concrete during 2002 and 2004, was selected as a typical structure for thermo-chemical-mechanical analysis. A birth-and-death technique is adopted to address the existence and nonexistence of the concrete. Corresponding elements in the finite element model are made active when a fresh concrete slab is poured. Thus, the incremental pouring process of concrete can be simulated in the FE model.For mass concrete structures, thermal stresses are a major concern, and temperature control measures must be taken during construction. There are multiple material and structural factors that impact thermal stress, such as concrete hydration properties, thermal and mechanical boundary conditions, the construction schedule and temperature control measures; for simplification, these conditions are not described in detail. In subsequent studies, these details will be discussed, and the simulation results will be compared with the monitored values.Based on the parameter studies and numerical validation in The temperature and stress evolution processes are discussed for further comparative analysis. Thus, twelve typical points on the crown cantilever are selected, and points ①, ②, ③, ④, ⑤ and ⑥ are on the upstream profile (exterior areas of the dam), whereas points (1), (2), (3), (4), (5) and (6) are distributed over the midplane (interior areas of the dam). Accordingly, points ① and (1), points ② and (2), points ③ and (3), points ④ and (4), points ⑤ and (5), and points ⑥ and (6) are at six different elevations. The position distribution of the typical points is shown in For the nodes on the downstream profile of the dam section, the temperature rises to a certain extent and then changes with air temperature, while the temperature of the nodes on the midplane rises higher and drops more slowly due to the poor heat dissipation conditions. Therefore, for points distributed in the interior areas of the dam, the shrinkage compensating effect is superior to that of the points distributed on the exterior areas of the dam. As shown in Moreover, In this work, a coupled thermo-chemical-mechanical model is proposed to study the expansion characteristics and mechanical responses of mass concrete structures. Focusing on the chemical-physical responses of mass concrete structures, parameter studies and numerical simulations were conducted. The major achievements are as follows:The coupled thermo-chemical-mechanical hydration model separates the hydration degree of the cementitious material and the magnesium oxide. In addition, the heat release is determined by the hydration degree of the cementitious material, while the autogenous volumetric deformation is determined by that of magnesium oxide.The thermo-chemical model is numerically implemented in the finite element method. In each load step of the finite element analysis, the hydration of both the cementitious material and the magnesium oxide can be updated synchronously.The activation energy of magnesium oxide hydration, which is an important parameter in hydration kinetics, has rarely been reported in the literature. To overcome the problem, a mathematical derivation method for obtaining the activation energy is introduced.Numerical simulations are conducted, and the results of the comparison of the experimental temperature and autogenous volumetric strain curves show that the hydration model in this work provides a relatively high accuracy.The model is also applied in a case study on an arch dam, and the hydration degree of magnesium oxide within mass concrete, which can lead to strain compensation for shrinkage caused by temperature drop, is highlighted. The increase in temperature  and expansion volumetric deformation (hydration of MgO) of the concrete on the upstream and downstream surfaces lags behind that of the inner regions.The differences of cement hydration degree for the inner and exterior regions and that of magnesium oxide hydration degree show not to be synchronized; this may be caused by the difference of cement hydration activation energy and MgO hydration activation energy. Meticulous numerical simulations and quantitatively contrastive analyses with current traditional model as well as monitoring data should be scrutinized in future work.


Implant related infection is one of the most frequent complications in orthopaedic and trauma surgery. Local antibiotic treatment strategies are becoming part of the prevention and treatment methodology for this fearful complication. To date, there are two coatings available on the market, both with a polylactic acid base. Current evidence supports the use of these types of coatings in the prophylaxis of periprosthetic infections and fracture-related infections. However, their therapeutic use has been less investigated. The purpose of this article is to summarise recent evidence relating to the clinical application of antibacterial hydrogels and coatings in orthopaedic and traumatology surgery and indicating which future applications may benefit from it. Implant-related infection is one of the most frequent complications in orthopaedic and trauma surgery. It represents a great challenge for the orthopaedic surgeon and forces the patient to undergo frequent multiple surgical treatments, resulting in a functional deficit for said patient and an increase in expenditure for the national health systems.Periprosthetic joint infections (PJIs) have an increasing incidence that currently stands at around 1.3% ,3. In suFracture-related infections (FRIs) can have an even higher incidence, reaching 6–33% in certain districts  . Such inThere are two coating systems currently available on the market. The first is a biocompatible hydrogel, the Defensive Antibacterial Coating  composed by covalently bound hyaluronic acid and polylactic acid capable of forming a physical barrier against bacterial adhesion by releasing high concentrations of the surgeon’s chosen antibiotic or antifungal ,10. It sThe second system is an antibiotic coating available only for ETN PROtect intramedullary tibial nailing . The coating, which is applied directly in the production phase and then delivered to the surgeon already coated, consists of an absorbable poly  (PDLLA) matrix with gentamicin sulphate incorporated ,14. The The main features of both coatings are shown in p = 0.003). The use of this type of coating is analogous—in uncemented prostheses—to the antibiotic loaded bone cement in cemented prostheses. Not surprisingly, the antibiotics used in the study were the same as those added to the cement in cemented prostheses (gentamicin and vancomycin). The application of the gel does not affect the osseointegration of the prosthetic implant. This study was later supported by other evidence in the literature that confirm its effectiveness. A previous study shows that, in patients who underwent a cementless revision due to aseptic failure of the hip replacement, the incidence of infection was the main cause of short-term failure and that the application of the gel drastically reduces this occurrence (p = 0.0001) [The use of antibacterial coating in prosthetic surgery was initially validated by a European multicentric study . Romanò  0.0001) . In caseWith regard to mega-prostheses, Zoccali et al. showed a reduction in the risk of infection, similar to that in cases of prosthetic revision, with no evidence of infections in the treatment group at the 2-year follow-up .Although a routine use for all patients has not yet been put forth, a cost-benefit study proposed by Trentinaglia et al. simulated how the routine use of antibiotic gel on all non-cemented prosthetic surgery implants, similar to the use of antibiotic-loaded cement in cemented prostheses, would reduce the management costs of infected patients, with greater savings compared to other types of surface coatings, such as the silver-coating . RecentlOn the basis of the aforementioned evidence currently available in the literature, the authors recommend the use of antibiotic coatings in cases at increased risk of infection: revisions, mega-prostheses, but also patients with known systemic risks such as rheumatological diseases, diabetes, previous bone infections in other districts, and prostheses resulting from fracture or failure of the means of synthesis. Larger prospective multicentric studies are needed to establish whether a routine application to all prostheses implantations is indicated.p = 0.11), observing a significant difference in terms of hospital stay (p < 0.0001) [The application of hydrogel as part of a therapeutic strategy has been less investigated than its prophylactic efficacy and there are only case series that study its application. In these cases, the gel acts both as a local delivery system of a targeted antibiotic therapy and as protection to the newly implanted device, in a one or two stage exchange . In particular, its application can be useful when the revision strategy involves the implantation of a cementless revision prosthesis, in cases, that is, where bone cement cannot be used as a local antibiotic delivery system and the prosthetic interface in contact with the bone is left without targeted protection against the pathogen responsible for a PJI. In 2018, Zagra et al. tested the effectiveness of the gel in TSE compared to a control group  .In the same year, a non-inferiority study compared the use of gel in the OSE to the TSE without gel, observing similar relapse rates, with longer hospitalisation times and duration of systemic antibiotic therapy in the TSE group . RecentlTo date, there are no studies describing the use of antibiotic gel in debridement, antibiotic and implant retention procedures (DAIR) for acute peri-prosthetic infections. In our clinical practice, with regard to the DAIR surgical treatment protocol—along with the replacement of the mobile components, the irrigation with at least 9 L of physiological solution and antiseptic solutions (povidone iodine and hydrogen peroxide), the packaging of a new surgical field after the first debridement—the antibiotic gel is applied with the choice of antibiotic selected on the basis of the antibiogram, if available, before closing the joint capsule . HoweverThere is, on the other hand, literature regarding the efficacy of calcium sulphate antibiotic-loaded beads used as a local delivery system, which do not act as a coating, but are, however, capable of a longer-lasting targeted local antibiotic release . This caStaphylococcus aureus strain infection against which the pathogen was directed [The use of hydrogels as a carrier has also been tested in cases of extreme rescue, where other strategies were needed due to the impossibility of resorting to traditional techniques. Recently, the Lion NJI Study Group experimented the innovative potential of hydrogels as a local delivery system of bacteriophages. In this study, Ferry et al. investigated the anti-biofilm activity of bacteriophages incorporated in the hydrogel, demonstrating their bactericidal capacity in vitro and presenting a clinical case of rescue, which failed, though not due to a recurrence of the directed . The comp = 0.03). The application of the gel did not affect the formation of the bone callus.The efficacy and safety of the DAC in this field were tested via a multicentric study . In thisp = 0.031) [In tibial fractures, which are burdened by an increased risk of infection compared to other districts due to their more frequent exposure and trauma of the surrounding soft tissues, the use of an antibiotic coating based on gentamicin has proven to be an effective strategy in patients at high risk of infection. A recent systematic review studied all the cases in which the nail was used: of the 105 patients available for follow-up, 4 developed an FRI (3.81%) and 3 a superficial surgical site infection (2.86%) . However= 0.031) . On the In our experience, based on the aforementioned evidence, the application of antibiotic coatings is recommended in cases of open fractures, in the definitive internal fixation treatment .Its use can also be recommended in cases where the patient has clinical characteristics of high risk of infection: diabetic patients, smokers, morbidly obese and those with poor soft tissue envelopes. The use of either vancomycin, gentamicin, or both, is re-modulated on the basis of available antibiotic bone cement experiences.There is very little literature regarding the therapeutic use of gels in FRI. The available reports envisage the use of these antibiotic coatings as part of a two-stage strategy based on a first resection time and a subsequent restorative time, in which the coating protects the final implant . In a caWith regard to the hydrogel DAC, the only study dealing with post-traumatic bone infections is the study by Corona et al., in which they evaluated the effectiveness of the gel in protecting the mega-prostheses implanted to fill the infected post-traumatic bone defects. . At a miFrom the available data, the application of the antibiotic gel appears to be a promising strategy for the protection of the new implants also in cases of FRI, however they need to be confirmed with prospective studies containing a wider range of cases. In the experience of the authors, the application of the gel on the plate and screws positioned during the reconstructive surgery of the Masquelet technique allows an additional protection, directed at the pathogen isolated during the first surgical stage, though correct management of the perioperative antibiotic therapy is irreplaceable .The clinical application of antibiotic gels and coatings is becoming more and more prominent within the prophylaxis and multidisciplinary treatment of implant-related infections. Its clinical results are promising though based mainly on low-number retrospective studies, especially in the area of fracture-related infections. Prospective randomized studies are needed in order to determine their effectiveness in different situations.