Coarse aggregate in concrete is basically free from sulfate corrosion. If the influence of the coarse aggregate in the concrete is not eliminated, the change amount of the concrete ultrasonic pulse velocity value is directly used to evaluate the damage degree of sulfate corrosion in the concrete, and the results are often inaccurate. This paper presents an evaluation method of corrosion damage for the sulfate-attacked concrete by CT, ultrasonic velocity testing and AHP methods. CT was used to extract the coarse aggregate information in the specimen, and the proportion of coarse aggregate on the ultrasonic test line was calculated based on CT image analysis. Then, the correction value of ultrasonic pulse velocity (UPV) of the concrete structure was calculated, and the sulfate corrosion degree of concrete structure was evaluated using the analytic hierarchy process (AHP). The results show that the evaluation method proposed in this paper could more accurately evaluate the corrosion damage in the sulfate-attacked concrete structures, and the evaluation results were more in line with reality. The durability of concrete is very important to the service life of civil infrastructure, and sulfate erosion is one of the most critical factors affecting the durability of concrete structures ,2. Some At present, a large number of studies have been carried out on the mechanism of sulfate attack. The results generally show that sulfate attack is mainly divided into two categories: chemical corrosion and physical  corrosion ,14. ChemAs an important material in infrastructure construction, concrete has been widely used in structures such as house construction, highway tunnels, and bridges . In the To confirm the proportion of coarse aggregate in a concrete structure, it is necessary to obtain an image of the internal structure of the concrete. Computed tomography (CT), as a non-destructive testing method, is widely used to explore the internal structure of concrete and its development ,29,30,31In addition, the distribution of coarse aggregates in the concrete structure is not uniform, and the UPV of a survey line cannot reflect the overall corrosion degree of the concrete structure. Therefore, in this article we evaluated the overall corrosion of concrete structures through UPV in multiple directions. In the process of concrete corrosion, the more severe the corrosion, the greater the impact on the overall performance of the concrete structure. By assigning weights to the UPV in different test directions, the overall corrosion situation of the concrete structure can be more accurately reflected. AHP, being an expert-driven data mining technique, was introduced by Saaty ; it is uIn this study, the samples were taken from the corroded section of a highway tunnel in Chongqing, China. The specific experimental steps are shown in The concrete blocks were made into 50 × 100 mm cylindrical samples for dry–wet cycle accelerated corrosion experiments. In the experiments in this paper, each immersing/dry cycle was 24 h . Every eight days was a cycle, and this experiment was carried out for two cycles. The experimental samples were tested by ultrasonic and CT before the experiment and after the end of each cycle. In theory, the proportion of coarse aggregate on the ultrasonic measurement line can be obtained by only one CT scan test of the sample. In order to determine the accuracy of the evaluation method proposed in this article, we performed CT on the specimen after each dry–wet cycle and calculated its porosity changes.E) and its density  .(1)V=f.In the equation, The above evaluation method for the corrosion degree of concrete components can more comprehensively consider the corrosion degree of concrete in all directions so as to calculate the relative corrosion coefficient of concrete components more completely.In this part, we explain the calculation process of the concrete relative corrosion coefficient in detail with AHP.The UPV in the medium reflects the properties of the material indirectly. With the development of material damage, the longitudinal wave speed will also decrease . Next, wIn the equation, According to the value of In addition, in the table We can obtain the judgment matrix (Equation (5)) according to We can approximate the value of the evaluation factor weight vector with the following Equation (6):Calculation of the normalized weight can be conducted using Equation (7):The accuracy of pairwise comparisons was calculated through the consistency index (CI). However, the consistency of judgement was checked by calculating the consistency ratio (CR). The CR controls the balance in which weights are assigned . The accBecause this is a three-factorial matrix, the CI for a matrix was calculated using the following Equation (9):According to the random index (RI) table , the RI Finally, the AHP was used to obtain the weight value of each direction and then put into Equation (3) to obtain the relative concrete corrosion coefficient.After obtaining the concrete corrosion coefficient, we put forward a set of evaluation classifications of the concrete corrosion degree. First, we defined the absolute damage index (ADI) as per Equation (10):The evaluation classification of the relative corrosion degree is shown in The coarse aggregate of a concrete structure will not change under sulfate attack. Therefore, we only needed to perform a CT scan on the specimen and then obtain the coarse aggregate information corresponding to the ultrasonic survey line and extract it; the specific process is shown in In this article, we took three-directions of the UPV of the specimen for measurement; thus, only three-directional coarse aggregate information needed to be extracted from the CT images for analysis. First, we extracted the slice corresponding to the location of the ultrasonic survey line, and then used the watershed algorithm to segment the pores, cement and coarse aggregate of the concrete and, finally, extracted the slice image containing only the coarse aggregate.The coarse aggregate in the specimen of this article was limestone (Limestone) material. In order to remove the impact of coarse aggregate on the overall sound velocity of the specimen, we collected limestone from the site with the same material as the coarse aggregate in the specimen tested this time and formed them into two cylindrical samples of 50 × 50 mm as shown in The correspondence between the ultrasonic survey line and the extracted coarse aggregate slices is shown in We used CAD software to mark the length of the coarse aggregate that the survey line passed through. The specific marking method is shown in The proportion of coarse aggregate on the ultrasonic survey line was obtained as shown in Table 6According to Equation (11), the corrected values for UPV without the effect of coarse aggregate are shown in The specimen in this article was taken from a corroded section of a highway tunnel in Chongqing, China, which has experienced severe sulfate corrosion. Therefore, through the accelerated indoor test, the corrosion rate of the specimen used in this paper was faster than the new concrete specimen.In Taking into account the heterogeneity of the concrete materials, the AHP-based corrosion assessment method of concrete structure proposed in this paper was used to evaluate the sulfate corrosion of the samples. First, we calculated the corrected UPV values for each experimental state according to Equation (2). The specific values are shown in It can be seen from relative corrosion coefficient results that the concrete structure calculated by the measuring value were all mild corrosion, the range of changes was small. However, from the apparent change in the concrete see , it can In order to verify the correctness of the evaluation method proposed in this paper, we carried out CT scanning tests on the concrete specimen at each experimental stage and used the scanning results to reconstruct the pores of the concrete specimen in three dimensions as shown in Judging from the three-time pore structure distribution of the concrete samples in In this paper, the porosity of a three-dimensional reconstructed model was calculated, and the change in the porosity of the concrete with the height of the concrete sample was obtained as shown in the The porosity of the three-dimensional reconstructed model was calculated, and the change in the porosity of the concrete with the height of the concrete sample was obtained as shown in (1)A CT-based analysis method for the proportion of the length of the coarse aggregate in concrete along an ultrasonic survey line was proposed. The internal structural characteristics of concrete can be accurately extracted using CT scanning, and the distribution and size of the coarse aggregate in the concrete specimen were obtained using Avizo image processing software and determined the proportion of coarse aggregate length on a certain ultrasonic test line;(2)A method for analyzing the influence of removing coarse aggregates in concrete structures on UPV was proposed. In general, the proportion of coarse aggregate in concrete structure is relatively large (up to approximately 40%), and its ultrasonic speed was large (up to approximately 6000 m/s). The coarse aggregate in the concrete was basically free from sulfate corrosion. If the influence of the coarse aggregate in the concrete is not eliminated, the change amount of the concrete ultrasonic pulse velocity value was directly used to evaluate the damage degree of sulfate corrosion in the concrete, and the results are often inaccurate. By calculating the proportion of coarse aggregate on a certain ultrasonic test line, the correction value of ultrasonic pulse velocity (UPV) of concrete structure was obtained. The effect of coarse aggregate on the concrete structure on the value of the UPV of the concrete specimen was eliminated, reflecting small changes in the value of the UPV of the concrete specimen caused by the cement matrix and pores so that the corrected change amount of the value of the UPV of the concrete could more correctly reflect the degree of corrosion damage in sulfate-attacked concrete;(3)A method for evaluating the sulfate corrosion degree of concrete specimens based on AHP was constructed. By testing and correcting the UPV in multiple directions of the concrete sample and using the AHP method to calculate the weight and the overall relative corrosion degree makes the use of ultrasonic testing to judge changes in concrete structures under sulfate attack more in line with reality. The results of experimental and porosity changes showed that the overall relative corrosion evaluation results of concrete structures calculated by corrected UPV were more accurate.This paper proposed an evaluation method for corrosion damage in sulfate-attacked concrete based on the CT, ultrasonic pulse velocity testing and AHP. CT was used to extract the coarse aggregate information in the specimen, and the proportion of coarse aggregate on the ultrasonic test line is calculated. Then, the corrected UPV values of concrete structure were calculated, and the degree of sulfate corrosion of the concrete structure was evaluated combined with the analytic hierarchy process. The main conclusions are as follows:


Enterococcus, which accompanies a decrease in probiotics-related genera such as Lactobacillus, is commonly seen across antibiotic treatments. In addition, we found that these oral antibiotics had long-term negative effects on the intestinal microbiota and promoted the development of antibiotic-resistant bacterial strains. These results indicate that ampicillin, vancomycin, metronidazole, and neomycin have long-term negative effects and can cause irreversible changes in the diversity of the intestinal microbiota, thereby increasing the risk of host disease.Oral antibiotics remain the therapy of choice for severe bacterial infections; however, antibiotic use disrupts the intestinal microbiota, increasing the risk of colonization by intestinal pathogens. Currently, our understanding of antibiotic-mediated disturbances of the microbiota remains at the level of bacterial families or specific species, and little is known about the effect of antibiotics on potentially beneficial and pathogenic bacteria under the conditions of gut microbiota dysbiosis. Additionally, the question of whether the effects of antibiotics on the gut microbiota are temporary or permanent is controversial. In this study, we used 16S rRNA gene sequencing to evaluate the short- and long-term effects of ampicillin, vancomycin, metronidazole, and neomycin on the murine intestinal microbiota. We found that the changes in the intestinal microbiota reflected the antibiotics’ mechanisms of action and that dysbiosis of the intestinal microbiota led to competition between different bacterial communities. In particular, an increase in IMPORTANCE The intestinal microbiota is a dynamic community of hundreds of millions of microorganisms that play important roles in human health. However, treatment with antibiotics can disrupt the delicate balance of this community, leading to deleterious effects on the host such as inflammation and enhanced susceptibility to infection. To date, most studies of the effects of antibiotic treatment on the microbiota have focused on specific intestinal pathogens and bacterial families. However, few studies have investigated the effects of antibiotic treatment on the relative abundance of probiotic bacteria, pathogenic bacteria, and opportunistic bacterial pathogens in the gut. Turicibacter, Coprobacillus, and Lactobacillus produce lactic acid through glycolysis, which can provide intestinal epithelial cells with nutrition and regulate immune function , but the microbial richness of the Van, Met, Neo, and S-Mix groups decreased compared to that of the control group. Beta diversity analysis (P <0.05) groups decreased compared with that of the control group. The antibiotics used to treat these three groups are active against Gram-negative, Gram-positive, and both Gram-negative and Gram-positive bacteria, respectively. Neomycin and metronidazole target aerobic and anaerobic bacteria, respectively, but they had no significant effect on the diversity of intestinal bacteria. In terms of effect on the diversity of the gut microbiota, the combination of four antibiotics was inferior to ampicillin or vancomycin alone. This indicates that the combination of multiple antibiotics did not have the greatest impact on intestinal flora, and that the combination of these four antibiotics is not necessarily the optimal choice for eliminating the intestinal microbiota in experimental mouse models.First, we carried out an unweighted pair-group method with arithmetic means (UPGMA) cluster analysis to divide the samples into groups based on microbiota composition. Samples with high similarity in terms of microbiota composition were clustered into the same branch of the evolutionary tree. analysis  showed tRuminococcus and Coprococcus of the Firmicutes decreased, while Proteus in Proteobacteria and Bacteroides in Bacteroidetes increased. At the phylum level, Verrucomicrobia (P < 0.05) and Proteobacteria increased following vancomycin treatment, while Actinobacteria , and TM7 (P < 0.05) decreased; at the genus level, Oscilillospira (P < 0.05), Allobaculum, and Coprococcus of the Firmicutes decreased, while Proteus in Proteobacteria and Bacteroides in Bacteroidetes increased. Following treatment with metronidazole, at the phylum level, Actinobacteria, Bacteroidetes, and Cyanobacteria  increased, while Proteobacteria and Firmicutes decreased; at the genus level, Coprococcus of the Firmicutes decreased, while Sutterella in Proteobacteria, Prevotella, and Bacteroides increased. After treatment with neomycin, at the phylum level, Verrucomicrobia increased, while TM7 and Proteobacteria  decreased; it is worth noting that Allobaculum and Coprococcus (P < 0.05) of the Firmicutes increased. After treatment with the mixture, at the phylum level, Actinobacteria  and Verrucomicrobia increased, while Cyanobacteria, TM7 (P < 0.05), Firmicutes, and Proteobacteria decreased. Additionally, at the genus level, Ruminococcus, Allobaculum, and Coprococcus of the Firmicutes decreased, while Sutterella and Bacteroides of the Proteobacteria decreased.Considering the substantial impact of antibiotics on the richness and diversity of the intestinal microbiota, we next decided to study its impact on specific taxa. We compared the treatment group and the control group using the Wilcoxon test at the phylum and genus level (Tables S1 and S2). Coprococcus and Lactobacillus are two types of Gram-positive anaerobic bacteria that both contain strains of typical probiotics.In general, some genera showed a decrease in relative abundance, while others showed an increase. Enterococcus, a Gram-positive, facultative anaerobic bacterium that contains multiple pathogenic strains, should theoretically have been killed by Amp, Met, and Van; however, treatment with Amp and Van led to an increase in Enterococcus abundance, and Met had no major effect on its abundance. These findings suggest that the changes that we observed in the intestinal microbiota reflect not only the mechanisms of action of the antibiotics (Table S3), but also competition between different bacterial communities induced by intestinal microbiota dysbiosis. For example, the abundance of Coprococcus and Lactobacillus, which both contain a strain of typical probiotics, decreased in the four groups of Amp, Met, Van, and Mix, however, this was accompanied by an increase in the abundance of Enterococcus, which contains pathogenic strains. The abundance between the two species did not correlate exclusively with the type of antibiotic used, but showed a similar competitive correlation.Amp, Met, and Van all reduced the abundance of these two bacteria. On the other hand, Ruminococcus , which had previously decreased, was restored to baseline levels in the Ampicillin group; in the Vancomycin group, the abundance of Oscillospira  and Coprococcus  recovered. Parabacteroides and Escherichia, which had not previously reached the detection limit in the Neo group, were detected 1 month after neomycin treatment had stopped. The abundance of Bacteroides , which had decreased, Allobaculum , and Coprococcus , which had increased, returned to baseline levels in the Mixture group. In addition, the abundance of the genera Proteus and Enterococcus, which had been detected prior to antibiotic treatment, did not reach the detection limit, and Ralstonia, which did not appear prior to treatment, was detected 1 month after withdrawal of the antibiotics.Next, we investigated the ability of the murine intestinal microbiota to recover 1 month after antibiotics had been withdrawn. We focused on those bacteria whose relative abundance changed significantly during antibiotic treatment. As shown in After antibiotic treatment, the abundance of some bacteria in the intestinal microbiota returned to their baseline levels. However, the abundance of most of the microbiota components was altered, in some cases permanently, and the microbiota composition following antibiotic withdrawal was different from that observed before treatment. Our findings show that while the abundance of some intestinal microbiota components was restored to pretreatment levels, the abundance of most of the intestinal microbiota components did not recover, and instead remained elevated. The microbiota composition of groups treated with a single antibiotic exhibited less recovery than that of the groups which received a mixture of antibiotics. These changes could increase the risk of intestinal infections and promote inflammatory responses. Our findings suggest that patients who have been prescribed antibiotics should also be supplemented with potentially beneficial bacteria to help restore the balance of their intestinal flora as soon as possible. One study found that probiotics are associated with a reduction in antibiotic-associated diarrhea , 29.Bacteroides  increased. We speculate that long-term antibiotic use led to the appearance of resistant strains in the intestinal microbiota. When a population of bacteria is exposed to an antibiotic, the frequency of resistant clones will increase over time. We suggest that this effect also applies to the entire microbiome, with various microorganisms differing in their susceptibility to different antibiotics, and that new steady-state levels will be reached as the frequency of some susceptible species decreases or they become extinct , which received either normal sterile water (control group) or continuous treatment with a mixture of antibiotics in their drinking water  for 55 days (L-Mix group). Fecal samples were collected at 11 time points, and four of these were chosen for analysis: days 5, 15, 40, and 55. Principal-component analysis (PCA)  showed t extinct , 31.Coprococcus and Lactobacillus, and an increase in the abundance of genera with pathogenic potential, such as Enterococcus. Previous studies have suggested that the decrease in the relative abundance of bacteria with beneficial potential observed after antibiotic use is due to a reduction in the absolute levels of bacteria with beneficial potential because of decreased microbiota diversity , vancomycin (V0045000), metronidazole (M3761), and neomycin (33492) were purchased from Sigma-Aldrich .n = 5 per group) were maintained in a specific pathogen-free room in the Experimental Animal Center at Tongji University, in cages with free access to water and food and a 12-h/12-h light/dark cycle. After 10-week of acclimation, the mice were fed in seperate cages. We had a total of 24 cage mice, numbered sequentially, and we randomly generated numbers up to 24 using the Microsoft Excel “RANDBETWEEN” function. The mice were organized into groups based on the generated numbers, and antibiotics were added to the drinking water based on the weight of the mice. There were six short-term experimental groups : control, Amp (100 mg/kg ampicillin), Van (50 mg/kg vancomycin), Met (100 mg/kg metronidazole), Neo (100 mg/kg neomycin), and S-Mix . In addition, there were two long-term experimental groups : control and L-Mix . The Amp, Van, Met, Neo, and S-Mix groups received antibiotics for 14 consecutive days, followed by a 30-day washout period, and finally by antibiotic administration for an additional 14 days. The L-Mix group received antibiotics for 55 days. After an overnight fast at the end of the feeding period, mice were deeply anesthetized using tribromoethanol . Blood was taken by removing an eyeball and centrifuged at 1,000 × g for 10 min at 4°C to obtain plasma. After the experiment, mice were euthanized by cervical dislocation. There were no adverse events. The ethics committee of Tongji University approved all protocols used in this study.Eight-week-old C57BL/6 mice were obtained from Shanghai SLAC Laboratory Animal Co., Ltd. Mice  according to the manufacturer’s instructions. DNA was quantified with a Qubit Fluorometer using a Qubit dsDNA BR assay kit , and the quality was checked by running an aliquot on 1% agarose gel.GTGCCAGCMGCCGCGGTAA-3′) and 806R (5′-GGACTACHVGGGTWTCTAAT-3′). Both primers were tagged with Illumina adapter, pad, and linker sequences. PCR enrichment was performed in a 50-μL reaction mixture containing 30 ng template, both tagged PCR primers, and PCR master mix. The PCR cycling conditions were as follows: 95°C for 3 min; 30 cycles of 95°C for 45 s, 56°C for 45 s, and 72°C for 45 s; and a final extension for 10 min at 72°C. The PCR products were purified using Agencourt AMPure XP beads and eluted in elution buffer. Libraries were evaluated using an Agilent Technologies 2100 Bioanalyzer. The validated libraries were then sequenced on an Illumina HiSeq 2500 platform  following standard Illumina protocols and generating 2× 250-bp paired-end reads.The V4 variable region of the bacterial 16s rRNA gene was amplified with degenerate PCR primers: 515F (5′-https://github.com/cjfields/readfq). Joint pollution reads were removed, n-containing reads were removed, and low-complexity reads were processed. Samples were distinguished based on barcode and primer. After this, we used FLASH software   . Using ov1.2.11) . Accordiv1.2.11) . phytoolv1.2.11)  were useP values of <0.05 were considered statistically significant. When the number of groups was two, the rank-sum test was used for analysis of variance, and the Wilcoxon rank-sum test was used for two-sample comparisons (in R wilcox.test). When the number of groups was greater than two, the Kruskal-Wallis test for multisample comparisons was used .Data are expressed as mean ± standard error of the mean, and PRJNA636223.The original 16S rRNA sequence data are available from the NCBI under accession number


Hydatid cystic disease (HCD) is primarily a disease of sheep and cattle. Human beings are accidental hosts. It is prevalent in the Tibet Autonomous Region (TAR) of China. In pregnancy, it can cause many complications.We present a multigravida with breech presentation at 37 weeks of pregnancy in whom a large pelvic hydatid cyst and multiple hepatic hydatids were diagnosed by ultrasonography. The large pelvic hydatid cyst was drained through the posterior fornix under the guidance of ultrasound, and an external cephalic version was performed. A healthy baby was delivered vaginally with head presentation at term.HCD during pregnancy presents with management difficulty. It is important to formulate individualized treatment plans according to the actual situation of the patient and the local level of treatment.The online version contains supplementary material available at 10.1186/s12884-022-05180-2. Echinococcus granulosus (E. granulosus) [E. granulosus [E. granulosus [Hydatid cystic disease (HCD) is a zoonotic infection of sheep and cattle caused by the larval stage of the tapeworm nulosus) . Humans anulosus . HCD is anulosus . The Tibanulosus . Women aanulosus . CurrentDuring pregnancy, the diagnosis of HCD is much more important because a decrease in cellular immunity can cause a rapid increase in parasitic growth, and the cysts enlarge . HCD canA 19-year-old woman, gravida 2, para 1, was admitted to a secondary hospital at 37 weeks of gestation with breech presentation. Her pregnancy was complicated by multiple hepatic hydatids (the largest cyst: 6.0*4.3 cm) , lungs (25%), muscles (5%), bones (3%), kidneys (2%), spleen (1%), and other sites (1%) . It is sMany studies have suggested that ultrasound is the gold-standard screening test for HCD since it can show the number of cysts and their locations and relationships with other structures , 12. SpeThe ideal treatment for HCD has not been fully determined , and manIn this case, the patient truly hoped for vaginal delivery. However, the large pelvic hydatid cyst obstructed the birth canal, and the fetus was mispresented. The patient had been operated on for abdominal echinococcosis before, and the adhesion might have been serious. Hence, even if Caesarean section is performed, the difficulty might increase, especially in secondary hospitals, where the form of medical care provided to patients is affected by geographical location due to how long it takes to transfer patients, the nonavailability of blood banks and the lack of advanced medical facilities. Based on the location of the cyst, we modified the percutaneous treatment and opted to drain the cyst through the posterior fornix under the guidance of transabdominal ultrasound. There have been few reports of treatment adopting this procedure. After confirming that the patient did not have any complications, we performed an external cephalic version for the woman, and she finally had a successful vaginal delivery. This individualized treatment not only met the requirements of the patient but also caused minimal damage to the patient and was costless and effective.In conclusion, HCD during pregnancy presents with management difficulty. It is important to formulate individualized treatment plans according to the actual situation of the patient and the local level of treatment.Additional file 1: Video 1. Draining the cyst through the posterior fornix under the guidance of transabdominal ultrasound.


The kaolinite content is principally responsible for the durability performance of Limestone Calcined Clay Cement (LC3), which calls into question its global applicability. The clay supply has a significant impact on the LC3 system’s reduced carbon footprint advantage. The influence of kaolinite concentration from two separate clays (collected in East South-East Europe) on the durability performance of concrete was investigated in this study. The low-kaolinitic clay had 18% kaolinite, while the medium-kaolinitic clay contained around 41% kaolinite. The compressive strength, chloride intrusion, electrical conductivity, surface resistivity, and sorptivity index were measured on concrete after 28 days. Furthermore, the pore structure development of these mixtures was investigated in relation to the kaolinite content of the mixtures. The reactivity test was performed on clays to measure their reactivity levels within the cementitious system. The results show that kaolinite content has a moderate effect on compressive strength, but it has a considerable effect on other durability indices. When compared to the Portland cement mixture, the chloride migration and diffusion coefficients were reduced by 50% and 36%, respectively, in the combination with a medium kaolinite content (more than 40%). The low-kaolinitic clay, on the other hand, achieved 60% of the chloride penetration resistance of the medium-kaolinitic clay. Furthermore, low-kaolinitic clay has been demonstrated to be suitable for low-carbon concrete in moderate exposure conditions. The global climate has changed dramatically in recent decades. Since the pre-industrial era, global warming has led to a temperature increase of 1.1 °C . TypicalIn general, thermal activation of kaolinitic clays leads to the formation of metakaolin, which gives the clays their reactivity. In the LC3 system, metakaolin reacts with portlandite, water, and sulfate to form C-A-S-H, ettringite, and AFm phases ,15. OtheClays with the recommended kaolinite cannot be found everywhere. Flegar et al. found that most of the clays collected in Croatia had no more than 20% kaolinite ,22,23,24The primary focus of this study was to analyze the performance of concrete with two different clays collected from East South-East Europe: one with a moderate amount of kaolinite and the other with a very low kaolin content. LC3 systems were formulated using these two clays to evaluate their durability in terms of electrical resistivity, chloride penetration, and water absorption. The aim of the research was to compare their durability and identify critical properties which are the most impacted by the kaolinite content. In addition, the effect of kaolinite content on the binding of chlorides and pore structure was systematically evaluated. Portland cement of type CEM I 42.5R (as per EN 196-1) was used in all mixtures as a primary binder. Two different clays were used, labeled A and B. The kaolinite of raw clays was determined using thermogravimetric (TG) analysis, and the mass loss between 400 °C and 600 °C was attributed to the dihydroxylation of kaolinite . LimestoThree aggregate classes were utilized, including two coarse aggregate classes 16/8 and 8/4) and one fine aggregate class (0/4).  and 8/4 In addition, a commercial superplasticizer (SP) with a solids content of 35% was used to ensure sufficient workability. Similarly, 1% gypsum was added to each mixture (in LC3 systems) of blended cement to prevent false settings produced by the system’s under-sulphation . All mixThe entire experimental program was divided into three categories: reactivity, durability properties, and pore structure development. The layout of the experimental plan is depicted in A reactivity test was conducted using TAM Air isothermal calorimeter with 8 channels  as per ASTM C1897-20  to deterClinker, calcined clay, limestone, and gypsum were manually mixed to obtain a homogenous mixture prior to concrete mixing. The highest capacity of the pan mixer used to mix the concrete was 70 L. The order of mixing was similar for each batch including the control mixture. The initial mixing of the dry components for two minutes was followed by the addition of 90% of the water and further mixing for two minutes. In the final phase, the superplasticizer was mixed with the remaining water for a further three minutes. In total, the mixing time met the requirement mentioned by the superplasticizer manufacturer to achieve the maximum dispersion of admixture. After mixing, the slump, wet density, temperature, and air content were measured immediately. Three concrete specimens of 15 cm × 15 cm × 15 cm were prepared to measure the compressive strength after 7 and 28 days of curing, and the test parameters and procedures followed the EN 12390-3 standard. Dnssm) is obtained, calculated by the Nernst-Plank equation expressed in Equation (1).dx is the average measured depth of chloride penetration after the test duration, while other parameters were taken from the NT BUILD 492. Cylindrical specimens of 20 cm height and 10 cm diameter were prepared to test the chloride penetration resistance of the mixtures. After 28 days of curing, the cylindrical specimens were split diametrically into three slices with a thickness of 5 cm. Chloride penetration resistance was measured after 28 days of curing using Rapid Chloride Permeability Test—PROOVE´it , as per NT BUILD 492 [De)P were determined by fitting the total chloride contents in second Fick’s law according to NT BUILD 443,C is the measure of chloride content at depth (x) and exposure time (t). The values of apparent chloride diffusion coefficients could be extracted after fitting the measured chloride contents. The free chloride content of each depth was also determined as water-soluble chloride, according to ASTM C1218. After the determination of free chloride and total chloride content, the bound chloride was determined as a difference between the total and free chloride. Chloride diffusion coefficients of each were evaluated based on NT BUILD 443 , and theI) is measured as the initial current by imposing voltage (V) to the specimen, and other parameters were taken from the standard.The electrical conductivity of each mixture was determined after 28 days of curing according to ASTM C1760 . The iniThe surface resistivity of each mixture was determined by Wenner’s four-probe resistivity meter on the sides of cylindrical specimens, which was used to determine the chloride transport coefficients . The mea2 solution. The specimens were supported by wooden rollers, and the solution level was restricted to within 2 mm of the surface. The specimen’s weight was measured after 3, 5, 9, 12, 16, 20, and 25 min. After weighing the samples, they were conditioned for one day in a saturated calcium hydroxide solution. The sorptivity index was calculated using Equation (4),F’ is the slope of the best fit line between mass gain and the square root of time, average thickness ‘d’, SVM, and S0M are the vacuum weight and initial weight of samples.Sorptivity, the rate of absorption in concrete, is commonly used to evaluate the resistance of concrete to moisture penetration via capillary absorption. This factor was identified as a major contributor to the initial penetration of chloride into the specimen , and thiPore structure distribution of all concrete mixtures was measured after 28 days of curing by Autopore 9500 Mercury Intrusion Porosimetry (MIP), . After the curing, the samples were collected from each mixture and the hydration was stopped by the solvent exchange method . In thisThe porosimeter is equipped with two different devices, i.e., low pressure and high pressure. The final pressure applied was 206 MPa, which covered the pore entry radius up to 5 nm. The translation of MIP data into pore volume versus pore size was done by use of the Washburn equation . The surFurthermore, the bound water of these two clays were determined as 10.9% for clay A and 9.4% for clay B. All the concrete mixtures were targeted for the slump between 90–120 mm. The values of fresh properties are given in The electrical conductivity and surface resistivity of each mixture are displayed in The chloride transport coefficients for each mixture are shown in After evaluating the chloride profile of each mixture, the total chloride content was separated into bound and free chloride contents based on Equation (4). As shown in After 28 days of curing, the pore structure development of each mixture was depicted in Furthermore, the total pore volume of each mixture divided into the classification of macro, capillary, and gel pores based on their entry diameter was analyzed . The difThe higher reactivity of calcined clay can be directly attributed to the presence of kaolinite ; clay wiThe mix with calcined clay A and calcined clay B achieved 84% and 65% of compressive strength compared to concrete mix with CEM I, respectively. In a blended system, the degree of hydration of the clinker plays a crucial role on the pozzolanic reaction. For example, if the clinker replacement with metakaolin is excessively high, there will not be enough portlandite for the pozzolanic reaction from metakaolin to occur ,39. TherLC3 mix with clay A had greater resistance to capillary absorption than LC3 mix with clay B. In general, the addition of SCMs, along with the combined pozzolanic and filler effects, results in a more complex pore network and a decrease in the water absorption from external environment ,41. FiguCompared to other pozzolanic materials used in concrete, the LC3 system is renowned for its higher electrical resistivity and chloride ingress, especially with high kaolinite content. In the case of LC3-A, the surface resistivity was significantly higher than other mixes, which is in accordance with previous research. LC3-B mixes showed comparable resistivity to CEM I mix. The higher surface resistivity of the LC3 system can be attributed to the differences in the kinetics of microstructural development in the binder systems, as well as to the presence of denser microstructure in the LC3 systems ,43. The In both chloride penetration resistance tests, concrete LC3-A demonstrated superior performance compared to concrete mixes CEM I, CEM II and LC3-B. There are several reasons for this improved behavior, all confirmed in this study and in the literature, which include pore structure refinement, bulk conductivity, chloride binding, and pore solution chemistry ,49,50,51After the resistivity, the binding capacity of the LC3 system is considered to be one of the important parameters to influence the chloride penetration . As showThe pore structure of a cementitious system is a well-known parameter which has influence on most of the hardened properties of concrete. In the case of the LC3 system, most of the researchers have reported the better pore refinement compared to other systems. Further, Dhandapani et al. reported that the threshold pore entry diameter and critical pore entry diameter were more refined in the early ages compared to the Portland and fly ash system . AdditioAccording to several researchers, the quantity of capillary pores affects the chloride penetration in the concrete. But in this investigation, LC3-A, which displayed the lowest chloride transport coefficients, obtained a much higher number of capillary pores. Unlike the capillary pores, the gel porosity obtained in both clays was similar, but the number of macro pores is much higher in LC3-B. Therefore, the influence of gel/capillary porosity on chloride adsorption has yet to be revealed with more scientific evidence. In total, chloride penetration showed higher dependency on the bulk resistivity over chloride binding and pore structure. Finally, the low-grade clay outperformed the ordinary Portland cement system and proved its high potential for use in the concrete. The compressive strength was found to be satisfactory even with low kaolin clay, even though higher kaolinitic clay was needed to attain comparable strength to that of CEM I and blended cement. Concrete with the higher kaolinitic clay was able to achieve around 85% of compressive strength compared to CEM I after 28 days.Chloride penetration, electrical activity, and sorptivity of the concrete improved significantly with higher kaolinite content. Chloride diffusion and migration resistance improved by at least 50% compared to Portland cement system with higher kaolinitic clay. Among clays, the chloride penetration resistance differs by 30% and the sorptivity indices value differs by 41%. The kaolinite content was found to be very important in durability performances of LC3 concrete.Electric resistivity of the LC3-based concrete dominantly influenced the chloride penetration over the chloride binding and pore structure.In the pore structure parameters, the pore refinement  controlled the chloride penetration, while the capillary pore volume was not identified as an important factor in the chloride penetration in the LC3 system in this study.Low-kaolinite clay (18% in this study) could be a potential material to make concrete for mild exposure conditions, while higher grade kaolin clay (42% in this study) would be needed for aggressive exposure conditions.The main aim of the current study was to analyze the durability of LC3 concrete prepared with low- to medium-kaolinitic calcined clay found in East South-East Europe. In the LC3 system, the impact of the alkali content on the development of compressive strength was discovered. The high alkali content weakens compressive strength, especially in early age. Following conclusions are drawn from the study:


Although there was no difference in the total IgG levels in patients with ischemic DCM, the serum concentrations of IgG4 were significantly higher than the corresponding values in the control group . In conclusion, we found that patients with ischemic cardiomyopathy had increased blood levels of IgG4. Additional studies with a larger number of patients are needed to support and explain this finding.Immunoglobulin is a group of proteins participating in process of inflammation. One of its subtypes is Immunoglobulin Gamma-4 (IgG4) which is related to a rare disease called IgG4-related disease and characterized by a process of fibrosis—deposition of fibers in different organs and inflammation, resulting in tissue damage and dysfunction including the heart muscle and vessels. There is a paucity of information regarding the potential link between of IgG4 and cardiovascular diseases. The purpose of this study is to assess the serum levels of IgG4 in patients with dilated cardiomyopathy (DCM), a disease characterized by cardiac muscle dysfunction of ischemic and non-ischemic origin. Ischemic heart disease is a disease in which heart muscle is damaged by inappropriate blood supply caused by blood vessel obstruction and may cause heart muscle dysfunction. Ninety-eight patients with ischemic and non-ischemic cardiomyopathy were included in this study. The serum concentrations of IgG4 were measured. Patients with DCM had significantly higher levels of IgG4 compared with the healthy control group . Although there was no difference in the total IgG levels in patients with ischemic DCM, the serum concentrations of IgG4 were significantly higher than the corresponding values in the control group . This was altered by gender and smoking. (4) Conclusions: The patients with ischemic DCM had increased serum concentrations of IgG4. Future studies are warranted to explore the potential role of an IgG4-mediated process in patients with heart failure with reduced LVEF.(1) Background: Immunoglobulin gamma subclass 4 (IgG4) is a serum protein belonging to the immunoglobulin superfamily. It has a central role in certain immune-mediated conditions defined as IgG4-related disease. There is a paucity of data regarding the potential association of IgG4 and cardiovascular diseases. Our aim is to study the serum levels of IgG4 in patients with ischemic and non-ischemic dilated cardiomyopathy (DCM). (2) Methods: patients with ischemic and non-ischemic DCM were included in this study. Non-ischemic DCM was defined as a left ventricular ejection fraction (LVEF) < 40% without coronary artery disease (CAD). Ischemic DCM was defined as a LVEF < 40% and proven CAD. The serum concentrations of IgG4 were measured by turbidimetry. (3) Results: Overall 98 patients with cardiomyopathy had significantly higher levels of IgG4 compared with the control group (77.4 ± 64.0 vs. 50.3 ± 28.8 mg/dL,  Dilated non-ischemic cardiomyopathy is one of the three traditional classes of cardiomyopathy, along with hypertrophic and restrictive cardiomyopathy . The mosIgG4-related disease (IgG4-RD) is a recently recognized autoimmune disease with pathological features that are consistent across a wide range of organ systems. This entity may involve the pancreas, salivary glands, and many other organ systems . An IgG4There have been many reports of the potential involvement of IgG4-related immune activation in cardiovascular diseases, such as inflammatory abdominal aortic aneurysms, lymphoplasmacytic aortitis, and pericarditis ,13,14. RAn increased serum concentration of IgG4 was found in patients with angiographically proven coronary artery disease (CAD), suggesting that the IgG4-related immuno-inflammatory process may play a role in the development and progression of coronary atherosclerosis, or alternatively, may mirror ongoing vessel wall inflammation . The potIn this study, we attempted, therefore, to explore the possible association between serum concentrations of IgG4 and non-ischemic dilated cardiomyopathy. As elevated levels of IgG4 were reported in patients with CAD, we investigated the serum concentrations of IgG4 in patients with ischemic cardiomyopathy.Consecutive patients with heart failure with reduced left ventricular ejection fraction (HFrEFs) referred to our heart failure clinic between October 2010 and June 2013 comprised this prospective study. All participants signed informed consent forms. Patients with non-ischemic (those with a left ventricular ejection fraction (LVEF) < 40% in whom CAD was excluded by coronary angiography) and age-, LVEF-, and New-York Heart Association Functional Class (NYHA-FC)-matched patients with ischemic cardiomyopathy (patients with a LVEF < 40% in whom CAD was proven by coronary angiography) were included in this study. The demographic and echocardiographic data of the patients were collected and analyzed. Patients with primary valvular disease, mechanical valve prosthesis, unstable angina, recent myocardial infarction (within three months), and coexisting cardiomyopathy with a known etiology  were excluded. Patients with oncological diseases (or receiving chemotherapy), autoimmune or allergic diseases, chronic infections, and inflammatory processes were excluded. Patients in whom there was a suspicion that LVEF reduction was caused by a known clinical condition  were excluded. Blood samples for CRP, ST2, NT-proBNP, and IgG4 levels were drawn. Since the normal ranges of IgG4 widely vary between populations, volunteers without known cardiac diseases were recruited, and their blood samples were drawn for levels of IgG4 to establish normal ranges of IgG4. This control group was compared with the study population by demographic data, comorbidities, and medications taken. The protocol conformed to the ethical guidelines of the Helsinki Declaration, and it was approved by our human research institutional review board.Blood samples were obtained from all patients. The samples were then centrifuged within 15 min, and the serum was stored at −80 °C. The serum concentrations of IgG and IgG4 were determined by turbidimetry and an enzyme-linked immunosorbent assay (ELISA) . The serum concentrations of NT-proBNP, the high-sensitivity C-reactive protein (hsCRP), and ST2 were measured by ELISA .p < 0.05 was considered significant. Statistical analysis was conducted using IBM SPSS version 21.0 .The mean, standard deviations, and interquartile ranges are presented, and a nonparametric Mann–Whitney test was performed to determine the statistical significance of the differences between the two groups. The original data were compared between the groups using nonparametric Kruskal–Willis tests. Wherever the Kolmogorov–Smirnov test showed a normal distribution, the data between the three groups were compared using a parametric t-test. p = 0.9 and NYHA FC, p = 0.7). Hypertension, diabetes mellitus, and hyperlipidemia were more prevalent among patients with ischemic cardiomyopathy . The patients developed ischemic cardiomyopathy at least three months after acute cardiac syndrome or coronary involvement. No patients had pancreatitis, salivary or lacrimal glands disease, tubulointerstitial kidney disease, thyroiditis, or idiopathic fibrosis in any organ system. Significantly higher levels of NT-proBNP, CRP, and ST2 were seen in patients with cardiomyopathy compared with the controls. Higher levels of ST2 were obtained in patients with ischemic cardiomyopathy compared with patients with idiopathic cardiomyopathy . No difference was found in the levels of NT-proBNP and CRP between patients with ischemic and idiopathic cardiomyopathy (p = 0.037) in patients with cardiomyopathy.Ninety-eight patients with dilated cardiomyopathy admitted to our cardiac failure clinic were recruited. The baseline characteristics of the patients are presented in myopathy . A weak p < 0.01).Forty-six volunteers without known heart diseases  were included in the study to define the normal levels of IgG4. Twenty-five percent of them had a diagnosis of hypertension, and 6% of them had hyperlipidemia treated with statins. The baseline characteristics of the controls are presented in p < 0.01). The levels of IgG in the three groups showed no significant difference . When separately comparing the patients in different functional classes, no statistically significant differences were found in the levels of IgG4 . When including gender and relevant comorbidities into the regression analysis, gender and smoking influenced the relationship between ischemic DCM and IgG4 levels . The results are summarized in The levels of IgG4 in patients with ischemic cardiomyopathy, non-ischemic cardiomyopathy, and the control group are presented in In this pilot study, we provided the first reported results of an increased concentration of IgG4 in patients with heart failure with reduced LVEFs, suggesting a link between elevated serum concentrations of IgG4 and ischemic dilated cardiomyopathy.IgG4-related disease (IgG-RD) is a relatively novel autoimmune entity initially described in Japan in 2001 ,23. In tAmong the four immunoglobulin G (IgG) subclasses , circulating levels of IgG4 are the lowest (10–135 mg/dL) and account for less than 5% of the total IgG in healthy subjects. IgG4 is regarded as an anti-inflammatory protein and one of its roles is to competitively bind antigens that cause immune reactions and thus eliminate them from the system. This anti-inflammatory role of IgG4 led researchers to believe that IgG4 may not have been a causative factor, but it instead mirrored an ongoing or recent inflammation, while the primary causative factor remained to be defined .In the last decade, several case reports describing the potential involvement of IgG4 in cardiovascular diseases were published. The most frequently reported cardiovascular presentations were aortitis (causing aortic aneurysms) ,29,30,31The overexpression of several T-helper type-2-related cytokines, such as interleukins 4, 5, and 13 and anti-inflammatory cytokines, such as interleukin 10 and transforming growth factor-β (TGF-β) were demonstrated in IgG4-related immune reactions . Most paST2, a soluble IL-1 receptor, is a biomarker reflecting pathophysiological processes, including inflammation and fibrosis. ST2 plays an important role in heart failure, represents a burden of congestion, and is especially related to left ventricular (LV) remodeling ,57. IncrThe findings of our study suggested that similar inflammatory mechanisms described in autoimmune diseases may play a role in the inflammatory response of myocardium to both ischemic injury and volume overload, leading to heart failure. Recently, Sakamoto et al. described increased IgG4 levels in patients with CAD without heart failure, suggesting that IgG-4-related immune system activation plays a role in the pathogenesis of coronary artery disease . Taking Atrial fibrillation (AF) was reported in IgG4-related disease . HoweverA certain impact on the levels of IgG4 can be expected from the medications that our patients were taking. Angiotensin II, for example, has several roles in cardiac loading condition regulation, and it was shown to signal the production of pro-inflammatory cytokines . The ACEA statistically significant difference in terms of IgG4 levels was found between the ischemic DCM and control groups, but not between non-ischemic DCM and control groups, suggesting that IgG4 may be mostly associated with inflammation as part of the atherosclerotic process and is less relevant in the case of the inflammatory process, leading to LV remodeling and myocardial fibrosis. Additional studies with larger number of patients will be able to elucidate this finding.The results of this study suggested that IgG4-driven processes may cause inflammatory vascular injury, myocardial ischemia, and subsequently, ischemic cardiomyopathy. Considering these findings, we hypothesize that IgG4 plays a role in modifying the inflammatory process, leading to LV remodeling in patients with HFrEFs.The main limitation of this study was the lack of histopathology. Elevated serum levels of IgG4 may not have necessarily proven the causal role of IgG4 in LV remodeling and myocardial fibrosis. As we mentioned before, the results of our study suggested that IgG4 may play a role either in inflammation within atherosclerotic plaques or in inflammation leading to myocardial fibrosis. Thus, future studies on the immune histopathology of both myocardium and atherosclerotic plaques are needed. If a causal role of IgG4 in ischemic myocardial damage is established by histopathology, it may change the current management of patients with ischemic heart disease, as disease-modifying therapies may be helpful in preventing LV remodeling.Another limitation of the study was the small sample size. However, being a hypothesis-generating study, its purpose was to raise the question of a possible link between an IgG4-related process and myocardial involvements in patients with HFrEFs by estimating the blood concentration of IgG4 in the patient population.In this pilot study, we found elevated serum levels of IgG4 in patients with heart failure and impaired LV function, suggesting the possibility of an association between IgG4-related inflammation and dilated cardiomyopathy of an ischemic origin. However, this study failed to show a significant elevation of the levels of IgG4 in patients with non-ischemic dilated cardiomyopathy. Future studies including a larger number of patients and more homogenous groups are needed to explore the potential role of an IgG4-mediated process in patients with heart failure with reduced ejection fractions.


MET gene in his tumor. After savolitinib treatment, the patient’s condition promptly improved, efficacy evaluation indicated partial remission, and the patient was alive and remained progression-free at 15 weeks at the time of reporting. No obvious adverse reactions occurred. Besides, another case of a female gastric cancer patient with MET amplification who received savolitinib monotherapy as a third-line treatment that remained progression-free at 12 weeks was also reported. This report provides a new reference for understanding MET abnormalities in gastric cancer and offers a possibility for future application of MET tyrosine kinase inhibitors in the therapy of gastric cancer with MET abnormalities. Also, it suggests that sequencing of MET can be considered a routine target in advanced gastric cancer patients.Gastric cancer is one of the most common malignant tumors and patients show a short survival, those combined with bone marrow invasion have a median survival of only 37 days. Here we reported the treatment of a 47-year-old male with advanced gastric cancer and complicated with bone marrow invasion and extensive metastases, who did not tolerate chemotherapy, under monotherapy with savolitinib, a MET receptor tyrosine kinase inhibitor. Before treatment, the patient was in severe pain and presented with thrombocytopenia and hemorrhagic anemia. Savolitinib was given based on amplification and rearrangement of the  Gastric cancer (GC) is the fifth most common cancer and ranks third in cancer-related deaths . The medMET gene-encoded protein c-mesenchymal-epithelial transition factor  receptor) is a tyrosine kinase receptor that modulates cell proliferation, growth, survival, apoptosis, and epithelial-mesenchymal transition. Abnormal activation of MET, which promotes tumor cell proliferation and metastasis, involves MET exon 14 skipping mutation, MET amplification, and MET protein overexpression , hemoglobin (66 g/L), and normal leukocytes (6.14 × 109/L). Tumor markers evaluation showed elevated CEA (103.30 µg/L), CA125 (36.00 U/mL), and CA19-9 (1321.73 U/mL). Enhanced computed tomography (CT) evidenced that the gastric fundus and body were thickened (in-situ hybridization showed negative Epstein Barr Virus ambiguous. A bone marrow smear (of the left posterior superior iliac spine) showed a large number of metastatic cancer cells distributed in pile, absence of megakaryocytes, and few platelets (MET amplification (copies in biopsy and plasma: 19.7 and 18.1 respectively), and MET-suppression of tumorigenicity 7 (ST7) rearrangement .A 47-year-old male was admitted for “low back pain and weight loss for 20 days”. He had a six-year history of type 2 diabetes mellitus and no other significant past or family medical histories. He was unable to walk at admission, with a Karnofsky performance status (KPS) score of 60 points and a pain number rating scale (NRS) score (0 to 10 points) of 8 points. Physical examination showed systemic mucosal pallor, gingival bleeding, a few ecchymoses on the right lower abdomen skin where insulin was injected, and lumbosacral vertebral tenderness. Blood test indicated severe low platelets  was started when no bleeding symptoms were shown. However, three days later (nineteen days after admission), dark stools and nasal mucosal bleeding appeared, and platelet count dropped to 12 × 109/L, thus S-1 was stopped. Twenty-one days after admission, the patient further developed fever, pulmonary infection, and acute left heart failure, which represented an extremely critical condition. Considering his intolerance of traditional chemotherapy as well as the significant abnormalities of the amplification and rearrangement of MET in his tumor, savolitinib was given to the patient  along with antibiotics and supportive treatments. After savolitinib treatment for four days, platelets recovered to 27 × 109/L. Bone pain symptoms were significantly relieved and the dosage of analgesics was reduced. Eighteen days after savolitinib treatment, platelets recovered to 81 × 109/L, the thrombopoietic agents were stopped, then the patient was discharged. Fifty-five days after savolitinib treatment, the patient returned for a follow-up session. He was able to walk, had a KPS score of 80 points, and a pain NRS score of one point. Physical examination showed no signs of skin petechiae, ecchymoses, and lumbosacral vertebral tenderness. Blood test indicated normal platelets (188 × 109/L), hemoglobin (111 g/L), and leukocytes . Tumor markers significantly decreased . CT re-examination showed that gastric fundus and body wall were thinner  plus supportive treatments. His hemoglobin and platelets slightly and transiently increased after blood transfusion but rapidly decreased. Eleven days after admission, the patient received one dose of 240 mg nivolumab. However, the transfusion effect declined after repeated platelet transfusion probably due to the positive anti-platelet antibodies. To block the effect of platelet antibodies, intravenous immunoglobulin  was infused several times before subsequent platelet transfusion. Sixteen days after admission, induction chemotherapy with low-dose tegafur-gimeracil-oteracil potassium (MET amplification (9.1 copies in biopsy), microsatellite stable, and tumor mutation burden 3.95 mutations/Mb. She was diagnosed as cT4aN3M1 stage IVB GC , extensive lymph node metastases in perigastric, retroperitoneal, and mesenteric regions, massive abdominal-pelvic ascites, with MET amplification). After an 8-month first-line therapy of nivolumab plus S-1 and oxaliplatin , and a 4-month second-line chemotherapy of paclitaxel-albumin, she had a KPS score of 70 points and a pain NRS score of 4 points , her primary tumor lesion and metastases markedly progressed both in size and quantity, with multiple new metastases in bones. She could not tolerate continued chemotherapy. Considering that MET amplification was detected in her tumor (9.1 copies), she received savolitinib monotherapy as a third-line treatment. By the eighth week, she had a KPS score of 90 points, abdominal pain relieved (NRS score of 0 points), and gained 10 kg in body weight. CA19-9 dropped from > 12000 U/ml pretreatment to 2704.83 U/ml, CEA from 26.27 ug/L to 6.73 ug/L. CT re-examination showed PR , immunotherapy, and targeted therapy are mainly used to treat advanced GC  antibodies, is often needed for the therapy of autoimmune diseases based on its contribution to anti-inflammatory and immunomodulatory activities . In clinPharmacokinetics of a single dose of S-1 showed that the mean half-life of its active components are between 1.9-13.1 hours . Our patMET in the tumor of this patient attracted our attention. MET is located on 7q21-31. Since the 1980s, MET exon 14 skipping mutation, MET amplification, and MET protein overexpression have been associated with tumor cell proliferation and metastasis -TKI resistance  of 42.9%, a median progression-free survival (PFS) of 6.8 months, and a median OS of 12.5 months  had significant longer median PFS and higher ORR than the MET-independent subgroup    and GC which is related to MET abnormalities. In a single-arm phase II study (NCT02127710) of PRCC patients treated with savolitinib, patients in the MET-driven subgroup  . A phase% vs 7%) . However% vs 7%) . These iMET amplification is present 1% to 10% GC  was distinctly lower than that of patients with a lower copy number (o 10% GC . Previou5 months . Lee et y number .MET copy number greater than 10 (incidence 3.5%) treated by savolitinib monotherapy was 50%, and their PFS were 4-6 months (MET status), 1 of 2 patients with GC achieved SD , rather than point mutation in multiple tumors, and is believed to be a tumor suppressor gene . Introducing the rearranged gene to ALK-TKI-sensitive cell line induced resistance to ALK inhibitors, and this resistance was reversed by combining treatment with MET-TKIs   . These fMET was highly amplified and co-existed with MET-ST7 rearrangement. In the situation that routine chemotherapy was not well tolerated and the patient’s condition was extremely critical, considering the significant abnormalities of his MET gene as well as the published clinical data and drug accessibility, savolitinib monotherapy was selected. After savolitinib treatment, the patient’s condition promptly improved, his platelets returned to normal, anemia and bone marrow invasion disappeared. Tumor efficacy evaluation indicated PR and maintained over 15 weeks, no obvious adverse reactions occurred. We cannot completely rule out the possibility that the treatment effect is the result of a combination of all three treatments , this is the limitation of our report. But taking into account that the patient received only one dose of nivolumab and 3-day low-dose S-1 before savolitinib treatment, accompanied by repeated IVIG which could accelerate nivolumab’s clearance, his condition was still rapidly deteriorating, we believe that the anti-tumor activity of savolitinib played a major role in his treatment strategy.The male case reported in this article is an advanced GC patient with bone marrow invasion and extensive metastases, whose MET amplification, providing a potential and effective treatment option for such patients.In general, this report of savolitinib monotherapy validated the prominent efficacy of savolitinib in the treatment of advanced GC with MET abnormalities, who responded to savolitinib monotherapy promptly and positively. It provides a new reference for understanding MET abnormalities in GC, and offers a possibility for future application of MET-TKIs in GC patients. Also, it suggests that sequencing of MET can be considered a routine target in advanced GC patients.Here we report the treatment of aggressive advanced GC patients with The original contributions presented in the study are included in the article/Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.WY, LS, ZZ, and MD contributed to the implement of the treatment. WY and LH contributed to the collection, analysis and interpretation of data, drafting and revision of the manuscript. SY contributed to the conception of the treatment, revision and approval of the final manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (No.81702312) in the medical writing assistance and publication fees of the paper.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.


Magnetic resonance electrical properties tomography (MR‐EPT) is a technique used to estimate the conductivity and permittivity of tissues from MR measurements of the transmit magnetic field. Different reconstruction methods are available; however, all these methods present several limitations, which hamper the clinical applicability. Standard Helmholtz‐based MR‐EPT methods are severely affected by noise. Iterative reconstruction methods such as contrast source inversion electrical properties tomography (CSI‐EPT) are typically time‐consuming and are dependent on their initialization. Deep learning (DL) based methods require a large amount of training data before sufficient generalization can be achieved. Here, we investigate the benefits achievable using a hybrid approach, that is, using MR‐EPT or DL‐EPT as initialization guesses for standard 3D CSI‐EPT. Using realistic electromagnetic simulations at 3 and 7 T, the accuracy and precision of hybrid CSI reconstructions are compared with those of standard 3D CSI‐EPT reconstructions. Our results indicate that a hybrid method consisting of an initial DL‐EPT reconstruction followed by a 3D CSI‐EPT reconstruction would be beneficial. DL‐EPT combined with standard 3D CSI‐EPT exploits the power of data‐driven DL‐based EPT reconstructions, while the subsequent CSI‐EPT facilitates a better generalization by providing data consistency. A hybrid method for electrical properties tomography (EPT), which combines deep learning EPT (DL‐EPT) and contrast source inversion EPT (CSI‐EPT), is presented. Its accuracy and precision are investigated by means of realistic electromagnetic simulations at 3 and 7 T. The presented hybrid method shows potential improvements compared with standard EPT methods, since it exploits the power of data‐driven DL‐based EPT reconstructions, while the subsequent CSI‐EPT algorithm facilitates a better generalization by providing data consistency. CSFcerebrospinal fluidCSIcontrast source inversionDLdeep learningEMelectromagneticEPselectrical propertiesEPTelectrical properties tomographyGMgray matterMR‐EPTmagnetic resonance electrical properties tomographyRRErelative residual errorSNRsignal‐to‐noise ratioWMwhite matter.1σ and relative permittivity εr) is of high interest for different applications such as improving the local specific absorption rate quantification used in, for example, hyperthermia treatment planning or safety assessment in MRI.Knowledge of in vivo tissue electrical properties .Inverse methods like contrast source inversion electrical properties tomography (CSI‐EPT)Recently, a new approach, called deep learning‐electrical properties tomography (DL‐EPT),In this work, a two‐step approach is proposed, where Helmholtz‐based reconstructions  and deep learning reconstructions (DL‐EPT) are used as data‐driven initializations for 3D CSI‐EPT. We show that an accurate initialization guess provided by DL‐EPT improves CSI‐EPT reconstructions, while CSI‐EPT has the potential to improve tissue structure of DL‐EPT reconstructions.22.13 grid. For these B^1+ field simulations, the object is bounded to the reconstruction domain (128×128×56 voxels), to prevent influences from tissues outside the reconstruction domain on the B^1+ field.Electromagnetic (EM) field simulations were performed using the commercial finite‐difference time‐domain EM simulation software XFdtd . At 3 T a high‐pass quadrature birdcage body coil  resonant at 128 MHz was simulated, surrounded by a shield , while for simulations at 7 T a high‐pass quadrature birdcage head coil  resonant at 300 MHz was used, surrounded by a shield . The head of the male human body model , μ the permeability of the tissue, which is assumed to be equal to that of free space, and ε0 the permittivity of free space. If the left‐hand side of Equation  obtained from realistic EM simulations at 3 T performed in Sim4Life  with noise superimposed were used to train the network. The head models were obtained by changing conductivity and permittivity values of the male (Duke) and female (Ella) human head models from the Virtual Family, and by including geometrical transformations such as compression/dilatation, rotation, and translation.Deep learning EPT is a data‐driven approach, where a surrogate model based on accessible MR quantities is learnt. Following the procedure indicated in Mandija et al.,2.2.3χ^ describing the EPs and the contrast source w^=χ^E^, where E^ is the electric field strength. The functional that is minimized is given byρ^ is the mismatch between measured and modeled data, r^ describes the discrepancy in satisfying Maxwell's equations, and the superscripts ‘sc’ and ‘inc’ denote the scattered and incident part of the EM fields  containing the average expected EP values  was used as initialization. We refer to these standard CSI reconstructions as H‐CSI.Three‐dimensional CSI‐EPT is an iterative method that minimizes a cost functional based on models of the contrast function 2.2.4As hybrid approaches, we used the performed MR‐EPT and DL‐EPT reconstructions as initialization masks for 3D CSI‐EPT reconstructions. Hereafter we call these two hybrid approaches MR‐CSI and DL‐CSI.Note that DL‐EPT reconstructions are available only at 3 T. Therefore, for DL‐CSI reconstructions at 7 T, we also used as initialization step the DL reconstruction at 3 T.2.3B^1+ fields. Then reconstructions are performed for a realistic SNR value as indicated by Gavazzi et al.B^1+ is 22 at 3 T, while it is 92 at 7 T.For all these five methods, EP reconstructions are first performed on data with signal‐to‐noise ratio (SNR) ≈ 1000 by adding Gaussian noise to the real and imaginary parts of the simulated complex Since EP reconstruction methods may lead to voxels with unrealistic EP values, minimum and maximum constraints were applied to the final reconstructions, that is, bounding the conductivity in the range [0–2.6] S/m and the permittivity in the range [1–100], where the maximum values are approximately 20% higher than the maximum EP values present in the ground‐truth dielectric models.x^ depicts the true conductivity or relative permittivity and x˜ the reconstructed one, and the norm is the Euclidean norm defined over the complete domain of interest.For all these reconstructions, mean and standard deviation values were computed in the white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) regions as a proxy of accuracy and precision of these reconstruction methods. Moreover, to evaluate the overall reconstruction accuracy among the investigated EP reconstruction methods, the global relative residual error (RRE) was computed as3B^1+ data using the standard 3D CSI‐EPT (H‐CSI) and the two hybrid CSI‐EPT approaches (MR‐CSI and DL‐CSI). All the results are obtained after 500 CSI iterations (taking around 60 minutes on an Intel i7‐6700 CPU for this reconstruction domain size), at which point the mismatch functional has decreased to a value of about 5×10−5.Figure |E^|‐field region. However, in the low |E^|‐field region (ventricles), conductivity reconstructions are still erroneous. MR‐CSI permittivity reconstructions shows severe distortions throughout the brain, reflecting the severe boundary errors of standard MR‐EPT reconstructions . The introduction of noise results in nonsignificant differences for H‐CSI reconstructions at both 3 and 7 T. This is in contrast to MR‐CSI, for which initialization maps, that is, EP maps obtained from standard Helmholtz MR‐EPT reconstructions, are extremely sensitive to noise  as a proxy of accuracy and precision.B^1+ data. For a direct quantitative comparison, the computed RRE in the whole domain is also reported in the figure for each reconstruction method.Figure |E^|‐field region. These errors appear as artificial bands/shadow artifacts, which are intrinsically caused by the homogeneous initialization. MR‐CSI is strongly affected by the reconstruction errors present in MR‐EPT, which is used as an initialization guess. Although the RRE is lower compared with MR‐EPT reconstructions, the quality of MR‐CSI is still poor. DL‐CSI reconstructions show good‐quality EP maps. The combined conductivity and permittivity RRE values of DL‐CSI are lower compared with H‐CSI at both 3 and 7 T, showing an advantage in using DL as the initialization guess. Artifacts such as the artificial bands present in H‐CSI reconstructions are highly reduced in DL‐CSI. Improvements are also observed with respect to DL‐EPT  into a hybrid reconstruction approach, that is, by providing MR‐EPT or DL‐EPT reconstructions as an initialization guess for CSI‐EPT. By doing so, CSI provides data consistency for MR‐EPT or DL‐EPT reconstructions, that is, the data need to satisfy Maxwell's equations, while MR‐EPT and DL‐EPT reconstructions provide, in principle, a better initialization guess for CSI‐EPT compared with the standard approach, which uses a simple homogeneous mask.Reconstructions obtained with CSI‐EPT depend on the map provided as initialization guess. If a homogeneous mask is provided (H‐CSI), sharp tissue boundaries are in principle reconstructed for a noiseless situation only after a larger number of iterations .If available methods like MR‐EPT are used as the initial guess, improvements can be observed in noiseless cases. However, for realistic scenarios (SNR=100), MR‐EPT reconstructions are severely affected by noise. As shown in this work, this also corrupts MR‐CSI reconstructions.B^1+, resulting in more accurate conductivity reconstructions at 3 and 7 T compared with the other methods presented in this work. DL‐CSI is able to provide data consistency, which, in principle, can allow higher fidelity in the reconstructed tissue structures. For permittivity reconstructions, we did not observe a substantial improvement in the reconstruction accuracy for DL‐CSI compared with DL‐EPT. Still, DL‐CSI reconstructions at 7 T show an improvement compared with DL‐CSI reconstructions at 3 T, indicating the benefit of high field strength MRI for permittivity reconstructions.DL‐EPT is more noise‐robust than MR‐EPT, as the adopted network was trained on noisy data. The training of each network takes approximately 5 hours on a GPU NVIDIA Tesla P100 16‐GB RAM, while DL‐EPT reconstructions can be performed within a minute. An important issue for DL‐EPT is the need for a large training dataset to allow for better generalization, that is, to use DL‐EPT for in vivo models that have different features from the ones the algorithm was trained on. Indeed, initial results for in vivo cases show that geometric variability in training datasets is a major cause of reconstruction errors for DL‐EPT.B^1+ field magnitude and phase with increasing field strength. A weakness of CSI‐EPT is that knowledge of the transmit phase is required, which is not directly available from MRI measurements. For this purpose, the transceive phase assumption is often applied, but this becomes less accurate at higher field strengths.A limitation in this work is that DL‐EPT reconstructions were not available at 7 T, since the network was only trained on simulated noisy data at 3 T. We believe that by using 7 T DL‐EPT reconstructions in the future, DL‐CSI reconstructions can improve further due to the higher imprinting of EPs in the measured fields, leading to higher spatial variations in the In conclusion, the combination of noise‐robust DL‐EPT reconstructions and 3D CSI‐EPT reconstructions allows, in principle, better generalization, since CSI‐EPT introduces data consistency for the subject at hand. This might reduce the need for an exhaustive training dataset for DL‐EPT. Meanwhile, using DL‐EPT as initialization for CSI‐EPT improves the quality and accuracy of standard 3D CSI‐EPT reconstructions.1+ data of the Duke head model. These reconstruction are used as initialization for MR‐CSI and DL‐CSI. Note that a DL‐EPT network at 7 T is not available and these reconstructions are therefore not included. Conductivity (a‐h) and permittivity (i‐p).Figure S1: MR‐EPT and DL‐EPT reconstructions from 3 T and 7 T BClick here for additional data file.TABLE S1 The mean and standard deviation of the reconstructed EPs for the segmented regions of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) for the Duke head model for two noise levels at 3 and 7 T. The difference in averages between the different SNR cases in MR‐EPT (and thus MR‐CSI) is due to the applied minimum and maximum constraintClick here for additional data file.


The goal of this study was to determine the coefficient of permeability as well as the rate of carbonation of concrete constructed with rice husk ash (RHA) as a partial replacement for cement  and two different concentrations of soap solutions . The microstructural studies of RHA, and carbonated samples have been conducted by using Scanning Electron Microscope (SEM) and X-Ray Diffraction (XRD) analysis. According to this study, the carbonation depth of concrete made with 1% and 2% soap solution concentration and without rice husk ash decreased by 11.89% and 46.55%, respectively. From the results, it may also be observed that the carbonation depth of concrete made with up to 10% replacement of cement by rice husk ash led to maximum carbonation resistance, while more than 10% replacement of cement showed higher carbonation depth. It is also observed that the coefficient of permeability of concrete with 2% soap solution significantly decreased as compared to the 1% soap solution and control mix. It may be observed from the SEM images that 0% soap solution (M1) concrete has a very rough concrete surface which may indicate more voids. However, 2% soap solution concrete has a much smoother surface, which indicates a smaller number of voids. Furthermore, the SEM images showed that the soap solution helps in filling the voids of concrete which ultimately helps in reduction in permeability. Energy Dispersive X-Ray Analysis (EDX) of concrete with 0% (M1) and 2% (M6) soap solution disclosed that the concrete with 2% soap solution (M6) exhibited more silica element formation than the concrete with no soap solution (M1). Carbonation occurs in concrete because the calcium bearing phases present are attacked by carbon dioxide of the air and converted to calcium carbonate. When the pH of concrete is reduced to about 9 or below, the passive layer of the steel reinforcement is destroyed and corrosion of the steel takes place [Durability is one of the important parameters that must be taken into consideration during the construction of reinforced concrete (RC) structures. The permeability and carbonation of concrete are the two major parameters that lead to the corrosion of reinforcement in RC structures. These days, the world is more concerned about reducing the generation of CO CO2 gas . Utilizabonation . Because2), which results in the pH 12.5 for fresh concrete [Rice husk ash is an industrial waste of the rice industry and dumping of RHA is also a major problem for the industry. The partial replacement of cement by RHA reduces the dependency on cement as RHA is a rich source of silica. It also helps in reducing the problem of RHA dumping . When paconcrete ,8. Concrconcrete  had prep2 emissions by 25% while increasing cost efficiency by 65% throughout the concrete manufacturing process. The study’s results show that building practices have become more environmentally friendly, and also point to potential new avenues for RHA’s waste management.Ozturk et al.  revealedVishavkarma and Harish  have cheAccording to Abdila et al.  the use Amin MN et al.  stated tEdward Scripture et al.  had prepIn this paper, the problem of carbonation has been tackled by replacing the cement with RHA at different concentrations of the soap solution. The effect of replacement of cement by RHA at different soap solution concentrations on the compressive strength of concrete structure was studied. The effect on carbonation and permeability of concrete structure also been discussed in this paper at different concentrations of soap solution and at different ratios of RHA.The ordinary Portland cement (43 grade) cement was used, satisfying Indian standards IS: 8112-1989 . Soaps a3, fine aggregate 732.94 kg/m3 and coarse aggregate 1223.34 kg/m3 was used. Concrete cubes of size 150 × 150 × 150 mm were prepared with three replicates for two concentrations of soap solution  and different replacement levels of rice husk ash in place of cement . Soap solution of concentration 1% and 2% was prepared by weight with pH value 12.Mix design as per IS 10262:2009  of M20 gThe slump value of the concrete was kept between 50 mm to 65 mm using suitable doses of MasterGlenium ACE 30 super plasticizer , which i2 cylinder was attached to the carbonation chamber. After 70 days of accelerated carbonation exposure, carbonation depth on each concrete cube was measured by splitting the cube into two halves and spraying the 1N phenolphthalein indicator on the new split surface. This indicator changed the color of the uncarbonated part to dark pink whereas the carbonated part was colorless. The carbonation rate coefficient was calculated from the results of carbonation depth using the square root equation as given in Equation (1).x’ is depth of carbonation, ‘t’ is time of accelerated carbonation exposure and ‘k’ is carbonation rate coefficient.Concrete cubes were taken out from the curing tank at the age of 7 and 28 days and compressive strength of the cube was tested for each set as per IS 516:1959 . After 2k is coefficient of permeability, Q is discharge in ml, A is area of specimen, T is time in sec, H is head of water and L is length of specimen.The permeability of the concrete cubes was also measured at the age of 42 days (28 days moist curing followed by 14 days laboratory conditioning) . As per Compressive strengths of different mixes at 7th and 28th day for 1% and 2% soap solution and different percentages of rice husk ash are given in 2. The carbonation rate coefficient was calculated using square root formulae. From The carbonation depth of the concrete made with all mix combinations were determined at the accelerated carbonation exposure age of 70 days through spraying phenolphthalein solution on the split surface as depicted in The coefficients of permeability of concrete mixes M2 and M6 are 3.44% and 85.86% compared to that of concrete M1, respectively. From The above-mentioned observation may due to the effect of soap solution in concrete mixture. Soap is a water reducing agent and it makes the cement surface particles hydrophilic after absorption. HO-C-H, O-H, COOH, HO-C-C=O are the different active groups in the molecule which promote this adsorption. These agents are mainly anionic, which gives a negative potential to the particles. This results in the orientation of the water dipole, thus facilitating its mobility due to the prevention of close approach to particles. Soap also influences the form of crystallization products of hydration, the rate of hydration and the establishment of a rigid structure in the cement paste. The properties of the absorbed layer at the surface particle reduces the water content. The water reducing agent does not change capillary structure but decreases the water binder ratio and gives the desired flow.SEM images of M1 and M6 are shown in iThe 28 days compressive strength of concrete containing 1% and 2% soap solution decreased by 8.4% and 15% compared to that made without soap solution and RHA.iiThe carbonation depth of concrete made with 1% and 2% soap solution concentration and without rice husk ash decreased 11.89% and 46.55%, respectively.iiiThe carbonation depth of concrete made with up to 10% replacement showed maximum carbonation resistance, while more than 10% replacement of cement showed higher carbonation depth.ivThe coefficient of permeability of concrete for 2% soap solution significantly decreased compared to that 1% soap solution and control mix.vIncreasing the percentage of rice hush ash content has a negligible effect on the coefficient of permeability of concrete made with 2% soap solution concentration.viFrom these results, it is concluded that the reduction in coefficient of permeability is mainly because of the soap solution.viiThe rice husk ash carbonation depth has been reduced but only up to 10%, and any further replacement increases the carbonation depth.From the result of compressive strength, it is observed up to 10 percent replacement of cement by rice husk ash showed negligible variation in 28 days compressive strength compared to that of the control mix irrespective of soap solution concentration. Moreover, it was found that:


The development of broad-spectrum antibiotics to control multidrug-resistant bacteria is an outdated business model. This strategy has led to the introduction of highly effective antibiotics, but their widespread use has contributed to the emergence of even broader antibiotic resistance. In a strategy to combat antimicrobial resistance, we believe that the use of narrow-spectrum antibiotics should be promoted. This should involve both the repositioning of old antibiotics and the reorientation of research and development towards new narrow-spectrum antibiotics with a low ecological impact. These antibiotics could be prescribed for common conditions such as sore throats and cystitis, which account for the bulk of antibiotic use in humans. Narrow-spectrum, targeted, microbiome-sparing antibiotics could help control antibiotic resistance while being economically sustainable. Their development and production should be supported by governments, which would ultimately benefit from reduced health care costs. The annual number of deaths due to antibiotic resistance is estimated at 33,000 in Europe and 35,000 in the USA ,2. GlobaThe ability of bacteria to become resistant to antibiotics is a systematic process directly related to antibiotic use . The unnMost new antibiotics in the pipeline are broad-spectrum compounds with a high ecological impact, driving up resistance rates ,9. To coTo avoid the threat of a post-antibiotic era, we believe this vicious circle must be broken.Our objective in this viewpoint is to promote our vision of the means to confront the dearth of new antibiotics and to call for a paradigm shift in antibiotic research, by focusing on antibiotics with a low ecological impact and a narrow spectrum that can be used extensively. After providing our interpretation of the history of antibiotic production in Modern research in antibiotics began with Paul Ehrlich and accelerated after World War II with a Golden Age during the 1950s and the 1960s ,15. It wSince the 2000s, bacterial resistance has increased rapidly with the emergence of new resistance enzymes spreading in hospitals but also among the general population, namely plasmid-mediated cefotaximases among extended-spectrum beta-lactamase-producing bacteria (CTXM ESBLs) and then carbapenemases with New Delhi metallo-beta-lactamases (NDMs) in India and Oxacillinase-48 (Ox48s) in Africa ,22,23. TOne of the main strategies has been to restrict the use of classes of molecules identified as particularly resistance-generating (carbapenems and fluoroquinolones) ,26. AnotThis list, which was established to respond to the problem of highly resistant bacteria, has unfortunately only addressed the issue of the fight against antibiotic resistance from a therapeutic rather than a preventive perspective. The adage “prevention is better than cure” has been forgotten, and the development of antibiotics with a low ecological impact has not been considered. The increase in resistance rates seems to create new market opportunities for antibiotics. The expected number of sales is fundamental for the pharmaceutical industry because clinical development of antibiotics is costly and risky. Only 20% of antimicrobials entering phase one will ever be marketed for medical use. The commercialization of an antibiotic only becomes profitable for a laboratory shortly before the loss of its licence. Antibiotics have been produced specifically to treat infections caused by highly resistant bacteria, but the absolute number of infections caused by highly resistant bacteria is relatively low in countries able to purchase these new antibiotics. As soon as the new broad-spectrum antibiotics become available, antibiotics stewardship policies will restrict the prescription of these molecules: firstly, by limiting prescriptions to documented infections with highly resistant bacteria  and, secEach newly approved antibiotic thus captures a smaller and smaller share of the market for shortened treatment durations and thus achieves very disappointing sales . In view of this situation, governments have implemented strategies to support the production of antibiotics by the pharmaceutical industry. Two strategies are in place: “pushes” to propel new drug candidates produced by small companies through funding and special approvals; and “pulls” to support the next step after marketing approval ,34,35. These strategies have had many favourable effects with a significant increase in new antibiotics being marketed. Unfortunately, only about ten molecules in development today are microbiome-sparing antibiotics. On the other hand, most new antibiotics target the same resistant bacteria (carbapenem-resistant enterobacteria). The competition generated by this phenomenon, also known as “me too”, has contributed to disappointing sales by fragmenting the market . The firWe reviewed published papers focusing on antibiotic production and antibiotic history. MEDLINE was searched through PubMed with June 2022 as the publication date limit, using MESH terms. The MESH terms included «antibiotic access»; «antibiotic innovation»; «financial incentives»; «antimicrobial resistance»; «narrow-spectrum antibiotics»; «ecological impact».Antibiotics can be classified according to their spectrum (narrow or broad), their ability to remain active against highly resistant bacteria or their ability to spare the patient’s microbiota. Public health authorities, researchers and industry need to work together to define and meet the needs through a four-fold approach. Funders, governments and health insurers should establish target product profiles according to their needs and specific epidemiological characteristics for the production of new antibiotics. These should fall into two distinct categories: (1) broad-spectrum antibiotics designed to be effective against highly resistant bacteria with low anticipated sales (niche products), and (2) “microbiome-sparing antibiotics” with high anticipated use. Old molecules can be repositioned by proposing new indications that require innovation in prescribing methods. For example, temocillin was forgotten for many years, then remarketed and positioned as an alternative to carbapenems in infections due to 3GC-resistant Enterobacteriaceae . The shoMany old narrow-spectrum antibiotics can be positioned in good practice guidelines based on existing literature or recommendations. For example, penicillin V used in the treatment of strep throat in Scandinavian countries could be included in other national guidelines . AnotherIn recent years, the concept of the ecological impact of antibiotics, described 20 years ago, seems to have undergone a revival. The evaluation of the ecological impact of antibiotics in patients is defined by A. Andremont et al. as follows: “it encompasses the emergence and spread of resistance genes and resistant strains as well as changes in the distribution of microbial populations in the human commensal flora or environmental flora” . All new antibiotics on the market have been designed to address the problem of multidrug resistance without any consideration for their potential ecological impact. Multidrug resistance is in many situations a marginal issue with respect to all prescribed antibiotic therapies. However, these therapies contribute to the emergence of multidrug resistance because of their broad spectrum and their ecological impact. Following the logic of “prevention is better than cure”, we propose to develop narrow-spectrum molecules with a low ecological impact. This strategy would drastically reduce the selection pressure on commensal flora and contain the emergence of resistance. On the other hand, the narrow spectrum of the antibiotic limits its use to a precise indication; for example, bacterial cellulitis can be treated with penicillin G . PenicilThis concept, introducing the notion of “targeted microbiome-sparing antibiotics”, has recently been supported by Alm in 2020  and AvisMore than a dozen new narrow-spectrum antibiotics are currently being developed. For example, murepavadine (POL7080) is an inhibitor of LptD, a membrane protein involved in surface lipoprotein (SLP) transport, with a very narrow spectrum restricted to Pseudomonas aeruginosa . AfabiciIt would then be possible to prescribe narrow-spectrum antibiotics that spare the individual’s microbiota. The almost exclusive use of narrow-spectrum molecules would require a significant shift in antibiotic prescription patterns. The systematic use of broad-spectrum antibiotics in the probabilistic treatment of infections has atrophied our diagnostic skills. Thus, a third-generation cephalosporin will be equally effective on a community skin, lung or digestive infection. Broad-spectrum antibiotics have not stimulated our clinical ability to distinguish viral infection from bacterial infection. Nor has the use of broad-spectrum antibiotics fostered the search for and use of rapid microbiological diagnostic tools to identify the pathogen and de-escalate to narrower-spectrum antibiotics. The use of narrow-spectrum antibiotics requires a precise diagnosis, supported by modern and rapid biological methods, and their use would recompose the set of recommendations for antibiotic therapy. In general practice, many microbial infections involve only a narrow array of bacteria. For example, strep throat, streptococcal cellulitis and all urinary tract infections could benefit from narrow-spectrum probabilistic treatment targeting only enterobacteria or streptococci. At the hospital level, the development of rapid molecular techniques now allows for rapid de-escalation strategies or even immediate documented treatment, making it possible to spare broad-spectrum molecules ,51. AbbaThe indications for broad-spectrum molecules would be reduced to the rare severe septic states with no identified source of infection. By promoting the systematic prescription of narrow-spectrum antibiotics as part of an antimicrobial stewardship program, the indications for narrow-spectrum antibiotics would be very broad, leading to a “profitable” market for the pharmaceutical industry. To support the transition from broad-spectrum to narrow-spectrum antibiotics, health authorities could require that any new application for marketing authorization be subject to an assessment of the impact of antimicrobials on the human flora . This apThe pharmaceutical industry’s main response to the issue of antimicrobial resistance has been to produce new broad-spectrum antibiotics that are still ineffective against multidrug resistant bacteria, thus amplifying antibiotic resistance. In order to combat this phenomenon, antibiotic stewardship programmes aim to restrict the use of these new antibiotics. The development of broad-spectrum antibiotics to control multidrug resistant bacteria is thus an obsolete business model. In our opinion, it is now essential to redirect research and development towards new, narrow-spectrum antibiotics with a low ecological impact. These antibiotics could be prescribed for common conditions such as sore throats and cystitis, which account for the bulk of antibiotic consumption in humans. Narrow-spectrum, targeted, microbiome-sparing antibiotics could help control antibiotic resistance while being economically sustainable. Their development and production should be supported by governments, which would ultimately benefit from reduced health costs. The pharmaceutical industry must reorient research and development in antibiotic therapy towards the production of narrow-spectrum antibiotics with a low ecological impact.