Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, leading to a large global cancer burden. Hepatocyte growth factor (HGF) and its high-affinity receptor, mesenchymal epithelial transition factor (c-Met), are closely related to the onset, progression, and metastasis of multiple tumors. The HGF/c-Met axis is involved in cell proliferation, movement, differentiation, invasion, angiogenesis, and apoptosis by activating multiple downstream signaling pathways. In this review, we focus on the function of the HGF/c-Met axis in HCC. The HGF/c-Met axis promotes the onset, proliferation, invasion, and metastasis of HCC. Moreover, it can serve as a biomarker for diagnosis and prognosis, as well as a therapeutic target for HCC. In addition, it is closely related to drug resistance during HCC treatment. Hepatocellular carcinoma (HCC) is the sixth most common cancer and the fourth leading cause of cancer-related death in the world , and itsSystemic treatments with sorafenib or lenvatinib followed by regorafenib, nivolumab, or ramucirumab have been demonstrated to improve survival . Among tHepatocyte growth factor (HGF) and its high-affinity receptor, mesenchymal epithelial transition factor (c-Met), are closely related to the onset, progression and metastasis of multiple tumors. The HGF/c-Met axis has a pivotal role in normal liver growth, regeneration, and protection . Inapproin vitro experiments as a hepatocyte mitogen  homology domain β-propeller, the known HGF β chain binging site. The second and third hotspot are known as the HGF α chain, localized on blade five of the SEMA domain and immunoglobulin-plexin-transcription factor (IPT) homology domains 2–3, respectively. The fourth hotspot is not previously correlated with the HGF binding site, which is across the plexinsemaphorin-integrin homology domain (PSI)-IPT 1 domains. C-Met, activated by the canonical pathway or the non-canonical pathway is involved in cell proliferation, motility, angiogenesis, invasion, and apoptosis.The canonical mode of c-Met activation involves the binding of HGF to c-Met, which induces homodimerization and autophosphorylation of the cytoplasmic domain of c-Met and then triggers downstream signaling pathways, including the mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) , phosphain vivo experiments. (VI) Autocrine Met-induced-activation is due to ectopic Met expression in cells yielding HGF, especially in acute myeloid leukemia  Des-γ-carboxy prothrombin (DCP) is secreted from HCC cells and activates c-Met because it contains two structural regions that are similar to HGF . Due to leukemia . (VII) mleukemia . Deregulleukemia . (IX) Slleukemia .The HGF/c-Met axis has an important role in cellular behaviors, such as cell proliferation, migration, survival, morphogenesis and the epithelial–mesenchymal transition (EMT) . Moreovein vivo and in vitro studies have demonstrated that HGF/c-Met play a critical role in the development of various human cancers . HGF/c-Met signaling pathways are uncontrolled in human cancer via overexpression of HGF or c-Met, gene amplification, mutational activation of c-Met, down-regulation of Met-targeted miRNA, binding to other ligands, autocrine signaling, or abnormally high HGF levels. Deregulated activation of c-Met contributes to a few aspects of tumor progression, such as inducing neoplastic cells to disaggregate from the tumor mass, eroding basement membranes, infiltrating stromal matrices, and finally colonizing new tissues to form metastases  and suppressor of cytokine signaling 1 (SOCS1)  can contIn addition to the above, cooperation of the HGF/c-Met pathway with MUCI  or β-catA study carried out by Kaposi-Novak has found that a Met-regulated expression signature correlated vascular invasion rate and decreased mean survival time and microvessel density in a subset of human HCC and liver metastases . Wang etin vitro and in vivo trials In the in vitro trial, compared with adenovirus alcohol dehydrogenase (AdH1)-null or mock-infected cells, proliferation of MHCC97-L cells, which had high c-Met expression, were inhibited by adenovirus AdH1-siRNA, and c-Met expression also decreased. The MHCC97-L cells were arrested at G1-G0 phase. In the in vivo study, the proliferative indices of adenovirus AdH1-siRNA/Met-injected mouse tumors were lower (23.4%) than the adenovirus AdH1-null injected tumors (69.8%) and mock-injected tumors (72.8%). C-Met expression was obviously reduced by adenovirus AdH1-siRNA/Met injection. In addition, some studies have found lncRNAs can promote HCC cells proliferation, migration, and even invasion. According to the study of Zhang, lncRNA FLVCR1-AS1 sponges miR-513c and increases c-Met expression in HCC cells, which induces HCC progression  . SeveralTo investigate the invasion and metastasis effect of HGF/c-Met signaling in HCC, Liu and colleagues conducted a study using two different HGF-treated HCC cell lines, Hep3B and HepG2. The Hep3B HCC cell line was p53 deficient and overexpressed c-Met after treatment with HGF. Loss of p53 expression reinforced HGF/c-Met signaling, which promoted invasion and metastasis by upregulating Snail expression . Xie et The liver is an organ filled with blood vessels that rely on angiogenesis for cellular regeneration . LikewisAlthough new treatments have been used in HCC patients and provided possible cures, the long-term survival rate is still poor due to late diagnosis and high recurrence. Therefore, sensitive and specific diagnostic or prognostic biomarkers are urgently needed. Although the HGF/c-Met axis is an emerging study target, the possibility of its use in diagnosis and prognosis has been studied in addition to its mechanism in HCC.In the study by Some studies also suggested that the HGF/c-Met axis has prognostic value for patients with HCC . OverexpAs mentioned above, there are five therapies that can prolong the expected lifespan of patients with HCC including, surgical resection, liver transplantation, local ablation, TACE and sorafenib. Only 40% percent of patients with early stage HCC are eligible for potentially curative treatments , which prolong median survival times over 60 months . For patin vitro and in vivo trials (So far, there are six Met inhibitors developed and they have been tested in 10 HCC clinical trials . Small mo trials . Additioo trials . Moreoveo trials . PHA6657Also, several clinical trials are  being caHowever, there is currently no effective method for treating HCC based on traditional monotherapy with TKIs. In a previous phase II randomized controlled clinical study, Tivantinib, a highly selective c-Met inhibitor, improved median time to progression and OS time in patients with Met-high advanced HCC compared with placebo . Howeverin vitro and in vivo trials (Fortunately, using potential miRNAs for suppressing aberrant c-Met signal is an emerging and promising therapy strategy that bypasses traditional approaches  Table 2Table 2. o trials . miRNA-2o trials . Also, mo trials . MiR-93 o trials . Thus, wo trials . MoreoveAlthough c-Met inhibitors show a survival benefit for advanced HCC, there has also been some toxicity and adverse effects demonstrated. For instance, compound 8 was a potent and highly selective ATP competitive c-Met inhibitor. Moreover, compound 8 showed good oral bioavailability and good half life and moderate plasma clearance and volume distribution. In addition, Compound 8 also demonstrated effective tumor inhibition. However, it increased heart rate, cardiac output, and induced myocardial degeneration in mice and thus was terminated as a preclinical candidate . Also, aTo solve the side effects mentioned above, several therapy strategies have been suggested. Among them, specifically targeting the downstream mediators of c-Met involved in tumor progression is a promising method, including the Grb2 SH2 domain, Src, MAPK, STAT3, Shp2 , and FakRecently endosomal processing has been demonstrated to play a pivotal role in the progression of HCC . ReceptoCentella asiatica (In recent years, more and more studies have found that natural compounds can inhibit the progression of liver cancer. For example, deguelin can suppress tumor angiogenesis on vascular endothelial cells by decreasing autocrine VEGF and repressing HGF-induced c-Met signaling pathways, thereby inhibiting HCC progression . Also, Casiatica  could reC-Met inhibitor therapy has failed to result in satisfactory outcomes in phase III clinical trials for HCC. Therefore, it is urgent to understand mechanisms and find new strategies such as effective combination therapies. Several studies have shown resistance in c-Met inhibitors due to various mechanisms. First, c-Met inhibitors only affect high-expression c-Met patients with HCC. Thus, enrolled low-expression c-Met patients with HCC could lead to the occurrence of resistance in c-Met inhibitors. Second, as mentioned above, c-Met inhibitors which target the interaction between HGF and c-Met may lose efficacy owing to cell attachment , gene amNew therapeutic strategies have been developed against the mechanism of c-Met inhibitors resistance described above. Among them, combined c-Met inhibitors and other pathway inhibitors is a promising treatment. For example, combined inhibition of both c-Met and EGFR pathways could repress the tumor growth of HCC . AdditioRecently, a growing body of evidence suggests that aberrant activation of HGF/c-Met signaling is associated with resistance of target therapies , includiIn conclusion, although the tivantinib phase III trial failed and the reason is not clear, the role of c-Met inhibitors in treating HCC can not be denied. C-Met inhibitors are still mainstream of research and deserve more research on its cause of failure and new clinical trials. miRNAs, natural compound and herbal medicines are emerging treatments of HCC which can inhibit multiple pathways including c-Met signaling pathway. But it also means that there may be other side effects. The advantage of c-met downstream pathway inhibitors is that they are highly targeted and have little side effects, but this requires us to further understand the key targets of HCC. The drug resistance may be due to the heterogeneity of liver cancer cells and combination therapy may be a good solution.The HGF/c-Met axis has an important role in cellular behaviors such as cell proliferation, migration, survival, migration, morphogenesis, and the EMT. Moreover, it is also essential for liver formation, growth, regeneration and protection and angiogenesis during embryonic development and in adulthood after injury. Especially in chronic liver diseases, inflammation decreases hepatocytes and increases the need for c-Met activity to promote hepatocyte proliferation, regeneration and suppress inflammation. Nevertheless, the aberrant activation of c-Met and downstream signaling pathways through overexpression of HGF or c-Met, gene amplification, mutational activation of c-Met, down-regulation of Met-targeted miRNA, binding to other ligands, autocrine signaling or abnormally high HGF levels initiates and drives tumorigenesis and promotes tumor growth, invasion, metastasis, and angiogenesis in HCC. In the progression of liver cancer, c-Met is regulated by various factors such as miRNAs and SOCS1. Furthermore, c-Met cooperates with other signaling pathways such as MUCI or β-catenin in promoting tumorigenesis. Therefore, the treatment of liver cancer with c-Met as a target is a potential and promising therapy strategy. So far, six c-Met inhibitors have entered clinical trials and have been shown to inhibit tumor growth and invasion. Moreover, selective c-Met inhibitors are superior to non-selective c-Met inhibitors in the treatment of liver cancer due to their low toxicity. However, the failure of the tivantinib phase III trial suggests that we need to further study the causes of failure and the feasibility of c-Met inhibitors in treating HCC.In addition, we should also consider the relationship between c-Met inhibitors and liver disease, although there is no clinical evidence that c-Met inhibitors worsen liver function. In chronic liver diseases, c-Met expression is increased to promote hepatocyte proliferation and inhibit inflammation. C-Met inhibitors suppress this positive regulation and may accelerate advanced liver disease. Meanwhile, liver diseases affect the drug pharmacokinetics, pharmacodynamics, reduce enzyme activity, impair hepatic clearance of drugs and even change the interplay between drugs. These effects may alter the dose of the drug needed to reach the desired blood concentration and induce novel toxicities. Thus, we should consider whether patients with Child-Pugh B or C disease can tolerate the dose established in clinical trials because in the past, most clinical trials were conducted in patients with Child-Pugh A disease.Besides c-Met inhibitors, many new therapeutic strategies have been developed, such as the use of miRNAs to regulate HGF/c-Met signaling pathways to inhibit liver cancer progression, targeting endocytosis and more downstream molecules, Hic-5 as a therapeutic strategy to reduce side effects of c-Met inhibitors, as well as herbal treatments. c-Met is also involved in the resistance mechanism of sorafenib, which can be solved by the combination of c-Met inhibitor and sorafenib. For the self-resistance of c-Met inhibitors, the combination of c-Met inhibitors and other inhibitors can be used to solve this problem, such as FGFR and EGFT inhibitors, autophagy inhibitor and anti-PD1 treatment. Whether HGF/c-Met can be used as independent diagnostic and prognostic markers still requires further research, but HGF/c-Met in combination with other diagnostic and prognostic markers is valuable. In general, the mechanism of the HGF/c-Met pathway involvement in liver cancer requires more research, and c-Met inhibitors are a potential and promising therapeutic strategy in patients with HCC.ZR and ZY proposed the study and the guarantors. HW, BR, and JL performed the research and wrote the first draft. All authors contributed to the interpretation of the study and to further drafts.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.


Unlike the notched specimens for conventional concrete fracture tests, this paper introduces a deformation-controlled uniaxial tensile test on an un-notched specimen. The surface of the dog bone-shaped specimen is a second order parabolic curve, and the gradual change in the specimen shape does not lead to extreme stress concentrations. Another significant feature of the tension test set-up is that it is built with three hinges, to accommodate the alignment of the specimens. The specimen preparation, test conditions, and the tension test set-up are explained in detail. The fracture energy of the concrete is determined by the obtained complete softening curves. The fracture energy is found to increase with age, going towards a horizontal asymptote as concrete hardened in a tested age range of 1 day to 90 days. Moreover, the rate of development of the fracture energy was found to be higher when compared to tensile strength and stiffness. The tensile property of concrete at a very early age, in this case as early as the time of the initial setting of the concrete, is essential for the study of cracking control. However, there is very limited relevant information available, especially on the direct measurement of the fracture energy or the complete tensile softening curves for early age concrete. This is mainly due to practical problems, for instance, very early age concrete specimens with a low degree of hydration cannot yet support their own weight without applying any loads ,2. FractThis paper introduces a deformation controlled uniaxial tensile test on un-notched specimens. The surface of the dog bone-shaped specimen is a second order parabolic curve, and the gradual change in the specimen shape does not lead to extreme stress concentrations. Another significant feature of the tension test set-up is that it is built with three hinges to accommodate the alignment of the specimens. The specimen preparation, test conditions, and the tension test set-up will be explained in detail. Based on the measured complete softening curves through a uniaxial tensile test on an un-notched specimen, some preliminary results concerning the development of fracture energy of early age concrete will be presented.As shown in This parabolic-shaped specimen is cast by an additional splitting mold inside the standard gyratory mold that is commonly used in asphalt concrete research, as shown in The specimen is demolded within 24 h from the time of mixing, and stored in a curing room at 20 °C and 100% relative humidity. On the pre-designated test day, the excess material outside the parabolic shape is cut off. To protect the specimens, especially the specimens tested at very early ages  against being damaged during the cutting process, the specimen is placed in a cutting mold, as shown in After cutting the excess material, the specimen is glued to the end caps that are used to transfer the load to the specimen in the uniaxial tensile test. Despite the use of the cutting mold, the acquired cutting surface can still be somewhat non-parallel, due to the slight movements of the cutting blade and some freedom in positioning it, especially when cutting the last portion of the excess material. Zhou  has concThe TU Delft tension set-up with 3 hinges, developed as part of the Asphalt Concrete Response project , is usedTo compensate for misalignment, the TU Delft tension set-up introduced a third hinge, which is able to move horizontally to accommodate possible small deviations . The actIn the present study, there is no straight part of the parabolic surface specimen. Thus, the full specimen length of 90 mm is used as the control length for the concrete specimen. Three linear variable differential transformers (LVDT) with a measurement length of 90 mm are installed at 120° intervals. One type of LVDT, Solartron AG 1, with a measuring capacity of ±1 mm, is used. The connection of the LVDTs to the caps is by means of a set of rings. One ring has three holes at 120° intervals in which the LVDTs are clamped, while another is a massive ring on which the LVDTs are placed. After the specimen is placed between the lower two hinges and instrumented with LVDTs, a small pre-load (approximately 0.2 kN) is applied to ensure that there is no play in the setup components, more specifically, the hinges.In order to study the evolution of the concrete properties during hardening, the uniaxial tensile tests are performed at different concrete ages: 1, 2, 3, 5, 7, 14, 28, and 90 days for each mixture. All the specimens are cured at 20 °C and 100% relative humidity. The average axial deformations measured with the 3 LVDTs were used as the feedback control signal for test control. The applied deformation rate that was much lower than previous reports of uniaxial tension tests for concrete, as it was 0.1 μm/s for the specimens older than 3 days . HoweverIn the pre-peak region, the measured deformation includes three components: specimen, caps, and glue layers. It has been found that the higher the concrete modulus and the thicker the glue layer, the smaller the percentage of specimen deformation to the measured overall deformation. For a matured concrete having a modulus of 40,000 MPa, 1.5 mm thick glue layers, and 30 mm of measuring distance on the steel caps, the deformations of the steel caps and glue account for 14.8% of the measured deformation by the LVDTs . Thus, iThe load is measured by a load cell that was placed between the top hinge and the middle hinge, as shown in  Hordijk .F-δ relation of a specimen with an age of 5 days is illustrated in curve a in F-δ relation could not be determined by a compression test in which a deformation at zero load level is used to correct the deformation. In the present study, the origin of the F-δ relation is retrieved through back analysis. Firstly, the deformation of the specimen has been corrected though subtracting the deformation of the caps and the glue layers from the raw experimental data (curve b). Similarly, the external force applied on the fracture face has also been corrected by excluding the self-weight. The initial slope of the corrected curve (curve c) is linearly extrapolated until the intersection point with the horizontal axis of the deformation. Lastly, this intercept deformation value is then used to define the corrected F-δ relation through the origin (curve d).The raw experimental As shown in At the peak load:In the post-peak regime:The Equations (1) and (2) are put into Equation (3). Thus, the crack opening 2) is the area of the fracture surface considering the tortuosity of the fracture surface. Lastly, In a deformation controlled uniaxial tensile test on concrete, the fracture energy Previous researchers have pointed out several problems in the determination of fracture energy according to three-point bending tests on notched beams ,21,22. Te energy . In the  studies ,25,26, wAnother problem in the determination of the fracture energy is the real area of the fracture surface. The area of the projected fracture plane is considered to be underestimating the true area of the fracture surface . This isarihaloo  is used llerborg  concludeIn order to evaluate the risk of thermal cracking in a hardening concrete pavement, adequate descriptions of the time-dependent concrete properties are extremely important. However, the early age concrete mechanical properties commonly obtained through laboratory-cured specimens under relative constant curing conditions do not accurately represent the properties of field-placed concrete that experiences varying temperatures. The degree of hydration is considered to be a very fundamental parameter, therefore, the degree of hydration-based formulations of early age concrete mechanical properties can be considered more applicable to describe the evolution of hardening concrete under field conditions then time-based formulations .In the present study, a degree of hydration-based formulation was calculated as a fraction of heat released to describe early age concrete mechanical properties.released . The coeEc under tension is calculated according to CRD-C 166 (1992): “Standard Test Method for Static Modulus of Elasticity of Concrete in Tension”. The chord modulus of elasticity is used as the modulus of elasticity, which is the slope of the chord drawn between 10% and 50% of the ultimate load on the pre-peak force-deformation curve [a, b, c, and the ultimate values at the end of the reaction are summarized in RD-C 166 92: “Stanc is smallest compared to that for tensile strength and elastic modulus, which indicates that the fracture energy develops much faster than the tensile strength and the elastic modulus of concrete. The present experimental results tend to confirm the tendency found in a few earlier studies [According to the regression analysis of the calculated fracture energy in the present study, the value of coefficient  studies ,5,6,8. G studies  proposedVery few experimental data were reported on the fracture properties of early age concrete. A summary of these data are shown in The tension set-up developed in the present study worked very well for obtaining the fracture energy of concrete at early age. Due to the adopted small specimen size, very fast servo system, and stiff testing frame, a stable experiment and a complete softening curve were obtained, even for concrete specimens with an age as early as 24 h. Based on an extensive deformation controlled uniaxial tensile test program on two typical pavement concrete mixtures used in Belgium, the following conclusions can be drawn:The applied parabolic shape of the concrete specimens ensured that the crack occurred near the center of the specimen, where it was in the intended state of more or less uniform stress. Moreover, this parabolic-shaped specimen, with a considerable reduction of cross-section area (nearly 60%) at mid-height, let the cracks initiate far enough from the end caps to prevent the influence of confinement there.The loading rate of 0.1 μm/s, corresponding to a measuring length of 90 mm, proved successful in preventing the crack from growing explosively for concrete with an age greater than 48 h, as no snap-back was observed in the post-peak region of all the measured force-deformation curves. A lower loading rate of 0.05 μm/s was subsequently found to provide a stable complete uniaxial tension test for concrete with an age of 24 h.The fracture energy, uniaxial tensile strength, and elasticity modulus were all found to increase with age, going towards a horizontal asymptote as concrete hardened in a tested age range of 1 day to 90 days. More work is needed to identify factors such as aggregate size, water to cement ratio, loading rate, etc., that affect the tensile properties of very early age concrete.Gluing the specimen to the loading plates may be impossible on a very early age concrete specimen, and the proposed tension test set-up and test procedures in the present study might be not suited for the very early age concrete (less than 24 h). An indirect method, such as a horizontal tensile test, might be an alternative option for obtaining softening curves for very early age concrete.


Since high quality natural aggregates are becoming scarce, it is important that industrial recycled products and by-products are used as aggregates for concrete. In Japan, the use of recycled aggregate (RG) is encouraged. Since, strength and durability of recycled aggregate concrete is lower than that of normal aggregate concrete, the use of recycled aggregate has not been significant. In order to improve physical properties of concrete using recycled coarse aggregate, blast furnace slag sand has been proposed. Recently, blast furnace slag sand is expected to improve durability, freezing, and thawing damage of concrete in Japan. Properties of fresh and hardened concrete bleeding, compressive strength, and resistance to freezing and thawing which are caused by the rapid freezing and thawing test using liquid nitrogen is a high loader than the JIS A 1148 A method that were investigated. As a result, concrete using treated low-class recycled coarse aggregate and 50% or 30% replacement of crushed sand with blast furnace slag sand showed the best results, in terms of bleeding, resistance to freezing and thawing. In Japan, disposal sites have been decreasing due to active industrial works. In addition, resources of natural aggregate for producing concrete has been decreasing due to protection of the environment. Therefore, there the need for concrete which can reduce environmental impact by using aggregate from industrial by-products has been increasing. In particular, the use of recycled aggregate has been desired over recent years in Japan. In Japan, Industrial Standards (JIS), has three types of recycled aggregates which are classified as class H, class M, and class L. Legal improvement for practical use of recycled aggregate has been progressing steadily. However, concrete using recycled aggregate is rarely used on the market, because its standing in quality assurance and cost performance is hampered. Strength and durability of concrete using low quality recycled aggregates as JIS class M and L are also generally much lower than that of normal concrete due to high absorption and other factors ,2,3,4,5.Recent research in Japan, carried out by the Japan Society of Civil Engineers (JSCE) has been focusing on the use of blast furnace slag sand to produce more durable concrete. JSCE suggested that resistance to freezing and thawing is improved, drying shrinkage can be reduced, and resistance against chloride ion diffusion is improved . In addiThe cement used was the JIS R 5210 standard Portland cement (OPC) and JIS R 5211 type B blast-furnace slag cement (BB). BB was blended cement with cement replacement levels of 30%–60% ground granulated blast furnace slag for mitigation of alkali–silica reaction. Blast furnace slag sand  was used. These were from Okayama Prefecture (Fukuyama City and Kurashiki City), Japan. These two slags have different particle sizes. All specimens and mix proportions are shown in Concrete bleeding was tested according to JIS A 1123.After 24 h from casting concrete, all specimens were demolded and cured in water at 20 °C ± 2 °C. The curing period for each test varied as described below.Their compressive strength was tested according to JIS A 1108. Cylindrical specimens measuring 100 mm in diameter and 200 mm on height were used. Compressive strength tests of specimens were performed at 7 and 28 days, respectively.A rapid freezing and thawing test using liquid nitrogen was performed using equipment shown in nP: Relative dynamic modulus of elasticity (%), V0: Ultrasonic pulse velocity at 0 cycle (km/sec.), Vn: Ultrasonic pulse velocity after n cycle (km/sec.).A cylindrical specimen (100 mm diameter and 200 mm high) with an age of 28 days was placed in the center of a cooler container with a lid. Next, it was blown with liquid nitrogen for 30 s and then immersed in hot water with a temperature of 45 °C–50 °C for 5 min. After removing the specimen from hot water, a sensor was placed at a position of 5 mm height from the bottom of the specimen and ultrasonic pulse time was measured following ultrasonic testing as showed in Here, mixes containing blast furnace slag cement type B showed poor performance in the rapid freezing and thawing test. Therefore, these mixes were tested according to JIS A 1148 (A method).The relationship between bleeding capacity and elapsed times after mixing is shown in 3/cm2 at 240 min. In particular, the bleeding capacity of BFS5-50 significantly exceeded the quality regulation of the bleeding capacity ≤0.3 cm3/cm2, which is limited by “Recommendation (draft) for shrinkage crack of reinforced concrete buildings” established by the Architectural Institute of Japan.The final bleeding capacity of concrete mixes with OPC is presented in 3/cm2, regardless of type and blending ratio of BFS. It is assumed that bleeding water was retained by irregularities and fine particles coated on the surface of RG.The final bleeding capacity for BFS1.2-50 was similar compared with N-N, the particle size of BSF1.2 was smaller than BFS5, and the viscosity of mortar became high. The bleeding capacities for mixes with RG were less than 0.1 cm2 at seven days and 15–20 N/mm2 at 28 days.The compressive strength for mixes with OPC is presented in 2. The reason for low strength of BFS5-100 was considered to be due to voids formation as a result of bleeding and decrease in interface adhesion between coarse aggregate and the mortar.When compared with N-R at seven days, strengths with RG and BFS were similar. At 28 days they decreased to 5–10 N/mm2 remaining in the cement paste or coated mortar of RG.The relative dynamic modulus of elasticity obtained from the rapid freezing and thawing test for OPC specimens are presented in 2 does not deposit around the aggregate [2 at 70 °C is about half of its value at 0 °C in 2 in water is an exothermic process, and it also adheres to Le Chatelier’s principle. A lowering of temperature thus favours the elimination of heat liberated through the process of dissolution and increases the equilibrium constant of dissolution of Ca(OH)2, and so increases its solubility at low temperature. This counter-intuitive temperature dependence of solubility is referred to as “retrograde” or “inverse” solubility. Ca(OH)2 deposits around the aggregate in ordinary concrete. Ca(OH)2 dissolves more easily in water at low temperature due to water being accumulated in a gap made by dissolved Ca(OH)2 [2 does not deposit around the aggregate. Moreover, it was shown that this is effective even for recycled concrete using low quality recycled coarse aggregates, which are not popular due to their assumed resistance to freezing and thawing.Relative dynamic modulus of elasticity of RG and BFS mixes showed improvement, when compared to the concrete with RG only. For this reason, it is noted that Ca(OH)ggregate  when BFS Ca(OH)2 . When BFRelative dynamic modulus of elasticity obtained from rapid freezing and thawing test for the BB-cement mixes are presented in 3/cm2 or less when the mix ratio of blast furnace slag sand was 50% or less. It is thought that bleeding water was retained by irregularities and fine particles coated at the surface of RG.Bleeding capacities were observed to be 0.1 cmCompressive strength due to usage of RG and BFS was lower than that of the normal aggregate concrete. At 28 days the strength for the BFS and RG mixes with BB-cement were similar to mixes with OPC.Resistance to freezing and thawing was improved by mixing the blast furnace slag sand, and the relative dynamic modulus of elasticity of concrete using RG and BFS with OPC after the freezing and thawing test was approximately 80%.The following conclusions were obtained from this study:Hence, it was found that mixing 50% blast furnace slag sand was effective for bleeding and resistance to freezing and thawing. In the future, we would like to further examine characteristics of strength and drying shrinkage. In addition to putting this into practical use for recycled aggregate concrete with blast furnace slag sand.


An ability of different molecular potentials to reproduce the properties of 2D molybdenum disulphide polymorphs is examined. Structural and mechanical properties, as well as phonon dispersion of the 1H, 1T and 1T’ single-layer MoS Group 6 transition metal dichalcogenide (G6-TMD) two-dimensional 2D) nanomaterials , and espD nanomatgraphene ,4.Both synthetic and natural bulk transition metal dichalcogenides have layered structures with two primary distinguished allotropic forms, 2H and 3R, belonging to the hexagonal crystal family, but differing in a sequence of arrangement. Strong triple layers of metal-sulphur-metal are weakly bounded by the van der Waals forces, similar to graphene in graphite .Three polymorphs of single-layer molybdenum disulphide have been synthesised, namely the most thermodynamically stable semiconducting 1H-MoS 1T-MoS2 . In 1H-MS2 phase .The most accurate methods of solid state physics are based on quantum mechanics, unfortunately, with the accuracy of the methods their cost increases. The number of atoms and the number of timesteps that can be analysed with the first-principles method using either energy minimisation or ab initio molecular dynamics (AIMD) is highly limited. For typical computational resources currently available, the use of these methods is limited to several hundreds of atoms for less than about several picoseconds. These restrictions justify the need for more approximate methods, such as molecular methods .In general, there is a lack of perfectly transferable interatomic potential that would work with the various materials and systems we are interested in. Some are more transferable, others less . It depeAccording to the author’s best knowledge, there are no publications where the performance of different molecular potentials for molybdenum disulphide is analysed for all phases of SL MoSnd so in  the resund so in , the geond so in .A partial comparison of different potentials for the 1H phase SL MoSd, e.g., ,13,14. Tl, e.g., ,16,17,18The paper is organised as follows. Following the above Analysing the available literature concerning phases of SL MoSAb initio computations by means of the density functional theory (DFT) ,21 and tTo strengthen the reliability of the calculations as an exchange-correlation (XC) functional, three approximations were initially checked for their ability to reproduce the geometry of 1H-MoSon (LDA) ,27, clason (LDA)  and modion (LDA) . To provon (LDA)  was utilaccuracy level 4 (accuracy = 4 matches the default settings of ABINIT). The cut-off energy in line with ONCVPSP pseudopotentials of the plane-wave basis set was fixed at 35 Ha (952.4 eV) with kptrlen = 35.0 . In all the present ABINIT computations, the metallic occupation of levels with the Fermi–Dirac smearing occupation scheme and tsmear (Ha) = 0.02 was applied.All the computations were done by a proper adjustment of their precision, what was achieved by automatically set up the variables at Initial data defining unit cells of SL 1H-MoSken from  and thenThe cohesive energy the arge box :(2)Ec .In order to examine the elastic  stability of all the structures, positive definiteness of the elasticity tensor was verified  by compuM-K-Z-C-Y-To compute phonons, DFPT was used ,23. The )  of the s) ,38, compThe molecular statics (MS) method  ,39,40 siTo get the elastic constants, utilised ,43.For the phonon calculations, phonoLAMMPS  45] wa wa45] waEcMoS,  generalised gradient approximation (GGA) a = 3.220 Å, h = 3.121 Å and with the modified Perdew–Burke–Ernzerhof GGA for solids (PBEsol) a = 3.165 Å, h = 3.120 Å, a similar trend can also be observed in other papers [The first step of the ab initio calculation was to select the exchange-correlation (XC) functional that most accurately reproduces the experimental geometry of 1H-MoS 3.116 Å , while tr papers . Once agr papers ,52,53 anhP3 in Pearson notation, PhP3, PoP6, P2The basic cell for the SL 1H-MoSectively . AlthougDetermined from DFT calculations structural and mechanical properties, namely, lattice parameters, average cohesive energy, average bond length, average height, 2D elastic constants and 2D Kelvin moduli, of the three analysed SL MoSCalculated with the use of molecular statics and different molecular potentials, twelve structural and mechanical properties, namely, lattice parameters, average cohesive energy, average bond length, average height, 2D elastic constants and 2D Kelvin moduli, of the SL 1H-MoSThe computed twelve structural and mechanical properties of the SL 1T-MoSThe identified thirteen structural and mechanical properties of the SL 1T’-MoSLet us now analyse the cumulative performance of the analysed potentials for all SL MoSPhonon spectra along the appropriate high symmetry q-points , calculaase, see . When wease, see ,60,61,62Analysis of the computed curves in found in ,60.Let us now compare the phonon spectra for SL MoSA systematic quantitative comparison of Stillinger–Weber, REBO, SNAP and ReaxFF potentials for the reproduction of the properties of 2D molybdenum disulphide polymorphs was presented. To compare the potentials, the structural and mechanical properties and phonon dispersion of single-layer phases 1H, 1T and 1T’ MoSThe transferability of analysed molecular potentials leaves much to be desired.Three potentials: SW2016, SW2017 and REBO demonstrate the best quantitative performance.None of the above three potentials correctly reproduces the dynamical stability of all SL MoSOnly the REBO potential distinguishes three different 2D molybdenum disulphide allotropes.Two potentials, ReaxFF and SNAP, demonstrate significantly lower quantitative efficiency.It seems that the low transferability of the analysed potentials is a result of the improper fitting of their parameters.To increase the transferability of potentials, the number of configurations to be taken into account in the parameter optimisation process should be significantly increased.We can conclude that:I hope that the observations made here will help other researchers to choose the right potentials for their purposes and will be a suggestion for parametrising new potentials for SL MoS


Bridge structures nationwide across the United States are aging and in need of repair or, in some cases, full replacement. Repair decisions are common among bridge owners because of the economic feasibility when compared to the higher cost of full replacement of damaged or deteriorated bridge components such as girders. Using a proper repair approach, as a long-term or just a short-term solution, can lead to benefits that could not be achieved otherwise such as considerable savings in both time and cost. Additionally, an appropriate repair approach can help avoid adverse environmental impacts, interruptions to service, overburdening of nearby infrastructure, and local opposition to construction. The main objective of this paper is to provide a synthesis of the repair methods and materials for reinforced concrete bridge girders proposed in research studies, i.e., state-of-the-art as well as state-of-the-practice established methods. Different steps in the general repair procedure are explained first. Next, a detailed description of three common bridge girder deficiencies, i.e., shear, flexural, and fire damage, is provided. For each damage type, the main causes and common solutions found in the literature are presented. The authors then provide specific recommendations to each repair procedure. This is intended to enable researchers, engineers, and decision makers to compare the available repair methods more conveniently to find the optimal repair approach for specific projects based on economic and environmental requirements as well as structural and construction conditions. A majority of the United States’ transportation infrastructure is over 50 years old . Among tThe available options applicable to a bridge with damaged girders are “leave and monitor”, “repair”, or “replacement” of the girders. Harries et al.  classifiThe main objective of this study is to gather the information about different materials and methods of bridge girder repair implementation that have been used so far in practice or merely proposed through research projects. More than 200 studies have been reviewed and summarized here with a focus on the repair of reinforced concrete (RC) bridge girders which contribute to more than 60% of the bridge inventory in the US . For thiThe main steps in a typical repair procedure can be summarized in eight steps: (1) inspection and monitoring; (2) making the first decision on choosing a repair material; (3) making the second decision on choosing the repair method; (4) surface preparation; (5) repair design (6) application of repair material; (7) prestressing of repair material, if applicable; (8) anchorage system; and (9) strand splicing, if needed. A summary of the state-of-the-art and practice on each of the eight steps is presented next.This may be performed on a periodic or usage basis, or motivated by reports of damage or extreme loading to determine the severity of the damage, cause, and prognosis ,23. The If repair is needed, then the next step is to choose an appropriate repair material. Availability and durability of the material, ease of handling on site, cost-effectiveness, type and condition of the structural element, and the targeted enhancement in the structure are factors that should be considered in making this decision . Common Fiber-reinforced composites, as shown in Depending on the type of the matrix used, fiber-reinforced composites are categorized into three groups: polymeric composites, cement-based composites, and hybrid composites.Polymeric composites: Polymeric composites  are fibers embedded in a polymeric resin such as unsaturated polyester, epoxy, vinylester, phenolic, and polyurethane resins. Epoxy resins are the most common matrix in structural repair applications due to their characteristics such as good adhesive properties, low shrinkage during curing, and resistance to environmental degradation ,33. PopuCement-based composites: Use of fibers with cementitious matrix instead of epoxy resin was proposed in the early 1980s, but did not gain that much attention until the late 1990s. Cementitious matrix has several advantages over conventional epoxy resins in terms of fire resistance, performance under ultraviolet (UV) radiation, permeability, thermal reversibility, and cost. Additionally, having similar mechanical, chemical, and physical properties as the concrete substrate is another advantage. Unlike the FRP installation safety requirement because of the characteristics of the used resins, installation of cementitious matrix can be done merely by simple troweling techniques and protective equipment for typical concrete applications. Further, unlike FRP, cementitious matrix can be applied to wet surfaces, and thus the project will not be affected by weather conditions as much. The different types of cement-based composites include sprayed concrete, textile-reinforced mortar (TRM), textile-reinforced concrete (TRC), fiber-reinforced concrete (FRC), fiber-reinforced cementitious mortar (FRCM), and mineral-based composites (MBC) ,36,37,38Hybrid composites: Different fiber-based composites can be combined together as a hybrid to enhance the strengthening efficiency. For example, they can provide a progressive failure pattern to compensate for the loss of ductility that is observed in traditional fiber-reinforced materials . AdditioUsing steel plates for the strengthening of concrete elements started in the 1960s as a fast and economical solution compared to the demolition of the structure. Ever since, it has been traditionally used for the strengthening of structural concrete members in different forms such as rods, bars, tendons, plates, strand splice systems, and steel jackets. The main benefit of steel material is its well-known properties. Nonetheless, using steel comes with the common major concerns on poor corrosion resistance and difficulty in handling on site ,29.Other less common or emerging materials used for the repair of RC bridge girders are ultra-high-performance fiber-reinforced concrete (UHPFRC or just UHPC), aluminum alloy, ferrocement, shotcrete, innovative concrete mixes made with waste material, and coatings and sealers. Each of these materials has been used in a number of repair projects due to their specific benefits and the availability of the material ,43,44,45After the repair material is chosen, the next decision is to choose a proper way for the application of the material to the damaged girder. There are several factors affecting this decision ,46,47:  or circular cross-section (bars), manufactured using the pultrusion process. Bars can be sandblasted or deformed, but studies have indicated that deformed bars have a better bond performance. Further, it has been demonstrated by some researchers that strips can lead to a more effective repair since they provide an increased surface area between the FRP and adhesive interface, with strips failing in tension rupture and achieving full composite action with the concrete ,55. FiguThe NSM method improves the fire resistance and impact damage resistance of the strengthened member compared to the EB method since the repair material is placed inside of the concrete instead of being exposed on the concrete surface, and also as a result of the increased contact area. Additionally, there is no change of dimensions in this technique, keeping the cross-section of the girder the same ,50,54. HIn the case of overheight vehicle collision and damage to the prestressed girder strands, NSM might not be the best repair choice. This is because the thickness of the strand splicing equipment used for repairing the prestressing strands can conflict with cutting grooves into the concrete surface in particular locations . AdditioEven when using the NSM method, premature debonding can still occur, resulting in incomplete use of the tensile capacity of the common FRP repair material. This is more likely to happen in beams with T-shaped or I-shaped cross-sections. Additionally, studies have indicated that in the NSM method, detachment of the cover concrete in which the NSM reinforcement is used might occur which prevents the repair approach to work in full capacity. Therefore, it might not be possible to fully utilize the tensile strength of the repair material using the NSM or EB methods, unless proper anchorage is provided. This motivated another method which is embedding reinforcing materials well inside the girder, i.e., into the concrete core beyond the cover or surface grooves, to increase the bonding. This is because the concrete core handles the stress transfer to the strengthening material, and compared to the concrete cover, it can provide better confinement, and thus improved bond behavior. Additionally, in this deep embedment technique, protection against fire and vandalism is even more effective than the NSM method ,57. FiguSurface preparation, i.e., cleaning and roughening the surfaces of composites is a critical step in the repair process which can improve bond strength. An improperly prepared surface can result in debonding or delamination. Sandblasting, water jetting, grinding, brushing, air pressure, rounding of corners, pressure washing the concrete surface, surface patching, and nylon peel-ply techniques are commonly used for this purpose. Failure in proper surface preparation can result in damage to the repair material due the delamination of the concrete substrate ,59,60,61It is recommended to remove slightly more concrete rather than too little unless it affects the bond of prestressed strands. If patching is going to be done after unsound concrete removal, the chipped area should at least be one inch deep and should have edges as straight as possible, at right angles to the surface. Air-driven chipping guns or a portable power saw can be used for cutting the concrete. However, care should be taken not to damage the strands or the reinforcement .In case there are cracks on the girder, they should be filled with proper materials, i.e., patching. There are several patching methods and the most common five ones are discussed. (1) The dry pack method: which is suitable for holes having a depth nearly equal to the smallest dimension of the section, such as the core or bolt holes. The method should not be used on shallow surfaces or for filling a hole that extends entirely through the section or member. (2) The mortar patch method: which is appropriate for concrete members with shallow defects that require a thin layer of patching material such as in honeycombs, surface voids, or areas where concrete has been pulled away with the formwork. (3) The concrete replacement method: where the defective concrete is replaced with machine-mixed concrete that will become integral with the base concrete. This is preferred when there is a void extending entirely through the section, or if the defect goes beyond the reinforcement layer, or in general if the volume is large. (4) Synthetic patching: this method is beneficial where Portland cement patches are difficult or impractical to apply. Examples are patching at freezing temperatures or patching very shallow surface defects. In these situations, epoxy- and latex-based products can be used. Epoxies can be used for a variety of purposes such as bonding agent, binder for patching mortar, adhesive for replacing large broken pieces, or as a crack repair material. Small deep holes can be patched with low-viscosity epoxy and sand, whereas shallower patches require higher-viscosity epoxy and are more expensive. Although epoxies offer excellent bond and rapid strength development, they are hard to finish and usually result in a color difference between the patch and the base concrete. Therefore, it is suggested that epoxy mortars be used only in situations where exceptional durability and strength are required. Latex materials are used in mortar to increase its tensile strength, decrease its shrinkage, and improve its bond to the base concrete, thus helping to avoid patch failure due to differential shrinkage of the patch. Latex is especially useful in situations where feathered edges cannot be avoided. (5) Epoxy injection: this method is used to repair cracks or fill honeycombed areas of moderate size and depth. It becomes an important part of the repair process, specifically for corrosion-damaged girders in which cracking and spalling of the concrete is commonplace. Epoxy injection should be done only by appropriately trained personnel ,62. FiguAs part of the surface preparation, the surface of the concrete is usually polished until fine aggregates are exposed . This imThe concrete surface should be cleaned before the application of the repair material. This can be done using a variety of methods including pressurized air and acetone or water jetting and pressure washing . It is uIn order to increase the performance of the repair that will be applied on the concrete substrate, a primer might be applied to the concrete surface. One example procedure is presented in , where aAASHTO Guide Specifications for Design of Bonded FRP Systems for Repair and Strengthening of Concrete Bridge Elements (latest version is 2013).AC125 Acceptance Criteria for Concrete and Reinforced and Unreinforced Masonry Strengthening Using Externally Bonded Fiber-Reinforced Polymer (FRP) Composite Systems (latest version is 2012). AC125 is issued by ICC Evaluation Service to establish minimum requirements for the issuance of evaluation reports on FRP composite systems under the 2012, 2009, and 2006 International Building Code (IBC) and the 1997 Uniform Building Code (UBC).ACI 440.3R Guide Test Methods for Fiber-Reinforced Polymers (FRPs) for Reinforcing or Strengthening Concrete Structures (latest version is 2004).ACI 440R Report on Fiber-Reinforced Polymer (FRP) Reinforcement for Concrete Structures (latest version is 2007).ACI SP-215 Field Applications of FRP Reinforcement: Case Studies (latest version is 2003).ISIS Design Manual No. 4, FRP Rehabilitation of Reinforced Concrete Structures, issued by the Canadian Network of Centers of Excellence on Intelligent Sensing for Innovative Structures (latest version is 2008).Design of the repair is an important step to make sure that the chosen repair material is applied in a configuration that can provide sufficient strength and durability. Different design approaches might be required depending on the type of the damage, extent of the damage, the expected durability of the repair, availability of the resources for the application of the repair, etc. Additionally, design optimization techniques might be used to achieve the most efficient outcome . In the The next step after surface preparation is the application of the repair material. Depending on the repair approach being used, i.e., EB technique, NSM method, or embedded reinforcement, the repair material should be applied in different ways and configurations. The process for the application of the repair material for each method is briefly described in this section, while the repair configuration, which mostly depends on the type of girder deficiency, is described in The EB repair techniques using FRP materials are usually implemented in three ways: 1) wet layup, (2) pre-preg, or (3) pre-cured. In the wet layup approach see , the res wet layuFirst, grooves are made into the concrete surface, and the concrete in between the cuts is chiseled away. Then, the groove is cleaned, and dust is removed using compressed air. In order to have a clean final appearance, tape can be applied to the sides of the grooves. The strengthening material  is fastened into the groove using a filler material . Finally, the adhesive surface is leveled using a trowel and the tape is removed prior to the curing of the adhesive . The proTo increase the efficiency of the repair, the material for both EB and NSM methods can be prestressed. Prestressing was first utilized for strengthening bridges in the 1950s . It enabFor cases of high peeling or shear stress, an anchorage system might be used in order to delay the debonding of the strengthening system such as FRP materials. A proper anchorage system might allow the use of a strengthening plan that otherwise would not meet the design code provisions, allowing the repair material to continue carrying load even after debonding occurs and thereby increasing its contribution. It can enable greater strengthening or the use of a wider range of possible configurations and material properties. Different anchorage systems have been introduced so far depending on the strengthening approach that they are used with. Some examples include: additional horizontal strips of the repair material, embedment of the repair material into the beam flange through precut grooves with adhesive bonding, various mechanical anchorage systems involving bolts and plates, and fan-shaped textile-based anchors ,34,71,73The fiber-based anchors have the advantage of being light-weight and non-corrosive. Additionally, since the use of FRP-based or textile-based materials is commonplace for girder repair, using a compatible anchor material is also advantageous . A drawbfpu). In order to increase their efficiency, the splices should be staggered as illustrated in When one or more prestressing strands in a prestressed girder are damaged, strand splicing can be used to do the repair. It is a fast, efficient, and cheap repair method for reconnecting damage or broken prestressing strands in order to restore the prestressing force. Strand splices alone cannot be relied on for fully restoring the ultimate strength of the strands or the element that is being repaired. That is because they are limited to developing 85% of the nominal strength of the strands they are joining  concrete crushing, (2) prestressed strand and/or steel reinforcement being exposed which makes them more susceptible to further damage and corrosion, and (3) prestressed strand loss. Harries, Kasan  indicateFor flexural repair using the EB technique, it is often recommended that the repair material is applied to the soffit of the girder since the material near the neutral axis is less efficient in strengthening the element . This isIn this method, similar to the flexural repair using the EB technique, the repair material should be applied to the soffit of the girder through grooves to have the best efficiency. This section provides recommendations for the repair of girders with flexural deficiency, based on the repair case studies found in 151 studies, including both research and real-life applications of the repairs which are both critical for achieving a sufficient understanding of a repair technique. Eight different methods were found in the literature: (1) EB FRP sheets on the soffit + EB FRP U-wraps or complete wraps ,151,152;The most common anchorage system found in the literature is transverse U-wraps evenly spaced along the entire length of the girder or at parts where it is necessary. The U-wraps enhance the bond behavior of the FRP sheet attached to the tension side of the girder as a means of flexural strengthening. They also help in reducing crack propagation in the concrete section. While continuous CFRP U-wraps are also common for the repair of impact-damaged girders, Graeff  showed tThe most commonly used material for the repair of impact-damaged girders seen in the literature is CFRP in the form of sheets and strips. However, as mentioned before, the choice of the repair approach, including the repair material and repair adhesive, highly depends on the specific project requirements and available resources. Based on the previous discussion, the recommended repair process for flexural or impact damage is presented in Fire hazards for bridges are caused by crashing vehicles, burning of fuels in the vicinity of the bridge, arson, and wildfire . Fire daHigh temperatures resulting from a fire hazard can adversely affect the performance of epoxy resins. Therefore, in the case of considering FRP-based repair and epoxy resin materials for a bridge, ACI 440 recommends ignoring the capacity contribution of the FRP. This is a major issue in the utilization of the most common materials, i.e., FRP materials, in the repair of bridge structures. Two proposed solutions to this problem are: (1) the use of cement-based adhesives instead of epoxy, which has been exhibited in part of the shotcrete repair of a bridge in Texas after intensive fire damage ; or (2) Based on the brief discussion above, if an appropriate repair option is needed for a bridge prone to fire hazard or a fire-critical bridge, one of the following three recommended approaches can be considered: (1) use of FRP-based repair with a cement-based adhesive instead of epoxy; (2) use of FRP-based repair with a cement-based fireproof coating; or (3) use of cement-based repair such as shotcrete with or without complementary FRP repairs such as confining FRP U-wraps.Bridge girder repair is an important topic due to the aging of bridge structures in the US and because full girder replacement is not favorable due to the associated higher costs and longer downtime causing traffic shutdowns and inconvenience. The goal of this study is to provide a comprehensive reference for researchers, engineers, and decision makers to compare different repair approaches for RC bridge girders, and find the best method that suites their specific repair problem to provide the highest economy, efficiency, and safety. Three main girder deficiencies in bridge structures are identified and discussed herein, which are shear deficiencies due to corrosion and exposure of the shear reinforcement, flexural deficiencies due to vehicle impact damage, and fire damage.The choice of a repair approach is highly dependent on the specific conditions of a project . However, the following methods were found to be the most common and efficient means of repair, and hence recommended in case a quick decision is needed. For shear repair, either EB CFRP U-wrap  or NSM CFRP laminates on the web with no need for anchorage or above-head installation can be used. For flexural repair, EB CFRP sheets on the soffit can be used in addition to EB discontinuous CFRP U-wraps. For fire repair, the use of cement-based adhesives instead of epoxy and/or fireproofing of FRP layers is recommended.


Progressive implementation of the different interventions showed a concrete complementarity of these actions. Combined actions in ASPs could lead to a significant decrease in antibiotic use, especially regarding critical antibiotic prescriptions, while being well accepted by prescribers.Multiple modes of interventions are available when implementing an antibiotic stewardship program (ASP), however, their complementarity has not yet been assessed. In a 938-bed hospital, we sequentially implemented four combined modes of interventions over one year, centralized by one infectious diseases specialist (IDS): (1) on-request infectious diseases specialist consulting service (IDSCS), (2) participation in intensive care unit meetings, (3) IDS intervention triggered by microbiological laboratory meetings, and (4) IDS intervention triggered by pharmacist alert. We assessed the complementarity of the different cumulative actions through quantitative and qualitative analysis of all interventions traced in the electronic medical record. We observed a quantitative and qualitative complementarity between interventions directly correlating to a decrease in antibiotic use. Quantitatively, the number of interventions has doubled after implementation of IDS intervention triggered by pharmacist alert. Qualitatively, these kinds of interventions led mainly to de-escalation or stopping of antibiotic therapy (63%) as opposed to on-request IDSCS (32%). An overall decrease of 14.6% in antibiotic use was observed ( Clostridium difficile infections incidence, and health costs savings [In 2015 in Europe, 671,689 cases of infections with antibiotic-resistant bacteria features occurred, leading to 33,110 deaths, corresponding to 6.44 deaths per 100,000 population and 874,541 disability adjusted life-years (DALYs) [ savings ,13. One  savings ,15.Nowadays, cross-disciplinary medical project funding is limited by the current economic healthcare situation. Despite many warnings from French and European infectious diseases societies about the crucial need for ASPs, raising funds and dedicating time to implement these strategies are still difficult, especially when the short-term economic benefit is not obvious ,17,18.In France, ASPs are not fully implemented and the current system relies on supporting prescribers mainly through training and on-request infectious diseases specialist consulting . TraininIndeed, the practical way to link together these interventions is not clear and neither the complementarity of these actions nor the acceptance of physicians towards unsolicited advice have yet been evaluated. Based on recent publications ,25,26,27Over the entire analysis period, 7508 stays involved the administration of antibiotic therapy, of which 1316 received an intervention. At least one intervention was carried out for 1430 stays, corresponding to 2046 interventions noted in the electronic medical records (EMRs) .The overall acceptance rate for the proposals was 88%, with a variation according to intervention types ranging from 68 to 92% . The disThis complementarity is also illustrated when comparing advice type according to different kinds of interventions. Regarding IDSCS interventions, 341 of 1053 interventions (32%) were either a lack of antibiotic initiation, a therapeutic de-escalation, a cessation of all antibiotics, or a reduction in treatment duration with a 92% acceptance rate. On the other hand, 535 proposals (51%) were either a therapeutic escalation or an extension of antibiotic therapy with a 92% acceptance rate.Of the 501 proposals made during PHARM-cATB interventions, 316 (63%) were either a therapeutic de-escalation, a cessation of all antibiotics, or a reduction in the duration of treatment with a 76% acceptance rate. Only 69 proposals (14%) consisted of a therapeutic escalation or an extension of antibiotic therapy with an 84% acceptance rate .p = 0.096). Nor was there any significant difference regarding in-hospital mortality in patients with deep infections (267 (7.31%) versus 266 (6.9%); p = 0.37) or 30-DRR (8.2% (293) versus 7.7% (296) in 2019, p = 0.44).There were 3561 inpatients with deep infections hospitalized in the eight wards who benefited from the whole ASP from January 2016 to May 2017 versus 3839 from January 2018 to May 2019. The clinical and demographic characteristics of these patients are summarized in 1000PD) in 2017 versus 287 DDD1000PD in 2019; p = 0.03). Carbapenems use was moderate and stable over time . A slight increase in injectable third-generation cephalosporins use was observed . There was a significant decrease of fluoroquinolones use of 63%  (1000PD in 2017 versus 474 DDD1000PD in 2019 (p = 0.016). Moreover, the reduction in fluoroquinolones use was more noticeable between April and December 2018 . This decrease continued until the end of the analysis. An effect on carbapenems use took longer to appear, but a clear decrease was observed from January to June 2019   . We alsoctively) .Ninety-five physicians that participated in the ASP were surveyed for satisfaction, of which 49 responded. All physicians were satisfied with the dedicated phone line provided and wanted on-request IDSCS to be continued, as well as LAB-M interventions. Regarding PAF actions, only 2/32 physicians were not satisfied with this kind of intervention and did not wish for it to be carried on. All results are summarized in We demonstrated that implementation of a whole ASP combining solicited and unsolicited interventions is possible and that the different modes of intervention are complementary. The multimodal ASP implemented in the hospital of Bassin de Thau (HBT) led to a decrease of antibiotic use, especially fluoroquinolones, without impacting deep infection mortality. We also observed a slightly decreased trend in the length of hospital stay in these patients.Staphylococcus aureus bacteremia clinical cases, PAF, preprescription authorization for certain antibiotics, specific interventions depending on infection type or clinical department, microbiological laboratory interventions, and so on [Many ASP strategies have already shown their efficacy; for example, development and implementation of facility-specific clinical practice guidelines for common infectious diseases syndromes, IDS systematic referral for nd so on ,24,28,29nd so on . Thanks Antibiotic use analysis also revealed the same pattern. Interestingly, the decreased consumption accelerated after implementation of PAF methods, suggesting a stronger impact of interfering methods on overall antibiotic use. Similar results were found by Tamma et al., whose study highlighted the effectiveness of this method and its major impact on antibiotic use in a cross-over trial . AccordiWe did not find evidence of any statistically significant differences on mean LOS, 30-DRR, or mortality between the two periods. However, we observed a downward trend in the mean LOS with a decrease of 0.6 days of hospitalization per stay. Indeed, the reduction in antibiotic consumption, particularly intravenous antibiotics, might lead to a reduction in adverse effects and an earlier discharge of patients. The absence of statistical significance might be because of a lack of power for this criteria; however, it was not the primary endpoint of this study. In the literature, some arguments tend to confirm this hypothesis: Sasikumar et al. showed a significant impact of IDS interventions on mortality and medical stay costs, especially for ICU stays . AlthougThese data highlight the importance of using a multimodal strategy when setting up an ASP, keeping in mind that different interventions would respond to different needs. The 2016 IDSA guidelines emphasized PAF and preprescription authorization methods, while underlining the potential for better acceptance of PAF as prescriber autonomy is maintained . In our We show that they may be implemented within French hospitals considering their efficiency and their complementarity to other methods. It is important to note that, without an EMR, it is challenging to set up such a program with unsolicited interventions.Nevertheless, this kind of program is time-consuming and labor-intensive; indeed, PAF interventions represented 10 h of work per week for one IDS and one pharmacist, while LAB-M interventions counted for 5 h of work, without including intervention retranscription in the electronic patient record . This organization requires dedicated medical time for this activity, as recommended by European Society of Clinical Microbiology and Infectious Diseases (ESCMID) .There are limitations to our study. The impact on antibiotic resistance was not assessed because of the short-term study design. This key outcome will be analyzed after several years of operating under the program in order to compare antimicrobial resistance before and after implementation of this system. Our study did not include medico-economic analysis. Nevertheless, the 0.6 days of stay decrease for inpatients with ID diagnosis would allow some healthcare cost saving, despite this result not being statistically significant. We were also not able to set up, in parallel to our ASP, an educational program that could lead to improved practitioner adherence as well as antibiotics prescribing over the long term . Indeed,Finally, there was a center’s effect limiting the extrapolation of our results as our study took place in a small hospital with less than 300 beds for the medicine, surgery, and obstetrics departments. The small hospital size likely facilitated the rapid establishment of this multidisciplinary system. One of the reasons of our success is probably the direct and confident relationship established between the IDS, the pharmacist, the microbiologist, and the prescribers, which may not be possible to install in other settings. Additional multicentric studies are needed to confirm our results and go further.Two hospitals  and university hospital of Montpellier (UHM)) created a shared infectious disease specialist (IDS) position to sequentially implement an innovative multimodal ASP within HBT. The HBT is a 938-bed hospital with establishments providing care for dependent elderly people (376 beds); psychiatric unit (57 beds); geriatric and follow-up care and rehabilitation unit (167 beds); and acute care unit, medicine, surgery, and obstetrics unit (274 beds). On the whole, 406 beds are provided with an electronic medical record (EMR).The infectious disease EMR pattern was duplicated from UHM to HBT to allow IDS response in real time with a complete traceability in the patient EMR for each intervention .Several interventions centralized by the same IDS were progressively implemented:January 2018: Simultaneous implementation of (i) a dedicated phone line for the infectious diseases specialist consulting service (IDSCS), (ii) weekly intensive care unit multidisciplinary clinical team meetings (ICU-M), and (iii) IDS intervention triggered by a bi-weekly microbiological laboratory meeting (LAB-M) for the revision of antibiotics based on microbiological data . In addition, monthly educational training on antibiotic use was proposed to all residents of the hospital.April to December 2018: Establishment of PAF interventions in association with pharmacy unit members. Initiation of critical antibiotics prescription review (PHARM-cATB) in April 2018. This consists of a systematized analysis of critical antibiotics prescription , and carbapenems) performed twice a week within the eight wards with the greatest antibiotics use, with feedback to the prescriber.Initiation of longer than 7 days antibiotics prescription review (PHARM-7d) in December 2018. A systematized analysis was performed on the whole hospital with feedback to the prescriber.Each intervention was noted in the EMR in real time and was analyzed to evaluate intervention acceptance. An intervention was defined as having been followed if the proposed antibiotic type, duration, and dosage were accepted by the prescribing physician. The whole system organization is summarized in 1000PD), was calculated with ConsoRes® software [The complementarity of the different actions was assessed by the quantitative and qualitative analysis of all interventions traced in the EMR . Antibiotic consumption, defined in daily dose of antibiotics per 1000 patient-days (DDDsoftware  for the An anonymous satisfaction survey was sent after 12 months of implementation of the system to all clinicians, followed by two reminder letters.2 test for qualitative variables. Comparisons between the two periods were performed using a χ2 test for mortality and readmission rate, a Mann–Whitney U test for the mean LOS, and a linear regression test to analyze antibiotic consumption.Comparisons between the two periods were made using a χThis study was conducted according to the principles of the declaration of Helsinki and in compliance with International Conference on Harmonization/Good Clinical Practice regulations. According to the French law, the study was in accordance with the recommendations of the local ethics committee, without the need for consent.This study is among the first to analyze the complementarity and impact of combining different strategies, especially interventionist methods, developed within ASPs. This system set up with reasonable human resources could easily be transposable to size-equivalent hospitals. A good acceptance rate of PAF interventions and clear complementarity of the different types of actions, leading to a major decrease in fluoroquinolones use and overall antibiotic use, without a negative impact on mortality or 30-DRR, are key points of this study.Further studies are needed to strengthen the scope of our results, including multidisciplinary and educational programs; long-stay healthcare structures; analysis of discharge prescriptions; and giving a more important role to PAF interventions, which currently are likely not sufficiently developed ,40. As t


Carbon dots (CDs)-based logic gates are smart nanoprobes that can respond to various analytes such as metal cations, anions, amino acids, pesticides, antioxidants, etc. Most of these logic gates are based on fluorescence techniques because they are inexpensive, give an instant response, and highly sensitive. Computations based on molecular logic can lead to advancement in modern science. This review focuses on different logic functions based on the sensing abilities of CDs and their synthesis. We also discuss the sensing mechanism of these logic gates and bring different types of possible logic operations. This review envisions that CDs-based logic gates have a promising future in computing nanodevices. In addition, we cover the advancement in CDs-based logic gates with the focus of understanding the fundamentals of how CDs have the potential for performing various logic functions depending upon their different categories. In many fields of science, carbon dots (CDs) have grabbed significant attention due to their unique chemical and physical properties. These properties include nontoxicity, inexpensive synthesis, and excitation dependent fluorescence performance ,2. In 203 carbon atoms inside CDs was demonstrated. Recently, the crystalline structure of CDs was studied by some researchers. These crystal structures can be classified as CDs having a graphitic crystalline core and others having non-graphitic crystallinity . Ty. Ty3 carLogic operations are performed by the molecules using one or more inputs and producing measurable output signals. Logic gates are the elementary building block for any digital system, where there is a certain relationship between the input and output signal based on a certain logic. The seven basic logic gates include AND, NOT, NOR, XOR, OR, NAND, and XNOR. Along with it, there are integrated logic gates, such as INHIBIT (INH) and IMPLICATION (IMP) circuits. These logic gates have several applications, such as AND gates being used for data transfer, while NAND gates are used in alarms and buzzers. They are used in circuits that involve processing and computation. In 1993 for the first time, Silva et al. explored the ability of the molecules to perform logic operations . The logCDs can be considered as the green carbonaceous nanomaterial possessing great potential to replace the conventional fluorophore  and siliCDs based logic gates can be categorized based on their displayed logic output. For this review purpose, we have categorized the CDs based logic gates as single output, combinational output, sequential output, and reversible systems . 6+ 6+ [2+ [2 H2S [3+ , Hg2+, aiothiols , Hg(II),iothiols . A multi signals . Apart fThe output of the combinational logic operation is the instant response to their current input state as logic 0 or logic 1. This type of output depends upon the combination of the input all the time. Thus, the combinational logic circuit is termed as ‘memoryless’. Combination logic circuits combine or connect simple logic operations to build a complex logic circuit. Tang et al. demonstrated the combinational nano logic gate with a dual output channel. The supramolecular assembly based on CDs showed two distinctive patterns of logic function at two different emission wavelengths of 440 nm and 490/545 nm. The output channel at 490/545 nm consists of a combination of two INHIBIT gates . The sup2+, S2-, Cu2+, and pH 2 for IMP, NOR, and AND logic operation [+, Fe3+, and Fe2+, while the fluorescence output was recorded at 440 nm along with magnetic intensity. A fluorescence-based NOR-INHIBIT and MR-based (XOR-INHIBIT)-OR sequential logic system was demonstrated successfully [Unlike combinational output, the third category is the sequential output in which the output depends on both present inputs and previous output. In contrast to combinational output, it has a memory, so the output varies based on the input. Qu et al. designed multiple single and sequential DNA-based logic gates. These types of logic gates were inspired by B to Z-DNA transition induced by functionalized CDs. The logic gate was constructed based on FRET between CDs and DNA intercalators and fluorescence quencher for CDs. Single AND functions were established at 585 nm and NAND logic at 465 nm. Similarly, AND + INHIBIT and NAND + INHIBIT sequential circuits were constructed at 585 nm and 465 nm, respectively . Fluoresperation . RecentlThe reversible system is interesting because it allows the reassessment of the output . The advThe majority of the CDs based logic gates depend upon the changes in the fluorescence response of CDs. These changes either in FI or wavelength make them potential candidates for performing various logic operations, such as AND, OR, NOR, INHIBIT, IMPLICATION, etc. . DiffereBetween static and dynamic quenching, dynamic quenching dominates the FRET quenching process as energy transfer takes place in an excited state . AnotherThe design of CDs for performing logic functions is generally based on five categories : Pristin2+ ions, which was retrieved with the addition of D- Penicillamine [The first category of design based on the synthesis procedure is the direct interaction of CDs with the analytes in their pristine form. The interaction is possible due to the presence of the different functional groups on the CDs surface. Hu et al. have used the as-prepared CDs for the determination of auramine O. In their work instead of fluorescence intensity (FI), the appearance of two peaks was taken as an output. They demonstrated dual emission, which is the auramine O-stimulated response . Chattopillamine .2+ detection [2+ and cysteine as inputs [6+) and cysteine were detected using red emissive CDs via dual modes, such as colorimetry and fluorescence by Dong et al. The red-emitting CDs constructed an AND logic gate [2+ and glutathione was achieved by down and upconversion CDs with high quantum yield (QY) −62%. The logic operation was obtained through the “ON-OFF-ON” process [3+ and F- sensing. An AND molecular logic gate was devised with the help of Fe3+ and F- as chemical inputs [The following year, in 2017, Hu et al. designed CDs for sensing glyphosate (Gly) based on fluorescence resonance energy transfer (FRET). The logic function is based on FI quenching of CDs in presence of Gly due to energy transfer between the donor (CDs) and acceptor (Gly) . In the etection , respectetection . Later, s inputs . Chromiugic gate . A dual  process . Recentll inputs .2+, DOX, and tDNA and phosphorescence-ON as an output signal [The second category includes the functionalization of the CDs. The functionalization imparts specific molecular recognization abilities to the CDs depending upon the organic molecule used to functionalize the surface. Qu et al. for the first time reported spermine-functionalized CDs (SC-dots) to induce right-handed B DNA to left-handed Z DNA transition under physiological conditions. Furthermore, a variety of logic gates were constructed based on FRET between fluorescent CDs and DNA intercalators, such as Ethidium bromide (EB) and FI quenching of CDs with iodide ions . Namasivt signal .6+ and ascorbic acid (AA), and also as an antibacterial agent. The logic operation was based on the inner filter effect (IFE) [2+ and S2. The INHIBIT Boolean logic is influenced by the FI quenching and recovery process in presence of analytes [For the limited tunability of the CDs spectrum, it is essential to improve the homogeneity of local electronic structure by controlling the size of sp2 domains, the surface functional group through surface passivation. Thus, the electronic properties of CDs were systematically modulated with ethylenediamine and different amino acids, such as cysteine, lysine, histidine, and arginine by Kuei and group. This kind of derivatization resulted in tuning the selectivity of sensing metal cations. The logic gates obtained from the fluorescence response of CDs depend on the fluorescence quenching in presence of metal ions . Das et ct (IFE) . In anotanalytes .3 (silver nitrate) and NaOH (sodium hydroxide) as inputs. The output signal was the presence of an absorption peak at 405 nm due to the formation of AgNPs/N-CDs nanocomposites [3+ and AA sensing, cellular imaging, and logic gate applications. The FI of doped CDs was quenched with the addition of Fe3+ due to photoinduced electron transfer (PET), which was further recovered by AA addition [2+ and biothiol sensing and further an IMPLICATION logic gate was created [2+ and GSH and an AND logic gate was constructed based on their sensing behavior [The third type of design is based on doping. The electronic characteristic of the CDs can be effectively adjusted with chemical doping, which further improves their optical properties . Zhao etmposites . There aaddition . In anot created . The N dbehavior . Not onlbehavior .3+) doped CDs (Ho-CDs), which exhibited pH responsiveness for both FI and magnetic resonance (MR) signals. In this study, the inputs were H+, Fe2+, or Fe3+, and the change in FI and MR signals served as an output for multilevel logic operations [For better feasibility and biomedical application, it is important to investigate dual readout logic devices. Yi et al. synthesized holmium  may provide great applications for CDs-based logic gates owing to its advantages over steady-state FI detection ,79,80. T


He was successfully treated with a 9-month course of prednisone, secondarily associated with rituximab when an AHA relapse occurred. As this patient presented with an unusual association of rare diseases, we wondered whether there was a link between the two conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4+ plasma cells as a result of broken tolerance to autologous FVIII. To test this assumption, we determined the anti-FVIII IgG subclasses in our patient and in a control group of 11 AHA patients without IgG4-RD. The FVIII inhibitor was mostly IgG4, with an anti-FVIII IgG4/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient; similar values were observed in non-IgG4-RD AHA patients. As a second hypothesis, we considered whether the anti-FVIII activity could be the result of a non-specific autoantibody production due to polyclonal IgG4+ plasma cell proliferation. To test this hypothesis, we measured the anti-FVIII IgG4/total IgG4 ratio in our patient, as well as in several control groups: 11 AHA patients without IgG4-RD, 8 IgG4-RD patients without AHA, and 11 healthy controls. We found that the median [min-max] ratio was higher in AHA-only controls (2.4 10-2 [5.7 10-4-1.79 10-1]), an oligoclonal setting in which only anti-FVIII plasma cells proliferate, than in IgG4-RD-only controls (3.0 10-5 [2.0 10-5-6.0 10-5]), a polyclonal setting in which all IgG4+ plasma cells proliferate equally. Our patient had intermediate ratio values (2.7 10-3 at diagnosis and 1.0 10-3 at relapse), which could plead for a combination of both mechanisms. Although no definitive conclusion can be drawn, we hypothesized that the anti-FVIII autoantibody production in our IgG4-RD AHA patient could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4+ plasma cell proliferation.We report the observation of a 75-year-old patient referred for cervical lymphadenopathies. A pre-lymphadenectomy blood work revealed an asymptomatic elevation of aPTT with low factor VIII (FVIII) levels and high anti-FVIII antibodies titers, consistent with acquired hemophilia A (AHA). Histological work-up of a cervical lymphadenopathy revealed benign follicular hyperplasia with IgG4 Althougd organs . The invd organs .Acquired hemophilia A (AHA) is a rare and severe bleeding disorder caused by the development of autoantibodies against coagulation factor VIII (FVIII). AHA can be idiopathic or associated with other diseases, including immunologic disorders (mainly rheumatoid arthritis and systemic lupus erythematosus) . Occurre+ plasma cell proliferation.Here, we report the case of a patient presenting with this association, in whom we investigated whether the anti-FVIII autoantibody production was related to the IgG4In order to study the immunologic associations between AHA and IgG4-RD, results obtained in our patient were compared to three control groups. The first control group consisted of 11 patients with a diagnosis of AHA (based on low FVIII plasma levels and detectable anti-FVIII activity) and no evidence of IgG4-RD . The second control group consisted of 8 patients with a diagnosis of IgG4-RD [based on the 2019 ACR/EULAR classification criteria ] and no Relevant clinical and biological data were retrospectively collected from medical records. Additional analyses needed for this study were performed on remaining blood samples initially collected for patient care.Plasma FVIII levels were determined by one-stage clot assay, using Triniclot APTT-HS  and FVIII-deficient plasma  on Sysmex CS-2400 . The Bethesda assay was used to determine inhibitor potency, with inhibitor concentrations ≥ 0.6 BU defined as positive. We used the Nijmegen-modified Bethesda assay , 9 , on the fully automated Optilite® turbidimetric analyzer . Each assay comprised a specific antiserum for the targeted IgG subclass, and specific calibrators and controls that have been calibrated against the ERMDA470k certified reference material.Total IgG and IgG subclass measurements were performed on patient sera according to the manufacturer’s instructions using commercially available Optilite®, Takeda, Vienna, Austria) overnight at 4°C. After blocking with PBS-3% bovine serum albumin (BSA), plasma diluted in PBS-3% BSA was incubated for 1 hr at 37°C. Bound IgG1, IgG4, or total IgG were revealed using HRP-conjugated monoclonal anti-human Fc IgG1 , IgG4  or IgG , respectively, and the OPD substrate . As a standard, the recombinant anti-FVIII monoclonal IgG4 ). Histological examination revealed benign follicular hyperplasia with elevated IgG4/IgG ratio and no evidence of lymphoma Figure 2Overall, our patient was considered to have IgG4-RD-associated AHA and was started on oral prednisone 1mg/kg/day for both diseases. This led to a regression of parotid and lymph node enlargement, a decrease in serum IgG4 levels, a progressive correction of FVIII and aPTT values, and a suppression of anti-FVIII plasma activity Figure 1Nine months after treatment withdrawal, the patient relapsed. This was characterized by a new increase in IgG4 serum levels without organ involvement; and by a decrease in FVIII plasma levels with elevated anti-FVIII autoantibodies but without bleeding Figure 1+ plasma cells as a result of broken tolerance to endogenous FVIII. To test this assumption, we tried to determine the subclass of the anti-FVIII IgG, both in our patient and in a control group of 11 patients diagnosed with AHA but with no evidence of IgG4-RD.As this patient presented with an unusual association of rare diseases, we wondered whether there was an immunopathogenic link between the 2 conditions. Our first hypothesis was that the anti-FVIII autoantibodies could be directly produced by the proliferating IgG4FVIII inhibitor was mostly of the IgG4 subclass, with an anti-FVIII IgG4/IgG1 ratio of 42 at diagnosis and 268 at relapse in our patient with IgG4-RD-associated AHA Table 2.Our second hypothesis was that an undetectable anti-FVIII activity exists physiologically within the normal human IgG4 repertoire, and that the polyclonal expansion of this repertoire observed during IgG4-RD increases the anti-FVIII fraction above detection thresholds Figure 3-2 (5.7 10-4-1.79 10-1). In this setting, the anti-FVIII antibody production could be considered to be the result of broken tolerance to endogenous FVIII and oligoclonal expansion of a pathogenic plasma cell contingent . In this setting, the detected anti-FVIII activity is most likely the result of a bystander antibody production due to polyclonal IgG4+ plasma cell proliferation.In the IgG4-RD without AHA control group, the median anti-FVIII IgG4/total IgG4 ratio was 3.0 10-4 and 7.0 10-5, respectively). This might comfort the hypothesis of a usually undetectable, non-specific physiological anti-FVIII activity, that increases above detection levels during IgG4-RD.In the healthy control group, most subjects had no detectable anti-FVIII IgG4, except for HC#4 and #5 who had anti-FVIII IgG4/total IgG4 ratios in ranges similar to that of the IgG4-RD-only patients  may be at work in our patient.In our patient, anti-FVIII IgG4 represented only a small proportion of the total serum IgG4, with a ratio of 2.7 10+ plasma cells  a polyclonal proliferation of IgG4+ plasma cells occurred that increased a bystander anti-FVIII activity that exists physiologically below detection levels.We report here a case of AHA associated with IgG4-RD, an unusual combination of 2 rare immunological diseases, with a favorable outcome under corticosteroids and rituximab. We postulated that there could be an immunopathogenic relationship between the 2 conditions, and explored 2 pathophysiological hypotheses: (1) broken tolerance to endogenous FVIII induced an antigen-driven oligoclonal proliferation of IgG4In our patient, both diseases were diagnosed according to standard-of-care recommendations: the patient met the clinical, serological and histological items of the ACR/EULAR 2019 classification criteria for IgG4-RD ; and theSo far, the co-occurrence of AHA and IgG4-RD has only been reported in 3 published cases  Table . FollowiAnother article reported the observation of a patient presenting with AHA and high serum IgG4 levels . HoweverAs to investigate the possibility of a pathophysiological relationship between AHA and IgG4-RD in our patient, we explore 2 distinct hypotheses.+ plasma cells driven by broken tolerance to endogenous FVIII. We found that anti-FVIII IgG were indeed mostly of the IgG4 subclass in our patient. Interestingly, this was also observed in another IgG4-RD-associated AHA case  than in IgG4-RD-only controls   Figure 4+ plasma cell proliferation.We report herein the observation of a patient with IgG4-RD and AHA, an unusual combination of two rare diseases, and show the FVIII inhibitor was mostly an IgG4 autoantibody. Although no definitive conclusion can be drawn from our work, we hypothesize that the anti-FVIII autoantibody production could be the result of both broken tolerance to FVIII and bystander polyclonal IgG4The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.All individuals listed as authors met the ICMJE guidelines for determining authorship. SSa, EJ, BL, DL, SL-D, and LT contributed to the conception and design of the study. EJ, BL, JR, SDe and SL-D performed the experiments and acquired the data. SS constituted the database. SS wrote the first draft of the manuscript. EJ, BL, DL, SL-D, and LT made major contributions to the manuscript. RD performed the histological work-up, provided the iconography for 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.