Saccharina latissima fucoidans (SL-FRO and SL-NOR) regarding their potential biological effects against age-related macular degeneration (AMD). Primary porcine retinal pigment epithelium (RPE), human RPE cell line ARPE-19, and human uveal melanoma cell line OMM-1 were used. Cell survival was assessed in tetrazolium assay (MTT). Oxidative stress assays were induced with erastin or H2O2. Supernatants were harvested to assess secreted vascular endothelial growth factor A (VEGF-A) in ELISA. Barrier function was assessed by measurement of trans-epithelial electrical resistance (TEER). Protectin (CD59) and retinal pigment epithelium-specific 65 kDa protein (RPE65) were evaluated in western blot. Polymorphonuclear elastase and complement inhibition assays were performed. Phagocytosis of photoreceptor outer segments was tested in a fluorescence assay. Secretion and expression of proinflammatory cytokines were assessed with ELISA and real-time PCR. Fucoidans were chemically analyzed. Neither toxic nor antioxidative effects were detected in ARPE-19 or OMM-1. Interleukin 8 gene expression was slightly reduced by SL-NOR but induced by SL-FRO in RPE. VEGF secretion was reduced in ARPE-19 by SL-FRO and in RPE by both fucoidans. Polyinosinic:polycytidylic acid induced interleukin 6 and interleukin 8 secretion was reduced by both fucoidans in RPE. CD59 expression was positively influenced by fucoidans, and they exhibited a complement and elastase inhibitory effect in cell-free assay. RPE65 expression was reduced by SL-NOR in RPE. Barrier function of RPE was transiently reduced. Phagocytosis ability was slightly reduced by both fucoidans in primary RPE but not in ARPE-19. Fucoidans from Saccharina latissima, especially SL-FRO, are promising agents against AMD, as they reduce angiogenic cytokines and show anti-inflammatory and complement inhibiting properties; however, potential effects on gene expression and RPE functions need to be considered for further research.Fucoidans from brown algae are described as anti-inflammatory, antioxidative, and antiangiogenic. We tested two  Saccharina latissima (SL), also known as sugar kelp or kombu, is a brown algae species from the family Laminariaceae. It grows along the coast of North America and Europe. Together with other Laminaria species, it forms kelp forests in the sublittoral zone below the low-water line. It is already widely used as food source and has a high-protein and low-fat content. As brown seaweed, it contains fucoidans, also known as sulfated fucans. Fucoidans are a group of sulfated polysaccharides which form complexes with alginates and cellulose in the cell wall of the algae, contributing to the robustness and protection against dehydration and environmental factors such as tides and water composition . Data were calculated relative to untreated control, set to 100%. Fucoidans displayed a slightly stimulating effect in the higher concentrations, but their effect did not reach statistical significance. Overall, they showed no antiproliferative effects. Concerning OMM-1, viability was successfully decreased to 37 ± 2% or 35 ± 2% with 500 µM H2O2 (p = 0.0011/0.0001) and to 64 ± 4% or 67 ± 2% with 25 µM erastin (both p = 0.0001), both after 24 h of stimulation. Cell viability was only slightly increased by fucoidans after oxidative stress insult, with 50 µg/mL fucoidan showing the best effect, but this condition did not reach statistical significance. Concerning ARPE-19, cell viability was reduced by 250 µM H2O2 and 20 µM erastin with 36 ± 13%  and 42 ± 11 or 40 ± 13% , respectively. Again, fucoidans did not display any relevant or statistically significant protective effects.Oxidative stress is one of the major pathological factors of AMD, and photoreceptors and RPE are exposed to a high amount of oxygenic radicals . We usedRPE cells secret high levels of VEGF, as VEGF is important for the fenestration of choroidal endothelial cells, but excessive secretion of VEGF strongly contributes to wet AMD . We invep = 0.0015/0.0144/0.0004).Concerning ARPE-19, cell viability was not influenced after three days and remained stable around 100%. SL-NOR did not reduce VEGF secretion  at any tp = 0.0230); for all other concentrations, it remained stable around 100%. VEGF secretion (p = 0.0219) and to 0.637 ± 0.036 [arb. unit] at 10 µg/mL (p = 0.0049). SL-NOR reduced VEGF to 0.626 ± 0.033 [arb. unit] at 1 µg/mL (p = 0.0037) and to 0.612 ± 0.030 [arb. unit] at 10 µg/mL (p = 0.0029).In primary RPE, cell viability was slightly reduced by 100 µg/mL SL-FRO to 82 ± 4% (ecretion  was reduFucoidan SL-FRO and SL-NOR (50 µg/mL) were tested for their anti-inflammatory properties. RPE were treated with fucoidans for one and three days with and without 1 µg/mL LPS, 10 µg/mL PIC, 50 ng/mL TNF, or 10 ng/mL Pam. Supernatants were collected for 24 h and evaluated in IL-6  and IL-8p = 0.0077). After three days of stimulation both fucoidans reduced PIC induced IL-6 secretion. SL-FRO reduced it to 216 ± 331 pg/mL (p = 0.0250) and SL-NOR completely diminished it to 0 ± 0 pg/mL (p = 0.0030).Regarding IL-6 secretion, all used proinflammatory agents were able to activate RPE cells to secrete IL-6 (with exception of Pam after three days), while neither of the tested fucoidans activated IL-6 secretion. LPS lost this proinflammatory effect after three days when applied together with SL-NOR. Conversely, SL-NOR increased IL-6 secretion together with TNF compared to TNF alone with 3265 ± 1401 pg/mL compared to 2060 ± 1346 pg/mL (p = 0.0415). After three days of stimulation, SL-FRO and SL-NOR significantly reduced PIC-induced IL-8 secretion to 1388 ± 1065 pg/mL and 1208 pg/mL, respectively, compared to PIC control with 2080 ± 1224 pg/mL (p = 0.0020/0.0004).Concerning IL-8 secretion, both fucoidans slightly increased cytokine secretion, but this effect was diminished after three days. In general, all proinflammatory agents activated IL-8 secretion for both tested time points. After one day of stimulation, both fucoidans tended to decrease LPS, PIC, and Pam-induced IL-8 secretion, whereas SL-NOR significantly decreased PIC-induced IL-8 secretion to 1791 ± 1371 pg/mL compared to 2792 ± 1302 pg/mL (IL6) and IL-8 (CXCL8 or IL8) was assessed. Gene expression for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as endogenous control for normalization. Relative fold gene expression level RQ (=2−ΔΔCT), minimal RQ (RQ Min), maximal RQ (RQ Max), and p-value (student’s t-test) against untreated control or PIC control were evaluated with Thermo Fisher Connect . In addition, compared to PIC SL-NOR reduced IL6 expression. Taken together, after three days of stimulation SL-FRO rather activates interleukins expression whereas SL-NOR reduces it.Three days of stimulation: Compared to control, PIC increased IL8 expression slightly but not significantly. SL-FRO significantly increased IL8 expression up to 50.009 (p = 0.0070). This effect was even stronger by dual stimulation with PIC with an RQ of 120.378 (p = 0.0100). Compared to PIC control, SL-FRO displayed a stronger IL8 activation with RQ = 13.500 (p = 0.0210) on its own. Together with PIC it increased IL8 expression up to 32.496 (p = 0.0090). Taken together, while PIC increases interleukin secretion, its effect on gene expression is less pronounced. Obviously, the effect of the fucoidans on cytokine secretion is not mirrored by their effect on gene expression.Seven days of stimulation: Compared to control, PIC increased Typical structure-dependent activities of fucoidans include polymorphonuclear (PMN) elastase inhibition and complement inhibition . Both coFucus vesiculosus fucoidan (Sigma fucoidan , respectively. SL-NOR plus PIC condition was significantly lower than PIC alone (p = 0.0308).Densitometric evaluation showed that PIC significantly reduced RPE65 expression to 0.610 ± 0.515 (p = 0.0020) and SL-NOR to 3 ± 2 (p = 0.0060). Of note, fucoidans and PIC nullified the phagocytosis reducing effects when applied together in comparison to their single treatments.Primary porcine RPE and human RPE cell line ARPE-19, respectively, were treated with 50 µg/mL SL-FRO or SL-NOR with and without 10 µg/mL PIC for three days. A phagocytosis assay was conducted. Blue cell nuclei were counted per hand and green labeled beads per Fiji software. The beads number was set in relation to the cell nuclei as an estimate for cell number ARPE-19: . For ARPFucoidans are marine polysaccharides from brown algae cell walls which display a variety of promising biological activities throughout the literature, e.g., antioxidative, anticoagulant, and immunoregulatory effects . But theLaminaria hyperborea as well as the commercially available Fucus vesiculosus fucoidan from Sigma-Aldrich displayed the most promising activities in antiangiogenic and antioxidative activities  were calculated via the concentration-dependent inhibition curves.Elastase inhibitory activity of the fucoidans was examined by a fluorogenic microplate assay  using elastase from human polymorph nuclear granulocytes (PMN)  and the substrate I-1270 . The assay was performed as previously described . The con50 (µg/mL) of the fucoidans were calculated via the concentration dependent inhibition curves.Complement inhibiting potency of the fucoidans was investigated by assessing their effect on the lysis of sheep erythrocytes induced by classical pathway activation  as previously described . As compUveal melanoma cell line OMM-1 (RRID: CVCL_6939)  was kindHuman RPE cell line ARPE-19  is an immortal cell line from an adult donor with age of 19 . Cells wPrimary porcine RPE cells were prepared from pig eyes as previously described . Eyes weAll cells were cultivated at 37 °C in a humidified 5% incubator.2O2  or 25 µM erastin , and ARPE-19 were treated with fucoidan for 30 min, followed by 250 µM H2O2 and 20 µM erastin, respectively. Regarding inflammation, cells were treated with 1 µg/mL LPS , 10 µg/mL PIC , 50 ng/mL TNF , or 10 ng/mL Pam2CSK4 . Depending on the assay, different stimulation times were used as indicated in the result section.Depending on the experiment, cells were treated with 1, 10, 50, or 100 µg/mL fucoidan. Regarding oxidative stress assays OMM-1 were treated with fucoidan for 30 min before stress insult was applied by adding 500 µM HCell viability was determined with MTT assay . After w2 confluence was determined  as described in the manual of the master mix. Gene expression of pression . ΔCT  lysis buffer, incubated for 45 min on ice. Lysis buffer contained 1% NP-40 substitute (Sigma-Aldrich), 150 mM NaCl , 50 mM Tris (Sigma-Aldrich), as well as 1:100 phosphatase inhibitor cocktail I and II and proteinase inhibitor . Protein concentration was determined with BioRad protein assay as described by the manufacturer . Bovine serum albumin was used for standard calibration curves. Protein content was measured with Genesys 10 Bio  at 595 nm. Proteins were separated with SDS-PAGE in 12% acrylamide gel (15 µg protein amount per sample). The gels were used for western blotting in a wet tank procedure. After transferring proteins, the membranes were blocked with 4% skim milk . Membranes were incubated with primary antibodies at 4 °C overnight on a shaker . Horseradish peroxidase (HRP) conjugates were added for one hour depending on the host of the primary antibodies . As substrate for the HRP, Amersham ECL Western Blotting Detection Reagent  was used. Chemiluminescent signal was detected with MF-ChemiBIS 1.6 . Band volumes were evaluated with TotalLab TL100 (Biostep). Band volumes of β-actin were used for normalization.Protein expression of RPE65 and CD59 of treated primary porcine RPE cells was assessed with western blot as previously described . Media whttps://imagej.net/software/fiji/downloads (accessed on 8 August 2022). For evaluation measured beads were set in relation to number of cell nuclei.For phagocytosis assay confluent RPE cells on collagen I coated cover slips were used  followed by post-hoc Dunnett’s multiple comparison test. PCR data were evaluated with Thermo Fisher Connect and integrated student’s t-test. Data with p values ≤ 0.5 were marked as significant. In general, all significances were calculated between all conditions with the assay control (marked with *) as well as between fucoidans plus proinflammatory agent with proinflammatory agent alone (marked with +).Diagrams, means, standard deviation, and visual formatting were made with Microsoft Excel and PowerPoint . For statistical analysis, GraphPad Prism 9  was used. Normality was checked with the Shapiro–Wilk test. All data of this study showed Gaussian distribution. Relative data were tested with one-sample Saccharina latissima from Norway (SL-NOR) and the Faroe Islands (SL-FRO) concerning possible beneficial effects against age-related macular degeneration-related pathogenic mechanisms and concerning the maintenance of RPE cell function. It was been previously shown that fucoidans from these species can exert antiangiogenic and antioxidative activities. Primary porcine retinal pigment epithelium was used as well as the human RPE cell line ARPE-19 and the human uveal melanoma cell line OMM-1. We detected no antiproliferative effects in any tested cell model but also no antioxidative effects against erastin or H2O2 in ARPE-19 and OMM-1. Interleukin 8 gene expression was reduced by SL-NOR. Vascular endothelial growth factor, interleukin 6, and interleukin 8 secretion were reduced by both fucoidans in retinal pigment epithelium. SL-FRO fucoidan additionally reduced vascular endothelial growth factor in ARPE-19. The reduction of CD59 (protectin) expression due to pro-inflammatory stimulus was ameliorated by the fucoidans. Both fucoidans showed complement and elastase inhibitory effects. Retinal pigment epithelium-specific 65 kDa protein was reduced by SL-NOR but not SL-FRO. Barrier function of retinal pigment epithelium by fucoidans was only transient. Phagocytosis ability was not influenced in ARPE-19 (with or without proinflammatory activation). The fucoidans reduced phagocytosis in primary retinal pigment epithelium, which was lost after inflammatory insults. Taken together, two promising fucoidans from Saccharina latissima were characterized, which both displayed anti-inflammatory, antiangiogenic, as well as complement inhibitory properties. However, the effect on RPE function and gene expression need to be taken into consideration for further development, which renders SL-FRO to be of higher interest.The goal of this study was to test two fucoidans from


The long-term performance of the concrete–polymer cement mortar (PCM) interface under environmental exposure is crucial to the safety of the PCM overlaying method as the environmental exposure of the repaired structures caused further degradation of the interface, leading to a significant reduction in intended service life. This study investigates the durability enhancement effect of silica fume of the concrete–PCM interface, considering an individual action of elevated temperature  [constant (short and moderate duration) and cyclic conditions] and moisture content [continuous immersion and wetting/drying (W/D) cycle]. Our previous research confirmed that the use of silica fume forms more C-S-H with strong binding force and enhances the interfacial bonding strength due to the denser microstructure at the interface, and it is expected to be utilized for durability purposes under the aforementioned exposure conditions. Under all elevated temperature exposure conditions, the reduction percentage of the interfacial performance corresponding to the respective reference specimens reduced significantly with the inclusion of silica fume with overlay material. The occurrence of interface fracture at lower load and a greater number of pure interface fracture modes observed in normal PCM specimens compared to modified PCM specimens indicates a positive influence of higher adhesion with better durability of modified PCM overlay with substrate concrete. Under both conditions of moisture content, significant reduction in interfacial strength was observed in normal PCM specimens. In all cases, the reducing ratio of interfacial strength was higher in normal PCM compared to modified PCM, indicating a positive influence of silica fume under moisture content. Furthermore, silica fume inclusion shifts the fracture mode from pure interfacial fracture to composite fracture mode, indicating a positive response of silica fume to improve the resistance of interface fracture under moisture content. Conclusively, the use of silica fume improves concrete–overlay layer adhesion and enhances the bonding durability under environmental exposure. The performance of mortar or concrete significantly improves with the use of functional polymer materials or admixtures, as observed in several past experimental studies ,3,4,5,6.In practice, the strengthened structures are put into immediate service based on achieving adequate substrate concrete–repair materials bond strength in a short duration. In many cases, the short-term strength gain of the strengthened members does not ensure long-lasting and durable repairs because the long-term properties of the substrate concrete and repair material can be significantly different from the properties measured at early ages. The strengthened members are frequently located in harmful media and severe environments in the service life stage, causing early degradation and performance deterioration . The durTemperature and moisture are considered to be one of the major factors affecting the durability of concrete structures. Temperature in some regions of the world, especially in the tropical zone or some parts of North America, rises up to 60 °C in summer. This temperature rise due to global warming or non-sustainable development also accelerates the further deterioration of the concrete structures ,47. ConcOur previous research ,29,30 coAlthough different individual and coupling environmental conditions have an impact on the concrete–PCM interfacial bond, the influence of some of the individual environmental conditions on the concrete–PCM interface was considered as an experimental parameter on a priority basis. Considering the aforementioned issue, Series-I of this study investigates the durability enhancement effect of silica fume of the concrete–PCM interface, considering an individual action of elevated temperature  for constant [short (at 60 °C for 3 days) and moderate duration (at 60 °C for 36 days)] and cyclic conditions [day–night and seasonal variation] in the laboratory. In Series-II, the performance evaluation of the bond strength considering durability enhancement was explored under different moisture content conditions [continuous immersion in water up to 96 days and up to 24 W/D cycles]. Current experimental data can provide some theoretical foundation to researchers and structural engineers on the PCM overlaying method of deteriorated concrete structure strengthening under harsh environmental conditions. The findings of this research can help the practitioner in selecting a suitable repair overlay material and the manufacturer of PCM to produce new PCM with improved functionality to use under severe environmental conditions.Substrate concrete with a target compressive strength of 40 MPa was used in this experimental work. It was fabricated by mixing commercially available normal Portland cement, coarse aggregate, fine aggregate, tap water, water reducer, and air-entraining agent. The specific properties of the different constituents of substrate concrete are mentioned in our previous study . The sub2O3 (4.07%), SiO2 (16.39%), SO3 (2.57%), CaO (74.07%), and Fe2O3 (2.90%).The second type of material was the pre-mixed PCM containing poly acrylic ester (PAE) provided by the company. All the ingredients were mixed by the manufacturer in a specific ratio to fabricate gray-color PCM powder. At the time of the application, a water–binder ratio of 15% was used in this study as per the company’s recommendation to prepare the PCM mix. X-ray fluorescence (XRF) analysis was performed to evaluate the elemental oxides of the PCM used in this study. The major constituents observed using XRF analysis were Al2/g, a relative density of 150–700 kg/m3, a specific gravity of 2.2–2.3 and an average particle size of 0.15 µm is used in this study. The use of silica fume causes a need for more water, as the high surface area and small particle size of silica fume demand more water. A small amount of silica fume results in less C-S-H at the interface, whereas material stagnation is caused by using a large amount of silica fume , indicating a highly significant effect of the exposure condition on the interfacial bonding strength. Similarly, the level of significance of the other exposure condition under moisture were obtained by comparing the calculated and critical F-value and tabulated in F-value for the modified PCM specimens (5.17) under W/D cycle exposure was smaller than the normal PCM specimens (14.92). This confirmed that the exposure condition of W/D cycle has less effect on the modified PCM–concrete interface compared to the interface of normal PCM–concrete that have a highly significant effect under W/D cycle. The statistical analyses result also confirmed that the exposure condition of continuous wetting  conditions and two moisture content exposure conditions to simulate continuous immersion in water and simultaneous wetting and drying (W/D) cycle up to 96 days were investigated and the following conclusions can be drawn.The concrete–PCM interfacial bond strength significantly reduces with the exposure at elevated temperature (60 °C).The use of normal PCM (without silica fume) alone as an overlay material results in a higher percentage decrease in bond strength under both short-duration (3 days) and long-duration (30 days) exposure at constant 60 °C temperature. The combined use of PCM and silica fume significantly decreases the reduction percentage of bond strength. A delay in the occurrence of interface fracture (at higher load) and the higher number of specimen failures in composite fracture mode in modified PCM cases indicate higher concrete–overlay material adhesion with better durability under constant temperature exposure.The reduction percentage further increases under day–night and seasonal variation exposure conditions, resulting in more detrimental influence of the cyclic elevated temperature on the interfacial bonding strength. The use of silica fume with PCM led to an optimal solution in terms of bond strength, PCM–concrete adhesion, thus improving the durability of the concrete–PCM interface under cyclic temperature conditions. Both W/D cycle and continuous immersion conditions have a significant effect on the bond properties of the concrete-to-normal PCM interface. Compared to normal PCM mortar, however, use of modified silica PCM mortar significantly improves bond strength and led to more ductile failure due to the multiple cracking behavior, which dispersed more uniformly the shear stress transfer at the concrete–PCM interface under moisture content exposure.The influence of moisture content after the same length of exposure under continuous immersion results in lower a reduction in PCM interfacial strength with and without silica fume compared to the exposure under wetting and drying cycle.The concrete–PCM interface is the most critical component in the PCM overlaying method. To evaluate the overall performance of the strengthened structures, it is necessary to consider the effects of environmental degradation on the interface. The obtained data confirm the suitability of the PCM overlaying method with silica fume under harsh environments as it provides adequate concrete–overlay material bond and enhances adhesion and durability under elevated temperature and moisture. However, the results from this study are restrained to a limited duration of exposure. Additional data should be developed with a longer duration of exposure of about 2–3 years in the future to infer longer-term applicability and to predict the service life of strengthened structures accurately under harsh environmental conditions.


In particular, as compared to the Nit group, both the CH and TAP groups had significantly smaller penetration areas (p < 0.05). In conclusion, this ongoing investigation indicates that nitrofurantoin penetrated dentinal tubules better than calcium hydroxide or triple antibiotic paste. The aim of this study is to assess and analyze the intratubular penetration of the intracanal medications nitrofurantoin (Nit), triple antibiotic paste (TAP), and calcium hydroxide (CH). Sixty freshly extracted single-rooted teeth were acquired and decoronated to a standard length of 15 mm. To prepare specimens up to size F3, rotary ProTaper instrumentation was employed. The prepared teeth were divided into three groups, each of which received one of the tested intracanal medicaments: Group I , Group II (triple antibiotic paste), and Group III (nitrofurantoin). Using a size #30 Lentulo spiral, a freshly prepared therapeutic paste was placed into the canals, and the intracanal medicaments were allowed to set in the incubator at 100% humidity. The samples were subsequently sliced perpendicularly to their long axis using a precision saw and assessed under a scanning electron microscope to assess the depth of penetration of intracanal medicaments at the coronal, middle, and apical portions of the root canal dentin. The data were analyzed using one-way ANOVA and Tukey’s post hoc test. The statistical analysis revealed a significant difference between the experimental groups in the quantity and depth of sealer penetration ( Intracanal drugs play an important role in battling against pathogens in the root canal. These drugs are crucial in modern endodontic therapy, where the focus is typically placed in shaping and completely cleaning the root canal, which might take precedence over the selection of intracanal disinfectants. When endodontic therapy cannot be completed in a single visit, intracanal medicaments are usually indicated as a crucial technique to address the continuous problem of tenacious intracanal bacteria, which have been proven to grow between treatment sessions . The funOne of the key objectives of endodontic therapy is to successfully limit pathogen development and proliferation inside the complex network of the root canal space. Once a microbial infection has taken hold, these resistant bacteria can invade the dentin isthmus, apical delta, lateral canal, and primary root canal. This broad penetration, on the other hand, poses a substantial barrier for standard biomechanical preparation approaches, which may not always be successful in completely eradicating all harmful microorganisms. As a result, intracanal medicaments must penetrate deeply into the intricate network of dentinal tubules to effectively address intracanal bacteria, avoiding the creation of chronic and recurring infections. By guaranteeing that these medications reach the dentin’s deepest depths, the therapy can seek to not only remove existing infections but also to develop a strong defense against the reemergence of pathogenic bacteria. As a result, complete pathogen elimination and the avoidance of chronic infections inside the root canal system are emphasized as critical goals in effective endodontic therapy .Bacteria have an important role in the genesis and progression of pulpal and periapical diseases. At depths ranging from 200 to 1500 μm , they en2+) and hydroxyl (OH−) ions contributes greatly to CH’s capabilities, including its expected antibacterial effect, tissue dissolution, tooth resorption prevention, and hard tissue regeneration encouragement [Calcium hydroxide (CH) is a prevalent intracanal medication that may eradicate microorganisms that dissolve organic tissue, and relieve inflammation. This material has a high pH, ranging from 12.5 to 12.8. The dissociation of calcium  has emerged as a remarkable choice among these pastes. TAP is differentiated by its strong antibacterial properties, making it a formidable candidate for the management of difficult endodontic circumstances. In addition, TAP has received praise for its biocompatibility, which aligns it with the criteria of modern endodontic therapy, which prioritizes the preservation of both the patient’s health and the integrity of the treated tooth. Hoshino et al.  implemenNitrofurantoin (Nit) is a nitrofuran compound which has broader antibacterial action against both Gram-positive and Gram-negative bacteria. It is an effectively known oral antibiotic that is used to treat urinary tract infections (UTIs) as well as infections caused by multidrug-resistant bacteria. Notably, studies have shown that Nit is particularly efficient against E. faecalis, even when other antibiotics’ effectiveness is decreased ,16.Alrahman et al.  evaluateA combined total of 60 newly removed 60 single-rooted single-canaled mandibular premolar teeth were cleaned with an ultrasonic scaler of calculus and other debris before being kept in saline and awaiting usage. A power analysis was performed with G*Power version 3.0.1 . A total minimum calculated sample size of 60 samples  would require to yield 80% power to detect significant differences, with an effect size of 0.42  and a siThe teeth with an apical diameter preoperatively coinciding with #20 k-file were only selected for standardization of instrumentation till #30 apical diameter. A water-cooled double-sided disc moving at low speed in a handpiece was implemented to decoronate teeth at the cementum–enamel proximity, leading to a uniform root length of 15 mm. By introducing a K-file size #10 (Mani), the canal patency was validated. The working length was identified by inserting a K-file size #15 into the apical foramen and subtracting 1 mm from this measurement. The teeth were then all instrumented applying the Pro Taper universal rotary system (Dentsply) and prepared to F3 apical diameter. The root canals were then irrigated with 3 mL of 5.25% sodium hypochlorite in between each file while instrumenting them with a 27-gauge needle, which was 1 mm shorter than the working length, followed by 3 mL of saline solution and 3 mL of 17% EDTA for 1 min to eliminate the smear layer. Finally, the canals were rinsed with 3 mL of saline solution and dried with sterile absorbent paper points (Dentsply) before being categorized into three groups . The calcium hydroxide powder was blended in a 1:1 ratio with distilled water using a glass slab and a stainless-steel spatula.In search of the appropriate TAP paste concentration for usage in clinical settings (1 g/mL), the compounding of United States Pharmacopeia (USP) grade antibiotic powders, particularly metronidazole, ciprofloxacin, and minocycline, was performed with utmost accuracy and care. This was achieved by mixing 1 g of the aforementioned granules with 1 milliliter of pure sterile water .To attain the desired consistency, a thick paste-like mixture was created by combining a crushed tablet of Niftas  to obtain NIT powder using distilled water (DW). To improve its characteristics, Methylcellulose (MC) powder from Akshar Chemicals Ltd. Dahej, Gujarat, India, was incorporated into the NIT solution. To produce 100 mg/mL of NIT paste, 100 mg NIT + 1 mL DW + 80 mg MC were combined .By employing a size #30 Lentulo spiral anchored to a contra-angle handpiece and micromotor, the prepared pastes were inserted into the root canals. To prevent leaking, the coronal openings of the root canals were stuffed with temporary filling materials  and sealed with compact cotton pellets. Following that, the specimens were kept in an incubator for three weeks at a temperature of 37 °C and a humidity of 100%.Each of the samples was sectioned perpendicularly to its long axis using a precision saw at a moderate speed while being cooled by water to assess the penetration of medications. Each tooth was cut into three slices with apical, middle, and coronal depths of 4, 7, and 10 mm and a thickness of around 2 mm. Each specimen was placed within a circle-shaped self-curing acrylic resin mold, and a scanning electron microscope  was used to determine the extent of the penetration of the medications. Using a calibrated measuring instrument built into the microscope, measurements for the depth of penetration of the intracanal medications were recorded in the coronal, middle, and apical thirds of the root canal at a magnification of 200×.p’ value was 0.05 or below, all of the results were deemed statistically significant. Version 19 of SPSS  was the program utilized.The data were input into Microsoft Excel 2010. For each group, the descriptive data for penetrations were presented as means and standard deviations (SDs). Analysis of variance (ANOVA) was used to compare the penetrations of the three groups, and Tukey’s post hoc analysis was used to compare groups on a pair-wise basis. When the test’s ‘p < 0.001 * and F = 98.724. p-values of 0.001. The results showed a statistically significant disparity in penetration between the three groups at the overall level, with p-values of 0.001, emphasizing the statistical significance of the discrepancies.p-values of 0.001.p-values of 0.001.The eradication of infections and their metabolites is the major goal of endodontic therapy. To accomplish this, a mix of instruments, irrigation solutions, and medications should be employed . An intrDentinal tubules have been estimated to have a diameter of 2 to 4 µm. The scanning electron microscope has already been shown to be an excellent instrument for measuring the extent of material penetration into these complex dentinal tubules in prior research investigations. This is partly due to its excellent ability to offer complete and realistic visual depictions of dentinal tubules and their contents, allowing researchers to investigate the complexities of these microstructures with great accuracy. Nonetheless, it is critical to recognize that using this powerful imaging technology comes with its own set of obstacles. Conducting systematic analysis at lower magnification levels, in particular, can be intrinsically challenging, and the sample preparation procedure has the potential to contribute unwanted outcomes that may impair the accuracy of the outcomes. As a result, while the scanning electron microscope provides a significant glimpse into what is occurring in dentinal tubules, researchers must take caution in both its use and the related preparations to ensure the validity of their results .The smear layer, material chemical and physical attributes, and tooth morphology all have an effect on material penetration into dentinal tubules . The useNitrofurantoin is a powerful antibacterial agent with an extended track record of success in treating lower urinary tract infections (UTIs). Multiple trials have also shown that it is effective against Enterococcus faecalis . AlrahmaTo the best of our knowledge, no data on the depth of penetration of nitrofurantoin paste into the complicated network of dentinal tubules has been published in the scientific literature. The primary goal of this study was to investigate the intratubular penetration of three different intracanal medications: nitrofurantoin, triple antibiotic paste, and calcium hydroxide. The use of a scanning electron microscope substantially aided our investigation, allowing for a detailed assessment of the amount to which these medications entered the complicated network of dentinal tubules. We commenced our investigation based on our initial null hypothesis, which stated that there would be no substantial difference in the intratubular penetrations among these medications. Interestingly, our findings deviated significantly from this notion. They determined that the nitrofurantoin group penetrated the dentinal tubules much deeper than the triple antibiotic paste and calcium hydroxide groups. As a result, we were forced to reject the null hypothesis, indicating that the intratubular penetrations of these drugs differed considerably.Each endodontic intracanal medicament has the capacity to affect the physical and mechanical characteristics of the radicular dentin. The efficacy of intracanal medicine was much stronger in the coronal third, less effective in the middle third, and least effective in the apical third , with aGiven that root canal infections are so complicated, antibiotic combinations may be required to treat the diverse bacterial flora involved with such illnesses. In accordance with a particular study, the most effective component of the triple antibiotic paste against E. faecalis is minocycline. Minocycline, a semisynthetic tetracycline derivative, is effective against both Gram-positive and Gram-negative bacteria .2) and a triple antibiotic paste can possibly promote the ongoing development of the pulp–dentin complex in cases involving immature necrotic teeth, pointing to antibacterial properties as a contributing factor [In a retrospective study, Bose et al.  suggesteg factor ,31,32. Ag factor  investig2) is one of the most commonly employed intracanal medicaments in the field of endodontics. Notably, both short-term and long-term applications of Ca(OH)2 within the root canal have revealed possible negative aspects since they might have an unfavorable effect on the chemomechanical properties of the root dentin. This impact might be linked to the high pH values associated with calcium hydroxide, which can harm the surface collagen of the root dentin. While pure Ca(OH)2 may not be considered particularly effective as a broad-spectrum root canal medicament, various research studies have offered evidence demonstrating that it has limited efficacy against rigid, resistant pathogens that occur frequently within the root canal system [Calcium hydroxide (Ca(OH)l system . This, i−). This dynamic mechanism is critical in keeping a constant pH level inside the root canal environment. As a result, the antibacterial effect of calcium hydroxide is greatly enhanced, while the potential for the pH to drop is minimized by the dentin’s own buffering characteristics. These diverse activities add to the complicated interplay of elements that characterizes calcium hydroxide’s role as an intracanal medicament in endodontic therapy [When calcium hydroxide particles reach the complicated network of dentinal tubules, they come into direct contact with the microorganisms that thrive there, acting as a direct source of dissociated calcium ions. These calcium hydroxide particles dissolve in water over time, resulting in the formation of hydroxide ions (OH therapy .The nitrofurantoin group had a considerably better depth of penetration in the apical third than the triple antibiotic paste and calcium hydroxide groups. This might be due to a variety of causes, including the miniscule size of the nitrofurantoin particles, which allows for deep penetration into the dentinal tubules to eliminate pathogens that have made their way there. Furthermore, the presence of characteristics such as uneven secondary dentin apical surfaces, auxiliary root canals, and the resorption or healing of resorption sites in the apical area may contribute to nitrofurantoin’s improved penetration. The triple antibiotic paste had the highest mean intratubular penetration in this study, whereas calcium hydroxide had the lowest .TAP is not adequately eliminated from the root canal system, according to Birkhoff et al. , regardlNitrofurantoin and antibiotic combinations, particularly minocycline, have the potential for prolonged persistence inside the dentin. Although the conceivable negative effects of the other intracanal medications are unknown, these residual intracanal medications within the dentin may create drug-resistant microorganisms or result in cytotoxic consequences. As a result, future research should be carried out to improve the removal efficiency of nitrofurantoin paste when it is utilized as an intracanal medicament.In conclusion, our research found a substantial difference in penetration depth between calcium hydroxide, triple antibiotic paste, and nitrofurantoin. Nitrofurantoin paste, in particular, penetrated deeper into the dentinal tubules than both calcium hydroxide and triple antibiotic paste under the conditions of this study. Notably, all of the investigated medications showed a similar decline in penetration depth from the coronal to apical areas. These findings highlight the relevance of substance selection in maximizing treatment results and provide useful insights for clinical and research applications in dentistry and medical settings.


IgG4-related or IgG4-associated hypophysitis is a rare disease characterized by the infiltration of IgG4-positive plasma cells into pituitary gland tissue. Gangliocytomas in the sellar region are also extremely rare and are associated with pituitary adenomas in the majority of cases. Sellar mucosa-associated lymphoid tissue (MALT) lymphoma is an exceedingly rare condition. In this study, we present a case of IgG4-associated hypophysitis coexisting with MALT lymphoma and gangliocytoma. However, to elucidate the potential pathophysiological relationship, it is imperative to gather additional cases of IgG4-related hypophysitis accompanied by MALT lymphoma and gangliocytoma. IgG4-related hypophysitis, a rare condition affecting the sellar region, has been increasingly reported in recent years. It can manifest as an isolated disease or as part of a multisystemic disorder. However, it is worth noting that the majority of IgG4-related hypophysitis cases are not associated with other neoplastic diseases .In this report, we present a biopsy-confirmed case of IgG4-associated hypophysitis coexisting with MALT lymphoma and gangliocytoma.In May 2018, a 53-year-old female presented with a 1-month history of worsening right visual acuity and headaches. Prior to this, she had been in good health. Endocrine assessment revealed abnormal secretion of prolactin and thyroid hormone . MRI exaIn January 2019, the patient was readmitted due to severe binocular vision loss and debilitating headaches. Ophthalmic vision examination revealed further deterioration in the right eye, with vision reduced to perceiving only light. Simultaneously, vision in the left eye was limited to half a meter in front. Pituitary hormone assessment indicated persistently disturbed prolactin and thyroid hormone secretion . MRI exaGiven the rapid decline in vision and severe headaches of the patient. A craniotomy procedure via pterional approach was performed for the “tumor” resection. During the procedure, we observed that the lesion exhibited rich blood supply, firm texture, and complete encasement of the optic nerve and internal carotid artery. Consequently, a subtotal resection was performed. Postoperatively, the patient received a physiologic dose of hydrocortisone. Although she experienced complications such as diabetes insipidus and hypernatremia in the perioperative period, pituitary hormone assessment gradually returned to normal. Furthermore, postoperative headaches were alleviated, and partial restoration of vision was achieved.On pathological examination, we initially performed immunohistochemical staining for CD56, syn, and cga to confirm the presence of neuroendocrine tumors; however, the results were negative. Subsequently, we continued to test for CK8/18 and CK to verify the presence of meningioma, and the results remained negative. Next, we performed immunohistochemical staining for GFAP to confirm the presence of glioma, and the results were again negative . After rFollowing the definitive diagnosis, the patient was initiated on high-dose glucocorticoid therapy: prednisone 40 mg/day for 4 weeks, followed by a tapering dose over the next 3 months. We have been monitoring the patient’s progress; unfortunately, she declined further serologic and imaging evaluations.We present a unique case of biopsy-proven IgG4-associated hypophysitis coexisting with MALT lymphoma and gangliocytoma, which, to the best of our knowledge, has not been reported previously. Over a span of 6 months, the lesion in the sellar region rapidly enlarged, resulting in severe vision loss in both eyes. To preserve vision, the patient underwent emergency surgery, leading to substantial removal of the lesion. Pathological examination confirmed the diagnosis of IgG4-associated hypophysitis coexisting with MALT lymphoma and gangliocytoma. Subsequently, the patient received low-dose glucocorticoid treatment for a duration of 2 years. During a 3-year telephone follow-up, the patient reported significant improvement in vision. Unfortunately, the patient declined further imaging studies, preventing a comparison with preoperative images.IgG4-related disease is a chronic, progressive inflammatory disorder characterized by fibrosis that can affect multiple organs. It can often be misdiagnosed as malignancy, infection, or other immune-mediated diseases. The disease is characterized by mass lesions, elevated serum IgG4 levels, infiltration of IgG4-positive plasma cells, and tissue fibrosis . At presFor the diagnosis of the case, firstly, in the histopathological examination, the presence of mononuclear infiltration in the pituitary gland, characterized by abundant lymphocytes and plasma cells, with over 10 IgG4-positive cells per high-power field, fulfills Leporati’s diagnostic criterion 1. Secondly, the patient underwent MRI examination, revealing the presence of a mass in the sellar region. Although no thickening of the pituitary stalk was identified, this finding largely satisfies Leporati’s diagnostic criterion 2. Thirdly, our patient received glucocorticoid therapy, and although no imaging examination was conducted, there was evident improvement in symptoms, which also substantially meets Leporati’s diagnostic criterion 5. Lastly, confirmation of the diagnosis requires meeting diagnostic criterion 1 alone, thus establishing this as a case of IgG4-related hypophysitis.Differentiation of IgG4-related hypophysitis from other rare diseases in the sellar region is still necessary. One such disease is mixed pituitary adenoma-gangliocytoma, which predominantly affects female patients and is characterized by the secretion of one or more pituitary hormones, including growth hormone (GH) and prolactin (PLR), with a higher prevalence of growth hormone secretion . DiagnosGlucocorticoids are currently recommended as the first-line treatment for IgG4-related disease, unless contraindications are present . Our patMucosa-associated lymphoid tissue (MALT) lymphoma, first reported in 1984, demonstrates a slow clinical progression , 11. SelGangliocytomas are rare and benign neuronal cell tumors that are predominantly found in the hypothalamic and sellar regions. They often coexist with pituitary adenomas, mainly of the growth hormone (GH) type , 15. SinThe origin of gangliocytoma remains unclear, and there are three hypotheses regarding its mechanism of development: (1) it originates from the hypothalamus and produces growth hormone-releasing hormone, leading to hyperplasia of pituitary cells , 21; (2)In conclusion, we report the first case of biopsy-proven IgG4-related hypophysitis accompanied by MALT lymphoma and gangliocytoma. Although the patient did not fully recover pituitary function and vision, her headaches were significantly relieved, and disease progression was prevented through surgical and medical interventions. We hope that our treatment approach can provide valuable insights and guidance for future cases.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Ethics Committee of General Hospital of Western Theater Command. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.DZ: Investigation, Writing – original draft. LJ: Conceptualization, Writing – original draft. TY: Writing – review & editing. JC: Supervision, Validation, Writing – review & editing. YM: Project administration, Resources, Writing – review & editing.


Cast-in-place anchors are being increasingly used in many applications including building construction, bridge, and power plants. The anchorage to concrete systems are subjected to tensile, shear and combined loads from a variety of loading circumstances including static, dynamic, and shock loading. Despite extensive studies on these systems, reliable numerical models for predicting the behavior of these anchors are still limited. Therefore, this paper investigated the tensile behavior of cast-in-place anchorage to concrete systems, to propose an effective model for reproducing anchorage behavior using finite element (FE) methods. Experiments and code-based models for the anchorage system in tension were used to evaluate the numerical models for cast-in-place anchors in concrete, and the most suitable model, with advantages in accuracy and saving analysis time, was chosen. Finally, the FE model was used to study the tensile capacity and related dynamic increase factor for various strain rates, anchor diameters, and embedment depths. These anchorage systems are subjected to shear, tensile, and combination loads that may be static or dynamic, including seismic, impact, and blast loading. Numerous studies have examined the potential effects of factors on the tensile or shear behavior of the anchors, such as edge distance, anchor diameter, embedment depth, and anchor spacing. One of the most crucial factors is embedment depth since it impacts the pull-out strength and the projected locations where the anchors break in a cone shape when subjected to tensile load4. The pull-out strength is significantly affected by anchor embedment depths, as well as anchor diameter. Concrete cone breakout failure at embedment depths of 80 mm, 100 mm, 120 mm, and 130 mm and failure behavior for steel at 310 mm embedment depth were also evaluated6. The pull-out strength is an important parameter to the bond-slip effect and is significant for predicting the bond-slip behavior of the entire structure. The equations for predicting bond strength under various conditions  have been proposed in previous research13.In particular in the anchorage zone, pull-out tests are required to understand how anchors and concrete interact. In order to as precisely as possible mimic designed or as-built conditions, the test technique is meant to be a performance test. Research on the pull-out strength of anchors under static and dynamic tensile loading has been published15. Figure When a steel anchor is subjected to tensile loading, five failure modes are typically observed: anchor bolt failure, concrete cone breakout failure, side face blowout failure, concrete splitting, and anchor pull-out. Anchor bolt failure happens when the strength of the anchor is less than the applied tensile stress or the anchor strength is lower than the ultimate load for the other models of failure. Concrete cone breakout failure occurs at shallow embedment depths when the tensile stress applied to the anchor bolt exceeds the strength of the concrete. When there is not enough edge spacing, side face blowout failure occurs. Due to insufficient concrete member depth, concrete splitting occurs when the tensile strength of the concrete is less than the bolt strength. When the friction between the anchor and the concrete is less than the applied tensile load for the anchors without head, an anchor pullout failure occurs22.Numerous previous experimental investigations and simulation results have examined the behavior of deformed bars removed from a concrete block under monotonic loading. Most published research has found the ascending branch of the bond-slip curve to be the most important part, and prediction programs that have analytically described pull-out behavior have only been based on the mechanical contact component28. Recently, non-perfect bond models that pay particular attention to the mechanics of mechanical interaction and friction have been reported32.In order to minimize the quantity of experimentation, a numerical simulation is used with experimental studies to better understand the influence of various features and parameters. Due to the considerable development of these models and software applications over the last few decades, the use of numerical techniques to predict bond-slip interface behavior based on the FE method has dramatically expanded. A perfect bond, which prevents any relative slip between the reinforcing bar and concrete, was taken into account by several authors when modeling the interface33 investigated FE research on concrete under compressive load. Based on the previous studies, strain rate had significant influence on the kind of failure behavior of concrete at a 17 34. Based on the previous studies, the dynamic increase factor (DIF), which is a bilinear function of the strain rate, is critical for the development of structures under high strain rate.There has been limited investigation of the effects of dynamic loads including impacts and blast on the anchorage of concrete systems, compared to the studies that have examined the effects of dynamic loads on concrete or steel materials. Tedesco et al.35 and Lee et al.36 researched how strain rate affected the behavior of steel. Yu et al.35 investigated the influence of strain rate on DP600 steel  steel with a strength of approximately 6000 MPa) with strain rate from 36. The authors determined that the specimen’s composition and the stress-strain behavior are both effected by the strain rate. The degree of grain deformation increased together with the strain rate. According to the authors, the steel fractures were created by plastic instability at the adiabatic shear zones. This suggests that the loading speed on the anchorage of a concrete system can be the main variable determining bond-slip behavior.Yu et al.The contact-based anchorage model or contact function is a general definition that can be used in most FE method programs. The one-dimensional (1D) slide line model, which can simulate bond-slip behavior similar to the real behavior, has been developed in the LS-DYNA program. As a result, the contact-based anchorage model has been widely used to examine earlier hypotheses concerning the interaction between cast-in place anchorage of concrete systems, and the 1D-slide line model has had certain limitations when it comes to simulating the behavior of cast-in-place anchorages of concrete systems.Therefore, the main purpose of this study is to propose an effective model to predict the pull-out strength of a cast-in-place anchor based on the 1D-slide line model. Firstly, a FE method-based anchor model was developed with a contact function and the simulated response was validated with a previous experiment. Next, to reduce the computational time of the contact-based anchor model, simplified anchor models with bond-slip effects between rebars and the surrounding concrete (1D-slide line model) were developed. Then, the bond-slip models proposed from previous experimental studies were investigated to identify which model was appropriate for the simplified model. To maintain structural safety and to reduce or prevent anchorage failure under high-speed dynamic loading, the best proper model was investigated when subjected to various strain rates of loading ranging from the static strain rate of entclass1pt{minima39. 1D-slide line models were used by Shi et al.40 to simulate pull-out responses in RC beam elements and the responses were validated with experimental findings. To investigate the bond properties of bars in the post-yield regime, Shima et al.41 performed pull-out tests on bars with an equal embedment length, and one of their test specimens was used to perform a FE analysis.The structural responses of RC structures were dramatically affected by the bond-slip effects between steel reinforcing bars and concreteUtilizing the experimental data from the previous research works, it was determined that the proposed model in the FE analysis could accurately represent the bond-slip behavior of bars in RC structures. The bond stress of reinforcing bars is greatly influenced by the concrete strength and reinforcement geometry, such as the rib face angle, spacing and height. Several studies have also been carried out, and various empirical equations have been proposed based on the test results, as shown in Table 7 only investigated the effect of the compressive strength of concrete to predict the bond stress of the pull-out test. Eligehausen et al.8 investigated pull-out tests with headed studs embedded in large concrete blocks. The embedment depth was varied from 130 to 520 mm and a concrete block with dimensions such as a length of 4 m, width of 2 m and thickness of 0.6 m. The authors proposed the formula for the pull-out test considering the effect of parameters such as rebar diameter and the compressive strength of the concrete.The CEB–FIP model code9 investigated 284 available tests of normal-strength concrete and high-strength concrete. Tepfers10 carried out a pull-out test with concrete with a compressive strength of 24.6 MPa, reinforcing bar diameters from 16 to 25 mm, and vertical concrete cover thickness from 12 to 90 mm. The authors classified the bond behaviors between the reinforcement and concrete into elastic, plastic stages, and presented these behaviors as functions of the tensile strength of the concrete, the concrete cover thickness, and the diameter of the steel reinforcement.On the other hand, Esfahani et al.11 studied the bond of high strength concrete using fourteen pull-out tests. The compressive strength of the concrete was 70 MPa and the tensile strength of the steel was 500 MPa. Bar diameters were investigated from 12 to 36 mm. The author proposed an equation for calculating the bond stress depending on parameters such as concrete cover, rebar diameter, embedded depth of rebar, and the compressive strength of the concrete.Hadi13 investigated the effect of more parameters while proposing an equation from a nonlinear regression analysis of the test results of beams with lap splices. This reflected the effect of concrete cover, rebar diameter, embedded depth of rebar, and the compressive strength of the concrete and moment gradient on the strength of lap splices.Orangun et al.A typical average bond stress and slip curve was obtained from their pull-out tests as shown in Fig. c is the concrete cover thickness, d is the diameter of the rebar, The followings should be noted: There are many FEM-based programs that can be used to study a variety of interactions between rebar and concrete under different loads. Currently, there are two widely used modeling methods, (1) merging nodes between anchor and surrounding concrete meshes and (2) implementing contact option  between the rebar and surrounding concrete meshes.42 investigated the behavior of post-installed adhesive anchoring systems under tensile loading by merging the nodes between anchor, adhesive and concrete to create contact between them. Because this method uses mesh nodes to create interaction between anchor and concrete, this process is arduous as it requires extra effort in meshing. Thus, some mesh distortions may be found in the analysis process. As a result, this method cannot accurately present the failure behavior between anchor and concrete.For the merging node approach, Sartipi et al.44 used the contact function to simulate interaction between anchor and concrete and investigate the tensile behavior of the anchorage systems, including ultimate force and displacement capacity, load-displacement behavior and the failure models of the undercut and adhesive anchors under different strain loading rates, ranging from 45 also simulated the shear behavior of cast-in-place anchorage to concrete systems by using contact-based method.To implement contact options (contact-based model), Ahmed et al.The contact-based method is the most reliable method for modeling the bond between anchor and concrete, as well as predicting the failure behavior between anchor and concrete. However, this modeling method is time consuming because of the contact function between the anchor and surrounding concrete meshes. As an alternative, the authors propose an effective modeling method that balances computational time and accuracy, using a bond-slip modeling method, because the bond slip relationship is crucial to understanding the large-scale mechanical characteristics of composite materials and structures. In this work, an analytical model is created to determine the bond-slip relationship at the anchor-substrate concrete contact (interface).46. The main goal of the study was to evaluate the headed anchor bolts’ capacity to support an axial tension load on a concrete cone. Test specimens with different embedment depths of 50 mm, 150 mm, and 450 mm were used. The concrete block size was 47 was us48 while the steel anchor was modelled using the PIECEWISE_LINEAR_PLASTICITY model representing bilinear material behavior.The solid elements for the anchor and concrete block were formulated using a constant stress. There are two different methods that consider interaction between the steel anchor and the concrete, either CONTACT_AUTOMATIC_SURFACE_TO_SURFACE (contact function with friction) or CONTACT_1D (1D-slide line model). The concrete block was modelled using the Karagozian and Case Concrete model (MAT_072R3)47, the non-automatic contacts function can be utilized for implicit analysis whereas the automated contacts function are suitable for explicit analysis. Automatic contacts can notice penetration occurring from both side of the element as considering the thickness of the element.The FE software (LS-DYNA) offers several different contact options. Generally, there are two types of surface contact: automatic contacts and non-automatic contacts. According to LSTC (2014)The contact interactions between the anchor, anchor head and concrete block were defined in the current investigation using the CONTACT_AUTOMATIC_SURFACE_TO_SURFACE function. The penetration depth  and failure modes (such as splitting or pull-out failure modes), the model code describes the relationship between tensile load and displacement . Constricting forces in relation to the concrete cover and anchorage details can be used to assess the bonding state. There are two scenarios to be considered in the interaction between anchor and concrete, perfect bond and bond-slip. The bond-slip is the relative displacement of concrete and reinforcing material. The term “bond of reinforcement” refers to the ability of the concrete and a reinforcing bar to transfer stress.The CEB–FIP model code was used to describe the tensile load-displacement performance in the FE modelsIn an RC construction, a crucial mechanism activates the composite action between concrete and steel. The 1D-slide line model in LS-DYNA and the model code’s tensile displacement relationships are compared in Fig. 46. For 8 mm and 24 mm diameter anchors with 50 mm and 150 mm embedment depths, respectively, the FE analysis obtained concrete breakout cone diameters of 189 mm and 510 mm. The experimental findings by Eligehausen et al., who indicated that the concrete cone breakout diameter was less than The FE analysis revealed a concrete cone breakout failure mechanism, as shown in Fig. Figure 7, Eligehausen et al.8, Esfahaniet et al.9, Tefers10, Hadi11, and Orangun et al.13 as shown in Fig. Because the 1D-slide line model was effective for predicting the response of the anchor model, as well as minimizing the analytical time, this model will be investigated using various models to find the best suitable model. The prediction of tensile load-displacement curves with various models included experimental results and FE models based on different previous theories, such as CEB–FIPOn the other hand, the closest displacement compared to the test belonged to the Orangun model with 4.76% and 11.51% for the embedded depth of 50 mm and embedded depth of 150 mm, respectively. The maximum strength of all models did not significantly change as compared to the experiment, as shown in Tables The ratio of maximum strength errors and the ratio of maximum displacement errors of the 1D-slide line model between the experimental and simulated responses are shown in Figs. Based on this investigation, the Orangun model was found to produce better agreement than the other models. However, the CEB–FIP model also had reasonable predictions for the relationship between the tensile load-displacement curve, with 1.2% and 19.05% for the maximum strength and displacement of an embedded depth of 50 mm, and 1.81% and 3.8% for the maximum strength and displacement of an embedded depth of 150 mm. Thus, the proper 1D-slide line models selected to simulate the interaction between the anchor and concrete were the CEB–FIP and Orangun models.13 simulates bond-slip behavior with minimum errors among the considered models referenced as the ’best fit model’ Eqs.  were used in this parametric analysis to investigate the effect of different design parameters (embedment depth and anchor diameter) on the behavior of the anchorage system considering strain rate effects. The various models were developed with 8 mm, 12 mm, 16 mm, 20 mm and 24 mm diameter steel anchors and embedment depths of 50 mm, 75 mm, 100 mm and 150 mm. The effect of the design parameters on the anchorage system’s capacity were investigated under various strain loading rates, starting with a low strain rate of 53. Varied loading conditions can be applied to concrete structures at various strain rates using various testing equipment. Static loads can be applied using hydraulic testing equipment at strain rates ranging from The capacity of concrete constructions is influenced by the amount of applied strain rate. At strain rates between 55, while the Young’s modulus remains constant54. This is a result of the steel structure’s deformations and dislocations, which increase under high strain rates56. Under low strain rates or quasi-static loads, the deformation of the steel material is almost homogeneous and is influenced by slip and twin plastic deformation mechanisms, which is another mechanism of plastic deformation. Twinning is a surface defect and involves the shearing of an element by a fixed magnitude, based on the characteristics of the element structure. However, where the strains are extremely concentrated along a restricted area, known as the adiabatic shear band, the deformation of the steel material at high strain rate is more complicated. These shear bands operate as the source of cracks that eventually lead to fracture. Several factors, including the chemical makeup of the steel components, strain rate, and heat treatment, have an effect on the formation of the shear band in steel at high strain rates57.The mechanical characteristics of the steel material are affected by the strain rate. The yield and tensile strength of steel increase as the strain rate increases58:The DIF versus strain rate, which is the ratio of dynamic to static strength, is typically used to explain how strain rate affects concrete strengths. A DIF was added to the KCC model to account for the strain rate effect, expressed as followsFor compressive:Numerical models of cast-in-place anchorage to concrete structures were developed in order to examine the tensile behavior of the anchors at low strain rates. To examine the effects of low strain rates on the behavior of cast-in-place anchor systems, strain rates of The contact area between the cast-in-place anchor and concrete increased with the increase in anchor diameter from 8 to 24 mm, which also increased the anchorage’s tensile strength. This figure shows that the peak loads of diameters from 8 to 12 mm for strain rates of To determine the effect of high strain rates on the behavior of cast-in-place anchor systems, strain rates of Figure 36. In this part, the effect of DIF on the anchorage to concrete system was investigated in order to predict the response of the cast-in-place anchorage to concrete system, with varying anchor embedment depth from 50 to 150 mm, and anchor diameters from 8 to 24 mm. For comparison with a cast-in-place anchor capacity at higher strain rates, the baseline strain rate of The DIF is defined as the dynamic to static strength ratio of a cast-in-place anchor. The effect of DIF on the strength of concrete (tensile and compressive strength) or the strength of rebar (ultimate and yield strength) has been reported by previous researchFigures For the anchor embedded depth of 50 mm, the slope of DIF versus strain rate curve did not appear for anchor diameters from 8 to 16 mm, as shown Fig. Table On the other hand, the ultimate tensile capacity and DIF increased as the anchor embedded depths and diameters increased. The ultimate tensile changed from 97.62 to 663.73 kN and the DIF changed from 2.62 to 4.25 as anchor embedded depths increased from 50 to 150 mm, respectively, at a strain rate of Finally, the anchor embedded depth was determined to have a significant effect on the ultimate tensile and DIF at a strain rate of 7 and Orangun model13 were determined to be the proper models to achieve accurate results and save analysis time.The contact-based and 1D-slide line models approaches (implementing bond-slip behavior) could reasonably predict the interaction between the cast-in-place anchor and concrete. The 1D-slide line approach with the CEB–FIP model code46.The contact-based and 1D-slide line models well predicted the failure behavior of the cast-in place anchorage system by detecting reasonable concrete breakout cone diameter. The 1D-slide line models with the CEB–FIP model code and Orangun model reasonably predicted concrete breakout cone diameters of 166 mm and 510 mm for embedded depths of 50 mm and 150 mm, respectively, less than The maximum tensile load was not significantly changed for anchor diameters less than or equal to 12 mm, and slightly increased for anchor diameters more than or equal 16 mm under low strain rate, from The relationship between the ultimate tensile load and the strain rate was a bilinear trend for anchor embedded depths from 75 to 150 mm and anchor embedded depth of 50 mm with an anchor diameter of more than 16 mm. The relationship between the ultimate tensile load and the strain rate was a linear trend for an anchor embedded depth of 50 mm with an anchor diameter of less than or equal to 16 mm. The ultimate tensile load and DIF of the cast-in-place anchors increased as the strain rate increased from The anchor embedded depth had a significant effect on the ultimate tensile and DIF at a strain rate of The models of cast-in-place anchorage to concrete systems under impact or blast loading are also effective for depicting the exact behavior of cast-in-place anchorage to concrete systems. This study recommends using FE simulations for the DIFs of the anchorage system with respect to the embedment length and anchor diameter. This recommended approach can help more accurately predict the response of the anchorage system under impact or blast loads.An effective model for predicting the pull-out capacity of cast-in-place anchors was investigated using FE analysis. Cast-in-place anchor diameters of 8 mm to 24 mm with anchor embedded depths of 50 mm and 150 mm were investigated. The main conclusions obtained from the FE analysis of the cast-in-place anchors can be summarized as follows:


The utilization of recycled aggregate (RCA) in preparing recycled concrete (RAC) is an effective measure to solve the increase in construction waste. Furthermore, applying RAC to flexural members is a viable practice. The addition of steel fiber to RAC to prepare steel fiber recycled concrete (SFRAC) solves the performance deterioration caused by the recycled aggregate, so it is necessary to study the effects of the recycled aggregate replacement rate and fiber–volume ratio on the crack resistance and bending performance of SFRAC beams. In this study, 13 beams were designed and manufactured, with the water–cement ratio, recycled aggregate replacement rate, and fiber–volume ratio as the primary variables, and the cracking moment and ultimate moment of the SFRAC beams were systematically studied. The results show that the cracking and ultimate moments of the SFRAC beams increased with decreases in the water–cement ratio or with increases in the fiber–volume ratio and were unaffected by the replacement rate of recycled aggregates. Based on the experimental results and theoretical analysis, a calculation model and formula for the cracking moment were established. The ultimate bearing capacity of SFRAC beams can be accurately determined using the ACI 318 and ACI 544 standards. The research results serve as a valuable reference for the design of SFRAC beams, effectively address the issue of performance degradation in RAC structural members, and promote the use of green building materials. Concrete, as the primary building material in the construction industry, is experiencing rapid growth worldwide. The annual consumption of concrete is estimated to exceed 10 billion cubic meters . At the Due to the presence of microcracks and holes, recycled aggregate concrete (RAC) exhibits weaker performance compared to ordinary concrete . RecycleThe incorporation of steel fibers into concrete has been found to improve its strength, toughness, and crack resistance. This enhancement leads to overall improvements in concrete’s strength and deformation performance ,21,22,23A literature review showed that SFRAC has good bending performance . The rel(i)Water–cement ratio: Recycled concrete with three water binder ratios of 0.55, 0.4, and 0.3 was studied.(ii)Recycled aggregate replacement rate (by a mass fraction): Four recycled aggregate replacement rates of 0, 30%, 50%, and 100% were studied.(iii)Steel fiber volume fraction: Five different steel fiber contents of 0, 0.5%, 1.0%, 1.5%, and 2.0% were adopted.This study mainly investigates the effects of the following parameters on the flexural behavior of concrete beams:The concrete cube compression, axial compression, and splitting tensile strength standard tests were carried out to examine the effects of water–cement ratio, recycled aggregate replacement rate, and fiber volume fraction on compressive strength and tensile strength.2, average length (lf) of 35 mm, mean diameter (df) of 0.55 mm, and aspect ratio (lf/df) of 63. The performance indexes of the longitudinal tensile steel bar and stirrups of the test beam were measured according to GB/T 228.1-2010. The ultimate strength, yield strength, and elongation of the steel bars with a diameter of 16 mm were 623 MPa, 483 MPa, and 24%, respectively. The ultimate strength and elongation of the steel bars with a diameter of 8 mm were 493 MPa and 41%, respectively.Common Portland cement P.O 42.5 was used in the experiment, and its performance meets the GB 175-2007  requiremAs shown in Thirteen reinforced SFRAC beams were made, all of which had a rectangular section of 30 cm × 20 cm (height × width), a length of 300 cm, and a calculated span of 270 cm. The reinforcing bars are shown in Concrete Structure Test Method Standard (GB/T50152-2012) [All beams were loaded at four points to failure by the distribution beam on the universal testing machine. The test was carried out according to the loading method and procedure of the 52-2012) . Before All beams were gradually and evenly loaded to failure. The damage photo of beam C45R50F0.5 is shown in According to the test results in According to the test results in The cracking moment of the RAC beam decreases with the increasing replacement rate of the recycled aggregate . As showThe basic mechanical properties test of SFRAC and the bond performance test of the steel bar and SFRAC demonstrate that the compressive strength of SFRAC and the bond strength of the steel bar and SFRAC decrease with the increasing replacement rate of recycled aggregate. When the ultimate bending state is reached, the bond strength between the steel fiber and the concrete spanning the crack in the tensile region of the SFRAC beam decreases with the increasing replacement ratio of the recycled aggregate, and the tensile force of the steel fiber decreases. Meanwhile, the compressive strength of concrete at the compression part of the beam also decreases, making the ultimate bearing capacity of the SFRAC beam lower than that of the steel fiber ordinary concrete beam. As shown in There is no specification for the steel fiber recycled concrete beam design or the calculation of the cracking moment and ultimate bending moment. In order to study the applicability of the formula in the existing specification to the SFRAC beam, the typical working conditions in the research and the analytical formula are compared.The test beam’s cracking moment is calculated using ACI 544.4R-88  and ACI ACI 544.4R-88  and ACI In order to establish a calculation model of crack resistance and the bearing capacity of the normal section of the SFRAC beam, the elastic–plastic steel stress–strain relationship model is used based on the assumption of the flat section. SFRAC in  is adoptThe test results demonstrate that the compression zone of SFRAC is in the elastic phase when the steel SFRAC beam is about to crack, and the stress distribution is approximately triangular. The stress distribution in the tension zone is a curve, which can be simplified into a trapezoidal distribution, as shown in D = Te + Tp + T in From the force equilibrium condition D, Te, Tp, and Ts on the neutral axis, the following can be found:According to the moment balance of In order to simplify the calculation, the resistance moment plasticity coefficient Simultaneous Formulas (3) and (5):γrfm is shown in b, h, As, and αE are known. When μ is obtained, xc, μ is given a small initial value, and then μ until the difference is less than 0.01. The calculation is terminated, and the final value of μ is obtained. The calculation process is cumbersome, and the calculation program is compiled. The calculation and analysis results of the test data are listed in The procedure to calculate γfrm of the SFRAC beam is larger than that of the ordinary concrete beam. Therefore, the effects of the recycled aggregate replacement rate and the steel fiber characteristic content on the SFRAC beam can be considered by introducing the crack resistance influence coefficients α2 and β2 based on 7.2.4 in the Concrete Structure Design Specification (GB 50010-2010) [h and mγ are consistent with the specification [2 and β2 are cracking resistance influence coefficients. The test data are conducted with fitting analysis; α2 = −0.12 and β2 = 0.29.As shown in 10-2010) ;(8)γfrmfication  and α2 aThe mean value, mean square, and coefficient of variation of the measured value are 1.55  and 1.33are 1.55 , respectACI 318  and EuroThe normal section stress distribution of the normally reinforced concrete beam at its ultimate state is shown in The ultimate bending moment without SF beam is calculated by using ACI 318-2014 :(13)a=fyThe theoretically calculated values and the measured values of the ultimate bending moments of all test beams are compared, as shown in The calculation results of the data in the existing literature are shown in (1)The cracking and ultimate moment of SFRAC beams are higher than those of ordinary concrete reference beams.(2)The cracking and ultimate moment of SFRAC beams increase with the decrease in the water–cement ratio. The water–cement ratio decreases from 0.55 to 0.3, and the cracking moment and ultimate moment of SFRAC beams increase by 32.2% and 7.6%, respectively.(3)The cracking and ultimate bending moment of SFRAC beams are significantly higher than those of reference beams, and the cracking and ultimate moment of SFRAC beams increase with the increase in the steel fiber volume ratio. Compared with recycled concrete beams without steel fiber, the cracking moment and ultimate moment of SFRAC beams are increased by 12.6% and 24.8%, respectively, when the volume fraction of the steel fiber is 2.0%.(4)After adding recycled aggregate, the cracking moment and ultimate load of steel-fiber-reinforced concrete beams decrease, but the replacement rate of recycled aggregate has little effect on the cracking moment and ultimate load of SFRAC beams. When the replacement rate of recycled aggregate is increased from 30% to 100%, the cracking moment of the SFRAC beam is increased by 0.6%, and the ultimate moment is decreased by 4.7%.(5)Considering the influence of the recycled aggregate replacement rate and fiber volume ratio, the calculation formula of the cracking moment of SFRAC beams is established, and the prediction accuracy is better than ACI318 and Eurocode 2.(6)The calculated values of the ultimate bending moment bearing capacity based on ACI 318 and ACI 544 agree with the experimental values, which can reasonably predict the bending bearing capacity of SFRAC beams.(7)Steel fiber recycled concrete is a material with good performance, and the performance of SFRAC beams with 100% recycled aggregate replacement rate is still higher than that of ordinary concrete benchmark beams, so SFRAC can be used for general load-bearing beam structural members. Applying SFRAC to structural members increases the resource utilization of construction waste and meets the requirements of sustainable development and the transition to green building materials and technologies. In addition, the fatigue performance of SFRAC beams is also a point worthy of further study to expand its engineering application scope.This study focused on the bending performance of SFRAC beams under different water–cement ratios, recycled aggregate replacement rates, and steel fiber volume fractions. The main conclusions are as follows:


MET gene alterations in lung cancer patients mainly include exon 14 skipping and gene amplification, which are the key therapeutic targets and drive resistance to tyrosine kinase inhibitors (TKIs).MET, such as MET fusions, are much rarer (0.26%), as reported in a Chinese non-small cell lung cancer (NSCLC) cohort.MET fusions, such as KIF5B-MET and HLA-DRB1-MET, were reported as oncogenic drivers and showed favorable responses to crizotinib.,MET fusions have been found to mediate resistance to EGFR-TKIs. With the application of comprehensive genomic analyses in clinical samples, an increasing number of MET fusion partners have been identified; however, the clinical and molecular characteristics of patients harboring such MET fusions remain to be investigated in large cohorts.MET gene spanned almost the complete coding sequence (CDS), and 20 breakpoints were in exon 15, adjacent to the tyrosine kinase domain. Nearly half  of the partner breakpoints were in intergenic regions (IGRs), which were referred to as IGR-MET , ST7 (n = 4), CAPZA2 (n = 3), CD47 (n = 2), and HLA-DRB5 (n = 2).In this retrospective study, a total of 47 MET fusions with an intact kinase domain (KD) were detected in 44 lung cancer patients  whose ba IGR-MET B. CanoniMET fusions were detected in the baseline samples of 29 patients (Group 1), a small proportion of which were accompanied by MET amplification  and MET exon 14 skipping , which was strongly associated with IGR-MET . Similarly, EGFR mutations were significantly enriched in IGR-MET samples .MET fusion detection between baseline plasma and tissue samples was only 33.3% (5/15), while that of plasma and other liquid biopsies exhibited a much higher consistency . The variant allele frequencies (VAFs) of MET fusions in 11 baseline samples were the highest among all detected alterations (maxVAF = MET fusion VAF), suggesting a potential oncogenic role for those MET fusions  compared to the passenger-like subgroup . For example, P05 with a baseline DNAH14-MET fusion as a potential driver benefited from crizotinib treatment for ten months  was the most common mutational signature  harbored MET fusions in their post-treatment samples; however, five of them had paired baseline samples that lacked MET fusions -based NGS assay in an early-stage lung adenocarcinoma patient who exhibited a robust response to crizotinib.MET fusions was uncovered by functional in vitro experiments.DNAH14-MET fusion, which might be the oncogenic driver. As for passenger-like MET fusions , they may not affect the responses to EGFR-TKIs for patients with actionable EGFR mutations.The first MET KD rearrangements from 5965 Chinese NSCLC cases (0.25%), two-thirds (10/15) of which were canonical MET fusions.MET fusions were identified in their study, and one patient acquired a TES-MET fusion after 13 months of treatment with icotinib. In the current study, we identified five acquired MET fusions following treatment with EGFR- or VEGR-TKIs, which may represent potential resistance mechanisms, especially in patients without canonical resistance mutations. However, due to the low incidence of MET fusions, we could not validate our findings in external public datasets with large cohort sizes. Additionally, this was a single-center study with potential regional bias and the restricted cohort size may have also weakened the power of our statistical analyses.Zhuo et al identified only 15 patients with MET fusions are not considered biomarkers for the administration of TKIs as MET exon 14 skipping. Cheng et al investigated the genomic and clinical characteristics of MET exon 14 skipping in a large Chinese cohort and identified 175 lung cancer patients with such alterations.MET exon 14 skipping were TP53 (43%) and EGFR (17%). Similar findings were also observed in our study. Notably, however, only one active clinical trial (NCT04739358) investigating the efficacy of tepotinib in MET-driven NSCLC patients with central nervous system metastasis included NGS-detected MET fusions as an eligibility criterion. Thus, the clinical impacts of MET fusions remain to be investigated in prospective studies or clinical trials.Currently, MET fusions in lung cancer patients to date, and not only systematically investigated fusion partners, subtypes, and breakpoint preference, but also characterized concurrent mutation profiles, mutational signatures, and the tumor mutational burden of different MET fusion subtypes such as IGR-MET versus canonical fusions. Thus, the findings of this study provide valuable information for understanding the oncogenic or resistance mechanisms of MET fusions.Our study investigated the largest dataset of MET fusions in the largest lung cancer cohort to date. Both baseline and acquired MET fusions were identified, which might serve as oncogenic and resistance mechanisms against EGFR-TKIs, respectively. In addition, the NGS of multiple sample types could promote the use of personalized treatments by providing comprehensive molecular portraits.In conclusion, we comprehensively investigated the clinical and molecular characteristics of This study was approved by the Ethics Committee for the First Hospital of China Medical University (No. 20180551230). Written informed consent was obtained from each patient prior to sample collection and publication.BJ: conceptualization, methodology, formal analysis, data curation, writing-original draft. YM: formal analysis, visualization, writing-original draft. QW: visualization, investigation, writing-original draft. QO: validation, writing-review & editing. YS: validation, writing-review & editing. SX: supervision, project administration, writing-review & editing.All data generated or analyzed during this study are included in this published article and its supplementary information files.Yutong Ma, Qian Wu, Qiuxiang Ou, and Yang Shao are employees of Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China. The other authors declare no competing financial interests.