The huge demand for concrete is predicted to upsurge due to rapid construction developments. Environmental worries regarding the large amounts of carbon dioxide emanations from cement production have resulted in new ideas to develop supplemental cementing materials, aiming to decrease the cement volume required for making concrete. Palm-oil-fuel-ash (POFA) is an industrial byproduct derived from palm oil waste’s incineration in power plants’ electricity generation. POFA has high pozzolanic characteristics. It is highly reactive and exhibits satisfactory micro-filling ability and unique properties. POFA is commonly used as a partially-alternated binder to Portland cement materials to make POFA-based eco-efficient concrete to build building using a green material. This paper presents a review of the material source, chemical composition, clean production and short-term properties of POFA. A review of related literature provides comprehensive insights into the potential application of POFA-based eco-efficient concrete in the construction industry today. Bindingper year . For exaper year . The wor the air . The gre the air . The con to 2012 .3 hectares in the year 2014. In Indonesia, farming of PO was confined to 6500 × 103 hectares in 2012 [Elaeis Guineensis is a PO tree known as an ornamental plant in 1870 in the southeast of Asia countries  [6 tons of PO plantation are produced annually and burnt after removing oil from the mushy palm product at 800–1000 °C as heater fuel to create mist for electricity production and extraction of PO [However, incorporating supplementary cementing material (SCM) decreases cement in concrete; consequently, this sustainable construction method lessens greenhouse gas emissions, saves energy, reduces energy consumption, and protects natural resources . Palm oi in 2012 . At pres in 2012 . For exaalaysia) ,14. In Pon of PO . POFA ison of PO . In Malaon of PO . Howeveron of PO . To overon of PO ,17,18. Pon of PO ,20,21. Pon of PO ,20 and eon of PO ,23. POFAon of PO ,24,25.2 levels produced by OPC manufacturing. The use of PO-based biodiesel could decrease the present emissions level of greenhouse gas by almost 62% [Several scholars attempted to reduce the utilization of OPC by producing environment-friendly concrete that uses certain by-product materials ,23,26,27most 62% . This paPOFA is an engineering byproduct ,22,23,262 [In the clean production-process-of-POFA ash, large amounts of residues, such as fibers, nutshells, and EFBs, are produced from palm oil mills and burnt at heating between 800 and 1000 °C as fuels to afford steam for electricity production in the PO mills ,16,30,392 ,36. POFA2 ,16,30,322 ,23,32,40The refining process of POFA can be operated by selecting one kilogram of POFA and fill into a graduated cylinder . The wat2 (42–66%) and the secondary compounds are Fe2O3 and Al2O3, the loss-on-ignition  and SO3  differs between 62.5 and 183 µm. These results are more significant than that of cement (up to 20 µm) [ground POFA = 0.35 µmDOPC = 0.2 µmDunground POFA = 0.07 µmDu = (DOPC/Dground POFA) = 2.86Cc = (Dunground POFA)2/(Dground POFA × DOPC) = 0.35Cu (uniformity coefficient) is more than 2, and Cc (coefficient of gradation) is limited to 0.30 and 1. Therefore, M-sand is quite rated and is within zone C BS882:1992 [C882:1992 .The size and shape of particles differ between ground and unground-POFA ,22,91. Rnt up to  µm [20,3o 20 µm) . After go 20 µm) ,92. From2 content reduced with the increased substitution of SCM material, pozzolanic reaction and fineness [2, albeit, the C2ASH8, C–S–H and the mass loss of ettringite improved with protracted curing. Moreover, workability is generally decreased as the content of POFA rises due to the higher fineness of POFA, whose high surface area can absorb more water [POFA fineness is found to develop the concrete strength attributable to its density, and homogeneity ,63,75,81fineness ,22,30,38re water ,94,98.POFA is employed in high volumes to decrease the heat of hydration (HoH) of concrete ,100,101.Reportedly, the inclusion of 30% ground-POFA contributed to 15% lower temperature, showed the lowermost temperature greater than OPC concrete and decreased the total heat release . This fi−6 micro-strain, correspondingly, while the control samples is 557 × 10−6 µm-strain at 182 days [−6 µm-strains, correspondingly, while the control sample is 785 × 10−6 µm-strains [The findings of the drying shrinkage (DS) test of water- and air-cured samples are presented in 182 days ,49,62. S-strains ,69,92. H-strains ,32,104. -strains . The ver-strains . Moreove-strains ,60. ThesReportedly, the increase in POFA content may be caused by a high porosity due to the permeable nature of POFA ,106,107.2 of hydrated paste, including the bubbles between hydration products and aggregates. Therefore, making a more solid concrete because the unground POFA ash could increase impermeability of concrete via pore refinement [2 exposed to natural air for 28 days [2 in the presence of POFA is due to low lime content [2 outflow. Therefore, the concrete matrix became denser with a decrease in porosity [3 formed in the attendance of CO2 [This effect relies on the hydrated paste and the w/c ratio. It is revealed that the upsurge in the content of unground POFA lessened the air-dry densities of concrete the content of Ca(OH)finement ,39. Meanfinement . The tot 28 days ,32,61,73 28 days . Unreact 28 days ,81,99. M content ,74. The porosity ,29, cause of CO2 . Howeverresearch .50cm slump flow test methods. The fresh properties of POFA are described in the subsequent subsections.The fresh POFA concrete has a different performance compared to normal fresh concrete. POFA concrete has several properties at the fresh state, such as workability, setting time, segregation, slump loss, bleeding, and shrinkage. All are related to the numerous POFA mixtures properties and generally assessed through J-Ring, T2 content with sand particles of 45 mm size and 0.35 water–binder (w/b ratio) showed good workability [50cm slump flow, segregation index, and V-funnel flow time [Reportedly, the volume of additional 12% water content in POFA and 6% naphthalene-sulfonate-based SP dosage, by weight, is a significant gradient that is necessary for regulating workability and strength ,75,88. Vkability  studied low time . The addlow time . In anotlow time . The un-low time . Howeverlow time ,64. Theslow time ,65. Alsolow time . The conlow time ,64. HoweIt is found that POFA concrete is affected by several parameters for instance aggregates quantities, cement hydration, ambient conditions, evaporation, types and interrelation between different materials, moisture contents, mixture proportions and total water content ,115,116.The POFA concrete setting time usually differs with the degree of fineness of ash and percentage of substitution, informing that the use of-POFA in concrete can perhaps defer the initial and final setting times ,118,119.3S and may not increase the setting time of POFA concrete [Furthermore, permeable POFA particles captivated water having no such contribution in hydration reaction, increasing the setting time of pastes ,78. Repoconcrete ,30. It wQuite a few studies found a little segregation in all concrete mixes contained numerous POFA contents ,92,117. To study the effect of curing on solidified concrete characteristics, POFA-based concrete samples are frequently exposed to two different curing conditions, known as air and water curing. The strength of POFA concrete at the two curing conditions is explained in For concrete to realize potential strength and durability, it should have adequate water content for the cement hydration and a temperature that’s tributary for maintaining this chemical action at a fast and continuous rate ,75. All The POFA concrete cured deprived of high heat can be used to other zones outside precast-concrete elements ,57,121. After setting, the concrete is required to harden in order to resist live and dead loads sufficiently. Subsequent sections provide a review of the hardened properties of POFA, including flexural, tensile and compressive strengths, the heat of hydration (HoH), modulus of elasticity (MoE), rate of strength development, and stress-strain behavior .2 and SiO2 of ground-POFA and that released from the hydration of cement, in the inclusion of water, via the reaction of pozzolanic and develops a secondary C–S–H, had a positive contribution at motivating the interaction between the aggregates and cement paste, leading to an upsurge of the concrete strength at a long-term [Compressive strength  is the song-term . Moreoveong-term . Howeverong-term ,59.Reportedly, the concrete comprising up to 30% ground-POFA found that splitting tensile strength (STS) was marginally more significant than that of ordinary concrete. The highest value was obtained in concrete with 20% POFA ,130,131.Reportedly, the flexural strength of POFA concrete could significantly improve by integrating unlike sorts of small artificial fibers, for instance, polypropylene and PVA, through the linking influence during the macro-and micro-cracking of the POFA concrete texture under flexural load ,92,133. Furthermore, the use of up to 15% eggshell dust augmented the concrete flexural strength . However2. Such a reaction produced C–S–H and improved the strength [2, resulting in C–S–H-and hydrated calcium aluminates enhancing the interaction between the paste and the sand [Strength activity index  is an istrength ,63. At athe sand .2, from 69.02% to 59.17%. The improved composition can enrich the PA and significant packing influence, thus improving the strength [2, MgO, SO3, and water absorption in the mixes led to a high PA [The pozzolanic activity (PA) of POFA is commonly measured with respect to cubes samples’ strength with-and-without pozzolan rendering to ASTM C 311 . The PA strength . Moreove high PA ,83,113.2 liberated through cement hydration and creates the internal microstructure of dense concrete, thus advancing the MoE of concrete [Modulus of elasticity (MoE) is hugely associated with the concrete compressive-strength such as POFA; a high hydration rate could be detected in a dense POFA texture, leading to a high MoE ,47,138. concrete . The hybconcrete . Moreoveconcrete ,33,67. Mconcrete  reportedconcrete . This prconcrete .Normally POFA is used as PCR in the production of concretes and used in several RC applications  with volMoreover, POFA ash can potentially fabricate unfired green blocks/bricks that can decrease carbon emission, thus making a maintainable construction element that could avoid and manage pollution and environmental deprivation ,86. The 2 emissions in the air and the cement cost. The short-term properties of POFA are auspicious for the making of concrete. Based on this review study, the fineness of POFA is acted as a strong character in concrete. However, the great fineness of POFA increases its micro-filing and PA ability, thereby leading to enhancing the mechanical and durability characteristics of concrete. POFA-based eco-efficient concrete composite presents a similar and, from time to time, a superior recital than normal concrete in withstanding aggressive environments. More investigation is recommended to validate the valuable influences of POFA on numerous concrete properties, and therefore inspire the inclusion of POFA in concrete production.The majority of preceding research concentrated on POFA concrete characteristics, such as their high compressive strength and pozzolanic activity, rather than on the micro-fine morphological properties. Most of these studies also ignored some components. For instance, artificial and natural fibers and alkaline activator solutions affect the strength of the POFA concrete matrix. Further, a binder paste that contains a small size of carbon nanofiber reveals excellent stability and sensitivity properties in POFA concrete. The subsequent noticeable conclusions can be strained based on the sightings from this study review about palm-oil-fuel-ash in a mortar/concrete. The inclusion of POFA as a partial cement replacement in a concrete composite could resolve the dumping and ecological issues produced by the PO industry’s dust, reduce the ecological hazards assumed by the OPC plants, and decrease the COTo investigate the influences of POFA on the slump loss and plastic shrinkage as well as the air content of concrete and examine the influences of POFA on the rheological characteristics, such as plastic viscosity and yield stress of concrete.To examine the impress of POFA on the bond, tensile, fatigue, impact, shear, and flexural strengths of concrete; and to study the feasibility of POFA concrete in resisting aggressive environment.To study the influences of POFA on the autogenous, creep, water absorption, and shrinkage.To investigate the characteristic of high fineness POFA in order to improve the microstructure that results in a highly impermeable matrix, and to prove the potential use of POFA materials in the making of ultra-high-strength and SCC concretes, to expand the strength of POFA in a hardened state using fibers.To further survey the possible applications of POFA in building green structures and future maintainable cities with a decreased carbon footprint.Further investigations are highly-imperative to prolong the utilization of POFA in SCC concretes. Albeit, POFA has a potential binder as a PCR up to a particular substitution level of OPC deprived of initiating any negative influence on the concrete’s mechanical properties. In the conclusion of this review study and to approve the favorable influences of POFA on some short-term properties of concrete, making POFA as an alternative PCR in concrete, several research investigations are recommended for future studies:


The practice of antibiotic prophylaxis for the prevention of infective endocarditis (IE) has undergone a major paradigm shift over the past few decades. From the earlier practice of antibiotic prophylaxis for all patients undergoing dental procedures, since 2006, the American College of Cardiology/American Heart Association (ACC/AHA) guidelines have now narrowed down the indications to use it only in patients at high risk for IE. A true concern for antibiotic resistance remains eminent when used without appropriate indications. Through this case presentation of IE and the associated preceding use of antibiotics, we take this opportunity to explain the appropriateness of prophylaxis in patients from different risk groups. We also shed some light on alternative, effective, and, yet, harmless measures for the prevention of IE in patients at low risk. Antibiotics for the prevention of infective endocarditis (IE) have been in routine clinical practice without much supportive clinical data until the publication of the 2006 American College of Cardiology/American Heart Association (ACC/AHA) guidelines limiting indications for their role . UpdatedTransient bacteremia can commonly follow dental procedures but do not always necessarily require gingival manipulation. It can also potentially occur at a low grade/intensity with inadequate dental hygiene. Reduction in bacteremia with antibiotic prophylaxis has not prevented IE significantly . In factAccording to the ACC/AHA Task Force as of 2017, there have been no randomized controlled trials performed to show the benefit of antibiotic prophylaxis in low-risk patients [A 53-year-old African American female with well-controlled non-insulin dependent diabetes mellitus (hemoglobin A1c 5.8) presented to the emergency department with a four-week history of generalized fatigue, malaise, and 20 lb weight loss, along with a two-week history of right upper quadrant pain, subjective fever, nausea, and vomiting. The patient underwent dental root extraction five weeks prior to admission. Although she did not have a prior history of endocarditis or a prosthetic valve, she was given one dose of two grams amoxicillin for endocarditis prophylaxis, which she took the day before the procedure. On arrival, the patient was in sepsis, with a temperature of 101.9° F and blood pressure of 96/60 mm Hg but attained hemodynamic stability after appropriate fluid resuscitation. Physical examination was significant for tender hepatomegaly.3, negative for ova and parasites. The initial blood cultures drawn on admission and the fluid aspirate from hepatic lesions both grew Streptococcus intermedius (gram-positive cocci in clusters) with low penicillin minimal inhibitory concentration (MIC). The patient subsequently underwent a transesophageal echocardiogram revealing a one-centimeter aortic valvular vegetation without associated valvular dysfunction , she developed endocarditis as the effective duration of action of administered antibiotic had already elapsed . Guidelines provide recommendations regarding the patient population at risk, the choice and the timing of such antibiotics (one hour before the procedure) . Hence, al.used rats as the animal model for the induction of experimental endocarditis with continuous low-grade and intermittent high-grade bacteremia. It showed that both these mechanisms potentially induced experimental endocarditis. This data support the hypothesis that cumulative exposure to low-grade bacteremia  does represent a genuine risk of IE in humans [We take this opportunity to pose another critical question: how do we reduce the possibility of IE in low-risk patients without the use of antibiotics? A 2014 study by Elshibly et al. showed that simple oral hygiene with a total of one-minute exposure to high-potency mouthwashes killed viridans group streptococci organisms and suggested a significant reduction of IE . A studyn humans . However In the end, we pose several important questions through this case review:1. What is the effective role of IE prophylaxis after all?2. Mechanism of bacteremia, continuous low-grade  versus high-grade bacteremia  or both?Transient bacteremia can commonly follow dental procedures but does not always necessarily require gingival manipulation. Reduction in bacteremia with antibiotic prophylaxis has not prevented IE significantly, but inappropriate antibiotic use  can potentially lead to antibiotic resistance. There have been no randomized controlled trials performed to show the benefit of antibiotic prophylaxis in low-risk patients, thus needing further studies in this perspective. A key concern is correctly identifying the population at risk and educating them about appropriate indications and the timing of effective antibiotic prophylaxis prior to the procedure. Until then, adequate dental hygiene on a regular basis is important to prevent continuous low-grade bacteremia  to control viridans group streptococci.


Neutrophil activity is increased at the earliest stage of inflammation in the affected organs, as well as the presence of HLA-B*5 and increased IL-17, which appears to play a major role in neutrophil activity.5 IgG4-RD is a rare, multiorgan condition characterized by histologic features, and accurate clinical diagnosis can be challenging due to the atypical manifestations or the presence of overlapping autoimmune diseases like BD or antineutrophil cytoplasmic antibody-associated vasculitides.6Some conditions that were previously thought to be unique clinical syndrome are now recognized as a clinical manifestation of IgG4-RD. IgG4-RD physiopathological basis is the presentation of autoantigens by plasmablasts or B cells to CD4 cytotoxic T cells, which produce pro-fibrotic cytokines such as IFN-γ, IL1-ß and TGF-ß.


The development of sustainable, environmentally friendly insulation materials with a reduced carbon footprint is attracting increased interest. One alternative to conventional insulation materials are foamed geopolymers. Similar to foamed concrete, the mechanical properties of geopolymer foams can also be improved by using fibers for reinforcement. This paper presents an overview of the latest research findings in the field of fiber-reinforced geopolymer foam concrete with special focus on natural fibers reinforcement. Furthermore, some basic and background information of natural fibers and geopolymer foams are reported. In most of the research, foams are produced either through chemical foaming with hydrogen peroxide or aluminum powder, or through mechanical foaming which includes a foaming agent. However, previous reviews have not sufficiently addresses the fabrication of geopolymer foams by syntactic foams. Finally, recent efforts to reduce the fiber degradation in geopolymer concrete are discussed along with challenges for natural fiber reinforced-geopolymer foam concrete. However, thermal insulation reduces the heating and cooling demands of buildings and therefore reduces the energy demand ..2O2 , which consequently leads to a lower dry density of the samples  mixed foaming and (2) pre-foaming. In the mixed-foaming method, foam is generated during the mixing process after adding a surfactant. In contrast, in the pre-foaming method, a pre-made foam is mixed with the concrete slurry ,79.2O/Na2O ratio and the Si/Al ratio on the properties of the final geopolymer foam. The XRD results of the different mixtures show that samples with a higher Si/Al ratio exhibit a lower amount of crystalline structures. However, an increasing crystallinity can be observed in samples with a higher H2O/Na2O ratio. The increased amount of water also leads to a poor homogeneity of pore size distribution, a lower thermal conductivity and reduces the early strength of the final geopolymer. In contrast, a lower Si/Al ratio leads to a higher strength [Hajimohammadi et al. reported their research on geopolymer foam concrete, based on granulated blast-furnace slag (GBFS), synthesized by mixing a pre-made foam into the geopolymer mixture. Three different geopolymer mixtures with the same amount of pre-made foam were prepared to investigate the impact of the Hstrength .Another study of Hajimohammadi et al. investigates the effect of different amounts of xanthan gum  on the pore structure of fly ash-based geopolymers. The pre-made foam was prepared by mixing the foaming agent sodium dodecyl sulphate (SDS) and water. The increasing xanthan gum concentration reduces the collapse of the voids and leads to finer pores and, therefore, to a smaller pore size distribution compared to the control sample without xanthan gum. The compressive strength at 28 days is improved by up to 34% by a xanthan gum concentration of 0.45 wt. %. Furthermore, they reported a slight decrease in the thermal conductivity with an increasing amount of stabilizer. The samples with 0.45 wt. % xanthan gum showed a thermal conductivity of 0.21 W/(m K) compared to the control, with a thermal conductivity of 0.26 W/(m K) .Besides the chemical and mechanical foaming technique, foam concrete can also be fabricated by embedding hollow spheres into a binding matrix. These so-called syntactic foams exhibit attractive mechanical and thermal properties. The most common hollow spheres, used for syntactic foams, are cenospheres, hollow glass micro-balls, hollow polymeric microspheres, and ceramic and metal hollow particles. Notably, the air- or inert gas-filled cenospheres are useful for the fabrication of syntactic foams due to their beneficial properties. The beneficial properties include lightweight, small size and spherical shape ,87,88,893, an average compressive strength of 17.5 MPa and thermal conductivity of 0.28 W/mK [3, compressive strength of 36.5 MPa and thermal conductivity of 0.173 W/(m K) [3) with 50 wt. % hollow microspheres, 17.9 MPa in compressive strength for samples (641 kg/m3) with 40 wt. % hollow microspheres and 22.1 MPa in compressive strength for samples (782 kg/m3) with 30 wt. % hollow microspheres [3, and the compressive strength was about 33.5 MPa. In contrast, the density of the samples with hollow phenolic microspheres was about 1280 kg/m3 and a reported compressive strength of about 22.5 MPa [Hajimohammadi et al. manufactured geopolymer foam concrete using cenospheres, fly ash, ground granulated blast-furnace slag and sodium metasilicate. They reported achieving a density of 978 kg/m.28 W/mK . Wang et W/(m K) . Shao etospheres . Zhang eLike aerated concrete, the properties of geopolymer foam concrete can also be improved using additives. Notably, fibers have shown a great impact on mechanical properties. ,55,90. H3 and a thermal conductivity of about 0.26 W/(m K). However, the high amount of foaming agent leads to an increased presence of large pores and therefore a compressive strength of 9.5 MPa. The addition of fibers to the un-foamed samples also leads to a reduction in compressive strength and density. The un-foamed geopolymer samples without fibers achieved a compressive strength of 54 MPa and a density of 1.61 g/cm3, whereas the samples with fibers achieved a compressive strength of 36 MPa and a density of 0.7 g/cm3 [3 for samples foamed with a surfactant, from 0.9 to 1.7 g/cm3 for samples foamed with hydrogen peroxide and from 0.7 to 1.7 g/cm3 for samples foamed with hydrogen peroxide and a surfactant. Furthermore, they reported the behavior under fire conditions of the fiber-reinforced and foamed geopolymer samples. The geopolymers reinforced with PVA fibers (thickness: 50 mm) show within 100 min a higher resistance under simulated fire conditions compared to the basalt fiber-reinforced geopolymers [3, thermal conductivities of 0.06–0.07 W/(m K) and reporting flexural strengths of 1.5–1.9 MPa [Rickard et al. manufactured fiber-reinforced metakaolin-based geopolymer foam concrete using 1 wt. % polypropylene fibers and different amounts of aluminum powder as a foaming agent . They reported that the addition of 0.06 wt. % aluminum powder leads to a density of 1.0 g/cm.7 g/cm3 . Masi etpolymers . Lee et –1.9 MPa . Abdolla–1.9 MPa .Some researchers also use natural fibers such as hemp or abaca for the reinforcement of geopolymer foam concrete. Galzerano et al. investigated lightweight geopolymer concrete, reinforced with hemp fibers for use as insulating materials. The hemp-based geopolymer was synthesized by adding a hemp fiber grid to a slurry composed of metakaolin and sodium silicate. In order to obtain a geopolymer foam, a foaming agent composed of silicon metal powder and a mixture of vegetable surfactants was used. The SEM images show the fracture surface of the geopolymer foam reinforced with hemp fibers. The high alkaline pH of the geopolymer system leads to chemical treatment of the fibers and, therefore, strong adhesion between the geopolymer matrix and hemp fibers is observed. Higher magnifications in particular exhibit excellent interfacial bonding between the matrix and fiber due to an etching of the fiber surface . Ngo et The variable quality, composition and mechanical treatment of natural fibers make comparisons between research efforts difficult.The improvement in the interfacial bonding between the matrix and fiber to avoid pulled-out fiber.The improvement in the foam stability causes a large total area of foam, and the subsequent high surface energy leads to instability of the system.Fiber-reinforced geopolymer foam concrete has the potential of being an alternative to conventional thermal insulation materials. Besides the research that has been conducted, the field of fiber-reinforced geopolymer foam concrete, especially with natural fibers, faces many challenges. Some of these challenges are listed below.Regarding the improvement in foam stability, one possible solution is presented by Krämer et al. They investigated a new approach for foam stabilization in concrete based on three phases. This three-phase-foam consists of a water/surfactant dispersion and is stabilized via nanoparticles by a Pickering emulsion ,97. In g2 emissions. The present review describes the most important research findings related to fiber-reinforced geopolymer foam concrete and includes the topics natural fibers, foaming methods and recent efforts to reduce the fiber degradation in geopolymer concrete. The results show that the addition of natural fibers  improves the flexural and compressive strength as well as the thermal conductivity of foamed geopolymers. Furthermore, the combination of natural fibers and nanoparticles leads to higher durability of the fibers within the geopolymer matrix. However, these composites face many challenges, such as the improvement of the fiber–matrix adhesion or foam stability. Additionally, the variable quality, composition and mechanical treatment of natural fibers also make comparisons between research efforts difficult. Therefore, regarding the recent drive for sustainable alternatives, further studies will be required to replace the conventional thermal insulating materials with natural fiber-reinforced geopolymer foam concrete. Promising approaches are chemical treatment of fibers, combinations of natural fibers and nanoparticles and the use of adjusted foaming methods. Life cycle assessment and fire resistance of natural fiber-reinforced geopolymer foam concrete have not been reviewed in this paper, but they have been noted in some research studies and may represent challenges in the development of sustainable insulating materials based on natural fibers and geopolymer foam.The development of geopolymer foam concretes as sustainable thermal insulating materials is an important step toward more environmentally friendly buildings. Conventional thermal insulating materials, such as extruded or expanded polystyrene, mineral wool, foam or aerated concrete, have several disadvantages, including high-embodied energy, being based on non-renewable resources and high CO


The optimal treatment for resectable esophageal cancer remains unclear. This network meta-analysis compares the efficacy of different treatments. PubMed, Embase, and the Cochrane library were systematically screened. Randomized controlled trials comparing the efficacy of different treatments for resectable esophageal cancer were included. Hazard ratios (HR) for overall survival (OS), progression-free survival, or disease-free survival, and odds ratios for locoregional recurrence and distant metastasis rates were identified as the measurements of efficacy. A Bayesian network meta-analysis was performed. In this study, 26 studies were included. Patients received either surgery alone; neoadjuvant chemotherapy (CT), neoadjuvant radiotherapy (RT), or neoadjuvant chemoradiotherapy (CRT) followed by surgery; or surgery followed by adjuvant CT, adjuvant RT, or adjuvant CRT. Neoadjuvant CRT followed by surgery  and neoadjuvant CT followed by surgery compared with surgery alone were the only two showing statistically confident improvement on OS. Ranking analysis showed that neoadjuvant CRT with surgery was likely to be the best option in terms of efficacy. Therefore, for patients with resectable esophageal cancer, neoadjuvant CRT with surgery is the optimal treatment. Future studies should focus on the optimization of neoadjuvant CRT regimens. Esophageal cancer is the sixth leading cause of cancer-associated mortality worldwide due to its highly aggressive nature and poor prognosis . The lonTraditional pair-wise meta-analysis cannot integrate all the evidence of different treatments at the same time, and the network meta-analysis offers the opportunity to perform both direct and indirect treatment comparisons among randomized studies simultaneously. Due to the lack of conclusive evidence and the difficulties in the conduction of adequately designed multidimensional clinical trials, this systematic review and network meta-analysis evaluates the relative efficacy of neoadjuvant or adjuvant CT, RT, or CRT and surgery or surgery alone for patients with resectable esophageal cancer in RCTs.This network meta-analysis was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) extension statement for network meta-analysis  therapy” and “adjuvant (postoperative) therapy” and “chemotherapy or radiotherapy  or chemoradiotherapy ” and “esophageal  or esophagogastric  junction cancer ” within the restriction of “randomized controlled trial” and “English language”  or squamous cell carcinoma (SCC) of the esophagus or gastro-esophageal junction and were fit for potentially curative surgery.Trials that compared any two or more different treatments  in patients with resectable esophageal cancer.For trials comparing neoadjuvant (C)RT or adjuvant (C)RT with other treatments, the prescription dose of RT set in the protocol should be more than 20 Gy.Trials that reported at least one of the following clinical outcome measures: OS, defined as the time from randomization until the last follow-up or death; progression-free survival (PFS), defined as the time from randomization to first progression  or the last follow-up or death; disease-free survival (DFS), defined as the time from R0 resection to disease recurrence or the last follow-up or death; the number (or the rates) of treatment failures due to locoregional recurrence and distant metastasis.Only full-text articles published in English were included. If multiple publications of the same trial were retrieved, the most recent and informative publication was included. Studies also enrolling patients with gastric cancer were excluded for potential bias due to the heterogeneity of patient characteristics.Two authors were responsible for screening the titles and abstracts of the retrieved references. The full texts of the included studies were assessed based on the aforementioned criteria. Any discrepancies were resolved by consensus and arbitration by a panel of senior authors. Data on trial details , treatments, and outcomes  with their 95% confidence intervals (CI) for OS, PFS, or DFS and the number of patients experiencing locoregional relapse or distant metastasis or rates of locoregional recurrence and distant metastasis) were extracted.The quality of each eligible study was evaluated by the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) . The entire scale comprises the following domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, selection of the reported result, and overall bias. According to the detailed guidance of RoB 2, each domain could be judged as any of the three levels: low, high, or unclear risk of bias. The associated data were extracted and assessed using predefined fields.Publication bias was assessed by visual inspection of the funnel plot.The HR for OS was proposed as the primary interest of efficacy, which takes into account the timing and censoring of survival status. To obtain the HR and its standard error, three approaches were applied (1): For studies that reported the summary statistics, HR was directly collected, and standard error was calculated from CI (2). In the absence of summary statistics, some studies published the Kaplan–Meier curve with at-risk table. Using a method proposed by Tierney , survivaBayesian network meta-analysis (NMA) was carried out to synthesize all therapeutic options within a mixed treatment comparison framework using R 3.6.0. A random effects model was prioritized to address the study-specific effects that were a component of overarching distribution. To be objective, uninformative prior distribution was given to all parameters. The node-split method was used to assess inconsistency.The estimates of relative effects and 95% credible intervals (CrI) were reported. In addition, the surface under the cumulative ranking (SUCRA) scores were calculated as well.n = 2542); neoadjuvant CT (n = 1222), neoadjuvant RT (n = 150), or neoadjuvant CRT (n = 1278) followed by surgery; or surgery followed by adjuvant CT (n = 518), adjuvant RT (n = 380), or adjuvant CRT (n = 78). The main characteristics of all studies are reported in A total of 26 articles were eligible for the NMA , 11–32. No included trials were judged as high risk of bias concerning study design , which ap > 0.05) except for NRT-S versus NCT-S (p = 0.026) in the subgroup analysis of SCC for OS . Second to it, a substantial difference was also observed in neoadjuvant CT followed by surgery compared with surgery . Adjuvant CRT apparently demonstrated a similar impact on OS although with some level of uncertainty . Besides this, the NMA also shows a trend but not a statistically confident OS benefit of neoadjuvant RT  compared with surgery alone.Sixteen studies reported HRs for PFS/DFS or Kaplan–Meier curves for manipulation. In terms of PFS/DFS, neoadjuvant CRT  was also associated with the most robust survival advantage across different treatment options, followed by neoadjuvant CT . Adjuvant CRT  presented nonconfident OS benefit  were 0.76 (0.65–0.89) and 0.81 (0.7–0.94), respectively. A trend in favor of adjuvant CRT was also found in SCC: HR (95% CrI) was 0.73 (0.49–1.08). For patients with AC, neoadjuvant CRT was apparently associated with better survival . Neoadjuvant CRT with surgery ranked first (SUCRA scores: 0.79 and 0.87) in both histology types.Ranking analysis based on SUCRA scores showed that neoadjuvant CRT with surgery (0.85) was most likely to be the best option in terms of OS benefit. Subsequently, the other treatments were ranked as follows: surgery with adjuvant CRT (0.80), neoadjuvant RT with surgery (0.54), neoadjuvant CT with surgery (0.51), surgery with adjuvant RT (0.40), surgery with adjuvant CT (0.29), and surgery alone (0.11). When different histology types were considered, treatment with the greatest probability of being ranked first was still neoadjuvant CRT. Moreover, neoadjuvant CRT was also most likely to be ranked first for PFS/DFS as well as reducing the rates of locoregional recurrence and distant metastasis. To minimize potential bias, sensitivity analysis by the HR calculation method was conducted. When we grouped together studies for which the HRs were obtained by the first two aforementioned approaches, the network meta-analysis showed similar results to primary analysis , and neoadjuvant CRT may reduce distant metastasis by decreasing tumor burden, inhibiting tumor growth, and preventing intraoperative dissemination. Therefore, we believe the improved locoregional control and reduced distant metastasis both contribute to the improved OS by neoadjuvant CRT.Several considerations should be mentioned when interpreting the results of our NMA. First, even though tests for inconsistency were almost all negative, with the subgroup analyses consistent, the variability in patient populations, treatments, and procedures might not be ignored. Second, we used aggregate data instead of individual patient data, and some unknown or uncontrolled confounding factors may exist. Third, the sample sizes for some treatments were limited: 78 patients included in the adjuvant CRT arm and 150 in the neoadjuvant RT arm. Although adjuvant CRT and neoadjuvant RT ranked second and third in the ranking analysis, even ahead of neoadjuvant CT, some uncertainties might exist, which could also be explained by the wider 95% CrIs, and therefore, the results of ranking analysis should be taken cautiously. Additionally, here we cannot definitively conclude about the optimal CT regimen or RT scheme as the included studies used different agents and radiation dose fractionation. However, a platinum-based CT and a total RT dose of 40–50 Gy as administered in most trials may be reasonable options.Despite these limitations, this NMA aggregated high-quality prospective RCTs of neoadjuvant and adjuvant treatments, summarized and interpreted a wider picture of the evidence base in spite of some head-to-head trials lacking at the moment, and identified the most effective approach through analysis of several different clinical outcomes. The only previously published NMA, conducted by Pasquali in 2016, indicates that neoadjuvant CRT followed by surgery is the only one that could significantly improve OS of patients with resectable esophageal cancer compared with other neoadjuvant or adjuvant treatments . HoweverThis NMA provides evidence that, for patients with resectable esophageal cancer, neoadjuvant CRT and surgery is the optimal strategy in improving the survival, especially for esophageal SCC. Neoajuvant CT might be an appropriate alternative in selected cases. Further studies should focus on the optimization of the most effective neoadjuvant CRT regimens for resectable esophageal cancer.The original contributions presented in the study are included in the article/ZH conceived the study and revised the manuscript. MY, YB, and ZM performed the searches and collected raw data. YM and YW checked the data and performed statistical analysis. MY and YW drafted the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by National Key Research and Development Program (2017YFC1311000).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.


Immunoglobulin G4 (IgG4) associated autoimmune hepatitis (AIH) has been recognized as a type of autoimmune disease that responds to corticosteroid. The diagnosis is based on elevation of the serum IgG4 level, abundance of IgG4 enhanced plasma cell infiltration in the portal region of the liver, and satisfaction of the criteria for “definite AIH” under the revised International Autoimmune Hepatitis Group (IAIHG) scoring system. However, the clinical course of the disease is unclear.A 65-year-old man with jaundice and peripheral blood eosinophilia.His IAIHG and simplified score was compatible with definite AIH and his IgG4 level was elevated. Magnetic resonance imaging did not reveal abnormalities in the hepatobiliary system or pancreas. A liver biopsy revealed interface hepatitis with IgG4 positive plasma cell infiltration in the portal region, without evidence of bile duct injury. He responded to 4-week period of induction prednisolone therapy and had no recurring symptoms under maintenance therapy of 5 mg prednisolone during the 3-year follow up.This was a rare case that demonstrated an association between IgG4 associated AIH and the presence of peripheral blood eosinophilia. Autoimmune hepatitis (AIH) is an inflammatory liver disease characterized by chronic inflammation of the liver,positivity for autoantibodies, increased immunoglobulin level, and histological evidence of interface hepatitis and lymphoplasmacytic infiltration . In contA 64-year-old man presented with a 2-month history of progressive, painless jaundice, loss of appetite, and a recent weight loss of 6-kg. He reported a history of uninvestigated, self-limited jaundice with prodromal symptoms occurring 2 years before. His past medical history was negative for peripheral mononeuropathy as well as allergic disease, including allergic rhinitis, sinusitis, and bronchial asthma. He was a non-smoker and did not consume alcohol/supplements/herbals. He also denied previous or ongoing use of drugs. Physical examination was unremarkable except for signs of jaundice and body itching. Complete blood count findings were remarkable for an elevated absolute eosinophil count (AEC) of 2592 cells/μL. Blood chemistry findings included serum total protein, 11.71 g/dL; serum albumin, 2.54 g/dL; total bilirubin, 8.10 mg/dL; direct bilirubin, 6.48 mg/dL, serum aspartate aminotransferase (AST), 385 IU/L; alanine aminotransferase (ALT), 429 IU/L; alkaline phosphatase (ALP), 123 IU/L; and prothrombin time-international normalized ratio, 1.11. Serologic tests were negative for infection with Human Immunodeficiency Virus as well as hepatitis A, B, C or E. The patient’s autoantibody testing (using indirect immunofluorescent method) showed anti-nuclear antibody (ANA) was positive with titer at 1:80 and cytoplasmic pattern while smooth muscle antibody (SMA), anti-mitochondrial antibody and anti-neutrophil cytoplasmic antibodies were negative. The patient’s serum IgG concentration level was 5222 mg/dL (reference range: 548–1768 mg/dL), and his IgG4 concentration level was 1780 mg/dL (reference range: 3.9–86.4 mg/dL). Magnetic resonance imaging (MRI) revealed no abnormalities in the hepatobiliary system or pancreas.A percutaneous ultrasound-guided liver biopsy was performed Fig. . The patThe IgG4-related disease has recently been defined as a systemic, chronic, relapsing, multiorgan, fibroinflammatory condition. It commonly involves the pancreas, biliary tract, salivary glands, lacrimal glands, and kidneys . The hepHowever, it has recently been postulated that there is an association between IgG4-related disease and autoimmune hepatitis, and this has given rise to the disease concepts known as “IgG4 hepatopathy” . AccordiAn important question is whether IgG4-AIH is a subtype of classic AIH or a subtype of IgG4-related disease that involved liver. Previous reports suggest that IgG4-AIH should be differentiated from classic AIH . Most baAnother important aspect of our case was the presence of peripheral blood eosinophilia and the abundance of eosinophilic infiltration in the biopsied liver specimen. IgG4 and IgE share a common immune response pathway. Allergic immunology triggers T-helper 2-type immune response that promotes secretion of IgG4 and IgE and induces peripheral blood and tissue eosinophilia . There aIn conclusion, we report a rare case of IgG4-AIH with peripheral blood eosinophilia and absence of symptoms related to other organ of IgG4-related disease. The identification of “Definite AIH” based on both IAIHG and simplified AIH score, high serum IgG4 level, and an accumulation of IgG4-positive cells in the liver were necessary for our diagnosis. Glucocorticoid treatment is the first line treatment for this condition and, in our patient, produced a good response. Although the presence of peripheral eosinophilia may possibly help diagnose this disease, further studies are needed to confirm this and to clarify the clinical course and optimal treatment of IgG4-AIH.


Several lines of evidence have confirmed the magnitude of crosstalk between HGF/c-Met axis  and non-coding RNAs (ncRNAs) in tumorigenesis. Through activating canonical or non-canonical signaling pathways, the HGF/c-Met axis mediates a range of oncogenic processes such as cell proliferation, invasion, apoptosis, and angiogenesis and is increasingly becoming a promising target for cancer therapy. Meanwhile, ncRNAs are a cluster of functional RNA molecules that perform their biological roles at the RNA level and are essential regulators of gene expression. The expression of ncRNAs is cell/tissue/tumor-specific, which makes them excellent candidates for cancer research. Many studies have revealed that ncRNAs play a crucial role in cancer initiation and progression by regulating different downstream genes or signal transduction pathways, including HGF/c-Met axis. In this review, we discuss the regulatory association between ncRNAs and the HGF/c-Met axis by providing a comprehensive understanding of their potential mechanisms and roles in cancer development. These findings could reveal their possible clinical applications as biomarkers for therapeutic interventions. Cancers are initiated by genetic preconditions and epigenetic alterations, accompanied by various mechanisms, most of which are still unclear /c-mesenchymal-epithelial transition factor (c-Met) axis is an essential mediation axis that regulates cellular biological events including cell proliferation, migration and morphogenesis and tumor biological processes such as angiogenesis and drug resistance , circRNA, lncRNA, and so on  in common human cancers are summarized. Also, a comprehensive understanding of their potential mechanisms and roles in cancer development are provided. These findings could open a broader horizon for investigators to engage in exploring the molecular mechanisms in cancer development and progression.HGF, also known as scatter factor, is located on chromosome 7q21 and is a member of the peptidase S1 family of serine proteases, but is short of peptidase activity  thus promoting angiogenesis  as essential miRNA-regulators have emerged as therapeutics scavenging oncogenic miRNAs. Recently, they have exposed exciting insights into tumorigenesis. LncRNA HOTAIR was found to be overexpression in GC tissue and cells, particularly in diffuse-type GC. In addition, lncRNA HOTAIR knockdown remarkably impaired migration, invasion and metastasis both OS predominantly originates from mesenchymal cells of long bones and has a high prevalence in children and young adults. It usually starts as a monoclonal disease and quickly progresses into a polyclonal disease. It is regarded as one of the most complicated cancers in terms of molecular aberration  was higher in metastatic OS tissues than non-metastasis OS tissues or corresponding normal tissues. In the same study, elevated levels of serum lncRNA MALAT1 predicted worse clinical outcomes in OS patients. The silencing of lncRNA MALAT1 was shown to inhibit proliferation, migration, and invasion of OS cells. Bioinformatic and molecular analyses revealed that lncRNA MALAT1 served as a ceRNA of c-Met and SOX4 by directly targeting miR-34a/c-5p and miR-449a/b  was remarkably downregulated. Further BCa is the most frequent cancer of the urinary tract Grayson, . ChlyomaCRC is a public health concern and accounts for over 10.2% of all cancer cases, representing 1.8 million new cases per year  upregulation and miR-1 downregulation are required to elicit the highest level of MET expression. Induced miR-1 expression reduces MET levels and impairs MET-induced proliferation, migration and invasion processes. Notably, a feedback loop between miR-1 and MET has also been revealed. Most likely, MET targeting could result in both abrogations of MET-dependent signaling and some recovery of miR-1 level , it has been reported that transient transfection of miR-34a mimics into glioma and medulloblastoma cell lines remarkably inhibits cell proliferation, invasion, survival, and cell cycle progression by targeting c-Met, Notch-1, and Notch-2  is the most epidemic neoplasm of the female genital tract worldwide. Despite the great development in early identification and treatment, an abundant number of cases of advanced ECs are still diagnosed  represents a unique and major health concern all over the world. A study by Xu et al. indicated that miR-143 inhibited OSCC cell mobility by suppressing phospho-c-Met expression through targeting CD44 v3 , miR-199a-3p is known as a tumor attenuator. Huang et al. revealed that miR-199a-3p was downregulated in RCC primary tumor and cell lines, and this loss was associated with advanced tumor-lymph node-metastasis (TNM) stage and Fuhrman grade. Reintroducing miR-199a-3p in RCC cell lines inhibited proliferation and led to the arrest ofG1 phase by negatively regulating c-Met, thus suppressing HGF/c-Met axis and it's downstream signaling such as Akt, ERK1/2 and mTOR , the crosstalk between ncRNAs and HGF/c-Met axis has a significant effect on tumor growth and progression. Several reports have shown that some miRNAs (such as miR-449b and miRNA-3666) act as tumor suppressors that inhibit TC growth and reduce apoptosis by decreasing the levels of MET protein rather than its transcription  is one of the major histological subtypes of esophageal cancer in China. Currently, there are limited therapeutic options for the disease because of limited understanding of its molecular mechanism. MiR-1 functions as a crucial tumor inhibitor in ESCC . Its overexpression is associated with a decrease in acquisition of MET, cyclin D1, and CDK4 (oncogene and cell cycle-related proteins), which eventually lead to are duction in cell growth and enhanced cell apoptosis Multiple myeloma (MM) is the second most general hematological cancer in globe with poor survival on account of high recurrence  is a highly invasive neoplasm in childhood. In 2019, Cui et al. revealed a vital role of crosstalks between ncRNAs and HGF/c-Met axis in HB. LncRNA ZFAS1 is a snoRNA host gene locating in chromosome 20q13.13. They found that lncRNA ZFAS1 was overexpression in HB tissue and correlated with malignant pathological features and poor prognosis through tissue microarray analysis. Furthermore, they also showed that lncRNA ZFAS1 served as a ceRNA to regulate RALY by sponging miR-193a-3p and played an oncogenic role during HB progression via HGF/c-Met pathway during HB development  is the most frequent lymphoid malignancy all over the world. MET was reported to be upregulated in DLBCL and predicted poor outcomes. Cheng et al. investigated that elevated lncRNA TUG1 expression could facilitate cell proliferation and decrease apoptosis In this review, we have summarized the crosstalk between HGF/c-Met axis and ncRNAs in common multiple human cancers, which has improved our understanding on the pathogenetic mechanism of tumor occurrence and development. However, further studies are required to fully explore the interaction between ncRNAs and HGF/c-Met axis in cancer. Despite the evidence presented here, the precise interactions between ncRNAs and HGF/c-Met axis, and how these interactions affect tumorigenesis and progression of cancers are still largely unknown. This implies that additional controlled and large-scale clinical studies are required before cancer-specific ncRNAs and HGF/c-Met inhibitors can be recommended for clinical diagnosis and treatment.Taken together, deeper understanding of HGF/c-Met axis will reveal beneficial avenues and generate new hypotheses regarding cancer pathogenesis and treatment.ZY, ZR, and RS proposed the study. XL, JC, LL, XC, SS, and GC performed the research and wrote the first draft. ZR and ZY are the guarantors. All authors contributed to 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.


Although fiber reinforced polymer (FRP) bars have proved their usefulness in the case of reinforced concrete flexural elements, there are still limited data on their performance in such structures under compression. Despite multiple benefits of using FRP bars as the reinforcement in concrete elements, their potential application as main reinforcement in compressed elements is still very controversial, mainly due to the limited amount of published research results. The presented work partly fulfills this knowledge gap. Two series of theoretical analyses—one based on the stress distribution in the cross-section and the second using the finite elements method (FEM)—with reference to the experimental results are presented. The analyses concern basalt FRP, glass FRP, and steel-reinforced concrete elements under axial compression. There are derived calculations of load–displacement relations and stress values in bars. Damage progression was analyzed as well. Main findings are as follows: (1) a good agreement between calculated failure loads and experimental results has been achieved; (2) potential negative influence of FRP reinforcement on the compressive capacity of the reinforced element should not be neglected; (3) nonlinear FEM analysis is useful in predicting the maximum value of load and damage zones; (4) stress values of only about 100 MPa  were obtained in non-metallic bars. The results might be useful for the further establishment of design rules. Fiber reinforced polymer (FRP) composite bars are increasingly being used as an alternative to steel rebars in concrete structures. Their use is beneficial due to a higher corrosion resistance, tensile strength, electromagnetic indifference, and lower weight when compared to steel rods .It is also worth mentioning that FRP bars are highly environmentally friendly material. Not only does the use of FRP materials lengthen the life cycle of a construction due to their high corrosion resistance ,3,4, butGlass fibers—glass fiber reinforced polymer (GFRP);Carbon fibers—carbon fiber reinforced polymer (CFRP);Aramid fibers—aramid fiber reinforced polymer (AFRP);Basalt fibers—basalt fiber reinforced polymer (BFRP);Hybrid  fibers—hybrid fiber reinforced polymer (HFRP).The most commonly used composite bars are made of:Japanese standard ;Canadian standards for buildings  and bridAmerican standard ;Italian standard .The use of non-metallic bars in concrete elements increases the durability of the structure and reduces the amount of necessary repair work. Due to the high reliability of these types of bars, they are often used in components such as bridges and viaducts . In addiBoth—the above standards and the research carried out so far—focus mainly on aspects related to bendable elements, such as slabs and beams . Dimensions of the elements are 150 mm × 150 mm × 750 mm. The reinforcement scheme is shown in Tests and analyses concern axially loaded concrete elements with different reinforcement types. The sets of the specimens have been summarized in cm,cubef = 41 MPa. It corresponds to the value cmf = 32.8 MPa, when concerning the maximum value of the concrete stress in the cross-section of the reinforced element [ckf = 25 MPa. The cubic specimens have been stored in air-dried conditions before the compression tests—in the same way as the reinforced specimens in the experimental part.Concrete has been used with the medium value of compressive strength established experimentally on 150 mm concrete cubes as per  on fcm,c element . CharactStirrups in all specimens were made of Rb500W steel . Three tThe stand  consistecmf—compressive strength of concrete (32.8 MPa);n—2 for concrete not higher class than C50/60;cε2—minimum value of strain, for which the stresses gain compressive strength value, 2‰ for concrete not higher class than C50/60;cuε2—maximum value of concrete strain, 3.5‰ for concrete not higher class than C50/60.For the purposes of the analytical method, the stress-strain relation for concrete derived by an Equation (1) has been used :(1)σc={fConstitutive model of steel was assumed as elastic-plastic with the parameters shown in N—normal force;M—bending moment;siA—area of singular bar;siσ—stress value in a singular bar;n—quantity of bars;cσ—stress value in concrete;ccA—compressed concrete area;2ν—the distance from the center of gravity of the concrete cross-section to the most compressed edge;ia—spacing of reinforcement from the most compressed section edge;ca—the location of the resultant force of the compressive stress block taken from the area ccA, measured from the compressed edge of the cross-section.The maximum value of load has been calculated based on the balance of loads in the reinforced cross-section . PrelimiAbove described designations concerning strain and stress distribution are presented in cε2 = 2‰—in the whole, equally compressed cross-section.Assuming no eccentricity of the load (no bending moment), the strains in the cross-section with symmetrical reinforcement could be assumed to have the same value—without considering the influence of composite bars .In the case of the metallic bars method, based on Equations (2) and (3), it is commonly used to assume maximum values of loads in the cross-sections for design purposes. In the case of non-metallic reinforcement, there is still not enough data confirming experimentally the influence of FRP reinforcement on the capacity of the element. In this article, two values of the capacity of the element have been proposed and analyzed:x—distance from the point on the height of the cross-section to the most compressed section edge;h—height of the cross-section;cε2 = 2‰;cuε2 = 3.5‰;a—calibrating parameter.The values of strains in the ultimate limit state  can be calculated as follows:a). The stress values in the bars have been calculated on the basis of their modulus of elasticity, while concrete relations described by Equation (2) have been used. Afterwards, values of M and N have been calculated as per Equations (2) and (3) and the value of eccentricity e has been calculated according to the following formula:The values of stresses have been calculated for various strain distributions σcfcmLinear growth of concrete stresses until failure has been assumed in the tensile range. Modulus of elasticity and tensile strength of concrete has been established by following equations :(8)Ecm=2Dilatation angle—assumed value in following FEM analysis: 36;Eccentricity—0.1;bf0/cf0—1.16;κ—0.667;Viscosity parameter—0.Additionally, the Concrete Damaged Plasticity (CDP) model widely described in  was applcd and td are defined on the basis of the following equations:E0—undamaged modulus of deformation;Parameters for the damage evolution analysis  have been calculated as per . Damage Same assumptions as in the analytical model see  have beeDeformations of the specimens during the test were simulated by controlling displacements and rotations in reference points. Axial compression deformations were provided by moving down the upper reference point (and as a result pushing the upper rigid body onto the concrete element). Geometric nonlinearity has been considered. x).Apart from axially compressed element simulation, there has also been carried out analyses of eccentricity influence ;Calculated with the use of analytical method FEMN.Obtained from FEM analysis in ABAQUS In An analysis  has beenRcN) instead of medium values used in all other calculations in this article.Additionally, probabilistic analyses in usual designing procedures give additional safety reserves. It is related to the fact that values of material strength are intentionally lower than expected medium values. Therefore, in The influence of an unintentional eccentricity of the load should be taken into consideration when designing steel-reinforced elements according to , and shoIn After gaining the maximum value of the load, a sudden decrease in load value can be observed. The sudden drop in the capacity might be related to the fact that at that moment of FEM simulation a highly compressed area appeared in the middle height of the specimen. Plasticization processes of concrete propagated vividly and damage parameter in that area increased. This highly compressed area is easily visible on the damage map for post-failure stage see . As a reThe load–displacement curve for FRP-reinforced specimens reveals some similarities to the non-reinforced specimen in terms of curve course as far as the maximum value of the load. In some cases, even the negative impact of FRP bars on the capacity of the element might be observed. The main difference, though, concerns the post-failure state. When concerning the non-reinforced element, the analysis is interrupted just after gaining the maximum value of the load, while FRP-reinforced (as well as steel-reinforced) elements could still be able to sustain a reduced value of the load.Concerning the G8 specimen a, the faCorners of the specimen ;Medium height of the specimen—most significant in the failure stadium .In The maps of damage zones, with the failure of the BFRP-reinforced specimens (designation: B8), are shown in In The maximum values of stresses in bars calculated in this simulation are much lower than the compressive strength of FRP. Therefore, one of the composite’s main beneficial characteristics (high strength) has a minor significance in the case of axially compressed reinforced concrete elements.FRPs have already been proven to be a material with multiple advantages . The benefits of using composite bars as a replacement for steel reinforcement have been confirmed in multiple applications for the elements under flexural load. As there is still only a limited amount of studies concerning compressed elements with internal FRP reinforcement, intensive research is needed in this area in order to establish proper design procedures.In this article, there are provided results of experimental and theoretical analyses of compressed concrete elements reinforced with BFRP, GFRP, and steel bars. In particular, their influence on the behavior of axially compressed concrete columns was examined.Perfect axial compression is almost impossible in the real behavior of the construction element—the load is expected to be moved from the center of the cross-section due to various factors. One of these factors might be the imperfection of a specimen preparation. Typically, the influence of second-order effects should also be considered as created deformations can increase the eccentricity of the load effect. In this article, theoretically assumed concentric compression has been compared to the results obtained for the small values of load eccentricity—1 and 2 cm . In thisDifferences between calculated and measured failure loads are, in the case of the FEM model, at the level of up to 6%  for mostAssumption of even small eccentricity  resulted in reduction in calculated failure force values, therefore in most cases they were lower than obtained experimentally A good agreement between calculated failure loads and experimental results has been proven for most of the analyzed specimens. The difference  in the maximum value of load might be influenced by geometric tolerances . When designing axially compressed elements, the influence of unintentional load eccentricity (not less than 2 cm ) should (2)When comparing values of loads calculated with the use of FEM analysis for non-reinforced and FRP-reinforced elements, FRP compressed elements have in some cases lower values of load. The potential negative influence of FRP reinforcement on the compressive capacity of the reinforced element should not be neglected. A positive influence on the compressive capacity for other specimens has been calculated as not higher than 5%. On the basis of the load–displacement curve , it shou(3)Nonlinear FEM analysis has appeared to be useful in predicting the maximum value of load as far as damage zones, in which plasticity processes and cracking might start and propagate for FRP- and metallic-reinforced compressed elements.(4)Stress values of only about 100 MPa-much lower than FRPs’ compressive strength, have been obtained in bars for above-described analyses. Therefore, the benefits of using non-metallic reinforcement in compressed concrete elements should be seen in their high corrosive resistance, electrical indifference, or ecological friendliness rather than in their high strength. However, analyses of interaction between FRP bars and different types of concrete  are also recommended.The main conclusions of performed analyses are as follows:The analytical and FEM, as well as the experimental results, presented in this article have given valuable data on FRP compressed elements’ behavior. However, results for only six specimens have been considered. Additional experimental and analytical investigations should be carried out so the validity of the presented methods could be confirmed. After such validation, the proper designing rules could be established. Some analogies to currently existing design rules for metallic-reinforced compressed elements might be implemented, for example, concrete stress distributions or necessity of considering the unintentional eccentricity of a load.


Acute ischemic stroke is a serious disease that endangers human health. In our efforts to develop an effective therapy, we previously showed that the potent, highly selective inhibitor of soluble epoxide hydrolase called 1-trifuoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) protects the brain against focal ischemia in rats. Here we explored the mechanism of TPPU action by assessing whether it could preserve blood-brain barrier integrity and reduce apoptosis in the brain during permanent middle cerebral artery occlusion in male Sprague-Dawley rats. TPPU administration at the onset of stroke and once daily thereafter led to smaller infarct volume and brain edema as well as milder neurological deficits. TPPU significantly inhibited the activity of soluble epoxide hydrolase and matrix metalloproteases 2 and 9, reducing 14,15-DHET levels, while increasing expression of tight junction proteins. TPPU decreased numbers of apoptotic cells by down-regulating the pro-apoptotic proteins BAX and Caspase-3, while up-regulating the anti-apoptotic protein BCL-2. Our results suggest that TPPU can protect the blood-brain barrier and reduce the apoptosis of brain tissue caused by ischemia. Ischemic stroke, caused by a cerebrovascular blockage, leads to death and long-term disability in many patients around the world . IschemiAstrocytes and vascular endothelium in the brain produce endogenous neuroprotectors called epoxyeicosatrienoic acids (EETs), which bind to receptors and thereby activate signal transduction cascades involving cAMP/PKA, PI3K-Akt, and MAPK . EETs caTherefore, inhibiting sEH has attracted much attention as a potential therapy to protect brain tissue from hypoxic or ischemic damage following stroke . The enzmax) and larger area under the concentration–time curve than adamantyl-containing urea-based inhibitors. In other words, TPPU is absorbed rapidly, absorbed efficiently and eliminated slowly, so it can persist in the blood longer than other hydrolase inhibitors. In this way, TPPU offers greater metabolic stability (The synthetic compound 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) inhibits sEH activity in the central nervous system , thus intability . TPPU istability . TPPU catability . These pIn the present study, we examined whether TPPU could protect against ischemia-induced BBB damage and apoptosis in the brain. We examined the effects and mechanism of TPPU in rats subjected to permanent MCAO (pMCAO). We focused on the potential effects of TPPU on the expression of three tight junction proteins  whose down-regulation in cerebral ischemia compromises the BBB . We alsoin situ Cell Death Detection kit were purchased from Sigma . Silicon-coated surgical nylon monofilaments were purchased from Guangzhou Jialing Biotechnology . Polyclonal antibodies against sEH and the tight junction proteins Occludin, ZO-1 and Claudin-5 were obtained from Affinity Biosciences . Antibodies against the apoptosis proteins Caspase-3, BAX, and BCL-2 were obtained from Cell Signaling Technology . Antibody against the loading control GAPDH was purchased from Bioworld . Horseradish peroxidase-conjugated secondary anti-rabbit antibody was obtained from EarthOx . TPPU was dissolved in DMSO and stored at 4°C. Before use, it was diluted with physiological saline to reduce the DMSO concentration to 5%.TPPU, dimethyl sulfoxide (DMSO), 2,3,5-triphenyltetrazolium chloride (TTC), and the Healthy adult male Sprague-Dawley rats  were purchased from the Wenzhou Medical University Laboratory Animal Center . Only male rats were used because estrogen can mitigate cerebral infarction following MCAO . All expand water ad libitum.Rats were fed in a controlled environment  and provided with food Of the 138 animals, 102 were subjected to pMCAO using the intraluminal filament technique as described . In brieThe 10 sham rats were injected intraperitoneally 5% DMSO as control. The 50 rats subjected to pMCAO were immediately randomized into five groups and injected intraperitoneally with TPPU  in 5% DMSO or with 5% DMSO vehicle . Each group contained 10 animals. The TPPU and DMSO animals were injected once immediately after pMCAO, then killed on day 1. In the initial phase of the study, 60 animals were sacrificed at 24 h after surgery, and brains were analyzed in order to determine the best TPPU concentration. This concentration was then used in subsequent experiments with the remaining 78 animals. Each of the six groups contained 13 animals and were subdivided into “1 day” or “3 days”. Rats killed on day 1 after pMCAO were injected with TPPU (1 mg/kg) or 5% DMSO once immediately after the procedure. Rats killed on day 3 after pMCAO were injected with TPPU or 5% DMSO once a day for 3 days after the procedure. Animals that died during or after the procedure were not analyzed.At 24 h after surgery, rats were euthanized with 1% pentobarbital sodium (40 mg/kg) and evaluated using the modified neurological severity scores (mNSS) protocol , involviAt 24 h after surgery, rats were sacrificed using 1% pentobarbital sodium (40mg/kg), the entire brain was sectioned into 2-mm slices using a rat brain mold , and serial coronal sections were stained with 2% TTC at 37°C for 30 min. Infarct areas in the ipsilateral hemisphere were quantified using Image-Pro Plus 6.0 . Relative infarct volume was calculated as previously described  to minimThe degree of cerebral edema was assessed using wet-to-dry weight ratios. Rats were anesthetized after pMCAO for 24 h. Brains were divided into left and right hemispheres, and the infarct hemispheres were weighed on an electronic balance with an accuracy of 0.01 mg and then dried in an oven at 65°C for 72 h. Dried brain tissues were reweighed to calculate brain water content as: (wet weight–dry weight)/wet weight × 100% .The mortality rate of an animal group was calculated as the number of dead rats divided by the total number of rats originally allocated to the group .At 24 and 72 h after surgery, rats were sacrificed using 1% pentobarbital sodium, the heart was exposed and perfused with 0.9% sodium chloride, then fixed with 50 mL of 4% paraformaldehyde dissolved in phosphate-buffered saline (PBS). Brains were removed and immersed in the same fixative for 24 h to make paraffin blocks. Brain tissues were sectioned into 5-µm thick slices, cortical sections were stained with hematoxylin-eosin as described , and stag for 20 min. The supernatant was incubated with 14,15-EET for 1 h, and levels of 14,15-DHET were assayed using a commercial ELISA  based on absorbance at 450 nm .Brain cortex tissue was homogenized in 4 volumes of cold 20 mmol/L Tris-HCl (pH 7.4) containing 0.32 mol/L sucrose and 1 mmol/L EDTA. The homogenate was centrifuged at 1000 g for 10 min, then the supernatant was transferred to a clean tube and centrifuged at 10,000 in situ Cell Death Detection Kit as described  2 and 9 in brain cortical ischemic penumbra were assayed using gelatin zymography as described . Equal vg for 20 min at 4°C, and protein concentration in the supernatant was assayed using the BCA Assay Kit (Beyotime Biotechnology) according to the manufacturer’s instructions. The clarified lysates were boiled and stored at -20°C. Equal amounts of proteins (30 μg) were fractionated on 10% SDS-PAGE, then transferred to 0.45-μm or 0.20-μm polyvinylidene fluoride (PVDF) membranes. Membranes were analyzed by Western blotting as previously described  containing the protease inhibitor phenylmethylsulfonyl fluoride , the lysate was centrifuged at 12,000 escribed : they wet test, and differences among more than two groups were examined by one-way ANOVA. Inter-group differences in mortality rate were assessed using the chi-squared test. Statistical significance was defined as p < 0.05.Data were analyzed using SPSS 17.0  and reported as the mean ± SEM. Statistical differences between two groups were assessed using Student’s Rats were subjected to pMCAO, immediately followed by injection of TPPU at 0, 0.5, 1, 1.5, or 2 mg/kg. As expected, pMCAO led to a large infarct volume in the ipsilateral hemisphere not seen in the sham-operated animals, and TPPU reduced the infarct volume to varying degrees , and TPPU partially reversed these changes. These results suggest that the protective effects of TPPU against ischemic injury may involve the down-regulation of soluble epoxide hydrolase and inhibition of MMP2 and MMP9 activity.Expression of sEH is normally widely distributed in neuronal cell bodies and processes . Levels As expected, pMCAO significantly reduced expression of the tight junction proteins ZO-1, Occludin and Claudin-5 in peri-ischemic cortical tissue Figure 4Permanent MCAO led to a large number of apoptotic cells in the penumbra, which was not observed in sham-operated animals  to reduce the level of apoptosis in the penumbra. The decrease in sEH and 14,15 DHET levels should lead to accumulation of protective EETs because TPPU is a noncovalent sEH inhibitor that binds to the enzyme in a kinetically reversible process . Our finTPPU, first mentioned in 2010 , was synin vitro studies have shown that TPPU at 0.1 mg/kg can lead to concentrations higher than the IC50 values , which ensures an appropriate microenvironment for normal neuronal function . By contvia at least two mechanisms to protect brain tissue following stroke: preserving BBB integrity and reducing apoptosis. Future work should seek to clarify how TPPU exerts these effects, including whether EETs or their bioactive metabolites are the mediators. Future studies should also seek to examine whether and how TPPU reverses apoptosis in astrocytes, neurons, or both cell types.Cerebral ischemia stroke gives rise to neuronal death, at least in part by activating apoptosis. Ischemia causes the production of reactive oxygen species that injure mitochondria, activating the pro-apoptotic protein BAX, which induces mitochondrial release of cytochrome C and activation of Caspase-9 . SubsequIn summary, our results suggest that inhibiting sEH with TPPU can mitigate ischemia-induced apoptosis in brain tissue and BBB damage by increasing EETs levels. Further work in animals and ultimately humans is needed to identify the mechanisms of TPPU action and its downstream targets. This drug may turn out to be effective against ischemic stroke.The datasets generated for this study are available on request to the corresponding authors.All experiments were approved by the Institutional Animal Care and Research Committee of Wenzhou Medical University, and procedures were carried out in accordance with the US National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.All authors bear responsibility for the integrity and accuracy of the data in the study. LZ: conceived the study and drafted the manuscript. SX, XW, and JC: developed the methods and performed experiments. FM and YC: analyzed the results. JY and ZC: supervised the project. XY and ZH: designed the study and acquired funding.This study was supported in part by grants from the Sichuan Science and Technology Agency Research Foundation (2018JY0164), the National Natural Science Foundation of China , the Medical and Health Research Science and Technology Plan Project of Zhejiang Province (2018KY523), and the Public Welfare Science and Technology Plan Project of Wenzhou City .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.


Methionine (Met) is the first limiting amino acid in broiler feeds and for balancing dietary Met and methionine+cysteine (Met+Cys) levels. DL-2-hydroxy-4-methylthio butanoic acid (HMTBA) and DL-methionine (DLM) are typical feed additives. The relative bioavailability value (RBV) describes the nutritional value of HMTBA relative to DLM and is important for adequate, precise, and cost-effective broiler nutrition. The current broiler feeding trial revealed an average RBV of 63% compared to DLM and the inclusion of an internal standard into the experimental design allowed for validation of the methodological approach. Evaluation of the utilization of supplemental Met sources for Met+Cys deposition in body protein provided further evidence for a higher efficiency and, thus, nutritional value of DLM over HMTBA.p < 0.05). Across all performance parameters, the RBV of HMTBA was 63% and that of DLM65 was 58%. All RBV estimates of HMTBA and DLM65 were significantly lower than 88% (p < 0.05). Cumulative efficiency of DLM for Met+Cys deposition in body protein was higher than that of HMBTA at any dose, confirming the determined RBV. Using DLM65 as an internal marker allowed for validation of the methodology.Knowledge about the nutritional value of methionine sources is highly important for their appropriate application in terms of animal and economic performance. Therefore, a broiler feeding trial was conducted to determine the relative bioavailability value (RBV) of DL-2-hydroxy-4-methylthio butanoic acid (HMTBA) compared to DL-methionine (DLM). DLM diluted to 65% purity (DLM65) served as the internal standard, with a known RBV of 65%. A total of 1920 d-old male broilers were used in the three-phase feeding trial comprising 16 treatments including a basal, Met+Cys-deficient diet and 5 graded DLM, HMTBA, or DLM65 levels. Growth performance and carcass quality data were subjected to multi-exponential regression analysis. Increasing levels of any Met source significantly improved all performance parameters compared to the negative control ( Supplemental methionine (Met) sources are commonly used to precisely meet the sulphur amino acid requirements of broilers. The global production capacity for supplemental Met sources is estimated to be >1 million tons, from which the majority is supplied as dry DL-methionine  followed by liquid DL-2-hydroxy-4-methylthio butanoic acid  .Various publications and literature reviews indicated an RBV of about 65% for HMTBA compared to DLM in broilers on a product-to-product basis ,4,5,6. HStill, the experimental setup has been a matter of discussion. Liu et al.  and AgosThe experiment was conducted according to the guidelines of the Animal and Human Welfare Codes/Laboratory practice codes in the Netherlands. The protocol was approved by the Ethics Review Committee under project number AVD246002016450. The experiment was conducted in the facilities of Schothorst Feed Research, 8200 AM Lelystad, The Netherlands.2) had one feeder, a line of drinking nipples, and wood shavings as bedding material. Ambient temperature was gradually decreased from 34 °C at arrival of chicks to 20 °C at 35 days of age. Light was continuously on for the first 24 h to give birds the opportunity to readily find feed and water. After that, the light schedule was 22L:2D during one day, and then changed to 8L:4D:10L:2D during the remaining experimental period, complying with the EU legislation of a minimum of six hours of darkness from the second day onwards [A total of 1920 day-old male Ross 308 (average BW: 39.1 ± 0.46 g) were allocated to 96 floor pens of 20 broilers each. Each pen (2 m onwards .Birds and feed were weighed at day 0 (placement) and at the end of each feeding phase at days 11, 28, and 35, allowing for calculation of body weight gain (BWG), feed consumption (FI), and feed conversion ratio (FCR). On day 35, two birds per pen, which were close to the average BW of the pen, were selected for carcass evaluation and individually weighed. The carcasses were chilled for 4 h before being cut up. Carcass weight was defined as plucked, bled, and eviscerated carcasses without head, neck, and feet. Carcass yield (CY) was expressed as percentage of BW. Breast meat weight included both musculus pectoralis major and musculus pectoralis minor (without skin). Breast meat yield (BMY) was expressed as percentage of BW.®, Evonik Operations GmbH, Essen, Germany; min. 99% DL-Methionine), HMTBA , or DLM65   . Starch jk is the dependent variable, µ is the overall mean, Blockj is the block effect (j = 1…6), Treatmentk is the effect of treatment (k = 1…16), and ejk is the residual error.Raw data were evaluated for outliers per measurement period and significant outliers (outside the range of mean ± 2.5 times SD) were excluded from statistical analysis. If at least one of the response parameters FI, BWG, or FCR was identified as an outlier, the entire record for that experimental unit was excluded. Accordingly, one replicate of treatment 7 was excluded. The experimental data were analyzed by ANOVA using Genstat for Windows (17th version). Treatment means were compared by least significant difference, as shown in the following model:For the RBV determination of HMTBA and DLM65 compared to DLM, data were analyzed by simultaneous multi-exponential function  using Gep ≤ 0.05 were considered statistically significant, whereas 0.05 < p < 0.10 was considered a trend.Data are presented as means. Values with max is asymptotic maximum response at infinite intake, b is Y-intercept or response to zero intake, c is the parameter related to the inflection point or shape, and k is the parameter related to the scale of the data.Met+Cys deposition estimates were used for the determination of the marginal and cumulative efficiency of Met sources. To estimate the deposition of Met and Cys in body protein, concentrations of these amino acids in broiler body protein are required. As no whole body analyses were included in this study, average concentrations of 3.5 g/kg Met, 2.8 g/kg Cys, and 6.3 g/kg Met+Cys in body weight were assumed, respectively. These concentrations were obtained from Khan , who exaWhile cumulative efficiency was determined by relating the Met+Cys deposition above basal treatment against product intake, marginal efficiency was using 1 derivation of the above 4-parameter logistic equation:Analyzed values of amino acids in the experimental diets from all phases were in close agreement with the calculated values . Recoverp < 0.05) and reduced FCR by 22, 22, and 23% (p < 0.05) for DLM, HMTBA, and DLM65, respectively. Moreover, birds of these treatments achieved 5–7% higher BW than suggested by the broiler breeder [p < 0.05) and BMY by 62, 60, and 63% (p < 0.05) for DLM, HMTBA, and DLM65, respectively. Moreover, responses reported in p < 0.05). These relative responses confirm that the main pre-requisites for an appropriate RBV determination were successfully met such as: (1) a common starting point  where dietary Met+Cys was clearly deficient, (2) three or more supplementation levels of each test product were included in the study, and (3) graded supplementation of the products resulted in graded dose–responses [Increasing levels of either DLM, HMTBA, or DLM65 improved growth performance  and carc breeder  at the hesponses . The latesponses  and Ullresponses  drew sucesponses . Responsesponses .p < 0.05) as this is the basis for comparison. HMTBA contains a minimum of 88% methionine hydroxy analogue, while the remainder is water and impurities. Met sources were supplemented on a product basis and, therefore, an RBV of maximal 88% could be expected. Based on all the evaluated parameters, the average RBV of HMTBA and DLM65 compared to DLM was 63% and 58%, respectively. The average RBV of 58% for DLM65 was close to the expected value of 65% (because of dilution to 65% purity), providing evidence for the appropriateness of using a simultaneous dose–response approach to determine the RBV of nutrient sources. Indeed, there was a difference of 7% points, but the results of this study fit well to earlier findings [p < 0.05).One objective of this study was to determine the RBV of HMTBA and DLM65 relative to DLM and, as outlined above, all respective requirements were met. Responses to increasing levels of DLM, HMTBA, and DLM65 and respective regression analyses are shown in findings ,12,13  as liquid HMTBA. In terms of cumulative utilization, DLM outperformed HMTBA at any supplementation level, until maximal Met+Cys deposition was achieved with 5991 mg HMTBA/bird. At this level, curves of both products converged.