Indirect coculture of HL‐1 cells with LPS‐stimulated 3T3‐L1 conditioned medium (CM) significantly increased IL‐6, TNF‐α and TGF‐β1 expression and decreased SERCA2a and p‐PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca2+ handling dysfunction. MET attenuated the RAP‐induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF‐dependent EAT remodelling and AF vulnerability by MET.Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF‐dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6‐week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP‐induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa‐B (NF‐κB) phosphorylation; up‐regulated interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α) and transforming growth factor‐β1 (TGF‐β1) levels in LA and EAT; decreased peroxisome proliferator‐activated receptor gamma (PPARγ) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro The aims of this study were as follows: (a) to determine the impact of AF on EAT remodelling and the role of AF‐dependent EAT remodelling in atrial fibrosis and AF maintenance; (b) to evaluate whether MET reverses AF‐dependent EAT remodelling.22.1This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Committee governing the Ethics of Animal Experiments of the Wuhan University. Dogs were anesthetized with 3% sodium pentobarbital and ventilated with a positive‐pressure respirator . The initial dose of sodium pentobarbital was 1 mL/kg and an additional 2 ml/h was administered. All efforts were made to minimize suffering.2.2Eighteen male beagle dogs  were supplied by the Center of Experimental Animals at the Medical College of Wuhan University. Animals' age and bodyweight before after interventions are presented in Table 2.3AF was induced in canine using long‐term RAP.2.4Standard ECG limb leads were recorded at the baseline before pacemaker implantation and after 6‐week RAP. Left and right‐sided thoracotomies were performed at the fourth intercostal space. Multielectrode catheters were secured to allow pacing and recorded from the left and right atrial appendage (LAA and RAA) and left and right atria (LA and RA). The electrophysiological parameters, including effective refractory period (ERP), ERP dispersion, window of vulnerability (WOV) and AF duration, were measured as previously described.After 6 weeks, electrophysiological parameters were remeasured, anaesthetized animals were killed and hearts were removed. Left atrial posterior wall and adjacent EAT samples were collected and immersed in 4% paraformaldehyde or snap‐frozen at −80°C for further analysis. Fasting blood samples were collected at the baseline and before measuring electrophysiological parameters and stored at −80°C for further analysis.2.5TM) were cultured and maintained in Dulbecco's modified Eagle's medium (Gibco) with 25 mmol/L glucose, supplemented with 10% FBS and 100 U/mL penicillin‐streptomycin. HL‐1 and 3T3‐L1 were incubated in a humidified atmosphere with 5% CO2 at 37°C.Murine atrial myocytes, HL‐1, were provided by Dr Li  with the permission of Dr Claycomb . Cells were cultured with Claycomb Medium supplemented with 10% foetal bovine serum (FBS), 100 U/mL penicillin/streptomycin, 0.1 mmol/L norepinephrine and 2 mmol/L L‐glutamine. Mouse 3T3‐L1 pre‐adipocytes  and cultured in fresh FBS‐free medium for another 24 hours. The conditioned medium (CM) of 3T3L1  was collected from the four groups after centrifugation . When the plated HL‐1 confluence was 70‐80%, 200 µL of each CM was added to the HL‐1 medium for 48 hours.LPS and MET treatment affected the concentration of adiponectin (APN) in 3T3‐L1 CM. To validate the role of APN in modulating the interaction between HL‐1 and 3T3‐L1, APN (1 µg/ml)  was added to the HL‐1 medium when treated with 3T3L1 LPS CM for 48 hours. A schematic diagram of the in vitro experiments is shown in Figure After the indicated experiments, the supernatants of intracellular proteins were collected with their appropriate reagent and stored at − 80°C for subsequent assays.2.73T3‐L1 LPS + MET conditioned medium was neutralized by an adiponectin antibody . Initially, 2 μg of APN antibody was added to 1 mL of CM and agitated at 35‐50 rpm at 37°C for 1 hour. Then, a 20 μL of resuspended Protein A/G PLUS‐Agarose  was added to the CM. Next, the mixture was incubated and rotated at 4°C overnight. The supernatant  was collected by centrifugation  and used to treat HL‐1 cells.To assess the potency of the antibody neutralization, the beads were washed with PBS and collected by centrifugation. After washing, the samples were dissolved in a 5 × sodium dodecylsulphate sample buffer by boiling. The immunoprecipitate and supernatants were then separated by sodium dodecyl sulphate‐polyacrylamide gel electrophoresis and immunoblotted using APN antibody.2.8LA and EAT samples were fixed in 4% paraformaldehyde, embedded in paraffin and sliced into 5‑μm‐thick sections. Adipocyte size was examined by calculating its Feret's diameter from haematoxylin and eosin (H&E)‐stained sections.2.9ROS content in the LA and EAT tissue was detected by staining the frozen slices of fresh tissue with dihydroethidium  following the manufacturer's instructions. In brief, all sections were stained by DHE  in the dark, briefly washed and analysed with a fluorescence microscope. The generation of red fluorescence was used to measure ROS content. For each section, DHE fluorescence was quantified by the mean fluorescence intensity of 5 optical fields using Image‐Pro 6.2 software.2.10Quantitative detection of interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α), transforming growth factor‐β1 (TGF‐β1), adiponectin (APN) plasma concentration, LA myocardium and EAT were performed using a canine‐specific enzyme‐linked immunosorbent assay (ELISA) kit following the manufacturer's protocol . In brief, 100 mg of tissue from the LA or EAT was minced and homogenized in 1 mL RIPA lysis buffer (Beyotime). The resulting suspension was sonicated with an ultrasonic cell disrupter to obtain a clear solution. The homogenates were centrifuged for 5 minutes at 10 000 ×g. Supernatants were collected and either assayed immediately or aliquoted and stored at ≤ −20°C.HL‐1 and 3T3‐L1 cell medium supernatants were collected after centrifugation. APN and TNF‐α concentrations were detected using mouse‐specific ELISA kits according to the manufacturer's protocol.2.112+ homeostasis, cytosolic Ca2+ was measured with Fluo‐4 AM  according to the manufacturer's instructions. In brief, HL‐1 cells in a 6‐well plate were treated with 3T3L1 CM for 48 hours and then washed with PBS and incubated with 1 μmol/L Fluo‐4 AM for 30 minutes in PBS at room temperature (24°C). They were washed three times with PBS and incubated for an additional 15 minutes in the absence of Fluo‐4AM. The fluorescence intensity was determined at an excitation wavelength of 485 nm and an emission wavelength of 525 nm with a fluorescence microplate reader (Biotek Synergy H4). Representative pictures were taken with a fluorescence microscope.To detect the effect of 3T3 L1 CM on HL‐1 cytosolic Ca2.12Free fatty acid (FFA) and triglyceride (TG) levels in EAT were measured by biochemical kits (Jiancheng) with the kit instructions.2.13Western blot and qPCR were conducted following standard procedures as described in the Online Supplement. The primer sequences used for real‐time PCR are listed in Table 2.14https://www.r‐project.org/). All values are expressed as mean ± SD. Statistically significant differences between means were assessed by ANOVA and Tukey's honestly significant difference test for comparisons between two groups. P < .05 was considered statistically significant.Statistical analyses were performed using R‐3.4.3 (33.1P < .05).ERPs at the LA, RA, LAA and RAA are shown in Figure P = .01); MET, however, reversed the increased dispersion   Figure .P < .01). MET significantly attenuated the increase in AF duration ; however, AF duration in the RAP + MET group remained higher than that in the sham‐operated group (P = .03) ; However, MET reduced AF inducibility from 84.16% to 63.75% (P = .02) , which was attenuated by MET WOV   following burst pacing compared to that in the sham‐operated group  Figure . AF indu) Figure . In addi) Figure . These d3.2P < .01). MET significantly reduced atrial fibrosis   Figure .P < .05)  Figure . Represe) Figure  and S3.P < .01) in the RAP group than that in the sham‐operated group; and MET effectively decreased the FFA and TG levels in EAT   Figure ,G.3.3P < .05)     Figure , the pho) Figure . Consist) Figure .P < .05)  . No significant difference in APN level in the LA among the three groups was observed, even though MET tended to increase the APN level in the LA (P > .05) . Compared to the plasma concentration in the sham‐operated group, after 6‐week RAP, IL‐6 plasma concentration increased and APN plasma concentration decreased ; MET reversed these changes   in the EAT, LA and plasma of each group. RAP significantly increased IL‐6, TNF‐α and TGF‐β1 concentration in EAT and LA; MET attenuated the RAP‐induced expression of IL‐6, TNF‐α and TGF‐β1  Figure ,G. In co) Figure , and MET) Figure . At the ) Figure A,C. TNF‐) Figure B,D.3.4P > .05) , but MET significantly up‐regulated PPARγ protein expression (P < .01)  Figure .There wa) Figure , indicatP < .01). MET attenuated the RAP‐induced decrease of AdipoR1 expression in LA and EAT    Figure .P < .05)   Figure ,G. Pre‐t) Figure ,G. As sh3.6P < .05)   Figure .P > .05)  . Phospho‐NF‐κB p65 (Ser536), IL‐6 and TNF‐α levels in the MET CM group were still lower than those in the Control CM group (P < .05). These results demonstrated that MET increases adipocyte APN production and secretion and plays a critical role in suppressing the adipocytes and cardiomyocytes inflammatory interaction.There was no significant difference in HL‐1 intracellular PPARγ and APN expression among all treatment groups  Figure ,H. Howev) Figure ,H. Infla3.72+ homeostasis is critical for cardiomyocyte function. To detect the effect of adipokines on Ca2+ homeostasis in HL‐1 atrial myocytes, the cytosolic Ca2+ of HL‐1 cells were detected with Fluo‐4 AM after 3T3‐L1 CM treatment. Cytosolic Ca2+ content was indicated by Fluo‐4 AM fluorescence intensity. HL‐1 cells treated with LPS CM showed cytosolic Ca2+ overloading with the highest fluorescence intensity among the four groups (P < .05)   Figure . Compare) Figure .2+ handlings that were responsible for regulating the Ca2+ homeostasis in HL‐1 cells. The sodium‐calcium exchanger (NCX) is mainly responsible for Ca2+ extruding from the cell to prevent overloading of intracellular stores. Phospholamban （PLN） is an inhibitory protein that controls the reuptake of Ca2+ into the sarcoplasmic reticulum(SR) by the sarcoplasmic reticulum Ca2+‐ATPase2a (SERCA2a). Phosphorylation of PLN dissociates the molecule from SERCA and stimulates the reuptake of Ca2+ into the SR. As shown in Figure P > .05), while the phosphorylation level of PLN and SERCA2a expression were significantly decreased under LPS CM    Figure ,G. In ad) Figure . These d3.82+ homeostasis. To determine whether the decrease in APN contributed to atrial myocyte inflammatory response and calcium dyshomeostasis, APN (1 µg/mL) was added when HL‐1 was treated with 3T3‐L1 LPS CM. As shown in Figure 2+ handling, APN reversed the decrease in PLN phosphorylation and SERCA2a down‐regulation induced by LPS CM . In term of inflammatory cytokine expression, APN attenuated LPS CM treatment induced IL‐6, TNF‐α, and TGF‐β1 up‐regulation .The APN concentration in 3T3‐L1 LPS CM was lower than that in LPS + MET CM and MET CM. LPS CM treatment increased the inflammatory cytokine expression in HL‐1 cells and disturbed CaM Figure   down‐regulation and inflammatory cytokine up‐regulation in HL‐1 cells. However, 3T3‐L1 LPS + MET CM with a high APN concentration or APN treatment reversed these alterations. A previous study demonstrated that APN decreases the expression of inflammation response genes and increases the expression of SERCA2a in H9C2 cells.2+ reuptake decrease during AF.2+ homeostasis by APN may provide valuable information to treat AF.APN may have an impact on cytosolic CaMET may regulate the interaction between EAT and the atrial myocardium through regulating APN production. Interestingly, MET seems to exert minute effects on PPARγ/APN expression in cardiomyocytes. PPARγ in the adipose tissue may, therefore, respond better to MET in the myocardium because of tissue specificity. Therefore, we inferred that the cardioprotective effects of APN mainly arise from the adipose tissue and not from the myocardium. MET not only exhibits an anti‐inflammatory effect by inhibiting ROS/NF‐κB signalling during AF, but also via the APN system.4.4Atrial remodelling is critical for the pathogenesis of atrial fibrillation.In addition, MET can modulate several signalling pathways including AMP‐activated protein kinase signalling (AMPK), which has a potential role in cardiac electrophysiology and arrhythmia.4.5This study had several limitations. Firstly, although HL‐1 cells are the most commonly used atrial cardiomyocyte cell line, HL‐1 cells represent artificial cardiomyocytes. Secondly, the effect of MET on the cellular and molecular electrophysiology of cardiomyocytes was of interest but beyond the scope of the study; thirdly, there was a lack of structural and hemodynamic data from cardiac MRI scans and the EAT volume was not measured; finally, the operation procedures may have impacted the concentration of inflammatory mediators and AF inducibility. However, as the operation procedure and operation time were similar among the three groups, our data were comparable.5RAP resulted in increased AF vulnerability and atrial remodelling, accompanied by remodelling of EAT adipokines production profiles. AF‐dependent EAT remodelling may occur, at least partially contributing to AF susceptibility. MET reduced AF vulnerability and atrial fibrosis, up‐regulated PPARγ/APN expression in EAT and down‐regulated pro‐inflammatory adipokines expression in LA and EAT. MET may be a potential therapeutic option to prevent and treat AF.The authors report no relationship that could be construed as a conflict of interest.Biao Li and Qiming Liu planned and designed the experiments. Biao Li, Baojian Zhang, Fan Bai and Jiayi Li, and Fen Qin conducted the experiments. Biao Li, Na Liu, Chao Sun, Yichao Xiao and Tao Tu collected and interpreted the data. Biao Li drafted the article, Sunny S. Po, Qiming Liu and Shenghua Zhou revised the manuscript.The data that support the findings of this study are available from the corresponding author upon reasonable request.Supplementary MaterialClick here for additional data file.


This paper describes a method for a bilayer lipid membrane (BLM) formation using a perforated sheet along with an open chamber. Microscopic observation of the formed membrane showed a typical droplet interface bilayer. We proved that the formed membrane was a BLM based on electrical measurements of the membrane protein α-hemolysin, which produces nanopores in BLMs. Unlike the conventional approach for BLM formation based on the droplet contact method, this method provides aqueous surfaces with no organic solvent coating layer. Hence, this method is suitable for producing BLMs that facilitate the direct addition of chemicals into the aqueous phase. Bilayer lipid membranes (BLMs) are widely used as artificial cell membranes for research on plasma membranes, membrane proteins, and various membrane-associated biomolecules ,2,3,4. AThe droplet contact method is generally carried out using aqueous droplets submerged in organic solvents. Hence, DIBs are formed in organic solvents. This configuration makes it difficult to inject some chemicals, such as drug candidates; in addition, the aqueous phase from the outside impedes the fundamental studies of membrane proteins. Similarly, for the development of odorant sensors, the oil layer on DIBs inhibit the penetration of volatile compounds, which are mostly lipophilic, into an aqueous phase. The addition of chemicals and the exchange of the isolated aqueous phase can be conducted using a pumping system or superabsorbent polymer with fluidic channels connected to a BLM formation chamber ,16. The Herein, we propose a method of BLM formation involving a promising system for a chemical addition and gas absorption into an aqueous phase in contact with the BLMs. To establish such a BLM formation system equipped with an air–water interface, only a small amount of organic solvent along with an open chamber device is used. In this study, as a first proof of concept for BLM formation, as indicated in As the device material, we used a polymethylmethacrylate (PMMA) film and plate  for fabrication of the perforated sheets and an open chamber device, respectively. An amphiphobic coating reagent  was obtained from AGC SEIMI Chemical Co., Ltd.  for surface treatment of the PMMA film.sn-glycero-3-phosphocholine (DOPC), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)  were purchased as commercialized products, and n-decane  was used as the solvent for the lipid solution prepared in this study. A nanopore-forming protein α-hemolysin (αHL) was used (Merck KGaA). A concentrated stock solution of αHL (20 μM) was prepared by dissolution of αHL lyophilized powder using ultrapure water from a Milli-Q system . Ag/AgCl electrodes  were prepared in advance by dipping in a commercial bleach agent overnight. Other chemicals were obtained from Wako Pure Chemical Industries, Ltd.  and Sigma-Aldrich Co. . All reagents were used without further purification.Lipid molecules dissolved in chloroform, 1,2-dioleoyl-2 area) with a narrow through-slit, as observed in the top view of We fabricated perforated T-shaped PMMA (Acryplen) sheets with a thickness of 75 μm and pore diameters of 500, 600, 700, and 800 μm. An open chamber device made of PMMA (Acrylight) was processed into a gourd-shaped well  for surface modification of the PMMA . To estin-decane containing a lipid mixture (20 mg/mL) of DOPC and DOPE at a 3:1 weight ratio) was deposited on each side of the sheet. The component of the lipid mixture was determined according to our previous study [As shown in us study .The open chamber was completely coated with the same fluorinating agent and filled with 60 μL of a buffer solution . The perforated sheet loaded with the lipid solution was manually dipped into the buffer solution in the open chamber using tweezers. Owing to the transparency of the PMMA, we could observe the through-hole of the sheet using a microscope  from outside the chamber even when the sheet was submerged in the aqueous solution inside the chamber. In addition, we investigated the effect of fluorination of the perforated sheet on the liquid retention in the chamber and the efficiency of the BLM formation.To electrically confirm whether the membranes formed were BLMs, we added an αHL solution with a final concentration of 1–3 nM into the chamber. The ion currents passing through the BLM using the αHL were recorded with a wired in-house developed amplifier  every 1 To verify the efficacy of the PMMA fluorination, we confirmed the contact angles of the buffer solution and the lipid solution. Fluorination increased the surface tension of the droplets in either case. The fluorination provided more water-repellent properties to the PMMA surface, which achieved repellency a. The coFrom outside the chamber, we observed the through-hole of the sheet in the chamber filled with a buffer solution, as shown in Because the PMMA surface is hydrophobic, an aqueous solution without a surfactant does not spread when applied to the narrow PMMA-enclosed spaces. However, leakage of the buffer solution from the slit at the chamber bottom is often encountered when a bare PMMA sheet and chamber are used. It seemed that the leakage was caused by a decrease in the surface tension of the buffer solution owing to the amphiphilic property of the lipid molecules. As shown in the upper image of We further confirmed the formation of BLM by electrically observing the incorporation of the nanopore-forming protein, αHL. As schematically shown in the upper image in We obtained positive signals caused by αHL (1–3 nM) in BLMs with several pore diameters (500–800 μm). We also defined the criteria of positive signals as stepwise ion current changes, as shown in n-decane, was used with our proposed method. Therefore, it is expected that the produced solution surface will not be covered with an organic solvent layer. In case that entire n-decane solution (1 μL) spreads in the top surface of the chamber (24.7 mm2), the expected thickness of the n-decane layer on the buffer solution is about 40 μm at a maximum, which would quickly disappear due to its volatility. In the actual experiment, we observed that the n-decane droplet mostly remained on the T-shaped perforated sheet due to the fluorination when we dipped the sheet in the buffer solution. Therefore, even if the n-decane layer formed on the surface of the buffer solution, it would soon volatilize and eventually an air-water interface would appear. Because the exposed air–water interface will help the penetration of volatile compounds from outside into the aqueous phase, our proposed system is potentially adequate for odorant sensing with olfactory receptors reconstructed in a BLM system [Unlike a conventional method for producing DIBs, only a small amount of organic solvent, 1.0 μL of M system . AlthougM system  will proWe demonstrated a BLM formation by dipping an acrylic perforated sheet partially coated with a lipid solution into an aqueous solution in an open chamber. For a highly reproducible BLM formation, the perforated sheet and open chamber required a surface fluorination. The pore diameter of the perforated sheet ranged from 500 to 800 μm (thickness of 75 μm) and met the requirement for BLM formation. The authenticity of the BLM formation was validated through a nanopore formation with αHL. Owing to the use of a small amount of organic solvent in the BLM formation method, it is expected that the surfaces of the aqueous solutions will become exposed to ambient air. Hence, we consider this configuration of the BLM system to be suitable for additional chemical injection from the outside and the absorption of airborne molecules from the atmosphere into the liquid phase.


The serum concentrations of TARC in the IgG4-RD patients were significantly higher than those of the pSS patients and HCs. The serum TARC concentration of the IgG4-RD group was positively correlated with the IgG4-RD responder index (IgG4-RD RI) score and with the number of organs involved, but it was not correlated with the serum IgG4 level or eosinophil number in the IgG4-RD patients’ peripheral blood. The patients who had lung involvement had higher serum TARC concentrations. In vitro, TARC clearly induced the formation of plasmablasts from the IgG4-RD patients’ peripheral blood mononuclear cells. Collectively, our data suggest that a systemic increment of TARC may contribute to the development of IgG4-RD through an aberrant induction of plasmablasts.High serum concentrations of thymus and activation-regulated chemokine (TARC) are observed in allergic diseases such as atopic dermatitis and bronchial asthma. Frequent allergic symptoms have been reported in patients with IgG4-related disease (IgG4-RD). We investigated the pathogenic role of TARC as a biomarker in IgG4-RD patients. We evaluated the serum concentrations of TARC from 29 IgG4-RD patients, 28 primary Sjögren syndrome (pSS) patients, and 23 healthy controls (HCs) by enzyme-linked immunosorbent assay (ELISA). We analyzed the correlations between the TARC concentrations and the subjects’ clinical parameters. To investigate the biological effect of TARC on the pathogenesis of IgG4-RD, we evaluated the  TARC has affinity as a ligand for the C-C chemokine receptors CCR4 and CCR8, which are predominantly expressed by Th2 cells, and TARC induces Th2-dominant inflammatory reactions4.TARC (thymus and activation-regulated chemokine), also known as C-C Motif chemokine ligand 17 (CCL17), is expressed in the thymus and is produced by dendritic cells, endothelial cells, keratinocytes, and fibroblasts5. The measurement of serum TARC concentrations has already been clinically applied as a useful marker reflecting the disease activity of atopic dermatitis6.TARC has an important role in allergic diseases such as atopic dermatitis and bronchial asthma. High serum concentrations of TARC are observed in patients with atopic dermatitis, and its concentration is closely related to disease activity7. It has been reported that the bronchial epithelium of patients with bronchial asthma expresses TARC8. The blockade of the TARC/CCR4 axis by using anti-TARC antibodies and anti-CCR4 antibodies was reported to attenuate airway inflammation in a murine model of asthma10. In light of these reports, TARC has been suspected to be involved in the pathogenesis of allergic diseases, and TARC may thus have potential as a therapeutic target.The concentration of TARC is also reported to be elevated not only in serum but also in sputum of patients with bronchial asthma11.Immunoglobulin G4-related disease (IgG4-RD) is a relative new disease entity which is characterized by the elevation of the serum IgG4 concentration, tumor-like swelling of involved organs, and the infiltration of IgG4-positive plasma cells. Multiple organs are involved, such as the salivary and lacrimal glands, thyroid, lymph nodes, pancreas, bile duct, kidney, and lung; tissue fibrosis and sclerosis occasionally cause serious organ damage12. A subset of IgG4-RD patients suffer from allergic diseases, and they also show elevated serum IgE levels and eosinophil counts14. Conversely, elevated serum IgG4 concentrations are also observed in allergic diseases16. Th2 cytokines have been thought to be responsible for the production of IgG4. Th2-related mRNA expressions such as those of interleukin (IL)-4, IL-5, IL-10, and GATA-3 were elevated on CD4+ T cells from patients with IgG4-RD17. Elevated mRNA expressions of IL-4, IL-5 and IL-10 were also observed in labial salivary glands (LSGs) of patients with IgG4-RD18. The numbers of Th2 cells in peripheral blood were increased in IgG4-RD patients who had concomitant allergic diseases19.The pathogenesis of IgG4-RD is not yet clear. Both an allergic and an autoimmune disorder have been speculated to be responsible for the pathogenesis18. However, the systemic condition and the effects of TARC in IgG4-RD are not known. We conducted the present study to determine the relationships between serum TARC and several clinical parameters of IgG4-RD patients, and we performed an in vitro experiment to evaluate the underlying effects of TARC on the introduction of plasmablasts.Based on the above-described findings, we hypothesized that TARC is involved in the pathogenesis of IgG4-RD through the activation of Th2 cytokines. In fact, an increased mRNA expression of TARC in the local site of LSGs has been reported in IgG4-RD patientsThe subjects’ serum concentrations of TARC were analyzed by ELISA. All of the serum samples from the IgG4-RD patients were obtained on the day before any type of immune-suppressive therapy (including glucocorticoids) was initiated. The ELISA revealed that the serum concentrations of TARC were significantly higher in the IgG4-RD group (mean 486.1 pg/ml) than those of the pSS and HC groups at mean 121.3 pg/ml and 254.2 pg/ml, respectively Fig. .Figure 1To investigate the usefulness of the serum concentration of TARC for the diagnosis of IgG4-RD, we then generated receiver operating characteristics (ROC) curves for TARC to distinguish the patients with IgG4-RD from HCs or the patients with pSS. The area under the curve (AUC) for IgG4-RD vs HCs was 0.81 and the cut-off value of TARC was 296.5 pg/dl, with relatively high sensitivity (82.8%) and specificity (73.9%) Fig. . AdditioTo clarify the functional significance of TARC in IgG4-RD, we further examined the correlation between the serum concentration of TARC and clinical parameters in the patients with IgG4-RD including the serum IgG4, IgG, and IgE concentrations, the eosinophil count, the IgG4-RD RI score, the number of organs involved, and allergic history. Our analyses revealed that the IgG4-RD patients’ serum concentrations of TARC were positively correlated with the IgG4-RD RI score and the number of organs involved, but not correlated with the serum IgG4 level or the eosinophil number in peripheral blood Fig. . No diffWe analyzed the relationship between the serum TARC concentration and the organs involved. Of all of the organs shown in Table The number of organs involved positively correlated with TARC concentration. Because of that, the number of organs involved can affect the result that the high concentration of TRAC was observed in patients with lung involvement. To determine whether the number of organs involved as a predictor for lung involvement or not, we conducted the univariate analysis. However, the number of organs involved didn’t show significance as a predicting factor for lung involvement . Taken together, we could not find evidence that widespread disease is a predictor of lung involvement in our cohort. Moreover, there is no significant association between lung involvement and allergic symptoms by using Fisher’s exact test .Since our data showed that the serum concentration of TARC was elevated in the patients with IgG4-RD and correlated with the IgG4-RI score and the number of organs involved, we hypothesized that a systemic increment of TARC might contribute to the development of IgG4-RD.in vitro experiments using PBMCs from the patients with IgG4-RD. The isolated PBMCs were incubated with or without TARC for 7 days. We then used flow cytometry to analyze the percentage of follicular helper T (Tfh) cells (CD45RA− CXCR5high among CD4 + T cells) and plasmablasts (CD38+ CD27+ among CD3− CD19+ B cells) after stimulation with TARC. We observed that there was no significant difference in the induction of Tfh cells between the culture conditions with and without TARC 8, CCL2, CCL5, and CCL11 were significantly lower in patients with pSS than healthy controls20. Furthermore, the systemic manifestations of SS were reported to be low21, whereas IgG4-RD systemic organ involvement was reported to be frequent22. These clinical characteristics of each disease may explain the differences observed in serum TARC concentrations between IgG4-RD and pSS groups. Taking the past and present findings together, we speculate that a systemic elevation of TARC might be responsible for “the dissemination in space-like” nature of IgG4-RD which affects multiple organs.The local mRNA expression of TARC was elevated in LSGs of patients with not only IgG4-RD but also SS23. However, a tissue biopsy is an invasive procedure, and there are some lesions that are difficult to perform a biopsy for diagnosis of IgG4-RD. It is thus desirable to establish a noninvasive way to increase the pre-test probability for diagnosis of IgG4-RD. With the use of TARC >296.5 pg/dl for distinguishing IgG4-RD from the healthy individuals in the present study population, the sensitivity was relatively high (82.8%). However, it must be kept in mind that TARC is associated with other diseases such as atopic dermatitis and bronchial asthma7.The ROC curve generated by the ELISA results in the present study showed that TARC may be useful as a marker to distinguish individuals with IgG4-RD from healthy persons. The diagnosis of IgG4-RD presents some limitations. The definite diagnosis of IgG4-RD requires a biopsy, which is useful to detect characteristic findings such as lymphoplasmacytic infiltrations with a predominance of IgG4-positive plasma cells in the affected tissue8. The pathogenesis of IgG4-related pulmonary disease (IgG4-PD) is not yet known, but a possible relationship between asbestos exposure and IgG4-PD has been reported24. In light of these reports, it is possible that chronic inflammation in the respiratory system may be involved in the TARC-mediated pathogenesis of IgG4-RD.Interestingly, we observed that the serum concentration of TARC was elevated in the patients with lung involvement. In patients with bronchial asthma, TARC has been reported to be elevated not only in serum but also in the bronchial epitheliumOur analyses also showed that the serum TARC concentration in the IgG4-RD patients were not significantly different between the patients with and without allergic symptoms. TARC might be involved in the specific pathogenesis of IgG4-RD independently of the presence of allergy.in vitro experiments showed that TARC induced plasmablasts from PBMCs isolated from the patients with IgG4-RD. Tfh cells are reported to be necessary for B-cell differentiation including plasmablasts in the germinal center (GC)25, and hyperplasia of the GC with the infiltration of Tfh cells is observed in the involved organs of IgG4-RD patients26. Plasmablasts are thought to be play a central role in the developing pathophysiology of IgG4-RD. The number of peripheral plasmablasts in IgG4-RD patients was reported to be higher than those of healthy controls28. Another study revealed that peripheral plasmablasts show oligoclonal expansion, and their number decreases with clinical improvement after B-cell depletion therapy using rituximab29. Taking these findings together, we speculate that a TARC-mediated induction of plasmablasts might play an important role in the development of IgG4-RD. However, our investigation could not clarify the mechanisms by which TARC induces plasmablasts.Our present 30. The same study showed that Tfh2 cells in vitro induced the differentiation of naïve B cells into plasmablasts in IgG4-RD patients30. The expression of CCR4 (a receptor of TARC) was reported in IgG+ B cells, and TARC induced B-cell migration31. Although we have not analyzed Tfh2 subsets since no increase in Tfh was observed in the culture condition with TARC, we speculate that TARC may skew B cells toward to plasmablasts, directly. Of note, the percentage of plasmablasts from healthy controls was not significantly different between the cultures with and without TARC. This result suggests that plasmablasts from patients with IgG4-RD may have increased sensitively to TARC. Further research is required to elucidate the precise mechanisms underlying the induction of plasmablasts by TARC.It is notable that the numbers of peripheral Tfh2 cells, one of the subsets of Tfh cells, are reported to expand in patients with IgG4-RD and correlate with disease activityIn conclusion, our data suggest that a systemic elevation of TARC may be involved in the development of IgG4-RD through an aberrant induction of plasmablasts. TARC could become a novel therapeutic target of IgG4-RD.23.We analyzed blood samples from individuals treated at Nagasaki University Hospital  during the 8-year period from 2009 through 2017. A total of 29 patients with IgG4-RD , 28 patients with primary Sjögren syndrome (pSS) , and 23 healthy controls (HCs)  were included. There is no significant difference in the disease duration between IgG4-RD patient group and pSS patient group . Clinical features and laboratory test data were collected from medical records. All of the IgG4-RD patients fulfilled the comprehensive diagnostic criteria for IgG4-RD (2011)32. Rhinosinusitis, bronchial asthma, and drug-allergy were defined as allergic symptoms13.Organ involvement was determined by a review of the patient’s history, physical examination findings, imaging results, laboratory studies, and tissue biopsies. Imaging included ultrasound, computed radiography, computed tomography (CT), magnetic resonance imaging, gallium scintigraphy, and positron emission tomography/CT. The demographic characteristics of patients with IgG4-RD are summarized in Table 33.All of the pSS patients fulfilled the 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren’s SyndromeThis study was performed in accordance with the Declaration of Helsinki and all of the patients and HCs gave their informed consent to participate in the study and have their data published. The study was approved by the Institutional Review Board of Nagasaki University .The TARC concentration in serum from the human blood samples was measured by a Human TARC enzyme-linked immunosorbent assay (ELISA) kit . Blood samples were centrifuged within 30 min at 1500 rpm at 4 °C for 5 min, and the liquid phase of the sera was stored at −80 °C until use. Each assay was performed in triplicate independently.We isolated peripheral blood mononuclear cells (PBMCs) from the blood samples using density-gradient centrifugation on Sepmate and RosetteSep DM-L Density Medium . Isolated PBMCs were stained for flow cytometry with antibodies (Abs) against CD3 , CD4 , CD45RA , CXCR5 , CD19 , CD27 , or CD38  for 30 min at 4 °C. Stained cells were analyzed by multiparameter flow cytometry  using FlowJo ver. 10 software (BD Biosciences).5) in RPMI 1640 medium with 10% fetal bovine serum  plus penicillin/streptomycin were incubated for up to 7 days at 37 °C (in 5% CO2) in 48-well round-bottomed plates with or without human recombinant TARC . After stimulation with TARC, the PBMCs were harvested and stained for flow cytometry. The resulting data are representative of four independent experiments.PBMCs were isolated using density-gradient centrifugation on Sepmate and RosetteSep DM-L Density Medium. The isolated PBMCs  for more than two groups. Spearman’s correlation coefficient with two-tailed p-values was determined in the analysis of correlations. A receiver operator characteristic (ROC) curve was described to distinguish IgG4-RD from HC by the levels of TARC. Fisher’s exact test was used to compare categorical variables. To determine the number of organ involvement as a predictor for lung involvement, univariate analysis was conducted by Wilcoxon’s test. All statistical analyses were performed in GraphPad Prism ver. 7.0  or JMP Pro 14 software . P-values <0.05 were considered significant .


An essential requirement exists for a single exhaustive source of anthropometric databank in Iran. Available information about Iranian bodily dimensions is not applicable to the general population due to the sample of people investigated. This study aimed to present the first Iranian anthropometric databank by estimation.After a systematic review, 24 relevant sources of information were found and included. No time limit was considered. The method of Rapid Anthropometrics Scaled for Height was used.st, 5th, 25th, 50th, 75th, 95th, and 99th were calculated, stratified by sex.Overall, 36 bodily dimensions were estimated, for which the seven percentiles of 1The resulting tables can be claimed as the most representative anthropometric databank for Iranian general 20–64 yr population now. Data are suitable for practical purpose and are applicable in both occupational and community setting. The main principle of ergonomics is to design the activity to match the characteristics of the user. On the other word, if an instrument, a workplace or a system is intended for human use, then its design should be based upon the characteristics of its human users. This principle, so-called “user-centered design”, could result in many enhancements in terms of functional efficiency, comfort, health, safety and quality of life . In contHowever, human beings are not all the same. Their anthropometric , physiological, Biomechanical and psychological characteristics differ from one to another. In addition, factors such as age, sex, race, job, diet, physical exercise and so on influence human body dimensions , 2. ThesBecause of the above mentioned human inter and intra-individual changes, the majority of developed and developing countries have produced their own anthropometric databank. Some examples include anthropometric data of Asian , 4, AfriSince anthropometric surveys are often costly and time-consuming, ergonomists prefer to prepare anthropometric databases based on more simple methods such as estimation rather than measurement. One of the most widely employed methods of estimation is that proposed by Barkla  and RoebAn important need for appropriate anthropometric source on Iranian body characteristics exists among national ergonomists and designers. Recently, existed anthropometric data for Iranian population is not sufficiently comprehensive with respect to both sample size and representativeness . Therefom was calculated using following formula  was obtained as arithmetic mean of em (s) and scaling ratios (Es) related to the standard deviations. Calculations were made as a function of sex.Then, scaling ratio  and health problems  or conducted on children were excluded. Repeated datasets (i.e. same data published in more than one source) were also removed. As presented in For the target population, we have selected recent nationwide surveillance on noncommunicable disease risk factors, which in our knowledge is the best representative of the general population in terms of sample size, age, sex, socio-economic, and geographical distribution. Using a random multistage cluster sampling method, the study measured, among other variables, stature of 79,611 Iranian rural and urban citizens  aged from 20 to 64 yr with standardized and calibrated instruments  have been completely observed by the authors.


In this work, the failure process of non-corroded and corroded reinforced concrete (RC) columns under eccentric compressive loading is studied using the acoustic emission (AE) technique. The results show that reinforcement corrosion considerably affects the mechanical failure process of RC columns. The corrosion of reinforcement in RC columns leads to highly active AE signals at the initial stage of loading, in comparison to the non-corroded counterparts. Also, a continuous AE hit pattern with a higher number of cumulative hits is observed for corroded RC columns. The spatial distribution and evolution of AE events indicate that the reinforcement corrosion noticeably accelerates the initiation and propagation of cracking in the RC columns during compressive loading. The AE characteristics of corroded RC columns are in agreement with the macroscopic failure behaviors observed during the damage and failure process. A damage evolution model of corroded RC columns based on the AE parameters is proposed.  Corrosion of steel is the major cause of deterioration in the serviceability and sustainability of reinforced concrete (RC) structures, especially for those in the chloride-laden environment ,2,3. As Many efforts have been made on evaluating the mechanical performance of corroded RC columns ,15,16,17Acoustic emission (AE) is a transient elastic wave generated due to the rapid release of energy from sources within a material or structure ,20, whicHowever, most previous studies using AE primarily are limited to the non-corroded flexural RC members. There are several fundamental differences in terms of mechanical responses between a flexural member (e.g. beam) and a compressive member (e.g. column). Also, the in-service RC structures under loading are constantly subjected to steel corrosion ,36; as sThis paper aims to study the AE characteristics and space–time evolution of the corroded RC columns subjected to eccentric compression. Also, a damage evolution model of RC columns based on the AE parameters is proposed based on the test results. The RC columns with an identical dimension of 120 × 120 × 750 mm were studied. The ordinary Portland cement (OPC)  blended with ground granulated blast-furnace slag (GGBS), river sand with fineness modulus of 2.64, and crushed limestone coarse aggregate with a continuous 5–20 mm gradation were used. The adopted mixture proportion of concrete (by weight %) was binder: water: sand: coarse aggregate = 1.0: 0.53: 2.0: 3.0, as shown in The specimen configuration with the detailed reinforcement layout is shown in To investigate the influence of corroded reinforcement on the mechanical performance of RC columns, two types of small eccentric columns  with different corrosion levels were prepared. One was non-corroded while another was partially corroded, both of which had the same configurations and materials. t is time (seconds); lossM is steel mass loss (g); F is Faraday’s constant, which represents the amount of electrical charge in one mole of electron amperes; Icorr is current (amperes); FeM is the atomic weight of metal (56 g for Fe).corri is the current density, and s,0A is the surface area of the steel to be rusted. To induce corrosion of reinforcements, the impressed current method was adopted in this study. The setup for accelerating the corrosion process is shown in The monitoring systems including the loading system, AE signal data acquisition system, and the load and displacement recording system are shown in The major characteristic parameters of AE include the signal amplitude and energy, hit number, rising time, and duration, with their corresponding physical meanings shown in The eccentric static loading was applied to the specimens by using the four-post universal testing machine. In the test, the upper end of the column was connected with a ball bearing hinge support, while the lower end of the column was connected with a one-way knife hinge support. Three transducers were arranged on the bending side of the column to measure the lateral deflection. In total five strain gauges were arranged with two on tensile and compressive sides each and another three on the lateral side, as shown in The cracking behavior of the corroded RC column induced by reinforcement corrosion is shown in m is the weight loss, and im and fm are the mass of the reinforcement before and after corrosion, respectively:To obtain the accurate corrosion rate of the reinforcements embedded in the corroded RC column, the specimen was further broken down and the reinforcement cage in it was taken out after the bearing capacity test. According to the standard ASTM G1-03, the corrosion products were thereafter removed by mechanical and chemical cleaning, the mass of each corroded reinforcement was weighed, and the actual corrosion rate generally defined as the weight loss percentage of the original state was calculated per Equation (3) , where ∆For better illustration, the results expressed as average values of weight loss both for longitudinal steel bars and stirrups are listed respectively in The failure characteristics of the non-corroded column are as follows. The failure first occurred on the compressive side near the axial force; the concrete was crushed and a transverse crack appeared in the concrete on the tensile side at the midspan of the column. When approaching the ultimate bearing capacity, many longitudinal cracks developed rapidly on the lateral side near the axial force. When the ultimate bearing capacity was reached, the crushed concrete burst out suddenly with a loud sound, accompanied by the steel bars that buckled outwards in the shape of a lantern in the corresponding section area. The concrete cover of the longitudinal steel bars was seriously flaked, while a relatively small wedge-shaped spalling of concrete formed on the cover between the longitudinal reinforcements. The failure was sudden and brittle without obvious signs indicated.It is observed that the primary difference of failure between the corroded column and the non-corroded column is that the concrete cover was merely peeled off in the case of the corroded column. The failure mode of the corroded column is the same as that of the non-corroded one, both of which are characterized by concrete crushing in the pressure zone, and an obvious appearance of a through crack that appeared in the middle part of the tension zone. When the corrosion column was approaching the ultimate load, the majority of originally rust-swelled cracks in the compression zone were further developed and followed by the concrete cover falling off along the cracks, which is different from the failure characteristics of the non-rust eccentric column. Compared with the non-corroded column, there was less concrete crushing and sudden burst, and the accompanying sound was not as significant and crisp as that of the non-corroded eccentric column when it reached the ultimate bearing capacity. Most of the concrete cover was peeled off as a whole spanning 1 to 3 stirrup spacings. The main reason is that the corrosion of the longitudinal steel bars and stirrups results in the rust expansion force and the stirrups can not restrain the concrete cover effectively.The load-vertical displacement responses of the RC specimens are displayed in The load-mid-span flexural deflection responses of the RC specimens are shown in The load–strain responses of RC specimens are shown in It can be seen that both corroded and non-corroded RC columns experienced a long time of energy release before failure. However, the corroded column shows more energy peaks, as well as higher intensity of peak energy at failure. It is likely due to different failure modes due to reinforcement corrosion. It was observed that for corroded concrete, not only the concrete in the compression zone was severely crushed, the concrete cover was also peeled off in a large area. By contrast, the non-corroded column did not experience any considerable peeling off of its concrete cover, as can be seen from In comparison to the non-corroded column, the slope of the curve in the second stage of the corroded column is relatively high. This is probably due to the additional energy release upon loading due to the pre-existing stress and damage from reinforcement corrosion. In the third stage, the magnitude of suddenly released AE energy of the corroded column is considerably higher than that of the non-corroded counterpart. For the corroded column specimen, as considerable spalling and loss of surface materials occurred in the second stage, the load was mainly carried by the core concrete. As such, the highly intensive AE that signals release in the third stage of the corroded column is related to the crushing of core concrete. D, can be defined by the relative damage of AE energy, as follows: N(V) is the cumulative energy value of AE when the load level is V (V is defined as the magnitude ratio of the load applied over the ultimate bearing capacity), and PN is the total AE energy of RC columns at failure.AE energy is a crucial index of the instantaneous elastic wave energy of material caused by the rapid release of local strain energy generated by loading. It can be the representative description of AE parameters, as it is closely related to the degree of the damage and the release of energy. Considering that the energy of AE is a macroscopic manifestation of microscopic changes, the damage factor, V, the cumulative energy of AE increases exponentially. Therefore, the exponential function is proposed to establish the mathematical model of load level and AE cumulative energy value,The damage evolution model of RC column can be rewritten as:(1)The AE characteristics of RC columns are in strong agreement with the macroscopic mechanical behaviors observed during the loading and failure process. The reinforcement corrosion considerably affects the mechanical performance of columns, causing the concrete cover to spall during compressive loading.(2)The presence of corroded rebar makes the AE signals highly active at the initial stage of loading, in comparison to the non-corroded counterpart. Also, a continuous AE hit pattern with a higher number of cumulative hits was observed for the corroded RC column, while the hit event is almost absent at the early loading period for the non-corroded case.(3)The spatial distribution and evolution of AE events indicate that the reinforcement corrosion considerably affects the initiation, propagation, and cracking evolution in RC columns.(4)The concrete damage evolution equation presented by AE parameters can quantitatively describe the effects of corrosion damage on the mechanical performance of concrete.This paper studies the acoustic emission (AE) characteristics of corroded reinforced concrete columns under eccentric compressive loading. The following conclusions can be drawn:


This study was aimed to explore the secular trends of antibiotic utilisation in China’s hospitals over an 8-year period.We retrospectively analysed aggregated monthly antibiotic procurement data of 586 hospitals from 28 provinces in China from January 2011 to December 2018. Information including generic name, procurement amount, dosage form, strength, the route of administration, and geographical data were collected. Population weighted antibiotic utilisation were expressed in DDD per 1000 inhabitants per day (DID). WHO’s ‘Access, Watch, Reserve’ categorization was also adopted to analyse antibiotic utilisation.Between 2011 and 2018, total antibiotic utlisation in China’s hospitals increased by 39.6% (from 4.8 DID in 2010 to 6.7 DID in 2018). Antibiotic utilisation was stable or had moderately decreased in 13 provinces, while in the other 15 provinces they had substantially increased. Cephalosporins were the most consumed antibiotics, accounting for 26.9% of the total antibiotic utilisation (1.8 DID/6.7 DID). In 2018, antibiotics in the Access category comprised 19.4% of the total utilisation (1.3 DID/6.7 DID), where antibiotics in the Watch category comprised the largest proportion of 71.6% (4.8 DID/6.7 DID). Population-weighted antibiotic utlisation was greater in secondary hospitals than in tertiary hospitals (7.3 DID vs 6.6 DID). The utilisation of oral forms was almost two times the amount of parenteral forms in secondary hospitals, whereas in tertiary hospitals the amounts were about the same.Despite efforts have been made towards restricting antibiotic use by the Chinese government, antibiotic utilisation demonstrated an upward trend after the medical reform. The increase of last-resort antibiotics raises serious concern for public health. Current patterns of antibiotic utilisation demonstrated that gaps are existed towards the global target set up by the WHO. To better facilitate proper antibiotic use, more efforts are needed to explore the appropriateness of antibiotic use at the individual level. Selection pressure from antibiotic use is considered to be one of the most important drivers of antimicrobial resistance (AMR), which is a growing public health threat of broad concern to the world . At the To address this issue, China has taken many measures to strengthen antimicrobials management such as the designation of antibiotics as prescription drugs in 2003, and the introduction of guidance for clinical use of antibiotics in 2004 . NationaWe have studied the short-term trends of antibiotic utilisation by analysing the antibiotic procurement data  in China’s tertiary hospitals before . HoweverAggregated monthly antibiotic procurement records of 586 hospitals from 28 provinces were retrospectively analysed for the study period from January 2011 to December 2018.All the data was obtained from China Medicine Economic Information (CMEI), an observational database containing information of drug procurement records in medical institutions from 28 provinces (out of 34) across the country . The database covers more than 1000 city-level public hospitals, including outpatient and inpatient, across mainland China. The procurement records of participating hospitals, which were all public hospitals, account for approximately 40% of total drug procurement at city-level public hospitals in China . Since aWe extracted monthly antibiotic procurement data from the CMEI database. Information including the generic name, procurement amount, dosage form, strength, the route of administration, and geographical data were collected. Hospital names were concealed to protect confidentiality.Procurement data were categorized according to Anatomical Therapeutic and Chemical (ATC) classification J01  expressed in defined daily dose (DDD) as a measurement unit, following the recommendation of the WHO Collaborating Center for Drug Statistic Methodology . The DDDTo make the procurement data consistent with the international standards, the data were converted into DDD per 1000 inhabitants per day (DID) at the level of the active substance. Based on the following two assumptions, eq. i: Coverage inhabitants in a given year;Yi: Total population in a given year in province i;Pi: Number of sample hospitals in province i;ni: Number of total hospitals in province i;Ni: Number of inpatients and outpatients in sample hospitals in province i;mi: Number of inpatients and outpatients in all hospitals in province i.MIn addition to ATC classification, we adopted ‘Access, Watch, Reserve’ (AWaRe) categorization established by WHO as part of the update of the WHO Model List of Essential Medicines in 2017 to analyse the antibiotic utilisation .To derive a comparable metric of antibiotic utilisation across time, we calculated the compound annual growth rate (CAGR) of antibiotic utilisation .2\documC2018: Total antibiotic utilisation for the year 2018 (expressed in DID).C2011: Total antibiotic utilisation for the year 2011 (expressed in DID).p < 0.05 was considered to indicate statistical significance.All the relevant census data for calculating inhabitants were collected from China Health Statistics Yearbook and China Statistics Year Book . Linear Between 2011 and 2018, total antibiotic utilisation in China’s hospitals increased by 39.6% (from 4.8 DID in 2011 to 6.7 DID in 2018). The CAGR of the total antibiotic utilisation was 4.3%. In 2018, antibiotics in the Access category comprised 19.4% of total utilisation (1.3 DID/6.7 DID), whereas antibiotics in the Watch category represented the largest proportion of all – 71.6% (4.8 DID/6.7 DID). The percentage of antibiotics in the Access, Watch and Reserve categories was stable during the study period.Cephalosporins were the most consumed antibiotics, accounting for 26.9% of the total antibiotic utilisation in 2018 (1.8 DID/6.7 DID), followed by combinations of penicillins with 22.4% (1.5 DID/ 6.7 DID) and fluoroquinolones with 10.4% (0.7 DID/6.7 DID). The largest absolute increase between 2011 and 2018 was observed for combinations of penicillins (0.6 DID), cephalosporins (0.3 DID), and fluoroquinolones (0.2 DID). The most important relative increase from 2011 was observed for carbapenems , tetracyclines , other antibacterials  , combinations of penicillins  and penicillins with extended spectrum . , while in the other half (15 provinces) they had substantially increased between 2011 and 2018. Most of the increases were observed in underdeveloped regions, such as Inner Mongolia, Yunnan, Gansu, and Guizhou. Eastern coastal regions consumed more antibiotics compared with central and western regions  and 19.7% (1.3 DID/6.6 DID) of total amount in secondary and tertiary hospitals, respectively, whereas antibiotics in the Watch category had the largest proportion of 68.5% (5.0 DID/7.3 DID) and 72.7% (4.8 DID/ 6.6 DID), respectively. Antibiotics in the Reserve category in tertiary hospitals increased from 4.1% (0.3 DID/ 7.3 DID) to 7.6% (0.5 DID/ 6.6 DID) during the study period  from 2011 to 2015 and rose by 7.4% (6.8 DID to 7.3 DID) from 2015 to 2018. In tertiary hospitals, antibiotic utlisation increased each year, and a 43.5% increase was observed between 2011 and 2018 (4.6 DID to 6.6 DID). The utilisation of oral forms was almost two times the amount of parenteral forms in secondary hospitals, whereas in tertiary hospitals the amounts were about the same  of antibiotic consumption in the hospital setting in 24 EU/EEA countries  , whilst When looking at the pattern of antibiotic utilisation, we found that cephalosporins were continuously the most consumed antibiotics in China’s hospitals, followed by combinations of penicillins, which were often defined as extended-spectrum antibiotics, and quinolones. This pattern was similar to the previous studies conducted in other regions of China , 19, as Population-weighted antibiotic utilisation was greater in secondary hospitals than in tertiary hospitals. As more severe patients were admitted in tertiary hospitals compared with secondary hospitals, we speculated that more potential inappropriate use of antibiotics might exist in lower level hospitals. Studies found that diseases, such as diarrheal illness, colds, pharyngitis, acute bronchitis, were likely to be prescribed antibiotics in rural and underdeveloped regions –37, althThe findings of this study are subject to several limitations. First, the hospitals in the database were on a voluntary basis instead of mandatory participation, especially the proportion of secondary hospitals in the study was relatively low, therefore could bring selection bias. Besides, the sample hospitals in our study were all public hospitals and the sample size was relatively small, however, since the number of patient visits in public hospitals was more than 85% of total patient visits in China , and theDespite efforts have been made towards restricting antibiotic use in the past decade by the Chinese government, antibiotic utilisation demonstrated an upward trend after the medical reform. The increase of antibiotic utilisation, especially the increase of last-resort antibiotics raises serious concern for public health. Current patterns of antibiotic utilisation demonstrated that gaps are existed towards the global target set up by the WHO. To better facilitate proper antibiotic use, more efforts are needed to explore the appropriateness of antibiotic use at the individual level.Additional file 1: Table S1. Antibiotic utilisation in China’s hospitals between 2011 and 2018.


Blood tests revealed no elevated tumor markers, with the exception of a mildly elevated interleukin‐2. Based on the above results, thoracoscopic biopsy was performed due to the suspected recurrence of lung cancer or malignant lymphoma. The histopathological examination of the nodule revealed immunoglobulin G4 (IgG4)‐related inflammatory pseudotumor. The serum IgG4 levels were elevated . No additional treatment was required because all nodules were observed to have disappeared naturally on a follow‐up CT scan performed two months after the surgical biopsy. The patient has been followed‐up for two years without recurrence.A 75‐year‐old woman underwent thoracoscopic right upper lobectomy for lung cancer. A histopathological examination showed adenocarcinoma, pT1aN0M0 stage IA1. At six months after surgery, chest computed tomography (CT) revealed pericardial nodules that had not been detected before pulmonary resection. Postoperative CT performed two months later revealed that the nodules were growing and FWe report a case of pericardial immunoglobulin G4‐related inflammatory pseudotumor that appeared after right upper lobectomy for lung cancer, and which naturally disappeared without any treatment.There was an immunoglobulin G4‐related inflammatory pseudotumor which appeared as multiple nodules in the pericardial space, and this should be kept in mind when considering the differential diagnosis of intrapericardial nodules. We report a case of pericardial immunoglobulin G4‐related inflammatory pseudotumor that appeared after right upper lobectomy for lung cancer, and which naturally disappeared without any treatment. Immunoglobulin G4 (IgG4)‐related disease can involve multiple organs, particularly exocrine organs, such as the pancreas, salivary glands, and biliary tract,We herein report a case of IgG4‐related inflammatory pseudotumor with pericardial nodules after right upper lobectomy for lung cancer.18 fluorodeoxyglucose‐positron emission tomography (FDG‐PET) showed a maximum standardized uptake value of 9.87 . The operation was performed in the right lateral decubitus position with three ports via the left thoracic cavity. The nodules were found within the pericardial sac Fig ; two nodThe final histopathological examination of the nodules revealed IgG4‐related inflammatory pseudotumor. Numerous IgG4‐positive cells were found on immunostaining and the ratio of IgG4 staining to total IgG staining was approximately 40% Fig . The patIgG4‐related disease can involve virtually every organ. The most frequently involved sites are the pancreas, bile ducts, gallbladder, liver, salivary glands and kidneys, with manifestations generally recognized as a mass at one or more sites mimicking a neoplasm.In the present case, the nodules found in the pericardium were growing during two months of follow‐up; we therefore suspected the recurrence of lung cancer and resected the pericardial nodules. However, considering that the pericardium was not treated at the time of right upper lobectomy and that the pericardial nodules that appeared six months after surgery for lung cancer had a higher SUV max than the primary lung cancer (SUV max 1.55), it was possible to follow‐up the patient with CT scan rather than perform a risky surgical biopsy. There are few reports regarding pericardial events after lung cancer surgery, other than recurrence. In these cases, the reported causes of pericardial effusion include residual undrained blood and the prevention of lymphatic drainage after mediastinal dissection.It is difficult to obtain a correct diagnosis of pericardial tumor. In this report, we failed to consider IgG4‐related disease as a differential diagnosis before surgical biopsy and surgical resection was required to make a correct diagnosis based on a histopathological examination. Some reports have described elevated serum levels of soluble IL‐2 receptor in cases of IgG4‐related disease.Previous studies have proposed that FDG‐PET is superior to other imaging modalities for the diagnosis of IgG4‐related disease. Several reports have shown the abnormal uptake of the tumor; however, there was no significant difference in abnormal uptake between IgG4‐related disease and other malignant tumors. FDG‐PET can define more lesions than conventional imaging methods by providing the whole‐body metabolic condition and morphological abnormality, and it can serve as a sensitive tool in assessing organ involvement and disease distribution.To our knowledge, there are no previous reports on IgG4‐related disease with pericardial nodules. Based on this case report, it was shown that IgG4‐related disease should be included in the differential diagnosis of pericardial nodules and it might be important to measure serum soluble IL‐2 receptor.Although IgG4‐related disease in the pericardium is rare, we should consider this disease in the differential diagnosis of patients with pericardial nodules.The authors have no conflicts of interest to declare.


Dear Sir,Escherichia coli UTI cases. This finding is interesting as pivmecillinam and nitrofurantoin are increasingly being recommended and used over trimetoprim for UTI in men in Scandinavia [In light of the increased resistance to fluoroquinolones other oral non-fluoroquinolone antibiotics are increasingly being used for lower urinary tract infection (UTI) in men in Scandinavia , but witndinavia ,2 due tondinavia ,4. But rE. coli UTI in patients where the general practitioners chose to have the urine sample analyzed in a clinical microbiological department. In the first study, we investigated the outcome of six different oral antibiotics for UTI caused by E. coli with and without ESBL production [We have recently published two large cohort studies on oduction , and fouoduction  investigPivmecillinam and nitrofurantoin have shown excellent efficacy in treating UTI in women and have been recommended as first-line options for UTI in women for a while . Thus, ipost hoc analysis of the previously used cohort, using the same methodology as in the two original articles [E. coli bacteria initiated on trimethoprim, pivmecillinam or nitrofurantoin with indication for UTI ; long-term prophylactic therapies were excluded; treatment failure measured as redemption of a new antibiotic for UTI or admission to hospital due to UTI within 30 d. The objective was to investigate the three most commonly prescribed antibiotics in Denmark for UTI in men and compare the risk for treatment failure with each other adjusting for resistance, age and for multiple input comparisons.With regards to the above, we conducted a articles ,7: a retE. coli group [E. coli UTI in men based on the higher prevalence of resistance for the latter antibiotic alone. But as a retrospective study of this design comes with obvious limitations and risks for confounding trimetoprim should similarly not be recommended over pivmecillinam and nitrofurantoin based on this finding alone. Before changes to and any firmer recommendations can be made, pharmacological studies to investigate the best dosage in men for these antibiotics with succeeding clinical prospective studies are needed.Interestingly, the results showed trimethoprim to have significantly lower treatment failure than both pivmecillinam and nitrofurantoin, respectively, both when adjusting for the higher trimetoprim resistance or not . (This oli group ). The reli group ,7) the dE. coli UTI in men and more studies are much needed.As for now, the data are insufficient to make any recommendations on which of these three oral antibiotics are to be currently recommended for


Subtropical natural exposure may significantly affect the bonding behavior of fiber reinforced polymer (FRP) externally bonded to concrete. To study the effect of subtropical natural climates on the FRP-concrete interface, natural exposure tests and an analytical approach were carried out on specimens externally bonded with carbon fiber reinforced polymer (CFRP) and basalt fiber reinforced polymer (BFRP). The bilinear bond stress-slip relationships for different exposure periods were derived from the experimental results of the strengthened reinforced concrete (RC) beams. Based on these bond-slip relationships, the full-range behavior of shear stress along the bond length and debonding load can be obtained through the analytical solution. The testing and numerical results showed that subtropical natural exposure can greatly affect the bond behavior of CFRP-concrete and BFRP-concrete interfaces in the early exposure period. In the late exposure period, the bond behavior was basically stable. With the increase of exposure time, the position of maximum shear stress tended to move backward, which indicated that the behavior of the FRP-concrete interface was weakened by natural exposure. Compared to the CFRP-concrete interface, subtropical natural exposure has greater influence on the bond behavior of the BFRP-concrete interface. Reinforced concrete (RC) structures can be effectively strengthened by external bonding of fiber reinforced polymer (FRP) composites for the convenience and efficiency. This technique has been demonstrated by many researchers and has become popular more than two decades years. Extensive research has revealed that bond strength of the FRP-concrete interface is crucial to the performance of FRP-strengthened concrete structures.In recent years, more and more studies have begun to pay attention to the effect of severe environments, such as humidity, temperature, chloride, and acidic environments on FRP-strengthened concrete structures ,2. The eFrom the above literature review, it can be seen that many studies involving the interfacial durability caused by hydrothermal environment focused on the accelerated aging method ,11,12. HHowever, the performance of FRP-concrete under outdoor subtropical exposure is still under investigation. Shukur Abu Hassan  conducteTo date, the experimental methods for studying the interfacial behavior of FRP-concrete are pull-off tests, which can be divided into three different types, as shown in The objective of the present study is to propose an analytical model of bending test to describe the degradation of the FRP-concrete interface under natural subtropical climates. To better simulate the actual situation of concrete structures strengthened with FRP, bending tests were chosen and designed as shown in The structural behavior of bending test is more complex than that of single-shear and double-shear tests. To find the bond-slip relationship, the stress distribution, and the slip along the length of FRP-concrete bond interface, the differential equations of the interfacial slip and the solution of the differential equations in different stages were set up in this section.The beam in Some assumptions were provided before establishing the differential equations: the beam weight has no effect on the interfacial stress; the behavior of three components  are linear elastic; the cross section of beam remain plane; the adhesive layer is subjected to shear deformation, and FRP is assumed to experience tensile deformation; and the thickness and width of concrete, adhesive layer, and FRP plate are constant. Based on these assumptions, the slip and stress of the FRP-concrete interface can be derived by the following equations:The horizontal equilibrium equations of the FRP-concrete interface were set up as follows:From Equations (1)–(6), the second order differential equation can be obtained as follows:x = 0) shown in x = 0, respectively; x = 0 is obtained by:The beam in shown in , respectThe bond-slip relation is a vital parameter to describe the interfacial behavior of FRP-concrete interface. So far, six types of available bond-slip models for FRP-concrete interfaces have been provided as follows: (a) elastic-plastic model, (b) cutoff model, (c) bilinear model, (d) Popovics’ model , (e) thiThe bilinear bond-slip relationship is composed of an initial elastic ascending branch, descending branch, and debonding stage. Bond shear stress increases linearly until it reaches the maximum bond stress, In the model, the ascending branch and descending branch are characterized by three values: maximum bond stress  and (11), the differential equation can be solved to obtain the interfacial slip, interfacial shear stress distribution along the adhesive interface, and the ultimate load under the effect of natural subtropical climate exposure. As shown in the bond-slip relationship, the behavior of FRP-concrete interfaces can be divided into the ascending stage, descending stage, and debonding stage.x, increases. This stage is the elastic stage, during which the interfacial shear stress is less than maximum stress, The expressions for the slip and shear stress of the FRP-concrete interface and the tensile stress in FRP plate are derived:The boundary conditions n days of subtropical natural exposure, the elastic stage ends, and the bond-slip of FRP-concrete interface from the beginning location –(22), interfacial slip, interfacial shear stress, tensile stress in FRP plate, and the length of the softening zone of the FRP-concrete interface in the descending stage can be calculated.At the end of this stage, the interfacial slip at At the beginning of this stage, the interfacial slip at The exposure process of the specimens was performed in a natural subtropical environment in Guangdong Province, China. The most prominent feature of this area is a hot and rainy summer. The annual temperature of the natural environment and concrete structures are shown in In this study, a total of six specimens were tested. The tests were carried out with two variables: (1) types of FRP  and (2) exposure periods . In this study, FRP used in this paper were CFRP and BFRP. CFRP sheets were UT70-30 and BFRP sheets were produced by Zhejiang Shijin Basalt Fiber Co., Ltd. The adhesive used for bonding FRP to concrete was epoxy adhesive. The properties of the CFRP, BFRP, and resin epoxy were given by the manufacturer and are listed in The concrete prepared for all specimens was ordinary strength concrete cast in the lab. The weight ratio of the main ingredients of concrete was cement (1.0): water (0.64): sand (2.02): gravel (3.59). Three cylindrical test blocks were tested, and the average compressive strength after 28 days of curing was 30.5 MPa. The characteristics of materials used in the test are summarized in Four-point bending experiments were carried out in this paper and all specimens were loaded on a hydraulic machine of 500 kN capacity. Displacement-controlled monotonic loading history was adopted, and the loading was applied by a two-point loading system. The distance between the two loading points and two supports were 100 mm and 310 mm, respectively. Monotonic loading was applied with a constant rate of 0.2 mm/min. Force sensors were installed on both load cells to record applied loads. During each test, the linearly variable differential transducer (LVDT), with a range of 50 mm and an accuracy of 0.01 mm, was positioned at the mid-span to measure the deflection of specimens.To record the strains on FRPs, a total of eight strain gauges were externally bonded along the length of FRP at an interval distance of 20 mm, as shown in The results from the bending tests on specimens for bond behavior between FRP-concrete are presented, while considering the effect of type of FRP and exposure time. Description of ultimate loads, failure modes, and strains of FRP under different loads are reported.Subjected to natural exposure in the environment, the concrete surface of the specimen turned white, and FRP sheet was light green compared to reference. There is no significant difference in the surface of the specimens with exposure period of 180 days and 360 days.The failure mode of most specimens was debonding of the FRP-concrete interface, and the concrete with a different thickness was attached to FRP. At the beginning of the failure process, there was a subtle sound at the mid-span of the beam. As the loading increased, some oblique cracks began to appear on the surface of the concrete with popping sounds and finally resulted in debonding of FRP from concrete. For reference specimens without aging, the failure mode of specimens with CFRP was concrete shear followed by debonding failure, while the specimens with BFRP occurred with debonding failure. The failure mode of specimens subjected to natural exposure in the environment was debonding failure on FRP-concrete interfaces. The failure modes of all specimens are shown in The effect of exposure time on bond behavior of the FRP-concrete interface can be described through At the beginning of loading, only the first and second strain gauge near the mid-span had strain value. Moreover, the value of the first strain gauge nearest the mid-span was much larger than the second strain gauge. As the load increases, the strains on FRP at far distances began to appear, and the strains near the mid-span increased dramatically. When the FRP debonded at the mid-span, the interface stress was rearranged and the strain on far distance reached maximum value, followed by the fully debonding of FRP from the concrete surface. As the applied load was close to the ultimate load, the value of the strain gauge far from the mid-span was small, indicating that the ultimate load of specimens would not increase with the increase of bond length.The results of Based on the data of The average bond stress, The slip, These points were fitted to the ascending and descending stages to obtain the bond-slip relationship between the CFRP-concrete interface and the BFRP-concrete interface after different exposure periods. The major bond parameters for bond-slip relationship are listed in ◆The maximum bond shear stress, ◆The slip, ◆Whether for the CFRP-concrete interface or BFRP-concrete interface, the exposure time had a great influence on the interface stiffness. As the exposure time increased, the interface stiffness degraded rapidly in the ascending and descending stages. During the ascending stage, reductions of 18.9% and 36.8% were observed for interface stiffness of CFRP-concrete and BFRP-concrete in the early exposure period, while they decreased 15.4% and 8.4% in the late exposure period. The results showed that the early stage of exposure had a greater effect on stiffness degradation. Otherwise, similar trends were observed in the descending stage, in which the early stage of exposure had a greater effect on stiffness degradation and the maximum degradation reached 37.8%.The difference of two different type interfaces was that bond behavior of the BFRP-concrete interface was weaker than that of the CFRP-concrete interface, which was mainly characterized by smaller maximum shear stress, larger slip, and poorer stiffness. In terms to test results, the bond-slip relationships of FRP-concrete exposed to natural subtropical environments were derived in To validate the proposed model, its predictions were compared to the experimental results. When the predictions were in good agreement with the experimental results, the proposed model provided an analytical approach to obtain the bond shear stress distribution of FRP-concrete and debonding load, in terms of the bond stress-slip relationship of the FRP-concrete interface.◆Input some major parameters of a certain type of bond stress-slip relationship, such as ◆x position was in the ascending or descending stage. If it is still in ascending stage, then the procedure enters cycle (1), otherwise it enters cycle (2).Take a small load as the initial load and set the load increment, ◆After entering cycle (2), cycle (1) stops and Equations (20)–(23) are used in the descending stage.◆x position reaches x position is debonded. The shear stress is rearranged, and the procedure entered into the debonding stage. In this stage, the debonding load is obtained.When the slip at the Based on the bond stress-slip relationship of FRP-concrete interfaces exposed to different exposure times, the bond shear stress distribution of FRP-concrete interface and debonding load can be determined by the following computing procedure. The procedure is outlined in the flow chart in Every bond-slip relationship of specimens under different exposure periods  was substituted into the computing procedure. The shear stress distribution along the bonding length under different loads are illustrated in It can be seen from the figure, that at the initial stage of loading, the bond shear stress of the CFRP-concrete and BFRP-concrete interface near the mid-span was large, while the shear stress in other regions was almost zero. It indicated that the shear interface stresses were mainly focused on the mid-span and do not transfer to the far-end. Furthermore, as the load slowly increased, the position where the maximum shear stress appeared moved backward, and the position at the far end began to show shear stress. The shear stress near mid-span reached zero first and debonding occurred. The shear stress distribution was rearranged, and shear stress near deboning zone increased rapidly.Moreover, the transferred shear stresses throughout the FRP under different exposure periods also showed that with the increase of exposure time, under the same load, the position of maximum shear stress tended to move backward. It indicated the behavior of the FRP-concrete interface was weakened by natural exposure.The theoretical calculations and experimental values of debonding load under different exposure periods are compared in A bilinear bond stress-slip relationship of CFRP-concrete and BFRP-concrete interfaces after different natural exposure periods were obtained through experimental dates. Major parameters of the bond-slip relationship showed that the bond behavior was greatly affected in the early exposure period and was basically stable in the late.Compared to reference beam without exposure, the maximum shear stress (Bond behavior of the BFRP-concrete interface was weaker than that of the CFRP-concrete interface, which was mainly characterized by small maximum shear stress, large slip, and poor stiffness.The analytical model presented was versatile, because once the bond behavior of FRP-concrete was inputted into structures strengthened with FRP, the full range behavior of FRP-concrete under different loads can be evaluated and the debonding load of specimens can be derived.With the increase of exposure time, the position of maximum shear stress tended to move backward, which indicated that natural exposure can impair the behavior of the FRP-concrete interface.Bond strength of the FRP-concrete interface is crucial to the performance of FRP reinforcement of concrete structures, and the natural subtropical climate will degrade the bond behavior. To study the effect of natural exposure on the behavior of CFRP-concrete and BFRP-concrete interface, concrete specimens bonded with CFRP and BFRP were exposed to a natural subtropical climate for 0, 180, and 360 days. Test results and analytical solutions for the full-range behavior of interfaces were presented in this paper. The findings are novel, and the main conclusions are summarized as follows:


The purpose of this paper is to determine the random spatially varying elastic properties of concrete at various scales taking into account its highly heterogeneous microstructure. The reconstruction of concrete microstructure is based on computed tomography (CT) images of a cubic concrete specimen. The variability of the local volume fraction of the constituents  is quantified and mesoscale random fields of the elasticity tensor are computed from a number of statistical volume elements obtained by applying the moving window method on the specimen along with computational homogenization. Based on the statistical characteristics of the mesoscale random fields, it is possible to assess the effect of randomness in microstructure on the mechanical behavior of concrete. The macroscopic mechanical properties of heterogeneous materials consisting of multiple phases such as particle-reinforced composites and concrete are significantly influenced by their underlying microstructure and can be determined through numerical homogenization. The application of homogenization methods in the analysis of multi-phase materials offers an efficient alternative over direct simulation of the microstructure in terms of required computational resources. The key issue in homogenization methods is the linking of micromechanical characteristics with the random variation of material properties at higher scales, which is usually established using Hill’s macro-homogeneity condition . In thisThe highly heterogeneous microstructure of concrete is responsible for its complex mechanical behavior. Therefore a wide variety of methods have been developed for the accurate reconstruction of concrete microstructure mostly based on image processing and random fields. The geometrical characteristics of aggregates are statistically analyzed in  by proceThe mechanical properties of concrete are determined using computational homogenization in a number of publications. Constantinides and Ulm  confirm The purpose of the present paper is to provide a complete probabilistic description of the spatial variation of the elastic properties of concrete taking into account its highly heterogeneous microstructure, which is reconstructed using CT images of a cubic concrete specimen. The variability of local volume fraction of the constituents  is quantified first. Mesoscale random fields of the elasticity tensor are computed subsequently from a number of SVEs obtained by applying the moving window method on the concrete specimen along with computational homogenization. Based on the statistical features  of the random fields, it is possible to assess the effect of randomness in microstructure on the mechanical behavior of concrete.The paper is organized as follows: In Computed Tomography (CT) has its origins in the medical field and refers to a computerized X-ray imaging procedure in which a patient is struck by a narrow X-ray beam that rotates at a certain speed around the patient’s body. While the CT procedure has been applied mainly for medical purposes, the gradual increase in available CT equipment and the improvement of the cost factors have led to other utilizations, such as the exploration of the microstructure of heterogeneous materials . When thThe absorbed or scattered radiation of a material can be measured in Hounsfield units (HU). HU is a quantitative scale that reflects the linear transformation of the original linear attenuation coefficient measurement  with their corresponding resolution . Each piEquation . Then, bIn this work, the medical CT scan was conducted at the laboratory of Magnitiki Patron S.A. , which hsoftware  has beenA fundamental assumption in the homogenization process is the statistical homogeneity of the heterogeneous medium . This med denotes a characteristic size of the fillers, e.g., the average dimension of aggregates, the mesoscale parameter L denotes the size of the volume element and the macroscale parameter A basic principle for the existence of the RVE is separation of scales as defined below :(2)d≪L≪LThe statistical characteristics of the apparent elasticity tensor of concrete are computed by analyzing a set of random mesoscale models or SVEs. These are obtained by applying the moving window technique on a cubic concrete specimen reconstructed based on a set of 2D CT images see . Figure The stress and strain fields on a mesoscale realization of concrete over Bδω :(4)σ¯∫∂Bδt∫∂Bδt(7)∫In general the 3D elasticity tensor The unknown macroscopic elasticity components b based on its coordinates:The imposed displacements on the boundary nodes of each SVE are calculated through the prescribed uniform strain tensor using the following equation:i and boundary nodes b. The macroscopic stress tensor is then calculated as a volume average by:b.The BVP which has to be solved is as follows:i = 1, 2, 3, 4, correspond to different window sizes and thus different total numbers of SVEs  variability of the constituents of concrete can be studied next. Equation  with corA, B, respectively. The total number of SVEs is  large δ . The autIn this paper, the random spatially varying apparent elasticity tensor of 3D concrete microstructures has been computed using CT images of a cubic specimen for the reconstruction of concrete microstructure and computational homogenization.A complete probabilistic description of the spatial variation of the elastic properties of concrete has been achieved through computation of the respective mesoscale random fields. In this way, it was possible to assess the effect of randomness in microstructure on the mechanical behavior of concrete based on the statistical characteristics  of the random fields.A moderate to large variability of the local volume fraction of the constituents  has been observed depending on the scale factor This was reflected on the moderate to high COV of the apparent axial and shear stiffness, meaning that microstructural uncertainty can lead to substantial random spatial variation of the mechanical properties of concrete.The computed random material property fields can be used for the stochastic FE analysis of concrete structures.The consideration of the interfacial transition zone (ITZ) between cement paste and aggregates and the determination of random fracture properties could constitute the subject of future research.