Irrational use of antibiotics is a major driver of development of antibiotic resistance, which heavily threatens population health worldwide. Understanding the mechanism of physician’s antibiotic prescribing decisions is increasingly highlighted to promote prudent use of antibiotics. Therefore, the current study aimed to fill the gap, modelling physician’s antibiotic prescribing and identifying the potential intrinsic and external determinants of antibiotic prescribing in primary care.A total of 428,475 prescriptions from 499 prescribers in 65 primary care facilities in Hubei of China were audited. Teixeira Antibiotic Prescribing Behavioral Model (TAPBM) was referred as theoretical basis to identify intrinsic and external predictors of antibiotic prescriptions. A questionnaire survey was conducted, covering potential physician’s intrinsic determinants  and external factors both in individual level  and institutional level . A two-level path analysis was performed linking potential determinants of antibiotic use with physician’s actual practices.p < 0.05), but higher knowledge and attitudes failed to translate into antibiotic prescribing practices . Instead, external factors played a more important role and physician’s antibiotic use was significantly associated with patient pressure , time pressure , financial incentives  and institutional environments . The prescribers who were male  or had lower qualification  were also more likely to prescribe antibiotics than others.About 44.28% of the prescriptions contained antibiotics, with 9.28% containing two or more antibiotics. The multi-level path analysis revealed that knowledge was a significant predictor of attitudes  and external  factors. A systematic approach is required to curb over-prescription of antibiotics. Apart from educating prescribers, it is equally important, if not more, to educate patients, break incentives and nurture professional culture within organization to reduce the overuse of antibiotics.The online version of this article (10.1186/s13756-019-0592-5) contains supplementary material, which is available to authorized users. Antibiotic resistance (AR), one of the most serious public health issues, threatens population health and socioeconomic development of all nations over the world . It not Irrational use of antibiotics is a major driver fueling the development of AR , 4. PromMany studies have attempted to understand how and why physicians prescribe antibiotics irrationally , 9. KnowTeixeira suggested a comprehensive framework for studying prescribing practices . It consAlthough the TAPBM has been widely endorsed by the research community , there i2 and 59.02 million populations. Hubei had a gross domestic product (GDP) of $8915 per capita in 2017, ranking at number 11 among all (34) provinces in China. It is classified as a middle-high income region based on the criteria of the World Bank [This study was conducted in Hubei, a province in central China covering a land of 185.9 thousand kmrld Bank .The study setting was restricted to primary care facilities, which included both urban community health centers (UCHCs) and rural township health centers (RTHCs). In 2017, Hubei had 347 UCHCs and 1137 RTHCs, receiving 23.03 million and 56.00 million outpatient visits, respectively . Over-prThis study adopted the TAPBM as an overarching framework. The TAPBM extended the widely-accepted Knowledge-Attitudes-Practices (KAP) theory and included considerations of external determinants of antibiotic prescribing practices .Intrinsic determinants: knowledge and attitudes are the core of intrinsic determinants of antibiotic prescribing practices. Knowledge can influence prescribing behaviors directly or indirectly through influencing attitudes [ttitudes . The knottitudes , 9, suchExternal determinants: when physicians prescribe medicines, they are likely to take considerations of many external factors apart from relevant clinical standards and guidelines. Pressures from patients, peers, employers, governments, and the public may sway antibiotic prescribing decisions. These factors can exert impacts on prescribing practices directly or indirectly through influencing attitudes [ttitudes .Previous studies showed that patient requests for antibiotics increased antibiotic prescribing dramatically, especially when the physicians felt that they did not have enough time to explain details to their patients , 29. It Formal and informal institutional and system arrangements also play an important role in shaping prescribing decisions. Several studies in the European countries showed that antibiotic prescribing practices are associated with the culture of an organization  , 32 and In this study, the TAPBM framework was adapted considering the availability of relevant data and measurements. We adopted a two-level modelling approach, covering the effects of individual (physician) factors and institutional (cluster-level) factors. The individual-level measurements included both intrinsic (e.g. characteristics of prescribers) and external (e.g. perceived pressures) indicators. The institutional-level measurements were represented by two proxy indicators: urban/rural location and socioeconomic status of the servicing community Fig. . We chosPercentage of prescriptions containing antibiotics = Number of prescriptions containing antibiotics / Total prescriptions × 100%;Percentage of prescriptions with combined use of antibiotics = Number of prescriptions containing two or more antibiotics / Total prescriptions × 100%;Two indicators were calculated to measure antibiotic prescribing practices in line with the World Health Organization (WHO) recommendations :PercentaKnowledge: Antibiotic prescribing knowledge was measured with 11 items that were commonly used in previous studies [ studies , 22, 37,Attitudes: Attitudes of the physician respondents were measured using the 11-item Knowledge and Attitudes regarding Antibiotics and Resistance (KAAR-11) scale, which has been fully validated in previous studies [ studies . The KAA studies .Individual characteristics of prescribers: These included the demographic characteristics (gender and education) and the professional experiences  of the participants. All of the physician respondents were general practitioners. Therefore, clinical expertise was excluded in the analysis.Perceived patient pressure: Respondents were asked “how many percent of patients you see expect antibiotic prescriptions” and “how often the patient expectation influences your decision of antibiotic prescribing”. The latter was rated on a five-point Likert scale ranging from “1 = always” to “0 = never”. Scores of the two questions were multiplied as an indication of patient pressure (ranging from 0 to 100).Time pressure: Respondents were asked to estimate the average duration (minutes) of consultations for each patient visit, with a lower duration indicating higher time pressure.Household income: Respondents were asked to estimate their annual household income (Chinese Yuan ¥) over the previous year. The household income was classified into four categories: < 40,000; 40,000-79,999; 80,000-119,999; ≥120,000.The characteristics of the participating primary care institutions were measured with two indicators: rural/urban location and socioeconomic status of the servicing community. All of the participating primary care facilities were public institutions governed by the same policy and regulatory framework. The socioeconomic status was classified based on GDP per capita of their local districts: high (top four districts) vs low.The questionnaire was pilot tested in 23 physicians from 3 primary care facilities. They were asked to explain why they chose or did not choose certain answers. The feedback was used to modify the questionnaire. Of the 30 tested questionnaire items, 9 were rephrased and no items were deleted or added  of UCHCs and 4.1% (46/1137) of RTHCs, respectively. Details about the sampling approach have been published elsewhere .The physicians who prescribed antibiotics independently in the participating primary care facilities were eligible for this study. To minimize bias, only those who prescribed ≥100 prescriptions three months prior to the commencement of the questionnaire survey of prescribers were invited to participate in this study.Prescription data from January 1st to March 31st, 2018 were extracted either from the participating primary care institutions or from the medical administration system of the local governments. These included the name of the institution, the ID number of the prescriber, patient ID, date of the prescription, and the type, volume and price of the medicines prescribed.A questionnaire survey of prescribers in the participating primary care institutions was conducted from April 23rd to June 6th, 2018. A pair of trained investigators visited each primary care facility and invited all of the physicians working at the time to complete the questionnaire. An informed written consent was obtained before the respondents self-completed the questionnaire. The survey took about 15 min. Completed questionnaires were returned to the investigators immediately. The investigators examined the completeness of the returned questionnaires. Missing items, if existed, were re-filled through a supplementary interview. A token gift ($1.65) was given to the participants.In total, 712 physicians agreed to participate in the survey, representing 93.44% of all physicians in the participating institutions. About 664 complete questionnaires were returned, of which 499 met the inclusion criteria and passed logic check. This resulted in an effective response rate of 70.08%.The prescription outcome indicators were calculated from the extracted prescription database and then mapped into the questionnaire survey data in line with the ID number of the prescribers. The two institutional variables were obtained from the classification system of the statistics bureau of Hubei government and mapped into the questionnaire data in line with the name of the institutions.t tests for continuous variables with a normal distribution.We compared the differences of respondents between the urban and rural settings, using Chi-square (or Fisher’s exact) tests for binary variables, Wilcoxon rank-sum tests for continuous variable without a normal distribution, and Student A two-level path analysis was performed to test the TAPBM using a mixed effect model. Institutional variations in the individual knowledge, attitudes and prescribing practices were treated as a random effect, with the random intercepts being further predicted by the institutional (cluster-level) variables. The analysis adopted the maximum likelihood with robust standard error (MLR) estimation, which can be applied for variables without a normal distribution. The fitness of data into the model was assessed using three criteria , 41: RMSp value < 0.05 was considered statistically significant.The statistical analyses were performed using STATA (version 12.0) and Mplus (version 6.0). A p < 0.001). Compared with the UCHC respondents, those from the RTHCs were younger, had lower qualifications, lower professional titles, shorter experiences in clinical practices, and lower household income (Table p = 0.001).About 21.64% of respondents worked in the UCHCs. Over half of the UCHC respondents were women compared with only 23.53% in the RTHCs (p < 0.001)  contained antibiotics and 9.28%  contained two or more antibiotics. Those from the RTHCs were more likely to prescribe antibiotics than their UCHC counterparts. But the differences were only statistically significant in the combined use of antibiotics (p = 0.073), although those from the UCHCs were more likely to give a correct answer to antibiotic prescriptions for anaerobes (p = 0.048) and to the standards of antibiotic use in primary care (p = 0.003).The respondents had a mean knowledge score of 6.11 (SD = 1.46) about rational antibiotic prescriptions. The percentage of respondents giving a correct prescribing answer was very low: 5.01% for upper respiratory tract infections, 11.22% for renal failure, 29.06% for methicillin resistant staphylococcus, 46.49% for bacterial pneumonia, and 41.28% for antibiotic treatments crossing the blood-brain barrier. No overall knowledge difference appeared between the UCHC and RTHC respondents (p = 0.006), but blame others for the development of AR (p = 0.017), and prescribe antibiotics for defensive purpose (p < 0.05).The respondents had a mean KAAR-11 score of 27.56 (SD = 3.46). Compared with the UCHC respondents, those from the RTHCs were more likely to recognize AR as a public health problem (p = 0.001) and greater impacts of patient pressure (p = 0.026) compared with their UCHC counterparts.The study participants perceived high levels of patient pressure on antibiotic prescribing. On average, over half (54.91%) of the patients were reported to have an expectation on antibiotic prescriptions. This resulted in a mean patient pressure score of 25.63% (SD = 21.41%) weighted by perceived influence of patient requests. The RTHC physicians perceived higher patient expectations (p = 0.007), indicating a lower time pressure.On average, the physician respondents spent 10.58 min (SD = 6.47) for each patient consultation. The length of patient consultation was longer in the UCHCs than in the RTHCs , although better knowledge was associated with positive attitudes toward rational use of antibiotics . Female physicians were less likely to prescribe antibiotics  but more likely to use two or more antibiotics  compared with their male counterparts. Higher qualifications were associated with less prescriptions of antibiotics . Professional title, experience of clinical practices, and continuing education were not significant predictors (p > 0.05) on knowledge, attitudes and practices in antibiotic prescribing  and higher use of antibiotics . Higher time pressure was associated with higher use of antibiotics , although it failed to predict attitudes toward rational use of antibiotic . Higher household income was associated with lower use of antibiotics  and lower combined use of antibiotics .External factors: perceived higher patient pressure was associated with negative attitudes towards rational use of antibiotics . The facilities servicing communities with a higher socioeconomic status were less likely to prescribe antibiotics  and less likely to use combined antibiotics . The institutional variables did not predict the knowledge and attitudes of physicians (p > 0.05).At the cluster-level, rural location was a significant predictor of higher use of antibiotics  in Scotland . But in Clearly, interventions targeting prescribers alone on their knowledge and attitudes are not enough to curb over-prescriptions of antibiotics. In another study using the theory of planned behavior, we also found that antibiotic prescribing is not under the volitional control of physicians .Individual characteristics of prescribers can shape antibiotic prescribing practices. Several studies revealed that female physicians are less likely to prescribe antibiotics , 45, conHigher medical qualifications were found to be associated with less antibiotic prescriptions in this study after adjustments of knowledge levels. This may be attributable to the professional culture. Formal and systematic medical training may boost the confidence of practitioners  and encoIt appears that external factors play a more important role in predicting antibiotic prescribing. Similar to findings of other studies , 49–52, There is no direct evidence in this study to prove that antibiotic prescribing practices are associated with financial incentives. However, low household income of physicians was found to be associated with high antibiotic prescriptions. Such a link was also documented in some previous studies . DespiteThe institutional variations in antibiotic prescribing practices are concerning. Rural health facilities and those servicing communities with a low socioeconomic status are relatively poorly resourced. But they are more likely to prescribe antibiotics than their better-off counterparts. China is not alone. Similar phenomena were also observed in Italy , SwitzerPolicy interventions targeting external factors associated with antibiotic prescribing are essential. Although medical education by itself is important , it can To address the external determinants revealed in this study, several interventional strategies should be highlighted according to the empirical evidence published in the literature:(1) Better communication skills and “wait-and-see” approach may help physicians to deal with patient pressure for antibiotics –65. A st(2) Patients can be educated through social marketing campaigns to improve their understanding on the use of antibiotics and subsequently reduce requests for antibiotics . However(3) There is a need to improve governance and management competencies in primary care. The funding system should encourage prescribers to make decisions based on the clinical conditions of their patients, not financial gains , 70. A pAntibiotic prescribing is a complex process shaped by both intrinsic  and external  factors. A systems approach is required to curb over-prescription of antibiotics in China. Apart from educating prescribers, it is equally important, if not more, to educate patients to ease the pressure from patient requests. Management also plays an important role in changing prescribing behaviors.The link between high use of antibiotics and low socioeconomic status is concerning. Further studies are warranted to explore the underlying reasons of higher antibiotic use in rural and low socioeconomic settings in China.Additional file 1:Table S1. Survey instrument. (DOCX 33 kb)


Breast cancer remains a global challenge, and further chemopreventive therapies are still immediately required. Emerging evidence has revealed the potent anti-cancer effects of biguanides, Metformin (MET) and phenformin (PHE). Thus, to explore an efficient chemopreventive strategy for breast cancer, the antiproliferative effects of the combination of MET and PHE against breast cancer cells were assessed. Cytotoxicity of the drugs individually and in combination against T47D and MDA-MB-231 breast cancer cells were assessed using MTT assay and the median-effect method was used to analyze the precise nature of the interaction between MET and PHE. Besides, the expression levels of hTERT after 48 hr drug exposure were determined using qRT-PCR.  Based on the cytotoxicity assay, both MET and PHE further inhibited the growth of MDA-MB-231 cells compared with T47D cells. It was found that MET+PHE reduced the IC50s of MET and PHE in both cells drastically more than the single treatments in a synergistic manner. Importantly, MET+PHE showed higher antiproliferative effect with smaller IC50 values against MDA-MB-231 cells than against T47D cells. P<0.001).Real-time PCR results revealed that hTERT expression was significantly reduced in both breast cancer cell lines treated with MET+PHE than the single treatments. In comparison between two types of breast cancer cells, it was detected that MET+PHE could further decline hTERT expression in MDA-MB-231cells than in T47D cells (It is speculated that the combination of MET and PHE may be a promising and convenient approach to improve the efficiency of breast cancer treatment.speculated that the combination of MET and PHE may be a promising and convenient approach to improve the efficiency of breast cancer treatment. Moreover, about 40,610 women are estimated to die from the cancer  and phenformin (PHE)  were prepared from the cell bank of the Pasteur Institute of Iran. phenformin, metformin, streptomycin, and dimethyl sulfoxide -2,5 diphenyltetrazolium bromide (MTT) powder were supplied by Sigma-Aldrich; RPMI 1640 and fetal bovine serum (FBS) were purchased from Gibco BRL ; sodium bicarbonate and penicillin G were purchased from Merck ; First Strand cDNA Synthesis Kit was purchased from Fermentas ; and SYBR Green was purchased from Roche (Germany). All chemicals were used without further purification.In vitro cytotoxicity 2 at 37 °C.RPMI 1640 medium supplemented with 10% FBS and 1% penicillin/streptomycin were used to culture T47D and MDA-MB-231 breast cancer cells. The cells were incubated in a humidified atmosphere containing 5% CO4 cells/well were cultivated in 96-well plates for 24 hr and then, treated with serial concentrations of MET , PHE  and MET+PHE. After 48 hr exposure time, the medium was replaced with fresh medium and 2 mg/ml of MTT was added to each well and plates were covered with aluminum foil and incubated for 4 hr at 37 °C. Thereafter, the content of the wells was removed and 200 μl pure DMSO and 25 μl Sorensen’s glycine buffer were added. In the next step, the absorbance of each well was read at 570 nm using ELISA plate reader (Bio-Tek Instruments) with reference wavelength of 630 nm. Cytotoxic activity was studied using MTT cell viability assay after 48 hr treatment of cells with MET, PHE, and their mixture. Metabolically active cells decrease the tetrazolium constituent of MTT to purple colored formazan crystals. Briefly, 2 × 10RNA extraction, cDNA synthesis, and real-time PCR=2 - ΔΔCt.In this research, the mRNA level of the hTERT gene was studied, using real-time RT-PCR. T47D and MDA-MB-231 cells were treated with different concentrations of MET, PHE, and MET+PHE for 48 hr. After drug exposure time, total RNA was isolated using the Trizol reagent by referring to the manufacturer protocol. Then, the quantity and quality of total RNA were assessed based on OD260/280 ratio measurements and electrophoresis on 1.5% agarose, respectively. To gain cDNA, equal amounts of RNA were taken from all samples and reverse transcribed using RevertAid First Strand cDNA Synthesis Kit (Thermo scientific). Next, the level of hTERT gene expression was determined by the quantitative real-time PCR method using specific primers  , and HotStatistical analysisP-values less than 0.05 were considered significant.All experiments were done in three replicates and values displayed are representative for at least three independent experiments. Graph Pad Prism 6.7 was used for statistical analysis. All results of the experiments were expressed as the mean ± standard deviation (Mean ± SD). Levels of the statistical significance were measured using the paired Student t-test when comparing two groups, or by two-way ANOVA. Cytotoxicity and synergistic effectMTT assay was applied to assess the cytotoxic effects of MET, PHE and MET+PHE on T47D and MDA-MB-231 breast cancer cells after 48 hr treatment. The results showed that both MET and PHE significantly inhibited T47D and MDA-MB-231 cell growth in a dose-dependent manner . 50) values for the drug formulations against MDA-MB-231 cells for 48 hr incubation time. Based on the data analysis of the cytotoxicity assay, the IC50s of both MET and PHE for MDA-MB-231 cells were lower than T47D cells, indicating enhanced sensitivity of the TN phenotype. Also, it was found that the combination of MET and PHE led to a drastic reduction in IC50s of MET and PHE in two cell types relative to the single treatments. According to the IC50 values, MET and PHE in combination form showed higher antiproliferative effect with smaller IC50 values against MDA-MB-231 cells relative to the T47D cells. The precise nature of the interaction between MET and PHE in combination form was further analyzed by the median-effect method, where the CI values higher than, equal to, or lower than 1 indicate antagonism, additivity, or synergism in drug combinations, respectively . AccordihTERT expressionTo further explore the mechanisms involved in MET and PHE combination-mediated inhibition of breast cancer cells, qRT-PCR was applied to measure the expression levels of the hTERT gene. Therefore, the expression levels of the gene were determined after 48 hr drug treatment of breast cancer cells. P<0.05).Real-time PCR results showed that various concentrations of MET and PHE inhibited hTERT gene expression in T47D and MDA-MB-231 cells in a dose-dependent manner. As shown in In the current work, the cytotoxic effects of MET and PHE combination were assessed against T47D and MDA-MB-231 breast cancer cells. The investigation revealed high capability of the combination to decrease the proliferation of breast cancer cells through suppression of hTERT expression.We found that MET and PHE single treatments displayed antiproliferative effects against both types of breast cancer cells in a dose-dependent manner. The findings are consistent with those from previous reports that revealed the inhibitory activity of MET and PHE on the growth of different types of breast cancer cell lines -22. in vitro and in vivo, evidently since MET needs an organic cation transporter (OCT) to penetrate cancer cells  progenitors . In co-cer cells . As a therapeutic for diabetes, PHE application was withdrawn from clinical application in relatively few countries in the late 1970s, due to a higher incidence of lactic acidosis in patients with renal failure relative to MET treatment, however, it was recently reported that supplementation of PHE with 2-deoxyglucose may prevent the risk of lactic acidosis . Hence, MDA-MB-231 is a triple-negative breast cancer (TNBC) cell line with aggressive features and resistant to several anti-cancer drugs. Furthermore, MDA-MB-231 cells are for p53 and tumor-suppressor kinase LKB1, which make the cells even more resistant to anti-cancer agents . LKB1 isIn this study, we evaluated whether combining MET with PHE has a greater cytotoxicity effect against T47D and MDA-MB-231 breast cancer cells than the single treatment of the drugs. Our results suggest that MET and PHE in combination form were strongly effective in killing the cancer cells. The combination of MET and PHE markedly decreased cell growth in two breast cancer cell types relative to the single treatments in a synergistic manner. The combination of MET with chemotherapeutic agents such as paclitaxel, carboplatin, epirubicin, doxorubicin, 5-FU, and cyclophosphamide have been extensively reported -30. ReceIn one of the few studies, PHE plus oxamate  was assessed against various cancer cell lines including breast cancer, tonsil epithelial cancer, melanoma, and colon cancer . It was Remarkably, MET experiences a variety of molecular mechanisms when it merges with various anti-cancer agent drugs. Inhibition of HIF-1, p-gp, and MRP1 expression plays a major function and is the major mechanism of MET when combined with anti-metabolites. On the other hand, activation of the AMPK/mTOR pathway is the major mechanism of MET in combination with hormone modulating drugs . Additioet. al., telomerase activity can be regulated through MET treatment in various cancer cells. It was shown that MET strongly inhibits proliferation of endometrial cancer cells in a dose-dependent manner. Moreover, MET caused hTERT reduction, G1 arrest, and apoptosis induction (To explore the mechanisms involved in MET and PHE combination-mediated inhibition on breast cancer cells, the expression levels of the hTERT gene were assessed and our data suggest that the synergistic cytotoxic activity of the combination involves simultaneous inhibition of hTERT expression. Based on a study by Cantrell nduction . In the present study, the alteration in hTERT expression levels was surveyed to explain the molecular mechanism of MET and PHE combination-mediated synergistic anticancer effects. Nevertheless, deep exploration is required to provide exact mechanisms involved in the synergistic anticancer effects of the combined MET and PHE. Furthermore, considering some hurdles such as poor water solubility and low cellular uptake, which limit the effectiveness of the drugs, using co-nanodelivery systems may improve their bioavailability and cause strong synergistic anticancer effects against breast cancer cells -42. . According to these results, it can be suggested that the combinatorial chemotherapy based on MET and PHE may be a rational and cost-effective strategy for breast cancer therapy. The present work revealed that the combination of MET and PHE synergistically exerts growth inhibitory effects against T47D and MDA-MB-231 breast cancer cells through down-regulation of hTERT expression levels


The main objectives of this study are (1) to investigate the effects of heating and cooling on the static and dynamic residual properties of 35 MPa (5000 psi) concrete used in the design and construction of nuclear reactor auxiliary buildings in Korea; and (2) to establish the correlation between static and dynamic properties of heat-damaged concrete. For these purposes, concrete specimens (100 mm × 200 mm cylinder) were fabricated in a batch plant at a nuclear power plant (NPP) construction site in Korea. To induce thermal damages, the concrete specimens were heated to target temperatures from 100 °C to 1000 °C with intervals of 100 °C, at a heating rate of 5 °C/min and allowed to reach room temperature by natural cooling. The dynamic properties (dynamic elastic modulus and dynamic Poisson’s ratio) of concrete were evaluated using elastic wave measurements  before and after the thermal damages. The static properties  of heat-damaged concrete were measured by the uniaxial compressive testing in accordance with ASTM C39-14 and ASTM C469-14. It was demonstrated that the elastic wave velocities of heat-damaged concrete were proportional to the square root of the reduced dynamic elastic moduli. Furthermore, the relationship between static and dynamic elastic moduli of heat-damaged concrete was established in this study. The results of this study could improve the understanding of the static and dynamic residual mechanical properties of Korea NPP concrete under heating and cooling. Auxiliary buildings of a nuclear reactor are often located adjacent to the reactor containment structure in a nuclear power plant (NPP). These buildings house most of the auxiliary and safety systems associated with the reactor, such as radioactive waste systems, chemical and volume control systems, and emergency cooling water systems. Many parts of the structures, systems and components (SSC) in NPP auxiliary buildings are made of concrete materials that help in disaster prevention by minimizing environmental impacts. This is achieved by preventing outflow of radioactive materials in extreme conditions such as nuclear accidents. In addition, concrete in the structures provides the environment necessary for operation of NPPs by protecting SSC in service state. Unlike typical structures, concrete in NPPs could be exposed to heating and cooling conditions in a variety of temperature environments. From the perspective of safe and reliable operation of NPPs, it is important to understand the variation of mechanical properties of NPP concrete according to heating and cooling actions, to develop an effective method for the condition assessment of heat-damaged concrete in structures, and, if needed, to decide proper maintenance strategies .There are various testing methods for evaluating heat-induced damages in concrete. An initial level of the evaluation relies primarily on visual inspection and sounding (or hammer tapping). However, visual inspections provide only superficial information and the results depend on the experience of the inspector. The sounding method is subjective in nature and requires experienced inspectors to obtain accurate results. Furthermore, assessments of local components based on destructive tests (or invasive test) have been used to acquire more detailed information on physical and chemical changes in heat-damaged concrete. Various analysis techniques could be used in the laboratory  . HoweverThe NDT methods based on elastic wave velocity measurements  have gained popularity for the condition assessment of heat-damaged concrete, both in the field and laboratory. Some researchers have evaluated the dynamic elastic modulus of heat-damaged concrete by measuring the resonance frequency of cylindrical or prismatic concrete in the laboratory ,4,5,6. SIt is of importance to obtain the correlation between static and dynamic mechanical properties of heat-damaged concrete for the reliable condition assessment of concrete in structures exposed to various heating and cooling conditions. Static mechanical properties  of heat-damaged concrete have been studied extensively in the literature and summarized by previous researchers ,13,14. Hquations : (1)Vp=ESpecial cares should be needed to evaluate the dynamic mechanical properties of concrete, non-homogeneous but statistically isotropic material, from the elastic wave velocity measurements because different wave velocity measurements  before C597M-16  and ASTMThe concrete used in this study had a strength of 35 MPa (5000 psi), used for the design and construction of nuclear auxiliary buildings in Korea. The concrete specimens (100 mm by 200 mm cylinder) were fabricated using materials directly sourced from a batch plant located in an actual NPP construction site in Korea. The concrete was made of type 1 Portland cement, siliceous aggregates , with water-to-cement ratio of 0.4 and nominal maximum aggregate size of about 25 mm (1 inch). Details of the concrete mix proportion is confidential and not provided in this study. Forty-three concrete cylinders were cast in 100 mm by 200 mm plastic molds in accordance with ASTM C31/C31M . Thirty-The concrete specimens were heated inside a programmable electric furnace that can control a temperature history for heating a. The elT = c0eγt, where c0 is a constant dependent on a target temperature in a unit of °C; γ is cooling rate about −0.14/h for all concrete specimens and the different target temperature levels; T is temperature of the concrete and t is time in a unit of hour).In this study, the temperature of the electric furnace was kept constant around the target temperature until the core temperature of concrete caught up with the surface temperature. The heated concrete cylinders were thus presumed to reach the thermally-steady-state condition at target temperatures. Specifically, the steady state condition was defined as the temperature when the core of the concrete was equal to the surface temperature of the concrete, or when the internal temperature increment rate fell below 0.5 °C/min. After reaching the steady state condition, the heat source of the electric furnace was turned off and naturally cooled in an airtight state. In the cooling period, temperature decrease in concrete follows an exponential function   as follows:t through the material, the time delay in the measurement system mt should be subtracted from the time directly measured from the time signals rt as follows:mt  caused by coating, cables and equipment was determined by measuring the travel time of an ultrasonic pulse when the tips of the receiver and the source transducers are in contact. In the velocity calculation, the longitudinal length of specimens L was measured from concrete cylinders just before the UPV (ultrasonic pulse velocity) measurements.To obtain the actual wave travel time terature , and an terature . The intLf and transverse Trf modes.The free-free resonance frequency (FFR) test was used to measure unconstrained compressive wave velocity and shear wave velocity of heat-damaged concrete cylinders. CV and SV were calculated using Equations (8) and (9), respectively.Lf and Trf are fundamental resonance frequencies for longitudinal and transverse modes, respectively, measured by the FFR test; L is the length of a concrete cylinder  as follows 2/14.10 [km/s]2), 10% (1.35 [km/s]2/12.57 [km/s]2) and 12% (0.64 [km/s]2/5.25 [km/s]2) of the initial values at room temperature, respectively. Further increase of the temperature from 600 °C to 1000 °C decreased the square values of the three velocities, with a slower reduction rate, and dropped the values to almost zero at 1000 °C.PV, CV, and SV) shown in 2 → CaO + H2O) causes shrinkage of concrete and changes in the microstructure of cement pastes. At the temperature between 500 °C to 600 °C, the phase of quartz (SiO2) in aggregates converts from α to β, which causes a volume expansion of about 0.45%, and promotes microcracking with increasing internal stress of concrete, especially for siliceous aggregate concrete [Abrupt decrease of elastic wave velocities of concrete , M is the mass of specimens in kg and D is the diameter of a cylinder in m. The dynamic elastic moduli gradually decreased with temperature, and at 1000 °C, dropped by about 90% of sound concrete. STM C215  as follod,PE, d,CE and d,SE are dynamic elastic moduli of concrete based on pV, cV and sV, respectively; and d,PE, d,CE, and d,SE) are shown as open circles with black, blue, and red colors, respectively. Note that d,PE and d,SE values in For comparison, three dynamic elastic moduli were evaluated from the three elastic wave velocities using Equations (18)–(20).d,LRE) with different Poisson’s ratios. First, d,CE values are close to d,LRE values, with RMSE (root mean square error) of 0.31 GPa, regardless of Poisson’s ratio. In contrast, d,PE and d,SE values based on Poisson’s ratio of 0.2 slightly deviated from d,LRE values, with RMSE of 1.04 GPa and 0.63 GPa, respectively. It was observed that the d,PE and d,SE values determined on the basis of measured dynamic Poisson’s ratios  resulted in smaller RMSE  and Popovics [3). Interestingly, although proposed at room temperature, the static and dynamic moduli relations proposed by Lydon and Balendran [Popovics  proposedalendran  and Popoalendran  showed galendran  showed aT increased from 20 °C to 1000 °C. At 1000 °C, the concrete lost about 95% of initial strength at 20 °C. tandards ,34,35. T ACI 216 . In contsE and compressive strength cF for both normal-strength and high-strength concrete:ACI 318  and ACI k1 and k2 are a correction factor for the type of coarse aggregates and supplementary cementitious materials, respectively. The static elastic modulus predicted by the equations, proposed by ACI 363 committee [Noguchi et al.  proposesommittee  and Noguommittee , was in ommittee , this apAn approximate expression relating the static elastic modulus and compressive strength was obtained by non-linear regression using the following power function relationship:a = 0.01425 and b = 1.994, with the least R-square of 0.9826. The RMSE between the measured and predicted static elastic modulus using the proposed curve was 1.148 GPa, which shows good agreement between the experiments and the model’s predictions. Regression analysis was performed using the Nonlinear Least Squares method and the Trust-Region algorithm in the MATLAB curve fitting toolbox. In this study, the best-fit curve was obtained at (1)Residual static mechanical properties  of NPP concrete in Korea decreases as maximum exposed temperature increases. However, it was observed that exposure to high temperature affects the two residual mechanical properties of concrete in different ways: The heat-induced damages decrease the elastic modulus of concrete more rapidly than the compressive strength of concrete. The residual compressive strength decreases linearly with increasing temperature from 20 °C to 1000 °C. At 1000 °C, the residual compressive strength is about 10% of the initial strength at room temperature. In contrast, the residual static elastic modulus decreases more rapidly with increasing temperature from 20 °C to 600 °C. At 600 °C, the residual modulus is only 10% of the initial value.(2)The residual dynamic elastic modulus of concrete decreases as the severity of heat-induced damage increases. At the same temperature, the dynamic elastic modulus was slightly greater than the static elastic modulus. The relationship between static and dynamic elastic moduli of heat-damaged concrete was established in this study. An interesting finding in this study is that the experimental results of heat-damaged concrete are in good agreement with famous equations relating static and dynamic elastic moduli of solid concrete at room temperature.(3)The three wave velocities (unconstrained and constrained compressive wave velocities and shear wave velocity) of heat-damaged concrete are mainly dominated by residual dynamic elastic modulus: the square of the wave velocity of concrete is proportional to the dynamic elastic modulus of the concrete. This relationship is consistent with the elastic wave propagation theory established for isotropic and homogenous solid materials.(4)This study is based on the results of experiments using concrete employed at an actual nuclear power plant construction site in Korea. Therefore, this study could contribute to better understanding of the static and dynamic mechanical properties of heat-damaged concrete in NPPs in Korea. However, this study is based on experiments in a laboratory using a single concrete mixing proportion (35 MPa NPP concrete in Korea) and only one type of heating and cooling process. Therefore, more studies based on various concrete mixture proportions and heating and cooling scenarios are needed to gain generality of the results in this study.A series of experimental studies was performed to investigate the effects of heating and cooling on the static and dynamic residual properties of 35 MPa (5000 psi) concrete used in the design and construction of nuclear reactor auxiliary buildings in nuclear power plants (NPPs) in Korea. The specific conclusions obtained from this study are summarized as follows:


Antibiotics require more prudent prescribing, dispensing and administration than other medicines because these medicines are at a greater risk of antimicrobial resistance (AMR). Studying the current medicine use practices and factors affecting the prescribing of an antibiotic would help decision makers to draft policies that would enable a more rational use of medicines.A prospective, descriptive, and cross-sectional study was conducted to assess the current prescribing practices including antibiotics use in six community pharmacies in Asmara. A total of 600 encounters were reviewed using the WHO core prescribing indicators between May 5 and May 12, 2019 using stratified random sampling technique. Descriptive statistics and logistic regression were employed using IBM SPSS® (version 22).The average number of medicines per prescription was 1.76 and 83.14% of the medicines were prescribed using generic names while 98.39% of the medicines were from the National Essential Medicines List (NEML). The percentage of prescriptions containing antibiotics was 53%. The number of encounters containing injections was 7.8%. Patient age, gender and number of medicines prescribed were significantly associated with antibiotic prescribing at bivariate and multivariable models. Subjects under the age of 15 were approximately three times more likely to be prescribed antibiotic compared to subjects whose age is 65 and above (Adjusted Odds Ratio (AOR): 2.93, 95%CI: 1.71–5). Similarly, males were more likely to be prescribed antibiotic than females . Subjects to whom three to four medicines prescribed were two times more likely to be prescribed an antibiotic compared to those who were to be prescribed one to two medicines per encounter . A one-unit increase in the number of medicines increased the odds of antibiotic prescribing increased by 2.02 units .This study found that the percentage of antibiotics being prescribed at the community pharmacies in Asmara was 53% which deviated significantly from the WHO recommended values (20–26.8%). Furthermore, the percentage of encounters with an injection was 7.8% lower than the WHO value of 13.4–24.0%. Patients’ age, gender and number of medicines were significantly associated with antibiotic prescribing. The World Health Organization (WHO) defines rational use of medicines as giving the right medicine, for the right patient, at the right dose, for the right duration and at the right (lowest) cost to them and their community . DiffereJudicious use of antibiotics in the ambulatory setting contributes to the rational use of antibiotics as a whole because antibiotic consumption in the community setting is an important part of the general antibiotic consumption. Outpatient pharmacies are good starting places where information regarding antibiotic use in the community could be gleaned from. According to the Center for Diseases Control (CDC), 30% of all antibiotics prescribed in outpatient clinics in the United States are unnecessary. Even when antibiotics are needed, states the study, prescribers are often inclined to prescribe medicines that may be less effective and carry more risk over the “first-line” medicines recommended by essential medicines list (EML) or national guidelines .Low income countries (LIC) suffer from an increased burden of infectious diseases, shortage of medicines and competent healthcare professionals. Prescribers when faced with shortage of medicines are more likely to prescribe irrationally. AMR rates are higher in LIC as compared to high income countries (HIC) and irrational medicine use is higher in developing countries than the developed world , 14, 15.There are many factors which could affect whether a patient is prescribed an antibiotic or not. Gender and age could determine the extent of antibiotic prescribing. A study done in the UK reported that females received 43% more antibiotics than males, and adult females were more likely to receive an antibiotic than either children or elderly .WHO in collaboration with the International Network of Rational Medicine Use (INRDU) has developed a group of indicators to assess the use of antibiotics in health facilities. The three main indicators are prescribing indicators, facility indicators and patient care indicators. These set of indicators could be used as benchmarks to enable the introduction of antibiotic stewardship programs (ASPs) in different healthcare settings , 3, 15. Eritrea, a small developing country in the horn of Africa, is faced with the challenges of irrational medicine use and implementing rational use of medicines. A recent study conducted in the inpatient setting of a tertiary Eritrean hospital reported a high rate of antibiotic use . Thus stThe introduction of ASP requires the study of antibiotics prescribing behavior in inpatient and outpatient settings as a benchmarking tool before its implementation. Given the notable difference in socio-economic standing among different countries, the prescribing indicators of developing countries deviate significantly from the WHO reference targets [2]. It is our hope that this study would serve as a starter for a much broader study of antibiotics and the introduction of ASPs in Eritrean hospitals.To the best of our knowledge there is no such published research conducted in Eritrea and thus the status of prescribing behavior is unknown. The aim of the study was therefore to assess the current prescribing behavior using WHO core medicine prescribing indicators and to determine the association of patient gender, age and total number of medicines prescribed with antibiotic prescribing.A descriptive and cross-sectional study with a quantitative approach was conducted prospectively to assess prescribing behavior and factors associated with antibiotic prescribing.Eritrea has a total of 49 community pharmacies and 39 drug shops. Out of the 49 community pharmacies, 13 are governmentally owned. Six of the governmentally owned community pharmacies are found in Asmara. Two of them are found inside the national referral hospitals: Orotta and Halibet. Besides, the majority of patients who cannot find their medicines inside the Out-patient department (OPD) pharmacies of hospitals get their medicines from these six governmentally owned community pharmacies located in Asmara because of the better availability and affordability of medicines in these pharmacies. The study was carried out in six governmentally owned community pharmacies in Asmara, the capital city of Eritrea with a population of 427, 183 according to a 2017 report . A “presAccording to WHO, at least 600 encounters should be included to study current prescribing practices of a facility . A stratData was collected from prescriptions prospectively between May 5 and May 12, 2019 by three pharmacists. All the necessary data required to measure the prescription indicators were then entered into a WHO standard prescription indicator collection form. To avoid ambiguities in the definition of an “antibiotic”, a previously set definition by WHO  was emplp < 0.05.The collected data were double entered on CSPro Software (version 7.0) and exported to Statistical Package for Social Sciences  for statistical analysis. Descriptive summaries of the socio-demographic variables were computed using mean, standard deviation (SD) or median interquartile range (IQR) as appropriate. The association between antibiotic prescribing and its predicting factors was explored using logistic regression. Odds ratio with 95% confidence interval was reported in all logistic regression analyses. All analyses were considered significant when A total of 600 prescriptions were analyzed, corresponding to 600 patients, of which 60.3% were female and 38.8% male with a median age of 25 (IQR: 42) Table .Table 1A total of 1055 medicines were prescribed. The average number of medicines per prescription was 1.76 (Standard Deviation (SD): 0.85). Most of the medicines were prescribed by generic name (83.14%). Almost all the prescribed medicines (98.39%) were on the Eritrean essential medicines list. Antibiotics were prescribed in 331 encounters (53%). Forty seven prescriptions had injections amounting to 7.8% of encounters Table .Table 2n = 106/326), Oral Rehydration Salt (ORS) (n = 31/326), omeprazole (n = 22/326) and ibuprofen (n = 21/326).Of the total number of medicines prescribed, 349 (33.1%) were antibiotics. The most commonly prescribed antibiotics were: amoxicillin (42.1%), ciprofloxacin (20.1%), co-trimoxazole (9.5%) and amoxicillin-clavulanate (4.9%). Medicines most commonly co-prescribed with an antibiotic were: paracetamol , gender (p = 0.002) and number of medicines prescribed (p = 0.025) were significantly associated with antibiotic prescribing at the bivariate level (Table Age (el Table .Table 4N = 600) =50.71, p < 0.001 indicating that the model was able to distinguish between respondents who had prescribed to antibiotics and did not. Moreover, good fit was observed as per the Hosmer-Lemeshow goodness fit test . The model as a whole explained between 8.5% (Cox and Snell R-squared) and 11.4% (Nagelkerke R-squared) of the variance in antibiotic prescription and correctly classified 63.0% of those who had antibiotic prescription. Sensitivity of the model, percentage of the group with antibiotic prescription that had accurately identified by the model was 58.3%. Moreover, the specificity was 64.2%.The full model containing all predictors was statistically significant, χ2 , gender (p = 0.013) and number of medicines prescribed (p = 0.014) were still significantly associated with antibiotic prescribing. Subjects under the age of 15 were approximately three times more likely to be prescribed antibiotic compared to subjects whose age is 65 and above . Similarly, males were more likely to be prescribed antibiotic than females . Subjects to whom three to four medicines prescribed were two times more likely to be prescribed antibiotic compared to those who were to be prescribed one to two medicines per encounter  . As the number of medicines prescribed increases by one unit, the odds of antibiotic prescribing increased by 2.02 units .There is a significant increase in antibiotic prescribing with an increase in the number of medicines prescribed . This is slightly higher than the 46% for the Africa Region 0–26%. Th and 58.1We found that in 7.8% of all the encounters at least one injection was included Table . This fiPrescribing using generic name permits dispensers to substitute therapeutic equivalents when one particular brand is not available and generic medicines are cheaper which ensures better availability in the market. Generic name prescribing was 83.1%, lower than the recommended 100% Table . Better Almost all (98.83%) of the medicines were prescribed from the EML Table , this isIn our study 71.9% (251/349) of the antibiotics were on the Access group while 22.1% (77/349) were in the Watch group and no single antibiotic (0%) was from the Reserve group. And 6% (21/349) of the antibiotics were ungrouped in these three classes. From the Watch group, Ciprofloxacin accounts for 90.1% of the total medicines used in the category. Therefore the use of Ciprofloxacin in the community needs to be carefully monitored.This study found significant association of antibiotic prescription with patients’ age, gender, and number of medicines Table . Being uP < 0.001; OR = 2.68, 95%CI 2.20–3.25) [Our study found that males were more likely to receive an antibiotic than females, similar to a study in Bangladesh  and in E20–3.25) .Since the study was a cross-sectional one, the results might not reflect the seasonal variation of medicine use. Furthermore, the findings of the study were based on the capital city, Asmara, so it might not be generalized to the whole country. Further nationwide studies are needed to get the complete picture of medicine use in the country.Our study revealed that the prescribing indicators in the public community pharmacies in Asmara showed deviation from the WHO standard. The percentage of prescriptions which contained an antibiotic was 53% which is double of the optimal values set by WHO (20–26.8%) and the percentage of encounters with an injection was 7.8% lower than the WHO value of 13.4–24.0%. Average number of medicines prescribed per encounter, adherence to EML and percentage of encounters with injection were in compliance the WHO recommended values. Patient age, gender and number of medicines per encounter showed significant association with antibiotic prescribing.To promote generic prescribing and comply with the INRDU/WHO recommendations, regular updating and wide dissemination of National Standard Treatment Guideline and should be promoted, extensive continuing education programmes targeting prescribers should be introduced. At the hospital level, the Medicines and Therapeutic Committees (MTCs) should be strengthened and new MTCs set up in hospitals where no such committees exist. Based under the supervision and recommendation of MTCs ways of introducing Antibiotic Stewardship Programmes (ASPs) should be diligently sought.


Varicella is a highly contagious childhood disease. Generally benign, serious complications necessitating antibiotic use may occur. The objective of this study was to characterize the rate, appropriateness and patterns of real-world antibiotic prescribing for management of varicella-associated complications, prior to universal varicella vaccination (UVV) implementation.Pooled, post-hoc analysis of 5 international, multicenter, retrospective chart reviews studies . Inpatient and outpatient primary pediatric (1–14 years) varicella cases, diagnosed between 2009 and 2016, were eligible. Outcomes, assessed descriptively, included varicella-associated complications and antibiotic use. Three antibiotic prescribing scenarios were defined based on complication profile in chart: evidence of microbiologically confirmed bacterial infection (Scenario A); insufficient evidence confirming microbiological confirmation (Scenario B); no evidence of microbiological confirmation (Scenario C). Stratification was performed by patient status (inpatient vs. outpatient) and country.Four hundred one outpatients and 386 inpatients were included. Mean (SD) outpatient age was 3.6 (2.8) years; inpatient age was 3.1 (2.8) years. Male gender was predominant. Overall, 12.2% outpatients reported ≥1 infectious complication, 3.7% ≥1 bacterial infection, and 0.5% ≥1 microbiologically confirmed infection; inpatient complication rates were 78.8, 33.2 and 16.6%, respectively. Antibiotics were prescribed to 12.7% of outpatients and 68.9% of inpatients. Among users, β-lactamases (class), and clindamycin (agent), dominated prescriptions. Scenario A was assigned to 3.9% (outpatients) vs 13.2% (inpatients); Scenario B: 2.0% vs. 6.0%; Scenario C: 94.1% vs. 80.8%.High rates of infectious complications and antibiotic use are reported, with low rates of microbiological confirmation suggesting possible antibiotic misuse for management of varicella complications.The online version of this article (10.1186/s12889-019-7071-z) contains supplementary material, which is available to authorized users. Varicella zoster virus (VZV) is a highly contagious disease infecting between 2 and 16 per 1000 individuals annually worldwide . GeneralAlthough usually following a benign course of disease, varicella can result in serious complications. In pediatric inpatient populations, the most commonly observed are skin and soft tissue infections, and neurological complications . In addiRecently, concerns over antimicrobial resistance have increased . ProposeThis was a post-hoc analysis of 5 multicenter, retrospective chart review studies conducted as part of MARVEL . Burden of illness associated with varicella in patients ≤14 years of age was evaluated in Argentina (2009–2014) , HungaryEligible patients were inpatients and outpatients with a primary varicella diagnosis by the pediatrician indicated in their patient chart. Outpatients were those who visited the doctor’s office, outpatient clinic/department of hospital, or emergency department (ER) without hospitalization for varicella. Inpatients were defined as those admitted to a hospital for primary varicella, including those initially seen in an outpatient setting.Patients, in an approximate 1:1 ratio of outpatients to inpatients, were identified by investigators, who screened patient charts in their practices from the most recent year to 5 years previously until the target sample size was reached. The date of the first varicella report was identified, and each chart was reviewed from this date until resolution of disease, or date of last contact, if the resolution date was unavailable. Patients were excluded if they received prior varicella vaccination, presented with a second case of varicella, or had herpes zoster.Sociodemographic characteristics, medical history, as well as disease parameters were extracted from patient charts. Varicella-related clinical complications were identified and profiled by complication type , infection type , and microbiological confirmation (yes/no).Antibiotics use, defined as type, dose, and duration of use, were obtained from the patient chart from the date of onset to the date of resolution or last patient contact.All analyses were reported for the total cohort, stratified by patient status (outpatient vs. inpatient), and country. Descriptive statistics were produced for all study variables  for continuous variables, and number and percentage for categorical variables.Distribution of varicella complications was assessed descriptively as the number and proportion of patients with ≥1 clinically diagnosed infectious complication, ≥1 clinically diagnosed bacterial infection, and ≥ 1 microbiologically confirmed bacterial infection. Proportions by complication type were reported for overall clinically diagnosed infectious complications. All “other” complications were coded using the Medical Dictionary for Regulatory Activities, version 18.0/19.0, and were reported by system organ class.The number and proportion of patients reporting use of ≥1 antibiotic was ascertained. Among antibiotic users, the mean number of antibiotics prescribed and duration of use (days), was assessed. Additionally, the number and proportion of patients prescribed ≥1 antibiotic by class and top 5 agents (within the pooled cohort) was evaluated.Scenario A: evidence of a confirmed bacterial infection Scenario B: insufficient evidence to confirm/refute bacterial infectionScenario C: antibiotic prescribed without information confirming a bacterial infectionScenario D: potentially redundant antibiotic use, defined as number of antibiotics prescribed greater than the number of infectious complications.Data collected did not allow for a direct link between infection type and antibiotic prescribed. Instead, antibiotic users were classified as having received antibiotics under 4 prescribing scenarios based on their complication profile present in the patient chart . In addition, for patients classified according to Scenario C and Scenario B/C, the number and proportion reporting ≥1 antibiotic by class and agent was assessed.Cumulative number of days of annual VZV-related antibiotic use was calculated based on previous estimates for the number of inpatient and outpatient cases of varicella by country , 11–13, Statistical analyses were performed using SAS® software version 9.4 .n = 150, 19.1%); Hungary ; Mexico (n = 152 (19.3%); Peru  and Poland . Mean (SD) age in the total outpatient population was 3.6 (2.8) years; inpatients were found to be slightly younger that outpatients [mean (SD): 3.1 (2.8) years], and included more males  , distributed across the following locations: Argentina  and 2 outpatients (0.5%)  among outpatients and 68.9% (n = 266/386) among inpatients (Table The proportion reporting use of ≥1 antibiotic was 12.7% (n = 39/54). Generally, lincosamides were 2nd after β-lactam agents in terms of frequency of use in inpatients , 53.5% (=23/43)], respectively] ; ceftriaxone , cefuroxime , penicillin  and cefalexin ; both Hungarian and Polish inpatients, however, reported cefuroxime as the leading antibiotic agent prescribed, [24.4%  Poland  and Argentina (~ 2.6 million days)  and Scenario B/C  is presented in Table n = 14/16)], and Scenario B/C populations  (Table n = 9/51) and inpatients  with cefuroxime the most common inpatient antibiotic under Scenario C   duration of use of antibiotics prescribed according to Scenario C was 7.0 3.3, 14.7) days and 5.5  days for outpatients and inpatients, respectively; for Scenario B/C classified antibiotics, duration was 7.9  days in outpatients, and 10.4  days in inpatients  and inpatient (78.8%) settings are considerable, with approximately 33% of all inpatient complications involving a bacterial infection, of which > 15% were confirmed microbiologically. Consequently, almost 70% of the inpatient cohort, and an additional 12.7% of outpatients, were prescribed ≥1 antibiotic agent for the treatment of varicella-related complications, for which skin and soft tissue infections were predominant.It is estimated that between 37 and 78% of all-cause pediatric hospital visits worldwide, and 20% of pediatric ambulatory care setting consultations, result in an antibiotic prescription –16. ThisThe top five most commonly prescribed antibiotic agents, in this pooled population, were clindamycin, ceftriaxone, cefuroxime, penicillin, and cefalexin, with β-lactam agents consistently identified as the most frequently prescribed class. These findings are consistent with the Worldwide Antibiotic Resistance and Prescribing in European Children (ARPEC) point prevalence survey, which ascertained inpatient pediatric antibiotic prescribing patterns across 41 countries . ResultsAs the initial study design did not allow for a definitive link to be made between complication and antibiotic, an exact post-hoc classification of antibiotic use was not possible. Instead, to approximate antibiotic prescribing patterns, a set of conservative assumptions were implemented, guiding patient classification into four prescribing scenarios. Consequently, the majority of patients were administered antibiotics without sufficient data in their patient chart to confirm/refute microbiological confirmation (Scenario B), accounting for just over 80% of inpatients and 94.1% of outpatients. Patients under Scenario C (approximation to ‘inappropriate use’) accounted for 6% of inpatients and 2% of outpatients. Recent studies report between 33 and 50% of in-hospital pediatric antibiotic prescriptions are deemed inappropriate –19, withS. pneumoniae [Although the majority of children managed in an outpatient setting did not require antibiotic treatment, antibiotic use in the 5 studied countries was high, and the annual estimated number of cumulative days of antibiotic use was found to range from approximately 80,000 days in Hungary to over 2.5 million days in Argentina. Antimicrobial resistance (AMR) a serious worldwide health problem, has the potential to transform common pathogens into dangerous infections . Latin Aeumoniae , 24. Thieumoniae . Avoidaneumoniae .The burden of varicella may also be addressed through immunization programs. Monovalent or combination  varicella- containing vaccines are approved in immunocompetent children ≥12 months of age in each of the five countries studied ; ArgentiThe current findings should be interpreted in consideration of the study limitations. A major limitation of the current study, as discussed above, relates to the fact that the post-hoc study design prevented a definitive link between antibiotic use and type of complication. Consequently, definitive “use classification” could not be assigned, and the assumptions implemented may have resulted in over or underestimation of rates across different prescribing scenarios. A further limitation is related to the assessment of antibiotic use by class and agent: as prescribing patterns are subject to regional variations and differences in clinical practice guidelines, the rates observed for the total inpatient and outpatient populations may be skewed due to inconsistencies in prescribing practices across countries. Furthermore, the slightly higher number of outpatients in Peru may have skewed the results for the total outpatient population towards the Peruvian data. The lack of information about the type of pathogens and antibiotic susceptibility is another constraint. Finally, the retrospective chart review design of the individual studies contributes to 1) a selection bias due to an overrepresentation of care-seekers, potentially including a subset of patients with more severe disease, 2) an information bias, as data extracted from medical charts is subject to missing, inconsistent or erroneous information, and human error during transcription.Regardless of limitations, the reported high rates of infectious complications and antibiotic use are indicative of high varicella-associated patient, caretaker, and healthcare burden , 11 as wAdditional file 1:Table S1. Definitions of Prescribing Scenarios by Complication Profile. (DOCX 16 kb)Additional file 2:Table S2. Patients reporting ≥1 antibiotic by agent and mean duration of antibiotic use, among antibiotic users by patient status and country (DOCX 24 kb)Additional file 3:Table S3. Cumulative Days of Antibiotic Use by Country based on Annual Number of Pediatric Varicella Cases (DOCX 21 kb)Additional file 4:Table S4. Patients reporting ≥1 antibiotic by agent, and mean duration of antibiotic use, for patients administered antibiotics under Prescribing Scenario C and Scenario B/C- by patient status and country (DOCX 20 kb)


The following study investigates the involvement of optic neuropathy in IgG4-related ophthalmic diseases (IgG4-ROD) based on the magnetic resonance imaging (MRI) data, and different imaging features of IgG4-ROD related optic neuropathy related to other orbital diseases.This retrospective study included 225 patients with IgG4-RD admitted at two ophthalmology centers between January 2014 and December 2017. Twenty-six patients had both pre-therapeutic orbital MRI and optic never injury. The causes of optic neuropathy were analyzed, and the special sign in MRI to diagnose IgG4-ROD was also evaluated.Twelve cases had inflammation of the optic nerve sheath, while 14 cases had compression due to extraocular muscles and pseudo tumor masses. Two cases had hypertrophic cranial pachymeningitis, while one case had hypophysis involving optic chiasma.The most common causes of optic nerve injury in IgG-4 ROD are inflammation of optic nerve sheath, compression of extraocular muscles, pseudo tumor mass and hypertrophic cranial pachymeningitis, and hypophysis involving optic chiasma. IgG4-related disease (IgG4-RD) is a chronic inflammatory disorder characterized by IgG4-positive lymphoplasmacytic infiltrative lesions and elevated serum IgG4 levels , 2. TargEyes are often the first most frequent site associated with IgG4-RD . A numbeOptic neuropathy may be involved in IgG4-ROD, and it can lead to severe injuries. However, this type of disease is more likely misdiagnosed as other orbital inflammatory diseases, such as optic neuritis, Graves’ disease, inflammatory pseudotumor, lymphoma, sarcoidosis and so on . IgG4-ROHence, the purpose of this study was to investigate the radiological features of optic neuropathy from IgG4-ROD in Chinese patients. Furthermore, we suggest a radiological diagnostic criterion for optic neuropathy cases diagnosed as IgG4-ROD.This retrospective study included 225 patients with IgG4-RD admitted at two ophthalmology centers between January 2014 and December 2017. Ocular manifestations were the first symptoms of IgG4-RD. IgG4-RD was diagnosed based on the Japanese Comprehensive Diagnostic Criteria for IgG4-RD : (1) cliThe exclusion criteria were: ocular manifestations were not the first symptoms; pretherapeutic MRI was insufficient for an adequate interpretation; absence of IgG4 testing during the pathology examination; thyroid-related eye diseases and lymphoma and other orbital- related diseases; ocular exam that was insufficient for analysis; patients without visual loss  or optic neuropathy (optic atrophy or papilledema).A flowchart illustrating the selection of patients is shown in Fig. Ophthalmic examinations included slit lamp examination and pupillary reactions in unilateral or bilateral. Visual acuity was examined by the standard table of vision logarithms at 5 m. Those unable to read any letters at the distance of 1 meter were further examined by finger counts, hand movements, or perceiving light. Visual field was performed by Humphrey field Analyzer . Digital fundus photographs were obtained using nonmydriatic fundus photography. Binocular digital photographs were taken using a 45° high-resolution fundus camera ; and retinal fundus images were centered on the optic disc.The MRI of the orbit was evaluated using MRI-3.0 T . Scanning sequences and parameters were the following: coronal T1-weighted Fast spin-echo ; Gd-DTPA 0.1 mmol/kg was used as contrast agent for enhanced MRI, and was combined with fat suppression scan technique. The MR imaging of patients was evaluated by two experienced neuroradiologists (12 and 8 years of imaging experience). From the coronal imaging plane, each extraocular muscle was measured in 2 dimensions (millimeters): maximum diameter and maximum short axis [A total of 26 patients met the inclusion criteria Table . The malThe manifestations of optic nerve injury were visual impairment, visual field detection, papilledema or optic atrophy. The most common manifestations of optic nerve sheath inflammation were mild visual impairment, mild papilledema and peripheral visual field defect Fig. .Fig. 2Th, Fig. Compression was observed in more than half of patients with optic neuropathy, including hypophysis involving the optic chiasm  and MRI –17. In tn = 14) found that 50% of patients with IONE had IgG4-ROD [IONE is the main sign for differentiating optic nerve sheath inflammation of IgG4-ROD from other orbital diseases. The orbital region is the first most frequent site of the head and neck region associated with the suffering from IgG4-RD. , 4 The mIgG4-ROD .Our study has few limitations. This is a study with retrospective design that was conducted only in two centers, thus non-controlled investigation and treatment protocol were considered as limitations. In addition, only 26 cases were included in this study, which means that future studies should include bigger sample size.The most common imaging feature of the optic nerve for IgG4 is compression, while inflammation of the optic nerve sheath is the main reason affecting the visual function. Enhancement of optic nerve sheath is very likely to be combined with dacryoadenitis and infraorbital nerve enlargement. In addition, IONE and infraorbital nerve downwards resulted as important indications for the diagnosis of IgG4-ROD.


The evolution of antibiotic resistance is far outpacing the development of new antibiotics, causing global public health concern about infections that will increasingly be unresponsive to antimicrobials. This risk of emerging antibiotic resistance may be meaningfully altered in highly AIDS-immunocompromised populations. Such populations fundamentally alter the bacterial evolutionary landscape in two ways, which we seek to model and analyze. First, widespread, population-level immunoincompetence creates a novel host environment with disrupted selective pressures. Second, within AIDS-prevalent populations, the recommendation that antibiotics be taken to treat and prevent opportunistic infection raises the risk of selection for drug-resistant pathogens.To determine the impact of HIV/AIDS on the emergence of antibiotic resistance–specifically in the developing world where high prevalence and economic challenges complicate disease management.We present an SEIR epidemiological model of bacterial infection, and parametrize it to capture HIV/AIDS-attributable emergence of resistance under conditions of both high and low HIV/AIDS prevalence.We demonstrate that HIV/AIDS-immunocompromised hosts can be responsible for a disproportionately greater contribution to emergence of resistance than would be expected based on population-wide HIV/AIDS prevalence alone.As such, the AIDS-immunocompromised have the potential become wellsprings of novel, resistant, opportunistic pathogen strains that can propagate into the broader global community. We discuss how public health policies for HIV/AIDS management can shape the evolutionary environment for opportunistic bacterial infections. Escherichia coli, Streptococcus pneumoniae, Mycobacterium tuberculosis, Clostridium difficile, and Staphylococcus aureus, each of which includes strains unresponsive to at least one antimicrobial agent. [The rapid emergence of antibiotic resistant microbes represents a worldwide health risk since development of antibiotics is being outpaced by the evolution of resistance.  Factors l agent. , 3We expect the risk of emergence to be magnified in regions where selection for drug-resistant pathogens is particularly high. Thus, we consider the potential for Human Immunodeficiency Virus- (HIV-) and Autoimmune Deficiency Syndrome- (AIDS-)prevalent populations to serve as hotbeds of emerging resistance. One of the most important tools in opportunistic infection management among the AIDS-immunocompromised is a constant regimen of antibiotics.  However,For these reasons, populations with a high prevalence of active AIDS cases represent novel environments with unique selective pressures leading to potentially drastically different probabilities of emergence of antibiotic resistance, relative to those expected in an immunocompetent population. This is particularly concerning in resource-poor regions where access to full courses of antibiotics may be limited by drug availability and economic constraints.   compartmental model. We paramFully and functionally immunocompetent hosts can still contribute to antibiotic resistance. Thus, we use our model to quantify the relative contribution to the emergence of resistance from both fully immunocompetent and HIV/AIDS patients (HIV/AIDS+) receiving highly active antiretroviral treatment (HAART+). We also compare the actual contribution to emergence attributable to AIDS-immunocompromised hosts to that which would be expected based on AIDS prevalence alone. We do so by computationally reducing HIV/AIDS prevalence to zero in both countries and then measuring the magnitude of the corresponding decreases in infection prevalence and total emergence. Finally, holding antibiotic adherence constant among infectives, we calculate total emergence as a function of gradually increasing HIV/AIDS prevalence.Our model examines the relative rate of emergence of antibiotic resistance in populations whose collective immunosuppression and prescribed antibiotic use patterns disrupt the selective pressures typically exerted on bacterial pathogens by host immune function and medically recommended antibiotic-taking behavior.The vast difference in HIV/AIDS prevalence that exists between Indonesia 0.46%) and Swaziland (27.4%) % and Swa suggestssuperscript, and bacterial infection status and adherence to antibiotics by subscript. (All possible super/sub-script combinations appear in We defined our population according to four descriptors: immune (HIV/AIDS) status, HAART adherence, bacterial infection status, and antibiotic adherence, by which all individuals were classified. We denote immune and HAART status by Considerable variability in antibiotic adherence–and in the prevalence of TB and HIV/AIDS–exists worldwide. The model was therefore run under all combinations of tuberculosis prevalence, host immune status, and antibiotic adherence under parameters representing the HIV/AIDS prevalence in both countries.In both Indonesia and Swaziland, and under conditions of both high and low TB prevalence , we calTo quantify the impact of AIDS-immunocompromised hosts on overall TB prevalence, as well as total emergence, we conducted a trial in which HIV/AIDS prevalence was computationally reduced to zero for each population. We thus calculated the total emergence and total bacterial infections contracted in a fully immunocompetent population without changing the overall host population size or prevalence of infectives. Comparing these two parameters between HIV/AIDS-absent and HIV/AIDS-prevalent populations provided the expected AIDS-attributable increase in emergence. We used this increase to test the neutral assumption that the percentage of emergence associated with each type of infective host should be equivalent to the prevalence of that host category within the total population. For example, in Swaziland, 27.4% of the population is HIV/AIDS+.  Within tFinally, to investigate the full range of AIDS-attributable potential impacts on antibiotic resistance emergence we conducted a trial in which we varied HIV/AIDS prevalence in 5% increments ranging from zero to 30.0%. , we exp––, I+–, and I+ +. In each of the eight possible combinations of Swaziland vs Indonesia, high TB prevalence vs low, and with or without AIDS, we compiled 100 000 samples using Latin hypercube sampling. From these samples, we tested most parameters of the system against the disease burden outcomes to determine which of those parameters were most influential. Note that some of these parameters are basic parameters, from which other parameters are derived.  indicates that intervention strategies with partially-adherent individuals may not be effective , but that strategies targeting untreated individuals may be.The sensitivity to θ The particular impact of When we explored the full range of potential impacts of HIV/AIDS prevalence on emergence of antibiotic resistance, we found that as prevalence increases, we also see a near-linear increase in expected population-wide emergence . This reHighly AIDS-prevalent populations represent a novel pathogen environment due to the combination of widespread immunoincompetence and antibiotic use. In such populations, antibiotics are used more frequently, and for longer periods of time, to treat and guard against opportunistic infections affecting the AIDS-immunocompromised.  This treIn consideration of these circumstances, as well as the high degree of antibiotic misuse that is characteristic of the developing world,  we expecDespite the considerable difference in HIV/AIDS prevalence that exists between Indonesia and Swaziland, the effect of HIV/AIDS on emergence in Indonesia was still concerning–especially in light of our assumption that only 7% of those with HIV/AIDS are actively immunocompromised due to lack of HAART treatment.  Despite i.e., without including parameters for intra-host strain competition or secondary resistant infections arising out of host-to-host or horizontal transmission. We therefore recognize that our results represent a conservative estimate of emergence. Accordingly, future work will address the propagation of resistance that occurs when susceptibles are exposed to resistant infections.Swaziland’s HIV/AIDS prevalence is currently the highest in the world,  yet, HIVThe increased likelihood of resistance emergence that occurs within AIDS-prevalent host populations represents a previously unrecognized global health risk that can be entirely ascribed to the novel environment created by the presence of widespread, population-level immunosuppression. We must begin to consider cross-disease implications for long-term treatments, since emergence of resistance is not solely limited to target bacteria, but also occurs within the greater host microbiome due to both selective pressure and horizontal gene transfer.  This typWe demonstrated that a significant proportion of antibiotic resistance is attributable to AIDS-immunocompromised hosts. Therefore, we must also consider the associated impact–and potential tradeoff between individual and public health–that arises in the context of antibiotic regulation and policy recommendations for treating infection in the developing world. Even discounting the health behavioral choices made by AIDS-immunocompromised individuals, limited and/or excessive access to antibiotics, coupled with the potential for distribution by medical professionals unfamiliar with optimal administration protocols, , 26 ensuS1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.


Papillary renal cell carcinoma (pRCC) is the 2nd most frequent histological type of kidney cancer and accounts for approximately 15% of all renal cell carcinoma. It has a poorer prognosis than clear cell RCC (ccRCC) with a lack of standard treatments.MET amplification. The patient was enrolled in the UNICANCER-sponsored AcSé crizotinib trial (NCT02034981), designed to give an access to crizotinib for patients with tumors harboring a genomic alteration on one of the biological targets of the drug. With 2nd line crizotinib (250 mg twice/day), the patient had a very good tolerance, a partial response in the target lesions using RECIST 1.1, and a 19 months’ clinical efficacy.We report the case of a 51 year old man with a metastatic pRCC  progressive after sunitinib, with a In metastatic pRCC with a MET amplification, crizotinib maybe a potential met-inhibitory therapeutic option. MET pathway have been described in several tumors , and particularly in pRCC where 75% of hereditary pRCC have activating mutations in the Tyr/Kin domain [MET-amplified mpRCC successfully treated during 19 months with the MET-inhibitor crizotinib within the French AcSé- crizotinib program [Papillary renal cell carcinoma (pRCC) is the 2nd most frequent histological type of kidney cancer and accounts for approximately 15% of all renal cell carcinoma (RCC). The classifications distinguish two types of pRCC: type 1  and type 2 . The prognosis of metastatic pRCC (mpRCC) is worse than in clear cell RCC (ccRCC), with a median PFS around 6 months and a median OS around 12 months, versus 10.5 months and 15.7 months respectively for ccRCC . MET pron domain , 5. HereWe describe a patient born in 1961, a manager in the food processing industry, diagnosed with a right renal mass of 50 mm in February 2012, leading to a partial right nephrectomy. Histopathological examination revealed a tubulo-papillary renal cell carcinoma, type 1, grade 2 of Fuhrman, 20% of necrosis, without vascular embolus or peri-renal infiltration, R0, pT1bNx, vimentin +, CD 10+. In September 2013, an abdominal computed tomography scan (CT scan) showed a nodular peritoneal infiltration (right peri-colic), with a sub-cutaneous nodule of the right flank, a mild intraperitoneal effusion in the Douglas pouch, and a pre-rectal nodule. After a control CT scan, confirming the stability of the lesions, surgery was performed. The pathological findings  and the patient was classified in the favorable-risk group according to Heng criteria. Repeat CT scan revealed peritoneal carcinomatosis.The patient was referred to our Comprehensive Cancer Center in April 2014, with a post-operative abdominal mass. His medical history included cigarette smoking (20 packs/year), thyroidectomy (supplementation), non-insulin-dependent mellitus diabetes (metformin) and hypertension . Clinically, he weighed 78 kg for 1.80 m, Karnosky performance scale was 80% and physical examination revealed induration of the abdominal scar. The laboratory tests were normal . The result showed a MET amplification . The absence of chromosome 7 and 12 polysomy was verified in a complementary FISH.After a multidisciplinary board, a treatment by anti-angiogenic sunitinib started in May 2014. Toxicity was mild with grade 1 nausea, grade 2 oesophagitis, and abdominal ascites requiring three ascitic drains. The increase of the peritoneal carcinomatosis was observed on the follow-up CT scan. For this progression, complementary IHC were performed  allowing patients with activating genomic alterations in one of crizotinib target genes suffering from a malignancy other than its approved indication to access crizotinib. The patient commenced crizotinib 250 mg twice/day in November 2014. During the treatment, the patient had a very good performance status (ECOG 0–1), with a 100% professional activity and a stable weight. The only adverse events were grade 1 diarrhoea and asthenia, and no grade 2 or more toxicity was observed. After 3 months of crizotinib, the CT scan demonstrated stable disease, and after 15 months a partial response of − 59% in the target lesions (hepatic dome: 25 to 10 mm / left colonic flexure carcinomatosis: 36 to 15 mm). The Fig. 4981 alloIn March 2015, the patient noticed a progression of a left painless inguinal adenopathy of 54 mm, without progression of the other peritoneal lesions and a normal bone scan. In accordance with the protocol, a volumetric-modulated radiotherapy delivered a dose 35 Gy (10 fractions of 3.5 Gy) and crizotinib was stopped from the day before to the day after the radiotherapy. In November 2015, the periodic CT scan revealed a new node relapse . A CT-guided biopsy confirmed the diagnosis of papillary renal cell carcinoma, that still expressed C-MET 100% (score 3+). Therefore, due to the success of the first treatment, a 2nd radiotherapy was performed (42.5 Gy).Crizotinib was continued for another 6 months, with a good tolerance  and clinical efficacy. As presented in the comparative CT scans of Fig. On May 2016, after 19 months of crizotinib, a relapse was observed with ascites and the patient was treated with axitinib. Three months later, the patient died of progression.MpRCC can be an aggressive disease with a lack of standard treatments, as the most classical drug in 1st line (sunitinib) was only studied in small phase II studies. In 2015, Ravaud et al. treated 61 patients with sunitinib (15 type 1 mpRCC / 46 type 2) with a modest median PFS of 6.6 months (type 1) and 5.5 months (type 2) and only 7/61 partial response . Data coMET amplification led to use crizotinib in 2nd line with a 19 months’ efficacy, and a very good tolerance . The multidisciplinary collaboration of pathologist, molecular biologist, radiation oncologist and medical oncologist led to this successful example of personalized medicine via MET targeting. Interestingly, Diamond et al. described a pRCC patient with an activating MET gene mutation, pretreated by sunitinib and everolimus, with a long response to a tyrosine kinase inhibitor (TKI: PF-04217903) [MET copy number amplifications are more frequent in pRCC  than intracellular domain MET mutations (21%) [Here, we present the case of a man with a mpRCC, progressive after sunitinib, for which the diagnosis of ns (21%) ; moreoveMET implication in pRCC was made in 1997 with the discovery that hereditary pRCC patients had a germline missense mutation in the MET proto-oncogene (7q3 locus), leading to constitutive activation of the MET protein [n = 164) described MET mutations in 17 tumors, mainly in type 1 pRCC and in the tyrosine kinase domain (14/17), and discovered an alternate MET RNA transcript leading to a constitutive activation of MET in a ligand-independent manner [Biologically, the proof of  protein . Recentl protein . And it  protein . Anothere domain /17, and MET-amplification (n = 2) and only 1/18 patients (5%) with a gain of chromosome 7 responded. Second, tivantinib  had very poor outcomes in PFS (median: 2 months) and OS (median 10 months) and had a 0% response rate (n = 70) [n = 109) [This biological evidence for the implication of MET in both hereditary and sporadic pRCC have led to design trials with MET inhibitors in pRCC , 16. Hown = 109) . Interesn = 109) . This trConcerning crizotinib, this treatment is a currently available MET-ALK-ROS1 inhibitor, with a favourable toxicity profile, and is well known by medical oncologists for the treatment of non-small cell lung cancer , 22. At Our case report illustrates and reinforces this finding that crizotinib is more active in MET driven pRCC, and that a precise molecular diagnosis is crucial for the optimal care of pRCC. This precision treatment (crizotinib) was possible thanks to an original biology-driven national French program (AcSé crizotinib NCT02034981), giving access to crizotinib for patients with identified activating genomic alterations in the crizotinib target genes, with a safe monitoring . Today, In conclusion, the molecular documentation of MET in pRCC seems crucial, as MET inhibitors like crizotinib are effective, safe, and nowadays available.


Immunoglobulin G4-related disease is a fibroinflammatory systemic disease that is characterized by focal or diffuse organ infiltration by immunoglobulin G4-bearing plasma cells. Immunoglobulin G4-related disease may affect any organ, and a high index of suspicion is necessary for early detection to avoid irreversible fibrosis, organ dysfunction, and death. Tumor-forming lesions are common radiological features of immunoglobulin G4-related disease that need to be differentiated from malignancies. The diagnostic approach requires the integration of clinical, biochemical, and radiographic manifestations with classic histopathologic features, which remain crucial to diagnosis. The histology of immunoglobulin G4-related disease is determined by a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis in the presence of increased immunoglobulin G4-positve plasma cells. Although immunoglobulin G4-related disease forms a distinct, clinically independent disease category, many questions and problems remain unanswered, especially on its pathogenesis and the role of immunoglobulin G4. Advances in the understanding of immunoglobulin G4-related disease are likely to change the diagnostic approach in the future and create potential targets for therapeutic purposes. Here we describe the concept of immunoglobulin G4-related disease and the most recent knowledge in the clinico-pathological characteristics on this emerging disease. This study can guide clinicians in early diagnosis and prevent unnecessary surgical resections. Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic immune-mediated disease that can affect any organ in the body. IgG4-RD was first described by Sarles et al.  in 1961 IgG4 is the least abundant in the IgG subclass and accounts for <5% of the total IgG in healthy individuals . The oveThe exact mechanism of IgG4-RD remains unknown. One proposed mechanism is linked to Th2 cells, which are involved in the regulation of IgG4 production. Th2 cells secrete interleukins , which activate B cells to switch to IgG4 and IgE  demonstrThe clinical presentations of IgG4-RD are widely variable and can manifest in one or more organs synchronously or metachronously. IgG4-RD usually presents as a subacute or chronic process, and it can range from mild localized symptoms to major tissue damage and subsequent organ failure. Most patients are not constitutionally ill, so fever, malaise, night sweats, or weight loss are unusual . TumorouImaging is usually the first diagnostic tool to identify the tumorous swellings that occur in patients with IgG4-RD. Computed tomography (CT) may delineate a focal or diffuse pseudotumoral swelling of organs and identify the extent of multiorgan involvement. However, multiorgan involvement may be better assessed by 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) ,21. ImagThe pancreas was the first organ associated with increased serum levels of IgG4 ,25. Two IgG4-related sclerosing cholangitis is commonly associated with type 1 AIP. Solid mass lesions in hilar and perihilar ducts show close resemblance to primary sclerosing cholangitis and cholangiocarcinoma . Given tMikulicz’s disease, which consists of symmetrical swelling of the lacrimal and salivary glands, is now recognized as IgG4-related dacryoadenitis and IgG4-related sialoadenitis (IgG4-RS) . BilaterIgG4-RD can cause orbital inflammation that involves the lacrimal glands, extraocular muscles, orbital soft tissues, sclera, nasolacrimal duct, and trigeminal nerve; it is sometimes accompanied with bone destruction and development of a saddle nose deformity . Unlike Sinonasal manifestations of IgG4-RD, although rare, have been reported and are now a recognized entity with two patterns of presentation . PatientThyroid gland IgG4-RD includes Reidel’s thyroiditis and fibrosing Hashimoto’s thyroiditis. Reidel’s thyroiditis is a chronic fibrosclerotic disorder that was first described by Reidel  in 1896;IgG4-related kidney disease (IgG4-RKD) usually becomes clinically obvious when there is renal dysfunction or discovered incidentally as multiple low-density lesions on imaging . Common IgG4-related retroperitoneal fibrosis (IgG4-RRPF) is characterized by chronic inflammatory and infiltration of fibrotic tissue in the periaortic or periiliac retroperitoneum that encases adjacent structures . DiffereIgG4-related lymphadenopathy (IgG4-RL) may be seen incidentally in excisions made for extranodal disease or detected in patients with symptomatic systemic IgG4-RD . IgG4-RLClinical symptoms observed in patients with IgG4-related lung disease are nonspecific and include cough, chest pain, and dyspnea . Low-graHelicobacter pylori treatment  are met. The diagnosis of IgG4-RD is considered probable when (a) and (b) are met. When (a) and (c) are present, it is deﬁned as possible diagnosis. Treatment is generally advocated in patients with either a definite and probable diagnosis especially in patients with an active disease.Although the histopathological findings can provide strong supportive evidence for the diagnosis of IgG4-RD, correlation with the clinical presentation and radiographic findings is often required to make a definitive diagnosis. Some organ-specific diagnostic criteria exist for certain organs such as IgG4-related sclerosing cholangitis , but conMost patients with IgG4-RD respond to corticosteroids, which remain the first line of treatment. A suggested treatment scheme based on the international consensus guidance statement ,75 on thConventional corticosteroid sparing drugs, such as azathioprine, mycophenolate mofetil, and methotrexate, are widely used either to achieve additional immunosuppression or as steroid sparing agents . Both prRituximab, an anti-CD20 monoclonal antibody, induces B-cell depletion to result in a decrease in IgG4-positive plasma cells and serum IgG4 ,78. In aIgG4-RD is a widely recognized systemic disorder that exhibits pathological features, which remain consistent in any affected organ. Substantial progress has been achieved in the diagnosis and management of IgG4-RD, but many questions remain unanswered in determining the pathogenesis that lies behind the disease, which may be the key to the development of an effective targeted therapy. The clinical manifestations of the disorder are usually nonspecific and vary from organ to organ; thus, detection in early stages can be challenging. Irreversible fibrosis and organ failure can develop if untreated, so clinicians in various specialties should be aware of the disease. The diagnostic approach is complex and requires a combination of clinical, laboratory, and radiological examinations with typical pathological findings. Corticosteroids remain the first line of therapy in active IgG4-RD, but adverse effects of the drug and disease recurrences on reduction or termination of therapy highlight the need for favorable therapy. Rituximab appears to be a promising agent in the treatment of IgG4-RD, but its efficacy needs to be evaluated in large clinical controlled trials.