In the diagnosis of IgG4-related sclerosing cholangitis (IgG4-SC), differentiation from extrahepatic cholangiocarcinoma (ECC) is extremely important but is still a clinical challenge. This study aimed to elucidate the usefulness of peroral cholangioscopy (POCS) for the differential diagnosis between IgG4-SC and ECC.POCS findings for bile duct stricture were retrospectively evaluated in 17 patients with IgG4-SC diagnosed at the Hiroshima University Hospital and 53 patients with surgically resected infiltrating ECC. Mucosal surface, dilated vessels , and easily bleeding were compared between the groups.P <  0.001). The frequency of caliber alteration and disruption of dilated vessels was significantly less in IgG4-SC . The sensitivity and specificity of POCS in the diagnosis of ECC were 96 and 89%, respectively. Dilated vessels in IgG4-SC were observed significantly more frequently in the extrapancreatic bile duct, especially the hilar bile duct (P = 0.006). Concerning image evaluation, the interobserver agreement was κ = 0.719, and the intraobserver agreement was κ = 0.768 and 0.754.The stricture sites of IgG4-SC evaluated by POCS were 10 extrapancreatic bile ducts and 9 intrapancreatic bile ducts. In patients with IgG4-SC, smooth mucosal surface was observed in 89% (17/19), dilated vessels in 58% (11/19) , and easily bleeding in 0%. Irregular mucosal surface and easily bleeding were observed significantly more frequently in ECC (both Characteristic POCS findings of the stricture sites in IgG4-SC were smooth mucosal surface, dilated vessels without caliber alteration and disruption, and lack of easily bleeding. These POCS findings are extremely useful for distinguishing between IgG4-SC and ECC. IgG4-related sclerosing cholangitis (IgG4-SC) is characterized by elevation of serum IgG4 levels, and dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall. Similar to autoimmune pancreatitis (AIP), IgG4-SC is recognized as a biliary manifestation of a systemic disorder termed IgG4-related disease . Since iIgG4-SC is classified into four types based on the site of strictures due to cholangiography and diseases to be distinguished . Of the Peroral cholangioscopy (POCS) is an examination method that allows direct observation of bile duct mucosa by inserting a small diameter cholangioscope transpapillary into the bile duct. POCS is useful for the differential diagnosis between benign and malignant bile duct stricture –10, and The aim of this study was to clarify the characteristic POCS findings of IgG4-SC and the usefulness of POCS in differentiation between IgG4-SC and ECC by evaluating the findings in detail.A total of 70 patients, including 17 patients with IgG4-SC and 53 patients with surgically resected infiltrating ECC who underwent POCS at Hiroshima University Hospital between April 2008 and December 2017, were enrolled in this study, and POCS findings were retrospectively examined. The infiltrating ECC consisted of macroscopically nodular type and flat infiltrating type . IgG4-SCWritten informed consent was obtained from all patients and their families before endoscopic retrograde cholangiopancreatography (ERCP) and POCS were performed. This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of Hiroshima University Hospital .All POCS was performed by using a conventional dual-operator mother-baby technique. One of the two video cholangioscopes  was used as a baby scope. A therapeutic duodenoscope  was used as a mother scope.First, ERCP was performed, and endoscopic retrograde naso-biliary drainage (ENBD) was performed regardless of the presence or absence of jaundice and acute cholangitis. Detailed evaluation of the bile duct was performed by cholangiography via ENBD catheter. In patients with jaundice or acute cholangitis, POCS was performed after they improved. In contrast, in patients without jaundice or acute cholangitis, POCS was performed 2 to 4 days after the initial ERCP. Immediately before POCS was performed, a saline solution was injected into the bile duct via ENBD catheter to thoroughly irrigate the inside of the bile duct. To avoid artifacts of the lesion by guidewire manipulation, the mother scope was inserted while passing the ENBD catheter through the working channel, and the a 0.025-in. guidewire was placed. After the small endoscopic sphincterotomy or papillary balloon dilatation using a balloon catheter with 6 mm diameter was performed, the cholangioscope was inserted into the bile duct with passage over the guidewire. The bile duct lumen was observed while irrigating with the saline solution through the working channel of the cholangioscope. Conventional white light endoscopy was mainly used for observation, and narrow band imaging (NBI) was used as necessary. All POCS procedures were performed under conscious sedation of the patient with intravenous administration of pentazocine and midazolam by two experienced endoscopists. Following POCS, biopsies from the stricture were performed under fluoroscopic guidance using a conventional biopsy forceps , if necessary. After performing POCS, ENBD and intravenous administration of an antibiotic was carried out in all patients for the purpose of preventing acute cholangitis.Dilatation: presence of vessels whose calibers are twice or more than twice the calibers of surrounding reference vessels.Tortuosity: presence of vessels which are unpredictably twisted or bent.Abrupt caliber alteration: presence of vessels whose calibers abruptly become less than one half or more double the original size.Disruption: presence of vessels which have a dead end.All cholangioscopic images were stored as both video and still images and were evaluated by two endoscopists with over 15 years of experience (Y.I. and M.S.). Based on previous reports , the POCIn an independent substudy, the inter- and intraobserver agreements of POCS images for differentiating between IgG4-SC and infiltrating ECC were assessed by an endoscopist with 11 years of ERCP experience (T.T.) and an endoscopist with 8 years of ERCP experience (N.S.). All 72 stricture sites were evaluated. Several white light images and NBI images of each stricture site were selected. All selected images were randomly arranged for pattern assessment by the two readers who were blinded to the final diagnosis of the lesion. Strictures were evaluated based on the characteristic POCS findings of IgG4-SC and infiltrating ECC in this study. Two readers diagnosed the image of one pattern in 1 day, and diagnosed another pattern 2 weeks later.P values < 0.05 were considered statistically significant.Statistical analyses were performed using JMP Pro 12.2.0 . The Chi-square test or Fisher’s exact test were used for the comparison of proportions. The clinical profiles of all 17 patients with IgG4-SC who underwent POCS are shown in Table The patients with ECC were 37 men and 16 women, with a median age of 71 years . The locations of tumor were perihilar bile duct in 30 patients and distal bile duct in 23 patients. The preoperative diagnosis of cholangiocarcinoma was obtained pathologically in 40 patients (75%), and the sensitivity of bile juice cytology, brushing cytology, and forceps biopsy were 43% (22/51), 48% (24/50), and 63% (32/51), respectively. The surgical procedures were pancreatoduodenectomy in 22 patients, right hepatectomy in 14 patients, left hepatectomy in 3 patients, extended right hepatectomy in 5 patients, hepatopancreatoduodenectomy in 5 patients, and bile duct resection in 4 patients.Regarding POCS-related complications, acute cholangitis was seen in two patients of ECC, but it improved rapidly by conservative therapy. There were no other complications, such as acute pancreatitis and liver abscess.POCS findings were evaluated at 19 sites of bile duct stricture in 17 patients with IgG4-SC Fig. .Fig. 1COn the other hand, the mucosal surface of ECC was irregular in 91% 48/53) of the patients . There was no significant difference in the frequency of dilated vessels (P = 0.070). Regarding the morphology of dilated vessels, there was no difference in the presence of tortuosity, but abrupt caliber alteration and disruption were found significantly more frequently in patients with ECC than patients with IgG4-SC . When the POCS findings of malignant stricture were defined as irregular mucosal surface, presence of dilated vessels with abrupt caliber alteration and disruption, or easily bleeding, the diagnosis of ECC was 96% (51/53) for sensitivity and 89% (17/19) for specificity.A comparison of POCS findings between IgG4-SC and ECC is shown in Table P = 0.006). There was no significant relationship between the property of mucosal surface and the site of stricture, but the mucosal surface of intrapancreatic bile duct stricture was smooth in all patients. In terms of the relationship between the site of stricture and the site of AIP lesion, intrapancreatic bile duct stricture was accompanied by enlargement of the pancreatic head in all nine patients. In contrast, there was no significant difference in POCS findings between perihilar cholangiocarcinoma and distal cholangiocarcinoma.POCS findings, site of stricture, and site of AIP lesions in patients with IgG4-SC are shown in Table P <  0.001 and 0.003, respectively). There was no significant difference in the frequency of dilated vessels between two groups, but the abrupt caliber alteration and disruption were found significantly more frequently in patients with perihilar cholangiocarcinoma than patients with perihilar IgG4-SC . In comparison between distal IgG4-SC (intrapancreatic and middle bile duct) and distal cholangiocarcinoma, there was also a significant difference in terms of the property of mucosal surface and presense of easily bleeding . Furthermore, the frequency of dilated vessels was significantly higher in patients with distal cholangiocarcinoma than patients with dital IgG4-SC (P = 0.016).A comparison of POCS findings between IgG4-SC and ECC based on the stricture site is shown in Table The kappa value of interobserver agreement between T.T. and N.S. was 0.719. The kappa value of intraobserver agreement were 0.768 (T.T.) and 0.754 (N.S.).In this study, the usefulness of POCS in the differential diagnosis between IgG4-SC and ECC was examined. The diagnostic criteria of IgG4-SC  has beenThe advantage of POCS is that it allows direct visualization of strictures in detail. In this study, favorable diagnostic performance of POCS  for distinguishing between ECC and IgG4-SC was obtained by focusing on the property of mucosal surface, the presence of dilated vessels and their morphology, and presence of easily bleeding. On the other hand, dilated vessels were frequently observed in the stricture of perihilar IgG4-SC, so it is essential to carefully observe the morphology of dilated vessels to distinguish them from perihilar cholangiocarcinoma. Another advantage of POCS is that it allows targeted biopsy. In this study, fluoroscopy-guided transpapillary biopsy was selected instead of cholangioscopy-guided biopsy. This is because the video cholangioscopes used in this study did not allow irrigation with saline solution during biopsy and the pathological diagnosis was not easy with small samples obtained with available ultrathin biopsy forceps. Recently, a systematic review  demonstrThe characteristic POCS findings at the stricture of IgG4-SC such as smooth mucosal surface, dilated and tortuous vessels without abrupt caliber alteration and disruption, and absence of easily bleeding are considered to reflect its pathological features. The smooth mucosa is considered to reflect the characteristic pathological findings of IgG4-SC in which the main focus of inflammation is under the epithelium of the bile duct, and the epithelium is relatively preserved. Dilated and tortuous vessels have also been reported by Itoi et al.  and YasuRegarding the relationship between the stricture site of IgG4-SC and the POCS findings, the mucosal surface was smooth in most patients regardless of the stricture site, but the dilated vessels were found significantly more frequently in the hilar bile duct than in the intrapancreatic bile duct. The characteristic pathological findings of IgG4-SC, such as marked lymphocytic and plasmacytic infiltration, infiltration of IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis are not different depending on the site of bile duct . On the This study found that there were several significant differences between the POCS findings of stricture of IgG4-SC and ECC. However, the evaluation of POCS findings is not well established, lacks objectivity, and the interobserver disagreement can be a significant problem. To the best of our knowledge, this is the first study to examine the reliability of POCS images using a mother-baby scope system. Both the inter- and intraobserver agreement had a kappa value of 0.7 or more, indicating that the reliability of POCS in distinguishing between IgG4-SC and ECC is good.This study has some limitations. First, it was a retrospective study based on a relatively small number of patients. Second, only one patient with IgG4-SC underwent surgical resection; therefore, histological findings could not be effectively compared with POCS findings for patients with IgG4-SC. The diagnostic criteria  and the The characteristic POCS findings of the stricture site of IgG4-SC were smooth mucosal surface, dilated tortuous vessels and lack of easily bleeding. The dilated and tortuous vessels in IgG4-SC had less abrupt caliber alteration and disruption compared to those in ECC, and were frequently found in the extrapancreatic bile duct, especially in the hilar bile duct. Detailed observation of biliary strictures with POCS may help differentiate IgG4-SC from ECC and prevent unnecessary major surgery. In addition, it is necessary to accumulate the number of patients to clarify the POCS findings of IgG4-SC.


At the patient level, the most important factor associated with HAIs was antibiotic use, since patients receiving at least one antimicrobial were more likely to be infected than those who did not receive antimicrobials . The analysis of the prevalence of antibiotic use indicated a significant trend across years of the PPSs: 50.5% of patients received at least one antimicrobial agent in 2016, 55.2% in 2017, and 53.7% in 2018 (p < 0.001). The most common indication for antimicrobial prescription was medical prophylaxis, while third-generation cephalosporins represented the most frequently used class of antimicrobial agents, followed by fluoroquinolones and combinations of penicillins. Our study confirms that HAIs still remain a major public health issue, which could be intensified by antibiotic abuse. This raises the need for infection prevention and control and antibiotic stewardship programs aimed to improve knowledge about appropriate antibiotic prescription and to reduce the use of broad-spectrum antimicrobials.Repeated point prevalence surveys (PPSs) of healthcare-associated infections (HAIs) and antibiotic use are crucial to monitor trends over years at regional level, especially in countries with decentralized healthcare systems. Here, we reported the results of three PPSs conducted in Sicilian acute care hospitals  from 2016 to 2018, according to the European Centre for Disease Prevention and Control protocol. Overall, prevalence of patients with at least one HAI was 5.1% in 2016, 4.7% in 2017, and 5.1% in 2018, without a significant trend over years ( Healthcare-associated infections (HAIs) are one of the major threats for public health worldwide, due to their significant impact on mortality, hospital stays, and assistance costs ,3,4,5,6.p < 0.001). In line with ageing populations, we also noted an increasing percentage of surgical interventions (p < 0.001), a higher McCabe severity of illness score (p < 0.001), and a higher probability to be exposed to invasive devices  from 2016 to 2018.The present study used data from 18,852 patients surveyed during the three PPSs in Sicilian acute care hospitals. Specifically, patients involved in each survey were 6448 in 2016, 5974 in 2017, and 6430 in 2018. p = 0.434). From a total of 1037 HAIs for which information was available, the most frequently reported types were pneumonia (29.6%), urinary tract infections (19.1%), and surgical site infections (13.3%), with no significant changes in the top-three ranking from 2016 to 2018 (p = 0.024). No significant trends were evident for pneumonia and surgical site infections  and with a higher proportion of patients who underwent surgery (p < 0.001), who received fatal or rapidly fatal diagnoses (p < 0.001), and who were exposed to invasive devices . We also observed an extremely higher prevalence of antibiotic use in infected patients than in their non-infected counterparts (p < 0.001). The logistic regression analysis confirmed much of these findings. In fact, patients with a fatal or a rapidly fatal diagnosis were more likely to be infected , as well as those who were exposed to intubation or central venous catheter . However, the most important factor associated with the infected status was the prevalence of antibiotic use, so much that patients receiving at least one antimicrobial were approximately 19 times more likely to be infected than those who did not receive antimicrobials .In p < 0.001). However, there was no significant correlation between prevalence of HAI and that of antimicrobial use (p = 0.634). By contrast, we noted a slight but significant correlation between the number of patients surveyed and prevalence of HAI , while treatment of a community-acquired infection increased (p = 0.017). A significant trend was also observed for the treatment of a hospital infection, which was characterized by a negative peak in 2017 (p < 0.001).The indication for antimicrobial use was documented in patients’ medical records for 12,841 prescriptions . In genep < 0.001; From 2016 to 2018, third-generation cephalosporins represented the most frequently used class of antimicrobial agents, followed by fluoroquinolones and combinations of penicillins. In particular, we observed a decreasing trend of fluoroquinolones use from 2016 to 2018 . Patients’ characteristics, prevalence of HAIs and antibiotic use, and indications for treatment were compared across years of PPS using the Chi-squared test or the Analysis of Variance (ANOVA). We also compared patients’ characteristics between infected and non-infected individuals using the Student’s t-test or the Chi-squared test. Accordingly, results were reported as frequency and percentage or mean and SD. We further applied a logistic regression analysis to assess factors that were mainly associated with HAIs. Results were reported as ORs with their 95%CIs. A In conclusion, this is the first study examining the trend of HAIs and antibiotic use in Sicily, using data from repeated PPSs. In particular, we confirmed that HAIs still remain a major public health issue, which could be aggravated by antibiotic abuse. This raises the need for IPC and antibiotic stewardship programs aiming to improve knowledge about antibiotic prescription and to reduce the use of broad-spectrum antimicrobials. Organizing and carrying out constant HAI surveillance definitely enhances the awareness of healthcare workers at each level, but considerable efforts to harmonize the interpretation of definitions are still needed.


This paper presents the results of tests on high performance concrete (HPC) prepared and cured at various ambient temperatures, ranging from 12 °C to 30 °C . Special attention was paid to maintaining the assumed temperature of the mixture components during its preparation and maintaining the assumed curing temperature. The properties of a fresh concrete mixture  and properties of hardened concrete  were studied. It has been shown that increased temperature (30 °C) has a significant effect on loss of workability. The studies used the concrete slump test, the flow table test, and the Vebe test. A decrease in the slump and flow diameter and an increase in the Vebe time were observed. It has been shown that an increase in concrete curing temperature causes an increase in early compressive strength. After 3 days of curing, compared with concrete curing at 20 °C, an 18% increase in compressive strength was observed at 40 °C, while concrete curing at 12 °C had a compressive strength which was 11% lower. An increase in temperature lowers the compressive strength after a period longer than 28 days. After two years of curing, concrete curing at 12 °C achieved a compressive strength 13% higher than that of concrete curing at 40 °C. Freeze–thaw performance tests of HPC in the presence of NaCl demonstrated that this concrete showed high freeze–thaw resistance and de-icing materials  regardless of the temperature of the curing process, from 12 °C to 30 °C. Temperature is an important factor which influences the hydration process of cement and the properties of concrete mixture and hardened concrete. It is known that the rate of reaction of cement hydration grows with increasing temperature. The consequence of this is a faster increase in the strength of concrete in the early stage of maturation ,2,3.The influence of temperature on the cement hydration process has been the subject of many studies. It has been found that, in the early stages of maturation, the rate of hydration of the alite significantly increases along with an increase in temperature, but later (from 28 to 90 days) it decreases depending on the type of cement . After aStudies on the microstructure of hydrated cement phases at different temperatures have shown that temperature also influences the morphology, type, and number of hydrate phases formed. At higher temperatures, the more heterogeneous distribution of hydrate phases and formations of shorter needle-shaped ettringite crystals are observed . MoreoveThe results of the authors of the study  indicateThe studies presented in the paper  indicateCement pastes with the addition of fly ash, volcanic ash or granulated blast-furnace slag, cured in the temperature range from 10 °C to 60 °C were tested in the study . It was In , it was Tests of cement pastes cured at temperatures ranging from 5 °C to 50 °C carried out after a longer period of time (up to 91 days) showed that the cement pastes cured at the lowest temperature was hydrated to the greatest extent . These aSumming up the results of the research conducted by various authors, it should be stated that the increase in temperature leads to the acceleration of the hydration process of Portland cement, with the distribution of hydration products being more irregular. This results in increased compressive strength in the early stages of curing. Increased temperature also makes the distribution of cement hydration products uneven and increases the porosity of the resulting structure. The consequence of this is a reduction in compressive strength after a longer curing period. This also applies to cement pastes containing mineral additives, although, in the case of additives, such as fly ash or granulated blast-furnace slag, the scale of the phenomenon is smaller, which can be explained by the reduction in hydration heat of binders with these mineral additives.The influence of temperature on the cement hydration is reflected in the properties of the concrete mixture and hardened concrete. The production of concrete mixtures at elevated temperatures causes many problems due to the accelerated hydration process of the cement. In addition, the concrete mix has a higher water demand due to evaporation. The influence of temperature on the workability of normal strength concrete is well recognised—increasing temperature leads to workability deterioration ,20. The The consistency of the concrete mixture also depends on the effectiveness of chemical admixtures at elevated temperatures. Schmidt et al.  demonstrThe paper in  shows thAn increase in ambient temperature generally results in a loss of workability of the concrete mixture. The reason for this phenomenon is both the acceleration of the cement setting process and the faster evaporation of the mixing water at higher temperatures.The influence of temperature on the properties of hardened concrete is similar to that of cement pastes . IncreasThe most susceptible to excessive heating are massive elements, where the cooling surface is small in relation to the mass of the concrete mixture being caste. The negative phenomena caused by excessive heating can be minimized by proper selection of binder composition .There are methods to minimise the adverse effects of increased temperature on concrete properties. These include: reducing the cement content in concrete; partial replacement of the cement by mineral pozzolanic and hydraulic additives; the use of cement with low hydration heat; thermal control of aggregates; the use of cool water or the addition of crushed ice to the concrete mixture. In practice, good results are achieved by introducing granulated blast-furnace slag and fly ash into the cement ,31,32.The influence of temperature on the properties of normal strength concrete is widely recognised. An increase in the curing temperature also increases the early strength; however, it reduces the strength of the concrete later on and has a negative impact on its durability, which is related to the cement hydration process. However, it should be noted that the influence of temperature on the properties of High Performance Concrete (HPC), which is particularly sensitive to temperature changes due to the relatively low w/c ratio and the use of high range water reducing admixtures (HRWR), is much less well-known.Apart from the heat generated by the hydration reaction, the temperature of the concrete mixture is also influenced by the temperature of the mixture components, the ambient temperature, and the heat generated by friction as a result of mixing. The temperature of the aggregate is of particular importance, because its content in concrete is relatively high. The temperature of aggregate and water generally corresponds to the ambient temperature, while the temperature of cement stored in silos can be much higher, which further increases the temperature of the concrete mixture.This paper presents the results of a study on the influence of temperature on the properties of a fresh concrete mixture and hardened HPC containing a polycarboxylate superplasticizer and an addition of silica fume. The tests were carried out at both increased (30 °C) and lowered (12 °C) concrete curing temperatures, but within the range of the practical applicability of concrete. The compressive strength and concrete mix density were tested at temperatures of 12 °C, 20 °C, 30 °C and 40 °C. Special attention was paid to achieving the desired temperature of the mixture components and maintaining this temperature while making the mixture and curing the concrete.2/kg. The chemical composition of the cement is shown in The concrete (HPC) was made with Portland cement CEM I 42.5 R (CEM I), with a specific surface area (Blaine) of 440 mA superplasticizer based on polycarboxylates (SP) was used as a HRWR. The SP was added in the amount of 1.5% in relation to the mass of cement.Silica fume (SF) was used as the mineral additive, an amount of 10% in relation to the mass of cement. According to the manufacturer’s specification, the chemical composition of SF is as follows: The concrete mixture was made of natural fine aggregate . The same procedure for adding ingredients to the mixer and a constant mixing time of the concrete mixture at all temperatures were applied. The mixing procedure used is shown in Concrete mixtures were made at temperatures of 12 °C, 20 °C, 30 °C and 40 °C. In order to stabilise the temperature of the components, the cement, silica fume, aggregate and water were kept at a controlled, assumed temperature for at least 72 h before the concrete mix was made, using climate chambers.Every effort was made to keep the temperature in the room where the concrete mix was prepared at the assumed level. The temperature was increased using an appropriate heating system and air heater units. Tests at lowered temperatures were carried out in the winter period, which made it possible to maintain the assumed temperature.The particle size distribution of cement was tested with the use of the Mastersizer 3000 laser particle analyser , and the wet method. Isopropanol was used as the dispersant. The test was carried out with an obscuration range of 10–15%. The presented test results are an average of at least 3 measurements.Physical properties of aggregates such as bulk density, specific density and water absorption were tested in accordance with standards EN 1097-3:2000, EN 1097-6:2013 and EN 1097-6:2013, respectively.Consistency testing by the concrete slump test was performed according to EN 12350-2:2011. This test consists of placing and compacting the concrete mixture in a truncated cone shaped mould. The result of the test is the decrease in the height of the concrete mixture immediately after removing the mould.Consistency determination with the flow table test was carried out according to EN 12350-5:2011. This test consists of placing the mixture in a truncated cone on a plate and then, after lifting the mould, 15 cycles of lifting and free falling of the upper table plate are performed. The result of the test is the flow diameter of concrete mixture.Consistency determination with the Vebe test was carried out according to EN 12350-3:2011. The result of the test is the time of vibration of the mixture placed in the cylinder until the level of the mixture in the cylinder is completely consolidated.Testing of the consistency of the concrete mixture using the concrete slump test, the flow table test and the Vebe test was carried out immediately after mixing the ingredients, as well as after 30 and 60 min. The concrete mixture was mixed at slow speed until testing.The air content of the concrete mixture was determined in accordance with EN 12350-7:2011 by means of a pressure gauge. Testing using a pressure gauge is based on Boyle–Mariotte’s law and consists in the fact that a known volume of air at a certain pressure combines in a tightly closed container with an unknown volume of air contained in a concrete mixture sample.The density of the concrete mixture was determined according to EN 12350-6:2011. This method consists in determining the weight of a concrete mixture, completely filling a container with a known volume.The density of the concrete was determined according to EN 12390-7:2011, hydrostatic method. The method consists in determining the mass and volume of a concrete sample by determining the mass of displaced water. The test was carried out on cubic samples of 100 mm side.Tests of concrete water absorption were carried out using the method described in the PN-B-06250:1988 standard, after 28 days of concrete curing. Each time the test was performed on 3 cubic samples with a side dimension of 100 mm. The samples were first saturated in water to constant mass and then dried at 105 °C to constant mass.The compressive strength was tested according to EN 12390-3:2011. The test was carried out using the Controls MCC8 strength press . The test was carried out on cubic samples of 100 mm side. The concrete samples cured for more than 28 days were taken out of water and cured at laboratory temperature (20 ± 2) °C until the test.Testing of the depth of penetration of water under pressure of the concrete was carried out in accordance with EN 12390-8:2011. Each time, the test was carried out on 6 cubic samples of concrete with a side of 150 mm, cured before the test for 28 days in water.The tests of concrete resistance to cyclic freezing and thawing in the environment of de-icing salt were performed according to EN 12390-9:2007, using the ”slab test”. This test consists in determining the weight of scaled material from the concrete sample surface after 7, 14, 28, 42 and 56 freezing and thawing cycles in the presence of 3% NaCl solution. Then, 4 cubic samples of concrete with a side of 150 mm were used for the test, which were cured for 7 days at 12 °C, 20 °C or 30 °C. The remaining curing and preparation period of the test was carried out in accordance with EN 12390-9:2007.The freeze–thaw durability was also tested according to Polish standard PN-B-06250:1988. The test is carried out on 12 cubic concrete samples with a side dimension of 100 mm, 6 of which undergo 300 freeze/thaw cycles. The result of the test is a loss of compressive strength of the tested samples, compared to the other 6 ”witness samples’’. Before testing, the samples were cured for 28 days at 12 °C, 20 °C or 30 °C water temperatures.k = 4.30 (for 3 samples) k = 3.18 (for 4 samples) and k = 2.57 (for 6 samples).All test results presented in this paper are average values for a minimum of three measurements. The uncertainty values given are the expanded uncertainty of measurement with an expansion probability of approximately 95% and a corresponding expansion factor of Consistencies in the concrete mixture were tested by three methods. This was necessary because consistency differed significantly from one temperature to another and only one of the methods give results outside the range of applicability of this method.Similar results were obtained using the flow table test and the Vebe test. The flow diameters and Vebe time depending on the temperature as well as the time of the test are shown in The results of the consistency test using the flow table test  showed aThe workability of the concrete mixture has also decreased significantly in up to 60 min. Moreover, at 30 °C, the decrease in flowability was so great that after only 30 min correct measurement was impossible (both the Vebe test and the flow table test).The presented results of the concrete mixture consistency tests showed that an increase in temperature causes a loss of workability. This effect is particularly visible at 30 °C. At this temperature, the workability of the concrete mixture is lost after only 30 min. The observed phenomenon is mainly the effect of increasing the rate of water evaporation from the concrete mixture at elevated temperature and accelerated cement hydration process ,21, as weratures ,35. In pThe results of air content tests in the concrete mixture depending on the curing temperature and testing time are presented in As shown in The concrete mixture density tests showed that the temperature in the tested range (from 12 °C to 40 °C) does not have a significant influence on this parameter. Differences in the results of density determination did not exceed the measurement error . SimilarThe concrete density tests showed that in the range from 12 °C to 30 °C, an increase in temperature causes a slight increase in the concrete density. However, it should be noted that these differences are minimal, slightly exceeding the error of measurement of the test method .The results of the water absorption tests of the samples of concrete cured at different temperatures showed that in all cases the obtained values were at a very low level. The least absorbent is the concrete cured at 20 °C, and the largest is the concrete cured at 30 °C , howeverThe results of compressive strength testing of concrete samples depending on curing temperature  are shown in As can be seen from the data in The increase in the compressive strength of concrete in the initial period of time (up to 7 days), with an increase in the curing temperature, can be explained by the acceleration of the cement hydration process . HoweverConcrete cured at 12 °C and 20 °C achieved similar strength values at the age of 2 years (about 130 MPa), while concrete made at 20 °C achieved this strength much faster. It can therefore be concluded that a temperature of 20 °C is the most favourable, due to the increase in strength over time. Decreased early concrete strength at low temperatures is also confirmed by the results of the research presented, for example, in .The results of penetration depth tests of the concrete samples cured at 12 °C, 20 °C and 30 °C showed that no significant differences were observed in the values of this parameter  which isThe high concrete tightness shown in the test for the depth of penetration of water under pressure contributes to the durability of the concrete. This is confirmed by the results of the freeze–thaw durability tests carried out with two methods: the method according to PN-B-06250 and the method according to EN-12390-9.The results of concrete freeze–thaw durability tests using the method according to PN-B-06250 are presented in The HPC subjected to 300 freezing and thawing cycles shows no cracking or significant mass loss. The decrease in compressive strength is highest for the concrete prepared at 12 °C (8.6%) and lowest for the concrete prepared at 30 °C (1.7%). The reason for the observed phenomenon may be the fact that, on the day of the beginning of freezing (28th day of maturation), the concrete samples curing at lower temperatures had not yet obtained sufficiently high strength.The results of tests of resistance of the concrete samples matured at 12, 20 and 30 °C to cyclic freezing and thawing in the presence of de-icing salt are shown in the table .The scaling masses under the influence of cyclical freezing and thawing of concrete with simultaneous action of salt solution were minimal. Thus, the influence of the concrete curing temperature on the freeze–thaw durability result of this method has not been demonstrated. At the same time, the assessment according to the Borås criterion proves that the designed concrete is of very good quality, regardless of the curing temperature applied.HPC is increasingly used in civil engineering. The assessment of the influence of temperature on the properties of concrete is particularly important because of the application of HPC concrete at both elevated and lowered temperatures. This paper presents the results of research on the influence of ambient and curing temperature on the properties of the concrete mixture and hardened HPC.Consistency tests carried out using various methods have shown that HPC mixtures made at different ambient temperatures (within the range of 12 °C to 30 °C) have extremely different consistencies. The slump of the concrete mixture made at 20 °C (160 mm) was almost twice as high as at 12 °C (280 mm) and almost five times lower than at 30 °C (20 mm). This dependence was demonstrated by keeping the mixture ingredients for 72 h before executing the mixture at the assumed test temperature.The results of the fresh concrete mixture consistency tests confirm that the HPC mixture is very sensitive to temperature increases. The reason for this could be the faster evaporation of water which, combined with the low water–binder ratio, results in a clear decrease in workability. This effect is also influenced by the acceleration of the cement hydration reaction. Losing workability of a concrete mixture at elevated temperatures can significantly hinder its application. This is indicated by the results of consistency tests as well as air content in the concrete mixture at 30 °C.Temperature has been shown not to have a significant effect on properties, such as density, water absorption, and depth of water penetration under pressure. The indicated parameters for the concrete samples prepared at different temperatures differed slightly.Compressive strength tests carried out over a period of 3 days to 2 years on concrete samples prepared at temperatures of 12, 20, 30, and 40 °C showed that the rate of compressive strength growth increases with increases in temperature. The concrete prepared at 40 °C reached 99 MPa after only three days , while at 12 °C the concrete reached 74.5 MPa . This confirms that at elevated temperatures the cement hydration rate increases, resulting in a faster increase in concrete compressive strength in the first 28 days of curing.After 28 days, the highest compressive strength was achieved by the concrete maturing at lower temperatures. At the age of two years, concrete produced at temperatures of 12, 20, 30, and 40 °C reached compressive strengths of 135.6, 134.8, 124.5, and 119.7 MPa, respectively.As shown, an increase in the temperature of concrete curing results in a decrease in its compressive strength after a long period of time, compared with concrete cured at lower temperatures. This may be due to the fact that a faster rate of hydration results in hydration products with a more irregular structure and higher porosity, which negatively affect compressive strength after a longer curing time.The results of the freeze–thaw durability tests performed using the Polish standard method and the ‘’slab test’’ show that HPC is resistant to freeze–thaw. The decrease in compressive strength after 300 freezing and thawing cycles was relatively small and amounted to a maximum of 8.6%, compared with samples not subjected to cyclic freezing and thawing, in the case of the concrete prepared at the lowest temperature of 12 °C. For the concrete cured at 20 °C and 30 °C, the strength drop was 4.3% and 1.7%, respectively. This may be due to the fact that, at the start of the test (28th day of curing), the concrete stored at lower temperatures reached a lower compressive strength than the concrete stored at higher temperatures.The freeze–thaw durability tests in the presence of a NaCl solution showed minimal scaling of the concrete surface, which is proof of very good freeze–thaw durability of the tested HPC, regardless of its preparation temperature.This study shows a significant influence of lowered and increased temperature on the properties of the concrete mix and hardened HPC concrete, especially in terms of consistency and compressive strength. This points to directions for further research, which should include studies of the rheological parameters of the HPC concrete mix and its changes over time. Research aimed at demonstrating the influence of curing temperature on the cement hydration process for binders used in HPC concrete (with a low water–binder ratio) should also be carried out. Future research should include changes of hydrate phases over time.


Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a newly recognized, systemic disease. Membranous nephropathy is the most common glomerular lesion in IgG4- related kidney disease. However, the lack of relationship with IgG4-related kidney disease and monoclonal gammopathy of undetermined significance (MGUS) warrants investigation of the potential mechanisms.A 62-year-old patient was diagnosed with IgG4-RD, tubulointerstitial nephritis, retroperitoneal fibrosis. After 2 years, she was presented with proteinuria, hypoproteinemia, facial, and bilateral lower limb edema. Furthermore, this patient exhibited deposits of IgG k of monoclonal hyperplasia, and bone marrow plasma cell count was 2.5%.The patient was diagnosed with nephrotic syndrome, acute kidney injury, and MGUS. The pathological diagnosis was IgG4-related tubulointerstitial nephritis, IgG4-related membranous nephropathy.The patient was treated with intravenous methylprednisolone (40 mg daily), which was changed to oral prednisone 50 mg/d after 2 months.After 1 month, the patient exhibited a rapid response only with corticosteroid, and experienced partial remission of serum albumin and proteinuria.This case may suggest a possible relationship between IgG4-RD and MGUS, provide some guidance for investigating the mechanism between them. Immunoglobulin G4-related disease is a recently identified clinical entity characterized by increased serum IgG4 levels and infiltration of IgG4-positive cells into various organs.2The present study was approved by the Ethics Committee of the Cangzhou Central Hospital, located in Cangzhou City, Hebei Province, China. Informed consent for publication of anonymized case details was obtained from the patient. In June 2015, a 62-year-old woman was referred to a local hospital for the first time with a 1-month history of fatigue and anorexia. Her urinalysis was normal, and renal function parameter values were serum creatinine (sCr), 899 μmol/L, blood urea nitrogen, 20.57 mmol/L. Abdominopelvic computed tomography revealed bilateral hydronephrosis, ureterectasia, and a normal size kidney. She was diagnosed with obstructive nephropathy and acute kidney disease. Double-J stents were inserted into the bilateral ureters, after which sCr level dropped from 899 μmol/L to 366 μmol/L. Ten days before admission, she was diagnosed with “urinary tract infection”. Her weight was 63 kg, blood pressure was 165/85 mm Hg and, except for a palpable right cervical lymph node, the remainder of the physical examination was unremarkable. Lymph node biopsy revealed chronic lymphadenitis and reactive lymphoid proliferations. Immunohistochemical analysis revealed IgG4 and IgG + plasma cells < 40%, IgG4-positive plasma cells < 10 cells/high-power field (HPF). Ultrasound of the kidney yielded normal findings. Abdominal computed tomography revealed retroperitoneal fibrosis. Results of laboratory investigations are summarized in Table Because this patient had a high erythrocyte sedimentation rate and high levels of IgG and C-reactive protein, plasma cell disease was plausible. However, bone marrow aspiration revealed mature plasma cells (2.5%), and electrophoresis and immunofixation of 24 hour urine collection was normal; as such, evidence supporting the diagnosis was insufficient. The clinical presentation, together with retroperitoneal fibrosis, palpable right cervical lymph node, and markedly increased serum IgG4 levels led to a diagnosis of IgG4-RD. The patient was treated with antibiotics before oral prednisolone 30 mg daily because she had a history of urinary tract infection. Two months later, laboratory results were as follows: globulin (GLB) 37 g/L; sCr, 94 μmol/L; IgG 15.53 mmol/L; and 24 hour urinary protein, 0.74 g proteinuria/d (urine volume 2.55 L). Prednisolone regulation decreased until drug withdrawal, and uridine triphosphate level returned to normal. The patient felt well and, therefore, was not followed-up for 2 years.In March 2017, she was referred to the authors’ department for the second time with edema of the lower limbs. Except for facial and bilateral lower limb edema, the remainder of the physical examination was unremarkable. Ultrasound of the kidney was normal and computed tomography of the abdomen revealed no retroperitoneal fibrosis. Other laboratory results are summarized in Table Due to suspected autoimmune disease, renal biopsy was performed. The specimen assessed under light microscopy contained 17 glomeruli, of which 5 were globally sclerotic, while 1 glomerulus exhibited cell fibrotic crescent formation. Non-sclerosed glomeruli exhibited a minimal increase in the mesangial matrix. Glomerular basement membranes were slightly thickened. Fine subepithelial deposits on the glomerular capillary walls were noticed on segmental glomerular basement membranes on PAM-Masson trichrome staining Fig. A, 2B. RoImmunofluorescence staining for IgG4 subclasses revealed diffuse and global deposits of IgG1 and IgG4 along the glomerular capillary walls and interstitium Fig. A, 5B. Th3In this case, we reported a patient diagnosed with IgG4-RD who developed MN and MGUS. The specific findings speculated an association between IgG4-RD and MGUS. The concept of IgG4-RD was recently recognized by Kamisawa et al in 2003. The name and definition of IgG4-RD were established in 2010. Criteria used to diagnose IgG4 disease are as follows: clinically, diffuse/localized enlargement, or mass formation in 1 or more organs, and high serum IgG4 level (> 135 mg/dL); and, pathologically, > 10 IgG4+cells/HPF and IgG4+/IgG cell ratio > 40%. IgG4-RD has been observed in many organ systems, including the pancreas and other gastrointestinal sites, salivary or lachrymal glands, lung, breast, lymph node, and retroperitoneum.,15,16 It is characterized by high serum IgG4 levels and IgG4-positive cell-dense infiltrate.IgG4-RD is a recently recognized, distinct, systemic disease with unique histopathological features. Initial reports describing extra-pancreatic manifestations associated with autoimmune pancreatitis appeared in the literature have improved the understanding and recognition of this distinctive systemic disease. A small case series reported that 28 of 34 (83%) IgG4-RD patients had IgG4-RKD.,20 However, it has been noted that Japanese cases differ from those in the West. Approximately 98% of IgG4-RD patients had kidney disease. In the kidney, IgG4-RD manifests most commonly as TIN. IgG4-related TIN is diagnosed based on a combination of clinical, serological, and radiological findings, along with pathological features. Patients with IgG4-TIN are usually ≥ 65 years of age, of which the majority (80%) are male.,20 Patients with IgG4-RKD often exhibit lesions in other organs, although others may exhibit involvement in only a single organ. Almost 80% of IgG4-TIN patients have elevated levels of serum total IgG or IgG4. Under light microscopy, IgG4-TIN exhibits a plasma cell-rich interstitial inflammatory cell infiltrate. In addition, characteristic fibrosis is considered to be an important diagnostic finding. Fibrosis exhibits a “storiform” pattern, as seen in the kidney. Immunostaining for IgG4 plasma cells is helpful in distinguishing IgG4-TIN. Dense lymphoplasmacytic infiltrate with 10 IgG4 plasma cells/HPF and/or IgG4/IgG plasma cell ratio ≥ 40%. Recent publications from Japan and North America have proposed diagnostic criteria for IgG4-TIN.,20 Our patient was an elderly woman with retroperitoreal fibrosis, a palpable right cervical lymph node, high levels of serum IgG, IgG4, and acute renal injury, with typical features of kidney biopsy. Considering these factors, we confirmed the diagnosis of IgG4-related TIN.IgG4- related kidney disease (IgG4-RKD) is a comprehensive term for renal lesions associated with IgG4-RD.,24 Using immunofluorescence, IgG, and C3 global staining in GBM, immunofluorescence staining for IgG subclasses revealed that IgG4 was deposited in GBM. Immunostaining for phospholipase A2 receptor is negative. IgG4-related MN should be suspected in IgG4-RD patients with significant proteinuria, and those with MN on renal biopsy, and an appropriate clinical history should be evaluated for IgG4-RD. Our patient presented with significant proteinuria and hematuria during the second hospitalization. This suggested the presence of glomerular disease in addition to IgG4-related TIN. Kidney biopsy revealed MN. Medical history was significant for retroperitoneal fibrosis, and a palpable right cervical lymph node was also likely due to IgG4-RD. Moreover, circulating anti-PLA2R antibodies were negative, which suggested that MN was IgG4-related membranous glomerulonephritis.MN is the most common glomerular lesion in IgG4-RKD and, among them, 7% to 10% of patients have IgG4-TIN. MGUS requires serum monoclonal protein and bone marrow plasma cell levels to be < 3 g/dL and 10%, respectively. Accordingly, our patient could be diagnosed with MGUS. Meanwhile, monoclonal gammopathy of renal significance should be suspected when the monoclonal protein plays a direct role in kidney disease. Monoclonal protein studies should be performed to match the monoclonal protein in circulation with monoclonal deposits in the kidney. Treatment of monoclonal gammopathy of renal significance-related kidney diseases should be tailored to the clone responsible to protect the organs. A kidney biopsy of our patient revealed that κ light and λ light chains were deposited along the glomerular capillary walls, and she exhibited a sensitive response to hormone. Therefore, it was ruled out that monoclonal protein deposited in the kidney caused IgG4-RD. However, it remains unclear whether IgG4-RD could cause MGUS. One study reported that patients with IgG4-RD with or without renal insufficiency had increased serum free light chain levels. Another study showed that approximately 1-half (43%) of the IgG4-RD patients exhibited an increased and abnormal κ:λ ratio. Usually, an abnormal ratio is associated in the context of monoclonal gammopathy. We found no reports that IgG4-RD could cause MGUS. According to the results of our study, there is a possible relationship between IgG4-RD and MGUS, which could be due to an unknown underlying mechanism(s) of development that warrant further investigation.In addition, the patient exhibited deposits of IgG k of monoclonal hyperplasia, and bone marrow plasma cell count was 2.5%. MGUS is characterized by the presence of a monoclonal gammopathy without end organ damage.,31 A small case report described a response to rituximab in IgG4-RD patients refractory to steroid treatment. In a series of IgG4-MN patients, 7 were treated with various drugs, 2 of whom exhibited a rapid response only with corticosteroid treatment. In view of our case, corticosteroid therapy was useful in IgG4-related membranous glomerulonephritis. As for MGUS, treatment is not recommended until progression to multiple myeloma, and appropriate monitoring of patient is essential.In a major series involving IgG4-TIN patients, 90% with elevated sCr levels at presentation, once treated with steroids, exhibited decreased sCr levels at follow-up, IgG4-TIN has a sensitive response to hormone, similar to other organ manifestations of IgG4-RD.Clinicopathologic analysis: Jing Yi Sun.Conceptualization: Xiao Ying Ma, Hai Ping Xu, Fu Yun Sun.Data curation: Xiao Ying Ma.Formal analysis: Xiao Ying Ma.Funding acquisition: Fu Yun Sun.Investigation: Xiao Ying Ma, Fu Yun Sun.Methodology: JingYi Sun.Project administration: Fu Yun Sun.Resources: Fu Yun Sun.Software: Xiao Ying Ma.Supervision: Xiao Ying Ma, Fu Yun Sun.Validation: Fu Yun Sun.Visualization: Fu Yun Sun.Writing – original draft: Xiao Ying Ma.Writing – review & editing: Xiao Ying Ma, Yuresha Surangani Siyabalagaba Gedara.


We describe the trend of antibiotic prescribing in out-of-hours (OOH) general practices (GP) before and during England’s first wave of the COVID-19 pandemic. We analysed practice-level prescribing records between January 2016 to June 2020 to report the trends for the total prescribing volume, prescribing of broad-spectrum antibiotics and key agents included in the national Quality Premium. We performed a time-series analysis to detect measurable changes in the prescribing volume associated with COVID-19. Before COVID-19, the total prescribing volume and the percentage of broad-spectrum antibiotics continued to decrease in-hours (IH). The prescribing of broad-spectrum antibiotics was higher in OOH , but a consistent decrease in the trimethoprim-to-nitrofurantoin ratio was observed OOH. The OOH antibiotic prescribing volume diverged from the historical trend in March 2020 and started to decrease by 5088 items per month. Broad-spectrum antibiotic prescribing started to increase in OOH and IH. In OOH, co-amoxiclav and doxycycline peaked in March to May in 2020, which was out of sync with seasonality peaks (Winter) in previous years. While this increase might be explained by the implementation of the national guideline to use co-amoxiclav and doxycycline to manage pneumonia in the community during COVID-19, further investigation is required to see whether the observed reduction in OOH antibiotic prescribing persists and how this reduction might influence antimicrobial resistance and patient outcomes. GP practice prescribing during routine hours accounts for about 85% of primary care antibiotic items prescribed [Antimicrobial Resistance (AMR), the loss of effectiveness of anti-infective  medicines, jeopardises our ability to treat infections . Progresescribed . In Englescribed . A rangeescribed . Antibioescribed ,11. Despescribed . There aescribed ,14. LimiThere is little research exploring OOH antibiotic prescribing and limited AMS interventions specifically tailored to this setting . HoweverThe aim of this study is to investigate any changes in OOH antibiotic use prior to and during England’s first wave of the COVID-19 pandemic. Antibiotic prescribing in OOH settings measured in terms of antibiotic items represented 3.3–3.6% of the total primary care antibiotic prescriptions from 2016 to 2019. .p < 0.05). For the same period, there was no statistically significant change in the number of items prescribed monthly in OOH (p = 0.42). Measured by the number of items, penicillins remained the most commonly prescribed antibiotic group (61.6%) by OOH GPs, followed by tetracyclines (11.2%) and macrolides (10.30%), which were the same as for IH GPs. Each year, the proportion of broad-spectrum antibiotics  to the total prescription volume was the highest in August, both among IH and OOH GPs. The prescription volume peaked each year in December for both IH and OOH GP . Prior tp < 0.05) compared with in-hours  (p < 0.05). While a decrease of 0.02% per month was observed in the proportion of prescribed broad-spectrum antibiotics in OOH, this is insignificant (p = 0.06).The proportion of broad-spectrum antibiotics to total antibiotic prescribing in OOH was consistently higher  . Before While the OOH prescribing of ciprofloxacin and cephalosporins remained stable within each year, the prescribing of co-amoxiclav, amoxicillin and doxycycline peaked in December every year, with the seasonality indicating a high use of amoxicillin in winter to treat respiratory tract infections . In 2020Between 2016 and 2020, there has been a consistent reduction in trimethoprim prescribing and the trimethoprim-to nitrofurantoin-ratio in OOH settings  from 1.9The trend of the OOH antibiotic prescribing volume between January 2016 and February 2020 remained stable. Since March 2020, there has been a decrease of 5088 items per month (95% CI: −6264.4 to −3912.0). The predicted monthly OOH antibiotic prescribing volume is presented in p < 0.05). In OOHs, though the proportion of broad-spectrum antibiotic prescribing showed no significant overall change prior to March 2020, it started increasing by 1.4% per month  since.Since March 2020, the proportion of broad-spectrum prescriptions rose in both settings. In IH, the downward trend of the proportion of broad-spectrum prescribing switched direction and started to rise from March, increasing by 0.7% per month  in England . The posWe cannot rule out a changing epidemiological profile of infectious diseases due to COVID-19 as a possible factor in the decline in OOH antibiotic prescribing, resulting from control measures and a consequent reduced transmission of other respiratory tract infections. Indeed, PHE’s OOH GP syndromic surveillance data indicates that although on average 23% of all OOH GP contacts in England between 2009 and 2019 were due to acute respiratory infection , OOH GP Our study has two limitations. The first limitation is associated with the quality of the publicly available data. Not all of the prescribing centres in the NHS BSA prescribing data can be identified in the NHS Digital classification of organisations. Therefore, we had to exclude those prescribing records where the setting could not be assigned. This accounted for 0.04%  of the total prescribing records. Second, our analysis did not capture how OOH consultations were delivered, especially during COVID-19, when an increase in remote consultations was observed in IH GPs . ResearcDespite the limitations, this study provides the first critical insight into antibiotic prescribing in OOH before and during the COVID-19 pandemic and provides the scope for future research. The ongoing monitoring of consultations, antibiotic prescribing and AMR resistance is required to detect any unintended consequences of the change in antibiotic prescribing in OOHs seen in this study. For instance, the increase in co-amoxiclav use in OOH might lead to a rise in the incidence of Clostridium difficile infections in the community. In the current landscape, we also need to investigate OOH service provisions to better understand the factors influencing prescribing decision-making in OOH. As of 2013, the responsibility for commissioning OOH services in England was delegated to CCGs, which are independent statutory bodies governed by GPs to buy services for the local community from providers including hospitals, social enterprises, voluntary organisations and private firms . The conThis study did not require ethical approval as it employed publicly available data. Out-of-hours antibiotic prescribing data: We extracted records of electronic-based prescriptions of each prescribing centre in England between January 2016 and June 2020 from the NHS Business Service Authority (BSA) ,30. The Population data: We extracted the mid-year estimates of the population in each region and CCG from the Office for National Statistics (ONS) for the years 2016 to 2019 . We report the trend in the OOH antibiotic prescribing volume in England from January 2016 to June 2020. Using the number of items as the measure of the prescribing volume, the trend is compared with IH GP antibiotic prescribing. We examined key agents in the antibiotic QP primary care component, including nitrofurantoin, trimethoprim, amoxicillin, co-amoxiclav (amoxicillin and clavulanic acid), ciprofloxacin and cephalosporins . In addiAll descriptive and statistical analyses were performed in STATA 15 .This study has provided an insight into the impact of COVID-19 on antibiotic prescribing in OOH settings in the UK. Further investigation is required to see whether the observed reduction in OOH antibiotic prescribing persists and how this reduction might influence AMR and patient outcomes. Monitoring OOH prescribing requires the same primacy as IH prescribing in order to develop antimicrobial stewardship programmes with relevant underpinning evidence. This is all the more important since, in particular, the boundaries between IH and OOH may have different meanings for the healthcare user in the current and continuing context of COVID-19.


Autoimmune pancreatitis is a special form of chronic pancreatitis with strong lymphocytic infiltration and two histopathological distinct subtypes, a lymphoplasmacytic sclerosing pancreatitis and idiopathic duct centric pancreatitis. Immunoglobulin G4-associated cholangitis may be present at the time of autoimmune pancreatitis type 1 diagnosis or occur later over the course of the disease. Immunoglobulin G4 is considered reliable but not an ideal marker for diagnosis of autoimmune pancreatitis type 1 with reported sensitivity between 71–81%. It is essential to differentiate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis as the treatment and prognosis of the two diseases are totally different. It was the aim of the study to find a marker for immunoglobulin G4-associated cholangitis that would distinguish it from primary sclerosing cholangitis.We performed a retrospective analysis of patients with autoimmune pancreatitis at our outpatient clinic. Patients from the primary sclerosing cholangitis registry were taken as a control group. Blood samples for the measurement of immunoglobulin subclasses were analysed at the time of diagnosis.Patients with autoimmune pancreatitis and immunoglobulin G4-associated cholangitis had higher values of immunoglobulin G2 when compared to autoimmune pancreatitis alone or primary sclerosing cholangitis with a high specificity (97%) and high positive predictive value (91%). In patients with normal or low immunoglobulin G2 or immunoglobulin G4, a high level of immunoglobulin G1 indicated primary sclerosing cholangitis.Immunoglobulin G1 and immunoglobulin G2 can distinguish patients with immunoglobulin G4-associated cholangitis from those with primary sclerosing cholangitis. Autoimmune pancreatitis (AIP) is a special form of chronic pancreatitis with a strong lymphocytic infiltration and two histopathological distinct subtypes, lymphoplasmacytic sclerosing pancreatitis (type 1) and idiopathic duct centric pancreatitis (type 2).IgG4-associated cholangiopathy (IAC) may be present at the time of AIP type 1 diagnosis or occur later over the course of the disease.It is essential to differentiate sclerosing cholangitis with AIP from primary sclerosing cholangitis (PSC) as the treatment and prognosis of the two diseases are totally different.IgG4 is considered reliable but not an ideal marker for diagnosis of AIP type 1 with reported sensitivity between 71–81%. IgG1 and IgG2 can distinguish patients with AIP-related cholangitis (IAC) from those with PSC.1 It was first described by Sarles et al. in 19612 and coined as AIP in 1995 when clinicopathological similarities to autoimmune hepatitis were described.3 It soon became apparent that AIP type 1 is part of a systemic disease defined by fibrosclerosis and elevated immunoglobulin G4 (IgG4) known as IgG4-related disease (IgG4-RD).4 These systemic manifestations, from the AIP type 1 perspective, are called ‘other organ involvement’ (OOI) and of these, a special form of cholangitis, then called immune or IgG4-associated cholangitis (IAC) is the most frequent manifestation.5Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis with strong lymphocytic infiltration and fibrosis as the pathological characteristics and two histopathological subtypes: lymphoplasmacytic sclerosing pancreatitis (AIP type 1) and idiopathic duct centric pancreatitis (AIP type 2).6 Most of the small, uncontrolled trials showed no significant benefit with the use of oral steroids in patients with PSC.6 On the other hand, AIP is a disease with a good response to steroid treatment.5 Diagnosing IAC and differentiating it from PSC is a major clinical challenge.7 IAC may precede AIP, be present at the time of AIP diagnosis or it can occur later.8 Similar to the endoscopic retrograde cholangiopancreatography/ magnetic resonance cholangiopancreatography (ERCP/MRCP) classification of PSC,9 a classification for cholangitis in AIP was proposed10 that became part of the Japanese guidelines.11 Nevertheless, to establish the diagnosis by imaging alone is difficult when signs of AIP are sparse or absent.Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by progressive destruction of the bile ducts and development of cirrhosis.12 or a modification13 of the original M-ANNHEIM criteria.14 IgG4 is useful but not an ideal biomarker for diagnosis of AIP type 1.15 Several other serum markers for AIP have been determined, including autoantibodies against lactoferrin, carbonic anhydrase II, the serine protease inhibitor kazal type 1 gene (SPINK1), ubiquitin, trypsinogens and N-glykan.1618 However, none of these are globally available for routine clinical testing. Furthermore, there are no markers available to identify IAC as part of the AIP type 1/IgG4-RD syndrome either. From a clinical perspective, it is essential to differentiate cholangitis with AIP from PSC, as the treatment and prognosis of these two diseases are different.19The diagnosis of AIP and accompanying OOI can be made according to the international consensus diagnostic criteria (ICDC)/Honolulu criteriaWe tested all IgG subclasses in order to determine their usefulness to differentiate AIP with IAC from PSC. Here we describe elevated levels of IgG2 as a marker for IAC (that are not present in PSC) and elevated levels of IgG1 in patients with PSC (significantly higher compared to AIP patients).12 Remission was defined as an absence of clinical symptoms and resolution of the pancreatic and extrapancreatic manifestations on imaging. Relapse was defined as a recurrence of symptoms with the reappearance of pancreatic or extrapancreatic abnormalities on imaging. The following IgG subclasses serum levels were considered as normal: total IgG: 6.7–14.5 g/l; IgG1: 2.8–8.0 g/l; IgG2: 1.15–5.7 g/l; IgG3: 0.24–1.25 g/l; IgG4: 0.05–1.25 g/l.We performed a retrospective analysis of patients with AIP at the outpatient clinic at the Department of Digestive Diseases of Karolinska University Hospital in Stockholm, Sweden between September 2007–October 2018. Patients from the PSC registry from the department with proven histology were taken as a control group. The demographic, immunological and clinical characteristics of both groups were recorded and analysed . The diaThe study was approved by the local ethics committee .2) from models including and excluding the variable of interest were used to quantitatively measure the diagnostic performance of IgG4 alone, IgG2 alone, and of the addition of IgG2 or IgG4 to the other biomarker.Differences in the distribution of patient characteristics across groups were assessed with the Fisher exact test for categorical variables and the non-parametric Wilcoxon rank-sum test (Mann-Whitney U test) for continuous variables. The prognostic ability of IgGs to distinguish AIP from PSC was assessed using receiver-operating characteristic (ROC) curves, generated by plotting the sensitivity vs 1-specificity, giving the ideal test both a sensitivity and a specificity equal to one. The area under the curve (AUC) was used as a measure of the diagnostic efficiency of the test. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of single and combined IgGs were calculated with respective 95% confidence intervals (CIs) based on the binomial (Clopper-Pearson) exact method. The diagnostic performance of IgG2, IgG4 and their combination to differentiate AIP from PSC was further assessed using a logistic regression model, in which IgG2 and IgG4 were dichotomised as high (>5.7 g/l for IgG2 and >1.25 g/l for IgG4) vs low or normal. Changes in the likelihood ratio value . All From the patient registries, we included 142 patients where all IgG subclasses were measured, 69 with AIP type 1 and 73 with PSC (p<0.0001) and IgG4 (p<0.0001) distinguish patients with AIP from patients with PSC. Using ROC curve analysis, the AUC for the differentiation between AIP and PSC was 0.74 for IgG2 and 0.75 for IgG4, and was lower than 0.6 for total IgG, IgG1 and IgG3 (2 with one degree of freedom (df) was 22.6 (p<0.0001) for IgG4 compared to 34.5 ((p<0.0001) for IgG4. Both addition of IgG4 to IgG2 (LRΔχ2 (1 df) = 25.3, p<0.0001) and IgG2 to IgG4 (LRΔχ2 (1 df) = 13.5, (p = 0.0002) increased significantly the diagnostic performance compared to IgG2 and IgG4 alone .Firstly, we compared the distribution of characteristics of patients with PSC with that of patients with AIP (and IgG3 . The diap = 0.04).Similar analysis for the comparison of AIP patients with and without IAC was performed  is displayed in p = 0.006), while no difference was observed for IgG3. Furthermore, high IgG2 or IgG4 levels were observed in 31% of the patients and identified those with AIP ; high IgG1 with low or normal IgG2 and IgG4 levels was observed in 27.5% of the patients and identified those with PSC . The condition of the remaining 59 patients (41.5% of our series) with low or normal IgG1, IgG2 and IgG4 remained undetermined.Furthermore, we evaluated the diagnostic performance of IgG, IgG1 and IgG3 among patients with low or normal IgG2 and IgG4 (p = 0.0009) or had a relapse . Relapse was also more frequent in AIP patients with a high IgG4 level than in patients with a normal IgG4 level . Data on the association between the presence of IAC and IgG levels and disease remission and treatment in patients with AIP are presented in Supplementary Material Table s2.A higher proportion of AIP patients with IAC than AIP patients with no IAC required stenting . The first patient had IgG4 of 26.2 and IgG2 of 12.2. A second patient (treated with corticosteroids (CST), CellCept and cyclosporine) had IgG4 of 8.2. In a third patient, the IgG4 was 19.4 g/l. We had no IgG2 in the diagnosis. In controls after CST IgG2 was 11.2 and IgG4 0.27, respectively. In a total of 10 patients we had follow-up values after therapy. In six patients, elevated IgG2 normalised after the treatment, and in four patients IgG2 remained elevated despite CST treatment.Histology revealed the typical features of IAC  includin5 Here we describe elevated levels of IgG2 as markers of IAC that were not present in PSC or AIP without cholangitis.AIP type 1 is part of the systemic IgG4-RD with IAC as the most frequent OOI.20 Furthermore, between 3–30% of IgG4-RD patients have normal serum IgG4 concentrations;21 however, they may suffer from significant disease including AIP with IAC.5 Different IgGs bind to different receptors and distinct genes encode six human receptors for IgG.22 IgG1 and IgG3 bind to all human receptors for IgG; IgG2 binds not only to FcγRIIAH131, but also has a lower affinity to FcγRIIAR131 and FcγRIIIAV158; IgG4 binds to FcγRI, FcγRIIA, IIB and IIC and FcγRIIIAV158.22 Consequently, IgG1 and IgG2, distinguishing IAC, bind to different receptors than IgG4.For AIP type 1, the only clinically available serum marker is elevated total IgG or IgG4 in the blood, despite efforts to identify other more specific markers. Slight elevations of IgG4 concentration are seen also in other diseases such as pancreatic cancer.23 however, with no correlation to distinct clinical features. Elevated serum IgG subclass levels were also reported in a series encompassing several autoimmune diseases, including primary Sjögren syndrome (SS), systemic sclerosis, SLE and primary biliary cirrhosis (PBC) and showed a significantly increased level of IgG1 and IgG3 compared with those in healthy controls.24 In this study, IgG2 was significantly reduced in SS and SLE compared to healthy subjects and indifferent in PBC.24 In another study in autoimmune rheumatological disease,25 elevated levels of IgG1 were present in 55% of primary SS, 50% of secondary SS and 30% in the lupus and myositis groups, respectively .In other autoimmune diseases such as systemic lupus erythematosis (SLE), differential expression/elevation of IgG subclasses has been reported with significantly higher levels of IgG1, IgG2 and IgG3 in SLE as compared to healthy controls,26Making the distinction between isolated SS (Mikulicz’s disease) and IgG4-RD, IgG2 was only found elevated in those having IgG4-RD, including AIP, but not in those with isolated SS.27 Elevation of serum IgG2 was described in two cases as a precursor to classical IgG4-RD in a patient with periorbital xanthogranulomatosis28 and in another patient with tubulointerstitial nephritis.29 There are other rare conditions described resembling IgG4-RD but they are negative for IgG4, both in serum and tissue, while IgG2 was again significantly elevated in tubulointerstitial nephritis.31 Patients with these conditions and elevated IgG2 are clearly clinically distinguishable from patients with IAC with and without AIP or PSC.Similarly, significant elevations of serum IgG2 and tissue IgG2 plasma cells were described in orbital IgG4-RD in comparison with non-IgG4 orbital inflammation, suggesting that IgG2 may play a role in IgG4-RD.Retrospective analysis and lack of data on serum values of IgG subclasses before and after steroid treatment are the main limitations of the study. It is worth noticing that IgG subclasses can be slightly elevated in different groups of patients, but the differentiation of pancreatic cancer and classic chronic pancreatitis can be determined clinically.32 in contrast to IAC11 which, in selected cases, can be treated by steroids only without stenting.33 Imaging findings of AIP-IAC and PSC on endoscopic retrograde cholangiography (ERC), magnetic resonance cholangiography (MRC) and computed tomography (CT) showed that the combination of ERC and MRC with cross-sectional images, may be helpful in differentiating between AIP, IAC and PSC.19 High serum IgG2 in those who are IgG/IgG4 positive and elevated IgG1 in those who have low or normal IgG2 and IgG4, indicating PSC, in this context can be considered an additional aid in establishing the one condition and/or excluding the other.From a clinical perspective, to positively identify a chronic cholangitis as being part of the IgG4-RD syndrome, i.e. IAC vs PSC is of the utmost significance. PSC does not respond to steroids or even biologicalsHigh IgG2 or IgG4 levels identify patients with AIP, while high IgG1 in those with low or normal IgG2 and IgG4 levels identifies patients with PSC.Click here for additional data file.Supplemental material, sj-pdf-1-ueg-10.1177_2050640620916027 for Immunoglobulin G subtypes-1 and 2 differentiate immunoglobulin G4-associated sclerosing cholangitis from primary sclerosing cholangitis by Miroslav Vujasinovic, Pia Maier, Hartwig Maetzel, Roberto Valente, Raffaella Pozzi-Mucelli, Carlos F Moro, Stephan L Haas, Karouk Said, Caroline S Verbeke, Patrick Maisonneuve and J-Matthias Löhr in United European Gastroenterology Journal


Clostridioides difficile infection (CDI) incidence rate, and mortality in the patients’ group admitted from ED to medical wards. The ASP implementation was associated with a reduction of antibiotic use and costs. A mild but sustained LOS decrease in all medical wards and a significant downward trend of CDI incidence rate were observed, while mortality did not significantly change. In conclusion, the implementation of our ED-based ASP has demonstrated to be feasible and safe and might clinically benefit the hospital admitted patients’ group. Further research is needed to identify the most suitable ASP design for ED and the key outcome measures to reliably assess its effectiveness.Antibiotic resistance is increasing worldwide. The implementation of antibiotic stewardship programmes (ASPs) is of utmost importance to optimize antibiotic use in order to prevent resistance development without harming patients. The emergency department (ED), cornerstone between hospital and community, represents a crucial setting for addressing ASP implementation; however, evidence data on ASP in ED are poor. In this study, a 4-year, non-restrictive, multi-faceted ASP was implemented in a general ED with the aim to evaluate its impact on antibiotic use and costs. Secondly, the study focused on assessing the impact on length of hospital stay (LOS),  In order to address this issue, antibiotic stewardship programs (ASPs) have been developed with the aim of optimizing clinical outcomes while minimizing unintended consequences2 and have been successfully implemented in medical, surgical and intensive care units. Systematic reviews have shown, with convincing level of evidence, that the introduction of hospital wide ASPs results in reduction of antibiotic usage3, antibiotic resistance4, and adverse drug events, such as nephrotoxicity and Clostridioides difficile infections (CDIs)5.The inappropriate prescription of antibiotics represents one of the most important preventable factors contributing to the spread of antibiotic resistance8, likely because many of the strategies commonly adopted by ASPs may be difficult to be implemented in the ED9. There are logistical system- and provider-level issues making the ED a critical environment for addressing interventions to reduce the inappropriate antibiotic prescription rate10,including ED overcrowding8, high turnover of patients9, diminished continuity of care due to high variability of practitioners11, and therapeutic decisions made frequently by a single ED practitioner in a rapid decision making process often without meaningful microbiologic information12. Furthermore, since ED sits at the interface between community and hospital, the antibiotic selection in ED has the potential to affect the antibiotic usage of both the discharged and the admitted patients with important downstream implications. In fact, antibiotic regimens started in the ED are often maintained even when another clinician has assumed care of the patient11.There is a paucity of literature pertaining to ASPs in the emergency department (ED)et al., advocating the implementation of ASPs within the ED due to the far-reaching consequences that prescriptions in this setting might have on patient outcomes. The statement underlined the need to shift attention to EDs to define which of the multiple antibiotic stewardship strategies are most feasible in this setting7. In this context, the Centers for Disease Control and prevention promoted the development of the MITIGATE toolkit (A Multifaceted Intervention to Improve Prescribing for Acute Respiratory Infection for Adults and Children in Emergency Department and Urgent Care Settings), a six-core component framework for implementing non-restrictive intervention (mostly education and audit and feedback) in the ED13. Besides this example, very few guidance documents are available on this topic. Therefore, in response to this lack of evidence and in a bid to underline the relevance of the topic, the European Society of Clinical Microbiology and Infectious Diseases has recently started the process for developing clinical guidelines on ASPs in the ED.In 2013 a “call to action” was published by May Aim of this study was to assess the impact of a non-restrictive ASP intervention in a non-surgical ED of a tertiary university hospital on reducing the use of antibiotics and related costs. The secondary aim was to evaluate the clinical impact of the ED-based ASP intervention on the hospital-admitted patients’ group.We conducted a prospective quasi-experimental study using an interrupted time-series (ITS) analysis between 2014 and 2017. The study setting was the non-surgical ED of the University Hospital of Tübingen, a 1.513-bed tertiary care teaching hospital. The hospital includes different medical and surgical specialties: liver, kidney and bone marrow transplant units, a paediatric unit, a maternity ward, and a dialysis unit. The ED has 22 beds, equally distributed between the emergency room and the short term observation ward. The ED service is carried out by three personnel shifts. Two internal medicine physicians are permanently employed in the ED, whilst four senior internal medicine residents are on 6-12-month rotation. Three and two practitioners carried out the day and night shift, respectively. During the study period, there were yearly about 10.000 patient contacts, with approximatively 6000 hospitalizations. Before the ASP no official internal guidelines on antibiotic therapy and no routine infectious disease specialist visits were available for the ED.The ASP was designed and carried out by a dedicated team, including two infectious diseases physicians, one infectious diseases resident, one clinical microbiology resident and two study nurses. The intervention model was exclusively non-restrictive. The ASP was composed of a one-year pre-intervention phase (Phase I), a 2-year multifaceted intervention phases , followed by one year of post- intervention phase .The ASP program included the following core elements:Prospective epidemiological and clinical data collection Development and dissemination of guidelines on appropriate antibiotic empiric treatment . The whole ASP team developed the internal guidelines based on hospital epidemiological resistance data, on clinical and epidemiological patients’ data collected in the Phase I, and on the most relevant national/international therapeutic guidelines regarding the main infectious diseases syndromes. The guidelines were made available in written pocket-sized format and distributed to the whole ED staff.Education . The ASP team had weekly meetings with ED staff to discuss the validation of the guidelines and the local ecology. The ED staff carried out the on-line course “Antimicrobial Stewardship: Managing Antibiotic Resistance” promoted by the University of Dundee, United Kingdom and the British Society for Antimicrobial Chemotherapy .Prospective audit and feedback . At least two members of the ASP-team reviewed daily each antibiotic prescription in ED, in accordance with the guidelines. The following patient data were collected and entered into a database: age, gender, underlying comorbidities, diagnosis and antibiotic prescription(s), including name, posology, length and administration route, length of hospital stay (LOS) and mortality. Microbiological data on antibiotic resistance were also gathered. The feedback was provided through weekly newsletters, reporting the compliance rate with the guidelines, the antibiotic use  and the microbiological isolates with the antibiotic resistance profile. The newsletters also included the most relevant publications of the month. Additionally, monthly meetings were held focusing on the discussion of the most relevant clinical cases in which antibiotics were deemed to be inappropriate. The participation of the ED team to these meetings was strongly supported. An example of the newsletter is displayed in the Supplementary Figure Active infection diseases consultation service : in the second phase a specialist consultation service conducted by three infectious diseases physicians were active 24 h seven days a week.Random audit and periodical feedback : a feedback was provided quarterly through newsletters briefly summarizing the antibiotic use.The design of the ASP program and time line of the applied interventions are detailed in the Supplementary Figure https://www.whocc.no/atc_ddd_index/). Antibiotics were classified following the ATC therapeutic subgroup J01 . The DDD data were retrieved from the hospital pharmacy records for the time-frame January 2014 - December 2017 and reflected the monthly amount of antibiotics dispensed to the ED. To capture potential shift in use, overall DDDs were also stratified into three groups  in accordance with the 2019 World Health Organization (WHO) AWARE classification14. Secondary outcomes were: yearly antibiotic costs calculated in EUROs/100 PDs, and clinical outcomes including LOS, monthly CDI incidence  and in-hospital all-cause mortality. The clinical outcomes were measured in the inpatients group, that includes the patients enrolled in ED ASP and admitted to the hospital. These patients were followed until hospital discharge or death.The primary outcome was the total monthly  antibiotic use in ED, measured as DDD per 100 patient days (DDD per 100PDs) according to the 2014 Anatomical Therapeutic Chemical (ATC) Defined Daily Dose Index delivered by the World Health Organization (15. The ITS included four period segments: pre-intervention phase I (January to December 2014), intervention phase II (January-December 2015), intervention phase III (January-December 2016) and post-intervention phase IV (January- December 2017). Estimates for regression coefficients corresponding to the effect sizes of a change in level and a change in trend along the study phases were obtained. A change in level was defined as the difference between the observed level immediately post-ASP and the predicted level by the pre-ASP trend. A change in trend was defined as the difference between the pre and post-ASP slopes. Newey-West standard errors with a maximum lag of 2 was considered for the autocorrelation structure. The other outcomes were analysed using Chi-square test and ANOVA. The trend of antibiotic costs was studied using Poisson regression. A p value less than 0.05 was regarded as significant. All statistical analyses were carried out using STATA version 14.2 . The methods were carried out in accordance with relevant guidelines and regulations. The informed consent was taken from all ED health-care providers involved in the study. The Ethics Committee of the University of Tübingen declared that no ethics approval was necessary since the study was considered as a quality improvement intervention.Statistical analyses were conducted using an ITS model in accordance with the Cochrane Effective Practice and Organization Care recommendations (EPOC)Overall, the ASP intervention included 42886 patients evaluated in ED receiving an antibiotic treatment during the whole study period. The yearly admission rate to the hospital was similar in the four phases Table .Table 1N14, an homogeneous DDD reduction in each of the AWARE antibiotic group was observed  95% −67.50 to 5.27, p 0.092) at the beginning of phase II and a further decrease of 7.20 DDD/100 PDs  at the beginning of phase III  in the phase I, to 358.7 EUROs/100 PDs (SD: 189 EUROs/100 PDs) in the phase II, 262.5 EUROs/100 PDs (SD: 162 EUROs/100 PDs) in phase III and 263.3 EUROs/100 PDs (SD: 162 EUROs/100 PDs) in the phase IV (p < 0.001).Overall, 26852 patients out of 42886 (62.5%) were admitted to the hospital wards Table .The ASP implementation has determined an overall decrease of LOS of the inpatients group admitted in all the five medical wards throughout the study phases. A statistical significant LOS decrease by 0.5 days, 0.7 days and 0.6 days was recorded in the gastroenterology, hepatology and infectious diseases ward , in the hematology, pneumology and oncology ward , and in the nephrology, endocrinology and angiology ward  respectively , the reduction of the incidence was more remarkable during the phase II, in which the change in level further decreased by 0.23%  and the change in trend achieved the statistical significance   in phase I, 3.7% (238/6322) in phase II, 2.4% (259/6831) in phase III and 2.1% (224/6923) in phase IV , alongside the antibiotic costs might reflect a cumulative effect of the various persuasive interventions implemented stepwise. Worthy of note, the greatest decline of both outcomes was observed in phase III. The intensified “prospective audit and feedback” approach, the core element of this phase, may have played a crucial role in enhancing the clinicians’ knowledge and adherence to the guidelines and consequently to an improved appropriateness of prescription19.Notwithstanding the several challenges hampering a successful ASP implementation, our ED-based ASP intervention has been shown to be feasible and efficacious even when no restrictive measures were adopted. The use of an entirely persuasive approach represents, in fact, a relevant strength of our ASP. In accordance with a Cochrane systematic review, the non-restrictive strategy, embedding a high potential for educational opportunities, usually results in more sustained positive effects on the clinicians’ professional practice, in comparison with the restrictive approach22. However, very little literature is available for the ED. A German study observed a statistically significant decrease of the overall mean antibiotic use by 22% after the implementation of a non-restrictive 6-year ASP in a large academic ED7. A similar finding was reported in a general surgery ED in Italy. The implementation of a stewardship bundle based on education and diffusion of hospital guidelines for surgical prophylaxis and infections led to a significant drop of the antibiotic use by 18%23.The positive impact of ASPs on reducing the antibiotic use has been widely assessed in several inpatient settings24. The most common adopted metric, the DDD, is regarded as highly inaccurate25 and might be discordant for several frequently prescribed antibiotics, since the administered dosage in clinical practice differs from the DDD suggested by the WHO26. An addtional common metric, the days of therapy (DOT), also poses challenges in its application in the context of the ED. First, DOT requires patient-level data that might not be obtainable in all institutions. Second, DOT computation relies on calendar days during which the patient receives antibiotic(s) and, consequently, DOT is strongly influenced by patient’s time of admission.These findings, although promising, should be interpreted and compared with caution. The main issue, not hindering a reliable comparison of antibiotic use within and across hospitals, resides in the lack of standardized quantity metrics for antibiotic use, which largely differ across similar settings and providers, and for specific medical populations28. Among these, the Standard Antimicrobial Administration Ratio (SAAR), developed by Centers for Disease Control and Prevention, seems to be the most feasible. By aggregating various patients care locations and antibiotic categories, the SAAR enables a risk-adjusted antibiotic use comparison across multiple hospitals. However, this metric is not easily applicable in European hospitals, due to the different structure of healthcare systems and the lack of shared databases with accessible electronic health records28.In order to address the issue, innovative standardized evidence-based metrics for antibiotic use have been proposedet al., including five studies, described a cost reduction of 33.9% after ASP implementation3. Notably, the impact of ASPs implementation on costs saving could be even greater, despite not reliably measurable. In fact, beyond the costs referred to the direct costs of the antibiotic agents, there are several indirect expenditures that are supposed to drop alongside;29 such as from the adverse drug events30.The ASP implementation led to a significant drop in antibiotic cost by two third along the whole study period. Although not specifically assessed in the ED setting, inpatients ASPs have led to remarkable cost savings for health systems. A meta-analysis published in 2016 by Karanika Since the ED represents the cornerstone between community and hospital setting, we hypothesized that an appropriate antibiotic selection in ED might have a relevant impact along the entire care continuum and ED patients who were admitted to hospital would intuitively benefit. The reduction of both LOS and CDI incidence rate observed in the medical wards seems in fact to support the concept of “downstream effects”.11. From this perspective, the upstream selection of appropriate antibiotic treatment in ED might have a positive effect downstream in the hospital wards, leading to reduced number of antibiotic starts, shorter treatment lengths and earlier switch-to oral administration.With regard to the LOS, a mild but sustained decrease has been shown in all medical wards throughout the study phases. Although some confounders affect this measure, the improvement of the patient care in ED, result of our ASPs, might partly explain this finding. As observed in the clinical practice, the antibiotic therapies started in ED are frequently kept unaltered during the whole hospital stay of the patients, regardless the change of healthcare providers, mainly because of their reluctance to deescalate or even to discontinue33, whilst the efficacy of entirely non-restrictive ASP implementation has been much less investigated35.The CDI incidence rate showed a downward trend throughout the study phases. Interestingly, the protective effect of ASPs on CDI rate has been widely described for restrictive ASP interventions focusing on the “high risk antibiotic classes”It is hard to evaluate how likely the CDI reduction could be directly related to the ASP implementation, since it was implemented in a different setting and, more importantly, several other co-interventions  have been regularly employed in the hospital during the study period.36, it could be hypothesized that the improvement of antibiotic management might preserve the gut microbiota37, resulting belatedly in a reduction of CDI.Notably, the reduction of antibiotic use was greater in Phase II, whilst the greater reduction of CDI incidence was recorded in Phase III. Since the development of CDIs is strongly related to prolonged antibiotic use38.A strength of our study was the use of a Cochrane validated method to measure the antibiotic use, providing the best evidence for evaluating ASP in a quasi-experimental research setting, when a randomized trial is not applicable39. Third, the lack of a control group not receiving the intervention did not allow appraising confounders and counterfactual outcomes.Nonetheless, this study had some limitations. First, the single-center nature of the study might limit its generalizability to other ED settings, especially with different local antibiotic resistance rates. Second, the relatively small amount of DDDs per antibiotic classes did not allow to perform a reliable subgroup analysisIn conclusion, the implementation of our multi-faceted non-restrictive ED-based ASP has demonstrated to be feasible and safe and may clinically benefit the hospital admitted patient group acting on LOS and CDI incidence rate. More research is needed to define the most appropriate ASPs design for the ED and the most suitable key outcome measures to reliably assess its effectiveness.Supplementary Information.