This work aims to investigate different predictive models for estimating the unconfined compressive strength and the maximum peak strain of non-structural recycled concretes made up by ceramic and concrete wastes. The extensive experimental campaign carried out during this research includes granulometric analysis, physical and chemical analysis, and compression tests along with the use of the 3D digital image correlation as a method to estimate the maximum peak strain. The results obtained show that it is possible to accurately estimate the unconfined compressive strength for both types of concretes, as well as the maximum peak strain of concretes made up by ceramic waste. The peak strain for mixtures with concrete waste shows lower correlation values. The construction industry is considered the largest consumer of non-renewable natural resources and it is also an important generator of waste . The higOne of the main solutions that stimulate the reuse of construction and demolition waste (CDW) is its use in the manufacture of concrete. However, the main problem in the use of this type of aggregate is focused on the high absorption capacity due to the presence of ceramic material and mortar adhered to the surface of the aggregates ,6, especThese new concrete solutions made with recycled aggregates have very different behaviours and one of the main variables that most affects performance is the percentage of replacement of natural aggregates. In this sense, numerous studies have analysed the behaviour according to different mix proportions ,15,16, sWhen the execution of these type of concretes is carried out, it is essential to have tools that allow us to predict their behaviour considering the different mix proportions and curing ages . However, the high variability of mix proportions based on the substitution of recycled aggregates and their typologies with the consequent diversity of results, increases the difficulty of establishing strength prediction models occuring in conventional concretes ,21. MoreTogether with the strength values, it is often very useful to know the maximum strain associated with concretes. In this sense, Eurocode 2  providesThe use of CDW as a substitution for aggregates increases the heterogeneity of concrete solutions, showing very different behaviours, if adequate selection and treatment of waste is not carried out . In thisIn order to cope with the limitation previously shown, various full-field optical methods have been developed, among which, Digital Image Correlation (DIC) stands out. This method allows us to obtain a full field of displacements and strains through the use of correspondence procedures based on correlations and numerical differentiation algorithms . Thanks Considering the heterogeneous nature of these materials and the variability of their behaviour, it is worth highlighting the importance of carrying out the DIC approach to analyse the spatial distribution of the displacements and strains suffered throughout the specimen. The 3D-DIC approach allows us to obtain a large amount of data that facilitates statistical analysis and the estimation of properties . In thisAs a consequence, this paper aims to progress understanding in the mechanical characterization of non-structural concretes manufactured with construction and demolition waste through generating predictive models of compressive strength and peak strain. For this, the tests of mechanical characterization of concrete with different mix proportions and curing ages will be integrated together with the 3D-DIC approach for the analysis of the strains suffered during the breaking tests. Within the Materials and Methods section, we describe the materials used in the mixture as well as the experimental and numerical strategies adopted. In Structural concretes are designed for structures and elements for building or for public works, usually designed for compressive stresses of 25 MPa at 28 days [On the one hand, CDWRCon is obtained from concrete, cement mortar and prefabricated concrete parts, including untreated aggregates and natural stone aggregates treated with hydraulic binders and other fractions (content < 0.1%) of floating material, cohesive materials (clay and soil), metals (ferrous and non-ferrous), wood, gypsum and non-floating plastics and rubber. Meanwhile CDWRCer is obtained from concrete, including concrete products, cement mortar, prefabricated concrete parts and ceramic materials, showing a continuous granulometry with concrete and ceramic material aggregates. The CDWRCer components are the same as CDWRCon with the addition of other materials as parts of clay (bricks and tiles), calcium silicate masonry, non-floating aerated concrete and glass.Rc80, Rcu90, Rb10−, Ra10−, X1−, FL5− and the CDWRCer aggregates are classified as Rc40, Rcu50, Rb50−, Rg2−, FL5− .Ru = Unbound aggregates .Rb = Ceramics .Ra = Asphalt.Rg = Glass.FL = Floating materials.X = Other impurities .According to the categories established in the UNE-EN 13242 standard , the CDW2−, FL5−  , metals (ferrous and non-ferrous), wood, gypsum, non-floating plastics and rubber. The CDWRCer has an amount of gypsum that represents 5.2% in the general classification of the components, not corresponding to the class established by the standard for this type of material. The gypsum is prejudicial to concrete due to its composition of sulphate and, therefore, it is necessary to consider a sulphate resistant cement.It is noteworthy that the UNE-EN 13242  standardCu = 75.0, and curvature coefficient, Cc = 2.1, were obtained. The high value of the uniformity coefficient shows the high size variation obtained in the unclassified crushing. The curvature coefficient, 1.0 ≤ Cc ≤ 3.0, defines the CDWRCon and the CDWRCer as well-graded and with a low compressibility, a high compactness and correspondingly suitable for use on construction sites.Additionally, a granulometric study was carried out. In this case it was compared the granulometric curves of both concretes (CDWRCon and CDWRCer) with respect to the Bolomey dosing (reference curve) in accordance to the standard UNE EN 933-1 . This reThe results of this comparison are shown in Identically, the granulometric curves of the CDWRCer and Bolomey dosing are shown in From the results obtained it is possible to conclude that both groups have the right proportions of sand and gravel to make the necessary concrete for non-structural applications. SE4 = Sand Equivalent, UNE-EN 933-8 [EN 933-8 .LA = Los Angeles coefficient, UNE-EN 1097-2 [N 1097-2 .AM = Methylene blue (UNE EN 933-9) [N 933-9) .OM = Organic Matter content, UNE 103204 [E 103204 .SS = Soluble Salt content, UNE 103205 [E 103205 .fWA = Water Absorption Fine aggregate, UNE-EN 1097-6 [N 1097-6 .cWA = Water Absorption Coarse aggregate, UNE-EN 1097-6 [N 1097-6 .SO3 = acid soluble sulphate content, UNE-EN 1744-1 [N 1744-1 .S = sulfur compounds total content, UNE-EN 1744-1 [N 1744-1 .lpcm = light contaminant content, UNE-EN 1744-1 [N 1744-1 .Humus = light organic contaminant in humus content, UNE-EN 1744-1 [N 1744-1 .where: SE4 sand equivalent, gives a value of 55.9 in CDWRCon. This value is lower than the common values of natural aggregates. The sand equivalent for CDWRCer is even lower than the CDWRCon with a value of 45.3. This difference is motivated by the existence of parts of clays (bricks and tiles), as well as calcium silicate masonry elements that reduce the sand lecture and SE4 value. Since non-structural recycled concretes (NSRC) are not subjected to any specific exposure class, the aggregates shall be accepted if satisfy the requirement AM ≤ 0.3 f/100.The quality of the fines, expressed as LA coefficient of 43.0 for CDWRCon. The resistance to fragmentation in CDWRCer, with LA = 52.0, is lower than CDWRCon. This difference is motivated by the presence of bricks, tiles and calcium silicate masonry. So, the coarse aggregates have an abrasion resistance between 40 and 55, being possible to make non-structural concrete with a minimum characteristic strength of 15 N/mm2.Fragmentation resistance offers an The organic matter test provided a 0.14% value in CDWRCon. The content of soluble salts dissolved in distilled water for CDWRCon was 1.1%. The CDW has a high-water absorption coefficient, higher than natural aggregates. In the CDWRCon, the high absorption was associated with the porosity of the concrete. The water absorption coefficients are bigger in CDWRCer. In the coarse fraction, the absorption coefficient was 6.2% for CDWRCon and 10.7% for CDWRCer. This difference is associated with the absorption of clay materials, bricks and tiles. The fine fractions have absorption coefficients similar for both materials.AS0.8 class of acid soluble sulphate. The CDWRCer presents a greater content of these parameters, relating to the declared classes (DeclaredAS and DeclaredS), with a content of 2.1 and 1.2 to acid soluble sulphate and of sulphur compounds, respectively.According to UNE-EN 13242 standard , the CDWR ≤ 62.5 MPa. As an additional feature looking for the best termination, a white cement has been chosen, with a whiteness content ≥85%.The blinder used for manufacturing the concrete was a cement type BL II/B-LL 42,5 R. This cement has the following components: (i) a Clinker content comprised between 65–79%; (ii) a Limestone content of 21–35%; (iii) a Chloride content: ≤0.10; (iv) a Sulphate content: ≤4.0; and (v) a soluble toilet chromium VI content ≤ 0.0002%. It has a beginning setting of: ≥60 min and an end setting of: ≤720 min. The expansion is less than 10 mm. Resistance at 2 days: ≥20 MPa and resistance at 28 days in the interval 42.5 ≤ This section shows the 3D digital image correlation (3D DIC) strategy used for obtaining a full field of displacements in the different concrete samples tested. The concrete solutions were evaluated by means of compression tests according to guideline UNE-EN 12390-3 . In ordeIn order to capture the displacements and strains suffered by the concrete solutions during compression tests, a 3D-DIC approach was used. The acquisition of these images was carried out using a low-cost 3D-DIC prototype similar to the developed by Garcia-Martin et al.  Figure . This prThe synchronization of both cameras was carried out by means of a PLC that allowed us the programming of simultaneous shots. Furthermore, it was connected to a Quantum data acquisition platform b,c, alloThe application of the DIC approach requires the presence of a speckle pattern that provides random intensity variations on the surface of the samples. In this sense, the aerosol technique allows us to create speckle patterns with millimetre or submillimetre spot size on the surface of the specimens . The proAn orientation phase was carried out ahead of the data acquisition. This phase allowed us to pass from the 2D images to a 3D point cloud. From the present case study, the Solav et al.  strategyr, computed from the images’ coordinates ;  are the image coordinates corrected from lens distortion; k1, k2, k3 are the radial distortion parameters; and p1, p2 are the decentering distortion parameters.Firstly, the inner calibration of the cameras was obtained by using the BA method. This method allowed us to minimize the overall re-projection error of the control points (corners of squares) extracted from a calibration pattern. Therefore, lens distortion can be corrected by using a non-linear distortion model, replacing the idealized coordinates with those corrected, according to a Gaussian radial distortion model (Equation (1)). In order to guarantee the accuracy and quality of this process, it is necessary to capture a set of images, generally between 50 and 100 , of a fldx, dy) and the object coordinates . This algorithm provides a linear solution of 11 mathematical parameters equivalent to the non-linear model of 9 geometric parameters. The system can be solved knowing at least six points (Equation (2)). In this case a non-planar calibration object is used in which there are control points with their known 3D coordinates. Furthermore, the DLT algorithm allows us to obtain the 3D coordinates of a specific point by using the 2D coordinates of this point in at least two images.px and py are the image point coordinates and L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11 correspond to the 11 mathematical parameters of the DLT.Once the lens distortion has been corrected, the DLT algorithm allows us to relate the image coordinates  into smaller areas called subsets . The degThe use of the ZNCC correlation allows for matching homologous points with pixel accuracy. In order to obtain a sub-pixel accuracy, the use of the following two-fold approach is required : (i) a bL1–L11) obtained in the orientation process were used along with image coordinates  of the points obtained from DIC. In this way, the real coordinates of each of the points  can be calculated by means of Equation (4), following a least-square strategy. Since the external orientation was performed with a calibration object with known 3D coordinates, the X, Y, Z coordinates are obtained in the global coordinate system for all cameras.Once the correlation process has been carried out, it is possible to perform the three-dimensional reconstruction of the corresponding points, thus obtaining a point cloud associated with the centres of the subsets placed within the ROI. To this end, the DLT parameters  the predictive model for the unconfined compressive strength (UCS); and (ii) the predictive model for the maximum strain. As stated in the Introduction, the DIC approach is an added value in terms of the possibility of analysing the heterogeneous behaviour of the material and studying the maximum strains in the closest area to failure. This advantage allows us to establish a model to predict peak strain more precisely from the compressive strength of the concrete studied.On the one hand, different models have been proposed for predicting the compressive strength ,22,23 focε1 is the peak strain; cmf is the compressive strength at 28 days; and %RCA is the percentage of replacement with recycled coarse aggregates.Concerning the strain predictions, some design codes assumed a constant value of 0.002, meanwhile other models directly relate compressive strength with peak strain, such as the one provided by González-Fonteboa et al.   . This fit-Student test. Complementary to both regression strategies, several statistical analyses were carried out with the aim of evaluating the statistical significance of the inputs. These tests were: (i) the analysis of variance (ANOVA) test, (ii) the Levene´s test; and (iii) n−1) (Equation (7)). The sum of these indices is the total Sobol’ index whose value is equal to 1.V(Y) is the variance of the model; i = V(E(Y|Xi))V is the first order partial variance; ij = V)V is the second order partial variance, etc.iS is the first order Sobol’ index and ijS is the second-order Sobol’indices.The mathematical model can be finally expressed as a relationship in which there are three inputs bounded by the experimental data, which allows us to obtain a prediction of the final output value. According to this, a good practice compromises the analysis of the influence of each input in the final output. From the present study, it was decided to carry out a sensitivity analysis based on the Monte Carlo simulation (MCS). This method allows us to generate equiprobable situations, which could be considered as suitable sampling points for a subsequent sensitivity analysis. Within this context, one of the most used strategies to carry out sensitivity analysis is the estimation of the Sobol’indices . These iw/c) in order to achieve good concrete workability. In addition, the variability in these values allows us to extend the validation range in modelling.A total of 38 tests were carried out following the guideline UNE-EN 12390-3 , 19 of wIn order to optimize the configuration to be used during the 3D-DIC test, a preparation stage was carried out. The steps followed in this process were as follows: (i) application of the speckle pattern; (ii) definition of the Ground Sampling Distance (GSD), lens aperture and stereo angle; and (iii) geometric calibration and orientation of the cameras.Firstly, a speckle pattern was applied using the aerosol technique b. The quThe success of the 3D-DIC approach depends strongly on the GSD of the images and the stereo angle of the cameras. In this sense, an angle that is too high allows for a better precision in depth, but a lower precision in the plane, and an angle too small allows a better precision in the plane at the cost of a higher uncertainty in depth. Under this basis, the acquisition system was placed at 1.25 m with respect to the specimen a, achievTaking into account that the tests were performed on different days, the camera orientation procedure described in The external orientation was carried out applying the DLT procedure, for which an image of a 125 mm diameter cylindrical object was captured c. The caIn order to obtain the displacement and strain on each test specimen, the 3D-DIC approach defined in The strains suffered by the specimen were captured at different locations. To this end the following strategy was used: (i) creation of several virtual extensometers to evaluate the longitudinal strains b; (ii) eWith the aim of obtaining a wide population, 22 virtual extensometers were placed in each specimen with a separation of 5 mm. In this sense, it is worth mentioning the high differences found between the values of the different virtual extensometers, which indicate the high heterogeneous behaviour of these materials. This heterogeneity can be seen in the high CoV corresponding to the virtual extensometers of some sample specimens shown in the t); (ii) the water–cement ratio (w/c); and (iii) the percentage of material belonging to the class Rc + Ru (RcRu) established by UNE-EN 13242 standard [Rc corresponds to concrete, concrete products, mortar and concrete masonry parts, and Ru correspond to untreated aggregates and natural stone aggregates treated with hydraulic binders.The concrete strength model was obtained by using the MLR approach. This analysis was carried out with the assistance of the IBM SPSS Statistics software . The input variables considered during this stage were: (i) the time .The obtained coefficients and the Student’s t-test results are shown in t is rupture time (days), w/c is water-cement ratio and RcRu is material belonging to the class Rc + Ru. There is a validity range to the significance of the model that is shown in Rc + Ru is between 54.99 and 90.74. Therefore, the equation that represents the best fit is Equation (8).In order to understand which variables are the most relevant in the strength prediction model of the recycled concrete, a Sobol sensitivity analysis was carried out. A total of 500,000 simulations were performed in order to carry out this analysis through a Monte Carlo Simulation. For each of the simulations, the input variables were modified within the ranges obtained from the experimental results.Rc + Ru percentage is the variable that least affects the prediction. The great similarity between the first and the total Sobol’indices highlights the absence of a second-order effect.The inputs evaluated for predicting the maximum strain of the concretes were the compressive strength, the curing age and the water–cement ratio. Scatterplots with a linear trend are shown in The results in this case, for the simple regressions, also show a low correlation and outliers in The following transformations were used during the adjustment: (i) a square root for the peak strain; (ii) a cubic root for the UCS; and (iii) a fifth root for the rupture time. As a result of the transformations carried out, it was possible to obtain an adjustment for the concrete manufactured with CDWRCon with a Pearson’s correlation coefficient value of 0.859, with the determination coefficient as 0.738 and a standard error of 0.090 .The analysis of variance (ANOVA)  showed tw/c ratio. The results show that these variables are not significant (sig. > 0.050). These values indicate the presence of anomalies that prevent obtaining an accurate prediction model for this type of concrete.The obtained coefficients and the Student’s t-test results are shown in 2 coefficient can be considered as acceptable, the parameters are not correct and the predictions for values of the inputs differ from those used to generate the model, which may result in erroneous predictions. In order to determine what happens in the CDWRCon model, the data used to calculate the model were analysed individually and compared with the CDWRCer data. A greater data dispersion was found for the concretes made up by concrete waste, while ceramics have a more uniform distribution with no empty ranges . This isOn the other hand, the model for the concrete manufactured with CDWRCer yielded a better adjustment with a Pearson’s correlation coefficient value of 0.917, while the determination coefficient is 0.840 with a standard error of 0.085 .The analysis of variance (ANOVA)  is similt statistic, between 2.442–5.036. These results indicate that all the variables are significant (sig. < 0.050) and the model seems to have a correct behaviour in this case.The Student’s t-test results  show a gt is rupture time (days); UCS represents the unconfined compressive strength (MPa); and w/c is the water-cement ratio.Therefore, the peak strain prediction model can be represented by the Equation (9).Further, the data obtained from the strain prediction model were subjected to a validation analysis. Thus, the predictions for the experimental data were simulated and compared with the results obtained during the campaign. A mean discrepancy of 6.1% was obtained for the CDWRCer model. These results were considered acceptable taking into account the low peak strain values as well as the precision required in this type of prediction.In order to understand which variables are the most relevant in the strain prediction model of the recycled concrete, a Sobol sensitivity analysis was carried out. A total of 500,000 simulations were performed to carry out this analysis through a Monte Carlo Simulation. For each of the simulations, the input variables were modified within the ranges obtained from the experimental results .This work aimed at investigating a predictive model for the determination of the UCS and the maximum strain in non-structural concretes made up by two types of recycled waste: concrete and ceramic wastes. The inputs required for fitting these models have been obtained by means of an extensive experimental campaign, which include granulometric analysis, physical and chemical analysis, and compression test among others. It is worth mentioning the use of the 3D-DIC as a remote sensing approach able to obtain a full-field of strains. This property allows us to accurately determine the peak strain of the concrete, which showed a high heterogeneity depending on the area considered. Within the predictive model strategy, the simple regressions yielded low correlation values for the individual variables, so finally an MLR model was adjusted and showed that there is a good correlation between all the variables considered together. In addition, the transformations of variables made it possible to minimize errors. This highlights the need to incorporate different variables to obtain a correct predictive model.Rc + Ru are able to predict the UCS with a determination coefficient of 0.848 within the validity range, with a standard error of 0.137. The coefficients showed that the w/c ratio has the greatest influence on compressive strength. On the one hand, the adjustment obtained using MLR demonstrates that the variables’ rupture time, water-cement ratio and On the other hand, the strain prediction model allows for estimating the peak strain as a function of three input variables: rupture time, unconfined compressive strength and water/cement ratio. The sensibility analysis showed that the UCS has the greatest influence on peak strain. Thus, the strength value obtained from the previous model can be employed to estimate the peak strain.2 coefficient of 0.840 is supported by several statistical analyses that verified the statistical significance of the inputs, as well as the low discrepancy in the verification with the experimental data. However, the results obtained for the concrete manufactured with concrete waste model show more anomalous values with a low R2 coefficient and less satisfactory results during statistical analysis. These results show the complexity of establishing a prediction model for this type of concrete, making a larger population necessary to carry out the adjustment, which will try to be integrated into future research.The results obtained for the concrete manufactured with ceramic waste can be considered satisfactory, since the Rw/c in the compressive strength and maximum strain. To this end, the use of superplasticizers will be planned.One of the main future works will focus on scaling up the data from experimental campaigns in order to achieve a database that allows us to contrast and scale the results of the modelling and check the error. Along with this, one of the main interests focuses on the use of the full-field data provided by the 3D-DIC approach to evaluate other properties that could be of great interest in this type of concrete, such as elasticity, shrinkage or behaviour at the aggregate-cement interface. For this purpose, other types of tests, such as bending tests, could give rise to greater possibilities regarding the analysis of these properties under a 3D-DIC approach. Additionally, further dosages will be carried out in order to improve the influence of the Additionally, the proposed methodology will be implemented in concrete with other types of recycled aggregates that allow for higher performance for structural uses and thus be possible to carry out numerical simulations with the properties obtained.


To quantify the frequency of antibiotic treatments attributable to specific enteric pathogens due to the treatment of diarrhoea among children in the first 2 years of life in low-resource settings.Secondary analysis of a longitudinal birth cohort study, Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED).This study was conducted at eight sites in Bangladesh, Brazil, India, Nepal, Peru, Pakistan, South Africa and Tanzania.We analysed 9392 reported diarrhoea episodes, including 6677 with molecular diagnostic test results, as well as 31 408 non-diarrhoeal stools from 1715 children aged 0–2 years with 2 years of complete follow-up data.We estimated incidence rates and the proportions of antibiotic use for diarrhoea and for all indications attributable to the top 10 aetiologies of diarrhoea. We estimated associations between specific aetiologies and antibiotic treatment, and assessed whether clinical characteristics of the diarrhoea episodes mediated these relationships.Shigella and rotavirus were the leading causes of antibiotic treatment, responsible for 11.7% and 8.6% of diarrhoea treatments and 14.8 and 10.9 courses per 100 child-years, respectively. Shigella and rotavirus-attributable diarrhoea episodes were 46% , and 19%  more likely to be treated with antibiotics, respectively, compared with other aetiologies. Considering antibiotic uses for all indications, these two pathogens accounted for 5.6% of all antibiotic courses, 19.3% of all fluoroquinolone courses and 9.5% of all macrolide courses. Among indicated treatments for dysentery, Shigella and Campylobacter jenjui/Campylobacter coli were responsible for 27.5% and 8.5% of treated episodes, respectively.Shigella and rotavirus were disproportionately responsible for antibiotic use due to their high burden and severity further strengthens the value of interventions targeted to these pathogens. Interventions against Campylobacter could further prevent a large burden of indicated antibiotic treatment for dysentery, which could not be averted by antibiotic stewardship interventions.The evidence that  The multisite birth cohort design of this study with intensive twice-weekly home visits allowed capture of all antibiotic exposures for any indication including instances where antibiotics were obtained without prescriptions.The use of quantitative molecular diagnostics for a broad range of enteric pathogens allowed us to appropriately assign aetiology to diarrhoea episodes prompting antibiotic treatment.A limitation was that the indication for antibiotic use was not known and was therefore inferred by the overlap between treatment and diarrhoea symptoms.Shigella and Campylobacter, which are on the WHO priority pathogen list for concern about AMR.Diarrhoea is a major cause of antibiotic treatment among children, especially in low-income and middle-income countries (LMICs), because of both the high incidence of diarrhoea and frequency of treatment. In the multisite Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) birth cohort study, the incidence of diarrhoea during the first two years of life was 273.8 episodes per 100 child years,Because there is uncontrolled access to antibiotics in many LMICs, children often receive antibiotics without seeking care.9 10Shigella, enterotoxigenic Escherichia coli (E. coli) (ETEC), Campylobacter and Cryptosporidium appropriately broadens the vaccine value proposition and could inform priority-setting for the development, evaluation and implementation of these interventions.14Influenza and pneumococcal conjugate vaccines have been found to reduce antibiotic use through the prevention of respiratory illnesses.To estimate the preventable burden of antibiotic use for diarrhoea that could be achieved by vaccines or other pathogen-specific interventions, we quantified the amount of antibiotic use that could be attributed to the treatment of specific causes of diarrhoea in the MAL-ED birth cohort study.The study design for MAL-ED has been described elsewhere.2Campylobacter jenjui/Campylobacter coli (C. jejuni/C.coli), Cryptosporidium, norovirus, rotavirus, sapovirus, Shigella, typical enteropathogenic E. coli (tEPEC) and heat stable ETEC (ST-ETEC).Pathogens were detected among all stool samples collected from children with complete follow-up. To extract total nucleic acid, the QIAamp Fast DNA Stool Mini Kit (Qiagen) was used.j, that is, Because multiple pathogens were frequently detected in stool during antibiotic-treated diarrhoea episodes, detection of a pathogen alone was not sufficient to assign aetiology and attribute antibiotic use. To identify the pathogens responsible for diarrhoea treated with antibiotics, we calculated pathogen-specific attributable fractions (AF) of antibiotic-treated diarrhoea using generalised linear mixed-effects models (GLMM) that associated pathogen quantity detected with presence in diarrhoeal versus non-diarrhoeal stools, as previously outlined.We calculated attributable incidence rates of antibiotic use for each pathogen per 100 child-years as the product of the AF and the total incidence of antibiotic courses for diarrhoea identified by surveillance. We also calculated the proportion of all antibiotic use that was attributable to each pathogen as the product of the AF and the proportion of all antibiotic courses that were given for diarrhoea. To quantify appropriate antibiotic use, we calculated the proportion of pathogen-attributable antibiotic use that was for dysentery. All results were stratified by age, site and antibiotic drug class.To assess whether specific pathogens were associated with antibiotic treatment, we estimated risk ratios (RR) for the association between specific pathogens and antibiotic treatment using the pathogen-specific AFe as a continuous exposure. We used the Poisson approximation for log-binomial regression with generalised estimating equations to account for repeated episodes within each child. Estimates were scaled to represent the difference between complete attribution  and no attribution. Estimates were adjusted for site, age as a quadratic spline, sex and the Water, Assets, Maternal Education, Income (WAMI) index, a measure of socioeconomic status.18Shigella and rotavirus on antibiotic treatment, the pure natural direct effects (PNDE), the total natural indirect effects (TNIE) through the diarrhoea severity score and dysentery (Shigella only) and the proportions mediated by diarrhoea severity and dysentery using the inverse OR weighting approach to mediation analysis with weights truncated at the top 1%.To further assess whether diarrhoea severity mediated the associations with antibiotic treatment, we estimated the total effects of For the parent study, ethical approval was obtained from the Institutional Review Boards at each of the participating research sites and at the University of Virginia School of Medicine  (14595). For the current study, we obtained ethical approval at the University of Virginia School of Medicine  (22398) and Emory University  (STUDY00003285).It was not possible to involve patients or the public in the design, conduct, reporting or dissemination plans as this was a secondary data analysis of a study conducted in 2009–2014.These analyses included 1715 children with 9392 reported diarrhoeal episodes and 38 085  stool samples with valid qPCR results for the 10 pathogens included . CaregivShigella had the highest incidence of antibiotic use of 14.77 (95% CI: 13.25 to 16.84) courses per 100 child-years, followed by rotavirus , sapovirus , adenovirus 40/41  and ST-ETEC   and 8.6% (95% CI: 7.7 to 9.8) of antibiotic treatments for diarrhoeal episodes, respectively (o 10.71) . Shigellectively . These t10.1136/bmjopen-2021-058740.supp1Supplementary dataShigella was the leading cause of antibiotic use in India, Nepal, Peru, Pakistan and South Africa. In contrast, sapovirus was the leading cause in Brazil and Peru, adenovirus 40/41 was the leading cause in Bangladesh and ST-ETEC was the leading cause in Tanzania (Shigella were responsible for 50.99 (95% CI: 42.72 to 62.14) and 45.79 (95% CI: 39.70 to 54.61) courses per 100 child-years at this site alone, respectively  of antibiotic treatments overall. Therefore, specific enteric pathogens were responsible for a lower proportion of all antibiotic exposures for any indication. Overall, 3.2% and 2.4% of all antibiotic courses given were attributable to ectively . Both weShigella (27.5%) and C. jejuni/C. coli (8.5%), respectively (Shigella (18.7%) and C. jejuni/C. coli (18.6%) were for dysentery. The AF of antibiotic treatments for dysentery compared with watery diarrhoea did not differ for the other pathogens, and less than 10% of antibiotic treatments attributed to the other pathogens were for the treatment of dysentery.Focusing on indicated antibiotic treatments, the highest proportions of antibiotic use for dysentery were attributed to ectively . These tShigella-attributable diarrhoea episodes were 46% more likely to be treated with antibiotics compared with all other episodes (adjusted risk ratio (aRR): 1.46, 95% CI: 1.33 to 1.60), and rotavirus-attributable episodes were 19% more likely to be treated  , and rotavirus-attributable episodes were 21% more likely to be treated . The associations between Shigella and rotavirus and antibiotic treatment were consistent across most sites, excluding Tanzania and Nepal  and India .After adjustment for age, site, sex and socioeconomic status, to 1.31) . The assnd Nepal . UniquelShigella, respectively  that had introduced rotavirus vaccine prior to the study. Rotavirus vaccine coverage is high (>70%) and availability has expanded to all countries included in the MAL-ED study (excluding Bangladesh),Because diarrhoea was responsible for more than a quarter of antibiotic treatments in the MAL-ED study, interventions that target specific enteric pathogens could reduce antibiotic selection pressure and make an important contribution to efforts to combat AMR. We found that These results are consistent with a similar analysis of facility-ascertained moderate-to-severe diarrhoea conducted in GEMS,Shigella were disproportionately more responsible for antibiotic use than would have been expected based on the age-specific incidence of disease. Because point-of-care diagnostics were not available, treatment decisions were not made based on known aetiology but were rather likely due to unique features of the clinical syndromes caused by these pathogens. Indeed, we found evidence that the associations between Shigella and rotavirus and antibiotic treatment could be explained by the fact that these pathogens cause more severe disease. Unsurprisingly, since Shigella is the leading cause of dysentery for which treatment is recommended, dysentery also mediated the relationship between Shigella and antibiotic use. Because diarrhoea severity and dysentery only explained a portion of the relationships, there may be other subjective indicators for treatment that were insufficiently captured by the severity metrics captured.The contribution of most enteric pathogens to antibiotic use was in proportion to their contribution to diarrhoea overall. However, in addition to being the leading causes of diarrhoea in the first and second years of life, respectively, rotavirus and Shigella was responsible for approximately 1 in 8 uses of fluoroquinolones and 1 in 18 uses of macrolides. Shigella vaccines in developmentWhile the contribution of individual enteric pathogens to total antibiotic use was limited (<5% for each pathogen), reductions of these magnitudes would be comparable or larger than the effect of most existing antibiotic stewardship interventions.Shigella and Campylobacter, would also have the direct benefit of potentially preventing antibiotic-resistant disease. Shigella and Campylobacter are on the WHO priority pathogens list for research and development of new antibiotics due to increasing AMR.Shigella spp. was 65% and 29%, respectively, in Asia and Africa in 2007–2009. Moreover, resistance rates were higher among children with diarrhoeal illnesses than adults .et al found similar results regarding resistance to ciprofloxacin (fluoroquinolone) and erythromycin (macrolide) in Campylobacter in individuals from Asia and Africa who presented to care in Qatar. Nearly three-quarters and two-thirds of individuals from Asia and Africa, respectively, were infected with Campylobacter isolates resistant to ciprofloxacin, while a smaller percentage were resistant to erythromycin (7.1% in Asia vs 14.3% in Africa).28Interventions that reduce the incidence of bacterial diarrhoea episodes requiring antibiotics, particularly due to Shigella and Campylobacter were detected in 10% and 28% of all non-diarrhoeal stools collected in MAL-ED,Finally, because subclinical carriage of these and other bacterial enteropathogens is highly common among young children in LMICs,Because prescriptions and/or caregiver-reported indications for treatment were unavailable, this analysis was limited by attributing antibiotic use to diarrhoea based on the temporal overlap of symptoms. Furthermore, information on specific drug given and dosing were not available, and antibiotic courses were defined based on antibiotic-free days rather than the intended duration.Shigella and rotavirus were disproportionately responsible for antibiotic use due to their high burden and severity strengthens the value proposition for rotavirus and Shigella vaccinesThe evidence that


IgG4-related sclerosing cholangitis, a biliary manifestation of an IgG4-related disease, belongs to the spectrum of sclerosing cholangiopathies which result in biliary stenosis. It presents with signs of cholestasis and during differential diagnosis it should be distinguished from cholangiocarcinoma or from other forms of sclerosing cholangitis (primary and secondary sclerosing cholangitis). Despite increasing information and recently established diagnostic criteria, IgG4-related sclerosing cholangitis remains underdiagnosed in routine clinical practice. The diagnosis is based on a combination of the clinical picture, laboratory parameters, histological findings, and a cholangiogram. Increased serum IgG4 levels are nonspecific but are indeed a part of the diagnostic criteria proposed by the Japan Biliary Association and the HISORt criteria for IgG4-SC. High serum IgG4 retains clinical utility depending on the magnitude of elevation. Approximately 90% of patients have concomitant autoimmune pancreatitis, while 10% present with isolated biliary involvement only. About 26% of patients have other organ involvement, such as IgG4-related dacryoadenitis/sialadenitis, IgG4-related retroperitoneal fibrosis, or IgG4-related renal lesions. A full-blown histological finding characterized by IgG4-enriched lymphoplasmacytic infiltrates, obliterative phlebitis, and storiform fibrosis is difficult to capture in practice because of its subepithelial localization. However, the histological yield is increased by immunohistochemistry, with evidence of IgG4-positive plasma cells. Based on a cholangiogram, IgG-4 related sclerosing cholangitis is classified into four subtypes according to the localization of stenoses. The first-line treatment is corticosteroids. The aim of the initial treatment is to induce clinical and laboratory remission and cholangiogram normalization. Even though 30% of patients have a recurrent course, in the literature data, there is no consensus on chronic immunosuppressive maintenance therapy. The disease has a good prognosis when diagnosed early. IgG4-related sclerosing cholangitis (IgG4-SC) is a biliary manifestation of IgG4-related disease (IgG4-RD). IgG4-RD is an immune-mediated fibroinflammatory disease that can affect almost any organ. The disease may present either as diffuse fibroinflammation or as the formation of inflammatory pseudotumors in the affected organ. Typical histological signs for IgG4 disease are IgG4-enriched lymphoplasmacytic infiltrate, obliterative phlebitis, storiform fibrosis, and variable presence of eosinophils in affected organs –3. Most IgG4-RD is a relatively new disease entity with unification of a host of previous clinical entities under the umbrella term “IgG4-RD” only achieved in 2012 [The diagnostic criteria for IgG4-SC have not yet been unified, with the HISORt and Japan Biliary Association criteria sharing many similarities but also some important differences , 11There is controversy around whether type 1 IgG4-SC should be considered IgG4-SC or simply AIP with associated biliary sclerosisThere are only limited epidemiological data on IgG4-SC, some of which evaluate the occurrence of IgG4-SC only indirectly. There are several reasons for this. IgG4-RD is a new disease, whose diagnostic criteria have only recently been accepted worldwide. This has raised global awareness of the disease, but the disease does not have its own unique International Statistical Classification of Diseases and Related Health Problems ICD-10) code, which complicates epidemiological studies. The concept of IgG4 disease was preceded by information about its individual organ manifestations. The most studied one is autoimmune pancreatitis (AIP), which IgG4-SC is typically associated with. Most literature data come from Japan. The first mention of AIP dates back to 1995; however, the diagnostic criteria for AIP were first proposed by the Japan Pancreas Society in 2006 , 9. In t code, whAnother factor that affects epidemiological studies is the interpretation of type 1 IgG4-SC, which is associated with a lower rate of bile duct stenosis and is mostly associated with the AIP. One group of experts does not approve of this type, because it believes that such stenosis could be caused by external compression of the intrapancreatic portion of the bile duct by the inflamed pancreatic tissue and not by inflammation of the bile duct .The other group of experts presumes that type 1 IgG4-SC may occur even without concurrent AIP, which is supported by case series, large series, and even histological findings , 13–16.Exclusion of type 1 IgG4-SC would have a significant impact on epidemiological data, because type 1 IgG4-SC occurs most frequently and according to Tanaka makes up to 64% of all IgG4-SC .These studies have several limitations, and it is generally assumed that they underestimate the real incidence and prevalence. In 2011, Kanno et al. conducted the Nationwide Epidemiological Survey of Autoimmune Pancreatitis in Japan with the following results: the overall prevalence rate of AIP was 4.6 cases per 100,000 inhabitants and the annual incidence rate was 1.4 per 100,000 inhabitants . Based oAn indirect estimate of the prevalence of IgG4-SC can be obtained from case series data on the percentage of IgG4-RD cases with biliary involvement. In 2015, Inoue et al. analyzed a cohort of 235 patients from 8 Japanese IgG4-RD centers, 64% of whom had histologically verified disease. Pancreatic involvement was present in 60% and bile duct involvement in 13% of them . On the IgG4-SC is a disease of elderly patients. Most patients are diagnosed in the 6th-7th decade; the disease has not yet been described in children and adolescents , 29. OnlIgG4-SC is a disease of unknown etiology with a multifactorial pathogenesis. IgG4-RD typically presents with polyclonal hypergammaglobulinemia and elevated serum IgG4 levels . Some auIgG4 physiologically makes up to 3–6% of the total amount of IgG . We do nPhysiologically, IgG4 is formed as a result of strong or repeated antigen stimulation to induce tolerance . ElevateGenetic predisposition plays an important role in the development of IgG4-SC. HLA serotypes DRB1∗0405 and DQB1∗0401 are more common in IgG4-SC in the Japanese population, though not in other ethnic groups , 50. In The leading theory of the pathogenesis of IgG4-SC is an aberrant interaction between innate immunity, T-cell immunity, and B-cell immunity.β (TGF-β), are present in the bile duct tissue. Costimulation of B cells with IL-4 and IL-10 increases IgG4 production [β overproduction plays a very important role in the fibrogenesis of patients with IgG4-SC [Activation of nucleotide-binding oligomerization domain-containing protein 2 (NOD-2) and toll-like receptor (TLR) on monocytes or basophils of IgG4-AIP patients activates the B-cell-activating factor (BAFF), leading to an enhancement of the IgG4 response. In an animal model, activation of TLR3 and TLR4 leads to immune-mediated cholangitis, pancreatitis, and sialoadenitis . Macrophoduction . On the  IgG4-SC .Chemokines play an important role in IgG4-RD. CCR8 expression was detected in half of Th2 lymphocytes and in 60% of FOXP3 Tregs . CCR8-po+ B-cells, CD20+ B-cells, and naive B-cells compared to the healthy population [+ B-cells and CD20+ B-cells were not altered. An increase of memory B-cells was observed only in patients who relapsed within two years of follow-up [Patients with IgG4-RD have higher counts of plasmablasts and plasma cells but lower counts of CD19pulation , 68. IL-pulation . Remissiollow-up .γ, IL-1β, IL-2, and tumor necrosis factor-α). Subsequently, the Th-2 immune response is activated, leading to disease progression. An increased production of BAFF from monocytes and basophils and IL-10 from memory Tregs leads to increased production of IgG4, while upregulation of TGF-β from memory Tregs leads to fibrogenesis [Okazaki et al. developed a pathogenic theory of IgG4-SC formation. So far, an imprecisely defined antigenic stimulus (self-antigen or microorganism) causes a decrease in naive Tregs, leading to the induction of a Th-immune response with the release of proinflammatory cytokines . Type 3 and type 4, which are associated with hilar stenosis, must be distinguished from CC. Endoscopic retrograde cholangiopancreatography (ERCP) with biliary tract biopsies, or endoscopic ultrasonography (EUS) and intraductal ultrasonography (IDUS), is necessary.Approximately 90% of IgG4-SC patients have concomitant AIP , 29, 30.  The diagnosis of IgG4-SC is based on a combination of four criteria:A typical cholangiogramLaboratory findings of elevated IgG4 antibodiesThe presence of a systemic involvementHistological examinationThe aim is not only to determine the diagnosis of IgG4-SC as accurately as possible but also to exclude diseases with diametrically different treatment and prognosis, such as pancreatic cancer, PSC, and CC. Of the diagnostic methods, MRCP is sufficient in some cases; however, in most of the patients, ERCP with biliary tract biopsies, endoscopic ultrasonography-guided fine-needle aspiration of the pancreas or IDUS is required.Currently, two diagnostic criteria are accepted in the diagnosis of IgG4-SC: the HISORt criteria, which were taken from the AIP diagnostic criteria and found their application mainly in Europe and USA, and the Japan Biliary Association criteria, which are used mainly in Japan and China. Both are based on a combination of the four diagnostic methods mentioned above. However, they differ in the definition of a certain and probable diagnosis of IgG4-SC.In 2008, Ghazale et al. proposed applying the criteria originally created for the diagnosis of AIP to the diagnosis of IgG4-SC-HISORt . Based oIn 2012, the Japan Biliary Association introduced diagnostic criteria that define a definite, probable, and possible diagnosis. They are listed in Thus, we can conclude that the HISORt criteria emphasize a typical cholangiogram; a typical histological finding is not necessary for the definitive diagnosis, while serological evidence of elevated IgG4 antibodies has the same diagnostic weight as the histological finding. Systemic impairment is only an additional criterion for a probable diagnosis. On the other hand, the Japanese criteria emphasize the role of histology and in some ways elevate the evidence of a well-defined organ involvement meeting the criteria for IgG4 disease above the elevated serum IgG4 alone.A typical pathological finding is localized subepithelially and leads to a thickening of the biliary tract wall even in sections that appear normal on the cholangiogram.Almost 90% of patients with IgG4-SC have AIP; therefore, it is necessary to classify IgG4-SC into IgG4-SC associated with AIP and isolated IgG4-SC from the beginning, as both forms have separate diagnostic criteria.It is also necessary to classify IgG4-SC according to the cholangiogram from the beginning. IgG4-SC types 1, 2, 3, and 4 differ in differential diagnosis.The following organ manifestations are diagnostically significant: sialoadenitis/dacryoadenitis, retroperitoneal fibrosis, and IgG4-related kidney disease.The importance of ruling out hepatobiliary malignancy was emphasized by adding “no neoplastic cells detected” to the histology criteria.Good prognosis is predicted by a good response to corticosteroids, and response to steroids has become a separate diagnostic criterion. Because some malignant lesions may also respond to steroids, cytological or histological examination is always recommended before using steroids. Steroid effectiveness should be assessed based on ERCP and/or MRCP imaging within two weeks after their administration.New imaging modalities, such as EUS and IDUS, are important in differential diagnosis.New diagnostic criteria were published in 2021 by the Japan Biliary Association . These fThe Japanese Clinical Diagnostic Criteria for IgG4-related sclerosing cholangitis are listed in IgG4-SC often has a dramatic course but ultimately a good prognosis given a good response to corticosteroids and a comparable risk of developing malignancies as the general population.p=0.010) [The clinical picture is dominated by abdominal pain and jaundice, which is the most common symptom in patients with IgG4-SC. In the above-mentioned retrospective study of Tanaka et al., which evaluated 527 IgG4-SC patients from Japan, 35% of patients had jaundice . Similarp=0.010) .Jaundice was twice as common in IgG4-SC patients in the United States and the United Kingdom, where it occurred in 77% and 74% of patients, respectively , 30. SudDecompensated liver cirrhosis is rare in IgG4-SC. The most common manifestation in these patients is bleeding from the esophageal varices, which occurred in 0.9% of them .Association with IBD is rare in IgG4-SC; it does not exceed 5% and is usually an intestinal manifestation of IgG4-RD. On the other hand, up to 90% of patients with IgG4-SC have concomitant AIP , 29, 30.AIP is the most common, but not the only, systemic manifestation of IgG4-RD in patients with IgG4-SC. Many of them have extrapancreatic manifestations of IgG4-RD, such as retroperitoneal fibrosis, sialodenitis and dacryoadenitis (Mikulicz disease), mediastinal lymphadenopathy, or renal involvement. Lung involvement is manifested with nodule creation, pulmonary fibrosis, or interstitial lung disease. Retro-orbital disease, aortic involvement, and neurological symptoms, such as progressive encephalitis and pituitary mass causing hypopituitarism, are rare. Based on recent data, approximately 26% of IgG4-SC patients had extrapancreatic manifestations, with a higher rate in those with concomitant AIP , 20. IgGThe incidence of CC is low in patients with IgG4-SC and varies from 0.09% to 0.7% in individual studies. This stands in contrast to PSC patients who have a 160-fold higher risk of CC compared to the general population and lifetime prevalence of 5–10% , 75–78.The IgG4 antibody is one of the four subclasses of immunoglobulin G. Normally, it accounts for less than 5% of the total IgG value. According to some authors, 74–88% of patients with IgG4-SC have elevated serum IgG4 levels  of 1.35 g/L) , 29, 79.Not only are IgG4 antibodies specific for IgG4-RD but also they are elevated in some patients with bronchial asthma, pemphigus, and atopic dermatitis. Elevated serum IgG4 levels are also present in some patients with PSC and in some patients with hepatobiliary malignancies, which complicates differential diagnosis. For PSCs, elevated serum IgG4 levels were present in 9–26% of patients , 82–91. These facts have led to the dilemma of whether the cutoff for IgG4 is set correctly, especially for the differential diagnosis of IgG4-SC from CC. The most problematic group in this respect appears to be patients with IgG4-SC types 3 and 4, without AIP, but it turns out that a cutoff of 1.35 g/L is not sufficient even to distinguish IgG4-SC from PSC. Boonstra et al. showed that the ULN cutoff for IgG4 (1.4 g/L) yields a sensitivity of 90% with a specificity of 85% for IgG4-SC. Increasing the cutoff level to 2 × ULN increased the specificity to 98%; however, it decreased the sensitivity of IgG4 to 70%. The highest specificity for IgG4-SC was achieved when applying the 4 × ULN (sIgG4 > 5.6 g/L) cutoff with a sensitivity of 42% [Ohara et al. evaluated the cutoff values for IgG4 between each cholangiographic type of IgG4-SC and patients with other diagnoses: pancreatic carcinoma (PCa), PSC, and CC. The cutoff values were 1.19 g/dL for type 1 IgG4-SC versus PCa , 1.25 g/dL for type 2 IgG4-SC versus PSC , and 1.82 g/dL for types 3 and 4 IgG4-SC versus CC . Increasing the cutoff to 2.08 g/dL increased the sensitivity for IgG4-SC types 3 and 4 to 100% . DiffereTherefore, other laboratory differential diagnostic markers were sought. Boonstra et al. used individual IgG subtypes for differential diagnosis. In patients with an sIgG4 >1.4 and <2.8 g/L, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved specificity and allows one to distinguish IgG4-SC from PSC .Literature data on IgG4 levels in patients with IgG4-SC without AIP and IgG4-SC + AIP differ. While Nakazawa et al., Graham et al., and Takagi et al. have sporadically shown that patients with the isolated IgG4-SC form have lower serum IgG4 levels, in a recent study by Naitoh et al., patients with IgG4-SC associated with AIP had serum IgG4 levels that were comparable to those of patients with IgG4-SC without AIP , 94, 95.Unlike PSC and CC, patients with IgG4-SC have elevated IgG4 levels not only in serum but also in bile. A cutoff of 113 mg/dl has 100% sensitivity and specificity for IgG4-SC .Bile duct visualization is the key in the differential diagnosis of bile duct stenoses. As a rule, it reflects the basic morphological changes in the bile duct wall which accompany stenoses. In the case of IgG4-SC, there is diffuse subepithelial lymphoplasmacytic inflammation of the wall of both intra- and extrahepatic bile ducts with fibrosis, with a preserved epithelial layer . This paThe most common findings on cholangiogram are segmental (>3 mm) and long (>10 mm) strictures with prestenotic dilatation and stricture of the distal common bile duct , 98, 99.A long stricture and segmental stricture were the most common findings on the cholangiogram in patients with IgG4-SC without AIP. Naitoh et al. reported these findings in 65.1% of patients with IgG4-SC without AIP. On the other hand, these patients had a relatively high band-like stricture and pruned-tree appearance (11.4% and 4.1%) typical of PSCs, making it difficult to diagnose IgG4-SC without AIP .p=0.045) [p < 0.01). An important diagnostic feature is the wall thickness in IgG4-SC in areas without stricture on the cholangiogram, which was significantly greater than that in the case of CC (p < 0.0001). This study provided evidence for the inclusion of type 1 IgG4-SC: it showed that, in most patients with IgG4-SC type 1 with AIP, stenosis is due to thickening of the inflamed wall (73% of patients) and not external compression by the inflamed pancreatic tissue [The thickening of the bile duct wall in IgG4-SC is circular, usually extends beyond the extent of the stenosis, and has a smooth inner and outer edge. It is visible in CT scans and on MRCP but is more precisely diagnosed by IDUS and EUS, allowing reliable differential diagnosis with CC. Wall thickening in the stricture-free area was found to be significantly more common in patients with IgG4-SC on IDUS than on EUS  . Naitoh c tissue .The same authors in another paper showed that more than 50% of patients with IgG4-SC without AIP have wall thickening at a nonstricture region. This number is significantly lower than that in patients with IgG4-SC with AIP; however, wall thickening at a nonstricture region is useful for diagnosing IgG4-SC without AIP .The aim of the histological examination is not only to confirm IgG4-SC but also above all to rule out malignant stenosis. To exclude cancers, it is important to perform a transampullary bile duct biopsy and bile duct brushing cytology . ImmunohMarked lymphoplasmacytic infiltrationEosinophilic infiltrationMore than 10 IgG4-positive plasma cells per high-power microscopic field in biopsy and >50 per high-power field in resection specimensA high IgG4/IgG-positive cell ratio (>40%)Storiform fibrosis which often contains lymphocytes and plasma cellsObliterative phlebitis, in which the venous lumen is closed by inflammatory cells and fibrosis , 71IgG4-SC is characterized by the following histological findings:p < 0.001) [The histological criteria are the same for patients with IgG4-SC with AIP and patients with IgG4-SC without AIP . Bile du< 0.001) . Marked < 0.001) . Other a< 0.001) . We can < 0.001) .Several studies have confirmed a typical histological finding in ampulla of Vater tissue in patients with IgG4-SC with AIP affecting the head of the pancreas , 102. ItThe utility of liver biopsy in the diagnosis of IgG4-SC is relatively low. Lesions of IgG4-SC may be observed in the biopsy specimen, but a fully developed histological finding is rare. An exception is the work of Deshpande et al. who found that 6/10 patients with IgG4-SC had more than 10 IgG4-positive plasma cells/HPF on a liver biopsy and 70% of IgG4-SC patients had intrahepatic biliary strictures. IgG4-SC patients presented higher portal and lobular inflammatory scores compared to PSC patients. Eosinophiles were found in portal-based fibroinflammatory nodules in 50% of IgG4-SC patients . PatientSymptomatic patientsAsymptomatic patients with cholestasisPatients with subclinical disease that can lead to severe or irreversible organ failure The following are indications for treatment:Corticoids are the first line in the treatment of IgG4-SC. The goal of treatment is to induce and maintain remission. This is defined as remission of symptoms, achievement of a biochemical response, decrease of IgG4 levels, and normalization of the cholangiogram. The indication for corticosteroid therapy is unquestionable, with the only exception being perhaps patients whose current health status contraindicates corticosteroid therapy . Response to empiric corticosteroid treatment is an auxiliary diagnostic criterion. Corticosteroids also have a place in the treatment of disease relapse.p=0.401). Therefore, the question arises as to whether a lower initial dose should be used in patients at risk for diabetes mellitus. There is no work that specifically targets patients with IgG4-RD and diabetes mellitus. However, we can conclude that the initial dose of corticoids will affect the likelihood of disease relapse. This is confirmed by the findings of a study by Shirakashi et al. who showed using multivariate analysis of data from 152 IgG4-RD patients that patients treated with an initial dose of 0.4–0.69 mg/kg/day of prednisolone showed lower relapse rates than those treated with an initial dose of <0.39 or >0.7 mg/kg/day [The recommended initial dose of prednisone is 0.6–0.8 mg/kg body weight daily for 2–4 weeks, followed by a reduction of 5 mg/week over 2-3 months , 107. Thg/kg/day . The effg/kg/day .The need for maintenance treatmentDuration of maintenance treatmentMaintenance doseBile duct stenting before corticosteroid therapyThe role of steroid-sparing therapyThe following issues are open questions in the management of IgG4-SC:The first three issues arise from two facts. On the one hand, the reduction and discontinuation of corticotherapy lead to a relapse of the disease in about 30% of those with IgG4-SC . Risk faSimilar results were reported from a UK cohort in which 97% of patients with AIP, including IgG4-SC with AIP, responded to steroid treatment, but 50% relapsed after cessation of steroids and 2% during steroid therapy . The JapIn case of relapse, reintroduction of corticosteroids is indicated, possibly in combination with other immunosuppressive treatments.Corticosteroid-resistant patientsCorticosteroid-dependent patientsThose patients where corticosteroid treatment is limited due to adverse reactionsThe treatment of relapseNonsteroidal immunosuppressants are currently a second-line treatment and are indicated inThe combined use of nonsteroidal immunosuppressants with steroids to induce remission is a matter of debate. The authors of the International Recommendation for the Treatment of IgG4-RD did not find a uniform answer to this question either .Rituximab has been shown to be effective in inducing, maintaining remission, and treating relapse in patients with IgG4-RD, including IgG4-SC. It is a monoclonal anti-CD20 antibody that induces B-cell depletion, which may play a key role in the treatment of IgG4-RD. The effect of rituximab in patients with IgG4-RD is described in case series and case reports; however, no randomized prospective clinical study has been performed yet.p=0.02) [p < 0.05), though only 42% of patients achieved normal levels [The work of Ebbo et al. which evaluated the effect of rituximab in 33 patients with IgG4-RD in inducing and maintaining remission and treating relapse is valuable. There, 93.5% of patients achieved a clinical response to rituximab treatment, and 51.5% were able to discontinue corticoids. After discontinuation of rituximab, 41.9% of patients relapsed, whereas long-term rituximab treatment was associated with longer relapse-free survival  . Similarp=0.02) . Carruthl levels .There are controversial views on the use of rituximab in the induction of remission as a first-line treatment in high-risk patients with high IgG4 levels and multiorgan involvement. It can be used as an off-label therapy in corticosteroid-resistant and corticosteroid-dependent patients, as well as corticosteroid-intolerant patients, or for the treatment of relapse. The recommended dose is 1 gram intravenously every 15 days. Maintenance therapy with rituximab is associated with longer relapse-free survival and may represent a novel treatment strategy, especially for difficult-to-treat patients with IgG4-SC. Difficult-to-treat patients should be identified on the basis of the IgG4-responder score, which is a reasonable index to assess disease activity . The scop=0.23). In the follow-up, treatment with steroid-sparing immunosuppressants failed in 45% of patients. Some had a second relapse treated with rituximab. This treatment was successful in 83% of patients [Azathioprine, 6-mercaptopurine, mycophenolate mofetil, and methotrexate are other second-line treatment options. Their effects in patients with IgG4-RD, including IgG4-SC, are poorly studied; again, available are data mainly in patients with AIP. A Mayo Clinic study evaluated the effect of steroid-sparing immunosuppression, azathioprine 2.0–2.5 mg/kg/day, 6-mercaptopurine 1 mg/kg/day, and mycophenolate 750–1000 mg b. d., in 76 patients with relapse of AIP. Relapse-free survival was similar in patients treated with combination therapy (steroids plus immunosuppressants) compared to patients treated with a steroid in monotherapy (patients .The work of Huggett et al. who evaluated the effect of azathioprine at a dose of 2 mg/kg/day as an add-on therapy to corticoids in the treatment of relapse in patients with AIP was more favorable for second-line treatment. Treatment was ineffective in 19% and azathioprine was not tolerated in 31.7% of patients. In these, mycophenolate 500 mg–1,000 mg b. d., methotrexate 15 mg weekly, or mercaptopurine 1 mg/kg/day was used as an alternative, and the treatment was well tolerated. At the end of follow-up, 58% of patients maintained remission with second-line treatment without corticoids .The initial effect of corticoids is very prompt, so most patients do not need bile duct stenting prior to corticotherapy , 122. ExIgG4 sclerosing cholangitis is an important part of differential diagnosis of bile duct stenosis. It is a disease with a very good prognosis if the diagnosis is made early. Despite increasing information and recently updated diagnostic criteria, the diagnosis is relatively difficult in routine clinical practice. Initial corticosteroid therapy is effective in inducing remission; maintenance treatment with corticosteroids reduces the likelihood of relapse but does not completely prevent it and is associated with a risk of side effects. Therefore, there is an unmet need for randomized prospective studies to evaluate new maintenance treatment strategies, including the use of steroid-sparing treatment regimens and B-cell reduction therapy to prevent relapse and long-term complications of this disease.


Objective: Statistical literacy (SL) of physicians, i.e. the ability to use and interpret statistical numbers in the context of science, is an essential prerequisite for risk estimation and communication. Together with scientific reasoning and argumentation (SRA) skills, SL provides the basis for evidence-based practice. Several studies suggest that in medical students both skills are underdeveloped. The aim of the present study was to investigate these skills in practicing physicians and how these skills were acquired. Methods: Data collection in N=71 physicians was conducted online and as paper pencil. SL was assessed with multiple-choice items. SRA skills evidence evaluation and drawing conclusions were measured with a decision scenario. Results: Study results indicated that physicians have medium levels of SL  and SRA . Skills development via autodidactic learning activities  was reported significantly more often than development during formal medical education , t(71)=-9.915, p<.001, or in extracurricular activities , t(71)=4.673, p<.001. The active involvement in research seemed decisive: The number of publications and time spent in research significantly correlated with SL, r(71)=.355, p=.002; respectively r(71)=.280, p=.018. SRA skills were predicted by the type of MD-thesis, β=-.380, p=.016, and working in research, β=3.355, p=.008. Conclusion: Active involvement in research activities seems to be a very important factor for the development of both SL and SRA skills. The implementation of systematic fostering of these skills during formal medical education seems warranted. Following Sackett et al. 1997) regarding the modern definition of evidence-based medicine, scientific reasoning skills are considered essential together with physicians’ expertise for best possible decision-making in the best interest of the patient 997 regar, 3]. Fo. Fo3]. FBased on the framework by Fischer et al. 2014), SRA can be defined as the competence of comprehending and applying scientific working methods and their results when solving problems , SRA can. SRA canVarious studies suggest an intertwining of SRA and SL, with Anderson et al. (2013) stating that the latter is needed to evaluate scientific evidence  and FranHowever, a collective statistical illiteracy has been observed among physicians , 18]. S. S18]. SIn a study by Anderson et al. 2014), 52% of the participating physicians answered only two (or fewer) of four questions regarding statistical concepts correctly . This is14, 52% oIn summary, SL and SRA seem to be underdeveloped in medical students and better developed in physicians. However, the development of SL and SRA may not necessarily happen within formal education and the question remains how, where, and when this development occurs. The present study should contribute to the discussion when and how to best foster SL and SRA skills in lifelong learning of physicians by applying a test instrument comprising various aspects of SL and SRA. It aimed at providing further insights into these skills in physicians and to identify demographic factors and learning opportunities that may be associated with the development of these skills. Our explorative research questions were:RQ1. Statistical literacy and SRA skillsa. To what extent are SL and SRA skills developed in physicians? b. To what extent does SL predict SRA skills of physicians?RQ2. Education and skills developmenta. How, where, and when do physicians develop SL and SRA skills? b. Which demographic factors are related to the development of SL and SRA skills?N=71 German-speaking physicians , from different work settings and locations in our study: hospital (n=44), outpatient sector (n=3), research (n=8), study program (n=2) and administration (n=2), (n=12 NA). A MD-thesis, a scientific work as optional part of the medical study program , was completed by 58 participants and 9 were currently working on it. Despite the modest sample size, we consider our sample representative with regard to scientific experience, as a MD-thesis is very common in Germany. The mean age of participants was 40 years   who initiated the ongoing validation process with 217 economics, social sciences, and medical students from LMU Munich . The tesDemographic and biographic parameters of the participants were assessed with a special interest in their working history and environment . Questions were adapted from a study by Epstein et al.  and compStatistical literacy was measured with multiple choice items based on validated instruments , 18], , , to asseThe assessment of SRA skills focused on the two epistemic activities EE and DC with a decision scenario in a medical context  and provided two separate overall scores for EE and DC . For EE, participants had to evaluate four pieces of evidence , 31], , , includiThen, the participants rated the persuasiveness (Likert 1-6) of 20 arguments, which were extracted from the presented evidence and assigned a level of argument strength from 1 (lowest) to 4 (highest). For 13 participants, the evaluation of 1 to 5 arguments out of 20 was missing. In order to avoid dropouts of these cases, the respective values were imputed from the average of the respective item. The participants’ ratings for scientific quality were compared to the ratings of scientific quality by the authors, resulting in a measure of similarity for EE and DC. The range of these measures was from 0-10 (EE score) and 0-60 (DC score) with zero indicating no similarity. https://www.lamapoll.de/], a survey tool optimized for mobile applications, or as paper pencil (return rate 16.5% online and 66.7% paper pencil). Average duration was approximately 45 minutes. Participants were invited via mailing lists and personal contacts.The study was completed by the participants either online with LamaPoll [T-tests, one-factorial ANOVAs, and linear regression models were calculated to assess differences and the association of demographic factors with SL and SRA. Probability values less than .05 were considered significant. Data in natural verbal language (free text in demography section) underwent independent thematic analysis by two authors to extract common themes.Statistical analyses were performed with IBM SPSS 25. Descriptive and frequency data were computed for primary analysis and Cronbach’s alpha for internal consistency. Extensive outlier analyses were conducted and all required prerequisites for statistical analyses, such as normal distribution and homoscedasticity, were tested. t-tests and ANOVA were fulfilled, unless indicated otherwise below. We included 71 completed questionnaires . On average, physicians evaluated the evidences concordantly with the authors' evaluation, EE score: M=7.75, SD=1.85 (77%). The ratings for argument quality were in accordance with the authors’ rating, DC score: M=37.20, SD=5.35 (62%). Statistical literacy and DC were significantly inversely correlated, r(71)=-.272, p=.022. However, no correlation was found between SL and EE, r(71)=.198, p=.098, nor EE and DC, r(71)=.138, p=.256.The 71 physicians' average score in SL was M=4.78, SD=1.13, Likert 1-6 scale) rather than during their study program , t(71)=-9.915, p<.001, or in extracurricular activities , t(71)=4.673, p<.001. In a free-text box, participants added various other learning opportunities, such as massive open online courses, higher education, workshops, and learning through peer reviews and feedback =.271, p=.033. Having completed or working on the MD-thesis showed no effects on SL, EE, or DC. However, these results have to be treated carefully, as the prerequisites for ANOVA were not fulfilled in our sample with only four participants without a MD-thesis. The fostering of critical scrutiny of study results presented by other researchers during the preparation of the MD-thesis was positively correlated with SL, F=12.737, p=.001, partial η2=.156 and the type of authorship in publications, F=3.886, p=.004, partial η2=.230. Regarding the postgraduate phase, a one-factorial ANOVA showed a significant main effect of having worked in research on SL, r(71)=.28, p=.018, as was the number of publications, r(71)=.36, p=.002.Time spent in research was significantly associated with better SL, p=.041, when the Likert value of the MD-thesis supervisor’s content-related support was increased by one point. Additionally, the form of the MD-thesis  was associated with EE, with experimental and clinical design being positively related to EE skills, β=-.380±.154, p=.016, R2=.187, F=4.353, p=.041. DC was higher when participants indicated to have already worked in research, β=3.355±1.229, p=.008, R2=.314 F=7.448, p=.008. Regarding SRA, linear regression models revealed that the corresponding score in EE increased by β=.314±.150, We found average statistical literacy of physicians (59%), a rather high-level EE score (77%) and a medium-level DC score (62%). SL did not predict the SRA skills of physicians. Due to the focus on SL rather than the combination of basic numeracy and SL , our tesEE and SL scores were not correlated. DC and SL were inversely correlated. In contextual frameworks, SL has been regarded as a prerequisite for SRA  and in aWe explored how, where, and when physicians developed SL and SRA skills. They indicated to have acquired scientific skills mostly in an autodidactic manner, in higher education outside of their medical study program, or in extracurricular activities. Better SL was associated with the fostering of critical scrutiny of study results during the time spent working on the MD-thesis, in research or having worked in research, the number of publications, and the type of authorship. Our findings are in line with Schmidt et al. (2017), who found that having an advanced degree other than MD or statistic courses were positively associated with SL. A study with physicians, residents, and final year medical students in Thailand showed – not surprisingly – that having recently completed a statistical workshop led to higher SL scores . HoweverIn the present study, better EE was associated with having been responsible for a research project (e.g. the MD-thesis) with experimental or clinical design and having content-related support by the supervisor. These findings are in line with the subjective impression of German medical graduates with a MD-thesis who rated their scientific skills higher compared to those working on it . HoweverN=71 to be satisfactory. While generalizability is potentially limited, our sample seems representative for the German-speaking medical education system which produces large numbers of medical doctoral degrees. The addition of numerous demographic variables yielded insights on how, where, and when scientific skills were acquired and helped to identify potential associated factors. This study built upon an innovative approach by the authors to assess SL and SRA skills in university students . The incDue to the broad age range in our sample, participants may have been exposed to different learning experiences in formal medical training and, depending on the place of study, may also have studied in reformed curricula. This could potentially have influenced their skills development and lead to further individual differences. In our study, we did not gather data on specific study programs, courses, and their descriptions, in which physicians might have acquired their skills. Already, the test instrument used in this study may be considered extensive and time consuming for physicians, as was indicated by 11 participants in their feedback. We assessed SL and SRA skills in German-speaking physicians together with a thorough analysis of demographic variables. The active involvement in research apparently plays an important role in the development of these skills and might in consequence enhance evidence-based practice. As most participants indicated to have acquired these skills post-graduate and in an autodidactic manner, we argue to formalize and intensify the acquisition of these skills in medical study programs. Medical education curricula should include more statistical training and aim to get students involved in research more often, e.g. by offering inquiry-based learning  where stThis work was supported by the German Federal Ministry of Education and Research  and an intramural grant of the Förderverein WiFoMed of the Medical Faculty of LMU Munich. The authors would also like to thank Wolfgang Gaissmaier for his valuable comments and suggestions to the present study.The authors declare that they have no competing interests.


Reassessing the continuing need for and choice of antibiotics by using an antibiotic “time out’’ program may reduce unnecessary treatment. This study aimed to explore the effect of an antibiotic stewardship program (ASP) on the antibiotics consumption, incidence of resistant bacterial infections and overall hospital mortality in a tertiary medical center during the study period 2012–2014. An ASP composed of multidisciplinary strategies including pre-prescription approval and post-approval feedback and audit, and a major “time out’’ intervention (shorten the default antibiotic prescription duration) usage was introduced in year 2013. Consumption of antibiotics was quantified by calculating defined daily doses (DDDs). Interrupted time series (ITS) analysis was used to explore the changes of antibiotics consumption before and after intervention, accounting for temporal trends that may be unrelated to intervention. Our results showed that following the intervention, DDDs showed a decreased trend in overall , in both intensive care unit (ICU) and non-ICU, and in non-restrictive versus restrictive antibiotics. Importantly, ITS analysis showed a significantly slope change since intervention , whereas the incidence of carbapenem-resistant and vancomycin-resistant pathogens did not change significantly. Moreover, annual overall mortality rates were 3.0%, 3.1% and 3.1% from 2012 to 2014, respectively. This study indicates that implementing a multi-disciplinary strategy to shorten the default duration of antibiotic prescription can be an effective manner to reduce antibiotic consumption while not compromising resistant infection incidence or mortality rates. Clostridium difficile outbreaks and antibiotic resistance, and recommended as a major strategy to combat antibiotic resistance by major guidelines3. The US Centers for Disease Control and Prevention (CDC) also have summarized several core elements for inclusion in hospital ASPs since 20144. A recent meta-analysis reviewed the efficacy and effect of ASPs on clinical and economic parameters and concluded that hospital ASPs result in significant decrease in antimicrobial consumption and cost, and the benefit can be higher in the critical care setting. Moreover, ASPs may improve infections due to specific antimicrobial-resistant pathogens and the overall hospital length of stay5.Antimicrobial stewardship programs (ASPs) have been proven effective for optimizing antibiotic use and minimizing adverse events, such as 6. ASP implementation may require flexibility among different sizes and types of hospital4. Indeed, ASPs targeted towards specific pathogens or infections and specialized environments or hospital settings have been proposed10; however, in most countries worldwide, legislation forcing health care providers to optimize their use of antimicrobial therapy has not yet been enacted14. In Taiwan, ASPs have also been implemented in several settings19. For example, pre-prescription approval is a commonly adopted strategy that has been implemented in several medical centers19, in some cases including modifications of post-prescription feedback/audit, such as blood culture-guided review19, or exemption of pre-prescription approval for intensive care unit setting18. Conversely, a persuasive strategy was adopted in a community-based hospital17.In general, interventions to improve antibiotic prescribing practices can be conceptualized as restrictive  or persuasive , as noted by Davey et al.2. Several studies had demonstrated the effect of re-evaluation of antibiotic therapy20. Interestingly, the default duration of initial antibiotic prescription has rarely been evaluated in prior studies20. While timely reassessment of antibiotic has been used as a gold standard, this strategy can be compromised by the realities of a heavy clinical load or shortage in ID specialists. In 2013, the Centers for Disease Control, ROC (Taiwan) initiated a nationwide institutionally based project that promoted and encouraged major hospitals to implement and/or improve their ASPs. As a major member institution participating in this program, we implemented a new multi-disciplinary strategy to improve our ASP. This study aimed to evaluate the impact of an ASP, incorporating a shortened default duration of antibiotic prescription with pre-prescription approval and post-prescription feedback and audit, on the antibiotics consumption, incidence of resistant bacterial infections and overall hospital mortality.An antibiotic “time out” prompts a reassessment of the continuing need for and choice of antibiotics when the clinical picture is clearer and more diagnostic information is availableThis study is approved by the Institutional Review Board (IRB) of Taipei Veterans General Hospital. The data was retrospectively collected containing de-identification characteristics and database of antibiotic consumption from Department of Infection Control, Taipei Veterans General Hospital. A waiver of informed consent was approved by the Taipei Veterans General Hospital IRB and all methods were carried out in accordance with the principles of the Declaration of Helsinki. Taipei Veterans General Hospital is a 2941-bed tertiary care academic medical center located in northern Taiwan. The institute contains bone marrow transplantation unit as well as solid organ transplantation units. The study period is from year 2012 to 2014. Supplementary Table An antimicrobial stewardship program was initially established in this institution in 1974. This antimicrobial stewardship program included formulary restriction, which required pre-prescription approval, except for patients in the intensive care unit, who often have an urgent need for antibiotics due to severe infections, and post-prescription review, feedback and audit performed by Infectious Disease (ID) physicians. This program was computer-assisted and preset a default antibiotic duration of 14 days before the initiation of a newer antimicrobial stewardship program in 2013. Most intravenous antibiotics were restricted by the pre-prescription approval, except for first and secondary generation cephalosporins and penicillins, as listed in Table The new ASP was divided into two parts Fig. . 1) In  In 1, PaDuring the study period (year 2002–2004), several interventions were also gradually implemented. (1) Bacterial identification was gradually shifted to Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF) during the study period. (2) Appropriate culturing was required before hospital inpatients received empirical antibiotics if their physician prescribed restricted antibiotics for new-onset fever. (3) In the emergency room (ER), clinical physician could use restricted antibiotics without ID physician approval; however, appropriate culturing was required before ER doctors prescribed any antimicrobial agent. In critical septic patients in the ER, 2 sets of blood cultures were obtained. (4) Culture reports from the past 3 days were highlighted when providers logged into the patient’s electronic medical records. (5) In addition, reminders regarding culture reports were sent by text message to the business cell phones of attending physicians. These strategies served as reminders to providers to re-evaluate antimicrobial use after a culture report became available. Given the fact that multiple-interventions were gradually implanted during 1st quarter of 2013, we determined Apr. 2013 as a specific time point for differentiating the time period before and after the intervention of ASP for subsequent time-series analysis on the impact of ASP on antimicrobial consumption of antibiotics see “”.21, and expressed as DDD per 1000 patient-days. Nosocomial infections were defined according to the definition of the Centers for Disease Control and Prevention, and nosocomial infection density was defined as the incidence density rate of nosocomial infections (expressed as events/per 1000 patient-days.)Consumption of antibiotics was quantified by calculating defined daily doses (DDDs) according to the Anatomical, Therapeutic and Chemical Classification System/DDD System of the World Health OrganizationAcinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Escherichia coli (CREC) and carbapenem-resistant Klebsiella pneumoniae (CRKP).To evaluate the safety of this program, selective quality indicators were monitored by infection control nurses, including the rate of patient mortality, incidence of healthcare-associated infections (HAI) and detection rate of healthcare-associated drug-resistant organism including vancomycin-resistant enterococci (VRE), carbapenem-resistant 23. The trends in antibiotics consultation (DDD per 1000 patient-days) before and after the introduction of the ASP in Apr 2013 were compared by calculating the slope change. We used the SPSS TSmodel which applies an autoregressive integrated moving average (ARIMA) model for time series analysis, detail of which has been described by others24. A p value < 0.05 was considered statistically significant. Analyses were performed using SPSS version 19.0 .Linear regression analyses were used to examine the trends in seasonal antibiotic consumption, mortality, incidence of HAIs, and detection of HA-MDROs before and after the intervention. Pearson’s correlation coefficients were applied to determine the relationships between the program implementation and trends in antibiotic consumption. Interrupted time series (ITS) analysis was adopted to account for temporal trends of antibiotics consumptions and to evaluate longitudinal impact of the introduction of ASP. ITS analysis is an approach for evaluating the effectiveness of population-level health interventions that have been implemented at a clearly defined timepointBefore the intervention, seasonal antimicrobial consumption of all antibacterial agents ranged between 1436 to 1405 DDD/1000 patient days. There was a numerical decrease in total antibiotic consumption following the second quarter of 2013 Fig. . BecauseThere are four types of carbapenems used in our hospital: ertapenem, imipenem, meropenem and doripenem. Trends in the consumption of these carbapenems did not show a declination during the study period and notably the absolute consumption (DDDs) of either group 1 or group 2 carbapenems was low Fig. .The annual hospital-acquired infection density rates during study period were 3.37, 3.34 and 3.43 per 1000 patient-days in 2012, 2013, and 2014, respectively. The annual detection rates of drug-resistant pathogens are shown in Table Since multiple-interventions were gradually implanted during 1st quarter of 2013, we determined Apr. 2013 as a specific time point for differentiating the time period before and after the intervention of ASP for subsequent time-series analysis on the impact of ASP on antimicrobial consumption of antibiotics. As shown in Fig. 25. According to data from the Taiwan CDC, a total of 1595 critical influenza cases were identified in 2012; the number of critical cases declined to 965 in 2013 but increased to 1721 in 201425. Critical influenza patients were often hospitalized and had diseases complicated by secondary bacterial infections27, and these factors might have resulted in additional antibiotic usage28. Therefore, the significant decline observed in the number of critical influenza cases might have also partially contributed to reduce concomitant antibiotic consumption in 2013. In addition, during the period in which the new ASP was implemented, culture report reminders were sent to physician electronic devices, and the clinical application of MALDI-TOF may have facilitated decision-making in attending physicians; these factors may have made de-escalated and targeted (narrow spectrum) antimicrobial therapy possible. The inclusion of ID clinical pharmacists in decision-making may have also contributed to decreased antimicrobial consumption.The ITS analysis confirmed the impact of ASP implantation on the antimicrobial consumption, showing a significant slope change (in decreasing direction) on antibiotics use following time trends during the study period Fig. , and the29. It is likely that implementation of an ASP applicable to a broad class of antibiotics may reduce the antibiotic selection pressure.In current study most antibiotics consumption (except for carbapenems) declined after our intervention with shortened default antibiotic prescription period Figs. , 3, 4, 531. It is worthy of further study to observe the long-term trend of carbapenem consumption in association with resistant strains in our institute.The trend of carbapenem consumption was not changed significantly by the intervention Fig. . The rel33. Although many studies of ASPs have shown reductions in resistant infections, a few studies have demonstrated opposing results. A Brazilian study identified a higher rate of resistant infections following implementation of a bundled ASP  when compared to the rates associated with the conventional ASP 34. In our study, urgent use of restricted antibiotics with a post-prescription audit was allowed in ICU settings  was implemented was relatively short (2 years), and it is possible that a longer duration is needed to see a reduction in resistant infections.Our data showed that a shortened default antibiotics prescription duration did not compromise crude in-hospital mortality. Shortening of the number of default days pushes clinical prescribers to re-evaluate the patient; whereas priorly the clinical physician usually did not de-escalate therapy or discontinued unnecessary drugs. On the other hand, shortening the default duration of antibiotics seemed to not affect the rates of major resistant infections Table . Notablyngs Fig. ; this stOur study has some limitations. First, our data were obtained by periodically measurement of the antibiotics consumption in the entire medical center, the patient characteristics and populations may change overtime therefore it is difficult to compare patients’ characteristics given the fluctuation of population over time. Moreover, there is lack of details regarding numbers of patients in ICU, days of ICU, as well as type of nosocomial infections in ICU. Our interventions may have less impact on antibiotics consumption due to urgent use of antibiotics and complexity of disease status as well as common emergence of resistance strains in ICU.In summary, the implementation of a multi-disciplinary strategy to shorten the default duration of antibiotic prescriptions was effective at reducing antibiotic consumption while not compromising the rates of resistant infections or mortality.Supplementary Information.