IgG4-related ophthalmic disease (IgG4ROD) is a phenotype of IgG4-related disease (IgG4RD) with ophthalmic involvement. The pathological IgG4+ plasmacyte count has only been used for diagnosis. We aimed to explore its possible clinical value in the management of IgG4ROD.Fifty-five pathologically diagnosed IgG4ROD patients were included, and their clinical, pathological, serological, and radiological findings and treatment outcomes were reviewed and analyzed. The pathological IgG4+ plasmacyte counts in lesions from different anatomic sites were compared, and their association with serum IgG4 concentrations, systemic involvement, and relapse risk was analyzed.p = 0.975). The pathological IgG4+ plasmacyte count positively correlated with the IgG4 concentration in peripheral blood . The serum IgG4 concentration and the pathological infiltrating IgG4+ plasmacyte count were significantly higher in patients with extraophthalmic involvement . The areas under the receiver operating characteristic (ROC) curve (AUCs) of the serum IgG4 level and pathological IgG4+ plasmacyte count for identifying systemic involvement were 0.897 (p < 0.001) and 0.759 (p = 0.015), respectively. The patients with relapse had higher levels of serum IgG4, more germinal centers (GCs), and infiltrating IgG4+ plasmacytes in lesions. Multivariate Cox regression analysis revealed that a pathological IgG4+ plasmacyte count of > 150/high-power field (HPF) and an elevated serum IgG4 level of > 500 mg/dL were risk factors for relapse after steroid treatment.The patients were divided into groups according to the anatomic site of their biopsied lesions, namely, the lacrimal gland, extraocular muscle, and orbital soft tissue. No significant difference was found in the pathological IgG4+ plasma cell counts among these groups (Lesions from different ophthalmic sites in IgG4ROD patients have similar counts of IgG4+ and IgG+ plasmacytes. The quantity of pathological IgG4+ plasmacytes corresponded to the serum IgG4 concentration in patients with IgG4ROD and could be meaningful in identifying systemic involvement and predicting subsequent relapse. IgG4-related ophthalmic disease (IgG4ROD) is a recently recognized condition characterized by tumefacient ophthalmic lesions infiltrated by IgG4-positive (IgG4+) plasmacytes . The hisAccumulating studies of IgG4RD have demonstrated the usefulness of serum IgG4 levels in evaluating dynamic disease severity and monitoring relapse –9. AutoiIgG4ROD describes IgG4RDs that occur in ophthalmic sites, including the lacrimal glands, trigeminal nerves, extraocular muscles and other orbital soft tissues . The hisThis study was a retrospective review. Consecutive patients with a diagnosis of IgG4ROD referred to the Eye and ENT Hospital of Fudan University were selected between 2016 and 2020. No corticosteroid or immunosuppressive treatment was given in the 3 months prior to when tissue and blood samples were obtained. Serum IgG4 concentration was measured using the IgG4 latex-enhanced immunoturbidimetric kit . All the biopsy samples were excised from the major ophthalmic lesions. The biopsy sections of all the patients were reviewed by one experienced pathologist after ruling out all potential alternative diagnoses. A histopathological diagnosis of IgG4ROD was made in accordance with the diagnostic criteria proposed in 2014 [Formalin-fixed and paraffin-embedded sections were stained with hematoxylin and eosin (HE). Slides of immunohistochemical staining of IgG4 and IgG (or CD138) were reviewed. IgG4+ plasma cells were counted in 5 nonoverlapping high-power fields (HPFs) with the highest density of stained positive cells at × 40 magnification. The average count was recorded. The average number of IgG+ plasma cells was also calculated in the fields where IgG4+ plasma cells were counted. Furthermore, HE-stained biopsy slides were morphologically screened for the presence of germinal centers (GCs), which was confirmed according to CD21 staining. The average number of GCs from 5 low-power fields (LPFs) with the densest concentration of lymphoid follicles at 5× magnification was counted.The electronic clinical records of all the patients were retrieved. All the patients underwent an extensive medical examination, and patients’ symptoms, laterality, and lesion locations were recorded. All 55 patients underwent axial and coronal magnetic resonance imaging (MRI) or computed tomography (CT) scans of the orbit, head, and neck before biopsy. Major ophthalmic lesions were classified by their anatomical location. Extraophthalmic lesions of the head and neck were determined by analyzing radiological images and performing a physical examination. Serum IgG4 concentration examinations were performed on peripheral blood from 31 patients at the time of diagnosis. The history of steroid treatment was recorded, and the treatment response and subsequent relapse after glucocorticoid regimens were reviewed. All the patients were followed up for more than 1 year.t test. Linear regression analysis was performed to analyze the association between histopathological factors and serum IgG4 levels. Receiver operating characteristic (ROC) curve analysis was used to calculate the area under the curve (AUC) to identify diagnostic values of the counts of IgG4+ plasmacytes and serum IgG4 levels for IgG4ROD. Univariate and multivariate Cox regression analyses (enter method) were performed to identify the potential clinicopathological risk factors for relapse and their hazard ratios (HRs). Variables with p < 0.1 in the univariate Cox regression were included in the multivariate analysis. Kaplan–Meier survival curves and log-rank tests were performed to compare the effect of different grades of IgG4+ plasmacyte infiltration on IgG4ROD relapse. p < 0.05 was considered statistically significant. All statistical analyses were performed with SPSS statistics v.25 and R-project 4.1.2.The analyses of the pathological counts of IgG4+ and IgG+ plasmacytes and GCs among the three groups were conducted using one-way ANOVA and LSD tests. The logarithm of the serum IgG4 level was introduced in a parametric test for the concentration following the lognormal distribution in IgG4ROD. The difference in the histopathological and serological findings between the groups with and without extraophthalmic involvement was analyzed using the unpaired Student’s Fifty-five consecutive patients  were histopathologically diagnosed with IgG4ROD according to the diagnostic criteria. Fifty-one patients' IgG4 immunostaining sections demonstrated > 50 positive cells per HPF; although the IgG4-expressing plasmacytes per HPF were less than 50 in the 4 remaining patients, they were diagnosed with IgG4ROD based on the criterion of an IgG4+/IgG+ ratio > 40%. Bilateral lesions were found in 27 (49.1%) patients, and the rest exhibited unilateral lesions. The locations of the lesions were as follows: lacrimal gland, 43 (78.2%); extraocular muscle, 19 (34.5%); intraconal orbital soft tissue, 15 (27.3%); extraconal orbital soft tissue, 23 (41.8%); infraorbital nerve, 8 (14.5%); and conjunctiva, 1 (1.8%).All the biopsy samples were excised from the major ophthalmic lesions: 38 (69.1%) from the lacrimal gland, 6 (10.9%) from the extraocular muscle, 1 (1.8%) from the conjunctiva, and 10 (18.2%) from orbital soft tissues . All the IgG4ROD samples except one sample obtained from the conjunctiva were divided into three groups based on the anatomic location of the biopsy: the lacrimal gland group, the extraocular muscle group, and the orbital soft tissue group. Histopathologic examination of all the samples showed marked lymphocyte and plasmacyte infiltration. Monomorphous B cells and atypical lymphocytes was suspected focally in 6 cases and 2 cases, respectively. Detection of gene rearrangement was negative in these samples.p = 0.008, the lacrimal gland group vs. the extraocular muscle group, p = 0.005, Fig. GCs were observed in all the patients and were further confirmed by reviewing immunostaining for the follicular dendritic cell marker CD21 .The pathological IgG4+ plasmacyte counts were positively correlated with the number of GCs in ophthalmic lesions  of the 31 IgG4ROD patients whose peripheral blood had been tested at diagnosis. The serum IgG4 levels are indicated with medians and quartiles, and the median concentration was 376 mg/dL (interquartile range 139 to 866 mg/dL). As shown, the frequency of the serum IgG4 level in the IgG4ROD patients displayed a highly skewed distribution  of the 55 histopathologically diagnosed patients with IgG4ROD had extraophthalmic lesions of the head and neck. These lesions were observed on the pituitary gland in 2 patients, the parotid gland in 5 patients, the submandibular gland in 7 patients, the lymph nodes in 2 patients, the thyroid gland in 1 patient, the pterygopalatine fossa in 8 patients, and the cheek skin in 2 patients. Compared with those without multiorgan involvement in the head and neck, the patients with multiorgan involvement exhibited significantly higher serum IgG4 concentrations and pathological counts of infiltrating IgG4+ plasmacytes. These patients also presented a higher ratio of pathological IgG4+ plasmacytes to IgG+ plasmacytes and a higher rate of bilaterality (Table % of the p < 0.001), 0.759 , and 0.669  were maintained for at least 2 months after the initial glucocorticoid treatment to prevent relapse. Forty-one (91.1%) of the 45 patients who took glucocorticoids responded well, and clinical remission was not achieved in the remaining patients. Twenty-four (58.5%) of the 41 patients in whom remission was achieved suffered recurrence during the follow-up period. Thirteen (54.2%) of the 24 relapses occurred within 6 months following steroid treatment. As shown in Table p = 0.027) and elevated serum IgG4 levels > 500 mg/dL  were risk factors for relapse , pathological GC and IgG4+ plasmacyte counts, and the level of serum IgG4 were associated with relapse Table . MultivaHistopathological features and immunohistochemical staining results provide supportive evidence for the diagnosis of IgG4RD. Although all conditions within the spectrum of IgG4RD are associated with lesions rich in IgG4+ plasma cells, a certain variability in the count exists across organs. Generally, lesions in exocrine glands such as the lacrimal glands tend to have strikingly more IgG4+ plasmacytes than organs such as the pancreas and retroperitoneum, with a predominance of fibrosis. We summarized the samples from lesions in the lacrimal glands, extraocular muscles, and orbital soft tissues. Lesions in the extraocular muscles and orbital soft tissues shared similar pathological features with those in the lacrimal glands . Severalp = 0.363, p = 0.940 and p = 0.236, respectively) [Even though an elevated serum IgG4 concentration is not sufficient to diagnose IgG4RD, its clinical interpretation has been established. There is convincing evidence that the serum level of IgG4 in patients with multiple organ involvement is higher and correlated with disease activity . In our ctively) , 16, 18.We investigated the potential value of the count of IgG4+ plasmacytes to identify systemic involvement. Because extraorbital imaging was not performed in most patients, we chose extraophthalmic lesions of the head and neck to represent systemic conditions. It has been reported that the head and neck region is the second most common site for IgG4RD after the pancreas . The patApart from the function in identifying systemic involvement, we also investigated the role of IgG4+ plasmacyte-related pathological findings in predicting relapse. Consistent with a previous study, the patients with elevated pretreatment levels of serum IgG4 were more likely to experience relapse after steroid treatment. The patients with relapse also tended to have more infiltrating IgG4+ plasmacytes and more GCs in lesions. Multivariate Cox regression analysis indicated that a > 150/HPF IgG4+ plasmacyte count and a > 500 mg/dL serum IgG4 level were risk factors for relapse. The practical value and quantity of pathological IgG4+ plasmacytes corresponded to the serum IgG4 concentration in patients with IgG4ROD.The GC, the discrete lymphoid structure where high affinity B cells are selected and differentiate into plasma cells, is responsible for the generation of high-affinity IgG antibodies . CompareTaken together, this study demonstrated that the serum IgG4 level, which has been reported in previous studies, is of practical value in identifying systemic involvement and predicting relapse. The pathological IgG4+ plasmacyte count reflects the inflammation in localized lesions and is associated with local recurrence. It can also be used to identify systemic conditions with a lower specificity compared to that for the serum IgG4 level. The serum IgG4 level can be influenced by previous treatment, but baseline counts of pathological IgG4+ plasmacytes are always stable. This objective advantage of the pathological IgG4+ plasmacyte count over the serum IgG4 level lends itself to the management of IgG4ROD.There were some limitations in this study. First, the subjects were limited to patients who were diagnosed pathologically by only one pathologist. We sent the questionable samples to Fudan University Shanghai Cancer Center for pathology consultation to reduce possible bias. Second, systemic imaging examinations were not performed to evaluate extraophthalmic involvement, and the serum IgG4 concentration was tested only in some patients. Due to the lack of sufficient information on systemic conditions, our results on systemic involvement might not be accurate. Third, some patients were referred to us after receiving oral or intravenous steroid treatment and experiencing recurrence elsewhere. Low-dose oral corticosteroid was only maintained long term in several patients with severe systemic conditions. This could influence the analysis of response to steroids and relapse.In conclusion, our results suggest that various lesions from different ophthalmic sites provide similar quantitative results regarding IgG4 and IgG staining in patients with IgG4ROD. The number and ratio of IgG4+ plasmacytes are positively correlated with the serum IgG4 level. Both higher serum IgG4 levels and more infiltrating IgG4+ plasmacytes are associated with systemic lesions and relapse. The pathological IgG4+ plasmacyte count may be of practical value in the management of IgG4ROD.


The article deals with experimental and numerical research of the layered reinforced concrete slab with plastic inserts. The investigated layered reinforced concrete slab is made of prefabricated and monolithic reinforced concrete layers. Voids were formed in the plate with spherical plastic inserts. With reference to the built-up bars theory, the paper proposes an analytical method for calculating the deflection of the layered reinforced concrete structures in non-linear stage, when bond between layers is partially rigid. The article also focuses on the numerical simulation of the layered slab, compares the estimated theoretical values of deflection with the experimental values and assesses the shear stiffness of the bond of prefabricated and monolithic concrete layers for calculating the deflection of the reinforced concrete slab. Paper presents the parametric analysis of deflection dependence on shear stiffness and the width of the contact zone of the layers. It was established that proposed analytical method and numerical analysis properly characterise the behaviour of the slab. Calculation results were close to experimental data. Moreover, it was determined that performance of this type of slab is highly influenced by shear stiffness of the bond between the concrete layers. Analysis confirmed that slab fails when bond is damaged, and layers slip in the support zone. In construction practice, prefabricated monolithic reinforced concrete slabs are used for the installation of overlays in multi-storey buildings. A prefabricated monolithic overlay slab is a layered reinforced concrete structure consisting of prefabricated components and a layer of monolithic concrete. Filigree/Omnia prefabricated monolithic overlay slab is produced from residual reinforced concrete formwork and a layer of concrete cast in situ ,2. Such Thickness of the residual formwork (prefabricated part of the slab) ranges from 40 to 100 mm. Slab is reinforced with a reinforcing mesh that withstands tensile stress and has an anchored three-dimensional steel truss incorporated into the slab structure. Truss increases the stiffness of the residual reinforced concrete formwork and improves the bond between the prefabricated reinforced concrete slab and the monolithic concrete layer. Truss bars at the bottom act as tensile reinforcement .2 into the environment [To reduce the self-weight of the overlay structure, the monolithic layer of the overlay may include hollows. In this case, hollows are suggested to be formed by using plastic inserts ,4, as shironment , which dironment ,4.A number of sources ,4,7,8,9 Structural performance of many different layered structures highly depends on the condition and properties of the bond between the layers ,21,22,23A. M. Ibrahim et al., 2019  and J. VReinforced concrete slab with plastic inserts is a structurally, economically and ecologically advanced structural member, which is increasingly used in modern construction. Studies have been carried out on concrete slabs with plastic void formers. However, most of studies have not analysed the behaviour of semi-precast concrete slabs, which has significant advantages over a typical voided concrete slabs. This article provides findings on structural properties, concrete layer bond behaviour of layered concrete slab with plastic inserts. In addition, this paper proposes an analytical method for calculating deflection during a non-linear loading stage, when bond between layers is partially rigid.The deflection of the layered structures is greatly influenced by the stiffness of the bond between the layers. Thus, for calculating the deflection of flexural layered reinforced concrete structures, three loading stages are identified: At stage 1, the structure works elastically and the bond between the layers is rigid; stage 2 involves plastic deformations of concrete when the member is cracked but the bond between the layers is rigid; stage 3 assumes a partially rigid bond between the layers. All stages are shown Uncracked section, where reinforcement and concrete deform together, and full section area of concrete is considered;Cracked section, where the tensile zone of concrete section area is ignored.At stages 1 and 2, the deflection of the layered reinforced concrete slabs is determined by applying the known methods for calculating flexural reinforced concrete structures . In thiDeflection is calculated with reference to the formula:The average curvature of the flexural slab is calculated as follows:β = 1.0; under long-term load, The distribution coefficient can be obtained by using the following formula:s theory  can be aBy evaluating the partial stiffness of the bond between the layers, the deflection of the two-layer prefabricated monolithic reinforced concrete slab is calculated as follows:The ratio describing the flexural stiffness of the layered slab is calculated as follows:The factor assessing the shear stiffness of the bond between the layers:The overall stiffness of the two-layer prefabricated monolithic reinforced concrete slab:The factor describing the stiffness of the flexural layered slab:The factor assessing shear stiffness of the bond between the layers:The effective cross-sectional area of the cracked layer:The moment of inertia of the cross-section of cracked layer:The height of the compressive zone of the cross-section of the cracked layer is calculated from first moment of area equilibrium equation. First moment of area is calculated with respect to the top of layer cross-section:In this article analytical calculations were done by transforming the cross-section with spherical voids into an I-beam type of cross-section. Both cross-sections  in the layered reinforced concrete slab, the analysis of stress distribution at the characteristic points of the cross-section was performed. The analysis was carried out at six loading levels, which are presented in Normal stress distribution was proposed at levels B, C, D, E, F and shear stress—at levels A, C, D, E, F of an acting load. Load levels can be seen in Normal stress is determined in three sections (Under acting load A (when bond between concrete layers is not damaged), shear stress at the end of the slab is equal to The analysis of normal stress distribution in section The analysis of stress in section In normal section The numerical analysis has disclosed that normal cracks in the slab appear near the voids in the sections. Calculations have shown that higher stresses are concentrated near the voids and are significantly lower in concrete webs. The maximum compressive stress was observed in the areas of plastic inserts next to the load application points. Stress distribution along the length of the slab is shown in The results of analytical calculations and numerical simulation are compared with the findings of experimental tests published by Ibrahim et al. .The research of Ibrahim et al. determined that slab failed under load of 35 kN. Under a force of 25 kN, shear deformations in the bond of the layers are observed. An experimental slab load-deflection diagram is shown in A comparison between the calculated deflections and the experimental deflection values was performed in order to validate the chosen analytical calculation method and numerical simulation results. Deflection diagrams can be seen in The deflection was also calculated using the Eurocode 2 methodology. In this case it is assumed that the bond between the layers is completely rigid at all stages of loading. Load-deflection curve is linear throughout stage 1. Here concrete does not crack and behaves elastically. At stage 2, the concrete cracks. Since this methodology does not consider partial rigidity of the bond, at stage 3 the structure behaves the same as in stage 2. At the maximum load of 35 kN, the deflection value compared to the experimental one is lower by 42%, which can be seen in Parametric analysis was carried out by varying shear stiffness modulus The influence of contact zone width on the deflection was also analysed. Deflection was calculated by employing the analytical method. The obtained results showed that considering the total width of the slab , deflection values start to differ slightly from experimental ones. Theoretical method based on built-up bars theory can be considered to be suitable for stiffness analysis of the slab.Numerical model of layered concrete slab with plastic inserts has been built in FEA software DIANA. At stages 1 and 2, deflection results of numerical simulation were particularly close to experimental deflection values. At stage 3 numerical values start to differ slightly from ones determined in experimental study. By comparing the results, it can be stated that numerical simulation is an eligible method for stiffness analysis of layered reinforced concrete slabs with plastic inserts.Numerical stress distribution analysis shows that when shear stress value exceeds the strength of the layer bond in the support zone, layers slip relatively to each other. When analysing normal stress distribution, it becomes apparent that bottom reinforced concrete layer is the first one to crack. Calculations have shown that higher stresses are concentrated near the voids and the loading points and are lower in concrete webs.Parametric analysis of the slab has shown that shear stiffness modulus and the width of contact zone between the layers have non-linear influence on the deflection of layered flexural members.Relatively small amount of available experimental data might be a limitation of this study. More experimental tests of layered concrete slabs with plastic inserts and tests of layer bond stiffness should be performed in order to completely validate the proposed analytical method.


Data on antibiotic consumption in the community were collected from 30 EU/EEA countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in the composition of the main antibiotic groups.For the period 1997–2017, data on consumption of antibiotics, i.e. antibacterials for systemic use (ATC group J01), in the community, aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Antibiotic consumption was analysed based on ATC-3 groups, and presented as trends, seasonal variation, presence of change-points and compositional changes.In 2017, antibiotic consumption in the community expressed in DDD per 1000 inhabitants per day varied by a factor 3.6 between countries with the highest (Greece) and the lowest (the Netherlands) consumption. Antibiotic consumption in the EU/EEA did not change significantly over time. Antibiotic consumption showed a significant seasonal variation, which decreased over time. The number of DDD per package significantly increased over time. The proportional consumption of sulphonamides and trimethoprim (J01E) relative to other groups significantly decreased over time, while the proportional consumption of other antibacterials (J01X) relative to other groups significantly increased over time.Overall, antibiotic consumption in the community in the EU/EEA did not change during 1997–2017, while seasonal variation consistently decreased over time. The number of DDD per package increased during 1997–2017. In order to fight this global problem, comparable and reliable information of antibiotic consumption is essential.The methods for collecting and analysing the data are described in the introductory article of this series.Antibiotics were classified in 10 ATC groups: β-lactam antibacterials, penicillins (J01C), other β-lactam antibacterials (J01D), macrolides, lincosamides and streptogramins (J01F), quinolone antibacterials (J01M), tetracyclines (J01A), sulphonamides and trimethoprim (J01E), other antibacterials (J01X), amphenicols (J01B), aminoglycoside antibacterials (J01G) and combinations of antibacterials (J01R). Due to limited consumption of the last three groups, these were combined and their consumption was presented as ‘other antibiotics’.The evolution of the number of DDD per package over time was assessed using a linear mixed model. The temporal trend, seasonal variation and presence of change-points in antibiotic consumption were assessed using a non-linear change-point mixed model fitted to quarterly data expressed in DDD per 1000 inhabitants per day from 1997 to 2017.JAC Online  in the community, expressed in DDD and packages per 1000 inhabitants per day for all participating countries between 1997 and 2017 is available as The proportion of antibiotics ATC J01) represented by the main ATC-3 groups is presented in Table  represenThe most frequently consumed antibiotics in the community in 2017 were the β-lactam antibacterials, penicillins (J01C), with proportional consumption  ranging from 27.88% (Poland) to 66.39% (Denmark). The proportional consumption ranged from 0.22% in Denmark to 23.96% in Greece for other β-lactam antibacterials (J01D), from 4.77% in Sweden to 26.29% in Luxembourg for macrolides, lincosamides and streptogramins (J01F), from 2.46% in Norway to 21.49% in Cyprus  for quinolone antibacterials (J01M), from 2.51% in Italy to 28.22% in the United Kingdom for tetracyclines (J01A), from 0.07% in Lithuania to 7.55% in Finland for sulphonamides and trimethoprim (J01E), from 0.17% in Ireland (nitrofurantoin (J01XE01) consumption not included) to 27.46% in Norway for other antibacterials (J01X), and from 0.01% in Portugal to 1.51% in Malta for other antibiotics .Figure The best fit was obtained for a model including two change-points: one in the first quarter of 2004 and another in the last quarter of 2008. The final model fits the observed data well Figure . The lonBased on the final fitted model, antibiotic consumption in the community in 1997 was significantly above average in Belgium, Greece and Slovakia, and significantly below average in Austria, Denmark, Estonia, Germany, the Netherlands, Sweden and the United Kingdom  significantly decreased over time relative to consumption of all other groups Table . The proTrends of proportional consumption of antibiotic groups in individual countries are shown in Figure We demonstrated that EU/EEA antibiotic consumption in the community expressed in DDD per 1000 inhabitants per day did not change significantly during 1997–2017. In an international study analysing the trend of total  antibiotic consumption in 76 countries expressed in DDD per 1000 inhabitants per day, consumption remained stable among high-income countries between 2000 and 2015. Given that the majority of the EU/EEA countries belong to the high-income category, this is consistent with the results of our study.Clostridioides (Clostridium) difficile infections as predicted by mathematical modelling.,The analyses also revealed seasonality of antibiotic consumption in the community, which was observed for all EU/EEA countries and decreased significantly over time. This may result in a reduction in the incidence of We explored countries’ ranking based on antibiotic consumption expressed in DDD per 1000 inhabitants per day or in packages per 1000 inhabitants per day, and found these to be similar. However, since the average number of DDD per package significantly increased between 1997 and 2017, this finding is time-dependent. Both metrics can be used to summarize a country’s overall antibiotic consumption. In countries solely dispensing complete packages, a package may be considered as a surrogate for a prescription (and hence one treated patient), although some patients may only need half a package while others may need two or more packages. However, in countries where pharmacies dispense the exact number of singe units to fulfil a prescription, e.g. the Netherlands and the UK, the number of packages is not a suitable metric and the number of prescriptions instead of the number of packages should be monitored. The DDD is a technical unit defined as the assumed average maintenance dose per day for the main indication of a substance in adults. For antibiotics, the DDD is based on the treatment of infections of moderate severity. Its standardization and updates to take into account changes in prescribing practices make the DDD an international standard for surveillance of consumption of medicinal products, including antibiotics.The inter-country variability in consumption of antibiotics (ATC J01) expressed in DDD per 1000 inhabitants per day was substantial. This has also been reported for European countries that are not part of the ESAC-Net, but covered by the WHO Europe Antimicrobial Medicines Consumption Network in which consumption varied by a factor of 4.3, from 36.4 DDD per 1000 inhabitants per day in Turkey to 8.5 in Azerbaijan.,Despite changes in DDD values in 2019, which mostly affected the β-lactam antibacterials, penicillins (J01C), this group remained the most consumed antibiotic group in all 30 EU/EEA countries . This finding confirms that of previously published studies.To further broaden our understanding of appropriate prescribing and the variations between and within EU/EEA countries over time, more detailed data on antibiotic use  and antimicrobial resistance rates, and information on treatment guidelines at the national level would be needed.Nevertheless, the data on antibiotic consumption in the community in EU/EEA countries, available from ESAC-Net, together with the tools of compositional and longitudinal data analyses provided in this series may enable countries to evaluate their own antibiotic consumption by linking their country-specific change-points to possible explanations, e.g. targeted surveillance initiatives or the implementation of national guidelines. In addition, it allows countries to evaluate the impact of public awareness campaigns and important policy changes for a more prudent use of antibiotics in the community.While this study has a major strength in the number of participating countries and the completeness of their recorded data, it has a major limitation in the aggregated nature of the collected data. Because the data only contained information on countries’ antibiotic consumption rates, we were unable to distil any findings by age (e.g. children or elderly) or gender. In addition, the aggregation prevents a distinction between high-but-appropriate and inappropriate antibiotic prescribing, which is deemed quintessential in fighting overconsumption of antibiotics. For a discussion on the limitations of the statistical approach used in this study and potential explanations for the common change-points detected through these analyses, we refer to the tutorial paper in this series.In conclusion, while antibiotic consumption did not change significantly during 1997–2017, seasonal variation decreased.dkab172_Supplementary_DataClick here for additional data file.


The coefficient simultaneously describes the form of changes in trait expression caused by genes in the social environment and predicts the evolutionary consequences of those IGEs. Here, we report a striking mismatch between theoretical emphasis on ψ and its usage in empirical studies. Surveying all IGE research, we find that the coefficient ψ has not been equivalently conceptualized across studies. Several issues related to its proper empirical measurement have recently been raised, and these may severely distort interpretations about the evolutionary consequences of IGEs. We provide practical advice on avoiding such pitfalls. The majority of empirical IGE studies use an alternative variance-partitioning approach rooted in well-established statistical quantitative genetics, but several hundred estimates of ψ (from 15 studies) have been published. A significant majority are positive. In addition, IGEs with feedback, that is, involving the same trait in both interacting partners, are far more likely to be positive and of greater magnitude. Although potentially challenging to measure without bias, ψ has critically-developed theoretical underpinnings that provide unique advantages for empirical work. We advocate for a shift in perspective for empirical work, from ψ as a description of IGEs, to ψ as a robust predictor of evolutionary change. Approaches that “run evolution forward” can take advantage of ψ to provide falsifiable predictions about specific trait interactions, providing much-needed insight into the evolutionary consequences of IGEs.The interaction effect coefficient  This class of models describes the evolutionary consequences of social environments and is rooted in conceptual and mathematical descriptions of the process by which genes expressed in socially interacting individuals can affect the expression of their partners’ phenotypes  or the matrix Ψ of pairwise interaction coefficients between n traits where ψ estimates.Previous work provides comprehensive guidance for researchers wishing to empirically quantify IGEs by measuring the interaction coefficient j, of an interacting partner, represented by the prime, can be considered part of the focal individual’s environment  (Centrocercus urophasianus) in which variation in female sexual receptivity can be simulated  , roboticimulated , or expeimulated .ψ is that it provides predictive information about likely evolutionary impacts of IGEs across generations , or implicitly dependent on ψ. As a general principle, the magnitude and sign of ψ in such cases determine the effects that IGEs have on evolutionary outcomes in various scenarios. This predictive property of the interaction coefficient arises from its integral and general role in modifying evolutionary responses to selection in the original trait-based models of ψ have been probed in considerable depth.A less well-studied but equally important feature of erations . In the  of IGEs , to meta of IGEs , sexual  of IGEs , sexual  of IGEs , social  of IGEs , game th of IGEs , models  of IGEs , and modψ itself . In eachψ are likely to be violated in empirical studies that attempt to measure it. Such risks of incorrect measurement and interpretation are inherent to any empirical work that tests assumptions or predictions of theoretical models, as the latter are reductive by design and living study systems are complex and difficult to control. In recent years, however, some of the assumptions of trait-based IGE models have been usefully characterized and corrected on a theoretical basis, which can help to better align theoretical predictions with empirical evidence about the evolutionary consequences of IGEs.A number of important technical assumptions about the measurement of ψ require eliminating confounds that arise from the nongenetic environments in which individuals develop or interact. Nongenetic environmental contributions to trait expression in both focal and interacting individuals are assumed to be randomly distributed with a mean of zero and uncorrelated , and off-diagonals of the matrix represent IGEs involving 2 different traits in respective interactants . Note that off-diagonal IGEs may also involve feedback if trait i affects trait j and trait j affects trait i. The measurement problem arises because of environmental covariance between focal and interacting partners. In all cases of on-diagonal IGEs, but especially for IGEs of intermediate magnitude, this confounding environmental effect inflates the magnitude of IGE estimates indicated by ψ , ψ estimates that we found in our literature review (see below), 68 estimates concerned on-diagonal IGEs. However, of the 55 on-diagonal ψ estimates published after ψ, but it can substantially change interpretations about the consequences of IGEs by making evolutionary predictions about interacting traits with feedback markedly more conservative.Here,  nonzero . Of the ψ was estimated for an important larval fitness trait, mass, in the burying beetle Nicrophorus vespilloides. Estimates of IGEs with feedback on larval mass using experimentally evolved focal larvae and sibling larvae with whom they shared a mouse carcass to feed upon. The focal and interacting larvae had evolutionary histories of parental care versus no parental care. The only larval trait measured was larval mass; a reciprocal IGE with feedback as the mass of focal larvae on a carcass could be reasonably expected to be influenced by the mass of its interacting partners on the same carcass. The Bijma correction was applied. For example, when both focal larvae and their carcass-mates had an evolutionary history lacking parental care, the interaction coefficient was positive: ψ provided a more conservative, though still compelling, prediction about the contribution of reciprocal IGEs on larval mass to evolutionary transitions between sibling rivalry and parental care. In general, inflated estimates of ψ severely impact evolutionary inference about the role of IGEs. This is particularly true for large absolute values of ψ, because relative change in phenotypic evolution does not scale linearly with change in the interaction coefficient. Rather, it can approach infinity as ψ approaches its maximum absolute magnitude , Ψ to variance components provides a powerful method for converting commonly estimated quantities in variance-partitioning experiments to ψ estimates which can then be compared systematically across different contexts or studies to gain broader insight into the prevalence and characteristics of IGEs. In this case, the social additive genetic variance component M in the American Bellflower, Campanula americana   (McGlothψ(group) . Such anψ(group) . Anotherψ in cases where different traits in focal and partner individuals are measured. For example, if an experimenter sought to estimate ψ by manipulating the genotype of interacting partners, shared rearing or other environmental experience could inflate the apparent relationship of any traits measured in the two individuals  and their fitness phenotypes measured  occur when ψ varies by strain or genotype. GxG IGEs are also readily detected using variance-partitioning approaches , ψ which increases its value tends to enhance the evolutionary effects of corresponding IGEs  . The wide majority of focal traits in these articles were behavioral (203 traits), 29 were morphological and 6 were chemical . The interaction coefficient, for example, was estimated through the measurement of focal trait variation assessed against interacting partners from different genetic lines, species, populations and generations  and in response to different experimental conditions such as predation regimes or presence of exogenous agents such as ethanol  . For the ethanol .ψ ranged between −1.14 and 2.00 : χ 2 = 27.6, P < 0.001). Thus, off-diagonal IGEs, which represent potential IGEs involving 2 different traits, are less likely to be mutually reinforcing in the sense that evolutionary responses attributable to these IGEs would tend to accelerate trait elaboration.Empirically estimated values of rom zero . Interesψ exceeding 1 because the Bijma correction cannot be applied as it would result in an imaginary number. This necessitated removing 13 values of ψ . There were too few studies reporting estimates of ψ, and even fewer reported with their associated error, to warrant a meta-analytical approach, and we examined raw reported values to avoid over- or under-inflating estimates of absolute magnitude : χ 2 = 43.31, p-value < 0.001). Estimates for on-diagonal versus off-diagonal IGEs were 0.292 and −0.023, respectively. In aggregate, these patterns suggest a general tendency for IGEs with feedback to be more prone to strong, mutually augmenting evolutionary responses, but it is impossible to exclude the possibility that the pattern arises from biases in the types of traits studied by researchers. Nevertheless, it is a striking pattern that merits further systematic consideration—are reciprocal IGEs with feedback generally positive and of greater magnitude, and if so, why should that be the case? An intriguing possibility is that there is a general, directional constraint on the responsiveness of trait expression during social interactions, such that it is more likely that an organism flexibly increases expression of a given trait after or during social interaction, than decreasing its expression. Although counterexamples exist, such as can be observed in winner-loser effects during contests, future work would benefit from considering whether escalation, rather than de-escalation, is a more likely outcome across a range of interaction types.The values of IGEs also varied. We used the Bijma correction on all on-diagonal IGEs reported in the literature  to obtain reliable estimates, and tested the difference in value between on-diagonal and off-diagonal IGEs. For this test, we removed absolute values of agnitude . The resnal IGEs   within studies. We were able to assess reported statistical significance for 209 values of the interaction coefficient, and almost half of these (99 of 209) were significant at ψ without controlling for multiple testing. The application of corrections for false discovery rate in evolutionary and behavioral ecology (among other life sciences fields) is not without controversy, and care must be taken to balance a suitably conservative interpretation against the aims of the study . The risk of spurious significance is likely to be heightened in studies that report numerous IGE estimates across multiple conditions, lines, or other contexts. However, where the aim of a study is primarily descriptive or a hypothesis-generating exercise, and the purpose of characterizing IGEs using ψ is not to infer evolutionary dynamics that have happened but is instead to discover potential IGEs for later experimental follow-up, it is advisable to consider effect sizes, statistical power, and independently replicate key findings rather than rely on statistical significance as the sole criterion for confidence.Both across and within studies, t α=0.05 . The staψ and its empirical measurement in IGE studies is perhaps not surprising given the availability of an alternative approach to measuring IGEs—variance partitioning—which is based on established and widely practiced techniques in statistical quantitative genetics. In this approach, which is explained in further detail in ψ; to quote the authors of the original description of the interaction effect coefficient, “It is of interest to evaluate ψ for a number of characters. Unfortunately, this is logistically difficult.” . For these reasons, we envision 2 main “running-evolution-forward” approaches for IGE work. The first is artificial evolution in laboratory conditions, where experimental confounds are more readily controlled or accounted for in experimental design. Microbial and invertebrate systems would appear more suited to such an approach for practical reasons, but we note that IGE studies in the lab increasingly take advantage of genetic resources in vertebrate systems such as inbred mouse lines (Mus musculus) and guppies (Poecilia reticulata)  which have been extensively studied in Scotland (Teleogryllus oceanicus and Gryllus campestris) which have been monitored in Hawaii and Spain, respectively (Poecilia reticulata) which have been studied over time in replicate river systems in nature  , 2020. TScotland , field cectively , and Trin nature . As withψ can play a powerful role in setting up clear, falsifiable predictions about traits of interest in experimental approaches. Research estimating the interaction coefficient ψ has provided satisfying insights on the evolutionary dynamics of interacting phenotypes at particular, fixed moments. However, evolution is dynamic, and that of social interactions is expected to be particularly dynamic as IGEs can introduce an element of volatility (The interaction coefficient latility . Future esab056_suppl_Supplementary_Table_S1Click here for additional data file.esab056_suppl_Supplementary_Table_S2Click here for additional data file.


We hypothesize that sexual size dimorphism together with strong maternal investment drive these differences. By contrast, we find no differences in foraging ecology between sexes in West Greenland narwhals and observe no influence of size on trophic level. This may reflect the influence of interspecific competition in West Greenland, where the distributions of belugas and narwhals overlap, and/or geographical resource partitioning among different summer aggregations of narwhals. Our results suggest that sex and size variations in diet are population dependent, and probably the result of varying ecological interactions.Intraspecific variation in resource use by individuals of different age, sex or size may reflect differing energetic requirements and physiological constraints. Males and females often show differences in diet owing to sexual size dimorphism, different life histories and/or habitat use. Here, we investigate how sex and size influence the long-term foraging ecology of belugas and narwhals in Greenland, using stable isotopes of carbon and nitrogen from bone collagen. We show that males have a higher trophic level and a larger ecological niche than females in West Greenland belugas and in East Greenland narwhals. In addition, for these two populations, we find that  AnimaIn the marine environment, differences in foraging ecology between sexes are particularly strong in pinnipeds –11, wherDelphinapterus leucas) and narwhals (Monoceros monoceros), in Greenland. The two Monodontidae species coexist in West Greenland, while only narwhals are distributed in East Greenland (a). Both species can occur in sex-specific and mixed-sex groups [Here, we investigate sex and size variation in the long-term foraging ecology of the two Arctic toothed cetaceans, belugas  and nitrogen (δ15N) in soft tissues, which have turnover rates of several months [δ13C reflects the feeding habitat  and δ15N the trophic level [Boreogadus saida), polar cod  and capelin  appear to be the main summer prey of both whale species [Reinhardtius hippoglossoides), capelin and squid (Gonatus fabricii) are believed to be important prey [The foraging ecology of belugas and narwhals has been studied using stomach contents and stable isotopes of carbon . All samples represented sub-adults or adults. δ13C and δ15N values for 14 WG belugas and 11 WG narwhals were from [We obtained 300 mg of bone powder from the skulls of 27 belugas and 40 narwhals from West Greenland (WG), and 39 narwhals from East Greenland  within populations. Owing to some of the skulls being fragmented or otherwise broken, we were able to obtain skull measurements for 81 of the 106 belugas and narwhals investigated .To investigate the association between the size of individuals and their isotopic compositions, we ran a linear regression between skull length (used as a proxy for body length ) and δ13C), and Bayesian standard ellipses (SEAB) for each population/group. We estimated SEAB using 105 posterior draws, a burning of 103 and a thinning of 10, and used SEAB to test for differences in niche width among populations/groups (i.e. the proportion (p) of draws of the posterior distribution of the SEAB in which the area of one population/group was smaller than the other). We evaluated isotopic niche similarity between two populations/groups as the proportion (%) of the non-overlapping area of the maximum-likelihood fitted ellipses of the two.We compared isotopic niche  among populations, and between groups  within each population, using Bayesian multivariate ellipse-based metrics implemented in the packages SIBER and rjags –63. We c. 3. 3.1δ13C and δ15N . Detailed results are provided in the electronic supplementary material, text. This observed niche partitioning may be the result of interspecific competition, or of differences in dietary preference. Our findings are consistent with studies indicating that—despite prey overlap between species [Gadus morhua) and other fishes such as redfish (Sebastes mentella) [Our results indicate resource partitioning of belugas and narwhals in West Greenland. The species occupy distinct, yet slightly overlapping (9%), ecological niches, with belugas showing higher bone collagen  species ,41–43,46entella) , which fentella) . Althougentella) ,43,49,51et al. 2019 [We did not include prey isotopic data, as these are available from soft tissue samples only ,44,65 anal. 2019  and tropal. 2019 . This sual. 2019 , we findδ13C and δ15N in West Greenland than in East Greenland . This finding supports the long-term habitat segregation of narwhals west and east of Greenland, as has been shown by telemetry studies [et al. 2013 showed that Baffin Bay narwhals, whose main prey are benthic fish species including halibut, Arctic cod and polar cod, have a less pelagic diet than East Greenland narwhals, which consume a larger proportion of capelin [δ13C and δ15N in West relative to East Greenland is also reported in fishes [For narwhals, we find regional differences, with no niche overlap and higher  studies , and is  capelin . Higher n fishes  and othen fishes , suggest. 3.2δ13C does not differ significantly between sexes in any population (p > 0.05), our results indicate sex and size differences in the foraging ecology of West Greenland belugas and East Greenland narwhals based on δ15N . Males have significantly higher δ15N  and larger ecological niches than females  and higher δ15N . The pattern is stronger than that reported using skin tissue from belugas sampled in southeast Baffin Island, where older individuals show marginally higher (<0.5‰) δ13C and δ15N [Larger belugas and East Greenland narwhals tend to have higher and δ15N , again pWe hypothesize the sex-specific differences in foraging ecology observed in West Greenland belugas and East Greenland narwhals are driven by a combination of sexual size dimorphism and maternal investment, as has been observed in pinnipeds ,8,9,16. p < 0.01; The significantly positive correlation between trophic level and size is observed in male belugas and male East Greenland narwhals , and the size of the ecological niche is similar between sexes  only, in particular in females  for West Greenland narwhals influenced our results . We do not observe any differences between sexes within the one locality (Qaanaaq) from which we had a sufficient sample size for sex comparison . Thus, including several localities probably does not influence our findings of a lack of sex differences in the foraging ecology of West Greenland narwhals. Among certain localities, we recover variation in δ15N, although we observe no variation in δ13C . This may reflect geographical partitioning within the large West Greenland (i.e. Baffin Bay) population, which is composed of several stocks [We investigated whether combining sampling across four locations (Qaanaq, Melville Bay, Uummannaq and Qeqertarsuaq, figure 1l stocks ; every yl stocks . We sugg. 4We report long-term differences in foraging ecology between sexes in West Greenland belugas and East Greenland narwhals. These findings probably reflect a combination of sexual size, dimorphism, maternal investment and a deep-diving lifestyle. However, we find no differences in diet between sexes in West Greenland narwhals, indicating that sex differences in foraging ecology are population specific, and may be driven by intra- and interspecific competition. Our study highlights the applicability of stable isotope analysis of bone collagen for revealing long-term dietary differences among individuals with different life histories or physiological needs, which may remain undetected in the analysis of soft tissues with shorter turnover.Click here for additional data file.


The aim of this study was to analyse characteristics of paediatric antibiotic use in ambulatory care in Hungary. Data on antibiotics for systemic use dispensed to children (0–19 years) were retrieved from the National Health Insurance Fund. Prescribers were categorised by age and specialty. Antibiotic use was expressed as the number of prescriptions/100 children/year or month. For quality assessment, the broad per narrow (B/N) ratio was calculated as defined by the European Surveillance of Antimicrobial Consumption (ESAC) network. Paediatric antibiotic exposure was 108.28 antibiotic prescriptions/100 children/year and was the highest in the age group 0–4 years. Sex differences had heterogenous patterns across age groups. The majority of prescriptions were issued by primary care paediatricians (PCP). The use of broad-spectrum agents dominated, co-amoxiclav alone being responsible for almost one-third of paediatric antibiotic use. Elderly physicians tended to prescribe less broad-spectrum agents. Seasonal variation was found to be substantial: antibiotic prescribing peaked in January with 16.6 prescriptions/100 children/month, while it was the lowest in July with 4 prescriptions/100 children/month. Regional variation was prominent with an increasing west to east gradient . The identified characteristics of paediatric antibiotic use suggest that prescribing practice should be improved. Antimicrobial resistance (AMR) is a major public health concern worldwide . One of According to the European surveillance report on antimicrobial consumption for 2017, the EU/EEA population-weighted mean consumption of systemic antibacterials in ambulatory care was 21.8 DDD/1000 inhabitants/day, ranging from 10.1 in the Netherlands to 32.0 in Spain , where DThe objective of this study was to provide updated and detailed information on the scale and patterns of paediatric antibiotic use in ambulatory care in Hungary in 2017. Differences across age groups and sexes, and seasonal and regional variations of paediatric antibiotic use were assessed. The influence of prescribers’ characteristics  on paediatric antibiotic use was also analysed.In total 6,792,714 antibiotic prescriptions were dispensed and redeemed at pharmacies in 2017 in Hungary. Almost one-third  of these prescriptions were issued for children , with a As shown in Boys in the youngest age group (0–4 years) were exposed to substantially higher antibiotic use compared to the girls. Concerning all children (0–19 years), antibiotic exposure was slightly higher in girls, due to the higher prescribing rate for girls aged 15–19 years.Regarding patterns of antibiotic use , broad-sOverall, thirty active agents were used in the paediatric population in 2017, and the DU-90 segment (the number of drugs accounting for 90% of drug use ) consistDuring the study period, primary care paediatricians (PCPs) were responsible for the majority (57.5%) of paediatric antibiotic prescriptions issued in ambulatory care. As shown in Both the scale and patterns of paediatric antibiotic use showed regional differences within the country. Regarding the scale of paediatric antibiotic use, an increasing west to east gradient has been detected see a. The hiSeasonal variation was substantial see , with moThis is the first in-depth study on paediatric antibiotic use in ambulatory care in Hungary, covering certain characteristics of paediatric antibiotic use that are rarely evidenced in the international literature .Despite different age groups being analysed in other countries, it is still apparent that antibiotic use in children under 19 years of age in ambulatory care in Hungary (108.28 prescriptions/100 children/year) is relatively high compared to data from Germany (0–14 years of age: 42.8 prescriptions/100 children in 2018) , FinlandIn our study, the highest antibiotic exposure was detected in the youngest age group (0–4 years), similarly to the cross-national study of Holstiege et al.  , the natThe highest antibiotic exposure of the youngest age group may be related to the immature immune system of those 0–4 years old that renders them more susceptible to infections  and the Regarding sex-specific differences, the overall prescribing rate was slightly higher for girls. However, we observed variations across the different age groups. Boys in the youngest age group (0–4 years) received significantly more outpatient antibiotic prescriptions than girls. This may be related to the higher susceptibility of boys to infections ,21,22,23Overall, broad-spectrum penicillins, cephalosporins and macrolides were frequently prescribed for children in Hungary, with the highest proportion of broad-spectrum agents being prescribed for the youngest age group (0–4 years). This might be explained by the frequent use of broad-spectrum penicillins  for the treatment of acute otitis media . SimilarIn Hungary, co-amoxiclav was found to be the most frequently used antibiotic in children of all age groups. Although commonly prescribed antibiotics vary by country, co-amoxiclav is often the most widely used antibacterial agent in children, e.g., in Italy (Viareggio and Emilia Romagna region) ,28, LatvPCPs were found to prescribe the majority of antibiotics for children (0–19 years). Due to a lack of recent studies regarding antibiotic prescribers’ specialty in other European countries, we can only compare our data to the results of one study from a US state (Tennessee) published in 2016. In line with our findings, this study reported that paediatricians accounted for 57% of total outpatient antibiotic prescriptions in children .Another finding of our study was that physicians aged 65 and older tended to prescribe less broad-spectrum agents than their younger colleagues. This might be explained by the fact that they were also familiar with older, narrow-spectrum agents, such as phenoxymethylpenicillin (penicillin V). Overall, our study revealed that the majority of physicians prescribed more broad-spectrum antibiotics than narrow-spectrum agents. A systematic review revealed the reasons behind this phenomenon, reporting the factors that influence antibiotics prescribing. These include patients’ expectations, the severity and duration of the infection, diagnostic uncertainty, fear of potentially losing patients, and the influence of pharmaceutical companies . SimilarPrescribing broad-spectrum agents was found to be common practice by all doctors, irrespective of their specialty. Otolaryngologists prescribed broad-spectrum antibacterials more often than others, probably because they treat more complicated cases.There was a more than 2.5-fold difference between the counties with the highest and the lowest paediatric antibiotic consumption. This is considerably higher than the 1.9-fold regional difference reported from Germany in 2018 . The lowRegarding the percentage of narrow-spectrum penicillins, cephalosporins and macrolides, an odd regional variation was found in Hungary. This may indicate a difference in prescribing habits in different counties (regions). The reason for why substantially higher proportion of narrow spectrum antibiotic consumption was found in the westernmost area of the country (Vas county) remains unclear, and needs further investigation to reveal what contributed to this more optimal prescribing practice.The highest monthly antibiotic prescription rates in the paediatric population were observed during the winter season, peaking in January. Seasonal fluctuation of outpatient antibiotic use in the general population across Europe has been described before , and it The use of a large, population-based dataset covering the whole population as well as the good drug coverage (see below in the methods) are the main strengths of our study. However, we were not able to evaluate the appropriateness of prescribing, nor were we able to analyse the correlation between diagnoses and antibiotic use in this study. One year of data might be regarded as suboptimal to report seasonal variation. However, as the year 2017 was not extraordinary in terms of antibiotic use or overall seasonality, this limitation might not affect the implications on seasonal variation .This was a population-based, descriptive, retrospective study pertaining to the year 2017. Information on the use of systemic antibiotics—Anatomical Therapeutic Chemical (ATC) code J01—was obtained from the National Health Insurance Fund of Hungary , which contains information on reimbursed drugs dispensed in Hungary prescribed in ambulatory care. As almost all available antibiotics are reimbursed in Hungary, the database provides information for ~95% of total antibiotic dispensing. As NEAK is the only public health insurance fund in Hungary, the database has 100% population coverage. Reimbursed prescriptions issued by general practitioners of any kind such as PCPs , as well as specialists and dentists, prescribed for patients in ambulatory care and patients visiting private practices are included in the dataset. A more detailed description of paediatric healthcare in Hungary is provided in a manuscript by Laszlo et al. .Analysis was focused on children aged 0–19 years. Data were stratified by age group of patients , age group of physicians , speciality group of physicians , region , and month of antibiotic dispensation. Antibiotic use was expressed as the number of prescriptions per 100 inhabitants in the age group concerned per year or per month. Population data were derived from Eurostat. The proportion of broad-spectrum penicillins, cephalosporins and macrolides, as defined by the European Centre for Disease Prevention and Control [High paediatric outpatient antibiotic exposure with a suboptimal pattern was detected in Hungary, especially among children in the youngest age group (0–4 years). The considerable regional variation and the disproportionately high seasonality of antibiotic use in children may also suggest suboptimal prescribing practices. The revealed characteristics of paediatric outpatient antibiotic use can support planning antibiotic stewardship interventions and can serve as a basis for more detailed qualitative research.


A timely knowledge of concrete and ultra-high-performance concrete (UHPC) strength is possible through the so-called strength-equivalent time (Et) curves. A timely knowledge of concrete strength is useful, for instance, to precisely determine when the shores of a hardening structural element can be safely removed. At the present time, the preparation of the strength-Et curves requires time-consuming and labor-intensive testing prior to the beginning of construction operations. This paper proposes an innovative method to derive the strength-Et and total heat-Et curves for both normal strength and UHPC. Results confirmed that the proposed method is fast, inexpensive, self-calibrating, accurate and can detect any variation of the concrete mix proportions or components quality. In addition, the quality of predictions of strength–maturity curves can be constantly improved as the specimens’ population increases. Finally, results obtained with the proposed method were compared with those obtained using standard methods, showing a good agreement. MI computes the effect of both time and temperature on the degree of reaction α of concrete for any curing regime. Cement hydration is faster at high curing temperatures and inversely slower at low curing temperatures. Curing temperatures also influence the hardening properties of the cementitious composite [In this paper research is presented whose objective is to provide an accurate method to predict the strength of commercial concretes at any time. A second objective of this research is to detect when the mix changes and thus the prediction of the strength is not accurate. The method, composed by a testing apparatus and a model, is conceived to be inexpensive and auto-calibrating, adapted to be used on the field. Predictions of concrete strength are made using the so-called strength–maturity curves. A strength−maturity curve is used to predict the strength of industrial concretes at any time during the hydration process. These curves are constructed in laboratory for a specific mix design. Norms are available to prepare such curves since 1977 and today are mentioned in design norms [omposite . The lawomposite . In addiMI curve is available for a specific concrete, in order to know the strength at a time t*, it will suffice to monitor the internal temperature history of a hardening structural element made of the same concrete, convert the internal temperature history T(t) into a MI, enter into the strength–MI curve the value of MI (t = t*) and read the corresponding concrete strength.In fact, once a strength–MI [tequivalent-time E(t) is a very well-known model used to compute MI from the recorded temperature history of concrete and, in turn, to construct the strength–MI curves t [tE(t) is based on the well-known Arrhenius’ law. Such a law is used to determine the rate of a chemical reaction [T(t) of the hydrating concrete. The time history can therefore be converted into tE(t) history at a reference temperature using the following Equation [tE(t) represents the equivalent time (expressed in days) at a constant temperature, (T = 20 °C in this paper); t and t0 represent the considered time frame; aE is the activation energy which characterizes the sensitivity of concrete hydration processes to the temperature (expressed in kJ/mol); R represents the universal gas constant, which is 8.314 J/(K mol); rT and T are, respectively, the reference  and the observed temperature (expressed in K or °C). tE(t) histories are useful because at the same value of tE(t), a concrete property  is supposed to have the same value independently of the temperature history T(t) that brought to that value of tE(t) [tE(t) curve is known for a specific concrete property, the value of that property at any time t* can be estimated by simply monitoring the internal temperature history T(t) and, using Equation (1), to determine tE(t*). The tE(t) histories are supposed to be directly related to α(t) histories [Many linear and nonlinear formulas are available to determine MI ,5. In thcurves t ,10,11,12curves t ,14,15,16reaction . The timEquation :(1)Et(t)of Et(t) .Thereforistories ,20,21,22tE(t) can be calculated only if the aactivation energy E is known. aE can be viewed roughly as the energy level that the reactant molecules must reach (and overcome) before a reaction can occur. For binders, the activation energy is often called “apparent activation energy” [aE is representative and can give correct predictions. UHPC often contain a mix of cement and pozzolans and hardens at high pace, and therefore a little error of the activation energy might result in large prediction errors. Methods to derive aE are always based on a simple assumption: At the same degree of reaction α*, a given physical property of concrete P(α) will assume the same value P(α*) = P* independently of T(t) used to reach α*. Among the concrete properties used to derive aE, and consequently both tE (t) and MI, there are the total heatHQ(t) released by the hydrating concrete  and the compressive strength of the concrete. Many methods to determine aE are available, some of them are standardized [aE and, in turn, to construct the strength–MI curve for both normal-strength and ultra-high-performance fiber-reinforced concretes, by using a semi-adiabatic calorimetry technique. This method also allows to determine the α(t)–tE(t) curve, thus providing a powerful tool for quality control of hardening of cement-based materials in concrete batching plants as well as to explain the evolution of the mechanical properties of these composites [aE for the range of the rate hydration that is most adapted to the case at hand. Although many semi-adiabatic apparatuses and related models have been developed for concrete quality control, to the best of the authors’ knowledge, none presents the above-mentioned features. energy” ,21 sincemposites . The modtE (t), the equivalent time, is related to α(t), the degree of reaction of concrete. The latter is linked to HQ(t), the total heat released by the hydrating concrete at time t. HQ(t) can be obtained by the following Equation:HQ(t) is the total heat released by the hydrating concrete, expressed in kJ; m is the mass of the sample, expressed in kg; cC is the specific heat of the cementitious material, expressed in kJ/(kg K); and ΔGT is the difference between the adiabatic temperatures at time t0 and t, expressed in K or °C. ΔGT is measured using an adiabatic calorimeter. As m and cC are considered constant, QH(t) is directly related with the Gadiabatic temperature rise T; see Equation (2). As drawn in the Equation below, the degree of reaction has been found to be a function of the total heat released under adiabatic conditions, as follows:α(t) is the degree of reaction at the time t, Q(t) and Q (t = ∞) are, respectively, the total heat released at the time t and the total heat released in the whole reaction under adiabatic conditions, both expressed in kJ. It is therefore safe to assume that the normalized curve of the temperature rise ΔGT (t)/ΔGT (t = α(t); see Equations (3) and (4). When the reaction is completed no further rise in temperature equals to no further heat generated (=100% degree of reaction achieved).GT (t) and ΔGT . The adiabatic HQ(t) can be determined by an adiabatic heat test: GT is measured on a hydrating concrete specimen for which all exchanges of heat with the surrounding environment have been somehow suppressed .As stated above, GT of a concrete specimen are special molds with a system that measures the internal temperature of the specimen. Such a system is connected to a thermostatic device  installed in the external surface of the mold. The thermostatic device promptly matches the internal temperature of the concrete measured by the sensor and therefore eliminates any flux of heat to and from the specimen. Therefore, the concrete specimen hydrates in adiabatic conditions. Unfortunately, for practical purposes, the adiabatic test is not adapted due to the complexity of suppressing all heat exchanges between the specimen and the environment. For this reason, many semi-adiabatic devices have been developed to determine the adiabatic heat release of concrete.The most common apparatuses for measuring If the heat exchanges are not completely suppressed, the temperature rise measured is called the semi-adiabatic temperature rise. A semi-adiabatic calorimeter (SAC) is generally a cylindrical chamber heavily insulated with the best insulating material available see .GT. In particular, Ng. et al. [GT is the adiabatic temperature rise of concrete sample at the time t; VT is the volumetric mean temperature of concrete sample inside a SAC; PT is the placing temperature of concrete sample; λ is the heat-loss compensation factor which is observed in semi-adiabatic apparatus; ST is the mean temperature of the concrete sample surface; AT is the SAC surface temperature close to the ambient. In Equation (5), all temperatures can be measured with simple thermocouples, while the heat-loss compensation factor λ must be calculated. λ can be assumed, measured, or estimated experimentally.The specimens of fresh concrete are placed into the chamber. Although the specimen is heavily insulated, a heat loss cannot be avoided. Nevertheless, the heat losses can be estimated, and therefore, the semi-adiabatic temperature rise can be converted into . et al.  have staQH(t) of concrete specimens, there are the QAB and the Langavat calorimeters [λ and the heat capacity of the calorimeters. This is required because the heat-loss compensation is made by estimating the heat absorbed by the insulation. These two devices were not designed to calculate aE. However, the QAB calorimeter can be easily modified and used for this purpose, as is proposed in this paper. SAC is both a simplified and a modified version of the QAB, whose reliability has been confirmed by several works [Among the most used methods to determine the adiabatic rimeters . Both derimeters  and requal works ,31,32,33λ could be obtained by simply calibrating the apparatus using hot water. In particular, a specimen of water at high (and known) temperature is inserted into the chamber of a SAC  can be easily determined, it is therefore established that a semi-adiabatic temperature rise can be transformed in GT.The value of  SAC see . Temperat method . A more g et al.  who applaE, Equations (1) and (2) are used: two identical specimens of hydrating concrete are supposed to have released the same quantity of heat per unit of mass, when the reaction is completed ) and also at whatever degree of reaction α. If the objective is to determine aE by using adiabatic heat curves, two conditions have to be satisfied:It must be possible to measure or derive the adiabatic heat of hydration of two specimens; see The two specimens must not have the same initial temperature and temperature rise.In order to derive GT. GT values derived for both specimens are finally normalized to the specimen weight. The normalized adiabatic temperature rises ΔGT (t)/ΔGT (t = α(t) according to Equations (3) and (4). Speed and superposition methods [aE. A variant of both methods is the equivalency points method [aE for every point of equal α(t) of two specimens. The equivalency point method determines aE by simply calculating for two different temperature histories T1(t) and T2(t) of two different specimens the values of Et1(1t) and Et2(t2) up to a common degree of reaction α*. By equating the two values of tE, the activation energy is determined.If both conditions listed above are satisfied, the semi-adiabatic temperature rise of the two specimens can be measured and therefore converted into  methods  can be us method  that allaE is to construct two or more SACs working in parallel on concrete specimens sampled from the same batch. The two specimens must have a different initial temperature to ensure they will not have the same T(t), in agreement with It is evident that the fastest procedure to obtain λ of Equation (6) is known. Thanks to the test procedure presented by Ng et al. [λ values each time a test is run, making the apparatus auto-calibrating. In order to verify the suitability of the self-calibration procedure of the SAC, a calibration test similar to the Nordtest method was also performed. This is important because λ value tends to slightly vary with the temperature of the specimen. Hot water was inserted in the SAC chamber, and temperatures were monitored at the location shown in Heat loss compensation of the semi-adiabatic temperature rise can be achieved only if g et al.   and 0.0475 (concrete). The calibration tests therefore agree with the principle presented by Ng et al. [λ value can be found. Furthermore, a new λ value is obtained each time a test is run. Consequently, it is easy to control if the values obtained are reasonable and stable at the typical temperatures recorded. It should be noted that a λ value calculated by Ng et al. [λ that characterizes building insulation materials.Calculated g et al. , as a sig et al.  is not tIn order to prove the suitability of the proposed method for commercial concretes of different mixture composition, two concretes were investigated see : a commeMixing was performed using a high shear rotating pan mixer. This mixer was chosen because it is close to the efficiency of the industrial mixers used for the production in large scale of the concrete materials similar to those here investigated; see aE values of UHPC. First, the SAC tests were conducted on specimens at different initial temperatures, as proposed in H, SACQ(t) curves were compensated by using Equation (5) to obtain HQ(t) of each series as a function of the time. Then Equation (4) was used to determine α(t) for each specimen. Finally, using the principle of equivalency points explained in aE was determined for each couple of series . aE values obtained for the three series are listed in α(t).To maintain the repeatability of the SAC test, three UHPC series were tested. Data collected were used to determine three different aE. The first one was related to the use of the smoothing algorithm Savitzy–Golay. The second one was due to the fact that often H, SACQ (t) curves are both overlapping and crossing, thus making more complex the determination of the correct aE value. Both sources of uncertainties are easily eliminated by simply repeating regularly the SAC tests in order to have a significant number of values. Using a basic regression technique, the incoherent data can be filtered. The signature provided by HQ(t) curves and the temperature measurement are also useful to signal the occurrence of a sudden change of quality of commercial UHPC. In fact, in order to meet the designer’s requirements, e.g., self-compacting UHPC, thixotropic UHPC and projected UHPC, the producers adapt the UHPC mixture (compounds and plasticizers). In a previous work [aE and HQ(t) curves were not affected by this phenomenon.All these calculations were made using a commercial computational code. Data reduction included also a curve smoothing based on the Savitzky–Golay algorithm. Two types of incertitude were encountered in the determination of ous work , a commeinitial point t0, i.e., the moment at which the hydration begins. Controversial opinions about methods for the identification of t0 as well as the determination of the setting time are found in the literature [Another incertitude concerns the determination of the terature ,22.The graphical method proposed by Viviani et al.  was usedaE; see aE value of 30.614 kJ/mol, in agreement with data found in the literature [In order to confirm the results provided from SAC tests, a standard test (ASTM 1074) was performed to determine the value of terature ,20. ThisMI curve was developed to determine the strength of the UHPC at any time. Most points along the strength–MI curve were determined for the early age of UHPC. A single value of aE proved to be sufficient for the 28-day strength. The strength–MI curve was developed specifically for a precaster whose main need was to cast a relevant number of post tensioned beams in less than 20 h. The standard test mentioned above also provided and aE value. The obtained strengtht–E(t) curves were confirmed by plotting independent strength test values in Finally, a strength–tE(t) curve is representative of the hydration process of the cement-based material, for the ambient temperature and time of strength desired [tE(t). A sensitivity analysis allows uncovering the effect of the errors on the predictions of strength–tE(t) curves, which is caused by the determination of different aE values, as already discussed above. A sensitivity analysis was therefore performed: the aE value was changed by a ±10% value, and the strengths at 1, 3 and 28 days were recalculated. The maximum difference between the original predicted value and the values obtained by altering aE value were lower than 6.5%, 5% and 3% for 1, 3 and 28 days of tE(t), respectively  curves are available, and thus, it is possible to calculate an approximation of the evolution of the α(t) of each specimen as a function of the tE(t); see Equation (3). α(t) curves calculated via a SAC test, which are expressed as a function of tE(t) at 20 °C for UHPC specimens. Different batches of cement-based materials can lead to a small scatter between α(t) curves, as can be observed in One of the interesting points in the use of the SAC method is that t0 of hydration were the same presented in aE value was determined for each couple of series; see α(t).Three couples of OC-C30/37 series presented in aE value was verified also by performing the standard test ASTM 1074, as presented in aE value of 42.916 kJ/mol, in agreement with data found in the literature. This comparison confirms the accuracy provided by the method presented in this paper for any concrete class . A strength–MI curve was developed to determine the strength of OC-C30/37. A single value of aE proved to be sufficient for the 28-day strength.α(t) for OC-C30/37 series as a function of the equivalent-time at 20 °C is reported in The evolution of OC-C37 proved to be a good structural concrete for general purposes, but it is not an ideal candidate for the type of field that relies heavily on Maturometry to speed up the construction planning. In fact, aE of representative concrete specimens, from normal-strength to ultra-high-performance fiber-reinforced concretes. Once aE value is determined, an accurate plot about the evolution of the rate of reaction α(t) and therefore the strength–MI curve is computed. Most of the theoretical background on which the SAC test is based has been already validated by other studies and practitioners [aE values, as the number of specimens tested increases. There are no particular risks using this technique as far as the users have an adequate knowledge of concreting and concrete. Some risks arise when the predictions of the strength–MI curves are provided on the basis of hardened specimens monitored under similar temperature profiles. In fact, cement-based materials showing a strong crossover effect [aE and evolution of α(t).The proposed method shows a great potential. It can be used to quickly derive the itioners ,28,29,30r effect , might uAnother important point for this technique is that the specimens should be of equal mass; otherwise, the curves of the temperature might cross each other making the data collected useless (most of the times). Hence, the specimens’ holders must be completely filled, and their weight controlled. Finally, the degree of hydration–Et curves see  constituThe SAC test is an accurate, inexpensive, fast and self-calibrating method to calculate the activation energy of cement-based materials;The quality of predictions of strength–maturity curves provided by the proposed method can be constantly improved as the specimens’ population increases;The SAC test is a good quality control tool since it can detect any variation of w/c ratio, change of quality or type of cement, compatibility problems with a new plasticizer and unexpected change of the mix proportions;aE under a much different temperature. A method which can overcome this limitation is the resistivity model based on Winner bounds, even though available data show that it is still not suitable for concrete due to the poor electrode contact and non-uniformity caused by the presence of coarse aggregate.This fast and inexpensive method to control quality of any concrete class is limited by the fact that values for the activation energy are obtained under specific temperature conditions and might not accurately represent the value of This paper presents a fast and inexpensive method to determine the strength–Et evolution of both normal-strength and UHPC concretes. Results provided by the proposed method were compared with those obtained by standard tests, showing great agreement. Based on the results of this research, the following conclusions can be drawn: