To study the dynamic mechanical characteristics and constitutive relation of concrete materials under freeze–thaw (FT) cycle conditions, C35 concrete was taken as the research object in this paper, and FT tests were carried out with a freeze–thaw range of −20–20 °C and a freeze–thaw frequency up to 50 times. By using the separated Hopkinson pressure bar (SHPB) system, impact compression tests of concrete specimens under different FT cycle actions were developed, then the dynamic fracture morphology, fracture block distribution, stress–strain curve, peak stress and other dynamic mechanical properties of concrete were analyzed, and the influence law of FT action and strain rate was obtained. Through introducing the freeze–thaw deterioration damage factor and the stress damage variable, the dynamic visco-elastic damage constitutive equation of freeze–thawed concrete was constructed based on component combination theory. Furthermore, the damage evolution process and mechanism of freeze–thawed concrete materials were revealed. The research results show that the dynamic mechanical properties of concrete under a freeze–thaw environment are the combined results of the freeze–thaw deterioration effect and the strain rate strengthening effect. The dynamic visco-elastic damage constitutive model established in this paper can effectively describe the dynamic mechanical properties of freeze–thawed concrete, and has the characteristics of few parameters and good effect. The stress damage evolution path of concrete goes backward with the increase of FT cycles and the development speed gradually slows down. The greater the difference in FT cycles, the greater the difference in stress damage path. The cold areas in China are widely distributed, and the seasonal and permanent cold areas account for more than three quarters of China’s land area. In recent years, with the rapid development of the economy, there are more and more projects built in the cold region, such as the Qinghai–Tibet Railway, the Sichuan–Tibet Railway, the China–Russia and China–Kazakhstan Oil Projects, as well as many long tunnels and dams. As a kind of material widely used in railway, highway, dam, tunnel and other cold region engineering, concrete will suffer from freeze–thaw damage in the long service of freeze–thaw environment. Under the action of the freeze–thaw cycle, the residual moisture in the interior pores will continuously freeze and thaw, and then cause the continuous development of the internal pores, the performance of the concrete structure will be greatly affected, easily causing structure cracking, deformation and even instability failure ,2. ThereThe above studies on the mechanical properties of freezing-thawing concrete are of great significance for guiding the prevention of freezing-thawing injury in civil engineering in cold regions. However, most of them focus on the static mechanical properties. Studies have shown that ,11 concr−4–103 s−1. Due to the good fitting accuracy, the Z-W-T model has been widely used in simulating constitutive relations of brittle materials such as concrete and rock [The constitutive model is one of the important bases on which to study the strength and deformation of concrete, and reflects the stress–strain curve, the most basic mechanical property of concrete . The comand rock ,16. NeveDirected at C35 concrete suffering from different numbers of freeze–thaw cycles , a series of impact compression tests was carried out on a Φ50 mm  separated Hopkinson pressure bar (SHPB) system in this paper. The dynamic fracture morphology, fracture block distribution, stress–strain curve, peak stress and other dynamic mechanical properties of concrete were analyzed, and the influence law of freeze–thaw cycle and strain rate was obtained. By introducing the freeze–thaw deterioration damage factor and the stress damage variable, the dynamic visco-elastic damage constitutive equation of freeze–thawed concrete was constructed based on component combination theory. The damage evolution process and mechanism of freeze–thawed concrete materials were revealed.3, an initial setting time of 208 min, a final setting time of 260 min, a bending strength of 8.6 MPa, a compressive strength of 51 MPa, and the volume stability was qualified. The coarse aggregate was 5–16 mm continuously graded gravel. The fine aggregate was continuously graded medium river sand, with a fineness modulus of 2.42. Before the concrete was prepared, the soil in the river sand was washed clean and the sand was then placed in a drying box to dry for 24 h. The water was laboratory tap water and conformed to the specification requirements. Fly ash was secondary ash, fineness 43 μm, density 2.4 g/cm3, moisture content about 5%. The pH value of the water-reducing agent was 7–9, the water-reducing rate was about 20%–35%, and the solution was prepared with a concentration of 26%–28%.C35 concrete was applied in this experiment, the proportion of the basic materials of Portland cement, stone, sand, water, fly ash, and water reducing agent was 1:3.80:2.03:0.56:0.40:0.02. The Portland cement was P.0.42.5 ordinary Portland cement produced by Shaanxi Qinling Cement Building Materials Limited Liability Company, with a density of 3.05 g/cmThe mixture was placed into a 100 mm × 100 mm × 100 mm steel mold, and compacted on the shaking table. After 24 h, the mold was removed for 28 days of curing in the standard curing room. Through coring and cutting, the specimens were processed into cylinders with a diameter of 50 mm and a height of 25 mm. Then the two end faces of the specimen were polished to ensure that the non-parallelism and non-perpendicularity were both less than 0.02 mm . On thisAccording to the “standard for test methods of long-term performance and durability of ordinary concrete (GB/T 50082-2009)”, frost resistance tests for concrete include the fast freezing method and the slow freezing method. The slow freezing method is suitable for the determination of concrete specimens under conditions of gas-freeze-water thawing. The fast freezing method is suitable for speciments under conditions of water-freeze-water thawing.The FT cycle test in this paper adopted the slow freezing method and was performed in an automatic low-temperature freeze–thaw chamber . According to clause 4.1.4 of the “Standard for test methods of long-term performance and durability of ordinary concrete (GB/T 50082–2009)”, “the time required from the time the specimen is installed to the time when the temperature drops to −18 °C should be within (1.5–2.0) h, and the temperature in the freezing-thawing chamber shall be maintained at (−20–−18) °C during freezing”, “the freezing time of each FT cycle should not be less than 4h”, “Immediately after the freezing, water with a temperature of (18–20) °C should be added, and the melting time should not be less than 4 h. After thawing, it is deemed that this freeze–thaw cycle has ended, and the next freeze–thaw cycle can be started”.Considering the above standard requirements, the temperature range and cooling rates were determined as follows. The freeze–thaw temperature variation range was −20–+20 °C, and freeze–thaw cycles were carried out 0, 10, 20, 30, 40 and 50 times, respectively. The time-history curve of one FT cycle is shown in Aiming at the concrete suffering from different numbers of FT cycles , uniaxial impact compression tests under different strain rates were carried out on a Φ50 mm SHPB system . The diameter of the sieve holes was 0.5, 1, 2.36, 4.75, 9.6, 16 and 19 mm, respectively. After the screening test, the quality of the subscreen of each stage was weighed by a high-sensitivity electronic scale. The scale–mass distribution law of concrete fragments under different conditions is shown in As can be seen from According to the mass–frequency relationship , the disThe natural logarithm on the both sides of Equation (1) is taken to getrM/TM)~lnr coordinate system, the slope of the fitting line was In the ln−lnr coordinate system, indicating that the distribution of the concrete fragments had fractal characteristics. This was because the distribution of the mesoscopic cracks and pores inside the concrete conformed to the fractal theory, and had self-similarity under different scales. The freeze–thaw deterioration and the impact crushing process were the direct results of crack extension; therefore, the crushing blocks of the specimens subjected different numbers of freeze–thaw cycles and different levels of impact loading also showed a certain self-similarity, that is, they satisfied the power law characteristics, and it was a fractal of statistical significance. In summary, the concrete material had fractal properties from the microscopic damage to the macroscopic fracture, and the smaller the fragment size, and the more serious the material breakage.It can be found in It can be drawn from The dynamic stress–strain curves of the freeze–thawed concrete are shown in It can be drawn from By comparing In conclusion, the dynamic mechanical properties of concrete under a freeze–thaw environment are a result of the combination of freeze–thaw deterioration and strain rate enhancement.Dynamic peak stress, the basic mechanical parameter, is taken as a characteristic index, and the relative loss of peak stress is defined as the freeze–thaw degradation effect factor; thenChange laws of the freeze–thaw degradation effect factor N is the number of FT cycles, and a and b are fitting parameters. By statistical regression, the fitting correlations were 0.92, 0.84 and 0.80, respectively, under different loading conditions, suggesting that Formula (5) could better reflect the changing law of the freeze–thaw degradation effect factor with the FT cycles.Variation rules of the dynamic peak stress of freeze–thawed concrete with strain rate are shown in c and d are fitting parameters. When the FT cycles were 0, 10, 20, 30, 40 and 50, the fitting correlations were 0.99, 0.80, 0.98, 0.99, 0.93 and 0.84, respectively, which indicated that the linear expression could well reflect the change rules of dynamic peak stress with strain rate.As the internal structure of concrete is not homogeneous, and contains many defects, the strength of each micro-element is not the same. For the convenience of study, and considering the continuity of concrete damage in the loading process, it is assumed that the concrete is divided into several micro-elements with different defects. The micro-elements are divided into small ones, and meet the duality of size, that is, on the one hand, their size is large enough to contain enough micro-joints, micro-cracks and other micro-information from the microscopic perspective, while on the other hand, from the macroscopic point of view, their size is small enough to be considered as a particle of continuous damage mechanics.The test results showed that the dynamic mechanical properties of freeze–thawed concrete mainly reflected the evolution process of micro-cracks under the thermal and force coupling action. That is to say, the dynamic mechanical properties of freeze–thawed concrete are the composite damage evolution of freeze–thaw fracture and stress-damage fracture, and the stress–strain curve will show certain differences when the freeze–thaw action or strain rate is changed. Therefore, it is necessary to reflect the above basic physical facts reasonably and appropriately in order to establish the dynamic constitutive equation.D was damage variable, In this paper, freeze–thaw degradation effect factor On this basis, according to the component combination theory, concrete can be regarded as a union of a damaged body and a viscous body, and the influence of the strain rate can be reflected through the viscous body. Finally, the dynamic damage constitutive model of freeze–thaw concrete was derived.D had the following relationship with Concrete is obviously a brittle material under freeze–thaw action and impact load, and its plastic strain is very small. Therefore, the plastic deformation part can be ignored . The conD wasStudies have shown that ,25,26,27D can be further simplified asAs concrete is a kind of multiphase composite material, it contains many micro-cracks and micro-defects. In other words, it has initial damage. Therefore, the damage threshold value was set as 0 in this paper, namely Because concrete has properties of both viscous liquid and statistical damage, it can be regarded as a combination of the parallel connections of a viscous body and a damaged body , as showBased on the component combination theoryEquation (11) is the dynamic visco-elastic damage constitutive equation of freeze–thawed concrete. The unknown parameters in the equation can be obtained by inversion analysis based on the test results.The Z-W-T model is shown in The Z-W-T model is composed of a nonlinear elastomer in parallel with two Maxwell models. The first Maxwell model  can be regarded as linear elasticity, that is, Formula (12) can only take the first term. The SHPB test can be regarded as an approximately constant strain rate loading process. Therefore, the Z-W-T model expression can be written as followsFurthermore, the Z-W-T model expression after considering the damage wasWe took cases of FT0 with different impact velocities and an impact velocity of 8.8 m/s with different numbers of FT cycles as examples. Based on the test results, the visco-elastic constitutive model proposed in this paper and the Z-W-T model commonly used to describe the dynamic mechanical properties of concrete were respectively used for comparative study. The comparison results are shown in It can be seen from D.The damage of freeze–thawed concrete under impact load included two parts: freeze–thaw deterioration damage and impact stress damage. Among these, the freeze–thaw degradation damage is described by the freeze–thaw degradation factor As shown in According to Equation (10) and As shown in D decreased gradually, and the slope of initial stress damage curves decreased constantly. This suggests that although the total damage of freeze–thawed concrete under impact load, which was the coupling result of freeze–thaw deterioration damage and impact stress damage, increased with the increase of the number of FT cycles, and as well as the freeze–thaw deterioration damage factor, while the stress damage value decreased. This was because the greater the number of FT cycles, the more serious the freeze–thaw deterioration; and the lower the residual energy consumption performance of the specimen was, the fewer the cracks generated by the specimen’s absorption of impact incident energy, namely, the smaller the stress damage was.The test results show that the freeze–thaw action and impact velocity have a significant influence on the dynamic fracture morphology, fracture block distribution and dynamic stress–strain curve of concrete, and the dynamic mechanical properties of freeze–thawed concrete are the coupling results of freeze–thaw deterioration effect and strain rate strengthening effect.By introducing the freeze–thaw deterioration damage factor and the stress damage variable, the dynamic visco-elastic damage constitutive model was deduced based on component combination theory. It can effectively describe the dynamic mechanical properties of freeze–thawed concrete, and has the characteristics of few parameters and good prediction accuracy.The stress damage evolution path of concrete goes backward with the increase of FT cycles and the development speed of stress damage gradually slows down. The greater the difference in FT cycles, the greater the difference of the stress damage path.


The total courses administered were fewer in beef (330.7 × 10−3 DCDvet/year) than in dairy farms (1034.1 × 10−3 DCDvet/year). The use of the highest priority critically important antimicrobials (HPCIAs) was higher (p = 0.0033) in dairy than in beef herds. In terms of DDDvet, the parenteral fluoroquinolone administration ranked second and fourth on dairy and beef farms, respectively; the consumption of beta-lactams was ten times higher on dairy than on beef farms. Our results confirm that intensive dairy management practices are associated with increased antibiotic consumption and highlight the necessity to strengthen the existing stewardship programs by involving all stakeholders in effective antimicrobial resistance reduction plans.The overuse of antibiotics in livestock contributes to the antibiotic resistance pandemic. The assessment of the actual antibiotic consumption is crucial in limiting the expansion of the problem effectively. The aim of this study was to provide the first qualitative and quantitative analysis of antimicrobial usage using data from paper-based registers on dairy and beef farms located in the Umbria region, Italy. Antimicrobial therapies of a one-year period were collected from 101 farms with at least 50 cattle each. Defined daily doses (DDD The pandemic of antibiotic resistance (AMR) poses a global threat for human health. Human-to human transmission of antibiotic-resistant bacteria is the main way of acquiring and spreading AMR; however, other ecosystems also contribute to its emergence and dissemination. Among them, livestock is considered to play an important role ,2,3. TheIn Europe, the European Medicines Agency (EMA) has been monitoring antibiotic consumption in animal production since 2010, through the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) project. The project has collected data on antibiotic sales and an open-access database and yearly reports have been provided to the public since 2011. The unit of measurement is a result of the weight of the active substance sold in each country, expressed in mg, adjusted by the animal population of the same country (population correction unit (PCU)). According to the early ESVAC reports, Italy was among the European countries with the highest antibiotic consumption in agriculture . DespiteThe analysis of national sales data has made the identification of antibiotic consumption trends possible. Even more importantly, a correlation between antibiotic consumption and antibiotic resistance at the country level has been shown . HoweverUntil 2019, data on antibiotic consumption on farms in Italy were available on paper registers. This registration was mandatory for the prescribing veterinarian and under the control of public veterinary services. According to the law ,11 the rThe systematic collection, collation, and analysis of consumption data on Italian farms using paper registers were not feasible at a national level. Therefore, the Italian Ministry of Health launched a new system for the collection of antibiotic consumption data in 2015. The system, which became mandatory in 2019, is based on the direct digitalization of antibiotic sales and the use of antibiotic prescription records .The livestock sector varies greatly in different geographic regions of Italy. In northern Italy, where intensive systems are more common, there exists a population of 3,961,224 beef and dairy cattle . In central Italy, the population is reduced to 391,606 cattle, of which 55,468 are in the Umbria region . In central and southern Italy, a less intensive livestock system is widespread for both dairy and beef cattle. In cow-calf line and rural dairy farms, farmers are far from implementing a smart livestock system and tradition-bound behaviors are often applied in farm management , therebyAccording to European priorities and to satisfy consumer demands for welfare-friendly animal-derived products, the Umbria region implemented Measure 14 on animal welfare in the context of the Rural Development Program 2014–2020. The Measure involved 72 dairy farms  and 268 beef farms . Actions included in the Measure have been implemented to increase animal welfare, the health status of livestock, farm biosecurity, and drug use through commitments voluntarily chosen by breeders. In a five-year program, farms have been supported both with on-field audits, followed by data collection for assessment, analysis, and monitoring of management practices on the herds. The activities related to Measure 14 and the constant presence of trained technicians in the territory allowed, for the first time in this area, a more detailed data collection in the farms involved, which were chosen to represent the reference population for the present study.In the sampled farms, paper-based registers were used for the determination of antibiotic consumption. The aim of this study was to provide a qualitative and quantitative characterization of the actual antimicrobial usage recorded on paper-based registers on sample beef and dairy farms located in the Umbria region. The obtained results could represent a stepping stone for further analysis, which will be based on more advanced digital prescription registers.The study involved 101 cattle herds, of which 54 (53.5%) were beef and 47 (46.5%) were dairy . The sampled farms represented 4% of the total cattle breeding farms in the Umbria region with at least one animal (101/2496) and 40.9% of those with at least 50 cattle units (101/247). No statistical differences were observed between the sample and the latter regional subpopulation in terms of the distributions of herd sizes on either livestock category (beef: p = 0.0109).The herd size of dairy farms was significantly higher than that of beef farms  animals that underwent antibiotic treatment during the observation periods, almost 12,000 antibiotic therapy courses were recorded .The percentage distribution of treated animals per individual reason for treatment on each farm type is shown in Beef and dairy cattle were treated for different reasons. On beef farms, the principal causes of antibiotic treatments were respiratory  and gastrointestinal diseases ; septicemia , reproductive diseases , and locomotory diseases  were less common. Eighty-two percent of treated beef cattle received an injectable drug (1802/2192).In dairy herds, 41% of antimicrobial therapy cases were related to udder health management; these included mastitis  and the dry period . Respiratory , reproductive , and gastrointestinal diseases  were also reported as treatment causes. Fifty percent of dairy cows being treated (4828) were subjected to systemic treatment administration; udder health disorders accounted for 871 of these cases (18%). Treatments to which no reason was assigned accounted for 21.8% on beef farms (478/2192) and 18.8% on dairy farms (1833/9742).vet)/year and is presented per livestock specialization and by administration route in The overall average antibiotic consumption was expressed in defined course doses . The intrauterine route was the second most popular choice of antibiotic administration (42.7 × 10−3 DCDvet/year), followed by oral preparations (6.6 × 10−3 DCDvet/year), and intramammary administration (1.3 × 10−3 DCDvet/year).Regarding beef farms, on average 280.1 × 10−3 DCDvet/year of antibiotic consumption was registered in total; intramammary treatments accounted for more than 50% of this mean (349.5 × 10−3 DCDvet/year for lactating cow treatments and 185.3 × 10−3 DCDvet/year for dry cow treatments). The rest of the antibiotics were administered chiefly systemically , while intrauterine pessaries accounted for 60.4 × 10−3 DCDvet/year.In dairy herds, a mean of 1034.1 × 10vet/year) via any administration route on beef and dairy farms are shown in Boxplots of the total annual antibiotic consumption (DCDp < 0.0001).A Wilcoxon rank sum test revealed a highly significant difference between the two breeding categories in terms of relative overall antimicrobial usage (vet)/year and DCDvet/year and are presented per antimicrobial class in Data on the average consumption via parenteral, oral, and intrauterine administration routes for beef and dairy farms were expressed in defined daily doses  for each administration route, per active ingredient (AI) and antimicrobial class (C) or combination of substances (SC) and combination of classes (CC) are available in −3 DDDvet/year was administered via the parenteral route on beef farms. At least one injectable drug was consumed by 52 farms over the course of the observation year (The results obtained showed that a mean of 756.6 × 10ion year .−3 DDDvet/year), penicillins (157.9 × 10−3 DDDvet/year), and aminoglycosides (120.3 × 10−3 DDDvet/year). Penicillins were the first-choice antibiotic class in terms of farms (41/54); apart from these, aminoglycosides and fluoroquinolones were the only two other classes selected by at least half of the sample   .−3 DDDvet/year), fluoroquinolones (294.5 × 10−3 DDDvet/year), and penicillins (247.9 × 10−3 DDDvet/year); moreover, tetracyclines, macrolides, and aminoglycosides accounted for more than 100 × 10−3 DDDvet/year each   . On the ctively) .The use of polymyxins (colistin) was registered only in few farms (five beef and five dairy farms) and was found only in combination with ampicillin.−3 DDDvet/year).Boxplots of the annual antibiotic consumption via the parenteral route per individual antibiotic class and with regard to beef and dairy farms are shown in p < 0.0001), fluoroquinolones (p < 0.0001), and tetracyclines (p = 0.0004), but not for the other antibiotic classes  and 32% of the dairy farms (15/47) (As can be gathered from  (15/47) .−3 DDDvet/year and 29.2 × 10−3 DDDvet/year, 9.4 × 10−3 DDDvet/year and 27.4 × 10−3 DDDvet/year, and 5.6 × 10−3 DDDvet/year and 33.4 × 10−3 DDDvet /year, respectively)  .Oral administrations of polymyxins (colistin) were recorded only on two dairy registers and were used exclusively in combination with ampicillin.vet/year administered, intrauterine pessaries accounted for 6% and 13% of the treatment courses on beef and dairy farms, respectively . The mean of cephalosporins IV per se was 235.8 × 10−3 DDDvet/year and this class had the highest consumption peak.Lactating cows were primarily given cephalosporins I or penicillins with clavulanic acid ; taking into account all combinations, these classes represented altogether more than half of the total DDD−3 DCDvet/year, with the most represented classes being cephalosporins I  and penicillins  (Dry cow therapies registered on average 185.3 × 10et/year) .−3 DCDvet/year, representing 20% of the total average consumption. On dairy farms, almost two-thirds of the total therapy courses contained beta-lactams .A comparison of the total amount of beta-lactams with other molecules per administration route and breeding type is shown in vet/year consumed per breeding type, antibiotic category, and administration route are shown in According to the WHO classification of molecules with the highest priority , the dis−3 DCDvet/year, were almost exclusively administered via the parenteral route, and accounted for approximately half of the total antibiotic consumption ; these were mainly injectable drugs (251.9 × 10−3 DCDvet/year) or intramammary therapies (123.6 × 10−3 DCDvet/year)  .vet/year via non-intramammary routes in both livestock categories.On average, HPCIAs accounted for approximately 50% of the total DCDp = 0.0038), beta-lactam consumption (p < 0.0001), and HPCIA consumption (p = 0.0033); these results applied to non-intramammary therapies  will allow the analysis of antibiotic consumption at several levels, e.g., for a single animal category or for the cause of treatment. This system is being introduced nationwide in an effort to overcome geographical differences. The data obtained will allow for the comparison of farms and identification of indicators for antibiotics prescription and use. Preventive actions will be implemented, to promote more judicious and responsible antibiotic prescribing and in the long term to decrease AMR of animal pathogens. In the veterinary sector, antimicrobial use is often described at a wholesale level ,16,17. DTo our knowledge, this is the first study in Italy describing the use of antimicrobials on cattle farms with the use of paper-based registers as the sole source of information.The choice of collecting antimicrobial consumption data that were self-reported by farmers and/or by on-farm veterinarians involved certain difficulties. Unwritten or illegible information on paper registers was impossible to recover and meant excluding from the study the relative individual treatment being recorded. Additionally, the non-usability of further information on the animals being treated, owing to the heterogeneity of the compilation methods adopted among registers, did not allow analyses at the age category level. Nevertheless, this was an observational study based on already available data, thus offering a retrospective evaluation of antimicrobials actually administered on farms.As in previous studies ,19,20, tvet) emphasize the contribution of intramammary therapies, which are calculated in a defined number of injections per cow and not per kg of liveweight. Moreover, even within the intramammary route, the balance can vary between the lactating cow and dry cow treatments (DCTs), depending on the specific dose-based metric chosen. For instance, some authors [vet), and three tubes correspond to one therapy cycle (1 DCDvet) for a single infected teat. On the other hand, DCTs typically consist of a one-shot treatment for the whole udder (four tubes). Thus, doses per day cannot actually be defined, whereas in terms of complete therapy courses, four tubes used during the dry cow period count as one course. This is the reason why only DCDvet were assigned by the EMA to DCTs. Therefore, DCDvet is the correct metric to use for fair comparisons.The absence of a single internationally recognized method to quantify antimicrobial consumption makes direct comparisons with other studies and among different countries or production sectors hard, as has been described in other studies ,22,23. T authors  employedvet/DCDvet values, the use of some active ingredients (AIs), although observed, was not included in the antimicrobial use calculations. Even though the use of these substances was not significant, an upload of the EMA’s reference tables of DDDvet/DCDvet values is recommended in order to include all antimicrobial formulations authorized in Italy.Owing to the lack of the specific DDDThe following point-by-point discussion of the obtained results provides a complete overview of the quantitative and qualitative analyses performed in this study. Existing literature will be included to compare data, to draw parallels between the dairy and beef sectors at both national and international levels, and to support considerations on the use of beta-lactams and HPCIAs.As expected, data on the treatment reasons varied depending on the livestock specialization. In beef farms, as has already been reported by Brault , respiraThe parenteral route of administration was used by all dairy farms and the great majority of beef farms; in contrast, the oral and intrauterine routes were used only by 20–30% of the farms.vet administered parenterally was almost 10 and 30 times greater than the ones registered for the intrauterine and oral routes. On dairy farms, this route of administration was second only to the intramammary route.On beef farms, the absolute number of DDDCompared to mass medication, the parenteral route is associated with a reduced risk of treating healthy animals and of antibiotic sub-dosing and it is characterized by a rapid onset of action and good bioavailability ,33. PareThe popularity of the parenteral route described in our study is not surprising; in the bovine sector, antibiotics are not usually administered via the oral route, either to avoid a disruption of the ruminal microbiota or to prevent drug inactivation by the ruminal flora . Calves https://www.vetinfo.it/j6_prontuario/public/).The ranking of parenteral antibiotics showed that penicillins, macrolides, aminoglycosides, and fluoroquinolones were used on the greatest number of farms . On the The high proportion of farms administering parenteral penicillins is not surprising, as this antibiotic class ranks second for injection preparation in Italy, according to the percentage of sales reported by EMA .vet was compared in our sample, macrolides and third-generation cephalosporins, two HPCIAs, were the most important antibiotic classes consumed in beef and dairy farms, respectively. This confirms the relevance of parenteral administration in terms of antibiotic consumption.In contrast, when the number of parenteral DDDThe principal administration route for the high percentage of antibiotics prescribed for udder health was the intramammary one. This finding corroborates the results of other studies ,25,26,37vet, the intramammary therapies for lactating cows were almost twice as many as those for dry cows. This result is in contrast with what has been reported in other studies, where the amount of antibiotics used for DCT was higher than the one used for intramammary therapy [The results of the present study highlighted that at least one DCT was recorded for almost all dairy farms, however, in terms of DCD therapy ,27; as w therapy , a highe therapy . In thisThe most represented classes were cephalosporins IV and I for lactating cows, while penicillins and cephalosporins I were preferred to cephalosporins IV for DCTs. These results could be compared with those of a study conducted in Pennsylvania where cephalosporins VI and I were the most chosen classes for mastitis, and cephalosporins I and penicillin were most frequently chosen for DCT .The choice of antimicrobial classes for DCT was in line with the suggestions of the national guidelines on the prudent use of first-choice antimicrobials on dairy farms . On the The correct selection of antibiotics for DCT, aimed at managing subclinical mastitis, could probably be attributed to the minor concern caused compared to lactating cows with clinical symptoms of mastitis where efficacy and withdrawal period influence the choice of antibiotics.Except for potentiated sulfonamides and rifamycins for lactating cow therapies and DCTs, respectively, the consumption of which was minimal, the remaining used class were beta-lactams. In fact, this was the most represented category of intramammary formulations on the market, considering their half-life, bioavailability, spectrum of action, and suitability to treat intramammary infections.Macrolides and tetracyclines were not used; these are bacteriostatic antibiotics and are not suggested for intramammary treatments, as not only phagocytosis is reduced in the mammary gland, but also milk interferes with their action .Amphenicols, a first-choice antimicrobial class , were noIn this study, a high proportion of farms used antibiotics classified as HPCIAs. From 2010 to 2017, there has been a decrease in the overall consumption of antibiotics in the veterinary sector in Italy . HoweverIn our study, HPCIAs were generally administered via two routes; the parenteral route was used on both dairy and beef farms and the intramammary route was used only on dairy farms.vet on dairy farms was almost the same as the overall HPCIA consumption on beef farms, thereby confirming the importance of antibiotic consumption for udder health.The consumption of HPCIAs via the intramammary route in terms of DCDAs stated above, macrolides and third-generation cephalosporins, two HPCIAs, were the most important antibiotic classes administered via the parenteral route in beef and dairy farms, respectively. The use of macrolides is usually associated with the treatment of bovine respiratory disease (BRD) in cattle ,39. Howevet, fluoroquinolones were used via the parenteral route, ranking second on dairy farms and fourth on beef farms. The use of this antibiotic class is of concern, as it has been discontinued in many European countries in the veterinary sector [In terms of DDDy sector ; accordiy sector . Colistiy sector ,41. Consy sector .Overall, a high variation in the parenteral administration of HPCIAs, was observed in our sample, as is shown in In our study, we observed that the oral consumption of antibiotics was lower on beef than on dairy farms. It should be noted that on dairy farms, the number of young calves is usually higher than on beef farms. In dairy herds, calves are separated from their mothers and kept in single cages for the first weeks of their lives; this allows frequent health checks and prompt therapy if a disease occurs. By contrast, on beef farms located in the Umbria region, calves are usually nursed by their mothers. These different management practices, which make oral administration easier on dairy farms, may justify our results. The same trend was observed for the parenteral route; the consumption registered on dairy farms was twice as much as that registered on beef farms. The high consumption of antibiotics on dairy farms has been attributed to udder-related problems by some authors ,30. In oThe increased antibiotic consumption trend on dairy farms was further supported by data on beta-lactams and HPCIAs. Overall, the consumption of beta-lactams was 10 times higher on dairy than on beef farms, whereas the consumption of other antibiotics was comparable . Even wiThe study population consisted of a sample of cattle farms recruited from September 2017 to April 2018, according to the following criteria: voluntary participation to Measure 14 of the Rural Development Program -Umbria 2014–2020 and herd size of at least 50 livestock units.The sampled farms were categorized according to their management and production target into either dairy or beef farms.The enrolled farmers signed an informed consent form approving the use of data from their farms for the purposes of this research. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by IZSUM.Data on antimicrobial consumption were extracted from paper-based registers, where according to the law ,10,11 alThe structure of an on-farm paper-based register is described with respect to each treatment in A lack of data homogeneity and a non-negligible percentage of missing data across different registers led to the exclusion of some variables from the dataset, e.g., the ID/s and the age category of the treated animal/s; unwritten or illegible exact amounts of medication, imposed the exclusion of a few records  from the dataset. Therefore, apart from quantitative details on each antibiotic administration, the information actually employed in this study concerned the number of treated animals and the reason of treatment .To provide a rough estimate of the total recorded treatment courses and evaluate the treatment causes over a year-long period within each livestock specialization, the total number of cattle that were subjected to antibiotic treatment was calculated without identifying the animal; thus, an animal was counted as many times as it received at least one antibiotic administration.Given the considerable number of diagnoses, all reported treatment causes were grouped by the body system involved  or the relevant category . Less common causes  were merged into “others” see .vet and DCDvet for antimicrobial veterinary medicinal products. These metrics were established within the context of the ESVAC project in order to provide technical units of measurement that take into account dosing substance, and pharmaceutical formulation differences among species [Data on consumption were analyzed using the European Medicine Agency’s dose-based metrics; DDD species .First, each recorded administration was expressed as the number of minimal dosage units ; then, it was converted into mass of active ingredients (mg) according to the qualitative and quantitative composition of the specific drug.vet administered yearly per farm was calculated for each AI as follows:With respect to the injectable medicines (P) and the oral preparations (O), the number of DDDveweight ,25,26. Tvet/year administered via the parenteral or the oral route.Analogous were the computations of the nDCDvet administered per year and farm was calculated for each combination of active ingredients (CAI) as follows:vet value was the defined number of intramammary injections administered daily per teat or the defined number of intrauterine devices administered daily per animal [vet instead of the DDDvet values, computations of nDCDvet/year  were performed in a similar manner (see Equation (2)).With regard to intramammary products for lactating cows (IM-LC) and intrauterine treatments (IUT), the number of DDDr animal . By emplvet values have been allocated to DCTs by the EMA, the analysis of DCTs only included nDCDvet/year, with the relative computation being analogous to the nDCDvet/year , with the DCDvet value being the defined number of intramammary injections administered per udder for a therapy cycle.As no DDDvet/DCDvet values, the use of some AIs, although observed, was not included in DDDvet/DCDvet calculations. Specifically, parenteral therapies containing one of the following AIs were recorded: thiamphenicol, sulfamonomethoxine, dicloxacillin (second AI after ampicillin), sulfamerazine (third AI after sulfadimidine and sulfathiazole); the oral use of procaine benzylpenicillin (second AI after chlortetracycline) was also recorded , local treatments of dermatitis or reproductive disorders were not included in this analysis  code (combination of active substances), the antimicrobial use was presented for each administration route by antimicrobial class or by a combination of antimicrobial classes accordingly.Taking into account the fact that the DDDvet/year. Assessments of overall antimicrobial consumption per livestock category were conducted by nDCDFurther specific evaluations were also carried out for beta-lactams and HPCIAs. Beta-lactams included cephalosporins and penicillins with or without clavulanic acid. According to the WHO classification , HPCIAs ® 11.2 statistical software . A map representing the territorial distribution of farms was edited through Qgis 2.18 (https://www.qgis.org/it/site/). Normality of data distributions were checked with the use of the Shapiro-Wilk test. The Student’s t-test was used to compare statistically the sizes of the beef and dairy herds. With respect to each livestock category, the same test was performed to compare the herd sizes in the sample with those in the regional subpopulation of cattle farms with at least 50 animals. Then, the Wilcoxon rank sum test was employed in order to assess statistical differences in consumption between the two livestock categories. The significance level was set at α = 0.05. Bivariate statistical analyses were conducted using Stata® (StataCorp LP).Descriptive statistics were performed using Microsoft Excel 2013 (Microsoft Corporation) and StataThe results presented and discussed in this paper constitute the first qualitative and quantitative analysis of the actual antimicrobial usage recorded by paper-based registers on sample dairy and beef farms located in the Umbria region, Italy. These results will serve as a stepping stone for further analyses based on more advanced digital prescription registers being developed in Italy and in other countries.The lack of a single universally recognized standardized method for analyses presented a limitation in the interpretation and discussion of the data. As has already been stated in other papers, shared international standards of data collection and monitoring systems will be crucial in achieving the proposed objectives to reduce AMR worldwide.vet values is recommended, taking into account the molecules authorized in the country level.An update of the reference tables of the DDD/DCDThe results of this study highlighted how dairy production was associated with a higher risk of antimicrobial use. This is reasonable, taking into consideration the higher fragility of dairy cattle, owing to a shorter productive life and higher specialization. In addition, more intensive management systems that were correlated with herd size in the literature could have been contributing factors. As expected, udder health was confirmed as the principal cause of antibiotic treatment, therefore a crucial factor to manage in order to rationalize antibiotic consumption.The role of HPCIAs cannot be overlooked, as their use has already been limited or strongly reduced in different countries. Within the parenteral route, the most frequently used method of drug administration, fluoroquinolones represented the second and fourth most frequent antibiotic class used in dairy and beef farms, respectively. Thus, the results of this study highlight the necessity to strengthen the already existing stewardship programs at all levels and involve all potential stakeholders in an effective antimicrobial resistance reduction plan.


Future trending topics will concern nanomedicine challenges and technology-related applications, with a special attention toward the orientation and ordering of mesophase-separated morphologies.In this systematic review, a total of 45,143 publications on block copolymers, issued between 1952 and 2019, are analyzed in terms of number, source, language, institution, country, keywords, and block copolymer type, to find out their evolution and predict research trends. The number of publications devoted to block copolymers has been growing for over six decades, maintaining a consistent level throughout the last few years. In their majority, documents came out of the United States, although more recently, Chinese institutions are those displaying the largest production. Keywords analysis indicated that one-third of the publications concerned synthesis, around 20% explored self-assembly and morphological aspects, and another 20% referred to block copolymer applications in solution. In particular, 2019 confirmed the expansion of studies related to drug delivery, and in minor extent, to a deeper view of self-assembling. Styrene–butadiene–styrene block copolymer was the most popular in studies covering both basic and industrially oriented aspects. Other highly investigated copolymers are PEO- Block copolymers are a class of polymers formed by two or more homopolymer fragments joined together by covalent bonds. Due to their usual reciprocal insolubility, the chemically different blocks easily segregate to form intermolecular phase-separated morphologies either at the solid state or in solution. The size, the periodicity in the nanoscale, the ordering, and the orientation of such microphases in the solid state may, in principle, be controlled by fine-tuning block molecular weights, molecular weight distribution, composition, the interaction parameters between block components, and also the conditions of self-assembly . For bloAll these, nowadays, apparently basic considerations on block copolymers are the result of decades of investigations and publications, which also had the effect to enable their use as a tool for nanomaterial fabrication (after some processing or as templates), model for behavioral studies, vehicle for drug delivery, additive in photovoltaic cells, precursor for nanocarbons, industrial compatibilizing agent, and many other potential applications. For an exhaustive view of such fundamental or applicative topics, the reader will be referred to specialized references throughout this work or may refer to recently published reviews ,5,6.This systematic review aims to analyze most of the bibliographic data concerning the worldwide block copolymer research, in terms of number of publications, source, language, institution, country, keywords, and block copolymer type. Using tools and methodologies typically applied in bibliometry, noteworthy conclusions may be drawn, from the identification of the main countries and institutions working in the field to the evaluation of milestones and specific topics and their evolution. That is with the presumption of being able to understand where the research field comes from, how the actual situation is, and predict where it is going. Keeping in mind the title of a famous talk by Feynman , the finA complete search from the Elsevier Scopus abstract and citation database was carried out using the search query [KEY(“block copolymer*”) OR TITLE files and conveniently processed by Microsoft Excel. Alternatively, any other spreadsheet could be used for clean up and transformation. Data are shown as bar, pie, or line charts, as well as area cartogram, bibliometric networks, or word clouds. In particular, geography data were obtained from the Wikipedia public domain through Microsoft Excel Office 365. Bibliometric networks, namely communities of countries and associations, were visualized using the VOSviewer version 1.6.14  on the bThe evolution of the number of publications on block copolymers from the very beginning, with the first publication directly mentioning block copolymer synthesis in 1952  to 2019 Most publications on block copolymers are articles (85.3%) or conference papers (10.3%) . In thirIn order to discuss the impact of publications, their citations are briefly analyzed. To date , the documents dealing with block copolymers have an h-index of 343, with 41 articles or reviews having more than 1000 citations. The three most influent publications have ca. 10,000 , ca. 330All the top 15 institutions , each acThe apparent leading position of the United States’ investigations is confirmed by the analysis by country , where tMacromolecules [Langmuir or Soft Matter, conveyed the interest in block copolymers toward a better comprehension of interface phenomena [Polymer, Journal of Polymer Science Part A: Polymer Chemistry, Macromolecular Chemistry and Physics, Macromolecular Rapid Communications and European Polymer Journal showed trends similar to Macromolecules, although with less emphasized changes. During the last years, top positions were also occupied by recently established journals, such as Polymer Chemistry and the open access journal Polymers. The evolution of the 10 journals that published the highest number of articles on block copolymers over the last 30 years, and those standing in the top 5 positions in 2019 is visible in olecules ,29,35,41henomena  and matehenomena , respectNature (21 documents) [Science (43) [Journal of the American Chemical Society (463) [Angewandte Chemie (357) [Nature Materials (40) [Progress in Polymer Science (109) [Amongst the most influential journals that published a quantitatively small but qualitatively important series of articles, it is worth citing the multidisciplinary journals cuments) ,40,44 annce (43) ,26, the ty 463)  and Angeie (357) ,46, and 3  and Anals (40) ,36,47 ance (109) ,48.The analysis of keywords was carried out by discarding all those that were obvious, such as ‘block copolymer’, ‘block copolymers’, ‘copolymer’, ‘polymer’, or ‘article’, and gathering together those that are very similar to each other in a single unifying term. As an example, the keyword ‘synthesis’ also includes ‘copolymerization’, ‘polymerization’, and ‘synthesis ’. The keyword ‘nanoparticles’ concerned both the direct use of block copolymers for controlling metal nanoparticle fabrication and especially their use for the formation of polymeric nanoparticles in solution, which are intended as micelles, nanospheres, nanocapsules, and polymersomes. Therefore, ‘nanoparticles’ and ‘micelles’ were considered together and jointly account for 20.4% of publications, whereas the use of block copolymers for ‘drug delivery’ is by far the most investigated application (around 13%). In addition, one of the keywords of the last group formed by the two most common class of copolymers as keywords, namely ‘polyethylene oxides’ (20.0%), mostly refers to their application in solutions. Finally, the ‘polystyrene’-based copolymers include investigations on self-assembly and applications either in solid state or in solution and appear in almost 14% of documents. A first qualitative attempt to follow the change in the focus of investigations over almost 70 years is visualized by the word clouds of the top 20 keywords in the periods 1952–1984, 1998–1999, 2009, and 2019 , each ofblock–poly(propylene oxide)–block–poly(ethylene oxide) (PEO–b–PPO–b–PEO) copolymers, and especially for the materials traded as Pluronic©, is mostly related to their biocompatibility and use as vehicles for diagnostic and therapeutic agents [Styrene–butadiene–styrene (SBS) block copolymer, one of the few industrially available, appears as the most used over the period, both in investigations covering basic aspects  and in ic agents , and in c agents . From 20c agents  and polyc agents . Also thN-isopropylacrylamide) (PNIPAM), poly(3-hexylthiophene) (P3HT), and polyacrylonitrile (PAN), especially in publications related to their capacity to respond to temperature stimuli (30–50 publications per year since 2010) [Three other diblock copolymers, such as those based on PS-PMMA , PS–PEO,ce 2010) , in photce 2010) , or as pce 2010) , respect(1)After the first 20 years with just a few publications per year on block copolymers, and then a slow increase of their number until 1992, the interest grew rapidly in the following decades, reaching a maximum of ca. 2300 publications in 2012. The years between 2013 and 2019, with a constant production of around 2000 documents per year, suggests the achievement of a maturity level .(2)As common in many fields, original articles were by far the most common type of publications (85.3%) , and Eng(3)The top 15 institutions are mainly from the United States, China and Japan; apart from some large national agencies, the Tokyo Institute of Technologies was the most productive institution . Only a (4)Macromolecules is the journal that published the highest number of block copolymer-related documents and continuously occupied the first position in the last 30 years The analysis of the top 15 keywords indicated that approximately one-third of publications concerned synthesis  , around The changes in the focus of block copolymer research could be envisaged from the evolution of keywords (word clouds in (6)The most representative block copolymer types found in publications since 2000 range from the most commonly used SBS to the peculiar block copolymers based on PNIPAM (thermoresponsive systems), P3HT (application in photovoltaics), and PAN (nanostructured carbon precursor), through the commercial Pluronic© family and other amphiphilic copolymers as those based on PCL and PLA (applications as delivery vehicles) . The sucAnalyzing the bibliometric data on block copolymer research worldwide, from 1952 to 2019, the following conclusions may be drawn:With respect to the initial Feynman-like question on the perspectives for block copolymer research, in our opinion, future trending topics will concern nanomedicine challenges and technology-related applications, with a special role played by the fine-tuning of processing conditions to control the orientation and ordering of mesophase-separated morphologies, to establish complex hierarchical features. A deep look into current investigations makes us speculate on the potential held by some hot papers. In particular, we would like to envisage a bright future for applicative challenges concerning the integration of specific block copolymers into large-scale manufacturing, namely in (i) all-polymer solar cells by fully conjugated donor–acceptor block copolymers , (ii) so


The overuse of antibiotics is a serious public health problem in China, causing a high rate of antimicrobial resistance. This study identified the trends of antibiotic consumption in China to provide evidence for further intervention.The six-year surveillance data on antibiotic sales from 2012 to 2017, which served as a proxy for consumption, were collected from 39 public health care facilities in Shandong province, including three tertiary hospitals, six secondary hospitals, and 30 primary health centers. Based on the Anatomical Therapeutic Chemical (ATC)/DDD methodology, antibiotic consumption was formulated in defined daily doses (DDD) per 1,000 inhabitants per day (DID).The total antibiotic consumption among all health care settings increased from 16.07 DID in 2012 to a peak of 17.44 DID in 2015 and then decreased to 11.35 DID in 2017 with a 34.90% reduction. J01C , the most frequently used antibiotic class, accounted for 36.32% of the total DID. Consumption of carbapenems increased from 0.029 DID in 2012 to 0.08 DID in 2017. Parenteral antibiotics accounted for nearly 40% of the total consumption. Compared with the 2012 figures, the 2017 consumption showed a small increase in hospital sector that was compensated by the decrease in community care.A substantial reduction in total antibiotic consumption was observed in China from 2012 to 2017. However, the extensive consumption of broad-spectrum antimicrobials, high proportion of parenteral antibiotic use, and increased use of last-resort antibiotics attracted public health concerns. Antimicrobial resistance (AMR) driven by antibiotic consumption is a growing threat to global public health . China iAdministrative Regulations on the Clinical Application of Antimicrobial Agents, which is regarded as the strictest control on antibiotic prescription to date  in the same year was CNY 7267.82 billion . About 4The 39 public health care facilities in this study were sampled hierarchically from three cities based on geographical and socio-economic factors. The breakdown was three tertiary hospitals, six secondary hospitals, and 30 PHCs. Data were derived from the drug information management system at each facility. The collected information contained generic name, unit strength, pack size, quantity of packs, route of administration, price, amount of sales, and manufacturer information.Microsoft Excel 2010 was used for data management and analysis. Sales data were coded in accordance with Anatomical Therapeutic and Chemical (ATC) classification and measured by defined daily dose (DDD) based on recommendations of the WHO Collaborating Center for Drug Statistic Methodology . RecordsIn the ATC classification system, drugs are classified in groups at five different levels. Within the ATC subgroup J01, 98 unique chemical substance names were identified in single or combination antibiotics. They were first aggregated into 24 ATC-4 classes and then into 9 ATC-3 groups. We calculated the DDDs for systemic antibiotics (J01) and its subsequent subgroups, such as penicillin (J01C) and penicillin with extended spectrum (J01CA). A full list of subgroups is displayed in The antibiotic sales were finally converted into DDD per 1,000 inhabitants per day (DID) at the level of the active substance. As there was no direct access to the exact number of population covered by the sample facilities, we calculated the weighted population as a proxy based on the following equation. This calculation process was under two assumptions: no significant difference existed in (1) the distribution of the sample facilities and (2) the population distribution covered by the sample facilities .Y: Covered inhabitants in a given year;Pi: Total population in a given year;ni: Number of sample facilities;Ni: Number of total facilities.We collected the relevant census data for calculating inhabitants from the Shandong Health Statistics Yearbook  and ShanThe total consumption of antibiotics among all health care settings in Shandong increased from 16.07 DID in 2012 to a peak of 17.44 DID in 2015 and then decreased to 11.35 DID in 2017, with a 34.90% reduction , accounting for 36.32% of total consumption, followed by J01D , J01F  and J01M .During the study period, penicillin consumption (J01C) was volatile, as illustrated in Overall, the use of cephalosporins (J01D) declined over the years, from a peak of 6.05 DID in 2013 to 3.42 DID in 2017  consumption from 2.63 DID in 2013 to 1.66DID in 2017. Macrolides and lincosamides accounted for 83.13% and 16.87% of the total J01F consumption in 2017, respectively. The consumption of quinolone antibacterials (J01M) started at 2.07 DID in 2012, increased to 2.96 DID in 2015, and then decreased to 1.33 DID in 2017. Fluoroquinolones (J01MA) were the most commonly used quinolone products in Shandong, accounting for 72.93% of the total consumption of quinolones.The consumption of carbapenems increased steadily between 2012 and 2017, from 0.029 to 0.08 DID, whereas that of glycopeptides remained stable. These two classes of antibiotics were only used in hospitals  . Over thIn addition, a comprehensive reform of public hospitals has been carried out nationwide since 2015 . The corPenicillin was found to be the most consumed antibiotic in this study. This is in line with the results found in Europe and the United States . HoweverThe most used antibiotic agent was amoxicillin, followed by amoxicillin and beta-lactamase inhibitor, levofloxacin, azithromycin, and benzylpenicillin. These results are comparable to those of a study conducted in 48 primary health care facilities sampled from six provinces in China  and consFindings in this study showed a declining antibiotic use. This may be partly attributed to the fact that antibiotics are forced into three categories based on doctors’ prescription rights , which was part of the antibiotic stewardship campaign in 2012 . This meThe use of carbapenems and glycopeptides, which are often regarded as the last-line treatment for multidrug-resistant bacteria, remains at a very low level in Shandong, because their use is highly restricted and requires pre-authorization. Notably, however, carbapenems consumption more than doubled during the study period. The surveys in other regions in China had a similar finding and indicated that imipenem, meropenem, and biapenem were the mainly used agents . Its incSeveral studies have indicated a very high level of antibiotics consumption in primary health care facilities in China . In thisAlthough there has been a decline of 3.49 DID since 2012, the parenteral antibiotics presented nearly 40% of total consumption and more than 80% of total expenditure in 2017. The high prevalence of antibiotics and injections may be related to the inertia in a physician’s practice and high demands of patients . In manyThe importance of this study lies providing up-to-date evidence on antibiotics consumption in China by different levels of health care facilities in Shandong province. Valuable information could be provided to national and provincial governments for developing more clearly targeted antibiotic stewardship policies. The limitations of this study are as follows. First, the antibiotic consumption data were only collected from 39 public health care institutions. Total consumption of antibiotics in Shandong province might be under-estimated. However, the trends and patterns of antibiotic use can be correctly reflected. Second, the population denominator used in this study did not consider patient flow between regions; this study may have underestimated antibiotic consumption. Finally, this study analyzed antibiotic sales data, which do not directly reflect the actual use of medicines and types of infections requiring antibiotics. The appropriateness of antibiotic prescribing practices was also not evaluated. Although the method used is internationally accepted, the resulting DDD and DID data cannot be followed back to the demand of the individual patient. In the future, prescription analysis and AMR monitoring must be combined to assess antibiotic consumption based on population, which can inform better the decision-making and improve clinical significance.This study revealed a substantial decline in antibiotic consumption in China in 2012-2017, and a consistent preference for penicillins, cephalosporins, macrolides, and fluoroquinolones. The large consumption of broad-spectrum antimicrobials, high proportion of parenteral antibiotic use, and increased use of last-resort antibiotics attracted public health concerns. Using antibiotics in secondary and tertiary hospitals may be the key to controlling medical costs. Continued efforts are needed to obtain more evidence to inform policies and thereby optimize antibiotic prescribing and minimize antibiotic resistance.All datasets generated for this study are included in the article/supplementary material.YS and TZ contributed to the conception and design of the study. YS organized the database. YS, ZH, and KS conducted the statistical analysis. YS finished the first draft of the manuscript. All authors made contributions to manuscript revision and read and approved the submitted version.This study was funded by the National Natural Science Foundation of China (grant number 71503149), the Innovation Project of Shandong Academy of Medical Sciences, and Academic promotion programme of Shandong First Medical University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Additive manufacturing with cement-based materials needs sound approaches for the direct, seamless integration of reinforcement into structural and non-structural elements during their fabrication. Mineral-impregnated Carbon-Fibre (MCF) composites represent a new type of non-corrosive reinforcement that offers great potential in this regard. MCF not only exhibits high performance with respect to its mechanical characteristics and durability, but it also can be processed and shaped easily in the fresh state and, what is more, automated. This article describes different concepts for the continuous, fully automated integration of MCF reinforcement into 3D concrete printing based on layered extrusion. Moreover, for one of the approaches presented and discussed, namely 3D concrete printing with MCF supply from a continuous, stationary impregnation line and deposition of MCF between concrete filaments, a feasibility study was performed using a gantry 3D printer. Small-scale walls were printed and eventually used for the production of specimens for mechanical testing. Three-point bend tests performed on two different beam geometries showed a significant enhancement of both flexural strength and, more especially, deformability of the specimens reinforced with MCF in comparison to the specimens made of plain concrete.  In recent years, Digital Concrete Construction (DCC) has increasingly attracted the attention of the construction industry and research groups. Several pilot projects have already demonstrated the high potential of the new digital production technologies ,2,3. In As yet, the solutions frequently used suggest the discontinuous placement of steel bars between individual concrete layers  or printFew publications have addressed the integration of reinforcement directly into the 3D-printing process. The most straightforward approach is working with short, dispersed fibres so that the reinforcement is part of the composite material deposited by extrusion ,18,19,20Another approach is to equip the concrete printhead with a device that automatically places steel wire immediately in front of the nozzle. Then, a concrete filament that covers the wire is extruded through the nozzle ,23,24,25A promising alternative concept suggested by Marchment and Sanjayan  uses insThe article at hand describes a new approach formulated by this article’s first two authors and soon to be patented. Said approach promises to overcome the above-mentioned drawbacks and restrictions related to the use of steel cable or strips of textile while enabling both horizontal and vertical reinforcement of printed concrete elements. This technology builds on a novel composite, i.e., Mineral-impregnated Carbon-Fibre (MCF), developed in recent years at the Institute of Construction Materials of the TU Dresden ,28,29. TIn prior publications, the impregnation technology was presented, and the mechanical performance of this novel type of reinforcement was investigated ,28. In cThe implementation of MCF reinforcement directly into the additive manufacturing process requires sound solutions for the continuous impregnation of carbon roving, the transport/supply of the roving to the printhead, and finally the integration of the reinforcement into the concrete. Various processing techniques are applicable and are presented and discussed in this section. Note that the approaches suggested can be realised with different manipulators for moving the printhead. In the following, a gantry-based manipulator is shown as the base, but the technology can be used with other robotic systems as well. Note that gear dimensions are not provided in this article on purpose. Generally, the presented setups can be scaled to any size needed to meet the requirements of particular application scenarios.High-quality impregnation of the entire carbon-fibre roving with the mineral-based suspensions is a prerequisite for any processing technique presented in this article. This ensures sound interaction among the individual CF filaments and very good bonding of the yarn with the concrete matrix. Firstly, a carbon-fibre roving is uncoiled from the spool, levelled, and guided towards a suspension bath. At this stage, pre-treatments such as plasma modifications  or preweIn this approach, the production of MCF and the actual 3D concrete printing are two successive steps with a certain time gap in between. Although not integrated in a continuous process, this approach has some advantages. It excludes potential collisions of the guided MCF with the printhead moving along the path, thus reducing drastically the possibility of process errors. Furthermore, this approach offers the highest flexibility in respect of the use of various robotic systems and the printing of complex geometries.In the first step, MCF roving is produced as described in As shown in A further option is the impregnation of CF yarn(s) by means of a compact device attached directly to the printhead; see To integrate MCF reinforcement into printed concrete, two different ways are conceivable within the framework of extrusion-based 3D printing: (1) integration of the MCF directly into the printed concrete filament, and (2) deposition of the MCF onto a printed concrete filament and overprinting it with the subsequent concrete filament. Additional requirements within both approaches can be (1) the free start and stop of MCF supply and integration into concrete and (2) an adjustable degree of reinforcement. Obviously, these requirements increase the level of sophistication of the printing system but increase its flexibility and the overall efficiency in the purposeful use of the reinforcement. The integration of reinforcement directly into the concrete filament is an approach pursued recently in several research projects ,23,26. FIn the second approach, the MCF reinforcement is placed between two subsequently printed concrete layers. The first part of the setup is as described above. However, the tube channelling the MCF does not insert the yarn into the nozzle, but rather deposits it in front of the nozzle just before it passes the same spot. While the MCF reinforcement is being placed, the previously printed concrete filament acts as a substrate; then, the roving is immediately covered by the following printed concrete layer extruded by the printhead; see Concrete structures usually require reinforcements in all three spatial directions to deliver adequate load-carrying capacity in relevant loading scenarios. While no fully automated production of concrete elements reinforced in all three spatial directions has been realised so far, the suggested approaches of integrating MCF into 3D concrete printing do bring the additive technology close to this goal. The possibility of depositing reinforcement in the x–y plane is obvious for both approaches presented in The placement of reinforcement out of the horizontal plane is possible with both approaches while the limitations concerning the possibility of reinforcement overlaps remain in the case of integrating the MCF directly into the concrete filaments. On the one hand, inclined printing paths can be created, as already demonstrated for 3D printing without reinforcement, e.g., by purposely varying the thickness of concrete layers  or by dedeposition of one, two, or several rovings next to each other,bundling of several rovings into a thicker strand before integrating them into concrete,use of CF yarns with different fineness,variation of concrete filament dimensions, etc.Finally, it should be noted that the degree of reinforcement in printed concrete can be varied by:The particular concrete printer setups for implementing these approaches are under development at the TU Dresden.MCF reinforcement is a carbon yarn impregnated with a mineral-based suspension. In this study, SIGRAFIL C T50-4.4/255-E100 produced by SGL Group  and containing approximately 50,000 individual CF filaments was used. The composition of fine-grained concrete used for 3D printing in this investigation was adapted from the previous studies at the TU Dresden ,36,37. NMixing of the impregnating suspension was conducted in two steps. Firstly, all ingredients were premixed using a standard kitchen blender. Subsequently, a T 50 digital ULTRA-TURRAX® was used for two minutes at 7000 rpm to disperse all mineral fines completely. The impregnation process was executed according to The 3D printable concrete was produced using a single-shaft pan mixer. Solid materials were first mixed in the dry state for two minutes, followed by adding the fluid components. The initial rotational speed of 25 rpm was increased to 45 rpm after one minute and subsequently maintained for four minutes.3D concrete printing was performed with MCF supply from a continuous, stationary impregnation line, thus using the one-step process described in The gantry robot and all associated motors and sensors were controlled using a customized software utilizing LUA scripting embedded in a graphical user interface (GUI). Instructions for printing the specimens, i.e., coordinates, velocities, directions, and material flow parameters, were predefined in the scripts or manually controlled through the GUI.The MCF supply was arranged in such a way as to enable the nearly stress-free deposition of the reinforcement. For this purpose a roller-based feeder for the backside of the nozzle was developed; see Six days after the printing process, the MCF-reinforced concrete was prepared for mechanical testing. To assess the effectiveness of this novel reinforcement, beam specimens of two different geometries were sawn out of the printed walls: (1) dimensions of 120 mm × 40 mm × 40 mm, with the MCF reinforcement located centrally; see Three-point bending tests were performed at an age of 7 days using a path-controlled Zwick-Roell 1200 with a load cell of 600 kN; see t,MCF, compressive force in concrete Fc,C and the distance, or leverage, between the two forces. While the exact location of MCF reinforcement could be measured at the cracked cross-sections, the height of the compression zone was assumed to be 5% of the specimen height and the shape of compressive stress curve was assumed to be rectangular. The calculated forces Ft,MCF fell within the range of 2.2 to 4.6 kN, i.e., 3.1 kN on average, which corresponds to tensile stress in the carbon filaments of 1177 to 2462 MPa, i.e., 1659 MPa on average.To assess the effectiveness of the reinforcement, the tensile force at failure was estimated. In doing so, the bending moment in the cracked cross-section, the middle of the beam, was expressed by the tensile force in the MCF reinforcement FThe flexural performance of the specimens with a cross-section of 20 mm × 25 mm and the MCF located in the tension zone differed significantly to that of the specimens with a cross-section of 40 mm × 40 mm; see t,MCF could not be performed here.The observed final failure mode was delamination and spalling of the concrete cover, which was accompanied by a yarn pull-out; see The authors have proposed and critically discussed various approaches to implementing Mineral-impregnated Carbon-Fibre (MCF) reinforcement in additive manufacturing by layered extrusion. These approaches vary in the mode of MCF supply to the printhead and in the fashion in which the reinforcement is integrated into the printing process as such. While the individual options presented exhibit certain advantages and disadvantages depending on the application scenario, in total, they clearly demonstrate the high flexibility and adaptability of the new technology in its prospective employment in digital construction. However, much work needs to be done to implement the approaches into real manufacturing facilities. The first step towards this was done with a feasibility study reported in the article. The implemented approach was 3D concrete printing with MCF supply from a continuous, stationary impregnation line and deposition of the MCF between concrete filaments. A gantry robot was used as 3D printer to produce small-scale walls, from which specimens for mechanical testing were cut out. Three-point bend tests demonstrated a significant increase in flexural strength for the specimens reinforced with MCF in comparison to the specimens made of plain concrete. An even higher impact—enhancement by an order of magnitude—was observed with respect to the deformability of the beams. In ongoing research at the TU Dresden, further approaches will be realised, tested, and presented in respect of their feasibility and reinforcing effectiveness.In the follow-up research, several issues are to be addressed that were not in the focus of the present publication. The first aspect is the effect of the rheological properties of printable concrete on the integration process of MCF reinforcement and the bonding between MCF and concrete. Secondly, the production process of MCF itself and the mode of the MCF supply to the printhead need to be illuminated with respect to the resulting mechanical properties of the composite. In addition, the effect of the modalities of the printing process, e.g., time intervals between the layers, needs clarification. Next, deformation- and failure-behaviour should be more closely investigated for various loading modes such as bending, uniaxial tension, and shearing. Furthermore, the technology needs to be proved on complex geometries with three-dimensional reinforcement. Finally, the shrinkage behaviour and durability of MCF-reinforced printed concrete elements are to be studied.


In this review, we explore various aspects of SL function and highlight distinct areas of agriculture that may benefit from the use of synthetic SL analogues, and we identify possible bottlenecks. Our objective is to identify where the contributions of science and stakeholders are still needed to achieve harnessing the benefits of SLs for a sustainable agriculture of the near future.Strigolactones (SLs) represent a class of plant hormones that regulate developmental processes and play a role in the response of plants to various biotic and abiotic stresses. Both  Some of the synthetic SLs that have been produced so far include GR24 , which is mediated by the receptors D14 and KAI2, respectively, is dependent on the structural variations in the chiral carbon orientations at the junction of the BC and D‐rings  complex and targets the downstream repressors of karrikin and SLs signalling for degradation by ubiquitination  using SL‐biosynthesis mutants  treatment suggests that SL induces expression changes in fungal genes involved in respiration, production of chitin oligosaccharides, and transcriptional reprograming in the fungus . There are reports of increased nodulation of alfalfa inoculated with Sinorhizobium meliloti following SL (GR24) treatment , in principle, independent of auxin signals . There are also reports of their involvement in moderating auxin canalization from buds to the main stem through the internalization of the auxin export protein (PIN1), thereby maintaining apical dominance , probably due to the high cost of SL synthesis and the knowledge gap on any potential off‐target environmental risks and/or side‐effects from SL degradation products. Targeted research is therefore needed to understand the specificity of various SLs, the importance of time of application, the possible dose‐dependent environmental risks above or belowground, SL effects on soil microbiota at the community level beyond the effects on a single species or genus, and so on. Importantly, SLs should be properly acknowledged and emphasized in studies in which the effects of SLs are evident, just like with other hormones. Also, collaboration among all stakeholders  is inevitable for the eventual large‐scale application of SL products. Finally, regulatory advocacy and public awareness may be necessary to provide law makers, farmers, and the general public with the correct information about SLs on which to base their judgements.et al., et al., Striga‐resistant cv SRN‐39, which exudes a high orobanchol to 5‐deoxystrigol (5‐DS) ratio, recruits a different bacterial community than high 5‐DS/orobanchol‐exuding genotypes  using CRISPR/Cas9‐targeted mutation of the CCD8 SL‐biosynthesis gene  showed distinctive and differential gene‐expression levels in root tissues, and in response to exogenous auxin, respectively, suggesting that SL biosynthesis and function may be altered at the allelic level  has been used to demonstrate SL effects on plant–microbial interactions at the community level organisms at both the individual and community levels , CLA was reportedly converted directly to orobanchol through the action of an as‐yet‐unknown enzyme(s) , oxidation, epoxidation, ring cleavage, and lactonization steps have been postulated to result in the unique SL zealactone from CLA  influence the SL profile produced  and root‐knot nematode (Meloidogyne incognita), based on its cross‐talk with other hormones, like jasmonic acid, salicylic acid, and abscisic acid (ABA)  the soil microbiome by plants, other beneficial agricultural implementations of SLs in the soil are the control of parasitic weeds and defence against diseases. Parasitic weeds pose a serious threat to agriculture, considering the long viability of their seeds in the soil and their spread to other agricultural fields , Ha et al.  in Kalliola et al. (d10 and d17) and insensitive (d3) mutants had a high ABA accumulation in the shoot, resulting in drought tolerance, whereas the mutant, d27, was deficient in ABA and susceptible to drought  and its high expression in the SL‐deficient and insensitive mutants suggest that D27 may be involved in SL–ABA crosstalk. A further investigation of the aforementioned contrast using Arabidopsis single and double mutants of SL signalling (max2), ABA biosynthesis (aba2), and ABA guard cell signalling (ost1) in Kalliola et al. (MAX2‐mediated stress response. This ABA‐independent (MAX2‐mediated) stress response, however, may be a concerted role of the strigolactones–karrikins paralogous pathways, since both molecules signal through MAX2. Also, microarray analysis of the max2 mutant in Ha et al.  resulted in a transcriptional downregulation of SL biosynthesis genes. Such ABA regulation of SL biosynthesis may depend on the direction of the reversible conversion of all‐trans‐β‐carotene to 9‐cis‐β‐carotene by DWARF27, since both hormones share all‐trans‐β‐carotene as a common precursor  suggest that mutations in SL biosynthesis genes may contribute to ABA (in)sensitivity  and a three‐point deletion (NtCCD8B), and the exogenous ABA treatment of these mutants resulted in a three‐fold boost in the gene expression of NtCCD8B but not NtCCD8A. Interestingly, however, the gene expression of NtCCD8A under phosphate starvation (nutrient stress) was six‐fold higher than that of NtCCD8B, suggesting that allelic variations in SL biosynthesis genes may also influence response mechanisms to different stresses.Other reports re‐emphasize that the basis of the aforementioned ABA–SL crosstalk may be upstream of their respective biosynthesis pathways. Wang et al.  demonstr, et al.  differedet al., et al., et al. (WT) and SL‐depleted (SCSL) scions on to wild‐type (RSWT) and SL‐depleted (RSSL) root stocks to investigate drought responses  induced the expression of SL biosynthetic genes in the shoot, which was similarly observed in the SL‐depleted root stock grafted on wild‐type scion (SCWT/RSSL) under irrigated conditions. The graft combinations with wild‐type scions were more drought tolerant than the graft with SLs‐depleted scion. This suggests that local SLs availability in the shoot may be critical for drought tolerance response. In fact, Visentin et al. ‐overexpressing lines in Petunia hybrida, it was shown that an optimization of SL transport could release the feedback inhibition on SL biosynthesis and boost plant rooting properties  suppressed shoot branching in max2  locus, a maize homologue of BRC1  and tb1 mutant and the double mutant (tb1‐Zmccd8) revealed that although SLs may not completely regulate the TB1 gene in maize, they have significant additive effects on shoot branching and plant height under limited TB1 allele dosage , may be of higher agronomic value, and tiller number may be associated with the production of less SLs  to delay anthocyanin accumulation and ripening  between plant species may differentially affect microbial communities. Research efforts to identify the respective SL biosynthesis pathways in distinct plant species would aid our understanding of such effects. It is essential to understand the roles that plant developmental stage, root architecture, environmental conditions, soil types, and so on play in the interactions between SLs and microbial communities. For this, the fundamental biology of SLs needs to be understood; for instance, the downstream signalling components in plants and perception in microbes, and the mechanisms of SL molecular and physiological interactions. The use of targeted mutation techniques (like CRISPR/Cas9) and population‐based studies could unlock the genetic basis of SL effects and potential for heritability. Key for this improved understanding is the use of pure SLs instead of racemic mixtures in SL studies, as different isomers may signal through different pathways (Scaffidi In conclusion, many of the beneficial effects described herein are highly aligned with the sustainability criteria; for example: the better use of natural resources, such as soil nutrients; and the increase of crop resilience, particularly in relation to climate change threats. New SL‐based technologies will represent a substantial paradigm shift in the area of crop protection by moving from a classic pest/disease control approach to more of a crop enhancement effect that harnesses the soil potential.HJB, ADM and CS initiated the idea of the paper. EBA, TM and HJB reviewed the scientific literature. CS and ADM contributed on the industrial aspect of the manuscript.