Idiopathic pulmonary fibrosis (IPF) is a progressive disease with no curative pharmacological treatment. The most used animal model of IPF for anti-fibrotic drug screening is bleomycin (BLM)-induced lung fibrosis. However, several issues have been reported: the balance among disease resolution, an appropriate time window for therapeutic intervention and animal welfare remain critical aspects yet to be fully elucidated. In this study, C57Bl/6 male mice were treated with BLM via oropharyngeal aspiration (OA) following either double or triple administration. The fibrosis progression was longitudinally assessed by micro-CT every 7 days for 4 weeks after BLM administration. Quantitative micro-CT measurements highlighted that triple BLM administration was the ideal dose regimen to provoke sustained lung fibrosis up to 28 days. These results were corroborated with lung histology and Bronchoalveolar Lavage Fluid cells. We have developed a mouse model with prolonged lung fibrosis enabling three weeks of a curative therapeutic window for the screening of putative anti-fibrotic drugs. Moreover, we have demonstrated the pivotal role of longitudinal micro-CT imaging in reducing the number of animals required per experiment in which each animal can be its own control. This approach permits a valuable decrease in costs and time to develop disease animal models. Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease for which no curative pharmacological therapy exists, which is characterized by progressively impaired pulmonary function and a median survival of 2–4 years after diagnosis .Animal models play an essential role in selecting the most promising drug candidates to advance into the clinic. However, a very limited number of such compounds have translated into effective therapies to date, with many having failed to reach the primary endpoints in clinical trials , 3.This unsuccessful translation of early promise into clinical benefit for IPF patients is a waste of financial resources, ultimately reducing the opportunity for conducting future trials.A possible explanation could be related to the nature of currently available animal models, which cannot fully replicate human pulmonary fibrotic disease .Although bleomycin (BLM)-induced fibrosis is the most used and best-characterized model either to investigate lung fibrotic mechanisms or to screen drugs, a comprehensive guideline reporting optimal doses, routes and frequency of BLM administration is still lacking.The BLM model does not fully reproduce human IPF, and its limitations are well-known.First, it is challenging to balance the development of a sustained fibrosis with current standards for animal welfare practices, as animals tend to lose weight and show signs of distress , 5. MoreSeveral studies have pointed out the different responses to BLM among different mice strains and genders ; as concHence, the American Thoracic Society (ATS) and National Institute of Health (NIH) recommended using both genders for lung anti-fibrotic drugs screening since they respond differently to BLM , 7–9.We have already set up our drug screening in the female model of BLM with two weeks for pharmacological intervention .Following ATS and NIH suggestions, we intended to develop a mouse model of BLM-induced lung fibrosis in male, however, extending the window for therapeutic intervention up to three weeks and performing the primary screening in both genders.In light of the different sensitivity among genders we applied lower BLM dosages than we did in females , 10, expOur main objective was to identify the ideal BLM dose regimen to reach an appropriate balance between sustained lung fibrosis up to 28 days and animal welfare in C57Bl/6 male mice, highlighting the pivotal role of micro-CT in animal modeling.The extended therapeutic window to 3 weeks allows to reveal side effects due to longer drug exposition, as well as lighting up more in-depth the anti-fibrotic efficacy already in primary screening.Micro-CT has been well-documented to play an important role in decreasing intra-experimental variability, and, as a result, significantly reducing the number of animals used per experiment, in agreement with the 3R’s principles . In partexp) were derived from CT scans and compared with histological measurements at the final time-point.In this study, longitudinal micro-CT imaging was performed on the same mice at 7, 14, 21 and 28 days to assess the pulmonary fibrosis progression. Five quantitative parameters . Animals were housed five per cage under standard conditions at our animal facility, in compliance with the procedures and principles outlined in the European Directive 2010/ 63 UE, Italian D.Lgs 26/2014 and the revised “Guide for the Care and Use of Laboratory Animals” . All animal procedures were conducted in an AAALAC  certified facility at Chiesi Farmaceutici and were authorized by the Italian Ministry of Health with protocol number 841/2019-PR and by the internal AWB . Animals were acclimatized upon arrival to the local vivarium conditions  for 7–10 days. All appropriate measures were taken to minimize pain or discomfort in the animals; the pain was evaluated daily through a Visual Analogue Scale (VAS) ranging from 0 to 10 by a designated veterinarian or trained technicians. Signs of dyspnoea, body weight loss ≥ 20% and VAS ≥6 were considered as humane endpoints.All studies were conducted in 7-8-week-old male C57Bl/6 mice (purchased from Pulmonary fibrosis was induced using bleomycin hydrochloride (Baxter) diluted in 50 μL saline via a double  or triple  oropharyngeal administration (OA) under 2.5% isoflurane anaesthesia, as previously described , 10, 11.Animals’ lungs were scanned longitudinally at days 7, 14, 21 and 28 by Quantum GX Micro-CT . Each mouse was anesthetized with 2% isoflurane and positioned supine inside the micro-CT. Images were acquired with the following parameters: 90KV, 88μA over a total angle of 360° in 4-minute-total scan time using the ‘high speed’ scan mode with respiratory gating. The 3D reconstructed datasets in the expiration phase of the breathing cycle were analysed by the Perkin Elmer Analyze software . A semi-automatic segmentation was used to define airways and aerated lungs, whereas manual segmentation was performed in animals with very low- or non-aerated areas to obtain the total lung volume map . The imaexp.FRC was then normalized on total lung volume and expressed as FRC/VAnother functional CT parameter, i.e. air/tissue ratio (A/T), was derived and measured as follow:According to this definition, dense and scarce aerated lungs are associated with a lower gas/tissue ratio, thus this parameter can be used to quantify progression of lung fibrosis.Dasit XT 1800J, Sysmex).Mice were sacrificed by anaesthetic overdose followed by abdominal aortic bleeding. Bronchoalveolar lavage fluid (BALF) was collected by gently washing the lungs three times with 0.6 mL sterile solution . The BALF samples were centrifuged for 10 mins at 4°C, and the cell pellet was resuspended in 0.2 mL of BAL solution to count white blood cells (WBC) and relative subpopulations with an automated cell counter  and three sections for each lung sample were stained with Masson’s Trichrome (MT) and scored on a scale of 0 to 8. The fibrosis alterations were blindly assessed on Ashcroft score modified by Hubner et al. by two independent researchers with experience in animal models of lung fibrosis , 19. TheGraphPad Software Inc., San Diego, CA, United States). All data are presented as mean ± SEM. One or two-way analysis of variance (ANOVA) was performed, followed by Dunnett or Tukey’s multiple comparison post-hoc tests to compare different experimental groups. Normal distribution was assessed through a Shapiro-Wilk test accompanied by a visual inspection of QQ-plots. The sample size was calculated with A-priori Power Analysis (G*Power Version 3.1.2) considering Ashcroft Score as an endpoint. For all the applied tests, a p-value <0.05 (*) was considered as statistically significant. Spearman correlation analysis was used to estimate the relation between the micro-CT parameters and Ashcroft score.Statistical analyses were performed using Prism 8 software  of hypo-aerated tissue from day 14 to day 28, followed by a significant augment of non-aerated areas (p<0.01) at day 21 and 28 . As regaAs expected, the saline group had 77–80% normo-aerated tissue with 20–23% hypo-aerated tissue throughout the study .Animals treated with a double dose of either 10 or 15 μg BLM had a significantly higher (p<0.01) lung volume with respect to saline at days 7 and 14, whilst no differences between groups were seen at days 21 and 28 . On the As regards the air/tissue ratio, at day 7 no differences between the groups receiving double BLM and saline were revealed. However, a markedly lower ratio (p<0.01) was observed in mice receiving either 10 or 15 μg BLM at days 14 and 21. Between days 21 and 28, the air/tissue ratio slightly increased in the 10 μg group but was not significantly different than in saline at day 28. In the 15 μg BLM group the ratio stabilized from 21 to 28 days, being still considerably lower with respect to saline (p<0.01) at the final time-point . In the exp was not affected by either double nor triple BLM administration at 7 days. However, from day 14 to 21 its significant decline was observed in all BLM-treated groups compared to saline mice (p<0.01). At day 28, FRC/Vexp remained significantly lower compared to saline (p<0.01) in all BLM-treated groups, except for the group receiving the double dose of 10 μg BLM which reinstated  in all groups receiving BLM compared to the saline group . No statSpearman correlations between micro-CT readouts and Ashcroft score were performed . PositivAt day 28, after animals’ euthanasia, the BALF was harvested and leukocytes were counted. As expected, the total WBC were significantly increased in all the groups receiving BLM, compared with saline (p<0.01) . A signiAs concerns leukocyte subpopulations, macrophages were markedly higher in the group receiving the double dose of 15 μg BLM compared to saline (p<0.05), whereas the double dose of 10 μg evoked a moderate, non-significant increase . On the Double (10 μg) and triple (6 μg) BLM administration were selected to further investigate the kinetic of the lung inflammation comparing the number of leukocytes in a time course experiment .Even though total WBC in either BLM groups were significantly higher than saline across the study, their levels were slightly higher in mice receiving the triple BLM dose with respect to those treated with the double OA. However, no significant differences were revealed among the two BLM groups at any time-point . MoreoveAnimal models play a crucial role either in understanding the pathobiology of fibrosis or in drug discovery. Animals of different species, gender and age, as well as different BLM dose regimens have been used to induce lung fibrosis , 20, 21.In this study, BLM dosages and the administration scheme were readjusted in male C57Bl/6 mice, as they have been reported to be more susceptible to BLM-induced fibrosis with respect to female mice , 10.Thus, we tested lower BLM doses compared to those used in female mice  applyingWe hypothesized lower multiple doses of BLM might decrease acute toxicity and trigger sustained lung fibrosis up to 28 days, thus enabling an extended time window of 3 weeks (day 7 to 28) for pharmacological intervention, guaranteeing animal welfare throughout the experiment.Micro-CT was performed longitudinally and the data were integrated with ex-vivo outcomes to select the best BLM regimen. Longitudinal imaging drastically reduced the number of mice per group and the intra-experimental variability, since the progression of the disease could be monitored in the same subjects , 22, 23.Moreover, non-aerated regions, reflecting the most severe fibrotic lesions, were found to be dose-dependently related to BLM. This was highlighted in mice treated twice with the highest BLM dose, in contrast with those receiving the double OA at 10 μg, in which a moderate fibrosis was detected. In order to assess lung fibrosis, besides considering the degrees of lung aeration, other micro-CT parameters, such as the total lung volume, the air/tissue ratio and the FRC normalized on total lung volume were proposed.exp which significantly declined at the fibrotic stage. We believe that all the micro-CT parameters need to be considered when evaluating either disease development or response to anti-fibrotic drugs.The increase of total lung volume in all BLM-treated mice at day 7 could be provoked by acute lung inflammatory phase, associated with fluid accumulation (edema) in the lungs . OverallIn agreement with the micro-CT data, histological analyses, depicted as Ashcroft score and its frequency distribution, revealed that all the BLM groups developed a sustained fibrosis ranging from 3.5–5.However, the Ashcroft distribution marked a dose-dependent response to BLM, as only the higher doses either in double or triple regimen, increased significantly the percentage of severely injured areas, in line with non-aerated tissue detected by micro-CT. Moreover, we found highly significant Spearman coefficients correlating Ashcroft score with all CT parameters.A dose-dependency was also revealed in inflammatory BAL cell counts, among the groups that underwent to the triple dose regimen, as the group receiving 6 μg had more prominent leukocytes infiltrate, driven mainly by lymphocytes. These data confirmed that when splitting the amount of BLM in three administrations, even slightly different amounts of BLM could result in a markedly different outcome after 28 days.To further elucidate the kinetics of inflammation and fibrosis in the model we evaluated BAL cells populations at different time points in mice receiving either the double (10 μg) or triple (6 μg) BLM dose. We showed that the variations in BLM dose and regimen produced modest effects on the inflammatory phase, as no significant differences in BAL cells were revealed at day 7. Moreover, macrophages were higher in animals receiving the triple OA at later time points, indicating a key role for this cell type as a driver of fibrosis, as already reported in the classical BLM model .Based on our findings, the higher doses applied with both protocols were able to trigger a sustained fibrosis up to 28 days.However, although the double 15 μg BLM dose induced moderate body weight loss, histological quantification revealed a total Ashcroft score close to 5 with predominant severe fibrotic lesions. These findings, along with micro-CT outcomes, revealed a significant increase in non-aerated areas as well as a marked decrease in air/tissue ratio, which led us to consider this protocol as too severe. On the other hand, the triple administration corroborated our hypothesis: both 5 and 6 μg doses were able to induce relevant changes in lung fibrosis markers detected by micro-CT and histology, without causing excessive distress and body weight loss in animals.In drug discovery, the balance between the severity of the disease model and animal welfare is crucial, as pharmacological studies require animal manipulation once or twice daily, which may cause further stress. Moreover, the evaluation of the anti-fibrotic activity of novel compounds would require a sustained, but not excessively severe BLM-induced fibrosis. However, whether the lung fibrosis elicited in this model by the triple OA of 6 μg BLM can be modulated by a reference compound remains to be evaluated and will be addressed in future studies. We believe that a disease model triggering a sustained pulmonary fibrosis until day 28, allowing three weeks of pharmacological intervention, could be very useful to evaluate compounds for primary drug screening.In this study, we showed the pivotal role of micro-CT in developing an optimized mouse model of lung fibrosis. Micro-CT technology is increasingly being recognized as a fundamental translational tool in preclinical studies, as it allows investigators to get relevant three-dimensional information about disease progression as well as to detect regional differences within the lung parenchyma. Furthermore, longitudinal measurements can be carried out from each subject in a non-invasive manner, thus enabling a significant refinement of animal studies as well as a reduction in sample size.exp, provides a wide and detailed overview of the disease progression. These parameters represent useful tools to select the optimal protocol for BLM studies to be used for primary drug screening, corroborated by ex-vivo measurements.Overall, this will permit a considerable decrease in costs and time to develop disease models. Moreover, the quantification of normo-, hypo- and non-aerated areas and functional parameters such as air/tissue ratio and FRC/VThe continuous refinement of animal models and the integration with in-vivo imaging techniques (e.g. micro-CT and PET/CT) might be helpful within the drug discovery process, in order to increase the reliability of preclinical data and facilitate drug candidates’ translation into the clinic. Even though PET/CT can’t be used for primary screening due to its cost and complexity, this imaging technique could be extremely useful to better profiling the most promising anti-fibrotic drugs before clinical applications, as it enables to investigate the capacity of a drug to modulate the expression of relevant disease biomarkers by using specific probes .However, as concerns secondary screening, different disease models are more suitable , 23, whi0.1) and compliance of respiratory system (Crs) [Furthermore, ventilatory parameters such as forced vital capacity (FVC), forced expiratory volume in the first 0.1 second (FEVem (Crs)  provide Based on our findings, we identified a triple dose of 6 μg BLM as the optimal regimen to induce a sustained lung fibrosis that doesn’t spontaneously revert after 21 days, thus extending the time window for pharmacological treatment from 2 to 3 weeks.S1 Fig(A) Representative coronal micro-CT lung slices and 3D renderings at the end of expiration phase of saline at 7, 14, 21 and 28 days. (B) Lung aeration degrees expressed as percentage of normo-, hypo- and non-aerated tissues detected at 7, 14, 21, 28 days for the saline group. (C) Representative coronal micro-CT lung slices and 3D renderings at the end of expiration phase of triple OA of 7.5 μg BLM group at 7 and 14 days. (D) Lung aeration degrees expressed as percentage of normo-, hypo- and non-aerated tissues detected at 7 and 14 days for the triple OA of 7.5 μg BLM group. (E) Longitudinal quantification of air/tissue ratio in triple OA of 7.5 μg BLM. Data are shown as mean ± SEM. The statistical differences were calculated by two-way ANOVA followed by Tukey’s test . N = 5 per group.(TIF)Click here for additional data file.


Background: The appropriateness of antibiotic prescriptions in primary care has not been well evaluated in China in recent years. Furthermore, the impact of coronavirus disease 2019 (COVID-19) on antibiotic prescriptions has not yet been investigated in China. We aimed to assess the appropriateness of antibiotic prescriptions and to evaluate the potential association between the COVID-19 pandemic and antibiotic prescriptions in primary care settings of Yinchuan, a city in China.Methods: This study included 155 primary care institutions and 10,192,713 outpatient visits. Outpatient prescriptions were classified as appropriate, potentially appropriate, inappropriate, or not linked to any diagnosis for antibiotic use following a validated evaluation scheme. Interrupted time-series analyses were performed to assess the effects of the COVID-19 pandemic on antibiotic prescriptions in Chinese primary care facilities.Results: During the study period, 1,287,678  of 10,192,713 outpatient visits in primary care resulted in antibiotic prescriptions. Among 1,287,678 antibiotic prescriptions, 653,335 (50.7% [50.6–50.9]) were inappropriate, 463,081 (36.0% [35.8–36.1]) were potentially appropriate, 171,056 (13.3% [13.1–13.5]) were appropriate, and 206 could not be linked to any diagnosis. Furthermore, patient, physician, and institutional factors were associated with inappropriate antibiotic prescriptions; there was an overall decreasing trend in the proportions of inappropriate antibiotic prescriptions, with the highest level in 2017 (67.1% [66.8–67.5]) and the lowest in 2021 (40.8% [40.3–41.3]). A total of 1,416,120 individual antibiotics were prescribed, of which 1,087,630 (76.8%) were broad-spectrum and 777,672 (54.9%) were classified in the World Health Organization’s “Watch” category. In addition, the COVID-19 pandemic was associated with changes of −2.8% (−4.4 to −1.3) in the level and 0.3% (0.2–0.3) in the monthly trend of antibiotic prescription rates, as well as changes of −5.9% (−10.2 to −1.5) in the level and 1.3% (1.0–1.6) in the monthly trend of the proportions of inappropriate antibiotic prescriptions.Conclusion: More than half of the antibiotic prescriptions were inappropriate during the study period in primary care in Yinchuan. The COVID-19 pandemic may be associated with a decrease in the overall and inappropriate use of antibiotics in primary care settings in China. Inappropriate use of antibiotics is a major driver of antimicrobial resistance (AMR) , which iChina is the largest LIMC and second largest consumer of antibiotics worldwide . SurveilThe primary care system in China consists of urban and rural components: CHSCs and their satellite station sites (CHSSs) in urban areas, and THs and their outreach VCs in rural areas . These i2. The gross domestic product in 2019 was 189.7 billion, among which the tertiary industry accounted for 52.8% in this city. The gross domestic product per capita was 83,492 Yuan, ranking in the middle range of all Chinese cities  were excluded because less than 10 months of data were uploaded; the remaining 155 institutions (51 CHSCs/THs and 104 CHSSs/VCs) were included in the final analyses.We assessed antibiotics for systemic use according to ATC code J01. Three other antibiotics, including metronidazole, tinidazole, and ornidazole, were also included because these antibiotics are mainly used to treat anaerobic bacterial infections in China . SupplemIn this study, multiple prescriptions of drugs and diagnoses from the same patient on the same day in the same primary care institution were treated as one visit.China gives equal attention and weight to TCM and allopathic medicine in primary care; thus, TCM care is widely provided in primary care institutions, often jointly with allopathic medical care . In thisAntibiotic prescription rates were calculated as the percentage of outpatient visits that ended with antibiotic prescriptions for different diagnostic categories in urban and rural primary care. Antibiotic prescriptions were classified into one of the four mutually exclusive categories as applied in previous studies : “appropAntibiotic prescriptions were examined overall and by area type , institution level (CHSCs/THs and CHSSs/VCs), patient gender, age group , payment type (by insurance or full out-of-pocket), and year of outpatient visit (2017–2021), as well as physician characteristics, including age , gender, and education level. Antibiotic prescription patterns were identified by calculating the proportions of different forth-level ATC categories, broad-spectrum agents, and WHO AWaRe categories.Descriptive statistics of the outcome measures for the entire study group, as well as for different diagnostic categories and subgroups, were calculated. The Clopper-Pearson exact method was used to calculate the 95% confidence intervals (CIs) of the antibiotic prescription rates. The simultaneous 95% CIs for multinomial proportions of antibiotic prescriptions for all four appropriateness categories were estimated using the Goodman method . A multiTwo sensitivity analyses were performed for the appropriateness classification of TCM diagnoses. First, all TCM diagnoses were classified as tier 2 diagnoses. Second, all TCM diagnoses were classified as tier 3 diagnoses. The appropriateness category was reassigned to each antibiotic prescription using the tier-fashion method mentioned above and the proportion of each appropriateness category was recalculated. We also calculated the diagnosis category-standardized antibiotic prescription rates using the disease spectrum of the whole population during the whole study period as the standard population to check whether the differences between subgroups were due to changes in the disease spectrum of visits.Interrupted time series analyses using segmented linear regressions were conducted to assess the impact of the COVID-19 pandemic on antibiotic prescription rates and proportions of inappropriate antibiotic prescriptions. Given the delay of the intervention effect, March 2020, when the WHO declared COVID-19 a pandemic, was set as the time when the pandemic began to have an impact, according to descriptive trend analyses and previous studies .Interrupted time series analyses regression models were fitted for outcome measures (antibiotic prescription rates or proportions of inappropriate antibiotic prescriptions) with the following equation:β1 is the baseline slope of the outcome variable until the COVID-19 pandemic period. β2 represents the change in the level of the outcome that occurred immediately following the pandemic and β3 represents the slope change in the outcomes after the COVID-19 pandemic. The SAS software X12 procedure was used to identify seasonal variations in antibiotic prescriptions. This method is an adaptation of the United States Bureau of the Census X-12-Auto-Regressive Integrated Moving Average model, which produces a seasonally adjusted time-series . Statistical analyses were performed using SAS 9.4  and Stata 16.0 .This study was approved by the Ethical Review Board of Peking University Health Science Center . Informed consent was not required because we used anonymized routine data.A total of 10,192,713 outpatient visits from 155 primary care institutions were included in this study. Among these visits, 6,240,795 (61.2%) occurred in urban areas and 5,376,777 (52.8%) occurred in CHSCs/THs. In addition, 1,358,368 (13.4%) visits were made by children, 4,684,654 (46.0%) were made by men, and 8,059,694 (79.1%) were paid with insurance. Of all visits, 56.6%  were served by physicians aged 40 years and older, 5,707,639 (56.0%) by female physicians, and 7,695,231 (75.5%) by physicians with an education level of high school and below .Overall, 12.6%  of the 10,192,713 outpatient visits resulted in antibiotic prescriptions. Antibiotic prescription rates were 7.4% (7.4–7.5) and 20.8% (20.8–20.9) in urban and rural primary care institutions, respectively . Among tAntibiotic prescription rates before and after standardization for the various subgroups are shown in Among all 1,287,678 visits that resulted in antibiotic prescriptions, 653,335 (50.7% [50.6–50.9]) were considered inappropriate, 171,056 (13.3% [13.1–13.5]) were appropriate, 463,081 (36.0% [35.8–36.1]) were potentially appropriate, and 206 (0.02% [0.0–3.0]) visits could not be linked to valid diagnostic records . The antThe sensitivity analyses  showed tA total of 1,416,120 individual antibiotics were prescribed, of which 1,087,630 (76.8%) were broad-spectrum antibiotics . OverallA significant decreasing trend was observed in both the antibiotic prescription rates and proportions of inappropriate antibiotic prescriptions before the COVID-19 pandemic, with a monthly change of −0.2%  and −0.8% (−0.9 to −0.8), respectively . COVID-1Using a large prescription database with over 10 million outpatient visits, we measured antibiotic prescriptions in both urban and rural primary care facilities in a Chinese city. We estimated that 12.6% of outpatient visits in primary care resulted in antibiotic prescriptions during the study period, whereas 50.7% of these antibiotic prescriptions were considered inappropriate. This study extended the evidence from our previous studies on inappropriate antibiotic prescriptions in Chinese secondary and tertiary hospitals  and addeA survey conducted 10 years ago estimated that 52.9% of outpatient visits in CHSCs and THs in six provinces of China received antibiotics, and 60.4% of these antibiotic prescriptions were inappropriate . CompareThe increasing use of antibiotics in LMICs has been the most important driver of the dramatically increasing global consumption of antibiotics , with thSimilar to our previous findings in secondary and tertiary hospitals , tier 3 We found that some institutional, patient, and physician characteristics might be associated with inappropriate antibiotic dispensing. Primary care institutions in urban areas and higher-level institutions of CHSCs/THs were associated with fewer inappropriate antibiotic prescriptions, probably because they were better equipped and had more experienced healthcare professionals , which iWe found that the COVID-19 pandemic was associated with a decrease in overall and inappropriate antibiotic prescriptions in Chinese primary care facilities, with immediate levels decreasing in March 2020, and increasing trends thereafter. Similar effects have been observed in other studies . The COVThis study has several strengths. We provided the most recent and comprehensive data on antibiotic prescriptions in primary care settings in a mainland China city using an unprecedentedly large sample of prescription data. The method for assessing the appropriateness of antibiotic prescriptions used in this study was mainly based on the ICD-10, suffering little effect of personal knowledge and experience. This method has been well validated  and can In conclusion, the antibiotic prescription rate was under the required control level, and inappropriate antibiotic prescription tended to decrease gradually in primary care settings in the city of Yinchuan. However, inappropriate antibiotic prescriptions are still highly prevalent in Chinese primary care settings, with over half of all antibiotics prescribed inappropriately during the study period. A systematic antibiotic stewardship program focusing on multiple factors is needed to further optimize antibiotic prescriptions in primary care settings. Furthermore, the COVID-19 pandemic might have had an effect on reducing antibiotic prescription rates and inappropriate antibiotic prescriptions in primary care settings.


In recent years, concrete technology has advanced, prompting engineers and researchers to adopt advanced materials to improve strength and durability. Steel-fiber-reinforced concrete (SFRC) represents the substantial modification of concrete materials to improve their structural properties, particularly their flexural and tensile strength. Whether SFRC is stronger than conventional concrete depends on a variety of variables, including the volume, size, percentage, shape, and distribution of fibers. This article provides a comprehensive discussion of the properties of SFRC, such as durability, fire resistance, and impact resistance or blast loading, as well as the application of SFRC in structural members including beams, columns, slabs, and walls. The application of steel fibers in various types of concrete, including pre-stressed, pre-cast, self-compacting, and geopolymer concrete, was also examined in this comparative analysis review, and recommendations for the future scope of SFRC were identified. Over the past decade, recycled steel fibers (RSFs) have been shown to be a promising replacement for industrial steel fibers (ISFs) due to their reduced environmental impact and lower recycling costs [Advancement in material science has become vital in the recent years. Concrete is one of the most significant materials globally, being an effective material for several applications, such as building dams, bridges, buildings, tunnels, and many other structures. Concrete, despite being considered the most common building material above other materials such as steel, wood, or composite systems, has its disadvantages, including its low tensile strength and brittleness ,2. Improng costs ,18,19. Fng costs ,20. FiguIn recent decades, the use of SFRC has steadily expanded due to its desirable features. It is presently used not just in conventional industrial and civil constructions, but also in several other fields, such as highway paving, airports, earthquake- and impact-resistant structures, bridges, and tunnels . Fiber-rThe proposed article begins with a discussion of the significance of steel fibers in the civil engineering industry, including their durability, impact resistance, and thermal performance. The use of industrial waste steel as fibers in concrete to address the related environmental issues is also discussed. In addition, we address the use of steel fibers in structural elements such as beams, columns, slabs, and walls, as well as the corresponding experimental parameters for flexural strength, compressive strength, and shear resistance. The use of steel fibers in various types of concrete is then presented, including self-compacting, geopolymer, pre-cast and pre-stressed concrete.Failure mechanisms in steel-reinforced concrete are also discussed. Numerous references from recent years that demonstrate the current state of the development of SFRC were analyzed. The practical applications of steel fibers in blast loading are described, and recommendations for future research topics are provided.The mechanical strength properties of steel fibers are useful as a primary factor for predicting the durability, fire resistance, and impact resistance of concrete. SFRC performs well in resisting tensile cracks through increased flexural strength, improving the ability of thinner structural elements to withstand heavy monotonic and cyclic loads compared to conventional concrete, regardless of its grade ,41,42.3, 100 × 450 × 450 mm3, 150 × 150 × 550 mm3, and 100 ×100 × 1000 mm3 to test their toughness, impact resistance, freeze–thaw resistance, drying shrinkage, and abrasion resistance. The coarse aggregate was replaced with electric arc furnace (EAF) steel slag and steel fiber reinforcement in variations of around 0, 30, and 60 mm; hence, the toughness and flexural strength were enhanced in a combined effect, and the 60 mm variation provided the best results. Frazao et al. [3 was applied. The tensile strength can be reduced at an extreme level of corrosion for SFRSCC. The various types of steel fibers, their geometric configurations, and their tensile strengths are presented in Steel fibers produce effective outcomes by enhancing the durability of concrete. Kim et al.  experime3, resulting in the steel fibers showing mass variation compared with the barley straws and decreasing the porosity. Moghadam and Izadifard [According to zadifard  tested b2 emissions; additionally, under the application of sulfuric acid solutions, it showed better durability. Usman et al. [Dezhampanah et al.  experimen et al.  used sten et al.  tested tn et al.  also expn et al.  used micn et al.  tested d2 emissions than standard concrete. Singh [Salmasi and Mostofinejad  conductee. Singh  tested sConcrete should perform well against fire as it has low conductivity. Steel fibers can protect concrete from excess fire damage, and they have good thermal properties . SerranoJin et al.  tested hImpact resistance is defined as the ability of concrete to resist frequent blows without spalling and cracking . ChoudhaKim and Yoo  investigYoo et al.  experimeMahakavi and Chithra  evaluateSteel fibers can be utilized in structural elements to draw a strength comparison with conventional concrete. This section discusses the implementation of steel fibers in the following structural elements to assess performance via shear, compression, and tension tests: beams, columns, slabs, and walls.Experimental studies have been published in the literature investigating the flexural and shear strengths of reinforced concrete (RC) beams containing steel fibers. The results have shown that steel fibers can be adopted to enhance both flexural and shear strength.Flexure is a primary parameter of beams for predicting concrete behavior under tension. Karimipour and Ghalehnovi  utilizedYoo and Choo  experimeSarmiento et al.  examinedShear tests in beams assess the shear strain, shear stress, and shear modulus. They help to predict beam failure under shear. Algassem et al.  tested 1Joshi et al.  applied Ismail and Hassan  evaluateSteel fibers enhance the performance of columns under compression, and the addition of various volume percentages of steel fibers helps assess the behavior of columns under different loading conditions.A compression test, i.e., the application of compressive force, is the best and easiest way to predict a concrete’s health status. Atea  tested t2, observing better compressive strength performance. Nematzadeh et al. [Jang and Yun  experimeh et al.  experimeh et al.  assessedh et al.  investigh et al.  developeSteel fibers are essential ingredients for wall structures, as they enhance strength and durability. Zhao and Dun  developePetkune et al.  carried Steel fibers are becoming a vital material for application around the edges and joints of slabs to resist cracks. Soltani et al.  experimeAlongside incorporating steel fibers into conventional concrete, they would be a beneficial addition to other types of concrete, such as pre-stressed concrete, pre-cast concrete, self-compacting concrete, and geopolymer concrete.Pre-stressed concrete improves the tensile properties of structural elements; hence, the addition of steel fibers can further enhance its strength and durability. Paramasivam et al.  comparedNarayanan et al.  incorporPre-cast concrete containing steel fibers improves structural performance in terms of cracks and ductility. Mohamed and Nehdi  developeMajain et al.  investig2 emissions and increased waste reuse [Due to the high environmental impact of conventional concrete production, the development of geopolymer concrete is considered the most important innovation in the construction sector . The addte reuse .The current literature still has gaps related to research on the effect of steel fibers on parameters such as setting time, thermal conductivity and resistance, abrasion resistance, carbonation resistance, freeze/thaw resistance, corrosion resistance, electrical resistance, electrical resistivity, sorptivity, and chemical and electrical resistance . NeverthLiu et al.  experimeBlast-resistant concrete provides more flexibility to ensure safety against blasts; however, steel fibers enhance the strength of concrete with or without reinforcement conditions. Foglar et al.  experime2 to assess blast response via the shock-wave method for an RC square slab with dimensions of 550 × 50 mm. A cylindrical shock wave was created with a gel-like explosive, and the steel fibers proved effective by improving the blast behavior; the authors implemented a similar experiment with various sizes of hooked-end fibers, and the numerical simulation obtained more effective results for shorter fibers [2) under a shock tube experiment at the University of Ottawa (Canada). A 2D FEM was also developed, and the results showed that the steel fibers were effective for improving blast resistance in terms of controlling damage and reducing displacement. Gong et al. [Luccioni et al.  experimer fibers . Li and r fibers  tested tg et al.  presenteSFRC increases resistance to crack propagation and permeability, which are primary factors for increasing corrosion; the inclusion of anti-corrosion chemicals in steel fibers helps to resist corrosion . Tang anLiu et al.  applied Failure scenarios in concrete incorporating steel fibers must be observed to provide adequate structure safety. Tóth et al.  experimeTo evaluate the structural behavior of S-UHPC composites, static experiments were conducted, and a finite element (FE) model was developed and validated based on the experimental results. In addition, a parametric study was conducted to summarize the failure modes of the push-out test and investigate the mechanism of steel fibers’ influence on the structural behavior of S-UHPC composite beams. In conclusion, an analytical model for predicting the ultimate strength of S-UHPC composite beams was proposed and compared with existing design codes. The outcome was positive and advantageous . High-peDecades of research have been conducted on steel fibers in structural applications, and as a result, steel fibers have become a popular research topic in civil engineering. Researchers are currently exploring several innovative ideas to make the best use of steel fibers in concrete. In this article, we discussed numerous previously published, high-quality works on SFRC; we will now compare their findings.The presence of steel fibers in concrete enhances mechanical properties such as flexural strength, compression, and splitting tensile strength. However, the flexural strength improves significantly more than the compression and splitting tensile strength, so SFRC is superior to conventional concrete.SFRC provides superior resistance to cracking compared to conventional concrete; however, the steel fibers must be evenly distributed in the concrete without any gaps, and a vibrating machine is essential for SFRC to achieve the desired results.Due to their superior resistance, strength, and flowability, hooked, straight, crimped, and twisted steel fibers are more commonly used than other forms, allowing for their easy distribution across entire portions of concrete.Hooked-end steel fibers provide greater efficiency compared to other forms of steel fibers due to the presence of strong, secure elements, and they can produce greater pull-out resistance; therefore, they can be used in structural applications to improve the performance of concrete.SFRC provides superior fire resistance properties compared to conventional concrete, thereby enhancing the durability to some degree, and it also consistently outperforms conventional concrete under blast loading conditions, thereby aiding in the protection of structures from such impact or dynamic loading conditions.Steel fibers cannot serve the same purpose as primary reinforcements, so rebars should be considered as the primary source of reinforcement in concrete. Steel fibers are used to stop cracks from spreading, because rebars cannot stop cracking. Consequently, by adding additional support, steel fibers can be used to increase the strength of reinforced concrete.If steel fibers are used in combination with rebars, the dimensions of the structural members could be limited, because steel fibers improve resistance to dynamic and impact loads and resist material disintegration, thereby eliminating the need to design beams with large dimensions.We recommend that the future scope of SFRC research should focus on enhancing the system’s overall performance and efficiency to obtain improved data. The predicted areas for future progress are listed below ,128,159.Further research is necessary regarding a more effective experimental process to assess the fire resistance of SFRC; hence, heavily damaged beams should be used for experiments to predict optimal resistance against fire.Dynamic pull-out experiments should be performed to evaluate the dynamic behavior of UHPC, and advanced test machines should be used for impact tests incorporating comparisons with various types of steel fibers.Steel fibers are often improperly distributed and poorly orientated in concrete; hence, several parameters, such as casting length, mixture viscosity, flowability, and casting height, should be considered to optimize their distribution.Both AC and DC conditions should be implemented in electric railway tunnels for future research on corrosion resistance.Experiments involving shotcrete should be improved by using various fly ash and steel fiber content proportions and water/binder ratios, and durability can be analyzed through multifactor coupling.To assess the fiber–matrix bond under acid attack, reactive mass transport modeling must be considered. Several experimental tests with varying loads and types of steel fibers should be developed.The current article provided a review of the properties and applications of steel fibers in civil engineering. The best implementation strategies for enhancing steel fiber usage were discussed by summarizing the fundamental guidelines and techniques extracted from previously published peer-reviewed studies. The primary conclusions from this review article are provided below.The article highlighted the significance of steel fibers in the construction industry according to previously reported studies. The most detailed and insightful studies were presented, along with detailed experimental data, including comparisons of RC structures with and without steel fibers.Steel fiber properties such as impact resistance, durability, and fire resistance were presented. Experiments such as chloride ion penetration tests, ultrasonic pulse velocity tests, compression tests, and abrasion resistance tests were also discussed.In this study, the critical performance of SFRC was thoroughly evaluated using both experimental and analytical data. In addition to related parameters such as shear and compression strength, the methodologies applied to evaluate the use of concrete containing steel fibers for primary structural elements such as beams, columns, slabs, and walls were discussed.The various shapes and volumes of steel fibers used in SFRC as well as their application in various types of concrete, such as geopolymers, SCC, and pre-cast and pre-stressed concrete, were reviewed. This article also discussed the operational evaluation and performance of SFRC under blast loading, as well as its performance under corrosive conditions.After reviewing previous articles, we concluded that SFRC can be used to produce conventional RC members with higher impact resistance, boosting their resistance to local damage and spalling. SFRC can limit fracture development and crack widening, supporting the use of high-strength steel bars without excessive crack width or deformation under service loads.SFRC increases the ductility of conventional RC elements, hence enhancing their dynamic stability and structural integrity. SFRC also enhances the shear resistance of RC members. As a result, failure due to slab punching shear can be minimized.After a thorough review of the literature, we concluded that steel fibers can be used in flat slab structures for punching shear resistance and military structures for resistance against blasts or impact loading in addition to conventional rebars. Steel fibers may also be used in temporary structures such as drain slabs without rebars, but care must be taken to ensure that there will be less load impact.Due to their superior resistance to cracking and dynamic loading, SFRC structures are more expensive to build than conventional concrete structures, but their long-term maintenance costs are nearly equivalent.


Antibiotic resistance is a serious global threat to human and animal health. In this study, we explored perceptions of work to contain antibiotic resistance with a focus on the environment. Nine stakeholders from six different areas were interviewed in 2018. A short information update was given by informants from four of the areas in 2021. Interview transcripts were analyzed by conventional content analysis. The stakeholders’ perceptions were concluded in three categories: “examples of actions taken to combat antibiotic resistance”, “factors influencing work”, and “factors hindering work”. All informants reported having a role to play. Some of them were very engaged in this issue, whereas among others, antibiotics and resistance were just one part of a general engagement. To be able to act, the policymaker stakeholders asked for more knowledge about antibiotics in the environment and possible actions to take. Actions from the government were requested by several informants. Coordination of the work to combat antibiotic resistance in the environment was not recognized and the One Health approach was known at policy level but not among practitioners. Still, actions seemed to be coordinated, but this was, according to the stakeholders, based on findings from research in their area rather than on strategies developed by national authorities. Antibiotic resistance is a global threat to human and animal health ,2. The nThe Swedish government published its first action plan in 2016 . When prThis study is part of the ABRCARRO —an international project which aims to explore and describe how national action plans against antibiotic resistance were developed, implemented, monitored, and evaluated in Sweden, South Africa, and Swaziland. The project includes interviews with different categories of stakeholders, policymakers at government level, and professionals in human, animal, and environment/agriculture sectors, as well as policy document analyses. In this paper, we explore efforts to contain antibiotic resistance in the environment in Sweden.Studying how actors and organizations work to contain the spread and development of antibiotic resistance in the environment is challenging. To begin with, it is known that the use of antibiotics has accelerated the development and spread of resistance in microbial populations . HoweverSecondly, the problem of working to contain antibiotic resistance in the environment is multifaceted in such a way that multiple sectors must be involved to have some sort of impact. To reach effectiveness, organizations and actors generally not linked to each other most probably need to work together for the same goal. Research on how this can be experienced is sparse. Thus far, knowledge of actual Swedish efforts to contain antibiotic resistance in the environment, and how they are perceived, is limited. Further exploration is needed.The aim of the present study was to explore and describe how informants working on environmental issues in a strategic selection of health and public sectors in Sweden perceive their own work, as well as other work in Sweden, to contain antibiotic resistance in the environment.According to the explorative approach of the topic, a qualitative research design based on interviews was chosen ,16. By aOur aim was to include informants involved in work to contain antibiotic resistance in the environment. We therefore approached individuals working at six strategically selected health and public service areas, see A semi-structured interview guide was used, based on an interview guide previously used by the research group when studying perceptions of antibiotic resistance work in the human healthcare sector. Some questions were adapted to the purpose of the present study. The interview guide was first pilot tested on two informants working in the human and animal sectors, respectively. Results from these studies are presented elsewhere ,19. The During the interviews, informants spoke freely and shared their thoughts and understandings. The interviewer followed up with different probing questions, depending on what the informant was telling, for either more information or clarification. Author IB conducted the interviews during the period April to June 2018 at a place selected by the informant, usually at their workplace. The interviews lasted on average 47 min, with a range of 25 to 72 min. All interviews were tape recorded and transcribed verbatim by another person, and then the transcripts were checked and corrected, if necessary, by IB before the analysis process started.An inductive approach was used, with no predefined codes or categories. Author IB conducted the analysis, supported by author MR who acted as co-reader. The interviews were first read through to get an overview of the content. Next, interviews were read line by line and meaning units were picked out, given codes, and condensed. At this point each meaning unit and code was given an id-number to facilitate the analysis process. Meaning units were then sorted based on the codes, codes were merged and renamed in repeated steps, and codes that did not concern antibiotics or antibiotic resistance were taken away. Thereafter, all transcripts were sorted based on the new codes, and the content of each code was examined. The codes were rearranged in subcategories and three main categories were chosen in a final step to organize and present the content of the interviews as follows: Informants’ perceptions of actual efforts to contain antibiotic resistance in the environment, their perceptions of factors influencing their work, and factors hindering their work. All findings describe informants’ perceptions. Ethical approval was sought from and granted by the Regional Ethics Board in Stockholm (Reg number: 2017/1999-31).Data collection took place in 2018 whereafter the interview material was analysed. However, the manuscript was not completed for a period of nearly four years. Thus, to be able to present current experiences, the authors felt that an update of the material would be of value. All informants were therefore contacted by email in the autumn of 2021. The aim was to obtain knowledge about the informants’ experiences and engagement in efforts to contain antibiotic resistance, and if they differed or were similar as to the time of the first interview in 2018. To help recall what they had said at the first interview, each informant was shown the findings generated from their interview. The informants were asked three questions: (1) whether the informant or their organisation worked in the same way as they did in 2018, or if it had changed, and if so how; (2) whether the informant had noted any new function or organisation which coordinated work against antibiotic resistance development and spread in the environment; and (3) whether there were any changes in cooperation in the work to contain antibiotic resistance. The answers to the email questions are summarized at the end of the results section.We present our findings in three main categories . They arThe informants talked about many different actions, which they thought could contribute to combat antibiotic resistance. These actions were identified as subcategories in our analysis. Due to the large differences in work areas involved, and for a better understanding of the contribution of each specific area, the following presentation of the content of this subcategory is sorted according to the informants’ areas of work.The informant from the Environmental Protection Agency declared the agency had only recently become involved in this work and had so far found it difficult to find its role. The task of the agency was, according to the informant, to describe the state of the environment by sampling water, sediment, fish and wild animals, but antibiotics and antibiotic resistance were not a major issue. This cooperation between agencies started a few years ago, it was around then that some people started to talk about it […] and since then, it has grown […] although just here it is really not a major question.”“(M2)The informant gave examples of networks and platforms the agency was engaged in, both nationally, at EU level, and globally. According to this informant, antibiotics or antibiotic resistance were seldom the main focus in the environmental networks.The medical research informant expressed explicit engagement in antibiotic resistance issues, and creating new knowledge in this field, for example, studying how genes are exchanged, and how resistance is spread through plasmids and viruses. We know that genes are spread by plasmids, the informant explained, and we do know that resistance can be transferred, but we do not know to what extent. The researcher informant furthermore described a role as a teacher at a medical school, teaching medical students to always think carefully before choosing infection treatment, and to always refrain from antibiotics when possible. To contain antibiotic resistance in the environment, as well in humans and animals, both safe use of antibiotics, and decreasing the use of antibiotics was required, stated the informant.I understand if you have, for example, a blood-poisoning and someone who is acutely ill, then I fully understand, it is clear then that antibiotics should be used I think, because then it is a matter of saving lives, it is the grey areas where I think you have to be more careful.”“(M9)Safe antibiotic use, with narrow-spectrum antibiotics, and decreasing the use of antibiotics was brought up by the pharmaceutical company informant as ways to contain antibiotic resistance. It was therefore important to focus on keeping narrow-spectrum antibiotics commonly used in Sweden, as well as a wide assortment of dosage strengths and package sizes. According to this informant, individual adaption of antibiotics dispensed to patients, making sure the quantity of prescribed antibiotics does not exceed treatment duration, was fundamental for safe use and optimal antibiotic treatment. Our most important task is, right now, to maintain a large assortment and a wide range. Which is the basis for being able to eh, treat optimally and not drive resistance.”“(M10)This informant noted that the company had been involved in starting up a multisectoral collaboration platform which gathered representatives from both healthcare and authorities, aiming to ensure access to antibiotics in Sweden. The company’s interest here, the informant continued, was to enable discussions about which antibiotics the companies should fight to keep and develop, and which strengths and package sizes to focus on.The pharmacy informants stated that decreasing the use of antibiotics, as well as safe use of antibiotics, were necessary to contain antibiotic resistance. Staff at pharmacies have a role here, informants said, and this was to provide patients packages of antibiotics adapted to their prescription, i.e., not give extra tablets that may be kept and used later for self-treatment, and by counselling patients on medication use and relief of adverse effects. You should be given an adapted amount to take home” […] “yes, we also sell lactic acid bacteria, and some can help during an antibiotic treatment, counteract diarrhoea and such that could be an obstacle to completing the cure, so it can actually help someone complete their treatment.”“(M6)Furthermore, the pharmacy informants brought up the fact that pharmacies have systems to collect medical waste, where all kinds of medicines are collected and sent for destruction, with no special focus on antibiotics. One informant worked in a pharmacy chain which had employed a specific person to work with environmental aspects of medicines, including antibiotic production. This chain was deeply involved in the issue of antibiotic waste at antibiotic production sites, and tried to reach the public, politicians and authorities through seminars, podcasts, YouTube films and newspaper articles, hoping to create debate. Another activity mentioned by the informant was a campaign driven in cooperation by pharmacy chains, directed to the public, to not take antibiotics for common colds.Hospitals have systems to manage medical waste, and the hospital wastewater is connected to the city wastewater treatment system, said informants working in this area. Medical waste, which included antibiotic waste, was collected in separate bins by the ward staff, and then sent for incineration. According to one hospital informant, the hospital environmental department focused on writing routines for collection, sorting and management of medical waste, and following-up whether they were adhered to by staff. The hospital environment department was responsible for creating lists of approved products to be used in the hospital, one informant reported. One example of a product that the informant especially did not want in use at the hospital was detergents with silver, since, according to the informant, bacteria can develop resistance to silver, which can lead to increased antibiotic resistance. This hospital environmental department furthermore cooperated with the hospital’s local Strama-group (Strama is the Swedish strategic programme against antibiotic resistance) in their efforts to reduce the use of fluoroquinolones. Another task of the environmental department, according to the informant, was to set environmental demands when ordering hospital food. The informant believed buying ecological meat was a way to support lower antibiotic usage in food-animal production.There are certain substances, antibiotics that are extremely persistent in the environment, including fluoroquinolones that have long half-lives […] because we see a connection to the external environment or that effect, we have seen that, yes it makes sense to raise it as an environmental goal as well, so we can pursue this together.”“(M8)Wastewater treatment plants did not have a special focus on antibiotic resistance, according to informants working at these plants. Both informants believed that the use of high-quality wastewater treatment methods can contribute to containing antibiotic resistance. Both said they worked at plants which had decided to study and install new technology to improve water treatment, methods that reduce the discharge of bacteria. One plant was installing effective membranes, and the other ozonation technology. The latter method will also reduce drug residues, according to the informant.We had a project just a couple of years ago then, or yes, it ended well last year, […] but then we had, among other things, sampling up there, where we looked at bacteria, how much bacteria comes out of the membranes and how much antibiotic-resistant bacteria comes out. And it was basically zero.”“(M1)Ozone is a very powerful eh, oxidizing agent, it breaks down most drug residues eh, or drug molecules, eh, quite effectively. […] It has a very strong effect on bacteria as well, they break down, so it is very effective.”“(M5)Both informants described how sludge was managed in the plants, since sludge, after the treatment process, and control of salmonella, metal, and toxic products, was often used in agriculture. Most antibiotics coming to the wastewater treatment plant stick to the sludge, said informants, and were thus separated from the water. Monitoring was also conducted at city wastewater treatment plants, informants said. In one treatment plant, follow-ups focused on known toxic compounds and on bacteria. The other treatment plant had decided to study pharmaceutical residues with the highest concentration levels in wastewater, the informant reported. However, this did not include antibiotics.All informants stated that they or their organisation had a role to play in containing antibiotic resistance. However, many highlighted that Strama (the Swedish strategic programme against antibiotic resistance) was more directly involved in work against antibiotic resistance than their own organisation. A few talked about their personal engagement. One was very frustrated about the low activity to contain antibiotic resistance in Sweden and at the global level.Legislation to protect development of antibiotic resistance in the environment was not an option according to the informants. Legislation was not possible because we do not know which measures to take, said the Environmental Protection Agency informant. The researcher informant did not believe that new regulations were necessary, because factors in society that are important to contain antibiotic resistance, such as functioning healthcare and functioning infrastructure, already existed in Sweden, although they can be improved.There were different views among the informants on who governs or should govern work to contain antibiotic resistance. One said that healthcare and some social institutions should control the work, whereas another could not see who should be responsible. One informant concluded that there was no central governance in how to conduct the work in wastewater treatment plants. Many had, however, a clear belief that the issue must be on the national agenda. The national government has the resources and must decide what to do, said one informant. Several of the informants said it was difficult to determine whether enough resources were available for work to contain antibiotic resistance. One informant observed that pharmaceutical companies needed extra resources for development of new antibiotics, and another informant lifted the necessity of long-term funding to preserve existing antibiotics which were no longer profitable.Furthermore, financing was a factor that could affect the work of many informants. The researcher was dependent on funding for the research group. Informants from wastewater treatment plants applied for funding for monitoring and developing new treatment techniques. According to the informants, the funders were often national authorities and institutions, which in turn were funded by the government.All informants thought cooperation was important, and it was mentioned as a facilitating factor in work to combat antibiotic resistance. Reasons for wanting to cooperate were many, e.g., limited resources, the broadness of the issue and involvement of several sectors, or the fact that when working together, organizations could become stronger and were in a better position to make demands. Some informants emphasized the importance of international cooperation and said it was necessary because problems with antibiotic resistance were greater outside Sweden.Only a few informants knew about the One Health concept. The government authority informant had a general understanding of the concept, and the researcher informant was familiar with the concept. However, the concept One Health was not known among the rest of the informants.Setting environmental requirements on pharmaceutical production when purchasing drugs for hospitals, as well as for pharmacies, could be difficult according to informants working in these areas. As I have understood it, so this with procurements is quite tricky when it comes to drugs because it is difficult,there is not always good transparency so that you know how this is manufactured […] As I have understood it the pharmaceutical companies are quite like, it’s a bit difficult to get insight into what is done.”“(M4)Pharmacy chains cannot influence the production of prescription drugs, informants from this area noted, because Swedish pharmacies must dispense the “product of the period” . One pharmacy informant said that the pharmacy chain had tried to influence a national authority to set environmental requirements on prescription medications the pharmacy was required to deliver, but this had failed. They [TLV] refuse and say that we do what the state has ordered from us, that, they are a state authority, and they try to follow the guidelines and requirements that they have from the state.”“(M7)Nearly all informants remembered and mentioned the detection of high levels of antibiotics in a river close to a pharmaceutical manufacturing plant in India. The pharmaceutical company informant, reflecting on this from a supplier’s perspective, said that a single company cannot make demands on the production of the drugs they buy, and all companies must have the same requirements for this to work. There were two possible options, the informant continued: an alliance of all companies with common agreements, or demands of transparency set by a national authority. According to this informant, the company monitors what is financially feasible to implement and then balances the costs of production with the price they can negotiate with the benefits agency in Sweden. Maintaining a wide assortment of antibiotics was another challenge. The pharmaceutical company informant explained how the company tried hard to keep the assortment, but this could be difficult due to the fact that the market was shrinking. For this, is the challenge, one of the challenges with existing antibiotics that you have to keep them, they have to exist, there is like no future with them because you want to, you will have reduced use, no money for companies that want to make money.”“(M10)A general problem mentioned by the informants was that knowledge was lacking and it was therefore hard to know which measures to take. For instance, the Environmental Protection Agency had discovered antibiotics in water after treatment in treatment plants, and the researcher informant had been involved in detecting resistant bacteria in water and soil. However, as the informant from the Environmental Protection Agency expressed, we do not know what this means.…[antibiotics] is one of several chemicals, then you see it as a chemical substance. And if it comes out in water and sludge, then you have a cocktail of everything possible, it’s not certain that it is only the antibiotics that play a role, but rather that they interact with everything else that is there […] So it is very difficult to say which role antibiotics play there.”“(M2)Several informants called for actions from the politicians. Political actions were, for instance, requested to influence the pharmaceutical production sites to reduce pollution of antibiotics. Another suggestion was action from the government to initiate drug treatment at wastewater treatment plants. Two informants mentioned how different disciplines sometimes have conflicting priorities. One example was that the hospital hygiene department recommended the hospital to use disposable equipment to reduce infection, whereas the environmental department recommended the hospital to use less disposable equipment for environmental reasons. Another conflict reported by the researcher informant was between physicians and pre-clinical researchers. Physicians want to treat their patients with antibiotics, whereas researchers emphasize the importance of avoiding antibiotics as much as possible. This conflict was also mentioned by the informants from environmental departments. There were four informants who answered the questions. They represented a pharmacy chain, a wastewater treatment plant, the pharmaceutical company, and the Swedish Environmental Agency. Three informants were the same informants that had taken part in the interviews conducted in 2018. The Environmental Agency had a new representative in the cooperation platform against antibiotic resistance, and this person answered the questions. The informant from the wastewater treatment plant noted that ozone technology had been developed further and the antibiotic residues which were analysed were effectively removed. However, according to this informant, coordination and cooperation in work to contain antibiotic resistance in the environment had not changed since 2018.In the field of pharmaceutical products, new activities were mentioned. The work at the pharmacy had not changed, wrote the pharmacy chain informant, and the pharmaceutical company informant reported that the company had continued its work to keeping the broad assortment of narrow-spectrum antibiotic products in Sweden. Other engagements which were mentioned in 2018 had grown. The pharmacy chain had continued its engagement for transparency in pharmaceutical production and was now working together with all Swedish pharmacy chains in achieving transparency in the production of non-prescription drugs. The pharmaceutical company informant reported that the cooperative platform, which had recently been initiated in 2018, now gathered more partners, and the informant was now in the management team. The two informants mentioned new measures taken at policy level. These included governmental assignments for the Swedish Medical Products Agency (MPA) and for the National Dental and Pharmaceutical Benefits Agency (TLV), e.g., to organize an environmental premium for procurement of antibiotics, to strengthen access to older antibiotics, and to open a new knowledge centre for pharmaceutics in the environment, with the aim to spreading knowledge and stimulating measures and development in the area. The informant from the Environmental Protection Agency said that there was no major difference in how the agency was monitoring the environment compared to the year 2018. However, the antibiotic resistance issue had started to reach networks and platforms where the Agency was involved, and during 2018 to 2023, the agency will be distributing grants for drug treatment at wastewater treatment plants. The Swedish platform for agencies has a role to coordinate the work to combat antibiotic resistance, but the antibiotic resistance issue was still no big question at any environment agency, reported the informant.This study explored how a selected number of stakeholders from six different health and public service sectors and areas looked upon their role in combating antibiotic resistance. We found that all of them thought they had a role to play, and that their actions can be described in five subcategories: monitoring environment; developing knowledge; spreading knowledge; reducing antibiotics and bacteria reaching the environment; and activities for restrictive antibiotic use. Many informants were active in more than one of these subcategories. Another finding was that most of them felt a lack of governance in this work. In spite of this, their actions were in accordance with measures suggested in the Swedish national action plan. The One Health approach was only known by the policymaker informant and the medical microbiology researcher, but not among informants at the practical level.Bloomer and McKee  suggest This is the third interview study from our research group exploring how stakeholders from different sectors and areas, and from various levels, perceive their role and how they can contribute to containing antibiotic resistance. In total, 34 interviews were performed during a period of six months in the year 2018. At the time of analysis, interviews were divided into three parts: the human sector; the animal sector, and the environment sector. The rational for this was our perception that the work to contain antibiotic resistance were mainly going on in the sectors separately. Our first two studies focused on human medicine and animal production, respectively . In bothOur findings in the present study were different. All informants thought they had a role to play to combat antibiotic resistance and talked about activities they were involved in. However, they did not see any leadership of actions. Some of the stakeholders in our study expressed a personal engagement and they followed new findings from research in their area. This could probably explain why their actions were in line with the recommended actions and appeared to be coordinated according to the national action plan, even though they themselves did not seem to be aware of this plan. These stakeholders seemed to be ahead of the national plan in their requests for actions from authorities. A few years later, some of these requested issues were included in the updated national action plan. Other stakeholders in our study were waiting for information from the policy level. One example was the Swedish Environmental Protection Agency which was awaiting directions from the government to act. The Swedish Environmental Protection Agency could possibly take a role to lead the activities to combat antibiotic resistance in the environment. However, the agency had at the time of the interview just recently been involved in the national network of agencies against antibiotic resistance, and had not yet found its role. As the informant explained, they needed more knowledge about what it means when antibiotic residues are found in the environment, and about which measures to take before they can act. In the autumn 2021, the agency reported that the issue of antibiotic resistance in the environment still was no big question at environmental agencies, but that this question had started to reach the networks and platforms the agency took part in. Our findings are in accordance to the global situation in general, and less attention has been given to antibiotic contamination of the environment . A common finding in the three interview studies was that the One Health approach, with few exceptions, was only known at the policymaker level. Swedish agencies have worked together since an intersectoral coordinating mechanism was initiated in 2012 . This meCooperation between stakeholders at different levels was seen in our study in the animal production sector . To invoThe use of antibiotics is the main driving factor for antibiotic resistance development ,12. ThusInformants representing wastewater plants, environmental departments at hospitals, and pharmacies appeared to have a role in reducing pollution of antibiotics and other chemicals in the environment. Even here, collection of pharmaceutical waste can differ globally. A study in Ghana revealed that four out of five hospitals were without separate collection and disposal programs for waste management, and that large parts of the population had unused, leftover or expired medicines at home ,28. RuleThe Environmental Agency monitored toxic compounds in water and soil. However, the identification of antibiotics in treated water by the Environment Agency did not always lead to any action, the argument being that the board needed more knowledge about effective measures before actions could be taken. It is interesting to note that, in this manner, the Environmental Agency appeared to have the least engagement in work to contain antibiotic resistance in the environment. Lack of knowledge, and not knowing what measures to take, was considered problematic by other informants as well. Other problems included the inability to set environmental requirements when the pharmacies and hospital purchased medications, and the lack of central governance in how to conduct the work. These findings suggest the need for some sort of governance in work to contain antibiotic resistance in the environment. The Swedish strategic programme against antibiotic resistance (Strama) has played a central role in providing surveillance of antibiotic use and antibiotic resistance in Sweden since 1995. However, as long as there is a lack of knowledge about which methods have the best effect, it is difficult for an organization to lead the work to limit antibiotic resistance in the environment.Lack of resources and financing could affect the antibiotic resistance work of informants representing pharmaceutical companies and medical research. The pharmaceutical industry is slowly being incorporated into public health efforts regarding which products and how much of them are used . As noteThe first Swedish national action plan with a One Health approach was launched in 2016 . HoweverStrategies were further developed in the updated Swedish national plan from 2020, and issues that the informants in our study asked for have now been included . Now theThe main contribution of this qualitative study is its insight into the unique perspectives and perceptions of work to contain antibiotic resistance in the environment among a select number of informants working in areas that were supposed to have impact on environmental issues in Sweden. All informants perceived they had a role to play in containing antibiotic resistance in the environment. Our intention was not to present a representative survey of all stakeholders’ perceptions of work to contain antibiotic resistance in the environment. Our findings are thus based on the perceptions of a small sample size of informants and cannot be generalized. It was beyond the scope of this study to include perceptions of other stakeholders in other regulatory bodies or sectors also involved in work to contain antibiotic resistance in the environment. For example, there were no stakeholders from the animal sector included in this study. If other sectors than the chosen had been included, we would probably have identified other activities to reduce antibiotic resistance and resistant bacteria in the environment. A strength of the study is the qualitative design with interviews that allowed the informant to speak freely around the subject. This design gave us a rich material from each of the informants and good insights into their work from their perspective. The analysis was careful and structured to ensure trustworthiness, and was performed by two experienced qualitative researchers. The findings were further strengthened by the follow-up questions sent to the informants and the answers that were given from informants from four different areas.A One Health approach to contain antibiotic resistance means to simultaneously work to reduce the development and spread of antibiotic resistance in humans, animals, and in the environment. So far, there appears to be little coordination in the work to contain antibiotic resistance in the environment in Sweden. The stakeholders at the practical level were involved in activities in their own area which they perceived could have an impact on antibiotic resistance, but did not feel that they were included in a common program. Their actions seemed to be coordinated, but this was, according to the stakeholders, based on findings from research in their area rather than on strategies developed by national authorities. The One Health approach has been implemented and was known at the policy level in Sweden, but was not established at the practical level.


The existing studies lack research on the ductility of steel-reinforced high-strength concrete (SRHC) columns and current specifications restricted the use of high-strength concrete in steel-reinforced concrete (SRC) columns. To compensate for the shortcomings of the existing research and promote the application of high-strength concrete in SRC structures, we test six SRHC columns and one SRC column to examine the effects of the steel content, eccentric distance, and slenderness ratio on the ductility, bearing capacity, and failure mode of SRHC columns. Further, Abaqus finite element models are established to predict the influences of more parameters on post-peak ductility and analyze the relationship between strain development of the concrete and the decrease in bearing capacity of SRHC columns. The results show that the penetration of cracks into aggregate during failure is the primary reason for the poor ductility of the SRHC columns. Improving the confinement effect of the stirrups on concrete is the most effective measure to enhance the ductility of the SRHC columns. The decline in the stirrup spacing from 100 mm to 50 mm increased the ductility coefficient from 1.47 to 5.56. The effect of the steel content, stirrup strength, and slenderness ratio on the ductility coefficient of SRHC columns is less than 30%. After analyzing the reason for the error of current specifications, a modified formula with an error of less than 5% is developed.  Steel-reinforced concrete (SRC) columns have been widely used in long-span spatial structures and ultrahigh-rise buildings ,2,3. Sinfc) should not exceed 75 and 70 Mpa, respectively. JGJ138-2016  iIn order to explore the accuracy of the calculation results under different parameters, we compare the calculated and experimental results under various parameters in From the above analysis, it can be inferred that ignoring the constraining effect of the stirrups and overestimating the effect of steel are the main reasons for the error in the calculations of the specifications. In view of the above problems, this paper puts forward some suggestions for revising the formulas.The confinement effect of the stirrups can effectively improve the bearing capacity and strain of concrete. According to Zhao , the conke) to calculate the effective constraining force (fl’) of the stirrups as follows:W is the spacing of the longitudinal bars; s indicates the spacing of the stirrups; bc and dc represent the length and width of the stirrups, respectively; and ρcc stands for the ratio of the longitudinal reinforcement area to the constraint area.Due to the arching effect of the stirrup restraint, the lateral restraining force cannot be fully exerted in the weakly restrained area of the concrete. Therefore, Mander  equalizek) of concrete in the confined area to calculate the strength of the confined concrete as follows:fcc is the strength of the concrete under equivalent action and fc0 denotes the strength of the unreinforced concrete.Mander  proposedkca) to calculate the equivalent concrete strength of the whole section:AC is the section area of the specimen and AE indicates the concrete area of the stirrup-constrained zone.Since the concrete cover is not constrained, this paper proposes the constraint correction coefficient (γ) to evaluate the decrease in the bearing capacity of the columns caused by the concrete collapse when steel yields:Nd represents the decline in the bearing capacity of the column caused by concrete collapse; AC indicates the section area of the specimen; AE is the concrete area of the stirrup constraint zone; εa stands for the yield strain of steel; and εcu denotes the ultimate compressive strain of concrete.Since high-strength steel cannot reach the maximum strength simultaneous with concrete, the decrease in the bearing capacity of the columns caused by the early crushing of concrete must be considered. Nd. The formulas for calculating the bearing capacity of the column after correction based on code JGJ138-2016 [According to the abovementioned inferences, the strength of the equivalent constrained concrete replaces the concrete strength, and the decrease in the bearing capacity of the column caused by the concrete collapse when the steel yields is considered. Since the concrete of the column under eccentric compression only damages on the compressed side, the reduction in the bearing capacity of the concrete is taken as 1/4All the SRHC columns showed no apparent signs before failure. The analysis of the failure mode of the concrete revealed that the penetration of cracks into aggregate during failure was the main reason for the poor ductility of the SRHC columns.N–Δ curves declined dramatically. The constraining effect of the steel on the concrete could also reduce the descending slope of the curve.The stiffness of all the SRHC columns remained unchanged before failure, and after reaching the ultimate bearing capacity, the Increasing the steel content could improve the ductility of the SRHC columns, but the influence was less than 20%. Furthermore, the ductility of the SRHC columns did not correlate positively with their eccentricity. When the eccentricity rises from 0 to 40 and 120 mm, their ductility coefficient enhances by −19% and 28%. The effect on the ductility coefficient by the slenderness ratio is less than 2%.The Abaqus model considering the confinement effect on the concrete could precisely simulate the mechanical properties of the SRHC columns. The finite element analysis demonstrated that the ductility of the SRHC columns markedly improved by reducing the stirrup spacing. The enhance range on the ductility coefficient by the stirrup spacing can exceed than 200%. In addition, increasing the steel strength could enhance the bearing capacity and ductility of the SRHC columns simultaneously.Codes JGJ138-2016, EN1994-1-1-2004, and AISC360-16 underestimated the bearing capacity of the SRHC columns. The effects of the stirrup restraint and the decrease in the bearing capacity caused by the concrete collapse were the main factors affecting the accuracy of the code calculations. The correcting suggestions proposed herein could effectively enhance the accuracy of the specification methods for calculating the bearing capacity of steel-reinforced high-strength concrete columns.This work conducted compression tests and Abaqus finite element analysis of steel-reinforced high-strength concrete columns to analyze their failure mode and mechanical properties. In addition, different specifications were compared in terms of their accuracy in calculating the bearing capacity of SRHC columns, and suggestions for improving the accuracy of the calculation methods were proposed. The following conclusions could be drawn from the above findings:In this paper, measures to enhance the ductility of SRHC columns are proposed, but the solution to premature cracking of concrete cover has not been studied. While the addition of fibers in concrete can effectively hinder concrete cracking and improve the ductility of concrete. As a result, further research can be added in SRHC columns containing fiber.Limited by experimental conditions, the current research on the ductility of SRHC columns under eccentric load is insufficient. More parameters, such as steel form, steel strength, and cross section form can be investigated by experiment and numerical model on the SRHC columns under eccentric load.In the current research, compression tests and Abaqus finite element analysis are carried out on the SRHC columns. The measures on enhancing ductility and revisions on the calculation methods are proposed. However, further research of SRHC columns can provide more in-depth investigation on the following:


Background: The emergence of antimicrobial resistance (AMR) is affecting public health management in developing countries, including Bangladesh. Irrational and inappropriate use of antibiotics in healthcare settings has led to widespread drug resistance. To optimize antimicrobial usage to combat AMR and enhance infection treatment, the competence of healthcare workers in antibiotic prescribing is indispensable. We sought to determine the perceptions about antimicrobial resistance, antibiotic stewardship programs (ASPs), and antibiotic prescribing approaches among physicians at tertiary-care public hospitals in Bangladesh. Methods: From September to December 2020, we conducted a mixed-methods study in 9 tertiary-care public hospitals. Using a self-administered, semistructured questionnaire, we collected data on antibiotic stewardship and prescribing practices from 452 on-duty physicians. In addition, we conducted 16 key-informant interviews to explore AMR perceptions and determinants. Results: Only 43.8% of physicians were aware of the ASP, and none of the hospitals had any ASP initiative in place. Most of the participants (70.6%) recommended tailored training and antibiotic prescribing guidelines (63.7%) for effective ASP initiatives. More than half of the physicians (54.7%) preferred to receive regular monitoring and feedback on their routine antibiotic prescriptions from the stewardship program. In terms of the antibiotic prescribing approach, only 25.9% of physicians relied on microbiology lab findings, whereas 69.5% routinely employed oral or intravenous antibiotics. Also, 40.0% of physicians considered the patient’s ability to afford the antibiotic cost when recommending antibiotics. The qualitative investigation identified the use of broad-spectrum antibiotics, absence of guidelines, and inadequate laboratory support as factors contributing to AMR in the healthcare setting. Self-medication, over-the-counter dispensing, and patients’ economic instability to complete the dosage were also attributed to the irrational use of antibiotics. As a priority step, physicians advocated for intensive training on antibiotic advising, mass awareness campaigns on safe antibiotic usage and dispensing, and a restriction on the widespread sale of antibiotics from pharmacies. Conclusions: Despite favorable perceptions, the fundamental understanding of physicians regarding ASPs and rational prescribing of antibiotics needs to be improved through context-specific educational interventions and capacity building. In addition, a coherent and comprehensive policy is required for the development and implementation of antibiotic usage guidelines along with integrated ASP initiatives to combat AMR.Funding: NoneDisclosures: None