Iridoviridae), including Frog Virus 3 (FV3), are large dsDNA viruses that cause devastating infections globally in amphibians, fish, and reptiles, and contribute to catastrophic amphibian declines. FV3’s large genome (~105 kb) contains at least 98 putative open reading frames (ORFs) as annotated in its reference genome. Previous studies have classified these coding genes into temporal classes as immediate early, delayed early, and late viral transcripts based on their sequential expression during FV3 infection. To establish a high-throughput characterization of ranaviral gene expression at the genome scale, we performed a whole transcriptomic analysis (RNA-Seq) using total RNA samples containing both viral and cellular transcripts from FV3-infected Xenopus laevis adult tissues using two FV3 strains, a wild type (FV3-WT) and an ORF64R-deleted recombinant (FV3-∆64R). In samples from the infected intestine, liver, spleen, lung, and especially kidney, an FV3-targeted transcriptomic analysis mapped reads spanning the full-genome coverage at ~10× depth on both positive and negative strands. By contrast, reads were only mapped to partial genomic regions in samples from the infected thymus, skin, and muscle. Extensive analyses validated the expression of almost all of the 98 annotated ORFs and profiled their differential expression in a tissue-, virus-, and temporal class-dependent manner. Further studies identified several putative ORFs that encode hypothetical proteins containing viral mimicking conserved domains found in host interferon (IFN) regulatory factors (IRFs) and IFN receptors. This study provides the first comprehensive genome-wide viral transcriptome profiling during infection and across multiple amphibian host tissues that will serve as an instrumental reference. Our findings imply that Ranaviruses like FV3 have acquired previously unknown molecular mimics, interfering with host IFN signaling during evolution.Ranaviruses ( Iridoviridae), which comprises a group of emerging viruses that infect cold-blooded animals, including amphibians, fish, and reptiles [de facto cause diseases in other susceptible stages during the amphibian life cycle [Frog virus 3 (FV3) is a large ~105 kb), double-strand DNA (dsDNA) virus belonging to the Ranaviruses genus  and new founding members of other types of giant dsDNA viruses, advances in Ranavirus research contribute to delineate viral evolution and host tropism diversity among iridoviruses and NCLDVs, which can unveil evolutionary links among viruses associated with different cellular life forms [Among various Ranaviruses accounting for epizootics in amphibians, fish, and reptiles, FV3 is the best-characterized model and the prototype of the genus Ranavirus ,2. Histoaviruses ,13,14. Afe forms . HoweverEarly pioneering studies have resolved 47 viral RNAs and 35 viral proteins using gel electrophoresis in FV3-infected fish cells, and temporally classified them into early, immediate delay, and late genes along the viral infection cycle ,17. The de novo FV3’s transcriptome and conduct gene functional analysis using next generation sequencing (NGS)-facilitated metagenomics approaches [To complement recent virome studies and novel Ranavirus isolations, it is imperative to characterize proaches ,20. To eproaches ,22. The proaches ,22. In aproaches ,17, our proaches ,24,25. Iproaches ,24,25,26proaches ,22. The proaches ,24,25. OX. laevis research resource for immunology at the University of Rochester [® CCL-42) or baby hamster kidney-21 (BHK-21) cells (ATCC® CCL-10) were maintained in the suggested medium  supplemented with 10% fetal bovine serum , penicillin (100 U/mL), and streptomycin (100 μg/mL) at 30 °C with 5% CO2. FV3 was grown by a single passage in FMH or BHK-21 cells, and virus stocks were purified by ultracentrifugation on a 30% sucrose gradient. The virus load was assessed by plaque assays on a BHK-21 monolayer under an overlay of 1% methylcellulose (ATCC® CCL-102). Virus stocks were titrated using plaque assays of serially diluted viral stocks on BHK-21 monolayers to express as plaque forming units (PFU), as previously described [Outbred specific pathogen-free adult (1–2 years old) frogs were obtained from the ochester . All aniochester ,22. In bn = 5 per group). Animal infections were conducted by intraperitoneal (i.p.) injection of each animal with FV3-WT or FV3-∆64R at 1 × 106 PFU in 100 μL of amphibian phosphate-buffered saline solution (APBS) or only APBS for mock controls. At 0, 1, 3, and 6 days post-infection, animals were euthanized by immersion in bicarbonate buffered 0.5% tricaine methane sulfonate (MS-222), and indicated tissues were sampled and pairwise allotted for classical viral titration and gene expression analyses. The samples of three days post-infection were selected for further unbiased or targeted transcriptomic studies, as diagramed in Adult frogs at comparable ages and body weights were randomly allotted into mock controls and infected groups  for PCR-based assays or a column-based RNA/DNA/protein purification kit  for transcriptomic analysis. RNA integrity and concentration were evaluated with a NanoDrop 8000 spectrometer  and an Agilent 2100 Bioanalyzer  to ensure RNA samples with A260/A280 > 1.8 and RNA integrity number (RIN) > 7.0 qualified for the construction of sequencing libraries .1 to 1010 vDNA Pol II DNA copies cloned in a plasmid, as previously described [Quantitative PCR (qPCR) analysis was performed using 150 ng/reaction of DNA templates in an ABI 7300 real-time PCR system and PerfeCta SYBR green FastMix, ROX . To measure the FV3 genome copy number based on detection of FV3gorf60R, which encodes a viral DNA polymerase II (Pol II), a qPCR was performed against a standard curve generated using a serially diluted template DNA containing 10escribed ,29.X. laevis or FV3 virus through Xenbase [RNA samples used for RNA-Seq sequencing library preparation were pooled from three qualified extractions of each group, as indicated above. For sequencing libraries construction, mRNA purification, fragmentation, construction of sequencing libraries, and sequencing were performed using the Illumina Pipeline . Approximately 40 M clean reads per sample were generated for genome-wide transcriptomic analyses. The trimmed reads were further assembled and mapped to the reference genome/transcripts of  Xenbase  or NCBI  Xenbase , respect Xenbase . The traXenopus proteins of IFN signaling, especially those of IFN receptors and IFN regulatory factors (IRFs). The Blast searching programs were mainly through the NCBI Blast portal [We conducted extensive sequence- or pattern-based Blast searches against the FV3 reference genome (GenBank Accession No. NC_005946.1) using conservative domains in t portal  with thet portal , and wert portal .Multiple sequence alignments and views were done with a Jalview program. Protein structure models were simulated and visualized through combinative uses of the programs of PyMol, Chimera, and Phyre2 as described , as wellp < 0.05 was considered significant [Statistical analysis was conducted using one-way analysis of variance (ANOVA) and Tukey’s post hoc test. A two-sample F test was used for significant evaluation between samples/treatments. A probability level of nificant ,28.X. laevis frogs for well-controlled sample collection. As shown in FV3 infects anuran amphibians at various developmental stages, and is highly lethal in tadpoles. Adult frogs, by contrast, are more resistant to viral infection, and after viral clearance, a low level of quiescent viruses were isolated from apparently healthy frogs ,22,28. TFV3’s genome encodes 98 putative coding genes (FV3gorf1-98) as annotated along its reference genome . PreviouStatistical analyses of the RNA-Seq results revealed several interesting aspects: (1) FV3 may maintain a more complex transcript mixture in vivo than in a uniform cell line related to unsynchronized infection stages upon diverse cell types in tissues. Given that the viral transcripts were significantly detected in the kidney, spleen, liver, lung, thymus, and intestine, we concluded that the differential viral gene expression in different tissues resulted primarily from a systemic virus–host interaction initiated from intraperitoneal injection. (2) FV3-specific reads were significantly enriched in an increasing order in the intestine, lung, liver, spleen, and predominantly in the kidneys, but much less abundant in the skin and muscle, where FV3 replication may be negligible. (3) The transcript profiles of the FV3-∆64R mutant were nearly identical to the FV3-WT in the kidney, but qualitatively and quantitatively very different in other tissues. (4) The unbiased transcriptome study detected transcripts of the FV3 genome almost equivalently along both positive and negative strands, which confirmed the existence of viral coding genes at both strand orientations . FurtherAs mentioned, it is widely assumed that early (E) genes include encoding regulatory factors or proteins that mediate nucleic acid metabolism and immune interaction, whereas late (L) genes primarily take part in DNA packaging and virion assembly and releasing. Transcripts of FV3’s E genes are further classified into immediate early stable messages (IE-S), immediate early transient messages (IE-Tr), and delayed early (DE) transcripts ,17,18. FSeveral FV3 genes were previously assessed using FV3 knockout mutants, including FV3−Δ64R, FV3−Δ52L, and FV3−Δ82R, which contain molecular defects for regarding genes to putatively encode a vCARD-like protein, a β-hydroxysteroid dehydrogenase homolog (βHSD), and an IE-18kDa protein (ICP18), respectively ,22. Compcis-regulatory elements (CRE) in the promoter region of IFN or ISG genes, more variable IAD mediates protein–protein interactions with other transcription factors, and hence defines the functional diversity of different members in the IRF family [Xenopus IRF1/IRF2 (Norf76R), IRF3 (Norf13L and Orf19R), IRF4 (Orf41R), IRF6 (Norf42L), and IRF8 (Orf27R and Orf82R). In addition to the coding genes of the 98 FV3gorfs (Orf) annotated along the FV3 reference genome, some vIRFs were encoded by alternative coding frames (Norfs) and are newly predicted by this study with supportive transcriptomic data. This indicates an extended coding capacity of the FV3 genome beyond our previous understanding  IRF1 and IRF2 regulate T cell activation and enhance the Th1 immune response; (2) IRF3 and IRF7 are engaged in IFN production, signaling downstream innate immune recognition of various intracellular pathogens, including viruses; (3) IRF5 is involved in the regulation of inflammation and apoptosis, is structurally similar to IRF6, and the regulates proliferation and differentiation of keratinocytes; and (4) IRF9 is part of the IFN-stimulated gene factor 3 (ISGF3) complex that transmits type I and III IFN signals ,44,45. TXenopus il10rb. The detection of vFN3 mimics that primarily target type III IFN receptors is consistent with previous observations about FV3’s suppressive effect on IFN-λ expression in Xenopus [ Xenopus ,28, whic Xenopus . It is t Xenopus ,48,49.Frog virus 3 (FV3) represents a well-characterized model to study Ranavirus pathogens that are prevalent in worldwide habitats of amphibians, fish, and reptiles, and significantly contribute to the catastrophic amphibian decline ,7,8,9,10


Methodological mistakes, data errors, and scientific misconduct are considered prevalent problems in science that are often difficult to detect. In this study, we explore the potential of using data from Twitter for discovering problems with publications. In this case study, we analyzed tweet texts of three retracted publications about COVID-19 (Coronavirus disease 2019)/SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and their retraction notices. We did not find early warning signs in tweet texts regarding one publication, but we did find tweets that casted doubt on the validity of the two other publications shortly after their publication date. An extension of our current work might lead to an early warning system that makes the scientific community aware of problems with certain publications. Other sources, such as blogs or post-publication peer-review sites, could be included in such an early warning system. The methodology proposed in this case study should be validated using larger publication sets that also include a control group, i.e., publications that were not retracted. Certain manuscripts are retracted after publication, although they have been reviewed by colleagues in editorial peer reviews   that are later retracted? Are Twitter users who mention retracted publications informed about the paper status? Do they explicitly mention the issues why the publication has been retracted? These are the questions we try to answer in this case study by analyzing the tweets that mention three different retracted publications about COVID-19 (Coronavirus disease 2019)/SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and their retraction notices. Since Twitter is a very fast medium, tweets might be used as early indicators for problems with certain publications.https://retractionwatch.com/retracted-coronavirus-covid-19-papers/). As of 24 September 2020, Retraction Watch lists 33 COVID-19/SARS-CoV-2 papers as retracted. We selected the papers for this case study with the requirements that there is a Digital Object Identifier (DOI) and known publication date for the publication and its retraction notice and the dates of publication and retraction are at least 2 weeks apart:Bae et al.,  studied Wang et al.,  reportedProbably the most attention among the three publications was drawn to the study by Mehra et al., . They reThe World Health Organization (WHO) declared the 2019–2020 coronavirus outbreak a Public Health Emergency of International Concern .These three publications have received considerable attention in online media as can be seen from their Altmetric Attention Scores. Costas et al.,  studied In this short literature review, we focus on very recent publications dealing with retracted papers and those that additionally analyze the relation between retracted papers and altmetrics, in particular tweets. In the latter case, the literature is very sparse.n = 8612) and USA (n = 3179) followed by India (n = 934) and Japan (n = 874). Similar retraction frequencies were reported by Zhang et al., .”  between scientific, technological, and altmetrics impact, while a negligible correlation (Pearson's correlation coefficient below 0.2) between funding impact and the other kinds of impact was found. Shema et al.,  for extracting tweet identifiers for any tweets that mentioned either any of the three retracted publications or their retraction notices on Twitter. The tweet IDs of the tweets that mentioned any of the publications or retractions on Twitter were downloaded from the Twitter API. We connected to both APIs using R  has not been recognized. The terms ‘LOD' or 'limit of detection' cannot be spotted on either Figs. n = 53) or the paper after retraction (n = 50). The tweet texts are analyzed using two different time periods: (i) before the publication date of the retraction and (ii) since the publication date of the retraction.Figure Figure https://t.co/15qvCa0fvw”  were retweets as identified by their first two letters ‘RT’ followed by a whitespace. The first tweet that casted doubt on the employed flow cytometry methodology was posted on 9 April, 2020 and it reads “Lots of discussion on Twitter about this paper, however some questions outstanding: Does the flow cytometry actually show cell infection? Where is the positive control comparison using classically infected cells?” , both before publication of the retraction notice. Most of these 124 tweets , see Watson  results could be confirmed or not. If these studies demonstrate that tweet texts are a comprehensive source for indicating problems with publications, future studies could combine multiple warning signals for setting up a corresponding recognition system. Such automated systems can only provide hints. A careful check by experts in the field will be needed for verification or falsification of the suspicion of problems with publications.


Prophylactic antibiotic usage during delivery is a common practice worldwide, especially in low- to middle-income countries. Guidelines have been published to reduce antibiotic overuse; however, data describing the use of prophylactic antibiotics and clinician adherence to guidelines in low- to middle-income countries remain limited. This study aimed to describe the prevalence of prophylactic antibiotic use, factors associated with its use, and clinician adherence to guidelines. A retrospective review was conducted for all deliveries from 1 January 2016 to 31 December 2018 at a tertiary level hospital in Indonesia. The prevalence of prophylactic antibiotic use during delivery was 47.1%. Maternal education level, Ob/Gyn specialist-led delivery, a history of multiple abortions, C-section, premature membrane rupture, and antepartum hemorrhage were independently associated with prophylactic antibiotic use. Clinician adherence to the guidelines was 68.9%. Adherence to guidelines was the lowest in conditions where the patient had only one indication for prophylactic antibiotics . The findings showed that the prevalence of prophylactic antibiotic use during delivery was moderate to high. Adherence to local guidelines was moderate. Updating the local prescribing guidelines may improve clinician adherence. Bacterial infection during labor and delivery is one of the leading causes of maternal and neonatal mortality worldwide, accounting for about one-tenth of the global burden of maternal and neonatal deaths ,2. WhileReduction of bacterial infections is typically attempted by the prescription of prophylactic antibiotics during labor and delivery as a routine practice. Studies have shown that the use of antibiotics has reduced maternal infections and has improved neonatal outcomes. The incidence of neonatal sepsis has significantly declined since the introduction of guidelines by the Centers for Disease Control and Prevention (CDC) for the prevention of perinatal Group B Streptococcus (GBS) ,11. The These significant benefits of antibiotic use during labor and delivery have inevitably led to an increased use of antibiotics worldwide ,15. EvenAntibiotic consumption (including inappropriate usage) is the major cause of antimicrobial resistance. Therefore, more data on antibiotic use practices from low-income countries, including prophylactic antibiotic practices during delivery, are essential for guiding and controlling the overuse and misuse of antibiotics to mitigate the development of antimicrobial resistance. This study utilized data on antibiotic use during delivery from three consecutive years at a tertiary-level referral hospital in Indonesia. The aims were to describe the prevalence of prophylactic antibiotic use during delivery, the significant factors that were associated with prophylactic antibiotic use, and clinician adherence to local guidelines. From a total of 3957 recorded deliveries in the hospital during 2016–2018, the medical records of 3657 (92.4%) patients were retrieved: a total of 1087 of 1202 (90.4%) were from 2016, 1227 of 1338 (91.7%) were from 2017, and 1343 of 1417 (94.8%) were from 2018. Overall, the mean age of women who underwent delivery at this hospital was 29.9 years; and most of them were in the group age 17–35 (78.1%). Among the mothers, most were residents of Palembang city (63.8%) and most were high school graduates (72.9%). The gestational age of most deliveries was esidents . Across p < 0.0001). Of the 3657 deliveries, 2730 (74.7%) were given antibiotics during delivery. Of the given antibiotics, sixty-three percent were categorized as prophylaxis, which accounts for 47.1% of all deliveries. The prevalence of prophylactic antibiotic use was 63.6% for C-Section deliveries and 33.7% for vaginal deliveries. A marginal increase occurred at the end of 2018, but the proportion of women receiving prophylactic antibiotics decreased overall during the study, from 59.2% in 2016 to 46.2% in 2017 and to 38.1% in 2018 . The proAmong the conditions where prophylactic antibiotics were recommended, the most common condition was C-section, followed by PROM, and then preterm  deliveries . During The univariate analysis revealed significant associations of maternal educational level, place of residence, birth attendant, frequency of previous abortion, gestational age, mode of delivery, PROM, and antepartum hemorrhage with prophylactic antibiotic use. After adjustment, the associations between prophylactic antibiotic use and place of residence and gestational age lost their statistical significance. However, the associations between prophylactic antibiotic use and maternal education level, birth attendant, frequency of previous abortions, mode of delivery, PROM, and antepartum hemorrhage persisted .3, with an intrapartum temperature >38 °C, and with foul-smelling amniotic fluid were also more likely to be given ceftriaxone , , ) and , respectively). However, patients with PROM were more likely to be given ampicillin than ceftriaxone .The factors relating to the choice of using ampicillin and ceftriaxone, the most frequently used prophylactic antibiotics at the study site, were also analyzed. The use of ceftriaxone was more likely to be suggested by Ob/Gyns than by residents in training . Patients with C-sections with leukocyte counts > 15,000/mmp < 0.0001).Referring to the local guidelines on prophylactic antibiotic administration in delivery, of the 3657 patients who had deliveries, 2725 (74.5%) had at least one indication for prophylactic antibiotic administration, and 932 (25.5%) had no indication. Among the 2725 patients who had an indication for prophylactic antibiotics, 1654 (60.7%) received prophylactic antibiotics, while 1071 (39.3%) did not. Among the 932 mothers who had no indications for prophylactic antibiotics, 67 (7.2%) still received antibiotic prophylaxis. The overall adherence to prophylactic antibiotic use guidelines was achieved in 68.9% of all deliveries. However, over the years, the proportion of adherence significantly decreased, decreasing from 77.2% in 2016 to 71.2% in 2017 and to 60.1% in 2018 (p < 0.001). The highest adherence was noted in patients who had three indications (93.2%) followed by zero indications (89.6%) and two indications (77.3%), and the lowest level of adherence was in patients with one indication (59.3%). The number of indications for prophylactic use was also associated with guideline adherence , and it was the lowest when the patient only had one indication for prophylactic antibiotics  , antepartum hemorrhage , and foul-smelling amniotic fluid . However, adherence was significantly lower in more recent years  and 2018  compared to the year of 2016) with preterm deliveries , with forceps extraction compared to spontaneous vaginal delivery , with maternal fever , and with a maternal leukocyte count > 15,000/mm24–0.54) .2010) in Denmark, reported that prophylactic antibiotic use during delivery was 33%, similar to the prevalence in the USA and Canada  [This study demonstrated that the prevalence of prophylactic antibiotic use in all deliveries was 47.1%. The overall prevalence of prophylactic antibiotic use during delivery in the current study was higher than in higher-income countries. Stockholm et al., through the Danish Copenhagen Prospective Study on Asthma in Childhood (COPSACctively) ,28,29. Cctively) ,17. The More than 60% of the prophylactic antibiotic use was in C-section deliveries. We observed that despite the strong recommendation in the guidelines for prophylactic antibiotic use for C-section, the prevalence of the practice was nearly 65%, which was lower than expected. The main possible reason for this situation is that some patients who had C-section deliveries were already being treated with antibiotics for therapeutic purposes, such as for urinary tract infections or for intraamniotic infections. Therefore, the administered antibiotics were not considered prophylactic antibiotics and were beyond the scope of this study. Another possible explanation, although less likely, was the possibility of inadequate patient management documentation, including prophylactic antibiotic administration, in the medical record. Despite the significant improvement in medical data recording, inaccurate and incomplete medical records remain a worldwide problem ,31,32,333, and preterm deliveries  [3 [Our study also showed a significant decrease in prophylactic antibiotic use, which decreased from 59.2% in 2016 to 38.1% in 2018. However, this decline was followed by a significant decrease in the rate of clinician adherence to the guidelines. Therefore, the reduction in prophylactic antibiotic use may reflect an increased rate of non-adherence. Even though guidelines are believed to represent the best evidence and judgments, they are not fixed, mandatory protocols for healthcare providers. The decision to follow a guideline is independently based on the healthcare provider’s clinical judgment. The local guidelines recommend prophylactic antibiotics in C-section deliveries, PROM, cases of antepartum hemorrhage related to placenta previa, a maternal intrapartum temperature 7 weeks) . The loc7 weeks) ,40. In a7 weeks) . Antepar7 weeks) . Althoug[≥ 38 °C ,34. At o38 °C [3 ,41. This study found that, among the conditions recommended for prophylactic antibiotic administration, only C-sections, antepartum hemorrhage, and PROM were persistently associated with an increased risk of prophylactic antibiotic use. Maternal fever and isolated increased leukocyte counts were not associated with an increased risk of prophylactic antibiotic use but were significantly associated with non-adherence. These latter conditions were mainly adopted in the guidelines as part of a risk-based approach for neonatal GBS infection prevention . In someThis study found that cefazoline, the type of antibiotic recommended by the guidelines for C-sections, was rarely used. Ceftriaxone was one of the most used antibiotics for prophylaxis in the current study setting. Drug sustainability may explain the choice of ceftriaxone compared to cefazoline in the pharmacy, as the supply of the former tends to be more stable and affordable. Ceftriaxone was also more commonly used due to common knowledge among practitioners that this antibiotic has excellent bioavailability and effectiveness, a low toxicity profile, and a long half-life .This study showed that the healthcare providers had only moderate adherence to the guidelines, at 68%, regarding conditions indicated for prophylactic antibiotic. In general medical practices, a wide variation exists in terms of the guideline adherence rate, from 20% to nearly 100%. This rate varies according to the purpose of the guidelines, the definition of adherence employed, and the location of the study ,51. As eGiven that the antibiotic prescribing guideline was formulated to minimize the emergence of antibiotic resistance and optimized patient treatment, the hospital’s stakeholders need to review the guideline implementation on a regular basis. Local healthcare providers should be involved in guideline development and review processes. In settings where guidelines are not strictly followed, factors that determine the drug prescription in developing countries include economic incentives, stable supplies, fear of unfavorable outcomes, peer norms, and local medical culture . ConsultA significant association was observed between prophylactic antibiotic use and maternal education level, birth attendant, and history of multiple abortions. Our study had a high proportion of high school graduates, which may have lessened the power of our estimation; however, our study indicated that prophylactic antibiotics were given more frequently to high school graduates than to college graduates. A study by Stokholm et al. also found that education level was related to antibiotic use during pregnancy . Higher In this study, women with deliveries assisted by Ob/Gyns specialists were more likely to be given prophylactic antibiotics than women whose deliveries were assisted by residents. As the study site is a teaching hospital, most of the deliveries are assisted by a resident under the supervision of an Ob/Gyn specialist. If the delivery is too complicated and beyond the resident’s medical competency, the Ob/Gyn specialist then directly assists in the delivery. Therefore, this may explain the finding that Ob/Gyn specialists used more prophylactic antibiotics compared to residents. Previous studies have suggested that a physician’s experience may influence adherence to guidelines ,55, but Our findings suggest an association between a history of multiple abortions and prophylactic use. Pregnancy with a history of multiple abortions is frequently considered as a high-risk pregnancy due to its association with a higher risk of preterm birth, C-section deliveries, post-partum hemorrhage, PROM, and congenital malformation ,57,58; hThis study had several study limitations. The first limitation was that the data were obtained by reviewing medical records, and the documentation may have been incomplete, thereby leading to some information bias. However, we were able to minimize information bias given that most of the collected data in the medical records were complete. In addition, this study involved data collection on a large sample and covered over 90% of the total deliveries in the study period; therefore, it arguably represents the study site’s overall situation. A second limitation was the retrospective nature of the study, as this precluded any further elaboration on the association of the clinician’s characteristics regarding adherence. However, the main objective of this study was to describe the practice of prophylactic antibiotic use in general and not to focus on clinician adherence. A further limitation was that the results of this study reflect the conditions in a single center in Indonesia and may not be generalizable. However, considering the large amount of data that we were able to collect from three consecutive years and given the fact that our study site is a large hospital that serves all primary, secondary, tertiary care from multiple neighboring cities, to some extent, our study could represent other teaching and public hospitals in Indonesia. However, it may not represent other private hospitals that mostly serve the wealthier proportion of the Indonesian population. The prophylactic antibiotic practices between teaching and private hospitals may differ substantially.The study data comprised medical records from Mohammad Hoesin Hospital from 1 January 2016 to 31 December 2018. The hospital is a government-run teaching hospital and serves as the tertiary-level referral hospital for patients from five neighboring provinces. The hospital provides all primary, secondary, and tertiary care and has a near 1000-bed capacity. We identified all deliveries in this hospital based on the International Classification of Disease, 10th Revision, Clinical Modification (ICD-10-CM) codes  and consulted the paper-based medical records of each patient. The hospital’s electronic medical record database indicated that 3957 deliveries had occurred during this period. We were able to collect complete data from 3657 medical records (91.5%), while 338 (8.5%) of the paper-based medical records were either lost or had missing sheets and were not included in the data analysis. 3 [The variable of interest in this study was prophylactic antibiotic use during deliveries. We determined that a prophylactic antibiotic was given when written and when specified as a prophylactic antibiotic in the medical record by the physician in charge. We recorded the maternal conditions that were recommended by the local guidelines for the administration of prophylactic antibiotics. According to the local guidelines, all C-section deliveries (elective and emergency), PROM, and cases with antepartum hemorrhage due to placenta previa were recommended for prophylactic antibiotics ,36. In a,000/mm3 . The typWe also documented other sociodemographic and obstetric variables, such as the mother’s age, place of residence, level of education, birth attendant, multiple births, gravidities, parities, number of abortions, and foul-smelling amniotic fluid. p-value < 0.20 and the conditions that were recommended for antibiotic prophylaxis by the guidelines were then included in the final model to estimate the adjusted odds ratio. We derived the estimates (crude and adjusted odds ratio) with the corresponding 95% confidence intervals. A significance level of 0.05 was used in all of the analyses. The data processing and analyses were conducted using SAS®, version 9.4.The prevalence of prophylactic antibiotic use during deliveries from 1 January 2016 to 31 December 2018 was reported on a monthly basis. Poisson regression was used to assess the proportion of the use over the study period. Descriptive characteristics were summarized as frequencies and proportions. Comparisons between groups were assessed with the chi-square test. Logistic regression was used to assess the association of potential risk factors of antibiotic use and clinician adherence. Initially, each factor was tested individually in a univariate regression model. The variables with a Our study demonstrated a moderate to high prevalence of prophylactic antibiotic use in our hospital. Maternal education level, the birth attendant, multiple abortions, C-sections, PROM, and antepartum hemorrhage were associated with prophylactic antibiotic use. Individual clinical judgment plays a vital role in the decision for prophylactic use and may lead to a low rate of clinician adherence to antibiotic prescribing guidelines. Therefore, clinicians, local stakeholders, and policymakers should be actively involved to ensure the development of guidelines that are based on the best and most recent scientific evidence and incorporate local data to ensure successful guideline implementation.


Overuse of broad-spectrum antibiotics in secondary care is a key contributor to the emergence and spread of antimicrobial resistance (AMR); efforts are focused on minimizing antibiotic overuse as a crucial step toward containing the global threat of AMR. The concept of overtreatment has, however, been difficult to define. Efforts to address the overuse of medicine need to be informed by an understanding of how prescribers themselves understand the problem. We report findings from a qualitative interview study of 46 acute care hospital prescribers differing in seniority from three countries: United Kingdom, Sri Lanka and South Africa. Prescribers were asked about their understanding of inappropriate use of antibiotics. Prescriber definitions of inappropriate use included relatively clear-cut and unambiguous cases of antibiotics being used “incorrectly” . In many cases, however, antibiotic prescribing decisions were seen as involving uncertainty, with prescribers having to make decisions about the threshold for appropriate use. Decisions about thresholds were commonly framed in moral terms. Some prescribers drew on arguments about their duty to protect public health through having a high threshold for prescribing, while others made strong arguments for prioritizing risk avoidance for the patients in front of them, even at a cost of increased resistance. Notions of whether prescribing was inappropriate were also contextually dependent: high levels of antibiotic prescribing could be seen as a rational response when prescribers were working in challenging contexts, and could be justified in relation to financial and social considerations. Inappropriate antibiotic use is framed by prescribers not just in clinical, but also in moral and contextual terms; this has implications for the design and implementation of antibiotic stewardship interventions aiming to reduce inappropriate use of antibiotics globally. Antimicrobial resistance (AMR) is a health threat with potentially devastating global consequences O'Neill, . A key cAppropriate prescribing choices are typically defined as the right drug, administered at the right time, using the right dose, for the right duration , recruited from a total of seven different hospitals across the three countries. These countries and participating hospitals were selected based on existing collaborations between the research team, and included high and lower resource settings, with diverse challenges in terms of resourcing and patient population.In Sri Lanka and South Africa a significant proportion of medical care happens in the private sector  as our previous experience indicted that this would be a reasonable number to enable us to fully explore the issues. We continued to recruit participants to interviews in each country until the team agreed we had reached a point of data saturation  Some patients clearly having viral infections but they are on antibiotics. (SL 013)A related type of inappropriate prescribing described by participants was the use of antibiotics in the absence of any symptoms pointing to a bacterial infection. For example, participants reported cases where the mere acuity of a patient triggered a prescription of antibiotics despite the absence of any infection-specific symptoms.They just come into the emergency unit, and [they are…] getting antibiotics, even though they have a multitude of other reasons for their admission. (SA 012)So the inappropriate use will be you don't have any evidence that the patient's having bacterial infection. The patient might be unwell due to other reasons, for example they might have asthma exacerbation with very little evidence of infection. (UK 007)Participants also pointed to situations in which the diagnosis was unambiguous, where clear guidelines about antibiotic choice, dose, and duration existed, but the prescriber failed to prescribe in accordance with these guidelines without justification–resulting in the patient receiving an inappropriate antibiotic or the incorrect dose or duration of treatment.If there's a clear clinical scenario of infection that we know this is hospital-acquired pneumonia, and you know what kind of antibiotic is that, and you start prescribing a very broad spectrum, then you are not following guidelines, then you are just harming the patient. (SA 009)Overall, participants from all hospitals and countries shared similar opinions about what constituted an unambiguously clinically “incorrect” decision about antibiotic prescribing, or suboptimal antibiotic use. These types of incorrect or suboptimal uses of antibiotics were commonly seen as reflecting unjustified individual preferences and habits, a lack of appropriate knowledge, or, for more junior doctors a lack of experience or senior supervision. Organizational systems and processes were also seen as playing into this, for example, a lack of access to guidelines, workload and demand on practitioners, or inefficient systems for monitoring and regulating antibiotic use. Participants shared the view that these types of incorrect uses could and should be tackled to reduce antibiotic overuse.Beyond these shared definitions of incorrect antibiotic use, participants described gray areas of inappropriate use, where the appropriateness of prescribing decisions was less objectively clear. Participants recognized that many antibiotic prescribing decisions involved decision-making under uncertainty, where clinicians were using their clinical judgement to assess the likelihood of infection, the likely source of infection and infective agent, and therefore the best course of action. Prescribers had to make decisions about the threshold at which they would prescribe antibiotic treatment, and their certainty over whether they could use a targeted narrow-spectrum antibiotic as opposed to a broad spectrum antibiotic. This threshold might vary from patient to patient, depending on their vulnerability and level of risk , but also individual prescribers were seen to vary in their approach.[There] are generally two camps that you get with dealing with uncertainty. So you get the one which is very prone to jump in and do something, and that might be prescribing antibiotics […], which may or may not be appropriate. And then you get the other, which is more likely to just, to try to investigate and work out what's happening before giving an antibiotic. (UK 004)Under conditions of uncertainty, where judgements had to be made about where to set a threshold for prescribing, antibiotic use was less easy to classify as appropriate or inappropriate in objective terms. Participants recognized that setting a low threshold–i.e., erring on the side of caution and prescribing antibiotics to acutely ill patients “when in doubt,” was an easy and low risk approach to avoiding the risks of deterioration and death for their patients. They also recognized, however, that overuse of antibiotics had negative consequences for society by contributing to the problem of AMR. The tension between the interests of different stakeholders was well-understood by most. Where prescribers were prepared to set the threshold was seen as reflecting, to some extent, their experience and confidence in assessing risk and tolerating uncertainty.When I started working in this setting, I would be very over-careful of missing something. I think, as I got more confident, I start the conversation with “I don't like prescribing antibiotics. If I feel your child needs an antibiotic, I will give it. But I would prefer to rather wait and see” (SA 007)In considering how they judged whether their own, and others', levels of prescribing were inappropriately high or low, participants on drew on moral arguments in relation to balancing the interests of the different stakeholders. These arguments reflected participants' underpinning beliefs about what it meant, for them, to be a good doctor or good healthcare professional, and resulted in nuanced, and sometimes contradictory, accounts, of what was inappropriate and why.Some participants made moral arguments about the importance of considering their duty to broader society  when making decisions about antibiotic use under uncertainty. For some, appropriate antibiotic use was seen as being grounded in a consideration of the risks to society of excessive antibiotic use, balanced against their duty to their individual patients.It's kind of a public health like obligation, isn't it, to make sure that you're giving decent antibiotics correctly, to reduce resistant strains. (UK 009)So we have to balance that risk constantly. And I would say obviously people can argue that your individual patient takes priority, but then other considerations would be society as a whole, or the broader community has to be taken as the priority. […] You have to be cognizant of the fact that these treatment decisions you make on this patient has an impact on the next one and society as a whole. (SA 010)They made critical judgements about other clinicians who were quick to prescribe antibiotics or relied too heavily on broad spectrum antibiotics.For the vast majority of cases, the use of broad-spectrum antibiotics is […] a consequence of lackadaisical or poorly worked up clinical decision-making. […] You've got a better chance of getting [the patient] better quicker, because you're covering all possible ills. But it's not good medicine. (UK 002)While this reasoning sits in line with broader goals of antibiotic stewardship, conversely, other participants made counterarguments to this position, also grounded in moral terms. Although recognizing the tensions in balancing the interests of individuals and society, some participants framed their duty, and correspondingly their understanding, of what it meant to be a good doctor or healthcare professional, in terms of prioritizing the wellbeing of the individual patients in front of them. Although they recognized the clinical importance of treating patients appropriately, they minimized the risk of AMR and their responsibility for the problem, in comparison with the risks and their responsibilities for sick patients in front of them.I think I try to do what is good for the patient and that is the only thing […] The only agenda I have is that. (SL 007)As a doctor, the most important is the patient's interests, you know, so you try and do the right thing for that specific patient, and then, the other interests are probably less important. (SA 006)I have that sense at a societal level [of the problem of AMR], but my job as a doctor is to treat the person in front of me. […] so I don't balance… […I'm] just doing what I can to make the patient better. (UK 012)These participants drew on such arguments as justification for using antibiotics, and particularly broad spectrum antibiotics, when in doubt, even if this was at a cost of increased resistance.As a doctor we need to save patients, […] even if we think that this is broad-spectrum antibiotics, and [we should be concerned about] resistance with the [hospital] trust, but at that time I think the most important thing is to treat your patient well. (UK 005)As such, judgements about the appropriateness of antibiotic prescribing decisions could not always be pinned down in objective clinical terms. Instead, how participants justified their approach to antibiotic prescribing under conditions of uncertainty reflected their orientation to risk, and their position about what it meant to be a good doctor in terms of moral responsibilities. Participants took different standpoints in relation to where their duties as a doctor or healthcare professional lay, and therefore, what was and was not appropriate practice.Notions of whether levels of antibiotic prescribing were considered to be inappropriate were also contextually dependent: what could potentially be seen as over-use of antibiotics, or excessive reliance on broad-spectrum antibiotics, was re-framed in some cases by participants as a rational and appropriate response to the conditions in which they worked. Although they recognized such antibiotic use as excessive, they did not always see it as inappropriate in the context of the demands they faced and the resources available to them. This was a particularly common response from participants in low resource settings.Such challenging circumstances in low resource settings included conditions of high patient throughput–including high numbers of patients presenting at a late stage when they were acutely ill. Problems also arose when patients who had already taken (often unspecified) antibiotics in the community prior to coming into hospital–including antibiotics that had been prescribed without any microbiological testing, or had been purchased. This constrained the choices about how these patients could be treated once they arrived in hospital. It also meant that that waiting for microbiological tests prior to prescribing was commonly seen as futile, and this futility was exacerbated in some contexts by the lack of rapid and high quality testing services.When the patients come very late  by that time they will have at least more than one system affected. […] so we will again be using the broad spectrum even without [waiting] for the cultures and things like that (SL 003)Unfortunately, because our diagnostic tests are not that great, and turnaround times are poor, and sensitivities etc. are not that good, you might have to go [with] broad [spectrum antibiotics] (SA 012)Unsanitary and overcrowded environments were seen as vastly increasing the risk of hospital-associated infections, increasing the need to rely on antibiotics.We are seeing a lot of […] infections in our wards because we [don't] have the facilities, I mean like the beds are very close and they are not in separate parts, cubicles. (SL 015)In these cases, it was not the antibiotic use that was seen as wrong or inappropriate, but the precipitating conditions. Participants felt they were able to respond to these conditions only in the best way that they could. While these problems–access to hospitals and use of antibiotics in the community, and insanitary hospital environments–remained as they were, participants were able to justify high levels of antibiotic use and saw little opportunity for reducing their use.Other contextual factors that shaped views about whether antibiotic prescribing was the “right” thing to do, even at a cost of increased resistance, related to financial and social considerations. Although some participants flagged the problem of costs of excessive use of antibiotics for their organizations, others argued that financial and social considerations for patients could make antibiotic use the appropriate choice. In private hospitals, some argued that using broad-spectrum antibiotics could help reduce costs for patients arising from length of stay. In lower income settings, participants recognized that a hospital stay could be financially devastating for wage earners in families and had an impact on the economy: treating patients aggressively to get them well and out of hospital quickly was seen in some cases as a priority.Most people with private medical insurance, they have to […] get out of the hospital as soon as possible. They work for themselves, a lot of the people, they cannot afford to stay long in the hospital. So if you give […] a good broad-spectrum antibiotic to start off with […] it's a win-win situation all the way. (SA 004)Broad-spectrum benefit was, […] start medications, there will be improvement, so these people are working, I mean, going back to working. (SL 005)The interview findings from doctors and nurse prescribers across three countries and different hospital sites suggest ambiguities in opinions about what counts as inappropriate antibiotic prescribing and antibiotic over-use in hospital settings. Our focus in this paper was on how prescribers made judgements about the appropriateness of antibiotic use, and how they justified their own and others' use of antibiotics. In terms of prescribers' own understanding of appropriateness, there was consensus that antibiotic use under certain circumstances could be judged to be clinically “incorrect” . Not all decisions about antibiotic use could, however be judged as objectively appropriate/inappropriate in clinical terms. There was significant ambiguity about judgements of appropriateness of antibiotic use in case of diagnostic uncertainty. Such judgements were mediated by personal perceptions of working within the frames of risk and uncertainty, and participants' comfort in tolerating risk. As identified in previous research, this could vary dependent on individual training, experience, and seniority, but also on the extent of concern about the impact of negative patient outcomes, and the risk of personal and reputational damage  are clearly important. There is also a need, however, to address the moral aspects of prescribing decisions. This might involve including vignette-based debates in stewardship training, and providing opportunities for collective input to difficult decisions. We may also need more explicit societal debate, and the establishment of collective agreements around, the duty of prescribers to consider the interests of society in making antibiotic prescribing decisions (Tarrant et al., Our study suggests that inappropriate antibiotic use is framed by prescribers not just in clinical, but also in moral and contextual terms; this has implications for the design and implementation of antibiotic stewardship interventions aiming to reduce inappropriate use of antibiotics globally.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by University of Leicester Research Ethics Committee, Sri Lanka Medical Association Ethics Review Committee, and University of Stellenbosch Health Research Ethics Committee 1. The patients/participants provided their written informed consent to participate in this study.CT, AC, EC-B, DJ, NP, SM, and EK planned and designed the study. EK, CT, WN, and MB conducted interviews. CT and EK conducted the data analysis and drafted the first manuscript version. All authors helped to review and refine the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In order to analyze the influence of eccentric load on mechanical properties and damage process of concrete with initial damage, the eccentric load compression tests of concrete under different confining pressures were carried out with the help of PFC particle flow program. The results show that: the eccentric load does not change the relationship between peak stress, crack initiation stress and confining pressure of concrete under uniform load, but decrease the value of them. The peak stress increasing coefficient under uniform load is higher than that under eccentric load, and the peak stress increasing coefficient increases in a linear function with the confining pressure, and the increasing rate is approximately the same. Under uniaxial compression of eccentric load, a type I shear crack approximately parallel to the loading direction is formed, while under biaxial compression, a bending type shear crack with the lower tip of the initial crack as the inflection point is formed. The number of microcracks in concrete under uniform load and eccentric load can be divided into three stages: the calm period at the initial loading stage, the pre-peak expansion period from crack initiation point to peak point, and the rapid increase period after the peak. The concrete in the tunnel or the coal and rock mass in the sinking and driving engineering are often subjected to eccentric load due to the undulation of the mountain or the excavation of the project , The process of concrete crack initiation, propagation, penetration and failure under uniaxial compression was given by using CT imaging technology, and the damage fracture zoning theory for quantitative analysis of concrete damage evolution was proposed by using CT. With the continuous development of computer technology, numerical simulation method has been widely used in the study of mechanical damage characteristics of materials. Ansari et al.9 used particle flow code (PFC) software based on discrete element method to simulate the performance of pervious concrete specimens with different aggregate size and void ratio. By comparing with the test results, the reliability of using discrete element method to simulate the mechanical properties of pervious concrete was proved. Lian et al.10 used PFC to simulate the mechanical behavior of porous concrete under compression and tension. The accuracy and effectiveness of the simulation were verified by comparing with the experimental results and empirical formula. Huang et al.11 used the particle flow code (PFC) to simulate the strength failure behavior of three non- coplanar specimens under uniaxial loading, and four typical crack merging modes were determined, namely shear, tension shear mixing and tension. Through the analysis of the force field and displacement field, the evolution mechanism of cracks around the holes of granite specimens was revealed. In the framework of PFC, Song et al.12 proposed a three-dimensional multi-level stress corrosion model (MSC) to reproduce the mechanical properties of brittle geo materials and concrete under multi-level cyclic compression loading. The simulation results of MSC model are in good agreement with the experimental results. The results show that the MSC model can reproduce the cyclic loading mechanical properties of concrete specimens under different maximum and minimum load levels.On the mechanical properties and damage mechanism of concrete, scholars all over the world have carried out extensive research and achieved fruitful results. Yu et al.To sum up, scholars from all over the world have carried out extensive research on the mechanical properties and damage process of concrete under uniform load, but the research on the damage process of concrete under eccentric load is rarely reported, and most of the existing research is based on complete concrete samples, while the research on the mechanical law of concrete with initial damage is rare. Based on this, the mechanical properties and damage laws of concrete with initial damage under uniform load and eccentric load are studied by means of particle discrete element method on the basis of parameter calibration. The research results have important guiding significance for the engineering design of concrete and the formulation of monitoring early warning indicators.15.In this paper, PFC2D is used to simulate the eccentric compression test of concrete. PFC simulation software is based on DEM discrete element method, and the basic mechanical properties of materials are described by the motion of each particle and the force and moment acting on each contact point. Concrete is usually composed of a group of particles bonded by parallel bonds. The strength of concrete is achieved by parallel bonding between particles, and its essence is the cementation between particles. The program can track and show the crack initiation and growth process, and can distinguish the tensile crack and shear crack, which is widely used in concrete and other solid materialsThe numerical simulation model is consistent with the indoor test. The sample size is 100 mm in height, 50 mm in width, 0.25–0.415 in particle radius, and the number of particles is 12,392. The parallel bond contact model is used and the number of contacts is 23,682. In this paper, the initial fracture is established by deleting particles. The length of the initial fracture is 15 mm, the width is 0.5 mm, and the angle between the initial fracture and the horizontal direction is 45 degrees. The final numerical model is shown in Fig. 17, the set wall velocity can simulate the quasi-static loading in laboratory test, and the loading will stop when the post peak stress drops to 80% of the peak stress. When the uniformly distributed load is compressed, the load is applied by moving the upper and lower walls, and the confining pressure is controlled by moving the left and right walls. Under eccentric loading, five loading walls are built around the specimen. Under uniaxial compression, the two sides and the upper right walls are deleted after the specimen is pre-molding, and the uniaxial compression is realized through the remaining two walls. When biaxial compression is conducted, axial stress is applied through the lower wall and the upper left wall after pre-molding, while the other walls are subject to confining pressure. The schematic diagram of eccentric load uniaxial compression and biaxial compression loading is shown in Fig. The displacement loading method is adopted. The upper and lower walls are loading walls, and the moving speed of the wall is set to 0.05 m/s. According to the existing literature research results19. High-strength concrete samples with strength grade C60 were used in the laboratory test. The mix proportion for C60 concrete is shown in Table In the parallel bonding model, several mesoscopic parameters are involved, such as normal stiffness, tangential stiffness, friction coefficient and so on. These parameters will not only change the deformation and strength characteristics of the simulated object, but also affect its final failure mode, so it is necessary to calibrate the parameters according to the laboratory test resultsThe numerical simulation test of concrete under the same conditions as the laboratory test is carried out, and the simulation results are compared with those of the laboratory test. By continuously adjusting the meso parameters in the numerical simulation, until the macro mechanical parameters obtained by the numerical simulation are consistent with the indoor test results. The stress–strain curves obtained by numerical simulation and laboratory test and the failure mode of the sample are shown in Fig. Figure Before carrying out the numerical tests of concrete under different confining pressures, the deformation and failure processes of concrete under uniaxial compression of uniformly distributed load and eccentric load are simulated by means of particle flow simulation software. Figure The ratio of peak stress to uniform load in biaxial compression is defined as the peak stress increase coefficient. Under biaxial compression with uniformly distributed load, the increase factor of peak stress increases from 1.2278 at confining pressure 5 MPa to 1.80695 at 30 MPa, which increased by about 1.47 times. The peak stress increase coefficient of eccentric load under biaxial compression increased from 1.018 at confining pressure 5 MPa to 1.559 at 30 MPa, which increased by about 1.53 times. Figure n in the sample at the peak stress is determined first, and then the stress corresponding to 1% of n is found as the crack initiation stress of the sample. According to the above method, the crack initiation stress of concrete under uniform load and eccentric load compression under different confining pressure conditions is determined, as shown in Fig. In this paper, according to the method recommended by potyondy and cundall, the crack initiation stress of concrete is determined according to the change of the number of cracks in the simulation process. The number of cracks It can be seen from Fig. In order to analyze the influence of loading mode and confining pressure on the failure mode of concrete, the failure mode diagram at the time when the stress of the sample is 80% of the peak stress after failure is extracted, as shown in Figs. 20. When the confining pressure is 5 MPa, the macro cracks of the sample are approximately vertical to the initial cracks, and they are in the state of anti-wing cracks. The macro cracks do not reach the end of the sample, but penetrate from both sides of the sample, and the shear failure of the sample occurs. When the confining pressure is higher than 10 MPa, the shear failure of the specimen occurs mainly, and the macro cracks are X-shaped, and the turning points of the cracks on the left and right sides are located at the two tips of the initial cracks. With the increase of confining pressure, the distribution range and width of the macro cracks increase.It can be seen from Figs. When the specimen is subjected to uniaxial compression under eccentric load, the macro cracks are located in the direct loading area. There is a mode I shear crack approximately parallel to the loading direction in the middle of the specimen, which is connected with both ends of the initial crack and does not penetrate the specimen. Finally, the failure of the specimen is caused by the crack starting from the interface between the loading area and the non-loading area, and the inclined crack cuts out from the middle of the sample. After confining pressure is applied, due to the limitation of confining pressure, it is difficult for the crack initiated from the stress concentration position at the junction of loading area and non-loading area to propagate to the edge of the specimen, which changes into the increase of the failure range in this area. Due to the joint influence of confining pressure and loading area, some cracks are also produced in the non-loading zone. The macro cracks formed in the non-loading zone are inclined cracks connecting the end of the initial crack and the end of the specimen, while the through cracks leading to the failure of the specimen are still located in the loading zone. The through cracks are broken line shear cracks with the initial crack as the turning point.The macro cracks formed in the non-loading zone are inclined cracks connecting the initial crack ends and the end of the sample, and the cracks that cause the specimen damage are still located in the loading zone. The through cracks are the broken line shear cracks with the initial cracks as the turning point.In order to compare and analyze the difference of the number of microcracks under uniform load and eccentric load, the number of microcracks in the sample was counted when the post peak stress dropped to 80% of the peak stress. Figure Figure It can be seen from Fig. According to the turning point of the stress–strain region and the number of microcracks evolution curve, five times a–e are selected in Fig. It can be seen from Fig. It can be seen from Fig. Figure According to the turning point of the stress–strain region and the number of microcracks evolution curve, five times a–e are selected in Fig. Under the condition of uniform load and eccentric load, the peak stress of concrete increases linearly with the increase of confining pressure. The crack initiation stress increases as a quadratic function with the increase of confining pressure. At the same confining pressure, the peak stress and crack initiation stress of specimen under uniform load compression are higher than those under eccentric load compression.The peak stress increase factor is defined, and under the same confining pressure, the peak stress increase coefficient of uniform load compression is higher than that of eccentric load compression. With the increase of confining pressure, the peak stress increase coefficients of the two loading modes increase linearly, and the increase rates are approximately equal.The failure mode of concrete is influenced by initial damage, loading mode and confining pressure. Under uniaxial compression with uniformly distributed load, the macro fracture surface consists of the initial crack and the crack in the same direction as the initial crack. Under uniaxial compression with eccentric load, the cracks are located at one side of the loading zone, and mode I shear cracks are formed which are approximately parallel to the loading direction.With the increase of confining pressure, the failure mode of concrete under uniform load and eccentric load has little change. Under the condition of uniform load, the concrete mainly occurs X-type shear failure, and the X-type turning point is the two tips of the initial crack. Under the condition of eccentric load, the concrete mainly occurs broken line shear failure, and the main cracks are located in the loading area. Under the influence of the loading area and confining pressure, an inclined crack will also appear in the non-loading area.The evolution process of the number of microcracks in concrete under the conditions of uniform load and eccentric load can be divided into three stages: the calm period I at the initial loading stage, the pre-peak expansion period II from the crack initiation point to the peak point, and the rapid increase period III after the peak, and the evolution process of microcrack propagation in different stages is analyzed in detail.


Recently, the surfaces of concrete structures are impregnated to protect them against the environment in order to increase their durability. It is still not known how the use of these agents affects the near-surface hardness of concrete. This is especially important for experts who use the near-surface hardness of concrete for estimating its compressive strength. The impregnation agents are colorless and, thus, without knowledge of their use, mistakes can be made when testing the surface hardness of concrete. This paper presents the results of investigations concerning the impact of impregnation on the subsurface hardness concrete measured using a Schmidt hammer. For this research, samples of cement paste with a water–cement ratio of 0.4 and 0.5 were used. The samples were impregnated with one, two, and three layers of two different agents. The first agent has been made based on silanes and siloxanes and the second agent has been made based on based on polymers. The obtained research results allow for the conclusion that impregnation affects the near-surface hardness of concrete. This research highlights the fact that a lack of knowledge about the applied impregnation of concrete when testing its near-surface hardness, which is then translated into its compressive strength, can lead to serious mistakes. Among the available diagnostic methods intended for reinforced concrete structures, the non-destructive techniques, that do not affect the structure of the tested elements are very useful. The requirements concerning these methods are still changing, and therefore further development of techniques and devices for non-destructive testing is necessary. There is also a growing demand for educated personnel with a high level of knowledge, and therefore education in this field is becoming very important. Currently, non-destructive testing techniques are the subject of many scientific and technical conferences, and are used to diagnose civil engineering structures ,2,3,4. AOne well-known and recognized test among non-destructive methods is the near-surface hardness measurement . It enabNear-surface hardness measurements in addition to ultrasonic testing  can alsoThe results of sclerometric tests are influenced by many factors, as described in papers ,18,19. TPerforming near-surface hardness measurements is not complicated. It is more difficult to correlate the obtained results, followed by their translation into concrete strength. Scaling curves that allow compression strength calculations from correlated equations can be found in PN-EN 13791:2008  and in IThe European Union requires the unification of rules for the use of non-destructive methods  but the Impregnation with hydrophobic agents are, according to the standard , on of tElements that are subjected to environmental influences, e.g., concrete bridges, are most often impregnated using hydrophobic agents. There are colored  available on the market, but more often colorless hydrophobic agents are used to preserve the natural appearance of structures. It is still not known how the use of hydrophobic agents affects the near-surface hardness of concrete. This is especially important for experts who use the near-surface hardness of concrete for estimating its compressive strength. The impregnation agents are colorless, and thus without knowledge of their use, mistakes can be made when testing the surface hardness of concrete.Considering the above, this paper presents the results of investigations concerning the impact of impregnation on the subsurface hardness concrete measured using a Schmidt hammer. For this research samples of cement paste with a water–cement ratio of 0.4 and 0.5 were used. The samples were impregnated with one, two, and three layers of two different agents. First agent has been made based on silanes and siloxanes and the second agent has been made based on based on polymers.w/c = 0.4 obtained the compressive strength estimated equal to 45.15 MPa, in turn samples with a w/c ratio of 0.5 33.35 MPa. The samples were prepared from cement paste due to the fact aggregate affects the results of near-surface hardness measurements. Portland cement CEM I 42.5 from Górażdże  was used to make the samples which consists of Portland clinker in the amount of 95–100%, secondary components in the amount of <5%, and tap water.In this study, the effect of impregnating concrete (with the use of hydrophobic agents) on its near-surface hardness (assessed using near-surface hardness measurements) was investigated. For this purpose, 18 cubic samples of cement paste with a side length of 10 cm were made—9 with a water–cement ratio of 0.4, and 9 with a water–cement ratio of 0.5. The composition of the concrete mix is shown in After demolding, the samples were allowed to mature at room temperature for 28 days in 100% humidity. Fourteen visually superior samples were then selected and prepared for impregnation using hydrophobic agents according to the manufacturer’s recommendations. The impregnated surface was first cleaned with a damp cloth and then with a dry cloth and brush. Two impregnations were made using the following hydrophobic agents:3. The product has a low-molecular structure, and therefore has a high penetration capacity, does not clog pores, does not change the appearance of the impregnated surface, protects against dirt, and prevents efflorescence.A—based on silanes and siloxanes with a density of 1 g/cmB—based on a dispersion of polymers in water. It improves the resistance of the impregnated surface to the influence of weather conditions and UV radiation. When used with concrete tiles, it causes a “wet tile” effect, but does not cause shine. The hydrophobic agent is white, colorless after drying, and the total drying time is 8 h. The required interval between layers is 6 min.2.The hydrophobic agent was applied evenly by brush—one, two, and three coats, respectively, for the given samples in short intervals following the manufacturer’s recommended “wet on wet” principle. None of the hydrophobic agents caused any change in the appearance of the impregnated surface. The dosage was 250 mL/mw/c ratio; , the second number—number of impregnation layers, and the letter—type of hydrophobic agent.Thus, fourteen samples were prepared for further study, the details of which are presented in The tests were carried out using a Schmidt’s hammer type N-Proceq, Schwerzenbach, Switzerland. The tests were carried out in accordance with the standard . This isMeasurements were then made on the four sides of all the specimens. Most of the measurements were carried out at five measurement points, the distribution of which is shown in w/c = 0.4, all of the impregnated samples had a higher rebound number value than the samples without impregnation. The rebound number increased with the number of impregnation layers. The highest increase in the rebound number can be seen between the samples without impregnation and the samples with one impregnation layer. There is no increase in the rebound number between the samples with two and three impregnation layers, as can be seen in the graphs shown in For the measurements on the samples with The graphs above show that the impregnated samples have a higher rebound number value. For one impregnation layer, the samples have almost equal values. When the use of hydrophobic agent A, the rebound number increased by 5.57 units, while the use of hydrophobic agent B by 4.9, which is a difference of over 20% compared to the sample without impregnation.w/c = 0.5 with one and two impregnation layers, higher rebound numbers were obtained for the samples with hydrophobic agent A. For three impregnation layers, the sample with hydrophobic agent B obtained a higher value.For the samples with the w/c = 0.4 are shown in the graph in w/c = 0.5 show an increasing dependence with an increase in the number of layers of the hydrophobic agent, while the samples with hydrophobic agent A do not show this dependence. When the use of hydrophobic agent A, the rebound number increased by 4.89 units, while the use of hydrophobic agent B by 3.15, which is a difference of over 20% compared to the sample without impregnation.The results of the average rebound number for the specimens with w/c = 0.4 have higher variability than samples with ratio w/c = 0.5, as seen on w/c = 0.5 the variability is quite low.Samples with ratio w/c ratio. It is visible that with increasing number of impregnation layers, the hardness also increase.Rebound number comparison for samples impregnation using hydrophobic agent B presents w/c ratio on concrete strength—the lower the water–cement ratio, the higher the compressive strength of concrete and the higher the rebound number.As is well known, the water–cement ratio has a significant effect on the rebound number obtained during Schmidt hammer tests. This is related to the effect of the Rf-estimated compressive strength (MPa) and R-rebound number (-).To illustrate how concrete impregnation can affect the estimation of concrete compressive strength, the ITB scaling curve equation was used:w/c ratio 0.4 and 0.5. On their basis, the estimated compressive strength is presented in w/c ratio, greater differences in the results (of more than 3 MPa) can be noticed, which gives a 7% error. For the w/c = 0.5, the greatest difference is 6%.It can be concluded from the impregnation of concrete using hydrophobic agents affects its near-surface hardness, and consequently the results obtained in the correlation of the rebound number and its relation to the compressive strength of concrete;all of the samples impregnated using hydrophobic agents have a higher rebound number than the samples without impregnation;w/c = 0.4 of hydrophobic agent A, the rebound number increased by 5.57 units, while the use of hydrophobic agent B by 4.9. When the use for samples with ratio w/c = 0.5 of hydrophobic agent A, the rebound number increased by 4.89 units, while the use of hydrophobic agent B by 3.15. In both cases, the difference is over 20%;the rebound number increases with the number of impregnation layers. The highest increase in the rebound number can be seen between the samples without impregnation and the first impregnation layer. When the use for samples with ratio based on conducted research it is not possible to clearly state which hydrophobic agent allowed a higher rebound number to be obtained;w/c = 0.4 have higher variability than samples with ratio w/c = 0.5. Only after applying three layers does it drop to a similar level. Hydrophobic agent A works better on porous surfaces, therefore for ratio w/c = 0.5 the variability is quite low;samples with ratio w/c ratio. You can see that the more impregnation layers, the higher the hardness, differences between the impregnated and non-impregnated samples when estimating the compressive strength of concrete are up to 7%;for hydrophobic agent A the use of more than two layers does not increase the number of rebound. Hydrophobic agent B is more effective for samples with a higher after exceeding the specified impregnation thickness, there is no significant difference between the number of impregnation layers used; andw/c ratio.during the tests, higher values of the rebound number were obtained for the samples with a lower This paper presents the results of investigations concerning the impact of impregnation on the subsurface hardness concrete measured using a Schmidt hammer. For this research, samples of cement paste with a water–cement ratio of 0.4 and 0.5 were used. The samples were impregnated with one, two, and three layers of two different agents. First agent (A) has been made based on silanes and siloxanes and the second agent (B) has been made based on based on polymers. The research conducted in this study showed that:This research highlights an important fact that while testing the concrete with a near-surface hardness measurement and not knowing about the applied impregnation using hydrophobic agents, a big mistake can be made in transformation of the obtained values into the strength of concrete. With regards to further research in this direction, it would be worth investigating the influence of more layers and using a sample with different characteristics. It is also desirable to check other hydrophobic agent and to look at the microstructure of the samples.


Recurrent clinical deterioration and repeat medical emergency team (MET) activation are common and associated with high in-hospital mortality. This study assessed the predictors for repeat MET activation in deteriorating patients admitted to a general ward. We retrospectively analyzed the data of 5512 consecutive deteriorating hospitalized adult patients who required MET activation in the general ward. The patients were divided into two groups according to repeat MET activation. Multivariate logistic regression analyses were used to identify the predictors for repeat MET activation. Hematological malignancies  and chronic lung disease  were associated with a high risk of repeat MET activation. Among the causes for MET activation, respiratory distress  increased the risk of repeat MET activation. A low oxygen saturation-to-fraction of inspired oxygen ratio , high-flow nasal cannula oxygenation , airway suctioning , noninvasive mechanical ventilation , and vasopressor support  at first MET activation increased the risk of repeat MET activation. The risk factors identified in this study may be useful to identify patients at risk of repeat MET activation at the first MET activation. This would allow the classification of high-risk patients and the application of aggressive interventions to improve outcomes. The rapid response system (RRS) is used to identify clinically deteriorating patients and is used across several areas in hospitals . PatientTo analyze the clinical characteristics of patients with repeat MET activation in the general ward, this retrospective cohort study evaluated the data of consecutive adult patients with a sudden clinical deterioration that triggered an initial MET activation between 1 January 2012 and 31 December 2016 at Asan Medical Center. Repeat MET activation usually occurs within 48 h of a previous MET activation [The protocols of this study were approved by the Institutional Review Board of Asan Medical Center (2017-0601), which waived the need for informed consent due to the retrospective nature of the study. The data of all study patients were deidentified before analyses for confidentiality.The MET system was introduced in our hospital in March 2008. The MET consists of three intensivists, four ICU fellows, two internal medicine residents, and nine clinical nurse specialists (CNSs) with experience in critical care. Every duty is handled by a team of at least one intensivist or fellow, one resident, and two CNSs. The MET can be activated 24 h a day when (1) nurses or doctors call the MET for aid, (2) the MET CNS identifies a high-risk patient admitted to a general ward using the electronic medical record-based automatic screening system, which predefines patients’ vital signs or laboratory value thresholds, or (3) a code blue is announced for cardiopulmonary arrest as published previously . In our 2/FIO2 (SF ratio)), the SOFA score, the MEWS, and the result of MET activation . The MEWS consists of variables, including systolic blood pressure, pulse rate, respiratory rate, body temperature, and mental status [Data were collected prospectively using case forms and were analyzed retrospectively. The case forms were completed by the MET CNS, who participated in the MET activation and was trained in data collection methods to minimize bias in data collection. Variables included demographic characteristics, comorbidity, reasons for MET activation, vital signs, diagnostic and therapeutic interventions, patient disposition, laboratory data, the ratio of arterial oxygen saturation to the fraction of inspired oxygen concentration .Between-group differences were assessed using the chi-square test. Fisher’s exact test was used to compare categorical variables, while the Mann–Whitney U test was used to compare continuous variables. The results are expressed as number (%) for categorical variables and as median with interquartile range (IQR) for continuous variables, as most continuous variables were not normally distributed. Univariate and multivariate logistic regression analyses were used to identify factors associated with recurrent deterioration and repeat MET activation. Variables that were significant in the univariate analyses were adjusted and included in the multivariate analyses to investigate causality. The results of these analyses are reported as odds ratios (ORs) with 95% confidence intervals (CIs). Two-sided n = 487, 5.1%), procedure/education without clinical deterioration , cardiac arrest , an interval of >48 h between the first and second MET activations , transfer to ICU after the first MET activation , and activation with insufficient data for calculating the SOFA score and MEWS . Finally, 5512 patients were included in the analysis (n = 840) experienced repeat MET activation during the same hospital stay.Of 9468 patients who were identified, we excluded 3956 patients: patients with a DNR order before MET activation  and 48 h   . Repeat 2, MEWS, and SOFA score, as well as a significantly lower SF ratio, than the single activation group.The patients’ baseline characteristics are shown in p < 0.001), noninvasive mechanical ventilation , high-flow nasal cannula (HFNC) oxygenation , peripheral insertion of intravenous catheter , and vasopressor support  were more common in the repeat activation group than in the single activation group  or during hospitalization  was significantly higher in the repeat activation group. This was same for patients without any DNR order after MET activation  (Fifty-two percent (437/840) of the patients in the repeat activation group were admitted to the ICU. The likelihood of death within 28 days  . p < 0.001) and chronic lung disease  were associated with a high risk of repeat MET activation. Among the causes for MET activation, respiratory distress  increased the risk of repeat MET activation. Patients with a low SF ratio , HFNC oxygenation , airway suctioning , noninvasive mechanical ventilation , and vasopressor support  at the time of MET activation had a high risk of repeat MET activation.Seventeen variables were identified in the univariate logistic regression analysis and included into the multivariate logistic regression analysis . Hematolp < 0.001) or chronic lung disease (p = 0.011) was higher in the repeat activation group than that in the single activation group. Furthermore, the repeat activation group had a significantly higher FiO2 (p < 0.001), lower SpO2 (p < 0.001), and lower SF ratio (p < 0.001) than the single activation group. Regarding interventions, the rates of HFNC oxygenation (p < 0.001) and airway suctioning (p < 0.001) were higher in the repeat activation group than those in the single activation group.We performed a subgroup analysis of the data of patients with MET activation for a respiratory cause. We divided the patients into two groups according to repeat MET activation . Of the p < 0.001), a low SF ratio  at the time of MET activation, HFNC oxygenation , and airway suctioning .To identify the risk factors associated with repeat MET activation for a respiratory cause, we adjusted eight variables identified in the univariate logistic regression analysis and included them in the multivariate logistic regression analysis . The resWe performed a retrospective cohort study to identify the predictors for repeat MET activation in deteriorating patients admitted to a general ward. We found that repeat MET activation is independently associated with hematological malignancies, chronic lung disease at admission, vasopressor support, and respiratory distress-related factors, such as a low SF ratio, HFNC oxygenation, noninvasive mechanical ventilation, and airway suctioning after the first MET activation. Furthermore, we found that repeat MET activation for at-risk or deteriorating patients is common and associated with high hospital mortality.In our study, approximately 15% of deteriorating patients admitted to a general ward requiring MET activation experienced recurrent clinical deterioration and a repeat MET activation. This is similar to the rate of 17% reported in a study by Konard et al.  and CalzIn our study, repeat MET activation within 24 h of the first activation was more common among patients with repeat MET activation for the same reason in the first activation (50.1%). Calzavacca et al.  reportedIn our study, repeat activation was associated with a higher risk of in-hospital mortality, and these results are consistent with those of previous studies ,3,8. RepIn our study, repeat MET activation was associated with hematologic malignancies, chronic lung disease at admission, vasopressor support, and factors related to respiratory distress, such as a low SF ratio, HFNC oxygenation, noninvasive mechanical ventilation, and airway suctioning after the first MET activation. Previous studies have reported that repeat MET activation is associated with chronic liver disease at admission and procedures performed after the initial MET activation, including airway suctioning and noninvasive mechanical ventilation ,8,16. ToIn our system, although patients with respiratory distress are hemodynamically stable, noninvasive mechanical ventilation or HFNC oxygenation is performed and monitored by respiratory therapists, preferentially in the ward. Simultaneously, the MET monitors and manages the patient until the patient’s condition is stabilized. In settings with limited resources, high-risk patients may be managed with the time-limited trial of these interventions, provided there are adequate resources for close monitoring. However, any deterioration should prompt transfer to a higher level of care. Our results show that adequate assessment and monitoring are important when these interventions are performed in the ward.Notably, in our study, there were a significantly high number of patients with MET activation due to respiratory distress in the repeat activation group than in the single activation group. Furthermore, our study is the first to identify the risk factors for repeat MET activation for respiratory causes. Our results showed a higher risk of repeat MET activation for respiratory causes in patients with hematological malignancies, a low SF ratio at the time of MET activation, HFNC oxygenation, and airway suctioning. The condition of patients with clinical deterioration due to respiratory distress progressed slower than that of patients with deterioration due to septic shock or hypovolemic shock; these patients were managed initially with oxygen therapy. This means that it can be challenging to predict the prognosis of patients with respiratory distress; thus, a respiratory specialist might be needed in the MET. For these patients, mandatory rounds and early decision making concerning ICU admission may be helpful. The management of a deteriorating patient admitted to a general ward with repeat MET activation is clearly complex, as it is influenced by the patient, healthcare provider, and hospital’s characteristics ,8,13. ThHFNC oxygenation is superior to conventional oxygen therapies to improve dyspnea and oxygenation . HFNC is2/FiO2) [Fernando et al.  reported2/FiO2)  and can 2/FiO2) ,23. TherOur study has both strengths and limitations. Firstly, our study was performed in a single medical center. MET practice patterns and decision-making processes may differ in healthcare settings; therefore, the incidence of recurrent clinical deterioration and repeat MET activation may also differ with the institution. However, the observed incidence in our study was similar to that reported in the existing literature. Moreover, the challenge of patients with recurrent clinical deterioration and repeat MET activation is also common in other health organizations. Secondly, even with adjustment, undetected confounding variables (such as ICU resource availability) for repeat MET activation and patient outcomes may have been present, which may have led to incorrectly estimated associations. Thirdly, because invasive interventions such as noninvasive ventilation, HFNC oxygenation, vasopressor use, and frequent airway suctioning are routinely performed in the ward, the triage criteria for critically ill patients might differ in our hospital. Most healthcare facilities with limited ICU beds worldwide have similar practice patterns to ours ,8,16.Despite these limitations, the available data sources contained considerable data, including information on illness severity , which could help to further characterize patients at risk of repeat MET activation. The identified risk factors may be helpful to identify patients at risk of repeat MET activation and provide aggressive interventions to improve outcomes. Further studies in other healthcare settings are required to confirm our findings.Repeat MET activation increases in-hospital mortality rates. It is independently associated with hematologic malignancies, chronic lung disease at admission, MET activation for respiratory causes, such as a low SF ratio, HFNC oxygenation, airway suctioning, vasopressor support, and noninvasive mechanical ventilation at the first MET activation. Thus, patients with these characteristics should be targeted for specific care and policies aimed at improving outcomes.