According to the basic principle of dense packing of particles, and considering the interaction between particles, a dense packing model of granular materials in concrete was proposed. During the establishment of this model, binary particle packing tests of crushed stone and sand were carried out. The fitting analysis of the test results determines the relationship between the particle size ratio and the remaining volume fraction of the particle packing, and then the actual void fraction of the particle packing was obtained, based on which the water–binder ratio was combined to determine the amount of various materials in the concrete. The proposed concrete mix design method was used to prepare concrete, and its compressive strength and elastic modulus were tested experimentally. The test results show that the aggregate volume fraction of the prepared concrete increased, and the workability of the concrete mixture with the appropriate amount of water reducing agent meets the design requirements. When the water–binder ratio was 0.42, 0.47, or 0.52, the compressive strength of the concrete increased compared with the control concrete, and the degree of improvement in compressive strength increased with the decrease in water–binder ratio; when the water-binder ratio was 0.42, 0.47, or 0.52, the static elastic modulus of the concrete increased compared with the control concrete, and the degree of improvement in elastic modulus also increased with the decrease in water–binder ratio. The elastic modulus and compressive strength of the prepared concrete have a positive correlation. Findings show that the concrete mix design method proposed by this research is feasible and advanced in a sense. The concrete mix ratio is the proportional relationship between the amount of each constituent material in concrete, and the performance of concrete is closely related to its mix ratio. There are different methods for designing mix ratios in different countries. The American ACI method is simple and easy, and the concrete mix ratio can be determined by looking up the relevant forms . The BriAmong the constituent materials of concrete, coarse aggregate, fine aggregate, and cementitious materials are all granular materials, and it can be said that concrete is a dense solid formed by filling these granular materials with each other . AccordiThis research proposes a new method for designing thew concrete mix ratio. The method is based on the binary particle packing test of crushed stone and sand, and the relationship between the particle size ratio and the remaining volume fraction of particle packing is determined through the analysis of the test results. Furthermore, the actual voidage of the particle packing is obtained, and then the water–binder ratio is combined to determine the amount of various materials in the concrete. Then, the proposed concrete mix design method is used to prepare concrete, and its compressive strength and elastic modulus, the two most basic parameters in the design of concrete structures, are tested.Coarse aggregates, fine aggregates, and cementitious materials are granular materials in concrete. Considering the mutual filling of particles with different particle sizes, the particles are packed with the goal of achieving maximum compactness or minimum void ratio after the particles are mixed. The basic model expression for particle packing is as follows:Coarse aggregate volume fraction:Fine aggregate volume fraction:Volume fraction of cementitious material:3.Total volume fraction for particles packing:This packing model is proposed based on the theoretical dense packing between particles with different particle sizes; that is, fine aggregates are filled in the gaps of coarse aggregates, and cementitious materials are filled in the gaps of coarse and fine aggregates.When particles of different sizes are blended, they have a spatial influence on each other, described by the wedging effect . When coThe wedging effect makes the actual voidage of the particle pack larger than the theoretical voidage of the particle pack, and this interaction between the particles is related to the particle size ratio between the particles .Standard for Technical Requirements and Test Method of Sand and Crushed Stone (or Gravel) for Ordinary Concrete .Particles with sizes of 22.75, 17.5, 12.75, 7.125, 3.555, 1.77, 0.89, 0.45, and 0.225 mm were selected, and each size was the arithmetic mean of the adjacent sieve sizes of the standard sieve for concrete sand and gravel specified in 3;3; 3.The selected particles were combined in pairs and arranged into 20 groups according to the ratio of the particle size from small to large, and then the 20 groups of particles were subjected to particle packing tests. According to the basic model of particle packing (Equations (1) and (2)), the amount of coarse and fine aggregates is determined, and due to the wedging effect, there will be a residual number of particles in the actual packing process. The residual amount can be measured in the packing test, and the residual particle volume fraction is calculated asThe particle binary packing test and its results are shown in ix had a similar effect on the residual particle volume fractions ix increased, both ix exceeded 5, the effect of particles with a diameter of The relationship curve between the particle size ratio and the residual particle volume fraction is fitted from the test results, as shown in In order to simplify the model, the following assumptions were made: (1) the concrete packing system was composed of different materials, and each material took its volume average particle size as its characteristic particle size; (2) there was a large difference in particle size between the concrete composition materials, such as coarse aggregate, fine aggregate, and cementitious material. We ignored the influence between non-adjacent size particles; that is, we only considered the effects between coarse aggregate and fine aggregate and the effects between fine aggregate and cementitious material, while the effects between coarse aggregate and cementitious material were ignored.On the basis of the results of the particle packing test and the above assumptions, the basic model (Equations (1)–(4)) was modified, and the modified model expression is as follows:Actual volume fraction of coarse aggregate:Actual volume fraction of fine aggregate:Actual volume fraction of cementitious material:Actual total volume fraction for particles packing:Substituting the residual particle volume fractions into Equations (8)–(10), we get the following:Actual volume fraction of coarse aggregate:Actual volume fraction of fine aggregate:Actual volume fraction of cementitious material:Solved by Equations (12)–(14):Coarse aggregate actual voidage:Fine aggregate actual voidage:Actual voidage of cementitious material:(1) Cement: ordinary Portland cement with strength grade 42.5; the main components are shown in (2) Fine aggregate: river sand in Zone II; the main technical properties are shown in (3) Coarse aggregate: crushed stone, 5–25 mm continuous gradation; the main technical properties are shown in 3 and pH of 7.0–8.0.(4) Water reducing agent: highly efficient polycarboxylic acid water reducing agent, light yellow liquid with density of 1.1 g/cm(5) Water: drinking water.On the basis of the main technical parameters of the concrete constituent materials, the actual voidages of the granular material in the concrete were calculated from Equations (15)–(17), as shown in It can be seen from Three water–binder ratios of 0.42, 0.47, and 0.52 were selected, and the design slump of the concrete mixture was 70–90 mm.3 concrete is as follows:3; V—concrete volume, taken as 1 m3; ξ—the volume shrinkage coefficient is expressed as follows:yw is the volume fraction of water, expressed as follows:W/B is the water–binder ratio.The calculation process of the amount of crushed stone, sand, cement, and water in 1 m3 concrete, see C-1, C-2, and C-3 in Put Equations (8)–(10), (22), and (23) and various material parameters into Equations (18)–(21), and you can get the amount of crushed stone, sand, cement, and water in 1 mSpecification for Mix Proportion Design of Ordinary Concrete . The amount of the water reducing agent given in In Standard for Test Method of Mechanical Properties on Ordinary Concrete . In this method, there are three test pieces with a size of 100 mm × 100 mm × 100 mm in each group, and the test result is the average of the compressive strength test values of the three test pieces. The test results are shown in The test was performed in accordance with the concrete compressive strength test method specified in It can be seen from Standard for Test Method of Mechanical Properties on Ordinary Concrete . In the method, each group had six specimens with the size of 150 mm × 150 mm × 300 mm, which were cured for 28 d before testing. Among them, three specimens were used to test the axial compressive strength of concrete, and the other three specimens were used to test the elastic modulus of concrete. The test results are taken as the average value of the tested elastic modulus of the three specimens, as shown in The test was carried out according to the test method of elastic modulus of concrete under static compression specified in As can be seen from The relationship between stress and strain before the ultimate stress of the concrete under axial compression is shown in The concrete mix design method proposed in this study was based on dense particle packing. Since the aggregate was a granular material with the largest proportion in concrete, the volume fraction of aggregate in the concrete prepared by this method increased to different degrees. The volume fraction of aggregate is shown in Sections of the concrete specimen were randomly taken. The coarse aggregate information was extracted on the section using the IPP image processing software, and grayscale processing was performed, as shown in Concrete is a multiphase composite material composed of mortar, coarse aggregate, and an interface transition zone between the two. Since aggregate has a large volume fraction in concrete, especially coarse aggregate, it has a great influence on mechanical parameters such as compressive strength and elastic modulus under the conditions of a certain cementitious material and water–cement ratio .In concrete of group C, the higher aggregate volume fraction makes the aggregate more closely distributed in the concrete The design method of concrete mix proportion based on interparticle voidage proposed in the research is a kind of design method for concrete mix proportion according to the principle of dense particle packing.(2)The functional relationship between the particle size ratio and the remaining volume fraction of the particles is the basis for determining the actual voidage of the granular material in the concrete.(3)The coarse aggregates in the concrete prepared by the method proposed in this research are closely distributed, and even overlap each other, forming a relatively dense concrete core skeleton. Micro-cracks and defects in the interface transition zone of the concrete are also reduced to a certain extent.(4)In the concrete, there is an increase in aggregate volume fraction and a corresponding decrease in the amount of cement, and when an appropriate amount of water reducing agent is added, the workability of the concrete mixture meets the design requirements.(5)When the water–binder ratio was 0.42, 0.47, or 0.52, the compressive strength of concrete with ages of 3, 7, 28, or 90 d all increased compared with that of the control concrete at the same age, and the degree of increase in compressive strength increased as the water–binder ratio decreased.(6)When the water–binder ratio was 0.42, 0.47, or 0.52, the static elastic modulus of concrete increased compared with that of the control concrete, and the degree of increase in static elastic modulus increased as the water–binder ratio decreased, showing that the elastic modulus is positively correlated with the compressive strength.This research proposed a concrete mix design method based on the principle of dense packing of particles, and the method was used to prepare concrete. Compressive strength and elastic modulus of the concrete were experimentally studied. The coarse aggregate distribution and interface transition zone in the concrete were observed, and the following conclusions were drawn:


Antibiotic prophylaxis is commonly used when implanting a mid-urethral sling (MUS) for female stress urinary incontinence. Use of antibiotics may lead to adverse events and the development of antibiotic resistance. This study compared a variety of outcomes after MUS surgery with and without antibiotic prophylaxis using data from the national Norwegian Female Incontinence Registry.Preoperative and 6–12 months postoperative subjective and objective data from 28,687 patients who received MUS surgery from 1998 through 2017 were extracted from the registry. Categorical outcomes were compared between women with or without antibiotic prophylaxis using chi-square test for independence. Primary outcome was incidence of postoperative surgical site infection (SSI). Secondary outcomes were incidence of tape exposure, de novo or persistent urgency urinary incontinence, postoperative pain > 3 months, subjective and objective cure rates, and patient satisfaction.Antibiotic prophylaxis was used in 9131 and not used in 19,556 patients. SSIs and prolonged postoperative pain occurred significantly more often without antibiotic prophylaxis. Subjective and objective cure rates were significantly higher and tape exposures significantly lower in women not receiving prophylactic antibiotics. There were no significant differences in other outcomes.Antibiotic prophylaxis resulted in fewer women developing postoperative infections or prolonged postoperative pain after MUS surgery, but did not offer protection against tape exposure. The differences in cure rates were small and probably without clinical relevance. If a small increase in surgical site infections is accepted, the routine use of antibiotic prophylaxis can probably be omitted. Tension-free mid-urethral slings (MUS) are frequently used in the surgical treatment of female stress urinary incontinence (SUI) and mixed urinary incontinence (MUI) and are currently considered the gold standard . In thesIt is generally accepted that antibiotic prophylaxis should be used during implant surgery, and it is also recommended in clean-contaminated surgery according to the 2019 guidelines from the National Institute for Health and Care Excellence (NICE) . RegardlClostridium difficile colitis as well as the development of antibiotic resistance in the population. Therefore, some hospital departments prefer not to use antibiotic prophylaxis when performing MUS surgery.However, in addition to the economic cost of using antibiotics, there is a risk of adverse events occurring, such as allergic reactions, fungal infections and In Norway, nearly all female incontinence operations are carried out in gynecological departments in public hospitals under standard protocols, usually as day surgery. An unpublished survey performed by the senior author (Schiøtz) in December 2018 revealed that some Norwegian departments offering MUS procedures never use antibiotic prophylaxis while some always do. A few departments reported using antibiotic prophylaxis in high-risk cases only.The Norwegian Female Incontinence Registry was established in 1998 by a group of dedicated urogynecologists to evaluate the outcomes of incontinence surgery in Norway . The regIt has been suggested that some patients develop a chronic tape-related inflammatory tissue response or a chronic low-grade infection in biofilm along the tape that remains subclinical and undetected, but this might cause other problems such as tape exposure, de novo urgency urinary incontinence (UUI), persistent bothersome urgency symptoms and chronic pain in some cases requiring tape removal , 7. We hThis registry-based cohort study used data stored in the compulsory national Norwegian Female Incontinence Registry from all women who had undergone synthetic mid-urethral sling (MUS) surgery for stress urinary incontinence (SUI) or stress-dominant mixed urinary incontinence (MUI) in the period 1998 (inception of the registry) through 2017 with recorded follow-up data through 2018. Data extraction from the registry was done in January 2020. Retropubic tapes, transobturator tapes and minislings were all included. The extracted data were stratified based on the use of antibiotic prophylaxis. As the use of antibiotics are not routinely reported to the registry, this stratification was based on a survey performed in December 2018 in which the local doctor responsible for reporting data to the registry at all reporting hospitals was asked about their department’s guidelines for the use of antibiotic prophylaxis during MUS surgery. At the time of data extraction there were 38 reporting public hospitals and 1 reporting private hospital. The private hospital and one public hospital were excluded from the study because of not participating in the survey  or not having guidelines for antibiotic prophylaxis use . Beyond that, only women with no recorded follow-up data were excluded  registered at any time after surgery. SSIs are recorded as either superficial or deep in the registry. A subgroup analysis was therefore also performed on the women registered with deep (more severe) infections. Women registered with both deep and superficial SSIs were counted as deep. As the majority of urinary tract infections (UTIs) are treated outside the hospital at the general practitioner’s office and rarely reported to the registry, UTIs were not included as an outcome for this study. The secondary outcomes were as follows: (1) incidence of vaginal tape exposure (both symptomatic and asymptomatic), (2) incidence of persistent UUI, defined as urgency urinary incontinence index score ≥ 2 before and after surgery, (3) incidence of de novo UUI defined as a postoperative urgency urinary incontinence index score ≥ 2 among those with a preoperative score of 0, (4) subjective cure rate defined as a postoperative stress urinary incontinence index score ≤ 2, (5) objective cure rate defined as 0 g leakage on the postoperative cough/jump pad-weighing stress test, (6) patient satisfaction defined as the percentage of women answering “very satisfied” with treatment when given the choices “very satisfied,” “moderately satisfied,” “neither satisfied nor dissatisfied,” “moderately dissatisfied” and “very dissatisfied” and (7) prolonged postoperative pain defined as pain > 3 months following surgery. All secondary outcomes were calculated from the 6–12-month follow-up data except for the vaginal tape exposure data in which recorded cases at any time after surgery were counted. Furthermore, we calculated the patient number needed to treat (NNT) with antibiotic prophylaxis to avoid one case of postoperative SSI.The study was approved by the Regional Committee for Medical and Health Research Ethics of the South-East of Norway (reference no. 28964) as well as the Department Head and Institutional Personal Data Officer at Oslo University Hospital (OUS) having the legal responsibility for the Registry. All women had previously signed a consent form allowing the storage of data in the registry for quality assurance measures. Since only anonymous data from the registry were used for the present study, obtaining additional patient consent for the present study was not deemed necessary.Statistical analyses were done using Statistical Package for the Social Sciences (SPSS-PC), version 25. Differences in categorical data were tested using chi-square test for independence. The analyses for each outcome were done as per protocol in which women with missing data were removed from the denominator. A significance level of 5% was used. Due to the large number of women in the registry, no sample size calculations were needed.p < 0.01, deep: 0.5% vs. 0.2%, p < 0.01; Table p = 0.01); Table p < 0.01 and objective: 90.8% vs. 87.5%, p < 0.01; Table p < 0.01; Table At the time of data extraction, a total of 31,431 women were recorded as having had some form of incontinence surgery in the study period, among whom 28,687 matched the inclusion criteria; see the flowchart in Fig. The postoperative surgical site infection (SSI) rate in this study was significantly higher among women who did not receive antibiotic prophylaxis. However, even without such prophylactic treatment the incidence was low at 1.2%, and the number needed to treat with antibiotics to prevent one SSI was high at 166. A subgroup analysis on the even rarer, but potentially more serious deep infections also showed a significant difference, but the NNT was here even higher at 333.Clostridium difficile-associated diarrhea [The incidence of prolonged postoperative pain was statistically significantly higher among the women not receiving antibiotic prophylaxis (0.6% vs. 0.4%), but prolonged postoperative pain was rare in both groups. We found no overlap between women registered as having prolonged pain and the women registered with SSI; data not shown. These numbers are reassuring for hospitals and surgeons who prefer to carry out mid-urethral sling (MUS) procedures without giving antibiotic prophylaxis. Internationally, the reported incidence of SSI after MUS was 0.6–0.7% in the 2017 Cochrane systematic review . The patdiarrhea . Howeverdiarrhea .When a medical device such as a polypropylene mesh is implanted into the body, a complex and extensive series of foreign body reactions occurs, usually ending with the implant being accepted by the tissues and covered with a fibrous capsule –17. The MUS tape exposure is often asymptomatic, and the diagnosis may be missed unless a vaginal examination is carried out. In our study we found that tape exposure was noted significantly more often among women in the antibiotic prophylaxis group. We are unable to propose a biologically plausible explanation for why antibiotic prophylaxis might increase the risk of impaired wound healing. We therefore believe that this is a spurious finding and that the explanation is more likely that some of the operating departments have not diagnosed all their cases of asymptomatic tape exposure, while others have carried out postoperative vaginal inspection more frequently. Except for the finding of a slight reduction in the incidence of prolonged postoperative pain in the antibiotic prophylaxis group, there is little else in our results that supports the hypothesis that chronic inflammation or low-grade infection in biofilm along the implant results in more women developing pain, vaginal wound dehiscence or persistent or de novo urgency urinary incontinence as has been suggested by others , 7.The major strength of this study is the use of data from a large, compulsory national registry with nearly 100% completeness that encompasses all types of patients having been operated on by surgeons with different levels of experience in all regions of the country, minimizing the risk of selection bias that is often inherent in prospective, comparative trials. The study therefore has a high degree of external validity. The high number of patients also facilitates the use of robust statistics.As with all registry studies there are inherent weaknesses. It is inevitable that some complications are not reported correctly to the registry, and, as previously mentioned, we believe this applies to the reporting of tape exposure. If several departments with the same routines for using antibiotic prophylaxis consistently neglect to report certain complications, this could skew the results and cause a bias. However, we have no reason to believe that the non-reporting of infection was biased in this study; any underreporting would most likely be distributed equally among the groups. Regretfully, we could not evaluate the effect of antibiotic prophylaxis on postoperative UTIs. The incidence of postoperative UTIs recorded in the registry was only 0.4% (data not shown). As others have demonstrated rates of postoperative UTIs as high as 34% , we beliIn conclusion, in this study the total incidence of postoperative surgical site infections and the incidence of deep (severe) infections after mid-urethral sling procedures were significantly higher when prophylactic antibiotics were not used. However, in absolute numbers the SSIs were rare with a high NNT. In the secondary outcomes we found an increased risk of prolonged postoperative pain without antibiotic prophylaxis, but the incidence was very low in both groups. In all other secondary outcomes we found no consistent differences of clinical importance, but we note that antibiotic prophylaxis does not seem to offer protection against tape exposure or persistent or de novo urgency urinary incontinence. Consequently, we conclude that if one accepts the small increase in surgical site infections, the routine use of antibiotic prophylaxis can probably be omitted.


Urinary tract infections (UTI) are a common indication for antibiotic use in the emergency department (ED). With antibiotic resistance on the rise, it is essential that antibiotics be prescribed appropriately for UTIs. Our objective was to evaluate the appropriateness of antibiotic prescriptions by ED providers for uncomplicated cystitis and pyelonephritis.We conducted a retrospective study of females ages 2–50 years seen in an academic ED from January 2017 to April 2018 diagnosed with UTI. We assessed the appropriateness of discharge antibiotic prescriptions, as determined by adherence to clinical practice guidelines, best evidence for the particular indication (cystitis vs pyelonephritis for children and adults), and the local antibiogram.A total of 421 patients were included in this study. Of these, 60 children and 198 adults were diagnosed with cystitis, and 47 children and 116 adults were diagnosed with pyelonephritis. Treatment in the absence of true infection was common, with culture-confirmed UTI occurring in only 17/50 (34%) of children and 60/129 (47%) of adults diagnosed with cystitis, and 23/40 (58%) of children and 58/87 (67%) of adults diagnosed with pyelonephritis, among patients who had urine cultures. The type of antibiotic prescribed was appropriate in 53/60 (88%) of children and 135/198 (68%) of adults with cystitis, and 38/47 (81%) of children and 53/116 (46%) of adults with pyelonephritis. The most common inappropriate antibiotic types were beta-lactams in adults (n = 92), nitrofurantoin for pyelonephritis (n = 16), and amoxicillin (n = 15). Dosing and duration errors were also common, occurring in 122/279 (44%) of prescriptions of an appropriate antibiotic type. The frequency of errors in the type of antibiotic prescribed was similar among provider types .This study reveals room for improvement in antibiotic prescription practices across provider cohorts in the ED for the management of uncomplicated cystitis and pyelonephritis in females. Urinary tract infections (UTI) are common among females, accounting for upward of 10.5 million visits to physician offices and emergency departments (ED) per year.6Given the implications of inappropriate antibiotic prescription practices to individuals and populations, it is essential that providers appropriately select antibiotic treatment for the management of suspected UTIs. Guidelines from sources such as the Infectious Diseases Society of America (IDSA) and the American Academy of Pediatrics (AAP) can provide guidance.12To investigate antibiotic prescribing practices for suspected UTIs, we primarily sought to determine whether empiric antibiotic selection was appropriate for suspected UTIs in children and adults. Secondarily, we set out to analyze frequency of antibiotic prescription in the absence of true infection and whether variation in appropriate antibiotic selection existed between specific provider groups, including attending physicians, resident physicians, physician assistants, and nurse practitioners. We hypothesized that inappropriate antibiotics were frequently prescribed, that patients were frequently treated with antibiotics in the absence of true infection, and that variation existed between provider groups.International Classification of Diseases (ICD-10) codes for UTI: ICD-10 CM: N39.0 ; N30.00 (acute cystitis without hematuria); N30.91 ; N30.80 (other cystitis without hematuria); N30.0 (acute cystitis); N30.01 (acute cystitis with hematuria); N30.90 ; N30 (cystitis); N30.8 (other cystitis); N30.9 ; N30.81 (other cystitis with hematuria); N10 (acute pyelonephritis); and N12 (pyelonephritis). All data collection was conducted by PC after receiving training from KK. Approximately 5% of charts were reviewed by both authors independently to assess for congruency, including random charts and any cases in which there was uncertainty.The study was a retrospective analysis of females ages 2 to 50 years diagnosed with a UTI who were treated and discharged between January 1, 2017 – April 16, 2018, from an academic medical center ED. Females age 18 years or older were categorized as adults, while females under the age of 18 years were categorized as children. Institutional review board approval was obtained. We identified patients via an ED diagnosis of one or more of the following We excluded patients from this study if they had UTI complications ; had pre-existing renal or urologic disease ; were pregnant or up to six-weeks post-partum; were prisoners; had diabetes mellitus; or were immunocompromised. This included patients taking medications such as steroids, biologics, and chemotherapeutic drugs. We also excluded patients with recurrent UTI (had a UTI with or without antibiotic treatment within the prior month) and patients who were already prescribed an antibiotic for the current UTI prior to the ED visit.What do we already know about this issue?Previous studies have found overuse of antibiotics for urinary tract infections (UTI).What was the research question?To evaluate the appropriateness of antibiotic prescriptions for UTIs.What was the major finding of the study?Antibiotics were overused and inappropriate antibiotics were commonly prescribed for suspected UTIs.How does this improve population health?This study identified antibiotic misuse including overly broad antibiotics and overdiagnosis of UTIs, which can promote antimicrobial resistance.Patients were categorized as having uncomplicated cystitis or pyelonephritis based on their ICD-10 code. In cases where the ICD-10 code CM N39.0 for “urinary tract infection, site not specified” was used, the authors categorized patients as having either cystitis or pyelonephritis based on medical chart documentation of symptoms, vital signs, physical exam, and provider impression. Patients were assigned to the pyelonephritis cohort if they had fever, flank pain, or costovertebral angle tenderness.13E. coli isolates susceptible) were included. For adults, antibiotics recommended by IDSA guidelines were used.E. coli (more than 80% of isolates susceptible) and were included as appropriate.The primary outcome was the appropriateness of the antibiotic prescription for UTI, including the antibiotic type, dose, and duration. We determined a list of appropriate discharge antibiotics  using guWe did not include beta-lactams as appropriate options for adults in accordance with the IDSA guidelines, which recommend against routine use for UTI due to inferior efficacy, as there are numerous other antibiotic options for adults with favorable local susceptibilities. Allergies were reviewed during chart review, and no patients were allergic to all appropriate first-line options. There are no standardardized antibiotic recommendations in place in our ED. Our hospital antibiogram is available on the hospital infonet, and pocket cards are distributed periodically. It provides susceptibilities for various organisms for inpatients and outpatients, but does not provide empiric treatment recommendations for infection types, such as UTI.The secondary outcomes were the frequency of positive urine culture (when obtained) and the appropriateness of discharge antibiotic prescriptions between provider types . UTI was defined as growth of greater than or equal to 100,000 colonies of a single uropathogen via clean catch, growth of greater than or equal to 50,000 colonies of a single uropathogen via direct catheterization, or growth of greater than or equal to 50,000 colonies of a single uropathogen via clean catch in the presence of a positive urinalysis.During the study period, 421 patients met inclusion criteria . Common E. coli (80%).Urine cultures were performed in 73% of patients (306/421), with higher utilization of urine culture in patients with pyelonephritis  than in patients with cystitis  . The preThe appropriateness of discharge antibiotic prescriptions  is shownA total of 130 unique prescribers treated the 421 patients included in the study. We assessed the frequency of appropriate discharge medication prescription type, independent of dosage and duration, for cystitis and pyelonephritis combined across the following three cohorts: attending physician ; resident physician ; and advanced practice clinician . No difference was found between the groups (p = 0.926).In this study we found a number of areas for improvement in the initial management of female UTIs in an academic ED. Furthermore, we demonstrated that opportunity for improvement exists across all provider cohorts studied. These findings can guide improvement efforts for judicious use of antibiotics. Overtreatment of UTI was common, in particular for cystitis. As many as two-thirds of children who were treated for cystitis had a negative urine culture. Strategies to improve diagnostic accuracy and/or decrease unnecessary antibiotic treatment include the use of a decision aid, such as that by McIsaac et al for females with suspected cystitis.Strategies to reduce antibiotic overuse include delaying antibiotic prescription if infection is uncertain and discontinuing antibiotics if the urine culture results as negative. In a study by Knottnerus et al, many women were willing to delay antibiotic initiation for cystitis while awaiting urine culture result. More than half of these women experienced resolution of symptoms within a week without antibiotic therapy.21Overtreatment of UTIs was also found in the form of excessive antibiotic duration , particu25Clostridum difficile infections.E. coli resistance to amoxicillin being widespread.8Finally, we investigated the utilization of appropriate antibiotic types given the local antibiogram and evidence-based guidelines. Adherence to the IDSA recommendations can increase narrow spectrum antibiotic use and decrease unnecessary antibiotic days.st- and 2nd-generation cephalosporins. Furthermore, additional studies have been published since the IDSA guidelines in 2011 supporting efficacy of beta-lactams for the treatment of UTIs in adults.The most common deviation from IDSA guidelines in adults was treatment with beta-lactams . The sigThis study analyzed adherence to clinical guidelines and expert recommendations, assuming that these promote optimal care. Additional limitations of this study are associated with its retrospective design. The determination of antibiotic appropriateness relied on diagnosis of either cystitis or pyelonephritis; however, some patients had a non-specific diagnosis of “urinary tract infection, site not specified.” In this case, they were assigned to either the cystitis or pyelonephritis group based on the study team’s interpretation of the patient’s signs and symptoms. Errors in this designation by the study team would have affected the assessment of the appropriateness of antibiotics received. In an effort to check cohort assignment, we performed statistical analysis and found no significant difference in the appropriateness of discharge antibiotic type between patients whom the study team assigned to cystitis vs pyelonephritis and patients who had an ED diagnosis code for cystitis or pyelonephritis specifically (p > 0.05). Additionally, we did not assess why providers chose antibiotics that deviated from the recommendations, such as resistance in past urine cultures or lack of awareness of the guidelines. Furthermore, urine culture was used to assess presence of true infection; however, not all patients received cultures, which could affect our conclusions about the prevalence of true UTI in our study.This study reveals gaps in the management of children and adults with urinary tract infections, including administration of antibiotics in the absence of true infection and inappropriate choice of discharge antibiotic type, dose, or duration. These shortcomings occurred across all three provider types studied and represent areas for further education and quality improvement to promote antimicrobial stewardship.


Urinary tract infections in the elderly are common. Treatment with nitrofurantoin in men may not be sufficient if concomitant tissue involvement is present, resulting in treatment failure. The aim of this study is to determine the prevalence of nitrofurantoin failure in the elderly, and to assess the effect of gender and age. A retrospective observational study was conducted using a Dutch general practice medical record database of 21,789 men and 26,622 women aged 65 years or older in 2015. First, nitrofurantoin prescriptions in 2015 were analyzed. Nitrofurantoin failure (subsequent prescription of antibiotic within 30 days) for men, women, and different age categories were compared. The effect of age and gender was assessed using multivariate logistic regression. A total of 3537 patients had a first nitrofurantoin prescription in 2015; 506 men and 3031 women. Overall, 584 patients (17%) experienced nitrofurantoin failure; 135 (27%) men and 449 (15%) women. Male gender (odds ratio (OR) = 2.09, 95% confidence interval (CI) 1.68–2.61) and age  was associated with higher treatment failure. Our findings indicate that in a substantial number of elderly men, nitrofurantoin might not be the appropriate treatment. Nitrofurantoin, as a first choice in elderly men with urinary tract infections, should be reconsidered. Elderly people have an increased risk of urinary tract infections (UTIs). In men, the incidence of UTI increases with age, from 5 per 1000 patients per year in younger patients, up to 80 per 1000 patients at the age of 80 years [Cystitis in men is associated with a higher risk of complications than cystitis in women. Older men, in particular, may be at risk for significant morbidity  in case of nitrofurantoin failure . The guiThe aim of this study was to explore whether treatment failure occurs in routine practice, using medical records from a large general practice network to determine the prevalence of nitrofurantoin failure in elderly men and women, and to assess the effect of age on nitrofurantoin failure.A total of 48,411 patients in the Julius General Practitioners’ Network (JGPN) database were 65 years or older in 2015; 21,789 (45%) men and 26,622 women (55%). The mean age of all patients was 74 years, with mean ages in men and women of 73 and 75 years, respectively.A total of 29,261 antibiotic prescriptions for any cause were prescribed to 12,427 patients, i.e., 26% of the population under study received at least one antibiotic in 2015. Overall, 4712 (22%) of men and 7715 (29%) of women received at least one antibiotic prescription. Nitrofurantoin was the most commonly prescribed antibiotic, with 7060 (24%) of all antibiotic prescriptions; 815 (2.7%) prescriptions in men and 6245 (21%) prescriptions in women.A total of 506 men  were prescribed nitrofurantoin at least once in 2015, compared to 3031 women . Of the 506 men receiving a first nitrofurantoin prescription, 135 (27%) had nitrofurantoin failure . Of the In men, ciprofloxacin was most commonly prescribed following the first course of nitrofurantoin, whereas in women, this was fosfomycin .In our retrospective observational study using a Dutch general practice medical record database containing the prescription data of 21,789 men and 26,622 women aged 65 years or older, nitrofurantoin was the most commonly prescribed antibiotic. A total of 3537 patients had a first nitrofurantoin prescription in 2015, of which 584 patients (17%) experienced nitrofurantoin failure; 135 (27%) men and 449 (15%) women. Nitrofurantoin failure prevalence increased with age.The current study has a number of limitations. First, physicians’ diagnosis code of UTI and data on hospital admissions were not available from our database. As a proxy for UTI, we selected prescriptions of nitrofurantoin, because this is rarely, if ever, prescribed for anything other than suspicion of UTI. However, validity for prescribing nitrofurantoin and specific symptoms such as fever that indicate tissue involvement could not be investigated. Prophylactic nitrofurantoin prescriptions for recurrent UTIs, and nitrofurantoin prescriptions that were prescribed preventatively in case the patients’ symptoms would worsen, but in which patients eventually did not need or use the medication, were not excluded from the analysis. Additionally, data considering antibiotics prescribed at out-of-hours services were not available for analysis. Although the overall population was large, outcome numbers for subanalysis for specific age categories were smaller, making results more susceptible to random variations.The current study also has several strengths. A very large study population was used, increasing the power of the statistical analyses and reliability of the prevalence rates. This is further supported by the large amount of antibiotic prescriptions. The results are highly illustrative for the degree in which elderly cope with UTI, and the rate in which treatment failure occurs.Although other studies looking at nitrofurantoin treatment failure exist, this is the first study to investigate treatment failure in older adults specifically, only including antibiotics that are used for UTI and with a 30-day follow-up. The Dutch guideline reports a previous unpublished study by the Netherlands institute for health services research Nivel, that also estimated nitrofurantoin treatment failure at 27% in men of all ages . HoweverIn our study, the choice of the second antibiotic treatment was consistent with Dutch guidelines for women, as most women are prescribed either fosfomycin or trimethoprim (48% resp. 21%). In men, ciprofloxacin accounts for more than half of second antibiotic prescriptions after nitrofurantoin, followed by trimethoprim (17%). In the current Dutch guidelines, ciprofloxacin is recommended if there are signs of tissue involvement .Possible tissue involvement in UTIs in men may explain the higher failure of nitrofurantoin in men than in women, and why ciprofloxacin was selected in half of the men as second prescription. This hypothesis is supported by another study which showed that in more than 90% of men with febrile UTIs, prostate infection was involved . HoweverIn our study, we found that in more than a quarter of the men receiving nitrofurantoin, different antibiotic prescriptions for UTIs were necessary within 30 days. This indicates that in a substantial portion of the elderly men, nitrofurantoin might not be the appropriate treatment. More comparative studies for the efficacy of antibiotic treatment, specifically of nitrofurantoin, for UTIs in elderly men are needed. Due to the high prevalence of treatment failure and possible risk of severe morbidity, nitrofurantoin, as a first choice in elderly men with UTIs, should be reconsidered.n = 48,411). Age, gender and antibiotic prescriptions with corresponding dates were available for analysis. Prescriptions were recorded using the Anatomical Therapeutic Chemical (ATC) Classification System.This is an observational retrospective cohort study using routinely collected data. Data were obtained from the JGPN database. This database contains anonymized electronic medical records from 64 general practices, including 371,028 patients in The Netherlands, and is representative of the Dutch population . We seleWe analyzed all first nitrofurantoin prescriptions in 2015 of the cohort of 48,411 selected patients, the date of prescription being the index date. Probable failure of nitrofurantoin was defined as a prescription within 30 days after the index date for a different antibiotic that is recommended for UTIs, i.e., fluoroquinolones , fosfomycin, trimethoprim, amoxicillin/clavulanic acid, and trimethoprim/sulfamethoxazole. Other antibiotics such as amoxicillin, azithromycin, doxycycline or flucloxacillin were excluded from this definition, as these are likely to be prescribed for reasons other than UTIs. A second prescription of nitrofurantoin was excluded from the definition, as this was assumed to be a prolongation of the initial treatment, a prophylactic prescription, or a new episode of an uncomplicated UTI. Multivariate logistic regression was performed to assess the effects of age and gender on treatment failure. For data-analysis, Statistical Package for the Social Sciences version 25.0  was used.Research in the JGPN database is observational, and data are generated during routine care; enlisted patients are not approached individually for participation, but are adequately informed at the start of their enrolment, offering them the option to opt out . The MedThis retrospective observational study analyzed the prevalence of nitrofurantoin failure in UTI in elderly men and women. Our findings indicate that treatment failure occurred in a substantial number of elderly men, and nitrofurantoin might not be the appropriate treatment. Nitrofurantoin, as a first choice in elderly men with UTIs, should be reconsidered.


RCH) was defined to characterize the internal damage degree of CRBFC. The experimental results showed that, considering the mechanical strength and fracture damage behavior of CRBFC, the optimal crumb rubber replacement rate, basalt fiber content and water–binder ratio are 10%, 2 kg/m3 and 0.46, respectively. In addition, it was found that AE parameters can effectively characterize the fracture behavior of CRBFC. The fracture stages of CRBFC can be divided according to the cumulative AE hits and counts. AE amplitude value can be used as an early warning of CRBFC specimen fracture. Moreover, the fracture mode can be identified by RA and average frequency (AF) values variation during the loading process.Basalt fiber and crumb rubber, as excellent road material modifiers, have great advantages in improving the mechanical properties and fracture behavior of concrete. Acoustic emission (AE) is a nondestructive testing and real-time monitoring technique used to characterize the fracture behavior of concrete specimens. The object of this paper is to investigate the effects of crumb rubber replacement rate, basalt fiber content and water–binder ratio on the mechanical properties and fracture behavior of crumb rubber basalt fiber concrete (CRBFC) based on orthogonal test. The fracture behavior of a CRBFC specimen under three-point flexural conditions was monitored by AE technology and the relative cumulative hit ( In recent years, the output of waste tires has increased greatly with the rapid development of the automobile industry. Massive quantities of waste rubber are generated every year, leading to increasingly serious environmental pollution ,2. The wAdding fibers into concrete can effectively improve the mechanical properties and durability of concrete. Three-dimensional randomly distributed fibers can inhibit the initiation and expansion of cracks, reduce the stress concentration near cracks and improve the toughness of concrete ,15. The Acoustic emission (AE) is a nondestructive testing and real-time monitoring technology, which has been used to analyze the actual failure state and fracture behavior of concrete . The ela3, 4 kg/m3 and 6 kg/m3) and crumb rubber replacement rate  on the mechanical properties and fracture behavior of crumb rubber basalt fiber concrete (CRBFC) have been investigated by orthogonal test. The purpose of this study is to reduce the production cost of concrete, improve the mechanical properties of concrete and realize the recycling and reuse of waste rubber. In addition, a three-point flexural test of CRBFC was carried out with AE technology. The fracture behavior of CRBFC was evaluated based on visual analysis of AE parameters, and AE characteristic parameters were used as an early warning of concrete fracture. Moreover, the fracture mode of CRBFC was investigated by the AE representative analysis method , and the application of AE methods to concrete structures was certified.In this paper, the effects of water–binder ratio , basalt fiber content  and the hydrogen ions in carboxyl groups (–COOH) can be replaced by sodium ions and form carboxylates (–COONa). Carboxylates (–COONa) can provide a weak alkali environment around crumb rubber and improve cement hydration near crumb rubber . In addiThe procedures for sodium hydroxide solution pre-modified crumb rubber were as follows: (1) crumb rubber was soaked in 0.25 M sodium hydroxide solution for 24 h at room temperature; (2) crumb rubber treated with sodium hydroxide solution was washed with tap water until the pH of the washing water was close to neutral; (3) crumb rubber was air dried at room temperature.n(rm), where L refers to the orthogonal table, n refers to the number of experiments, m refers to the maximum number of factors, and r refers to the number of levels used by each factor.Orthogonal experimental design is a method to study multi-factor and multi-level experiments. According to the orthogonality, a few experimental schemes with enhanced representativeness were selected evenly from the whole experimental group and high-quality output can be obtained from the few experimental results . The selThe water–binder ratio, crumb rubber replacement rate and basalt fiber content have great influence on the mechanical properties of CRBFC. These three parameters were selected as orthogonal test factors and each factor had three levels, as shown in xiK refers to the sum of experimental results corresponding to the level i of factor x, xik refers to the average of experimental results corresponding to the level i of factor x, and xR refers to the range value of experimental results corresponding to factor x.Range analysis is a statistical method to judge the sensitivity of experimental results to each factor in an orthogonal test. The effect of each factor on the experimental result was judged by comparing the magnitude of the range. The larger the range, the greater the influence of each factor on the experimental results. The specific calculation process of range analysis is shown in Equations (1) and (2): F-test was used to verify the creditability of range analysis and accurately estimate the importance of each factor for the experimental results. The null hypothesis is that the given factor has no impact on the experimental results. The null hypothesis is rejected if the obtained F value is equal to or higher than the critical F value at the significant level. The higher the F value, the more significant the influence of the given factor on the experimental results is [fSS refers to the sum of square deviations of each factor. eSS refers to the sum of square deviations of error. fd refers to the degrees of freedom of each factor. ed refers to the degrees of freedom of error. fMS refers to the mean square of each factor. eMS refers to the mean square of error. F refers to the F value.Variance analysis based on the sults is . The calThe crumb rubber was added into the concrete to replace fine aggregate with an equivalent volume method. Unmodified crumb rubber was mixed into concrete as the control group to evaluate the effect of crumb rubber modified by sodium hydroxide solution on the strength of CRBFC. In addition, a control group without added crumb rubber and basalt fiber was prepared to evaluate the beneficial effects of crumb rubber and basalt fiber on the strength of concrete. The mix proportion of CRBFC is shown in The dispersion of crumb rubber and basalt fiber has a great effect on the strength of concrete. During the mixing process, crumb rubber and basalt fiber were added into the mixture step by step, and the specific mixing steps were as follows. (1) Put the coarse aggregate and fine aggregate into the blender and stir for 1 min. (2) Put the basalt fiber into the blender and stir for 2 min. (3) Put the premixed cement and crumb rubber mixture into the blender and stir for 1 min. (4) Put the water into the blender and stir for 3 min. The 100 × 100 × 100 mm and 100 × 100 × 400 mm specimens were casted. All the specimens were de-moulded after 24 h and cured for 28 d in a standard-cured room with a relative humidity of 95% and a temperature of 20 ± 2 °C.The compressive strength and flexural strength of CRBFC were tested according to national standard GB/T50081–2002 . The 100The variation in AE signal parameters is related to change in the internal structure of concrete. The elastic wave generated by damage to the internal structure of concrete propagates to the surface of the AE sensor and converts it into an electrical signal. The electrical signal is processed and calculated by the acquisition and analysis system into a set of signal parameters to characterize the digitized AE waveform. AE signal parameters collected by the AE measurement system are shown in In order to classify cracking modes, AE parameters are applied to calculate RA and AF values. AF is defined as count divided by duration; RA is defined as rise time divided by amplitude . The speThe fracture modes can be divided into shear mode and tensile mode. Compared with the tensile crack, the shear crack has a higher RA value and lower AF value, which is related to the energy wave released by the crack. The tensile crack releases energy in the form of a longitudinal wave, which has a faster propagation speed than a shear wave, with a large amplitude and short rise time. The shear crack releases energy mainly in the form of a shear wave, which has a slower propagation speed leading to a longer duration and rise time. In the three-point flexural test, the fracture behavior of CRBFC specimens was detected by the SAEU2S–6 AE acquisition and analysis system produced by Shenghuaxingye Technology Co., Ltd. . A SR150M 150kHz resonant AE sensor produced by Shenghuaxingye Technology Co., Ltd.  with a frequency range of 60–400 kHz was fixed on the side of the specimen through an elastic fixing band. Vaseline was used as a coupling agent to eliminate the air in the contact interface. The lead breaking test was used to ensure the AE sensor was contacted well. The specific arrangement of the AE sensor is shown in The experimental results of the compressive strength and flexural strength tests are shown in 3 and 10%, respectively.The range analysis of the compressive strength of CRBFC is shown in F critical values that define the significance of each independent factor: if the F value is greater than 19.0, the effect of the factor is the most significant; if the F value is between 9.0 and 19.0, the effect of the factor is significant; if the F value is between 3.0 and 9.0, the effect of the factor is less significant; if the F value is less than 3.0, the effect of the factor is least significant. F values of basalt fiber content and crumb rubber replacement rate are between 9.0 and 19.0, which indicates that these two factors have significant effects on the compressive strength of CRBFC. The F value of basalt fiber content is greater than that of crumb rubber replacement rate, which means the effect of basalt fiber content is more significant than that of crumb rubber. The F value of the water–binder ratio is between 3.0 and 9.0, which indicates that the water–binder ratio has a less significant effect on the compressive strength of CRBFC. The results are consistent with that of range analysis.The variance analysis of the compressive strength of CRBFC is shown in 3 and 10%, respectively.The range analysis of the flexural strength of CRBFC is shown in F value of basalt fiber content is greater than 19.0; this indicates that basalt fiber content has the most significant effect on the flexural strength of CRBFC. The F value of the crumb rubber replacement rate is between 9.0 and 19.0, which means the crumb rubber replacement rate has a significant effect on the flexural strength of CRBFC. The F value of the water–binder ratio is less than 3.0, which indicates that the effect of the water–binder ratio is least significant. The results are consistent with those of range analysis.The variance analysis of the flexural strength of CRBFC is shown in AE characteristic parameters could be used to analyze the fracture behavior of concrete. The AE parameters of nine orthogonal tests were analyzed to evaluate the effects of water–binder ratio, crumb rubber replacement rate and basalt fiber content on the fracture behavior of concrete. The load level is defined as the load at some point divided by the maximum load. The cumulative AE hits and counts vs. load level are shown in It can be seen from RCH) is defined and calculated by Equation (8). The RCH is positively correlated with the internal damage degree of concrete. The greater the RCH, the greater the internal damage degree of concrete and the closer the concrete specimen is to failure.xH refers to the cumulative hits at the x level and totalH refers to the cumulative hits when the specimen is damaged.AE hits could reflect the total and frequency of AE signals; it is constantly used to evaluate AE activity. The AE activity is related to the elastic wave released by the internal damage of concrete. The internal damage of concrete could be characterized by the AE hits. In order to clearly characterize the damage degree of concrete at different load levels, the relative cumulative hits  crack initiation stage, (II) crack expansion stage, and (III) failure stage. The critical point of the crack expansion stage and the fracture stage could be used to evaluate the internal damage degree of concrete before the macroscopic crack appears. The critical points of the fracture stage of nine orthogonal tests were determined based on the visual analysis of AE parameters. The load levels of the critical point of nine groups are about 0.9, so load level 0.9 is selected as the standard. If the critical point is lower than load level 0.9, it indicates that the corresponding concrete specimen has more internal damage and the fracture stage enters the failure stage; if the critical point is higher than load level 0.9, it indicates that the corresponding concrete specimen has less internal damage and the internal crack is still in the expansion stage. In order to clearly reflect the effects of water–binder ratio, crumb rubber replacement rate and basalt fiber content on the fracture process of CRBFC, the relative cumulative hits at load level 0.9 was analyzed by range analysis and variance analysis.RCH is shown in RCH, and the crumb rubber has the greatest impact on the RCH, followed by basalt fiber and water–binder ratio. The effects of water–binder ratio, basalt fiber and crumb rubber replacement rate on the RCH are shown in RCH increases first and then decreases with the increase in water–binder ratio, which is related to the degree of hydration of cement. The higher the degree of cement hydration, the denser the concrete and the less internal damage. The RCH increases with the increase in basalt fiber content. The appropriate amount of basalt fiber can inhibit the initiation and expansion of internal cracks, thus reducing the internal damage degree of concrete. However, excessive basalt fiber will destroy the compacted structure of concrete and cause more damage in the process of pulling out the fiber. The RCH decreases first and then increases with the increase in crumb rubber replacement rate. The appropriate amount of crumb rubber can improve the toughness and crack resistance of concrete, and the crumb rubber modified by sodium hydroxide can increase the hydration degree of cement, thus improving the concrete internal compactness. However, excessive crumb rubber will lead to weak bonding strength between the crumb rubber and cement, increasing the risk of internal damage to the concrete. In addition, it can be seen from 3 and 10%, respectively.The range analysis of RCH is shown in RCH that the F values of crumb rubber replacement rate and basalt fiber content are greater than 19.0, which indicates that these two factors have the most significant effect on the RCH. The F value of crumb rubber replacement rate is greater than basalt fiber content, which means the effect of crumb rubber is more significant. The F value of water–binder ratio is between 9.0 and 19.0, which indicates that water–binder ratio has a significant effect on the RCH. The results are consistent with those of range analysis.The variance analysis of The AE amplitude value vs. load level is shown in The RA and AF values vs. load level are shown in In this paper, the effects of water–binder ratio, basalt fiber content and crumb rubber replacement rate on the mechanical properties and fracture behavior of CRBFC were studied by orthogonal testing. The fracture process of CRBFC under a flexural load was monitored by AE technology. Based on the experimental results, the following conclusions can be drawn:1. Adding 0.25 M sodium-hydroxide-solution-modified crumb rubber can effectively improve the bonding strength between crumb rubber and cement, thus enhancing the compressive strength and flexural strength of CRBFC.RCH, the optimal levels of water–binder ratio, basalt fiber content and crumb rubber replacement rate are 0.46, 2kg/m3 and 10%, respectively.2. Based on the orthogonal analysis results of the compressive strength, flexural strength and 3. The positive synergistic effects of basalt fiber and crumb rubber can effectively improve the mechanical properties and fracture behavior of concrete and increase the practicability of basalt fiber and crumb rubber in the field of concrete.4. AE characteristic parameters have a great correlation with the fracture stages of concrete, and the fracture stages of CRBFC can be accurately divided according to the cumulative AE hits and counts. The mutation of AE amplitude value symbolizes the transformation of the fracture stage of concrete. AE amplitude can be used as an early warning of concrete structure fracture.5. The fracture mode of CRBFC is dominated by the shear mode at the failure stage. In addition, RA and AF values can be used as the evaluation index of concrete fracture mode, which could assist in the assessment of concrete damage.


According to the Centers for Disease Control’s 2015 Hospital Acquired Infection Hospital Prevalence Survey, 1 in 31 hospital patients was infected with at least one nosocomial pathogen while being treated for unrelated issues. Many studies associate antibiotic administration with nosocomial infection occurrence. However, to our knowledge, there is little to no direct evidence of antibiotic administration selecting for nosocomial opportunistic pathogens.This study aims to confirm gut microbiota shifts in an animal model of antibiotic treatment to determine whether antibiotic use favors pathogenic bacteria.We utilized next-generation sequencing and in-house metagenomic assembly and taxonomic assignment pipelines on the fecal microbiota of a urinary tract infection mouse model with and without antibiotic treatment.Acinetobacter calcoaceticus/baumannii complex, Chlamydia abortus, Bacteroides fragilis, and Bacteroides thetaiotaomicron. Moreover, antibiotic treatment selected for antibiotic resistant gene enriched subpopulations for many of these opportunistic pathogens.Antibiotic therapy decreased the number of detectable species of bacteria by at least 20-fold. Furthermore, the gut microbiota of antibiotic treated mice had a significant increase of opportunistic pathogens that have been implicated in nosocomial infections, like Oral antibiotic therapy may select for common opportunistic pathogens responsible for nosocomial infections. In this study opportunistic pathogens present after antibiotic therapy harbored more antibiotic resistant genes than populations of opportunistic pathogens before treatment. Our results demonstrate the effects of antibiotic therapy on induced dysbiosis and expansion of opportunistic pathogen populations and antibiotic resistant subpopulations of those pathogens. Follow-up studies with larger samples sizes and potentially controlled clinical investigations should be performed to confirm our findings. Acinetobacter calcoaceticus/baumannii complex or Clostridioides difficile [Clostridiodes difficile infection [Patients who acquire a nosocomial infection have approximately a 1 in 10 chance of mortality during their hospitalization . One of ifficile –7. The hifficile , 9. We aThe introduction of high-throughput sequencing technology has led to powerful advances in microbial community ecology composition and function assessments. Despite the extensive advancements in high-throughput sequencing there is a large portion of the human gut microbiome composition still uncharacterized. The two major sequencing methods used to assess microbial communities of human systems are amplicon sequencing and whole metagenome sequencing (WMS). While amplicon sequencing may provide enough information to assess composition, there are biases present, from amplification and primer selection, that cannot be ignored . AdditioRecently we applied a traditional read-mapping based method to the metagenome analysis of antibiotic treated mice and revealed a decrease of gut microbiota diversity and enrichment of antibiotic resistance genes (ARGs) in the gut . HoweverE.coli  to create the UTI model. Our previous study showed no discernable difference in the gut microbiome of naïve and urinary tract infection model mice [Experiments were conducted on BALB/c female mice  8 – 10 weeks old. The same strain, sex and age mice were obtained from the same vendor and the same location in the vendor facility. Mice were randomly allocated to control or treatment groups , each with 4 animals. Not all animals yielded sufficient amount of sequencing reads (> ~ 10 million per sample) and in the end 3 animals per group were used for subsequent sequencing analysis. To recapitulate the most common nosocomial infection, a urinary tract infection model previously described –17 was udel mice . TreatmeGenomic DNA extraction and sequencing was completed as previously described . BrieflySample outputs were processed into raw read fastq files with bcl2fastq2 . Host reads were removed by first aligning reads to an indexed mouse genome  databases with the taxonomy ID of 10,090) using BWA-MEM (version 0.7.12), then unmapped reads were extracted using SAMtools (version 0.1.18) with parameters “-h -f 4”, and the output was converted to fastq with Picard-Tools (version 2.1.1) SamToFastq function. Assembly was performed with SPAdes (version 3.12.0) using the recommended parameters “-k 21,33,55,77” with the –meta flag to initiate MetaSPAdes mode for paired end samples  . All scahttps://github.com/FDA/metagenome). Gene sequences were extracted from the retained scaffold using BEDTools [https://ftp.ncbi.nlm.nih.gov/blast/db/FASTA/nr.gz). To determine alignment coverage scaffolds greater than 500bps in length were aligned with BLASTn to NCBI nucleotide database (https://ftp.ncbi.nlm.nih.gov/blast/db/FASTA/nt.gz). BLASTn alignments to determine coverage were completed with the following parameters “-task megablast -evalue 1e-6 -max_target_seqs 1 -best_hit_score_edge 0.05 -best_hit_overhang 0.05 -window_size 0 -percent_identity 90”. BLASTx alignments to determine percent identity were completed with the following parameters “-max_target_seqs 1 -evalue 1e-6”. All BLAST alignments were completed using a local installation of the BLAST command line application BLAST + (version 2.3.0) [The MetaGeneAnnotator program  was usedBEDTools  and the BEDTools . Brieflyn 2.3.0) .https://cran.r-project.org/package=RSQLite). The top scoring hits for a predicted gene with at least 60% positive scoring matches were retained for lowest common ancestor analysis. Second, the full length of each scaffold was mapped to the NCBI NT database through BLASTn, and any scaffold with over 90% percent identity with any mouse sequences were removed. Third, the taxon id of the lowest common ancestor of all the retained top BLASTx hits was assigned to the scaffold. To determine the abundance of opportunistic pathogens we counted how many reads of each sample aligned to the genome of opportunistic pathogens using Bowtie2 (version 2.1.0). For plotting purpose, normalization was performed by multiplying mapped read counts by 1 million and then dividing by the total number of reads from the respective sample (reads per million). To determine the profile of antibiotic resistance genes for specific species present we aligned predicted genes using BLASTx to the CARD database  [Taxonomic assignment for scaffolds was performed in three steps. First, the top 10 hits from each predicted gene in a BLASTx alignment to the NCBI RefSeq database sorted by bitscore were retained and stored in an in-house developed SQLite database through the R package RSQLite  . Counts ARG counts and counts of reads mapping to opportunistic pathogens were normalized using edgeR’s default normalization method  and edgeR’s analysis functions, glmFit, and glmLRT were used to estimate the dispersion and test for differential abundance .To characterize the microbiome, filtered reads were mapped using BLASTn to the NCBI nucleotide database. To increase mapping rates, we performed de novo assembly of reads into scaffolds. A total of 313,519 scaffolds greater than 500 bps were created for the Control cohort. Ampicillin, Ciprofloxacin, and Fosfomycin-treated groups had 12,438, 25,171, and 5,331 scaffolds greater than 500 bps generated, respectively. Assembly in conjunction with de novo gene prediction see  increaseThrough a characterization method described in Kowarsky et al., we clasAcinetobacter calcoaceticus/baumannii complex and Chlamydia abortus species of opportunistic pathogens  following antibiotic treatment was Bacteroides fragilis, which had on average 17,678 reads per million in the Fosfomycin-treated samples. This is a 46-fold increase in the relative abundance from the control group, where this opportunistic pathogen had on average 376 reads per million  than the entire Acinetobacter calcoaceticus/baumannii population in the Control cohort (13 ARGs). The difference in antibiotic resistant gene diversity is even more stark when comparing these numbers relative to the total number of predicted genes in their respective sample. For example, the average number of relative Acinetobacter calcoaceticus/baumannii antibiotic resistant gene counts was 520  in Ampicillin treated mice and 0.17 in the Control cohort (Benjamini-Hochberg (BH) adj. p value = 0.00075)  and Chlamydia trachomatis  exhibited a statistically significant increase in Ampicillin cohort compared to Controls. We further examined the diversity profile of each treatment group and found that Ciprofloxacin treated mice had well over 500-fold more antibiotic resistant genes associated with Campylobacter coli  than Control  Fig. . Additiohttps://www.cdc.gov/hai/ca_uti/uti.html). Oral antibiotic administration to treat nosocomial infections, like hospital acquired UTIs, have been implicated in gastrointestinal microbiota dysbiosis, and secondary infections in human and mouse studies [Urinary tract infection (UTI) is the leading cause of hospital acquired infections worldwide . Previou studies –34. FurtAcinetobacter calcoaceticus/baumannii complex after antibiotic administration for a primary nosocomial infection [Acinetobacter calcoaceticus/baumannii, Chlamydia abortus, Chlamydia trachomatis, Bacteroides fragilis, and Bacteroides thetaiotaomicron after various antibiotic treatment. For other pathogens studied, for example Campylobacter coli in the Ciprofloxacin cohort, we found that while the relative abundance is not increased, the numbers of ARGs are, suggesting more ARG-enriched subpopulations were selected by the treatment. Interestingly, our previous study suggested that ARGs enriched in cohorts treated by one class of antibiotics are often resistant to other classes of antibiotics [Our results strongly support the previously described hypothesis with direct evidence of gut microbiota dysbiosis, opportunistic pathogen selection, and a higher percentage of selected opportunistic pathogens harboring antibiotic resistant genes occurring after oral antibiotic administration. Here, the reduction of our total sequencing reads, characterized scaffolds, and number of unique species present define the state of dysbiosis after antibiotic administration. Furthermore, the shift from Firmicutes to Proteobacteria, that we present in our results, is a known state of dysbiosis after antibiotic treatment  and durinfection , 39. We ibiotics . We alsoWe acknowledge several limitations of our studies. First, the number of animals in each cohort is small, and some animals were not included in the analysis due to insufficient number of sequencing reads. It is unknown whether the excluded animals would have any impact on the final results. Second, paired-end sequencing was completed on all samples except the entire Fosfomycin cohort, which was single-end sequenced. This potentially had several effects on our Fosfomycin results. For example, the number of scaffolds generated that passed our quality control measures were far lower in Fosfomycin than other cohorts. This was likely due to the method of assembly differences necessary to build the scaffolds, as reported in our methods. Additionally, the assembly process may have contributed to the differences seen in the characterization of scaffolds, where a larger portion of control and Fosfomycin scaffolds were characterized as novel. This large portion of novel scaffolds is expected for the control cohort as there is substantial evidence for a large unknown population of microbiota present in unperturbed gut microbiome . HoweverAdditional file 1: Table 1. Descriptive statistics of data processed by the analysis pipeline. For each sample in each cohort, the number of basepairs (BPs) in assembled contigs, the number of reads mapped to scaffolds, the number of predicted genes on scaffolds, and number of scaffolds classified into each of the three categories  are given.


MET）基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）的一种重要肿瘤驱动基因，针对MET 14外显子的跳跃突变的靶向治疗药物给患者带来新的希望。目前已经上市或者即将上市的MET抑制剂包括：克唑替尼、卡博替尼、沃利替尼和Tepotinib等。MET抑制剂的客观缓解率较高，并且安全性良好。但是，MET抑制剂的耐药不可避免，因此需要重视对于耐药机制的研究。肝细胞生长因子（hepatocyte growth factor, HGF）/MET信号通路抑制剂与其他药物的联合应用，对于抑制和逆转耐药可能发挥重要作用。间质-上皮细胞转化因子（mesenchymal-epithelial transition factor,  EGFR）突变、间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）重排和ROS1重排等, 2。针对这些靶点分别有不同种类的小分子酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）。间质-上皮细胞转化因子（mesenchymal-epithelial transition factor, MET）被认为是继EGFR、ALK和ROS1之后在NSCLC中的另一个重要肿瘤驱动基因和治疗靶点，目前受到越来越多的关注-5。MET基因的异常主要包括3种形式：MET 14外显子跳跃突变、MET基因扩增和蛋白过表达。其中，针对MET 14外显子跳跃突变的靶向药物最具发展和应用前景，本文中MET基因突变主要指MET 14外显子跳跃突变。目前，至少有7种针对MET基因突变的TKI已经上市或者正在进行临床试验，包括克唑替尼、卡博替尼、沃利替尼、Tepotinib、Capmatinib、Glesatinib和Merestinib，另外有更多的药物在进行临床前研究, 7。本文将结合MET 14外显子突变的特点，重点对这些药物的研究情况和临床应用进行综述，并提出未来MET抑制剂的发展方向和面临的挑战。在非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗中，针对特定肿瘤驱动基因的靶向药物发挥着极其重要的作用。目前已明确的靶点有表皮生长因子受体（epidermal growth factor receptor, 11.1MET基因位于人类7号染色体（7q21-31），长度约125 kb，同时含有21个外显子。由MET基因编码的蛋白为c-MET，也称为肝细胞生长因子受体（hepatocyte growth factor receptor, HGFR），是具有自主磷酸化活性的跨膜受体，属于酪氨酸激酶受体超家族，主要表达于上皮细胞。HGF是目前发现的c-MET的唯一配体，属于纤维蛋白溶酶原家族，主要表达于间质细胞。HGF能够与c-MET的细胞外结构域结合，促使c-MET发生二聚化、酪氨酸磷酸化，激活众多下游信号通路，如PI3K-Akt、Ras-MAPK、STAT和Wnt/β-catenin等，从而发挥促进细胞增殖、细胞生长、细胞迁移、侵袭血管及血管生成等效应。这在正常的组织发育和肿瘤进展中都发挥重要作用，即c-MET正常表达时促进组织的分化与修复，当调节异常时则促进肿瘤的增殖与转移。c-MET通路异常激活主要包括MET 14外显子跳跃突变、MET基因扩增和c-MET蛋白过表达3种类型。1.2MET 14外显子对应编码141个氨基酸，其所在的近膜结构域是c-MET的关键负性调控区，包含着E3泛素连接酶c-Cbl酪氨酸结合位点（Y1003），参与c-MET蛋白的泛素化和降解。MET 14外显子的基因突变会引起14外显子跳读（exon skipping），使得含有E3泛素连接酶c-Cbl结合位点的近膜结构域缺失，进而导致c-MET蛋白泛素化障碍、c-MET稳定性增加和降解率减低，引起下游信号的持续激活，最终成为肿瘤的驱动基因。c-MET主要由E3泛素连接酶c-Cbl主导降解。MET 14外显子跳跃突变的总体发生率大约在3%-6%, 12。美国癌症基因研究组通过对230例肺腺癌的mRNA和DNA高通量测序结果进行分析，发现约4%的肺腺癌存在MET 14外显子跳跃突变。Awad等利用二代测序的方法检测933例NSCLC患者的基因，发现28例（3.0%）NSCLC患者存在MET 14外显子跳跃突变。在肺肉瘤样癌中，MET 14外显子跳跃突变的发生率可能更高，达到约22%。在肺鳞癌中，MET 14外显子跳跃突变的发生率较低，约为2%。在中国人群中，其突变发生率可能明显低于高加索人群，Liu等分析1, 296例中国NSCLC患者的DNA，发现仅有12例（0.9%）患者具有MET 14外显子跳跃突变，这与Zheng等研究的结果相似（1.3%, 23/1, 770）。既往研究, 20显示MET 14外显子跳跃突变不与EGFR、ALK等NSCLC的其他驱动基因共存，提示其代表一种独立的肿瘤驱动基因，但是MET 14外显子跳跃突变可以与MET基因扩增和蛋白过表达并存。对于MET 14外显子跳跃突变、MET基因扩增和c-MET蛋白过表达三者之间是否存在必然联系，不同的研究有着不同的结果，目前尚无大规模的研究证据支持。在NSCLC中，2Met基因突变成为NSCLC中重要的治疗靶点。根据HGF/c-Met信号通路中作用位点的不同，可将靶向治疗药物分为三大类：抗HGF单克隆抗体、抗c-Met单克隆抗体和小分子TKI。前两者分别在细胞外与HGF和c-Met结合，从而阻止HGF与c-Met的结合及受体磷酸化，阻止信号传导；小分子TKI作用于膜内催化域从而阻止蛋白磷酸化，阻断信号传导。目前研究最多的也最具有治疗潜力的是小分子TKI，因此本文重点关注此类靶向药物。基于HGF/c-Met信号通路异常激活，MET基因突变的TKI（MET-TKI）可分为3种类型（Ⅰ型、Ⅱ型和Ⅲ型）。Ⅰ型TKI是ATP竞争性的，与MET主链中的氨基酸残基形成氢键，其中又分为Ⅰa型和Ⅰb型，区别在于Ⅰb型TKI可以结合的位点较少，不包括甘氨酸残基的G1163位点（类似于ALK的G1202和ROS1的G2032位点），因此特异性较高。临床常用的药物克唑替尼属于Ⅰa型MET-TKI，Tepotinib和沃利替尼属于Ⅰb型MET-TKI。Ⅱ型MET-TKI一般为多靶点TKI，不仅占据ATP结合位点，还能通过管家基因突变进入非活性DFG-out构象形成的疏水口袋，对产生二次突变的MET仍具有抑制作用，或许可以逆转由Y1230等突变引起的Ⅰ型MET-TKI耐药。卡博替尼属于Ⅱ型MET-TKI。Ⅲ型MET-TKI作用于与ATP结合位点完全不同的变构位点，目前尚没有药物进入临床研究阶段。根据作用机制，针对3下面将分别介绍目前已经上市、即将上市和正在进行临床试验的几种MET-TKI（3.1ALK、ROS1、MET等。目前其获批的适应证是ALK和ROS-1基因重排的NSCLC。克唑替尼作为Ⅰa型MET-TKI能够抑制c-MET的自身磷酸化，从而抑制下游信号通路、抑制细胞增殖和促进凋亡。2020年最新版美国国家癌症综合网（National Comprehensive Cancer Network, NCCN）指南（Version 3.2020）推荐克唑替尼可以用于MET基因扩增和MET 14外显子突变的晚期NSCLC患者，这是目前NCCN指南中推荐的唯一一个MET-TKI。这一推荐是基于临床试验的结果，例如在PROFILE-1001研究中招募了21例初治或者化疗后耐药的MET 14外显子突变的NSCLC患者，其中18例在初步报告时可评估疗效，在中位随访时间相对较短的5.3个月内，客观缓解率（objective response rate, ORR）达到44%。最新发表在Nature Medicine上的报道对PROFILE-1001进行了扩展，在69例MET外显子14突变的晚期NSCLC患者中评估克唑替尼的抗肿瘤活性和安全性。在65例可评估反应的患者中，ORR为32%（95%CI: 21%-45%）。因此，克唑替尼有希望在不久的将来也获得治疗MET基因突变的适应证。克唑替尼的常见不良反应包括视觉异常、消化道反应、肝功能异常、QT间期延长和心动过缓等。克唑替尼（Crizotinib）是多靶点药物，其作用于3.2MET、VEGFR2、KIT、RET和AXL。虽然卡博替尼已经上市，但其适应证是甲状腺髓样癌。初步研究结果显示卡博替尼对NSCLC可能也有一定疗效。例如Paik等报道1例晚期NSCLC患者同时存在MET 14外显子突变和MET扩增，应用卡博替尼治疗后肿瘤完全缓解。目前针对MET基因突变的Ⅱ期临床试验正在进行中。卡博替尼的不良反应主要包括腹泻、恶心呕吐等消化道反应，转氨酶升高，手足综合征，心脏毒性和高血压等。卡博替尼（Cabozantinib）是Ⅱ型口服MET-TKI，具有多靶点作用，包括3.3EGFR和KRAS野生型的NSCLC。目前该药物已完成“评价沃利替尼治疗MET外显子14突变的局部晚期或转移性肺肉瘤样癌和其他NSCLC患者的有效性、安全性和耐受性的多中心、开放Ⅱ期的临床研究”入组。中期结果显示ORR高达51.6%（16/31），与治疗相关的不良反应大部分为1级-2级，包括：恶心、呕吐、外周组织水肿和肝功能异常。目前沃利替尼正在进行中国食品药品监督管理局的上市申请。因此，沃利替尼可能成为在中国获批的第一款针对MET基因突变的靶向药物。沃利替尼（Savolitinib, Volitinib）是Ⅰb型口服MET-TKI，由我国和记黄埔公司和阿斯利康公司合作研发。临床前研究显示沃利替尼可抑制c-MET磷酸化和下游信号传导，对于多种异种移植模型具有抗肿瘤活性，也包括3.4MET 14外显子跳跃突变的晚期或复发性NSCLC患者。这是全球首个针对c-Met单一靶点的靶向药。其实在临床前的研究中，Tepotinib在多种肿瘤模型中都观察到抗肿瘤活性，无论MET激活是否依赖于HGF。Tepotinib的Ⅰ期临床试验是在包括肺癌在内的实体肿瘤中进行的，着重评价具有MET扩增或者高表达患者的有效性和安全性。而Tepotinib的获批是基于一项单臂、Ⅱ期VISION研究结果。该研究共纳入99例MET外显子14跳跃突变的NSCLC患者，接受Tepotinib治疗后的ORR达到42.4%，并且Tepotinib耐受性良好，最常见的治疗相关不良事件为周围水肿（53.8%）、恶心（23.8%）和腹泻（20.8%）。Tepotinib是Ⅰb型口服MET-TKI，2020年3月在日本获批上市，用于治疗不可切除、3.5MET外显子14跳跃突变的转移性NSCLC，包括初治患者和先前接受过治疗的患者，目前入组已结束。共97例患者入组，在初治患者中总ORR为67.9%，疾病控制率（disease control rate, DCR）为96.4%，中位无进展生存期为9.69个月。在经治患者中ORR为40.6%，DCR为78.3%，中位无进展生存期为5.42个月。受试者中约有一半的脑转移患者对Capmatinib应答（54%, 7/13）, 34。最常见的治疗相关不良事件包括周围性水肿、恶心、肌酐升高和呕吐等。该药也已进入药品审批程序，期望在不久的将来上市。Capmatinib是Ⅰb型口服MET-TKI。Capmatinib的Ⅱ期临床试验（GEOMETRY mono-1）是评估用于治疗携带3.6MET、VEGFR、RON和TIE-2。Ⅰ期临床试验显示其具有较好的安全性和一定的有效性。Ⅱ期临床试验正在进行中，入组MET扩增和MET 14外显子跳跃突变的晚期NSCLC患者。Glesatinib是Ⅱ型口服MET-TKI，作用靶点包括3.7MET、TIE-1、AXL、ROS1、DDR1/2、FLT3、MERTK、RON和MKNK1/2。临床前期研究显示具有较好的抗肿瘤治疗活性。Ⅱ期临床试验正在进行中，入组MET 14外显子跳跃突变的晚期NSCLC患者。Merestinib是Ⅱ型口服MET-TKI，作用靶点包括4MET 14外显子突变，还有一些药物作用于HGF/MET信号通路的其他靶点。例如：抗HGF单克隆抗体（Rilotumumab, Ficlatuzumab）、抗c-Met单克隆抗体（Onartuzumab, HLX55, SHR-A1403）。这些药物都在进行临床研究中，目前尚无一种成熟药物上市。这些药物的研究多用于与MET-TKI联合，从而抑制或者逆转MET-TKI的耐药现象。另外，MET-TKI也可以与其他靶向药联合，主要作用也是抑制或者逆转耐药。例如最新发表在The Lancet Oncology杂志上的研究显示，携带EGFR突变的晚期NSCLC患者，在接受EGFR-TKI治疗后出现耐药并伴有MET基因扩增时，联合应用沃利替尼和奥希替尼具有较好的疗效。因此这种联合治疗模式可能成为未来发展的方向。除了针对5MET基因是NSCLC的一种重要肿瘤驱动基因，与EGFR、ALK和ROS-1等存在互斥现象。MET-TKI是治疗NSCLC患者中具有MET基因突变人群的有效药物。从已上市药物Tepotinib和即将上市的药物沃利替尼、Capmatinib的临床试验结果看，针对MET 14外显子的跳跃突变的单药有效率较高，ORR均达到40%以上，并且安全性较好，必将成为未来的治疗希望。但是MET-TKI的耐药不可避免，因此下一步需要加强对于MET-TKI耐药机制的研究。另外，HGF/MET信号通路的抑制剂与其他药物联合应用也可能具有治疗潜力，对于抑制和逆转耐药发挥重要作用。总之，在肺癌的精准治疗时代，分子检测和靶向药物必将为MET基因突变的NSCLC患者带来更好的疗效和长期生存机会。


To reduce the environmental pollution from cement production and the damage to natural resources from aggregate mining in the concrete industry, a relatively new concrete, termed geopolymer recycled lump concrete (GRLC), which uses geopolymer as the binding material to replace traditional cement and uses large demolished concrete lumps (DCLs) to partly replace concrete, is prepared in this study. Cubic and cylindrical GRLC specimens containing fresh geopolymer concrete and DCLs were tested under axial compression with various parameters, including the compressive strength levels of both fresh geopolymer concrete and DCLs, and the replacement ratio of DCLs. The compressive behavior of the GRLC specimens was compared with traditional cement recycled lump concrete (CRLC) specimens, with test results showing that GRLC specimens possess higher compressive strength than CRLC specimens under the same experimental conditions, which is due to the strengthening effect that fresh geopolymer concrete has on the DCLs. From the scanning electron microscope pattern of the GRLC specimen, it is found that the geopolymer bonds well with the old mortar attached to DCLs. As the replacement ratio increases from 0% to 33%, the elastic modulus of GRLC increases by 5%–11% but Poisson’s ratio remains almost constant (in the 0.16–0.17 range). Based on the measured strength and the predicted results, which coincide with one another well, a modified method for predicting the compressive strength of GRLC cubic and cylindrical specimens is proposed. A large amount of solid waste is produced each year due to industrial production and structural dismantling. These solid wastes have a significant adverse environmental impact, such as occupying landfill space and contaminating water sources and air. To alleviate the adverse impact of solid wastes on the environment, the recycling of solid wastes in construction material has been extensively studied. For example, the reuse of various solid wastes in concrete ,2, brick2 emissions. The huge consumption of natural aggregates also damages the ecological environment and leads to the exhaustion of natural sand and stone resources. For the aforementioned issues, one possible solution is the replacement of Portland cement by green binder material and the recycling of solid waste into concrete for concrete production.With the mass expansion of cities and the rapid development of infrastructure construction in developing countries like China, the demand for concrete has witnessed a dramatic increase in the last few decades. Accordingly, the consumption of natural aggregates and Portland cement, as the main components of ordinary concrete, has also increased substantially. Cement production releases a great amount of greenhouse gases and dust, bringing serious air pollution; based on production data in 2016 [2 and consumes less energy during its production [Geopolymer, an environmentally friendly green binding material, is considered as a promising alternative to Portland cement by many researchers ,8,9. It oduction . Sofi etoduction  comparedoduction  reportedoduction  showed toduction  indicateDemolished concrete is a kind of common solid waste. As for the recycling of demolished concrete in concrete production, according to the literature, there are two different ways to do it: recycled aggregate concrete  and recyWhen the binding material in recycled aggregate concrete (Portland cement) is replaced by a geopolymer, the produced concrete is referred to as geopolymer recycled aggregate concrete. A few researchers have investigated the mechanical properties of geopolymer recycled aggregate concrete. Nuaklong et al.  found thIf a geopolymer is substituted for Portland cement as the binding material in recycled lump concrete, a new type of concrete is derived, termed ‘geopolymer recycled lump concrete (GRLC)’, as seen in In this study, the mechanical behavior of GRLC was investigated through cylindrical and cubic specimens under axial compression. The effects of replacement ratio, strength levels of DCLs and fresh GC on the compressive strength, elastic modulus, Poisson’s ratio and volumetric strain of GRLC were evaluated. The shape effect and size effect of GRLC specimens were also analyzed. Utilizing the experimental results obtained from the current study, a formula for predicting the compressive strength of GRLC is proposed. Based on the test results, it can be concluded that GRLC specimens possess better compressive performance than ordinary recycled lump concrete specimens. Therefore, GRLC may be used as a substitute for ordinary concrete in the future, with the application in similar engineering fields as that of ordinary recycled lump concrete.2O/SiO2) = 1 and a mass concentration of 40%. Commercially produced metakaolin with an average particle size of 0.017 mm and a density of 2530 kg/m3, and low calcium fly ash with an average particle size of 0.032 mm and a density of 2620 kg/m3, were sourced from suppliers in China. To prepare the geopolymer binder, a blend of fly ash (FA) and metakaolin (MK), with a mass ratio of 1:1, is activated by potassium silicate solution with molar ratio (K3 and 2470 kg/m3), with a particle size of 70–100 mm. The compressive strength of the two types of demolished concrete, measured by Φ100 × 100 mm cylinder core drilling samples, were 35.7 MPa and 51.6 MPa, respectively. The corresponding 150 × 150 × 150 mm cubic compressive strength was 35.7 MPa and 51.6 MPa, calculated through the relationship between cylindrical and cubic compressive strength of OPC concrete [3, and local river sand with a fineness modulus of 2.7 and density of 2580 kg/m3, were used in fresh concrete. Two batches of demolished concrete, with different strength levels, were crushed into two types of DCLs, respectively  were fabricated by mixing three types of fresh concrete with two types of DCLs. η of DCLs (20% and 33%) and the shape of the specimens . For example, “GC1-D2-33-Y” represents a cylindrical specimen made of GC1 fresh concrete and D2 demolished lumps, with a replacement ratio of 33%.Due to the large size of DCLs (70–100 mm), the cylindrical and cubic specimens with a characteristic size (the minimum size in a specimen) of 300 mm, namely Φ300 × 600 mm cylinders and 300 × 300 × 300 mm cubes, were used for axial compression tests on recycled lump concrete. Another test variable is the replacement ratio Since the water absorption of DCLs is relatively high , the DCLs were wetted before pouring into the mold in order to avoid the water in fresh concrete being absorbed by the DCLs. During casting, a layer of 20 mm thickness fresh concrete was first poured into the mold, then the DCLs and fresh concrete were added alternately. To evenly distribute the DCLs in the mixture, a vibrating poker was used to stir the mixture of DCLs and fresh concrete. After casting, specimens were covered with sacks and then cured at room temperature for 28 days prior to undertaking compression tests. The preparation process of GRLC specimens is illustrated in −5/s as specified in the ASTM C39 standard [Axial compression tests were conducted on GRLC and cement recycled lump concrete (CRLC) specimens through an electro-hydraulic loading machine with a capacity of 10,000 kN. The top and bottom surfaces of each specimen were coated with high-strength gypsum to ensure that the two loading surfaces were horizontal. The axial load was applied at a strain rate of 10standard . The defCubic specimens were only tested for the compressive strength of specimens, but cylindrical specimens undertook the measurement of the compressive strength, Poisson’s ratio, elastic modulus and volumetric strain. Therefore, three linear variable differential transducers (LVDTs), with a ±5 mm calibration range, were vertically fixed through two steel hoops around the periphery of the cylinders, to measure the axial deformations in the middle 2/5-height of the cylinders see a. To meaAfter axial compression tests, scanning electron microscope (SEM) analyses were carried out through Zeiss EVO 18 to investigate the microstructure of several GRLC specimens. Three 5 × 5 mm slices, with an interface transition zone between fresh GC and DCLs included, were taken from each broken specimen. The surfaces of these slices were coated with a thin layer of gold using a sputter-type coater to obtain clear images for SEM analysis .Under axial compression, crack development in the GRLC specimens was similar to that of GC specimens without DCLs. Until loading to about 80% of the peak load, no noticeable cracks formed on the surfaces of the specimens. With a further increase in the applied load, cracks appeared and quickly propagated. When the applied load attained the peak value, cracks almost ran through the whole height of the specimen. After the peak value, although the load decreased, the axial deformation (strain) increased, and diagonal main cracks formed. Finally, the concrete near the mid-height bulged out and fell-off, and the specimen failed. The cubic and cylindrical compressive strength of GRLC specimens and cubic compressive strength of CRLC specimens were measured. As a function of the replacement ratio, Combining The compressive strength ratio of the concrete cylindrical specimen to cubic specimen represents the shape effect on strength. fcu,com,300 denotes the compressive strength of 300 × 300 × 300 mm cubic CRLC specimens containing fresh concrete with old concrete, fcu,new,300 and fcu,old,300 represent the compressive strength of new (fresh) and old (recycled) concrete of 300 × 300 × 300 mm cubic specimens, respectively, and η is the replacement ratio of DCLs. On condition that the size effect on cubic compressive strength of fresh concrete, recycled concrete and CRLC are taken into account. Equation (1) can be modified to predict the cubic compressive strength of CRLC with other sizes, such as 150 × 150 × 150 mm cubic compressive strength [To predict the compressive strength of CRLC specimens, Wu et al.  proposedstrength .fcu,new,150-fcu,old,150| ≤ 15 MPa [When the strengths of new and old concrete are close, such as |≤ 15 MPa , Equatiofcu,new,300 is much higher than fcu,old,300 then the influence coefficient of fcu,old,300 is larger than 1.0 η1.1 > 1.0), and the influence coefficient of fcu,new,300 is smaller than 1.0 η0.86 < 1.0). This coincides with the observed trend that when the difference in strength between new and old concrete is higher, the influence of DCLs on the compressive strength of GRLC is more significant.However, if η and 1.1 η to 2.2 η and 1.3 η, respectively, due to the fact that the compressive strength of demolished concrete has greater influence on the compressive strength of CRLC cylinders than on that of CRLC cubes [For CRLC cylindrical specimens, the two exponents in Equation (1) were changed from 0.86 LC cubes .η and 1.1 η) were adopted for GRLC cubic and cylindrical specimens. That is, the cubic compressive strengths  in Equation (1) can be replaced by the cylindrical compressive strength of GRLC.Equations (1) and (2) were tentatively used for predicting the compressive strength of GRLC specimens. Since the effect of DCLs on the compressive strength of the GRLC cylindrical specimen is similar to that on the GRLC cubic specimen, the same exponents  and 0.83  for cube and cylinder, respectively, as reported in Ref. [fcu,300/fcu,150) and 0.91  for cubic and cylindrical specimens, respectively, based on the mean experimental results of GC1 and GC2 specimens . For normal-strength Portland cement concrete, the ratio of the compressive strength of specimens with a characteristic size of 300 mm to that of 150 mm can be taken as 0.87  is applicable to predict the compressive strength of GRLC cubic and cylindrical specimens. In case of |fcu,new,150-fcu,old,150| > 20 MPa, the prediction result using Equation (1) agreed well with the measured results. A comparison of the predicted compressive strength of GRLC specimens using Equation (1) or (2) with the measured results is shown in Since the geopolymer has a certain strengthening effect on DCLs, the application scope of the simplified formula, Equation (2), can be appropriately broadened to slightly reduce the negative impact of DCLs on the compressive strength of GRLC specimen. After trial calculation, it is found that when |Three LVDTs were installed around each cylindrical specimen to measure the vertical deformation, from which the vertical strain was calculated, and then the elastic modulus of GRLC specimens was determined .λ (the ratio of applied load to the peak load) of 0.4, were utilized to calculate Poisson’s ratio of GRLC specimens.Three vertical and three lateral strain gauges were mounted at mid-height around each cylindrical specimen. The data measured by these strain gauges, at a loading ratio υ of GRLC. Poisson’s ratio of GRLC is about 0.16–0.17, which is in the range of conventional OPC concrete (0.14–0.26) suggested in the CEB-FIP Model 2010 [del 2010 . Comparedel 2010 , Poissonεvol = ε1 + 2ε2, where ε1 is the vertical strain of the concrete , and ε2 is the lateral strain of the concrete , is often adopted to represent the volume variation of concrete under axial compression.Under axial compression, concrete experiences axial compaction and then lateral expansion, thus the volume of concrete changes. Volumetric strain, defined as σ/fc , the volumetric strain increases gradually and then turns to decrease until failure. This implies that the volume of the concrete shrinks first and then expands. The stress ratio σ/fc corresponding to the turning point on the curve, called the critical stress ratio, represents the stress ratio at which the concrete volume begins to expand but not continuing to shrink.The volumetric strain curves of GRLC cylinders, using GC1 and GC2 as fresh concrete, were plotted in As seen in From Comparing Axial compression tests were carried out on a great amount of geopolymer recycled lump concrete (GRLC) cubic and cylindrical specimens with different replacement ratios of recycled concrete lumps (DCLs) and strength levels in DCLs and fresh geopolymer concrete. Based on the experimental data, the fundamental mechanical properties of GRLC were evaluated and the following conclusions were drawn.Geopolymer concrete is well bonded with the old mortar in DCLs and has a certain strengthening effect on DCLs. Under similar conditions, the compressive strength of GRLC specimens is higher than that of ordinary cement recycled lump concrete (CRLC), but the shape effect of GRLC specimens is less significant than the latter.After a minor modification, the formula for predicting the cubic compressive strength of CRLC is applicable to predict the compressive strength of GRLC cubic and cylindrical specimens.With the replacement ratio of DCLs increasing, the elastic modulus of the GRLC specimens increases but Poisson’s ratio is kept in the 0.16–0.17 range.The critical stress ratio, which represents the stress level at which the volume of concrete begins to expand under axial compression, decreases with a decrease in the strength of DCLs or an increase in the replacement ratio of DCLs in GRLC specimens.In general, GRLC has comparable compressive performance, but lower energy consumption and carbon emissions during its production than that of CRLC. The latter has been used in practical construction. With the increasing concern to environmental protection, the use of GRLC in practical construction, as a promising substitution of ordinary concrete, is possible in the foreseeable future.