Acinetobacter baumannii isolated from hospital patients were distinguished with 99.92 ± 0.06% accuracy using the machine learning model. Meanwhile, we found that sensitive strains had a higher nucleic acid/protein ratio and antibiotic-resistant strains possessed abundant amide II structures in proteins. This study suggests that Raman spectroscopy is a promising method for rapidly identifying pathogens and detecting their antibiotic susceptibility.Rapid, accurate, and label-free detection of pathogenic bacteria and antibiotic resistance at single-cell resolution is a technological challenge for clinical diagnosis. Overcoming the cumbersome culture process of pathogenic bacteria and time-consuming antibiotic susceptibility assays will significantly benefit early diagnosis and optimize the use of antibiotics in clinics. Raman spectroscopy can collect molecular fingerprints of pathogenic bacteria in a label-free and culture-independent manner, which is suitable for pathogen diagnosis at single-cell resolution. Here, we report a method based on Raman spectroscopy combined with machine learning to rapidly and accurately identify pathogenic bacteria and detect antibiotic resistance at single-cell resolution. Our results show that the average accuracy of identification of 12 species of common pathogenic bacteria by the machine learning method is 90.73 ± 9.72%. Antibiotic-sensitive and antibiotic-resistant strains of  It has been estimated that almost 5 million deaths globally are associated with bacterial AMR, including more than 1.2 million deaths attributable to AMR in 2019 . The numMycobacterium tuberculosis needs more than 2 weeks for cultivation, sometimes up to 6–8 weeks  are performed simultaneously by the Vitek or BD Phoenix commercial systems in clinical microbiology . These s–8 weeks . MoleculRaman spectroscopy is a non-invasive, culture- and label-free technique that is able to monitor the chemical composition and metabolism of single live microorganisms in real time . The RamAcinetobacter baumannii isolated from hospital patients with 99.92% accuracy. Meanwhile, we found that antibiotic-resistant A. baumannii strains showed more abundant amide II structures in proteins and a lower nucleic acid/protein ratio than antibiotic-sensitive strains.In this study, we developed a method combining Raman spectroscopy with machine learning to identify a pathogenic bacterium and predict its antibiotic resistance rapidly and accurately at single-cell resolution. The average accuracy of identification of 12 species of common pathogenic bacteria by the machine learning model was 90.73 ± 9.72%. The optimal machine learning model predicted the antibiotic susceptibility of 2.2.1.A. baumannii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Salmonella enterica, and Vibrio parahaemolyticus), three species of gram-positive bacteria , and two species of fungi . Five clinical strains of A. baumannii (ST2 sequence type) were isolated from sputum of different patients in the intensive care unit of Cangzhou Central Hospital, Hebei Province, China. The five clinical A. baumannii strains all contained the carbapenem resistance gene oxa23, which was confirmed by PCR assays as previously described  medium or yeast extract peptone dextrose (YPD) medium with various culture times under different culturing conditions. The microbial cells were collected and suspended in 0.85% NaCl solution. A total of 20 μl suspended cells was injected in the sealed chamber for Raman spectral measurement. The Raman spectra were measured by laser tweezers Raman spectroscopy (LTRS) as previously described . Raman s2.3.−1 and 1815 cm−1 was selected for model training and model testing. We used algorithms based on random forest , support vector machine (selecting linear kernel), decision tree , bagging , and naive Bayes (no Laplace correction) to build models for training Raman spectral data. A 10-fold cross-validation of the training dataset was used to evaluate the robustness of the models. In this study, the training time for the five models was about 4 hours using a HP workstation . Independent spectra acquired from 80 single cells of each species were used to assess the performance of models. Sample identification included the processes of sample preparation (cell collection for 1–2 min), Raman spectral acquisition (integration time for 60–90 s), and species prediction (less than 30 s).The spectra were pre-processed as follows: Savitzky–Golay smoothing to remove noise and polynomial fitting to remove the fluorescence background, followed by min–max normalization. The spectral range between 555 cm2.4.A. baumannii strains  were first determined by the VITEK 2 instrument  according to the instruction manual. The antibiotics used in the test included imipenem, meropenem, ampicillin, cefoperazone, and cefepime. The reference strain and all the clinical isolates were cultured in LB medium without adding any antibiotics, and then the cells were harvested to acquire the Raman spectra. Data on the antibiotic resistance of each strain are listed in A. baumannii strains. An independent testing dataset of 1,255 spectra from six A. baumannii strains was collected for testing the predictive performance of the identification models and the antibiotic susceptibility detection model. The RF antibiotic susceptibility detection model with 101 decision trees was evaluated by 10-fold cross-validation. Subsequently, the model with the highest prediction accuracy was selected. The receiver operating characteristic (ROC) curve was used to assess the diagnostic accuracy of the antibiotic susceptibility detection model in terms of antibiotic resistance. The A. baumannii strains were grouped based on the antimicrobial susceptibility test .The antibiotic susceptibilities of all six ity test . The RamThe Raman spectral pre-processing, building machine learning models, PCA analysis, and statistical analysis were all performed using the R language (R ≥ 3.6.1). In this study, the main open-source packages of R included “caret” and “hyperSpec.”3.3.1.A. baumannii, Enterobacter cloacae, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Salmonella enterica, and Vibrio parahaemolyticus), three gram-positive bacteria , and two fungi . To minimalize batch effects on the final classification, we constructed a reference dataset of 3,982 spectra from bacteria and yeast under different culturing conditions to cover a more varied cellular physiological status and heterogeneity in the same species. The normalized average Raman spectra of the 12 pathogens with the standard deviations (SD) are shown in −1 (−1) and protein , support vector machine (SVM), naive Bayes (NB), bagging, and decision tree (DT). The Raman dataset of 3,982 spectra was used to train the machine learning models. We used 10-fold cross-validation to evaluate the discriminative ability of these models. In this process, one fold was randomly split out and used to validate the model trained by all the other nine folds. This process was repeated until each of the 10 folds had acted as the test set once. Taking into account the identification accuracy and successes occurring by chance, two metrics of accuracy and Cohen’s kappa  were utiC. albicans and C. neoformans, the accuracy of fungi identification reached 100%. The identification accuracies for the gram-positive bacteria S. epidermidis and S. pneumonia were 98.75%, higher than for S. aureus with an accuracy of 91.25%. The classifying accuracy for K. pneumoniae was 100%, the highest accuracy of the gram-negative bacteria. A. baumannii was the second highest accuracy, at 95%. The identifying accuracy for E. coli was 82.5%. The accuracies for the other three gram-negative bacteria  were between 75 and 83%.We further tested the models on the independent test dataset gathered from a separately cultured batch that consisted of 960 spectra for the 12 pathogens (80 spectra per pathogen). Four indicators including accuracy, kappa, recall, and F1 score were selected to evaluate the performances of the different machine learning models. The results suggested that the RF is slightly superior to SVM . The RF 3.3.A. baumannii strains isolated from patients in the intensive care unit  nit ICU;  as a profections , especiafections . Carbapeion WHO; . Rapid aion WHO; .A. baumannii strain (isolate code: ZB18051) and five multidrug-resistant strains  to acquire single-cell Raman spectra. To avoid the effects of residual antibiotics from cell culture when discerning the antibiotic-resistant strain, the multidrug-resistant strains and the drug-sensitive strain were cultured in the same LB medium without supplementing antibiotics. The 523 Raman spectra from the antibiotic-sensitive strain ZB18051 and four randomly selected multidrug-resistant strains  were collected to build a training dataset. The training dataset was used to train the antibiotic susceptibility detection model. A separate testing dataset, consisting of 1,255 spectra from six A. baumannii strains, was prepared for the model validation. First, we used the pathogenic identification models constructed previously to predict the 1,255 spectra of A. baumannii. The RF identification model achieved the highest identification accuracy of 95.86%, which is consistent with the previous prediction on 80 A. baumannii spectra  and specificity (true negative rate) were evaluated by the receiver operating characteristic (ROC) curve . The val strains . The A. aumannii . This reaumannii . This im3.4.A. baumannii contribute to the discrimination of antibiotic-resistance phenotypes, we sought to detect the corresponding physiological or metabolic features of bacterial resistance based on the Raman spectra. The Raman spectrum difference was calculated by subtracting the average spectrum of antibiotic-sensitive A. baumannii from the average spectrum of antibiotic-resistant A. baumannii. The Raman bands at 860–918 cm−1 (polysaccharides and proteins), 1,336–1,367 cm−1 (carbohydrates and proteins), 1,554 cm−1 (amide II of proteins), and 1,602 cm−1 (C–C or C–N protein bonds) were increased in the antibiotic-resistant strains (−1 (DNA/RNA Raman bands) were decreased in the antibiotic-resistant strains. In addition, the Raman peaks at 1,002 cm−1  and 1,281 cm−1 (amide III of protein) in antibiotic-sensitive A. baumannii were also slightly increased  was used to reduce the dimensionality of the spectra data and extract the main features. The first two principal components (PC1 and PC2) projected by the Raman spectral data accounted for 57.05% of the original variance. The scores plot of PC1 and PC2 suggested that the antibiotic-resistant and antibiotic-sensitive A. baumannii were completely separated in two clusters  was 2.20 in the antibiotic-sensitive strain, while the average ratio of I783/I1554 in the antibiotic-resistant strains was close to 4.58  to construct prediction models. Compared with the accuracy of the other models, the SVM and RF models had the best performance. The average accuracy of the RF identification model to identify 12 common clinical pathogens was 90.73%, and the RF antibiotic susceptibility detection model predicted the antibiotic susceptibility of ity vote . This meity vote . Moreoveity vote , which iA. baumannii strain, the Raman spectral differences of five antibiotic-resistant strains were almost consistent, especially at the Raman peaks of proteins  that show significant increased intensity. Since all five strains contain the oxa23 gene that encodes the oxacillinase enzyme, the stronger protein Raman peaks might be related to the high expression level of oxacillinase in vivo. In addition, the increased phospholipids , polysaccharides and proteins  in antibiotic-resistant A. baumannii might promote changes in the bacterial cell membrane, resulting in enhanced biofilm formation , the National Natural Science Foundation of China Grant (52091541 and 31970553), Senior User Project of RV KEXUE (KEXUE2019GZ05).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Approximately 80% of patients with hepatocellular carcinoma (HCC) experience recurrence within five years after surgery. Currently, there is no standard protocol for the application of neoadjuvant therapy in HCC, but neoadjuvant immunotherapy has been shown to influence the survival of patients with other tumors. This systematic review and meta-analysis aimed to assess the reported efficacy and safety of neoadjuvant immune checkpoint inhibitors (ICIs) for resectable HCC. An overview of 9 studies showed neoadjuvant ICIs provide therapeutic benefits in terms of histopathological response in resectable HCC and were well tolerated.p < 0.00001; MPR: OR = 0.38, p = 0.001). The pooled OR values for the incidence of grade 3 to 4 treatment-related adverse events and surgical delay rate were 0.26 and 0.05, respectively, which were significantly in favor of neoadjuvant ICIs . The subgroup analyses did not demonstrate superiority of one ICI over another ICI or combination therapy. The present study found that neoadjuvant ICIs were well tolerated by patients with resectable HCC and conferred therapeutic benefits in view of histopathological response results.Resectable hepatocellular carcinoma (HCC) has poor prognosis because of its high recurrence rate. Immunotherapy has been tried for neoadjuvant therapy as it has shown excellent performance in the treatment of advanced HCC. This systematic review and meta-analysis aimed to assess the reported efficacy and safety of neoadjuvant immune checkpoint inhibitors (ICIs) for resectable HCC. Electronic databases, including PubMed (MEDLINE), Embase, the Cochrane Library, and ClinicalTrials.gov were systematically searched to identify published and ongoing studies evaluating the efficacy and safety of neoadjuvant ICIs for resectable HCC up to October 2022. The odds ratio (OR) and 95% confidence interval (CI) were calculated. Heterogeneity and subgroup analyses were performed, and data quality was assessed. The study was registered with PROSPERO (registration number: CRD42022371495). A total of 193 patients from 9 studies were included in this meta-analysis. The overall pathological complete response (pCR) rate was 12.9% , and major pathological response (MPR) rate was 27.3% , indicating a favorable association with neoadjuvant ICIs (pCR: OR = 0.17,  Hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver cancers and has become the third leading cause of cancer-related mortality worldwide ,2. Althop < 0.001), but also extended median event-free survival (EFS) to 31.6 months  [Currently, there is no standard protocol to guide the application of neoadjuvant therapy for patients with HCC, either systemically or topically. Transarterial chemoembolization (TACE), sorafenib, and cytotoxic agents have been investigated as potential neoadjuvant therapies for the treatment of resectable HCC ,10,11. H= 0.005) . Given tThe published retrospective studies and case reports report that neoadjuvant monotherapy or combined immunotherapy before LR or liver transplantation can reduce the recurrence rate and mortality after surgery by achieving complete or partial pathological response ,24,25,26This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and checklists . No apprWe performed a systematic search of PubMed (MEDLINE), Embase, the Cochrane Library, and ClinicalTrials.gov to retrieve studies investigating the use of neoadjuvant immunotherapy in HCC published before 1 October 2022. Additionally, we searched for ongoing clinical trials on neoadjuvant immunotherapy in the management of HCC that were presented at international oncology conferences. Medical subject terms such as hepatocellular carcinoma, neoadjuvant therapy, and immunotherapy were used to conduct the search. Please refer to the All publications that met the following criteria were included: (1) The clinical trial included patients with resectable HCC; (2) Immune checkpoint inhibitors were used as neoadjuvant therapy; (3) The study reported at least one of the following primary outcomes: pathological complete response (pCR) defined as no viable tumor cells, major pathological response (MPR) defined as less than 10% residual viable tumor cells in the resected tumor, treatment-related adverse events (TRAEs) or grade 3–4 TRAEs, and surgical delay rate. Publications that met one of the following criteria were excluded: (1) Patients had unresectable primary or metastatic disease; (2) The number of included patients was less than 10; (3) The research outcome did not meet our specified outcomes; (4) Lack of valid or adequate data for assessing the efficacy and safety of neoadjuvant immunotherapy; (5) Repeated publications; (6) Reviews, meta-analyses, case reports, or case series.Two investigators (M.Z. and S.C.) independently identified and extracted articles for possible inclusion. Any discrepancies were resolved by submission to a third reviewer (P.L.). The full text of the identified articles was retrieved and analyzed. For each study, the following data were recorded: first author, year of publication, clinical trial, NCT number, intervention model, masking, study type, study phase, location, article type, main inclusion criteria, ICI drug, sample size, pCR, MPR, incidence of TRAEs or grade 3–4 TRAEs, and surgical delay rate.The selected studies were assessed for risk of bias using the assessment tool recommended by Cochrane Handbook 5.1.0, which includes the following: (1) random sequence generation; (2) concealment of allocation; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) completeness of outcome data; (6) selective reporting of outcomes; and (7) other bias. Two reviewers (M.Z. and S.C.) independently assessed the risk of bias. Disagreements were resolved through discussion or referral to a third reviewer (P.L.)2); if the heterogeneity was significant (p < 0.1) or greater than 50% (≥50%), a random-effect model was used; if insignificant (p ≥ 0.1) and lower than 50% (<50%), a fixed effect model was adopted. Subgroup analyses were performed on specific immune checkpoint inhibitors or in combination with other treatments. p < 0.05 was considered to be statistically significant.This meta-analysis was performed using non-comparative binary data in RevMan software version 5.3 (Cochrane Collaboration) because the majority of the included studies were single-arm clinical trials. The effect index (P) and its standard error SE (P) for uncontrolled binary data were calculated using the following formula: P = ln(odds) = ln (X/(n − X)); SE (P) = SE (ln(odds)) = √ (1/X + 1/(n − X)). The effect measures were the odds ratio (OR) and 95% confidence interval (CI) ,29. OR <We identified 594 citations based on the search strategy. After deleting duplicates, screening titles, and abstracts, and reviewing the available full texts, 9 studies with a total of 193 patients met the inclusion criteria and were included in the meta-analysis. The detailed strategy for study selection is shown in p < 0.00001; p = 0.69, I2 = 0%).pCR was reported in 8 studies with rates ranging from 5.9% to 25%. The mean pCR rate was 12.9% . The pooled results of the included trials demonstrated a statistically significant benefit of using neoadjuvant ICIs . The combined OR was 0.38  with a statistically significant difference (p = 0.001), indicating that neoadjuvant ICIs were beneficial , a fixed-effect model was adopted.The MPR to neoadjuvant ICIs was reported in three studies. The mean MPR rate was 27.3% , with a range of 17.6% to 33.3%. Individual ORs for each eligible study in terms of MPR were in favor of neoadjuvant ICIs . The Su Y et al. study [The incidence of treatment-related adverse events (TRAEs), as defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, is associated with the safety of neoadjuvant ICIs. No patients died as a result of TRAEs in any of the trials. The incidence of preoperative grade 3–4 TRAEs was 22.4% , and included pneumonitis, hepatitis, pruritus, maculopapular rash, myasthenia gravis, infection, lipase increase, and leukocyte reduction. A pooled analysis of seven studies revealed an OR of 0.26  and an acceptable safety profile for neoadjuvant ICIs . Among all patients who underwent surgical resection, one patient had a 2-week delay in surgery due to grade 3 pneumonitis and another patient had a surgery delay due to deterioration of liver function, which was not related to ICI treatment. The pooled OR  was in favor of neoadjuvant immunotherapy  and safety  initially demonstrated that neoadjuvant immune checkpoint inhibitors may have therapeutic advantages in terms of histopathological response and acceptable toxicity profiles in patients with resectable HCC.The mean pCR and MPR rates in our meta-analysis were 12.9%  and 27.3% , respectively, with a maximum pCR of 25%  and a mNeoadjuvant immunotherapy has proven to be feasible in other malignancies. Additionally, patients who achieve a significant pathological response to neoadjuvant ICIs have improved survival after surgery ,39,40,41In this study, the mean incidence of grade 3–4 TRAEs in 5 studies was 22.4% 95%CI, 15.5–29.3%), which was consistent with previously reported data in advanced HCC ,15,16,17.5–29.3%,Subgroup analyses in this study revealed no benefit of combined ICIs or ICIs in combination with anti-angiogenic drugs compared with monotherapy. There were no statistically significant differences in efficacy and safety across the various ICIs. Clinical trials of atezolizumab + bevacizumab, pembrolizumab + lenvatinib, and other ICIs and anti-angiogenic therapy combinations have demonstrated the superiority of combination therapy in patients with unresectable HCC ,50,51. AExploring treatment-related biomarkers is one of the important purposes of neoadjuvant therapy clinical trials. PD-L1 expression status has been used as a biomarker of treatment response in some malignancies, such as NSCLC and bladder cancer, while its use for guiding therapy in liver cancer remains controversial . The preThis meta-analysis had certain limitations. Half of the data were obtained from conference abstracts. Variabilities in study design, treatment regimens, inconsistent etiology of hepatocellular carcinoma, types of immune checkpoint inhibitors, and patient characteristics contributed to heterogeneity, thus limiting the strength of these findings. Additionally, subgroup analysis of PD-L1 expression status was not be performed due to the lack of data, and the effect of PD-L1 level on outcomes cannot be ignored. Lastly, long-term outcomes, such as recurrence-free survival (RFS), disease-free survival (DFS), and overall survival (OS), which can provide a more accurate indication of treatment efficacy, were not reported.Our findings suggest that, based on the results of existing studies, neoadjuvant immune checkpoint inhibitors provide therapeutic benefits in terms of histopathological response in resectable HCC and were well tolerated. Conclusive evidence awaits more data from long-term, large-scale clinical trials investigating neoadjuvant immunotherapy in patients with resectable HCC.


The antibiotic spectrum is not reflected in conventional antimicrobial metrics. Days of antibiotic spectrum coverage (DASC) is a novel quantitative metric for antimicrobial consumption developed with consideration of the antibiotic spectrum. However, there were no data regarding disease and pathogen-specific DASC. Thus, this study aimed to evaluate the DASC trend in patients with bloodstream infections (BSIs). DASC and days of therapy (DOT) of in-patients with positive blood culture results during a 2-year interval were evaluated. Data were aggregated to calculate the DASC, DOT, and DASC/DOT per patient stratified by pathogens. During the 2-year study period, 1443 positive blood culture cases were identified, including 265 suspected cases of contamination. The overall DASC, DASC/patient, DOT, DOT/patient, and DASC/DOT metrics were 226,626; 157.1; 28,778; 19.9; and 7.9, respectively. A strong correlation was observed between DASC and DOT, as well as DASC/patient and DOT/patient. Conversely, DASC/DOT had no correlation with other metrics. The combination of DASC and DOT would be a useful benchmark for the overuse and misuse evaluation of antimicrobial therapy in BSIs. Notably, DASC/DOT would be a robust metric to evaluate the antibiotic spectrum that was selected for patients with BSIs. Defined daily doses and days of therapy (DOT) are used to quantify antimicrobial consumption around the world ,2. TheseKakiuchi et al. developed a novel quantitative metric for antimicrobial consumption with antibiotic spectrum consideration to address the problems of conventional metrics . The indA total of 1443 positive blood cultures cases were identified that included 265 suspected cases of contamination during the 2-year study period. The relationships among DASC, DASC/patient, DOT, DOT/patient, DASC/DOT, and no. of patients per month are shown in The DASC/patient, DOT/patient, and DASC/DOT distribution, which were stratified by BSI pathogens are shown in The present study revealed that the DASC metric could be applied to antimicrobial use evaluation in BSI patients. Previous reports on spectrum scoring have evaluated the de-escalation strategy because conventional antibiotic use metrics do not mirror the antibiotic spectrum ,22,23,24In this study, parallel changes in DASC and DOT per month were observed. A low DASC/DOT score would indicate that there was no broad-spectrum antibiotic overuse, although both DASC and DOT increased in September 2020. Conversely, no DASC and DOT increment in January 2021 with a DASC/DOT increment would be indicative of broad-spectrum antibiotics overuse. The long-term use intervention or promoting antibiotic de-escalation would be needed during the periods according to the results of these metrics. In addition, the correlation analysis showed that DASC/DOT had no correlation with other metrics. DASC/DOT was an independent and robust metric that could evaluate the antibiotic spectrum consistent with the previous study . HoweverPathogen-specific DASCs were evaluated to provide utility ASP evaluation. The DASC and DOT of Gram-positive bacteria were higher than Gram-negative bacteria. Gram-positive bacterial infections need long-term antibiotic treatment, such as infective endocarditis. A high DASC was caused by a DOT increment, which was long-term antibiotic use. Conversely, a high DASC/DOT was observed in Gram-negative bacteria. Antibiotics that have activity against Gram-negative bacteria typically have high ASC scores . The metS. aureus bacteremia [Ideally, antibiotic use metrics should evaluate antimicrobial use appropriateness or standardization ,29,30. Tcteremia ,32. The cteremia ,32,33. Acteremia . An ASC cteremia . Fewer tClostridioides difficile infection, and cost saving. Third, the actual ASPs interventions were not evaluated. The previous study suggested that the efforts of ASPs to use narrow-spectrum antibiotics through empiric therapy or de-escalation are not evaluated in the DOT-based metrics [The present study has several limitations. First, this was a single-center pilot study conducted in Tokyo, Japan, and our findings cannot be generalized to another geographical area with different treatment standards and epidemiological BSI characteristics. Multicenter and large-size studies are needed. Second, this study overlooked the correlation between the metrics and outcomes, such as AMR,  metrics . FurtherIn conclusion, the study revealed that the DASC could evaluate antimicrobial use in patients with BSIs. The combination of DASC and DOT would be a useful benchmark for the evaluation of antimicrobial therapy overuse and misuse in BSIs. Notably, DASC/DOT would be a robust metric to evaluate the antibiotic spectrum that was selected for patients with BSIs. Disease and pathogen-specific DASC will be a benchmarking function that will lead to promoting antimicrobial stewardship because of the quantitative antibiotic spectrum evaluation.This retrospective study was performed at the Showa University Hospital, an 815-bed tertiary teaching hospital in Japan. Inclusions were in-patients with positive blood culture results during a 2-year interval from 1 April 2020 to 31 March 2022. Patient age, antimicrobial regimen, isolated microorganisms, and AMR data were extracted from patients’ medical records.Antimicrobial use data were collected from the initial blood sampling day for culture. DASC was calculated by the ASC score defined in the previous study . If an aBSIs were defined as organism isolation from positive blood culture. A suspected case of contamination was defined as isolating skin-resident or environmental bacteria from single blood culture which was not an identified specific infection focus ,37. BD BStaphylococcus aureus, Escherichia coli, Klebsiella species, Enterobacter species (including K. aerogenes), and Pseudomonas aeruginosa [P. aeruginosa was resistant to at least two of the following antimicrobials: fluoroquinolones, aminoglycosides, and carbapenems. Methicillin resistance in S. aureus was confirmed by oxacillin and cefoxitin testing. The double disk synergy test was used to determine ESBL production in E. coli and Klebsiella spp. Disks containing cephalosporins (ceftazidime and cefotaxime) were applied next to amoxicillin–clavulanic acid disks. Antimicrobial-resistant Enterobacter spp. was defined by its resistance to third-generation cephalosporins or carbapenems that include the isolation and identification of a minimum inhibitory concentration (MICs) of meropenem ≥2 µg/mL or MICs of imipenem ≥2 µg/mL and cefmetazole ≥64 µg/mL by the Japanese criteria [The isolated pathogens were divided into major bacteria that cause BSIs to evaluate pathogen-specific antimicrobial use metrics. Furthermore, the AMR was tested in five microorganisms: ruginosa . The cliruginosa . Antimiccriteria .p-values < 0.05 were considered significant. SPSS statistics version 23.0  was used to perform statistical analysis.Spearman’s rank correlation analysis was used to calculate the coefficient (ρ) among antimicrobial use metrics each month. Statistical tests were two-tailed, and The Showa University Research Ethics Committee  approved the study.


With the development of new concrete technology, high-strength concrete has been used worldwide. In particular, more economic benefits can be achieved by applying high-strength concrete-filled steel tube (HSCFST) columns in the concrete core walls of super high-rise buildings. A constitutive relation with high applicability for high-strength materials with different strength grades is proposed. Based on this constitutive model, a brick element model of 181 sets of axially compressed square HSCFST members is established and experimentally verified. The effects of the concrete strength, diameter-to-thickness ratio, and steel yield strength on the axial compressive capacities of these members were investigated based on finite element calculation results. The results showed that with an increase in the concrete strength, the ultimate bearing capacities of CS-CC, HS-HC, HS-CC, and CS-HC stub column members increased by 60%, 24%, 44%, and 21% at most, respectively. Additionally, as the steel yield strength increased, the ultimate bearing capacities of CS-CC, HS-HC, HS-CC, and CS-HC stub column members increased by 8.8%, 5.1%, 8.5%, and 5.2%, respectively, Hence, material strength has the greatest impact on CS-CC and HS-CC. The confinement effect of the square steel tube on the concrete weakens as the strength grade of steel or concrete increases. Notably, the confinement effect of steel tube on the concrete is strongest in CS-CC and weakest in the CS-HC. In addition, the confinement coefficients of square HSCFST stub columns with different combinations of concrete and steel strengths were analyzed. Based on the superposition principle in the ultimate state, a practical axial compressive capacity calculation formula for three types of square HSCFSTs is established. Compared with existing major design code formulas, the proposed formula is more accurate and concise and has a clear physical meaning. Due to their excellent structural properties, concrete-filled steel tube (CFST) columns have been widely applied in super high-rise buildings, urban bridges, long-span bridges, and engineering structures ,2,3. ComIn recent years, with the continuous development of materials technology, high-strength materials, such as high-strength steel (HSS), high-strength concrete (HSC), and ultrahigh-strength concrete (UHSC), have been gradually applied to engineering structures. HSS usually refers to steel with a nominal yield stress equal to or greater than 460 MPa . Comparefc ≤ 112.7 MPa, steel strength: 629 MPa ≤ fs ≤ 1022 MPa) and conducted extensive numerical analyses on the confinement effect, material, geometry, and contact method. They also evaluated the applicability of the design codes for the compressive strengths of square and rectangular stub columns based on the test results and numerical calculation results. Existing studies have found that the interactions between the steel tube and concrete are related to the strength of the two materials. Therefore, it is necessary to propose formulas for calculating the confinement coefficient and the corresponding bearing capacity that take into account the effect of different material combinations based on the study of the HSCFST stub columns.The steel tube has a lower confinement effect on the concrete, bearing capacity, and ductility in a square CFST column than in a circular CFST column, but square CFST columns are easy to connect and have large cross-sectional moments of inertia, high stability, and good adaptability in terms of earthquake and fire protection measures ,17. ReseIn this paper, three types of square HSCFSTs, namely, HSS tubes filled with normal-strength concrete (denoted as HS-CC hereinafter), HSS tubes filled with HSC (denoted as HS-HC hereinafter), and normal-strength steel tubes filled with HSC (denoted as CS-HC hereinafter) are used as the study object. The confinement coefficient of square HSCFST stub columns and a calculation formula for their axial compressive capacity are proposed based on the uniaxial constitutive relation of HSS and concrete proposed by Ding et al.  as well σ is the stress, Es is the elastic modulus (Es = 200 GPa), fs is the yield strength, fu is the ultimate strength, εy is the yield strain, εst is the strain corresponding to the end of the yield plateau, εu is the ultimate strength, and Est is the hardening modulus. Then, assuming that the stress of the steel remains constant as the strain increases, the stress–strain relation of the steel is shown in εst = εy, as shown in The uniaxial tensile stress–strain relation for steel proposed by Ding et al.  can be eεst of hot-rolled steel with a clear yield plateau should be 0.02 and that the fu and εu of hot-rolled steel with different strength grades are expressed as follows:εu,235 is the ultimate strength of Q235 carbon steel, where Q represents the yield limit of this material, and 235 refers to the yield stress being approximately 235 MPa.The literature suggests that the iσ and the equivalent strain iε are expressed as follows:σ1, σ2, and σ3 and ε1, ε2, and ε3 are the principal stresses and strains, respectively, of the outer steel tube and vs. is the Poisson’s ratio of the steel tube, which is defined as follows:Under axial compression, a CFST column is in a three-dimensional stress state due to the interactions between the steel tube and the core concrete. The equivalent stress A unified constitutive relation applicable to concrete with different strength grades has been previously proposed . The striA is the ratio of the elastic modulus to the peak secant modulus of the concrete, and iB is a parameter that controls the degree of attenuation of the elastic modulus of the ascending segment of the stress–strain curve.In the formula, the physical meaning of parameter y = σ/fc and x = ε/εc in Equation (7), where σ is the stress in MPa, fc is the axial compressive strength, fc = 0.4 fcu7/6, ε is the strain, εc is the peak compressive strain, and εc = 420 fcu7/18 × 10−6. At this time, i = 1, and A1 and B1 are the parameters of the ascending segment 2), and α1 is a parameter of the descending segment (α1 = 4 × 10−3fcu1.5 considering that the parameter of the descending segment is relatively low due to the high brittleness of concrete with a cube compressive strength exceeding 60 MPa).When concrete is subjected to uniaxial compression, To achieve the proposed stress–strain relation in the finite element model analysis, the Poisson’s ratio of the core concrete was defined as 0.2. The elastic modulus of concrete with different strengths is expressed as follows:Due to the limitations of experimental conditions and material properties, the large amount of collected HSCFST test data still cannot cover the parameter matching required for the study. Therefore, it is necessary to use the ABAQUS finite element calculation software for calculation and analysis. The interactions between the steel tube and core concrete can be rationally analyzed by adopting suitable element types and meshing, material properties (constitutive model), steel tube–concrete interface simulation, loading method, and boundary conditions.N–ε curve was negligible by testing the mesh convergence of the model with a coarse mesh. Therefore, the axial element size is selected to be 2.5 times the lateral element size. Based on the study of mesh convergence, the cross-sectional element size of the square column is set at B/10, where B is the width of the square steel tube, as shown in Both the outer steel tube and the core concrete are analyzed using refined modeling with three-dimensional eight-node brick elements (C3D8R), and each node has three translational degrees of freedom. In the study of mesh convergence, the optimal finite element mesh is determined to provide a relatively accurate solution at a relatively low computation cost. Hassanein  noted thνc) of concrete is set to 0.2 in the numerical simulation. The flow potential eccentricity e, the viscosity coefficient α, K, and fcc/fc are set at 0.1, 0.0005, 2/3, and 2/3, respectively. When the concrete strength is less than 100 MPa, the dilation angle is set to 40°, and when the concrete strength is greater than 100 MPa, the dilation angle is set to 30°. These parameter settings have been widely applied in finite element numerical simulations . The concrete is categorized into normal-strength concrete (fcu < 100 MPa) and HSC (fcu ≥ 100 MPa) according to the dilation angle, and the steel is categorized into normal-strength steel (fs < 500 MPa) and HSS (fs ≥ 500 MPa) according to whether the steel has a yield plateau.The strength distribution pattern of the test data points is shown in Nu,e/Nu,FE) of the measured ultimate bearing capacity  to the ultimate bearing capacity calculated based on the finite element model  is 1.02, with a dispersion coefficient of 0.038. The Nu,FE values are generally in good agreement with Nu,e, especially in the elastic stage, during which the measured and calculated curves basically overlap. The finite element modeling method used in this paper is applied to compare and analyze the axial compression test results of the square HSCFST stub columns provided in the literature. The verification of the typical finite element model is shown in B = D), length (L), and wall thickness (t) of the square HSS tube are set to 500 mm, 1500 mm, and 3, 6, or 10 mm, respectively. The steel content (ρs) is between 0.02 and 0.08, the yield strength of the steel (fs) is 235, 345, 460, 550, 690, 780, or 960 MPa, and the cube compressive strength of the concrete (fcu) is 40, 70, 100, 120, 150, or 180 MPa. To explore the optimal combination of concrete strength and tube strength, these concrete strength and steel yield strength values were paired up to form a total of 126 model groups, and the model parameters are shown in In the finite element model, the width (t) of 6 mm and steel yield strengths (fs) of 345, 460, 690, and 960 MPa. The effect of concrete strength on the mechanical properties of square HSCFST stub columns was analyzed using a steel tube wall thickness (N–L) curves of axially compressed square HSCFST columns with different fcu values. The effects of concrete strength on the mechanical properties of axially compressed square HS-HC, HS-CC, CS-HC, and CS-CC stub column members with a tube wall thickness (t) of 6 mm and concrete strengths (fcu) of 30, 60, 90, 120, 150, and 180 MPa were analyzed. The results show the following: (1) Under the premise that other parameters remain constant, the concrete strength fcu is one of the factors influencing the bearing capacity of the CFST members. The initial stiffness of the members is little affected by fcu, and the ductility increases with increasing fcu. (2) With an increase in the concrete strength, the ultimate bearing capacities of CS-CC, HS-HC, HS-CC, and CS-HC stub column members increased by 60%, 24%, 44%, and 21% at most, respectively. Hence, the concrete strength has the greatest impact on CS-CC, the second greatest impact on HS-CC, and the least impact on CS-HC.fs) on the load–displacement curves of axially compressed square HS-HC, HS-CC, CS-HC, and CS-CC stub column members with a tube wall thickness (t) of 6 mm and steel yield strengths (fs) of 235, 345, 460, 550, 690, 800, and 960 MPa were analyzed, as shown in fs, which indicates that the steel yield strength is one of the factors influencing the bearing capacity of the CFST members. As the steel yield strength increased, the ultimate bearing capacities of CS-CC, HS-HC, HS-CC, and CS-HC stub column members increased by 8.8%, 5.1%, 8.5%, and 5.2%, respectively. Hence, steel yield strength has the greatest impact on CS-CC and HS-CC, the second greatest impact on HS-HC, and the least impact on CS-HC.The effects of steel yield strength (B = 500 mm and t = 6 mm show the following: (1) Under the premise that other parameters remain constant, the ultimate bearing capacities of the members increase as the width-to-thickness ratio decreases. When the thickness t decreased from 5 mm to 3 mm, the bearing capacities of HS-HC, HS-CC, CS-HC, and CS-CC stub columns increased by 14%, 24%, 5%, and 13%, respectively. Hence, the width-to-thickness ratio (D/t) has the greatest impact on HS-CC and the least impact on CS-HC. (2) Compared with concrete strength and the steel yield strength, the width-to-thickness ratio has a greater impact on the initial stiffness of the members. The greater the width-to-thickness ratio of a member is, the greater the initial stiffness of the member.In summary, the influence of material strength and width-thickness ratio on bearing performance is complex. In order to explore the best configuration, it is recommended to use the linear weighting and optimization method proposed by Sojobi , which irσ,c = 2tθσ,s/(B − 2t). The confinement efficiency of the steel tube on the core concrete can be evaluated by the radial confinement coefficient and the time at which the longitudinal stress–strain curve of the steel tube intersects its circumferential stress–strain curve. rσ,c) decreases during the early loading stage but increases during the late loading stage, whereas the radial confinement coefficient (ηc) decreases constantly. (2) As the concrete strength grade increases, the rσ,c always decreases, whereas ηc decreases in the early loading stage but increases at the late loading stage. (3) During the loading process, the longitudinal stress of the steel tube gradually decreases after reaching the maximum point, while the circumferential stress of the steel tube gradually increases after reaching the minimum point. The intersection point of the longitudinal stress–strain curve and the circumferential stress–strain curve of CS-CC appears first, while that of CS-HC appears last because the HSC has not reached the peak stress when the common-strength steel buckles. Hence, CS-HC has the weakest confinement effect.The variation pattern of the longitudinal stress–strain curves and circumferential stress–strain curves of the steel tube used by Ding  can reflAc is the cross-sectional area of the concrete, Ac1 is the unconfined area of the concrete, Ac2 is the confined area of the concrete, B is the cross-sectional length or width of the steel tube of each strength grade, and t is the wall thickness of the steel tube of each strength grade. According to the stress distributions in Ac, Ac1, and Ac2 are expressed as follows:The model is simplified using the superposition principle and stress distribution analysis. Lσ,s) to the nominal yield strength (fs) of the steel tube and the ratio of the circumferential stress  to the fs of the steel tube at these three points varies with the ultimate strength of the specimen , as shown in the figures. When a square HSCFST stub column reaches its axial compressive capacity, the relation between the axial stress and the yield stress and the relation between the circumferential stress and the yield stress of the steel tube are as follows:The relation between the radial stress of the core concrete and the circumferential stress of the steel tube shown in Lf,c and the lateral stress rσ,c of the core concrete in the reinforced zone is as follows:The relation between the axial compressive strength Based on the static equilibrium condition of the cross-section, the following equation can be obtained:Nu) can be expressed as follows:K is the confinement coefficient of the square steel tube to the concrete. K values of the three types of square HSCFSTs and the K values of the CS-CC obtained from the literature. The CS-CC has the best confinement effect among the four types of CFSTs. Among the three types of square HSCFSTs, HS-CC has the best confinement effect, HS-HC has the second-best confinement effect, and CS-HC has the weakest confinement effect.According to Equations (11)–(15), the axial compressive capacity of the square HSCFST (N/(As + Ac) is compared due to the large differences in the cross-sectional sizes of square CFST stub columns used in different axial compression tests. Nu,exp to the Nu calculated based on the EC4-2004 is 0.99, with a dispersion coefficient of 0.172. The average ratio of Nu,exp to the Nu calculated based on the BS5400 is 1.39, with a dispersion coefficient of 0.142. The average ratio of Nu,exp to the Nu calculated based on the ACI standard is 1.07, with a dispersion coefficient of 0.160. The average ratio of Nu,exp to the Nu calculated based on the GB50936-2014 is 1.17, with a dispersion coefficient of 0.552. The Nu calculated based on Equation (16) is in best agreement with the Nu,exp.At present, Eurocode 4 (EC4)-2004 , the Bri(1)A refined 3D finite element model consisting of 181 sets of axially compressed square HSCFST members is established using the unified constitutive relation of steel and concrete.(2)fcu, and steel strength fs on the bearing capacity and confinement effect of the members. Increasing the steel yield strength and reducing the concrete strength will weaken the confinement efficiency of the steel tube to the concrete. Among the four types of CFSTs, CS-CC has the strongest confinement effect, while CS-HC has the weakest confinement effect. Compared with concrete strength and the steel yield strength, the width-to-thickness ratio has a greater impact on the initial stiffness of the members. The greater the width-to-thickness ratio of a member is, the greater the initial stiffness of the member.A total of 126 groups of examples were constructed to analyze the effects of the diameter-to-thickness ratio, concrete strength (3)Based on the equilibrium condition, a practical formula considering the confinement coefficient for the ultimate bearing capacity of square CFST stub columns under axial loading with different material matches was proposed. The proposed formula shows a better calculation accuracy and clearer physical meaning of HSCFST compared with major code formulae.


To investigate factors that influence antibiotic prescribing decisions, we interviewed 49 antibiotic stewardship champions and stakeholders across 15 hospitals. We conducted thematic analysis and subcoding of decisional factors. We identified 31 factors that influence antibiotic prescribing decisions. These factors may help stewardship programs identify educational targets and design more effective interventions. Few studies have assessed the range of factors that influence antibiotic decision making in acute-care settings. Understanding factors that influence these decisions can be an important prerequisite to identifying knowledge gaps and designing more effective antibiotic stewardship strategies. In this study, we identified factors that influence decision making about antibiotics across 15 hospitals in the Veterans’ Health Administration (VHA).Promoting antibiotic stewardship is important to combatting the spread of antibiotic-resistant bacteria, a public health threat. However, the implementation of antibiotic stewardship practices can be challenging because it involves changing providers’ knowledge, attitudes, and behaviors around antibiotic decision making. These sites made up the Veterans’ Affairs–Centers for Disease Control and Prevention Practice–Based Research Network (VA-CDC PBRN). Each site had a dedicated research coordinator who was trained by the study team to conduct qualitative interviews.During 2018–2019, the study team conducted semistructured interviews with 49 healthcare workers at 15 geographically dispersed VHA hospitals. Data on antibiotic use at these 15 hospitals have been published previously. Interviews also explored decisional factors that influence the use of any antibiotics for 4 common infections: pneumonia, urinary tract infections, intra-abdominal infections, and skin and soft-tissue infections. All interview guides can be found in the Supplementary Material.Interview participants included the antibiotic stewardship program physician and pharmacist champion at each of the 15 sites (n = 30), as well as other key stakeholders (n = 19) at 5 sites, including pharmacy administrators (n = 5), hospitalists (n = 5), ICU physicians (n = 5), and emergency department providers (n = 4). The interviews were designed to elicit perspectives on barriers and facilitators to the adoption of antibiotic management policies for fluoroquinolones and extended-spectrum cephalosporins, as previously described. First, transcripts were reviewed by the analysis team, and a code book was developed from the interview guide and from emergent content. The transcripts were then coded by consensus. Second, the analysis team subcoded intersecting segments for “decisional factors” surrounding antibiotic prescribing for “pneumonia.” The final phase involved 2 team members (E.E. and D.L.) expanding the subcoding process to apply the decisional factor subcodes to interview segments addressing the other infection types. To be considered relevant for analysis, a decisional factor must have been mentioned by at least 2 participants. After all relevant factors were reviewed, team members discussed broader categories for potential grouping. Ultimately, each factor was grouped into 1 of 5 categories based on group consensus.Each interview was audio-recorded on encrypted recorders, when possible, and was then transcribed. Transcripts from 47 interviews and detailed notes from 2 interviews were uploaded into MAXQDA, a qualitative data management software program . An interdisciplinary team of physicians with antibiotic stewardship expertise and qualitative analysts analyzed the transcripts using thematic analysis, subcoding, and categorization.The Veterans’ Affairs Central Institutional Review Board granted a waiver for written informed consent for participants in the semistructured interviews. The study team reviewed but did not document informed consent information with all participants.Table In total, 31 unique decisional factors were identified Table  and werePseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus.Some decisional factors that participants described were not well defined, such as “complicated infection,” “healthcare exposure,” or “septic.” For these terms, specific definitions were often not provided. As an example, the term “healthcare exposure” was frequently used to justify broader antibiotic therapy. A minority of participants expressed concern about this term, particularly in relation to pneumonia. According to one physician champion, “Studies have shown that the criteria or the scores to say this is ‘healthcare-associated pneumonia’ are no better than flipping a coin to identify somebody who has one of those resistant pathogens.” Instead of using the term “healthcare exposure,” a stewardship pharmacist champion explained that “we would try to do more risk factor-based therapy,” which would involve assessing specific risk factors for Our investigation of decisional factors revealed that providers consider >30 factors when making antibiotic prescribing decisions in acute-care settings. The influence of specific factors may differ across providers, but there was strong consensus that these prescribing decisions are complex.Although many of the identified factors may seem obvious to clinicians who prescribe antibiotics, few studies have tried to broadly identify the multiple facets of these decisions, as we have done. Some of the decisional factors we identified have also been described in prior research about antibiotic decision making in studies across different types of infections, different countries, and different healthcare settings.Our findings may help identify potential targets for educating prescribers about antibiotics. For example, some participants stated a preference for using oral antibiotics with high bioavailability or for using intravenous agents over oral agents, and this finding highlights an opportunity for antibiotic stewardship teams to better define when these pharmacologic properties are most clinically relevant. Although healthcare exposure was often cited as a reason to prescribe more broad-spectrum antibiotics, the nuances of which types of exposure truly increase the risk of antibiotic resistance may not be as well understood.Our study had several limitations. Although we enrolled a geographically diverse sample of providers, our findings may not be generalizable to non-VHA settings. Our interview guides were not created explicitly to parse out specific decisional factors. However, we would expect that if a decisional factor was relevant, it would have been raised by at least some of the 49 participants. We were able to identify decisional factors, but we were unable to assess the perceived importance of each of these factors in general and relative to different types of infections. To evaluate how participants prioritize these factors, our findings could be leveraged in future surveys and/or in-depth semistructured interviews that are specifically designed for this purpose.In summary, we have elucidated many factors that providers consider when making antibiotic prescribing decisions for common infections in acute-care settings. This information should be considered when developing and implementing antibiotic stewardship strategies, particularly strategies focused on education.


An essential problem of current construction engineering is the search for ways to obtain lightweight building structures with improved characteristics. The relevant way is the use of polymer composite reinforcement and concrete with high classes and prime characteristics. The purpose of this work is the theoretical and experimental substantiation of the effectiveness of combined-reinforced glass fiber polymer composite concrete (GFPCC) bending elements, and new recipe, technological and design solutions. We theoretically and experimentally substantiated the effectiveness of GFPCC bending elements from the point of view of three aspects: prescription, technological and constructive. An improvement in the structure and characteristics of glass fiber-reinforced concrete and GFPCC bending elements of a new type has been proven: the compressive strength of glass fiber-reinforced concrete has been increased up to 20%, and the efficiency of GFPCC bending elements is comparable to the concrete bending elements with steel reinforcement of class A1000 and higher. An improvement in the performance of the design due to the synergistic effect of fiber reinforcement of bending elements in combination with polymer composite reinforcement with rods was revealed. The synergistic effect with optimal recipe and technological parameters is due to the combined effect of dispersed fiber, which strengthens concrete at the micro level, and polymer composite reinforcement, which significantly increases the bearing capacity of the element at the macro level. Analytical dependences of the type of functions of the characteristics of bent concrete structures on the arguments—the parameters of the combined reinforcement with fiber and polymer composite reinforcement—are proposed. The synergistic effect of such a development is described, a new controlled significant coefficient of synergistic efficiency of combined reinforcement is proposed. From an economic point of view, the cost of the developed elements has been reduced and is economically more profitable (up to 300%). Currently, one of the most relevant areas in construction science and technologies is the search for rational combinations of building materials used, new technologies, and design solutions. The industry of polymer building materials and products is actively developing. An important issue is the search for ways to obtain lightweight building structures as thin as possible and have the smallest sections, while having improved characteristics and structure of the materials used. Considering all the above, the use of polymer composite reinforcement concrete of high class and prime characteristics is relevant and in demand from the point of view of science and practice.The improvement of reinforced concrete bending elements is the most relevant at the present time and has already been considered in many studies, for example, in ,13,14,15Using various types of fibers in concrete, the parameters of the distribution of fibers in the body of concrete and the recipe factors for obtaining fiber-reinforced concretes with improved characteristics have been studied in many works ,25,26,27Research on improving the characteristics and operation parameters of compressed ,31,32,33Finally, the works of the authors involved in the study of polymer composite concrete bending elements (beams) ,48,49,50We previously studied “the quantitative and qualitative aspects of the joint work of fiber in concrete in combination with polymer composite reinforcement, which gave good results in terms of physical and mechanical characteristics”, the most rational design solutions and showed good compatibility between fiber reinforcement and reinforcement with polymer composite rods ,52. DetaIn the study, a numerical calculation and an experimental test were carried out, including an analysis of scanning electron microscopy as well as an economic analysis of the effectiveness of the proposed solutions.The scientific novelty of the research is the recipe: technological, microstructural and constructive substantiation of the existence of a synergistic effect from the combined reinforcement with dispersed fiber and polymer composite reinforcement of improved bending elements made of heavy concrete. Qualitative and quantitative compositions of concrete, constructive solutions are given, and a mathematical apparatus has been developed to control the effectiveness of the proposed method. Theoretical prerequisites are substantiated from the point of view of the economic efficiency of the developed proposals.Thus, the purpose of this work is the theoretical and experimental substantiation of the effectiveness of combined-reinforced GFPCC bending elements as well as prescription, technological and design solutions related to the identification of the most rational parameters.(1)Determination of rational parameters in terms of formulation and technology;(2)Obtaining first, glass fiber-reinforced concrete and second, glass fiber polymer composite concrete bending elements of a new type with improved structure and characteristics;(3)Study from the point of view of theoretical concepts, as well as practical aspects of the structure of such materials and structures, as well as the study of their work from the point of view of experimental test and numerical calculation;(4)Development of theoretical provisions and substantiation of experimental proposals for the practical industry;(5)Identifying the most problematic bottlenecks to fill the scientific gap toward joint research between building materials science and building structures, tied to the theory of fiber fibers and polymer composite reinforcing elements.The objectives of the study are:The results of the study are proposed to be used in the construction of buildings and structures of increased responsibility in relation to extended bending reinforced concrete elements. Thus, the study is relevant in the field of design, construction, and production of building structures, solving the complex problem of the lack of scientific and engineering solutions.The study used non-additive Portland cement brand CEM I 52.5N of Novoroscement  GOST 31108-2020 “Common cements. Specifications”. The chemical and mineralogical composition, as well as the physic mechanical properties, are given in .In addition, in the research, granite crushed stone of Pavlovsknerud JSC  and fine aggregate–quartz sand of Quartz Sands LLC  was used. The prime properties of aggregates are presented in .Glass fiber Armplast  was used as dispersed reinforcing fibers, the physical and mechanical characteristics of which are presented in Steel reinforcement was from Tyazhpromarmatura  according to GOST 34028–2016 “Reinforcing rolled products for reinforced concrete constructions. Specifications” and polymer–composite reinforcement was produced by the Yaroslavl Plant of Composites  according to GOST 31938 “Fiber-reinforced polymer bar for concrete reinforcement. General specifications” . ReinforDetailed information about the polymer composites considered in the study is presented in ,54,55.“The calculation was carried out based on SP 63.13330.2018 , the manThe beam was designed as hinged for concrete classes B30 and B40, steel and composite reinforcement. The length of the beam remained constant, 3000 mm, and was not considered in the calculation of the maximum perceived moment. The calculation of the limiting value of the bending moment was calculated relative to the compressed zone of concrete according to SP 63.13330.2018 p.8.1.8  and the The numerical calculation program is shown in M is the ultimate bending moment.The ultimate value of the bending moment was calculated relative to the compressed zone of concrete following SP 63.13330.2018 p. 8.1.8.b is beam width, m; x is the height of the compressed zone, m; 2; a′ is the distance from the resultant forces in the longitudinal compression reinforcement to the nearest edge of the section (0.02 m).The value of x is determined by the formula:2; Here, the height of the compressed zone The boundary height of the compressed zone is determined by the formula:The values of relative deformations (a)ξ is the relative height of the compressed zone of concrete;For (b)For The calculation of rectangular sections was carried out depending on the height of the compressed zone according to Formula (3):The laboratory research program is shown in The concrete mixture was made in a laboratory concrete mixer BL-10 . First, the dry components were mixed for 60 s; then, the mixture was mixed with water and mixed until a homogeneous consistency was obtained. The fiber-reinforced concrete mixture was prepared according to the method described in .F is the breaking load, N; A is the area of the working section of the sample, mm2; α is a scale factor for converting the strength of concrete to the strength of concrete in samples of basic size and shape .Compressive strength tests of specimens “were carried out in accordance with GOST 10180 Concretes. Methods for strength determination using reference specimens”  on an “IThe strength of concrete in a series of samples was determined as the arithmetic mean of the strength of the tested samples in a series of six samples, of which four samples had the highest strength.In total, 4 series of concrete samples were made and tested. Two series are control samples without fiber, and the rest are samples reinforced with glass fiber . That is, in total, 24 sample cubes of two types of concrete were destroyed (12 of each type).The microstructure of samples with fibers was studied using a ZEISS CrossBeam 340 “microscope equipped with an Oxford Instruments X-Max 80 X-ray microanalyzer (Carl Zeiss Microscopy GmbH (Factory), Jena, Germany)” ,61.In addition, the study used testing and auxiliary equipment as well as measuring instruments used earlier in ,66,67,68The results of a numerical calculation of the height of the compressed zone of concrete of classes B30 and B40 and the limiting value of the bending moment of reinforced concrete beams with a cross-section of 400 mm × 400 mm and 400 mm × 600 mm with a diameter of reinforcement bars of 6 mm, 8 mm, 10 mm are presented in (1)The values of the bending moment of beams reinforced with polymer composite rebar are between the values of the moment of beams with steel reinforcement of class A800 and class A1000, slightly closer to A1000 reinforcement; this applies to each rebar diameter applied ;(2)The values of the bending moment of beams reinforced with glass-composite and basalt-composite reinforcement do not differ;(3)The values of the limiting bending moment do not change for different classes of concrete but depend on the dimensions of the section of the elements;(4)The ultimate bending moment of 400 mm × 600 mm beams is approximately 50% greater than that of 400 mm × 400 mm beams for each applied reinforcement diameter;(5)When replacing 6 mm reinforcement with 8 mm reinforcement, the ultimate bending moment of the beam increases by 77–82%, while an increase in the diameter of the rods from 8 to 10 mm leads to an increase in the bending moment by 54–58%;(6)An increase in the class of steel reinforcement from A400 to A600 leads to an increase in the ultimate bending moment of beams by 51–55%, from A600 to A800 by 32–35%, from A800 to A1000 by 24–26%;(7)The ultimate bending moment of members reinforced with GCR 800 × 50 and BCR 800 × 50 polymer composite rebar is 130–160% greater than that of members reinforced with A400 class steel rebar, 50–58% greater than with rebar A600, 14–17% more than with A800 rebar and 7–9% less than with A1000 rebar; this difference depends on the diameter of the reinforcement and the dimensions of the section of the element and is about 50%.As a result of a numerical calculation of the limiting value of the bending moment of reinforced concrete beams, as presented in Thus, the efficiency of bending elements with polymer composite reinforcement is practically comparable to the efficiency of bending elements with A1000 class steel reinforcement.(1)The height of the concrete compression zone of beams reinforced with polymer composite reinforcement exceeds the height of the concrete compression zone of beams with class A1000 steel reinforcement for bar diameters of 6 and 8 mm and is practically comparable to the values of the concrete compression zone of beams with class A1000 steel reinforcement for a diameter of 10 mm;(2)The values of the height of the compressed zone of concrete beams reinforced with glass–composite and basalt–composite reinforcement do not differ;(3)The values of the height of the compressed zone of concrete do not change with different sizes of the section of the elements but depend on the class of concrete used;(4)The compression zone height of B40 concrete is 28–32% less than the compression zone height of B30 concrete for each applied reinforcement diameter;(5)When replacing reinforcement with a diameter of 6 mm for reinforcement of 8 mm, the height of the compressed zone of the beam concrete increases by 125% for polymer composite reinforcement and up to 850% for A600 steel reinforcement, while an increase in the diameter of the rods from 8 to 10 mm leads to an increase in height compressed zone by 70% for PCR and 130% for A400;(6)An increase in the class of steel reinforcement depending on the diameter of the rods from A400 to A600 leads to an increase in the height of the compressed zone from 62% to 73%, from A600 to A800 leads to an increase from 47% to 300%, and from A800 to A1000 leads to an increase from 34% to 94%;(7)The height of the concrete compression zone of elements reinforced with GCR 800 × 50 and BCR 800 × 50 polymer composite rebar is 220–325% greater than that of elements reinforced with A400 class steel rebar, 97–967% greater than with fittings A600, 34–160% more than with fittings A800, and 0–34% more than with fittings A1000; this difference depends on the diameter of the reinforcement and the class of concrete and is about 28–32%.As a result of a numerical calculation of the height of the compressed zone of concrete of bending elements, as presented in The results of the laboratory experiment are presented in x and the limiting value of the bending moment M. Thus, according to the results of numerical calculation of improved combined-reinforced elements, a synergistic effect was revealed, which was found during the calculations and was subject to interpretation in the form of universal dependencies, which are given below.According to the results of experimental data, a synergistic effect was revealed, which manifests itself in an increase in the characteristics of the resulting bent reinforced elements due to the combined reinforcement with dispersed fiber and polymer composite reinforcing bars. Thus, we studied the parameters, some of which did not reveal specific dependencies and, thus, did not give grounds to consider them as an opportunity to obtain a synergistic effect. These are such characteristics as the relative height of the compressed zone and the boundary relative height of the compressed zone. Let us dwell in more detail on the height of the compressed zone x is the height of the compressed zone, B is the class of concrete, and A is the class of reinforcement.So, knowing that for standard-reinforced elements without improving the characteristics of concrete, whether it be polymer composite reinforcement or other reinforcement, for example, steel, we have a simple dependence of the form:The indicated dependence is canonical and is applied under the existing norms and rules for the calculation and design of building structures. However, in the bending elements proposed by us with an improved microstructure and improved characteristics, we are dealing with a new type of elements obtained based on the same technological and design templates.x but the height of the reduced zone, that is, k derived by us arises—a controlled significant coefficient of the synergistic efficiency of the combined reinforcement, and the dependence takes the form:k is a controlled significant coefficient of synergistic efficiency of combined reinforcement.However, as revealed as a result of a numerical calculation and physical experiments, the height of the compressed zone, like other characteristics, varies, and, depending on various factors, from an insignificant degree to a significant one. Thus, we believe that now we are dealing with an indicator of not the height of the compressed zone M and its dependence in the form:Similarly, the dependence for determining the moments of bending reinforced concrete elements changes; that is, the indicator by which its bearing capacity and operational reliability are evaluated. In addition, in standard calculations and technological processes, designers put M is transformed into k is a controlled, significant coefficient of synergistic efficiency of combined reinforcement.We introduce again our assumptions, which were confirmed by numerical and physical experiments; then, k, assigning to them the indices of those indicators, the function of which we find. Thus, k for the height of the compressed zone will look like k for the ultimate bending moment will look like In this case, it is necessary to distinguish between the coefficients Let us present a practical example based on experimental data, in particular, for one of the cases shown in the tables above.k lie in the region of the gains obtained for the height of the compressed zone and moments and range from 7 to 967. Of course, the controllability of this coefficient is ensured by the set of factors and recipe–technological parameters that are set during the design.Thus, we have proved numerically and experimentally the synergistic effect arising from the combined reinforcement of glass fiber polymer composite concrete bending elements and also presented universal dependencies for their determination. The ranges of the coefficients For a deeper analysis of the effectiveness of the effect of fiber on the structure of the composite, SEM analysis of samples with fiber was carried out. The microstructure of the sample reinforced with glass fiber is shown in Analysis of photographs of the microstructure of fiber-reinforced composite samples revealed different types of destruction. In particular, in Thus, in addition to the formulation and design aspects of obtaining fiber-reinforced concrete composites with improved characteristics, the technological aspect is also important, which consists in carefully selected modes of preparation of the fiber-reinforced concrete mixture and, in particular, the rational distribution of fiber in the volume of the concrete matrix ,52,61.In addition, an analysis of the cost of the types and classes of reinforcement considered in the study was carried out using the example of a diameter of 8 mm. Data taken from various catalogs of rebar sellers in Russia made it possible to compile the average cost per unit of production. The results of the analysis are presented in It is known that the most traditional type of reinforcement for reinforced concrete elements operating in bending is reinforcing steel of various grades. However, with all the demand for traditional reinforced concrete, it has several disadvantages, the main of which should be highlighted: the high cost of steel rods and the heavy weight of the resulting structures. In addition, at present, there are effective types of polymer composite reinforcement, such as glass composite reinforcement and basalt composite reinforcement, which make it possible to obtain bendable reinforced elements from heavy concrete with even more efficient work in structures.In this regard, we made a market analysis, which revealed that the cost parameters of basalt–composite reinforcement are the most preferable. At the same time, the cost of basalt–composite reinforcement, ceteris paribus, is almost two times less than glass-composite reinforcement, and their bearing capacities practically do not differ from each other. Thus, in our opinion, the best way to obtain the most efficient and rational building structures from heavy concrete, working in bending, should be made from GFPCC.Fiber reinforcement, as we have proved earlier ,61,62,63Let us consider and analyze the results we have achieved from three points of view. First, it is necessary to identify the effect that we achieved in the study in the prescription aspect. In particular, we have proved that fiber reinforcement increases the characteristics of concrete by 10–20% percent and improves its microstructure in accordance with ,52, whilAs for microstructural studies of fiber reinforcement, the obtained results of SEM analysis are in good agreement with the results obtained by us earlier in . On the The analysis of photographs of the microstructure carried out also continues and develops the results already obtained by us earlier in . The natNext, consider the constructive effect we have achieved, it consists of improving the performance of an improved design due to the synergistic effect of fiber reinforcement of bending elements and in combination of such dispersed reinforcement with polymer composite reinforcement with rods. In this regard, our results seem to be effective in comparison with the results of the authors ,13,14,15Finally, from a price point of view, the cost of our elements is reduced and is more economical, as confirmed by our economic analysis. This is in good agreement with the results of the authors ,48,49,50Thus, focusing on the comparison of experimental data and calculated data with the results of other authors, we note the advantages of our proposals, which are justified by the proven synergistic effect. In addition, the analysis of the results revealed the relationship between the initial parameters and components and technological, constructive and economic indicators of the structures being created.(1)Theoretically and experimentally substantiated the effectiveness of combined-reinforced glass fiber polymer composite concrete bending elements from the point of view of three aspects: prescription, technological and constructive.(2)The improvement of the structure and characteristics of glass fiber-reinforced concrete and glass fiber polymer composite concrete bending elements of a new type has been proven; the compressive strength of glass fiber-reinforced concrete with careful observance of rational parameters in terms of formulation and technology has been increased to 20%, the efficiency of glass fiber polymer composite concrete bending elements is comparable to the work of reinforced concrete bending elements with steel reinforcement class A1000 and higher.(3)k is proposed—a controlled significant coefficient of the synergistic efficiency of the combined reinforcement.Analytical dependences of the type of functions of the characteristics of bent concrete structures on the arguments are proposed—the parameters of combined reinforcement with fiber and polymer composite reinforcement; the synergistic effect of such development is described, and a new coefficient (4)From a price point of view, the cost of the developed elements is reduced and is economically more profitable (up to 300%), which is confirmed by the economic analysis.The prospects and direction of development of the research are planned in terms of bending elements made of heavy concrete with a differentiation of characteristics over the section as well as with the use of differentiated fiber reinforcement with fibers from various materials.


No relevant differences in age, American Society of Anesthesiologists (ASA) score and body mass index (BMI) between the groups were observed.Reducing the risk of periprosthetic joint infections (PJI) requires a multi-pronged strategy including usage of a prophylactic antibiotic. A history of penicillin or cephalosporin allergy often leads to a change in prophylactic antibiotic regimen to avoid serious side effects. The purpose of the present retrospective study was to determine incidence of PJI based on perioperative antibiotic regimen in total hip arthroplasty (THA), total knee arthroplasty (TKA) or unicompartmental knee arthroplasty (UKA). A review of all primary THAs, primary TKAs and primary UKAs, undertaken between 2011 and 2020 in a tertiary referral hospital, was performed. The standard perioperative antibiotic for joint arthroplasty (JA) in the analyzed tertiary hospital is cefuroxime. There were no differences in prophylactic antibiotic regimen over time. In 7.9% (211 of 2666) of knee arthroplasties and in 6.0% (206 of 3419) of total hip arthroplasties, a second-line prophylactic antibiotic was used. There was no statistically significant higher occurrence of PJI between the first-line and second-line prophylactic antibiotic in knee arthroplasties ( Reducing the risk of periprosthetic joint infections (PJI) requires a multi-pronged strategy including usage of a prophylactic antibiotic ,2,3. TheStaphylococcus aureus (MRSA) infection [A history of penicillin or cephalosporin allergy, however, often leads to a change in prophylactic antibiotic regimen to avoid potential serious side effects due to cross-reactivity ,4,5. Thenfection , whereasnfection .Previous studies have demonstrated that reporting a penicillin or cephalosporin allergy and the consequent use of a second-line prophylactic antibiotic is associated with significantly higher rates of surgical site infections after various surgical procedures ,7,8,9. HThe aim of this retrospective clinical study was to identify and compare the occurrence of PJI in patients who received cefuroxime as a prophylactic antibiotic before primary arthroplasty with patients who, due to reported allergies, received a non-cefuroxime prophylactic antibiotic. Patients were stratified into two groups, knee arthroplasty and hip arthroplasty, and analyzed independently. Additionally, PJI onset time was identified and compared between the aforementioned cohorts according to usage of prophylactic antibiotics.A total of 3698 total hip arthroplasties (THAs) and 2876 unicondylar knee arthroplasties (UKAs) and total knee arthroplasties (TKAs) undertaken between 2011 and 2020 in a tertiary referral hospital were screened for inclusion in the study . Cases wIn the present study, 7.7% (269 of 3419) of patients in the THA group reported a penicillin or cephalosporin allergy. Prophylactic antibiotic therapy with cefuroxime was given to 63 of 269 patients who reported the aforementioned allergies (23.4%). No allergic reactions were reported in those cases. In 206 of 3419 THAs (6.0%), due to reported allergies, a second-line (non-cefuroxime) prophylactic antibiotic was given , Table 1p = 0.028). Patients with reported allergies in the THAs group seemed to have a significantly higher mean BMI, 29.2 kg/m2 (SD 5.4), compared the mean BMI of the cefuroxime cohort, 28.0 kg/m2 (SD 4.8), with a p value of 0.001. (p < 0.001) (p < 0.001). On the other hand, ASA scores I and II were significantly more common in the cefuroxime cohort, p = 0.002 and p = 0.003, respectively. There were no other relevant statistically significant differences between the cohorts observed.The demographics of both the cohorts, cefuroxime and non-cefuroxime, are shown in f 0.001. . Females< 0.001) . The meaIn the UKA/TKA group, 10.1% (268 of 2666) of patients reported a penicillin or cephalosporin allergy. In 57 of 268 patients (21.3%), cefuroxime was given despite reported allergies. No allergic reactions were observed. A second-line, non-cefuroxime, prophylactic antibiotic was administered in 211 of 2666 (7.9%) UKAs and TKAs , Table 2p = 0.572). As in the THA group, in the UKA/TKA group, females also reported a penicillin or cephalosporin allergy significantly more often, at 77.3% (p < 0.001) (p = 0.009)  . ASA sco= 0.009) . There wp = 0.757) and in total hip arthroplasties (p = 0.820). Furthermore, there was no statistically significant higher occurrence of revisions due to PJI between the cefuroxime and non-cefuroxime cohorts in primary knee arthroplasties (p = 0.403) and in primary hip arthroplasties (p = 0.309)  . Occurre= 0.309) .Penicillin or cephalosporin allergy was reported in 7.7% of the THA group and in 10.1% of the UKA/TKA group. The proportion of reported penicillin or cephalosporin allergies in the present study is slightly lower than in most previous studies, which reported proportions between 10% and 20% ,14,15,16p = 0.403) or in total hip arthroplasties (p = 0.309)  . There aAccording to authors’ literature research, to date, only two studies have reported the incidence of PJI, where the majority of the allergic cohort received clindamycin as a second-line prophylactic antibiotic and are therefore comparable to the present study. However, the results of these studies are not uniform. On one hand, Stone et al.  reportedAdditionally, the occurrence of PJI over time was observed in the present study. Most of PJIs were observed in the first three months (early PJI), more frequently in the HTEP group, at 73.1% (49 of 67 reported PJI cases), compared to 54.2% 13 of 24) in the UKA/TKA group. Robertsson et al. [ of 24 inThe present study is the only study that used cefuroxime, a second-generation cephalosporin, as a first-line prophylactic antibiotic. Most of the aforementioned studies ,8,10,12 This study must be interpreted in light of important limitations. Owing to its retrospective design, there is a collection and selection bias. Due to follow-up or incomplete data, 489 patients were lost. It is possible that complications in some patients with small follow-up were treated in other hospitals. However, the analyzed institution is the biggest tertiary referral hospital in the region; therefore, not many cases are expected to be treated elsewhere. Secondly, there might be a change in the hygiene protocol or in the operating theaters used in the included years, unknown to authors of this study. However, a single-institution design limits some possible confounding variables. On the other hand, the limited number of patients due to the single-institution design and low overall infection rate could influence the detection of the prophylaxis effect on PJI occurrence. A statistical power analysis, however, did not confirm that suspicion. Moreover, in register studies where findings depend on the accuracy of coding, an over-diagnosis of PJI is possible. Thirdly, a lack of bacterial growth, in the present study defined as an aseptic revision, does not necessarily imply surgical site sterility. However, no significant differences in the rate of revision due to causes other than infection, depending on which prophylactic antibiotic was used, were found in the present study.This retrospective, single-center cohort study was approved by the University’s Ethics Board (1156/2022). All elective primary TKAs, primary UKAs and primary THAs, undertaken between 2011 and 2020 in a tertiary referral hospital, were identified. Cases with insufficient data were excluded from the study . RetrospThere were no variations in the preoperative washing protocol, the method of skin preparation, the hand hygiene solutions used or the type of sterilization of surgical equipment and no major differences in surgical approach throughout the study period. MRSA colonization status was not assessed. All patients presenting with possible PJI due to an elevated CRP and/or signs of local inflammation underwent a sterile aspiration of synovial fluid and microbiological analysis. Depending on the time of infection and clinical findings’ debridement and implant retention (DAIR), one- or two-stage revision arthroplasty, followed by long-term antibiotic suppression, was performed. The revision techniques for PJI remained the same throughout the study period.The chosen prophylactic antibiotic used before the primary, non-revision surgery throughout the study period was a single shot of 1500 mg intravenous cefuroxime. In the case of history of penicillin and/or cephalosporin hypersensitivity, antibiotic prophylaxis was adapted accordingly and was usually replaced by a single preoperative shot of clindamycin, either 300 mg or 600 mg. Antibiotics were administered intravenously during the induction of anesthesia, 30 min before the surgical incision.In case of a possible PJI, routinely, a sterile aspiration of synovial fluid was performed preoperatively, and at least three tissue samples and one sample of synovial fluid were obtained for culture intraoperatively. Synovial fluid was aseptically inoculated into aerobic and anaerobic blood culture bottles  and incubated for 14 days. Tissue samples were obtained from the subfascial tissue and the proximal and distal interfaces of the prosthesis. Each culture was transported, processed and analyzed according to international standards and the definitions of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) . TissuesThe main outcome measure of this retrospective study was to identify and compare the occurrence of PJI in patients who received cefuroxime as a prophylactic antibiotic before primary arthroplasty with patients who, due to reported allergies, received a non-cefuroxime prophylactic antibiotic. Additionally, PJI onset time was identified and compared between the aforementioned groups.p-value of <0.05 was considered statistically significant.Data were collected using Microsoft Excel  and analyzed with SPSS v.24 . The study cohort was described using descriptive statistics. Categorical variables were expressed as percentages of the total sample for those variable and continuous variables as means and standard deviation and follow-up time as median and interquartile range. A post hoc power analysis was performed, assuming non-inferiority between the groups. Using the revision rates and differences observed in the study, with an alpha of 0.05 and power of 0.9 and with the non-inferiority limit set to 2%, a sample size of 1610 was needed. Overall revision rate and PJI rate were calculated by determining the number of cases where revision and PJI occur. The differences between the groups were analyzed using the chi-squared test. The presence of an interaction and the role of confounding factors were evaluated. A There are no implications that the usage of clindamycin, as the second-line antibiotic, increases risk for PJI. However, the choice of prophylactic antibiotic could affect the pathogen spectrum and antibiotic resistance. Further analysis should be performed.


The calculations suggested two possible complex formations of 1:1 and 2:1 host-guest molecular ratio of β-CD with CBD and THC. The preferred orientation of all complexes in this study exhibited the hydrogen bonding between hydroxy-substituted benzene ring of CBD and THC with the β-CD’s secondary hydroxy groups at the wide rim. The calculated complexation energies indicate that formation of the 2:1 complexes  was more energetically favorable and chemically stable than the 1:1 complexes . However, the deformation energies of the host and the guest components in the 2:1 complexes  are much higher than those in the 1:1 complexes , which means the formation processes of the 2:1 complexes are more difficult due to the rigidity of the dimeric β-CDs. Therefore, the inclusion complexes of β-CD with CBD and THC are more likely to be in 1:1 host-guest ratio than in 2:1 molecular ratio. The results of this study supported the experimental results that the complexation constant of 1:1 β-CD/CBD (Ks = 300 M−1) is greater than that of 2:1 β-CDs/CBD (Kss = 0.833 M−1). Altogether, this study introduced the fitting parameters that could indicate the stability of the molecular fits in complex formation of each stoichiometry host-guest ratio, which are important for the assessment of the inclusion mechanisms as well as the relationships of reactants and products in chemical reactions.The complexation of β-cyclodextrin (β-CD) with cannabidiol (CBD) and Δ In 1964, Raphael Mechoulam, an Israeli chemist born in Bulgaria, made the initial discovery of THC and isolated it chromene group of THC and the hydrogen atom of the secondary hydroxyl at O3 of β-CD (O(THC) ··· H(O3H-β-CD)n-2).sp (component) is the dipole moment of the single-point energy of the guest or the host taken from the optimized complex. Dipole moment results from non-uniform distributions of positive and negative charges on the atoms inside the system. The dipole moment values of β-CD/CBD and β-CD/THC systems are closer to the dipole moment of free β-CD component than those of free CBD or THC, which means that the guest molecules are likely encapsulated inside the hydrophobic cavity of β-CD. The large |HOMO-LUMO| gap indicated that all inclusion complexes are as chemically stable as the free host and guest molecules. Complexation energy (ΔE) values are negative for all inclusion complexes which suggests that their formations are energetically favorable. Deformation energy sp (component) values compared to the dipole moments of isolated guest and host molecules. According to the values of ΔE and The results obtained from M062X/6-31G calculations for the 1:1 complexes are shown in In this section, 2:1 host-guest stoichiometry of β-CDs with CBD and THC inclusion complexes, wherein two β-CD molecules are fetched closer together, is investigated with three dimerized form of β-CDs: facing secondary portals , facing two primary portals , and facing primary and secondary portals , as shown in Molecular docking calculation results in Top, while its aliphatic chain is located in β-CDBottom, as shown in Top and its aliphatic chain in β-CDBottom n ··· H(OH-guest)). The second type, found only in HH/CBD Conf. III, is between the oxygen atom at O3 of β-CD and the hydrogen atom of the CBD’s hydroxyl group (O3(β-CD)n ··· H(O1H-CBD)). Due to its size, the hydroxy-substituted benzene ring of CBD and THC is always located near the wider side of a β-CD molecule.Starting from the molecular docking geometry of each complex, the geometry was fully optimized without any constraint using M062X/6-31G calculation. Ks = 300 M−1) is greater than that of 2:1 β-CDs/CBD (Kss = 0.833 M−1) [Finally, as suggested by molecular docking and density functional calculations, both of 1:1 and 2:1 host-guest stoichiometry of β-CD with CBD and THC are feasible. The calculated complexation energies indicate that the formation of the 2:1 host-guest ratio complex is more energetically favorable and chemically stable than the 1:1 host-guest ratio complex. However, the deformation energies of the host and the guest components in the 2:1 complex are much higher than those in the 1:1 complex, which means the formation process of 2:1 is more difficult. This explains why the experimental complexation constant of 1:1 β-CD/CBD (833 M−1) .The starting geometries of β-CD, CBD, and THC monomers were taken from the Cambridge Crystallographic Data Centre (CCDC) with deposition number 1,107,192 , 1,533,4The inclusion complex between β-CDs with CBD and THC molecules were constructed by molecular docking calculations using AutoDockTools 1.5.7 and AutoDock 4.2  softwareFull geometry optimization was performed on the monomers as well as the 1:1 and 2:1 host-guest stoichiometry inclusion complex structures with the Minnesota density functional  M062X/6-ompounds .The deformation energy (In summary, we investigated the molecular structures of β-CD/CBD and β-CD/THC complexes in 1:1 and 2:1 host-guest stoichiometry. The calculated complexation energy and the HOMO and LUMO gaps of the inclusion complexes were used to indicate the stability of the molecular fits of the complexes’ formation with each stoichiometry host-guest ratio, which demonstrate that the 2:1 host-guest ratio complexation is more energy favorable than the 1:1 host-guest ratio. According to the values of ΔE,