Is endotracheal aspirate culture (EAC) use variable across the US, and is EAC use associated with antibiotic use in children receiving mechanical ventilation?In this cross-sectional study of 31 pediatric hospitals and 152 132 patients in the US, EAC use varied widely between hospitals, and higher rates were correlated with increased antibiotic use. Patients who underwent an EAC culture were significantly more likely to receive antibiotics after adjustment for patient demographic characteristics, patient complexity, complex conditions, duration, and episodes of mechanical ventilation.In this study, EACs are associated with increased antibiotic prescribing in hospitalized mechanically ventilated children may represent an opportunity for diagnostic and antibiotic stewardship. Endotracheal aspirate cultures are commonly collected from patients with mechanical ventilation to evaluate for ventilator-associated pneumonia or tracheitis. However, the respiratory tract is not sterile, making differentiating between colonization from bacterial infection challenging, and results may be unreliable owing to variable specimen quality and sample processing across laboratories. Despite these limitations, clinicians routinely interpret bacterial growth in endotracheal aspirate cultures as evidence of infection, sometimes regardless of organism significance, prompting antibiotic treatment.To assess the variability in endotracheal aspirate culture rates and the association between culture rates and antibiotic prescribing among patients with mechanical ventilation across children’s hospitals in the US.Cross-sectional retrospective analysis of data obtained from the Children’s Hospital Association Pediatric Health Information System database between January 1, 2016, through December 31, 2019. Participants were all patients hospitalized with mechanical ventilation aged less than 18 years.A charge for an endotracheal aspirate culture on a ventilated day.Endotracheal aspirate culture rate and antibiotic days of therapy per ventilated days. For mechanical ventilation, clinical transaction classification codes for mechanical ventilation other unspecified ventilator assistance were used. To identify respiratory cultures, the laboratory test code for aerobic culture was used and relevant keywords  were used to identify sources in the hospital charge description master.R = 0.46; P = .009). In a multivariable model adjusting for patient-level and hospital-level characteristics and among patients with mechanical ventilation, each additional endotracheal aspirate culture was associated with 2.87  higher odds of receiving additional days of therapy compared with patients who did not receive and endotracheal aspirate culture.A total of 152 132 patients were identified among 31 hospitals. Among these patients, 79 691 endotracheal aspirate cultures were collected on a ventilator-day . The overall median rate of culture use was 46 per 1000 ventilator-days . The endotracheal aspirate culture rate was positively correlated with the hospital’s antibiotic days of therapy rate (In this study, notable variability was found in endotracheal aspirate culture rates across US pediatric hospitals and pediatric intensive care units, and endotracheal aspirate culture use was associated with increased antibiotic use. These findings suggest an opportunity for diagnostic and antibiotic stewardship to standardize testing and treatment of suspected ventilator-associated infections in pediatric patients with mechanical ventilation pediatric patients. This cross-sectional study characterizes the variability in the rate of endotracheal aspirate culture use and assesses the association between endotracheal aspirate culture use and antibiotic use across US pediatric hospitals. Therefore, some clinicians may have a low threshold to obtain endotracheal aspirate cultures (EACs) to evaluate for suspected VAP or VAT.5Ventilator-associated pneumonia (VAP) is the most frequently acquired infection in patients with mechanical ventilation and the second most common nosocomial infection in the intensive care unit (ICU).16 Sample collection and quality of specimens are variable, which may affect results.17 Endotracheal secretion samples are from a nonsterile site, making the differentiation between colonization and infection in the culture challenging. There is also a substantial amount of variability in the way EACs are processed and reported,18 which further complicates result interpretation and may be a factor in EAC unreliability. Clinicians may misinterpret reported growth of bacteria in EAC results as being an indicator of infection and then treat with antibiotics.20 Therefore, overuse of EACs may potentiate avoidable antibiotic treatment in patients with mechanical ventilation and contribute to avoidable harms such as Clostridioides difficile infections, antimicrobial resistance,21 and adverse drug reactions.23 Ultimately, EAC practices may vary widely within and across institutions. We aimed to characterize the variability in the rate of EAC use and assess the association between EAC use and antibiotic use across US pediatric hospitals.The results from EACs are relatively nonspecific for infection and may be unreliable.STROBE) reporting guideline for cross-sectional studies.This study was a retrospective multicenter cross-sectional analysis of clinical and billing data from the Pediatric Health Information System  from January 1, 2016, through December 31, 2019. PHIS is a national database that compiles administrative data including clinical and resource use from more than 49 children’s hospitals geographically dispersed across the US. Hospitals that did not continuously submit billing data to PHIS during the study period were excluded (n = 18). Data were obtained for all inpatient units and further stratified into ICU and neonatal ICU (NICU) groups for analysis. Of note, the ICU subgroup contained data from pediatric ICUs (PICUs) and pediatric cardiac ICUs because division of these units varies by hospital and is not easily distinguished in the PHIS database. This study was classified as exempt research (secondary research not requiring informed patient consent) per the University of Colorado institutional review board. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  procedure code for ventilation without mechanical ventilation CTC codes and patients with missing ventilation coding data were excluded (n = 4546) because the duration of ventilation could not be ascertained. To assess the accuracy of mechanical ventilation billing codes, we performed a validation using local Children’s Hospital Colorado data. This validation demonstrated that the use of ICD-10 codes for intubation and ventilation excluded data on patients with tracheostomy and made duration of ventilation undeterminable; they were therefore excluded.This study included all patients less than age 18 years who were hospitalized at a participating PHIS hospital during the study period and had at least 1 day of mechanical ventilation. We identified patients with mechanical ventilation as those with daily Clinical Transaction Codes (CTCs) for mechanical ventilation (n = 152 132), which includes all types of invasive ventilation . The CTC code is associated with a day of service each time it is used and allows for the calculation of ventilator-days for each patient. Patients who only had an Staphylococcus aureus screening, viral respiratory testing, anaerobic culture, and any additional testing unrelated to standard aerobic bacterial culture such as Pneumocystis direct fluorescent antibody and fungal testing. Rates of use were calculated for all inpatient units, the ICU subgroup, and the NICU subgroup.For this study, we defined the rate of EAC use as the total number of EACs billed for on a ventilated day per 1000 total ventilator-days. We identified EACs when the patient had a code for respiratory aerobic culture coinciding with a charge for ventilation on the same calendar day. Specimen source billing data were reviewed for consistency by a microbiologist (A.P.) and infectious disease physician (A.S.) and refereed by an additional infectious disease physician (S.K.P.). Because laboratory test descriptions and specimen source descriptions may be nonspecific , associated hospital charge description data were reviewed for details that specified the specimen source ; however, there was an insufficient volume of DOT. Rates of use were calculated for all inpatient units, the ICU subgroup, and the NICU subgroup.We defined the rate of antibiotic use as an antibiotic day of therapy (DOT) occurring on a ventilated day per 1000 ventilator-days. An antibiotic DOT was identified when the patient had a billing code for an antibiotic coinciding with a charge for ventilation on the same calendar day. We included a comprehensive list of antibiotics given via enteral or intravenous methods commonly prescribed for ventilator-associated infections (VAIs) , race and ethnicity , sex, the presence of any chronic condition, the patient’s cumulative number of ventilator-days and their number of ventilator episodes during the admission. Variables characterizing the hospital included case-mix index27 and geographic location . Patient race and ethnicity data were collected at each individual hospital at the time of patient registration, and were not determined by the investigators.28Characteristics associated with EAC use and antibiotic use were considered a priori and informed by previously reported associations conducted using the PHIS database.2 tests. The Shapiro-Wilk test was used to evaluate the distribution of each variable, and Pearson  and Spearman  correlation tests were used accordingly to assess the correlation between EAC use and antibiotic use. All correlation analyses were performed using R studio, version 1.4.1106 (R Studio). Covariates that were significantly associated with receiving an antibiotic on a ventilated day were entered into the final model for adjustment to accurately assess the association between EAC and antibiotic use in patients with mechanical ventilation patients.Characteristics were summarized using frequencies and percentages for categorical variables, and their association with EAC or antibiotic use was first compared using χPseudomonal, and anti-Staphylococcal). Covariates that had a significant univariate association with antibiotic use and determined a priori to be clinically relevant were included in the final model. Of note, the association between number of chronic conditions as well as individual chronic conditions and EAC use was assessed .Adjusted EAC use and antibiotic DOT rates per 1000 total ventilator-days were calculated using generalized linear mixed-effects models with Poisson distributions, controlling for hospital-level clustering and allowing for the presence of correlated data , nonconstant variability , and responses that are not normally distributed. We used the same approach to assess DOT per 1000 total ventilator-day values for all patients, patients in the ICU, patients in the NICU across institutions, and the antibiotic groups , non-Hispanic Black race , and presence of any chronic condition   . EAC use < .001) .P < .001), the number of cumulative ventilator-days a patient had , and the total number of ventilation episodes   to 119 per 1000 total ventilator-days  . Case-mi < .001) .P < .001), race  and cumulative ventilator days  , 1181 DOT per 1000 total ventilator-days in the ICU , and 740 per 1000 total ventilator-days in the NICU . Before adjustment, numerous variables were associated with antibiotic use including age  . Except for hospital geographic location, all patient and hospital characteristics that were significantly associated with receiving an antibiotic on a ventilator day were also significantly associated after adjustment. Non-Hispanic Black patients had significantly less odds of receiving antibiotics on a ventilated day than non-Hispanic White patients . Additionally, the odds of receiving an antibiotic was 1.55  times higher in patients with at least 1 chronic condition compared with patients without and odds of antibiotic use were higher in patients with more cumulative ventilator days .R = 0.46; P = .009). In the ICU subgroup, the EAC rate was positively correlated with the DOT for all antibiotics  and anti-Staphylococcal drugs . However, in this ICU subgroup, the EAC rate was not correlated with anti-Pseudomonal antibiotics . In the NICU subgroup, the EAC rate had a positive correlation with antibiotic DOT for all antibiotics , anti-Pseudomonal antibiotics , and anti-Staphylococcal antibiotics .Across all units, there was a positive correlation between EAC rate and DOT  and anti-Staphylococcal antibiotics  compared with patients with mechanical ventilation without EACs.After accounting for significant patient and hospital characteristics in the final model, patients who received EAC testing on a ventilated day had 3 times the odds of receiving an antibiotic than patients with mechanical ventilation who did not receive EAC testing . Patients with mechanical ventilation with EACs were also more likely to receive anti-29 After adjustment for patient and hospital characteristics, there was still a 10-fold difference in the highest and lowest hospital-level rate of EAC use, suggesting that differences in patient populations do not fully explain variability in testing frequency.In this observational study of EAC use in 31 pediatric hospitals from 2016 to 2019, we found variability in the rate of EAC use. Some patient-level characteristics were associated with higher EAC use such as age, presence of a complex chronic condition, cumulative ventilator-days, and the number of ventilation episodes, which aligns with clinical expectations. Some of the associations were not anticipated, such as non-Hispanic Black patients having a higher rate of EAC use but lower antibiotic use than White patients. More investigation is warranted for a better understanding of these observed differences in testing and treatment by race, which has been seen in other diagnostic evaluations.30 in pediatric populations. We aimed to explore whether trends could be found when focusing on anti-Pseudomonal or anti-Staphylococcal antibiotics because these organisms can cause chronic colonization and biofilm formation of airway devices.31 A strong correlation was not found for anti-Pseudomonal agents except in the NICU subgroup. Although this study included antibiotics prescribed only on ventilated days and medications commonly used to treat VAIs, billing data cannot provide the level of granularity to determine specific treatment indications. Particularly in the PICU setting, anti-Pseudomonal agents such as cefepime are commonly used for other infectious processes, so a portion of the captured antibiotic treatment may possibly be unrelated to VAI management.When examining the association between EAC and antibiotic usage, we found a moderate positive correlation. The multivariable modeling also showed increased odds of antimicrobial use in patients with mechanical ventilation who received more EAC testing. Overall, the antibiotic rates in this population with mechanical ventilation and associated variables align with prior studies35 For example, in the first of two ventilator-associated infection studies (VAIN),36 a multicenter study across 22 PICUs, antibiotic treatment was associated with the patient having had a positive EAC, and in the second VAIN study, implementing guidelines to de-escalate antibiotic treatment if the patient did not exhibit signs of respiratory infection was only successful in 27% of cases, largely owing to clinicians continuing treatment for positive EACs.37 Furthermore, recent reports from pediatric hospitals implementing clinical decision support for EAC testing were associated with significant reductions in EAC use and antibiotic prescribing for indication of VAIs.39 Therefore, we believe that in the present study, at least a portion of the EAC testing among hospitals with higher EAC use may be associated with higher antibiotic usage.Overall, one may expect that culture use is associated with antibiotic prescribing rates because clinicians will treat for suspected infections. The observational ecologic  design of this study cannot determine directionality or causality between EAC testing frequency and antibiotic usage. Specifically, we did not have the data to independently adjudicate appropriateness of individual EACs or specific antibiotic treatment indications. However, prior studies suggest that EAC testing may be associated with additional antibiotic treatment.42 Multiple studies have shown no association between bacterial growth or inflammation with clinical findings of respiratory infection across pediatric and adult populations.43 Various factors unrelated to the culture may affect the likelihood of infection such as inflammation, clinical status of the patient, and environmental exposures.44 Recognizing that VAI may have substantial morbidity if untreated, reporting of bacteria in EAC results presents a challenge for the clinician and may encourage antibiotic use regardless of the clinical relevance of the organism.24 The Infectious Disease Society of America recognized that EACs were less specific for infection and associated with more antibiotic use compared with bronchoalveolar lavage (BAL) specimens, but because of less patient risk and cost, the VAP guidelines recommended EACs over BAL cultures.45 Compounding these known limitations of EACs, variability occurs in sample quality, processing and reporting of EACs across US microbiology laboratories.18 Diagnostic stewardship interventions and formal guidelines for collecting, processing, and reporting for EACs are needed to support accurate interpretation and antibiotic treatment decisions for suspected VAI.A complicating feature of EACs is that the respiratory secretions are sampling a nonsterile body site; therefore EACs may be limited in their ability to differentiate between bacteria colonizing the airway from those acting as pathogens.46 and the present study further confirms interhospital variability in EAC testing practices. These descriptions are not isolated to pediatric care, lack of standardization, potential harms of EAC overuse, and diagnostic stewardship interventions have been proposed for adult patients with mechanical ventilation.49 Additional study is warranted to examine the association between EAC testing patterns and antibiotic use across the ages spectrum, emergency and ambulatory care settings, while also considering clinician and institutional factors.Clinician variability in pediatric VAI management practices has been describedThis study has limitations. A primary limitation of this study is the use of billing data, which can lead to misclassification. The use of ventilator-days to identify patients did not capture patients or EACs from tracheostomies if the patient was not ventilated. If an EAC was charged under a different billing code, it could have been omitted or some EACs may have been mislabeled and in fact been a different specimen. To optimize data validity, we excluded hospitals with inconsistent data reporting. Additionally, to ensure patients with mechanical ventilation were correctly identified, we back-validated PHIS data with Children’s Hospital Colorado patient data. To reduce the risk of misclassification of specimen type, we reviewed details of hospital charge descriptions. Although we captured important hospital and patient-level characteristics, billing data cannot reflect all the potentially relevant patient clinical condition details or local environment such as illness severity, indications for testing and treatment, the role of antibiotic stewardship programs, or clinician experience that may be associated with EAC and antibiotic usage. In particular, we could not distinguish the type of artificial airway .The results from this cross-sectional study found notable variability in EAC rates of use across pediatric hospitals, and EAC use was associated with higher odds of antibiotic use. Given the diagnostic limitations of EACs, these findings suggest that there may be opportunity for diagnostic and antibiotics stewardship to standardize EAC testing and treatment among children with mechanical ventilation.


Gastric cancer (GC) remains one of the most common deadly malignancies worldwide. Recently, several targeted therapeutics for treating unresectable or metastatic GC have been developed. Comprehensive characterization of the molecular profile and of the tumor immune microenvironment of GC has allowed researchers to explore promising biomarkers for GC treatment and has enabled a new paradigm in precision-targeted immunotherapy. In this article, we review established and promising new biomarkers relevant in GC, with a focus on their clinical implications, diagnostic methods, and the efficacy of targeted agents. Gastric cancer (GC) is one of the most common malignant tumors and is the fourth leading cause of cancer-related deaths worldwide . LocallyGC is a heterogeneous disease with diverse histologic and genomic subtypes. Based on genomic and epigenomic alterations, The Cancer Genome Atlas (TCGA) research program proposes four molecular subtypes of GC: Epstein-Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN) . These fTo date, only three molecular biomarkers have been demonstrated to predict responses to targeted therapies in GC : human eIn this review, we describe the key biomarkers in GC along with their clinical significance, detection methods, limitations, associated predictive markers, and targeted agents. In particular, we focused on well-established ) and emerging , fibroblast growth factor receptor 2 (FGFR2), Claudin 18.2 (CLDN18.2), and tumor-infiltrating lymphocytes (TIL)) biomarkers .Programmed death-1 (PD-1) is an inhibitory checkpoint receptor protein expressed on cytotoxic T cells and other immune cells . Some tuAs a biomarker, PD-L1 has some limitations that can affect its usefulness as a predictor of ICI response. One of these limitations is the intratumoral heterogeneity of PD-L1 expression. In GC, PD-L1 expression has been shown to display a high discordance rate not only between biopsy and surgically resected tissue but also between primary and metastatic tumors ,56,57. Tp = 0.0421) for advanced GC with a PD-L1 CPS ≥ 1 [p < 0.0001) [p < 0.0001, and PFS, HR 0.68, 98% CI 0.56–0.81; p < 0.0001). Additionally, patients with a PD-L1 CPS ≥ 1 showed a significant benefit for OS . These results indicate that nivolumab also provides greater efficacy and benefits in patients with a higher PD-L1 CPS.Monoclonal antibodies against PD-1 (pembrolizumab and nivolumab) have demonstrated efficacy in patients with advanced GC in large clinical trials. The Phase II KEYNOTE-59 trial showed durable responses to pembrolizumab treatment in patients with advanced or metastatic PD-L1+ GC . The tum CPS ≥ 1 . Nonethe CPS ≥ 1 . In the  0.0001) . The stu 0.0001) . The stuAnother reliable predictive biomarker for anti-PD-1 ICIs in GC is the molecular subtype. Kim et al. investigated the determinants of treatment response to pembrolizumab in metastatic GC patients according to TCGA molecular subtypes . PatientTIL is also a key biomarker that can be assessed in conjunction with PD-L1. Previous studies have reported that high TIL density and increased numbers of CD3+ or CD8+ T cells are associated with favorable prognoses in GC patients ,66. AddiHER2 is a member of the human epidermal growth factor receptor family  associated with tumor cell proliferation, adhesion, migration, and differentiation . Hetero-TP53, CDKN2A, PIK3CA, and KRAS mutations, are associated with HER2+ GC [CCNE1, PIK3CA, KRAS, CDK4, and CDK6 genes [TP53 mutation and CCNE1 amplification were the most commonly identified single nucleotide variants and copy number alterations, respectively, in these studies. The alterations of TP53 and CCNE1 were more significant in HER2+ GC than in HER2- GC [Overexpression/amplification of HER2 has been identified in 7–53% of GC cases and varies between studies ,75,76. OHER2+ GC ,17. AddiK6 genes ,17. TP53HER2 gene amplification status in cases of equivocal HER2 staining (IHC 2+). ISH results are considered to be positive when the HER2/chromosome enumeration probe 17 (HER2/CEP17) ratio is greater than 2. If CEP17 polysomy (≥ 3 copies of CEP17) presents with HER2/CEP17 < 2, then HER2 ≥ 6 is considered to represent ISH positivity [Currently, IHC and in situ hybridization (ISH) are recommended for the detection of HER2 overexpression/amplification . HER2 imsitivity .HER2 amplification by next-generation sequencing (NGS) [A major limitation of these slide-based HER2 assays is the intratumoral heterogeneity of HER2. Heterogenous HER2 overexpression is common in GC and has been reported to be present in 33–52% of cases ,74,76. Tp = 0.0046) [p = 0.01). The FDA approved trastuzumab-deruxtecan for HER2+ G/GEJ cancer based on these findings.Of the various biomarkers in use, HER2 overexpression/amplification is particularly important in GC because the targeted therapy trastuzumab is well-established for the treatment of HER2+ GC . Trastuz 0.0046) . Based o 0.0046) . The patPIK3CA signaling pathway , and (3) concurrent amplification of EGFR, MET, and CCNE1 [However, several HER2-targeting agents other than trastuzumab, including lapatinib, pertuzumab, and trastuzumab-emtansine, used as first- or second-line treatments failed to improve clinical outcomes in HER2+ GC patients ,80. The nd CCNE1 . Novel Hnd CCNE1 ,80. In fA recent phase III trial (KEYNOTE-811) reported that pembrolizumab could benefit patients with HER2+ GC . In KEYNVEGFR2 is a receptor tyrosine kinase which regulates angiogenesis. Activation of the VEGFR2 signaling pathway contributes to new vessel formations to promote the transportation of nutrients, oxygen, and growth factors necessary for tumor survival, proliferation, and metastasis . In GC, p = 0.047) in previously treated advanced G/GEJ adenocarcinoma [p = 0.017) compared to that of the placebo plus paclitaxel [p = 0.015) compared to that of the placebo in previously treated, biomarker-unselected patients with G/GEJ cancer in a randomized phase III trial from China [Ramucirumab is a human IgG1 monoclonal antibody against VEGFR2 which prevents ligand binding and activation signaling pathways in endothelial cells . Two phaarcinoma . Similarclitaxel . It is nom China . Howeverom China . Anotherom China . FruquinFuchs et al. retrospectively analyzed the predictive biomarkers in REGARD G/GEJ carcinoma patients . They inMET proto-oncogene encodes a receptor tyrosine kinase protein called hepatocyte growth factor (HGF) [The or (HGF) . MET actor (HGF) . Thus, tor (HGF) . MET oveor (HGF) ,27,29.MET gene is rare (~4%) [p < 0.0001), increased copy number gain , and MET gene amplification in GC [MET exon 14 skipping mutation is another mechanism that can result in discordance between protein overexpression and low gene amplification [MET exon 14 skipping mutations was investigated in a series of 230 solid tumor specimens, including 42 GC specimens. A total of 13 out of 230 tumors (5.7%) and 3 out of 42 GC (7.1%) had MET exon 14 skipping mutations. Notably, MET protein overexpression by IHC was identified in all MET exon 14-positive cases, whereas gene amplification was reported in only one case [In GC, MET protein overexpression, as determined by IHC, has been observed in up to 63% of cases , whereasre (~4%) , which ron in GC . Applicafication . This muone case .MET gene amplification  examination) as criteria to select patients who were eligible for MET-targeted therapies. Several trials have evaluated the efficacy of monoclonal antibodies that target MET in patients with advanced or metastatic MET+ GC. Onartuzumab and rilotumumab, which target MET and MET-ligand HGF, respectively, have been used in phase III trials as first-line treatment in combination with conventional chemotherapy but failed to improve the clinical outcome of GC patients with MET overexpression [Clinical trials have used both MET protein expression level (by IHC) and pression ,96. In apression . In thesMET gene amplification in a phase II trial [MET-amplified cancer cells and in GC patients in phase II VIKTORY umbrella trials [MET amplification had high response rates  to savolitinib monotherapy, and 70% of the responders had an enhanced MET copy number (>10 copies) [MET amplification, resulted in a short response or no response to savolitinib [MET-amplified NSCLC demonstrated that a high-level amplification group (MET/CEP7 ratio ≥ 4) responded to crizotinib with the highest ORR compared to medium- or low-level groups [MET amplification (≥6 copies), and the best ORR was 55.6% (95% CI 21.2–86.3), with a median PFS of 3.2 months (95% CI 1.0–5.4) and an OS of 8.1 months (95% CI 1.7–24.6) [MET exon 14 can be a potential candidate for targeted treatment. Two MET-TKIs, capmatinib and tepotinib, were approved in 2020 for the treatment of NSCLC harboring MET exon 14 skipping mutations [MET exon 14 mutations, targeted agents for this unique alteration may provide clinicians and patients with new treatment strategies.Additionally, selective MET-TKIs have been studied in GC patients. A highly selective small-molecule MET inhibitor, AMG 337, showed 18% ORR in advanced G/GEJ cancer patients with II trial . Savolita trials . In the  copies) . The stuolitinib . Thus, tolitinib ,99. A stl groups . In GC, .7–24.6) . Additioutations . In GC, FGFR2, including amplification, point mutation, and oncogenic fusions, have been identified in various types of cancers, including GC [FGFR2 gene amplification is known to be a poor prognostic factor in GC patients, and a high copy number (≥30) is significantly associated with a shorter PFS and OS [FGFR2 amplification is rare in GC, which varied from 4 to 7% in previous studies, depending on the country [FGFR2 is a member of the fibroblast growth factor receptor (FGFR) family of transmembrane tyrosine kinase receptors that regulate cell survival, differentiation, and proliferation ,103. Genuding GC . Among tS and OS . The pre country ,39.FGFR2 amplification is usually performed at the molecular level by ISH or NGS. These molecular-based analyses are time-consuming and expensive as screening methods. Considering the low frequency of FGFR2 amplification and its poor concordance with FGFR2 mRNA expression [FGFR2 copy number alterations with high sensitivity and specificity [FGFR2 gene amplification [Detection of pression , IHC coucificity . Membranfication . Hence, FGFR2 amplification may play a crucial role in tumor progression and lymphangitic metastasis in GC. Thus, tissue acquisition from distant metastases or primary tumors with extensive lymphovascular invasion could be adequate to accurately assay FGFR2 by IHC.Intratumoral heterogeneity of FGFR2b protein expression is frequent and has been observed in 55.5% of GC cases . InteresFGFR2-amplified GC cell lines and in patient-derived xenograft models [FGFR2 amplification or polysomy did not find that there was a survival benefit in the AZD4547 arm [FGFR2 gene amplification in a phase II clinical trial  [FGFR2 amplification (detected by circulating tumor DNA) were included and treated with bemarituzumab in combination with mFOLFOX6 as a first-line therapy, and the survival outcome was compared to the mFOLFOX6 plus placebo group. The median PFS was increased to 9.5 months in the bemarituzumab-treated patients compared to 7.4 months in the placebo group . The bemarituzumab arm also showed an improved median OS of 19.2 months vs. 13.5 months for the placebo group . Interestingly, in a subset of patients with ≥10% FGFR2b overexpression by IHC, the median OS for the bemarituzumab arm was 25.4 months compared to 11.1 months for the placebo  [Preclinical studies have shown that AZD4547, a selective TKI of FGFR1, 2, and 3, has antitumor activity in t models ,108. How4547 arm . RecentlT trial) . In the 23–0.74) . This fiCLDN18-ARHGAP fusion, is known to be associated with CLDN18.2 expression in GC [CLDN18-ARHGAP26/6 fusion has been detected in up to 15% of G/GEJ cancer patients, predominantly in the GS subtype and among young patients with poor prognoses [CLDN18-ARHGAP fusion-positive GCs [Claudin family proteins are one of the main components of tight junction complexes . Aberranon in GC . The chion in GC ,118,119.on in GC ,118,119.rognoses ,117. CLDtive GCs . In GC, tive GCs ,121,122.tive GCs ,42,43. Ative GCs ,124.p < 0.0005) and OS  of the patients compared to chemotherapy alone [Zolbetuximab is a chimeric IgG1 monoclonal antibody that binds to CLDN18.2 molecules on the tumor cell surface and induces antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity ,45. Two py alone . Based opy alone ,126.p < 0.0005) than in the overall population [In previous studies, CLDN18.2 expression in tumor cells was only determined by IHC . Membranpulation . Similarpulation . The ongpulation ,126. TheAberrant nuclear or cytoplasmic CLDN18.2 expression in IHC, as well as heterogeneity, is frequent in GC ,42. StroThe significance of TIL as a predictive biomarker for immunotherapy was briefly discussed in the PD-L1 section. An increased number of TILs is frequently identified in EBV+ and MSI-H GC and is associated with a favorable response to ICI treatment and prolonged OS. A recent study investigated the distinct immunological profiles of GC using TCGA data . EBV+ anA novel potent strategy, called TIL therapy, is based on adoptive cell therapy using TILs ,49. For Several trials have reported the clinical benefits of TIL therapy, mainly in metastatic melanoma ,48. A reWe reviewed the established and emerging biomarkers for GC treatment. GC is a histologically, molecularly, and immunologically heterogeneous disease. Various targeted therapies and biomarkers have been discovered based on an in-depth understanding of tumor molecular biology. Recent studies of the tumor immune microenvironment have also contributed to accurate predictions of chemotherapy and immunotherapy responses in GC. Targeted therapies for PD-L1 and HER2 have shown significant survival benefits in advanced GC patients with well-established diagnostic criteria. Anti-angiogenic therapy has demonstrated its efficacy in unselected patients, but additional predictive markers for treatment response should be further explored. Therapeutic agents targeting emerging biomarkers have remarkably improved patient survival or have achieved high ORR in clinical trials, but standardized diagnostic methods and interpretation guidelines should be established. Understanding the mechanisms of biomarkers, current diagnostic methods with limitations, and their implications for targeted therapy response is crucial in precision medicine. Comprehensive examination of these biomarkers in GC can provide better patient stratification and selection, allowing them to benefit from specific targeted therapies.


Antibiotic stewardship in medical institutions attempts to change the antibiotic prescribing “behaviors” and “habits” of physicians. Interventions abound targeting “problem prescribers,” or those physicians whose practice is out of line with physician peers. Thus, the locus of decision-making in antibiotic prescribing is thought to be the found with the individual physician. Based on 18 months of participant observation and in-depth interviewing of antibiotic-prescribing physicians at two medical institutions in the United States, this paper will question notions of antibiotic stewardship that center on individual “behaviors” and “habits.” Many physicians have taken to heart a reductionist approach in studies of antibiotic prescribing, including several physicians I encountered during research who enthusiastically located the benefit of my research in the ability to identify “what's wrong with us.” In this paper, I use two representative ethnographic case studies to argue that antibiotic stewardship interventions aimed at identifying and correcting “bad” physician practice limit the possibilities of understanding the social dynamics of the institution. Through an analysis of everyday encounters in the hospital setting, I show how decision-making in antibiotic prescribing can more productively be located between and among institutions, physicians, patient charts, and other hospital-based staff members . By demonstrating that  Antibiotic stewardship is very complex. Half of it is psychology. How do you make people do what they don't want to do? This is not medicine, it's not evidence-based medicine which is the thrust of what we were trained to do. I feel sometimes like a salesperson figuring out how people think. I don't understand this. This is a completely different field.” -Infectious disease practitioner“Antibiotic resistance is a global threat to our health and well-being. Though resistance to antibiotics is not a new phenomenon, only recently have countries like the United States begun to take on antibiotic oversight as one of the defining issues of our time. In recent approaches to combating antibiotic resistance in the United States, there has been a central focus on the policy of antimicrobial or antibiotic stewardship—the responsible use of antibiotics. Antibiotics are overused and misused on a regular basis, and thus antibiotic stewardship endeavors to bring errant use of antibiotics into line with appropriate practice.In attempts to correct inappropriate practice, antibiotic stewardship teamsantibiotic prescribing is a collective practice occurring through engagement with social and material surroundings.Through the use of ethnographic data collected during fieldwork at two medical institutions in an urban midwestern setting in the United States, I will demonstrate how individual physicians operate within a complex web of relationships and institutional protocols that emphasize the distributed, collective nature of antibiotic prescribing. I will use two representative ethnographic case studies to show that Social science research has established that there is a myriad of factors, such as professional influence  has published several guidelines for antibiotic stewardship in medical institutions including hospitals  of their colleagues in the direction of becoming stewards of antibiotics, meaning that they utilize antibiotics responsibly. “Problem physicians,” on the other hand, resist the advances of “champions” and continue prescribing antibiotics according to their own logics. While “problem physicians” are not seen as problematic by the institution as a whole, they are considered barriers to the implementation of antibiotic stewardship.The heart of the social dynamics of antibiotic stewardship in the United States is the idea that “good behavior,” which here means responsible antibiotic use, can be achieved through careful, targeted attempts at changing the prescribing habits of other physicians. The focus is on bringing outlier physicians more in line with the prescribing habits of a department or division of the medical institution. For example, in the surgery department an individual is overprescribing cefazolin, giving two times the amount of antibiotic compared with their peers. This individual becomes a “problem physician” to the antibiotic stewardship program that is succeeding with the other physicians in the department but is not seeing change in this prescriber. According to the principles of behavioral economics and behavioral psychology, this individual can be brought into line with their peers through the utilization of “nudges” . Importantly, these interrelated factors do not simply constitute context but influence understandings and behaviors of the individuals involved. In the following section, I introduce my fieldsite and describe the understandings of antibiotic stewardship leaders and antibiotic prescribing physicians at this site. By illuminating the social dynamics of antibiotic practice, I will show how antibiotic stewardship targeted at individual behavior is a reductionist approach that does not do justice to the real contexts of antibiotic use, leaving corresponding antibiotic stewardship interventions prone to failure.The research for this paper was conducted over an 18 months period at two adjacent medical institutions in the United States with outside support from the Wenner-Gren Foundation for Anthropological Research. The objective of the research was to understand antibiotic prescribing among hospital-based physicians. This objective was achieved by conducting participant observation and semi-structured interviews with specialists in infectious diseases (infectious disease practitioners and antibiotic stewards) and antibiotic prescribing non-specialists (intensive care unit practitioners). Ethnographic methods were chosen to illuminate the social milieu of the hospital through close observation and careful attention to cultural norms. Over 520 h of participant observation and over 39 h of semi-structured interviews were completed between July 2017, and December 2018.Two adjacent medical institutions in an urban midwestern city in the United States were chosen for this research. The first is a public teaching hospital with an over 20 years history of antibiotic control and antibiotic stewardship programs. The public teaching hospital shared an infectious disease fellowship program with the second institution, a private academic medical center with a more recent entrée into the world of antibiotic stewardship. The private academic medical center is a nationally-recognized center for orthopedic and geriatric care. Together, these institutions comprise a center for antibiotic stewardship as designated by the Centers for Disease Control and Prevention. This study is based at a single site for the purposes of analyzing specific iterations of antibiotic stewardship at a well-known duo of institutions, thus limiting the breadth of the study while allowing for a more in-depth look at local practice.As the researcher leading this study, I contacted infectious disease practitioners directly according to patient rounding schedules for the infectious disease consult service in the months of July 2017—January 2018. Once practitioners provided verbal consent, I joined individual infectious disease consult teams for their 2 weeks patient service. In total eight services were observed. Following the initial period of participant observation, I interviewed 25 infectious disease practitioners . Though some interviewed participants were also observed in the first part of the study, select additional participants were added based on their research interests and involvement in antibiotic stewardship.For the intensive care unit practitioners, similar methods were utilized. I contacted surgical intensive care unit practitioners directly according to patient rounding schedules for 1 week services in the months of April 2018—June 2018. Once practitioners provided verbal consent, I joined individual surgical intensive care unit consult teams for their 1 week patient services. In total 10 services were observed. At the end of each 1 week service I arranged to conduct a semi-structured interview with the attending practitioner (surgeon or anesthesiologist) and their physician fellow. The schedules for physician fellows follow a 1 month rotation, therefore fewer physician fellows were included in the study compared with attending practitioners.For all periods of data collection, fieldnotes were taken during participant observation. At the end of every day, fieldnotes were typed into a document held within a qualitative analysis software (MAXQDA). Semi-structured interviews were recorded and transcribed at a later date. Thematic coding Gibbs,  of typedEthical approval for the study was received prior to the start of data collection. All participants were informed about the research. All participants including the practitioners quoted in this paper provided verbal consent prior to involvement in the study and were informed that by giving their consent they may be included in a future publication of the study results. Furthermore, all participants were informed that they were free to leave the study at any point including during a scheduled interview. Participants mentioned in this article have been given pseudonyms used throughout the text as a safeguard to protect anonymity. The names of the medical institutions involved in this study are not disclosed to further protect the anonymity of participants.This ethnographic research focused on two medical institutions in the same urban area of the United States. Therefore, suburban or rural medical institutions were not included in the data collection. Additionally, antibiotic use varies regionally and this research was conducted in a single region of the United States. Though this study did not aim to include these variables in the data collection, future research is needed to address how social dynamics are altered based on geographic region and type of medical institution.The following ethnographic case study shows that antibiotic stewardship is predicated on the notion that improving antibiotic use necessitates altering the mindsets, thoughts, and behaviors of individual antibiotic prescribers. The former Chair of the Division of Infectious Diseases had increased the visibility of antibiotic control programs, and later antibiotic stewardship, in the institution. An early committee on the subject had made a simple antibiotic switch that saved the hospital system millions. Successes such as these gave antibiotic stewardship notoriety amongst hospital system heads. The current chair, Dr. Martin, had been at his post for the past 5 years, and was attempting to increase the efficacy of antibiotic stewardship by fostering collaborative relationships with “champions” in diverse specialties. I met regularly with Dr. Martin in the early days of my ethnographic fieldwork. He explained, “For your champions, they have to be willing to say “This is not right.” They get to influence their colleagues, their patients, all the people they work with. They get to really champion that (good antibiotic use).” For example, the infectious disease pharmacist who often made calls for antibiotic stewardship purposes was improving the chain of communication to floor pharmacists who managed certain areas of the hospital . Infectious diseases fellows were also involved in antibiotic stewardship, doing daily reviews of not only their own patient lists but antibiotic stewardship-specific lists. One such list involved all new cases of bacteremia (the presence of bacteria in the bloodstream) in the institution, which infectious disease fellows reviewed for antibiotic appropriateness and the potential need for an infectious disease consultation request. These additional pharmacists and fellows, through their involvement in antibiotic oversight, were recognized as antibiotic stewardship “champions.”The general approach to antibiotic stewardship on a practical level was to find errors in the data  and correct the error by speaking personally or through a formal channel such as consultation with the individual who had committed the error. I found it was a search and change mission that focused its efforts at ground level or the individual behaviors and habits of physicians. Throughout the course of my fieldwork, when trends became obvious to those on the antibiotic stewardship team, some additional steps might be taken such as giving a morning lecture to the targeted specialty or having a one-on-one conversation with the head of the targeted specialty. Additional methods of correction involve monitoring and restricting which antibiotics are available for use in the institution. By controlling the menu of antibiotic options for physicians, the stage is already set for a decision concordant with antibiotic stewardship policy. In other words, the behind-the-scenes work done by antibiotic stewards like Dr. Martin impacted the menu of options for physicians attempting to prescribe antibiotics.When antibiotic stewardship approaches still fails to create change among other physicians, the individual physician mindsets and thought processes are thought to be at fault. An antibiotic steward described the limits to her involvement in a patient case:“In the outpatient setting, you come in with a cold, you come in with a runny nose and a sore throat and a cough and you want antibiotics? There's no benefit. No! I'm not doing it. But in the inpatient setting it's not that cut and dried. It's not a “Yes” or “No.” There's so much gray. I've heard physicians say, “But is there a possibility that they would do better on the antibiotic? Because if there's even the slightest possibility then we'll give it.” It frustrates me because we don't live in a world of zero risk, you know, everything has a possible benefit and a possible risk. So we as individuals need to determine how comfortable we are with those possibilities.”Here, again, the individual physician is seen as the deciding factor for antibiotic use. Antibiotic stewards in my research emphasize good decision making among individual prescribing physicians as an ultimate goal of their practice. For example, Dr. Martin invited me to observe a talk he gave to the obstetrics and gynecology group of the institution in late July. Here, he talked about having the capability of deciding for oneself when to switch antibiotics. “You have to decide, because it is your practice”In fact, Dr. Martin often approached conversations about antibiotic stewardship from the perspective displayed above. “What's wrong with us?” Dr. Martin asked me 1 day before an antibiotic stewardship meeting as he gestured toward the other individuals in the room. He continued in this vein. “We want to learn about how we can improve our (antibiotic stewardship) program…because I do think it is all in here (he points at his head).” It was not uncommon at my fieldsite for physicians to question their own behavior, though certainly it was more common to question the behavior of others they interact with. However, what Dr. Martin identifies as the error in this case is the behavior or himself and others as individuals. He assumes that the error is behavior affected by the mind in a negative way. The something wrong, here, is guiding individuals in the wrong direction, away from appropriate antibiotic use. According to this framework, altering the mindsets of individuals would thereby create change at the level of antibiotic prescribing. “What I want to do,” Dr. Martin says, “Is find out what it is that makes a physician behave the way they do. Mindsets, concepts, whatever it is so that we (the antibiotic stewardship team) can intervene and improve (antibiotic) stewardship.” The day Dr. Martin lectured to obstetricians and gynecologists in late July, he was intervening where he saw the error occurring, which was at the individual level. In the next section, I will show how the focus on individuals and individual behavior eschews understandings of antibiotic prescribing practice as a collective practice occurring within weighted institutional contexts.whipples (patients who have undergone a Whipple procedure) 7 days so let's make sure we do that.” Another day in the unit, a different physician commented, “Dr. Kline is particular about pain control—ask him what he wants.” My notes continually referred to Dr. Kline as a surgeon with peculiar preferences for his patients, a “problem physician” who ensures their preferences are enacted.This ethnographic case study demonstrates how antibiotic decision-making in the surgical intensive care unit is carried out across multiple individuals and teams, thereby illuminating the limitations of a framing of antibiotic stewardship that focuses on individual behaviors. Surgeons at my fieldsite, as they are in much of the world, were known for their stubborn nature. Throughout my fieldwork, each medical institution had particular surgeons known to all rotating physicians. Certain names kept coming up in my notes. One recurring figure was Dr. Kline. The physician I was observing 1 week said, “Dr. Kline keeps One morning I was part of the group of resident physicians rounding with Dr. Tuttle on the surgical intensive care unit. These patients had undergone surgery and were not yet stable enough to begin recovery on the hospital floors or at home. Dr. Tuttle's team oversees the care of these patients and collaborates with the operating surgeons to decide trajectories for each patient's care. As we walk the floors that morning, I notice the following interaction unfold: Dr. Tuttle is engaged in conversation with the resident physicians as they discuss Mrs. Rodriguez, the current patient. Dr. Tuttle asks about fluids, chastising the resident physicians for not being more vigilant. “Fluids are like a vital in the intensive care unit, you need to trend those.” The new bacterial cultures were in, the resident physician copies down the results from the computer-on-wheels and conveys the message to Dr. Tuttle. The cultures showed growth, and the patient had a fever and hypotension. Now, vancomycin, cefepime, metronidazole,We continued rounding on patients for another hour and a half. Later in the morning, as rounds died down, Sarah the team pharmacist checked in with the resident physicians. She clarified the dose and duration of antibiotics for several patients, including Mrs. Rodriguez. For Mrs. Rodriguez, Sarah left two options. If Dr. Kline does want to change the antibiotics, it'll be to this combination and this duration (Sarah put a paper down in front of the resident). If Dr. Kline doesn't want to change the antibiotics, go ahead and get rid of the micafungin. Either way, she instructed the resident physician, “Check in with me before you enter the changes.”Dr. Tuttle and Sarah broke off to go to meetings while the resident physicians headed back to the work room to write their notes. I would often stay and write notes alongside the residents. After an hour of working independently, the resident physician in charge of Mrs. Rodriguez's case, Steve, picked up the work room phone and called one of Dr. Kline's resident physicians. Steve brought up the new bacterial culture results, Dr. Kline's resident physician confirmed that they've seen them. But there was a holdup. Unfortunately, Dr. Kline was in surgery at that moment. The choice was to try to reach Dr. Kline or move forward without his input. Dr. Kline's resident physician didn't ask to wait until Dr. Kline was out of surgery. Instead, with the bacterial culture results at hand Dr. Kline's resident physician decided that getting rid of micafungin was a good plan. There was no discussion of duration. Steve nodded, then confirmed the other antibiotics: vancomycin, cefepime, and metronidazole. Already, Dr. Tuttle's team was not solely responsible for the prescription of antibiotics for Mrs. Rodriguez. Steve, through his conversation with Dr. Kline's resident, had ensured that additional teams were involved.The resident physicians continued working for another hour, then we broke for lunch. I returned to the work room at 1 p.m. to a new update in Mrs. Rodriguez's case. The infectious diseases consulting team on her case had put their notes in the medical record. This team commented on bacterial cultures, antibiotic selection, and antibiotic duration, among other specialty-related topics. The infectious diseases recommendations suggested that removing micafungin is indeed the first step for Mrs. Rodriguez. However, the infectious diseases consult team also recommended removing metronidazole on the basis that the bacterial culture results did not show evidence of microbes that would be targeted with metronidazole, thus rendering it useless in Mrs. Rodriguez's case. Finally, the infectious disease consult team suggested only two additional days of antibiotic, arguing that the patient had already received 3 days and a total of 5 days was all that was necessary per the institution recommendations. Now, even more input had been solicited for Mrs. Rodriguez's case. The expanding number of individuals involved in the decision-making had reached well-beyond the original prescribing physician.At this point, Steve had gathered information from various teams regarding Mrs. Rodriguez's antibiotics. He wrote up his note in a hurry, he was being called in to another patient's room. The note was entered into the medical record, though the recommendations in his note were not put into action. Further action was required. Dr. Tuttle settled the case by signing the patient note and recommendations at just after 5 p.m. It was one of the last notes that she signed for the day. The completed recommendation? Dr. Tuttle commented that she agreed with Steve's characterization of the case and updates for the day. The antibiotics that will continue into tomorrow include vancomycin and cefepime, but not metronidazole or micafungin. Steve had written that the duration of antibiotics would total 7 days, or four additional days from the current date. Dr. Tuttle signed off on this duration. In the beginning, we have one team, even one physician, suggesting the course of action for a patient. Often, initial reactions like the one from Dr. Tuttle are taken as the most significant behavior in antibiotic decision-making. However, as I demonstrate here, this initial reaction was not the final say. In fact, the number of individuals involved expanded to include multiple teams. Later, the number of individuals shrunk again until the final action in the case was made: Dr. Tuttle signed the antibiotic recommendations.In “Encountering Local Antibiotic Stewards,” Dr. Martin searches for the reasons behind individual physician “behaviors” and “habits.” With his research agenda, Dr. Martin is determined to identify and ultimately change individual prescribers to come more in line with antibiotic stewardship recommendations. With the obstetrics and gynecology group, Dr. Martin attempts to reinforce the physicians' power and responsibility to prescribe appropriately, telling them “…it's your practice.” He walks through case studies of obstetrics and gynecology patients where antibiotics were prescribed and poses questions to the practice group about what antibiotic they would choose. By retraining the physicians, Dr. Martin is addressing what he sees to be the underlying concern with antibiotic overuse and misuse: there is something wrong with us.Dr. Martin is ultimately interested in improving antibiotic stewardship at the medical institution where he works. Both segments of the literature , the outcome could have been different. Additionally, had the team had several days to ruminate over the antibiotic choices, the outcome could have been different. During my research, I was constantly aware of the time pressures that physicians were placed under. Since notes in the medical record must be signed within the time limit set by insurance companies, notes end up getting signed by end of day (or night). Thus, the requirements of the structure of medical practice also shape the manner in which antibiotic decisions are made.In the context of the tendency of antibiotic stewards to locate the power of decision making within individual physicians, and in light of evidence to the contrary, a deeper analysis of the data reveals complex social dynamics and institutional structures of practice that are otherwise invisible. There has been emphasis placed on the “behaviors” and “habits” of antibiotic prescribers that hinder antibiotic stewardship such as “defensive prescribing”  how entrenched the idea of individual prescribers is at my field site, and (2) how difficult it is to give credit to a single prescriber given the other individuals and institutional surroundings that direct decision making. Thus, while the antibiotic steward's understanding of the way to change physician prescribing behavior follows the tenets of behavioral economics and social psychology suggesting that problems are the result of individuals making bad choices, I have argued here using iterative and inductive research (cf. Karen O'Reilly, Dr. Martin's perspective presented in this article is not unique among antibiotic stewards. In fact, it was the common view at my field site. In conclusion, I argue that while antibiotic stewardship programs often target individual physician prescribers, To optimize antibiotic use, antibiotic stewardship programs must appreciate the historic lack of input from the social sciences (particularly the qualitative social sciences, see Smith, The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by The Institutional Review Board of John H. Stroger Jr. Hospital of Cook County. Written informed consent for participation was not required for this study in accordance with institutional requirements.KR conducted the research for and wrote this article in its entirety.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The concrete cover is the basic protection of the reinforcement against the influence of external factors that may lead to its corrosion. Its effectiveness depends mainly on the composition of the concrete mix, including the cement used. Depending on external environmental factors that may aggressively affect the structure, various types of cements and concrete admixtures are recommended. The paper presents the results of tests that allow us to assess the effect of the type of cement used and the air-entraining agent on the effectiveness of the concrete cover as a layer protecting the reinforcement against corrosion. In order to initiate the corrosion process, the reinforced concrete specimens were subjected to cycles of freezing and thawing in a sodium chloride solution. The degree of advancement of the corrosion process was investigated using the electrochemical galvanostatic pulse technique. Additionally, the microstructure of specimens taken from the cover was observed under a scanning electron microscope. The research has shown that in the situation of simultaneous action of chloride ions and freezing cycles, in order to effectively protect the reinforcement against corrosion, the application of both blast-furnace slag cement and an air-entraining agent performed the best. Reinforcement corrosion is the main reason for reducing the durability of reinforced concrete structures ,2,3,4,5.For the above reasons, despite the increasing use of non-metallic reinforcement, the use of black steel is still the most popular in concrete structures. It is also important from the point of view of the existing elements of the structures. Therefore, solutions are still being sought that allow the most effective protection of this type of reinforcement against the influence of negative environmental factors that may lead to the development of corrosion on the surface of reinforcing bars ,17,18,19For structures where carbonation is the main risk, Portland cement is used for concrete. In concretes with Portland cement, the carbonation process is slower than in concretes with other types of cement, due to the higher content of calcium hydroxide, which is formed in the hydration of calcium silicates from Portland clinker ,21,22.3A compared to Portland cement [2, diffusion, and the corrosion of the reinforcement is severe [However, in concrete structures that may be exposed to chemical aggression, it is recommended to use the blast-furnace slag cements or cement with supplementary cementitious materials for concrete  and somed cement , the cond cement ,24,25,26s severe ,29,30,31Damage to the concrete cover and, consequently, an increase in the probability of corrosion of the reinforcement, may occur as a result of frost and cycled freezing and thawing of the liquid in the concrete pores. The internal stresses that arises can lead to numerous microcracks in the lagging, which reduces its tightness ,32,33,34Despite many publications on the protection of reinforcement in reinforced concrete structures against aggressive environmental factors (that may lead to the initiation and development of reinforcement corrosion) only a few concern research on the simultaneous effect of chloride ions and frost and are usually based on studies of real structures ,31. In tThe tests were performed using the non-destructive electrochemical galvanostatic pulse technique ,37,38,39(a)C_I_a specimens—specimens made of concrete with Portland cement and the addition of an air-entraining agent;(b)C_I_n specimens—specimens made of concrete with Portland cement, without the addition of an air-entraining agent;(c)C_III_a specimens—specimens made of concrete with blast-furnace slag cement and the addition of an air-entraining agent;(d)C_III_n specimens—specimens made of concrete with blast-furnace slag cement, without the addition of an air-entraining agent.The tests were performed on reinforced concrete specimens. The concrete mix was prepared using alternatively two types of cements: Portland cement  or blast furnace slag cement . Moreover, in both groups of specimens made with different cements, an air-entraining agent was used in half of them. In total, 24 specimens were used and divided into 4 groups, with 6 specimens in each group:3 are included in The components of a concrete mix for 1 mThe specimens were 210 mm × 228 mm × 100 mm. In each specimen, there were placed two parallel ribbed bars φ 8 mm diameter, made of BST 500 steel, placed 70 mm apart from the side edges of the specimen. The assumed cover was 25 mm .The specimens were made under identical conditions in the laboratory hall. The specimens were removed from the moulds the day after concreting and cured in water for a period of 14 days. After taking them out of the water, the specimens were stored in a laboratory hall at a temperature of 20 ± 2 °C and a relative humidity of 50 ± 5%. In order to initiate the corrosion process on the reinforcement, the samples were immersed in a 3% sodium chloride solution (3% NaCl) and simultaneously 120 cycles of freezing and thawing in a climatic chamber in temperature cycles from −18 to +18 °C.(a)stage I—reference measurements made 90 days after concreting the specimens, but before the freeze–thaw cycles;(b)stage II—measurements made 250 days after concreting the specimens, after 120 cycles of freezing and thawing.The measurements of estimating the size of the corrosion probability and the corrosive activity of the reinforcement included:The measurements were made using the non-destructive electrochemical galvanostatic pulse method. In addition, using a scanning electron microscope (SEM), the microstructure of selected specimens from each group was observed  after the freeze–thaw cycles.st), the resistivity of the concrete cover (Ɵ) measured on the concrete surface and the corrosion current density (icor). In order to measure the corrosion current density, it is necessary to polarize the reinforcing bar . Such a disturbance can be caused by an electrical impulse. Depending on the method of generating the pulse, different polarization methods have been developed. In the galvanostatic pulse method, the disturbance is generated by a current of a certain intensity.The non-destructive electrochemical galvanostatic pulse method is described in detail among others in ,39,45,46The measurements of the reinforcement steady-state potential and the concrete cover resistivity are called basic measurements. It should be noted that the values of these parameters are only estimates of the probability of the reinforcement corrosion risk in the investigated areas and the measurement results are not direct and are indications only, e.g., concrete cover resistivity depends significantly on the concrete composition on the top corrosion process .The so-called advanced measurements, which rely on additional measurements of the corrosion current density and make it possible to estimate the corrosive activity of the reinforcement and to predict its rate over time, are much more reliable.st), concrete cover resistivity (Θ) and the corrosion current density (icor). The main elements of the set include the control and recording device , silver-chloride reference electrode (Ag/AgCl) and calibration device. The elements of the set  fit into a medium-sized suitcase  set . This desuitcase a. The haMeasurements of the relevant parameters were performed at two measurement points for each rebar in each specimen. The measurement points were placed along the rebar position line at equal intervals every 70 mm b. Thus, The obtained results  were compared to the criteria for corrosion risk evaluation presented in Depending on the obtained values of the reinforcement half-cell potential and concrete cover resistivity, it was possible to conclude about the value of the corrosion probability of the reinforcement in the studied area, and on the basis of the value of the corrosion current density, it was possible to estimate the corrosion activity of the reinforcement. However, it should be noted that of the three parameters mentioned, the most reliable measurement is the corrosion current density, because this parameter is a direct measure of the corrosive activity of steel and allows us to estimate the rate of corrosion development on the tested rebar in relation to the current environmental conditions. The other two parameters, i.e., the half-cell potential of the reinforcement and the resistivity of the concrete cover, allow for an indirect and approximate estimation of the probability of corrosion in the area under investigation  indicating low corrosion activity. Such results may be related to the delayed setting time and the formation of a passive layer on reinforcement in concretes where the blast-furnace slag cement was used.The reference measurements (made before the specimens were subjected to freezing and thawing cycles) showed that the values of the corrosion current density measured at all the designated points in the specimens from groups C_I_a, C_I_n and C_III_a and in most points in the samples from the C_III_n group  were in cor = 5.0 μA/cm2  which indicated moderate corrosive activity. Only in four points did the corrosion current not density exceed icor = 4 μA/cm2.The results of the measurements performed after the completed 120 cycles of freezing and thawing the specimens in a 3% sodium chloride solution were already quite varied depending on what cement was used and whether or not an air-entraining agent was added. In samples C_I_a , in mostcor = 2.82 μA/cm2 to icor = 9.87 μA/cm2), but the results were more dispersive and there were more results with lower values than for the C_I_a specimens. The comparison of the results in both groups of specimens with a Portland cement shows that the use of an air-entraining agent does not reduce the corrosion activity of the reinforcement caused by the action of chlorides and frost. Moreover, in the C_I_n specimens (without the air-entraining agent), most of the results indicated lower corrosion activity of the reinforcement than in the C_I_a specimens. On the other hand, the addition of an air-entraining agent resulted in a more uniform corrosion activity of the reinforcement in the studied areas.In the second group of Portland cement specimens, C_I_n , in whiccor = 2.0 μA/cm2, which pointed to irrelevant corrosion activity of reinforcement. Only in eight points was the value of this parameter higher and equal to icor ≈ 3.3 ÷ 3.86 μA/cm2, which (despite a very aggressive corrosive environment) meant a low corrosion activity. The analysis of the results of the corrosion current density measurements carried out for specimens with blast-furnace slag cement showed that in C_III_a specimens, in which an air-entraining agent was used, the results of measurements of this parameter made after 120 cycles of freezing and thawing specimens in a 3% sodium chloride solution increased only slightly in relation to the reference measurements . At mostcor = 2.51 μA/cm2 to icor = 9.72 μA/cm2  turned out to be similar to the values obtained in the C_I_n specimens and amounted from i2 μA/cm2 . This prA similar analysis was performed based on the results of measurements of the reinforcement half-cell potential ; Table 4st = (−189 ÷ −300) mV, and were only five points lower than Est = −300 mV  performed after the specimens freezing and thawing cycles in a 3% NaCl solution, a clear influence of the air entraining agent on the reduction of the probability of rebars corrosion can be noticed. In C_I_a specimens (with Portland cement and an air-entraining agent), in most of the measurement points, the values of the reinforcement half-cell potential were E −300 mV , which m −300 mV . st = −300 mV, including 12 points lower than Est = −350 mV  were much lower—at 22 measurement points they exceeded E −350 mV , which ist = −200 mV  in almost all measurement points did not exceed E −200 mV , which ast ≈ −300 mV and lower, even reaching Est,2 = −521 mV , the values of the concrete cover resistivity obtained from the reference measurements were Θ = 1.2 ÷ 1.7 (kΩ·cm) and decreased slightly after the freezing cycles, to the value of Θ = 1.0 ÷ 1.6 (kΩ·cm) .However, in the specimens in which no air-entraining agent was used (C_I_n), the decrease in the value of the concrete cover resistivity was much greater: from: od Θ ≈ 1.2 (kΩ·cm) (reference measurements) to Θ ≈ 0.5 (kΩ·cm) (measurements after freezing cycles) as shown in The values of the concrete cover resistivity obtained from the measurements made on the specimens with blast-furnace slag cement were higher than for the samples with Portland cement. Reference measurements made on C_III_a specimens gave the values of Θ = 2.4 ÷ 3.9 (kΩ·cm) and fell after the freezing cycles to the value of Θ = 2.3 ÷ 3.2 (kΩ·cm) . On the other hand, in the specimens without an aerating agent (C_III_n), the difference between the reference values and those obtained after the freezing cycles was much greater, on average from Θ ≈ 3.5 (kΩ·cm) to Θ ≈ 1.8 (kΩ·cm) . Additionally, using a scanning electron microscope (SEM), the microstructure of concrete collected from the cover layer was observed for randomly selected samples from each group: C_I_a, C_I_n, C_III_a, C_III_n. In The paper presents tests that allow us to determine what type of cement (Portland cement or blast-furnace slag cement) and the addition of an air-entraining agent most effectively affect the properties of the concrete cover as a layer protecting the reinforcing bars against corrosion caused by the simultaneous action of chloride ions and frost.Based on the results obtained from the measurements of the corrosion current density (the most reliable parameter), it was found that after the specimens were subjected to 120 freezing and thawing cycles in a 3% NaCl solution, the lowest corrosion activity of the reinforcement was recorded on the reinforcement in C_III_a specimens, i.e., specimens made of concrete with blast-furnace slag cement and an air-entraining agent addition. On the other hand, the use of blast-furnace slag cement for concrete, but without adding an air-entraining agent (C_III_n specimens), although this cement should protect against chloride corrosion, does not reduce the corrosive activity of the reinforcement. The results obtained on C_III_n specimens are comparable to the results obtained on C_I_a and C_I_n specimens. On the other hand, concrete with the addition of an air-entraining agent in which Portland cement was used (C_I_a specimens) is not effective in protecting against the simultaneous effects of chloride corrosion and frost.The results obtained from the measurements of the reinforcement half-cell potential and the concrete cover resistivity were less reliable than the measurement of the corrosion current density and m might be influence by concrete mixture and age of evaluation. Nevertheless, they confirmed the previous analyses. Concrete in C_III_a specimens turned out to be more effective in reducing the probability of reinforcement corrosion.Moreover, it was found that the measurements of the concrete cover resistivity performed by the galvanostatic pulse method are not very reliable in the case of tests on young  specimens.The observation of the microstructure of concrete under a scanning electron microscope showed that the most compact structure is characterized by concrete with blast-furnace slag cement and the addition of an air-entraining agent taken from the C_III_a specimens.The assessment of the probability of corrosion in the tested specimens and the corrosion activity of the reinforcement were tested using the galvanostatic pulse technique. The use of this method made it possible to measure three parameters in a relatively uncomplicated and quick way, i.e., corrosion current density, half-cell potential of the reinforcement and resistivity of the concrete cover and the obtained values allowed for a comparative analysis of the tested specimens.


This research aimed to investigate the performance of prepacked aggregates fiber-reinforced concrete (PAFRC) with adequate acoustic characteristics for various applications. PAFRC is a newly developed concrete made by arranging and packing aggregates and short fibers in predetermined formworks, then inserting a grout mixture into the voids amongst the aggregate particles using a pump or gravity mechanism. After a one-year curing period, the effects of utilizing waste polypropylene (PP) fibers on the strength and acoustic characteristics of PAFRC mixes were examined. Compressive and tensile strengths, ultrasonic pulse velocity (UPV), sound absorption, and transmission loss were investigated on plain concrete and PAFRC mixtures comprising 0–1% PP fibers. The results revealed that the use of PP fibers slightly decreased the compressive strength and UPV of PAFRC mixes. The inclusion of waste PP fibers also significantly increased the tensile strength and sound insulation coefficient of PAFRC mixes, especially at higher fiber dosages. In the medium-to-high frequency ranges, more than 60% acoustic absorption coefficient was observed, indicating that PAFRC specimens have good sound insulation properties. In a modern lifestyle, noise is becoming a significant source of concern due to the adverse effects on many people’s lives in urban and rural regions. Noise pollution from various sources, such as cars, planes, power plants, and industry, is inconvenient and harmful to human health. As a result of these issues, considerable advancements in sound absorption materials, particularly in the construction sector, have occurred. There are several empirically verified constants for acoustic performance for homogeneous and isotropic materials, including absorption and reflection coefficients as well as acoustic impedance ,2,3. PreGrouting is done in one of two ways in the manufacturing of PAC—by gravity or by high-pressure injection pumps. Accordingly, the application and minimum aggregate size employed are essential factors to consider when selecting a proper technique for grouting amongst aggregates . As the Concrete comes in various forms, each with its characteristics that make it the most widely used construction material, including low cost, ease of development, and high compressive strength. However, when subjected to tensile loads, it performs poorly and exhibits brittle behavior. Furthermore, the performance of concrete components employed as sound and heat resistance materials is influenced by environmental circumstances, mechanical properties, and the components utilized in concrete . Thus, uResidents’ safety and well-being have become increasingly critical as the usage of structural concrete has increased. Concrete used as structural members must be adequately insulated against sound heat . ConsequFurthermore, with the advancement of non-destructive testing (NDT) technology and acoustic emission (AE) technique in terms of damage monitoring, recognition, and evaluation of concrete sound isolation property, the effects of fibers and their roles in a concrete matrix and the design of engineering structures have been investigated ,20,21,22Khankhaje et al.  pointed Karimipour et al.  also looThe effect of adding waste PP fibers on PAFRC’s acoustic characteristics was investigated to establish the possibility of adopting fiber enrichment as a noise reduction technique. As PP fibers are a waste product from the carpet industry, they are quite low priced, and their use has the added advantage of reducing environmental pollution. This research aims to determine the optimal amount of waste PP fibers necessary to enhance sound absorption in PAFRC concrete as a function of fiber content and grouting method across the frequency range of 0–4000 Hz.3 were used. The fibers used in this research are multi-filament PP fibers collected as waste fibers from carpet industries. Following the pre-mixes and the maximum aggregates, the fibers were cut at 30 mm and used in the main experiments. This study used ordinary Portland cement (OPC) to produce the high flowable grout mixture. Palm oil fuel ash (POFA) was also used as partial cement at the replacement level of 25%. POFA ashes were analyzed in accordance with ASTM C618-05 and categorized as class C ash. The properties and compositions of OPC and POFA are tabulated in PAFRC samples, unlike regular concrete, were produced in two stages. The necessary proportion of aggregates was mixed with the required dosage of PP fibers in the pan mixture as a dry mix. The aggregates and fibers were then positioned in the premeditated molds. After adequately placing aggregates, the grout mixture was injected into the molds, either by gravity or pump. This study used 5-mm diameter PVC pipes for the grouting procedure under gravity force and located at the center of cylindrical molds, as shown in NRC) is a single value that can be used to calculate a material’s ability to absorb sound, as shown in Equation (1) [α is the sound absorption coefficient at various frequencies.Furthermore, the cylindrical samples with sizes of 99 mm × 100 mm and 28 mm × 100 mm were utilized to assess the sound absorption coefficient, noise reduction, and transmission loss analyses of the PAFRC specimens. To this aim, an impedance tube test, as revealed in tion (1) . The souConcrete’s compressive and tensile strengths are essential for structural designs. 2. These SiO2 components react with hydration products from OPC and produce supplementary C-S-H gels at ultimate ages and, thus, enhance the strength performance of PAFRC mixes [Moreover, both the pumping and gravity mixes showed a similar compressive strength trend. The uniform and proper distribution of grout mixture through a pump with controlled pressure results in a high-quality matrix and, consequently, develops higher strength values than the gravity technique. In addition, the existence of POFA as partial cement in the grout mixture resulted in better matrix performance. It could be due to the pozzolanic behavior of POFA ashes, which contain a high amount of reactive SiORC mixes .The interaction of fiber effects such as crack propagation limitation and air void expansion could alter the compressive and tensile strengths of PAFRC mixtures. The addition of fibers could inhibit further cracks development and enhance tensile strength and ductility. The minimum and maximum enhancements in tensile strength of PAFRC mixtures with PP fibers, as shown in Non-destructive tests such as ultrasonic pulse velocity have been extensively used to evaluate long-term performance and monitor inner destruction progression in cement-based materials. An ultrasonic measurement on concrete should yield the speed and attenuation of longitudinal waves. The mechanical and durability properties, the microstructure of the matrix, the quality of bonds between components, and dispersed micro-damage all impact these ultrasonic parameters. Consequently, the observed ultrasonic waves speed and attenuation data can be used to evaluate the characteristics of concrete components during their service life. There have been few theoretical investigations into demonstrating ultrasonic waves propagation in the concrete matrix; ultrasonic research on concrete has traditionally been exclusively investigational, and hence, assessments based on ultrasonic testing have frequently been qualitative and data-driven .2) for this connection was 0.94 and 0.84 for the pumping and gravity groups, respectively, indicating a high level of confidence in the correlation amongst these two properties of PAFRC mixtures comprising PP fibers at various dosages. This correlation could be beneficial to monitor and predict the strength properties of concrete structures during their service life [The results demonstrated that the compressive strength and the UPV values followed the same pattern by adding PP fiber; hence, the results were correlated, as shown in ice life .Acoustic is the science and technology of sound in and around buildings. It investigates sound reflection, absorption, and insulation phenomena and uses what it learns for noise management and to design rooms with unique acoustic properties, such as concert halls and theaters. Sound insulation is perhaps the most common criterion to be met by practitioners. It is worth noting that many construction projects aim to improve their systems’ acoustic characteristics to the levels attained by concrete. In the past, the sound-insulating capabilities of walls were taken for granted. The sound absorption coefficient of a material, which is the incident sound energy that is absorbed by the medium and not reflected, determines how well it absorbs sound. The absorption coefficient of typical concrete ranges from 0.05 to 0.10. The sound absorption coefficient indicates how well concrete can inhibit sound transmission; a high number shows that concrete can effectively insulate sound . A standAs shown in 3, show substantial absorption at these low frequencies. When selective adsorption is required without affecting the remainder of the audible spectrum, the absorption between 1500 and 2500 Hz, which is thought to be the zone of highest frequency sensitivity for human hearing, is quite useful. One of these applications would be the absorption of road transportation in densely populated areas with speed limits of 40–50 km/h because the emission spectra for these infrastructures are characterized by significant tread noise in the medium and high-frequency bands [cy bands .NRCs for the mixtures reinforced with 1% PP fibers, for example, were 42.6% and 38.95% in the pumping and gravity procedures, respectively, which indicates the higher sound absorption properties of the reinforced specimens as compared to those of plain mixes with NRC values of 10.8% and 9.5%. The reinforced PAFRC mixes’ superior sound absorption ability could be due to the matrix’s linked fibers reflecting sound inside the voids [The noise reduction coefficient evaluated the sound absorption performance under various frequency circumstances. As revealed in he voids ,29. The 2) values more than 0.95. According to the findings, increased fiber doses improved the acoustic characteristics of the PAFRC blends. This result is consistent with Karimipour et al.’s [Furthermore, the inclusion of PP fibers shows that the concrete matrix and fibers are sufficiently bonded. The bundle of PP fibers provides good resistance against sound pollutions, resulting in increased sound absorption rates. Consequently, the sound began to vibrate and convert to heat . Furtheret al.’s  findingsNumerous noise sources depend on the application, and they all produce sound waves directly in the air. Airborne sound and structure carried sound is produced in residential buildings by above neighbors strolling across the floor, cellists, sanitary installations, and wall-mounted telephones. Vibrations are then sent straight to the structure . The sam2) values greater than 0.98. According to the findings, increasing the fiber dosages improved the acoustic properties of the PAFRC mixes. Furthermore, the density of a material has a substantial impact on TLC [3 decreases the density of the concrete matrix. It can be observed that with the addition of fibers and increase in fiber dosages, the TLC and STC of the reinforced PAFRC mixture significantly reduced. In this regard, Holmes et al. [t on TLC ,41,42. As et al.  looked aThe compressive strength of PAFRC mixes was marginally decreased when PP fibers were added, regardless of fiber dose. Due to the uniform circulation of grout under pressure, the pumping technique PAFRC specimens had greater strength values after one year of curing than the gravity technique PAFRC samples. Pozzolanic activity and hydration product development were both enhanced by the presence of POFA.The beneficial effect of PP fibers on improving the tensile strength was more considerable, likely owed to the bridging action and adequate bonding of fibers with the matrix. At one year of curing, the highest tensile strength of 5.2 MPa was recorded for the pumping method PAFRC mixture containing 0.6%, about 34% greater than that of 3.9 MPa noted for the plan mix.The attained UPV values for both grouting methods of PAFRC mixtures were recorded higher than 4400 m/s, indicating good quality concrete mixtures. Besides, the UPV and compressive strength values of PAFRC mixtures were correlated and demonstrated a linear relationship.The PAFRC mixes containing 0.2–1% PP fibers showed satisfactory sound absorption coefficients of up to 63% in the medium and high-frequency regions, which is comparatively higher than the 15% noted for the plain mixes. The average sound absorption and noise reduction of pumping group mixes were better than that of gravity method PAFRC mixes.The sound transmission class and sound transmission loss coefficient for PAFRC mixtures comprising PP fibers decreased associated with plain PAC mix. The function of fibers in the concrete matrix is to act as sound traps, and therefore, trap and absorb the sound that entered inside the matrix.The results of an experimental investigation into the mechanical and acoustic properties of PAFRC mixtures and how the combination of POFA and different dosages of PP fibers affect the performance of PAFRC are reported. Concerning the outcomes described in the current paper, the following conclusions could be drawn: