MET amplification detected by comprehensive genomic testing could be a good targeted option, although the prevalence is limited to less than 5% of all patients with gastric cancer.cMET is a proto-oncogene that has been extensively studied in gastric cancer. Gastric cancer (GC) is a heterogenous disease with varied histology and molecular profiling. It still implies a poor prognosis in stage IV. New targeted therapeutic options are being investigated. In this review, we analyzed all studies performed on gastric cancer with MET-inhibitors. In first-line therapy, the addition of MET-inhibition to chemotherapy did not show any benefit in allcomers. Different tyrosine kinase inhibitors (TKI) have been investigated in small cohorts with different diagnostic assays added to the inclusion criteria. Determining patients with gastric cancer who benefit from cMET inhibitors remains difficult. Potentially only Gastric cancer (GC) is an important cause of cancer worldwide with over one million new cases yearly. The vast majority of cases present in stage IV disease, and it still bears a poor prognosis. However, since 2010, progress has been made with the introduction of targeted therapies against HER2 and with checkpoint inhibitors (PDL1). More agents interfering with other targets  are being investigated. cMET is a less frequent molecular target that has been studied for gastric cancer. It is a proto-oncogene that leads to activation of the MAPK pathway and the PI3K pathway, which is responsible for activating the MTOR pathway. The prevalence of cMET is strongly debated as different techniques are being used to detect MET-driven tumors. Because of the difference in diagnostic assays, selecting patients who benefit from cMET inhibitors is difficult. In this review, we discuss the pathway of cMET, its clinical significance and the different diagnostic assays that are currently used, such as immunohistochemy (IHC), fluorescence in situ hybridization (FISH), the H-score and next-generation sequencing (NGS). Next, we discuss all the current data on cMET inhibitors in gastric cancer. Since the data on cMET inhibitors are very heterogenous, it is difficult to provide a general consensus on the outcome, as inclusion criteria differ between trials. Diagnosing cMET-driven gastric tumors is difficult, and potentially the only accurate determination of cMET overexpression/amplification may be next-generation sequencing (NGS). Gastric cancer (GC) is an important cause of cancer worldwide with over one million new cases per year and, in 2020, an estimated 769,000 deaths .Gastric adenocarcinoma is a heterogenous disease and is categorized in different subgroups based on histology , as well as on molecular profiling, microsatellite instability (MSI), Epstein–Barr virus (EBV), genomic stability (GS) and chromosomal instability (CIN). Apart from immunotherapy-sensitive MSI or EBV-driven gastric cancer, the prognosis in stage IV disease remains poor.The first-line standard of care therapy remains the doublet chemotherapeutic combination of platinum-based therapy  in combination with a fluoropyrimidine . Occasionally, a third cytotoxic agent is added . Over the last 15 years, molecular-driven targeted therapy has evolved rapidly. Patients with metastatic GC can be subdivided into two groups based on HER2 expression status: HER2 positive disease, meaning a 3+ score on protein immunohistochemistry (IHC) and a 2+ score on IHC followed by fluorescence in situ hybridization (FISH) of ≥2. For patients with HER2 positive disease, trastuzumab can be added to standard of care chemotherapy as the ToGA trial showed improved progression-free survival (PFS) and overall survival (OS) in HER2-positive patients [MET is a proto-oncogene which encodes for a transmembrane receptor with tyrosine kinase activity. In this review, we discuss how diagnostic testing of MET overexpression/amplification is performed in gastric cancer, and, next, provide an overview of all clinical studies that have been published with cMET inhibitors in gastric cancer.In 2015, VEGFR-2-inhibition was added in the second line with ramucirumab for gastric cancer in combination with paclitaxel . It showhttps://pubmed.ncbi.nlm.nih.gov/, accessed on 21 November 2022) as well as on clinical trials.gov  including cMET in gastric cancer. Search terms such as “Gastric cancer”, “cMET”, “gastro-esophageal cancer” and “c-MET” were used in different combinations. All background information regarding cMET was found by selecting articles from the search term: “cMET in gastric cancer” on Pubmed. From the 322 articles found, 51 were selected to include in this review.A literature search was performed of all studies published from 2008 until July 2022 on Pubmed  and a larger single-pass transmembrane beta-chain subunit (145 kDa). The extracellular domain contains three functional domains: the SEMA domain and the plexin-semaphoring-integrin (PSI) domain, together with four immunoglobulin-like regions in plexins and transcription factors (IPT 1–4). The intra-cellular part is subdivided into three domains: a juxtamembrane (JM) domain, a tyrosine kinase (TK) domain and a C-terminal multi-functional docking site (MFDS). These are all regulated by phosphorylation. Phosphorylation of the JM domain results in inhibition of the kinase domain and degradation of cMET, whereas phosphorylation of the TK domain results in upregulation of the kinase activity of cMET [osarcoma . The MET of cMET ,11.canonical activation of cMET. Alternatively, cMET can be activated in an HGF-independent manner, so-called non-canonical activation. For example, des-gamma-carboxyl prothrombin (DCP) is shown to induce cell proliferation via cMET-Janus kinase 1-STAT3 signaling by causing auto-phosphorylation in the cMET-PK domain in hepatocellular carcinoma [signal modifiers. Integrin α6β4 potentiates HGF-triggered activation of RAS and PI3K [cMET can become activated through homodimerization upon binding of HGF or “hepatocyte growth factor” through its HGF-ligand binding sites (IPT3–4 and SEMA domains), which leads to phosphorylation and activation of downstream signaling. This process is also called the arcinoma . cMET acand PI3K . Class Band PI3K . Transmeand PI3K . Functioand PI3K ,18,19,20and PI3K .MET amplification on chromosome 7 in mostly diffuse type gastric cancer and was indicative of poor prognosis [MET 2 exon showed skipping in 30% of cases, which also resulted in MET overexpression. In 17% (47/212) of gastric cancers, new variants of MET were skipped in exon 18 and 19. The removed exons encoded regions of the kinase domain. In up to 8% of cases, MET amplification could be detected [MET expression and amplification. Although these data were subject to a publication and selection bias, overexpression and/or amplification of MET was associated with poorer survival [The first relation between cMET and gastric cancer (GC) was described in 1992 in eleven gastric cell lines that showed the presence of rognosis . In a serognosis . Other srognosis ,25. In 2rognosis . Comprehdetected . Peng etsurvival . The comsurvival . An overHGF/cMET mutations are exceedingly rare. Activation of MET in gastric cancer is thought to be primarily a result of receptor overexpression and/or genomic upregulation (amplification/fusion) [The cMET tyrosine receptor kinase can be activated through protein overexpression, gene amplification, increased HGF ligand autocrine expression, enhanced paracrine ligand-mediated stimulation, inadequate cMET degradation, ligand-independent activation and, rarely, gene mutation. In gastric cancer, /fusion) .MET protein expression can be evaluated by immunohistochemistry (IHC), with confirmation of in situ hybridization (ISH), or by next generation sequencing (NGS). The most successful clinical experience comes from non-small-cell lung cancer (NSCLC) in which cMET alterations are found in 3–4% of all patients. The MET exon 14 skipping mutation is most common and, more rarely, also MET amplification can be found. In the past, protein immunohistochemistry (IHC) and mass spectrometry have been used to detect MET exon 14 mutations; however, it has been shown to be unreliable as a screening tool for MET-exon-14-positive patients. Sanger sequencing or RT-PCR can be used to detect MET alterations, and, in practice, next generation sequencing (NGS) is performed [Over the years, different methods have been developed to detect MET overexpression and/or amplification in gastric cancer, all of which have their advantages/disadvantages. erformed .Diagnostic determination of protein overexpression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has a long history in HER2-positive breast and gastric cancer .Several commercial MET antibodies exist to determine protein overexpression by IHC, although comparison of the performance has not yet been performed as of today. To detect MET protein expression by IHC, a slide with hematoxylin and eosin-stained sections is selected. The most commonly used antibody is SP44, a rabbit monoclonal anti-total MET antibody clone. The first test for scoring MET overexpression is performed by analysis of the percentage of positive tumor cells  with a staining intensity of 0 to 3+: negative (0), weak (1+), moderate (2+) or strong (3+). A cut point of >50% of tumor cells staining moderately or strongly has been associated with treatment benefit in NSCLC and is often used as a standardized cut-off of MET overexpression.MET amplification. This can be explained by the inclusion of lower levels of MET amplification not causing substantial protein expression, or expression that is being controlled post-transcriptionally [The second immunohistochemical technique for scoring MET overexpression is evaluated using the H-score. The H-score multiplies the percentage of cells with 1+, 2+ or 3+ staining by the percentage of positive cells (from 0% to 100%). The H-score ranges from 0–300 with ≥200 indicating overexpression, although the cut points do vary between studies ,34,35,36tionally .MET gene amplification is commonly assessed with an in situ hybridization technique (ISH) by a MET/CEP7 dual color probe set. This technique was developed to distinguish polysomy from true amplification, as polysomy typically does not result in response to targeted therapy. In MET polysomy every additional chromosome 7 will have a corresponding MET-gene location and this will not result in increase in the MET/chromosome 8 centromere ratio (MET/CEP7). In MET amplification, there will be an increase in MET copies on chromosome 7, resulting in an increase in the MET/CEP7 ratio. MET gene amplification can be defined using FISH or by gene copy number (GCN) > 5 based on the Cappuzzo criteria [MET amplification (MET/CEP7 ratio > 2.2) was only detected in 1% of patients with MET overexpression (H score ≥ 200). In gastric cancer, however, a MET IHC H-score of 150 had a 75% sensitivity and 78% specificity to detect MET amplification (MET/CEP7 ratio > 2.0 and GCN > 4.0) showing the difficulty of establishing a correlation between protein overexpression and its ability to detect MET amplification [criteria . Alternafication .MET amplification can be detected by next-generation sequencing (NGS) but strongly depends on the quality of the DNA  as it increases the background noise and makes detecting gene copy numbers more difficult [MET amplification is a rare oncogenic driver across all solid tumor types. The only pitfall is that MET polysomy and MET amplification may not be distinguished by some NGS assays and do not control for CEP7. Therefore, if possible MET amplification is detected, it preferably needs to be confirmed by in situ hybridization (ISH) [No standardized copy number nor cutoff has been determined as of today for next-generation sequencing. ifficult . As of ton (ISH) .MET exon 14 skipping; therefore, enrichment for NGS is necessary. Amplicon or hybrid-capture-based DNA NGS was initially used so as not to miss low-frequency alleles in a broad area of interest around MET exon 14, increasing the detection rate by up to 2.6%. Additionally, RNA testing increased the positive testing ratio to 3.9%. The reason RNA testing resulted in higher positive samples was that it only needed to detect exon 13–15 fusion mRNA creating the MET-driven phenotype of NSCLC [For instance, in NSCLC, there is a wide diversity of alterations leading to of NSCLC . Most ofMET amplification via the MET/CEP ratio of 2 or more, as well as the average of MET copies < or >5. A total of 1477 patients were screened, of which 1043 (81%) were deemed MET positive. A total of 608 patients were randomly assigned to receive rilotumumab plus ECX or placebo plus ECX [Rilotumumab is a monoclonal antibody that binds to the hepatocyte growth factor (HGF) and prevents it binding to the cMET receptor. In 2014, a randomized phase 2 study with rilotumumab was investigated in combination with epirubicin-cisplatin and capecitabine (ECX). Rilotumumab improved PFS in the combined arm with ECX to a median of 5.7 months compared to 4.2 months compared to placebo. The objective response rate (ORR) was 39% and the disease control rate (DCR) was 80% in the combined rilotumumab group . BecauseThe study protocol was stopped early because of a higher number of deaths in the rilotumumab group. In an additional analysis, no biomarker  could show a distinctive effect of the investigational drug. Preliminary analysis showed that rilotumumab was ineffective, with a median OS of 9.6 months compared to 11 months in the chemotherapy-alone group. Because of the high number of deaths, RILOMET II was closed shortly afterwards .MET amplification were reported within all patients. IHC was positive in 60% of all patients, though no further details were given about the threshold for MET positivity. A total of 162 patients were included in the study. MET amplification was detected in 3 out of a total of 100 patients. Progression-free survival and overall survival was comparable between all arms; so, no added benefit was shown of rilotumumab or panitumumab in the first-line treatment of gastro-esophageal cancer [Another first-line phase 2 randomized clinical trial was performed in 2014 in the MEGA trial comparing standard of care chemotherapy folfox to folfox + panitumumab or folfox + rilotumumab. No pre-set diagnostic cMET-assay was included, although cMET staining and l cancer .In the METGastric trial, onartuzumab was evaluated in a randomized phase 3 study in a first-line combination with a backbone of mFOLFOX6. Onartuzumab is a recombinant, fully humanized, monovalent monoclonal antibody that binds with the extracellular domain of cMET. It prevents HGF from binding to the cMET-receptor and, therefore, restricts intracellular signaling. In an earlier phase II trial, the combination onartuzumab-erlotinib (EGFR inhibitor) resulted in an improved overall survival in patients with non-small-cell lung cancer (NSCLC) who were cMET positive, defined as 50% of tumor cells staining with an IHC intensity of 2+/3+. Therefore, the same screening with immunohistochemistry (IHC) and a 50% cell ratio was used in this phase 3 trial in gastric cancer. The proportion of patients with higher expression intensity was almost doubled in this study (38% vs. 21%) compared to the RILOMET-1 study. Unfortunately, the phase 3 part of the study was terminated early as the parallel phase 2 part could not ascertain the right patient selection. From the patients eligible for analysis, no difference in ORR could be found between standard of care and addition of onartuzumab .MET amplification by ISH, defined by a MET/CEP7 ratio of ≥2, was found in 3 out of 4 patients with high IHC expression, although no relation could be found between any diagnostic marker and outcome [A phase 2 non-randomized single-arm trial included 65 patients with advanced gastric cancer treated with emibetuzumab, an immunoglobulin G4 monoclonal bivalent anti-cMET antibody that blocks cMET signaling by blocking ligand-dependent cMET activation, as well as internalizing the cMET-receptor to be degraded in a ligand-independent manner. Patients were included beyond progression in second-line chemotherapy and screened for MET protein expression by immunohistochemistry (IHC) to be 2+ or 3+ positive in more than 60% of tumor cells. Of the 15 patients that were included, no patients had a partial response, apart from one patient with a −22% reduction in the target lesion, although he developed ascites and was considered progressive disease.  outcome .MET-amplified patients with acceptable toxicity. AMG337 is a highly selective and potent small molecule inhibitor of cMET receptor signaling. A subsequent phase 2 study in patients with advanced esophagogastric cancer and other solid tumors who had received prior therapy was set up. Screening for MET amplification was performed by a central laboratory defined as a MET/CEP-7 ratio > 2.0. Over 2000 patients were screened of which 132 (6%) had a MET amplification; finally, 55 patients with measurable disease were enrolled. An ORR of 19% was reached in the cohort of esophago-gastric cancer, though not in other tumor types, but the study was terminated early as the study product could not uphold the earlier seen ORR of up to 62% in a small cohort of 13 patients. Among all the patients included in the analysis, the mean MET/CEP7 ratio was 7.7 (2.4–12.0) in the 8 responders and 7.1 (2.0–20.4) in the 39 non-responders; therefore, biomarker analysis did not show an association between the level of MET gene amplification and response to treatment. Possibly, the full potential of AMG337 could not have been investigated as this was a single-arm study and early termination likely influenced the final evaluation [A phase 1b study with AMG337 confirmed an overall response ratio (ORR) of 29.7% in aluation .ALK and ROS1 gene rearrangement in non-small-cell lung cancer (NSCLC). Several cases with MET amplification in esophagogastric cancer showed efficacy for crizotinib for which a phase II trial was designed. MET overexpression was determined by central testing and initial screening was based on an IHC of 2+ or 3+; MET amplification was assessed by FISH, and the number of cMET gene copies for inclusion was set at ≥6 copies. cMET was prospectively analyzed in 570 patients with esophageal/junction or gastric adenocarcinoma and MET amplification was found in 35 patients (=6.1%). Finally, 11 patients were enrolled, of which 9 patients started therapy with crizotinib. The median copy number of MET was 7 (range 6–11). A tumor response rate was achieved in 2/3 patients (67%) with a low tumor MET amplification, and in 3/6 (50%) with an intermediate tumor MET amplification. Unfortunately, the trial was prematurely stopped due to insufficient accrual [Crizotinib is a small molecule oral inhibitor of the anaplastic lymphoma kinase (ALK), c-MET/hepatocyte growth factor receptor (HGFR), and ROS receptor tyrosine kinases. Crizotinib is approved for  accrual .Capmatinib is an oral-type Ib cMET inhibitor that was studied within solid tumors of which nine patients with gastric cancer were treated. Patients were eligible after third-line treatment and inclusion was allowed based on immunohistochemistry (IHC), H-score > 150, MET/CEP7 ratio of ≥2 or a gene copy number of ≥5. Only two out of nine patients reached stable disease and no clear correlation between the different diagnostic techniques of MET overexpression and response was observed .MET amplification and an additional 22% increased copy number due to polysomy. Across both arms, no patients experienced a partial response (PR) and 15 patients had stable disease (SD). There was no difference in response rate between patients with MET amplification and/or polysomy compared to patients without a cMET-driven biomarker. The median PFS was 1.7 months, while the median OS was 7.4 months with intermittent dosing and 4.3 months with daily dosing. This suggested that cMET signaling may not be critical in patients with gastric cancer without MET amplification [Foretinib, is a small-molecule multikinase inhibitor that targets MET, RON, AXL, TIE-2 and VEGFR2 receptors. It binds in the adenosine triphosphate pocket of its targets, resulting in conformational change and kinase inhibition. Foretinib has been evaluated in a phase 2 single-arm multicentric study with two dose cohorts (intermittent vs. continuous dosing). No diagnostic cMET biomarker was mandatory to enter the study. Patients eligible for the study had progressed beyond first-line chemotherapy. Only three patients had fication .Tivantinib is a low-molecular-weight, orally available selective inhibitor of cMET. It disrupts cMET phosphorylation in a non-ATP competitive manner. It was studied in an open-label phase 2 single-arm multicenter trial. A total of 30 patients were included without the necessity of a pre-diagnostic cMET assay. Pretreatment of one or two systemic therapies was allowed. A total of 11 patients achieved disease control, although only stable disease was reached. The median PFS was 43 days, and the median survival time was 344 days. As for the earlier studies, although IHC and FISH was performed, no biomarker was correlated with clinical benefit .In 2017, a phase 1 run-in trial in solid tumors, and later phase 2, specifically for first-line esophago-gastric cancer, evaluated tivantinib in combination with folfox. A total of 34 patients was included in the phase 2 part and no pre-study diagnostic biomarker was necessary. The overall response ratio was similar to historic cohorts of standard chemotherapy folfox and no additional effect could be attributed to the addition of tivantinib. Moreover, no relation could be seen between IHC or MET protein expression .MET amplification and MET overexpression (IHC 3+) are two. In this study savolitinib, a class I cMET inhibitor and small molecule receptor tyrosine kinase inhibitor was used. The study investigated the targeted therapy in second-line and compared it to second-line paclitaxel/ramucirumab. The incidence of MET overexpression by IHC (3+) was 8.8% (42/479) in this group, while 17 (40.5%) of 42 MET-overexpressed tumors had MET-amplified tumors by next-generation sequencing (NGS) or FISH, and 25 (59.5%) patients had no MET amplification. The overall response ratio in the MET-amplified arm was 50% (10 of 20). Patients with high MET copy number (≥10 MET gene copies by tissue NGS) had high response rates to savolitinib. One patient with upfront peritoneal metastases could be curatively resected after downstaging with savolitinib and was still alive one year after surgery. This shows that truly MET-amplified gastric cancer patients can gain an additional benefit from targeted therapy and even show better overall survival compared to patients receiving standard of care second-line chemotherapy [The VIKTORY UMBRELLA trial is a basket study of patients with gastric cancer based on clinical sequencing and focuses on eight different biomarker groups of which otherapy .Other TKIs have been studied in different tumor types but no extensive data in gastric cancer can be found. Cabozantinib has been investigated thoroughly in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). It is a blocker of VEGFR-1 to 3, and the TAM family , as well as cMET . In the MET exon-14-skipping mutation resulting in an ORR of 46%. EMA recently approved the use of tepotinib in MET exon-14-skipping non-small-cell lung cancer [Tepotinib is a selective cMET inhibitor that interrupts the cMET signal transduction pathway. In the VISION trial in NSCLC, tepotinib 500 mg in 152 patients showed a partial response in 50% of patients with the g cancer .One small interventional trial was performed in a cohort of solid tumors refractory to standard therapy. No MET diagnostic assay was necessary to enter the study. IHC and FISH analysis were determined throughout the study. Two patients with gastric cancer entered the study and one patient reached a PFS of 4, 6 months into therapy after four prior lines of chemotherapy. Therefore, the efficacy of tepotinib in gastric cancer is still unknown . An overAmong all the studies performed within cMET in gastric cancer, not many successes have been achieved. The RILOMET-1, MEGA and METGastric study all included patients in first-line gastroesophageal cancer and did not show a significant benefit in addition to chemotherapy.MET amplification the cMET pathway is autonomously active regardless of the effect on the binding ligand.One of the possible reasons why rilotumumab and onartuzumab did not show an increased benefit in first line is explained by the mechanism of action. It is a ligand-dependent antibody and in MET amplification. Moreover, in gastric cancer MET amplifications are still limited to around 5% of all patients, and, therefore, using cMET-targeted therapy for all first-line patients with gastric cancer results in overtreatment in patients without a MET amplification. This also means that the efficacy of these cMET-specific treatments could potentially be underrated [Secondly, screening by positive immunohistochemistry for cMET is not an appropriate biomarker. Overexpression based on immunohistochemistry did not show the good correlation with cMET-activity as an oncogenic driver typically seen in derrated ,58,59.MET gene amplification by GCN ≥ 5 or the MET/CEP7 ratio ≥ 2 could not distinguish responders from non-responders. However, this study had a low number of patients, and as mentioned earlier, the gene copy number is possibly not a good marker to detect MET amplification.In the study with AMG337, a potential benefit in patients with gastric cancer with an ORR of 19% could be shown. Patients were included based on a FISH MET/CEP7 ratio ≥ 2.0, but no distinct difference was found in the MET/CEP7 ratio in the responder and non-responder groups. In the study with crizotinib and capmatinib, screening was also based on IHC, and prospective analysis of MET amplification, but, across all patients, no partial responses were seen. A total of 15 patients showed stable disease. Again, a low number of patients was included in the study to determine a clinically significant benefit. Tivantinb was combined with a folfox regimen in a phase 1, and later in a phase 2, open-label trial. Although, in total, 49 patients were treated, no difference was seen compared to a historical cohort of folfox alone. No specific biomarker analysis could distinguish patients in terms of outcome.Foretinib was studied without cMET-specific inclusion criteria based on a diagnostic assay but was monitored in the study. Three patients had a MET amplification was determined by NGS or FISH and an ORR of 50% was reached, showing the possible potential for cMET inhibitors in gastric cancer in a well-defined population.The VIKTORY umbrella trial showed the most successful response for savolitinib on cMET-inhibitors for patients with gastric cancer and compared this to paclitaxel/ramucirumab second-line therapy. MET overexpression, rarely, a FISH MET/CEP7 ratio ≥ 2, or no prescreening assay was needed. Studies without an inclusion strategy could not find an overt biomarker predicting cMET sensitivity. Diagnostic assays of MET overexpression/amplification are not as homogeneous in gastric cancer compared to non-small-cell lung cancer (NSCLC), where the MET exon-14-skipping mutation has been extensively investigated and a clear strategy has been set out.All the forementioned studies had a different inclusion strategy, e.g., No beneficial effect has been seen in addition to chemotherapy for allcomers in first-line gastric cancer. In the cohorts with TKIs, all patient groups remain limited, and the inclusion strategies all remain different, apart from the clear analysis of the VIKTORY umbrella trial, which detected most patients based on NGS analysis with a good ORR of 50%.MET amplification as well as MET overexpression, to determine treatment-related decision-making.The most important problem remains the need for clinically meaningful cut-off points, including the level of MET amplification by NGS or whole-exome sequencing could be the most accurate technique to predict MET-inhibitor sensitivity; however, confirmation by ISH will be important to distinguish true MET amplification from polysomy, depending on the type of NGS assay. More data on comprehensive genomic testing and MET inhibitors will be needed in other (basket) studies and further investigation will be needed to identify optimal predictive biomarkers under targeted therapy.Determining


Surgical antibiotic prophylaxis is an essential component of perioperative care. The use of prophylactic regimens of antibiotics is a well-established practice that is encouraged to be implemented in preoperative/perioperative protocols in order to prevent surgical site infections.The aim of this study was to emphasize the crucial aspects of antibiotic prophylaxis in abdominal surgery.Antibiotic prophylaxis is defined as the administration of antibiotics before contamination occurs, given with the intention of preventing infection by achieving tissue levels of antibiotics above the minimum inhibitory concentration at the time of surgical incision. It is indicated for clean operations with prosthetic materials or in cases where severe consequences may arise in the event of an infection. It is also suitable for all clean-contaminated and contaminated operations. The spectrum of action is determined by the pathogens present at the surgical site. Ideally, a single intravenous bolus dose should be administered within 60 min before the surgical incision. An additional dose should be given in case of hemorrhage or prolonged surgery, according to the half-life of the drug. Factors such as the patient’s weight, history of allergies, and the likelihood of colonization by resistant bacteria should be considered. Compliance with institutional protocols enhances the effectiveness of antibiotic use.Surgical antibiotic prophylaxis is associated with reduced rates of surgical site infection, hospital stay, and morbimortality. Surgical antibiotic prophylaxis reduces the rates of surgical site infections and mortality. It is indicated for high-risk clean surgeries, clean-contaminated surgeries, and contaminated surgeries.Antibiotic spectrum should be selected according to the local flora of the surgical site. Cefazolin is the most used antibiotic for surgical prophylaxis.The dose should be administered within 60 min before the surgical incision. However, some antibiotics should be administered 2 h before the surgical incision.Only one dose is usually sufficient for most cases. Additional doses must be given if the procedure lasts more than two antibiotic half-lives or in case of extensive hemorrhage, defined as more than 1500 mL in adults and 20 mL/kg in children.Prophylactic antibiotic administration up to 24 h is also acceptable.The best route of administration is intravenous. In most cases, the dose is given as a bolus. However, there is some evidence suggesting that continuous infusion is superior.The patient’s weight and history of antibiotic allergies should be considered when selecting the appropriate dose and antibiotic.Adherence to institutional protocols increases the effectiveness of antibiotic use.Resistant bacterial colonization, especially in the case of methicillin-resistant Staphylococcus aureus, should be considered.. These protocols encompass strategies such as nutrition, epidural or regional anesthesia, pain control, minimally invasive techniques, and aggressive postoperative rehabilitation. The central idea is to minimize surgical trauma and reduce risks, which results in reduced morbidity, mortality, costs, and hospital stay. Antibiotic prophylaxis is also included in these protocols.Perioperative care is as important as good surgical skills and technique. Therefore, many multimodal perioperative care protocols have been used worldwide.The benefits are unquestionable and have been clearly described in the literature. A study that included 49,000 patients from 21 meta-analyses, only from RCT, showed that antibiotic prophylaxis in surgery provides a remarkable reduction in surgical site infection (SSI), regardless of the wound contamination and type of procedure. Many problems can arise as a result of this, with the most common being higher SSI rates, bacterial resistance, and Clostridium difficile infection.However, inappropriate antibiotic use is very common. The main causes of inadequacy are excessive duration of antimicrobial prescription and failure in proper indication.The primary sources of information regarding surgical antibiotic prophylaxis are the World Health Organization Guidelines, the Guidelines of the Centers for Disease Control and Prevention, and the recommendations of the Surgical Infection Society published by the American College of SurgeonsThis position paper focuses on the most important aspects of antibiotic prophylaxis in abdominal surgery..The purpose of antibiotic prophylaxis is to prevent SSIs by reducing the microbial load at the operation site. To achieve this, the antibiotic must reach effective serum and tissue concentrations, specifically above the minimum inhibitory concentration of the antibiotic at the time of the initial skin incision. SSI is defined as the infection of the incision, organ, or space cavity following a surgical procedure. The infection of the incision is considered superficial when it involves the skin and subcutaneous tissue, and it is considered deep when it involves the fascia and muscle. It typically occurs within 30 days of the operation, or within 90 days in cases where prosthetic material was used. There are several risk factors associated with SSI, including wound classification, comorbidities, obesity, age, immunosuppression, and ASA classification. The risk is also influenced by appropriate surgical technique and perioperative care. Wound classification refers to the level of contamination of a surgical wound during the operation. It is considered the primary risk factor for SSI. A clean wound does not involve the respiratory, alimentary, genital, or urinary tracts. It is free from infection and inflammation. A clean/contaminated wound involves the respiratory, alimentary, genital, or urinary tracts under controlled conditions. A contaminated wound can occur due to a significant breach in sterile technique, substantial leakage from the gastrointestinal tract, acute non-purulent inflammation, infarcted or necrotic bowel (non-perforated), and fresh traumatic wounds. A dirty/infected wound exhibits purulence or an existing clinical infection, perforated viscera, devitalized tissue, or it is an open traumatic wound lasting more than 4 h  should be infused within 120 min before the surgical incision, as these drugs require longer infusion times.For most drugs, they should be administered within 60 min prior to the surgical incision. Similarly, administering antibiotics too close to the surgical incision has also been associated with increased infection rates. In a real scenario, it could be difficult to initiate antibiotic infusion precisely within this time interval. Some protocols suggest administering it at anesthetic induction.Antimicrobial infusions initiated more than 60 min prior to surgery have been associated with a higher rate of SSIs. This means that a single dose should be given within 60 min prior to the surgical incision. As previously mentioned, redosing may be necessary in cases of significant blood loss or prolonged surgeries. However, a duration of up to 24 h is also considered acceptable. There is no need to maintain antimicrobial prophylaxis solely due to the presence of drains or central intravenous catheters.There is strong evidence that, for most surgeries, the antibiotic should not be continued after the procedureIn cases of cardiovascular surgery, there is some controversy. Some guidelines recommend a prophylaxis duration of up to 48 h. However, these recommendations were based on healthy and non-obese patients.Antibiotic prophylaxis requires an effective spectrum, appropriate pharmacokinetics, low toxicity, and an appropriate duration, as well as maximum concentration in the tissues during the incision.The use of antibiotics and their distribution in obese patients, particularly in the context of obese surgical literature, lacks sufficient evidence. Less is known about the pharmacokinetics of antibiotics in patients with a body mass index (BMI) above 40 kg/m. Some physiological changes characteristic of morbid obesity has implications for drug kinetics, including increased cardiac output, total blood volume, renal clearance, fatty deposition in the liver, and alterations in plasma proteins.Obese patients absorb, distribute, metabolize, and excrete drugs differently. The relationship between body size, physiological variables, and pharmacokinetic parameters has been evaluated in the obese population. In this patient population, SSIs tend to have significant morbidity.The incidence of SSI in obese patients is high, and the current recommendations for antibiotic prophylaxis are inadequate.The best route of administration is intravenous. At the time of incision, the tissue and serum antibiotic levels should be at least at the minimum inhibitory concentration for the drug. Intravenous administration is fast, predictable, and reliable. The most common method is bolus infusion, although recent evidence suggests that continuous infusion may be superior. Naik etal., in a randomized study, evaluated intermittent bolus infusion of cefazolin (2 g every 4 h) compared with continuous infusion (500 mg/h). They demonstrated that continuous intraoperative infusions of cefazolin provide better plasma concentrations, even with lower infusion doses.Recent studies have shown better results for the use of continuous prophylactic antibiotic infusion when compared to intermittent bolus infusion. They observed higher concentrations of cefuroxime in both plasma and subcutaneous tissue when cefuroxime was administered continuously and concluded that patients who received the antibiotic through continuous infusion had higher concentration measurements.Skhirtladze-Dworschak etal. compared antibiotic prophylaxis with cefuroxime using intermittent bolus and continuous infusion methods, assessing their serum and subcutaneous tissue concentrations. The study analyzed the infection rate and its association with age, gender, preoperative weight, BMI, and comorbidities. The results showed that the rates of SSI were 4.16% in the group prophylactically treated with ampicillin/sulbactam, 1.98% for ertapenem, and 1.55% for continuous cefazolin. The authors concluded that the prophylactic use of cefazolin in continuous infusion yields very promising results.Ferraz etal. conducted a study comparing the continuous infusion of cefazolin with ampicillin/sulbactam and ertapenem in bariatric patients, evaluating their effects on the incidence of SSI. A total of 516 adult patients received cefazolin intraoperatively, with 284 receiving intermittent bolus infusion and 232 receiving continuous infusion. The study found that superficial SSIs were significantly reduced in patients who received antibiotic prophylaxis in the form of continuous infusion .Shoulders etal. studied the impact of intermittent in bolus cefazolin prophylaxis versus continuous infusion on the incidence of SSIs. A meta-analysis encompassing 13 RCTs compared the efficacy and safety of topical antibiotics with non-antibiotic agents in preventing SSI but demonstrated no reduction in the occurrence of SSI. When compared with intravenous administration, topical solutions have inferior results in terms of SSI rates. However, further trials are needed to assess the effectiveness of topical solutions in high-risk surgeries or selected patient groups.There are very limited data on topical solutions, except in the field of ophthalmology. Some older studies have shown efficacy compared to placebo. The rationale behind this is to reduce hydroelectrolytic imbalance and the need for intravenous fluids during the perioperative period. The concept of no bowel preparation in elective colorectal surgery is supported by a randomized trial from Finland , which showed no difference in terms of SSIs and overall morbidity between mechanical bowel preparation, oral antibiotic bowel preparation, and no bowel preparation.In colorectal procedures, both oral and intravenous antimicrobials can be used. The necessity of intravenous antibiotics is undisputed, but the question is whether they should be used alone or in combination with oral drugs. Oral antimicrobials are commonly administered alongside bowel preparation, which is a highly debated topic in the literature. Major perioperative care protocols such as Enhanced Recovery After Surgery and Acerto recommend limiting bowel preparation. However, if colon preparation is not performed, there is no need for oral antibiotics, and only intravenous administration is necessary.The most studied regimens include three doses of neomycin sulfate plus three doses of erythromycin or metronidazole. If bowel preparation is an option, it is recommended to include both oral and intravenous antibiotic prophylaxisC. difficile infection.Most of the problems related to antibiotic prophylaxis in surgery are caused by inadequate administration, leading to higher rates of SSIs, the development of resistant bacteria, and . In 41% of these cases, the antibiotic was necessary but not used, or it was unnecessary; in 29% of cases, the prescription took longer than necessary. The same study demonstrated that implementing an antibiotic stewardship program reduced the appropriateness rate to 36%. Major perioperative care protocols emphasize the importance of implementing an adequate antibiotic prophylaxis protocol.One study showed an appropriateness rate of almost 70% for prophylactic antibiotic use. They account for up to 20% of hospital-acquired infections. Most SSIs are caused by resistant bacteria.SSIs are associated with a 2–11-fold increase in mortality and prolonged hospital stays. They cause at least 35,000 deaths and result in $20 billion in healthcare expenditures. Data from the National Nosocomial Infections Surveillance (NNIS) System identified S. aureus as the most common cause of SSIs in the United States, accounting for 22.5% of infections. Of these, 49% were caused by methicillin-resistant S. aureus (MRSA). Other common resistant bacteria include extended-spectrum β-lactamase (ESBL) Escherichia coli, extended-spectrum β-lactamase and carbapenemase-producing (KPC) Klebsiella pneumoniae, Proteus mirabilis (ESBL), and Pseudomonas aeruginosa.Multidrug-resistant bacteria are responsible for more than 2.8 million infections in the United States every year. However, if a patient is colonized, there are several strategies that can be adopted, with most of them described for patients colonized by MRSA.Currently, routine screening and eradication for patients colonized by resistant bacteria are not recommended. Another strategy is the use of vancomycin. However, it is important to consider that vancomycin is not effective against methicillin-susceptible S. aureus. In such cases, some authors recommend combining vancomycin with another drug that targets the expected surgical-site pathogens. For example, cefazolin can be added for gram-positive cocci.The most common strategy is the use of topical 2% mupirocin administered three times a day intranasally, along with daily baths using 2% chlorhexidine for 5 daysThe correct use of antibiotic prophylaxis in gastrointestinal surgery is essential for achieving the best surgical results, minimizing the incidence of SSIs, reducing morbidity and mortality rates, and lowering costs. Therefore, surgeons should be familiar with administering the appropriate antibiotic to the right patient, at the optimal time, in the correct dosage, and for the appropriate duration. Adherence to institutional protocols should be encouraged as it can significantly improve surgical outcomes.


Inconsistencies between a protocol and its umbrella review (UR) may mislead readers about the importance of findings or lead to false-positive results. Furthermore, not documenting and explaining inconsistencies in the UR could reduce its transparency. To our knowledge, no study has examined the methodological consistency of the protocols with their URs and assessed the transparency of the URs when generating evidence.This study aimed to investigate the inconsistency of protocols with their URs in the methodology and assess the transparency of the URs.We searched medical-related electronic databases from their inception to January 1, 2022. We investigated inconsistencies between protocols and their publications and transparencies in the search strategy, inclusion criteria, methods of screening and data extraction, quality assessment, and statistical analysis.We included 31 protocols and 35 publications. For the search strategy, 39 inconsistencies between the protocols and their publications were found in 26 of the 35 (74%) URs, and 16 of these inconsistencies were indicated and explained. There were 84 inconsistencies between the protocols and their URs regarding the inclusion criteria in 31 of the 35 (89%) URs, and 29 of the inconsistencies were indicated and explained. Deviations from their protocols were found in 12 of the 32 (38%) URs reporting the methods of screening, 14 of the 30 (47%) URs reporting the methods of data extraction, and 11 of the 32 (34%) URs reporting the methods for quality assessment. Of the 35 URs, 6 (17%) were inconsistent with their protocols in terms of the tools for quality assessment; one-half  of them indicated and explained the deviations. As for the statistical analysis, 31 of the 35 (89%) URs generated 61 inconsistencies between the publications and their protocols, and 16 inconsistencies were indicated and explained.There was a high prevalence of inconsistencies between protocols and publications of URs, and more than one-half of the inconsistencies were not indicated and explained in the publications. Therefore, how to promote the transparency of URs will be a major part of future work. Umbrella reviews (URs) are clusters that encompass previously published systematic reviews or meta-analyses that consider many comparisons of interventions for the management of the same disease or condition, to provide an overall examination . URs notHowever, since a broad synthesis of data from many systematic reviews requires a high level of subject matter expertise and methodological skills, not all published URs follow clearly described, standardized methodology, which may reduce the credibility of evidence from URs ,4-6. PubInconsistencies may exist because of conscious or subconscious manipulation to reach the desired conclusion, which misleads readers about the importance of findings or causes false-positive results -13. In sThe primary aim of this study was to investigate inconsistencies between a protocol and its publication when developing an UR. The secondary aim was to assess the transparency of the URs when generating evidence.URs that met the following criteria were included: (1) A UR was defined as a quantitative or qualitative synthesis of medical-related systematic reviews, (2) a UR protocol and its publication along with their methodological descriptions were available, (3) URs’ protocols and their publications were published in peer-reviewed journals or preprints, (4) the UR was part of a study, (5) the UR was published in English. There was no restriction on the time frame of the studies. We excluded the following studies: (1) methodological reviews of URs, scoping or rapid reviews, qualitative reviews, integrative reviews, and evidence synthesis and (2) abstracts, conference proceedings, and letters to editors.A comprehensive literature search was performed in 7 medical-related databases, including PubMed, Embase, Web of Science, The Cochrane Library, Joanna Briggs Institute (JBI) Database of Systematic Reviews and Implementation Reports, PROSPERO, and Open Science Framework (OSF), from the inception of these databases to January 1, 2022. The search strategies were developed by an expert in literature searches (JT), and the full search strategies are presented in Table S1 in We managed all records using EndNote  software and removed duplicates using automatic and manual screening. The study selection was divided into 4 steps. First, 2 authors (LZ and ML) independently screened all URs’ protocols and publications using title, abstract, and full text, consecutively. Second, we read the full text of identified publications to find the protocols mentioned in the articles (JZ and LC). Third, for protocols that were not related to included publications in the previous step, the study names or standard abbreviations (where applicable) combined with the term “umbrella” were used to search PubMed, Embase, The Cochrane Library, and Web of Science for their publications . In cases where the same protocol was described in multiple publications, all related publications were included. Finally, the reference lists of included URs were manually searched for additional studies. Any disagreements were resolved through discussion between authors and, if necessary, consultation with senior authors (JZ and JT).We developed the data extraction form and revised it after piloting it on a random sample of 20% of included URs . The extracted data consisted of 2 parts: general characteristics and methodological characteristics. A list of extracted items is given in Table S2 in According to the JBI manual for URs , we asseThe frequency of inconsistencies and transparency were our primary outcomes. Median (IQR) was used for continuous variables, including the number of authors, journal impact factor, total number of studies included, and interval between the protocol and its publication, whereas frequency (%) was used for categorical variables. The statistical analyses were conducted with SPSS Statistics v26.0 (IBM Corp).The database search yielded 2716 records, and an additional 263 records were identified through other sources. Following the removal of duplicates and title and abstract screening, 88 protocols and 684 publications were screened using the full text. In total, we identified 31 protocols and 35 publications . The fulThe included URs were published between 2012 and 2021, and most of them  were published after 2016 . The intAll URs described the search strategy, and 39 inconsistencies between the protocols and their publications were found in 26 of the 35 URs (74%). Of 39 inconsistencies, 16 (41%) were indicated and explained in the publications .Of the 35 publications, 21 (60%) deviated from their protocols in the literature sources: 14 deviations occurred in the databases, and 12 URs generated deviations regarding other literature sources. Of the 21 URs, 3 (14%) indicated inconsistencies in the publications. Compared with the protocols, 1 publication expanded the range of language for included studies, and the other added language restrictions to the included studies. Although 3 publications did not describe language restrictions, their protocols did. In the 5 URs, 4 (80%) inconsistencies were disclosed in the URs. Regarding search times, 13 of the 35 (37%) publications differed from their protocols: 6 because of updates, 3 for other reasons, and the remaining 4 lacked an explanation.All URs described the inclusion criteria, and 31 of the 35 (89%) URs had inconsistencies between the protocols and their publications .For the participants, 13 of the 35 (37%) publications were inconsistent with their protocols. In the 13 URs, 5 described the participants in detail in the protocols but not in the publications. Compared with the protocols, 6 narrowed the inclusion of the participants, and 2 expanded the inclusion of the participants. Of the 13 publications, 5 (38%) indicated and explained the inconsistencies.Of the 35 URs, 16 (46%) generated the following inconsistencies between the protocols and their publications in the interventions: (1) 6 publications narrowed the scope of the interventions compared with the protocols; (2) compared with the protocols, the scope of the interventions was extended in 4 publications; (3) 3 publications were contradictory to the protocols; (4) 3 publications did not describe the interventions, while their protocols did. Of the 16 publications, 6 (38%) pointed out and interpreted the inconsistencies.Regarding the comparators, 10 of the 26 (38%) URs showed deviations between the protocols and their publications: 4 publications increased the number of comparators compared with their protocols, 4 protocols but not their publications described the comparators, and 2 publications removed comparators that were included in the protocols. Of these 10 URs, 4 (40%) publications indicated where the inconsistencies arose.Inconsistencies between the protocols and their publications in the outcomes were found in 19 of the 35 (54%) URs. The most common inconsistency was that the publications reduced the number of outcomes compared with their protocols (8 URs). The second was that the publications added outcomes (4 URs). The third was that the protocols but not the publications described the outcomes (4 URs). Finally, 3 publications changed the outcomes described in the protocols. Inconsistencies were indicated in 7 of the 19 (37%) publications.Inconsistencies between the protocols and their publications regarding the type of studies were found in 13 of the 35 (37%) URs: (1) 6 publications narrowed the inclusion of the study design compared with their protocols; (2) 5 publications expanded the inclusion of the study design, and 1 of them added inclusion of updated randomized controlled trials; (3) 2 protocols but not their publications described the type of included studies. The reasons for deviations were explained by 2 of the 13 (15%) URs.Other inclusion criteria were reported by 24 of the 35 (69%) URs, of which 14 (58%) URs reported the requirements for included studies, 11 (46%) URs reported the quality of included studies, and only 2 (8%) URs reported the requirements of the protocol. In the other inclusion criteria, there were the following inconsistencies between the protocols and their publications in 13 of the 24 (54%) URs: 8 inconsistencies in the requirements for included studies, 5 inconsistencies in the quality of included studies, and 2 inconsistencies in the requirements of the protocol. The inconsistencies were detailed in 5 of the 13 (38%) publications.The following inconsistencies between the protocols and their publications were found in the methods for screening, data extraction, and quality assessment : (1) 14 All URs described tools for quality assessment; the most common  was the JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses. The tools used in the protocols were changed in 3 publications, and 3 publications did not depict tools, while their protocols did. The deviations were indicated in 3 of the 6 (50%) publications.We found 62 inconsistencies between the protocols and their publications in 31 of the 35 (89%) URs, and 16 of the 62 (26%) inconsistencies were indicated and explained in the publications .Of the 35 URs, 18 described how to deal with the overlaps of primary studies between included systematic reviews. There were inconsistencies between 3 of the 18 (17%) protocols and their publications. Of them, 2 protocols gave ways to deal with overlaps, while their publications did not implement them; 1 publication added the calculation of the corrected covered area. None of the inconsistencies was indicated in the publications.Tools for assessing the certainty of the evidence were reported by 24 URs, and 20 of these URs used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Inconsistencies existed between 13 of the 24 (54%) URs and their protocols: 10 protocols but not their publications reported assessments of the certainty of the evidence, and 3 publications added tools for assessing the credibility of evidence that were not described in the protocols. Inconsistencies were detailed by 2 of the 13 (15%) URs.What findings to present and how to present them were described in 26 URs: 12 of the 26 (46%) URs generated inconsistencies between the protocols and their publications, and 3 URs indicated and explained inconsistencies in the publications. Compared with the protocols, inconsistencies could be categorized as follows: (1) 5 publications differed on whether to apply the “summary of evidence” table, (2) the forms of evidence presentation were changed in 5 publications, and (3) 2 publications changed the reported elements.All URs depicted the data analysis, and inconsistencies between the protocols and their publications were found in 9 of the 35 (26%) URs. Compared with the protocols, 3 publications removed quantitative analysis, 2 publications added quantitative analysis, 2 publications altered the rules for qualitative synthesis, 1 publication changed the quantitative analysis model, and 1 protocol did not describe the data analysis while the publication did. Of the 9 inconsistencies, 4 (44%) were detailed and explained in the publications.How to standardize the effect sizes was reported in 13 URs, and 11 of these 13 (85%) URs had inconsistencies between the protocols and their publications: 8 URs only reported it in the publications, and 1 UR only reported it in the protocol; regarding the standardization of dichotomous data, 2 publications were inconsistent with their protocols. Of the 11 inconsistencies, 2 (18%) were indicated and explained in the publications.Of the 35 URs, 21 described other statistical analyses, including subgroup analysis , sensitivity analysis , and publication bias or small study effects . Inconsistencies between the protocols and their publications were found in 14 of the 21 (67%) URs. Regarding subgroup analyses, 12 URs had inconsistencies with their protocols. Of the 12 URs, 9 only reported the subgroup analysis in the protocols, 2 only reported it in the publications, and 1 publication changed the subgroup analyses that were described in the protocol. Deviations between the protocols and their publications in publication bias or small study effects and sensitivity analysis were found in 4 URs and 1 UR, respectively. Of the 14 URs with inconsistencies, 5 (36%) detailed the inconsistencies in the publications.We identified 31 protocols and 35 publications of the URs. Inconsistencies between the protocols and their publications were found in all areas, with inconsistencies occurring most frequently in inclusion criteria and statistical analyses. In addition, less than one-half of the inconsistencies were indicated in the publications of URs, and the transparency of URs was inadequate.Our study showed inconsistencies in the search strategy between the protocols and their publications in 74% (26/35) of the URs, which was similar to previous result that indicated 77% of reviews changed the search strategy between the protocols and their publications . ChangesAlthough URs often aim to provide a broad overview of the evidence on a topic, it is still important to be specific about the inclusion criteria . These cIn terms of the statistical analysis, we identified that 89% 31/35) of the URs’ publications deviated from their protocols. This is similar to a finding for systematic reviews , in whic/35 of thOver one-half of the included URs dealt with overlaps of primary studies, which was consistent with the findings by Pieper et al , and 12 As for certainty of evidence, the most common inconsistency was that the GRADE was removed in the publications, which might lead to a diminished certainty of evidence generated by URs ,26. AlthResearch transparency can speed scientific progress, can increase trust in science, and is one of the core values of science ,43. In tPublishing a protocol in a peer-reviewed journal is a crucial way to improve transparency, by comparing the protocol with a completed UR to detect whether unintended and undocumented changes were made . HoweverScience pointed out that systematic reporting standards also contribute to the transparency of research [A study published in the journal research . For exaresearch . It provresearch ,44. TherTo the best of our knowledge, our study was the first study to assess inconsistent reporting between the protocols and the publications of URs in the methodology. Because we comprehensively analyzed each step of the development of an UR, our findings could be considered beneficial to the production of URs. However, there were some limitations in our study. First, only URs published in English were included. Second, our study conducted only an exploratory analysis with a relatively small sample size, so some inconsistencies may be overlooked. Third, some publications depict only part of the methodology of an UR, resulting in incomplete comparisons between protocols and publications. Last, there is no standard protocol to address the analysis of inconsistencies between protocols and their publications; therefore, we created our protocol and analysis process based on previous similar studies. There is potential for bias or that other factors were not included.There are several areas for future development in the methodology of URs, including (1) the specific combination of literature sources that could identify more available evidence, (2) development of a validated reporting quality tool specifically for URs, (3) appropriate and adequate use of statistical analysis in URs, and (4) modification to the GRADE so that it can be applied in URs. It is also beneficial if our study can help medical editors and scientific journals draw attention to whether a UR’s protocol exists and identify any unrecognized or unreasonable changes between the protocols and their publications during the editing process.There was a high prevalence of inconsistencies between protocols and publications of URs, especially in the inclusion criteria and statistical analysis. More worryingly, more than one-half of URs did not indicate and explain the inconsistencies, and the transparency was inadequate. Thus, the authors of URs should be required to describe and explain any deviation from their protocols. Our study provides further evidence that published protocols allow the tracking of any changes that have taken place, to assess the transparency of URs. Therefore, authors of URs are encouraged to publish their protocols, and journals are urged to accept protocols for publication. In addition, editors or peer reviewers could compare publications of URs with their protocols and check back to confirm whether the changes were indicated and explained.


The research presented in this article was conducted to evaluate the suitability of recycled foam concrete (RFC) as an ingredient in newly created cement mortars. The basis for an analysis was the assumption that the waste is collected selectively after separation from other waste generated during demolition. The motivation for the research and its main problem is a comparison of the performance of RFC used in various forms. RFC was used in two forms: (1) recycled foam concrete dust (RFCD) as a 25 and 50% replacement of cement, and (2) recycled foam concrete fine aggregate (RFCA) as a 10, 20, and 30% replacement of sand. The basic properties of fresh and hardened mortars were determined: consistency, density, initial setting time, absorbability, compressive strength, thermal conductivity coefficient, and heat capacity. Research is complemented with SEM observations. The properties of fresh mortars and mechanical parameters were decreased with the usage of any dosage of RFC in any form, but the thermal properties were improved. The required superplasticizer amount for proper consistency was raised four times for replacing cement with 50% of RFCD than for 25% of such replacement. The mix density dropped by about 8% and 9% for mortars with the replacement of 50% cement by RFCD and 30% sand by RFCA in comparison to reference mortar. A 30% decrease in initial setting time was observed for cement replacement. In the case of sand replacement, it was the opposite—an increase of 100%. The dry density decreased by about 14% and 11% for mortars with the replacement of 50% cement by RFCD and 30% sand by RFCA in comparison to reference mortar. Absorbability was raised by about two times after replacement with both RFCD and RFCA. Compressive strength after 28 days dropped significantly by 75% and 60%, and the thermal conductivity coefficient decreased by 20% and 50% with 50% RFCD added instead of cement and 30% RFCA replacing sand. It indicates greater efficiency in thermomechanical means from RFCA in comparison to RFCD. This material can be used especially in the production of plaster and masonry mortar. Linear correlations of dry density and thermal conductivity coefficient and the latter and compressive strength were proven as reliable for RFCD replacement of cement and RFCA replacement of sand in mortars with greater w/c ratio. The latter percentage increased by 4%pt. compared to the previous year. In Europe, the construction industry caused 40% of CO2 emissions, about 80% of which came from burning fossil fuels [2 emissions [The construction industry generated 37% of process- and energy-related COOne of the possible paths that can be followed to reduce these values is the usage of waste materials. This could be industrial waste, which has been the subject of other publications by the author ,5,6, dusIn this article, the author focused on the waste generated by the demolition of the insulation layers of an existing building. The material was used in the form of fine aggregate (recycled foam concrete aggregate—RFCA) as a substitute for sand, and dust was used as a substitute for cement (recycled foam concrete dust—RFCD). The reuse of this type of construction demolition waste (CDW) in newly constructed buildings fits into the global idea of sustainable development and circular economy. It also fits in with the idea of reducing energy consumption for heating and cooling of habitable spaces.3 [−1 K−1 for densities of 600 to 1600 kg/m3. Thus, after crushing foam concrete, lightweight aggregate can be obtained, and after grinding it, dust consisting of hydrated cement can be obtained. The compressive strength of foam concrete decreases proportionally to decreasing density. This is an exponential relationship. Compressive strength values according to [3 through 3–5 MPa for foam concrete with a density of 800 kg/m3, 10–12 MPa for foam concrete with a density of 1200 kg/m3 to 15–20 MPa for foam concrete with a density of 1400 kg/m3.Foam concrete is a material formed by mixing cement paste with a foaming agent . It may 3 ,24. The 3 . Sources3 ,26 reporrding to ,29,30,31Foam concrete waste can be used as a lightweight aggregate. Common lightweight aggregates used for lightweight concrete are expanded perlite ,33,34, vThere are many studies on the use of waste materials as an ingredient in new lightweight aggregate concretes. Materials used include recycled expanded polystyrene (EPS), polyurethane waste, and agricultural waste. Recycled Autoclaved Aerated Concrete (AAC) and Cellular Lightweight Concrete (CLC) are also known to be used. Some of these are referred to below.Based on the publication , recycleThe authors  report tThe publication  providesThe article  deals wiOther types of lightweight demolition waste are Autoclaved Aerated Concrete (AAC) and Cellular Lightweight Concrete (CLC). The effect of these wastes, when used as an aggregate, on the properties of new mortars is described in the article . The useAAC as a lightweight aggregate was also the subject of an article . PossibiThe article  also proThere are fewer reports on the use of powdered lightweight concrete as a replacement for cement. There are publications describing AAC concretes, but their production does not include a foaming agent, which can affect the properties of the concrete. The dust obtained by grinding foam concrete can be used as a replacement for cement or as an almost inert filler. This is much more popular. It is reported that with small amounts of dust used in this way, it is possible to obtain undeteriorated or even enhanced properties of the mixture and hardened concrete. One must consider the decreased consistency and the need to use water-reducing admixtures ,54,55,56The article  describeThe effect of AAC and CLC waste, used as a cement replacement, on the properties of new mortars is described in the article . When thJustification for addressing the topicThe research presented in this article was conducted to evaluate the suitability of specific demolition waste for reuse as an ingredient in cement mortars. Prospective uses for the composites so created could include traditional mortars as well as mortars with insulating properties for floor layers, roofs, or masonry mortars. A waste material from the demolition of an insulation layer made of foam concrete was used. The basis for a credible analysis was the assumption that this waste is collected selectively after separation from other waste generated during demolition. A particularly valuable aspect is the common determination of thermal and strength properties. The RFC was used in two different forms—dust (RFCD), which is a replacement for cement, and a fine aggregate of size 0–4 mm (RFCA). The usage of recycled foam concrete as a part of fine aggregate is present in many publications. However, the use of this material as a replacement for cement is much less well recognised. In this paper, the latter is also included, described, and compared with the former. According to the statements above, it is worthwhile to compare the possibility and amount of waste used if it is treated as a substitute for sand or cement. This article will partially fill the gap in publications on the use of waste foam concrete as a fine aggregate for cement composites.Cement mortars were prepared to assess the influence of RFC on the properties of cement composites. RFC was used in two forms: (1) recycled foam concrete dust (RFCD) with particles up to 0.063 mm or 0.125 mm, and (2) recycled foam concrete fine aggregate (RFCA) with particles up to 4 mm. Three series of samples were produced: (1) RFCD replacing 25% and 50% of cement, (2) RFCA replacing 10% and 20% of natural sand at water–cement ratio 0.5, and (3) RFCA replacing 10%, 20%, and 30% of natural sand at water–cement ratio 0.6 (denoted as (W+) symbol).As a binder, cement or cement-RFCD mixtures were used. Cement CEM I 42.5R was obtained from one of Polish cement manufacturers as a fine aggregate for mortars natural sand (NS) and recycled foam concrete aggregate (RFCA). CEN standard sand and tap water were used. PCE-based superplasticizer (SP) was used to maintain the same consistency for all mixes. SP was added regarding total binder mass, not exceeding 5% of it. Exact composition of mortars is given in RFC, which originated from an existing structure, was obtained from a demolition company. It played the role of insulation of flat roof structure. RFCA was crushed into 0–4 mm grade. In this form, it was used as a 10–30% replacement for natural sand. It is impossible to use more RFCA because of the consistency drop. After crushing, it was ground to obtain 0.0–0.250 mm and sieved to separate RCFD fractions of 0.0–0.063 mm and 0.0–0.125 mm, respectively. The former was used as a 25% replacement of cement. The latter was used as 25% and 50% replacement of cement. Bulk densities and grading of RFCA and NS are presented in Initial setting time: EN 480-2:2008 Admixtures for concrete, mortar, and grout—Test methods—Part 2: Determination of setting time ;Consistency: EN 1015-3:2000/A2:2007 Methods of test for mortar for masonry—part 3: determination of consistence of fresh mortar (by flow table) ;Density of fresh mortar: EN 1015-6 Methods of test for mortar for masonry—part 6: Determination of bulk density of fresh mortar ;Compressive strength: EN 196-1 Methods of testing cement—Part 1: Determination of strength ;Density of hardened mortar: EN 1015-10 Methods of test for mortar for masonry—part 10: Determination of dry bulk density ;Absorbability was tested on samples prepared for density test, cured in water for 28 days, weighted, and dried to constant mass;Microstructure observations: The examination was performed using an electron scanning microscope  equipped with an EDS analyzer;Thermal properties were assessed with ISOMET 2114 Portable Thermal Properties Analyzer . Samples used for these tests were cubic 10 × 10 × 10 cm. Determination of thermal properties using the ISOMET instrument is based on the ‘hot plate’ method and involves analysing changes in the surface temperature of the test sample in two phases. Firstly, while it is being heated at constant power, and secondly, while it is being cooled. Thermal conductivity (λ) Properties of mortars were tested according to European standards:Because of the significant decrease in consistency of mortars and, thus, the impossibility of conducting measurements for mortars containing both RFCD and RFCA, it was essential to use different methods to assess it. The superplasticizer (SP) was added in the proper amount to obtain the same or similar (13 ± 1 cm) diameter of flow. The amount of SP added collated with flow diameter is presented in 3. For w/c = 0.6, it was slightly lower at 2.28 g/cm3. With a 25% RFCD cement substitution, the density was lower but comparable regardless of the fraction of RFCD used. With 50% cement replacement, the density dropped to 2.13 g/cm3.The density of fresh mortars is given in 3 for mortar with w/c = 0.5 and w/c = 0.6, respectively. Differences can be seen for mortars with a 20% sand replacement with RFCA, where in the case of the composite with w/c = 0.5, large amounts of SP had to be used, which could lead to excessive aeration of the mix. This resulted in a large drop in density. This effect is not seen with mortars with w/c = 0.6. With a 30% sand replacement in the latter, the density dropped to 2.08 g/cm3, which still places this composite in the range of normal mortars.With a 10% sand substitution with RFCA, the density decreased to 2.16 and 2.14 g/cmInitial setting time is very important from a practical point of view. If the time is too long, the required mechanical properties will not be achieved quickly enough, and if it is too short, the workability period of the mix will be shortened. In the case of the mixtures tested, all times are within the desired range for practical reasons, even if they look too long. This is caused by the method, according to EN 480-2 , that reAn interesting relationship is noticeable. When replacing cement with RFCD, the initial setting time decreases compared to the reference mortar, while when replacing sand with RFCA, the time increases. When using 25% RFCD, the initial setting time decreases by about 30–35%, depending on the fraction of dust used. A reference mortar with w/c = 0.6 has a longer initial setting time than one with w/c = 0.5, which is entirely normal. The same relationship applies to mortars with 10% RFCA content. In this case, the initial setting time is approximately 50 and 60% longer than for reference mortars with w/c = 0.6 and 0.5, respectively. The initial setting time for a mortar in which 20% sand has been substituted for RFCA is even longer and may be considered impractical, but there are no standards describing the maximum initial setting time. The mixes C50, P20, and P30(W+) could not be examined because of exceeding the maximum dosage of SP to obtain standard consistency. Further adding of SP may lead to significantly unreliable results; thus, mixtures were not subjected to tests. Note that admixtures that accelerate the setting can be used to modify the initial setting time .The dry density of hardened mortars is similar to that of fresh mortars. The results are given in The absorbability of hardened mortars is ruled by an inverse relationship to density. The more recycled foam concrete material, the higher the absorbability of the mortars. The results can be seen in the graph in The compressive strength was tested on mortar samples with dimensions of 160 × 40 × 40 mm. Each type of mortar, at each date , was tested using six samples. In neither case was a standard deviation greater than 3% of the average value recorded. Results are given in The use of waste foam concrete as a replacement for cement reduces the strength of the composite compared to the reference mortar. This effect is evident in all terms. Detailed results are shown in RFCA used as a replacement for sand also reduced the compressive strength in all terms. The graphs are shown in Thermal properties were assessed with ISOMET 2114. Thermal conductivity (λ) c/λ, which connects compressive strength (fc) and thermal conductivity coefficient (λ) in the form of the thermomechanical index (φ), was proposed. Due to the lack of a physical connection, the authors decided not to include units for the value obtained from it. This index is of practical use, assuming that sufficiently high standards for the strength of the concrete are maintained. In this way, material selection can be optimised. The proposed solution seems reasonable due to the fact that most waste materials deteriorate mechanical properties, but some of them can improve insulating properties. Thinking about the equal importance of the mechanical performance of concrete and other characteristics makes the assessment of the material’s functionality a more complicated case. This is evident in the situation when a composition change of the concrete mix is followed by beneficial changes in some of the properties and unfavourable changes in other parameters. According to Nowak et al. , the aut2 ratios above 0.96.In Observations with the SEM revealed the normal microstructure of the reference sample. This is shown in Deterioration of mortar consistency by substituting part of the natural aggregate with recycled concrete aggregate is normal. This is caused by the increased absorbability of the recycled aggregate ,66. The Some SPs can lead to excessive aeration of the mix if used in overly large quantities . This isAn interesting relationship can be observed in the change in the initial setting time of mortars where cement or sand is substituted. When RFCD is used instead of part of the cement, the initial setting time decreases compared to the reference mortar, and when sand is substituted for RFCA, the time increases. In the first case, this is because of the addition of fine particles of hydrated cement to the mixture, which can act as crystallization nuclei and cause the products of this reaction to form in the inter-grain space . The secIt is difficult to compare exact values of compressive strength and thermal conductivity coefficient with results from the literature due to differences in the materials used and their proportions. The reported development of mechanical properties, density, and absorbability is similar to those reported in the literature for other lightweight aggregates ,67,68,71In the case of replacing cement with ground demolition waste originating from lightweight materials, there are far fewer studies. However, it can be seen that they can positively affect the compressive strength of cement mortars. This applies, however, to a limited amount of them. The results given in The research presented in this article was conducted to evaluate the suitability of specific demolition waste for reuse as an ingredient in cement mortars. The simultaneous determination of thermal and strength properties was performed. The aim of the research was to determine and compare the possibilities and amounts of waste used as a substitute for sand or cement.Waste from the production of foam concrete can be used in the preparation of mortars. When added in small quantities, it causes an acceptable deterioration in mechanical properties while improving thermal properties. This material can be used especially in the production of plasters and mortars.Replacing part of the sand with waste foam concrete improves the thermomechanical index, defined as the ratio between compressive strength and thermal conductivity coefficient. This shows the suitability of this material. Replacing part of the cement reduces the value of this index.There is no need to over-mill RFCD. The results of the density, absorbability, and compressive strength tests show that replacing the cement with RFCD with a maximum grain size of 0.063 mm and 0.125 mm in the same amount does not affect these values.The linear correlations of density—thermal conductivity coefficient and compressive strength—thermal conductivity coefficient are good for both the replacement of the cement part with RFCD and the sand part with RFCA.


The granules were analyzed for their chemical and physical properties as well as their compatibility in HPAC mixtures. These experiments included determinations of pore size distribution, thermal stability, porosity, specific surface and hydrophobicity, as well as fresh/hardened concrete experiments such as measurements of compressive strength, flexural bending strength, thermal conductivity and shrinking behavior. It was found that the type of aerogel has a major influence on the fresh and hardened concrete properties of HPAC, particularly compressive strength and shrinkage behavior, whereas the effect on thermal conductivity is not very pronounced.In previous work of this group, a structural lightweight concrete was developed by embedding silica aerogel granules in a high-strength cement matrix. This concrete, called high-performance aerogel concrete (HPAC), is a lightweight building material characterized by its simultaneous high compressive strength and very low thermal conductivity. Besides these features, high sound absorption, diffusion permeability, water repellence and fire resistance qualify HPAC as an interesting material for the construction of single-leaf exterior walls without any further insulation. During the development of HPAC, the type of silica aerogel was found to majorly influence both fresh and hardened concrete properties. To clarify these effects, a systematic comparison of SiO The construction industry is facing challenges resulting from climate change and political decisions in this context, such as increased demands on building insulation. In many countries of the northern hemisphere, solutions such as external thermal insulation systems with layers of different materials are state-of-the-art. However, these solutions are the object of criticism due to several aspects such as flammability, recyclability, growth of algae, limited architectural freedom and so on. One approach to the solution of these challenges is the so-called high-performance aerogel concrete (HPAC), which consists of silica aerogels embedded in a high-strength cement matrix. HPAC allows for concrete constructions combining load carrying and insulating properties without any additional insulation layers. Besides a remarkable relation between compressive strength and thermal conductivity, HPAC is characterized by high fire resistance, high acoustic insulation, low density, recyclability and free formability, which are highly desirable in conventional constructions as well as 3D printing ,2,3,4. GSince the first attempts to develop aerogel concrete in 2008 , the matThe influence of the hydrophobicity of aerogel granules on fresh and hardened concrete properties has not yet been systematically investigated and is therefore not sufficiently understood. The aim of the research presented in this study was to contribute to a better understanding of the relation between surface chemistry and concrete properties via a comparison of different aerogels. For this purpose, silica aerogels from different producers and with different hydrophobicity values were characterized intensively, as is subsequently presented. The mechanical properties of these aerogels are largely comparable with each other and are not considered to contribute to the strength of the composite: the compression strength of silica aerogels with the densities considered in this study is about a decimal power less in comparison with the strength of cement matrix . Thus, sAs mentioned before, aerogels with different hydrophobicity values and different mechanical properties were chosen for this study. From To compare the effects of different aerogel granules on fresh and hardened concrete properties, a reference concrete mixture, called HPAC_50-P100, served as a base. As can be seen from the mixture composition given in For a full understanding of aerogel behavior, thorough characterization is recommended. Therefore, a basic study was carried out for the different silica aerogels used in the HPAC composites.The thermal conductivity was measured using the heat flow meter apparatus HFM 436 Lambda from NETZSCH . The thermal conductivity of the aerogel granular material was measured using a box with a height of 20 mm and a ground 300 mm × 300 mm following EN 12664:2001 .v/v O2/N2).Thermogravimetric analyses were performed using a Thermo-Microbalance TG 209 F1 Iris from NETZSCH . All experiments were performed under the same conditions with a constant gas flow of 20 or 40 mL/min, a temperature gradient of 10 K/min and a temperature range from 25 to 800 °C. Afterwards, measurements were performed both under inert nitrogen atmosphere and under oxidative conditions with synthetic air .® II 1340 from Micromeritics™ . The skeletal density was calculated byThe skeletal density was measured with an AccuPyc® 1360 Envelope Density Analyzer from Micromeritics™ . The envelope density was calculated byThe enveloping density of an aerogel body is defined by the ratio of its mass to its volume. The measurements of the irregularly shaped porous aerogel granulate samples were determined using a GeoPycThe apparent density  was determined according to ASTM D2854 . It was With known skeletal and envelope density, the porosity was calculated bySorption methods were performed for the determination of the inner surface areas using a TriStar II 3020 from Micromeritics™  following DIN ISO 9277 . The cal3 concrete prisms. The concrete specimens were stored in mixed storage conditions according to DIN EN 12390-2 [The experiments on fresh concrete properties included determinations of bulk density, consistency, and air void content. The investigations of bulk density and air void content were performed in accordance with DIN EN 12350-6  and DIN  12390-2 , i.e., t 12390-2 . As the However, since the aerogels SUFA and SICLA are only produced on a laboratory scale, there were not enough granules to conduct all investigations for each aerogel.3 for amorphous to around 2.65 g/cm3 for crystalline (α-quartz) SiO2 [2 aerogels, however, skeletal density is lower and partially dependent on the synthesis route [The material density of bulk silicon oxide lies in the range of 2.19 g/cmtz) SiO2 . For amois route ,23. All Due to the limited information provided by the producers and the limited amounts of aerogel available for proper measurements, only a few envelope and apparent densities were measured.Through sorption methods, the pore properties seen in The majority of the mesopores of the samples from Cabot (P100 and P250F) and KEEY  are in the range of 7–9 nm, with some examples shown in Due to the limited amount of aerogel available for proper thermal conductivity measurements, only a few samples could be measured. The thermal conductivity of all samples is very similar and around 0.021 W/(m K), both from the performed measurement and the data provided by the supplier, as aerogels are generally very good thermal insulators. In order to show temperature dependence, P100 was measured accordingly, as seen in The thermal decomposition behavior, measured via thermogravimetric analysis, is shown in With this in mind, the general trends of less mass lost in air and also thermal reactions with oxygen starting at a lower temperature can be explained. Similar to previous data, P100 and SICLA > 10% behave very similarly in terms of thermal decomposition starting points and mass losses. SUFA was revealed to have a significantly higher mass loss, the result of a high alkyl content in the silica precursor instead of added hydrophobic agent. The same phenomena can be observed when performing these experiments on silica–hybrid aerogels.Detailed discussion of these values without knowing the precise composition of the aerogels and hydrophobic agent would not lead to further information and is therefore omitted in this section. The trends observed, however, still deliver important data for further use of these aerogels in concrete aggregates.The properties of fresh concrete are shown in The observations of flexural tensile strength paint a different picture and are displayed in The conductivity tests with a heat flow meter yielded single values varying from 0.260 W/mK (P100) to 0.446 W/mK (P100PYR). As already stated in In order to evaluate the hardened concrete visually, the samples were investigated with a light microscope . This test was primarily conducted to obtain information about the transition zone between the cement matrix and the aerogel particles and the possible resulting influences on concrete strength, as mentioned in A comparison of all HPAC specimens tested in this work regarding the water–cement ratio and concrete strength is shown in 2 = 0.76; no relevant trend was observed regarding the relation between the density of hardened concrete and flexural tensile strength.Opposed to this, the findings on the relation between the density of hardened concrete and compression strength are in agreement with the behavior of HPAC described in the literature  and the To work out possible influences of the aerogel’s hydrophobicity on the strength of the composite, mass losses determined via thermogravimetric analyses were compared with compressive strength values. Because of the aforementioned dependency of the strength on the density of the hardened concrete , this paDistinctive trends can be found if the influence of hydrophobicity on water demand is considered . This waAs mentioned in 3, fck = 8–100 MPa, λ = 1.35 W/mK) [3, fck = 20–25 MPa, λ = 0.55 W/mK) [Because the aerogel content was the same for each mixture, the differences regarding thermal conductivity must depend on the following parameters: (1) The conductivity of the granule itself may influence the conductivity of the composite material. (2) Aerogel granules may be ground while mixing, changing the amount of air voids in the composite as the intact aerogel particles convert to powder. (3) In concrete, air voids naturally occur as a result of the hydration process, where water is bonded chemically and physically. Thus, the water–cement ratio will influence the pore structure. Concretes with a more porous structure tend to have a lower thermal conductivity. It would not be sufficient to refer to the air void content of fresh concrete see , as micr35 W/mK)  or even For the determination of fresh and hardened concrete properties, a mixture containing Cabot P100 aerogel, called HPAC_50-P100 , served According to The grade of hydrophobicity turned out to have a major influence on the compressive and flexural strength. It was found that the hardened concrete bulk density and the water–cement ratio were in correlation with the compressive strength: while the first correlation for the compressive strength was positive as expected , the latThe type of aerogel granule also affected the shrinkage behaviors of the different mixtures: While there was no significant change found for different particle size distributions (P100 and P250F), the influence of the mechanical and chemical properties of the granules was found to be high. The shrinkage deformations measured for HPAC_50-SUFA were ~70% less compared to P100, which might be a consequence of the higher compressive strength and compression modulus of SUFA . HPAC_50To investigate the possible effects of the hydrophobicity of the aerogels in the contact zone between aerogel particles and the cement matrix, micrographs were produced . It was