Savolitinib is a highly specific inhibitor of the MET tyrosine kinase. Both preclinical and clinical studies have shown its potential as a treatment for various cancers, including non-small cell lung cancer (NSCLC) as well as breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. It can be used as a standalone treatment for NSCLC patients with MET mutations and in combination with EGFR inhibitors for those who have developed resistance. Moreover, it is being investigated as a neoadjuvant therapy. Furthermore, savolitinib has demonstrated efficacy in gastric cancer and may be effective in combination therapy. Additionally, it has shown effectiveness in treating renal cancer and other gastrointestinal cancers.MET mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with MET mutations and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with  MET proto-oncogene receptor tyrosine kinase have been well studied in non-small cell lung cancer (NSCLC). Mesenchymal epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs) such as crizotinib, capmatinib, tepotinib, savolitinib, and cabozantinib, which target MET exon 14 mutations, have been approved by the Food and Drug Administration (FDA). These FDA-approved MET TKIs are widely used as therapeutic agents worldwide [Cancer continues to be a major cause of death worldwide. Recently, large-scale genetic profiling in cancer has been utilized to identify additional therapeutic agents through genetic profiling . Consequorldwide ,3.MET TKIs are classified into three types based on their mechanism of action. Type I MET TKIs act as adenosine triphosphate (ATP) competitors and target the ATP binding pocket of the active form of the MET receptor. There are two subtypes of Type I inhibitors: Ia inhibitors, such as crizotinib, which target the amino acid residue known as G1163, and Ib inhibitors, such as capmatinib, tepotinib, and savolitinib, which strongly bind to the amino acid residue Y1230. Type II MET TKIs, such as cabozantinib, are also ATP competitors but bind to the inactive state of the MET receptor, inhibiting ATP-dependent activation by targeting the receptor’s inactive form. Type III TKIs are allosteric inhibitors . We willMesenchymal epithelial transition factor (MET), also known as c-MET or the Hepatocyte Growth Factor (HGF) receptor, is a tyrosine kinase receptor that is typically expressed in various cell types, including epithelial cells, endothelial cells, neurons, hepatocytes, and hematopoietic cells ,5,6,7,8.HGF is the ligand for MET, and its binding induces the dimerization of MET receptors and the subsequent phosphorylation of specific tyrosine residues, called Tyr1230, Tyr1234, and Tyr1235, within the kinase domain. This phosphorylation creates a docking site for proteins involved in RTK-mediated signal transduction, leading to the activation of downstream signaling pathways . One of HGF-bound MET receptors are normally ubiquitinated, and they are internalized via endocytosis, where they are either degraded or recycled back to the plasma membrane. Consequently, dysregulation of the MET signaling system is associated with various malignancies. Aberrant receptor trafficking, degradation, or disrupted recycling can result in sustained signaling, contributing to cellular transformation, oncogenesis, and metastasis.Abnormalities in the MET signaling system can arise from different mechanisms, including gene amplification, receptor protein overexpression, MET exon 14 junctional membrane skipping mutations (METex14), and MET gene chromosomal fusions . The assJuxtamembrane domain (JMD)-deleted MET was generated by MET exon 14 skipping mutations due to intronic mutations. The expression of MET-exon14 variants in cells disrupts the association with the CBL E3 ubiquitin ligase, reducing ubiquitination and prolonging the activation of signaling molecules. The phosphorylation of MET-Y1003 in the juxtamembrane domain is typically involved in CBL binding for ubiquitination. Therefore, MET-exon14 variants may have increased protein stability and enhanced signal transduction, contributing to oncogenesis ,20 FiguA.Abnormal activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon14 skipping, and other activating mutations B, is assMET exon14 skipping has been recognized as a true oncogenic driver, and MET TKIs targeting MET exon14 skipping mutations have shown significant improvements in clinical outcomes, including response rates and progression-free survival. Studies investigating the HGF/MET pathway have been conducted in various cancer types, including NSCLC, breast cancer, head and neck cancer, colorectal cancer, gastric cancer, pancreatic cancer, and other gastrointestinal cancers. Genetic alterations in the MET gene and pathway are common in solid tumors .MET overexpression is indeed believed to be one of the early dysregulations in the process of carcinogenesis. In the presence of hypoxia and inflammation, MET receptors are transcriptionally upregulated, leading to their overexpression. This overexpression contributes to tumorigenesis by promoting cell proliferation, inhibiting apoptosis, and enhancing cell migration. MET overexpression has been observed in various types of cancer, including epithelial, mesenchymal, and hematologic cancers. Additionally, MET can also be overexpressed in cancers with an activated genomic signature, including those with primary and/or secondary MET amplifications or MET exon 14 junctional membrane skipping mutations.During the characterization of HGF as a fibroblast-secreted protein that promotes motility and matrix invasion of epithelial cells, the induction of invasiveness into collagen by HGF was observed. HGF, a factor derived from fibroblasts, plays a role in facilitating the aggressive invasion of cancer cells. The microenvironment of metastatic tumors plays a crucial role in metastatic colonization and growth. Various stromal cells, including inflammatory cells, endothelial cells, and fibroblasts, contribute to the formation of the metastatic microenvironment. The function of HGF as a stromal cell-derived factor influences cancer cell invasiveness within the tumor microenvironment. Inhibiting HGF activity has been shown to prevent invasion induced by stromal fibroblasts.Additionally, MET receptors present in exosomes have been found to promote the formation of a metastatic microenvironment in metastatic melanoma . ExosomeSavolitinib is an oral medication classified as a selective MET inhibitor. It has been specifically developed for the treatment of several types of cancer, including NSCLC, breast cancer, head and neck cancer, colorectal cancer, gastric cancer, pancreatic cancer, and other gastrointestinal cancers. Preclinical studies have shown that savolitinib exhibits superior efficacy in these cancer types .Savolitinib is rapidly absorbed. Absolute oral bioavailability was 69%, the median maximum observed concentration was 3.5 h, and the mean terminal half-life was 6.1 h. 56% were found in urine and 38% in feces. Approximately 3% of the administered dose was excreted as unmetabolized savolitinib in the urine. Savolitinib has moderate tissue distribution, low to moderate clearance, and low accumulation. Most of the elimination of savolitinib occurs through metabolism via multiple pathways. Hepatic oxidative metabolism, followed by urinary and biliary excretion, were the major elimination pathways. The concentration at which half of the maximal Hs746t tumor reduction by savolitinib was achieved and the IC50 for MET inhibition were equal to 12.5 and 3.7 nM (free drug), respectively . There wSavolitinib demonstrated a well-tolerated safety profile consistent with previous clinical trials. Most adverse events were of grade 1 or 2 and resolved with dose adjustment or discontinuation. The most common treatment-related adverse events (TRAEs) were peripheral edema (56%), nausea (46%), and aminotransferase elevations (38%). The highest treatment-related grade 3 adverse event was AST elevation (13%) . Common Savolitinib had a well-tolerated safety profile consistent with previous clinical trials, with most adverse events being grade 1–2 and resolved with dose adjustment and discontinuation. The most common treatment-related adverse events (TRAEs) reported were hepatic dysfunction (4.3%), drug hypersensitivity reactions (2.9%), and pyrexia (2.9%). A treatment-related fatal SAE, tumor lysis syndrome, was reported in one patient. Pulmonary interstitial pneumonia and interstitial lung disease (ILD) did not occur with savolitinib, whereas ILD was observed with tepotinib and capmatinib.Savolitinib has been associated with the side effect of QTc prolongation, which refers to a lengthening of the QT interval on an electrocardiogram (ECG). In a study specifically examining QT/QTc, a single dose of 600 mg of savolitinib resulted in the highest root mean square ΔΔQTcF  of 12 milliseconds, observed 5 h after administration. However, savolitinib did not have any significant effects on other ECG intervals such as PR, QRS, QT, or RR intervals. The study found that QTcF prolongation occurred with a single dose of 600 mg of savolitinib, and a lesser increase of 5 milliseconds was noted with a dose of 300 mg. As a result, ongoing and future clinical trials involving savolitinib will include ECG monitoring to assess the clinical relevance of these observed QT changes ,29. One Resistance to MET TKIs is inevitable. Previous studies have suggested that savolitinib resistance in NSCLC is driven in part by MYC overexpression in H1993 cells . AccordiA 74-year-old woman with gastric cancer and extensive liver metastases experienced rapid disease progression following TS-1 chemotherapy. She was then treated with savolitinib. Initially, ctDNA analysis during the PR phase showed no MET amplification. However, after four cycles of savolitinib, her PR was confirmed radiologically, accompanied by a slight increase in MET copy number (2.7) and the emergence of a TP53 G245D variant with a 2% allele frequency in ctDNA. The tumor size decreased by 83.5% compared to baseline. Unfortunately, after six months of treatment, radiologic progression occurred. The patient exhibited high levels of MET amplification (13 copies) and a CDK6 copy number of 3.9 at the time of disease progression. Notably, there was strong concordance between the ctDNA and tumor tissue DNA derived from liver metastasis. Both samples displayed a resurgence of MET and CDK6 amplification, which was not detected during the PR phase. Additionally, the ctDNA sample obtained at the time of progression indicated the expansion of a clone containing the TP53 G245D substitution, evidenced by an increase in allele fraction from 2% (at the third follow-up) to 22% (at progression) .Several studies have demonstrated the predictive value of MET biomarkers in identifying patients who will benefit most from HGF/MET-targeted therapies administered as monotherapy or in combination . InflammThe VIKTORY  trial is the first and largest platform study in gastric cancer, supporting both the validity and clinical utility of tumor profiling. This study was designed to stratify patients with metastatic gastric cancer based on clinical sequencing and assign patients to one of 10 s-line treatment-related clinical trials, focusing on eight biomarker groups . The study showed that treatment cohorts assigned to biomarkers had encouraging response rates and survival compared to conventional second-line chemotherapy. Analysis of circulating tumor (ctDNA) showed a good correlation between high MET copy number by ctDNA and response to savolitinib .ctDNA biomarkers also allow longitudinal monitoring of clinical outcomes with savolitinib in patients with MET exon 14 skipping mutation-positive NSCLC and other NSCLC subtypes. Specifically, undetectable baseline MET exon 14 skipping mutations or post-treatment clearance may predict favorable clinical outcomes, and secondary MET mutations and other acquired genetic alterations may explain resistance to savolitinib .MET amplification and papillary renal cell carcinoma (PRCC) [Savolitinib has been shown to inhibit the growth of gastric cancer cell lines in in vitro studies. Additionally, in vivo studies have demonstrated anti-tumor activity in models of gastric cancer with a (PRCC) . A pharma (PRCC) .A phase 1 clinical trial was conducted in Australia (NCT01773018), involving 48 patients with locally advanced solid tumors. Savolitinib was administered at various doses, with a maximum tolerated dose of 800 mg. The trial showed the preliminary effectiveness of savolitinib in patients with papillary renal cell carcinoma who had MET gene copy number alterations. The most common adverse events reported were nausea (63%), vomiting 42%), fatigue (35%), and peripheral edema (27%). Savolitinib was considered tolerable, and the recommended phase 2 dose was established at 600 mg daily ,42.%, fatiguIn another phase 1 clinical trial conducted in China (NCT019855), involving patients with progressive tumors and MET mutations, savolitinib demonstrated a manageable safety profile and promising anti-tumor activity. Although no partial response (PR) was achieved, there was a significant reduction in tumor size in some lesions (55% and 27%). The most common treatment-related side effects included nausea (29.4%), vomiting (27.1%), and peripheral edema (21.2%). The recommended phase 2 dose of savolitinib in this trial was set at 600 mg once daily or 500 mg twice daily. There were similarities between the patients enrolled in the phase 1 clinical studies conducted in Australia, allowing for a comparative analysis of the results ,42.MET exon 14 skipping mutations. The trial included 70 patients who received savolitinib monotherapy until disease progression or unacceptable toxicity. The daily dosage ranged from 400 mg (less than 50 kg) to 600 mg (more than 50 kg) based on patient weight. Most enrolled patients were elderly and had advanced NSCLC with prior systemic treatment.A pivotal Phase 2 trial (NCT02897479) was conducted in China to assess the efficacy and safety of savolitinib in patients with non-resectable or metastatic NSCLC carrying the The trial analyzed the data using the Independent Review Committee (IRC) and investigator assessments in the full analysis set (FAS) and tumor response evaluable set (TRES). Among the TRES patients evaluated by the IRC, there were 62 patients. Most patients in the FAS had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Subset analyses were performed comparing different NSCLC subtypes and treatment experiences.With a median follow-up duration of 28.4 months, the trial demonstrated encouraging efficacy results. The median overall survival (OS) was 12.5 months, with 18-month and 24-month OS rates of 42.1% and 31.5%, respectively. Pretreated patients had a median OS of 19.4 months, while treatment-naive patients had a median OS of 10.9 months. Patients with primary squamous cell carcinoma (PSC) had a median OS of 10.6 months, while other NSCLC subtypes had a median OS of 17.3 months. Patients with brain metastases had a median OS of 17.7 months. No new safety concerns were observed with prolonged follow-up and exposure, indicating that savolitinib had an acceptable safety profile ,44,45.Currently, there are four phase 3 clinical trials investigating the efficacy and safety of savolitinib in various treatment settings for NSCLC patients.Phase 3b Study (CTR20211151) aims to evaluate the efficacy and safety of savolitinib in two cohorts of locally progressive or metastatic NSCLC patients with MET exon 14 skipping mutations in China. One cohort includes patients who have previously received platinum-based chemotherapy but have experienced disease progression or intolerable toxicity, while the other cohort consists of patients who have not received systemic chemotherapy for advanced disease. Patients in both cohorts are treated with savolitinib until disease progression or intolerable toxicity.Phase 3 Clinical Trial SACHI (CTR20211441), which is a randomized, two-arm, open-label, multi-organ study, is being conducted in China. It aims to evaluate the efficacy and safety of savolitinib in combination with osimertinib (an EGFR-TKI) compared to chemotherapy in Chinese patients with MET-amplified NSCLC who developed the disease after treatment with 1st to 3rd generation EGFR-TKIs. This trial has already started recruiting patients at multiple centers.SAFPRON Phase 3 Clinical Trial focuses on advanced NSCLC patients worldwide with advanced MET amplification or MET overexpression after treatment with osimertinib. It aims to evaluate the efficacy and safety of the combination therapy of savolitinib plus osimertinib compared to chemotherapy.SANOVO Phase 3 Clinical Study (NCT05009836) is evaluating the efficacy and safety of the combination therapy of savolitinib and osimertinib in patients with EGFR mutation-positive NSCLC and MET overexpression who have not received prior treatment.Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all lung cancers. It has considerable heterogeneity and may be associated with some known and/or unknown causative gene changes. NSCLC has a very poor prognosis, with significantly lower OS and 5-year survival rates compared to other types of lung cancer.MET exon 14 skipping mutation. MET exon 14 skipping mutation is most common in NSCLC. Mutations resulting in the loss of exon 14 in the MET gene lead to dysregulation and inappropriate signaling, which are associated with increased responsiveness to MET TKIs [NSCLC is increasingly treated with targeted therapies. Savolitinib is a highly selective MET-TKI for advanced NSCLC with a MET TKIs ,47.MET amplification is indeed more common in MET exon 14 skipping mutation NSCLC, with reported frequencies of 15–21%. MET amplification occurs about 4% in lung adenocarcinomas and 1% in squamous cell lung cancer. The overall incidence of MET exon 14 skipping mutations in NSCLC is 3% to 4% with untreated NSCLC or previously treated molecularly driven NSCLC, such as EGFR, and acts as a mechanism of acquired resistance. Adenocarcinoma has a relatively higher incidence than squamous cell lung cancer (1.5–2.0%). Pulmonary sarcomatoid carcinoma has 20–30% MET exon 14 skipping mutations [MET exon 14 skipping mutations itself occurs with higher frequency in Caucasian patients compared to Asian patients, and it is more frequently observed in smokers or ex-smokers. However, it is worth noting that approximately one-third of patients with MET exon 14 skipping mutation NSCLC are never smokers. Furthermore, the MET exon 14 skipping mutations is more commonly found in women than in men. In general, MET exon 14 skipping mutation NSCLC tends to occur in older individuals, with a median age of 74, which is higher than NSCLC cases with other molecular drivers [MET exon 14 skipping mutations, independent of expression of programmed death ligand-1 (PD-L1) [utations . The MET drivers . Data fr (PD-L1) .Savolitinib has demonstrated efficacy in first- and second-line settings, including in patients with NSCLC and aggressive pulmonary sarcomatoid carcinoma, and has an acceptable safety profile. It can also cross the blood-brain barrier and has demonstrated some activity against central nervous system metastases . PatientMET exon 14 skipping mutation-positive locally advanced primary lung adenocarcinoma. In one case, a patient received 5 weeks of neoadjuvant treatment with savolitinib and experienced a significant reduction in tumor burden and lymph node size. Subsequently, a successful lobectomy and lymph node dissection were performed, resulting in a pathological response of 50% and a post-operative pathological staging of pT1cN0M0, IA3 [Savolitinib has been shown to be effective in neoadjuvant chemotherapy for lung cancer, specifically in cases of 0M0, IA3 .MET exon 14 skipping mutations was successfully treated with savolitinib. After neoadjuvant savolitinib, the primary tumor shrank by 82%, and only 5% of the tumor remained viable at the time of subsequent radical surgery [In another study, three patients with locally advanced, unresectable NSCLC received induction therapy with savolitinib as a first- or second-line treatment after their disease had progressed following pre-operative chemotherapy. All three patients experienced a significant reduction in tumor size, with previously unresectable tumors becoming resectable after treatment with savolitinib . In a se surgery ,56.MET exon 14 skipping mutation in NSCLC who was initially unsure of intrapulmonary metastases and had recently undergone percutaneous coronary intervention for acute myocardial infarction. The patient received savolitinib at a dose of 600 mg once daily and experienced significant tumor shrinkage. After six months, no metastatic lesions were found, and the patient was diagnosed with early-stage lung cancer. A radical tumor resection was performed, and the patient recovered successfully [Another case report described a patient with the essfully .MET exon 14 skipping mutation NSCLC, particularly those who are not suitable candidates for surgery. It has demonstrated the potential to reduce tumor size, make previously unresectable tumors resectable, and improve pathological responses in the neoadjuvant setting.Based on these cases, savolitinib appears to be a valuable treatment strategy for patients with Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of NSCLC that accounts for a small percentage of primary lung cancers. PSC is characterized by poor differentiation and more aggressive behavior compared to other types of lung cancer. Survival rates for PSC are generally low, and patients with advanced disease have poor outcomes, including survival rates of less than 5% and shorter survival times ,58.MET proto-oncogene. The most common and well-studied mutation is the exon 14 skipping mutation, which is found in a significant proportion of PSC cases. In addition, amplification and overexpression of the MET gene have been observed in a smaller percentage of patients. These molecular alterations have important implications for targeted therapies in PSC [Recent studies have focused on gene mutations associated with PSC, particularly in the s in PSC .MET exon 14 skipping mutations in patients with locally advanced or metastatic NSCLC, including those with sarcomatoid histology. Preliminary data from the trial, involving 70 patients, demonstrated promising results. The treatment showed a notable ORR of 47.5% and a median progression-free survival of 6.8 months. Importantly, these positive outcomes were observed in patients who had not received prior MET inhibitor therapy.A Phase 2 clinical trial is underway to evaluate a treatment specifically targeting the MET exon 14 skip mutation) can be seen as a combination therapy with EGFR TKI [There have been studies in which MET TKI  demonstrated significant tumor suppressive effects in NSCLC cell line models with fication .n = 18) who had previously advanced disease after EGFR-TKI treatment [MET-amplified and EGFR mutant-positive NSCLC. The ORR was 49% in patients with MET amplification and an EGFR mutation. The combination therapy showed a manageable safety profile [Phase 1 Study : The combination of savolitinib and osimertinib was evaluated in patients with advanced NSCLC who had previously progressed on EGFR-TKI treatment. The study demonstrated the safety and resistance of Osimertinib and Savolitinib in patients with advanced NSCLC  was 32%, and the median duration of response was 8.3 months. Patients with high MET amplification or high threshold MET overexpression showed better efficacy [Phase 2 Study (SAVANNAH) evaluated the efficacy of savolitinib in combination with osimertinib in patients with efficacy .MET amplification and/or MET overexpression, with or without savolitinib. The SAFFRON trial is comparing the combination of savolitinib and osimertinib with platinum-based chemotherapy in patients with NSCLC after osimertinib treatment [The FLOWERS trial is investigating the efficacy and safety of osimertinib in patients with novel reatment .EGFR mutation, MET overexpression, and/or MET gene amplification) after Osimertinib treatment.A phase 3 trial, the SAFFRON trial (NCT05261399), is underway to compare savolitinib and Osimertinib combination therapy with platinum-based double chemotherapy in patients with disease-induced NSCLC  conducted in China evaluated the combination of savolitinib and gefitinib (a first-generation EGFR-TKI) in patients with advanced disease EGFRm and reatment .C.savolitinib + durvalumabMET mutations. The trial will include 30 patients with MET amplification and 30 patients with MET exon 14 skipping mutations. These patients will receive treatment with 1500 mg of durvalumab and 300 to 600 mg of savolitinib (once daily) for a 28-day treatment cycle. The treatment will continue until disease progression, death, or the occurrence of toxicity. The trial is currently ongoing.The ongoing SOUND Clinical Trial (NCT05374603) is an open-label, multicenter, exploratory clinical trial that aims to investigate the combination therapy of savolitinib and durvalumab in Chinese patients with EGFR wild-type topical or metastatic NSCLC who have MET gene, targeting MET may be a promising therapeutic approach. Savolitinib has demonstrated anti-tumor activity in patients with PRCC. In previous studies, MET-driven PRCC has shown better treatment response compared to MET-independent PRCC [Papillary renal cell carcinoma (PRCC) is the most common subtype of non-clear cell renal cell carcinoma and has a poor prognosis, particularly in advanced stages . Since sent PRCC ,68.The SAVOIR phase 3 clinical trial, a multicenter study, evaluated the efficacy of savolitinib compared to sunitinib, a standard treatment for advanced PRCC. The trial enrolled 60 patients, with most having chromosome 7 gain and no prior therapy. However, due to the availability of external data on progression-free survival (PFS) with sunitinib in patients with MET-driven disease, enrollment in the study was closed prematurely. Preliminary results showed that savolitinib had numerically greater median PFS, OS, and ORR compared to sunitinib. However, the difference in median PFS between the two groups (7.0 months for savolitinib and 5.6 months for sunitinib) was not statistically significant. Grade 3 or higher adverse events (AEs) were less frequent in the savolitinib group compared to the sunitinib group, and fewer dose modifications related to AEs were required. After discontinuation of treatment, a higher proportion of patients in the savolitinib group received subsequent anticancer therapy. Although the study had limited patient numbers and follow-up, savolitinib demonstrated promising efficacy and a more favorable safety profile compared to sunitinib in MET-driven PRCC. Further investigation is needed to determine the potential of savolitinib as a treatment option for MET-driven PRCC .The combination therapy of savolitinib and durvalumab showed remarkable effectiveness in overcoming drug resistance and demonstrated a high clinical response rate in exploratory MET-based metastatic papillary renal cell cancer. Durvalumab has side effects such as rash (48%), vomiting (43%), and diarrhea (39%) .MET amplification. Further genomic analysis showed that patients with a MET GCN > 10 by tissue next-generation sequencing had an ORR of 70% for savolitinib, inferring that the subset of patients with MET amplification experienced a greater absolute reduction in tumor burden [The phase 2 VIKTORY umbrella trial showed that in patients with metastatic and/or recurrent gastric adenocarcinoma, savolitinib monotherapy had an ORR of 50% (10/20) in the subset of gastric cancer patients with r burden .MET gene amplification in the tumor. After 39 days of daily treatment with 400 mg savolitinib, the patient achieved a PR, and both anemia and thrombocytopenia improved. No significant side effects were observed, and the patient remained progression-free for 14 weeks [A case was reported of a 35-year-old man with advanced gastric cancer and bone, adrenal, and lumbar-2 vertebral metastases. The patient was resistant to chemotherapy, in poor general condition, and had thrombocytopenia and anemia. NGS analysis revealed 14 weeks .MET amplification confirmed by FISH. With savolitinib treatment, the patient experienced a significant reduction in tumor volume, achieving a PR lasting six months. The maximum tumor diameter decreased by 47.7% compared to the baseline measurement. Genomic sequencing of ctDNA samples indicated that the patient had a non-shedding tumor, as no variants, including MET amplification or mutations, were detected across a 100-gene panel [Another case showed that a 31-year-old woman underwent a total gastrectomy in 2013 for stage pT4N3M0 gastric cancer. The tumor was a poorly differentiated tubular adenocarcinoma, and the patient was microsatellite stable and HER2-negative. Oophorectomy revealed MET IHC3+ and ne panel .MET gene amplification and rearrangement in the tumor. Following savolitinib treatment, the patient’s condition improved significantly, achieving partial remission. At the time of reporting, the patient had remained alive and free of disease progression for 15 weeks without any notable adverse reactions. Additionally, another female gastric cancer patient with MET amplification who received savolitinib monotherapy as a third-line treatment also showed no signs of disease progression for 12 weeks [The other case presented was a case study of a 47-year-old male with advanced gastric cancer, bone marrow invasion, and extensive metastases. The patient experienced severe pain, thrombocytopenia, and hemorrhagic anemia. Due to chemotherapy resistance, the patient underwent monotherapy with savolitinib. Savolitinib was administered based on the presence of 12 weeks .2 would be the recommended phase II dose. This combination therapy showed highly encouraging anti-tumor effects and resulted in sustained responses among patients with MET-amplified Gastric cancer in the subsequent phase II clinical trial [In a phase I trial, it was suggested that the combination of savolitinib at a dose of 600 mg once daily with docetaxel at a dose of 60 mg/mal trial .MET-amplified HCC progressing after 3 months on bevacizumab and sintilimab and maintaining PR for more than 8 months with manageable adverse events with savolitinib. This suggests that savolitinib may be a therapeutic option for MET-amplified HCC [Systemic treatment of hepatocellular carcinoma (HCC) includes immune checkpoint inhibitors, bevacizumab, and other TKIs. It is not the primary option of choice due to poor overall response and median progression-free survival. A case has been reported of a patient with fied HCC .MET-amplified inoperable colorectal cancer. They have RAS-wild-type mCRC and have previously been treated with standard therapies. MET amplification will be detected using a blood-based genomic profiling assay. Savolitinib may inhibit the growth of tumor cells by blocking some of the enzymes needed for cell growth. Patients receive oral savolitinib 600 mg daily on days 1–28. Cycles are repeated every 28 days in the absence of disease progression or unacceptable toxicity. The study aims to estimate the ORR of savolitinib in this patient population. Secondary objectives include evaluating progression-free survival, duration of response, safety, and tolerability. The study will also explore the correlation between tissue- and blood-based biomarkers and clinical outcomes. Blood samples will be collected at baseline and during restaging to determine if savolitinib eliminates MET amplification in circulating cfDNA [The phase II study (NCT03592641) is currently underway to determine how well savolitinib works in treating patients with ng cfDNA .MET. Therefore, targeting the MET/HGF pathway could be an option for adjuvant therapy in pancreatic cancer. One of the reasons for chemotherapy resistance in PDAC is the extensive desmoplastic reaction surrounding the tumor, which creates a physical barrier that hinders drug penetration. In this context, reducing the metastatic potential of cancer cells and reprogramming the dysfunctional tumor microenvironment could have potential benefits for the treatment of pancreatic cancer.Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), is a highly aggressive illness known for its tendency to spread early. It is characterized by a dense and collagen-rich supportive tissue called desmoplasia or stroma, which is primarily generated by pancreatic stellate cells (PSCs). PSCs have a role in communicating with cancer cells and other stromal cells, thereby facilitating the advancement of the disease. One specific pathway involving growth factors that potentially enables this interaction is the hepatocyte growth factor (HGF)/MET pathway. HGF is produced by PSCs, while its receptor MET is present in pancreatic cancer cells and endothelial cells . The actStudies of other MET TKIs such as cabozantinib, crizotinib, and capamatinib for pancreatic cancer have shown that studies suggest that TKIs such as savolitinib may be effective in pancreatic cancer. In 2013, Hage et al. examined the therapeutic potential of cabozatinib through in vitro studies. They observed that the effectiveness of gemcitabine, a commonly used chemotherapy drug, was enhanced even in pancreatic cancer (PC) cells that had developed resistance to high levels of gemcitabine. Additionally, they investigated patient-derived primary spheroidal cultures that were enriched in cancer stem cell markers and found that the agent demonstrated increased efficacy in these cultures as well .In vitro experiments showed a synergistic interaction between crizotinib and gemcitabine, as evidenced by the reduced growth of primary PDAC cells. Similarly, in vivo experiments revealed a synergistic effect on primary tumor growth. However, the impact of this combination on metastatic spread remains unclear and requires further investigation .MET expression and evaluate the cells’ response to capamatinib in the future. They observed that inhibiting MET decreased the proliferation and migration of PC cells induced by hepatocyte growth factor (HGF) [In an in vivo study utilizing mouse models of PC, treatment with capamatinib demonstrated a reduction in the movement of PC cells. The treatment group exhibited a 30% lymph node involvement, whereas the control group had a higher 60% involvement, indicating a potential suppression of metastasis. Furthermore, the researchers investigated various PC cell lines (human and murine) to confirm or (HGF) .Based on this, we believe that savolitinib, a MET TKI targeting the MET/HGF pathway, may be beneficial in the treatment of pancreatic cancer, and further studies may be conducted in the future.MET mutations. It has been developed for the treatment of non-small cell lung cancer, breast cancer, head and neck cancer, colorectal cancer, gastric cancer, pancreatic cancer, and other gastrointestinal cancers and has demonstrated good efficacy in preclinical and clinical studies.With the development of NGS technology, MET TKIs are being actively studied in addition to traditional targeting agents. Particularly, savolitinib, a small molecule, highly selective type Ib MET TKI, is being developed for the treatment of non-small cell lung cancer with MET mutations are found.In non-small cell lung cancer, savolitinib has shown promising anti-cancer activity in chemotherapy-resistant patients with single or combination therapy and has also shown promise in kidney, gastric, liver, and pancreatic cancers. Through interactions with the HGF/MET signaling pathway in the tumor microenvironment, we can expect savolitinib to be particularly effective in pancreatic cancer. The results of these preclinical studies are encouraging for further research, and savolitinib is expected to be a promising treatment for other types of cancer, including gastrointestinal cancers, where


Synthetic lethality (SL) is a promising strategy for anticancer therapy, as inhibiting SL partners of genes with cancer-specific mutations can selectively kill the cancer cells without harming the normal cells. Wet-lab techniques for SL screening have issues like high cost and off-target effects. Computational methods can help address these issues. Previous machine learning methods leverage known SL pairs, and the use of knowledge graphs (KGs) can significantly enhance the prediction performance. However, the subgraph structures of KG have not been fully explored. Besides, most machine learning methods lack interpretability, which is an obstacle for wide applications of machine learning to SL identification.We present a model named KR4SL to predict SL partners for a given primary gene. It captures the structural semantics of a KG by efficiently constructing and learning from relational digraphs in the KG. To encode the semantic information of the relational digraphs, we fuse textual semantics of entities into propagated messages and enhance the sequential semantics of paths using a recurrent neural network. Moreover, we design an attentive aggregator to identify critical subgraph structures that contribute the most to the SL prediction as explanations. Extensive experiments under different settings show that KR4SL significantly outperforms all the baselines. The explanatory subgraphs for the predicted gene pairs can unveil prediction process and mechanisms underlying synthetic lethality. The improved predictive power and interpretability indicate that deep learning is practically useful for SL-based cancer drug target discovery.https://github.com/JieZheng-ShanghaiTech/KR4SL.The source code is freely available at  Cancer is a group of human diseases for which interactions among many genes play crucial roles . TherefoComputational methods for SL prediction can be categorized into three types: statistical inference, network-based methods, and supervised machine learning methods . The sta2MF Another type of methods is supervised machine learning, which can be divided into traditional machine learning and deep learning methods. For instance, DiscoverSL uses multi-omics data  to extract gene features and employs random forest to predict SL pairs. SLIncorporating prior knowledge into the above supervised learning models can improve their interpretability. Knowledge graph (KG) is a graph-based data model to integrate structured knowledge using a network of entities (nodes) and relations between entities (edges of various types), which is a type of heterogeneous graph. The nodes and edges in a KG usually have well-defined descriptions which are easy to understand . KGs an. By explHowever, the above KG-based methods could fail to find some structures or patterns in a KG that are important for the predictions and interpretability for the following reasons. First, KG4SL and PiLSL randomly sample the neighbors for a gene or a pair of genes, and thus some important semantic structures of the KG may be excluded when learning the gene representations. Second, these methods are based on gene embeddings, i.e. two genes with similar embeddings are likely to have SL relationship. As such, KG structures are implicitly encoded into the latent embeddings, which makes it hard to find important graph structures directly. Although PiLSL has used the learned attention weights to extract important subgraphs as explanations, the attention weights of different layers may lead to different explanations. SLGNN selects the important entity types as explanations, whereas such entity types cannot explain the specific SL mechanisms. Therefore, it is urgently needed to develop an explainable AI model that is able to capture the crucial KG structures for SL prediction and interpretation.Path-based reasoning on KG has been widely used in recommendation systems, KG completion and drug-disease prediction . A “relaHere, we propose Knowledge Graph Reasoning for Synthetic Lethality (KR4SL), an end-to-end framework for explainable prediction of SL interactions. First, we design an encoder which automatically constructs multiple relational digraphs from a KG, and then performs reasoning within these graphs starting from the primary gene. Second, during the reasoning process at a layer, we combine the structure information of the relational digraphs and textual semantics of entities as propagated messages, and we further enhance the sequential semantics of the relational paths within each relational digraph. In this way, we can obtain powerful semantic representations for gene pairs to support SL predictions. Third, an attentive aggregation is conducted to distinguish the importance among different edges, so we can select the most important edges to form paths as explanations. Experimental results under two scenarios show that KR4SL achieves the best performance compared with all the baselines. By analyzing the explanations in two case studies, we find that our model can not only interpret the prediction process but also provide explanatory evidence for the predicted SLs consistent with biological prior knowledge. In summary, our contributions are as follows:We highlight the importance of deploying the structural information of relational digraphs from a heterogeneous graph for SL prediction.We present a novel KG reasoning-based model named KR4SL which learns the semantic representations of gene pairs by efficiently encoding the structural information of relational digraphs in the KG and the textual semantics of entities and enhancing the sequential semantics using a gated recurrent unit (GRU). In addition, it uses attention mechanisms to identify important subgraphs as explanations. In short, KR4SL integrates the strengths of path-based methods and GNN-based methods for KG reasoning and offers interpretability.We conduct experiments on a real dataset, under two different settings. The experimental results demonstrate that KR4SL has superior performance for SL prediction compared with multiple state-of-the-art models. In addition, through case studies, we show that KR4SL can provide intuitive explanations by revealing the prediction process and providing evidence that sheds light on biological mechanisms of SL.In this section, we first briefly exhibit the preliminaries and problem formulation, and then we introduce the detailed implementations of our framework.SL graph. We represent the observed SL interactions as a graph M is the number of genes and Knowledge graph. In addition to the SL interactions, we also have external knowledge about the functions of genes, such as pathways and biological processes. We represent these information as a KG Relational directed graph. Suppose that we have a heterogeneous graph qg and a target entity pg. The graph has K layers, and the nodes at a same layer are different from each other. In this graph, any path from qg to pg is a relational path with length K, as a form of kr is an edge pointing from a node in the k-th layer.Problem statement. Given a primary gene qg and the heterogeneous graph qg, and qg. Our task is to infer N genes from qg. To achieve this, we can cast all genes in qg and predict the scores for them. Then from the predicted scores, we select the scores of genes in qg, the designed encoder automatically finds relational paths and conducts reasoning along these paths. At each layer, the structural semantics of KG and the textual semantics  are fused as the passed messages, and sequential semantics of relational paths are enhanced through a GRU module  and one of its candidate gene pg (the target node), we repeat the following processes within K times:Before diving into the details of our model, we introduce the overall reasoning procedures. For a primary gene For a source node, find all the neighbors as the target nodes;Propagate the message from the source node to its target nodes and only calculate the representations of target nodes;Take target nodes as the source nodes for the next layer;Since the reasoning process is conducted within relational digraphs, we need to find the relational digraphs between a primary gene and all its candidate genes. A common approach is to extract subgraphs or paths for multiple gene pairs separately . HoweverK-hop relational digraph for K. Similarly, qg and an arbitrary entity K-hop relational digraphs with source entity qg aswhere K-th layer in Suppose that qg, we do not need to extract the relational digraph. Instead, we can recursively construct the union of all K-hop relational digraphs qg, using the strategy of dynamic programming  to train our model, through stochastic gradient descent strategy:where We performed experiments on SynLethDB dataset under two scenarios, i.e., transductive setting and inductive setting (see more details in Section 3.1.2). Our empirical study aims to answer the following research questions:RQ1: How does KR4SL perform compared to the current start-of-the-art methods?RQ2: How does the modeling of semantic information affect KR4SL?RQ3: Can KR4SL provide explanations about predicting gene pairs, and are these explanations reasonable to reflect SL mechanisms?The SL gene pairs we used are derived from SynLethDB-v2.0 . The genTo fully evaluate the performance of our model, we conducted experiments under the following scenarios.Transductive reasoning: Given a SL graph and a KG, the model infers the missed SL partners (or SL interactions) for a gene to complement the SL graph. In this setting, we split the dataset by gene pairs, thus the genes in the test set may exist in the training set.Inductive reasoning: The model infers SL partners for genes unseen during training. In this setting, the training set and the test set have disjoint sets of genes. This setting could further examine the generalization ability of the model.Recall that our model has no constraint on the number of negative gene pairs. During inference, for the primary gene, the model outputs the scores for all the candidate partner genes, and ranks the scores in descending order. Therefore, we leverage ranking metrics to evaluate the model performance, namely, NDCG@N , Precision@N, and Recall@N . Here, NFor transductive reasoning, we randomly split gene pairs as For inductive reasoning, we follow the general setting of link prediction tasks to split the datasets . The setL2 regularization is adopted. We tune the weight decay rate in . KR4SL-1h represents that the 1-hop neighboring genes of a primary gene are deemed as candidate partner genes, and similar notions for others. d is set to 16, and similar notions for others. From To test how the dimension of latent embeddings affects the model performance, we selected the embedding dimension in the range of . KR4SL-16d means that the size of latent semantic embeddings Since KR4SL is to infer SL pairs along relational paths within relation digraphs, the whole reasoning process can be unraveled. Furthermore, benefiting from the attention mechanism, we can select the important paths (or subgraphs) from original relational digraphs for the predicted SL pairs. Such paths (or subgraphs) can provide the reasoning evidence and also reveal the corresponding SL mechanisms. Specifically, for a primary gene and one of its predicted partners, we first extracted the 3-hop relational digraph for the two genes. To find paths as complete as possible, for the first two layers, we chose the edges with attention weights higher than a threshold (which is set to 0.9 according to the distribution of attention weights). We further selected edges at the last layer with attention weights within the top five. As such, we can obtain the complete paths or a subgraph with multiple paths. Here we show two cases drawn from the learned KR4SL so as to demonstrate the explainability of KR4SL.We first analysed the gene pair of BRCA1 and USP1. As a tumor suppressor gene, BRCA1 has an established role in DNA repair process. It can promote double-strand break repair through homologous recombination. USP1 is also crucial for DNA repair . By contAnother case is for ATM and ATR. ATR and ATM are signaling kinases that sense DNA damage and are major activators of DNA damage response . For ATMIn this article, we proposed an interpretable deep learning pipeline named KR4SL to recommend novel SL partner genes for primary genes using KG reasoning. Using dynamical programming to explore the subgraph structures in the KG, our model efficiently extracts the relational digraphs for a primary and all its candidate partners from a heterogeneous graph composed of known SL gene pairs and a biomedical KG. Each path within a relational digraph consists of a sequence of relations (i.e. triples in the KG), representing a rule supporting the process of KG reasoning. To capture the semantic information of the input graph, we designed an encoder which integrates the structural semantics of the graph, the textural semantics of entities in the KG and the sequential semantics of the extracted relational paths. Moreover, attentive aggregation is performed to distinguish important graph subgraphs that have contributed to the SL prediction significantly and hence can perform the role of model explanation. Experimental results under two settings demonstrate the superior performance of KR4SL. The case studies of subgraphs show that our model is explainable since it not only uncovers the reasoning process for the SL prediction but also provides evidence that sheds light on potential SL mechanisms.In the future, we plan to improve the interpretability based on this model. The extraction and interpretation of relational paths from the KG can be guided by biological prior knowledge . For insbtad261_Supplementary_DataClick here for additional data file.


In the hardened state, the properties studied were compressive strength and porosity at 15 h and 28 days, thermogravimetric analysis, and durability tests involving freeze–thaw cycles and accelerated carbonation. The results indicate the RAs lead to a decrease in slump flow. However, the substitution rate of aggregate replacement does not affect the compressive strength. This can be attributed to the optimized mix design, resulting in all SCC mixtures achieving the same compressive strength class of 30–35 MPa. As for the durability tests, the incorporation of recycled aggregates modifies the behavior of the concrete during freeze–thaw cycles. Throughout the 300 freeze–thaw cycles, all concrete mixtures exhibited a mass loss accompanied by a slight strain increase, but the materials remained visually intact. Additionally, the carbonation depth is strongly influenced by the rate of aggregate replacement due to changes in the microstructure, particularly in porosity.This work deals with the study of self-compacting concretes (SCCs) containing recycled aggregates (RAs) recovered from demolition waste and limestone filler as a partial replacement for natural aggregates (NAs) and cement, respectively. Four mix designs were developed and characterized in both the fresh and hardened states. In the fresh state, the properties studied included slump, sieve stability, and t This highlights the significant demand for concrete in construction activities throughout the continent. Specifically, in France, the production of concrete amounts to over 21 million tons per year. This substantial production volume contributes to the country’s construction industry, generating a considerable sales revenue of 19 billion euros, according to the French Federation of the Concrete Industry [Concrete is the most widely used construction material globally, with an annual production exceeding 10 billion m2eq [However, despite its advantageous qualities in terms of mechanical strength, durability, and cost-effectiveness, concrete has significant drawbacks related to its composition and manufacturing processes. The concrete industry is known for its high energy consumption and adverse environmental impact, particularly in terms of greenhouse gas (GHG) emissions. It is estimated that the production of concrete contributes to 5.2% of global GHG emissions. One of the main contributors to these emissions is cement production, which alone accounts for 52% of the total emissions associated with concrete. In France, for instance, the production of one ton of cement emits an average of 0.62 tons of CO2eq .Another concerning aspect is the extensive use of concrete in construction, which has additional negative consequences for the environment. One such consequence is the depletion of non-renewable natural resources, particularly sand and gravel, which are essential components of concrete production . The extIn addition to its contribution to global warming, the blatant use of concrete leads to a shortage of non-biodegradable natural resources, namely sand and gravel, which are essential for its manufacture . FurtherNowadays, the use of recycled aggregate in the manufacture of new concrete is becoming increasingly widely practiced. Recycled aggregate is obtained by processing concrete waste, demolishing structures, or reclaiming materials from other sources. The main advantage of using recycled aggregate is that it reduces the amount of construction waste sent to waste disposal sites, thus helping to preserve the environment. In addition, its use reduces the demand for natural materials, such as virgin aggregates extracted from quarries, thus helping to preserve natural resources. Although recycled aggregate may have slightly different particle sizes and properties compared to natural aggregates, it can be adapted and used effectively in the manufacture of concrete. Studies and research have been carried out to determine the appropriate proportions of recycled aggregate to use in each type of concrete, considering the required mechanical properties ,13. The Several current studies aim to find the appropriate mix design of low-carbon self-compacting concretes based on recycled gravel, obtained by adding a superplasticizer whose excess can lead to segregation and by incorporating mineralogical additives and recycled aggregate at relatively high rates , withoutIn fact, limestone fillers are widely used in the production of SCC . LimestoTo address the environmental issues associated with concrete production, the use of recycled gravel and alternative binders in concrete mix designs is indeed a necessary and viable solution. This approach helps to reduce the need for natural aggregates, as well as the depletion of natural resources and the carbon footprint. However, implementing these changes in concrete production does come with several significant challenges, namely rheological and mechanical performances, durability, and adaptability to the intended application.®  was replaced with limestone filler produced by Omya®  with a mass replacement ratio of 35%. Sand and coarse natural aggregates are classified as 0/4 and 4/12.5, respectively. Recycled aggregates are classified as 4/14, and their property classification is type 1 according to EN 206-1 [3 of the different constituents of the SCC. In fact, in the case of self-compacting concrete, the volume of binder paste should be around 40% of the total volume, to the detriment of the volume of aggregates.Experiments were carried out to investigate the partial or total replacement effect of aggregates by those resulting from the demolition of old buildings. The use of recycled aggregates would affect fresh and hardened properties of SCC. For all mix designs, cement (CEM I-52.5 R) provided by AALBORGEN 206-1 . Figure 500 according to the European standard EN 12350-8 [Following the steps presented in  12350-8 , critica 12350-8 , compres 12350-8 , thermog 12350-8 .2 concentration of 3%, a temperature of 23 °C and a relative humidity of 60%, in accordance with standard XP P18-458 [From the durability test point of view, the extreme freeze–thaw test was carried out on 3 test specimens measuring 10 cm × 10 cm × 40 cm for each mix design according to the European standard NF P 18-424 . The tes P18-458 . After 7As for viscosity, measured by the time it takes for the slump flow to reach a diameter of 500 mm (t500) and depicted in The water-accessible porosity and water absorption results at 28 days are presented in In standard concrete, a single ITZ exists, positioned between mortar and natural coarse aggregate. However, when incorporating recycled aggregate sourced from construction and demolition waste, a three-phase composite emerged. This composite includes aged natural aggregate, the associated cement mortar, and the previous ITZs between these materials. Consequently, the integration of recycled aggregate introduces at least two distinct types of ITZs into the concrete matrix . These nIn addition, due to the consistency required in the fresh state, the 100%RA contained more water than the other mix designs due to the high absorption of recycled aggregate, as shown in 2) at a temperature of between 400 and 480 °C, and the last relates to the decarbonation of the calcite phase (CaCO3) at between 750 and 850 °C [3 [In order to discuss the mechanical strength results, thermogravimetric size analysis was carried out on all concrete at 15 h and 28 d of curing. The results shown in d 850 °C . Further50 °C [3 . The fin50 °C [3  and cont2 penetration was proportional to the exposition time [2, which reduces the pH of the pore solution [3) to the detriment of the calcium silicate hydrate (CSH), the portlandite phase (Ca(OH)2), and calcium oxide (CaO), as shown by [2 uptake at 7 days of exposition. After that, the carbonation depth increased with the replacement rate of the recycled aggregates. In general, the accelerated carbonation results were in accordance with those for porosity related to the ITZ. Indeed, CO2 penetrates through the concrete’s pore network and reacts with the concrete’s old and new cementitious matrix [0.5 for all SCCs based on RA,  and 0.96 mm/day0.5 for the reference concrete (0%RA), which, for our mix designs, can be used in a carbonation exposure class of XC4 according to EN 206-1 [The accelerated carbonation results in ion time . This issolution , resultishown by . Moreoves matrix . Furthers matrix  and showEN 206-1 . This chEN 206-1 .500 viscosity, sieve stability, porosity and water absorption, mechanical strength, thermogravimetric analysis, freeze–thaw, and accelerated carbonation. The results obtained are encouraging and align with the specified requirements and intended applications. The findings are outlined as follows:The use of recycled aggregates reduces the time required to maintain consistency due to the fine particles present in the aggregates and their significant water absorption.The sieve stability of the 20%RA and 50%RA self-compacting concretes was greatly modified by the granular discontinuity, in contrast to homogeneous aggregate mix designs such as 0%RA and 100%RA.The recycled aggregates do not affect either the mechanical compressive strength or the binder hydration, as demonstrated by TG analyses.The self-compacting concretes tested exhibit good freeze–thaw resistance, and the difference between them is strongly related to the porosity. The 0%RA presents a quasi-linear behavior, and this increases with the higher replacement rate by 45%, 54%, and 110% for 20%RA, 50%RA, and 100%RA, respectively.0.5 for the 0%RA and about 1.8 mm/day0.5 for the other mix designs.The developed self-compacting concretes have a carbonation rate of 0.96 mm/dayThis study is part of an environmental transition process aimed at reducing the carbon footprint associated with construction materials and addressing the issue of non-biodegradable waste occupying vast landfill areas. The focus of this research was on investigating the properties of self-compacting concretes containing 35% limestone and recycled aggregates in both fresh and hardened states, including slump flow, tThe comprehensive experimental characterization campaign presented in this work and the resulting findings constitute valuable additions to the database on self-compacting concretes. Another study will be carried out on the application of these materials in a demonstrator building.


Pipistrellus pygmaeus in Frafjord, a small valley in the south-western corner of Norway (58° 50′N 6° 18′E) with an oceanic climate.Most temperate bats are regular hibernators in the winter. Knowledge about the length of their active season and how they adjust their nightly activity throughout the season, is critical to conservation. The characteristics of these are likely to vary with climate as well as latitude. This study investigated the flight activity of the soprano pipistrelle Activity was recorded with an ultrasound recorder throughout April 2018 to June 2019 at one site, with supplemental recordings in March to June 2020, i.e., covering all months of the year. Recordings at other nearby sites were made in the summers (June–August) of 2016, 2017, 2019 and 2020, as well as some of the last days in December 2019 to the first days of January 2020. Overall, soprano pipistrelles were recorded flying in all months of the year, but very few in December–March. Regular activity was recorded from late April or early May until late October, and some recordings were also made in November. The highest numbers of recordings were made in August and September. Social calls, i.e. male song flights, were recorded from April to November, with the vast majority in August and September. Nearly all recordings were made between sunset and sunrise.The soprano pipistrelle in this region showed regular activity through 6–7 months of the year. It adjusted its activity to the changing night length throughout the year, closely following sunset and sunrise. It was rarely recorded flying before sunset and almost never after sunrise. Most activity was recorded in the middle of the night, and social calls also followed this trend closely. Harems in late summer and autumn were confirmed in a bat box, which was also used for winter hibernation.The online version contains supplementary material available at 10.1186/s40850-021-00065-x. Insectivorous bats have evolved a number of adaptations. Among these are flight, echolocation, nocturnal hunting and hibernation. Several hypotheses have been suggested to explain their nocturnal hunting strategy; avoiding diurnal predators, avoiding competition with insectivorous birds or avoiding high daytime temperatures –3. AmongPipistrellus spp., are very small and often very numerous. Whereas several studies address the activity and behaviour of the common pipistrelle P. pipistrellus [P. pygmaeus were, for example, only identified and separated in the 1990’s [Pipistrelle bats, strellus –15, littstrellus , 17. Thee 1990’s . EarlierThe soprano pipistrelle is common in South Norway  and appeHollow trees or rock crevices are probably the natural nursery roosts of the soprano pipistrelle in Norway, but when available it prefers warmer, man-made structures such as buildings and bat boxes . WeatherMale pipistrelles of all species have characteristic “mating” displays, using particular vocalisations and behaviours to announce their presence and to attract females , 28. TheThis study describes the nocturnal activity of the soprano pipistrelle throughout the year and through the night. The main aims were to study how this bat adjusts its activity to the changing night length and the timing of the males’ social calls.n = 20,732 min, social calls at the main site n = 7036 min, and echolocation recordings at other sites n = 3194 min. The first soprano pipistrelle in 2018 was recorded in February .This study also confirmed that the soprano pipistrelle hibernated in Frafjord, even in sub-zero temperatures as does the common pipistrelle . HibernaAlthough the exact dates are not known, it is likely that soprano pipistrelle nursery roosts in Frafjord existed from May to early July. The bats then moved to mating roosts (harems) which lasted until the end of September or early October. Winter hibernation lasted from late October to late April, and, at least in the case of the wood-concrete bat box, could occur as a continuation at the harem site. A few bats moved between different sites during the winter months and some also hunted on warmer nights.Pipistrellus spp. in Northern Ireland [The main season of soprano pipistrelle activity in Frafjord was from the last days of April to the middle of October. This is very similar to the common pipistrelle in England , but the Ireland . At 50°  Ireland . Maier [ Ireland  observed Ireland . In FrafFlying soprano pipistrelles were encountered in all months of the year, but their main active season was between late April and late October, or 6–7 months. Very few flights were recorded during December–March, although bats hibernating in a bat box came and left also at this time. Their nightly activity closely tracked sunset and sunrise, with very few recordings outside this period. This implied changes in the length of the bats’ hunting period throughout the season, being shortest at mid-summer when the energy demands on reproducing females should be large. Male song flights were recorded from April until November, with most recordings in August and September. At this time, males gather harems of females, and such groups may continue to use a bat box for example, well into the winter and hibernation period. It appears that this study is the first to study the activity of this species throughout the year and comprehensively relative to sunset and sunrise. This knowledge should be of importance to conservation and management, which need information both about seasonal activity, habitat preferences, breeding roosts and winter hibernaculas. In Norway, the soprano pipistrelle is classified as of least concern (LC), but little is known about population size or trend.Soprano pipistrelles were studied in Frafjord (58° 50′N 6° 18′E). This is a small valley with steep sides running west to east in Rogaland county, on the SW coast of Norway Fig. . It has Bat sounds were recorded with an ultrasound recorder, Wildlife Acoustics SM2Bat . This recorder was in operation over more than a year, from 26 April 2018 to 27 June 2019, at a single site termed the main site  surrounding and including the main site described above . From October to December 2018, the nightly recording program was reduced to around 9 h from sunset, i.e. the recorder stopped before sunrise, to limit the huge amount of work needed to go through all the files generated. In 2020, the recordings started 1 h before sunset and ran until 1 h after sunrise.Because seven bat species have been recorded in Frafjord, all recordings had to be first identified to species. Files were first automatically scanned in Song Scope  using a species-specific identifier. The identified bat emissions were then manually checked and the files further searched by looking at spectrograms throughout the file and species identified. Every minute during which the sound of a soprano pipistrelle was identified represented one case, so that the sample size is the number of minutes in which a bat was identified  for Sandnes


What is the association between a multifaceted antibiotic stewardship initiative with antibiotic prescribing for respiratory conditions in a large urgent care (UC) network?This quality improvement study of 493 724 total UC encounters found a decrease in antibiotic prescribing for respiratory conditions from 48% (baseline) to 33% (intervention), with reductions of 22% at the start of the intervention and 5% per month throughout the 1-year intervention period.This study’s findings suggest that a multifaceted antibiotic stewardship initiative was associated with reduced antibiotic prescribing for UC respiratory conditions, and that such initiatives in large UC networks may decrease inappropriate antibiotic prescribing. Urgent Care (UC) encounters result in more inappropriate antibiotic prescriptions than other outpatient setting. Few stewardship interventions have focused on UC.To evaluate the effectiveness of an antibiotic stewardship initiative to reduce antibiotic prescribing for respiratory conditions in a UC network.This quality improvement study conducted in a UC network with 38 UC clinics and 1 telemedicine clinic included 493 724 total UC encounters. The study compared the antibiotic prescribing rates of all UC clinicians who encountered respiratory conditions for a 12-month baseline period  with an intervention period . A sustainability period  was added post hoc.Stewardship interventions included (1) education for clinicians and patients, (2) electronic health record (EHR) tools, (3) a transparent clinician benchmarking dashboard, and (4) media. Occurring independently but concurrent with the interventions, a stewardship measure was introduced by UC leadership into the quality measures, including a financial incentive.The primary outcome was the percentage of UC encounters with an antibiotic prescription for a respiratory condition. Secondary outcomes included antibiotic prescribing when antibiotics were not indicated (tier 3 encounters) and first-line antibiotics for acute otitis media, sinusitis, and pharyngitis. Interrupted time series with binomial generalized estimating equations were used to compare periods.The baseline period included 207 047 UC encounters for respiratory conditions ; the intervention period included 183 893 UC encounters . Antibiotic prescribing for respiratory conditions decreased from 47.8% (baseline) to 33.3% (intervention). During the initial intervention month, a 22% reduction in antibiotic prescribing occurred . Antibiotic prescriptions decreased by 5% monthly during the intervention . Antibiotic prescribing for tier 3 encounters decreased by 47% , and first-line antibiotic prescriptions increased by 18%  during the initial intervention month. Antibiotic prescriptions for tier 3 encounters decreased by an additional 4% each month , whereas first-line antibiotic prescriptions did not change . Antibiotic prescribing for respiratory conditions remained stable in the sustainability period.The findings of this quality improvement study indicated that a UC antibiotic stewardship initiative was associated with decreased antibiotic prescribing for respiratory conditions. This study provides a model for UC antibiotic stewardship. This quality improvement study compares antibiotic prescribing rates for respiratory conditions before, during, and after implementation of a multifaceted antibiotic stewardship initiative in a large urgent care network. Most outpatient stewardship interventions have been designed and evaluated in primary care (PC) settings or emergency departments (EDs), with few interventions being applied specifically to UC.11 Urgent care incorporates features common to PC settings  and EDs . Therefore, stewardship programs that best meet the needs of patients and clinicians in UC settings should understand and incorporate these characteristics.Recognition that unnecessary antibiotic prescribing is common in outpatient settings led the Centers for Disease Control and Prevention (CDC) to develop the Core Elements of Outpatient Antibiotic Stewardship.7 To improve prescribing, we developed an antibiotic stewardship program specifically designed for UC settings based on CDC Core Elements. The objective of the present study was to evaluate the association of this program with antibiotic use for respiratory conditions in UC encounters.Substantial variability in rates of antibiotic prescribing for respiratory conditions exists between clinics and clinicians across the Intermountain Healthcare (IH) UC system.SQUIRE) reporting guideline. The IH institutional review board approved this study and waived the need for obtaining informed consent for this minimal risk, evidence based, quality improvement study. The study is registered at ClinicalTrials.gov.12Intermountain Health is a nonprofit, integrated, health care delivery system that includes 24 hospitals and more than 185 outpatient clinics throughout the Mountain West. During the quality improvement study, IH operated 38 UC clinics, including 32 for patients of all ages (InstaCare) and 6 providing care exclusively to children younger than 18 years (KidsCare). InstaCare and KidsCare clinics are predominantly staffed by physicians. In addition, IH operates a direct-to-consumer telemedicine UC clinic (Connect Care) primarily staffed by advanced practice clinicians (APCs). This study followed the Standards for Quality Improvement Reporting Excellence  with a 12-month intervention period . In addition, we included a 12-month sustainability period  to evaluate subsequent prescribing trends.13 Our interventions were developed using 4 categories based on the CDC Core Elements: education focused on UC clinicians and patients  performed in-clinic education (peer-to-peer) and was a resource for cliniciansHandbook included all guidelines, patient educational material, and metric methodsMonthly update lectures at regional UC meetings and UC email newsletterUpdated clinical guidelinesInternal podcasts with antibiotic stewardship leadersClinician facing antibiotic stewardship webpage, including all project resourcesSystemwide antibiotic stewardship screensaversSymptomatic therapies checklistWatchful waiting or delayed antibiotic prescribing documentPatient facing antibiotic stewardship webpageFolding antibiotic education brochure placed in clinic lobby and examine roomsAzithromycin prescribing justification alertAddition of delayed antibiotic prescriptions in the EHRCreation of templated notes for common respiratory conditions to assist in documentation, billing, and ordering appropriate medicationsUpdated prepopulated antibiotic orders with guideline concordant regimensTransparent antibiotic prescribing dashboard that included all clinicians, clinics, and system level antibiotic prescribing metrics allowing for peer comparisonDashboard engagement was facilitated by including a dashboard link in all emails, within the EHR, and biannual data review with UC leadersLocal or regional television and radio interviewsPrint media: newspaper articles, IH circularsFacebook and Twitter postsCommitment posters and waiting room antibiotic stewardship messaging via table tents, desk wraps, and floor stickers7UC clinicians given the goal to individually prescribe antibiotics in fewer than 50% of their respiratory encounters. This target was identified by a preintervention analysis that showed 50% to be the median respiratory antibiotic prescribing rate for the UC service line.Abbreviations: EHR, electronic health record; IH, Intermountain Health; UC, urgent care.aNot a formal component of the intervention.14 with an individual target of lower than 50% prescribing  codes, and antibiotic prescriptions ordered. Each encounter was categorized into 1 of 5 clinical categories  based on ICD-10-CM codes.7 The respiratory category was further subcategorized and assigned tiered groups based on whether antibiotics were indicated: tier 1, antibiotics indicated ; tier 2, antibiotics sometimes indicated ; and tier 3, antibiotics not indicated .1 If diagnosis codes from multiple tiers were present, the category defaulted to the lowest tier . Encounters were excluded if no ICD-10-CM code was billed, if codes from multiple clinical categories were present , or if the clinician totaled fewer than 25 visits during the study period.Data were electronically extracted from the EHR for each encounter and included patient-reported demographic characteristics, clinician specialty , discharge Antibiotic prescriptions generated or administered  during UC encounters were captured as electronic orders, and topical or inhaled formulations were excluded. Delayed antibiotic prescriptions were created in the EHR for antibiotics traditionally used for sinusitis and acute otitis media (AOM), allowing for direct measurement of their use. Delayed antibiotic prescriptions counted as an antibiotic prescription in all measures.The primary study outcome was the change in antibiotic prescribing for respiratory conditions between the baseline and intervention periods. Secondary outcomes included the change in antibiotic prescribing for tier 3 respiratory conditions and the use of first-line antibiotics for AOM, sinusitis, and pharyngitis. First-line antibiotics were defined as penicillin or amoxicillin for pharyngitis and amoxicillin or amoxicillin-clavulanate for acute sinusitis and AOM. Additional outcomes included the percentage of respiratory conditions prescribed azithromycin and the use of delayed prescriptions for AOM and sinusitis.15 Data were extracted for the “Overall rating of care received during your visit” on a scale of 1 (very poor) to 5 (very good). Mean patient satisfaction scores for respiratory conditions were evaluated from January 1, 2019, through June 30, 2020, based on data availability.Balancing measures related to the potential unintended consequences of the intervention included patient satisfaction and ED visits or hospitalizations within 14 days of a UC respiratory condition. Patient satisfaction was assessed using data from an IH patient satisfaction survey administered by Press Ganey.16 Binomial generalized estimating equations were used to account for clustering among the clinicians and in the clinic. For the prespecified primary and secondary outcomes comparing the intervention with baseline period, regression models included time-based terms to estimate the slope per month for antibiotic prescribing in the baseline period, the change in prescribing at the start of the intervention, and the change from the period before the intervention to the intervention period. The same approach was used to compare the sustainability period with the intervention period. For each model, an odds ratio (OR) was estimated for antibiotic prescribing per 1 month change in the baseline period (the baseline period slope), the change in odds of antibiotic prescribing from the baseline period to intervention (the immediate change associated with the intervention initiation during July 2019), and the OR for antibiotic prescribing per 1 month change during the intervention (the intervention period slope). This OR was calculated using the linear combination of the terms for baseline slope and the change in slope over time from baseline to the intervention using estimate statements in PROC GENMOD. Because the intervention period overlapped with the onset of the COVID-19 pandemic (March 2020), we performed a sensitivity analysis to exclude any association with study outcomes by limiting the intervention period to July 1, 2019, through February 28, 2020. All modeling was performed in SAS, version 9.4 (SAS Institute Inc). Statistical significance was defined as a 2-sided P < .05 or 95% CIs excluding 1.An interrupted time series model was used to assess the association of the intervention with the primary and secondary outcomes.The baseline period included 493 724 total UC encounters, of which 207 047 (41.9%) were respiratory conditions. The intervention period included 471 136 total UC encounters, of which 183 893 (39.0%) were respiratory conditions. Among respiratory conditions, patient demographic characteristics were similar between baseline and intervention periods, including age , female sex (56.8% vs 56.4%), and race (92.0% vs 91.2% White). The intervention period showed an increase in the proportion of Connect Care visits (3.8% at baseline to 8.4% during the intervention) with a corresponding decrease in InstaCare and KidsCare visits. There was no change in the proportion of visits by MD or DO clinicians compared with APCs. Clinical and demographic characteristics for the baseline and intervention periods are compared in P = .11). During the initial month in which the intervention was implemented (July 2019), a 22% reduction in antibiotic prescribing  was observed. Antibiotic prescriptions continued to decrease by 5% each month during the course of the intervention . Similar decreases in antibiotic prescribing were observed across all clinic types . All clinics showed a decrease in antibiotic prescribing for respiratory conditions . Of clinicians who were present in both the baseline and intervention periods, 95% had a decrease in their individual antibiotic prescribing for respiratory conditions. During the baseline period, 38.5% of clinicians had a prescribing rate higher than 50%, compared with 10.2% during the intervention period . In a sensitivity analysis excluding the onset of the COVID-19 pandemic from the intervention period, the monthly decrease in antibiotic prescribing was slightly higher .Among respiratory conditions, antibiotic prescribing decreased from 47.8% during the baseline period to 33.3% in the intervention period . Table 2P = .04); however, when the intervention was activated, a 47% reduction in antibiotic prescribing was observed for tier 3 encounters  in its initial month. Antibiotic prescriptions for tier 3 encounters continued to decrease by 4% each month during the course of the intervention   ; Figure.P = .10). When the intervention was implemented, an 18% increase in first-line antibiotic prescribing was observed , but no further changes were observed over time   ; Figure.Among respiratory conditions, patient satisfaction changed minimally. During the baseline period, the mean response rating was 4.4 (of 2533 surveys) compared with 4.3 (of 2189 surveys) during the intervention period. For patients who received an antibiotic, the baseline period mean response rating was 4.5 compared with 4.4 during the intervention. For patients who did not receive an antibiotic, the baseline period mean response rating was 4.2 compared with 4.2 during the intervention.Hospitalizations within 14 days of a UC encounter occurred in 0.4% of encounters during the baseline period compared with 0.5% of encounters during the intervention period. This small increase was observed among tier 1 encounters (0.3% for baseline vs 0.4% for intervention), in which antibiotic prescribing did not change. Encounters in EDs within 14 days of a UC encounter  occurred in 8.1% of encounters during the baseline period and 8.6% of encounters during the intervention period. This small increase was observed after tier 1 UC encounters (6.5% for baseline vs 7.2% for intervention) and tier 2 encounters (7.2% for baseline vs 7.7% for intervention). There was no change among tier 3 encounters (9.6% for baseline vs 9.6% for intervention).The 1-year sustainability period included 391 608 UC encounters, of which 95 221 (24.3%) were respiratory conditions. Patient demographic characteristics were similar to the baseline and intervention periods. A greater proportion of patients visited Connect Care during the sustainability period (11.5%) compared with the intervention period (8.4%). Antibiotic prescribing for respiratory conditions was 25.5% in the sustainability period (vs 33.3% during intervention) . InterruWe developed an antibiotic stewardship program for UC in a large integrated health system. By the end of its initial 1-year implementation period, we observed an absolute reduction in antibiotic prescribing for respiratory conditions of 15%. Reductions in antibiotic prescribing were observed across all clinic sites and among nearly all clinicians. Improvements were also realized in antibiotic selection and prescribing for tier 3 respiratory conditions. Despite the substantial reduction in antibiotic prescribing, balance measures of ED visits and hospitalizations within 14 days of the UC encounter and patient satisfaction scores remained unchanged following the introduction of the intervention.19 Features of successful programs include the use of audit and feedback, clinician and patient education, EHR tools, and peer comparison or benchmarking. The interventions used in our program were integrated into the UC service line in a large health system.20 Although the antibiotic stewardship interventions themselves were novel for this health system, within this context, clinicians were familiar with several of the core components of the program, including regular updates to clinical guidelines that adhere to evidence-based practice, clinical decision support tools embedded in the EHR, and regular performance evaluations using standardized practice metrics.This study adds to growing evidence about effective outpatient stewardship programs, including those focused on UC settings.22 When outpatient stewardship interventions are incorporated into an integrated system already deeply engaged in quality initiatives, sustainability may be enhanced.We found that antibiotic prescribing rates did not revert to baseline rates after the intervention period. Unlike inpatient stewardship programs, which generally require longitudinal budgeted financial support to sustain implementation, an ongoing challenge for outpatient stewardship is program durability after implementation.24 and may have contributed to our findings. Notably, financial incentives have not been featured in multiple previous studies of outpatient stewardship interventions, nor are they included in the CDC Core Elements.Although not an explicit feature of our intervention, UC leadership added achieving an antibiotic stewardship quality measure as part of clinician compensation, along with the other elements of our intervention. Financial incentives have been shown to have a modest positive effect on reducing antibiotic prescribing25 We and others have reported on the association of the pandemic with antibiotic prescribing during UC visits.27 Changes in the case mix of patients seeking care in UC centers could potentially have influenced prescribing rates. However, a sensitivity analysis conducted in the present study excluding the period of the pandemic showed no difference in the primary outcome.The last 3 months of the intervention period overlapped with the onset of the COVID-19 pandemic. This overlap was associated with substantial health care disruptions and a reduction in outpatient antibiotic prescriptions nationwide.14 In addition to reductions in the overall rate of antibiotic prescribing for respiratory conditions, several other areas of antibiotic prescribing improved, including the use of azithromycin and delayed prescriptions. Because these areas were explicitly targeted by components of our intervention, they likely represent changes in clinical practice and were sustained beyond the intervention period.Our study evaluated a novel HEDIS  metric  for antimicrobial stewardship in the outpatient setting that avoids confounding due to changes in coding practices, and it is now endorsed by the National Committee for Quality Assurance.31 Assessing hospitalization rates after the implementation of an ambulatory antibiotic stewardship initiative is critical because small increases in hospitalizations could change the acceptability of these initiatives.We found no differences in several balancing measures of patient safety and patient satisfaction when comparing the baseline and intervention periods. This is important because of the relatively large reduction in antibiotic use for respiratory conditions that occurred with the intervention. Our observation that patient satisfaction scores were stable may provide reassurance to clinicians that practicing antibiotic stewardship is not associated with unintended consequences in patient satisfaction and other important dimensions of clinical care, including visit duration, both of which have been cited as barriers to mitigating antibiotic overuse.Our study has limitations. It was not a randomized design, which limits interpretation of causality. Our study was performed in 1 large integrated health system, a single geographic region, and required substantial resources. These factors limit its generalizability to other UC settings. The multifaceted nature of the intervention did not allow for determination of each component’s independent contribution to the measured outcomes. The findings regarding patient satisfaction were limited by the small sample size. Although our results suggest that there was no increase in severe disease as measured by ED visits and hospitalizations, because we did not prospectively enroll patients and assess symptoms over time, we cannot exclude the possibility that some illnesses not treated with antibiotics could have been prolonged. The intervention period was only 1 year; thus, its long-term sustainability and penetrance when confronted with changes in health care delivery demands are uncertain.The findings of this quality improvement study of a multifaceted UC antibiotic stewardship initiative in a large integrated health care system indicated a significant reduction in antibiotic prescribing for respiratory conditions by the end of the study period that was sustained with no detectable changes in unintended consequences. This study provides a model for UC stewardship in a large integrated health care system.