MET) factor-targeted therapies for the treatment of NSCLC, warrant the development of evidence-based consensus recommendations for the use of these agents. A Canadian expert panel was convened to define key clinical questions, review evidence, discuss practice recommendations and reach consensus on the treatment of advanced MET-altered NSCLC. Questions addressed by the panel include: 1. How should the patients most likely to benefit from MET-targeted therapies be identified? 2. What are the preferred first-line and subsequent therapies for patients with MET exon 14 skipping mutations? 3. What are the preferred first-line and subsequent therapies for advanced NSCLC patients with de novo MET amplification? 4. What is the preferred therapy for patients with advanced epidermal growth factor receptor (EGFR)-mutated NSCLC with acquired MET amplification progressing on EGFR inhibitors? 5. What are the potential strategies for overcoming resistance to MET inhibitors? Answers to these questions, along with the consensus recommendations herein, will help streamline the management of MET-altered NSCLC in routine practice, assist clinicians in therapeutic decision-making, and help ensure optimal outcomes for NSCLC patients with MET alterations.In Canada, the therapeutic management of patients with advanced non-small cell lung cancer (NSCLC) with rare actionable mutations differs between provinces, territories, and individual centres based on access to molecular testing and funded treatments. These variations, together with the emergence of several novel mesenchymal-epithelial transition ( MET) proto-oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor (HGF). Small molecule inhibitors of MET are recent additions to the NSCLC-targeted treatment armamentarium.Although non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related death , the molMET and its ligand, HGF, were characterized in the mid-1980s [MET gene were discovered by genome-wide analysis of families with hereditary papillary renal cell carcinoma [MET kinase domain have been described in several solid tumours, including NSCLC, glioblastoma, breast, renal and colon cancers, as well as cancers of unknown primary origin, suggesting that activated MET plays a significant role in the tumourigenic process in a wide range of cell types [id-1980s , and thearcinoma . Over thll types ,11.MET is a single-pass transmembrane receptor composed of extracellular, transmembrane, juxtamembrane and tyrosine kinase domains as well as a carboxyterminal docking site [MET is a binding site for HGF. Upon HGF binding, MET homodimerization results in the phosphorylation and activation of intracellular domains that stimulate several downstream signalling pathways, including the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB), mammalian target of rapamycin (mTOR), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways that promote cell migration, proliferation, and survival [ing site . The extsurvival ,14.MET gene, located on the long arm of human chromosome 7 (7q21–31), is approximately 125 kb in length and contains 21 exons [MET pathway in lung cancer occurs through gene mutations, amplifications, fusions, rearrangements, and protein overexpression [The 21 exons . Dysregupression .MET-activating alterations in newly diagnosed non-squamous NSCLC are gene amplification  and MET exon 14 (METex14) skipping mutations (occurring in 2% to 4% of cases) [MET-activating alterations are also reported in 10–20% of patients with acquired resistance to epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors. [MET alterations are sufficient to drive carcinogenesis both as a primary oncogenic driver and as a secondary driver of acquired resistance to targeted therapy [MET overexpression can be detected by immunohistochemistry (IHC) in as many as 20–25% of patients [MET IHC and MET genomic alterations is poor [The most common f cases) ,19,20,21ibitors. ,23 This  therapy ,24. Althpatients , the cor is poor .MET inhibitors in three clinically relevant MET alterations:METex14 skipping mutationsMET amplificationDe novo MET amplification in acquired resistance to EGFR inhibitorsSeveral clinical trials have reported positive outcomes with MET alterations and have created a need for consensus recommendations that can streamline and integrate diagnostic approaches to identify patients that can benefit from novel therapies. Moreover, due to the availability of other therapeutic options for these patients, including immune checkpoint inhibitors (ICIs), there is an added need for expert guidance on therapeutic approaches with optimal short- and long-term outcomes. Lastly, the therapeutic management of patients with advanced NSCLC and rare actionable mutations likely differs across Canada due to variations in access to molecular testing and drug funding, further highlighting the need for such recommendations.The trial results impact the management of NSCLC patients presenting with these three METex14 skipping mutations are detected in 2–4% of lung adenocarcinoma cases [ALK-rearranged lung cancer [EGFR/ALK/ROS1 [METex14 skipping mutations are usually mutually exclusive with other lung cancer-driving mutations, suggesting it is an independent oncogenic driver [METex14 skipping mutations had activating mutations in KRAS, EGFR or ERBB2, or rearrangements involving ALK, ROS1 or RET [METex14 skipping mutations, KRAS mutation was reported in 3% [TP53, loss of CDKN2A/B, and amplification of MET, MDM2, and CDK4/6 [METex14 lung cancers express PD-L1, the median tumour mutational burden (TMB) is lower compared with unselected NSCLCs [ma cases ,23,24, ag cancer . These mALK/ROS1 . METex14c driver ,20. In aed in 3% . Co-occud CDK4/6 ,22,23. Fd NSCLCs .METex14 skipping mutations has initially been reported in the NSCLC non- squamous subtype of pulmonary sarcomatoid carcinoma (PSC) [METex14 skipping mutations in patients with PSC was shown to be 7–8% [METex14 skipping mutations have also been found in a very small percentage of patients with squamous cell carcinoma (SCC). Lam VK et al. reported METex14 alterations in 4 out of 385 (1%) SCC patients [MET inhibitors in patients with METex14 skipping mutations, GEOMETRY mono-1 [METex14 skipping mutations had SCC histology).A high frequency of ma (PSC) , rangingma (PSC) ,31. Most be 7–8% ,33. METepatients . In two Y mono-1  and VISIY mono-1 , patientMETex14 NSCLC is generally associated with aggressive disease, resistance to anticancer therapies, and poor prognosis when not treated with MET inhibitors [METex14 skipping mutations is low (approximately 16%), with a median PFS of approximately 2–5 months [hibitors ,38,39,405 months ,41. For 5 months METex14 skipping mutations, the primary tumour seemed to present as solid and peripheral masses with a high frequency of multifocal and extrathoracic metastases, mainly to the bone, brain, and adrenal glands [In a retrospective analysis of radiological features of NSCLC patients harbouring l glands .MET amplification is thought to dysregulate MET pathway signalling via protein overexpression and constitutive kinase activation. De novo MET amplification occurs in approximately 1–5%  of NSCLC cases [LC cases ,44,45,46LC cases ,44,47.METex14 skipping mutations are most commonly reported with adenocarcinomas given the overall incidence of this histology, MET amplification is more frequently identified in squamous cell carcinomas (SCC) [MET amplification in tumours, and a history of ever smoking is more common in SCC than in adenocarcinoma  [MET amplification measured by MET gene copy number (GCN) status (≥5 copies/cell) does not appear to be associated with gender, smoking history, histology, or stage. Multivariable analysis showed that a higher MET GCN is significantly associated with shorter survival in SCC [While as (SCC) . Former < 0.001) . The magl in SCC .MET amplification tend to be younger (average age of 66 years), male, and smokers. MET amplification occurs more frequently as a subclonal event, often co-occurring with other pathogenic mutations , and is usually a late genetic event [MET amplification in METex14 lung cancer is found in approximately 15–20% of cases, indicating that MET dependency in lung cancer can be driven by synergistic genomic events [MET amplification is often present in other tumour types, including 6% of gastroesophageal carcinomas [MET amplification is associated with higher histologic grade, advanced disease, and unfavourable prognosis [Patients presenting with ic event ,49. Co-oc events ,38. MET rcinomas . In bothrognosis .MET amplification is a potential resistance pattern to EGFR inhibition in NSCLC, accounting for 5–22% of acquired resistance to first- and second-generation EGFR inhibitors [EGFR T790M-positive patients with acquired resistance to the third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib showed that MET amplification is the most common resistance mechanism (19%), followed by EGFR C797S mutation (7%) [MET amplification in 15% of samples [MET amplification is also detected in other oncogene-addicted NSCLCs including those with ALK rearrangements, in which 15% of tumour biopsies from patients relapsing on next-generation ALK inhibitors detected MET amplification [hibitors ,53,54. Iion (7%) . Similarion (7%) ,57. In t samples . MET ampfication .MET amplification causes resistance to EGFR inhibitors is associated with EGFR-independent phosphorylation of ErbB3 and downstream activation of the PI3K/AKT pathway, bypassing EGFR inhibition [MET amplification following osimertinib resistance tended to have inferior survival compared to patients without an increase in MET amplification  [The mechanism by which hibition . Patient months) .MET amplification after EGFR TKI may heterogeneously distribute the amount of metastatic sites; therefore, liquid biopsy may aid in detecting the alteration. A recent study showed that liquid biopsy could provide important insights into the heterogeneity of TKI resistance mechanisms in NSCLC [in NSCLC .MET expression and activity can be detected at the DNA, RNA, and protein levels. Assays commonly used in clinical trials include IHC to detect protein overexpression, fluorescence in situ hybridization (FISH) to identify gene amplification, reverse transcription polymerase chain reaction (RT-PCR) to detect gene mutations, and next-generation sequencing (NGS) to detect both amplifications and mutations, depending on the sample used .Dysregulated METex14 skipping mutations and MET amplification, with negative predictive values of 95% for MET amplification and 94% for METex14 skipping mutations [METex14 skipping mutations in patients with no or low vs. high MET expression by IHC [MET protein-expressing tumours demonstrate that only 10% of these patients had METex14 skipping mutations or MET gene amplification. The majority of cases with high MET expression  do not appear to be associated with alterations of the MET gene. Consequently, these findings do not support the use of MET IHC as a surrogate marker or screening for genomic MET alterations.Several studies demonstrate a poor correlation between IHC and utations ,26. An an by IHC . CombineMET testing must select a methodology or testing algorithm that integrates all other standard-of-care lung cancer biomarkers reported within the recommended turnaround time. The methodology should take into consideration all other factors associated with the addition of the assays to the existing workflow . The performance characteristics of the assays should be thoroughly validated with characterized samples representative of clinical practice, including small specimens. Other key considerations include the integration of complementary assays in order to respond to issues related to small specimens and assay failure/insufficiency rates, as well as cost-effectiveness.Laboratories aiming to implement clinical EGFR, ALK, ROS1, RET and BRAF) account for 15–20% of non-squamous NSCLC and rapid emergence of additional targets , a shift towards diagnostic platforms that allow multigene panel testing  is the most appropriate approach, as opposed to sequential single-gene testing such as FISH or RT-PCR. In this context, even if the relative number of patients with a specific molecular alteration represents only a small percentage of the whole NSCLC population, testing for new actionable drivers would have a minimal additional impact on service delivery. If sufficient numbers of mutations are included, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies [Considering that patients with currently approved clinically actionable alterations , liquid biopsy could be considered where available.MET alterations [Numerous studies have demonstrated a relatively good correlation between liquid and tissue biopsy results and the potential of liquid biopsy with cell-free DNA, including circulating tumour DNA (ctDNA), to detect actionable genomic alterations including erations ,73. ThusCirculating tumour DNA, a subset of total cell-free DNA, is released through lysis of apoptotic and necrotic cells, digestion of tumour cells by macrophages, or by direct secretion of DNA by tumour cells . The fraMET introns, the ability to detect copy number alterations, and the differences between approaches using ctDNA and those using both ctDNA and ctRNA . On top of this, the overall limitations of plasma-based NGS, including sensitivity as it relates to the stage and burden of disease, should be considered.When selecting a liquid NGS assay, one should consider the coverage of Rapid turnaround time for biomarker test results, especially in newly diagnosed NSCLC requiring therapy, is extremely important for timely treatment initiation. The College of American Pathologists recommends a maximum 10-day turnaround time from sample receipt in the laboratory to report generation . It is aMETex14 should be performed as part of a comprehensive panel that includes current standard-of-care biomarkers as summarized by international guidelines. All advanced stage non-squamous NSCLC patients, including patients with PSC and those without alterations in EGFR, ALK or ROS1 should be tested, regardless of clinicopathologic characteristics.Testing for METex14 skipping mutations should be initiated by the pathologist at the time of initial diagnosis in all patients diagnosed with advanced-stage non-squamous NSCLC.Reflex biomarker testing for METex14 testing in advanced SCC should be performed upon the oncologist’s request in treatment-eligible non-smokers.MET alterations in this population.Considering the availability of multigene panels, there is increasing consensus that smokers with advanced SCC that are treatment-eligible should also be considered for testing given the presence of Liquid biopsy should be considered if a tissue biopsy is unavailable, inadequate for molecular testing, when invasive procedures for tissue procurement are contraindicated, or when urgent treatment decisions are required and delays are expected with tissue testing.Negative results by liquid biopsy do not mean the absence of the target; if possible, reflex to tissue testing is recommended.METex14, are acceptable as valid indications for approved MET targeted treatments.Regardless of the type of biopsy (tissue or liquid), identified actionable genomic alterations, including The maximum acceptable turnaround time (from the acquisition of tissue to the oncologist having the report) for all biomarkers should not exceed 21 calendar days. In certain situations, accelerated testing should be available.Biomarker test results should be compiled and ideally reported in a single comprehensive biomarker report by the pathologist, including PD-L1 expression.METex14 skipping mutations are a heterogeneous group of indels and missense mutations that result in post-translational modifications detectable at the RNA level, which poses challenges and requires specific analytical and diagnostic considerations [METex14 samples has shown that DNA changes display remarkably diverse sequences, with variants extending deep into intronic non-coding regions adjacent to exon 14 [erations . Genomic exon 14 . Genomic exon 14 ,79,80.METex14 [MET amplicons [METex14 variant without confirmatory splicing alteration with RNA sequencing can be problematic in some circumstances.The main limitation of small DNA-based amplicon panels is improper coverage. Comparison of such panels with RNA-based anchored-multiplex (AMP)-PCR revealed a higher incidence of identified alterations in NSCLC samples tested by the RNA-based assay (4.2% versus 1.3%), with 6 of 10 AMP-PCR-positive results negative on the DNA-based assay . This isMETex14 . Howevermplicons . NonetheMETex14 also applies for hybrid-capture panels. This was shown in 252 driver negative NSCLC samples, based on a large DNA-based NGS panel that underwent AMP-PCR RNA sequencing [METex14-positive cases were revealed amongst other oncogenic fusions, of which five cases had intronic variants located as far as 40 bp away from the intron 13 splice site on manual review of the DNA sequencing data [MET exon 14), include large genomic deletions to primer binding sequences as well as bioinformatics filtering [METex14 detection.The role of complementary RNA sequencing for proper identification of quencing . Six , or an increase in the ratio of gene copies relative to other areas on the same chromosome  [Although ET/CEP7) .MET inhibitors define different cut-offs for MET amplification positivity. The PROFILE 1001 with crizotinib used MET/CEP7 ratios and defined cut-offs of ≥1.8 to ≤2.2 as low, >2.2 to <4 as medium, and ≥4 as high MET amplification [MET amplification positivity as MET GCN > 2.5 [Recent clinical trials with fication . The cutfication . FinallyCN > 2.5 .15.MET is included.When selecting an NGS panel for use in NSCLC, pathologists are encouraged to utilize an assay that provides copy number status, and to ensure that copy number coverage of 16.MET copy number status or copy number ratio, it is important that pathologists and end-users are aware of the particular cutpoints being used. While no definitive cutpoints have been established, practitioners are encouraged to monitor the emerging data on this topic.When reporting the 17.Users should be aware of any limitations to copy number assessment by NGS, such as low uniformity and low tumour content.18.MET amplification, such as FISH, can be utilized. This could include patients with resistance to EGFR TKI therapy.In select scenarios, single-gene tests for 19.MET IHC is not recommended as a screening tool for MET amplification, as the data indicate a poor correlation between MET IHC and MET amplification.20.MET amplification as a resistance mechanism, while recognizing the lower sensitivity of plasma-based assays compared to tumour tissue testing. The limitations of liquid NGS in general, as well as the particular assay, should be considered. However, MET amplification detected by plasma-based assays should be considered actionable.Liquid biopsy may be considered, particularly when testing for METex14 skipping mutations?What is the preferred first-line therapy for treatment-naïve patients with METex14 skipping mutations unexposed to MET inhibitors?What are the preferred subsequent lines of therapy for patients with EGFR or ALK mutations, but not those with METex14 skipping mutations. However, the number of patients included with these alterations in these studies has not been reported. Based on these trials, recent recommendations from the American Society of Clinical Oncology (ASCO) and Ontario Health  consider ICI ± chemotherapy as the standard of care for treatment-naïve EGFR and ALK-negative stage IV NSCLC [The results of the KEYNOTE 024 , KEYNOTEIV NSCLC .MET alterations . There was a trend toward longer median PFS with an ICI in patients with METex14 alterations (4.7 months) compared to those with MET amplification . Median PFS did not correlate with smoking status. Median OS was 25 months in patients with METex14 skipping mutations and 8.0 months in those with MET amplification. The objective response rate (ORR) in the entire MET cohort was 16%.A large international retrospective study (IMMUNOTARGET) assessed the benefits of ICIs in 551 patients with advanced NSCLC and oncogenic driver alterations . The stuMETex14 skipping mutations, a PD-L1 expression of 0%, 1–49%, and ≥50% was seen in 37%, 22%, and 41% of samples, respectively. The median tumour mutational burden (TMB) of tumours harbouring METex14 skipping mutations was lower than that of unselected NSCLCs, and there was no association between PD-L1 expression and TMB. Of the 111 cases, only 24 were response-evaluable, in whom the ORR was 17% and the median progression-free survival (PFS) was 1.9 months. Response was not enriched in tumours with PD-L1 expression ≥ 50% or high TMB. The authors concluded that occasional response to PD-1 blockade could be achieved; however, overall clinical efficacy was modest. In contrast to these data, some recently published small case series have reported response in about 50% of cases and PFS of over two years in patients treated with ICIs [Similar responses were achieved by Sabari et al. . Among 1ith ICIs ,94,95.METex14 skipping mutations confirmed that TMB is significantly lower in these patients compared to METex14 wildtype NSCLC (3.6 vs. 7.0 mut/Mb) [METex14 NSCLC was also enriched for high (≥50%) PD-L1 positivity compared to wildtype NSCLC (48% vs. 29%). The report, however, did not include other relevant patient characteristics , and the authors concluded that additional data are needed to determine the predictive role of these biomarkers for ICI response in patients with NSCLC harbouring METex14 skipping mutations. Several studies reported that PD-L1 expression in METex14 tumours could be relatively high (≥50% expression in 40–70%) [METex14 NSCLC, as well as the safety and efficacy of ICIs in this population; notably the balance between potential efficacy and toxicity associated with receiving TKIs, in particular crizotinib, following ICI therapy [A report on over 1300 NSCLC patients with  mut/Mb) . METex14 40–70%) ,96,97. T therapy ,98. Acco therapy . BiomarkMETex14 NSCLC is yet to be determined. Several factors are involved in therapeutic decision-making, including the severity of disease, smoking status (which could impact TMB), likelihood of response to ICIs, and the likelihood of rapid deterioration. Based on the limited evidence, there are some concerns that, similar to activity in other driver mutations (EGFR and ALK), monotherapy ICIs may not have robust activity in patients with METex14 skipping mutations. However, unlike patients with EGFR and ALK, where a majority of patients are non-smokers, 50% of patients with METex14 alterations present with a history of smoking. Patients with PSC tend to be very heavy smokers, and often respond well to ICIs, especially if there is high PD-L1 expression [METex14 skipping mutations.Based on clinical trial data and current practice, it is apparent that the optimal sequence of therapy in patients with pression ,100, whepression . Thus, tMET inhibitors, including both small molecule TKIs and monoclonal antibodies against MET or HGF have been in clinical development since the early 2000s [MET TKIs can be divided into type I and type II, based on their binding site  and type Ib . Type IbALK, ROS1 and MET alterations. The antitumour activity and safety of crizotinib (250 mg twice daily) was assessed in the PROFILE-1001 trial, which included 69 patients with advanced NSCLCs harbouring METex14 skipping mutations [MET alteration, either by splice-site region  or by mutation type . The median DOR was 9.1 months. Median PFS was 7.3 months and 54% of participants were progression-free at 6 months. Median OS was estimated at 20.5 months, with 6- and 12-month rates of 87% and 70%, respectively. Elevated transaminase levels and dyspnea were the most frequent grade 3 treatment-related adverse events (TRAEs), with each observed in 4% of participants. There was one case each of grade 4 hypophosphatemia, lymphopenia, pulmonary embolism, and one fatal case of treatment-related interstitial lung disease.Crizotinib is a multikinase inhibitor with strong activity against utations . ORR wasROS1 rearrangements  or MET deregulation  [METex14 skipping mutations, sixteen with MET amplification (threshold MET/CEP7 > 2.2), and one with both amplifications and METex14 skipping mutations. In the entire MET cohort, eleven patients (42%) had stable disease (SD), for an overall disease control rate (DCR) of 69%. With a median follow-up of 21 months, median PFS, median OS and DOR were 4.4 months, 5.4 months, and 3.7 months, respectively. Out of nine patients with METex14 skipping mutations, only one had a partial response, although five had SD (DCR 67%).The antitumour activity of crizotinib was also confirmed in a phase II prospective multicentre two-arm trial in patients with NSCLC with  n = 26) . Cohort MET alterations, the ORR with crizotinib in these patients is lower compared to that achieved with targeted therapy for many other NSCLC driver mutations. Although crizotinib was the first MET TKI to be evaluated in this patient group, more promising data have been reported with more selective agents.These trials indicate that although crizotinib has some activity in patients with MET inhibitor, in patients with METex14 skipping mutations (cohort A) [n = 65), ORR was 44.6%, median DOR was 10.8 months (n = 81), ORR was 45.7%, median DOR was 11.1 months, and median PFS was 10.9 months. Tepotinib was generally well tolerated across therapy lines, with mostly mild to moderate AEs and few discontinuations. The most common TRAE, peripheral edema , rarely led to discontinuation (4%). Other common AEs included nausea (26%), diarrhea (22%), creatinine increase (18%), and hypoalbuminemia (16%).The phase II VISION trial assessed the efficacy of tepotinib (500 mg once daily), a type 1b ohort A) . In trea8 months , and PFSMETex14 skipping alterations.Based on this data, Health Canada has issued a marketing authorization for tepotinib with conditions, pending the results of trials to verify its clinical benefit. In Canada, tepotinib is indicated for the treatment of adult patients with locally advanced unresectable or metastatic NSCLC harbouring EGFR wildtype, ALK-negative rearrangement, advanced NSCLC harbouring METex14 skipping mutations and/or MET amplification [METex14 skipping mutations were assigned to cohorts 4 (previously treated patients) or 5b/7 (treatment-naïve) and received 400 mg capmatinib twice daily. The primary endpoint was ORR based on blinded independent review committee (BIRC) assessment per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). The key secondary endpoint was DOR by BIRC. ORR in treatment-naïve patients (n = 60) was 67.9% for cohort 5b and 65.6% for cohort 7; the combined ORR for treatment naïve patients was 66.7%. Median DOR was 12.6 months for cohort 5b (n = 69) was 40.6% and median DOR was 9.7 months. A clinically meaningful median OS of 20.8 months in first-line (Cohort 5b) and of 13.6 months in relapse settings (Cohort 4) was also observed [In the GEOMETRY mono-1 trial, a multicentre, open-label phase II study evaluated the efficacy and safety of capmatinib monotherapy in adult patients with fication . Patientohort 5b . Median observed .Across all cohorts (364 patients), the most commonly reported AEs, regardless of causality, were peripheral edema , nausea (45%), vomiting (28%), and increased creatinine  . Grade 3METex14 NSCLC detected by an FDA-approved test.The U.S. Food and Drug Administration (FDA) granted accelerated approval to capmatinib for adult patients with metastatic METex14 NSCLCs (40 (57%) with adenocarcinoma, 25 (36%) with PSC and 5 (7%) with other NSCLC subtypes) were assessed in a multicentre, multi-cohort, single-arm phase II study [n = 13%), increased alanine aminotransferase (10%), and peripheral edema (n = 9%). Treatment-related serious adverse events occurred in 17 (24%) patients, the most common being abnormal hepatic function (4%) and hypersensitivity (2.9%).The efficacy and safety of savolitinib 600 mg (bodyweight ≥ 50 kg) or 400 mg (bodyweight < 50 kg) in unresectable or metastatic II study . At a meMETex14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy.Savolitinib has been granted conditional approval in China to treat patients with NSCLC with MET inhibitors are approved along with a companion diagnostic (CDx). The U.S. FDA has approved FoundationOne® Liquid CDx for use with capmatinib [METex14 skipping alterations in tissue (RNA) and liquid biopsy for tepotinib. The U.S. FDA, however, has not specified a CDx for selecting eligible patients for tepotinib [MET inhibitors as both first- and second-line therapy, the first-line choice should be based on patient characteristics , disease characteristics , as well as disease severity and the likelihood of fast rapid deterioration. In the Canadian context, one must also consider access to treatment and the balance between missed treatment opportunities while waiting to access MET-targeted therapy.In some countries, pmatinib . ArcherMepotinib . As curr21.METex14 NSCLC (non-squamous and squamous histology) that are eligible for treatment should be offered MET targeted therapy at some point during the course of their disease. Caution is needed when initiating a TKI post-ICI due to the potential increased risk of toxicity.Patients with advanced 22.METex14 skipping mutations, regulatory approval for this indication was not sought. Due to more robust efficacy, type 1b MET inhibitors  are preferred over crizotinib; however, crizotinib is listed on some provincial formularies and may be considered as an option if other therapies are unavailable.Although crizotinib has shown efficacy in patients with 23.MET inhibitors should be based on patient preference, toxicity profile, regulatory approvals, and access.The choice between type 1b 24.METex14 NSCLC may be offered first line therapy with MET-targeted therapy or other guideline-recommended standard of care approaches for patients without driver mutations. Based on current data with ICI in non-smokers and the evidence with MET inhibitors, an MET inhibitor is the preferred first-line therapy in non-smokers with NSCLC and METex14 skipping mutations.Patients with advanced 25.MET-targeted therapy, the guideline-recommended standard of care for advanced NSCLC patients without driver mutations should be offered as a subsequent line of treatment.For patients exposed to METex14 skipping mutations is similar [Brain metastases may develop in up to 20–40% of patients with stage IV NSCLC , and the similar . ActivitMETex14).An open-label, phase II study indicated the efficacy of ICIs in PD-L1 positive (PD-L1 expression ≥1%) stage IV NSCLC with brain metastasis, with 29.7% of patients achieving a response . 93% of The efficacy of crizotinib in patients with brain metastases is limited due to poor brain penetration; in humans, a low CSF-to-plasma ratio (0.26 to 1) has been reported .METex14 skipping mutations had brain metastases [In the GEOMETRY mono-1 trial, fourteen patients with tastases . IntracrMET alterations [In the VISION trial (Cohort A), 23 patients had brain metastases at baseline, 15 of which were evaluable by the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria . Twelve erations ,115,116.MET inhibitors, which include tepotinib and capmatinib, are valid therapeutic options for NSCLC patients with brain metastases harbouring METex14 skipping mutations. As data is limited in determining the efficacy of MET inhibitors for treatment of brain metastases versus local therapies with radiation or surgery, these patients require multidisciplinary discussions to determine their optimal care.Data with capmatinib and tepotinib indicate that selective type Ib 26.METex14 skipping mutations, the type Ib MET inhibitors tepotinib and capmatinib may be considered as reasonable therapeutic options in addition to other multidisciplinary approaches. Such cases should be discussed with a multidisciplinary team including but not limited to radiation oncologists, neurosurgeons and medical oncologists.For NSCLC patients with brain metastases harbouring MET GCN gain and amplification carries a poor prognosis. Yet, due to challenges associated with the detection and reporting of MET amplification in NSCLC, studies assessing the efficacy of different therapeutic approaches in patients with de novo MET amplifications are sparse. About 15% to 20% of patients with METex14 skipping mutations will also have an MET amplification [METex14 skipping mutation. Current data indicate the impact of GCN on response to MET inhibitors  [MET/CEP7 ≥ 5 represented only 0.34% of adenocarcinomas [MET amplifications in the Cohort B of the METROS study (threshold MET/CEP7 > 2.2), six (35%) achieved PR and six (35%) SD with crizotinib [In a small series, the ORR with crizotinib differed dramatically between cases with different R = 67%) . One shorcinomas . Out of izotinib .MET amplification category (≥4 MET/CEP7 ratio) treated with crizotinib was 38.1%, compared to 14% in patients with medium amplification category (>2.2 to <4 MET/CEP7 ratio) [MET amplification patients was 5.2 and 6.6 months, respectively, compared to a DOR of 3.8 and PFS of 1.9 months in patients in the medium category. MET amplification GCN ≥ 6 was detected by NGS in fifteen of nineteen (78.9%) patients. Of these, ORR was observed in six (40%), two of whom had concurrent METex14 skipping mutations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations.In PROFILE 1001, the ORR in patients with high 7 ratio) . Median MET FISH GCN ≤ 9  were closed for futility  at the interim analysis [In GEOMETRY mono-1, cohorts with analysis . CapmatiMET amplification. The liquid biopsy analysis will include all subjects who tested positive for MET amplification in plasma ctDNA (GCN ≥ 2.5), irrespective of the tissue biopsy result. Two additional tissue biopsy analysis sets may be explored irrespective of the liquid biopsy test result: first, subjects with GCN gain ≥ 4 and <6, and second, subjects with a GCN gain of ≥6. The first analysis presented at ASCO 2021 included 24 patients with MET amplification detected by Guardant360 liquid biopsy assay with MET GCN ≥ 2.5. Response rates in the seven patients that received tepotinib as first-line therapy was 42%, and 30% in the ten patients that were treated using it as second-line [Cohort B of the VISION trial is currently assessing the efficacy of tepotinib in patients with ond-line .MET inhibitors in patients with NSCLC and MET amplification, the number of evaluated patients in these trials is small, duration of the follow-up is short, and the amplification thresholds are not clearly defined and vary between the trials. On the other hand, current standard of care approaches for patients without actionable mutations (ICIs ± chemotherapy) lead to a median PFS of 8–9 months and a median OS of 16–30 months [MET inhibitors and evidence in support of ICIs ± chemotherapy, the panel concluded that ICIs ± chemotherapy should remain the standard of care in NSCLC with de novo MET amplification.Although preliminary evidence indicates activity of 0 months ,121,122.27.MET amplification, MET-targeted therapy could be considered through clinical trials at any line of therapy.In patients with advanced NSCLC with de novo 28.MET amplification, MET-targeted therapy could be considered after other standard therapies have been exhausted or in cases not eligible for standard therapies.In patients with advanced NSCLC with de novo MET amplification is a potential resistance pattern to first- and second-generation EGFR inhibitors in NSCLC [MET amplification is also recognized as a resistance mechanism to osimertinib in first- and subsequent-line therapy in patients with a T790M mutation. In the FLAURA trial, which evaluated first-line osimertinib in EGFR-mutated NSCLC patients [MET amplification was detected in 15% of the paired samples following first-line osimertinib, and 19% following progression on osimertinib in EGFR T790M positive patients.in NSCLC ,51,52. Mpatients , and thepatients , paired MET amplification following osimertinib resistance tended to have inferior outcomes compared to patients without an increase in MET amplification [MET amplification. As MET amplification causes resistance to EGFR inhibitors by activation of an EGFR-independent pathway [MET is required in order to overcome resistance to EGFR inhibitors.As patients with fication , there i pathway , targetiMET-dysregulated NSCLC who experienced disease progression while receiving first-generation EGFR inhibitors  [MET amplification (≥6 GCN).A phase Ib/II trial assessed the efficacy of capmatinib plus gefitinib in patients with EGFR-mutated, , n = 4) . The triMET overexpression (high IHC3+ or medium IHC2+) or MET amplification with acquired resistance to EGFR inhibition (the majority of patients were exposed to first- or second-generation EGFR inhibitors and only 2 out of 73 received prior osimertinib), also reported benefit from dual MET and EGFR inhibition (mean GCN ≥ 5 or MET/CEP7 ratio ≥ 2). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression  or MET amplification . Although the trial was terminated early due to poor recruitment, these findings suggest improved anti-tumour activity for tepotinib plus gefitinib compared to standard chemotherapy in patients with EGFR-mutant NSCLC and MET amplification. The investigators also suggested that the use of liquid biopsy for detection of MET amplification instead of tissue biopsy could be a convenient and less invasive method that might improve trial recruitment.The phase Ib/II INSIGHT trial  that comMET-amplified tumours (MET/CEP7 ratio ≥ 2 or mean GCN ≥ 5) progressing on first-generation EGFR TKI responded to savolitinib plus osimertinib [MET amplification and progression on previous osimertinib (SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) trials). The phase II INSIGHT 2 study (NCT03940703) is currently investigating tepotinib plus osimertinib in patients with EGFR-mutant NSCLC with acquired resistance to prior EGFR TKIs due to MET amplification.In the phase Ib TATTON trial, 64% of patients with EGFR mutation-positive NSCLC and mertinib . The resMET bispecific antibody, and lazertinib, a third-generation TKI, in both treatment-naïve and osimertinib-relapsed patients with EGFR mutated NSCLC [MET were identified by NGS in both liquid and tumour biopsies. Of seventeen patients with EGFR and/or MET-based resistance, the ORR was 47%, median DOR was 10.4 months, clinical benefit response rate was 82%, and median PFS was 6.7 months. IHC staining for EGFR and MET expression was explored as a potential biomarker for response. Among ten patients whose tumours stained high for EGFR and MET expression, 90% had a tumour response. Additional validation analyses with both NGS and IHC are needed to confirm these promising preliminary data and to identify patients most likely to benefit from the amivantamab and lazertinib combination.Recent data demonstrate promising activity of the combination of amivantamab, an EGFR-ed NSCLC . Osimert29.MET amplification should be considered for clinical trials evaluating MET inhibitors.Patients with advanced EGFR-mutated NSCLC progressing on first and second generation EGFR TKIs without a T790M resistance mutation or patients progressing on osimertinib regardless of line of therapy and who have a MET TKIs are not well characterized. Acquired MET kinase domain mutations in residues D1228 and Y1230 confer resistance to type I MET TKIs in vitro by weakening chemical bonds between the drug and the MET kinase domain [MET inhibitors like tepotinib, capmatinib, and savolitinib [Resistance mechanisms to e domain ,129. In olitinib .METex14 NSCLC with acquired resistance to a MET TKI revealed on-target resistance mediated by secondary MET kinase domain mutations and/or amplification in seven patients [MET TKIs resulted in partial responses.Analysis of twenty samples from patients with patients . Off-tarMET-altered NSCLC [METex14 skipping mutation and five with MET amplification) achieved a partial response to capmatinib, and fourteen had SD, yielding a DCR of 80%. Both patients with a partial response had received chemotherapy with pembrolizumab as intervening therapy between crizotinib and capmatinib. Among five patients who discontinued crizotinib for intolerance, DCR was 83%, including two patients with best tumour shrinkage of −25% and −28%. Intracranial DCR among four patients with measurable brain metastases was 100%, with no observed intracranial objective responses. Overall, median PFS and OS were 5.5 months and 11.3 months, respectively. MET D1228 and Y1230 mutations and MAPK alterations were recurrently detected in post-crizotinib, pre-capmatinib plasma. The mutations persisted in plasma during treatment with capmatinib. New and persistent MET mutations and MAPK pathway alterations were detected in plasma at progression while on capmatinib, suggesting that capmatinib cannot easily overcome the secondary mutations.Data indicate that capmatinib has modest activity in crizotinib-pretreated ed NSCLC . Two outMET TKIs  that bind to MET in a configuration that does not rely on interactions with the activation loop retained activity against MET D1228 and Y1230 mutations [MET TKI-pretreated patients may help answer whether preclinical sensitivity consistently translates into clinical response.In preclinical studies, class II utations . These outations . OngoingMET-targeted strategies employing MET antibodies or MET antibody–drug conjugates should be explored prospectively through clinical studies [METex14 skipping mutations showed anti-tumour activity in treatment-naïve and previously-treated patients, including patients previously treated with MET inhibitors [MET inhibitors with another targeted therapy seems to be an appropriate approach that requires further study.Based on current evidence, in the context of on-target resistance, additional  studies ,135,136.hibitors . For off30.MET alterations (either METex14 skipping and amplifications) resistant to MET inhibitors should be encouraged to enroll in clinical trials whenever possible. Patients progressing on type I MET inhibitors may be candidates for clinical trials with type II MET inhibitors or combination therapies.Patients with advanced NSCLC 31.MET-targeted therapy impacts patient outcomes; therefore, it is not recommended outside of clinical trials.There is currently no evidence that resistance profiling of the tumour post-MET alterations represent a diverse population regarding their clinical presentation, underlying histology, and genomic instability. As with other driver mutations, timely detection and initiation of appropriate treatment are key to optimizing outcomes. MET inhibitors are emerging as effective and safe options for patients with METex14 skipping mutations; however, their sequencing, among other available options, requires further study. Participation in clinical trials is recommended for patients with MET amplification because of unanswered questions including optimal assays and cut-offs, as well as other clinicopathological characteristics of these patients that might be implicated in therapeutic decision making. Upcoming results from ongoing clinical trials and the emergence of novel agents and combinations will further streamline the management of patients with MET-altered NSCLC.Lung cancer patients presenting with


Numerous studies evaluated the association of education level with misuse of antibiotics by the general population, yet divergent findings were reported. Therefore, a meta-analysis was conducted to summarize this association.A categorical and continuous dose–response meta-analysis of the association of education level with antibiotic misuse was undertaken. Summary odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated using random-effect model.The meta-analysis included 85 studies from 42 countries of different socioeconomic status. Compared to low education (≤ 9 years), medium education (> 9–12 years) is associated with 20% lower odds of antibiotic misuse in high-income countries , while high education (> 12 years) is associated with 14% lower odds of any aspect of antibiotic misuse . The association is more pronounced in Middle East  and countries of lower-middle economies . Inversely, in Europe, high education is associated with 25% higher odds of antibiotic misuse . Each additional year of education was associated with 4% lower odds of any aspect of antibiotic misuse in lower-middle economies  and in Middle East . Conversely, it was associated with 3% higher odds of antibiotic storage, a specific type of misuse .Individuals misuse antibiotics irrespective of their education level. Intervention programs to enhance the proper use of antibiotics should target all communities independent of their education level.The online version contains supplementary material available at 10.1186/s13756-022-01063-5. Antibiotic resistance continues to represent an essential public health problem despite efforts exerted worldwide to reduce the causes of the resistance. It affects all regions irrespective of the country socioeconomic status , and cauAntibiotic resistance is exacerbated by excessive use of antibiotics in agriculture, food and feed chain, imprecise antibiotic prescription by physicians, and misuse of antibiotics by the patients. Individuals tend to misuse antibiotics by consuming these drugs without medical prescription (self-prescription) or by using them based on medical advice but without adherence to the physician’s instructions such as modifying the prescribed dose, truncating or prolonging the treatment duration or not taking the antibiotics on time .The use of antibiotics without prescription is salient worldwide, with a pooled prevalence exceeding 75% in low- and middle-income countries .Previous reports also indicated that more than one-third of patients do not fully adhere to antibiotic treatment regimen , around Besides determinants of antibiotic misuse such as female gender, youth and old age, lack of access to healthcare facilities and easy access to antibiotics , 9, educWe registered this systematic review and meta-analysis in the PROSPERO database (Protocol ID: CRD42021233425) and carried it out according to PRISMA guidelines. The main outcome, antibiotic misuse in the general population, was defined as the occurrence of any of the following practices: unprescribed use of antibiotics (self-medication), non-adherence to treatment guidelines and storage of antibiotics leftover for future use.We searched Medline, EMBASE, the five regional bibliographic databases of the World Health Organization (WHO), the Conference Proceedings Citation Index-Science, and the Open Access Theses and Dissertations until January 2021. In Medline, we used the following search term without any language, date or other restrictions: (Socioeconomic Factors OR education) AND (antibiotic*) AND ((compliance) OR (adherence) OR (Nonprescription Drugs / administration & dosage* [MeSH]) OR (misuse) OR  OR (left-over)). We also ran the search using related free-text words. Then, we adapted the syntaxis to complete the search in the other databases. We manually checked the reference lists of included studies and those of relevant review reports to supplement the electronic search. The list of the examined review reports is provided in Additional file We included studies that (1) measured the association between education and any aspect of antibiotic misuse , (2) defined the measured level of education, (3) reported odds ratio (OR) or risk ratio (RR) and their 95% confidence intervals (CIs) or sufficient data for their calculation. We excluded from the meta-analysis studies that only compared students according to their university year.We collected information on: (1) study source: author’s last name and publication year, (2) settings and participants’ demographic characteristics, (3) study design, (4) exposure: levels of education, (5) for each education level: ORs and its 95% CIs, total number of participants, and number of individuals who reported antibiotic misuse. We extracted the ORs adjusted for the largest number of variables, (6) restriction, adjustment, or matching variables, and (7) type of antibiotic misuse. In studies reporting more than one type of antibiotic misuse, we extracted the data of all types of misuse, and treated each type of misuse as a separate study unit in the dose–response analysis. We contacted the authors to inquire about the number of individuals who misused and those who did not misuse antibiotics per each education level, when needed.In addition to data reported in the included studies, we obtained the classification of countries wellness  from the World Bank  and usedWe defined the term “dose” as the level of education in years. Education level classification varies between countries, hence, to standardize the education levels across studies of different parts of the world, we transformed it to years of education according to the education system used in each country. We set the dose as the midpoint of the upper and lower boundaries of each education level.We performed a dose–response meta-analysis using a one-stage mixed-effects model taking into account heterogeneity across studies . We carrTo facilitate tabular presentation of the summary ORs, and in line with other studies, we further recategorized education level into low (≤ 9 years), medium (> 9–12 years), and high (> 12 years) levels and used low education level as a referent.We applied a linear function to estimate a summary OR of antibiotic misuse associated with an increase of 1 year of education. Then, we flexibly modelled education using restricted cubic splines with 3 knots fixed at 10th, 50th and 90th percentiles of its distribution, and tested departure of the second spline from linearity.We undertook stratified dose–response analyses of the level of education with antibiotic misuse. The analysis was stratified by study design, type of antibiotic misuse, geographic region, country wellness, methods of exposure ascertainment, comparability (adjustment for age and gender), and publication year, using 2015, the year of publication by the World Health Organization of the global action plan against antibiotic resistance, as a cut-off limit .We appraised the quality of the studies included in the meta-analysis using the Newcastle–Ottawa Scale for cohort and cross-sectional studies , 18. TwoWe checked publication bias visually using funnel plot, and formally through Egger’s test  and the Out of 1458 identified studies, 85 fulfilled the inclusion criteria and were included in the meta-analysis , overall, medium education > 9–12 years) is not associated with antibiotic misuse   or non-adherence to treatment regimen . Nonetheless, high education level is associated with 41% higher odds of storage of antibiotics , compared to low education. The association with antibiotic storage was also observed for medium education level, yet with smaller magnitude  . In countries with lower-middle economy, high education is associated with 30% reduced odds of antibiotic misuse, compared to low education . Moreover, in these countries, each additional year in education is associated with 3% lower odds of antibiotic misuse  . In the European region, high education is associated with 25% higher odds of misuse . Similarly, in the continuous approach, every additional year in education is associated with 4% lower odds in the Eastern Mediterranean  and 2% higher odds in the European regions  .Pooled estimates from studies published after 2015 showed 19% lower odds of antibiotic misuse by individuals with high education level, compared to those with low education level . Every additional year in education was associated with 2% reduced odds of antibiotic misuse  as well as for 1-year increment . However, the association of high education with misuse was less strong among studies with validated questionnaire than among all studies taken together  Table . Studiesp value = 0.065), nor by the trim-and-fill analysis that did not suggest the addition of any study. As for those studies that assessed high education level, the funnel plot was also slightly skewed to the left , but the trim-and-fill analysis did not suggest the addition of any study.The funnel plot of studies reporting medium education level was slightly skewed to the left Fig. A, but pueft Fig. B. Egger’We carried out a systematic review and dose–response meta-analysis to summarize the association between education level as a dose and misuse of antibiotics by the general population. Data from studies included in the meta-analysis fit well with a linear association between education and antibiotic misuse. We found no association between a one-year increment in education and the occurrence of antibiotic misuse. In the categorical analysis, we observed that individuals with high education level are, in general, at lower odds of antibiotic misuse than those with low education level. However, these results were not confirmed for the European studies group and the storage-type group of misuse.The likelihood of using antibiotics without prescription as well as that of non-adherence to treatment is similar for low, medium and highly educated individuals. Notably, the odds of storing antibiotics at home for future need is larger for highly educated people than for those with low education level.People with low education are more susceptible to comorbidities and thus, are more exposed to medicines than individuals with higher education . EducatiHealth literacy significantly contributes to health status and medicines use . IndividThe odds of antibiotic misuse by highly educated people decreased after 2015, which could be related to the global efforts exerted by WHO as well as to the educational campaigns and antibiotic stewardship programs undertaken in many parts of the world to increase the awareness about antibiotic resistance , 39. HigThis meta-analysis has various strengths. To the best of our knowledge, it is the first to assess the association between education and antibiotic misuse. To allow for comparability across studies, we transformed the education level to years of education, adapting to the setting of each country, before establishing cut-off limits for categories of education levels. We also provided a summary measure of association per increase of 1 year of education. In addition, we presented stratified analysis by country wealth as proxy of socioeconomic status.Nonetheless, our study suffers from limitations. All except two studies included in the meta-analysis are of cross-sectional design, a design that, theoretically, does not allow for causal inference, due to the fact that exposure and outcome are measured concomitantly. However, education is not a transient factor, but a cumulative characteristic. The fact that exposure and outcome are measured concomitantly does not imply that the level of education may have been acquired after the occurrence of misuse.High amount of heterogeneity existed across studies. Meta-analysis experts highlight that heterogeneity is expected in any meta-analysis , especiaFurthermore, not all studies provided measures of association adjusted for potential confounders or reported restriction, matching or confounding variables. Studies that controlled for age and gender yielded a summary estimate closer to the null value than studies that did not control for those variables. Likewise, around one-third of studies used non-validated questionnaires. These studies yielded a pooled estimated farther from the null value than with validated instruments.Finally, although some elements of publication bias were observed in studies that assessed the association of high education with antibiotic misuse, this was unlikely to affect our results as showed by the absence of additional studies in the trim-and-fill analysis.This meta-analysis shed the light on the importance of orienting intervention programs to improve the rationale use of antibiotics to all communities independent of their educational level. It also pointed out on the considerable need for cohort studies that examined the association between education and antibiotic misuse and control the measures of association for potentially confounding variables. Measuring the interaction between various socioeconomic indicators such as income and education on antibiotic misuse, would help understand better the socioeconomic properties of antibiotic misuse and thus allow for better control.Additional file 1. Forest plot of studies examining the association between medium education and antibiotic misuseAdditional file 2. Forest plot of studies examining the association between high education and antibiotic misuseAdditional file 3. Additional reference lists: review reports and studies included in the meta-analysis


FTIR was used to characterize changes on the surface structure after introducing nanoparticles. The change of hydrophobicity was measured using a contact angle test. TEM test results showed that nanoparticles were successfully inserted between the graphene sheets. However, the content of Si on the surface was low, as the cage structure of POSS in the molecular chain was coated by epoxy groups. XRD tests indicated that nanoparticles facilitated the dispersion of graphene in EP-POSS. XPS characterized the chemical state and content of the elements, confirming that the addition of graphene can induce the enrichment of Si on the surface of EP-POSS, which had a shielding effect on the main chain and improved the hydrophobicity. Wear resistance and adhesion tests showed that, after the introduction of nanoparticles, the EP-POSS coating film met the requirements of graphene materials.Epoxy resin–polyhedral oligomeric silsesquioxane (EP-POSS) has excellent mechanical properties and hydrophobic properties. In order to adapt for application in sensor and photovoltaic fields, graphene, nano-SiO HowPOSS is characterized by a regular structure, small scale (about 1 nm), good compatibility, and excellent performance ,7. It caSome important discoveries have been made in the study of modified POSS materials ,18,19,202, and nano-ZnO, and the surface structure, hydrophobicity, microstructure, and crystal phase characteristics of the modified EP-POSS materials were studied by infrared spectroscopy (FTIR), contact angle, TEM, and XPS, respectively. Secondly, the physical properties of modified EP-POSS were verified using a wear resistance test and adhesion test.In this paper, based on the shortcomings of the studies above, EP-POSS was modified using graphene, nano-SiOThe rest of this article is divided into three parts. In the first part, the materials and test methods used for the modified EP-POSS are introduced. In the second part, the surface structure and properties of the modified EP-POSS are analyzed in detail. Finally, in the final section the research results are summarized.The EP-POSS resin was home-made in the laboratory; it was prepared by a condensation reaction with isopropanol (IPA), 5% tetramethylammonium hydroxide (TMAH) aqueous solution and γ- propyltrimethoxysilane (KH560), the specific preparation method is referred to in previous research . The mol2 nanoparticles with a particle size of 20 nm were purchased from Macklin Reagent Company ; ZnO nanoparticles were a 30wt% dispersion with a particle size of 30 nm, and were purchased from Macklin Reagent Company ; and the thickness of graphene was 0.2 nm, the size was 2 μm, and the specific surface area was 800 mm2/g, the graphene was purchased from Macklin Reagent Company . All substances were used without further processing after purchase.SiOEP-POSS/graphene was prepared by adding 6 wt% graphene to EP-POSS. The specific preparation method was as follows: 8.0 g EP-POSS and 0.5 g graphene were added into a centrifuge tube, stirred evenly, and dispersed ultrasonically for 30 min to obtain EP-POSS/graphene.2 was prepared by adding 6 wt% graphene and 6 wt% SiO2 to EP-POSS. The specific preparation method was as follows: 8.0 g EP-POSS, 0.5 g graphene, and 0.5 g nano-SiO2 were successively added into a centrifugation tube, and then the EP-POSS/graphene/SiO2 was obtained by ultrasonic dispersion after stirring evenly for 30 min.EP-POSS/graphene/SiOEP-POSS/graphene/ZnO was prepared by adding 6 wt% graphene and 6 wt% ZnO to EP-POSS. The specific preparation method was as follows: 8.0 g EP-POSS, 0.5 g graphene, and 1.67 g nano-ZnO dispersions were successively added into a centrifugation tube, and then the dispersions were stirred evenly and dispersed ultrasonically for 30 min to obtain EP-POSS/graphene/ZnO.Glass slides were coated with EP-POSS nanocomposite and dried at 150 °C for 15 min to obtain EP-POSS nanocomposite films with a thickness of about 30 μm.−1 and resolution of 2 cm−1 was used to test the tablet. XPS analyses used a Thermo Scientific ESCALAB 250Xi instrument , an aluminum X-ray source, and a working power of 200 W. The vacuum pressure range was 10−9–10−8 Pa, and Thermo Scientific Avantage 4.52 software was used for data collection and processing. A DX2700 X-ray diffractometer (XRD)  was used for characterization. The accelerating voltage was 40 kV, the current was 30 mA, the step angle was 0.02°, and the scanning range was 5–90°. The TEM test was performed using a JEM-2100F Japan Electronics Corporation to observe and analyzed the nanostructure characteristics of EP-POSS modified by nanoparticles. Referring to GB/T 5210  for the testing procedure, an Instron 23.8 million capacity testing machine was used, and the rate of increase in tension was 1 MPa/s. Referring to EN 6602 for the testing procedure, an RCA abrasion tester  was used, and the rotating friction was measured at over 5000 revolutions to test the volume loss.Before the measurements, the EP-POSS sample (0.1–0.2 g) was degassed in a vacuum at 110 °C for 12 h to remove impurities. The sample contact angle test data were recorded using an OCA 100 automatic video optical contact angle instrument from Dataphysics . A Bruker VERTEX 80v spectrometer , with a test wavelength of 400–4000 cm−1, which was the hydroxyl stretching vibration peak and H2O variable angle vibration peak. At the same time, the wide peak at 3442 cm−1 was the -OH stretching vibration peak and showed that a certain amount of moisture was found in the resin system, this was due to the large specific surface area of the graphene and nanoparticles. The C-H stretching vibration peaks at 2918 cm−1 and 2852 cm−1 and the C-O stretching vibration at 1201 cm−1 were enhanced after graphene was added to EP-POSS, which was due to the lattice defects at the edges of the graphene and the existence of a number of C-H and C-O bond structures. The peaks at 1105 cm−1 and 1040 cm−1 were Si-O-Si antisymmetric stretching vibration peaks and C-H in-plane bending vibration peaks, respectively. The peaks became dull after graphene was added, indicating that graphene and nanoparticles formed a complex with EP-POSS. The strength of the stretching vibration peak of Si-O at 788 cm−1 was slightly increased compared with the nearby peak of 742 cm−1, indicating that the addition of graphene with large specific surface area could weaken the shielding effect of the epoxy chain segment on the POSS group, resulting in the characteristic absorption peak of the stretching vibration of Si-O being slightly enhanced. SiO2 and ZnO inorganic nanoparticles were added to EP-POSS, and their infrared spectra did not change significantly compared with that of EP-POSS with only graphene added. Other test methods are explained below to characterize the impact of the inorganic nanoparticles.In order to study the changes of the surface structure of EP-POSS after the addition of nanoparticles, FTIR was used for structural analyses, and the infrared spectrum is shown in 2 can increase the content of Si element in EP-POSS, and nano-ZnO can improve the antibacterial effect of EP-POSS. so how does the introduction of nanoparticles affect the surface of EP-POSS? A contact angle test was used for characterization, and the test results are shown in 2 was added, the contact angle was significantly reduced to 58.9°, which showed that the introduction of SiO2 caused a sharp drop in hydrophobic properties compared to graphene. After ZnO/graphene was added, the contact angle was lower than that of SiO2/graphene and decreased to 44.5°, which indicated that the additional introduction of inorganic nanoparticles negatively affected the surface hydrophobicity.The introduction of nano-SiO2 and ZnO were added compared to graphene. To study the effect of the addition of inorganic nanoparticles on the surface morphology, the prepared film was tested using TEM. 2 and nano-ZnO added, respectively. It can be seen that there were SiO2 and ZnO nanoparticles between the graphene sheet structures, and the TEM image is obviously lighter than that in 2 and ZnO nanoparticles enter the gap between the graphene sheets and the graphene spreads out and the dispersion is more uniform. These test results show that the introduction of graphene improves the surface hydrophobicity compared to inorganic nanoparticles, and that the surface inertness and two-dimensional structure of graphene are the main sources of this effect. However, the addition of inorganic nanoparticles can improve the compatibility of graphene and EP-POSS.The contact angle analyses showed that the hydrophobicity of the EP-POSS surface was substantially reduced when nano-SiO2 diffraction peaks and 34.4° diffraction peaks are found. The diffraction peak of ZnO indicates that nano-SiO2 and ZnO have good dispersibility in EP-POSS. In 2 and ZnO were added, the characteristic peak of graphene weakened, which indicated that the addition of nano-SiO2 and ZnO helped graphene disperse in EP-POSS. The reason for this is that nano-SiO2 and ZnO are inserted into the graphene sheet, which reduces the van der Waals force and destroys the crystal phase structure between graphenes, so the characteristic peaks of graphene are significantly weakened. In addition, the EP-POSS molecular chain grows in the gap between the nanoparticles, and the compatibility between the POSS structure and the nanoparticles increases the compatibility of graphene in EP-POSS, which is in the microstructure shown using TEM. The compatibility mechanism is shown in Both POSS groups and nanoparticles in EP-POSS have a crystal structure. X-rays are diffracted when they pass through the crystal structure. The orientation and intensity of the diffraction lines in space are related to the crystal structure, so XRD is used to characterize the nanoparticles. The crystal phase structure of EP-POSS test results are shown in 2+ appeared at 1022 ev and 1045 ev, respectively, which indicated that there was a small amount of Zn(OH)2 in the added nanometer ZnO, and the two were compared in terms of the peak area. The ratio was 2.3:1. After SiO2/graphene was added, the surface Si content increases, and the Si content was 7.01%, but compared to the addition of the same amount of graphene, when SiO2 was not added, the Si content was 7.19% higher, and the Si-C structure content is higher at 6.78%. This result confirms that the addition of graphene can induce the enrichment of Si on the surface of EP-POSS, and that the Si-C structure bond length is smaller than the C-C bond, which has a stronger shielding effect on the main chain and improves hydrophobicity due to the inertness of the surface of graphene, poor compatibility in EP-POSS, and easy accumulation on the surface. Part of the EP-POSS will grow on the graphene sheet structure and weaken the epoxy segment coat on the POSS structure, so the surface Si content increases.XPS is a surface analysis method that uses X-ray radiation samples to measure the energy and quantity of photoelectrons to determine the binding energy of electrons to identify the chemical properties and composition of a sample’s surface. It can test the surface chemical information within 10 nm, with an analysis of the features of a small area and with high accuracy. To have a deeper understanding of the effect of graphene and inorganic nanoparticles on the surface structure of EP-POSS, XPS was used to analyze the surface elements. The full spectrum is shown in 2, which satisfies the application requirements of the coating. The wear resistance test shows that the friction volume loss was only 1.46 mm3, which reached the T level. After SiO2 and ZnO nanoparticles were added, the adhesion and wear resistance of EP-POSS nanocomposites still satisfied the application requirements, which shows that the addition of graphene, SiO2, and ZnO does not affect the performance of the coating.To verify the effect of the introduction of nanoparticles on the mechanical properties of the coating, EP-POSS nanocomposites were tested for adhesion and wear resistance. The test results are shown in 2, ZnO, and graphene inorganic nanoparticles were introduced into EP-POSS, the contact angle of EP-POSS nanocomposite was greatly reduced due to the hydrophilicity of the nanoparticles, which is not conducive to the hydrophobic properties of the EP-POSS coating, but the adhesion and wear resistance properties of the EP-POSS nanocomposite film meet the actual use requirements.Graphene has a low compatibility with EP-POSS, but the addition of inorganic nanoparticles can improve the compatibility of EP-POSS and graphene. This is because inorganic nanoparticles can be inserted into the sheet structure of graphene to reduce the interlayer interaction, and strengthen the compatibility between graphene and EP-POSS. The compatibility mechanism model is proposed. In addition, the introduction of graphene increases the content of Si-C bonds with high bonding energy, reduces the shielding effect on the cage POSS structure, which is beneficial to the improvement of hydrophobicity. However, graphene forms a stacked structure on the surface of EP-POSS, resulting in an increase in surface roughness, so the contact angle of EP-POSS does not change significantly after adding graphene. Then, SiO


Introduction. Despite its high accuracy, polysomnography (PSG) has several drawbacks for diagnosing obstructive sleep apnea (OSA). Consequently, multiple portable monitors (PMs) have been proposed. Objective. This systematic review aims to investigate the current literature to analyze the sets of physiological parameters captured by a PM to select the minimum number of such physiological signals while maintaining accurate results in OSA detection. Methods. Inclusion and exclusion criteria for the selection of publications were established prior to the search. The evaluation of the publications was made based on one central question and several specific questions. Results. The abilities to detect hypopneas, sleep time, or awakenings were some of the features studied to investigate the full functionality of the PMs to select the most relevant set of physiological signals. Based on the physiological parameters collected (one to six), the PMs were classified into sets according to the level of evidence. The advantages and the disadvantages of each possible set of signals were explained by answering the research questions proposed in the methods. Conclusions. The minimum number of physiological signals detected by PMs for the detection of OSA depends mainly on the purpose and context of the sleep study. The set of three physiological signals showed the best results in the detection of OSA. Nowadays, sleep disorders are divided into seven categories according to the prevailing international classification of sleep disorders ICSD-3): sleep breathing disorders, central hypersomnia, insomnia, isolated symptoms, parasomnias, sleep movement disorders, and circadian rhythm disturbances . Within : sleep bConsidering the pitfalls derived from PSG, several OSA screening approaches have been proposed as an alternative to PSG, such as questionnaires and home sleep apnea tests (HSAT). Questionnaires such as the Berlin questionnaire, STOP-BANG, or NoSAS have been developed to evaluate and screen patients with OSA . NonetheA large number of PMs to detect apnea have been developed, since the first classification of practice parameters concerning the use of PM devices to detect OSA was carried out by the AASM in 1994. Since this classification was released, the AASM has applied several updates to it; however, as a consequence of the exponential growth of technological advances in the clinical realm over the years, Collop et al.  proposedIn this classification, the AASM classified sleep studies into four types based on the number of channels or physiological signals on the PM: type I , type II , type III , and type IV  ,7,11.A large number of manufacturers have contributed to the development of commercial PMs for the detection of OSA over the years . CurrentFor the search for a minimum set of physiological parameters for OSA, a systematic review was performed. Before the review was conducted, both the main and the set of specific questions were formulated.Is there a minimum set of non-invasive parameters measured to diagnose, detect or monitor sleep apnea by in-home PM?Does the outcome (OSA detection) improve if the number of psychological parameters measured increases?What are the main requirements for the application of an in-home medical device to diagnose sleep apnea?Is there a set of minimum physiological signals that distinguish between detection of sleep and arousal?How does it affect the outcome (OSA detection) when PMs do not include oximetry measurement?What physiological signals are included in those PMs that meet the criteria of positive likelihood ratios (LR+) of ≥5 and sensitivities (Sen) of ≥0.825?The criteria for the inclusion and exclusion of papers and searches in databases are explained primarily in the Methods section. In the Results section, all publications that meet the criteria are analyzed, focusing on the number of physiological signals used and the precision in the detection of OSA. Finally, the discussion and the conclusion include a general interpretation of the results and the most relevant information extracted from the analysis. It is important to note that, contrary to another systematic review of PMs for OSA detection, the study does not focus on the features of medical devices, but on the physiological parameters collected by them.This review was carried out following the “The PRISMA 2020 statement”, an update of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline .According to , a PM fo▪Study type: randomized controlled and clinical trials, research and review articles, and conference publications, along with clinical guidelines.▪Population: studies with adult (>18) patients referred to sleep clinics with symptoms suggestive of OSA.▪Grouping of studies: Differentiation between review publications and any other type of publication at the end of the search.▪Outcome: set of physiological parameters of PM (preferably type III or type IV).▪Exclusion criteria are shown as following:▪The articles are not in English or German.▪Published data are not available.▪Studies are not related to monitoring or diagnosing OSA using a PM.▪Studies of which the publication dates are older than 10 years when the systematic review is performed (2011–2021). Collop et al. conducted a review of studies covering PMs published prior to 2011  OR “portable”[TITLE] OR “ambulatory”[TITLE] OR “device”[TITLE]) AND (obstructive sleep apnea OR hypopnea) AND (“detection” OR “diagnosis” OR “monitoring”). For ScienceDirect, the query used was as following: TITLE: (home OR portable OR device OR ambulatory) AND (“obstructive sleep apnea” OR hypopnea) AND (detection OR diagnosis OR monitoring). Finally, for the IEEE Xplore Digital Library search, the query used was as following: (“Full Text Only”: “obstructive sleep apnea” OR “Full Text Only”: hypopnea) AND (“Full Text Only”: detection OR “Full Text Only”: diagnosis OR “Full Text Only”: monitoring) AND (“Document Title”: home OR “Document Title”: portable OR “Document Title”: device OR “Document Title”: ambulatory).Six hundred and sixty-six references (before removing duplications) were collected from the databases . The records were downloaded in a text format, and after removing duplications, a total of 629 references were qualified for the data evaluation step. One hundred forty-four articles were selected after the evaluation of the publications by reading their titles and abstracts. Eventually, full-text reading took place, ensuring that the inclusion/exclusion criteria for the articles assessed were met. The number of the studies included in the systematic review was 58. Statistical methods were used to analyze 45 publications. The remaining 13 were used to answer the main/specific questions.The studies identified after the search explained in the above section were exported to the Mendeley free reference manager tool. Subsequently, duplicates were automatically identified and eliminated. The next step was to select the remaining publications, first by their titles and then by their abstracts. The titles and abstracts of non-duplicated publications were selected, and then all publications that did not relate to the topic were removed.The final step was the full reading of all the publications. For this purpose, a predefined form was filled with the data from the publication . The fields in the form were as following: paper name, year, SCOPER classification, PM sensitivity, PM specificity, LR+, AHI, population, arousal detection, and type of device. Those publications that consisted of reviews of several PMs were classified independently and reserved for answering the specific questions stated in the Introduction section.The PMs were classified according to the physiological parameters used for each independent study. This means that for publications using the same type of device, the variation proposed by Mendonça et al.  for the Statistical analysis was carried out using a suite of Python packages . Statistical data visualizations were presented to aid in understanding the results. Statistics were performed using Sen and specificity (Spe) reported by PMs and their relation to the number of physiological parameters used. As far as possible, statistics were presented to explain the relevant information collected during the systematic review.In this section, the central and specific questions stated in the Introduction section are answered and explained in detail.The statistical analysis with the information extracted from the publications in The combination of four physiological signals (13.3% of the PMs included in this study) reported the second-best result for the detection of severe OSA, only worse than the set of three signs. It should be noted that all but one four-channel PM included oximetry. Finally, the sets of five and six psychological signals represented 8.9% of the total each. For both AHI of ≥5 and AHI of ≥15, the PMs that used five signals obtained the second-highest result in terms of Sen. Taking into account the results of the statistical analysis, the minimum set of signals that a PM should collect to obtain the best result when it comes to detecting OSA is two or three. In general, considering all levels of OSA severity, PMs with three channels showed the best results.3O1xP2E4R3) drew the best agreement with PSG and obtained for AHI of ≥5, the highest Sen of 96.5%, and an Spe of 100%.Regarding the group of publications known as “Other(s)”, five studies address this question. Hesselbacher et al.  state thAs shown in A wide variety of publications in Other(s) highlight the importance of following the clinical guideline created by the AASM with a series of recommendations for the use of PMs for the detection of OSA at home ,65,66,682 desaturation [A total of seven publications from the group known as Other(s) address this question. According to Hesselbacher et al. , one of turation ,67. As aturation ,11.Although EEG or EOG is strongly recommended to detect awakenings, several alternatives have been proposed to work as surrogate signals in the detection of the sleep-wake state. Body movement, heart rates, and changes in sympathetic tone are surrogate signals used in the detection of sleep versus wakefulness ,66. Peri3C4O1P2E4R2A2 .From our statistical analysis with the publications of the group “Research and Commercial PM”, nine publications state that they detect arousals. The physiological parameters incorporated into these PMs ranged from three to six with a distribution of 33.33% for three signals, 33.33% for four signals, 22.22% for six signals, and 11.11% for five signals. The entire set of PMs was commercial devices, and seven of them included oximetry as one of their set of the collected physiological parameters. The two PMs which met the requirements of Sen of ≥0.825 and LR+ of ≥5 at AHI of ≥5 had a categorization of S3C2O1x   and P2R5The main inconvenience is related to the scoring of hypopnea and the classification of the severity of OSA. Pulse oximetry is required to calculate oxygen saturation levels . TherefoApproximately 51% of the PMs from the publications included in On the basis of the results obtained from our statistical analysis, the inclusion of oximetry did not greatly influence the final result among all the PMs analyzed in this study.Only four studies obtained results above the cut-off points set by Collop et al.  regardinThe difficulty in diagnosing patients with OSA is a widely known problem. This problem lies mainly in the bottleneck caused by the waiting list of patients with a high probability of having OSA due to the time required to perform PSG. In addition to this, sleep studies are also expensive. As a solution, for some time now, more and more PMs have been developed to facilitate OSA detection.The use of PMs for the diagnosis of OSA has been extensively studied and validated ,6,12,14.Although the AASM provides recommendations on PM use, they are not always followed. Based on the results obtained in this systematic review, the main objective when developing new PMs is usually to achieve the maximum patient comfort, together with adequate accuracy as close as possible to that obtained by PSG.As a general rule, the AASM recommends for HSAT monitoring a minimum of three physiological parameters: airflow, respiratory effort, and SaO2 ,62,70. IThis systematic review showed that not all PMs followed this recommendation. In contrast, the number of channels and the set of physiological signals collected varied widely. The statistical analysis of this study in In addition to the aforementioned studies that validate the use of PMs for OSA detection, there are other studies on features that PMs should include, along with the set of signals they should collect. For example, Mendonça et al.  concludeIn general, in this study, a wide variety of PMs measured physiological signals, and the results obtained by these PMs in the detection of OSA have been analyzed. Once the signal measurement has been carried out, the methods used to assess whether the patient has OSA have not been evaluated in this analysis. Therefore, the calculation methods, algorithms, etc. have not been evaluated. It is also an interesting field to study in the future.3C2O1x  [2R5A1  [Another important aspect addressed in this study is the use of oximetry by PMs and the search for a minimum set of signals to detect arousals. Regarding the use of oximetry, there is a large division, with practically half of the PMs analyzed including oximetry and the rest which did not include it see . There w+ = inf)  and P2R5+ = 8.5) . They alThe fact that there is no agreement on the selection of metrics for the presentation of results in the scientific publications selected in this systematic review implies that many metrics obtained by PMs have not been taken into account. Sensitivity and specificity were chosen as study metrics to assess the diagnostic accuracy of PMs, because most publications include them in their analyzes, and Collop et al.  stated aThe SCOPER classification was selected, because it allows the inclusion of many PMs that remain unidentified with the proposal on the use of PMs for OSA detection by the AASM. Specifically, the specification made by Mendonça et al.  has beenIn this systematic review, a distinction was made between the two types of publications. First, those articles contained information on the validity of PMs in the detection of OSA. Second, those publications that included reviews, book chapters, or publications could help answer specific questions, but were not appropriate for inclusion in the statistical analysis, as they did not evaluate a single PM in particular. This was to avoid the removal of relevant information, since the publications contained in In general, in response to the central question of this systematic review, it can be stated that the results are not significantly different from the guidelines developed by AASM in the number of physiological signals that are necessary to detect OSA. In contrast, the results of this review showed that there are a large number of signal combinations.There is a large body of literature on the use of PMs to detect sleep disorders such as OSA. However, there is a less variety in terms of the physiological signals that should be used to develop such PMs. In this article, we carried out a systematic review of publications that include PM to detect OSA. We analyzed the number and characteristics of the physiological parameters used by the PMs mentioned above. Some aspects of arousal detection or alternative oximetry were also studied.In summary, the answer to the main question of this systematic review after our statistical analysis is in agreement with the AASM recommendations. The set of three physiological signals for OSA detection is the best performing set. The set of the selected physiological parameters is affected by the type of sleep study, and the context in which it is found is greatly affected by the circumstances of the patient when using the device. On the other hand, increasing the number of physiological signals collected by PMs does not improve the overall results in OSA detection.