Evaluation navigation controlled gate of aging spillway on cavitation damage.

BACKGROUND: High-speed flow of clean water or water with sediment released from aging spillways may cause abrasion and cavitation on the concrete surface gradually. The occurrence of irregularities on the concrete surface can exacerbate the erosion problem. Which might jeopardize the safety of dams constantly, hence the rehabilitation efforts become urgent tasks in dam safety projects. METHODS: This study employs a 3D Computational Fluid Dynamics (CFD) model to quantitatively analyze the cavitation risk on the aging concrete surface of the Chay 5 spillway in Ha Giang, Vietnam, under various operation scenarios. There are two standards used to measure cavitation: the cavitation index (σ) which indicates the danger due to the drop of pressure in rapid flow, and the new gasification index (ß) which takes into consideration the formation and collapse of bubbles behind asperities. RESULTS: Three extreme flood cases may not result in potential cavitation because both σ and ß exceed critical thresholds. Regarding the six controlled gate scenarios with normal water level, the σ profiles are approximated 1,0 showing a low likelihood of cavitation damage while the ß values are smaller than 0.8, indicating a considerable risk of cavitation. Besides, the opening height of 100 cm poses the greatest risk of creating severe cavitation erosion in the concave area and slope portion. The flip bucket experienced the most vulnerable cavitation when the opening height is 400 cm. In addition, an approach to spillway surface rehabilitation involving specialized mortars has been presented. CONCLUSION: For aging conveyance structure, gasification index (ß) takes into account irregularities surface, providing a more comprehensive assessment of the likelihood of cavitation damage than cavitation index (σ). After rehabilitation with anti-shrinkage high abrasion resistance mortar, the entire spillway surface is smooth. This allows for reducing the cavitation risk and improvement of life service thereof.

Genotype by environment interaction across water regimes in relation to cropping season response of quinoa (Chenopodium quinoa).

Genotype × environment (GxE) interaction effects are one of the major challenges in identifying cultivars with stable performance across agri-environments. In this study we analysed GE interactions to identify quinoa (Chenopodium quinoa) cultivars with high and stable yields under different soil moisture regimes, representing control conditions, waterlogging and drought. Waterlogging and drought treatments were artificially induced using normoxia, a combination of hypoxia-normoxia, and 10% PEG (Polyethylene glycol) under hydroponic growth conditions, respectively. Both waterlogging and drought conditions significantly reduced the plant height (PH), number of leaves (NoL) and number of branches (NoB), stem diameter (SD), leaf area (LA) and dry weight (DW) of quinoa genotypes. The genotype, water regime, and genotype by water regime effects all significantly affected the measured quinoa traits. Based on the additive main effects and multiplicative interaction (AMMI) model for DW, the genotypes G18, Puno, Q4, 2-Want, Puno, Real1 x Ruy937 and Titicaca were found to exhibit tolerance and were stable across water regimes. A second-stage evaluation was conducted to test genotype × environment interaction effects in crop production field trials, selecting two contrasting seasons based on soil moisture conditions involving a diverse set of genotypes (58 varieties in total). Our results demonstrate significant variations in both growth and yield among the quinoa genotypes across the cropping seasons. The GGE analysis for grain yield indicate that field conditions matched to G × E under hydroponic experimental conditions and the cultivars G18, Q1, Q4, NL-3, G28, 42-Test, Atlas and 59-ALC were classified within a range of high productivity. Our findings provide a basis for understanding the mechanisms of wide adaptation, while identifying germplasm that enhances the water stress tolerance of quinoa cultivars at early growth stages.

Anti-Inflammatory Activity of Labdane and Norlabdane Diterpenoids from Leonurus sibiricus Related to Modulation of MAPKs Signaling Pathway.

Leonurus sibiricus, a widely cultivated herbaceous plant in Asian countries, exhibits diverse medicinal applications. Recent studies emphasize its pharmacological properties and efficacy in promoting bone health. Besides the known compounds and their pharmacological activities, in this study, we isolated and elucidated two new labdane-type diterpenoids, (3R,5R,6S,10S)-3,6-dihydroxy-15-ethoxy-7-oxolabden-8(9),13(14)-dien-15,16-olide (1) and (4R,5R,10S)-18-hydroxy-14,15-bisnorlabda-8-en-7,13-dione (2), a new natural phenolic compound, and a known compound from L. sibiricus using advanced spectroscopic techniques, including circular dichroism spectroscopy, high-resolution mass spectrometry, and 1- and 2-dimensional NMR. Among these, compound 1 demonstrated potent inhibition of nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) mRNA expression levels, followed by compound 2. Whereas compounds 3 and 4 do not exhibit effectiveness in RAW264.7 macrophages. Moreover, compound 1 suppressed pro-inflammatory markers induced by lipopolysaccharide (LPS) stimulation. Compound 1 also suppressed iNOS and cyclooxygenase-2 (COX-2) protein levels and downregulated pro-inflammatory cytokines. Additionally, compound 1 showed inhibition of the phosphorylation of p38, JNK, and ERK, key mediators of the MAPK signaling pathway. These findings indicate that a natural-derived product, compound 1, might be a potential candidate as an anti-inflammation mediator.

Alginate functionalized sugarcane cellulose-based beads to improve methylene blue adsorption from aqueous solution.

The study was carried out with the goal of synthesizing composite bead of cellulose, chitosan functionalized by sodium alginate using as an efficient and applicable adsorbent for methylene blue removal. Fabricating parameters of the material synthesis process like cellulose mass, sodium hydroxide concentration, immersing time and sodium alginate concentration were assessed in detail. The dye adsorption performance in water under the influence of pH, contact time, dye initial concentration, the material mass, shaking speed, temperature was also thoroughly evaluated. The results of advanced analyses showed that the beads were successfully synthesized with a rough surface and mesoporous structure. The adsorption isotherm and adsorption kinetics of dye adsorption process exhibited that the process was consistent with the Freundlich adsorption isotherm and the pseudo-second-order kinetic model, indicating a favorable physical adsorption process with multilayer of the dye on the adsorbent surface. The intra-particle diffusion model showed the strong dye adsorption by the beads occurred during the first two and half hours. The adsorbent could maintain its adsorption performance of 86 % for three times of regeneration. Finally, this study provided a recyclable and effective adsorbent for dyes separation from water.

Efficacy of Jasminum subtriplinerve Extract against 7,12-Dimethylbenz[a]anthracene-Induced Cancer in Mice.

Jasminum subtriplinerve Blume tea is a traditional Vietnamese medicine used to treat impetigo, menstruation issues, and painful menstrual hematometra. Previous studies have shown that extracts and isolated compounds from J. subtriplinerve possess diverse pharmacological properties, such as antioxidant, antibacterial, and antidiabetic effects. However, their potential anticancer effects and underlying mechanisms of action have not been clear. Here, we examined the effects of J. subtriplinerve extracts against three human cancer cell lines. We also conducted in vivo analyses using a mouse model of 7,12-dimethylbenz[a]anthracene-induced breast cancer, including an investigation of changes in histological sections. The effect of the J. subtriplinerve ethyl acetate fraction on cytokine levels (IL-2, PGE2, TNF-α) in serum was determined using ELISA kits. Results showed that the EtOAc fraction had the highest anti-proliferative activity (IC50 = 13.7 mg/ml) against the breast cancer (MCF-7) cell line, while the BuOH and water fractions did not show any anticancer effects. Additionally, the EtOAc fraction at a dose of 14.4 mg/kg was able to elevate IL-2 levels and suppress the expression of PGE2 in the serum of mice. A remarkable decrease in the percentage of death and tumor incidence in mice was achieved following treatment with the EtOAc fraction at a dose of 14.4 mg/kg. No abnormal parameters in blood were observed in the J. subtriplinerve treatment groups. These results suggest that J. subtriplinerve, when used as tea or a functional food, is nontoxic and has clear chemopreventive effects against breast cancer.

AMPK-Mediated Hypolipidemic Effects of a Salvia miltiorrhiza and Paeonia lactiflora Mixed Extract on High-Fat Diet-Induced Liver Triglyceride Accumulation: An In Vivo and In Vitro Study.

BACKGROUND: This study investigates the hypolipidemic effects of a mixed extract of Salvia miltiorrhiza and Paeonia lactiflora (USCP119) in HFD-fed hamsters and in vitro cellular models. METHODS: Over an 8-week period, HFD-fed hamsters were assigned to one of six groups: normal diet, HFD control, HFD with 50 mg/kg USCP119, HFD with 100 mg/kg USCP119, HFD with 50 mg/kg USCP119 twice daily (BID), and HFD with omega-3 fatty acids. Key outcomes assessed included body weight, serum triglycerides (TG), total cholesterol (TC), liver weight, hepatic TG levels, and epididymal fat. In cellular models, the impact of USCP119 on lipid accumulation and adipogenic markers was evaluated. RESULTS: USCP119 treatment at 50 mg/kg BID resulted in the lowest weight gain (15.5%) and the most significant reductions in serum TG and hepatic TG levels compared to the HFD control. The 100 mg/kg dose also led to substantial reductions in serum TG and TC levels and notable decreases in low-density lipoprotein cholesterol. USCP119 at 50 mg/kg once daily reduced TG and TC levels but was less effective than the higher doses. In cellular models, USCP119 was non-toxic up to 400 µg/mL and effectively reduced lipid accumulation, modulated adipogenic markers, and enhanced AMPK signaling, improving lipid metabolism and insulin sensitivity. CONCLUSIONS: All USCP119 treatments demonstrated effectiveness in managing hyperlipidemia and related metabolic disorders, with variations in impact depending on the dosage. The ability of USCP119 to reduce fat accumulation, improve lipid profiles, and enhance insulin sensitivity highlights its potential as a valuable dietary supplement for addressing high-fat diet-induced hyperlipidemia and metabolic disturbances.

Molecular characterization of emerging recombinant African swine fever virus of genotype I and II in Vietnam, 2023.

African swine fever virus (ASFV) recombinant strains pose new challenges for diagnosis and control. This study characterizes genotype I and II recombinant ASFV strains identified in northern Vietnam in 2023 through whole-genome sequencing and comparative genomic analysis. Seven ASFV-positive samples from six provinces were analyzed, with recombinant strains detected in Bac Giang, Phu Tho, and Vinh Phuc provinces. Isolates showed hemadsorption positivity despite having genotype I B646L, indicating their recombinant nature. Genome-wide analysis revealed 19 recombination breakpoints consistent with Chinese recombinant strains. Vietnamese isolates shared 99.86-99.98% nucleotide identity with Chinese recombinants, forming a distinct monophyletic group. Comparative analysis identified 50 SNPs and INDELs, with 39 variations found across Vietnamese strains, distinguishing them from Chinese isolates. Unique genetic markers in C962R, I329L, and MGF 505-11L genes distinguished Vietnamese recombinants from Chinese counterparts, while mutations in C122R and NP1450L differentiated all recombinants from parental genotypes. The central variable region (CVR) of the B602L gene showed diversity among Vietnamese isolates, while the I73R-I329L intergenic regions were recognized as in the IGR2 group. This study enhances understanding of recombinant ASFV evolution through homologous recombination and identifies new genetic markers for improved detection and characterization. The observed genetic diversity highlights challenges for existing diagnostic methods and vaccine development, emphasizing the need for continued surveillance and research into the functional implications of these genetic variations on ASFV pathogenicity and transmissibility.

Primary omental torsion with clinical masquerading as acute appendicitis and radiological key for diagnosis.

Omental torsion is a medical condition characterized by the twisting of the omentum along its longitudinal axis, which leads to compromised blood flow. This condition is rarely diagnosed before surgery and can present symptoms similar to other causes of acute surgical abdomen. This report details a case of primary omental torsion initially suspected to be acute appendicitis. The patient was admitted to the hospital with symptoms of lower right quadrant abdominal pain and mild fever. Computed tomography imaging revealed a twisted mass of fatty tissue with surrounding fat stranding changes, but no signs of appendicitis were found, indicating omental torsion. The patient underwent surgery to remove the twisted and necrotic omentum, leading to an improvement in symptoms. This case highlights the challenges in diagnosis and the crucial role of computed tomography imaging in managing this rare condition.

Restoration of Anterior Teeth Defect With Porcelain Laminate Veneer Using the Refractory Technique: A Case Report.

Anterior teeth play an important role in the aesthetic appearance of an individual. Hence, restoration of the anterior teeth has always been a significant concern for both dentists and patients worldwide. Indirect restoration using laminate veneers has revolutionized cosmetic dentistry by minimizing tooth preparation compared to full dental crowns. It also enhances vitality, color matching, and superior mechanical properties compared to direct composite restoration. The success of veneer restoration depends on case selection, material choice, and fabrication technique, tailored for every patient based on a thorough consideration of the existing lesion and the needs of the patient. This clinical report exemplifies the conservative treatment of a refractory defect on the labial surface of the maxillary central incisor using a minimal-thickness veneer fabricated from a refractory porcelain system.

Correction: Shape-controlled synthesis of micro-/nanosized Cu particles with spherical and polyhedral shapes using the polyol process.

[This corrects the article DOI: 10.1039/D4RA03643C.].

Ultrasound-Guided Sialendoscopy Surgery for Parotid Sialolithiasis Using Yttrium Aluminum Garnet (YAG)-Holmium Laser: A Prospective Case Series.

BACKGROUND: Parotid sialolithiasis is a common condition in middle-aged individuals, with most cases occurring in the submandibular and sublingual glands, followed by the parotid glands and minor salivary glands. The treatment of salivary gland stones, particularly those of the parotid glands, remains challenging. Endoscopic surgery using a yttrium aluminum garnet (YAG)-holmium laser for parotid sialolithiasis is a minimally invasive approach that provides effective treatment for patients. This study aimed to evaluate the outcomes of the endoscopic laser treatment of parotid sialolithiasis a YAG-holmium laser. MATERIALS AND METHODS: A prospective case series study was conducted on 21 patients diagnosed with salivary gland stones in the parotid gland based on clinical features and imaging findings (including ultrasound and computed tomography scans), from March 2022 to March 2024. These patients underwent sialendoscopy surgery using a YAG-holmium laser and were evaluated for surgical results at 2, 4, and 12 weeks. RESULTS: Cases with completely reduced symptoms accounted for 90.5%, whereas cases with partially reduced symptoms accounted for 9.5%. The ultrasound image of the salivary gland after surgery was significantly improved compared to that before surgery. After three months of surgery, most patients (90.5%) were satisfied. The postoperative complication rate was 14.3%, which included scarring at the opening of the salivary gland and in the salivary duct. CONCLUSION: Sialendoscopic surgery using a YAG-holmium laser for parotid sialolithiasis is a minimally invasive surgical intervention that leaves no scarring, reduces the risk of complications as seen in open surgery, and shortens the postoperative care time for patients.

Orthodontic Retreatment of an Adult Bimaxillary Protrusion Patient With Lingual Appliances and Premolar Extractions: A Case Report.

Orthodontic relapse and the demand for improved esthetics often necessitate retreatment in adult patients. This case report highlights the successful management of an adult female patient with bimaxillary protrusion, previously treated with a non-extraction approach. Treatment included lingual passive self-ligating appliances, premolar extractions, and mini-screws to reinforce anchorage. The patient's facial profile and dental esthetics were significantly improved after 20 months of treatment, achieving a stable occlusion and reduced bimaxillary protrusion. This case demonstrates that lingual appliances can be an effective and esthetic treatment option for complex orthodontic retreatment in adult patients. Careful biomechanical planning and attention to specific challenges, including torque control and bowing effect, are essential for successful outcomes.

How do food safety technical working groups within a One Health framework work? Experiences from Vietnam and Ethiopia.

BACKGROUND: Persistent challenges of fragmented, food safety management in low- and middle-income countries underscore the need for more robustly coordinated mechanisms. National food safety technical working groups, operating under a One Health framework, offer potential in streamlining coordination efforts to effectively address these challenges. However, more clarity regarding their formation and functioning is important for understanding how to best establish and support such groups. The aim of this study is to systematically document the development process of established groups in Vietnam and Ethiopia. METHODS: We assess the process used to establish and support the technical working groups against six critical success factors for multisectoral collaboration: drive change, define, design, realise, relate, and capture success. To do so, we review meeting minutes, Terms of Reference, and other related publications. RESULTS: The analysis underscores the importance of financial and technical support by development partners in initiating working groups while also highlighting the challenge posed by the absence of legal frameworks to secure government commitment. Embedding the technical working groups within existing government structures - such as One Health platforms - from the outset could help to ensure the active participation and sustainability of such groups. CONCLUSION: Both Vietnam and Ethiopia have established operational and institutionalized technical working groups to bolster national food safety efforts under a One Health framework. The approaches employed in these countries could serve as valuable models for others seeking to establish comparable multisectoral collaborative mechanisms to address emerging health risks.

Prognostic Value of the Lactate/Albumin Ratio for 28-Day Mortality in Pediatric Septic Shock: A Prospective Cohort Study.

Background Septic shock remains a leading cause of mortality in children. The lactate/albumin ratio (LAR) has emerged as a potential prognostic marker for mortality in septic shock, yet most existing research focuses on adults, with limited data available for pediatric populations, particularly in Vietnam. Objectives This study aims to evaluate the prognostic utility of the LAR in predicting 28-day mortality among children aged two months to 15 years with septic shock in Vietnam. Methods We conducted a prospective cohort study involving children diagnosed with septic shock at the largest pediatric intensive care unit (PICU) in the Mekong Delta, Vietnam, from July 2022 to June 2024. Clinical and laboratory parameters, including lactate and albumin levels, were measured at the time of septic shock diagnosis. Patients were followed for 28 days, with outcomes categorized as either survival or mortality. The prognostic performance of LAR was assessed through its discrimination and calibration capabilities. Results The 28-day mortality rate was 63.4%. LAR was significantly higher in non-survivors compared to survivors (p < 0.001). The area under the receiver operating characteristic curve (AUROC) for LAR was 0.91, indicating superior discriminatory power compared to lactate alone and comparable to albumin. Using a Youden index-derived cut-off of 1.84, LAR demonstrated a sensitivity of 84.6% and a specificity of 80%. Kaplan-Meier analysis and log-rank testing revealed significantly lower survival probabilities in children with LAR ≥1.84 (p < 0.05). The Hosmer-Lemeshow test confirmed good calibration of LAR in mortality prediction (p > 0.05). Conclusion The lactate/albumin ratio exhibits excellent discriminatory and calibration properties, making it a valuable tool for predicting 28-day mortality in pediatric septic shock. This ratio should be considered for routine use in clinical practice to improve prognostic assessments in this vulnerable population.

Characterizing PFASs in aquatic ecosystems with 3D hydrodynamic and water quality models.

Understanding how per- and polyfluoroalkyl substances (PFASs) enter aquatic ecosystems is challenging due to the complex interplay of physical, chemical, and biological processes, as well as the influence of hydraulic and hydrological factors and pollution sources at the catchment scale. The spatiotemporal dynamics of PFASs across various media remain largely unknown. Here we show the fate and transport mechanisms of PFASs by integrating monitoring data from an estuarine reservoir in Singapore into a detailed 3D model. This model incorporates hydrological, hydrodynamic, and water quality processes to quantify the distributions of total PFASs, including the major components perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS), across water, particulate matter, and sediments within the reservoir. Our results, validated against four years of field measurements with most relative average deviations below 40%, demonstrate that this integrated approach effectively characterizes the occurrence, sources, sinks, and trends of PFASs. The majority of PFASs are found in the dissolved phase (>95%), followed by fractions sorbed to organic particles like detritus (1.0-3.5%) and phytoplankton (1-2%). We also assess the potential risks in both the water column and sediments of the reservoir. The risk quotients for PFOS and PFOA are <0.32 and < 0.00016, respectively, indicating an acceptable risk level for PFASs in this water body. The reservoir also exhibits substantial buffering capacity, even with a tenfold increase in external loading, particularly in managing the risks associated with PFOA compared to PFOS. This study not only enhances our understanding of the mechanisms influencing the fate and transport of surfactant contaminants but also establishes a framework for future research to explore how dominant environmental factors and processes can mitigate emerging contaminants in aquatic ecosystems.

Terpenoids and steroids from aerial parts of Achillea alpina L. as PTP1B inhibitors: Kinetic analysis and molecular docking studies.

Achillea alpina L. (Alpine yarrow) is a noteworthy herb in the genus Achillea with many uses in vegetables and traditionally used to treat stomach disorders. In our continuous research on the chemical constituents and biological activities of medicinal plants, ten previously undescribed terpenoids including eight eudesmane-type sesquiterpenes (1-8), one nor-eudesmane-type sesquiterpene (9), one cyclo-geraniol derivative (10), and twenty-one known compounds were isolated and structurally elucidated from the aerial parts of A. alpina. Structures and absolute configurations of the undescribed terpenoids were identified using comprehensive spectroscopic analysis (NMR, HRESI-MS, and CD data) and computational methods (ECD and NMR calculation). Enzyme inhibitory assays showed that the isolated sesquiterpene (19), triterpene (22), and sterol (26) were protein tyrosine phosphatase 1B (PTP1B) inhibitors with IC50 values ranging from 14.87 to 23.09 µM in comparison with positive control - ursolic acid, showing IC50 value of 5.93 ± 0.16 µM. Further enzyme kinetics and molecular docking studies were performed to provide valuable insights into their mechanism of action.

Acute appendicitis induced by bone fragment ingestion: A pediatrics case report.

Acute appendicitis is an ordinary surgical emergency, typically attributed to luminal obstruction by fecaliths or lymphoid hyperplasia. However, ingested foreign bodies as an etiology are rare but increasingly recognized, particularly in pediatric patients. We present the case of a 9-year-old male patient who presented to the emergency department with symptoms consistent with acute appendicitis. Further investigation revealed the presence of a bone fragment within the appendix, leading to acute inflammation. Foreign body ingestion should be considered in pediatric patients with acute appendicitis. This case report underscores the importance of comprehensive clinical evaluation and appropriate diagnostic imaging modalities in guiding optimal treatment strategies.

Two New Steroidal Saponins with Potential Anti-Inflammatory Effects from the Aerial Parts of Gnetum formosum Markgr.

Gnetum formosum Markgr., a member of the Gnetaceae family, is distributed in Vietnam. This plant remains a botanical enigma with an unexplored diversity of chemical constituents and pharmacological effects. In this study, two new steroidal saponins, namely gnetumosides A (1) and B (2), were isolated from the aerial parts of G. formosum. Their chemical structures were elucidated using spectroscopic techniques, including high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) and NMR, along with chemical hydrolysis and comparison with the reported literature. The potential anti-inflammatory effects of the isolated compounds were evaluated by measuring lipopolysaccharide-stimulated nitric oxide (NO) production in murine macrophage cells. Notably, compound 1 exhibited the most potent inhibitory activity (IC50 = 14.10 ± 0.75 µM), comparable to dexamethasone. Additionally, the mechanisms underlying the observed anti-inflammatory effects were investigated through molecular docking and molecular dynamics simulations on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins. This study is the first to investigate the chemical constituents and pharmacological effects of G. formosum.

Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).