Daily Respiratory Research Analysis

IMPORTANCE: Awake prone positioning (APP) has shown inconstant associations with improved clinical outcomes in nonintubated patients with COVID-19 developing severe pneumonia. OBJECTIVE: To evaluate the effects of APP on the need for intubation or incidence of death among patients with COVID-19-related hypoxemic respiratory failure. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted at 20 hospitals in France and 1 hospital in Mexico between July 2020 and August 2021. The study included patients from wards and intensive care units. Adult patients (18 years or older) who were not intubated and required at least 3 L/min of oxygen flow due to COVID-19 infection were included and randomly assigned in a 1:1 ratio to either APP or standard care. Intention-to-treat statistical analysis was performed from September to December 2024. INTERVENTION: Patients randomly assigned to the APP group were offered the intervention lasting at least 6 hours a day. Patients randomly assigned to standard care had no positioning constraint, including no contraindication to spontaneous APP. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite criterion of intubation and/or death in the first 28 days of randomization. Prespecified secondary outcomes at 28 days of enrollment were days alive outside the intensive care unit (ICU), days alive outside the hospital, proportion of patients admitted to ICU (for patients not in ICU at baseline), and days alive and free from mechanical ventilation. A bayesian approach was used to provide insights into the complete distribution of the effect estimates. RESULTS: A total of 445 patients were included in the final analysis (mean [SD] age, 60 [11] years; 329 males [74%]; median [IQR] SpO2 to FIO2 [peripheral oxygen saturation to fraction of inspired oxygen] ratio, 150 [114-194] and 155 [109-221] in the standard care and APP groups, respectively). With a noninformative prior distribution, the posterior probability that APP decreased intubation and/or death compared with standard care was 93.8% (mean odds ratio [OR], 0.74; 95% credible interval [CrI], 0.48-1.09). For secondary outcomes, between the APP and standard care groups, the mean difference in the number of days alive and free from mechanical ventilation was 0.33 (95% CrI, -1.37 to 2.03) days; in the number of days alive outside the ICU was 1.28 (95% CrI, -0.78 to 3.34) days; and in the number of days alive outside the hospital was 1.55 (95% CrI, -0.22 to 3.32) days. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of nonintubated patients with COVID-19 and hypoxemic respiratory failure, daily APP of 6 hours showed a high probability of reduced endotracheal intubation and/or death over a wide range of prior distributions. These results support APP's use in patients with hypoxemic pneumonia due to COVID-19 infection. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04366856.

BACKGROUND: MET amplification is recognised as a de novo driver alteration in non-small-cell lung cancer (NSCLC) but treatment responses with existing MET inhibitors remain largely unsatisfactory. We aimed to investigate the antitumour activity and safety of vebreltinib, a potent and highly selective MET inhibitor, in patients with MET amplification-driven NSCLC. METHODS: KUNPENG was a multicentre, multi-cohort, single-arm, phase 2 trial conducted across 17 hospitals in China, in patients with locally advanced or metastatic NSCLC with MET dysregulation. Patients were eligible if they were MET inhibitor-naive, aged 18 years or older with MET amplification-driven NSCLC (gene copy number of six or higher), and progressed after previous standard chemotherapy or were ineligible for chemotherapy (cohort 2) or refused chemotherapy (cohort 3). Patients received 200 mg vebreltinib orally twice daily until disease progression or intolerable toxicity. The primary endpoint was the objective response rate, assessed by a masked independent review committee in the full analysis set. The study was amended to merge cohorts 2 and 3 due to slow accrual and was closed to enrolment on Nov 14, 2023. This trial is registered with ClinicalTrials.gov (NCT04258033). FINDINGS: Between Jan 17, 2020, and Nov 14, 2023, 145 patients were enrolled; of these, 86 patients (30 chemotherapy-treated and 56 untreated) from cohorts 2 and 3 were included in the current analysis. The median age was 65 years (range 48-82; IQR 59-71), 77 (90%) patients were male, and nine (10%) were female. All patients were Chinese. 42 patients had partial response, resulting in an objective response rate of 48·8% (42 of 86; 95% CI 38·3-59·4) per masked independent review committee. The median follow-up was 18·6 months (IQR 15·7-37·3). The incidence of grade 3 or worse treatment-related adverse events was 31% (27 of 86), predominantly abnormal liver function terms reported by the investigators (eight [9%]). Serious adverse events related to treatment were reported by 16 (19%) patients. 11 treatment-emergent adverse events leading to death occurred, of which one patient died of abnormal liver function, which was possibly related to vebreltinib treatment. INTERPRETATION: Vebreltinib showed antitumour activity in patients with MET amplification-driven advanced NSCLC who had previously received chemotherapy or were chemotherapy-naive. Further research is needed to validate these findings. FUNDING: Beijing Pearl Biotechnology and Avistone Biotechnology.

INTRODUCTION: Early cystic fibrosis (CF) lung disease monitoring is crucial for understanding responses to therapy and preventing progressive pulmonary decline. Structural lung disease (SLD) is a major cause of pulmonary decline in CF. We aimed to identify metabolites in CF bronchoalveolar lavage (BAL) associated with and predictive of SLD. METHODS: We applied untargeted metabolomics to 84 BAL samples from a cross-sectional cohort of 67 clinically stable children with CF aged 1-5 years across two sites. We used a linear mixed-effects model to select metabolites associated with SLD, BAL neutrophils, and myeloperoxidase (MPO) and neutrophil elastase (NE) activities. An independent longitudinal cohort of infants who either did or did not exhibit bronchiectasis by age 9 years was analysed to determine whether metabolites associated with SLD could also predict future lung disease. RESULTS: In the cross-sectional cohort, 10 BAL metabolites, including methionine sulfoxide (MetO), ornithine and CONCLUSIONS: We identified BAL metabolites associated with SLD, MPO and NE, detectable in the earliest stages of CF. MetO, %OxMet, NAcMet and ornithine predicted bronchiectasis development, outperforming established biomarkers. These metabolites reflect oxidising, proteolytic and other enzymatic activities of neutrophils, highlighting potential therapeutic avenues.