Royal Papworth Hospital is a specialist heart and lung hospital, located on the Cambridge Biomedical Campus in Cambridgeshire, England. The Hospital is run by Royal Papworth Hospital NHS Foundation Trust.The hospital is a world-leading cardiothoracic transplant centre and the biggest in the UK, having carried out more heart and lung transplants in 2019/20 than any other hospital. It is also home to the UK's biggest sleep centre, and is one of five hospitals commissioned by NHS England to provide Extra Corporeal Membrane Oxygenation (ECMO) to adults with severe respiratory failure.
QuestionIn patients at increased risk of pulmonary complications undergoing cardiac surgery, does prophylactic high-flow nasal oxygen therapy (HFNOT) initiated at the time of extubation have important clinical benefits vs the use of standard oxygen therapy (SOT)?FindingsIn this randomized clinical trial that included 1280 adults, HFNOT did not improve clinical outcomes compared with SOT.MeaningThese findings do not support the routine implementation of prophylactic HFNOT for noninvasive respiratory support following cardiac surgery. This randomized clinical trial investigates the use of high-flow nasal oxygen therapy in patients at high risk of pulmonary complications following nonemergent cardiac surgery and assesses the clinical benefits of this technique compared with standard oxygen therapy. ImportanceHigh-flow nasal oxygen therapy (HFNOT) is used for noninvasive respiratory support following cardiac surgery despite uncertainty about its clinical effectiveness or associated costs.ObjectiveTo determine whether prophylactic HFNOT in patients at increased risk of respiratory complications following cardiac surgery has clinical benefits compared with standard oxygen therapy (SOT).Design, Setting, and ParticipantsThis adaptive, parallel group, randomized clinical trial collected and analyzed data from 17 cardiac surgery centers in 3 countries between October 7, 2020, and June 19, 2024. Eligible participants included adults undergoing nonemergent cardiac surgery with any of the following risk factors for pulmonary complications: chronic obstructive pulmonary disease, asthma, lower respiratory tract infection in the last 4 weeks, a body mass index of 35 or greater, or currently or recently smoking for longer than 10 pack-years. Outcome assessors were blinded. A preplanned sample size re-estimation was conducted after 300 participants completed the 90-day follow-up.InterventionParticipants were randomized at a 1:1 ratio with concealed allocation to HFNOT or SOT administered for at least 16 hours immediately after postoperative extubation.Main Outcomes and MeasuresThe primary effectiveness outcome was days alive and at home (DAH) without increased support compared with baseline in the first 90 days (DAH90). Any day of increased support, including at home, would provide a value of 0 for that day. Secondary outcomes included DAH90 without considering the additional support component.ResultsA total of 1280 patients were recruited (mean [SD] age, 62.9 [10.5] years; 892 [69.7%] men; 640 in each group), of whom 1224 (95.6%) had complete DAH90 data. The primary outcome of median DAH90 was 0 (IQR, 0-79) for the HFNOT group and 0 (IQR, 0-87) for the SOT group (median difference, 0 [95% CI, 0-0]; P = .75). Secondary clinical outcomes, including DAH90 without considering whether additional support was required, were similar between groups.Conclusions and RelevanceIn this randomized clinical trial of HFNOT in patients at increased risk of postoperative pulmonary complications after nonemergent cardiac surgery, HFNOT did not improve DAH90 without increased support. These findings do not support the implementation of routine prophylactic HFNOT after cardiac surgery.Trial Registrationisrctn.org Identifier: ISRCTN14092678
In vitro antibiotic testing is important for guiding therapy and drug development. Current methods are focused on growth inhibition in bulk bacterial populations but often fail to accurately predict treatment responses. Here we introduce Antimicrobial Single-Cell Testing (ASCT), a large-scale live-cell imaging approach that quantifies bacterial killing in real time at single-cell resolution. By tracking over 140 million mycobacteria and analysing ~20,000 time–kill curves, we identify key determinants of antibiotic killing and its clinical relevance. For Mycobacterium tuberculosis, we found that drug-specific killing dynamics in starved bacteria, rather than growth inhibition or killing of growing cells, predict regimen efficacy in mice and humans. Extending this approach to Mycobacterium abscessus and comparing 405 bacterial strains, we show that antibiotic killing is also a genetically encoded bacterial trait (drug tolerance). We demonstrate that tolerance patterns cluster by antibiotic targets, identify a phage protein that modulates antibiotic killing, and show that strain-specific killing dynamics are associated with individual patient outcomes independent of drug resistance. Together, these findings establish a framework that reveals how drug properties and bacterial diversity shape treatment responses, offering a path to more effective and personalized therapies. Via high-throughput imaging and tracking over 140 million single mycobacteria, the authors show that drug- and strain-specific killing predict treatment outcomes, with potential to improve drug development and personalized therapy.
Temporary pacing wire (TPW) insertion is a potentially life-saving procedure. A TPW is most commonly inserted as an emergency procedure but can be electively inserted to cover surgery. Access is via a venous sheath to the right ventricular apex, outflow tract or right atrium. Complications include those related to venous access, infection and perforation of the heart by the lead.
OBJECTIVES:Eosinophilic bronchiectasis is defined by a blood eosinophil count (BEC) ≥300 cells/µL, but blood eosinophils imperfectly reflect airway eosinophilic inflammation. Here, we investigated the relationship between eosinophilic airway inflammation, blood eosinophils and clinical severity in bronchiectasis and explored the phenotype associated with eosinophilic bronchiectasis. METHODS:Sputum from 180 patients with stable CT-confirmed bronchiectasis was utilised to investigate airway levels of eosinophil proteins (eosinophil peroxidase (EPX), eosinophil derived-neurotoxin (EDN), eosinophil cationic protein (ECP), major basic protein (MBP) and Galectin-10 (Gal-10)) using a novel stable isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. To profile eosinophilic bronchiectasis, a nested analysis of patients with BEC <150 cells/µL (n=52) and ≥300 cells/µL (n=49) was conducted. RESULTS:Sputum concentrations of Gal-10, ECP and EDN were weakly but significantly associated with radiological severity, FEV1 and sputum culture positivity for Pseudomonas aeruginosa. Airway eosinophil protein concentrations did not associate with exacerbation frequency. Total eosinophil protein concentration moderately correlated with BECs (r=0.33 95% CI 0.14 to 0.49, p=0.0007). Nested analysis revealed increased sputum PCR-positivity for P. aeruginosa (26.7% vs 7.7%, p=0.033) and an increased frequency of patients showing signs of Aspergillus sensitisation (defined as Aspergillus-specific IgE titres >0.35 kUA/L, 24.5% vs 3.8%) in eosinophilic bronchiectasis. Sputum inflammatory biomarkers and clinical parameters did not differ between groups. CONCLUSIONS:LC-MS/MS can detect eosinophilic inflammation within bronchiectasis sputum. Weak associations between elevated airway eosinophil proteins, bronchiectasis severity and P. aeruginosa infection were observed. Direct measurement of eosinophilic airway inflammation provides additional information in addition to BECs. Eosinophilic bronchiectasis associated with P. aeruginosa infection and Aspergillus sensitisation.
Rationale Non-cystic fibrosis bronchiectasis (hereafter bronchiectasis) is a chronic and progressive respiratory disease. Neutrophilic inflammation plays a key role in the pathophysiology of bronchiectasis. Neutrophil serine proteases (NSPs), especially neutrophil elastase, have been associated with disease progression and poorer clinical outcomes. Current therapies do not directly target neutrophilic inflammation. Long-term macrolide use is recommended for patients with frequent exacerbations. Brensocatib, an oral, selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1, prevents activation of NSPs. In the phase 3, randomized, double-blind ASPEN trial (NCT04594369), treatment with once-daily brensocatib 10- or 25-mg significantly reduced the annualized rate of adjudicated pulmonary exacerbations over 52 weeks vs placebo; the 25-mg dose also significantly reduced lung function decline and numerically improved patient-reported symptoms. Here, we report ASPEN subgroup analysis findings in patients with or without maintenance macrolide use. Methods ASPEN enrolled patients with bronchiectasis and a history of pulmonary exacerbations in the 12 months prior to screening (adults [18-85 years], ≥2; adolescents [12-<18 years], ≥1). Patients were randomized to receive once-daily brensocatib (10- or 25-mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1). Subgroup analyses were explored in patients with or without maintenance macrolide use (≥3 months) at baseline. Endpoints were annualized exacerbation rate, time to first exacerbation, rate of severe exacerbation, change in post-bronchodilator forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and change in Quality of Life-Bronchiectasis Respiratory Symptoms Domain score (QOL-B RSS). Results Demographics were balanced, with some differences in baseline characteristics indicating greater disease severity among patients with maintenance macrolide use, including increased exacerbation rate and more exacerbations requiring hospitalization prior to enrollment. Patients with maintenance macrolide use experienced higher rates of exacerbations over the study period vs those without, regardless of treatment group (Table). Consistent with overall ASPEN results, brensocatib 10- and 25-mg reduced the annualized exacerbation rate, prolonged the time to first exacerbation, and increased the odds of remaining exacerbation-free in both subgroups (Table). Brensocatib 25-mg reduced both FEV1 and FVC decline, and numerically improved QOL-B RSS at week 52 vs placebo for patients regardless of baseline macrolide use (Table). Adverse events were similar across treatment groups, and consistent with the overall ASPEN results. Conclusions Consistent with the overall study population, both brensocatib doses reduced the annualized rate of exacerbations, and brensocatib 25-mg reduced lung function decline and numerically improved patient-reported symptoms regardless of maintenance macrolide use at baseline.
