Daily Respiratory Research Analysis

Extracellular adenosine triphosphate (ATP)-mediated purinergic signalling via P2X3 and heteromeric P2X2/3 ion channel receptors underlies hypersensitisation of vagal airway afferents in refractory chronic cough (RCC), making this pathway a key therapeutic target. Two pharmacological strategies have emerged: dual P2X2/3 receptor antagonism and selective P2X3 inhibition. While dual antagonists (gefapixant) demonstrate robust antitussive efficacy, their clinical use is limited by taste disturbance resulting from P2X2/3 inhibition in gustatory pathways. We conducted a systematic review and dose-response meta-analysis of randomised controlled trials evaluating purinergic receptor antagonists in RCC, with nine RCTs (21 active arms; N = 1,934) identified from major databases. The primary outcome was percentage change in 24-h cough frequency (24-h CF) versus placebo. Dual P2X2/3 antagonists produced greater reductions in 24-h CF than selective P2X3 antagonists (- 38.12% vs - 19.93%; p = 0.016), consistent with broader receptor blockade. However, selective P2X3 antagonists demonstrated a markedly improved safety profile, with substantially lower dysgeusia incidence (8% vs 51%; p < 0.0001), reflecting sparing of P2X2/3-mediated gustatory signalling. Dose-response analysis indicated steeper efficacy gains with dual antagonists but disproportionately higher taste-related adverse effects. Among selective agents, camlipixant (≥ 50 mg BID) achieved clinically meaningful cough reduction (- 34%) with minimal dysgeusia (5-7%). These findings demonstrate a mechanistically defined benefit-risk trade-off in purinergic receptor targeting, supporting selective P2X3 antagonism as a more favourable strategy for modulating ATP-driven airway sensory signalling in RCC while preserving tolerability.

Immune checkpoint inhibitors (ICIs) benefit only a subset of patients with metastatic non-small cell lung cancer (NSCLC), but current selection relies on tissue PD-L1 immunohistochemistry (IHC), which is invasive and prone to sampling bias. We developed and validated SCENT (Scalable Ensemble Transformer), a CT-based deep learning model for noninvasive prediction of PD-L1 status and immunotherapy outcomes. In this retrospective study, 972 stage IV NSCLC patients treated with ICIs at MD Anderson were analyzed; SCENT was developed and validated in 640 patients with paired CT and PD-L1 IHC, and clinical applicability was assessed in an additional 332 CT-only patients. Generalizability was evaluated in independent cohorts from Mayo Clinic (n=72) and the phase III LONESTAR trial (n=116), where paired baseline and 3-month CT enabled longitudinal assessment. SCENT classified PD-L1 status (50% or higher vs lower) in the MD Anderson cohort with AUC 0.84 (95% CI 0.799 to 0.882), specificity 83.9%, and sensitivity 85.3%, outperforming clinical and radiomics models; external validation achieved AUC 0.80 (Mayo) and 0.78 (LONESTAR). SCENT-derived PD-L1 stratified progression-free survival (HR 1.49, p<0.001) and overall survival (HR 1.40, p=0.009), comparable to IHC, and provided complementary prognostic value when combined with IHC, with concordant low-low patients showing the poorest survival (OS HR 1.45, p=0.008). In LONESTAR, serial SCENT-inferred PD-L1 status showed a borderline association with 3-month progression without paired post-treatment tissue confirmation. SCENT is a generalizable CT-based virtual biopsy for baseline PD-L1 prediction and complementary tissue IHC stratification, with longitudinal use requiring prospective validation.

INTRODUCTION: Postoperative pulmonary complications after upper gastrointestinal endoscopic procedures under general anaesthesia are clinically important and may be exacerbated by residual neuromuscular block. We evaluated whether antagonism of neuromuscular block with sugammadex rather than neostigmine is associated with improved respiratory outcomes in this setting. METHODS: We performed a retrospective multicentre cohort study using a federated health record network. Adults undergoing upper gastrointestinal endoscopy who received rocuronium and antagonism of neuromuscular blockade with either sugammadex or neostigmine were identified. Propensity score matched analysis was conducted. The primary outcome was failure of tracheal extubation, defined as postoperative ventilator dependence or tracheal reintubation within 30 days. Secondary outcomes included coded lung atelectasis and unplanned admission to an ICU. A prespecified subgroup analysis was performed in patients without chronic pulmonary disease. RESULTS: After matching, 15,730 patients were included (7865 per group). Failure of tracheal extubation occurred in 305 patients (3.88%) in the sugammadex group and 455 patients (5.79%) in the neostigmine group (risk ratio 1.49, 95%CI 1.30-1.72, p < 0.0001), an absolute risk reduction of 1.91% and a number needed to treat of 52. Sugammadex was also associated with lower rates of lung atelectasis or collapse (6.74% compared with 7.76%, p = 0.014) and unplanned ICU admission (8.27% compared with 9.45%, p = 0.009). In the subgroup without chronic pulmonary disease (4624 patient pairs), failure of tracheal extubation occurred in 3.05% and 4.97% and unplanned ICU admission in 6.66% and 8.54% after sugammadex and neostigmine, respectively (all p < 0.001). DISCUSSION: In this large cohort of adults undergoing upper gastrointestinal endoscopy, sugammadex use was associated with important reductions in tracheal extubation failure, lung atelectasis or collapse, and unplanned ICU admission compared with neostigmine, including in those patients without known chronic pulmonary disease. WHAT WE DID: We studied a large group of adults who had a camera test of their stomach or food pipe while under general anaesthesia. During these procedures, doctors used medicines to relax the muscles and then gave another medicine to reverse this effect at the end. We compared two reversal medicines, called sugammadex and neostigmine, to see which one led to better breathing outcomes after the procedure. WHY DID WE DO IT: After anaesthesia, some patients can have breathing problems if the muscle‐relaxing medicine has not fully worn off. This can lead to serious complications, like needing help to breathe again or being admitted to intensive care. We wanted to find out which reversal medicine is safer and helps patients recover their breathing more effectively. WHAT WE FOUND: We found that patients who received sugammadex were less likely to have breathing problems after their procedure compared with those who received neostigmine. They were less likely to need a breathing tube again, less likely to have parts of their lungs collapse and less likely to need unexpected care in intensive care. This was true even for patients who did not already have lung disease. Overall, sugammadex appeared to be the safer option for helping patients breathe normally again after anaesthesia.