Daily Respiratory Research Analysis

BACKGROUND: Circular RNAs have emerged as key regulators of vascular remodeling and promising therapeutic targets, yet their specific contributions to pulmonary hypertension (PH) remain largely unknown. METHODS: We identified a PH-related circular RNA, circMFN2, generated from the MFN2 (mitofusin-2) locus, which was significantly downregulated in the peripheral blood of patients with PH and in pulmonary arteries of Sugen/hypoxia-induced PH mice. Functional studies were performed in human pulmonary artery smooth muscle cells under hypoxic conditions and in Sugen/hypoxia mice treated intranasally with R8-circMFN2 (R8-peptide-modified liposomal circMFN2). Transcriptomic profiling, RNA-protein interaction assays, and mitochondrial function analyses were used to define the downstream mechanisms. RESULTS: circMFN2 overexpression significantly attenuated hypoxia-induced human pulmonary artery smooth muscle cell proliferation, migration, and mitochondrial dysfunction. RNA sequencing after circMFN2 knockdown revealed activation of gene networks associated with respiratory system diseases. Mechanistically, circMFN2 directly bound the RNA-binding protein IGF2BP3 (insulin-like growth factor 2 mRNA-binding protein 3), thereby blocking its stabilization of PDK4 (pyruvate dehydrogenase kinase 4) mRNA. This circMFN2-IGF2BP3-PDK4 regulatory axis limited PDK4-mediated metabolic reprogramming, restored mitochondrial fusion, reduced reactive oxygen species, and normalized oxidative phosphorylation. In Sugen/hypoxia mice, therapeutic intranasal delivery of R8-circMFN2 significantly improved pulmonary hemodynamics, reduced vascular remodeling, and downregulated PDK4 expression. CONCLUSIONS: circMFN2 functions as a hypoxia-responsive regulator that preserves mitochondrial homeostasis by restraining the IGF2BP3-PDK4 axis. Intranasal delivery of R8-circMFN2 establishes a translational potential for noninvasive circular RNA-based therapy to reverse pulmonary vascular remodeling and hemodynamic impairment in PH.

BACKGROUND: Low-dose computed tomography (LDCT) employed in lung cancer screening (LCS) programmes is increasing in uptake worldwide. LCS programmes herald a generational opportunity to simultaneously detect cancer and non-cancer-related early-stage lung disease, yet these efforts are hampered by a shortage of radiologists to interpret scans at scale. Here, we present TANGERINE, a computationally frugal, open-source vision foundation model for volumetric LDCT analysis. METHODS: Designed for broad accessibility and rapid adaptation, TANGERINE can be fine-tuned off the shelf for a wide range of disease-specific tasks with limited computational resources and training data. The model is pretrained using self-supervised learning on more than 98,000 thoracic LDCT scans, including the United Kingdom's largest LCS initiative to date and 27 public datasets. By extending a masked autoencoder framework to three-dimensional imaging, TANGERINE provides a scalable solution for LDCT analysis, combining architectural simplicity, public availability, and modest computational requirements. RESULTS: TANGERINE demonstrates superior computational and data efficiency in a retrospective multi-dataset analysis: it converges rapidly during fine-tuning, requiring significantly fewer graphics processing unit hours than models trained from scratch, and achieves comparable or superior performance using only a fraction of the fine-tuning data. The model achieves strong performance across 14 disease classification tasks, including lung cancer and multiple respiratory diseases, and generalises robustly across diverse clinical centres. CONCLUSIONS: TANGERINE's accessible, open-source, lightweight design lays the foundation for rapid integration into next-generation medical imaging tools, enabling lung cancer screening programmes to pivot from a singular focus on lung cancer detection toward comprehensive respiratory disease management in high-risk populations.

BACKGROUND: Since current opioid overdose deaths occur mainly from potent synthetic opioids with high affinity for the opioid receptor, such as fentanyl and carfentanil, it is important to determine the efficacy of naloxone, particularly the intranasal formulation, in reversing opioid-induced respiratory depression. This study evaluated effectiveness of 4 mg intranasal naloxone (Narcan®) in reversing moderate respiratory depression induced by fentanyl and sufentanil, in opioid-naïve individuals and self-reported daily opioid users. Sufentanil was compared to fentanyl because of its higher affinity for the opioid receptor than fentanyl. METHODS: In this prospective, crossover trial, 12 opioid-naïve individuals and 18 daily opioid users (morphine milligram equivalent of 291 (range 60-2250 mg/day) received continuous fentanyl or sufentanil infusions, titrated to achieve 30-40% reduction in ventilation (V̇E). Participants were administered Narcan® during steady-state respiratory depression. Primary endpoints included time to reversal of diminished V̇E and elevated end-tidal carbon dioxide concentration (pCO2). RESULTS: Narcan® restored V̇E within 2-4 min across all participants but showed delayed reversal of end-tidal pCO2 (11-17 min), with pCO2 recovery during sufentanil exposure in just 8 opioid-naïve individuals and 10 daily opioid users. Hysteresis analysis showed for V̇E-reversal onset/offset time (blood-effect-site equilibration half-life) of 0-1 min and end-tidal pCO2 2-11 min. Because of withdrawal symptoms, seven of eighteen daily opioid users participated once in the study. Study limitations included continuous opioid infusions that do not occur in real-world overdose settings. CONCLUSION: A single Narcan® dose reversed moderate fentanyl- and sufentanil-induced respiratory depression, though effectiveness varied by endpoint and opioid receptor affinity. Rapid V̇E-recovery suggests clinical utility of intranasal naloxone, but delayed and sometimes incomplete recovery of end-tidal pCO2, particularly during exposure to the high-affinity opioid sufentanil, indicating reversal inefficacy and persistence of respiratory instability. Further studies are needed to address optimal naloxone doses and alternative formulations to address high-dose potent opioid threats.