Daily Respiratory Research Analysis

The µ-opioid receptor (MOP) is a critical pharmaceutical target that mediates both the therapeutic benefits and adverse effects of opioid drugs. However, the large-scale neural circuit dynamics underlying key opioid effects, such as analgesia and respiratory depression, remain poorly understood, hindering the development of safer analgesics. Here, we present a multimodal experimental framework that integrates functional ultrasound imaging through the intact skull with behavioral and molecular analyses to investigate opioid-induced large-scale functional responses and their physiological relevance in awake, behaving male mice. Administration of major opioids-morphine, fentanyl, methadone, and buprenorphine-elicited robust, dose- and time-dependent reorganization of functional brain connectivity (FC) patterns, with magnitude scaling according to MOP agonist efficacy. This opioid-specific functional fingerprint is marked by decreased FC between the somatosensory cortex and hippocampal/thalamic regions and increased bilateral FC within the somatosensory cortex. Notably, this fingerprint was attenuated following tolerance induction and abolished by pharmacological or genetic MOP inactivation. Through power Doppler spectral analysis and lagged correlation measurements, we show that morphine perturbs temporal FC dynamics and the propagation of brain-wide oscillatory activity, disrupting critical-state dynamics. Importantly, we identify a dissociation between fast, transient processes-such as cerebral blood volume changes, locomotion, and respiratory depression-and slower processes driving FC reorganization, analgesia, and sustained MOP activation. This study provides mechanistic insights into opioid-induced network reorganization, establishes FC alterations as a reliable biomarker of opioid efficacy, and offers a framework for advancing the development of analgesic compounds with improved therapeutic windows and reduced side effects.

IMPORTANCE: Key clinical features of neonatal acute respiratory distress syndrome (NARDS) are broadly comparable to those observed in pediatric and adult ARDS; however, evidence is insufficient to recommend high-frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CMV) as the preferred first-line therapy. OBJECTIVE: To evaluate whether HFOV is superior to CMV in reducing bronchopulmonary dysplasia (BPD) and other neonatal adverse outcomes, including death, among preterm infants (≤34 weeks' gestational age) with NARDS. DESIGN, SETTING, AND PARTICIPANTS: This single-center randomized clinical trial conducted from August 1, 2019, to December 31, 2023, enrolled preterm infants born between 25 weeks 0 days and 34 weeks 6 days of gestation with NARDS who were stabilized with CMV. Data were analyzed from October to December 2024. INTERVENTION: Participants were randomly assigned to continue CMV or transition to elective HFOV. MAIN OUTCOMES AND MEASURES: The primary outcome was BPD, assessed using 2 definitions: definition 1, that of the 2001 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and definition 2, one based on 2019 research. Secondary outcomes included death, retinopathy of prematurity (higher than stage 2), necrotizing enterocolitis (stage 2 or higher), intraventricular hemorrhage (grade 3 or higher), air leak, and hemodynamically significant patent ductus arteriosus. Modified Poisson regression, ordinal regression, and Cox proportional hazards regression were applied for outcome risk assessment where applicable. RESULTS: A total of 386 preterm infants (230 male [59.6%]; mean [SD] maternal age, 29.9 [4.8] years) were randomized: 181 to elective HFOV and 205 to CMV. Overall, 154 (39.9%) and 83 (21.5%) developed BPD according definitions 1 and 2, respectively. Elective HFOV reduced the risk of BPD by 8.0% (34.3% vs 44.9%; relative risk, 0.92; 95% CI, 0.86-0.99) according to definition 1 and by 32.0% (17.1% vs 25.4%; relative risk 0.68; 95% CI, 0.45-1.00) according to definition 2 compared with CMV. No significant between-group differences were observed for death, higher than stage 2 retinopathy of prematurity, stage 2 or higher necrotizing enterocolitis, grade 3 or higher intraventricular hemorrhage, air leak, or hemodynamically significant patent ductus arteriosus. Sensitivity analysis excluding 44 participants who crossed over between treatment groups did not significantly attenuate the estimates. CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that elective HFOV reduced the incidence of BPD in preterm infants born at 34 weeks' gestation or earlier with NARDS compared with CMV. The results of this study suggest that elective HFOV is a promising strategy for preventing BPD in this high-risk population, especially the more severe forms linked to increased long-term morbidity and mortality. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03591796.

UNLABELLED: Background Post-tuberculosis lung disease (PTLD) causes significant disability in TB survivors. Pulmonary rehabilitation (PR) may offer effective disease management but lacks high-quality evidence in this underrepresented population. RESEARCH QUESTION: Compared to usual care, does a 6-week PR programme improve exercise capacity and health-related quality of life (HRQoL) cost-effectively in adults living with post-TB lung disease? STUDY DESIGN AND METHODS: We conducted a single-center randomised controlled trial with blinded outcome assessments, comparing PR vs usual care (UC) for adults with PTLD in Kampala, Uganda. Participants were randomised (1:1) to receive either PR or UC, with assessments at 6-weeks post-intervention. The primary outcome was change in exercise capacity measured by the Incremental Shuttle Walk Test (ISWT). Secondary outcomes included HRQoL, respiratory symptoms, psychological well-being and cost-benefit analysis. A generalized linear mixed model (GLMM) was used for the primary efficacy analysis (intention-to-treat) and a difference-in-differences analysis for secondary outcomes (modified intention-to-treat). RESULTS: Between November 2020 and September 2022, 178 adults with PTLD were assessed for eligibility and 114 randomised, Mean±SD age was 43.3±15.2 years and 65 (57%) were male. The post-intervention improvement in mean ISWT in the PR group was significantly greater than in UC by 54.36m (95%CI 17.22 to 91.51; p=0.004). We also observed significant improvements in HRQoL in PR greater than UC; (CAT score [-3.6 (95%CI -6.7 to -0.39); p=0.015] and CCQ total [-0.37 (95%CI -0.68 to -0.06); p=0.004]). The EQ-VAS and QALYs marginally improved in the PR vs UC (3.98 [95%CI -2.05 to 10.02]; p=0.191) and 0.02 [95%CI -0.02 to 0.05], p=0.334), respectively. The average cost of PR was US$6,468/QALY gained, equating to US$20,000/QALY gained after adjusting for purchasing power (below NICE's cost-effectiveness threshold). INTERPRETATION: In adults with PTLD, a 6-week PR programme elicited clinically and statistically significant improvements in exercise capacity and HRQoL compared with UC and was cost-effective.