Daily Respiratory Research Analysis

Breathing is generated by brainstem respiratory networks but can be controlled and modulated by forebrain activity. The recent clinical adoption of thalamic electrode implantation during intracranial electroencephalography (iEEG) provides a rare opportunity to examine the role of the human thalamus in respiratory control. Here, we tested whether thalamic stimulation alters breathing in 11 patients undergoing iEEG for epilepsy monitoring. Across 412 stimulation trials at 108 thalamic sites, thalamic stimulation induced central apnea in every participant. Apnea occurred in isolation without sensory or motor effects and without awareness of breathing cessation. Apnea occurred with stimulation of either the right or left thalamus and was observed across all ages, including participants as young as 22 months. Volitional breathing and speech were preserved, indicating that respiratory motor pathways remained functional. In contrast, except for the amygdala, stimulation of other forebrain regions including the hippocampus, insula, cingulate, and frontal, temporal, and parietal cortices did not affect breathing. Respiratory inhibition depended on thalamic location, occurring most consistently with stimulation of the ventral lateral anterior (VLa) and ventral anterior (VA) nuclei. A machine learning algorithm localized the focal apneic region within the anterior motor thalamus, centered in VLa and extending into VA. Identification of a focal apneic site in the VLa/VA motor thalamus expands thalamic function, revealing a forebrain node capable of overriding brainstem respiratory control. This circuit may coordinate breathing with volitional behaviors such as speech, and dysfunction of this circuit may play a role in central apnea disorders, including sleep apnea, SUDEP, and SIDS.

Sepsis-associated acute respiratory distress syndrome (SA-ARDS) is a life-threatening complication characterized by excessive pulmonary inflammation and pulmonary edema, lacking effective treatments. This study identifies the transcription factor BMAL1 in alveolar macrophages (AMs) as a key therapeutic target. Mechanistically, BMAL1 represses the expression of the glycolytic enzyme PFKFB3 by binding to the Pfkfb3 promoter, thereby inhibiting glycolysis, M1 polarization of AMs, and the generation of pro-inflammatory cytokines and reactive oxygen species (ROS). Based on this regulatory mechanism, a biomimetic nanoplatform, RM@TNT, is engineered for precise SA-ARDS therapy. Fabricated by hybridizing AM membrane-derived nanovesicles with ROS-responsive liposomes, the nanoplatform encapsulates tetrahedral DNA nanostructures (TNT) preloaded with nobiletin (Nob, a BMAL1 agonist) and Tuftsin (an AM-targeting peptide). Following inhalation, the AM membrane tropism of RM@TNT ensures prolonged pulmonary retention, prompting targeted TNT release within the ROS-rich pathological microenvironment. Tuftsin then precisely delivers TNT to AMs, where Nob is intracellularly released to activate BMAL1. This activation upregulates the BMAL1/PFKFB3 axis, suppressing AM glycolysis, inflammation, and oxidative stress. Treatment with RM@TNT resulted in significantly attenuated lung inflammation, injury, and edema, along with markedly improved survival in SA-ARDS mice. Collectively, this multimodal, targeted metabolic reprogramming approach is a highly promising therapeutic strategy for SA-ARDS.

BACKGROUND: Treatment success rates of multidrug-resistant and rifampicin-resistant tuberculosis (MDR/RR-TB) lag behind those for drug-susceptible TB. However, outcome definitions censoring follow-up at treatment completion may underestimate effectiveness and fail to capture relapse-free survival. METHODS: We conducted a retrospective national cohort study including all adults initiating individualized MDR/RR-TB treatment in the Republic of Latvia between 2005 and 2021. Demographic, clinical, and microbiological data were linked to long-term follow-up on relapse and vital status. Treatment outcomes were classified according to World Health Organization (WHO), TBnet (Tuberculosis Network European Trials Group), expert consilium, and long-term outcome definitions. Predictors of cure were assessed using Firth logistic regression. A landmark analysis at 18 months evaluated the association between treatment duration (≤9 months, 10-17 months, and ≥18 months) and relapse-free survival. FINDINGS: Among 1299 patients (median age 44 years; 74.9% male), cure rates were 4.8% (n = 62) under WHO definitions, 53.1% (n = 690) under TBnet definitions, and 60.8% (n = 790) under the consilium-based classification. Under long-term follow-up outcome definitions, 56.5% (n = 734) achieved cure and 76.9% (n = 999) achieved relapse-free survival. Receiving ≥3 susceptible drugs independently predicted WHO-defined treatment success (adjusted OR 6.53, 95% CI 2.22-31.69; p < 0.001). In the landmark analysis, treatment duration ≤9 months was associated with higher hazard of relapse or death compared with ≥18 months (HR 1.76, 95% CI 1.03-3.00; p = 0.038), whereas outcomes were similar for 10-17 months vs. ≥18 months (HR 0.71, 95% CI 0.42-1.22; p = 0.22). INTERPRETATION: In this national cohort treated with individualized MDR/RR-TB regimens, long-term relapse-free outcomes substantially exceeded treatment success defined at treatment completion. These findings support relapse-free survival as complement to end-of-treatment metrics. FUNDING: This study received no external funding.