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Background: Non-invasive ventilation (NIV) adherence is critical to its effectiveness, yet no standardized pediatric definition of "optimal" adherence exists, and population-level data are scarce.

Research question: What are adherence patterns to NIV in children, and which factors are associated with adherence in a provincial longitudinal cohort?

Study design and methods: Canadian retrospective longitudinal cohort study linking records from the Ontario Ventilator Equipment Pool to health administrative databases. We identified children <18 years prescribed NIV with telemonitoring (2020 to 2022) and ≥1 month of data. The adherence definitions explored were the adult definition of ≥4 hours/day (primary) and measures of any daily use, daily NIV hours, and data missingness ("days not used" = 0 hours recorded; "days no data" = no signal). Mixed-effects regression models were used to explore adherence factors.

Results: We included 237 children (mean age 12.9 years; 61% male) with 3,685 person-months of NIV data (median 13 [IQR 8-24]). Across person-months, mean adherence by the ≥4-hours/day definition was 69.6%. Child-level monthly mean (SD) adherence was 59% (32%) by this definition, and 68% (26%) for any use. Mean (SD) daily use when used was 7.5 (3.2) hours. Monthly "days not used" and "no data" averaged 5.1 (6.4) and 4.4 (5.0) days, respectively. Greater adherence was associated with younger age (2-percentage-point decrease per year increase; 95% CI, 1-3), having ≥3 complex chronic conditions vs none (14 percentage-points higher; 95% CI, 3-26), and longer time prescribed NIV (2-percentage-point increase per year; 95% CI, 1-3).

Interpretation: NIV adherence was moderate across definitions, with higher adherence among younger children, greater medical complexity, and those using therapy longer, highlighting the need for pediatric-specific adherence targets and home NIV support strategies.

Background: Congenital central hypoventilation syndrome (CCHS) is an ultra-rare genetic disorder caused by PHOX2B mutations. Patients lack central CO2 chemosensitivity and require ventilatory support during sleep. Children with CCHS have been reported to lack CO2-induced air hunger, but respiratory sensations and dyspnea have not been characterized in adults.

Research question: Do genetically characterized adult CCHS patients experience respiratory sensations and dyspnea during unassisted resting breathing and CO2 rebreathing, and along which dimensions?

Study design and methods: This was a prospective controlled observational study conducted on a convenience sample derived from a national cohort of an ultrarare disease. Thirteen adult CCHS patients carrying PHOX2B mutations underwent Multidimensional Dyspnea Profile (MDP) assessment during unassisted resting breathing and at the end of CO2 rebreathing. Healthy controls were studied under the same conditions.

Results: Before the study, none of the patients had spontaneously reported dyspnea or bothersome respiratory sensations. When prompted with the MDP during resting breathing, 9/13 patients described breathing unpleasantness (non-zero MDP-A1) versus 0/18 controls (p < 0.0001), and 12/13 fulfilled criteria for dyspnea defined as breathing awareness associated with negative affect. During CO2 rebreathing, ventilatory responses remained profoundly blunted, yet breathing unpleasantness increased. Compared with controls, patients had lower sensory and affective ratings, with less frequent air hunger (p = 0.0108). MDP ratings did not correlate with ventilatory response to CO2 or genotype.

Interpretation: Adult CCHS patients can experience conscious unpleasant breathing awareness at rest and retain a perceptual response to CO2 despite abolished or nearly abolished central chemosensitivity. These findings suggest respiratory interoceptive pathways beyond canonical brainstem chemosensitive circuits and support active multidimensional assessment of dyspnea in adult CCHS patients.

Background: Bronchiectasis in women of reproductive age is increasingly recognized, yet data on fertility and pregnancy outcomes remain limited.

Research question: What are fertility characteristics, pregnancy outcomes, and patient-reported reproductive health experiences in women with bronchiectasis?

Study design and methods: We conducted a multicenter, retrospective cohort study across EMBARC-affiliated centers including women with bronchiectasis and pregnancy between 2012 and 2023. Clinical, pulmonary, obstetric, and neonatal data were collected. In parallel, an international patient survey assessed fertility, pregnancy, and hormonal influences on disease. Statistical analyses included comparative and correlation testing.

Results: Eighty-three women contributed data from 121 pregnancies and 123 neonates. Mean age at conception was 29.5 years. Assisted reproductive technologies were used in 32.1% of pregnancies, more frequently in primary ciliary dyskinesia (PCD) than other etiologies (48.5% vs. 8.7%, P=0.004). Lung function remained stable during and after pregnancy. Exacerbations occurred in 58.6% of pregnancies. Mean gestational age was 38 weeks and mean birth weight was 2.99 kg. Pre-pregnancy FEV1 correlated with birth weight (ρ=0.42, P=0.001) and gestational age (ρ=0.25, P=0.042). Neonatal outcomes were generally favorable. Survey data (n=629) demonstrated an early onset of menopause in women with bronchiectasis diagnosed before age 50 years compared to after 50 years. Women with PCD reported difficulties conceiving more often than women with early onset bronchiectasis without PCD.

Interpretation: Pregnancy in women with bronchiectasis is frequently complicated by exacerbations and low neonatal birth weight. Subfertility is primarily driven by PCD, while non-PCD bronchiectasis shows rates similar to the general population. Pre-pregnancy lung function is associated with neonatal outcomes, supporting the importance of pulmonary optimization and multidisciplinary care before and during pregnancy.

Background: Black and Hispanic people with cystic fibrosis (PwCF) experience worse health outcomes. Health disparities are exacerbated by clinical research that does not adequately represent the diversity of the CF population.

Research questions: How do Black/African American and Hispanic/Latino(a) PwCF perceive clinical research? What are the barriers and facilitators to participation in research? Are there viable solutions to improve inclusion?

Study design and methods: Semi-structured, individual interviews were conducted with PwCF aged ≥18 years who identify as Black/African American race and/or Hispanic/Latino(a) ethnicity. Participants were recruited from six geographically diverse CF centers and through CF Foundation Community Voice, a CF community partner organization. The interview guide was created by a committee that included minoritized PwCF, research coordinators, and physician-scientists. Thematic analysis with inductive and deductive coding was used to analyze interview transcripts.

Results: Twenty PwCF were interviewed from 2024 to 2025. Drawing from a race-conscious adaptation of the Behavioral Model for Vulnerable Populations, we used domains of predisposing, need-based, and healthcare environment factors, as well as emergent themes relating to information and support needs. Participants discussed barriers to research participation that included narrow eligibility criteria (e.g., genotype requirements, health status) and logistical challenges such as time and cost. PwCF described a sense of isolation as persons of color with CF, which impacted sense of trust in CF care and research studies. They highlighted that racialized experiences, especially doubt surrounding their CF diagnosis, significantly impact willingness to participate. Solutions center around providing community support to address feelings of isolation and information needs to provide transparency about study design and intent.

Interpretation: Participation in clinical research is strongly influenced by an interplay of social, cultural, health, and systemic factors. Solutions to improve inclusion in trials center the needs of marginalized communities across all phases of study design and implementation.

Background: The ACCESS randomized double-blind controlled trial in hospitalized adults with community-acquired pneumonia (CAP) showed that adding clarithromycin to standard-of-care therapy accelerated clinical recovery within the first 72 hours after the commencement of treatment and reduced progression to organ dysfunction.

Research question: Does clarithromycin treatment modulate the circulating inflammatory protein profile in CAP, and can inflammatory endotypes identify patient subgroups with distinct clinical responses?

Study design and methods: Serum samples obtained from ACCESS trial patients at baseline and 72 hours were profiled using the Olink Target 96 Inflammation panel. Patients were grouped by treatment arm and by achievement of the trial's composite primary endpoint. After quality control, 70 proteins from 394 paired samples across 197 patients were analyzed to assess differential expression within and between groups over time, evaluate associations with clinical outcomes, and identify immune endotypes using unsupervised clustering.

Results: IL6 was selectively downregulated on day 4 in the clarithromycin arm, whereas IFN-γ, CXCL9, CXCL10, and SCF decreased over time across both treatment arms, consistent with resolution of inflammation. Among patients achieving the primary endpoint, IL6, CXCL9, CXCL10, and IFN-γ were suppressed only in clarithromycin-treated individuals. Clustering consistently identified two inflammatory endotypes with comparable SOFA, but distinct RSS scores. The endotype with lower RSS demonstrated higher IFN-γ and globally elevated inflammatory protein expression; in that endotype 90-day mortality was decreased with clarithromycin treatment.

Interpretation: Clarithromycin exerts measurable immunomodulatory effects in CAP, characterized by attenuation of pro-inflammatory cytokines, particularly IL6. The identification of distinct inflammatory endotypes suggests biological heterogeneity in CAP and supports future investigation of endotype-guided approaches to identify patients most likely to benefit from immunomodulatory therapies.

Clinical trial registration: ClinicalTrials.gov NCT04724044, EudraCT 2020-004452-15.

Background: Airway secretion retention is common in patients with acute respiratory failure (ARF), particularly in those requiring noninvasive respiratory support (NIRS). High-frequency chest wall oscillation (HFCWO) may improve airway clearance but critical care evidence remains limited.

Research question: Does adding HFCWO to standard care improve clinical outcomes in patients with bronchial hypersecretion and ARF requiring NIRS?

Study design and methods: We conducted a single-center randomized controlled trial in a RICU. Patients with ARF requiring NIRS, including high-flow nasal cannula (HFNC) and/or noninvasive ventilation (NIV), bronchial hypersecretion, and ineffective cough (peak cough expiratory flow <270 L/min) were randomized 1:1 to HFCWO plus standard care or standard care alone. The primary endpoint was therapeutic bronchoscopy. Secondary endpoints included hospital length of stay (LOS), RICU-LOS, NIRS duration, endotracheal intubation and mortality. Outcomes were analyzed using unadjusted and adjusted models accounting for age, sex, and main cause of hospitalization.

Results: Eighty-eight patients were enrolled (44 HFCWO, 44 control), with comparable baseline characteristics. Bronchoscopy was required in 6 patients (13.6%) versus 14 (31.8%) (unadjusted p=0.042); after adjustment the association did not retain statistical significance (adjusted OR 0.336, 95% CI 0.111-1.021; p=0.055). Secondary outcomes, analyzed without correction for multiple testing, are exploratory. Hospital stay (12 [10-15.5] vs 16.5 [13-21] days) and RICU stay (8 [7-10.5] vs 12 [9-17] days) were shorter, with adjusted reductions of 4.5 and 3.6 days. HFNC duration was shorter (6 [4-8] vs 9.5 [6-11.5] days) and remained significant after adjustment, whereas the reduction in NIV duration did not (adjusted p=0.166). No patient required intubation and mortality did not differ.

Interpretation: In this exploratory trial, HFCWO did not significantly reduce the need for therapeutic bronchoscopy after adjustment. Associated reductions in LOS and HFNC duration are hypothesis-generating and require confirmation in adequately powered multicenter trials.

Clinical trial registration: ClinicalTrials.gov: NCT05751707; Tuscany Ethics Committee (Protocol: 21987-10/17/2022).