Medicine and Pharmacology

Abstract: Increasing evidence suggests that acquired dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel occurs as a result of cigarette smoke exposure in Chronic obstructive pulmonary disease (COPD). CFTR-targeted therapies were developed for the treatment of genetic CFTR defects in cystic fibrosis, but they have not demonstrated consistent clinical efficacy in small trials of patients with COPD. Here, we aimed to characterise CFTR activity, other ion channels, and differentiation to cilia in primary bronchial epithelial cells (pBECs) from COPD donors, compare to healthy controls, and to determine the extent to which CFTR dysfunction can be rescued by clinically relevant CFTR modulators. Conditionally reprogrammed (CR) air-liquid interface (ALI) cultures of pBECs from healthy controls (n = 7) and COPD donors (n = 7) were comprehensively assessed for transepithelial electrical resistance, immunofluorescence, cilia activity, ion channel function and expression of cell markers at transcript level. COPD cultures exhibited reduced active area of ciliated cells, accompanied by significantly decreased forskolin/IBMX stimulated CFTR-mediated Cl- transport and ATP induced calcium activated chloride currents compared to healthy controls cultures, despite preserved CFTR mRNA expression. Treatment with CFTR potentiators (VX-770, GLPG1837 and Icenticaftor) resulted in modest and highly variable functional responses, with no statistically significant improvement compared with vehicle-treated control. Notably, CFTR function did not correlate with cumulative smoking exposure (pack-years), indicating that smoking burden alone does not predict the extent of acquired CFTR dysfunction. Collectively, these findings demonstrate that COPD airway epithelium exhibits intrinsic defects in ion transport and mucociliary differentiation consistent with acquired CFTR dysfunction phenotype but this is not readily reversible with the tested CFTR modulators. These results highlight fundamental differences between genetic and acquired CFTR dysfunction and underscore the need for alternative or combinatorial therapeutic strategies targeting epithelial dysfunction in COPD.

Abstract: Although poverty and tuberculosis are insidiously linked, knowledge of the relationship between social determinants of health (SDH) and post-tuberculosis lung disease (PTLD) is limited. This study aimed to analyze the association between physical function, pulmonary function, and SDH in individuals with PTLD (iwPTLD), considering the impact of social inequalities on physical performance. This cross-sectional study collected social data from 69 iwPTLDs using a standardized assessment form. The patients underwent pulmonary function testing via spirometry and body plethysmography, as well as respiratory muscle strength and quadriceps muscle strength (QMS) testing. They also completed the six-minute step test (6MST). The median value of steps climbed by participants on the 6MST was 88 (57–117), corresponding to 50.1% (34.9–73.2) of the predicted value. The mean QMS was 28.7 ± 11.9 kgf, with 11 participants (17.4%) showing QMS below the cutoff point. Spirometry revealed normal, obstructive, restrictive, and mixed patterns in 19 (27.5%), 20 (29%), 18 (26.1%), and 12 (17.4%) of the participants, respectively. Performance on the 6MST showed no statistically significant association with SDH. QMS showed a statistically significant association with treated sewage (W=84, p=0.026). Forced expiratory volume in one second showed significant correlations with education level (ρ=0.248, p=0.040), social protection (W=207, p=0.050, r=0.238), and treated water (W=24.5, p=0.029, r=0.264). Maximum inspiratory pressure showed significant correlations with education level (ρ=0.246, p=0.042) and treated water (W=20, p=0.021, r=0.280). The regression model for 6MST and QMS performance showed that 12% and 45% of the variability was explained by the studied variables, respectively. In iwPTLD, impairments in physical function and damage to lung function lead to deterioration of SDH. While the relationship between impairments in bodily function and SDH is weak to moderate, it should not be overlooked, as it may operate through indirect pathways.

Abstract: Background: Chronic occupational lung diseases (COLD) remain a major medical and social problem, often associated with persistent respiratory impairment, reduced exercise tolerance, and cardiovascular comorbidities. Conventional rehabilitation improves symptoms but may not fully address the complex pathophysiological mechanisms involved. Intermittent hypoxic–hyperoxic exposure (IHHE) has recently been proposed as an adjunctive rehabilitation strategy that may enhance adaptive physiological responses. Objective: To evaluate the efficacy and safety of IHHE as an adjunctive intervention in the rehabilitation of patients with COLD. Methods: A single-centered pilot study was conducted in 60 patients with clinically stable COLD. Participants were randomly assigned to an IHHE group (n = 30) or a sham control group (n = 30). The IHHE group underwent 12 sessions over 3 weeks using a ReOxy device, consisting of alternating cycles of hypoxic gas (FiO₂ ≈ 12%) and hyperoxic gas (FiO₂ ≈ 35%) delivered through a facial mask under continuous monitoring of oxygen saturation and heart rate. The control group received identical procedures with room air (FiO₂ ≈ 21%). All patients continued standard pharmacological therapy and pulmonary rehabilitation. Clinical and functional assessments included hypoxic tolerance tests, spirometry (FEV₁), blood pressure, dyspnea severity, and the six-minute walk test (6MWT). Results: After 3 weeks, the IHHE group demonstrated significant improvements in hypoxic tolerance, pulmonary function (FEV₁), and exercise capacity compared with baseline and the control group. The distance covered during the 6MWT increased, while dyspnea severity and bronchial obstruction decreased. Additionally, systolic and diastolic blood pressure showed significant reductions in the IHHE group. Improvements observed in the control group were smaller and generally not statistically significant. No serious adverse events were reported. Conclusion: IHHE appears to be a safe and effective adjunct to standard rehabilitation in patients with COLD, improving hypoxic adaptation, pulmonary function, cardiovascular parameters, and exercise capacity. These effects may be related to enhanced adaptive responses to hypoxia and modulation of inflammatory and oxidative pathways. Further studies are required to evaluate long-term benefits and optimize individualized IHHE protocols.

Abstract: Background: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is an important extra-articular manifestation of rheumatoid arthritis and is associated with impaired pulmonary function and poor clinical outcomes. Although interstitial abnormalities in RA-ILD have been widely studied, airway involvement, particularly small airway dysfunction, has received less attention. This study aimed to evaluate small airway function and impulse oscillometry parameters in patients with RA-ILD and to explore their associations with disease severity. Methods: This retrospective study included patients with RA-ILD who were treated at Beijing Jishuitan Hospital, Capital Medical University, between January 2021 and December 2025. Age- and sex-matched healthy individuals without pulmonary disease were included as controls. Clinical data, high-resolution computed tomography (HRCT) findings, pulmonary function parameters, and impulse oscillometry indices were collected. Small airway function was assessed using MEF25–75%, MEF50%, and MEF25%. Disease severity was evaluated using HRCT visual scores, the gender–age–physiology (GAP) score, and the composite physiologic index (CPI). Subgroup analyses were performed according to the presence of small airway dysfunction, HRCT subtype, and history of RA-related joint surgery. Correlations between airway function parameters and disease severity indices were analyzed. Results: A total of 255 patients with RA-ILD were included, including 85 men (33.3%), with a mean age of 67.53 years. Compared with controls, patients with RA-ILD had significantly lower BMI, FVC%, TLC%, and DLCO% (all P < 0.05). Small airway function parameters, including MEF25–75%, MEF50%, and MEF25%, were significantly reduced in the RA-ILD group. Impulse oscillometry showed significantly higher Z5, R5–R20, R5/R20, and Fres, and significantly lower X5 in patients with RA-ILD compared with controls. Patients with RA-ILD and small airway dysfunction had lower FVC% than those without small airway dysfunction (87.7% vs. 95.46%, P = 0.015), and their GAP scores tended to be higher, although the difference did not reach statistical significance (2.59 vs. 1.79, P = 0.055). Among different ILD subtypes, only MEF50% differed significantly among the UIP, NSIP, and other-pattern groups. No significant differences in airway function or disease severity were observed between patients with and without a history of RA-related joint surgery. Correlation analysis showed that MEF25–75%, MEF50%, and MEF25% were negatively correlated with GAP score and positively correlated with FVC%. MEF25–75% and MEF50% were also positively correlated with DLCO%. Conclusions: Patients with RA-ILD showed evidence of small airway dysfunction, increased airway resistance, and reduced airway compliance. Small airway function parameters were associated with FVC%, DLCO%, and GAP score, suggesting that small airway dysfunction may be related to disease severity in RA-ILD. Assessment of small airway function and impulse oscillometry may provide useful supplementary information for the clinical evaluation and monitoring of RA-ILD.

Abstract: INTRODUCTION: Delayed initiation of mepolizumab may influence long-term disease control and the achievement of clinical and functional outcomes in patients with uncontrolled severe asthma (SUA), but no definitive conclusions have yet been established regarding the optimal timing for biologic initiation. The aim of this study was to evaluate, in a real-world clinical setting, the effect of delayed mepolizumab initiation—from the moment patients first met EMA eligibility criteria— on the treatment response (using the EXACTO scale), clinical remission (according to SEPAR-REMAS criteria) and lung function at 12 months and 3 years after treatment initiation. MATERIAL AND METHODS: We conducted a retrospective observational cohort study including 148 patients with SUA treated with mepolizumab from January 2017 to November 2024 in our hospital. Patients were stratified into tertiles according to delay: ≤5 months, 6–19 months, and >19 months. Baseline demographic, clinical, and lung function characteristics were analyzed. RESULTS: Patients with shorter delay exhibited distinct significance baseline profiles, including higher eosinophil counts, lower IMB and current smoker, and better pre-treatment lung function (p< 0,05). Shorter delay was significantly associated with higher rates of good/complete response according to the EXACTO scale at both 12 months and 3 years (p< 0.05). Clinical remission rates were numerically higher in the early-treatment group, although differences did not reach statistical significance. No significant differences in lung function outcomes were observed between delay groups at either 12 months or 3 years. CONCLUSIONS: In conclusion, earlier initiation of mepolizumab after meeting EMA criteria is associated with improved clinical response, although it does not significantly influence remission rates or lung function recovery. These findings underscore the importance of timely treatment initiation and reinforce the relevance of accurate phenotypic and endotypic characterization to optimize biologic selection in SUA.

Abstract: Background/Objectives: Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant disorder caused by germline pathogenic variants in the FLCN gene. Although it carries a substantial lifetime risk of renal cell carcinoma, its earliest manifestations are typically pulmonary cysts and spontaneous pneumothorax, which are frequently misclassified as primary spontaneous pneumothorax, resulting in diagnostic delay and inadequate oncological surveillance. We aimed to characterise the real-world phenotypic spectrum of BHD encountered in a respiratory referral setting. Methods: We retrospectively describe seven consecutive patients with genetically confirmed BHD syndrome diagnosed at our tertiary referral centre between 2022 and 2024. Demographic data, smoking history, FLCN variants, pneumothorax episodes, HRCT findings, pulmonary function tests and extrapulmonary neoplasms were collected. Reporting followed the PROCESS 2020 guideline. Results: Mean age at genetic diagnosis was 53.1 years (range 41–64). All seven patients had multiple thin-walled pulmonary cysts on HRCT, with the typical basal, subpleural and paramediastinal distribution; three had a pneumothorax history. Despite largely preserved spirometry (mean FEV1 82.4% predicted), DLCO was reduced in five patients (mean 67.4% predicted) and was the most frequently affected functional parameter, although the overall functional picture was heterogeneous. Five patients had solid neoplasms (one renal, one colorectal, one thyroid/parathyroid, one ovarian, one lung adenocarcinoma). Conclusions: In this referral-based case series, pulmonary cysts were a constant finding and DLCO was the most frequently reduced functional parameter, although the functional picture varied across patients. These descriptive observations are hypothesis-generating and require prospective, controlled validation—including comparison with other diffuse cystic lung diseases—before any diagnostic algorithm can be proposed.

Abstract: Background/Objectives: Prior U.S. surveillance studies reported modest pulmonary hypertension mortality declines through 2020, but contemporary trends incorporating expanded combination therapy and novel therapeutics remain uncharacterized. This study analyzed primary pulmonary hypertension (PPH) mortality trends and demographic disparities from 2018 to 2024. Methods: A retrospective, population-based cross-sectional study was conducted using the CDC WONDER Underlying Cause of Death database (2018–2024, Single Race series). Deaths with ICD-10 code I27.0 as the underlying cause were identified. Age-adjusted mortality rates (AAMRs) per 100,000 population were standardized to the 2000 U.S. standard population. Deaths were stratified by sex, race, calendar year, and U.S. Census Region. Mortality rate ratios with 95% confidence intervals were calculated using exact Poisson methods. Results: From 2018 to 2024, 1,831 deaths were attributed to PPH. Annual deaths declined from 344 to 199, a 42.2% reduction, with the AAMR decreasing from 0.10 to 0.06 per 100,000 (estimated compound annual rate of change, 9.3%). Women accounted for 69.5% of deaths (female-to-male AAMR ratio, 2:1). Black individuals had the highest AAMR (0.10 vs. 0.06 per 100,000 for White individuals; Black-to-White ratio, 1.67:1). The South bore the highest burden (43.1% of deaths; crude rate, 0.09 per 100,000) while the Northeast had the lowest (12.3%; crude rate, 0.06 per 100,000). Conclusions: PPH mortality declined substantially from 2018 to 2024, coinciding with increased adoption of combination therapy and the introduction of sotatercept. Persistent disparities by sex, race, and geography suggest therapeutic advances may not be reaching all populations equitably, underscoring the need for targeted interventions to improve access to PAH-specific therapies.

Abstract: Interstitial Lung Diseases are a diverse set of fibrotic lung disorders that carry substantial morbidity and mortality. Since 2014, antifibrotic agents have been available for idiopathic pulmonary fibrosis (IPF), yet whether these therapies have translated into population-level mortality reductions remains unclear. We analyzed ILD mortality in the United States from 1999 to 2024 using CDC WONDER underlying-cause-of-death data (ICD-10 J84). Age-adjusted mortality rates (AAMR) per 100,000, standardized to the 2000 U.S. population, were calculated and stratified by sex and race. Over the 26-year study period, 505,816 deaths were attributed to ILD. Annual death counts doubled from 11,358 in 1999 to 22,849 in 2024, but the AAMR changed only modestly, from 4.2 to 5.1 per 100,000 (estimated AAPC +0.78%). This divergence points to population aging as the principal driver of rising absolute mortality rather than an increase in age-specific risk. Males died of ILD at roughly 1.65 times the rate of females throughout the study period, a gap that did not narrow over time. Among racial groups, White individuals consistently had the highest AAMR, and the White-to-Black disparity ratio widened from 1.48 in 1999 to 1.79 in 2020. No population-level AAMR reduction was observed in the post-antifibrotic era (2015–2024), though the AAPC decelerated from +1.17% to +0.22% per year.

Abstract: The mammalian respiratory system stands as a frontline barrier, constantly exposed to environmental insults, balancing defensive immunity with gas exchange. Historically considered sterile, the lung harbors a dynamic, low-biomass microbiome that evolves con-tinuously in response to pulmonary pathologies. Accumulating evidence underscores that respiratory health and structural recovery are not autonomous but are critically integrated with distal microbial systems, especially the intestinal tract, through the gut-lung axis (GLA). This review characterizes the GLA as a bidirectional communication highway fueled by immune pathways, microbial metabolites, and direct microbial translocations. During acute or chronic injuries, such as COVID-19, COPD, asthma, and idiopathic pul-monary fibrosis (IPF), the gut microbiota serves as a remote metabolic "rheostat". It delivers pivotal signaling molecules, such as short-chain fatty acids (SCFAs) and tryptophan me-tabolites (indoles), to determine whether the respiratory epithelium undergoes functional repair or maladaptive, fibrotic remodeling. Mechanistically, gut-derived butyrate enhances mitochondrial oxidative phosphorylation to supply the metabolic yield required for resi-dent progenitors, such as Alveolar Type 2 (AT2) cells, to transition from quiescence to pro-liferation. Conversely, critical lung illness disrupts this homeostasis via a "pathological circuit," where severe pulmonary inflammation drives gut permeability, fecal dysbiosis, and the subsequent translocation of pathogen-associated molecular patterns (PAMPs, such as LPS) or gut-associated bacteria back into the pulmonary circulation. This review highlights the systemic nature of lung regeneration, which depends heavily on intestinal health through the gut-lung axis. Ultimately, leveraging these remote microbial networks through precision postbiotics, dietary priming, or microbiota transplantation represents a crucial frontier in precision medicine to promote definitive alveolar repair.

Abstract: Background A novel fixed-dose combination of vilanterol 25-µg, umeclidinium 62.5-µg, and fluticasone furoate 200-µg (VIL-UME-FF) in dry powder inhaler (DPI) was developed by M/s. Zydus Healthcare Limited for managing persistent asthma. Methods In this phase 3, multicenter, parallel group, open-label, randomized trial, patients received either test (VIL-UME-FF DPI) or reference DPI (indacaterol 150-µg, glycopyrronium 50-µg, and mometasone furoate 160-µg; IND-GLY-MF DPI). The primary endpoint was change from baseline in trough forced expiratory volume-1 (FEV1) at week-12. Secondary endpoints included trough forced vital capacity (FVC), post-bronchodilator FEV1 and FVC, and asthma control test (ACT) score. Results A total of 258 participants (18-65 years) were enrolled (Test: 129; Reference: 129). The least square mean change in trough FEV1 at week-12 was 342.9 (21.3) ml for the test group and 327.6 (21.4) ml for the reference group (p=0.6141). The lower limit of 95% confidence interval for the difference between the groups was -44.19 ml, well-above the predefined non-inferiority margin (-150 ml). At week-12, trough FVC, post-bronchodilator FEV1 and FVC, and ACT scores were comparable between the study groups. Conclusion VIL-UME-FF DPI was non-inferior to IND-GLY-MF DPI in improving trough FEV1 and other efficacy parameters and was well-tolerated in Indian patients with persistent asthma.

Abstract: Background: Alpha-1 antitrypsin deficiency (A1ATD) is a hereditary disorder affecting approximately 1 in 2,000 to 5,000 individuals of European ancestry. While severe deficiency (PiZZ genotype) is well-characterized, the clinical significance of relatively intermediate deficiency states (serum A1AT 40-80 mg/dL), predominantly comprising PiSZ, PiMZ, and PiSS genotypes, remains poorly defined. This study aimed to compare hepatic and pulmonary outcomes in patients with moderate versus mild intermediate A1ATD. Methods: Using the TriNetX US Collaborative Network (43 healthcare organizations), we identified 1,410 adult patients with A1ATD (ICD-10 code E88.01) and serum A1AT levels between 40-80 mg/dL. Patients were stratified into two cohorts- 40-60 mg/dL (n=324) and 60-80 mg/dL (n=324) after 1:1 propensity score matching for age, sex, race, BMI, diabetes, and baseline laboratory values. Exclusion criteria included A1AT level of less than 40 mg/dL, pre-existing cirrhosis, and other chronic liver diseases. Primary outcomes included emphysema, COPD exacerbation, cirrhosis, hepatic decompensation, and mortality. Results: Following propensity matching, baseline characteristics were well-balanced except for albumin (4.0±0.8 vs 4.2±0.6 g/dL, p=0.001) and INR (1.4±0.6 vs 1.2±0.4, p=0.001). Patients with A1AT 40-60 mg/dL demonstrated trends toward increased emphysema risk (10.8% vs 7.4%; OR 1.51, 95% CI 0.88-2.61, p=0.133; HR 1.63, 95% CI 0.97-2.74, log-rank p=0.063) and cirrhosis (10.5% vs 7.4%; OR 1.47, 95% CI 0.85-2.53, p=0.169; HR 1.58, 95% CI 0.94-2.66, log-rank p=0.085). No significant differences were observed for COPD exacerbation (14.2% vs 13.0%, p=0.646), hepatic decompensation (4.6% vs 3.7%, p=0.555), or mortality (OR 1.07, p=0.854). Conclusions: The observed trends toward worse outcomes with lower A1AT levels (40-60 mg/dL range, likely enriched for PiSZ genotype) warrant further investigation in larger cohorts with genotype confirmation. Limitations include a lack of genotyping data, reliance on ICD-10 coding, and potential type II error due to limited sample size. These preliminary findings highlight an important knowledge gap in understanding disease burden among the more prevalent intermediate A1ATD.

Abstract: Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder characterized by recurrent upper airway collapse, intermittent hypoxemia, and increased cardiovascular risk. Obesity is the principal modifiable risk factor, and weight loss has been shown to improve OSA severity. Recently, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and the dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist tirzepatide have emerged as promising pharmacotherapies for obesity-related OSA. We conducted a systematic review in accordance with PRISMA 2020 guidelines to evaluate the impact of GLP-1 RAs (semaglutide, liraglutide) and tirzepatide on apnea-hypopnea index (AHI). Databases including PubMed, Google Scholar, and SciSpace were searched up to May 2026. Eligible studies involved adults with OSA receiving GLP-1–based therapies with quantitative AHI outcomes. A total of 40 studies were included. Tirzepatide demonstrated greater reductions in AHI (−25.3 to −29.3 events/h; 50.7%–58.7%) compared with liraglutide (−12.2 events/h; ~25%). Meta-analyses showed an overall AHI reduction of −16.57 events/h. These effects were largely mediated by weight loss, with additional evidence suggesting weight-independent mechanisms.GLP-1–based therapies, particularly tirzepatide, represent effective treatment options for obesity-related OSA, especially in patients with poor adherence to continuous positive airway pressure therapy.

Abstract: Background/Objectives: Airway inflammation and small airway disease (SAD) are key features of asthma. Inflammation can be assessed by blood eosinophil count (Eos) and exhaled nitric oxide (NO) parameters, including fractional exhaled nitric oxide (FeNO), bronchial NO flux (J’awNO), and alveolar NO concentration (CANO), the latter re-flecting distal airway inflammation. We aimed to evaluate the association between Eos and the degree of airway inflammation as specified by exhaled NO parameters, and their relationships with small airway obstruction assessed by spirometric and ple-thysmographic indices. Methods: We conducted an observational study of asthmatic outpatients who underwent spirometry, plethysmography, and exhaled NO measure-ments. Multivariable linear regression was used to estimate associations between Eos and FeNO, J’awNO, CANO, and small airway ventilatory function indices, adjusting for age, sex, body mass index, and treatments. Results: The analytic cohort included 121 patients (49 men; 72 women; median age 54.2 years). Small-airway obstruction and a range of airway inflammation severity were observed. Median (IQR) values were: FEF75 z-score −0.62 (0.96); FEF25–75 z-score −1.27 (1.29); RV z-score 1.26 (0.94); RV/TLC z-score 1.60 (1.10); J’awNO 60.20 nL/min (102.80); FeNO 23.61 ppb (37.61); CANO 3.80 ppb (4.12); and Eos 260 cells/µL (430). Log-transformed Eos (log[Eos]) was associated with FeNO, J’awNO, and CANO (adjusted β [95% CI]: 12.02 [9.35–14.69], 33.27 [25.34–41.19], and 1.14 [0.84–1.43], respectively). Log(Eos) was also positively associated with RV and RV/TLC, but negatively associated with FEF25–75, FEF75, and FEV1. Similarly, CANO was positively associated with RV and RV/TLC and inversely associated with FEF25–75 and FEF75. No significant associations were observed for FeNO or J’awNO. Conclusions: Blood eo-sinophils were independently associated with all exhaled NO parameters. The associa-tion between CANO and small airway ventilatory function indices supports a link between distal airway inflammation and SAD in asthma.

Abstract: Mitochondria regulate cellular energetics, redox balance, apoptosis, and inflammatory signaling in oral, airway, and systemic tissues. Hypoxia is a powerful modulator of mitochondrial function, with effects ranging from adaptive hormesis to overt injury. Cyclic altitude training, most delivered as intermittent hypoxic exposure or intermittent hypoxia training (IHT), has been proposed as a strategy to improve mitochondrial efficiency and exercise performance. By contrast, obstructive sleep apnea (OSA) exposes patients to uncontrolled chronic intermittent hypoxia (CIH), a pattern increasingly linked to endothelial dysfunction, ceramide-mediated mitochondrial dysfunction, insulin resistance, systemic inflammation, oral dysbiosis, and periodontitis. This narrative review covers intermittent hypoxia, mitochondrial biogenesis, hypoxia-inducible factor signaling, OSA, periodontitis, oral microbiome shifts, nitric oxide biology, and smoke-related mitochondrial injury. Appropriately dosed IHT can increase mitochondrial biogenesis, improve mitochondrial morphology, and augment oxidative capacity through pathways involving PGC-1alpha, hypoxia-inducible signaling, mitochondrial dynamics, and reactive oxygen species-dependent hormesis. In contrast, CIH in OSA promotes oxidative stress, sympathetic activation, endothelial injury, and inflammatory signaling and is associated with worse periodontal status and altered salivary microbiome profiles. Controlled IHT and OSA-related CIH, therefore, represent opposite ends of a hypoxia continuum, and mitochondrial health connects sleep-disordered breathing, periodontal inflammation, environmental exposures, and systemic cardiometabolic risk within a single conceptual frame. Sphingolipid signaling—particularly hypoxia- and toxicant-driven ceramide accumulation—connects CIH, inhaled environmental exposures, mitochondrial fragmentation, and the development of insulin resistance.

Abstract: Localized lower respiratory tract infection including unilobar and round pneumonia can be associated with hypoxia and oxygen requirements. Previous explanations include shunting of deoxygenated blood, a systemic inflammatory response syndrome and vasoconstriction.This is unexplained.The alternative hypothesis is that spread of fluid absorption inhibiting cytokines in the alveolar spaces of the inflamed lung is cause of hypoxia in localized lower respiratory tract infection by spread of Cystic Fibrosis Transmembrane Conductance (CFTR) dysfunction in alveolar epithelial cells to more areas including those not infected. There is no evidence of pulmonary shunting to explain hypoxia in localized pneumonia. Systemic inflammatory response syndrome (SIRS) related generalized increase in alveolar capillary barrier or pulmonary vasoconstriction not visible on a chest x-ray cannot explain the hypoxia detected in most patients. Confirmation of the hypothesis could be achieved using pulmonary MRI or high resolution CT to confirm spread of alveolar fluid accumulation from the localized pneumonia focus as opposed to generalized SIRS related pulmonary oedema together with cytokine and chloride measurement in bronchoalveolar lavage samples from the lung segments near the affected lung segment and unaffected contralateral lung. Ventilation/perfusion scintigraphy could investigate for involvement of vasoconstriction or micro-emboli from intravascular coagulation.Should the posed hypothesis be confirmed adjuvant strategies including small molecule CFTR activators, CFTR activating combination of beta-agonists, phosphodiesterase inhibitors and steroids could be used to treat hypoxia and CFTR activating low-intensity ultrasound explored.

Abstract: Paediatric rhinosinusitis (RS), particularly chronic rhinosinusitis (CRS), is a common inflammatory condition with a significant impact on quality of life and a well-recognized association with asthma within the framework of united airway disease. This review aims to evaluate the impact of RS on asthma control in children and explore its role as a modifiable determinant. Mechanistically, RS and asthma share key pathophysiological features, including type 2 inflammation, epithelial barrier dysfunction, and airway microbiome dysbiosis, supporting the concept of a unified inflammatory process across the respiratory tract. Clinically, epidemiological data demonstrate a high prevalence of coexisting RS and asthma, with consistent associations with poorer asthma control, increased disease severity, and higher exacerbation burden, even in cases of subclinical sinonasal inflammation. Emerging evidence suggests that appropriate management of CRS, including medical therapy and, in selected cases, surgical intervention, may improve asthma outcomes such as symptom control and lung function. However, the current evidence base remains limited, with a predominance of small, heterogeneous, and observational studies. RS therefore represents a potentially treatable trait in paediatric asthma, warranting systematic evaluation in children with difficult-to-treat disease. Further prospective and interventional studies are needed to clarify causality and define its impact on long-term outcomes.

Abstract: SRBD encompasses a spectrum of diseases that disrupt ventilation during sleep, that lead to fragmented sleep and impaired gas exchange. Their high prevalence and substantial neurocognitive and mental health outcomes make SRBD clinically significant across multiple medical disciplines. Traditional management includes lifestyle modifications and PAP. When non-surgical measures fail or anatomical factors predominate, a range of surgical approaches may be employed, such as UPPP or MMA. There are many notable emerging surgical advancements, such as hypoglossal nerve stimulation, transoral robotic surgery, and minimally invasive radiofrequency technologies that have offered improved outcomes for select patients. There are evolving advances in diagnostic tools, such as portable home sleep technologies and drug-induced sleep endoscopy, that further support precision-based care. Collectively, the expanding range of therapeutic and diagnostic innovations is enabling clinicians to deliver individualized care and improve long-term outcomes for patients with SRBD.

Abstract: Background/Objectives: Recent trends show a rising incidence of venous thromboembolism (VTE) that does not correlate with increased mortality; however, population aging and the proliferation of comorbidities are fundamentally reshaping the VTE patient landscape. The aim of this study is to evaluate potential differences in clinical characteristics, comorbidities, and survival rates between patients diagnosed with pulmonary embolism (PE) during the pre-pandemic period (2018−2019) and those diagnosed during the pandemic era (2020−2022). Additionally, as a secondary objective, we analyze the clinical profiles, risk factors, and survival outcomes of patients with and without COVID-19 infection during the 2020−2022 period. Methods: A retrospective observational study was conducted to analyse survival and comorbidities in patients admitted for PE at the Hospital Central de la Defensa ‘Gómez Ulla’ between 2018 and 2022, comparing two periods (2018−2019 and 2020−2022). In addition, a sub-analysis was performed within the second period group comparing patients with and without COVID-19. Results: It was observed that the majority of patients in the first period were men, while in the second period, 55% were women. With regard to comorbidity and risk factors, thrombophilia and dementia were more prevalent in the first period, while immobilization, a history of asthma, autoimmune diseases and infections were more prevalent in the second period. No differences were found with regard to mortality. Conclusions: Significant differences were observed between the two periods of the study with regard to age, gender, and some comorbidities. Patients with COVID-19 showed a greater tendency toward immobilization and a higher prescription of thromboprophylaxis during hospitalisation.

Abstract: Background: Continuous positive airway pressure (CPAP) is the primary treatment for Obstructive Sleep Apnea (OSA). Despite improvements in CPAP technology and management, adherence to therapy remains one of the main issues to be fixed. Methods: We conducted a narrative review through PubMed (1995-2025). Studies were selected by clinical relevance, methodological quality and expert consensus. Results: OSA treatment outcomes are poor when CPAP adherence is defined as four hours per night. The first step in improving adherence is active patient involvement. This involves explaining what OSA is, its consequences, what PAP therapy is, and its potential benefits. The right mask should be chosen for each patient; a nasal mask should be the first choice according to the Starling resistor model. OSA endotype and phenotype traits could be used to predict adherence, guide adjunct therapy, or suggest titration. Problems during the first night and the first month are the main predictors of future adherence. Strategies such as cognitive behavioral therapy or motivational enhancement can improve adherence, especially during the initial period. Long-term adherence can be predicted by the initial one and maintained with scheduled follow-up. Group meetings, telephone calls and telemedicine interactions are also a valid way of improving adherence. Conclusions: A Patients should initially be educated about how their symptoms are related to sleep apnoea and how CPAP treatment could resolve them. The key to improving CPAP adherence is to involve patients in personalised treatment with scheduled follow-up, particularly during the initial treatment period.

Abstract: Chikungunya virus (CHIKV), traditionally recognized as a mosquito-borne alphavirus that causes febrile illness and debilitating arthralgia, has increasingly been associated with atypical organ involvement, including respiratory manifestations. These observations raise important questions regarding whether respiratory symptoms reflect severe systemic disease or signal previously underappreciated respiratory exposure routes. This review aimed to synthesize current evidence on respiratory complications of CHIKV infection and to evaluate the plausibility of respiratory or aerosol-associated transmission. A systematic literature search of PubMed, EMBASE, and MEDLINE (Ovid) identified five eligible studies spanning clinical virology, outbreak surveillance, epidemiology, and experimental aerosol models. Across human studies conducted in India, Réunion Island, Puerto Rico, and Brazil, respiratory presentations—including pneumonia, dyspnea, and respiratory failure—were uncommon but consistently associated with increased hospitalization and mortality risk. Respiratory symptoms generally arose in the context of respiratory viral coinfections, systemic inflammation, or cardiopulmonary decompensation rather than primary viral tropism for the respiratory tract. Only one non-human primate study directly evaluated aerosol exposure, demonstrating that cynomolgus macaques could be infected via inhaled CHIKV, confirming biological plausibility but showing no evidence of enhanced respiratory pathology. Importantly, no epidemiologic data support human-to-human airborne or droplet transmission. Collectively, available evidence indicates that respiratory involvement serves as a marker of disease severity rather than a transmission route. Nonetheless, rare aerosol-acquisition events in laboratory settings underscore the need for continued vigilance, strengthened surveillance, and re-evaluation of respiratory risks as climate change and viral evolution expand CHIKV’s global footprint.