Medicine and Pharmacology

Abstract: Extracellular vesicles (EVs) released by cells carry a diverse molecular cargo, including proteins, lipids, nucleic acids, and mitochondria. In addition, EVs carry antioxidants and free radical producing enzymes like NADPH oxidases or other oxidases. Growing evidence suggests that EV cargo plays a critical role in intercellular communication and disease pathogenesis. In pulmonary hypertension (PH), circulating EV levels are elevated and can alter the function of recipient cells; however, whether EVs transmit functional mitochondria and the composition of their protein cargo remain poorly understood. To address this knowledge gap, we characterized the cargo of EVs in a rat model of Sugen5416 (SU; 20 mg/kg, i.p.)- and hypoxia (10% O₂)-induced PH. EVs were isolated from blood collected from the left ventricles of SU/hypoxia (SU/Hx) and SU/normoxia (SU/Nx) rats and analyzed using quantitative mass spectrometry–based proteomics and flow cytometry. Proteomic profiling revealed that EVs contain proteins involved in coagulation, complement and immune signaling, metabolism, receptor signaling, and cytoskeletal organization. Although EVs from SU/Hx rats exhibited an overall decrease in protein abundance, specific proteins involved in cytoskeletal structure, metabolism, immune signaling, and cell adhesion were preferentially enriched and contained reactive oxygen species-dependent and redox-sensitive post-translational modifications, implicating these molecular changes in mechanisms underlying PH progression. Importantly, EVs from SU/Hx rats contained a significantly greater abundance of functionally active mitochondria, as determined by the MitoTracker Red-to-MitoTracker Green signal ratio, while exhibiting lower levels of mitochondrial superoxide anions, as determined by MitoSOX fluorescence. Together, these findings demonstrate, for the first time, that EVs released from the pulmonary circulation in PH can transmit functional mitochondria and biologically active protein cargo capable of modulating vascular and systemic cellular responses.

Abstract: Tuberculosis (TB) remains a major global public health threat. Driven by unhealthy lifestyles, the prevalence of concomitant glucose and lipid metabolism disorders, primarily diabetes mellitus (DM) and dyslipidemia, continues to rise and overlaps substantially with high TB-burden regions, posing significant challenges to clinical management. Both DM and dyslipidemia independently increase the risk of pulmonary tuberculosis (PTB) caused by Mycobacterium tuberculosis and contribute to poor clinical outcomes; however, research on the combined associations of these comorbid conditions on PTB outcomes, as well as the underlying host–pathogen interaction mechanisms and host immunity, remains limited. Existing evidence indicates that DM and dyslipidemia mutually exacerbate one another through insulin resistance, impairing macrophage function. Recent studies further suggest that DM-associated chronic hyperglycemia can induce T-cell memory exhaustion, thereby adversely affecting clinical outcomes in PTB patients. Based on this evidence, we propose the working hypothesis that concomitant dysglycemia and dyslipidemia may exert a synergistic or additive detrimental effect on PTB outcomes through the interplay between insulin resistance and T-cell exhaustion, and that combined interventions integrating glucose-lowering, lipid-lowering, and anti-tuberculosis therapies may yield greater clinical benefits than single-pathway approaches. This review examines the associations between dysglycemia, dyslipidemia and clinical outcomes in patients with PTB, elucidates the host–pathogen interaction mechanisms, and proposes a working hypothesis to inform the optimization of precision treatment strategies.

Abstract: Musculoskeletal disorders are prevalent extrapulmonary comorbidities of chronic obstructive pulmonary disease, encompassing skeletal muscle dysfunction and compromised bone microarchitecture. However, the relative contributions of cigarette smoke (CS) exposure and acute viral exacerbation to muscle and bone pathology remain incompletely defined. Using male BALB/c mice exposed to CS for 8 weeks followed by influenza A virus (IAV) infection to model viral acute exacerbation of COPD, we assessed airway inflammation, tibial bone microarchitecture, hindlimb muscle mass, tibialis anterior (TA) contractile function, myofibre morphology, oxidative fibre composition, oxidative protein modification and calcium-handling protein expression, with ebselen used to interrogate redox-sensitive mechanisms. CS exposure and IAV infection induced robust airway inflammation, with the combined CS + IAV group showing the greatest inflammatory burden. CS exposure suppressed osteogenic matrix genes, including Ibsp, Spp1 and Bglap, and caused marked trabecular deterioration, reducing bone volume fraction (BV/TV) by 57% and increasing trabecular separation by 50%. Acute IAV infection alone also reduced BV/TV by 38%, indicating that a respiratory viral insult can rapidly compromise trabecular bone structure independent of CS exposure. In skeletal muscle, CS exposure reduced selected hindlimb muscle masses, induced TA myofibre atrophy, shifted myofibre size distribution towards smaller fibres and reduced oxidative fibre proportion, whereas IAV infection alone had limited effects on muscle mass or fibre-type composition. However, IAV challenge superimposed on CS exposure produced the greatest TA force deficit, despite limited evidence of additional muscle mass loss, and selectively increased oxidative protein modification, SERCA2 and STIM1 expression. Importantly, ebselen treatment was associated with preservation of muscle force, myofibre size and oxidative fibre proportion, and the absence of detectable increases in protein oxidation and calcium-handling protein expression. These findings indicate that CS exposure and acute IAV infection exert distinct but intersecting effects on bone and skeletal muscle, identifying trabecular bone as an unexpectedly sensitive target of acute viral infection, highlighting a dissociation between muscle quantity and muscle function during viral exacerbation, and supporting redox imbalance as a modifiable contributor to exacerbation-associated skeletal muscle dysfunction.

Abstract: Fibrotic interstitial lung disease (f-ILD) progresses at variable rates, and bulk cell densities discard the spatial information behind that variation. Free fatty acid receptor 2 (FFAR2) senses microbial short-chain fatty acids (SCFAs) and restrains macrophage inflammation, but its position in the human fibrotic lung remains unknown. We tested position rather than abundance. In cryobiopsy specimens from 10 patients with fibrotic idiopathic interstitial pneumonia, we combined chromogenic multiplex immunohistochemistry for FFAR2/Iba1 and CD163/Iba1 with deep learning-based image cytometry, mapped single-cell coordinates, and scored each subset’s proximity to stromal cells and the alveolar epithelium with three indices, including the colocalization index (CLI). Proximity of FFAR2-positive macrophages to stromal cells correlated with the 1-year change in forced vital capacity (FVC) (CLI: ρ=0.80, p<0.01) and in diffusing capacity for carbon monoxide (DLco) (CLI: ρ=0.83, p<0.05). Proximity to the alveolar epithelium correlated still more closely with the FVC change (CLI: ρ=0.87, p<0.01). CD163-positive macrophages showed no such association with FVC, and no index correlated with baseline lung function. In this preliminary cohort, the position of FFAR2-positive macrophages, not their abundance, marks a protective niche and nominates the SCFA-FFAR2 axis as a therapeutic target in f-ILD.

Abstract: Purpose: Respiratory-event rates quantify event frequency but do not describe how respiratory-related acoustic activity is expressed across an overnight recording. We investigated whether a score-defined digital acoustic representation captures information not reducible to annotated respiratory-event rate.Methods: We analyzed 32 overnight home respiratory polygraphy recordings from the APSAA dataset, including audio, respiratory annotations, and oxygen saturation. Twenty-eight recordings yielded at least one qualifying acoustic episode (8,512 episodes). Five acoustic features—episode density, relative intensity, duration, long-event occurrence, and temporal distribution—formed a composite score defining three acoustic phenotypes using fixed heuristic thresholds. Temporal compaction quantified short inter-episode intervals and was adjusted for episode quantity.Results: Scores were computationally reproduced with identical phenotype assignment in 28/28 recordings (mean absolute difference 0.0011; maximum 0.0046). Two recordings with comparable annotation-derived respiratory-event rates (30.45 vs 33.38 events/h; 217 vs 232 annotated events) and mean SpO₂ (91.75% vs 91.61%) contained 382 vs 5 acoustic episodes and scores of 0.685 vs 0.145. Load-adjusted temporal compaction differed among phenotypes (H=8.192, p=0.0166, ε²=0.248). The effect persisted after removing the historical 120-s interval exclusion (H=8.108, p=0.0174, ε²=0.244); residual association with episode count remained. The low- versus intermediate-score contrast was robust, whereas the high-score contrast was less stable.Conclusions: Overnight respiratory audio can provide reproducible digital acoustic phenotypes describing the amount and temporal organization of detected acoustic activity beyond annotated event frequency. These are signal representations, not clinical phenotypes or sleep stages. Repeated-night studies are required to establish within-person stability, transitions, and clinical meaning.

Abstract: Non-invasive respiratory support for acute hypoxemic respiratory failure (AHRF) remains controversial. Continuous positive airway pressure (CPAP) provides sustained positive end-expiratory pressure, while helmet interface (H-CPAP) may improve tolerance and re-duce air leaks. We aimed to evaluate clinical outcomes of H-CPAP delivered in a respira-tory intermediate care unit (RICU) by pulmonologists and identify early predictors of treatment failure. We conducted a prospective single-centre observational cohort study in-cluding consecutive adults with community-acquired pneumonia (CAP)-AHRF treated with H-CPAP in a RICU. H-CPAP success was defined as hospital discharge without in-vasive mechanical ventilation (IMV). Clinical, radiological, gas exchange, laboratory var-iables were collected at baseline and after 1 hour of H-CPAP. Among 1100 screened pa-tients, 198 met inclusion criteria. H-CPAP success occurred in 158/198 patients (79.8%), while overall in-hospital mortality was 9.1%. Success rates decreased with increasing AHRF severity. Lower haematocrit, bilateral pulmonary infiltrates, lower PaO₂/FiO₂ dur-ing H-CPAP, higher alveolar–arterial oxygen gradient, and higher APACHE II score were the main predictors of treatment failure. In selected patients with CAP-AHRF, H-CPAP delivered in a RICU was associated with high rates of avoidance of IMV and low in-hospital mortality. Early physiological and radiological variables identified patients at increased risk of H-CPAP failure with acceptable predictive performance.

Abstract: Background: Neoadjuvant chemo-immunotherapy is now a standard treatment for resectable non-small cell lung cancer (NSCLC) patients with clinical stage II–III disease. However, some patients do not respond to the treatment radiologically, and the surgical and pathological outcomes in such patients remain unclear. Methods: We conducted a multi-institutional retrospective analysis of patients who received neoadjuvant chemo-immunotherapy at 29 centers in Japan (CReGYT-04 Neo-Venus study). In this study, we focused specifically on radiological non-responders to neoadjuvant chemoimmunotherapy. Results: Of 124 eligible patients, radiological responses indicated a complete/partial response (CR/PR) in 84, stable disease (SD) in 35, and progressive disease (PD) in 5 patients. Nine patients (five with PD, two with SD, and two with PR) did not undergo surgical resection, and one SD patient had exploratory thoracotomy. Surgical outcomes, including minimally invasive approach rates, procedures, operation time, blood loss, and postoperative complications, were similar between patients with SD and those with CR/PR. Among 31 SD patients with available pathological data, a major pathologic response (MPR) was achieved in 26%, and pre-treatment PD-L1 status (p&lt;0.01) and a ≥50% decrease in the maximum standardized uptake value on FDG-PET/CT (p=0.03) were associated with MPR. Conclusions: Surgical outcomes were similar between the SD and CR/PR groups, and 26% of SD patients achieved MPR, supporting strategies that actively pursue surgical resection, even in radiological non-responders to neoadjuvant treatment.

Abstract: Background/Objectives: Obstructive sleep apnea (OSA) and pulmonary embolism (PE) share several risk factors, while emerging evidence suggests a potential patho-physiological link beyond these common determinants. We aimed to characterize the prevalence and severity of OSA in patients with acute PE and to investigate whether the apnea-hypopnea index (AHI) is independently associated with PE and its clinical course. Methods: In this prospective, single-center, case–control study, 128 consecu-tive patients with acute PE and 252 outpatient controls with other respiratory diseases underwent home respiratory polygraphy. In patients with PE, the sleep study was per-formed at least three months after the acute event. OSA was diagnosed and graded according to international consensus criteria. Logistic regression models were used to evaluate associations between AHI and PE, acute PE severity, chronic deep vein thrombosis (DVT), and venous thromboembolism (VTE) recurrence. Results: OSA was present in 55.5% of patients with PE, with severe OSA in 28.9%, compared with 42.1% and 13.9%, respectively, among controls (p = 0.013 and p = 0.001). Patients with PE had a higher AHI (21.21 ± 19.29 vs. 14.81 ± 14.26 events/h; p = 0.007) and oxygen desatura-tion index (19.86 ± 18.77 vs. 13.30 ± 13.79; p = 0.003). Each 10-events/h increase in AHI was independently associated with PE after adjustment for age, sex, BMI, and estab-lished VTE risk factors (OR 1.205, 95% CI 1.019–1.426; p = 0.029). AHI was not inde-pendently associated with intermediate-high/high-risk PE or chronic DVT. Among pa-tients who discontinued anticoagulation, VTE recurrence was higher in those with OSA (36.0% vs. 13.3%; p = 0.049). Conclusions: OSA is highly prevalent and frequently severe in patients with acute PE. Increasing AHI is independently associated with the presence of PE, supporting a clinically relevant link between sleep-disordered breath-ing and thromboembolic disease. Whether OSA contributes to recurrent VTE after an-ticoagulation withdrawal requires confirmation in larger prospective studies.

Abstract: Cheyne-Stokes-Respiration (CSR) manifests as a crescendo-decrescendo breathing pattern with alternating central events and is a common finding during sleep in patients chronic heart failure. Despite its high prevalence, well-defined diagnostic criteria and specific treatment options, the pathophysiology of CSR is not completely understood. Besides its occurrence in chronic heart failure, studies have shown an increasing likelihood with other cardiovascular disorders like atrial fibrillation or pulmonary hypertension and report an association with trigger factors like cortical arousals, fluid shifts and oxygen desaturations. In fact, hypoxemia tends to be neglected in patients with chronic heart failure due to an increased compensatory respiratory drive but is the most consistent finding in nocturnal CSR under conditions of high altitude. Therefore, based on the assumption of two parallel chemoreceptive systems to detect changes in arterial oxygen and carbon dioxide, the present work hypothesizes that the additional respiratory drive by hypoxemia (“hypoxic drive”) leads to an excess exspiration of the main controlled variable CO2 which destabilizes the respiratory feedback loop. Based on the current knowledge about CSR in the context of chronic heart failure and hypobaric hypoxemia as well as clinical observations, a pathophysiological concept on nocturnal CSR is outlined. The essential features of this theory include recurrent episodes of hypoxemia detected by peripheral chemoreceptors causing a temporarily increased respiratory drive which destabilizes respiration due to a time delay between peripheral sensation of pO2 and central chemoreception of pCO2. This pathophysiological theory explains the treatment efficacy of supplemental oxygen and may also apply to other clinical scenarios like metabolic acidosis in chronic kidney disease in which the temporal delay between the peripheral sensation of pH and the central detection of pCO2 may result in nocturnal periodic breathing.

Abstract: COPD involves progressive airflow limitation driven by chronic inflammation, largely triggered by cigarette smoke. Disease progression is linked to heightened Th17/IL-17 responses, with STAT3 playing a key regulatory role. Targeting STAT3 such as with the selective inhibitor Cryptotanshinone may offer a promising strategy to reduce COPD associated inflammation. This study aimed to evaluate the effects of Cryptotanshinone administration on the Th17 immune response in a murine model of chronic cigarette smoke exposure. C57BL/6 mice were exposed to cigarette smoke for six months, while controls breathed filtered air. From the fourth month, mice received intramuscular Cryptotanshinone treatment. Lung function, airspace enlargement, and STAT3/Th17 responses were assessed through respiratory mechanics, histology, immunohistochemistry, and ELISA. Cigarette-smoke reduced tissue elastance and increased alveolar enlargement. Cryptotanshinone attenuated structural damage but did not improve lung function. Smoke exposure elevated STAT3 and IL-17 positive cells and IL-17 levels, all of which were significantly reduced by treatment, indicating suppression of the STAT3/IL-17 inflammatory axis. Pharmacological inhibition of STAT3 with Cryptotanshinone mitigated structural lung damage and reduced Th17-driven inflammation in a chronic cigarette smoke exposure model. These findings reinforce the importance of the STAT3/Th17 axis in COPD pathogenesis and progression.

Abstract: Background: Romania continues to experience one of the highest tuberculosis (TB) burdens in the European Union/European Economic Area. During the COVID-19 pandemic, reduced inpatient capacity accelerated the use of ambulatory care for patients with drug-susceptible tuberculosis (DS-TB). This study evaluated treatment outcomes, outcome ascertainment, hospitalization requirements, and factors associated with unfavorable outcomes among patients managed through ambulatory TB services. Methods: We conducted a retrospective observational cohort study of adults with pulmonary or extrapulmonary DS-TB managed through ambulatory tuberculosis dispensaries affiliated with the “Marius Nasta” Institute of Pneumophthisiology, Bucharest, Romania, between January 2020 and December 2022. Treatment outcomes were defined according to World Health Organization criteria. Treatment success was calculated among patients with a determinate outcome and complemented by best-case/worst-case sensitivity analyses for patients classified as not evaluated. Factors associated with unfavorable outcome were assessed using Firth penalized-likelihood logistic regression. Hospitalization during treatment was analyzed as a secondary outcome. Results: The final cohort comprised 545 patients with DS-TB, with a mean age of 44.8 years and 56.1% being male. Among 308 patients with a determinate end-of-treatment outcome, 281 achieved treatment success and 27 experienced an unfavorable outcome, corresponding to a treatment-success rate of 91.2% (95% CI 87.5–94.1). However, 237 patients (43.5%) were classified as not evaluated; sensitivity analyses yielded treatment-success estimates ranging from 51.6% to 95.0%. Male sex was associated with unfavorable outcome in univariable analysis (OR 2.43, 95% CI 1.03–6.54; p = 0.042), but the association was no longer statistically significant after adjustment (aOR 2.70, 95% CI 0.90–10.67; p = 0.079). No other baseline factor was significantly associated with unfavorable outcome. Documented non-compliance was markedly more frequent among patients with unfavorable outcomes and was interpreted as a treatment-process indicator rather than a baseline prognostic factor. Hospitalization was required in 24 of 483 patients (5.0%), and adverse drug reactions were strongly associated with hospitalization (OR 5.95, 95% CI 2.55–13.72; p < 0.001). Conclusions: Structured ambulatory DS-TB care was feasible during the COVID-19 pandemic within a tertiary-care-linked dispensary network, with high treatment success among patients with known outcomes and a low requirement for hospitalization. However, the substantial proportion of patients without an evaluable final outcome limits interpretation of the overall success estimate. The findings emphasize the importance of complete outcome ascertainment, adherence support, adverse-event surveillance, and clear referral pathways in ambulatory TB programs. Prospective multicenter studies with comparator groups are needed to establish the long-term effectiveness, safety, and scalability of this model.

Abstract: Background/Objectives: Reduced physical activity (PA) and increased sedentary behavior (SB) are associated with adverse outcomes in chronic obstructive pulmonary disease (COPD). However, the factors associated with their long-term change remain unclear. We investigated the baseline factors associated with a longitudinal decline in PA and increase in SB. Methods: Stable outpatients with COPD who participated in both the SPACE (baseline) and E-PAC (follow-up) studies in Japan were analyzed retrospectively. At baseline, 29 clinical variables were assessed, including demographic and anthropometric data, nutritional indices (body mass index [BMI], upper arm circumference), pulmonary function, blood tests, and the lowest percutaneous oxygen saturation (SpO₂) during the 6-min walk test (6MWT). PA and SB were measured with a waist-worn triaxial accelerometer and expressed in metabolic equivalents (METs). Annual percentage changes were analyzed using Spearman’s rank correlation and multiple linear regression. Analyses were exploratory, with 95% confidence intervals reported. Results: Thirty-two men (median age 71.0 years; median follow-up 5.0 years) were analyzed. Greater annual declines in PA were associated with a poorer baseline nutritional status (lower body weight, BMI, and upper arm circumference), lower pulmonary function, and a lower lowest SpO₂ during the 6MWT (i.e., exercise-induced desaturation). A greater annual increase in SB was associated with a lower lowest SpO₂ and a higher baseline hemoglobin concentration. In multivariable models, BMI remained independently associated with the declines in total PA and in the duration at ≥3.0 METs. Conclusions: In this exploratory analysis, nutritional status, pulmonary function, and exercise-induced desaturation were associated with long-term behavioral changes in COPD, with BMI showing the most consistent association with the decline in PA. These hypothesis-generating findings require confirmation in a larger cohort.

Abstract: Pleural mesothelioma (PM) is an aggressive malignancy with limited therapeutic options, underscoring the need for novel therapeutic alternatives. Exosomes, a subset of extracellular vesicles mediating intercellular communication, have emerged as potential therapeutic platforms due to their ability to transfer functional biomolecules and modulate cellular responses. In PM, however, exosomes exert context-dependent effects: tumor-derived exosomes actively contribute to tumor progression, immune modulation, and therapy resistance, while exosomes of non-tumor origin or those subjected to engineering approaches may be exploited for targeted therapeutic delivery. This review discusses the mechanistic foundations of exosome biology relevant to PM and current preclinical efforts to harness exosomes as carriers of nucleic acids, small molecules, and immune-modulatory agents. It further evaluates the influence of exosome cell-of-origin and the intrinsic therapeutic paradox arising from the dual biological roles of exosomes. Finally, key translational challenges, including optimization of exosome source, cargo loading efficiency and manufacturing scalability are examined as major obstacles to clinical implementation. Addressing these challenges is essential for translating exosome-based strategies into more effective therapeutic interventions in this malignancy.

Abstract: Background: Computer-aided diagnosis (CAD) algorithms may be useful for the detection of pulmonary nodules, some of them early-stage primary lung cancers (LCs). Method: A CAD algorithm for the identification of pulmonary nodules in chest x-rays was used in a prospective cohort of patients without respiratory symptoms who underwent an x-ray. Chest x-rays were sorted according to the probability of the presence of a pulmonary nodule, and images placed in the highest percentiles by the algorithm were read by a radiologist, checked for previous diagnoses, and assessed for new primary LCs. Results: The radiological study confirmed the presence of a round opacities in 88 out of the 1842 chest x-rays placed in the highest percentiles (4.8%), 44 of which were found to be malignant (50%), and 7 of them undiagnosed primary LCs (7.9%). The CAD algorithm prompted a new diagnosis of primary LC in 0.4% of the sorted chest x-rays. Conclusion: A CAD algorithm prospectively identified chest x-rays with a high probability of pulmonary nodules among patients without respiratory symptoms. Radiologist-confirmed nodules were found in 4.8% of high-probability images, and previously undiagnosed primary lung cancers accounted for near 8% of confirmed round opacities and 1% of high-probability chest x-rays.

Abstract: Pulmonary hypertension (PH) is a heterogeneous clinical syndrome in which similar haemodynamic abnormalities may arise from distinct vascular, cardiac, pulmonary, thromboembolic, and molecular mechanisms. This complexity limits the ability of conventional classifications and risk scores to fully capture individual disease trajectories and treatment responses. Artificial intelligence (AI) offers a framework for integrating clinical data, electrocardiography, multimodal imaging, invasive haemodynamics, biomarkers, and multi-omics information across the PH care pathway. This review summarises current applications of machine learning and deep learning in early detection, diagnostic referral, right ventricular and pulmonary vascular phenotyping, molecular endotyping, risk stratification, and therapeutic decision support. Available studies show promising results for AI-assisted electrocardiographic screening, automated echocardiographic and cardiac magnetic resonance analysis, CT-based phenotyping, and multimodal prognostic modelling. Multi-omics approaches may further identify immune, transcriptomic, proteomic, metabolic, and genetic signatures relevant to biological endotyping and biomarker-driven trial enrichment. However, most evidence remains retrospective, derives from selected referral populations, and lacks robust external or prospective validation. No AI-based model currently supports routine drug selection or autonomous clinical decision-making. Future progress will require harmonised multicentre datasets and standardised acquisition protocols, transparent and interpretable models, and prospective studies demonstrating meaningful clinical benefit. AI should therefore be viewed as an emerging decision-support tool that may strengthen precision medicine in PH while complementing clinical expertise across diagnosis, phenotyping, risk assessment, and therapeutic stratification pathways.

Abstract: Small airway dysfunction and air trapping are increasingly recognized as important contributors to disease severity in severe asthma. Although type 2 (T2)-targeted biologics improve clinical outcomes, their effects on distal airway physiology remain incom-pletely characterized. We evaluated the longitudinal effects of biologic therapy on air trapping, lung function, and type 2 inflammatory activity in patients with severe asth-ma. In this prospective real-world study, 43 adults with severe asthma received benral-izumab (n = 16), mepolizumab (n = 21), or tezepelumab (n = 6). Clinical outcomes, pul-monary function parameters, static lung volumes, and fractional exhaled nitric oxide (FeNO) were assessed at baseline (T0), 3 months (T3), and 9 months (T9). The primary endpoint was the change in RV/TLC ratio, a physiological marker of air trapping and distal airway dysfunction. Biologic therapy was associated with significant improve-ments in asthma control and exacerbation burden. Mean asthma control test (ACT) score increased from 12.7 ± 0.6 to 23.5 ± 0.3 (p < 0.0001), while annual exacerbations decreased from 4.74 ± 0.27 to 0.63 ± 0.19 events per patient (p < 0.0001). Improvements were also observed in conventional spirometric parameters, with FEV₁ increasing from 80.3 ± 3.1% predicted at baseline to 96.3 ± 3.4% at T9 (p < 0.0001). The most pronounced functional changes involved air-trapping indices: RV decreased from 108.4 ± 6.0% predicted to 82.2 ± 4.1% (p < 0.0001), while RV/TLC decreased from 111.2 ± 5.0% to 83.7 ± 3.9% (p < 0.0001). FeNO progressively declined from 68.8 ± 6.7 ppb at baseline to 28.3 ± 2.9 ppb at T9 (p < 0.0001). T2-targeted biologics were associated with significant reductions in air trapping alongside improvements in clinical, functional, and inflammatory outcomes. The marked responsiveness of RV and RV/TLC suggests that assessment of air trapping may provide complementary information on treatment response beyond conventional spi-rometric measures and may represent a promising functional pharmacodynamic bi-omarker in severe asthma.

Abstract: Objective: To challenge the longstanding assumption that the sonographic Shred Sign and the Fractal Sign are synonymous and to redefine their diagnostic relationship in peripheral lung disease. Methods and Study Design: This prospective observational study analysed 700 consecutive comprehensive lung ultrasound examinations obtained from hospitalized patients. All patients underwent chest computed tomography (CT) and lung ultrasound as part of the routine diagnostic evaluation. Final diagnoses were established according to current international disease-specific guidelines by integrating clinical findings, laboratory investigations, CT imaging, microbiological studies, bronchoscopy, histopathology, and clinical follow-up, where appropriate. Morphological analysis was subsequently performed on the lung ultrasound examinations after diagnostic confirmation. Setting: Single tertiary university pulmonary referral centre. Participants: Seven hundred consecutive patients undergoing comprehensive lung ultrasound for peripheral lung disease. Primary outcome measure: Comparative assessment of the morphological characteristics of the Shred Sign across confirmed pulmonary diseases, focusing on boundary geometry, internal echotexture, air bronchogram dynamics, and airway patency. Secondary outcome measure: Identification and characterization of the True Fractal Sign, Non-Fractal Shred Sign, and Fractal Mimicry based on the combined morphological profile. Results: Among 700 examinations, 446 demonstrated an irregular pleural–parenchymal interface (Shred Sign). Of these, 127 exhibited fractal-like morphology; 126 fulfilled the criteria for a True Fractal Sign, whereas one lung cancer represented Fractal Mimicry. The remaining 319 cases were classified as Non-Fractal Shred Signs. True Fractal Signs were identified only in a subset of acute pneumonias, whereas Non-Fractal Shred Signs occurred both in acute pneumonias and in pulmonary infarction, tuberculosis, bronchiectasis, lung cancer, and other structural lung diseases. These findings demonstrate that the Shred Sign and the True Fractal Sign are distinct sonographic entities rather than synonymous findings. Conclusions: The Shred Sign is a broad descriptive sonographic pattern rather than a specific diagnostic entity. The True Fractal Sign represents a distinct geometric subtype associated with preservation of the alveolar branching architecture during acute exudative pneumonia. Based on these findings, we propose a novel four-pillar diagnostic tetrad integrating boundary geometry, internal shade, dynamic air bronchograms, and airway patency to differentiate True Fractal Sign, Non-Fractal Shred Sign, and Fractal Mimicry. This morphology-based framework may improve the diagnostic specificity of bedside lung ultrasound. The observation that many acute pneumonias lack a True Fractal Sign generates the hypothesis that preservation of fractal architecture depends on the integrity of the underlying lung structure and the stage of disease, warranting prospective validation.

Abstract: Background/Objectives: Perioperative chemoimmunotherapy has become an important curative-intent strategy for selected patients with resectable non-small cell lung cancer (NSCLC). However, most pivotal trials evaluate neoadjuvant therapy, surgery, and postoperative immune checkpoint inhibitor (ICI) treatment as an integrated regimen. Whether continued postoperative immunotherapy provides independent incremental benefit for all patients after effective neoadjuvant chemoimmunotherapy and complete resection remains unresolved. This review focuses on the adjuvant-phase dilemma and discusses how postoperative treatment may be refined according to response and residual risk. Methods: We performed a narrative review of major neoadjuvant and perioperative chemoimmunotherapy trials, indirect comparative analyses, pathological-response studies, circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) evidence, immune biomarker studies, and emerging data in driver-positive and real-world populations. Particular attention was given to evidence informing postoperative continuation, de-escalation, or intensification after neoadjuvant chemoimmunotherapy. Results: Current phase III perioperative trials demonstrate clinically meaningful activity but do not isolate the independent contribution of the adjuvant ICI phase. Pathological response provides the most accessible postoperative risk signal: pathologic complete response identifies the deepest-response group, major pathologic response represents an intermediate state, and non-major pathologic response or persistent nodal disease suggests higher relapse risk. ctDNA-based MRD offers dynamic risk refinement and may help identify patients with residual systemic disease, although prospective validation is required before it can guide routine treatment omission or escalation. Programmed death-ligand 1 (PD-L1), tumor mutational burden, tertiary lymphoid structures, B-cell signatures, radiomics, and pathomics may provide complementary information but are not sufficient as standalone decision tools. Driver-positive disease requires molecularly stratified perioperative strategies rather than unselected extrapolation from epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-negative trials. Conclusions: The key question in resectable NSCLC is shifting from whether perioperative immunotherapy is active to which patients truly require postoperative immunotherapy. Future trials should prospectively test response-guided strategies integrating pathological response, ctDNA-based MRD, immune contexture, baseline risk, and treatment feasibility.

Abstract: Chronic obstructive pulmonary disease (COPD) is a chronic progressive respiratory disease, characterized by respiratory symptoms and airflow limitation, and is one of the leading causes of morbidity and mortality worldwide. The evolution of the disease is associated with episodes of acute exacerbations (AECOPD), characterized by worsening symptoms and accelerated deterioration of lung function. Acute exacerbations of COPD have different severity, being mild, moderate or severe depending on how aggravated the patients’ symptoms are, but also depending on the pulmonary functional and biological changes. Around 70% of AECOPD are infectious in nature, through upper or lower respiratory tract infections. Often, exacerbations associated with lower respiratory tract infections are more severe and have a higher risk of unfavorable outcome compared to AECOPD associated with upper respiratory tract infections. Severe exacerbations require hospital management, most of them being treated in the intensive care unit (ICU). In this narrative review, we evaluated the frequency of different bacterial pathogens involved in severe COPD exacerbations associated with lower respiratory tract infections and the need for treatment in the ICU. Identifying patients with exacerbated COPD at high risk of respiratory infections especially with gram-negative bacilli is extremely important to choose the optimal treatment, thus reducing the risk of death.

Abstract: Background: While non-specific pleural empyema in children can be successfully managed with minimally invasive drainage and pleural puncture in 85–90% of cases. Tuberculous pleural empyema (TB empyema) exhibits high clinical resistance and frequently requires extensive thoracic surgical interventions. The choice of surgical extent directly depends on the disease stage and the presence of complications. Methods: We conducted a retrospective analysis of diagnostic and surgical outcomes in 85 children and adolescents (aged 4 to 17 years) with tuberculous pleural empyema treated between 1984 and 2022. TB empyema staging was performed using the American Thoracic Society (ATS) classification was adapted for tuberculous etiology. Results: Stage I TB empyema was diagnosed in 3 patients, Stage II in 7 patients, and Stage III in 75 patients. Patients with Stage I and II disease underwent video-assisted thoracoscopic (VATS) debridement of the empyema cavity. In Stage III, 75 patients underwent 79 surgical interventions of varying extents. Postoperative complications occurred in 2 patients (2.5%). This occurred as delayed lung re-expansion, which was successfully managed with repeat thoracentesis in one patient and chest tube drainage in the other. The overall 30-day postoperative mortality rate was 0.0%. No recurrences were reported during the 3-year follow-up period.Conclusion: Comprehensive treatment combined with timely surgical intervention achieves clinical cure in all patients. Early minimally invasive VATS interventions during Stages I–II prevent the need for more traumatic procedures, such as pleurectomy and lung resection, which are often required in Stage III disease.