Cystic fibrosis (CF) is a multisystem disease affecting epithelia of the respiratory tract, exocrine pancreas, intestine, hepatobiliary system, and exocrine sweat glands. Morbidities include progressive obstructive lung disease with bronchiectasis, frequent hospitalizations for pulmonary disease, pancreatic insufficiency and malnutrition, recurrent sinusitis and bronchitis, and male infertility. Pulmonary disease is the major cause of morbidity and mortality in CF. Meconium ileus occurs at birth in 15%-20% of newborns with CF. More than 95% of males with CF are infertile. Congenital absence of the vas deferens (CAVD) is generally identified during evaluation of infertility or as an incidental finding at the time of a surgical procedure. Hypoplasia or aplasia of the vas deferens and seminal vesicles may occur either bilaterally or unilaterally. Testicular development and function and spermatogenesis are usually normal.

Fracture healing is an evolutionarily conserved process that depends on the complex interplay of osteogenic, angiogenic, and inflammatory responses. Impaired bone healing is observed in up to 10 to 15% of patients with fractures and can lead to nonunion, which is the absence of bone healing. Here, we explore a role of neutrophil extracellular traps (NETs) in fracture healing and their association with nonunion. In both mice and humans, skeletal injury triggers rapid but transient NET formation at the fracture site. The combined genetic deletion of enzymes essential for NET clearance, DNase1 and DNase1-like-3, initially favors callus mineralization in the early healing phase. However, sustained NET elevation subsequently leads to impaired bone regeneration and fracture nonunion over the course of healing. Conversely, additional deletion of the NET-generating enzyme Pad4 improves bone regeneration and lowers nonunion rates. Mechanistically, NETs up-regulate cGas-Sting signaling, thereby collapsing the formation of type-H vessels, which couple osteogenesis to angiogenesis in the fracture callus. Pharmacological inhibition of cGas-Sting restored type-H vessels, enhanced bone healing, and prevented nonunion in DNase-deficient but not Pad4-deficient mice. In patients, serum NET markers declined during normal healing but were elevated in nonunion, correlating with excessive NET and STING accumulation in the callus. Therapeutically, the inhibition of NET formation with the Pad4 inhibitor GSK484 or the promotion of NET clearance with dornase alfa (recombinant DNase1) accelerated bone repair and prevented nonunion in preclinical models. These findings identify sustained NETs as a disruptor of fracture healing and a potential target for enhancing bone regeneration.

Pancreaticopleural fistula (PPF) is a rare complication of acute or chronic pancreatitis, resulting from the disruption of the pancreatic duct and abnormal communication between the pancreas and the pleural cavity. Patients often present with respiratory symptoms rather than abdominal complaints, making diagnosis challenging and frequently delayed. We report a case of PPF presenting as a rapidly recurrent right-sided pleural effusion in a patient with recurrent alcohol-related pancreatitis. A 48-year-old man with a history of recurrent alcoholic pancreatitis presented with progressive dyspnea and pleuritic chest pain. Chest radiography demonstrated a moderate-to-large right pleural effusion. Diagnostic thoracentesis yielded 2 L of dark maroon exudative fluid with a markedly elevated amylase level of 70,476 U/L. Drainage was performed in a symptom-guided manner, with the procedure terminated after symptom improvement, and the patient was monitored for re-expansion pulmonary edema. Despite initial symptomatic improvement, the patient developed rapid reaccumulation of effusion within 24 hours, necessitating pigtail chest tube placement. Due to persistent loculated pleural collections and inadequate drainage, intrapleural alteplase and dornase alfa were administered. Magnetic resonance cholangiopancreatography demonstrated a fluid tract extending from the pancreas into the right pleural cavity, raising suspicion for a PPF. Endoscopic retrograde cholangiopancreatography revealed chronic pancreatitis with obstructing pancreatic duct stones and a ductal defect. Complete stone extraction, pancreatic sphincterotomy, and pancreatic duct stent placement were successfully performed. The patient experienced complete resolution of the pleural effusion, with no recurrence following stent removal. This case highlights the importance of considering PPF in patients with recurrent pleural effusions and a history of pancreatitis, particularly when pleural fluid amylase levels are markedly elevated. Early recognition and endoscopic intervention can facilitate definitive treatment, prevent recurrent hospitalizations, and avoid repeated invasive pleural procedures.

Heterogenicity of efficacy of elexacaftor-tezacaftor-ivacaftor (ETI) therapy in the real world in younger children (6-11 years old) is not known.

The mechanism of COVID-19-associated acute kidney injury (AKI) remains incompletely understood. This study aimed to investigate the regulatory role of the C5a-C5aR1 axis in neutrophil extracellular trap (NET) formation in SARS-CoV-2 nucleocapsid (N) protein-induced AKI. An AKI mouse model with kidney-specific N protein expression was established using ultrasound-microbubble-mediated technology, and interventions with the C5aR1 inhibitor DF2593A or DNase I (Pulmozyme) were administered to detect renal neutrophil infiltration, NET deposition, C5a-C5aR1 expression, and renal function indices. The results showed that N protein expression significantly induced neutrophil infiltration and NET formation, accompanied by elevated serum C5a and upregulated C5aR1. Inhibition of C5aR1 or degradation of NETs effectively attenuated renal tubular injury and decreased serum creatinine, blood urea nitrogen, and kidney injury molecule-1 (KIM-1) levels. In conclusion, activation of the C5a-C5aR1 axis contributes to N protein-mediated AKI by driving NET formation, and targeting this axis may provide a potential therapeutic strategy for COVID-19-associated renal injury.

Muco-obstructive lung diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis, are characterized by the accumulation of highly viscoelastic mucus that compromises mucociliary clearance and fosters infection and inflammation. Mucoactive therapy, encompassing both true mucolytics and non-cleaving agents, seeks to restore airway patency by altering mucus structure, hydration, and transport properties, yet its clinical impact remains variable. This narrative review provides a critical reappraisal of the pharmacological actions and therapeutic outcomes of the main mucolytic agents: N-acetylcysteine (NAC), erdosteine, carbocisteine, bromhexine, ambroxol, and dornase alfa. Beyond their classical role in reducing mucus viscosity, these drugs exhibit pleiotropic effects, including antioxidant, anti-inflammatory, and immunomodulatory activities. Specifically, for thiol-based compounds, the action consists of breaking the disulfide bonds that stabilize the mucin network; for carbocisteine, it lies in modulating mucin glycosylation and chloride transport. Ambroxol and bromhexine act by stimulating surfactant secretion and enhancing mucociliary clearance. Finally, dornase alfa exerts an enzymatic effect on extracellular DNA, a key contributor to the tenacity of mucus in cystic fibrosis. Clinical evidence indicates that NAC and erdosteine can reduce exacerbation rates in COPD, carbocisteine shows benefit with prolonged administration, and dornase alfa remains a cornerstone in CF management. However, therapeutic efficacy is constrained by heterogeneous mucus composition, pharmacokinetic limitations, and disease-specific variability. A key interpretative message is that clinical benefit appears greatest when the dominant biophysical determinant of mucus pathology is specifically targeted, supporting a transition from broad disease-label prescribing to mechanism-informed, phenotype-aware mucolytic therapy. Emerging strategies, such as agents targeting mucin-DNA interactions and advanced inhalation delivery systems, promise improved specificity and durability. By integrating mechanistic insights with clinical data, this review underscores the need for personalized mucolytic therapy and innovative approaches to overcome current challenges in managing muco-obstructive lung diseases.

Pleural infection, including complicated parapneumonic effusion and empyema, remains a major management challenge, especially in patients who are poor surgical candidates. The Multicenter Intrapleural Sepsis Trial 2 (MIST-2) supports a six-dose regimen of intrapleural tissue plasminogen activator (tPA) plus dornase alfa (DNase), but the optimal duration of therapy in patients with persistent loculations remains uncertain. We describe a 62-year-old man with morbid obesity, New York Heart Association class III diastolic heart failure, and poorly controlled type 2 diabetes mellitus who presented with a complex, loculated left-sided empyema caused by Gemella sanguinis and Escherichia coli. Because of prohibitive operative risk, he was not considered a candidate for video-assisted thoracoscopic surgery. After incomplete improvement following the standard six-dose regimen, characterized by persistent fever, persistently elevated inflammatory markers, and residual loculations on repeat imaging, intrapleural therapy was extended for an additional six doses, for a total of 12 doses over six days. The patient had marked clinical and radiographic improvement, complete lung re-expansion, and no bleeding complications. This case suggests that, in carefully selected high-risk patients with persistent loculated empyema and no surgical option, extended intrapleural tPA-DNase therapy may be a feasible individualized strategy beyond the fixed MIST-2 protocol.

After musculoskeletal injury, a considerable proportion of patients develop heterotopic ossification (HO), the formation of bone at ectopic sites. Traumatic HO is a disabling condition, potentially resulting in loss of joint function and compression of neurovascular structures. Available treatment options are often unsuccessful, frequently necessitating surgical resection of HO lesions with a high risk of recurrence. Given that myeloid cells, including neutrophils and macrophages, are among the first cell types to infiltrate injured tissue, the present study explored the relationship of extracellular traps (ETs) with HO formation in humans and mice. Human HO sample analysis revealed the presence of different stages of ETosis, which are clinically associated with increased ET concentrations in the blood. Experimentally, genetic impairment of ET resolution through combined DNase1 and DNase1l3 deficiency led to increased traumatic HO in mice, whereas HO was strongly attenuated by additional deletion of the ET generator Padi4. Neutrophil depletion impaired local ET formation, reduced HO formation, and blunted genotype-specific differences in HO outcome. In osteogenic precursors, ETs promoted matrix mineralization, and inhibition of ETosis or degradation of cell-free DNA, a major ET component, resulted in reduced osteogenesis. Pharmacological facilitation of ET clearance by dornase alfa, a US Food and Drug Administration-approved recombinant DNase1, or inhibition of ETs by the PADI4 inhibitor GSK484, resulted in inhibition of traumatic HO formation in mice without adversely affecting systemic bone remodeling. Together, our clinical and experimental findings demonstrate that traumatic HO is mediated by targetable neutrophil-dependent mechanisms, with altered ET formation contributing to these effects.

Mucins are highly glycosylated proteins that form the structural basis of mucus and represent a key component of innate immunity at mucosal surfaces, particularly in the respiratory tract. Beyond their mechanical barrier function, mucins actively participate in pathogen trapping, regulation of mucociliary clearance, modulation of inflammatory responses, and maintenance of epithelial homeostasis. Dysregulation of mucin synthesis, composition, or transport contributes to mucus hypersecretion, impaired airway clearance, and chronic inflammation in respiratory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. This review summarizes current insights into mucin biology, including their biosynthesis, structure, classification, and regulation, with emphasis on the gel-forming mucins MUC5AC and MUC5B. The role of mucins in mechanical protection, host-pathogen interactions, control of inflammation, and coordination of innate immune responses is reviewed. Attention is given to the interplay between mucins, immune cells, and microbial communities in maintaining airway barrier integrity. The article further examines mucoactive therapeutic strategies aimed at restoring mucus barrier function. Expectorants, mucolytics, mucoregulators, and mucokinetic agents are reviewed with respect to their mechanisms of action and clinical relevance. Established drugs, including N-acetylcysteine, carbocysteine, dornase alfa, ambroxol, and hypertonic solutions, are considered alongside emerging molecular targets such as NF-κB-dependent regulation of mucin expression, calcium-activated chloride channels, MARCKS-mediated mucin exocytosis, purinergic signaling pathways, and NO/cGMP signaling. Non-pharmacological approaches, including airway clearance techniques and respiratory rehabilitation, are covered concisely. Conclusions: Overall, this review highlights mucins as dynamic regulators of innate immunity and underscores the need for mechanism-based, personalized mucoactive therapies to improve outcomes in chronic inflammatory airway diseases.

BackgroundFlexible bronchoscopy (FB) has become an essential diagnostic and therapeutic tool in pediatric intensive care units (PICUs). Despite increasing adoption, comprehensive data on FB's current use, clinical impact and safety in critically ill children, particularly those supported by extracorporeal membrane oxygenation (ECMO), remain limited. We aimed to describe the utilization, findings, microbiological yield and complications of FB in critically ill pediatric patients, including its diagnostic and therapeutic applications and associated physiologic effects.MethodsThis retrospective cohort study included all children aged 0-18 years who underwent FB in a quaternary PICU between January 2019 and December 2024. Data were abstracted from the electronic medical record and analyzed descriptively. Physiologic variables before and after bronchoscopy were compared using paired differences (Δ = post - pre).ResultsA total of 179 patients underwent 246 bronchoscopies. The median age was 61 months (IQR 17-172), and the median time from PICU admission to bronchoscopy was 4 days (IQR 1-11). All patients were mechanically ventilated, and 26% were supported with ECMO. The most frequent indications were evaluation of infection (30.3%), focal imaging abnormalities (25.0%), and surveillance bronchoscopy (15.4%). Increased airway secretions were observed in 50% of procedures. Airway plug removal (22.8%), bronchoalveolar lavage (20.7%), and Dornase alfa instillation (7.7%) were the most common interventions. Multiple findings and interventions often occurred during a single procedure. Concordance between bronchoscopic and non-bronchoscopic lavage cultures was moderate, with highest agreement for Pseudomonas aeruginosa (67%) and Candida (100%). Complications were infrequent: minor bleeding (4.9%) and transient desaturation (4.5%) were most common; no pneumothorax or mortality occurred. Physiologic parameters showed minimal change post-procedure.ConclusionsFlexible bronchoscopy is a safe and versatile diagnostic and therapeutic procedure in the PICU, including among ECMO-supported patients. The stable physiologic profile and low complication rate support its continued integration into multidisciplinary critical care practice.

This paper is part of a larger clinical practice guideline on the diagnosis and management of parapneumonic effusion and empyema in children, developed by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. In this report, the panel provides recommendations for intrapleural fibrinolysis with tissue plasminogen activator (tPA) alone over tPA and dornase alfa (DNase) in children (3 months to 18 years) with complicated parapneumonic effusion and empyema. The panel's recommendations are based upon evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.