Immuno-proteomic profiling reveals aberrant immune cell regulation in the airways of individuals with ongoing post-COVID-19 respiratory disease.

Some patients hospitalized with acute COVID-19 suffer respiratory symptoms that persist for many months. We delineated the immune-proteomic landscape in the airways and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with an elevated concentration of proteins associated with apoptosis, tissue repair, and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. A one-year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to the ongoing activation of cytotoxic T cells.

Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa.

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom's national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wild-type LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof of concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.

Epithelial senescence in idiopathic pulmonary fibrosis is propagated by small extracellular vesicles.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that affects 3 million people worldwide. Senescence and small extracellular vesicles (sEVs) have been implicated in the pathogenesis of IPF, although how sEVs promote disease remains unclear. Here, we profile sEVs from bronchial epithelial cells and determine small RNA (smRNA) content. METHODS: Conditioned media was collected and sEVs were isolated from normal human bronchial epithelial cells (NHBEs) and IPF-diseased human bronchial epithelial cells (DHBEs). RESULTS: Increased sEV release from DHBEs compared to NHBEs (n = 4; p < 0.05) was detected by nanoparticle tracking analysis. NHBEs co-cultured with DHBE-derived sEVs for 72 h expressed higher levels of SA-ß-Gal and γH2AX protein, p16 and p21 RNA and increased secretion of IL6 and IL8 proteins (all n = 6-8; p < 0.05). sEVs were also co-cultured with healthy air-liquid interface (ALI) cultures and similar results were observed, with increases in p21 and p16 gene expression and IL6 and IL8 (basal and apical) secretion (n = 6; p < 0.05). Transepithelial electrical resistance (TEER) measurements, a reflection of epithelial barrier integrity, were decreased upon the addition of DHBE-derived sEVs (n = 6; p < 0.05). smRNA-sequencing identified nineteen significantly differentially expressed miRNA in DHBE-derived sEVs compared to NHBE-derived sEVs, with candidate miRNAs validated by qPCR (all n = 5; p < 0.05). Four of these miRNAs were upregulated in NHBEs co-cultured with DHBE-derived sEVs and three in healthy ALI cultures co-cultured with DHBE-derived sEVs (n = 3-4; p < 0.05). CONCLUSIONS: This data demonstrates that DHBE-derived sEVs transfer senescence to neighbouring healthy cells, promoting the disease state in IPF.

Facial deformation following treatment for pediatric head and neck rhabdomyosarcoma; the difference between treatment modalities. Results of a trans-Atlantic, multicenter cross-sectional cohort study.

BACKGROUND: The four different local therapy strategies used for head and neck rhabdomyosarcoma (HNRMS) include proton therapy (PT), photon therapy (RT), surgery with radiotherapy (Paris-method), and surgery with brachytherapy (AMORE). Local control and survival is comparable; however, the impact of these different treatments on facial deformation is still poorly understood. This study aims to quantify facial deformation and investigates the differences in facial deformation between treatment modalities. METHODS: Across four European and North American institutions, HNRMS survivors treated between 1990 and 2017, more than 2 years post treatment, had a 3D photograph taken. Using dense surface modeling, we computed facial signatures for each survivor to show facial deformation relative to 35 age-sex-ethnicity-matched controls. Additionally, we computed individual facial asymmetry. FINDINGS: A total of 173 HNRMS survivors were included, survivors showed significantly reduced facial growth (p < .001) compared to healthy controls. Partitioned by tumor site, there was reduced facial growth in survivors with nonparameningeal primaries (p = .002), and parameningeal primaries (p ≤.001), but not for orbital primaries (p = .080) All patients were significantly more asymmetric than healthy controls, independent of treatment modality (p ≤ .001). There was significantly more facial deformation in orbital patients when comparing RT to AMORE (p = .046). In survivors with a parameningeal tumor, there was significantly less facial deformation in PT when compared to RT (p = .009) and Paris-method (p = .007). INTERPRETATION: When selecting optimal treatment, musculoskeletal facial outcomes are an expected difference between treatment options. These anticipated differences are currently based on clinicians' bias, expertise, and experience. These data supplement clinician judgment with an objective analysis highlighting the impact of patient age and tumor site between existing treatment options.

Social tipping dynamics for stabilizing Earth's climate by 2050.

Safely achieving the goals of the Paris Climate Agreement requires a worldwide transformation to carbon-neutral societies within the next 30 y. Accelerated technological progress and policy implementations are required to deliver emissions reductions at rates sufficiently fast to avoid crossing dangerous tipping points in the Earth's climate system. Here, we discuss and evaluate the potential of social tipping interventions (STIs) that can activate contagious processes of rapidly spreading technologies, behaviors, social norms, and structural reorganization within their functional domains that we refer to as social tipping elements (STEs). STEs are subdomains of the planetary socioeconomic system where the required disruptive change may take place and lead to a sufficiently fast reduction in anthropogenic greenhouse gas emissions. The results are based on online expert elicitation, a subsequent expert workshop, and a literature review. The STIs that could trigger the tipping of STE subsystems include 1) removing fossil-fuel subsidies and incentivizing decentralized energy generation (STE1, energy production and storage systems), 2) building carbon-neutral cities (STE2, human settlements), 3) divesting from assets linked to fossil fuels (STE3, financial markets), 4) revealing the moral implications of fossil fuels (STE4, norms and value systems), 5) strengthening climate education and engagement (STE5, education system), and 6) disclosing information on greenhouse gas emissions (STE6, information feedbacks). Our research reveals important areas of focus for larger-scale empirical and modeling efforts to better understand the potentials of harnessing social tipping dynamics for climate change mitigation.

Lung cancer screening provides an opportunity for early diagnosis and treatment of interstitial lung disease.

Interstitial lung abnormalities (ILA) can be incidentally detected in patients undergoing low-dose CT screening for lung cancer. In this retrospective study, we explore the downstream impact of ILA detection on interstitial lung disease (ILD) diagnosis and treatment. Using a targeted approach in a lung cancer screening programme, the rate of de novo ILD diagnosis was 1.5%. The extent of abnormality on CT and severity of lung function impairment, but not symptoms were the most important factors in differentiating ILA from ILD. Disease modifying therapies were commenced in 39% of ILD cases, the majority being antifibrotic therapy for idiopathic pulmonary fibrosis.

DNA Methylome Alterations Are Associated with Airway Macrophage Differentiation and Phenotype during Lung Fibrosis.

Rationale: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge about the epigenetics of AMs in IPF is limited. Objectives: To assess the role of epigenetic regulation of AMs during lung fibrosis. Methods: We undertook DNA methylation (DNAm) profiling by using Illumina EPIC (850k) arrays in sorted AMs from healthy donors (n = 14) and donors with IPF (n = 30). Cell-type deconvolution was performed by using reference myeloid-cell DNA methylomes. Measurements and Main Results: Our analysis revealed that epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm "clock" analysis indicated that epigenetic alterations in IPF AMs were not associated with accelerated aging. In differential DNAm analysis, we identified numerous differentially methylated positions (n = 11) and differentially methylated regions (n = 49) between healthy and IPF AMs, respectively. Differentially methylated positions and differentially methylated regions encompassed genes involved in lipid (LPCAT1 [lysophosphatidylcholine acyltransferase 1]) and glucose (PFKFB3 [6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3]) metabolism, and importantly, the DNAm status was associated with disease severity in IPF. Conclusions: Collectively, our data identify that changes in the epigenome are associated with the development and function of AMs in the IPF lung.

The Respiratory Microbiome in Chronic Hypersensitivity Pneumonitis Is Distinct from That of Idiopathic Pulmonary Fibrosis.

Rationale: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises after repeated exposure and sensitization to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease, but, to date, no study has investigated the composition of microbial communities in the lower airways in CHP.Objectives: To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects.Methods: We prospectively recruited individuals with a CHP diagnosis (n = 110), individuals with an IPF diagnosis (n = 45), and control subjects (n = 28). Subjects underwent BAL and bacterial DNA was isolated, quantified by quantitative PCR and the 16S ribosomal RNA gene was sequenced to characterize the bacterial communities in the lower airways.Measurements and Main Results: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both subjects with IPF and subjects with CHP included Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. However, in IPF, Firmicutes dominated, whereas the percentage of reads assigned to Proteobacteria in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the Staphylococcus burden was increased in CHP, and Actinomyces and Veillonella burdens were increased in IPF. The lower airway bacterial burden in subjects with CHP was higher than that in control subjects but lower than that of those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP.Conclusions: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF, and, notably, the bacterial burden in individuals with CHP fails to predict survival.

Magnetic resonance features and cranial nerve involvement in pediatric head and neck rhabdomyosarcomas.

PURPOSE: Rhabdomyosarcoma (RMS) is a malignant tumor frequent in children. The frequency and characteristics of cranial nerve involvement in pediatric head and neck (H&N) RMS have been scarcely reported. The aim of this study is to review a large cohort of pediatric head and neck RMS with an emphasis on cranial nerve involvement. METHODS: We retrospectively reviewed H&N RMS cases from 3 tertiary hospitals over a 10-year period. Cranial nerve involvement was defined as radiologically apparent tumor extension along a nerve and/or the presence of secondary signs. Scans were reviewed by two pediatric neuroradiologists, blinded to clinical data. RESULTS: A total of 52 patients met the inclusion criteria. Histologically, 39/52 were embryonal RMS, while 13/52 were alveolar RMS. Regional lymph nodes metastases were present in 19.2%. Cranial nerve involvement was present in 36.5%. Nerves were mainly involved as a direct extension of the mass through skull base foramina or after invasion of cavernous sinus, Meckel's cave, orbital apex, or stylomastoid foramen. CONCLUSION: Cranial nerve involvement is frequent in pediatric head and neck RMS and occurs secondary to "geographic" invasion due to direct extension through skull base foramina or cavernous sinus. These tumors never showed distant perineural metastatic disease as is seen in cases of adult head and neck carcinomas. This implies a different biological interaction between the nerves and these tumors in comparison to adult H&N tumors.

A persistent craniopharyngeal canal with recurrent bacterial meningitis: case report and literature review.

BACKGROUND: A persistent craniopharyngeal canal (PCC) is a rare but treatable anatomical abnormality that causes recurrent meningitis and should be considered as a differential diagnosis. CASE REPORT: We report a case of an 8-year-old boy who presented with recurrent meningitis associated to his PCC. Surgical repair was performed, and no further episodes occurred.

The Transferrin Receptor CD71 Delineates Functionally Distinct Airway Macrophage Subsets during Idiopathic Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defense of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor 1 (CD71)-expressing AMs in IPF is not known. Objectives: To assess the role of CD71-expressing AMs in the IPF lung. Methods: We used multiparametric flow cytometry, gene expression analysis, and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing or lacking CD71 in the BAL of patients with IPF and of healthy control subjects. Measurements and Main Results: There was a distinct increase in proportions of AMs lacking CD71 in patients with IPF compared with healthy control subjects. Concentrations of BAL transferrin were enhanced in IPF-BAL, and furthermore, CD71- AMs had an impaired ability to sequester transferrin. CD71+ and CD71- AMs were phenotypically, functionally, and transcriptionally distinct, with CD71- AMs characterized by reduced expression of markers of macrophage maturity, impaired phagocytosis, and enhanced expression of profibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target. Conclusions: Taken together, these data highlight how CD71 delineates AM subsets that play distinct roles in IPF and furthermore show that CD71- AMs may be an important pathogenic component of fibrotic lung disease.

Mapping Adolescents' Sense of Place and Perceptions of Change in an Urban-Rural Transition Area.

Landscapes are changing, with rural areas becoming increasingly urbanized. Children and adolescents are underrepresented in the sense-of-place literature. Our study aimed to understand how adolescent residents of a rural-urban transition area perceive and value their urbanizing landscape by examining sense of place and perceptions of landscape change. A Public Participation GIS approach, accompanied by a questionnaire survey, was applied to elicit responses from a sample of 747 students aged 12-18 in Colmenar Viejo, Madrid (Spain). Respondents' sense of "self-in-place" or home range was small, around 1 km, although valued places were identified up to around 17 km away, and occasionally further afield. Most responses were associated with urban land, with clear difference between the urban core, strongly associated with emotions, and the suburbs, with activities. Functional locations (i.e. sports facilities) and places which were valued for their social meaning (i.e. shopping malls), could be differentiated. Students were perceptive about change processes in the urban area, but not about those on the peripheral semi-natural land. Younger children were less aware than older children of spaces outside of the town and carried out fewer activities there. Females carried out fewer outdoor activities than male adolescents. In contrast to the adult population, students were more strongly focused on urban areas than on their surrounding rural landscapes. Here, awareness-raising and incentives are needed, particularly those encouraging females into the use of areas beyond the urban land. Our results suggest a lack of meaningful integration between the core city and the periphery, with lessons for urban planners.

Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear. OBJECTIVES: The aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection. METHODS: We measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined. RESULTS: Sputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro. CONCLUSIONS: Airway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic strategies for the prevention or treatment of bacterial infection in patients with COPD.

Is air pollution exposure linked to household income? Spatial analysis of Community Multiscale Air Quality Model results for Madrid.

This study explores the potential correlation between income and exposure to air pollution for the city of Madrid, Spain and its neighboring municipalities. Madrid is a well-known European air pollution hotspot with a high mortality burden attributable to nitrogen dioxide (NO2) and fine particulate matter (PM2.5). Statistical analyses were carried out using electoral district level data on gross household income (GHI), and NO2 and PM2.5 concentrations in air obtained from a mesoscale air quality model for the study area. We applied linear regression, bivariate spatial correlation analysis, spatial autoregression and geographically weighted regression to explore the relationship between contaminants and income. Three different strategies were adopted to harmonize data for analysis. While some strategies suggested a link between income and air pollution, others did not, highlighting the need for multiple different approaches where uncertainty is high. Our findings offer important lessons for future spatial geographical studies of air pollution in cities worldwide. In particular we highlight the limitations of census-scale socio-economic data and the lack of non-model derived high-resolution air quality measurement data for many cities and offers lessons for policy makers on improving the integration of these types of essential public information.

Revisiting the Great Ormond Street Hospital protocol for ward decannulation of children with tracheostomy.

INTRODUCTION: Tracheostomy decannulation is an important and final step in managing patients once the underlying issue requiring a tracheostomy resolves. However, no consensus exists on the optimal method to decannulate a paediatric patient. We revisit the Great Ormond Street Hospital (GOSH) tracheostomy decannulation protocol, a 5-day process involving downsizing the tracheostomy tube, capping, and observation, to evaluate its effectiveness and assess if changes to the protocol are required. METHOD: This is a retrospective study, reviewing patient records between April 2018 and April 2023 from a single quaternary care centre. Data extracted include comorbidities, age at the time of decannulation, duration of tracheostomy, reason for tracheostomy insertion, whether a decannulation attempt was successful or not, and the timings of decannulation failure. RESULTS: 66 patients that met the selection criteria underwent a decannulation trial between April 2018 and April 2023. 32 patients were male, and 34 patients were female. Age at attempted decannulations ranged from 1 year to 18 years, with an average age of 6.1 years. There were a total of 93 attempts at decannulation, with 51 (54.8%) successful attempts, 35 (56.5%) first decannulation attempt successes, and 42 (45.2%) unsuccessful attempts. 17 patients had 2 attempts at decannulation, and 4 patients had 3 or more attempts at decannulation. Of the unsuccessful attempts, patients mostly failed on capping of the tracheostomy tube with 33 failures (35.5%). CONCLUSION: The GOSH protocol achieved similar success rates to comparable protocols. The protocol's multi-step approach provides thorough evaluation and support for patients during the decannulation process, and its success on a complex patient cohort supports its continued use.

Pediatric Congenital Anterior Skull Base Encephaloceles and Surgical Management: A Comparative Review of 22 Patients Treated With Transnasally, Transcranially, or Combined Approach With a Review of the Literature.

BACKGROUND AND OBJECTIVES: Anterior basal encephaloceles are considered a rare entity and are often associated with midline cerebral abnormalities. Those with a large skull base defect and herniation of brain parenchyma in the neonate or young infant present unique challenges for surgical management. METHODS: We analyzed the neurosurgical administrative and operative databases between 1986 and 2022 to determine clinical presentation, operative approach, and outcome of basal encephaloceles. RESULTS: Over the 36-year period, 27 pediatric anterior basal encephaloceles were managed, of which 22 had full documentation and images allowing comprehensive review. Mean age at presentation was 5 years (SD 4.94). The majority were transethmoidal encephaloceles (59%), followed by the transsphenoidal-sphenoethmoidal type (32%). Overall, 91% were managed surgically by a transcranial, endoscopic, or combined approach. Four children required subsequent procedures, predominantly for persistent cerebrospinal fluid leak. No significant differences in proportion of patients requiring interval/revision surgery after initial conservative, endoscopic endonasal, or transcranial surgery was identified. Neither age at surgery nor size of the defect on computed tomography scan was associated with the need for revision surgery. Size of cranial defect was significantly smaller in the endoscopic group (P = .01). There was a historic tendency for younger children with larger defects to have a transcranial approach. With the addition of endoscopic skull base expertise, smaller defects in older children were more recently treated endoscopically. CONCLUSION: Basal encephaloceles are rare and complex lesions and are optimally managed within a skull base multidisciplinary team able to provide multiple approaches. Large skull base defects with brain parenchymal involvement often require a transcranial or combined transcranial-endoscopic approach.

Pedicled pericardial patch in tracheal reconstruction in children - Novel technique to provide vascularized tissue for salvaging difficult airways.

BACKGROUND: Management of large central airway defects are often complex. Children who present with these defects have multiple co-morbidities or have had previous surgeries. Surgical options include various tissue cover for these defects without longer term benefits. Vascularized autologous pericardial patch offers a better solution to these defects by providing vascularity and potential for remodelling in future. METHODS: 41 children (M:F of 24:17) were operated for large trachea-bronchial defects between January 2015 and August 2022. The median age of was 12 months with median weight of 8.9 kg (IQR 3.3 kg-17.7 kg) Causes leading to the central tracheal defect include failed repair of previous trachea-oesophageal fistula (TOF) (n = 21) and acquired fistula due to button battery injury (n = 11). Surgical repair consisted of autologous pedicled pericardial patch repair for the airway defect under cardiopulmonary bypass. RESULTS: There were two operative deaths related to extensive sepsis and necrosis of reconstructed trachea. Four children had further reoperation with additional patch. Bronchoscopy was used as surveillance in all these children, with use of airway stents (biodegradable stent) in 9 children. The median ventilation time was 8 days, with tracheostomy being needed in 5 for long term support. CONCLUSIONS: Autologous pericardial patch is a versatile technique and can be used to salvage large tracheal defects when other method have failed or not feasible. Tracheomalacia at the site of repair could be managed with biodegradable stents. Vascularity and ciliary function of the patch still needs to be evaluated.

Open and Thoracoscopic Aortopexy for Airway Malacia in Children: 15 Year Single Centre Experience.

OBJECTIVES: The objective was to report and analyse the characteristics and results of open aortopexy and thoracoscopic aortopexy for the treatment of airway malacia in a paediatric population. METHODS: We report a retrospective consecutive case series of paediatric patients undergoing aortopexy for the treatment of airway malacia at a quaternary referral centre between December 2006 and January 2021. Outcome measures included days to extubation, continued need for non-invasive ventilation, further intervention in the form of tracheostomy and death. RESULTS: 169 patients underwent aortopexy: 147 had open procedures (135 via median/limited median sternotomy and 12 thoracotomy) and 22 thoracoscopic. Mean follow up was 8.46 yrs (range 1-20 yrs). Most common site of airway malacia was the trachea (n = 106, 62.7 %), and 48 (28.4 %) had additional involvement at the bronchi with tracheobronchomalacia (TBM). 15 (8.9 %) had bronchomalacia (BM) only. Incidence of bronchial disease was lower in the thoracoscopic than open group (13.6 % vs 40.82 %; p < 0.0001). Mean time to extubation was 1.45 days, 2.59 days, 5.23 days in tracheomalacia, TBM and BM groups, respectively (p = 0.0047). Mean time to extubation was 1.35 days, 2 days, 3.67 days, and 5 days in patients with external vascular compression, TOF/OA, primary airway malacia, and laryngeal reconstruction, respectively (p = 0.0002). There were 21 deaths across the cohort, and all were in the open group. 71.4 % (n = 15) had bronchial involvement of their airway malacia. CONCLUSIONS: Open and thoracoscopic aortopexy are effective treatments for airway malacia in children. We have identified that involvement of the bronchi is a risk factor for adverse outcomes, and the optimum treatment for this patient cohort is still debatable. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Retrospective Study.

Mast cell activation disrupts interactions between endothelial cells and pericytes during early life allergic asthma.

Allergic asthma generally starts during early life and is linked to substantial tissue remodeling and lung dysfunction. Although angiogenesis is a feature of the disrupted airway, the impact of allergic asthma on the pulmonary microcirculation during early life is unknown. Here, using quantitative imaging in precision-cut lung slices (PCLSs), we report that exposure of neonatal mice to house dust mite (HDM) extract disrupts endothelial cell/pericyte interactions in adventitial areas. Central to the blood vessel structure, the loss of pericyte coverage was driven by mast cell (MC) proteases, such as tryptase, that can induce pericyte retraction and loss of the critical adhesion molecule N-cadherin. Furthermore, spatial transcriptomics of pediatric asthmatic endobronchial biopsies suggests intense vascular stress and remodeling linked with increased expression of MC activation pathways in regions enriched in blood vessels. These data provide previously unappreciated insights into the pathophysiology of allergic asthma with potential long-term vascular defects.