Computational Fluid Dynamic Modeling Reveals Nonlinear Airway Stress during Trachea Development.

Normative trachea dimensions and aerodynamic information during development was collected to establish clinical benchmarks and showed that airway development seems to outpace respiratory demands. Infants and toddlers' trachea exhibit higher aerodynamic stress that significantly decreases by teenage years. This implies large airway pathology in younger children may have a more substantial clinical impact.

Noninvasive analysis of the sputum transcriptome discriminates clinical phenotypes of asthma.

RATIONALE: The airway transcriptome includes genes that contribute to the pathophysiologic heterogeneity seen in individuals with asthma. OBJECTIVES: We analyzed sputum gene expression for transcriptomic endotypes of asthma (TEA), gene signatures that discriminate phenotypes of disease. METHODS: Gene expression in the sputum and blood of patients with asthma was measured using Affymetrix microarrays. Unsupervised clustering analysis based on pathways from the Kyoto Encyclopedia of Genes and Genomes was used to identify TEA clusters. Logistic regression analysis of matched blood samples defined an expression profile in the circulation to determine the TEA cluster assignment in a cohort of children with asthma to replicate clinical phenotypes. MEASUREMENTS AND MAIN RESULTS: Three TEA clusters were identified. TEA cluster 1 had the most subjects with a history of intubation (P = 0.05), a lower prebronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) compared with the other TEA clusters. TEA cluster 2, the smallest cluster, had the most subjects that were hospitalized for asthma (P = 0.04). TEA cluster 3, the largest cluster, had normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. Evaluation of TEA clusters in children confirmed that TEA clusters 1 and 2 are associated with a history of intubation (P = 5.58 × 10(-6)) and hospitalization (P = 0.01), respectively. CONCLUSIONS: There are common patterns of gene expression in the sputum and blood of children and adults that are associated with near-fatal, severe, and milder asthma.

Comparison of Mechanical Forces used in Open Tracheotomy versus Percutaneous Tracheotomy Techniques.

OBJECTIVE: To understand the etiology of tracheotomy-induced tracheal stenosis by comparing the differences in techniques and mechanical force applied with open tracheotomy (OT) versus percutaneous tracheotomy (PCT) placement. METHODS: This study is an unblinded, experimental, randomized controlled study in an ex-vivo animal model. Simulated tracheostomies were performed on 10 porcine tracheas, 5 via a tracheal window technique (OT) and 5 using the Ciaglia technique (PCT). The applied weight during the simulated tracheostomy and the compression of the trachea were recorded at set times during the procedure. The applied weight during tracheostomy was used to calculate the tissue force in Newtons. Tracheal compression was measured by anterior-posterior distance compression and as percent change. RESULTS: Average forces for scalpel (OT) versus trocar (PCT) were 2.6 N and 12.5 N (p < 0.01), with the dilator (PCT) it was 22.02 N (p < 0.01). The tracheostomy placement with OT required an average force of 10.7 N versus 23.2 N (p < 0.01) with PCT. The average change in AP distance when using the scalpel versus trocar was 21%, and 44% (p < 0.01), with the dilator it was 75% (p < 0.01). The trach placement with OT versus PCT had an average AP distance change of 51% and 83% respectively (p < 0.01). CONCLUSION: This study demonstrated that PCT required more force and caused more tracheal lumen compression when compared to the OT technique. Based on the increased force required for PCT, we suspect there could also be an increased risk for tracheal cartilage trauma. LEVEL OF EVIDENCE: NA Laryngoscope, 134:103-107, 2024.

Dynamic Volumetric Computed Tomography Angiography is an Effective Method to Evaluate Tracheomalacia in Children.

OBJECTIVE: Standard methods to evaluate tracheal pathology in children, including bronchoscopy, may require general anesthesia. Conventional dynamic proximal airway imaging in noncooperative children requires endotracheal intubation and/or medically induced apnea, which may affect airway mechanics and diagnostic performance. We describe a technique for unsedated dynamic volumetric computed tomography angiography (DV-CTA) of the proximal airway and surrounding vasculature in children and evaluate its performance compared to the reference-standard of rigid bronchoscopy. METHODS: Children who had undergone DV-CTA and bronchoscopy in one-year were retrospectively identified. Imaging studies were reviewed by an expert reader blinded to the bronchoscopy findings of primary or secondary tracheomalacia. Airway narrowing, if present, was characterized as static and/or dynamic, with tracheomalacia defined as >50% collapse of the tracheal cross-sectional area in exhalation. Pearson correlation was used for comparison. RESULTS: Over a 19-month period, we identified 32 children (median age 8 months, range 3-14 months) who had undergone DV-CTA and bronchoscopy within a 90-day period of each other. All studies were unsedated and free-breathing. The primary reasons for evaluation included noisy breathing, stridor, and screening for tracheomalacia. There was excellent agreement between DV-CTA and bronchoscopy for diagnosis of tracheomalacia (κ = 0.81, p < 0.001), which improved if children (n = 25) had the studies within 30 days of each other (κ = 0.91, p < 0.001). CTA provided incremental information on severity, and cause of secondary tracheomalacia. CONCLUSION: For most children, DV-CTA requires no sedation or respiratory manipulation and correlates strongly with bronchoscopy for the diagnosis of tracheomalacia. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:410-416, 2023.

Barriers to Pediatric Osseointegrated Bone-Conduction Hearing Devices.

OBJECTIVE: To identify social, demographic, and clinical barriers for implantation with Osseointegrated Bone Conduction Devices (OBCD) in pediatric candidates. STUDY DESIGN: Retrospective cohort study of 94 children who met standard OBCD implantation criteria. SETTING: Tertiary stand-alone children's hospital. MATERIALS AND METHODS: Retrospective chart review comparing demographic (age, race, state of residence, and insurance) and clinical (severity and etiology of hearing loss, medical comorbidities, and early intervention) factors impacting implantation. Members of the existing cohort were then contacted to obtain a better understanding of qualitative factors impacting surgical decision. RESULTS: Of the identified 94 surgical candidates, 47 (50%) underwent OBCD implantation. State of residence significantly impacted implantation rates, with children from the District of Columbia and Virginia being less likely to receive an implant than those from Maryland. Private insurance, race, and ethnicity did not impact rate of implantation (OR 2.8 [95% CI 0.78-10]; 1.34 [95% CI 0.44-3.68]; and 1.0 [95% CI 0.42-2.43], respectively). Children with anotia or microtia and children younger than 10 years old were less likely to have an implant (OR 10.6 (95% CI 1.74-65). Thirty-nine children participated in the qualitative portion. Themes that emerged as reasons to forgo implantation included a child's young age, planned reconstruction for microtia or atresia, and overall device functionality and usage. Thirtyseven children (39%) of the cohort declined surgery and currently wear a nonsurgical bone conduction aid regularly. CONCLUSION: Despite known benefits of implantation, only one-half of children who were candidates underwent OBCD. Unlike cochlear implantation, where insurance status is a major risk factor for implantation delay and underperformance, for OBCD, implantation barriers appear to be more multifactorial and include medical, demographic, and social factors.

Barriers to Decannulation After Double-Stage Laryngotracheal Reconstruction.

OBJECTIVES/HYPOTHESIS: To identify any potential barriers for decannulation in children undergoing double-staged laryngotracheal reconstruction (dsLTR) beyond the severity of disease itself. STUDY DESIGN: Case series with chart review. METHODS: We performed a retrospective chart review from 2008 to 2018 of 41 children who had undergone dsLTR as primary treatment for laryngotracheal stenosis at a stand-alone tertiary children's hospital. We examined the effect of demographic, medical, and surgical factors on successful decannulation and time to decannulation after dsLTR. RESULTS: Of the 41 children meeting inclusion criteria who underwent dsLTR, 34 (82%) were decannulated. Age, gender, race, insurance status, medical comorbidity, and multilevel stenosis did not predict overall decannulation. Insurance status did not impact time to decannulation (P = .13, Log-rank). Factors that increased length of time to decannulation were the use of anterior and posterior cartilage grafts (P = .001, Log-rank), history of pulmonary disease (P = .05, Log rank), history of cardiac disease (P = .017, Log-rank), and race/ethnicity (P = .001 Log-rank). CONCLUSION: In a cohort with a similar decannulation rates to previous dsLTR cohorts, we identified no demographic or medical factors that influenced overall decannulation. We did observe that pulmonary comorbidity, cardiac comorbidity, and race/ethnicity lengthens time to decannulation. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2141-2147, 2021.

Association of Estrogen Receptor Alpha Expression With Survival in Oropharyngeal Cancer Following Chemoradiation Therapy.

BACKGROUND: Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor α (ERα), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC. METHODS: To investigate associations among ERα and demographics, HPV status, and survival, we analyzed ERα mRNA expression of head and neck squamous carcinomas (HNSC) from The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) of pretreatment biopsy specimens from an independent group of 215 OPSC patients subsequently treated with primary chemoradiation (OPSC-CR). Associations among variables were evaluated with Fisher exact tests and logistic regression; associations with survival were evaluated with log-rank tests and Cox proportional hazards regression. RESULTS: Among 515 patients in TCGA, ERα mRNA expression was highest in HPV-positive OPSC. High ERα mRNA expression was associated with improved survival among those receiving chemoradiation (hazard ratio adjusted for HPV status = 0.44, 95% confidence interval = 0.21 to 0.92). In OPSC-CR, ERα was positive by IHC in 51.6% of tumors and was associated with improved overall, disease-specific, progression-free, and relapse-free survival (log-rank tests: P < .001, P < .001, P = .002, P = .003, respectively); statistically significant associations of ERα positivity with improved survival were maintained after adjusting for clinical risk factors including HPV status. CONCLUSION: In two independent cohorts, ERα is a potential biomarker for improved survival that also may represent a therapeutic target in OPSC.

Noninvasive Analysis of the Sputum Transcriptome Discriminates Clinical Phenotypes of Asthma.

INTRODUCTION: It is increasingly recognized that asthma is a heterogeneous disease. Therefore, it is possible that analysis of gene expression in the airway will reveal clinically meaningful transcriptional endotypes of asthma (TEA clusters). METHODS: We measured whole transcriptome gene expression profiles in the sputum and whole blood of 100 individuals with asthma and 12 control subjects using the Affymetrix HuGene ST 1.0 gene arrays. Unsupervised clustering was conducted using pathways from Kyoto Encyclopedia of Genes and Genomes (KEGG). This identified three TEA clusters that were correlated with clinical, physiologic, and inflammatory characteristics of the disease. TEA cluster 1 is a cluster of patients with asthma with a significantly higher rate of intubation (P = 0.05), a lower prebronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) than the other two TEA clusters. TEA cluster 2 has a higher rate of hospitalization for asthma (P = 0.04) and is heterogeneous. TEA cluster 3 is the largest cluster and has normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. TEA cluster 1 had the highest sputum Th2 gene signature (IL-4, -5, and -13) compared with the other clusters. A classifier was developed that predicts TEA cluster assignment using 53 predictive genes in the circulation. The classifier was applied to gene expression data of children from the Asthma Biorepository for Integrative Genomic Exploration (Asthma BRIDGE) consortium cohort and confirmed that TEA clusters 1 and 2 are associated with history of intubation (P = 5.58 × 10(-06)) and hospitalization (P = 0.01), respectively. CONCLUSIONS: Analysis of the sputum transcriptome reveals three TEA clusters with different clinical and physiologic characteristics of disease in children and adults with asthma. This suggests that there are common transcriptomic signatures in the blood in children and adults with asthma that are associated with features of severe asthma.

Metabolic profiling of Helicobacter pylori glycosylation.

Metabolic oligosaccharide engineering was used to profile glycoproteins of the human pathogen Helicobacter pylori.