Multilevel Airway Obstruction Phenotypes in Adult OSA.

Objective: To describe multilevel phenotypes of airway obstruction identified on drug-induced sleep endoscopy (DISE) in adults. Study Design: Retrospective chart review. Setting: Tertiary care center. Methods: Video recordings of DISE on adult patients were retrospectively scored. A cross-correlation matrix was created to detect significant correlations between DISE findings at anatomical subsites. Three multilevel phenotypes resulted from the matrix: complete collapse at the tongue base with complete collapse at the epiglottis (T2-E2), complete circumferential obstruction at the velum with complete lateral pharyngeal wall collapse at the oropharynx (V2C-O2LPW), and incomplete collapse at the velum with complete collapse due to tonsillar hypertrophy (V0/1-O2T). The mean difference (MD) and 95% confidence interval (CI) were calculated for demographic and polysomnogram metrics of each phenotype compared to all other subjects. Results: Phenotype 1 (T2-E2) (n = 88) had older ages (MD 5.784 years, CI [1.992, 9.576]), lower body mass index (BMI) (MD -1.666 kg/m2, CI [02.570, -0.762]), and smaller neck circumferences (MD -0.448 in., CI [-9.14, -0.009]) than the other phenotypes. Phenotype 2 (V2C-O2LPW) (n = 25) had higher BMIs (MD 2.813 kg/m2, CI [1.362, 4.263]), higher neck circumference (MD 0.714 in., CI [0.004, 1.424]), and higher apnea-hypopnea index (MD 8.252, CI [0.463, 16.041]). Phenotype 3 (V0/1-O2T) (n = 20) had younger ages (MD -17.697, CI [-25.215, -11.179]). Conclusion: Three distinct multilevel phenotypes of obstruction were identified on DISE, suggesting different anatomic subsites collapse in a nonrandom pattern. The phenotypes appear to represent distinct patient groups and their identification may have implications in terms of pathophysiology and treatment modalities.

Sleep Endoscopy Patterns in Six Adults With Trisomy 21 and Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is prevalent amongst individuals with Trisomy 21 (T21). This case series describes the results of drug-induced sleep endoscopy of six adult patients with OSA and T21 and compares the patterns of collapse to those observed in adults without T21. Predominantly hypopharyngeal airway collapse was found in four of the six (66.7%) subjects with T21, a much higher proportion than in the general population. This finding may implicate anatomic differences underlying the increased prevalence of OSA in individuals with T21 and may have treatment implications. Laryngoscope, 132:485-487, 2022.

Patterns of Obstruction on DISE in Adults With Obstructive Sleep Apnea Change With BMI.

OBJECTIVES: We describe drug-induced sleep endoscopy (DISE) obstruction patterns in adults with obstructive sleep apnea (OSA) based on body mass index (BMI). We also evaluate subgroups of patients with clinically significant obstruction patterns at the velopharynx and oropharynx. STUDY DESIGN: Retrospective chart review. METHODS: Single-institution, retrospective chart review of adults with OSA who underwent DISE with dexmedetomidine sedation from 2016 to 2018. Endoscopic findings were graded using VOTE (Velum, Oropharynx, Tongue base, Epiglottis) classification. Oropharyngeal obstruction was additionally graded with the modifier T when due to palatine tonsil tissue. Findings in patients who had BMI < 25, 25 ≤ BMI < 30, and BMI ≥ 30 were compared. RESULTS: One hundred and eleven patients (1 underweight, 23 normal weight, 56 overweight, and 31 obese) were reviewed. Patients with lower BMI were more likely to have more severe obstruction at the level of the tongue base (χ2 = 11.52, P = .021) and epiglottis (χ 2 = 10.56, P = .032). Conversely, patients with higher BMI were more likely to have complete concentric (grade 2C) velum obstruction (χ 2 = 16.04, P < .001) and more severe oropharyngeal obstruction (χ 2 = 9.65, P = .046). Patients with grade 2 oropharyngeal obstruction without tonsil obstruction had more severe concurrent velum obstruction compared to subjects with grade 2 T oropharyngeal obstruction (P = .009). CONCLUSION: In adults with OSA, BMI categories have significantly distinct obstruction patterns at all airway levels on DISE, and there appear to be distinct subgroups associated with certain velum and oropharynx collapse patterns. These findings may have important implications for positive airway pressure-alternative treatment. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:224-229, 2021.

Drug-induced sleep endoscopy findings in surgically-naïve obese vs non-obese children.

OBJECTIVE: To determine if drug-induced sleep endoscopy (DISE) findings are different in obese versus non-obese pediatric patients with obstructive sleep apnea (OSA) or sleep-disordered breathing (SDB). METHODS: Prospective, observational cohort study from June 2017 to June 2018 at a tertiary academic pediatric medical center that included surgically-naïve children ages 2-12 with diagnoses of OSA or sleep-disordered breathing. Subjects with a known diagnosis of craniofacial syndromes, genetic disorders, prior adenoidectomy or tonsillectomy, or chronic tonsillitis as the indication for surgery were excluded. Two groups were assessed for patterns of obstruction based on DISE videos at each anatomic airway level using a previously published DISE scoring system. The groups included obese subjects (BMI ≥ 95th percentile) and non-obese controls (BMI <85th percentile). Each video was graded by two blinded, fellowship-trained Pediatric Otolaryngologists. RESULTS: Fifty-one patients were included, 26 non-obese and 25 obese. Based on anatomic airway level, there was no statistically significant difference in airway obstruction at the velum (p = 0.134), adenoid (p = 0.592), lateral pharyngeal walls (p = 0.867), tongue base (p = 0.977), or supraglottis (p = 0.428) between obese and non-obese children. CONCLUSION: Our prospective study did not associate severity of obstruction with obesity status based on anatomic airway levels. Further studies are needed to elucidate the etiology of the high rate of persistent obstructive sleep apnea in obese children.

Short interfering RNA confers intracellular antiviral immunity in human cells.

Gene silencing mediated by double-stranded RNA (dsRNA) is a sequence-specific, highly conserved mechanism in eukaryotes. In plants, it serves as an antiviral defence mechanism. Animal cells also possess this machinery but its specific function is unclear. Here we demonstrate that dsRNA can effectively protect human cells against infection by a rapidly replicating and highly cytolytic RNA virus. Pre-treatment of human and mouse cells with double-stranded, short interfering RNAs (siRNAs) to the poliovirus genome markedly reduces the titre of virus progeny and promotes clearance of the virus from most of the infected cells. The antiviral effect is sequence-specific and is not attributable to either classical antisense mechanisms or to interferon and the interferon response effectors protein kinase R (PKR) and RNaseL. Protection is the result of direct targeting of the viral genome by siRNA, as sequence analysis of escape virus (resistant to siRNAs) reveals one nucleotide substitution in the middle of the targeted sequence. Thus, siRNAs elicit specific intracellular antiviral resistance that may provide a therapeutic strategy against human viruses.

Manganese-dependent polioviruses caused by mutations within the viral polymerase.

Viral RNA-dependent RNA polymerases exhibit great sequence diversity. Only six core amino acids are conserved across all polymerases of positive-strand RNA viruses of eukaryotes. While exploring the function of one of these completely conserved residues, asparagine 297 in the prototypic poliovirus polymerase 3D(pol), we identified three viable mutants with noncanonical amino acids at this conserved position. Although asparagine 297 could be replaced by glycine or alanine in these mutants, the viruses exhibited Mn(2+)-dependent RNA replication and viral growth. All known RNA polymerases and replicative polymerases of bacterial, eukaryotic, and viral organisms are thought to be magnesium dependent in vivo, and therefore these mutant polioviruses may represent the first viruses with a requirement for an alternative polymerase cation. These results demonstrate the extreme functional flexibility of viral RNA-dependent RNA polymerases. Furthermore, the finding that strictly conserved residues in the nucleotide binding pocket of the polymerase can be altered in a manner that supports virus production suggests that drugs targeting this region of the enzyme will still be susceptible to the problem of drug-resistant escape mutants.