A single nucleotide polymorphism in an IgA1 protease gene determines Streptococcus pneumoniae adaptation to the middle ear during otitis media.

Factors facilitating the chronicity of otitis media (OM) in children are, to date, not fully understood. An understanding of molecular factors aiding bacterial persistence within the middle ear during OM could reveal pathways required for disease. This study performed a detailed analysis of Streptococcus pneumoniae populations isolated from the nasopharynx and middle ear of one OM case. Isolates were assessed for growth in vitro and infection in a mouse intranasal challenge model. Whole genome sequencing was performed to compare the nasopharyngeal and middle ear isolates. The middle ear isolate displayed a reduced rate of growth and enhanced potential to transit to the middle ear in a murine model. The middle ear population possessed a single nucleotide polymorphism (SNP) in the IgA1 protease gene igA, predicted to render its product non-functional. Allelic exchange mutagenesis of the igA alleles from the genetic variant middle ear and nasopharyngeal isolates was able to reverse the niche-adaptation phenotype in the murine model. These results indicate the potential role of a SNP in the gene encoding the IgA1 protease, in determining S. pneumoniae adaptation to the middle ear during chronic OM. In contrast, a functional IgA1 protease was associated with increased colonisation of the nasopharynx.

Increased Platelet Aggregation in Children and Adolescents with Sleep-disordered Breathing.

Rationale: Sleep-disordered breathing (SDB) is associated with increased vascular resistance in children and adults. Persistent increased vascular resistance damages vascular endothelial cells-a marker of which is increased platelet activation.Objectives: This study compared whole-blood impedance platelet aggregation in children with clinically diagnosed SDB warranting adenotonsillectomy and healthy control subjects.Methods: Thirty children who had SDB warranting intervention clinically diagnosed by experienced pediatric otolaryngologists were recruited from adenotonsillectomy waitlists, and 20 healthy children from the community underwent overnight polysomnography to determine SDB severity (obstructive apnea-hypopnea index). Snoring frequency was collected from parents. In the morning, a fasting blood sample was taken, and whole-blood platelet aggregation was measured.Measurements and Main Results: Children with SDB exhibited increased platelet aggregation to TRAP (thrombin receptor-activating peptide) (children with SDB = 114.8 aggregation units [AU] vs. control subjects = 98.0 AU; P < 0.05) and COL antibody (96.7 vs. 82.2 AU; P < 0.05) and an increased trend in ADP antibody (82.3 vs. 69.2 AU; P < 0.07) but not aspirin dialuminate (82.1 vs. 79.5 AU; P > 0.05). No significant association was observed between either the obstructive apnea-hypopnea index and any aggregation parameter, but parental report of snoring was positively associated with TRAP aggregation (Kendall's τ-c = 0.23; P < 0.05).Conclusions: The finding of increased platelet aggregation is consistent with endothelial damage. This suggests that the profile of cardiovascular changes noted in adults with SDB may also occur in children with SDB.

Partial Adenoidectomy in Patients With Palatal Abnormalities.

BACKGROUND: Velopharyngeal insufficiency is a feared complication of adenoidectomies in patients with palatal abnormalities. Thus, the benefits of adenoidectomy in this population are less understood. The techniques of partial adenoidectomy aim to preserve velopharyngeal closure while sufficiently debulking the nasal airway to ameliorate obstruction and snoring. METHODOLOGY: Systematic review of online databases using a combination of search terms including "cleft palate," "submucosal cleft palate," "short palate," "adenoidectomy," "partial adenoidectomy," "subtotal adenoidectomy," and "powered adenoidectomy." Two independent reviewers assessed the eligibility of each study based on predefined inclusion criteria. RESULTS: From 323 studies identified, 8 were included. All were retrospective case series, except 1 prospective study. Study period ranged from 1.1 to 14 years (median 7.5 years). There were 172 patients with a cleft palate (n = 80), submucous cleft palate (n = 67) or another defined palatal abnormality [short soft palate (n = 14), bifid uvula (n = 4), questionable palatal mobility (n = 4) or incomplete CP (n = 3)] identified. Mean age was 5.5 years and just over half were male (58%). Nearly all patients showed improvement in nasal airway obstruction and snoring. The pooled risk for velopharyngeal insufficiency across all studies was 2 out of 122, which approximates to 1.6% of patients. There were very few complications. CONCLUSION: This is the first systematic review of partial adenoidectomy in patients with palatal abnormalities. Sub-total adenoidectomy in patients with submucosal cleft palate or repaired cleft palate appears to be a safe and efficacious procedure. There is; however, a need for prospective data collection using a standardized technique in large patient series required to properly assess outcomes.

A Prospective Study of the Incidence of Juvenile-Onset Recurrent Respiratory Papillomatosis After Implementation of a National HPV Vaccination Program.

Background: Recurrent respiratory papillomatosis is a rare but morbid disease caused by human papillomavirus (HPV) types 6 and 11. Infection is preventable through HPV vaccination. Following an extensive quadrivalent HPV vaccination program (females 12-26 years in 2007-2009) in Australia, we established a method to monitor incidence and demographics of juvenile-onset recurrent respiratory papillomatosis (JORRP) cases. Methods: The Australian Paediatric Surveillance Unit undertakes surveillance of rare pediatric diseases by contacting practitioners monthly. We enrolled pediatric otorhinolaryngologists and offered HPV typing. We report findings for 5 years to end 2016. Results: The average annual incidence rate was 0.07 per 100000. The largest number of cases was reported in the first year, with decreasing annual frequency thereafter. Rates declined from 0.16 per 100000 in 2012 to 0.02 per 100000 in 2016 (P = .034). Among the 15 incident cases (60% male), no mothers were vaccinated prepregnancy, 20% had maternal history of genital warts, and 60% were first born; 13/15 were born vaginally. Genotyped cases were HPV-6 (n = 4) or HPV-11 (n = 3). Conclusion: To our knowledge, this is the first report internationally documenting decline in JORRP incidence in children following a quadrivalent HPV vaccination program.

Relationship between Vascular Resistance and Sympathetic Nerve Fiber Density in Arterial Vessels in Children With Sleep Disordered Breathing.

BACKGROUND: Sleep disordered breathing in children is associated with increased blood flow velocity and sympathetic overactivity. Sympathetic overactivity results in peripheral vasoconstriction and reduced systemic vascular compliance, which increases blood flow velocity during systole. Augmented blood flow velocity is recognized to promote vascular remodeling. Importantly, increased vascular sympathetic nerve fiber density and innervation in early life plays a key role in the development of early-onset hypertension in animal models. Examination of sympathetic nerve fiber density of the tonsillar arteries in children undergoing adenotonsillectomy for Sleep disordered breathing will address this question in humans. METHODS AND RESULTS: Thirteen children scheduled for adenotonsillectomy to treat sleep disordered breathing underwent pupillometry, polysomnography, flow-mediated dilation, resting brachial artery blood flow velocity (velocity time integral), and platelet aggregation. The dorsal lingual artery (tonsil) was stained and immunofluorescence techniques used to determine sympathetic nerve fiber density. Sympathetic nerve fiber density was correlated with increased resting velocity time integral (r=0.63; P<0.05) and a lower Neuronal Pupillary Index (r=-0.71, P<0.01), as well as a slower mean pupillary constriction velocity (mean, r=-0.64; P<0.05). A faster resting velocity time integral was associated with a slower peak pupillary constriction velocity (r=-0.77; P<0.01) and higher platelet aggregation to collagen antigen (r=0.64; P<0.05). Slower mean and peak pupillary constriction velocity were associated with higher platelet aggregation scores (P<0.05; P<0.01, respectively). CONCLUSIONS: These results indicate that sympathetic activity is associated with change in both the function and structure of systemic vasculature in children with sleep disordered breathing.

Identification of the Bacterial Reservoirs for the Middle Ear Using Phylogenic Analysis.

Importance: The adenoid pad has long been considered a reservoir for bacteria in the pathogenesis of otitis media with effusion (OME). However, bacteria more reminiscent of external auditory canal (EAC) commensals are often demonstrated within middle ear aspirates. Objective: To compare the microbiota of the EAC, the middle ear with OME, and the adenoid pad to further clarify the true source of middle ear bacteria. Design, Setting, and Participants: Middle ear fluid (MEF) aspirates and EAC lavages were collected from 18 children with OME undergoing ventilation tube insertion from June 1, 2014, to August 31, 2015, at Women and Children's Hospital, Adelaide, Australia. Adenoid pad and MEF samples were included from a previous study. Samples were analyzed using sequencing of the 16S ribosomal RNA gene. Previously collected microbiota data from the adenoid pad were collated for analysis. Main Outcome Measures: Mean relative abundance of top bacterial genera for the MEF, EAC, and adenoid pad samples. Results: Eighteen pediatric patients with chronic OME (6 female; 12 male; mean [SD] age, 48 [36] months) were recruited prospectively, with 34 paired MEF and EAC samples. The MEF microbiota (mean relative abundance [SD]) consisted of Alloiococcus otitidis (37.5% [40.0%]), Haemophilus (14.4% [29.1%]), Moraxella (10.0% [26.4%]), Staphylococcus (8.2% [21.9%]), and Streptococcus (3.8% [13.1%]). The mean relative abundance (SD) microbiota of the EAC demonstrated a sparsity of classic otopathogens, including Haemophilus (0.3% [0.8%]), Moraxella (0.3% [0.7%]), and Streptococcus (0.2% [0.6%]), but had a high abundance of Alloiococcus (58.0% [44.1%]), Staphylococcus (20.8% [34.0%]), and Pseudomonas (3.2% [17.1%]). In contrast, based on previously collected data, the microbiota of the adenoid pad showed a high abundance of the classic otopathogens with a sparsity of EAC genera for Alloiococcus (0.1% vs 28.9%, respectively; P < .001), Haemophilus (25.2% vs 18.2%, respectively; P = .002), Staphylococcus (0.2% vs 10.8%, respectively; P = .02), Streptococcus (12.7% vs 4.2%, respectively; P < .001), and Pseudomonas (0 vs 2.1% respectively; P < .001). The microbiota of the MEF collected during 2 consecutive years were similar (Alloiococcus, 22.7% vs 37.5%; Haemophilus, 22.5% vs 14.0%; Staphylococcus, 10.9% vs 10.7%; Moraxella, 5.0% vs 9.7%; Corynebacteria, 6.2% vs 3.1%; Streptococcus, 4.8% vs 3.7%; and Pseudomonas, 1.1% vs 3.0%; P ≥ .05). Conclusions and Relevance: The EAC and the nasopharynx could serve as reservoirs for microbiota of the middle ear. Furthermore, the microbiota of the middle ear with effusion appear to be relatively stable over time and between populations with OME.

Cognition, temperament, and cerebral blood flow velocity in toddlers and preschool children with sleep-disordered breathing or behavioral insomnia of childhood.

BACKGROUND: Cognitive decrements, problematic behaviors, and increased cerebral blood flow velocities (CBFVs) have been reported in children aged 3-7 years with sleep-disordered breathing (SDB). Whether similar impairments exist in younger children or those with behavioral insomnia of childhood (BIC) remains unclear. This study aimed to compare cognition and temperament in children aged 1-5 years with SDB or BIC to healthy control children, and to investigate whether cognitive or behavioral deficits associated with sleep problems are related to changes in CBFV. METHOD: Toddlers and preschool-aged children (12-67 months) who had been referred for the clinical evaluation of SDB (n = 20) or BIC (n = 13) and a comparative sample of non-snoring healthy sleepers (controls; n = 77) were recruited from the community. Children underwent cognitive assessment (Mullen's Scale of Early Learning) and measurement of resting bilateral CBFV in the middle cerebral artery (MCA) using Transcranial Doppler. Parents completed temperament scales (Early Childhood or Childhood Behavior Questionnaire), a sleep problem questionnaire (Pediatric Sleep Problem Survey Instrument) and performed home-based pediatric sleep monitoring (Actigraphy and Sleep Diary). RESULTS: SDB children demonstrated impaired receptive skills, more hyperactive and energetic temperaments, and higher bilateral CBFV than controls and children with BIC. Logistic regression analyses indicated that impaired cognition, temperamental difficulties, and increased CBFV are independently associated with SDB. CONCLUSIONS: During early childhood, problematic temperaments, cognitive deficits, and altered cerebrovascular functioning are associated with SDB but not BIC. CBFV does not appear to mediate these daytime deficits and instead may be an independent outcome of SDB. The findings support the need for an early intervention in pediatric SDB.

The microbiome of otitis media with effusion.

OBJECTIVES/HYPOTHESIS: The adenoid pad has been considered a reservoir for bacteria in the pathogenesis of otitis media with effusion. This study aimed to characterize the middle ear microbiota in children with otitis media with effusion and establish whether a correlation exists between the middle ear and adenoid microbiota. STUDY DESIGN: Prospective, controlled study. METHODS: Middle ear aspirates adenoid pad swabs were collected from 23 children undergoing ventilation tube insertion. Adenoid swabs from patients without ear disease were controls. Samples were analyzed using 16S rRNA sequencing on the Illumina MiSeq platform. RESULTS: Thirty-five middle ear samples were collected. The middle ear effusion microbiota was dominated by Alloiococcus otitidis (23% mean relative abundance), Haemophilus (22%), Moraxella (5%), and Streptococcus (5%). Alloiococcus shared an inverse correlation with Haemophilus (P = .049) and was found in greater relative abundance in unilateral effusion (P = .004). The microbiota of bilateral effusions from the same patient were similar (P < .001). However, the otitis media with effusion microbiota were found to be dissimilar to that of the adenoid (P = .01), whereas the adenoid microbiota of otitis media with effusion and control patients were similar (P > .05) (permutational multivariate analysis of the variance). CONCLUSIONS: Dissimilarities between the local microbiota of the adenoid and the middle ear question the theory that the adenoid pad is a significant reservoir to the middle ear in children with otitis media with effusion. A otitidis had the greatest cumulative relative abundance, particularly in unilateral effusions, and shares an inverse correlation with the relative abundance of Haemophilus. LEVEL OF EVIDENCE: NA Laryngoscope, 126:2844-2851, 2016.

The endoscopic transseptal approach for choanal atresia repair.

BACKGROUND: There are many standard repair options for choanal atresia including puncture, dilatation and drilling of the atretic plate. Most of these techniques involve postoperative stenting, which may promote granulation and scarring, with possible progression to restenosis. This article describes a novel approach for choanal atresia repair without postoperative stenting. METHODS: This article describes our experience with this choanal atresia repair technique utilized in 16 pediatric patients and 1 adult patient across multiple tertiary pediatric and rhinology centers during 2008 through 2015. Seven cases were bilateral and 10 were unilateral. Surgery was performed using an endoscopic transseptal approach with preservation of the mucosa and creation of flaps. No stents or packing was used. The main outcome measures were: response to treatment based on endoscopic examination, need for further revision and incidence of complications. RESULTS: All patients underwent routine postoperative endoscopic inspection of their nasal cavity, postnasal space, and assessment of neochoanal patency. The neochoanae of all patients remained patent to a minimum follow-up duration of 9 months with most patients follow up for 2 years or more. Two neonatal patients required transfusion postoperation from intraoperative bleeding. Two pediatric patients developed postoperative respiratory complications. One patient required revision surgery for nasal vestibule scarring from incision made on the nasal alar to facilitate the initial endoscopic approach. CONCLUSION: This novel endoscopic transseptal repair technique is effective in the management of choanal atresia. Careful fashioning of mucosal flaps and the omission of stenting has resulted in lasting patency of the neochoanae.

Survey on the use of ototopical medications by New Zealand otolaryngologist/head and neck surgeons.

AIM: There is increasing awareness of the potential for ototoxicity with the administration of aminoglycoside eardrops in the presence of a non-intact tympanic membrane, whether that is due to a perforation or due to the presence of a patent ventilating tube. Expert panels in the USA, Canada, UK, and Australia have all advocated the preferential use of non-ototoxic topical antibiotics for the discharging middle ear and/or mastoid cavity. The advent of non-ototoxic fluoroquinolone eardrops provides the first real opportunity to prescribe topical therapy in accordance with such guidelines. METHOD: We surveyed practicing otolaryngology/head and neck surgeons in New Zealand to ascertain their clinical preferences as well as to gauge any impediments to utilising safer medical therapies. RESULTS: The major results of this survey, with a 72% response rate, are presented. Notably, a total of 24 cases of sensorineural hearing loss were reported that may have been caused by the use of topical ototoxic medications. CONCLUSION: Based on our survey results and current evidence available in the broader scientific literature, recommendations are made for the prescription of non-ototoxic medications in at-risk situations. However clinicians may be prevented from following such guidelines by the increased costs of these medications, thus leading to decreased patient compliance. There was widespread support for subsidies to be available for the prescription of non-ototoxic fluoroquinolone eardrops for appropriate indications.

Quality of life outcomes after ventilating tube insertion for otitis media in an Australian population.

OBJECTIVE: To assess the change in quality of life in a group of Australian children with recurrent acute otitis media (AOM) and/or otitis media with effusion (OME) who were treated with ventilating tube (VT) insertion. METHODS: Prospective pre- and post-intervention outcome study at the Women's and Children's Hospital, North Adelaide, South Australia. The Otitis Media 6-item (OM-6) survey was used as a measure of disease-specific quality of life prior to surgery and then again at 6 weeks post-operatively. Any patients who were listed for any additional ear, nose or throat (ENT) procedures at the same time were excluded. RESULTS: Complete responses for both pre- and post-surgery questionnaires were obtained from the parents of 53 patients. The age range was 11 months to 15.4 years (average 5.1 years), and 39.6% (n=21) were suffering from recurrent AOM whilst the remaining 60.4% (n=32) were suffering from OME. Overall ear-related quality of life was found to improve significantly following insertion of ventilating tubes (p<0.001), as was the mean OM-6 score (p<0.001). Furthermore, statistically significant improvements were noted in each individual domain making up the OM-6 survey (physical suffering, hearing loss, speech impairment, emotional distress, activity limitations and caregiver concerns). CONCLUSIONS: The disease-specific quality of life of a group of Australian pediatric patients with otitis media was found to significantly improve following insertion of ventilating tubes as measured by the OM-6 survey. Improvements were found in global ear-related quality of life, in the mean OM-6 score, as well as in all individual domains of the OM-6 survey.

Postoperative pain following coblation tonsillectomy: randomized clinical trial.

BACKGROUND: Tonsillectomy is one of the commonest surgical procedures, with postoperative pain being an important source of morbidity. Coblation (cold ablation) is a new technique for tonsillectomy, promoted by claims of reduced postoperative pain levels. This study was designed to compare postoperative pain after tonsillectomy using coblation and tonsillectomy using the standard dissection techniques. METHODS: Twenty adult patients underwent tonsillectomy, each having one randomly selected tonsil removed by dissection and the other removed by coblation. For each side, subjective pain levels were recorded on a daily basis for 10 postoperative days, using a visual analogue scale. RESULTS: Coblation tonsillectomy was significantly less painful than dissection tonsillectomy on day 1 (P < 0.001), day 2 (P = 0.003) and day 3 (P = 0.018). For all subsequent postoperative days, there was no significant difference in pain levels between the techniques. CONCLUSION: Coblation tonsillectomy causes significantly less pain during the first three postoperative days, when compared with dissection tonsillectomy. No demonstrable benefit was shown on days 4-10. The beneficial effects of coblation on early postoperative pain make it a potentially attractive technique for day-case tonsillectomy in adults with recurrent or chronic tonsillitis.

A blinded, randomized, controlled study on the effect of buffered 0.9% and 3% sodium chloride intranasal sprays on ciliary beat frequency.

BACKGROUND: There are conflicting reports regarding the effect of intranasal saline sprays on the various components of the mucociliary clearance system. This study evaluates the effect of normal saline and hypertonic saline on the ciliary beat frequency (CBF). METHODS: Eight healthy volunteers were randomized to receive 0.9% saline spray to one nostril and 3.0% saline spray to the other. Ciliated cells were collected, and the CBF was calculated using computerized microphotometry. RESULTS: Although neither solution significantly altered the CBF from baseline measurements, there was a significant difference between the CBFs of the two solutions at 5 minutes postadministration (9.1 Hz with 0.9% saline, 10.1 Hz with 3.0% saline, P < .05). This was a transient effect and was not seen when cells were examined at 60 minutes postadministration. CONCLUSION: The administration of hypertonic saline results in a significantly faster CBF 5 minutes after administration. This effect is not seen 60 minutes after administration.

Correlation between preoperative symptom scores, quality-of-life questionnaires, and staging with computed tomography in patients with chronic rhinosinusitis.

BACKGROUND: This study evaluates the correlation between preoperative symptoms, quality-of-life questionnaires (chronic sinusitis survey and 20-Item Sinonasal Outcome Test [SNOT-20]), and staging on computer tomography (CT). It consisted of a prospective cohort study of all consecutive patients undergoing surgery for medically nonresponsive chronic sinusitis, which took place at a tertiary care center. METHODS: Two hundred twenty-one patients completed the Chronic Sinusitis Survey (CSS) questionnaire and the SNOT-20. A visual analog scale (VAS) symptom score was completed also. The average age of the patients was 44.5 years and the male/female ratio was 1.3:1. The symptom scores of all three questionnaires were compared with the Lund-MacKay CT scan score of the sinuses. RESULTS: The median Lund-MacKay CT score was 12 (mean +/- SD, 12.7 +/- 5.7). There was no significant correlation between the SNOT-20 questionnaire and the Lund-MacKay CT score (p = 0.026; p = 0.764) and between the CSS and the Lund-MacKay CT score (p = -0.158; p = 0.058). Furthermore, there was no significant correlation between a single VAS symptom score relating to overall sinonasal symptom severity and the Lund-MacKay CT scan score (p = 0.135; p = 0.121). However, a weak but statistically significant correlation was found between the VAS score based on the sum of five sinonasal symptoms and the Lund-MacKay CT scan score (p = 0.197; p = 0.020). CONCLUSION: The score, based on the sum of five sinonasal VAS symptoms, correlates to the disease severity as measured by the Lund-MacKay CT scan score. The SNOT-20 questionnaire and the CSS symptom score do not correlate to the Lund-MacKay CT scan score, although a correlation was found between the CSS score and the Lund-MacKay CT score in various sub-groups of our patient population.

In vitro and in vivo metabolism of the anti-cancer agent CI-1040, a MEK inhibitor, in rat, monkey, and human.

PURPOSE: The use of in vitro and in vivo models using both rodent and non-rodent species plays an important role with regard to metabolism during the drug development process. In this study, we compared the metabolism of a MEK inhibitor (CI-1040) using in vitro and in vivo models with that observed in a cancer patient. METHODS: Radiolabeled CI-1040 was assessed for metabolism using rat and monkey liver microsomes and hepatocytes, as well as in Wistar rats and cynomolgus monkeys via oral administration. Human bile and plasma samples were obtained immediately after administration of CI-1040 to a patient with advanced colon cancer. A combination of HPLC-radiochromatography (HPLC-RAM), LC/MS and LC/MS/MS experiments were used to analyze all resulting metabolites. Unlabeled CI-1040 was administered (100 mg/day, QD) for 15 days to a patient suffering from colon cancer. Bile was collected by the insertion of a T-tube directly into the bile duct over a 14-h period. Metabolites were also monitored in the patient's plasma. RESULTS: Analysis of the metabolites in all species using in vitro and animal models demonstrated that CI-1040 undergoes extensive oxidative metabolism (14 metabolites identified) with subsequent glucuronidation of the hydroxylated metabolites. Metabolites were predominantly excreted through the bile in the animal models. CONCLUSIONS: Overall, the in vitro and animal models in combination provided comprehensive coverage for all metabolites observed in human bile and plasma. In conclusion, the results obtained in this study demonstrate the utility of conducting investigations across species in order to gain complete coverage for successfully predicting human metabolites of new compounds in development.