The A2ml1-Knockout mouse as an animal model for non-syndromic otitis media.

BACKGROUND: Inflammation and infection of the middle ear, known as otitis media (OM), is a leading cause of hearing loss and the most frequently diagnosed disease in children worldwide. Traditionally, mouse models for OM rely on inducing acute infection through inoculation of the middle ear, e.g. with the human otopathogen non-typeable Haemophilus influenzae (NTHi), and with very few genetic models with spontaneous or chronic OM. A2ML1 variants, including loss-of-function variants, were associated with susceptibility to OM in humans, but no animal model has been reported for A2ml1-related OM. Here, we report our middle ear findings in a mouse line with a CRISPR-induced knockout (KO) of A2ml1. METHODS: Mice were X-rayed prior to harvest to determine if there are craniofacial or skeletal abnormalities. Tissue from mouse middle ears, as well as other upper respiratory mucosal tissues, were harvested. The harvested middle ear bullae were examined under microscope and submitted for histologic preparation to study phenotypic indications of OM. RNA samples isolated from middle ear tissue were assayed for expression of genes correlated with A2ML1 expression in humans. RESULTS: Data from a total of 119 mice (35 wildtype, 40 heterozygous, 44 homozygous) are presented here, with each analyses being performed on subsets of these mice. There were no significant craniofacial differences by genotype (n = 22). Findings in mice with the A2ml1-KO indicated an increased incidence of OM (n=29; odds ratio = 11; CI: 1.1, 573.6; Fisher exact two-sided p = 0.02) with tympanic membrane perforations or thickening, as well as cases of middle ear effusion, inflammatory cells, or fluid from histologic sections. Dsp was upregulated in the middle ear tissues of homozygous mice (Wilcoxon test p = 0.001). CONCLUSION: Thus far, our results in this A2ml1-KO mouse line indicate spontaneous occurrence of OM and dysregulation of Dsp in the middle ear as a potential disease mechanism for A2ml1-related OM.

Hearing outcomes in children with pneumococcal meningitis in the PCV13 era.

INTRODUCTION: Streptococcus pneumoniae, is associated with the highest incidence of post-meningitic SNHL. The exact impact of 13-valent pneumococcal conjugate vaccine (PCV) on pediatric SNHL from pneumococcal meningitis is unknown. We aimed to identify clinical factors associated with post-meningitic SNHL (pmSNHL) from pneumococcal meningitis and describe its rates based on three time periods: pre-PCV, PCV-7 and PCV13 eras. METHODS: A retrospective case-control study was performed for patients 18 years and younger diagnosed with pneumococcal meningitis from January 1, 2010 to December 31, 2020 at Children's Hospital Colorado. Demographic and clinical risk factors between those with or without SNHL were compared. Detailed hearing outcomes of those with resulting SNHL are described. RESULTS: 23 patients with CSF cultures or Meningitis/Encephalitis Panel positive for pneumococcal meningitis were identified. Twenty patients both survived the infection and had audiologic evaluation. Six patients had pmSNHL, with 50 % affected bilaterally. The rate of pmSNHL from S. pneumoniae in the PCV-13 era at our institution was similar to historical rates from the pre-PCV and PCV-7 eras. Similar proportions of patients with pmSNHL completed PCV vaccination (66.7 %) compared to those without (71.4 %). Non-PCV-13 serotypes were responsible 83 % of patients with pmSNHL versus 57 % of patients without pmSNHL. CONCLUSIONS: Despite high rates of PCV-13 uptake in our cohort, pmSNHL was still common, severe, and commonly associated with non-PCV-13 serotypes. Non-PCV-13 serotypes may be contributing to the persistently high rate of post-meningitic SNHL and the severity of SNHL. Newer pneumococcal conjugate vaccines with expanded serotypes may help mitigate the SNHL associated with pneumococcal meningitis.

Rosai-Dorfman-Destombes Disease in the Pediatric Head and Neck.

BACKGROUND: Rosai-Dorfman-Destombes disease (RDD), or sinus histiocytosis with massive lymphadenopathy, is a rare form of non-Langerhans cells histiocytosis. It has a wide-ranging variability in presentation since first described in 1969 but much of its characteristics in children remain unknown. METHODS: A retrospective chart review of children diagnosed with RDD at a tertiary care children's hospital was conducted from 2000 to 2021. RESULTS: Twelve RDD patients were identified, with an average age of 7 years (SD 4.3). Males comprised 58% of the cohort, and African American ethnicity was most common (42%). Nodal RDD was found in 7 patients (58%). Nine patients (75%) presented RDD within the head and neck, 6 of whom had nodal RDD. The most common presentation was cervical lymphadenopathy, which most often involved levels V (67%), II (56%), III (44%), and I (11%), in order of frequency. Recurrence and persistence of disease after initial treatment was common, with 5 (42%) being disease free at the time of the last follow up. Fifty-eight percent (7/12) developed recurrence or had persistent disease and 4 required adjuvant systemic treatment with corticosteroids and/or chemotherapy. One patient succumbed after developing treatment related acute myelodysplastic leukemia (t-AML) from chemotherapy used to treat recurrent RDD. CONCLUSION: Pediatric RDD presents at a young age and most commonly involving cervical lymphadenopathy. Ongoing surveillance in the setting of persistence or recurrence without clearly defined prognostic risk factors is important.

Novel candidate genes for cholesteatoma in chronic otitis media.

Cholesteatoma is a rare and benign disease, but its propensity to cause erosive damage through uninhibited growth can be detrimental to hearing and health. Prior reports indicated a genetic component to pathogenesis in at least a subset of patients. In this study, we aimed to identify rare DNA variants in affected patients. The salivary DNA of six patients whose middle ear tissues were obtained during tympanoplasty/mastoidectomy surgeries were submitted for exome sequencing. Tissue samples from the same patients were previously submitted for mRNA sequencing and analyzed for differentially expressed genes (DEGs). From the generated exome sequence data, rare predicted-to-be-damaging variants were selected within previously identified DEGs, and the candidate genes within which these rare variants lie were used for network analysis. Exome sequencing of six DNA samples yielded 5,078 rare variants with minor allele frequency <.001. A total of 510 variants were predicted to be deleterious and 52 were found to lie within previously identified DEGs. After selecting variants based on quality control measures, 12 variants were identified all from one pediatric patient. Network analysis identified ten significant cellular pathways, including protein transport, viral process, regulation of catalytic activity and cell cycle, and apoptotic and rhythmic processes. We hypothesize that the candidate genes identified in this study may be part of key signaling pathways during the mucosal response to middle ear infection. The occurrence of multiple rare variants may play a role in earlier onset of cholesteatoma formation in chronic otitis media.

Intraoperative intravenous ibuprofen use is not associated with increased post-tonsillectomy bleeding.

OBJECTIVES: Intravenous (IV) ibuprofen was approved by the FDA for use in pediatric patients in November 2015. The objective of this study was to compare bleeding rates in pediatric tonsillectomy patients who received intraoperative intravenous ibuprofen versus those who did not. Secondary objectives included analyzing factors that correlated with return to the Emergency Department (ED) for pain or dehydration. METHODS: Charts were reviewed for all patients 0-18 years of age who underwent a tonsillectomy with or without adenoidectomy at a tertiary care children's hospital from 1/1/2017 through 5/21/2018. Demographic information and perioperative medications including the use of intraoperative intravenous ibuprofen were recorded. ED visits and operating room (OR) returns for bleeding were tracked for up to 30 days after surgery. RESULTS: 1085 charts were analyzed. Intraoperative IV ibuprofen was used in 132 cases (12.2%). Primary bleeds, defined as bleeding within 24 h of surgery, occurred in 1 (0.76%) of 132 patients who received IV ibuprofen, and 1 (0.10%) of 953 patients who did not receive IV ibuprofen. Secondary bleeds, defined as bleeds after 24 h from surgery occurred in 2 (1.52%) of 132 patients who received IV ibuprofen and 38 (3.99%) of 953 patients who did not receive IV ibuprofen. No statistical difference was found between the two groups in rates of overall (primary plus secondary) bleeding requiring return to ED (p = 0.759) or return to OR (p = 0.710). CONCLUSION: The observed bleeding rate after pediatric tonsillectomy was not statistically different in patients who received intraoperative IV ibuprofen versus those who did not receive this medication. LEVEL OF EVIDENCE: III.

Medicaid payer status and other factors associated with hospital length of stay in patients undergoing primary lumbar spine surgery.

OBJECTIVE: The Medicaid patient population and health care costs for spine surgeries among these patients have increased since 2010. Hospital length of stay (LOS) contributes appreciably to hospital costs for patients undergoing primary lumbar spine surgery (PLSS). The aim of this study was to identify independent risk factors for increased LOS in patients undergoing PLSS. PATIENTS AND METHODS: In a single-center retrospective study, we reviewed demographic and clinical data from electronic medical records for 181 consecutive adult patients who underwent PLSS involving 1-3 levels from July 2014 to July 2017. We performed regression analyses to identify independent risk factors for increased LOS and to quantify their effects as percent changes in LOS. RESULTS: Among 181 patients who underwent PLSS, the mean LOS was 3.57 days. Based on the Charlson Comorbidity Index (CCI) and American Society of Anesthesiologist (ASA) classification, patients with Medicaid insurance were healthier than non-Medicaid patients (mean CCI: 0.34 versus 0.65; p = 0.041, ASA: 1.71 versus 1.91; p = 0.046) yet Medicaid patients had a longer LOS compared with non-Medicaid patients (mean LOS: 4.03 versus 3.30 days; p = 0.047). There was no significant difference in discharge disposition between Medicaid and non-Medicaid patients (Home = 82.35 % versus 79.65 %; p = 0.855). Medicaid patients also had significantly less spinal levels involved in their surgery (1.44 versus 1.67; p = 0.027). Multivariable regression modeling identified independent risk factors positively associated with increased LOS as age (+1.0 % per year; p = 0.007), Medicaid insurance status (+28.7 %; p = 0.007), and CCI (10.1 % per increment in CCI; p = 0.030). Fusion surgery also was an independent risk factor for increased LOS when compared with laminectomy (-54.1 %; p < 0.001) or discectomy (-51.3 %; p < 0.001). CONCLUSIONS: Increasing age, Medicaid insurance status, higher CCI, and fusion surgery were independently associated with increased LOS after PLSS. This information is useful for preoperative patient counseling, shared decision-making, and risk stratification and may help to further ongoing discussion regarding contributors to rising health care costs. Findings of increased LOS among Medicaid patients will help direct efforts to identify factors that contribute to this health care expense.

Displacement of mandibular dentition during total arch distalization according to locations and types of TSADs: 3D Finite element analysis.

OBJECTIVE: The aim of this study was to evaluate the biomechanical effects of temporary skeletal anchorage devices (TSADs) on the mandibular dentition and mandible during total arch distalization according to locations and types of the TSADs using finite element (FE) analysis. SETTING AND SAMPLE POPULATION: A model of the mandible and teeth was used to build an FE analysis model. MATERIALS AND METHODS: Four FE models were constructed: Ramal plate (Type A), Sugawara plate (Type B), buccal shelf miniscrew (Type C) and interradicular miniscrew (Type D). A retraction force of 300 g per side was applied to the mandibular archwire. RESULTS: In the sagittal plane, the plates Type A and B showed more distal displacement than the miniscrew Types C and D, especially in the posterior teeth. Type A presented the greatest amount of distal displacement, followed by Types B, C and D. Type A was closest to the line of occlusion, which showed the lowest degree of buccolingual angulations of the molar crowns. Vertically, Type A showed a greater amount of extrusive displacement of the posterior teeth than the other types of TSADs, while Type B showed intrusive displacement of the molars. CONCLUSIONS: The ramal plate showed a greater amount of distal and extrusive displacement of the posterior teeth than the miniscrews. Therefore, clinicians should consider the displacement of mandibular dentition during total arch distalization according to types of the TSADs.