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Background: Current assessment techniques for determining whether a patient has normal interarytenoid anatomy, a deep interarytenoid notch, or a minor laryngeal cleft are highly variable. However, differentiating between these three entities is important, given it may distinguish whether a patient should be considered for surgical intervention. The Interarytenoid Assessment Protocol (IAAP) was developed to provide standardization of interarytenoid anatomy evaluations. We aimed to assess the reliability of the IAAP for assessment of interaytenoid mucosal height (IAMH) through a multi-institutional validation study., Methods: Reliability of the IAAP was assessed by 10 pediatric otolaryngologists all from different academic centers. 30 de-identified endoscopic videos of interarytenoid assessments were rated at two separate time points, 2 months apart. Intra-class correlation (ICC) coefficients with two-way models were used to evaluate inter- and intra-rater reliability., Results: Thirty endoscopic videos were collected for patients with a median (IQR) age of 4.9 years (59 months; range: 1 month to 20 years). On the first video assessment, inter-rater reliability was 0.74 (95% CI 0.63-0.84), and on the second video assessment, inter-rater reliability was 0.75 (95% CI 0.63-0.85) indicating strong inter-rater reliability. Overall intra-rater test-retest reliability was 0.75 (95% CI 0.69-0.79) indicating strong agreement. In almost half, 14 (46.6%) raters chose IAAP classification levels within 1 level of each other., Conclusions: Multi-institutional validation of the IAAP demonstrates strong inter- and intra-rater reliability for assessment of IAMH when evaluated through pictorial analysis. Standardization of anatomical evaluations may improve our ability to perform more reliable outcomes studies of pediatric pharyngeal dysphagia in the future., Level of Evidence: NA Laryngoscope, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: While management protocols of pediatric esophageal foreign bodies (EFBs) are well-delineated, resource utilization can be improved. This study's objectives were to explore hospital charges/costs for pediatric patients who present with EFBs and to identify patient risk factors associated with esophageal injury., Methods: A retrospective chart review of patients undergoing aerodigestive foreign body removal at a tertiary-care children's hospital from 2018 to 2021 was conducted. Data collected included demographics, medical history, presenting symptoms, EFB type, surgical findings, and hospital visit charges/costs., Results: 203 patients were included. 178 of 203 (87.7%) patients were admitted prior to operation. Unwitnessed EFB ingestion (p < 0.001, OR = 15.1, 95% CI = 5.88-38.6), experiencing symptoms for longer than a week (p < 0.001, OR = 11.4, 95% CI = 3.66-38.6) and the following presenting symptoms increased the odds of esophageal injury: dysphagia (p = 0.04, OR = 2.45, 95% CI = 1.02-5.85), respiratory distress (p = 0.005, OR = 15.5, 95% CI = 2.09-181), coughing (p < 0.001, OR = 10.1, 95% CI = 3.73-28.2), decreased oral intake (p = 0.001, OR = 6.60, 95% CI = 2.49-17.7), fever (p = 0.001, OR = 5.52, 95% CI = 1.46-19.6), and congestion (p = 0.001, OR = 8.15, 95% CI = 2.42-27.3). None of the 51 asymptomatic patients had esophageal injury. The median total charges during the encounter was $20,808 (interquartile range: $18,636-$24,252), with operating room (OR) (median: $5,396; 28.2%) and inpatient admission (median: $5,520; 26.0%) contributing the greatest percentage., Conclusions: Asymptomatic patients with EFBs did not experience esophageal injury. The OR and inpatient observation accounted for the greatest percentage of the hospital charges. These results support developing a potential algorithm to triage asymptomatic patients to be managed on a same-day outpatient basis to improve the value of care., Level of Evidence: 3 Laryngoscope, 134:4774-4782, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objective(s): To investigate the effectiveness of ciprofloxacin/dexamethasone in reducing granulation tissue post-tracheostomy in pediatric patients., Methods: This cohort study examined pediatric patients with a tracheostomy at a single academic institution from 2016 to 2020. Exclusion criteria included: deceased within 1 year (n = 38), >16 years of age (n = 21), decannulated within 1 year (n = 15), lost to follow-up within 1 year (n = 6), and revision tracheostomy (n = 2). Logistic regression or Wilcoxon rank-sum (α = 0.05) were used to compare demographic and clinical characteristics between patients who did and did not receive ciprofloxacin/dexamethasone within 1 year of their tracheostomy., Results: In this cohort, (n = 126, median age 5.2 months, 54.0 % male), 62.7 % received ciprofloxacin/dexamethasone within 1 year, with 27.8 % taking the nebulized form. Granulation tissue occurred in 81.0 % of cases, predominantly peristomal (69.8 %) and suprastomal (34.9 %). Notable complications included accidental decannulation (13.6 %), suprastomal collapse (11.2 %), and bleeding (7.2 %). Although granulation tissue was more common in ciprofloxacin/dexamethasone users (92.4 %) versus non-users (61.7 %) (OR: 7.55, 95 % CI: 2.73-20.9, p < 0.001), patients exhibited less frequent granulation tissue events after initiation (z = 3.88, p < 0.001). No significant differences in antibiotic resistance (p = 1.0) or endocrinology complications (p = 0.1) were found between those with and without ciprofloxacin/dexamethasone., Conclusions: We found a statistically significant reduction of granulation tissue incidence with ciprofloxacin/dexamethasone use and no significant differences in antibiotic resistance or endocrinology complications were noted. Future investigation is warranted to explore timing of ciprofloxacin/dexamethasone administration for granulation tissue and its role in managing and preventing tracheostomy complications., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Historically, head and neck lymphatic malformations (HNLM) have been managed through surgical and interventional procedures. Sirolimus was introduced in 2016 and has aided in symptomatic control of HNLM. The study objective was to assess healthcare utilization with the introduction of sirolimus for HNLM., Methods: An observational cohort study of LM patients treated between 2008 and 2022 at a tertiary care children's hospital was performed. 588 charts were reviewed; patients with isolated, non-syndromic HNLM and at least 2 years of follow-up were included (n = 45). Data included sirolimus use, complications, presence of tracheostomy and/or gastrostomy-tube, and number and costs of HNLM-related sclerotherapies, procedures, hospitalizations, and emergency room visits. For patients who received sirolimus, encounters two years prior to and after sirolimus initiation were recorded. For the non-sirolimus group, encounters two years after the initial clinic visit for HNLM were recorded. Statistical analysis was used to compare the groups., Results: Median age at first clinic visit was 1.8 years (range 2 days-41 years). Tracheostomy was present in 43 % of sirolimus patients compared with 3 % of the non-sirolimus group (OR: 24.0, 95%CI: 1.55-1490, p = 0.02). Patients on sirolimus experienced significantly fewer sclerotherapy visits (z = 2.08, p = 0.03) compared to the non-sirolimus group. Minimal sirolimus-related side effects were reported. Total HNLM-related costs were significantly less in the sirolimus group during treatment (median $448.13, range $0-$7041.28) compared with before treatment (median $17,069.24, range $1999.16-$211,848.50, z = 2.20, p = 0.03). Median costs associated with sclerotherapy were less for the sirolimus groups during treatment compared with the non-sirolimus group (z = 1.97, p = 0.04). In the sirolimus group, costs associated with HNLM-related hospitalizations were significantly less during sirolimus treatment compared with before (z = 2.20, p = 0.03)., Conclusion: Sirolimus has improved the clinical course for HNLM patients by decreasing number of procedures and healthcare costs, with limited side effects. Larger cohorts matching type of HNLM and age are needed to assess healthcare utilization benefits of sirolimus., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Pediatric epistaxis is a multifactorial disease entity. The objective of this study is to determine the socioeconomic and air-quality contributions to pediatric epistaxis. The study also evaluates the utility of diagnostic lab work as a predictor of bleeding rates and need for operative intervention., Methods: A case series of pediatric patients treated in an outpatient Otolaryngology clinic at a tertiary care children's hospital in 2021 for epistaxis was performed. Patients with nasal bone trauma (n = 8), consult while inpatient (n = 7), and those with nasal masses (n = 2) were excluded; 181 patients met inclusion criteria. Demographic, clinical, socioeconomic, and air quality (tropospheric ozone, particulate matter) data were recorded. Associations with persistent bleeding and operative interventions were evaluated using logistic regression, Wilcoxon rank-sum, and Spearman rank correlation., Results: Of the 181 patients, 75 (41.4%) were female. Forty-six of 181 (25.4%) had associated allergic symptoms. Twenty-six patients had allergy testing; 14/26 (53.8%) of these had positive results. Re-bleeding was more common in those with allergic symptoms (OR: 2.42, 95% CI: 1.22-4.78, p = 0.01). Patients with re-bleeding lived in counties with more days with ozone over the US standard (median 5 days, range 0-32 days) compared with those with no re-bleeding (median 3 days, range 0-32 days, p = 0.007). There was also an association between the number of visits for re-bleed and percent below poverty level (ρ = 0.259, p = 0.03) as well as the number of days with particulate matter levels over the US standard (ρ = 0.343, p = 0.01). Coagulopathy was present in 9/54 (16.7%) patients, with the majority being Von Willebrand disease (5/54, 9.3%). Easy bruising was not significantly associated with positive lab results., Conclusions: Environmental pollution, living in a zip code with more residents below the poverty level, and allergic rhinitis were positively associated with recurrent epistaxis. Understanding the geographic background of presenting patients may help direct workup and treatment options., Competing Interests: Declaration of competing interest None of the authors have any financial or personal relationships with other people or organizations that could inappropriately influence this work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: First health care professionals arriving at the bedside in tracheostomy-related emergencies are rarely the surgical subspecialists who placed the tracheostomy and are unfamiliar with the relevant anatomy and tracheostomy specifications for the individual patient. We hypothesized that implementing a bedside airway safety placard would increase caregiver confidence, understanding of airway anatomy, and management of patients with a tracheostomy., Methods: A prospective survey study was performed by distributing a tracheostomy airway safety survey before and after implementation of an airway safety placard in a 6-month study period. Placards emphasizing critical airway anomalies as well as emergency management algorithm suggestions designed by the otolaryngology team at the time of tracheostomy were placed at the head of the bed and traveled with the patient during transport around the hospital., Results: Of 377 staff members requested to complete the surveys, 165 (43.8%) responses were obtained, and 31 (8.2% [95% CI 5.7-11.5]) paired pre- and post-implementation responses were recorded. Differences were found in the paired responses, including increases in the domains of confidence ( P = .009) and experience ( P = .01) post implementation. Less experienced providers (≤ 5 y of experience) ( P = .005) and providers from neonatology ( P = .049) demonstrated improved confidence post implementation, which was not observed in their more experienced (> 5 y) or respiratory therapy counterparts., Conclusions: Given the limitations of a low survey response rate, our findings suggest that an educational airway safety placard initiative can be a simple, feasible, and low-cost quality improvement tool to enhance airway safety and possibly decrease potentially life-threating complications among pediatric patients with a tracheostomy. The implementation of the tracheostomy airway safety survey at our single institution warrants a larger multi-center study and validation of the survey., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Canonical pyroptosis is type of programmed cell death depending on active caspase-1, and the inflammasome carries out caspase-1 activation. Here, we showed that docosahexaenoic acid (DHA) induced ovarian cancer cell deaths in caspase-1-dependent manner. DHA increased caspase-1 activity and led to interleukin-1β secretion and gasdermin D cleavage while disulfiram inhibited DHA-induced cell death, suggesting that DHA triggered pyroptosis. Intriguingly, ASC, the molecule recruiting caspase-1 to inflammasome for activation, was dispensable for DHA-induced pyroptosis. Instead, we observed remarkable elevation in caspase-1 abundance concurrent with the activation of caspase-1 in DHA-treated cells. As ectopically overexpressing caspase-1 resulted in robust amount of active caspase-1, we reason that DHA activates caspase-1 and pyroptosis through the generation of excessive amount of caspase-1 protein. Mechanistically, DHA increased caspase-1 by specifically accelerating caspase-1 protein synthesis via the p38 MAPK /Mnk1 signaling pathway. We have uncovered an unknown pyroptosis mechanism in which caspase-1-dependent pyroptosis can occur without the participation of ASC/inflammasome., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Objective: Puberty has been shown to accelerate growth of vascular malformations, including lymphatic (LM) and venous malformations (VM). This study aims to compare the number of procedures performed before and after puberty in patients with LM and VM to assess whether the onset of puberty results in higher treatment frequency., Methods: A retrospective review of head and neck LM and VM patients who were evaluated between January 2009 and December 2019 was performed. Patient demographics, lesion characteristics, and procedural details were recorded. For the purposes of this study, 11 years or older in females and 12 years or older in males were the established cut-offs for the onset of puberty., Results: After initial screening of 357 patients, 83 patients were included in the study based on inclusion criteria. There were 34 patients with LM (41 %) and 49 with VM (59 %). The mean age at diagnosis was 6.1 ± 10.9 years (LM: 4.2 ± 7.0, VM: 7.4 ± 12.9, p = 0.489). 68 patients underwent treatments, which included sclerotherapy, surgical excision, and/or laser. For all patients, the average number of lifetime treatments when initiated before puberty was 3.78 ± 2.81 and when initiated after puberty was 2.17 ± 1.37 (p = 0.022). Patients diagnosed pre-puberty were more likely to undergo treatments vs. those diagnosed after puberty (OR 10.00, 95 % CI: 2.61-38.28, p < 0.001)., Conclusion: We found that the number of treatments was fewer in those who started treatment after puberty. This finding suggests that providers may elect to proceed with observation in asymptomatic patients, given that waiting until after the onset of puberty has not shown an increase in the procedural load on patients., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: In patients undergoing patent ductus arteriosus (PDA) ligation there is a significant risk of left vocal fold paralysis (LVFP) particularly in premature neonates who are small for gestational age. The objective of this study is to determine the incidence of LVFP in infants following PDA ligation and report on long-term outcomes in patients with LVFP., Methods: We performed a prospective study of patients undergoing PDA ligation in the newborn intensive care unit (NICU) between April 2004 and May 2014. Following PDA ligation, flexible laryngoscopy was performed to assess vocal fold mobility. Patients were then followed longitudinally to determine long-term outcomes., Results: A total of 163 infants underwent PDA ligation. Thirty-six patients (22%) developed LVFP following the procedure. Twenty-five percent of neonates <1500 g experienced LVFP versus 5% of patients >1500 g (p = 0.033). Patients with LVFP were more likely to require a feeding tube (64% vs. 19.6%; p < 0.05) and spent more time in the NICU (135 days vs. 106 days; p < 0.05). Twenty-four patients received long-term follow-up. Six (25%) had complete resolution of LVFP, 10 (42%) were compensated, and 8 (33%) demonstrated persistent LVFP with no improvement., Conclusions: The incidence of LVFP after PDA ligation is high especially in extremely low birth weight children. The majority of patients recovered well with time, but further surgical intervention was required in uncompensated cases. Long-term follow-up of these patients is needed to ensure improvement. Laryngoscope, 133:1257-1261, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: PHACE is a rare syndrome that can present with airway hemangiomas. Management for these patients is variable and the utilization of operative endoscopic airway evaluation has not been described. The objectives of this study were to identify the incidence of airway symptoms in patients being evaluated for PHACE syndrome and determine the utility of operative endoscopy., Methods: An IRB-approved retrospective cohort study was conducted on consecutive pediatric patients with head and neck infantile hemangioma (IH) evaluated in a multi-disciplinary vascular anomalies center between 2013 and 2019. Patients were included if they were being worked up for PHACE syndrome and had an otolaryngology evaluation. Demographics, clinical, and surgical variables were collected., Results: There were 317 patients with head and neck IH. Thirty-six patients met inclusion criteria. The majority of patients were female (31/36; 86.1%) and less than half of the patients (15/36; 41.7%) were eventually diagnosed with PHACE syndrome. Median age at presentation was 2 months (range 0-82 months). A total of 28/36 (77.8%) of patients were managed with propranolol. The majority of the patients presented without aerodigestive symptoms; however, 16/36 (44.4%) of patients presented with symptoms such as stridor, hoarseness, and dysphagia. A total of 20/36 (55.6%) of patients underwent operative endoscopy. A total of 8/20 (40.0%) of patients who underwent operative endoscopy had operative intervention. Of the entire cohort, only 2/15 (13.3%) patients diagnosed with PHACE were found to have a subglottic hemangioma. Both patients presented with stridor., Conclusion: Operative endoscopy remains useful in the workup of PHACE syndrome to identify subglottic hemangiomas, however there may be relatively low yield in asymptomatic patients. In office flexible laryngoscopy may be a less invasive means to examine the subglottic region. A multi-center prospective study would be necessary to evaluate incidence of subglottic hemangiomas in asymptomatic patients evaluated for PHACE.

Background: Noninvoluting congenital hemangiomas (NICH) are rare and poorly understood vascular tumors that are present at birth, characterized by lack of growth after birth and lack of involution. We report uncharacteristic cases of NICH hypertrophy occurring later in life., Methods: This is a case series describing the clinical presentation, management, and histologic characteristics of two cases of NICH hypertrophy., Results: Two patients with a NICH of the scalp experienced lesion hypertrophy in teenage or early adult life. Case 1 is a 14-year-old female who presented with a flat left parietal scalp lesion that at first grew slowly with the patient; however, over the span of months grew substantially resulting in an exophytic lesion. The patient had the lesion surgically excised. Case 2 is a 26-year-old female with NICH of left occipital scalp and posterior neck who noted new nodules on the inferior border of the lesion. MRA/MRI showed extension into the occipital calvarium, level V of the neck, and paraspinal musculature. The patient elected to observe given the extent of the lesion and her minimal symptoms., Conclusion: Although postnatal growth of NICH have been described, cases usually occur during the pre-adolescent period where growth is usually proportional to overall growth of the patient. This study describes two cases of rapid onset NICH hypertrophy occurring later in life. Knowledge of the potential for delayed hypertrophy may lead families to seek earlier intervention or opt for more definitive interventions. Additionally, recognition of these variable distinctions will contribute to a better understanding of CH and its various subtypes., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Bilateral myringotomy with tube insertion (BMT) is a common procedure performed in children. Appropriate follow-up is necessary to ensure management of postoperative sequalae. The objectives are to investigate (1) the relationship between insurance type and postoperative follow-up attendance and (2) the effect of follow-up on need for further care after BMT., Study Design: Retrospective cohort study., Setting: The study included patients <3 years of age undergoing BMT for recurrent acute otitis media at a tertiary care children's hospital within a single year and followed for 3 years. Patients were excluded if they had received a prior BMT; underwent a concurrent otolaryngologic procedure; or had a syndromic diagnosis, craniofacial abnormality, or any significant cardiac or respiratory comorbidity., Methods: Number of follow-up appointments, demographics, socioeconomic status, and postoperative outcomes were analyzed., Results: A total of 734 patients were included with mean (SD) age of 1.4 years (0.50). The majority of patients had private insurance (520/734, 70.8%). Patients with public insurance attended fewer postoperative appointments (1.5 vs 1.8, P < .001) and had a higher incidence of BMT-related emergency department (ED) visits (10.3% vs 3.8%, P = .001). There was no significance found when different insurance providers were compared. An adjusted multivariate regression analysis showed that patients with private insurance were more likely to attend postoperative appointments (odds ratio, 3.52 [95% CI, 2.12-5.82]; P < .001) and less likely to have a BMT-related ED visit (odds ratio, 0.42 [95% CI, 0.20-0.89]; P = .024)., Conclusion: Insurance type is related to outcomes after the treatment of recurrent acute otitis media with BMT. Future studies that survey individuals will help identify barriers that contribute to patient absence at follow-ups and need for subsequent ED visits.

Objective: Post-tracheotomy swallowing function has not been well described in the pediatric population. This study aims to (1) determine differences in swallowing functioning pre- and post-tracheotomy and (2) examine the association between postoperative dysphagia and indication for tracheotomy, age at the time of tracheotomy, and time between tracheotomy and modified barium swallow (MBS)., Methods: A retrospective chart review was performed on 752 patients who underwent a tracheotomy from 2003 to 2018 and had adequate documentation for review. Patients were included if they received a post-operative MBS. Descriptive statistics, logistic regression, and Fisher's exact test were used to analyze the data., Results: The cohort included 233 patients. The mean age at the time of tracheotomy was 25 months (±50.5). The indications for the tracheotomy were upper airway obstruction (110/233, 47.2%), chronic respiratory failure (104/233, 44.6%), and neurologic disease (19/233, 8.2%). The mean time from tracheotomy to post-operative MBS was 224 days (±297.7). Of the patients who had documented pre- and post-tracheotomy diets, nearly half of patients had improvement in their swallowing function after tracheotomy placement (82/195; 42.1%). Post-tracheotomy MBS recommended thickened liquids in 30.9% of the patients (72/233) and 42.5% (99/233) were recommended thin liquids. The remainder (62/233, 26.6%) remained nothing by mouth (NPO). Patients with neurological disease as the indication for the tracheotomy were more likely to remain NPO ( P  = .039)., Conclusion: A tracheotomy can functionally and anatomically affect swallowing in pediatric patients. The majority of our studied cohort was able to resume some form of an oral diet postoperatively based on MBS. This study highlights the need for objective measurements of swallowing in the postoperative tracheotomy patient to allow for safe and timely commencement of an oral diet., Level of Evidence: Level 3.

Objective: Evidence supporting the use of acid suppression therapy (AST) for laryngomalacia (LM) is limited. The objective of this study was to determine if outpatient-initiated AST for LM was associated with symptom improvement, weight gain, and/or avoidance of surgery., Methods: A retrospective cohort was reviewed at a tertiary-care children's hospital. Patients were included if they were diagnosed with LM at ≤6 months of age, seen in an outpatient otolaryngology clinic between 2012 and 2018, and started on AST. Primary outcomes were improvement of airway and dysphagia symptoms, weight gain, and need for surgery. Severity was assessed by symptom severity., Results: Of 2693 patients reviewed, 199 met inclusion criteria. Median age of diagnosis was 4 weeks (range: 0-29 weeks). LM was classified as mild/moderate (71.4%) and severe (28.6%) based on symptom severity. Severity on flexible fiberoptic laryngoscopy (FFL) was not associated with clinical severity. Weight percentile, airway symptoms, and dysphagia symptoms improved within the cohort. In total, 26.1% underwent supraglottoplasty (SGP). In multivariate analysis, only severe LM on FFL was predictive of SGP (OR: 7.28, 95%CI: 1.91-27.67, p = .004)., Conclusion: Clinical symptom severity did not predict response to AST raising the question of utility of AST in LM. Severity of LM based on FFL, not clinical severity, was associated with decision to pursue SGP. Prospective randomized trials are needed to better understand the role of AST in LM., Level of Evidence: Level 3., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Post-tonsillectomy hemorrhage (PTH) is a serious complication after a tonsillectomy. Utility of lab work at presentation for PTH was low. This study aims to determine the frequency and type of labs drawn at emergency department (ED) presentation and assess the incidence of uncovering a previously unidentified coagulopathy., Methods: A retrospective chart review was performed on pediatric patients who were seen in the ED after tonsillectomy at a tertiary care children's hospital from 2017 to 2019. Exclusion criteria were the following: no tonsillar bleed, history of known coagulopathy, treated by outside provider, ≥18 years old. Lab work included complete blood count (CBC), prothrombin time (PT), partial thromboplastin time (PTT), and von Willebrand factor (VWF)., Results: 364/723 (50.3%) patients met inclusion criteria. 179/364 (49.2%) patients were male and 309/364 (84.9%) patients were Caucasian. Average age at surgery was 8.12 years (SD = 4.0) and average post-operative day at presentation was 6 days (SD = 2.1). Operative control of bleed was performed in 68/364 (18.7%) patients. 334/364 (91.8%) patients had labs drawn in the ED. 64/334 (19.1%) patients were anemic (hemoglobin (Hgb) < 11), 46/334 (13.8%) patients had thrombocytosis (platelets>450,000), 10/334 (3.0%) had elevated PTT and 8/334 (2.4%) had elevated PT. Hematology was consulted in 14/364 (3.8%) patients of whom 6/14 were diagnosed with von Willebrand disease and 1/14 with factor VII deficiency. Aminocaproic acid was used in 8/364 (2.2%) patients due to elevated PTT in 3/8 and multiple episodes of bleeding in 5/8.3/364 (0.8%) patients needed a blood transfusion. No difference was found in incidence of abnormal lab work in patients who did and did not need operative control of bleed (p = .125). Of the 334 patients who had ED labs drawn, 7 (2.1%) had an uncovered coagulopathy., Conclusion: Uncovering incidental coagulopathies is rare in patients who present with PTH. Though anemia was the most common abnormality noted, only a small percentage required transfusion, with all having abnormal vital signs. Thrombocytosis was the next common abnormality, and this can be seen in an inflammatory state. Developing algorithms is necessary to better guide appropriate lab work in patients who present with PTH and to provide optimal value of care to patients., (Copyright © 2021. Published by Elsevier B.V.)

Triple negative breast cancer (TNBC) cells are generally more invasive than estrogen receptor-positive (ER + ) breast cancer cells. Consistent with the importance of activator protein 1 (AP1) transcription factors in invasion, AP1 activity is much higher in TNBC lines than ER + lines. In TNBC cells, robust AP1 activity is facilitated by both ERK and p38 MAPK signaling pathways. While ERK signaling pathway regulates AP1 activity by controlling the abundance of AP1 transcription factors, p38 MAPK signaling pathway does it by enhancing AP1 binding to AP1 sites without altering their abundance. Here, we show that p38 MAPK regulation of AP1 activity involves both MAPKAPK2 (MK2) and JAB1, a known JUN-binding protein. MK2 not only interacts with JAB1 but also directly phosphorylates JAB1 at Ser177 in TNBC cells. Interestingly, Ser177 phosphorylation does not affect JAB1 and JUN interaction. Instead, interfering with p38 MAPK signaling pathway or introducing an S to A point mutation at Ser177 of JAB1 reduces JUN recruitment to the AP1 sites in cyclin D1, urokinase plasminogen activator (uPA) and uPA receptor promoters. Moreover, knockdown of JAB1 diminishes >60% of AP1 transcriptional activity in TNBC cells. Taken together, these results indicate that MK2-mediated phosphorylation of JAB1 facilitates JUN recruitment to AP1 sites, thus augmenting AP1 activity. In line with the role of JAB1 in AP1 activity, silencing JAB1 leads to dramatic reduction in TNBC cell growth, in vitro invasion and in vivo tumor outgrowth. This study suggests that the p38 MAPK -MK2 signaling pathway promotes TNBC tumorigenesis by sustaining robust AP1 activity., (© 2021. The Author(s).)

Objective: (1) Review a multidisciplinary vascular anomalies center's practice regarding periprocedural anticoagulation for venous malformations (VM) and the associated risk of thromboembolic and disseminated intravascular coagulation (DIC) events. (2) Compare the risk of thromboembolic events and DIC post-procedure between head and neck (H&N) and extremity VM patients., Methods: An Institutional Review Board (IRB)-approved, retrospective chart review was performed on 120 VM patients. A thromboembolic event was defined as a thrombus formation post-sclerotherapy or post-surgery within 2 months in a distant or local venous structure not directly addressed by the procedure., Results: There were 39 cases involving the H&N and 81 cases based at the extremities. There were eight cases of post-procedure thrombus formation within the extremity VM group (8/71; 11.3%) as opposed to 0 cases in the H&N group (OR: 0, 95% CI .00-.09), p = .049. There was no difference in incidence of post-procedure thromboembolic events between those with elevated D-dimer (H&N: 0%, extremity: 22.7%, 5/22) and normal D-dimer values (H&N: 0%, extremity: 6.3% [1/16], P = .370). There was no difference in incidence of post-procedure thromboembolic events between those who received periprocedural anticoagulation (H&N: 0%, extremity: 21%, 4/19) and those who did not (H&N: 0%, extremity: 8.2%, 4/49), (Extremity: OR: 3.00, .67-13.50, P = .206)., Conclusion: Post-procedure thromboembolism is rare in the treatment of venous malformations, especially in the head and neck subsite. Regardless of anticoagulation use, there were no thromboembolic events for H&N VM patients. Such events are rare, and the odds may approach zero, especially with small sample size., Level of Evidence: 4 Laryngoscope, 131:1163-1167, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

PRKCI, the gene for protein kinase Cι (PKCι), is frequently amplified in ovarian cancer and recent studies have shown that PKCι participates in ovary tumorigenesis. However, it is unknown whether PKCι is differentially involved in the growth/survival between PRKCI-amplified and non-amplified ovarian cancer cells. In this study, we analyzed ovarian cancer patient dataset and revealed that PRKCI is the only PKC family member significantly amplified in ovarian cancer and PRKCI amplification is associated with higher PKCι expression. Using a panel of ovarian cancer cell lines, we found that abundance of PKCι is generally associated with PRKCI amplification. Interestingly, silencing PKCι led to apoptosis in PRKCI-amplified ovarian cancer cells but not in those without PRKCI amplification, thus indicating an oncogenic addiction to PKCɩ in PRKCI-amplified cells. Since small-molecule inhibitors characterized to selectively block atypical PKCs did not offer selectivity nor sensitivity in PRKCI-amplified ovarian cancer cells and were even cytotoxic to non-cancerous ovary surface or fallopian tube epithelial cells, we designed an EpCAM aptamer-PKCι siRNA chimera (EpCAM-siPKCι aptamer). EpCAM-siPKCι aptamer not only effectively induced apoptosis of PRKCI-amplified ovarian cancer cells but also greatly deterred intraperitoneal tumor development in xenograft mouse model. This study has demonstrated a precision medicine-based strategy to target a subset of ovarian cancer that contains PRKCI amplification and shown that the EpCAM aptamer-delivered PKCι siRNA may be used to suppress such tumors.

Objectives: The clinical significance of the interarytenoid mucosal height (IAMH) in pediatric dysphagia, ranging from normal anatomy to a laryngeal cleft, is unknown. This study seeks to evaluate a cohort of patients who underwent evaluation of their IAMH during microdirect laryngoscopy (MDL) for associations between IAMH and dysphagia as diagnosed on preoperative videofluoroscopic swallow study (VFSS)., Methods: A retrospective case series of 1,351 patients who underwent MDL between 2011 and 2016 were reviewed for intraoperative evaluation of IAMH using our interarytenoid assessment protocol. After exclusions, 182 patients were divided into three groups: 1) thickened diet: VFSS with recommendation for thickened liquids (n = 82 of 182; 45.1%), 2) normal diet: VFSS with allowance of thin liquids (n = 19 of 182; 10.4%), and 3) control: no VFSS performed (n = 81 of 182; 44.5%)., Results: There was no difference in IAMH between groups (P = 0.35). Power analysis was able to achieve > 80% power to detect an effect size of ≥ 0.5 (1-5 mucosal height scale). The majority of patients in each group had an IAMH above the false vocal folds (thickened diet: 57.3%, normal diet: 57.9%, control: 64.2%). There were similar percentages of patients in each group with an IAMH at or below the true vocal folds (thickened diet: 4.9%, normal diet: 5.3%, control: 6.1%)., Conclusion: There was no significant association between IAMH and preoperative thickened liquid recommendation in this cohort. This data fails to support the hypothesis that the IAMH is an independent etiological factor for pediatric pharyngeal dysphagia. Further studies comparing IAMH with outcomes after feeding therapy and surgery may better clarify this relationship between anatomy and physiology., Level of Evidence: 4. Laryngoscope, 129:2588-2593, 2019., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Fibrodysplasia ossificans progressiva (FOP) is a rare disorder that causes heterotopic bone formation leading to chest wall and spinal deformities. This case describes an 11-year-old female with FOP who presented in respiratory failure necessitating two emergent fiberoptic nasotracheal intubations. The patient had severe trismus, rotary flexion of the neck, and distortion of the airway. A three-dimensional printed model based off of a computed tomography reconstruction was created for an in situ simulation before the true procedure. The surgery and trach change were both uneventful. We propose that with careful preoperative planning, tracheotomy can be an appropriate option for FOP patients. Laryngoscope, 129:812-817, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: While the Benjamin-Inglis classification system is widely used to categorize laryngeal clefts, it does not clearly differentiate a type 1 cleft from normal anatomy, and there is no widely accepted or validated protocol for systematically evaluating interarytenoid mucosal height. We sought to propose the interarytenoid assessment protocol as a method to standardize the description of the interarytenoid anatomy and to test its reliability., Study Design: Retrospective review of endoscopic videos., Setting: Pediatric academic center., Subjects and Methods: The interarytenoid assessment protocol comprises 4 steps for evaluation of the interarytenoid region relative to known anatomic landmarks in the supraglottis, glottis, and subglottis. Thirty consecutively selected videos of the protocol were reviewed by 4 otolaryngologists. The raters were blinded to identifying information, and the video order was randomized for each review. We assessed protocol completion times and calculated Cohen's linear-weighted κ coefficient between blinded expert raters and with the operating surgeon to evaluate interrater/intrarater reliability., Results: Median age was 4.9 years (59 months; range, 1 month to 20 years). Median completion time was 144 seconds. Interrater and intrarater reliability showed substantial agreement (interrater κ = 0.71 [95% confidence interval (CI), 0.55-0.87]; intrarater mean κ = 0.70 [95% CI, 0.59-0.92/rater 1, 0.47-0.85/rater 2]; P < .001). Comparing raters to the operating surgeon demonstrated substantial agreement (mean κ = 0.62; 95% CI, 0.31-0.79/rater 1, 0.48-0.89/rater 2; P < .001)., Conclusion: The interarytenoid assessment protocol appears reliable in describing interarytenoid anatomy. Rapid completion times and substantial interrater/intrarater reliability were demonstrated. Incorporation of this protocol may provide important steps toward improved standardization in the anatomic description of the interarytenoid region in pediatric dysphagia.

Objectives: To describe the clinical presentation of lymphatic malformations (LM) and genotypically associated disorders and to summarize the recent literature regarding the genetic etiology of LM and provide a biologic correlation to medical and surgical management., Results: LM are congenital lesions derived from a developmental abnormality of the lymphatic vessels. The severity of disease varies widely and complications can occur with higher staged disease and those associated with a known constellation of symptoms. Somatic mutations of the PIK3CA gene have been found to be an etiologic factor in the development of LM and associated overgrowth syndromes. Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that inhibits the pathway downstream of PIK3CA . Preliminary studies in select groups of patients suggest that sirolimus has a role in the medical management of certain aspects of this disease., Conclusions: Discovery of LM molecular genetics has led to the possibility of targeted therapies and highlights the importance of precision medicine in rare diseases. Identifying genetic mutations in larger cohorts of patients with LM will lead to additional insights. Knowledge of the genetic basis for disease can then lead to discovery of directed medical therapy. A specific molecular diagnosis can also help families understand better why their child is different and provide accurate counseling for subsequent pregnancies., Level of Evidence: 6.

Background: Licorice is an herb extensively used for both culinary and medicinal purposes. Various constituents of licorice have been shown to exhibit anti-tumorigenic effect in diverse cancer types. However, majority of these studies focus on the aspect of their growth-suppressive role. In this study, we systematically analyzed known licorice's constituents on the goal of identifying component(s) that can effectively suppress both cell migration and growth., Methods: Effect of licorice's constituents on cell growth was evaluated by MTT assay while cell migration was assessed by both wound-healing and Transwell assays. Cytoskeleton reorganization and focal adhesion assembly were visualized by immunofluorescence staining with labeled phalloidin and anti-paxillin antibody. Activity of Src in cells was judged by western blot using phosphor-Src416 antibody while Src kinase activity was measured using Promega Src kinase assay system. Anti-tumorigenic capabilities of isoliquiritigenin (ISL) and 2, 4, 2', 4'-Tetrahydroxychalcone (THC) were investigated using lung cancer xenograft model., Results: Using a panel of lung cancer cell lines, ISL was identified as the only licorice's constituent capable of inhibiting both cell migration and growth. ISL-led inhibition in cell migration resulted from impaired cytoskeleton reorganization and focal adhesion assembly. Assessing the phosphorylation of 141 cytoskeleton dynamics-associated proteins revealed that ISL reduced the abundance of Tyr421-phosphorylation of cortactin, Tyr925- and Tyr861-phosphorylation of FAK, indicating the involvement of Src because these sites are known to be phosphorylated by Src. Enigmatically, ISL inhibited Src in cells while displayed no effect on Src activity in cell-free system. The discrepancy was explained by the observation that THC, one of the major ISL metabolite identified in lung cancer cells abrogated Src activity both in cells and cell-free system. Similar to ISL, THC deterred cell migration and abolished cytoskeleton reorganization/focal adhesion assembly. Furthermore, we showed both ISL and THC suppressed in vitro lung cancer cell invasion and in vivo tumor progression., Conclusion: Our study suggests that ISL inhibits lung cancer cell migration and tumorigenesis by interfering with Src through its metabolite THC. As licorice is safely used for culinary purposes, our study suggests that ISL or THC may be safely used as a Src inhibitor.

Objective To describe how deductible health plans affect parental decision making for common pediatric otolaryngology operations. Study Design A cross-sectional survey study. Setting Tertiary care pediatric hospital. Subjects and Methods Caregivers of patients aged <18 years were surveyed to assess factors in decision making related to common otolaryngologic surgical procedures, including outpatient tympanostomy tubes and adenotonsillectomy, between July 2015 and June 2016. Children in foster care and those who underwent nonelective surgery were excluded. Decision-making factors were statistically analyzed with univariate and multivariate ordinal logistic regression. Results A total of 155 caregivers completed the survey. The median age of the patient at the time of the surgery was 3 years. Surgical procedures included tympanostomy tube placement (51%), adenotonsillectomy (37%), tympanostomy tube placement with adenotonsillectomy (10%), and other (2%). The mean ± SD annual deductible per child was $1870 ± $140, and the mean maximum out-of-pocket expense was $3833 ± $235. The odds of having the deductible or out-of-pocket expense affect surgical decision making was greater for those covered under a high-deductible health plan (odds ratio = 2.27; 95% CI, 1.25-4.12; P = .007). Conclusion High-deductible health plans and out-of-pocket expenses can influence parental decision making for common otolaryngology operations, such as tympanostomy tube placement and adenotonsillectomy. Future studies are needed to determine if such policies affect access to care in the pediatric population.

Purpose of Review: This chapter will summarize the most recent literature regarding the current state of medical treatment for vascular anomalies., Recent Findings: Research into the biology of these anomalies has strengthened our understanding of each anomaly and has helped to pave the way for more tailored treatment options involving molecular and/or genetic targets., Summary: While there is still a role for surgical intervention, medical therapies that target the etiology of vascular anomalies may represent an alternative or adjunctive approach in the management of these lesions., Competing Interests: Conflict of Interest: Reema Padia, Catherine Bull, Randall Bly, Amy E. Geddis, and Jonathan Perkins declare no conflicts of interest.

Objective: To compare operation-specific decannulation rates between single-stage (SSLTR) and double-stage laryngotracheal reconstruction (DSLTR) when controlling for grade of airway stenosis., Methods: A systematic review and meta-analysis were performed using PubMed, EMBASE and Cochrane databases from 1970 to 2015 to examine primary SSLTR and DSLTR for subglottic stenosis in patients 18 years or younger. Primary outcome was decannulation or extubation after LTR. Failures included patients not decannulated or requiring additional open airway procedures prior to decannulation. Only studies providing outcomes delineated by airway stenosis grade were included. Non-English language studies and case reports were excluded., Results: There were 712 abstracts reviewed and 16 studies with 663 pooled patients included in the systematic review analysis. The metaanalysis included 5 studies. Overall, the operation-specific decannulation success was statistically significantly different between SSLTR [93.2% (N = 221)] and DSLTR [83.7% (N = 442)] (P<0.001). When controlling for stenosis severity, however, no difference was found in decannulation success between SS- or DSLTR except in the grade 3 group: Grade 1-100% (N = 6) vs. 100% (N = 6), (P = 1); Grade 2 - 84.9% (N = 106) vs. 83.3% (N = 138), (P = 0.72); Grade 3-80.2% (N = 101) vs. 69.7% (N = 238), (P = 0.03); Grade 4-33.3% (N = 6) vs. 50% (N = 58), (P = 0.67)., Conclusion: No difference in decannulation rates was seen between SSLTR and DSLTR when comparing similar grades of stenosis except in grade 3 stenosis. With worsening stenosis, the success rate declines with both methods. Prospective studies with standardized enrollment criteria and reported outcomes are needed to better understand the advantages and disadvantages of each approach., (Published by Elsevier B.V.)

Objectives Review the incidence of long-term sequelae after placement of tympanostomy tubes. Study Design Case series with chart review. Setting Multihospital network. Subjects Patients 0 to 3 years old undergoing tympanostomy tube (TT) placement. Methods A case series of 14,058 children between 2004 and 2010 was reviewed. The patients were followed for 5 years to determine number of repeated tube placements, need for surgical removal of tubes, and presence of perforation requiring repair. Results The study cohort included 14,058 children who underwent TT placement. The mean age at time of procedure was 1.4 years. A total of 14.4% of patients required a second set of tubes within the 5 years of follow-up studied, and 4.6% required 3 or more sets. Three percent required removal of a tube, and this occurred at an average time of 34.2 ± 17.6 months postplacement. In total, 5.1% had a resulting perforation after either tube extrusion or tube removal requiring myringoplasty. Conclusions The rate of multiple tube placements and myringoplasty and tympanoplasty to correct resulting perforations has yet to be studied in a single large population. This information allows for more detailed preoperative counseling to patients and families. Better characterization of these populations with accurate rates of sequelae can help to tailor treatment and preoperative counseling in the future.

Objectives: (1) Review effectiveness of adenotonsillectomy (T&A) for obstructive sleep apnea (OSA) in children with Prader-Willi syndrome (PW). (2) Examine the incidence of velopharyngeal insufficiency (VPI) after T&A in this population. (3) Compare outcomes of T&A in PW and Trisomy 21 (T21) patients., Methods: Outcomes after T&A in a PW cohort were retrospectively reviewed and compared to those in patients with T21., Results: The study cohort included 22 PW patients. They were compared to 47 T21 patients who also underwent T&A. Eighteen percent (N = 4) of the PW patients had postoperative VPI requiring a corrective procedure, while there were no patients within the T21 cohort who had identified VPI ( P < .05). In those patients that had a postoperative polysomnogram, the mean decrease in obstructive apnea-hypopnea index (OAHI) of the PW and T21 patients measured 8.4 and 4.7 points, respectively ( P = .3)., Conclusions: This study demonstrated a higher rate of VPI after T&A in PW children as compared to another at-risk cohort, T21 patients. While the OAHI decreased after T&A in both groups, a significant number of children with PW or T21 had persistent OSA. Further investigation into the optimal management of OSA, while preventing treatment complications such as VPI, is needed for children with these high-risk conditions.

Objective: Otitis media requiring tympanostomy tubes (OMwTT) is a prevalent disease process that has been previously shown to have a strong familial link. The impact from the environmental versus genetic contributions to this link is unknown. The objective was to determine the environmental involvement in the development of OMwTT., Methods: Using an extensive genealogical database linked to medical records, we evaluated the risk of OMwTT in children of probands as compared to children of controls, individually matched 5:1 on sex and birth year, from a conditional logistic regression model. The model included adjustments for geographic and socioeconomic environmental risk factors mapped to residence location of study subjects within 63 small health statistical areas of ∼33,500 persons each., Results: 37,814 case probands diagnosed with OMwTT and 181,339 controls were included in our analysis. Children of probands with OMwTT had an overall 2.5× higher risk of also having OMwTT as compared to the children of controls (p < 10 -9 ), independent of environmental factors (PM 2.5 [particulate matter] air pollution, education level of parents, and density of primary care providers)., Conclusion: After accounting for geographic and socioeconomic differences that may influence risk between cases and controls, our findings suggest evidence of a genetic predisposition in families of OMwTT patients. Further characterization of high-risk pedigrees is needed for future genomic studies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Dysphonia secondary to posterior glottic insufficiency (PGI) can be difficult to identify and correct. Inadequate arytenoid approximation from medial arytenoid erosion results in a breathy, soft voice. The anatomical location of the gap is difficult to correct by vocal fold injection laryngoplasty. This study reviews the presentation, evaluation, and treatment for pediatric patients who were identified with PGI., Methods: An Institutional Review Board-approved chart review was performed on all patients who were diagnosed with PGI at our institution from 2013 to 2015. We studied the presentation, workup, and treatment for these patients, including laryngoscopy, parent or patient-based voice impairment ratings, and response to treatment., Results: Seven patients were identified. Erosion of the medial arytenoid was identified on microlaryngoscopy for all of these patients. The patients had suboptimal improvement from injection laryngoplasty. Three patients underwent surgical correction with an endoscopic posterior cricoid reduction laryngoplasty (EPCRL) with significant improvement in voice, assessed by perceptual, laryngoscopic, and patient-based measures., Conclusion: The key diagnostic procedures to identify posterior glottic insufficiency include laryngoscopic findings of a posterior glottal gap, microlaryngoscopy with close inspection of the posterior glottis and medial arytenoids, and suboptimal response to injection laryngoplasty. The EPCRL is an effective procedure to treat dysphonia from PGI.

Objectives/hypothesis: Placement of tympanostomy tubes for recurrent or chronic otitis media is the most commonly performed ambulatory procedure in the United States. Etiologies have been speculated to be environmentally based, and studies have suggested a genetic component to the disease. However, no large-scale studies have attempted to define a familial component. The objective of this study was to determine the familial risk of otitis media requiring tympanostomy tubes (OMwTT) in a statewide population., Study Design: Retrospective observational cohort study with population-based matched controls., Methods: Using an extensive genealogical database linked to medical records, the familial risk of OMwTT was calculated for relatives of probands (46,249 patients diagnosed with OMwTT from 1996-2013) compared to random population controls matched 5:1 on sex and birth year from logistic regression models., Results: The median age at time of tympanostomy tube placement was 1 year (interquartile range, 0-2 years). First-degree relatives of patients with OMwTT, primarily siblings, had a 5-fold increased risk of OMwTT (P < 10 -16 ). Second-degree relatives were at a 1.5-fold increased risk (P < 10 -15 ). More extended relatives (third, fourth and fifth degree) showed a 1.4-fold increased risk (P < 10 -15 )., Conclusions: In the largest population-based study to date, a significant familial risk is confirmed in OMwTT, suggesting otitis media may have a significant genetic component given the increased risk found in close as well as distant relatives. This could be influenced by shared environments given a five-times risk observed in siblings. Further understanding the genetic basis of OMwTT and its interplay with environmental factors may clarify the etiology and lead to better detection of disease and treatments., Level of Evidence: 3b. Laryngoscope, 127:962-966, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Septoplasty and turbinate reduction (STR) is a common procedure for which cost reduction efforts may improve value. The purpose of this study was to identify sources of variation in medical facility and surgeon costs associated with STR, and whether these costs correlated with short-term complications., Methods: An observational cohort study was performed in a multifacility network using a standardized cost-accounting system to determine costs associated with adult STR from January 1, 2008 to July 31, 2015. A total of 4007 cases, performed at 21 facilities, by 72 different surgeons were included in the study. Total costs, variable costs, operating room (OR) time, and 30-day complications (eg, epistaxis) were compared among surgeons, facilities, and specialties., Results: Total procedure cost: (mean ± standard deviation [SD]) $2503 ± $790 (range, $852 to $10,559). Mean total variable cost: $1147 ± $423 (range, $400 to $5,081). Intersurgeon and interfacility variability was significant for total cost (p < 0.0001) and OR time (p < 0.0001). Intersurgeon OR supply cost variability was also significant (p < 0.0001). Otolaryngologists had less total cost (p < 0.0001), OR time/cost (p < 0.0001), and complications (p = 0.0164), but greater supply cost (p < 0.0001), than other specialties., Conclusion: There is wide variation in cost associated with STR. Significant variance in OR time and supply cost between surgeons suggests these are potential areas for cost reduction. Although no increased 30-day complications were seen with faster and less costly surgeries, further research is needed to evaluate how time and cost relate to quality of care., (© 2016 ARS-AAOA, LLC.)

Objectives/hypothesis: To determine the relative risk of having eosinophilic esophagitis (EoE) coexist with chronic rhinosinusitis (CRS) in probands and their families using the Utah Population Database (UPDB)., Methods: This retrospective observational cohort study with population-based matched controls utilized the UPDB, a genealogical database linked to medical records. It was used to identify CRS and EoE patients diagnosed at any age between 2008 and 2012. The familial risks of an EoE diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 530.13) in CRS probands, and vice versa, and their first- through fifth-degree relatives and spouses were calculated using logistic regression models in comparison to controls randomly selected from the Utah population and individually matched 6:1 on sex and birth year., Results: Probands with CRS demonstrated a 3.4-fold increased risk of having EoE themselves (P < 10(-15) ). First-degree relatives (parents, siblings, and children) of CRS probands had a 1.5-fold increased risk of having EoE (P < 10(-4) ), whereas more distant relatives did not show a significant increased risk. Spouses of probands had a 1.4-fold increased risk of having EoE (P = 0.055). Conversely, risk estimates of having CRS in EoE probands were consistent., Conclusion: We observed an increased risk of comorbid EoE in patients with CRS and their families. An association between CRS and EoE as comorbid conditions suggests that a familial component is contributing to the etiology of both diseases. Further analyses regarding the pathophysiology of the development of CRS in these specific patients will lead to a better understanding of both disease processes and may help target therapy., Level of Evidence: 3b. Laryngoscope, 126:1279-1283, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Review costs for pediatric patients with complicated acute sinusitis., Methods: A retrospective case series of patients in a pediatric hospital was created to determine hospital costs using a standardized activity-based accounting system for inpatient treatment between November 2010 and December 2014. Children less than 18 years of age who were admitted for complicated acute sinusitis were included in the study. Demographics, length of stay, type of complication and cost of care were determined for these patients., Results: The study included 64 patients with a mean age of 10 years. Orbital cellulitis (orbital/preseptal/postseptal cellulitis) accounted for 32.8% of patients, intracranial complications (epidural/subdural abscess, cavernous sinus thrombosis) for 29.7%, orbital abscesses (subperiosteal/intraorbital abscesses) for 25.0%, potts puffy tumor for 7.8%, and other (including facial abscess and dacryocystitis) for 4.7%. The average length of stay was 5.7 days. The mean cost per patient was $20,748. Inpatient floor costs (31%) and operating room costs (18%) were the two greatest expenditures. The major drivers in variation of cost between types of complications included pediatric intensive care unit stays and pharmacy costs., Conclusion: Although complicated acute sinusitis in the pediatric population is rare, this study demonstrates a significant financial impact on the health care system. Identifying ways to reduce unnecessary costs for these visits would improve the value of care for these patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To (1) determine adherence to American Academy of Otolaryngology-Head and Neck Surgery Foundation guidelines for pediatric tonsillectomy recommending routine administration of perioperative dexamethasone and against routine antibiotic administration among surgeons and hospitals in a multihospital network and (2) evaluate the impact of adherence on the risk of complications., Study Design: Case series with chart review., Setting: Multihospital network., Subjects and Methods: A case series of 15,950 children aged 1 to 18 years undergoing same-day surgery adenotonsillectomy (T&A) within a multihospital network from 2008 to 2014 was reviewed to determine whether dexamethasone and/or antibiotics were given in the hospital. The frequency of dexamethasone and antibiotic administration was compared among surgeons and hospitals in the years before and after the guidelines were published. The frequency of complications was compared in adhering vs nonadhering surgeons., Results: The study cohort included 15,950 children undergoing T&A at 19 hospitals by 74 surgeons. Of the patients before guideline publication, 98.4% (n = 7432) received dexamethasone compared with 98.9% of subjects after guideline publication (n = 8518). In total, 16.1% received antibiotics before the guidelines compared with 13.8% after. Prior to the guidelines, 27 of 74 surgeons (36%) routinely gave antibiotics. After the guidelines were published, 19 surgeons (26%) continued to give antibiotics more than 50% of the time. There was no difference in complication visits between adhering and nonadhering surgeons., Conclusions: Most hospitals and surgeons administered perioperative dexamethasone routinely. While the overall frequency of antibiotic administration decreased after the guidelines were published, a significant percentage of surgeons continued to give antibiotics routinely, suggesting the need for improved dissemination and implementation of guidelines to promote adherence., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Mammary stem/progenitor cells (MaSCs) maintain self-renewal of the mammary epithelium during puberty and pregnancy. DNA methylation provides a potential epigenetic mechanism for maintaining cellular memory during self-renewal. Although DNA methyltransferases (DNMTs) are dispensable for embryonic stem cell maintenance, their role in maintaining MaSCs and cancer stem cells (CSCs) in constantly replenishing mammary epithelium is unclear. Here we show that DNMT1 is indispensable for MaSC maintenance. Furthermore, we find that DNMT1 expression is elevated in mammary tumours, and mammary gland-specific DNMT1 deletion protects mice from mammary tumorigenesis by limiting the CSC pool. Through genome-scale methylation studies, we identify ISL1 as a direct DNMT1 target, hypermethylated and downregulated in mammary tumours and CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits CSC population. Altogether, our studies uncover an essential role for DNMT1 in MaSC and CSC maintenance and identify DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment.

Commensal gut microflora and dietary fiber protect against colonic inflammation and colon cancer through unknown targets. Butyrate, a bacterial product from fermentation of dietary fiber in the colon, has been implicated in this process. GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing T cells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 in colonic epithelium. Consequently, Niacr1(-/-) mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr10a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon., (Copyright © 2014 Elsevier Inc. All rights reserved.)

High abundance of c-Jun is detected in invasive breast cancer cells and aggressive breast tumor malignancies. Here, we demonstrate that a major cause of high c-Jun abundance in invasive breast cancer cells is prolonged c-Jun protein stability owing to poor poly-ubiquitination of c-Jun. Among the known c-Jun-targeting E3 ligases, we identified constitutive photomorphogenesis protein 1 (COP1) as an E3 ligase responsible for c-Jun degradation in less invasive breast cancer cells because depletion of COP1 reduced c-Jun poly-ubiquitination leading to the stabilization of c-Jun protein. In a panel of breast cancer cell lines, we observed an inverse association between the levels of COP1 and c-Jun. However, overexpressing COP1 alone was unable to decrease c-Jun level in invasive breast cancer cells, indicating that efficient c-Jun protein degradation necessitates an additional event. Indeed, we found that glycogen synthase kinase 3 (GSK3) inhibitors elevated c-Jun abundance in less invasive breast cancer cells and that GSK3β nonphosphorylable c-Jun-T239A mutant displayed greater protein stability and poorer poly-ubiquitination compared to the wild-type c-Jun. The ability of simultaneously enforced expression of COP1 and constitutively active GSK3β to decrease c-Jun abundance in invasive breast cancer cells allowed us to conclude that c-Jun is negatively regulated through the coordinated action of COP1 and GSK3β. Importantly, co-expressing COP1 and active GSK3β blocked in vitro cell growth/migration and in vivo metastasis of invasive breast cancer cells. Gene expression profiling of breast tumor specimens further revealed that higher COP1 expression correlated with better recurrence-free survival. Our study supports the notion that COP1 is a suppressor of breast cancer progression.

The importance of microRNAs (miRNAs) in biological and disease processes necessitates a better understanding of the mechanisms that regulate miRNA abundance. We showed that the activities of the mitogen-activated protein kinase (MAPK) p38 and its downstream effector kinase MAPK-activated protein kinase 2 (MK2) were necessary for the efficient processing of a subset of primary miRNAs (pri-miRNAs). Through yeast two-hybrid screening, we identified p68 (also known as DDX5), a key component of the Drosha complex that processes pri-miRNAs, as an MK2-interacting protein, and we found that MK2 phosphorylated p68 at Ser(197) in cells. In wild-type mouse embryonic fibroblasts (MEFs) treated with a p38 inhibitor or in MK2-deficient (MK2(-/-)) MEFs, expression of a phosphomimetic mutant p68 fully restored pri-miRNA processing, suggesting that MK2-mediated phosphorylation of p68 was essential for this process. We found that, whereas p68 was present in the nuclei of wild-type MEFs, it was found mostly in the cytoplasm of MK2(-/-) MEFs. Nuclear localization of p68 depended on MK2-mediated phosphorylation of Ser(197). In addition, inhibition of p38 MAPK promoted the growth of wild-type MEFs and breast cancer MCF7 cells by enhancing the abundance of c-Myc through suppression of the biogenesis of the miRNA miR-145, which targets c-Myc. Because pri-miRNA processing occurs in the nucleus, our findings suggest that the p38 MAPK-MK2 signaling pathway promotes miRNA biogenesis by facilitating the nuclear localization of p68.

The most important requisite in the care of ulcers in the heel region is replacement skin cover with adequate sensation. The dorsalis pedis flap appears adequate, but the anterior subcutaneous approach gives a pedicle of inadequate length to enable the flap to reach the most important posterior weight-bearing area. It was therefore decided to short-circuit the course of the pedicle by passing the whole flap through the interosseous membrane between the tibia and the fibula to enable the flap to reach the weight-bearing area without tension. After 10 meticulous cadaver and two post-traumatic limb dissections with angiographic confirmation, it appeared that such a flap was feasible and would satisfy all basic requirements. Clinically this technique was tried in two patients who were provided with sensate, well padded skin cover for the whole of the heel region.