Distinct Localization, Transcriptional Profiles, and Functionality in Early Life Tonsil Regulatory T Cells.

CD4+ regulatory T cells (Tregs) are key orchestrators of the immune system, fostering the establishment of protective immunity while preventing deleterious responses. Infancy and childhood are crucial periods of rapid immunologic development, but how Tregs mediate immune responses at these earliest timepoints of human life is poorly understood. In this study, we compare blood and tissue (tonsil) Tregs across pediatric and adult subjects to investigate age-related differences in Treg biology. We observed increased FOXP3 expression and proportions of Tregs in tonsil compared with paired blood samples in children. Within tonsil, early life Tregs accumulated in extrafollicular regions with cellular interactions biased toward CD8+ T cells. Tonsil Tregs in both children and adults expressed transcriptional profiles enriched for lineage defining signatures and canonical functionality compared with blood, suggesting tissue as the primary site of Treg activity. Early life tonsil Tregs transcriptional profiles were further defined by pathways associated with activation, proliferation, and polyfunctionality. Observed differences in pediatric tonsil Treg transcriptional signatures were associated with phenotypic differences, high proliferative capacity, and robust production of IL-10 compared with adult Tregs. These results identify tissue as a major driver of Treg identity, provide new insights into developmental differences in Treg biology across the human lifespan, and demonstrate unique functional properties of early life Tregs.

Two-Year Outcomes After Pediatric In-Office Tympanostomy Using Lidocaine/Epinephrine Iontophoresis and an Automated Tube Delivery System.

OBJECTIVE: Evaluate 2-year outcomes after lidocaine/epinephrine iontophoresis and tympanostomy using an automated tube delivery system for pediatric tube placement in-office. STUDY DESIGN: Prospective, single-arm. SETTING: Eighteen otolaryngology practices. METHODS: Children age 6 months to 12 years indicated for tympanostomy were enrolled between October 2017 and February 2019. Local anesthesia of the tympanic membrane was achieved via lidocaine/epinephrine iontophoresis and tympanostomy was completed using an automated tube delivery system (the Tula® System). An additional Lead-In cohort of patients underwent tube placement in the operating room (OR) under general anesthesia using only the tube delivery system. Patients were followed for 2 years or until tube extrusion, whichever occurred first. Otoscopy and tympanometry were performed at 3 weeks, and 6, 12, 18, and 24 months. Tube retention, patency, and safety were evaluated. RESULTS: Tubes were placed in-office for 269 patients (449 ears) and in the OR for 68 patients (131 ears) (mean age, 4.5 years). The median and mean times to tube extrusion for the combined OR and In-Office cohorts were 15.82 (95% confidence interval [CI]: 15.41-19.05) and 16.79 (95% CI: 16.16-17.42) months, respectively. Sequelae included ongoing perforation for 1.9% of ears (11/580) and medial tube displacement for 0.2% (1/580) observed at 18 months. Over a mean follow-up of 14.3 months, 30.3% (176/580) of ears had otorrhea and 14.3% (83/580) had occluded tubes. CONCLUSION: In-office pediatric tympanostomy using lidocaine/epinephrine iontophoresis and automated tube delivery results in tube retention within the ranges described for similar grommet-type tubes and complication rates consistent with traditional tube placement in the OR.

Differential Integrin Adhesome Expression Defines Human NK Cell Residency and Developmental Stage.

NK cells are innate immune cells that reside within tissue and circulate in peripheral blood. They interact with a variety of microenvironments, yet how NK cells engage with these varied microenvironments is not well documented. The adhesome represents a molecular network of defined and predicted integrin-mediated signaling interactions. In this study, we define the integrin adhesome expression profile of NK cells from human tonsil, peripheral blood, and those derived from human hematopoietic precursors through stromal cell coculture systems. We report that the site of cell isolation and NK cell developmental stage dictate differences in expression of adhesome associated genes and proteins. Furthermore, we define differences in cortical actin content associated with differential expression of actin regulating proteins, suggesting that differences in adhesome expression are associated with differences in cortical actin homeostasis. These data provide understanding of the diversity of human NK cell populations and how they engage with their microenvironment.

Ethical and Public Health Implications of Targeted Screening for Congenital Cytomegalovirus.

Congenital cytomegalovirus (cCMV) is the most common congenital infection and is associated with sensorineural hearing loss, developmental delays, and visual impairment. The clinical presentation of cCMV is variable, and the majority (80%-90%) of newborns will never manifest any clinical symptoms. Given the clinical heterogeneity of cCMV infection, it is challenging to identify which newborns may benefit from testing. Recently, certain states have implemented a targeted screening program in which newborns who fail the newborn hearing screen are tested for cCMV. Clinicians and legislative bodies have been propelled into debates about the ethical and moral permissibility of a targeted cCMV screening approach. Those who oppose this screening approach describe undue burden on patients, families, and the health care system because the majority of newborns who fail the newborn hearing screen and have cCMV will not go on to have any sequelae related to cCMV, including hearing loss. However, those who support this screening approach cite the importance of early detection and ongoing surveillance for hearing loss and developmental delays in this high-risk group of newborns. This debate will be considered by experts in the field.

Early experience with feasibility of balloon sinus dilation in complicated pediatric acute frontal rhinosinusitis.

BACKGROUND/OBJECTIVE: Complicated acute rhinosinusitis in the pediatric population is an uncommon problem that may affect the orbit or brain and is life-threatening. This condition requires surgical intervention with endoscopic sinus surgery for source control, and prior studies have demonstrated the safety of balloon sinuplasty in chronic frontal sinusitis. METHODS/RESULTS: We present our approach with a balloon sinus dilation hybrid procedure to resolve four distinct types of complicated acute frontal sinusitis in pediatric patients, including intracranial manifestations, intraorbital complications, and recurrent disease. All four patients were able to be managed operatively with frontal balloon sinuplasty. CONCLUSIONS: Prior efficacy has been demonstrated for chronic frontal sinusitis in the pediatric population. We demonstrate that frontal balloon sinuplasty is also feasible in the proper clinical setting for acute frontal sinusitis, even in the presence of regional complications or recurrent disease. LEVEL OF EVIDENCE: 4.

In-Office Tympanostomy Tube Placement in Children Using Iontophoresis and Automated Tube Delivery.

OBJECTIVES/HYPOTHESIS: Evaluate technical success, tolerability, and safety of lidocaine iontophoresis and tympanostomy tube placement for children in an office setting. STUDY DESIGN: Prospective individual cohort study. METHODS: This prospective multicenter study evaluated in-office tube placement in children ages 6 months through 12 years of age. Anesthesia was achieved via lidocaine/epinephrine iontophoresis. Tube placement was conducted using an integrated and automated myringotomy and tube delivery system. Anxiolytics, sedation, and papoose board were not used. Technical success and safety were evaluated. Patients 5 to 12 years old self-reported tube placement pain using the Faces Pain Scale-Revised (FPS-R) instrument, which ranges from 0 (no pain) to 10 (very much pain). RESULTS: Children were enrolled into three cohorts with 68, 47, and 222 children in the Operating Room (OR) Lead-In, Office Lead-In, and Pivotal cohorts, respectively. In the Pivotal cohort, there were 120 and 102 children in the <5 and 5- to 12-year-old age groups, respectively, with a mean age of 2.3 and 7.6 years, respectively. Bilateral tube placement was indicated for 94.2% of children <5 and 88.2% of children 5 to 12 years old. Tubes were successfully placed in all indicated ears in 85.8% (103/120) of children <5 and 89.2% (91/102) of children 5 to 12 years old. Mean FPS-R score was 3.30 (standard deviation [SD] = 3.39) for tube placement and 1.69 (SD = 2.43) at 5 minutes postprocedure. There were no serious adverse events. Nonserious adverse events occurred at rates similar to standard tympanostomy procedures. CONCLUSIONS: In-office tube placement in selected patients can be successfully achieved without requiring sedatives, anxiolytics, or papoose restraints via lidocaine iontophoresis local anesthesia and an automated myringotomy and tube delivery system. LEVEL OF EVIDENCE: 2b Laryngoscope, 130:S1-S9, 2020.

Pediatric thyroidectomies: A surgical subspecialty comparison.

OBJECTIVE: This study aims to establish the typical population, safety, and outcomes of pediatric thyroidectomies, specifically identifying surgical complication rates. Furthermore, the study compares management and complication differences between the two specialties that most often manage these patients - Pediatric General Surgery and Otolaryngology. METHODS: National Surgical Quality Improvement Program - Pediatrics (NSQIP-P) data between the years of 2012 and 2016 was reviewed and analyzed for patient characteristics, perioperative course and outcomes. Sub-group analysis was used to compare groups based on surgeon sub-specialty: Otolaryngology or Pediatric General Surgery. RESULTS: The study identified 516 cases pediatric patients operated on by Pediatric Otolaryngology (229; 44.4%) and Pediatric General Surgery (287; 55.6%). Overall, rates of surgical and medical adverse events were low (1.2% and 0.7%, respectively). Upon univariate analysis, there were no differences between specialties in surgical adverse events (p = 1.000), medical adverse events (p = 0.196), reoperation (p = 0.505), or readmission (p = 0.262). Indication for surgery differed between specialties, with benign neoplasm more common in the Pediatric Otolaryngology group (48.9% vs. 35.2%), and thyrotoxicosis more common in the Pediatric General Surgery group (43.9% vs. 23.1%) (p < 0.001). Compared to cases done by Otolaryngology, Pediatric General Surgery was independently associated with a shorter operative time (B: -31.583 min [95% CI: -42.802 to -20.364]; p < 0.001). CONCLUSION: Thyroidectomy in the pediatric population is a safe procedure with no differences in adverse outcomes noted when comparing Pediatric General Surgeons to Pediatric Otolaryngologists. Pediatric General Surgeons were observed to have a significantly shorter operative time.

A case of pediatric cervicofacial actinomyces masquerading as malignancy: Case report and review of the literature.

Cervicofacial actinomyces is an uncommon infection, especially in children. Notoriously low culture sensitivity and malignant appearance make diagnosis challenging. Treatment requires a prolonged antibiotic course often in conjunction with surgical debridement or drainage. We report an amorphous anterior neck mass in a 10-year-old girl due to actinomyces. Diagnosis required open biopsy after non-diagnostic fine needle aspirate and core needle biopsies. The patient responded well to six-week course of parenteral penicillin followed by six months of convalescent therapy with oral penicillin. In addition to a case discussion, we review cervicofacial actinomyces in the literature with a focus on pediatrics.

A population based analysis of the implementation of pediatric facemasks in girls youth lacrosse.

OBJECTIVE: To determine the incidence, relative risk reduction, odds ratio and absolute risk reduction of head and ear injuries associated with the implementation of pediatric facial eye guards in lacrosse events. STUDY DESIGN: Cross Sectional Review of a National Database. STUDY LOCATION: National Emergency Injury Survelliance System. METHODS: Our group retrospectively reviewed a nationwide sampling estimate of 809 patients who presented to emergency rooms with head and ear injuries during lacrosse events. The database was queried for lacerations, fractures, hemorrhages, abrasions and punctures associated with the face and ear. Incidence, relative risk, odds ratio and absolute risk reductions were calculated both five years before and five years after the introduction of the facial mask guard in 2006 to determine benefit. RESULTS: Of the 809 women's lacrosse injuries, 199 were localized to the facial region and 56 to the ear. After the implementation of the facial mask mandate, there was a significant decrease in the total incidence and relative risk of facial lacerations (P = 0.01, RR = 0.08 vs 0.01) and facial abrasions (P = 0.02, RR = 0.28 vs 0.12) respectively. Furthermore, there was a significant decrease in the odds of obtaining a facial laceration (OR: 0.16 95% CI:0.07-0.37), facial fractures (OR: 0.01, 95% CI:0.03-0.35) and abrasion (OR: 0.11, 95% CI:0.08-0.18) with facemask use. Unfortunately, there was no difference in total incidence, relative risk or odds of obtaining ear injury. CONCLUSION: It appears that the implementation of the mandate for female athletes to utilize the facemask starting in 2006 has provided a reduction in specific facial injuries. Further discussion should be continued in order to reduce further risk to the remaining head and neck region including the ears and neck with additional protective equipment.

CPAS: Surgical approach with combined sublabial bone resection and inferior turbinate reduction without stents.

OBJECTIVES/HYPOTHESIS: Congenital pyriform aperture stenosis (CPAS) is a form of nasal obstruction caused by congenital narrowing of the maxilla at the medial processes. Traditionally, surgical correction involves a sublabial approach with subperiosteal dissection, widening of the aperture by drilling, and the use of nasal stents postoperatively. Although this approach may lead to symptomatic improvement, it alone may fail to provide a patent airway secondary to unaddressed posterior narrowing. Additionally, the use of stents is problematic because they are prone to clogging and can cause internal nasal scarring and septal or alar necrosis. We present the surgical management of this condition in six patients using a novel approach that aims to correct these limitations by including both the traditional sublabial procedure and an endonasal reduction of the inferior turbinates, without the use of stents postoperatively. STUDY DESIGN: Retrospective chart review. METHODS: Review of the medical records of six consecutive patients aged 2 weeks to 7 months, who underwent repair of CPAS via a sublabial ostectomy and endonasal inferior turbinate reduction from 2009 to 2012. RESULTS: All six patients were clear of airway obstruction postoperatively and at follow-up. CONCLUSION: This is an alternative approach that leads to symptomatic improvement for CPAS patients without the morbidity associated with stent use. LEVEL OF EVIDENCE: 4.

Factors contributing to cost in partial versus total tonsillectomy.

OBJECTIVES/HYPOTHESIS: To examine differences between total tonsillectomy and partial intracapsular tonsillectomy techniques that may lead to differences in overall cost and resource utilization between these procedures. Preoperative, perioperative, and postoperative management and outcome factors were examined. STUDY DESIGN: Retrospective review at two university-based tertiary care hospitals from January 2007 to June 2010. METHODS: Pediatric patients with obstructive symptoms were divided into those undergoing total tonsillectomy and those undergoing partial intracapsular tonsillectomy. The records of 289 patients who underwent total tonsillectomy and 289 patients who underwent partial intracapsular tonsillectomy were reviewed. RESULTS: The average age of patients undergoing total and partial tonsillectomies was 5.0 years for both groups. Significant differences for patients undergoing total versus partial tonsillectomies were as follows: operative time (32.4 vs. 26.4 minutes, P < .0001), postanesthesia care unit (PACU) time (174 vs. 91.6 minutes, P < .0001), percent admitted postoperatively (21.5% vs. 1.7%, P < .0001), number requiring pediatric intensive care unit stay (3.5% vs. 0.3%, P < .05), number of readmissions after discharge (3.5% vs. 0.3%, P < .05), and number of postoperative emergency room visits separate from those requiring readmission (4.8% vs. 0%, P < .05). Factors that were not found to be significantly different included number of patients with postoperative hemorrhage and number requiring second operations for tonsillar regrowth. CONCLUSIONS: Previous studies have shown equivalent effectiveness between these two procedures; our study suggests decreased cost and resource utilization with partial tonsillectomy through reduced operative and PACU times and number of postoperative admissions and emergency department visits. As in all retrospective reviews, the findings are potentially confounded by unmeasured variables, including patient and demographic factors.

Not a "sound" decision: is cochlear implantation always the best choice?

OBJECTIVE: To review the candidacy criteria used to counsel parents of profoundly deaf children, to determine if these criteria have changed over time, and to evaluate eventual communication outcomes for these patients. DESIGN: Retrospective review of 483 pediatric cochlear implant candidates from September 1995 to December 2006 seen at a tertiary care pediatric hospital. RESULTS: Out of 483 implant candidates, 191 patients were initially felt not to be favorable candidates based on CI team evaluation. Of this group, 3 had insufficient records to review and were excluded. The remaining 188 patients underwent a detailed analysis of specific possible contraindications to implantation. This included audiologic, medical and psychosocial parameters. The data was divided into two time periods: Group 1 included 44 patients from 1995 to 2000, and Group 2 included 144 patients from 2001 to 2006. In Group 1, there was a higher percentage of children with language deprivation and developmental concerns and patients not ready, compared to Group 2 which had a higher percentage of families not ready and inadequate support systems. Group 1 had a higher percentage of patients who ultimately underwent cochlear implant, but otherwise the two groups were largely similar. CONCLUSION: Analysis of our data showed that the degree of concern that the cochlear implant team has in relationship to specific candidacy criteria has changed over time. Recommendations against a cochlear implant were often revisited after initial concerns were addressed. The use of a team approach, in conjunction with a validation tool, is important for establishing criteria for successful cochlear implantation in children to support appropriate counseling of patients and families and to plan post-implant management.

Ablation studies on the developing inner ear reveal a propensity for mirror duplications.

The inner ear develops from a simple ectodermal thickening known as the otic placode. Classic embryological manipulations rotating the prospective placode tissue found that the anteroposterior axis was determined before the dorsoventral axis. A small percentage of such rotations also resulted in the formation of mirror duplicated ears, or enantiomorphs. We demonstrate a different embryological manipulation in the frog Xenopus: the physical removal or ablation of either the anterior or posterior half of the placode, which results in an even higher percentage of mirror image ears. Removal of the posterior half results in mirror anterior duplications, whereas removal of the anterior half results in mirror posterior duplications. In contrast, complete extirpation results in more variable phenotypes but never mirror duplications. By the time the otocyst separates from the surface ectoderm, complete extirpation results in no regeneration. To test for a dosage response, differing amounts of the placode or otocyst were ablated. Removal of one third of the placode resulted in normal ears, whereas two-thirds ablations resulted in abnormal ears, including mirror duplications. Recent studies in zebrafish have demonstrated a role for the hedgehog (Hh) signaling pathway in anteroposterior patterning of the developing ear. We have used overexpression of Hedgehog interacting protein (Hip) to block Hh signaling and find that this strategy resulted in mirror duplications of anterior structures, consistent with the results in zebrafish.

Sir Charles Alfred Ballance: contributions to otology and neurotology.

STUDY DESIGN: A review of primary and secondary historical and scientific literature concerning the life and writings of Sir Charles Alfred Ballance (1856-1936). RESULTS: Sir Charles Alfred Ballance was a pioneer in otology and neurotology, responsible for many "firsts" in the field, including the complete removal of a cerebellopontine angle tumor with significant patient survival and grafting the mastoid cavity with epithelium to speed healing. He was a strict abdicator of the complete mastoid operation with ligature of the jugular vein and drainage of the lateral sinus, and he advanced many other neurotologic procedures during his lifetime. He successfully sectioned the VIIIth cranial nerve, relieving a patient from intractable vertigo, developed a meticulous system for treating the complications of suppurative infections of the mastoid, diligently studied facial nerve reanastomosis, and was the first to perform a spinal accessory to facial nerve anastomosis for the relief of facial palsy. Ballance published over 75 original articles and was the primary author on two landmark books concerning temporal bone and neurologic surgery. He was the leader of many surgical societies and maintained a life of research and science until his death. CONCLUSION: Sir Charles Ballance was a pioneer in neurotologic and skull base surgery and greatly advanced the field during its inception. This work focuses on the otologic and neurotologic endeavors of Sir Charles Alfred Ballance, bringing his accomplishments into modern relief.

A "synaptoplasmic cistern" mediates rapid inhibition of cochlear hair cells.

Cochlear hair cells are inhibited by cholinergic efferent neurons. The acetylcholine (ACh) receptor of the hair cell is a ligand-gated cation channel through which calcium enters to activate potassium channels and hyperpolarize the cell. It has been proposed that calcium-induced calcium release (CICR) from a near-membrane postsynaptic store supplements this process. Here, we demonstrate expression of type I ryanodine receptors in outer hair cells in the apical turn of the rat cochlea. Consistent with this finding, ryanodine and other store-active compounds alter the amplitude of transient currents produced by synaptic release of ACh, as well as the response of the hair cell to exogenous ACh. Like the sarcoplasmic reticulum of muscle, the "synaptoplasmic" cistern of the hair cell efficiently couples synaptic input to CICR.