Matthew G. Crowson

IRF2BP2 is a skeletal and cardiac muscle-enriched ischemia-inducible activator of VEGFA expression

We sought to identify an essential component of the TEAD4/VGLL4 transcription factor complex that controls vascular endothelial growth factor A (VEGFA) expression in muscle. A yeast 2-hybrid screen was used to clone a novel component of the TEAD4 complex from a human heart cDNA library. We identified interferon response factor 2 binding protein 2 (IRF2BP2) and confirmed its presence in the TEAD4/VGLL4 complex in vivo by coimmunoprecipitation and mammalian 2-hybrid assays. Coexpression of IRF2BP2 with TEAD4/VGLL4 or TEAD1 alone potently activated, whereas knockdown of IRF2BP2 reduced, VEGFA expression in C(2)C(12) muscle cells. Thus, IRF2BP2 is required to activate VEGFA expression. In mouse embryos, IRF2BP2 was ubiquitously expressed but became progressively enriched in the fetal heart, skeletal muscles, and lung. Northern blot analysis revealed high levels of IRF2BP2 mRNA in adult human heart and skeletal muscles, but immunoblot analysis showed low levels of IRF2BP2 protein in skeletal muscle, indicating post-transcriptional regulation of IRF2BP2 expression. IRF2BP2 protein levels are markedly increased by ischemia in skeletal and cardiac muscle compared to normoxic controls. IRF2BP2 is a novel ischemia-induced coactivator of VEGFA expression that may contribute to revascularization of ischemic cardiac and skeletal muscles.

Posterior semicircular canal dehiscence: CT prevalence and clinical symptoms.

Objective To estimate the prevalence of and symptoms associated with posterior semicircular canal dehiscence (PSCD) compared to superior semicircular canal dehiscence (SSCD) and nondehiscent semicircular canals (NDSC). Study Design Retrospective review. Setting Academic tertiary referral center. Patients Review of 412 temporal bone CT scans and associated patient records, excluding patients with prior mastoid or skull base surgery. Intervention(s) CT images (0.625 mm thick) were reviewed in the planes of the semicircular canals. Patient demographics and symptoms were tabulated and analyzed. Main Outcome Measure(s) Prevalence of PSCD and SSCD; degree of hearing loss; presence or absence of aural fullness, autophony, tinnitus, pulsatile tinnitus, disequilibrium, vertigo, and Tullio phenomenon. Results Review of the 412 CT scans revealed 5 cases of PSCD (1.2%) and 20 cases of SSCD (4.9%). All patients with PSCD were male, aged 16 to 73 years. One patient with PSCD reported tinnitus, autophony, disequilibrium, vertigo, and Tullio phenomenon; 2 patients reported only tinnitus and aural fullness, and 1 patient had no symptoms. PSCD was commonly associated with SSCD. There were no significant differences in symptoms between PSCD patients and the other groups. There were, however, statistically significant differences between SSCD patients and NDSC patients in the rates of autophony, tinnitus, and disequilibrium. Conclusion The prevalence of PSCD in patients undergoing temporal bone CT scans is considerably less than SSCD (1.2% versus 4.9%), and the 2 conditions commonly coexist. Given the small numbers in our study, we were not able to demonstrate any distinguishable clinical features for the PSCD patients.

A Systematic Review of Diuretics in the Medical Management of Ménière’s Disease:

Objective (1) Review evidence for the use of oral diuretic medications in the management of Ménière’s disease. (2) Analyze therapy-related hearing and vertigo outcomes. Data Sources Literature was obtained through directed searches of MEDLINE, EMBASE, Web of Science, EBSCO Host, Cochrane Reviews, and linked citations through seminal papers. We searched independent electronic databases for articles that reported the use of diuretics in patients with Ménière’s disease. Review Methods All articles of level 4 evidence or higher, per the Oxford Centre for Evidence-Based Medicine, were included with no limit for number of patients, duration of therapy, or follow-up period. Two independent investigators reviewed the articles for inclusion eligibility. Outcomes were tabulated, including subjective or quantitative measures of hearing, tinnitus, vertigo episode frequency, and medication adverse effects. Results Nineteen articles were included from 1962 to 2012 from 11 countries. Twelve retrospective case series, 4 randomized controlled trials, 2 case-control trials, and 1 prospective case series were identified. Six studies investigated isosorbide; 5, hydrochlorothiazide; 2, acetazolamide; 2, chlorthalidone; and 1 each of betahistine, hydrochlorothiazide, chlorthalidone, acetazolamide, hydrochlorothiazide-triamterene, and nimodipine. Eight (42.1%) studies reported hearing outcomes improvement. Fifteen (79.0%) studies reported vertigo outcomes improvement. Ten (52.6%) studies reported no side effects, and 4 studies (21.1%) reported abdominal discomfort. No significant morbidity or mortality was reported in any study. Conclusion Multiple low evidence–level studies report that oral diuretic therapy may be beneficial in the medical management of Ménière’s disease. Improvement in vertigo episode frequency was consistently reported, with less convincing evidence for improvement in hearing outcomes.

Clinicopathologic factors and adjuvant treatment effects on survival in adult head and neck synovial cell sarcoma

Synovial cell sarcoma is a rare soft tissue sarcoma. The purpose of this study was to investigate clinicopathologic factors and management on survival in primary synovial sarcoma of the head and neck.

Emerging Therapies for Sensorineural Hearing Loss.

OBJECTIVE To critically review and evaluate the proposed mechanisms and documented results of the therapeutics currently in active clinical drug trials for the treatment of sensorineural hearing loss. DATA SOURCES US National Institutes of Health (NIH) Clinical Trials registry, MEDLINE/PubMed. STUDY SELECTION & DATA EXTRACTION A review of the NIH Clinical Trials registry identified candidate hearing loss therapies, and supporting publications were acquired from MEDLINE/PubMed. Proof-of-concept, therapeutic mechanisms, and clinical outcomes were critically appraised. DATA SYNTHESIS Twenty-two active clinical drug trials registered in the United States were identified, and six potentially therapeutic molecules were reviewed. Of the six molecules reviewed, four comprised mechanisms pertaining to mitigating oxidative stress pathways that presumably lead to inner ear cell death. One remaining therapy sought to manipulate the cell death cascade, and the last remaining therapy was a novel cell replacement therapy approach to introduce a transcription factor that promotes hair cell regeneration. CONCLUSION A common theme in recent clinical trials registered in the United States appears to be the targeting of cell death pathways and influence of oxidant stressors on cochlear sensory neuroepithelium. In addition, a virus-delivered cell replacement therapy would be the first of its kind should it prove safe and efficacious. Significant challenges for bringing these bench-to-bedside therapies to market remain. It is never assured that results in non-human animal models translate to effective therapies in the setting of human biology. Moreover, as additional processes are described in association with hearing loss, such as an immune response and loss of synaptic contacts, additional pathways for targeting become available.

Does an Otolaryngology-Specific Database Have Added Value? A Comparative Feasibility Analysis

Objectives There are multiple nationally representative databases that support epidemiologic and outcomes research, and it is unknown whether an otolaryngology-specific resource would prove indispensable or superfluous. Therefore, our objective was to determine the feasibility of analyses in the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) databases as compared with the otolaryngology-specific Creating Healthcare Excellence through Education and Research (CHEER) database. Study Design Parallel analyses in 2 data sets. Setting Ambulatory visits in the United States. Subjects and Methods To test a fixed hypothesis that could be directly compared between data sets, we focused on a condition with expected prevalence high enough to substantiate availability in both. This query also encompassed a broad span of diagnoses to sample the breadth of available information. Specifically, we compared an assessment of suspected risk factors for sensorineural hearing loss in subjects 0 to 21 years of age, according to a predetermined protocol. We also assessed the feasibility of 6 additional diagnostic queries among all age groups. Results In the NAMCS/NHAMCS data set, the number of measured observations was not sufficient to support reliable numeric conclusions (percentage standard error among risk factors: 38.6-92.1). Analysis of the CHEER database demonstrated that age, sex, meningitis, and cytomegalovirus were statistically significant factors associated with pediatric sensorineural hearing loss (P < .01). Among the 6 additional diagnostic queries assessed, NAMCS/NHAMCS usage was also infeasible; the CHEER database contained 1585 to 212,521 more observations per annum. Conclusion An otolaryngology-specific database has added utility when compared with already available national ambulatory databases.

Preoperative Lumbar Drain Use During Acoustic Neuroma Surgery and Effect on CSF Leak Incidence

Objective: To determine if preoperative lumbar drain (LD) use reduces the incidence of postoperative cerebrospinal fluid (CSF) leak in patients undergoing acoustic neuroma resection. Methods: Retrospective review of 282 patients presenting for acoustic neuroma resection between 2005 and 2014. Results: Two hundred and eighty-two patients had a mean tumor size of 19.1 mm ± 10.2 mm. Twenty-nine (10.3%) patients developed a postoperative CSF leak. Two hundred and twenty patients (78.0%) received a preoperative LD, and 20 (9.1%) developed a CSF leak. Sixty-two (22.0%) patients did not receive a preoperative LD, and 9 (14.5%) developed a CSF leak. No significant difference in CSF leak frequency was observed with use versus no use of a LD (P = .23). Fifteen (5.3%) patients with an LD placed had a complication related to the LD. No significant difference in CSF leak frequency was observed with patient age, neurofibromatosis type-2 diagnosis, tumor size, or sidedness. Conclusions: Postoperative CSF leaks are among the most common complications of acoustic neuroma microsurgery. No formal guidelines exist for elective placement of a preoperative LD to lower the incidence of CSF leaks. Our reported CSF leak incidence with preoperative LD placement is not significantly lower than without LD use, and there is a complication rate associated with LD use.

Mini Review of the Cost-Effectiveness of Unilateral Osseointegrated Implants in Adults: Possibly Cost-Effective for the Correct Indication

An osseointegrated implant (e.g. bone-anchored hearing aid, BAHA) is a surgically implantable device for unilateral sensorineural and unilateral or bilateral conductive hearing loss in patients who otherwise cannot use or do not prefer a conventional air conduction hearing aid (ACHA). The specific indications for an osseointegrated implant are evolving and dependent upon the country or regulatory body overseeing the provision of these devices. However, there are general groups of patients who would be likely to benefit, one such group being patients with congenital aural atresia. Given the anatomical aberrancies with aural atresia, these subjects cannot wear ACHAs. Another group of patients who may benefit from an osseointegrated implant over an ACHA are patients with chronically draining otological infections. As the provision of an osseointegrated implant requires a surgical procedure, there are inherent direct and indirect costs associated with its use beyond those required for an ACHA. Consideration of outcomes and cost-effectiveness for the osseointegrated implant versus the ACHA is prudent prior to making policy decisions in a setting of limited health care resources. We performed a mini review on all available cost-effectiveness analyses of osseointegrated implants published in Medline. There are only 2 contemporary cost-effectiveness analyses published to date. There is limited quality of life data available for patients living with an osseointegrated implant. As a result, the cost-effectiveness of the osseointegrated implant, specifically the BAHA, compared to conventional hearing aid devices remains unclear. However, there are clear indications for the BAHA when a standard hearing aid cannot be used (e.g. chronic draining ear) or in single-sided severe-to-profound hearing loss with reasonable hearing in the contralateral ear. The BAHA should not be considered interchangeable with the ACHA with regard to cost-effectiveness, but rather considered as an effective option for the patient for the correct indication.

National Utilization and Forecasting of Ototopical Antibiotics: Medicaid Data Versus "Dr. Google".

Objectives: To forecast national Medicaid prescription volumes for common ototopical antibiotics, and correlate prescription volumes with internet user search interest using Google Trends (GT). Study Design: National United States Medicaid prescription and GT user search database analysis. Methods: Quarterly national Medicaid summary drug utilization data and weekly GT search engine data for ciprofloxacin-dexamethasone (CD), ofloxacin (OF), and Cortisporin (CS) ototopicals were obtained from January 2008 to July 2014. Time series analysis was used to assess prescription seasonality, Holt–Winters method for forecasting quarterly prescription volumes, and Pearson correlations to compare GT and Medicaid data. Results: Medicaid prescription volumes demonstrated sinusoidal seasonality for OF (r2 = 0.91), CS (r2 = 0.71), and CD (r2 = 0.62) with annual peaks in July, August, and September. In 2017, OF was forecasted to be the most widely prescribed ototopical, followed by CD. CS was the least prescribed, and volumes were forecasted to decrease 9.0% by 2017 from 2014. GT user search interest demonstrated analogous sinusoidal seasonality and significant correlations with Medicaid data prescriptions for CD (r = 0.38, p = 0.046), OF (r = 0.74, p < 0.001), CS (r = 0.49, p = 0.008). Conclusion: We found that OF, CD, and CS ototopicals have sinusoidal seasonal variation with Medicaid prescription volume peaks occurring in the summer. After 2012, OF was the most commonly prescribed ototopical, and this trend was forecasted to continue. CS use was forecasted to decrease. Google user search interest in these ototopical agents demonstrated analogous seasonal variation. Analyses of GT for interest in ototopical antibiotics may be useful for health care providers and administrators as a complementary method for assessing healthcare utilization trends.

Variation in the Use of Vestibular Diagnostic Testing for Patients Presenting to Otolaryngology Clinics with Dizziness

Objective We used a national otolaryngology practice–based research network database to characterize the utilization of vestibular function testing in patients diagnosed with dizziness and/or a vestibular disorder. Study Design Database review. Setting The Creating Healthcare Excellence through Education and Research (CHEER) practice-based research network of academic and community providers Subjects and Methods Dizzy patients in the CHEER retrospective database were identified through ICD-9 codes; vestibular testing procedures were identified with CPT codes. Demographics and procedures per patient were tabulated. Analysis included number and type of vestibular tests ordered, stratified by individual clinic and by practice type (community vs academic). Chi-square tests were performed to assess if the percentage of patients receiving testing was statistically significant across clinics. A logistic regression model was used to examine the association between receipt of testing and being tested on initial visit. Results A total of 12,468 patients diagnosed with dizziness and/or a vestibular disorder were identified from 7 community and 5 academic CHEER network clinics across the country. One-fifth of these patients had at least 1 vestibular function test. The percentage of patients tested varied widely by site, from 3% to 72%; academic clinics were twice as likely to test. Initial visit vestibular testing also varied, from 0% to 96% of dizzy patients, and was 15 times more likely in academic clinics. Conclusion There is significant variation in use and timing of vestibular diagnostic testing across otolaryngology clinics. The CHEER network research database does not contain outcome data. These results illustrate the critical need for research that examines outcomes as related to vestibular testing.