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To create a model of the anatomic distribution, recurrence, and growth patterns of recurrent respiratory papillomatosis (RRP).Prospective, multi-institutional cohort study.Adult patients with a diagnosis of RRP evaluated between August 1, 2018 and February 1, 2021 at six participating centers were invited to enroll. At each office or operating room encounter, laryngologists recorded the location and size of RRP lesions using a 22-region schematic. A generalized linear mixed effects model was used to compare region variations in lesion prevalence and recurrence.The cohort comprised 121 patients: 74% were male, 81% had been diagnosed with adult-onset RRP, and a plurality (34%) had undergone 0 to 3 RRP interventions prior to enrollment. Across the study period, the odds of a lesion occurring in the glottis was significantly higher (odds ratio [OR]: 26.51; 95% confidence interval [CI]: 11.76-59.75, P .001) compared with all other areas of the larynx and trachea. Within the true vocal folds, the membranous vocal folds had significantly higher odds (OR: 6.16; 95% CI: 2.66-14.30, P .001) of lesion occurrence compared to the cartilaginous vocal folds. Despite these strong trends in lesion distribution, there were no differences in the odds of lesion recurrence, growth, or in the time to recurrence, between anatomic subsites.RRP lesions are most likely to occur in the glottis, particularly the membranous vocal folds, compared with other regions of the larynx or trachea. However, all lesions demonstrate similar behavior with respect to recurrence, growth, and time to recurrence regardless of anatomic location.3 Laryngoscope, 132:2403-2411, 2022.

Mergers and acquisitions are mainly due to financial and technological innovations but could also be due to changes in the structure of the economy, which alters the optimal production functions of banks. Banks that seek to be operationally efficient would focus more on expanding their asset size, in the face of bad loans, leading to the acquisition of less efficient banks. This paper develops two‐stage inverse data envelopment analysis (DEA) models for estimating potential gains from bank mergers for the top US commercial banks. The results show additional intermediate and final outputs at different predefined target levels of technical efficiencies.

Flexible laryngoscopy, the gold-standard evaluation of the larynx and the pharynx, is one of the most commonly performed procedures in otolaryngology. During the coronavirus disease 2019 (COVID-19) pandemic, flexible laryngoscopy represents a risk for patients and an occupational hazard for otolaryngologists and any clinic staff involved with the procedure or endoscope reprocessing. Here we present a set of recommendations on flexible laryngoscopy performance during the pandemic, including patient selection, personal protective equipment, and endoscope disinfection, based on a consensus reached during a virtual webinar on March 24, 2020, attended by approximately 300 participants from the American laryngology community.

To determine adverse events after endoscopic flexible vs endoscopic rigid cricopharyngeal myotomy for treatment of Zenker's diverticulum (ZD).Systematic review of MEDLINE, Web of Science, CINAHL, Clinicaltrials.gov, and Cochrane Central Register of Controlled Trials for all years according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Additional studies were identified from review citations and a by hand search of manuscripts referencing ZD.A structured literature search was conducted to identify studies for this systematic review. Methodological Index for Non-randomized Studies (MINORS) criteria were applied to assess study quality. For inclusion, each study had to provide data for at least 10 adult patients who had undergone endoscopic ZD repair reporting clear association with the postprocedure course in each case. Data extracted included all reported adverse events, recurrences, follow-up, and operative times.In total, 115 studies were included. All but 8 were retrospective case series. Sixty-one reported series of patients after rigid endoscopic stapler repair, 31 after rigid laser repair, and 13 with other rigid endoscopic instruments. Twenty-nine flexible endoscopic studies were included. Mortality, infection, and perforation were not significantly more likely in either the rigid or the flexible group, but bleeding and recurrence were more likely after flexible endoscopic techniques (20% vs10% and 4% vs 0%, respectively). Dental injury and vocal fold palsy were reported rarely in the rigid endoscopic groups.Adverse events are rare after endoscopic Zenker's repair. The flexible approach minimizes exposure limitations and can be completed in some patients without general anesthesia. Transoral rigid approaches result in fewer revision surgeries compared with flexible diverticulotomy.

OBJECTIVE Race predicts overall mortality (OM) of laryngeal squamous cell carcinoma (LSCC) in the United States (US). We assessed whether racial disparities affect cancer-specific mortality (CSM) using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS Adults with LSCC from 2004 to 2015 were selected. Univariable and multivariable Cox proportional hazards and Fine-Gray competing-risks regression analysis adjusted for clinicodemographic factors defined hazard ratios (aHR). RESULTS We identified 14,506 patients. The median age was 63 years. Most were male (11,725, 80.8%) and white (11,653, 80.3%), followed by Black (2294, 15.8%). Most had early-stage disease (7544, 52.0%) and received radiotherapy only (4107, 28.3%), followed by chemoradiation (3748, 25.8%). With median follow-up of 60 months, overall 3- and 5-year OM were 34.0% and 43.2%; CSM were 16.0% and 18.9%, respectively. Black patients had higher OM than white patients on univariable (HR 1.35, 95% CI, 1.26-1.44, P

OBJECTIVES/HYPOTHESIS Various animal models have been employed to investigate vocal fold (VF) and phonatory function. However, biomechanical testing techniques to characterize vocal fold structural properties vary and have not compared critical properties across species. We adapted a nondestructive, automated indentation mapping technique to simultaneously quantify VF structural properties (VF cover layer and intact VF) in commonly used species based on the hypothesis that VF biomechanical properties are largely preserved across species. STUDY DESIGN Ex vivo animal model. METHODS Canine, leporine, and swine larynges (n = 4 each) were sagittally bisected, measured, and subjected to normal indentation mapping (indentation at 0.3 mm; 1.2 mm/s) with a 2-mm spherical indenter to quantify normal force along the VF cover layer, structural stiffness, and displacement at 0.8 mN; two-dimensional maps of the free VF edge through the conus elasticus were created for these characterizations. RESULTS Structural stiffness was 7.79 gf/mm (0.15-74.55) for leporine, 2.48 gf/mm (0.20-41.75) for canine, and 1.45 gf (0.56-4.56) for swine. For each species, the lowest values were along the free VF edge (mean ± standard deviation; leporine: 0.40 ± 0.21 gf/mm, canine: 1.14 ± 0.49 gf/mm, swine: 0.89 ± 0.28 gf/mm). Similar results were obtained for the cover layer normal force at 0.3 mm. On the free VF edge, mean (standard deviation) displacement at 0.08 gf was 0.14 mm (0.05) in leporine, 0.11 mm (0.03) in canine, and 0.10 mm (0.02) in swine. CONCLUSIONS Automated indentation mapping yielded reproducible biomechanical property measurement of the VF cover and intact VF. Divergent VF structural properties across canine, swine, and leporine species were observed. LEVEL OF EVIDENCE NA Laryngoscope, 129:E26-E31, 2019.

Objectives/hypothesis Although the primary goal of medialization laryngoplasty is to improve glottic closure, implant placement is also likely to alter the biomechanical properties of the vocal fold (VF). We sought to employ novel, nanoscale technology to quantify these properties following medialization based on the hypothesis that different medialization materials will likely yield differential biomechanical effects. Study design Ex vivo. Methods Nine pig larynges were divided into three groups: control, Silastic (Dow Corning, Midland, Michigan, U.S.A.) block medialization, or Gore-Tex (W.L. Gore & Associates, Newark, Delaware) medialization. Laryngoplasty was performed on excised, intact larynges. The larynges were then bisected in the sagittal plane and each subjected to dynamic nanomechanical analysis (nano-DMA) at nine locations using a 250-μm flat-tip punch and frequency sweep-load profile across the free edge of the VF and inferiorly along the conus elasticus. Results Silastic block and Gore-Tex implant introduced increased storage and loss moduli. Overall, storage moduli mean (maximum) increased from 38 kilopascals (kPa) (119) to 72 kPa (422) and 129 kPa (978) in control, Gore-Tex, and Silastic implants, respectively. Similarly, loss moduli increased from 13 kPa (43) to 22 kPa (201) and 31 kPa (165), respectively. Moduli values varied widely by location in the Silastic block and Gore-Tex groups. At the free VF edge, mean (maximum) storage moduli were lowest in the Gore-Tex group, 20 kPa (44); compared to control, 34.5 kPa (86); and Silastic, 157.9 kPa (978), with similar loss and complex moduli trends. Conclusion Medialization laryngoplasty altered VF structure biomechanical properties; Silastic and Gore-Tex implants differentially impact these properties. Level of evidence NA. Laryngoscope, 128:1163-1169, 2018.

Objectives/Hypothesis To describe the distribution of recurrent respiratory papillomatosis (RRP) lesions across 21 laryngeal anatomic regions in previously untreated patients at initial presentation to provide insight regarding the natural history of RRP. Study Design Multi-institutional, retrospective case series. Methods Initial laryngoscopic examination videos of 83 previously untreated patients with adult-onset RRP were reviewed. Papilloma locations were recorded using a 21-region laryngeal schematic. Multivariate analyses by anatomic subsite were conducted for the entire population and for subgroups stratified by sex, age, and proton pump inhibitor (PPI) usage. Heat maps were generated, hierarchically color coding the anatomic distribution of disease. Results In this cohort, RRP was most likely to occur on the true vocal folds (TVFs) and anterior commissure (P

Objective Recent reports highlight the efficacy of small interfering RNA (siRNA) targeting SMAD3 to regulate transforming growth factor β (TGF-β)-mediated fibroplasia in vocal fold fibroblasts. The current study sought to investigate SMAD3 expression during wound healing in vivo and quantify the downstream transcriptional events associated with SMAD3 knockdown in vitro. Study Design In vivo and in vitro. Methods Unilateral vocal fold injury was created in a rabbit model. SMAD3 and SMAD7 mRNA expression was quantified at 1 hour and 1, 3, 7, 14, 30, 60, and 90 days following injury. In vitro, multi-gene analysis technology was employed in our immortalized human vocal-fold fibroblast cell line following TGF-β1 stimulation ± SMAD3 knockdown across time points. Results SMAD3 mRNA expression increased following injury; upregulation was significant at 3 and 7 days compared to control (both P

Objective Given the recalcitrant nature of recurrent respiratory papillomatosis, targeted therapies to reduce disease burden are fundamental to improved patient care paradigms. We seek to demonstrate the safety of imiquimod injection into vocal fold mucosa by evaluating the degree of laryngeal edema, histopathologic changes to vocal fold structure, and serologic interferon α (IFNα) levels following injection. Study Design Preclinical. Setting Academic institution. Subjects and Methods Six New Zealand White rabbits underwent unilateral injection of 100 µg of sterile imiquimod (1 µg/µL), with 100 µL of normal saline injected into the contralateral vocal fold. Direct laryngoscopy was performed on days 3, 7, and 30 following injection. Larynges from 3 rabbits were harvested on postinjection day 7 for histologic analysis. The remaining 3 rabbit larynges were harvested on day 30. Serial serum samples were drawn for IFNα quantification via immunoassay. Results No signs of respiratory distress were observed at any point. Vocal fold appearance was not clinically divergent between imiquimod and control conditions via serial direct laryngoscopic evaluation. No inflammatory lesions or scarring were identified following injection. Histology showed no signs of acute inflammatory processes or changes in the control or imiquimod injection groups. Serum IFNα increased at days 3 and 7 following imiquimod injection ( P < .0001 and P = .0368, respectively), before returning to baseline by day 14. Conclusions Vocal fold imiquimod injection did not result in notable morbidity in this preclinical model. However, serum IFNα concentrations increased transiently. These data are critical to advance the therapeutic utility of this compound, particularly in the setting of recurrent respiratory papillomatosis.

Objectives/Hypothesis Quantification of clinical outcomes after vocal fold (VF) interventions is challenging with current technology. High-speed digital imaging and optical coherence tomography (OCT) of excised larynges assess intact laryngeal function, but do not provide critical biomechanical information. We developed a protocol to quantify tissue properties in intact, excised VFs using dynamic nanomechanical analysis (nano-DMA) to obtain precise biomechanical properties in the micrometer scale. Study Design Experimental animal study. Methods Three pig larynges were bisected in the sagittal plane, maintaining an intact anterior commissure, and subjected to nano-DMA at nine locations with a 250-μm flat-tip punch and frequency sweep load profile (10–105 Hz, 1,000 μN peak force) across the free edge of the VF and inferiorly along the conus elasticus. Results Storage, loss, and complex moduli increased inferiorly from the free edge. Storage moduli increased from a mean of 32.3 kPa (range, 6.5–55.38 kPa) at the free edge to 46.3kPa (range, 7.4–71.6) 5 mm below the free edge, and 71.4 kPa (range, 33.7–112 kPa) 1 cm below the free edge. Comparable values were 11.6 kPa (range, 5.0–20.0 kPa), 16.7 kPa (range, 5.7–26.8 kPa), and 22.6 kPa (range, 9.7–38.0 kPa) for loss modulus, and 35.7 kPa (range, 14.4–56.4 kPa), 50.1 kPa (range, 18.7–72.8 kPa), and 75.4 kPa (range, 42.0–116.0 kPa) for complex modulus. Another larynx repeatedly frozen and thawed during technique development had similarly increased storage, loss, and complex modulus trends across locations. Conclusions Nano-DMA of the intact hemilarynx provides a platform for quantification of biomechanical responses to a myriad of therapeutic interventions to complement data from high-speed imaging and OCT. Level of Evidence NA Laryngoscope, 2016

Objectives/Hypothesis Given that the vocal folds are active organs of respiration, reports of dyspnea in the context of glottic insufficiency are not uncommon. We hypothesize that improved glottal closure via framework surgery or vocal fold augmentation improves dyspnea symptoms. Study Design Retrospective review. Methods Charts of patients undergoing procedures to correct glottal insufficiency, either via vocal fold augmentation (VFA) or medialization laryngoplasty (ML) between December 2012 and September 2015 were reviewed (n = 189). Modified Borg Dyspnea Scale (MBDS) and Modified Medical Research Council Dyspnea Scale (MMRCDS) data were collected before and after intervention. Age, body mass index (BMI), and sex, as well as pulmonary and cardiac comorbidities were considered. Subgroup analysis was performed on individuals with subjective dyspnea prior to intervention. Results For the entire cohort, differences in the MMRCDS and MBDS were not statistically different pre- and postintervention (P = .20 and P = .12, respectively). Patients with BMI

Objectives/Hypothesis To investigate the role of Smad3 as a regulator of transforming growth factor (TGF)-β1-mediated cell activities associated with fibrosis in normal human vocal fold fibroblasts. We also sought to confirm the temporal stability of Smad3 knockdown via small inhibitor ribonucleic acid (siRNA). Vocal fold fibroblasts were employed to determine the effects of Smad3 knockdown on TGF-β1-mediated migration and contraction, as well as regulation of connective tissue growth factor (CTGF). We hypothesized that Smad3 is an ideal candidate for therapeutic manipulation in vivo based on its role in fibrosis. Study Design In vitro. Methods Knockdown of Smad3 via siRNA was performed in our normal human vocal fold cell line. Three-dimensional collagen gel contraction and scratch assays were employed to determine the role of Smad3 on TGF-β1-mediated contraction and migration, respectively. The role Smad3 in the induction of CTGF was characterized via sodium dodecyl sulfate polyacrylamide gel electrophoresis. The effects of Smad3 signaling on Smad7 messenger (m)RNA and protein were also quantified. Results Smad3 knockdown was temporally-stable up to 72 hours (P

Objectives/Hypothesis To optimize decellularization of porcine vocal folds (VF) and quantify human bone marrow-derived mesenchymal stem cell (BM-MSC) interactions with this matrix to provide a foundation for regenerative approaches to VF repair. Study Design and Methods Vocal folds were dissected from porcine larynges and three decellularization protocols were compared, each consisting of washes and mechanical agitations with different combinations of reagents. DNA content was analyzed via Quant-iT Picogreen assay and hematoxylin and eosin staining. Bone marrow-derived MSCs were then seeded onto the decellularized VF matrices. Morphology, metabolic activity, DNA content, and gene expression were assessed using LIVE/DEAD Cell Viability, alamarBlue Cell Viability Assay, Quant-iT Picogreen assay, and quantitative polymerase chain reaction, respectively. Results The most successful decellularization protocol removed 95% DNA content within 1 day, compared to several days required for previously described protocols. Histology confirmed the retention of extracellular matrix (ECM) and its components, including glycosaminoglycans, collagen, and fibrin, while void of nuclear/cellular content. Decellularized scaffolds were then seeded with BM-MSCs. Similar DNA quantities were observed after 24 hours of seeding within the VF-ECM scaffold when compared to cells on tissue culture plastic (TCP). LIVE/DEAD staining of the seeded VF-ECM confirmed excellent cell viability, and the metabolic activity of BM-MSCs increased significantly on VF-ECM compared to TCP. Endoglin gene expression decreased, suggestive of differentiation. Conclusion Porcine VFs can be efficiently decellularized within 5 hours using a combination of sodium deoxycholate and peracetic acid. Decellularized VF-ECM supported attachment and growth of human BM-MSCs, with evidence of differentiation. Level of Evidence N/A Laryngoscope, 2015

Therapeutic monocolonal antibodies (MAbs) are a new, rapidly growing class of medications that frequently have poorly characterized side-effect profiles. We present a patient who developed inflammatory lesions of the vocal folds in temporal relation to the initiation of alirocumab. Lesions of the vocal folds represent a previously unreported adverse effect of alirocumab therapy, making it the second MAb documented with such a side effect. The potential laryngeal effects of alirocumab specifically, and of MAbs more broadly, warrant investigation. Laryngoscope, 127:1652-1654, 2017.

Objectives/Hypothesis To determine oral human papilloma virus (HPV) colonization in patients with adult-onset recurrent respiratory papillomatosis (AO-RRP) and their long-term partners. Study Design Prospective, cohort study Methods Patients with pathology-confirmed AO-RRP and a small cohort of their long-term partners were subjected to a standardized oral rinse and swab protocol to obtain oral epithelial cells. DNA from these samples was extracted and subjected to both qualitative analyses via multiplex polymerase chain reaction as well as to a commercially available linear array assay for the determination of specific HPV subtypes. Results Samples were collected from 27 patients with AO-RRP and six long-term sexual partners. Qualitative analysis of agarose gel products using a multiple genotype primer cocktail suggested the presence of HPV DNA in oral rinse or swabs in 26 patients (96%) and four partner samples (67%). A subset of these positive patient samples was then subjected to genotyping; a spectrum of HPV subtypes was observed. Interestingly, HPV81 was identified in many samples. Conclusion Recent data suggest that less than 7% of the general population is HPV positive in the oral cavity. Our data suggest that the oral colonization rate is much higher in patients with AO-RRP. Additionally, long-term sexual partners of patients with RRP had a much higher rate of HPV positivity. These preliminary data may have implications for viral transmission and provide a framework for enhanced patient education as well as further investigation. Level of Evidence 4. Laryngoscope, 124:2785–2790, 2014

Objectives/Hypothesis To evaluate risk factors strongly associated with adult-onset recurrent respiratory papillomatosis (AO-RRP). Study Design Prospective, age- and sex-matched, case control. Methods Patients with AO-RRP and controls completed a computer-based, 89-item questionnaire across three academic institutions. Results Forty-eight AO-RRP patients were compared to 73 controls; 43 of the 48 AO-RRP patients were male (89.5%). The difference in the median number of lifetime sexual partners between AO-RRP (15) and controls (10) was significant (P = 0.0387). Additionally, an increased number of lifetime sexual partners (≥ 26) was associated with AO-RRP. No significant difference for the number of lifetime oral sex partners was observed between groups. Increased comorbidity, as quantified by the Charlson Comorbidity Index, was observed in patients with AO-RRP. AO-RRP and control groups were similar across many other variables, including birth history, smoking history, alcohol use, drug use, education, income, and the Short Form Health Survey scores. Conclusions AO-RRP was not associated with previously proposed risk factors for juvenile-onset RRP and may be associated with an increased number of lifetime sexual partners. Level of Evidence 3b. Laryngoscope 124:2338–2344, 2014

Objectives/Hypothesis To determine the efficacy of small interfering RNA (siRNA) targeting Smad3 to mediate fibroplasia in vitro, to investigate the temporal regulation of Smad3 following vocal fold (VF) injury, and to determine the local and distal effects of Smad3 siRNA VF injection. Study Design In vitro and in vivo. Methods In vitro, Smad3 regulation was examined at both the level of transcription and translation in a human VF cell line in response to Smad3 siRNA ± transforming growth factor β (TGF-β). Collagen transcription was also examined. In vivo, Smad3 messenger RNA (mRNA) expression was quantified as a function of time following rabbit VF injury. Also, the effects of injected Smad3 siRNA were assessed at local and distal sites. Results Smad3 siRNA knocked down Smad3 transcription and translation and limited TGF-β-mediated collagen mRNA expression with minimal cytotoxicity in vitro. In vivo, Smad3 mRNA increased 1 day following VF injury and remained elevated through day 7. Smad3 siRNA injection into the uninjured vocal fold had no local or distant effect on Smad3 mRNA at multiple organ sites. Conclusions These data provide a foundation for further investigation regarding the development of novel RNA-based therapeutics for the VF, specifically locally delivered siRNA for challenging fibrotic conditions of the VF. Level of Evidence NA Laryngoscope 124:2327–2331, 2014

Objectives/Hypothesis To provide the otolaryngologist an evidence-based sound review of glucocorticoid use for laryngeal pathology. Study Design Review of contemporary peer-reviewed literature as well as review articles. Methods A review of the literature regarding glucocorticoids as a therapeutic intervention for the treatment of benign laryngeal pathology and laryngeal manifestations of systemic disease was performed. Review included both systemic administration as well as local injection. Results Glucocorticoids, administered in the critical care setting for planned extubation, markedly reducing the risk of reintubation and remain a rudimentary pharmacologic adjunct in laryngeal manifestations of common autoimmune and inflammatory disorders. Intralesional injection has reduced the rate of surgical intervention for benign inflammatory primary laryngeal pathology. Conclusions Glucocorticoids are effective in the treatment of a number of laryngeal pathologies, through both systemic and intralesional administration. However, a clear consensus for utilization of glucocorticoids in the treatment of specific laryngeal disorders has yet to be published. Level of Evidence Laryngoscope, 124:1668–1673, 2014

Objectives/Hypothesis To characterize the videoendoscopic laryngeal findings in patients with a prior established diagnosis of laryngopharyngeal reflux disease (LPR) as the sole etiology for their chief complaint of hoarseness. We hypothesized that many, if not all, of these patients would present with discrete laryngeal pathology, divergent from LPR. Study Design Prospective, nonintervention. Methods Patients presenting to a tertiary laryngology practice with an established diagnosis of LPR as the sole etiology of their hoarseness were included. All subjects completed the Voice Handicap Index and Reflux Symptom Index, in addition to a questionnaire regarding their reflux diagnosis and prior treatment. Laryngoscopic examinations were reviewed by the laryngologist caring for the patients. Reliability of findings was assessed by interpretation of videoendoscopic findings by three outside laryngologists not involved in the care of the patients. Results Laryngeal pathology distinct from LPR was identified in all 21 patients felt to be causative of the chief complaint of dysphonia. Specifically, the most common findings were benign mucosal lesions and vocal fold paresis (29% each), followed by muscle tension dysphonia (14%). Two patients were found to have vocal fold leukoplakia, of which one was confirmed to be a microinvasive carcinoma upon removal. Conclusion LPR may be overdiagnosed; other etiologies must be considered for patients with hoarseness who fail empiric LPR treatment. Level of Evidence 4. Laryngoscope, 124:1420–1424, 2014

Objectives/Hypothesis Recent data have suggested that in-office potassium titanyl phosphate (KTP) laser treatment for benign vocal fold lesions yields significant reduction in lesion size with favorable effects on both mucosal wave and glottic closure. However, these previous studies omitted voice-related outcomes. We sought to compliment these previous data with voice-related outcomes in a cohort of patients undergoing KTP ablation of vocal fold polyps. Study Design Retrospective outcomes study. Methods Voice Handicap Index (VHI)−10 and acoustic measures were reviewed for 31 consecutive patients with benign vocal fold polyps treated with in-office KTP laser surgery. All data were analyzed statistically via a mixed model fit to analyze the data from each of three clinical visits. Results Across all patients, the mean VHI-10 scores decreased at first follow-up from 19.7 to 9.7 (P

Objectives/Hypothesis We hypothesize that the KTP laser has the potential to augment wound healing in a rat model, and this modality may serve as a therapeutic tool for the management of vocal fold fibrosis. Study Design Prospective, laboratory animal study. Methods Rats were subjected to either vocal fold injury ± KTP laser treatment at low energy to simulate clinically relevant endpoints. In addition, cohorts were subjected to therapeutic KTP laser alone. Endpoints included the analyses of gene expression data related to the acute inflammatory response and extracellular matrix deposition and organization. Results Therapeutic KTP treatment was associated with an additive effect on inflammatory gene expression in the context of the injured rat vocal fold mucosa. A similar additive effect was observed for matrix metalloproteinase gene expression, similar to data previously reported in the dermatology literature. However, histologically, the KTP had little effect on established vocal fold fibrosis. Conclusions These data are the first to attempt to provide mechanistic insight into the clinical utility of angiolytic lasers for vocal fold scar. Similar to previous data obtained in the skin, it appears that these effects are mediated by MMPs. Level of Evidence NA. Laryngoscope, 123:2189–2194, 2013

Objectives/Hypothesis: Life-support training emphasizes the primacy of airway management. Acquiring these skills requires practice and exposure to events. Otolaryngology residents lack standardized training in advanced airway skills. This project aimed to create such a program by using simulation-based methodology evaluated using specific educationally based tools. Study Design: Prospective cohort study. Methods: The program consisted of lectures and simulation-based training sessions designed to impart competency in a set of defined airway skills to otolaryngology residents. Only participating residents who completed the course (n = 12) were evaluated both before and after the course for their fund of knowledge through multiple-choice examinations and for clinical reasoning and technical skills as assessed by a panel of otolaryngologists in simulated difficult airway situations. Self-assessment tools were also incorporated. Results: The average multiple choice score was 12 of 27 (44%) before the course and 15 of 27 (55%) after the completion of the course (P = .001). Faculty assessment yielded a cumulative score of 80% and 91% pre- and postcourse, respectively (P = .002). Although all residents reported prior experience in a critical emergency airway situation, only one reported prior training in advanced airway skills. A significant increase in participants' self-perceived ability to carry out critical airway-related skills was observed. All respondents felt the course was effective. Conclusions: Simulation-based airway training courses can be effectively incorporated into existing educational curricula for otolaryngology residents, and their success can be measured using educationally based tools. With such a course, residents can be expected to demonstrate measurable improvement in clinical knowledge base, technical skills, and self-perceived ability to handle difficult airway situations. Laryngoscope, 2013

Aim This study was conducted to describe sleep problems in a sample of children with enuresis and to investigate the association between sleep and behavioural problems. Methods In this cross-sectional study, 100 children with enuresis were recruited from paediatric enuresis clinic. The children's sleep problems and behaviours were assessed by the Children's Sleep Habits Questionnaire and Child Behaviour checklist. Results The most frequently reported sleep problems were in daytime sleepiness, bedtime resistance and sleep anxiety subscales. Children with T-scores ≥ 60 in internalising, externalising and total behavioural problems had higher scores on daytime sleepiness subscale and total score than children with T-scores < 60. Multivariate logistic regression analysis revealed that daytime sleepiness subscale was significantly related to behavioural disturbances. Conclusions Sleep problems are common among this sample of children with enuresis, and the presence of sleep disturbance such as daytime sleepiness could explain the association between enuresis and disturbed daytime behaviour.

Objectives/Hypothesis: Although clinical dogma suggests the value of laryngeal visualization (flexible laryngoscopy and stroboscopy) in dysphonic patients, recently published clinical guidelines suggest that, in many cases, history and/or physical examination are sufficient to guide clinical decision-making regarding the timing of such examinations. We sought to prospectively quantify the diagnostic accuracy of history, laryngoscopy, and stroboscopy using direct laryngoscopy as the gold standard. Study Design: Expert survey. Methods: Six laryngologists were presented with vignettes including history and physical examination (HPE), laryngosocpy, and stroboscopy. Questions regarding diagnosis, the certainty of diagnosis, and subsequent management plans were posed. Operative findings via direct laryngoscopy were employed as a comparator. Results: The diagnostic accuracy of HPE was quite low (5%). The accuracy of diagnosis increased substantially following laryngeal imaging; 68.3% for both flexible laryngoscopy and stroboscopy. Particular diagnoses were more consistently identified; cancer, for example, was much more accurately identified on laryngoscopy (100%) and stroboscopy (100%) rather than HPE alone (33%). Cancer was selected as the diagnosis in 10 of 60 HPEs, though was only correct once and missed in five cases. In contrast, no diagnoses of cancer were missed following laryngoscopic and/or stroboscopic examinations. Conclusion: These findings confirm the value of laryngeal visualization (flexible laryngoscopy and stroboscopy) in dysphonic patients, and the lack of accuracy of history and physical examination in determining the diagnosis in patients with hoarseness. Laryngoscope, 2013

Objectives/Hypothesis: No studies to date have examined the clinical safety and efficacy of carboxymethylcellulose (CMC) for vocal fold injection. The current study investigates the voice outcomes and complications of CMC injection. Study Design: Retrospective review. Methods: All patients who underwent CMC injection from three independent sites in a 1-year period were reviewed. Voice outcomes in the form of voice handicap index-10 (VHI-10) and complications from injection were recorded. Results: Seventy-eight patients with VHI-10 results from 1 to 8 weeks after CMC injection were evaluated. Thirty-eight patients were treated for vocal fold immobility, and 15 patients underwent treatment for hypomobility, 15 for vocal fold atrophy, seven for scar/sulcus, one for previous laryngeal fracture, one for functional dysphonia, and one for persistent granuloma. In 60 patients with available VHI-10 data, overall improvement in voice was seen. There was a mean decrease in VHI-10 of 7.48 (26.4 to 18.9, P < .05), correlating to a 19.9% decrease. Forty-five patients (75%) showed a decrease in VHI-10, nine (15%) showed an increase, and six (10%) showed no change. Statistically significant differences were seen for patients with immobility (decrease of 8.6, or 31%) and hypomobility (decrease of 10.7, or 37.8%). There were no complications of vocal fold stiffness, inflammatory reaction, or scar in the 78 patients during the total follow-up period. Conclusions: CMC is a viable, safe, and efficacious material for the temporary treatment of glottic insufficiency in vocal fold immobility and hypomobility, with minimal risk of permanent adverse voice outcomes.

Electrical stimulation has been widely applied in medicine to combat microorganisms,1 enhance wound healing,2 and treat tumors,3 as well as promote strengthening and motor control of skeletal muscles.4,5 Common rehabilitation practice is to place electrodes on the skin to stimulate nerves supplying muscle groups of interest to increase strength.6,7 Neuromuscular electrical stimulation (NMES) has been used for decades on a wide array of muscle groups, but it was investigated for dysphagia rehabilitation in neurologically impaired patients in the late 1990s,8,9 and in 2002, the U.S. Food and Drug Administration (FDA) cleared a device for the treatment of dysphagia. Several meta-analyses have since evaluated the effect of NMES on swallowing rehabilitation and revealed a small but significant summary effect size.10,11 More recently, investigation of NMES has focused on its effects as an adjunct to traditional swallowing therapy in patients receiving treatment for locally advanced head and neck cancer.12 However, the FDA applies a general warning to all NMES devices to avoid stimulating over areas of malignancy.13,14 The concern is that applying electrical stimulation to the anterior neck may stimulate tumor growth if there is residual disease or recurrence following treatment. It is common practice to wait at least several months after radiation and/or surgical treatment before initiating NMES to minimize or resolve dysphagia. A drawback to delaying therapy is that by the time NMES has commenced, the patient typically has chronic dysphagia,15 making the condition more difficult to manage. If NMES in the setting of active malignancy proves not to enhance tumorigenic activity, then perhaps its benefit for dysphagia therapy can be enhanced by starting therapy earlier in the rehabilitation period. To our knowledge, there has never been an animal or human study investigating the effects of skin surface electrical stimulation (as in NMES) on an underlying malignancy, located deep to the skin surface but aligned with the location of electrical stimulation. Based on our review of the literature pertaining to electrodes inserted directly into tumors and resulting in tumor destruction,3, 16–21 we hypothesized that NMES will not increase underlying tumor burden.

Objectives/Hypothesis: Given the recent emergence of encouraging efficacy data regarding the utility of intralesional glucocorticoid (GC) injection for a variety of vocal fold pathologies, we sought to describe the location and expression pattern of the GC receptors within the vocal folds and quantify the effects of GCs on vocal fold fibroblasts. Study Design: In vitro, in vivo. Methods: Immunolocalization of the GC receptor was performed on normal rat vocal fold tissue. Receptor expression was also assayed in our human vocal fold fibroblast cell line. These cells were then treated with exogenous dexamethasone (DM) to quantify the effects of GCs on receptor expression, proliferation, transforming growth factor (TGF)-b–induced collagen secretion, and matrix protease synthesis. Results: Positive immunostaining for the GC receptor was found throughout the vocal fold with particularly strong staining in the epithelium and capillaries. Human vocal fold fibroblasts constitutively express the GC receptor, but this expression decreased in response to exogenous DM. DM also decreased fibroblast proliferation and TGF-b–induced collagen synthesis. DM also abrogated TGF-b–mediated effects on enzymes related extracellular matrix turnover. Conclusions: Our data are the first to provide mechanistic insight regarding the recently published favorable data regarding the utility of GCs in patients with vocal fold scar. Although further investigation is warranted, both the accessibility of this class of agents and the amenability to office-based procedures are likely to direct patient care models.

Objectives/Hypothesis. Prostaglandin (PG)E2 has been implicated in a variety of disease processes. It has been described as antifibrotic in the lower airway, yet scar-inducing in the skin. We seek to describe the effects of PGE2 on vocal fold fibroblasts and its interactions with transforming growth factor (TGF)-β1. In addition, we describe a novel organotypic model, a critical step in the development of therapeutic trials. Study Design. In vitro, ex vivo. Methods: Collagen secretion by human vocal fold fibroblasts (HVFF) was assayed in response to TGF-β1, PGE2, and specific EP receptor agonists. Basal HVFF migratory rate was also quantified in response to PGE2. TGF-β1 induced COX-2 mRNA expression/PGE2 secretion was assayed. Excised vocal folds were subjected to exogenous IL-1β; PGE2 secretion into the supernatant was then assayed. Results: TGF-β1-induced collagen secretion was blunted in a dose-dependent manner in response to PGE2. This effect appears to be mediated primarily through the EP1 and EP2 receptors. TGF-β1 induced COX-2 mRNA expression and PGE2 secretion. In our organ culture model, IL-1β stimulated PGE2 secretion in a dose-dependent manner. Conclusions: PGE2 is antifibrotic; this finding suggests that the upper airway response to this inflammatory mediator differs significantly from the lower airway. These data have important clinical implications for a variety of pathological processes. Furthermore, exogenous TGF-β1 elicits induction of COX-2, suggesting inherent complexity regarding these processes and PGE2 signaling, specifically. In addition, our organ culture model may prove useful as a means to quantify biological phenomena in the vocal folds.

Objectives/Hypothesis: Idiopathic ulcerative laryngitis (IUL) is a distinct, clinical entity that presents after a prolonged upper respiratory infection with cough. It is characterized by the development of bilateral ulcerations of the mid-membranous vocal folds followed by a protracted course of healing. The purpose of this review was to characterize the typical patient presentation, clinical findings, and prognosis. Study Design: Multi-institutional retrospective review Methods: Retrospective review of charts and videostroboscopic exams from patients with IUL at eight institutions. Results: Fifteen cases met the criteria for IUL and were included in the study. The mean age of the patients was 49 years, and 93% were female. All patients were nonsmokers. Multiple medical interventions were employed by the treating otolaryngologist during the course of the disease, none of which resulted in acute resolution of the ulcerations. The average time from initial presentation to resolution of the disease was 3.3 months. All of the patients reported that their voice was improved after resolution of the disease process. However, in the majority of the patients (60%) there were persistent vibratory abnormalities after resolution of the ulcerations. Conclusions: This is the first multi-institutional study to define the complete disease course of IUL and to establish diagnostic criteria. IUL is a rare yet well-recognized clinical entity; however, there is no established etiology for this condition and no definitive treatments have emerged. Further study is needed to establish the etiology/risk factors of this condition and to determine optimal medical management.

Objectives/Hypothesis: Although the potassium titanyl phosphate (KTP) laser is versatile, the variability in laser parameters for laryngeal pathologies and the lack of clinical efficacy data remain problematic. We provide preliminary data regarding these parameters for benign lesion regression. In addition, we describe a novel method for the quantification of the effects of the KTP laser on vocal fold (VF) lesions. Study Design: Retrospective chart review. Methods: Images were captured from examinations before and after in-office KTP treatment in patients with a range of benign lesions. Laser settings were noted for each patient. Imaging software was then used to calculate a ratio of lesion area to VF length. Ten percent of images were requantified to determine inter-rater reliability. Results: Thirty-two patients underwent 47 procedures for lesions including hemorrhagic polyp, nonhemorrhagic polyp, vocal process granuloma, Reinke's edema, cyst/pseudocyst, leukoplakia, and squamous cell carcinoma in situ. No statistically significant differences were observed with regard to the laser parameters used as a function of lesion type. Regardless, by 1 month following treatment, all lesions had significantly decreased in size, except nonhemorrhagic polyps. Similar data were obtained at 2-month follow-up. We then compared the pre-KTP lesion size with the smallest lesion size quantified during the 1-year follow-up period. All lesions were significantly smaller, with the exception of Reinke's edema. Inter-rater reliability was quite good. Conclusions: KTP laser effectively reduced VF lesion size, irrespective of the laser parameters used. In addition, our quantification method for lesion size appeared to be both viable and reliable.

Objective/Hypothesis: The 532-nm KTP laser is clinically useful to induce benign vocal fold lesion regression without a fibrotic response. Previously, we described an in vivo model for KTP-induced injury in the rat larynx. This study uses this model to correlate the KTP-induced histologic and biochemical changes with the absence of long-term vocal fold fibrosis seen in clinical scenarios. Study Design: In vivo. Methods: Unilateral vocal fold injury was induced via KTP laser at 10W (20mS pulse width) as described by our laboratory previously. Animals were subjected to serial endoscopic imaging from postoperative days 1 through 3. Animals were euthanized at 1 day, 4 weeks, and 12 weeks posttreatment and subjected to histologic analyses via hematoxylin and eosin and trichrome staining, as well as RT-PCR analyses for MMP-3, 9, transforming growth factor-beta (TGF-β), and COX-2 mRNA expression. Uninjured vocal folds were used as controls. Results: Our study revealed gross healing of the vocal fold mucosa by 3 days posttreatment, and an immediate, moderate inflammatory infiltrate with no subsequent ultrastructural changes on histology. MMP-3 and COX-2 expression increased transiently, although no changes were seen in expression of MMP-9, an MMP involved in extracellular matrix remodeling, or TGF-β, a profibrotic cytokine. Conclusions: These data suggest that the KTP laser induces a modest inflammatory response, selective MMP expression, and no long-term fibrotic processes in a clinically relevant simulation. Laryngoscope, 2011

Objectives/Hypothesis: To identify contemporary indications, treatment principles, technique, injection materials, complications, and success rates of vocal fold injection augmentation. Study Design: Multi-institutional retrospective review. Methods: Records of patients undergoing injection augmentation at seven university medical centers from July 2007 through June 2008 were reviewed for information regarding diagnosis, unilateral or bilateral injection, route of injection, anesthesia, treatment site (office or operating room), material used, reason for technique selected, and technical success. Results: In 12 months, 460 injections were performed, 236 (51%) in awake, unsedated patients, and 224 (49%) under general anesthesia. Indications included vocal fold paralysis (248; 54%), paresis (97; 21%), atrophy (68; 15%) and scar (47; 10%). Scar was more likely to be treated in the operating room (P = .000052). In awake patients, 112 (47%) injections were performed by transcricothyroid approach, 55 (23%) by peroral approach, 49 (21%) by transthyrohyoid membrane approach, and 20 (8%) by transthyroid cartilage approach. Neither technical success rate (99% vs. 97%) nor complication rate (3% vs. 2%) differed between awake and asleep techniques. The most common materials in the clinic setting were methylcellulose (35%), bovine collagen (28%), and calcium hydroxylapatite (26%); in the operating room these were calcium hydroxylapatite (36%) and methylcellulose (35%). Calcium hydroxylapatite was more likely to be used under general anesthesia (P = .019). Five-year data show that the use of injection in the awake patient rose from 11% to 43% from 2003 to 2008. Conclusions: Injection augmentation remains a safe, effective, and clinically practical treatment with a high rate of success, whether performed in the awake or asleep patient. The rapid adoption of awake injection over the past 5 years speaks to its clinical utility. Complication rates are low and equivalent to those under general anesthesia. Otolaryngologists continue to use a variety of techniques and materials to treat a range of conditions of glottic insufficiency. Laryngoscope, 2010

Objectives/Hypothesis: The potassium titanyl phosphate (KTP) laser is emerging as a potentially effective treatment for various vocal fold pathologies. To date, the precise mechanism(s) of action of this wavelength on the layered microarchitecture of the vocal fold remains unknown. The purpose of this study is to develop an in vivo model for the use of the KTP laser in the rat vocal fold and to characterize the potential of this model for future studies. Study Design: In vivo survival surgery. Methods: A model for videoendoscopic visualization and injury to the rat vocal fold was established using a microlaryngoscope and rigid telescope. Unilateral vocal fold injury was induced with the KTP laser at 10 Watts (W) 20 milliseconds (ms) pulse width. Animals were euthanized at 1 day post-treatment. Larynges were subjected to gross visual analysis and histological analyses via hematoxylin and eosin and trichrome staining. Results: Consistent endoscopic visualization and injury was obtained without significant operative morbidity or mortality. The KTP laser caused superficial blanching and minor edema in the vocal fold, which resolved grossly by 24 hours postinjury. A modest inflammatory cell infiltrate was observed 1 day following injury. However, no remarkable alterations to the vocal fold microarchitecture were observed in the acute period. Conclusions: We propose that this novel model simulates the clinical scenario of laser use for the vocal folds. Use of this model will allow us to further characterize effects, mechanisms, and therapeutic ef ficacy of this wavelength.

Iron storage disease (haemochromatosis) is thought to be the cause of many disorders unique to captive black rhinoceroses (Diceros bicornis). To establish reliable reference ranges for iron parameters, serum samples from 27 eastern black rhinoceroses (Diceros bicornis michaeli) from a translocation programme in Kenya were analysed and compared with the samples from 17 captive individuals. The transferrin saturation, serum iron concentration and gamma glutamyl transferase were significantly higher in the captive rhinoceroses, but these elevations were not evident when the results were compared with previously published data.

Despite the introduction of coronary stents and effective anticoagulation regimens, the treatment of ostial lesions is limited by high restenosis rates. Initial results have been published asserting that statin therapy is associated with a significant reduction in restenosis after stent deployment. However, no information is available about the effect of statins after ostial stenting. Between 1993 and 2000, 122 patients required ostial placement of coronary stents at the Royal Brompton Hospital in London, United Kingdom. Statin treatment was continued or begun in 52 patients with a documentated hypercholesterolemia. Follow-up was feasible in 97 patients undergoing successful stent implantation. Restenosis rate was lower in patients receiving statins, but did not differ significantly from the nonstatin group (34.6% as against 42.2%, P = 0.531).