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Purpose: The goal of this review is to provide sleep physicians, dentists, and researchers with an evidence-based overview of the literature on smart mandibular advancement devices (MADs) for the treatment of obstructive sleep apnea., Methods: A systematic literature search was conducted by two blinded reviewers and an information specialist. A smart MAD was defined as any MAD with additional functionality besides mandibular protrusion. The bibliographic databases Medline, Embase, and Scopus were used to identify relevant publications. Studies were included if they described any stage of development of smart MADs. A total of 3162 titles and abstracts were screened for their relevance. In total, 58 articles were selected for full-text screening, 26 of which were included in this review., Results: The overall quality of the available literature was low. Most of the studies were observational, clinical or applied-research articles. The authors classified MADs into two main groups: passive and active. Passive MADs measured patient data, most commonly patient compliance. Active MADs adjusted protrusion of the mandible in response to patient data and were found in various phases of technological readiness (in development, demonstration, or deployment)., Conclusion: Innovations in smart mandibular advancement devices most frequently track patient compliance. Devices measuring other health parameters and active, feedback-controlled, devices are increasingly reported on. However, studies demonstrating their added benefit over traditional methods remain sparse. With further study, smart mandibular advancement devices have the potential to improve the efficiency of obstructive sleep apnea treatment and provide new treatment possibilities., (© 2024. The Author(s).)

A multicenter cross-sectional diagnostic study was carried out including 45 children with nontuberculous mycobacterial cervicofacial lymphadenitis and controls. The tested immunoassay, detecting M. avium-specific anti-glycopeptidolipid-core immunoglobulin A antibodies, had inadequate diagnostic performance in the studied population and seems to be of no additional value in detecting cases of nontuberculous mycobacterial cervicofacial lymphadenitis., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Maxillomandibular advancement has been shown to be an effective treatment for obstructive sleep apnea; however, the literature focuses mainly on sleep-related parameters such as apnea-hypopnea index, respiratory disturbance index and Epworth sleepiness scale. Other factors that may be important to patients, such as esthetics, patient satisfaction, nasality, swallowing problems and so forth have been reported in the literature but have not been systematically studied. Together with an information specialist, an extensive search in Medline, Embase and Scopus yielded 1592 unique articles. Titles and abstracts were screened by two blinded reviewers. In total, 75 articles were deemed eligible for full-text screening and 38 articles were included for qualitative synthesis. The most common categories of non-sleep related outcomes found were surgical accuracy, facial esthetics, functional outcomes, quality of life, patient satisfaction, and emotional health. All categories were reported using heterogenous methods, such that meta-analysis could not be performed. There was lack of consistent methods to assess these outcomes. This work is the first to systematically review non-sleep related outcomes of maxillomandibular advancement. Despite growing interest in evaluating surgical outcomes through patient subjective experiences, this review points to the need of standardized, validated methods to report these outcomes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This retrospective study aimed to: (1) investigate the surgical accuracy of maxillomandibular advancement (MMA) in obstructive sleep apnea (OSA) patients, with a specific focus on maxillary and mandibular advancement and counter-clockwise rotation and (2) investigate the correlation between the amount of achieved advancement and the reduction in the relative apnea hypopnea index (AHI). Sixteen patients, for whom a three-dimensional virtual surgical plan was generated preoperatively and a computed tomography scan (CT) or cone-beam computer tomography (CBCT) was acquired postoperatively, were included. The postoperative CT or CBCT was compared to the virtual surgical plan, and differences in the mandibular and maxillary advancement and counter-clockwise rotation were assessed. Maxillary and mandibular advancement (median 3.1 mm, p = 0.002 and 2.3 mm, p = 0.03, respectively) and counter-clockwise rotation (median 3.7°, p = 0.006 and 4.7°, p = 0.001, respectively) were notably less than intended. A significant correlation was found between the planned maxillary advancement and the difference between the planned and actual maxillary advancement ( p = 0.048; adjusted R 2 = 0.1979) and also between the planned counter-clockwise rotation and the difference between the planned and actual counter-clockwise rotation for the mandible ( p = 0.012; adjusted R 2 = 0.3261). Neither the maxilla-first nor the mandible-first surgical sequence proved to be superior in terms of the ability to achieve the intended movements ( p > 0.45). Despite a significant reduction ( p = 0.001) in the apnea hypopnea index (AHI) from a median of 62.6 events/h to 19.4 events/h following MMA, no relationship was found between the extent of maxillary or mandibular advancement and AHI improvement in this small cohort ( p = 0.389 and p = 0.387, respectively). This study underlines the necessity for surgeons and future research projects to be aware of surgical inaccuracies in MMA procedures for OSA patients. Additionally, further research is required to investigate if sufficient advancement is an important factor associated with MMA treatment outcome.

Purpose: To identify potential predictors of surgical response to maxillomandibular advancement (MMA) in patients with obstructive sleep apnea (OSA) from the most common clinically available data (patient-related, polysomnographic, cephalometric, and surgical variables)., Methods: This was a retrospective study comprised of consecutive patients who underwent MMA for moderate to severe OSA. Relevant clinical, polysomnographic, cephalometric, and surgical variables were collected as independent variables (predictors). The association of the independent variables with a favorable surgical response to MMA was assessed in univariate and multivariate analyses., Results: In 100 patients (82% male; mean age 50.5 years), the mean apnea hypopnea index [AHI] was 53.1 events/h. The rate of favorable surgical response was 67%. Based on multivariate analysis, patients with cardiovascular disease (CVD) had 0.140 times lower odds of a favorable response to MMA (OR: 0.140 [0.038, 0.513], P = 0.003). For each 1-unit increase in central apnea index (CAI) and superior posterior airway space (SPAS), there were 0.828 and 0.724 times lower odds to respond favorably to MMA (OR: 0.828 [0.687, 0.997], P = 0.047; and 0.724 [0.576, 0.910], P = 0.006), respectively., Conclusion: The findings of this study suggest that the surgical outcome of MMA may be less favorable when patients with OSA have certain phenotypic characteristics: the presence of CVD, higher CAI and larger SPAS. If confirmed in future studies, these variables may guide patient selection for MMA., (© 2022. The Author(s).)

In sialendoscopy, ducts are dilated and the salivary glands are irrigated with saline. Contrast-enhanced ultrasound sialendoscopy (CEUSS), using microbubbles, may facilitate the monitoring of irrigation solution penetration in the ductal system and parenchyma. It is imperative to test CEUSS for its safety and feasibility in Sjögren's syndrome (SS) patients. CEUSS was performed on 10 SS patients. The primary outcomes were safety, determined by the occurrence of (serious) adverse events ((S)AEs), and feasibility. The secondary outcomes were unstimulated and stimulated whole saliva (UWS and SWS) flow rates, xerostomia inventory (XI), clinical oral dryness score, pain, EULAR Sjögren's syndrome patient reported index (ESSPRI), and gland topographical alterations. CEUSS was technically feasible in all patients. Neither SAEs nor systemic reactions related to the procedure were observed. The main AEs were postoperative pain (two patients) and swelling (two patients). Eight weeks after CEUSS, the median UWS and SWS flow had increased significantly from 0.10 to 0.22 mL/min ( p = 0.028) and 0.41 to 0.61 mL/min ( p = 0.047), respectively. Sixteen weeks after CEUSS, the mean XI was reduced from 45.2 to 34.2 ( p = 0.02). We conclude that CEUSS is a safe and feasible treatment for SS patients. It has the potential to increase salivary secretion and reduce xerostomia, but this needs further investigation.

Purpose: To investigate subjective efficiency outcomes after maxillomandibular advancement (MMA) surgery in obstructive sleep apnea (OSA) patients., Material and Methods: A prospective cohort study was carried out between December 2016 and May 2021, including 30 severe or treatment-refractory OSA patients treated by MMA surgery. All patients answered four validated questionnaires: the Epworth Sleepiness Scale (ESS), Functional Outcomes of Sleep Questionnaire (FOSQ), Mandibular Function Impairment Questionnaire (MFIQ), and EQ-5D-3L (i.e., EQ-5D and EQ-VAS). They also answered one custom-made questionnaire (AMCSQ). Questionnaires were requested to be filled out 1 week before surgery and at least 6 months after surgery., Results: The total preoperative and postoperative scores on the questionnaires were compared. The mean total ESS ( p < 0.01), FOSQ ( p < 0.01), EQ-5D ( p < 0.05), and EQ-VAS ( p < 0.01) scores showed significant improvement, which was in accordance with an improvement in the mean postoperative apnea/hypopnea index score ( p < 0.01). In contrast, the mean total MFIQ score ( p < 0.01) indicated a decline in mandibular function., Conclusion: This study confirms the hypothesis that MMA surgery in OSA patients improves outcomes, both objectively and subjectively, with the exception of postoperative mandibular function.

Purpose: This prospective cohort study aimed to assess early root migration after a coronectomy of the mandibular third molar at 2 and 6 months after surgery., Methods: We included all patients treated with a coronectomy of an impacted mandibular third molar. The primary outcome measure was the extent of postoperative root migration after 2 and 6 months. Migration was measured as the distance between the root complex and a fixed point on the inferior alveolar canal. The secondary aim was to identify factors (age, impaction pattern, and patient sex) that affected the extent of root migration., Results: One hundred and sixty-five coronectomies were performed in 141 patients (96 females and 45 males; mean age 33.1 years, SD 16.0). The 2-month checkup was completed by 121 patients that received 141 coronectomies. The 6-month check-up was completed by 73 patients that received 80 coronectomies. The mean root migrations were 3.30 mm (SD 2.53 mm) at 2 months and 5.27 mm (SD 3.14 mm) at 6 months. In the 2-6-month interval, the mean root migration was 2.58 mm (SD 2.07 mm). The extents of migration were similar during the 0-2-month interval and the 2-6-month interval (p = 0.529). Younger age was associated with greater root migration, and females experienced significantly greater migrations than males (p = 0.002)., Conclusion: Roots migrated more rapidly in the first two postoperative months, compared to the 2-6-month interval. Age was negatively correlated with the extent of root migration, and females showed significantly greater migrations than males., (© 2022. The Author(s).)

The primary aim of this study was to assess the association between clinical efficacy outcomes (i.e., polysomnography (PSG) results) of maxillomandibular advancement (MMA) and surgeons' experience. The second aim was to assess the association between the occurrence of postoperative complications of MMA and surgeons' experiences. Patients treated with MMA for moderate to severe obstructive sleep apnea (OSA) were enrolled in this retrospective study. The patient population was divided into two groups based on two different surgeons performing MMA. The associations between surgeons' experience on the one hand and PSG results and postoperative complications on the other hand were investigated. A total of 75 patients were included. There was no significant difference in baseline characteristics between the two groups. The reductions in apnea-hypopnea index and oxygen desaturation index were both significantly greater in group-B than group-A ( p = 0.015 and 0.002, respectively). The overall success rate after MMA was 64.0%. There was a negative correlation between surgeon experience and surgical success (odds ratio: 0.963 [0.93, 1.00], p = 0.031). No significant association was found between surgeon experience and surgical cure. Additionally, there was no significant association between surgeon experience and the occurrence of postoperative complications. Within the limitations of this study, it is concluded that surgeon experience may have little to no influence on the clinical efficacy and safety of MMA surgery in OSA patients.

Background: Multiple prediction models were developed for critical outcomes of COVID-19. However, prediction models using predictors which can be easily obtained in clinical practice and on dental status are scarce., Aim: The study aimed to develop and externally validate prediction models for critical outcomes of COVID-19 for unvaccinated adult patients in hospital settings based on demographics, medical conditions, and dental status., Methods: A total of 285 and 352 patients from two hospitals in the Netherlands were retrospectively included as derivation and validation cohorts. Demographics, medical conditions, and dental status were considered potential predictors. The critical outcomes (death and ICU admission) were considered endpoints. Logistic regression analyses were used to develop two models: for death alone and for critical outcomes. The performance and clinical values of the models were determined in both cohorts., Results: Age, number of teeth, chronic kidney disease, hypertension, diabetes, and chronic obstructive pulmonary diseases were the significant independent predictors. The models showed good to excellent calibration with observed: expected (O:E) ratios of 0.98 (95%CI: 0.76 to 1.25) and 1.00 (95%CI: 0.80 to 1.24), and discrimination with shrunken area under the curve (AUC) values of 0.85 and 0.79, based on the derivation cohort. In the validation cohort, the models showed good to excellent discrimination with AUC values of 0.85 (95%CI: 0.80 to 0.90) and 0.78 (95%CI: 0.73 to 0.83), but an overestimation in calibration with O:E ratios of 0.65 (95%CI: 0.49 to 0.85) and 0.67 (95%CI: 0.52 to 0.84)., Conclusion: The performance of the models was acceptable in both derivation and validation cohorts. Number of teeth was an additive important predictor of critical outcomes of COVID-19. It is an easy-to-apply tool in hospitals for risk stratification of COVID-19 prognosis., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Maxillomandibular advancement (MMA) has been shown to be the most effective surgical therapy for obstructive sleep apnea (OSA). Despite high success rates, there are patients who are considered as non-responders to MMA. In order to triage and inform these patients on their expected prognosis of MMA before the surgery, this study aimed to develop, internally validate, and calibrate a prediction model for the presence of surgical success for MMA in patients with OSA. Methods: A retrospective cohort study was conducted that included patients that had undergone MMA for moderate to severe OSA. Baseline clinical, polysomnographic, cephalometric, and drug-induced sleep endoscopy findings were recorded as potential predictors. Presence or absence of surgical success was recorded as outcome. Binary logistic regression analyses were conducted to develop the model. Performance and clinical values of the model were analyzed. Results: One hundred patients were included, of which sixty-seven (67%) patients reached surgical success. Anterior lower face height (ALFH) (OR: 0.93 [0.87−1.00], p = 0.05), superior posterior airway space (SPAS) (OR: 0.76 [0.62−0.92], p < 0.05), age (OR: 0.96 [0.91−1.01], p = 0.13), and a central apnea index (CAI) <5 events/hour sleep (OR: 0.16 [0.03−0.91], p < 0.05) were significant independent predictors in the model (significance level set at p = 0.20). The model showed acceptable discrimination with a shrunken area under the curve of 0.74, and acceptable calibration. The added predictive values for ruling in and out of surgical success were 0.21 and 0.32, respectively. Conclusions: Lower age at surgery, CAI < 5 events/hour, lower ALFH, and smaller SPAS were significant predictors for the surgical success of MMA. The discrimination, calibration, and clinical added values of the model were acceptable.

This retrospective cohort study aimed: (1) to analyze the influence of apnea-predominant versus hypopnea-predominant obstructive sleep apnea (OSA) on surgical outcome after maxillomandibular advancement (MMA); and (2) to evaluate whether MMA alters the presence of apnea-predominant to hypopnea-predominant OSA more than vice versa. In total 96 consecutive moderate to severe OSA patients, who underwent MMA between 2010 and 2021, were included. The baseline apnea−hypopnea index, apnea index, and oxygen desaturation index were significantly higher in apnea-predominant group, while the hypopnea index was significantly higher in hypopnea-predominant group (p < 0.001). No significant difference was found between apnea-predominant group and hypopnea-predominant group in the degree of advancement of A-point, B-point, and pogonion. Surgical success and cure were significantly higher in the hypopnea-predominant group compared to the apnea-predominant group, 57.4% versus 82.1% (p = 0.021) and 13.2% versus 55.5% (p = 0.012), respectively. Of the 68 (70.8%) apnea-predominant patients, 37 (54.4%) shifted to hypopnea-predominant after MMA. Of the 28 (29.2%) hypopnea-predominant patients, 7 (25%) shifted to apnea-predominant postoperatively. These findings suggest that preoperative hypopnea-predominant OSA patients might be more suitable candidates for MMA compared to preoperative apnea-predominant OSA patients. Additionally, MMA proved to alter the presence of apnea-predominant to hypopnea-predominant OSA to a larger extend than vice versa.

This systematic review aimed to comparatively evaluate the efficacy and safety of maxillomandibular advancement (MMA) and upper airway stimulation (UAS) in obstructive sleep apnea (OSA) treatment. A MEDLINE and Embase database search of articles on MMA and/or UAS for OSA was conducted. Twenty-one MMA studies and nine UAS studies were included. All the MMA studies demonstrated a reduction in apnea hypopnea index (AHI) postoperatively, and success rates ranged from 41.1% to 100%. Ten MMA studies reported pre- and postoperative Epworth sleepiness scale (ESS), and all but one study demonstrated a reduction in ESS. In the UAS studies, all but one demonstrated a reduction in AHI, and success rates ranged from 26.7% to 77.8%. In the eight UAS studies reporting pre- and postoperative ESS, an ESS reduction was demonstrated. No studies reported any deaths related to MMA or UAS. The most common postoperative complications after MMA and UAS were facial paresthesia in the mandibular area and discomfort due to electrical stimulation, respectively. This systematic review suggests that both MMA and UAS are effective and generally safe therapies for OSA. However, due to the limitations of the included studies, there is no evidence yet to directly compare these two procedures in OSA treatment.

Background: Acromegaly is an uncommon syndrome caused by growth hormone-producing pituitary adenoma or pituitary gland hypertrophy. Acromegaly is known to be characterized by progressive somatic disfigurement and a wide range of systematic manifestations. This case study describes a rare case of severe obstructive sleep apnea (OSA) caused by acromegaly., Clinical Presentation: A female patient presented to the consultant clinic with the chief complaint of progressively worsening sleep and was diagnosed with severe OSA. Because of a peculiar facial appearance of the patient, acromegaly was suspected and confirmed by the findings of hormonal analysis and magnetic resonance imaging (MRI). After transsphenoidal resection of the pituitary adenoma, her OSA was almost cured, with residual AHI of 5.5., Conclusion: This case highlights the importance of a comprehensive clinical examination of OSA patients. In every sleep-related breathing disorder case, sleep clinicians should be aware of alternate problems that could cause upper airway obstruction.

The aim of this study was to evaluate the clinical efficacy of maxillomandibular advancement (MMA) for obstructive sleep apnea (OSA) patients with a percentage of central and mixed apnea index in the total apnea-hypopnea index (CMAI%) ≧25%. Patients treated with MMA for OSA were retrospectively evaluated for baseline and postoperative patient data and polysomnographic results. The pre- and postoperative obstructive, central and mixed apnea parameters were compared. Of the included 78 patients, 21 patients (27%) presented with CMAI% ≧25% (median CMAI%, 49.1%; 35.9-63.8) prior to MMA. In 67% of these cases, MMA resulted in CMAI% <25 (median CMAI%, 6.1%; 2.1-8.9) and significantly improved the apnea-hypopnea index (AHI) (p < 0.001), the lowest oxyhemoglobin saturation (p < 0.001), central and mixed apnea index (p < 0.001), percentage of central and mixed apneas of total AHI (p = 0.004), central apnea index (p < 0.001), and mixed apnea index (p < 0.001). CMAI% ≧25% emerged in 25% of patients after MMA (median CMAI%, 49.1%; 35.9-63.8). Within the undeniable limitations of the study, it seems that the presence of CMAI% ≧25% should not be regarded as a contraindication for MMA in OSA patients., Competing Interests: Declaration of competing interest Nico de Vries is a member of the Medical Advisory Board of Night Balance. He is also an investigator for Inspire, Nyxoah and Jazz Pharmaceutics, consultant to Philips and Olympus. The other authors declare they have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction For the ambitious wind instrument player with severe malocclusion, the decision to undergo orthognathic surgery can be difficult.Aim To qualitatively explore and reveal key aspects of considerations for and outcomes of orthognathic surgery by interviewing a group of advanced and professional wind instrumentalists.Materials and methods One investigator, using a standardised questionnaire, interviewed seven cases. The interviews were analysed by two investigators who are knowledgeable about embouchure.Outcomes An ideal jaw relationship is not a prerequisite to achieving a professional career in music. Complete embouchure loss after surgery can be experienced due to changes in the position of incisors, lip relationship and tongue position relative to the shape of the oral cavity and as a result of neurosensory changes. Neurosensory recovery and 'wind instrument rehabilitation' takes at least six months, which was achieved in three out of five cases. The following temporary or permanent difficulties during playing after surgery were reported: onset of notes, high notes, leaps and intervals, and stable and well-tuned sound.Conclusion In view of the risks involved, orthognathic surgery in wind instrumentalists should only be considered when there is an (oral) health indication., (© 2022. The Author(s), under exclusive licence to the British Dental Association.)

Study Objectives: (1) To investigate if drug-induced sleep endoscopy (DISE) findings are predictive of surgical response for patients undergoing maxillomandibular advancement (MMA) for obstructive sleep apnea (OSA) and (2) to investigate the predictive value of the jaw thrust maneuver during DISE in terms of surgical response to MMA., Methods: A retrospective cohort study was conducted in patients with OSA who underwent a baseline polysomnography (PSG) and DISE followed by MMA and a 3- to 6-month follow-up PSG between September 1, 2011, and September 30, 2020., Results: Sixty-four patients with OSA (50 males [78.1%]; mean ± SD age = 51.7 ± 9.5 years; mean ± SD apnea-hypopnea index = 49.0 ± 20.8 events/h) were included. Thirty-nine patients were responders, and 25 were nonresponders. Adjusting for baseline characteristics and surgical characteristics (eg, age, baseline apnea-hypopnea index, degree of maxillary advancement), patients with complete anteroposterior epiglottic collapse had 0.239 times lower odds for response to MMA (95% confidence interval, 0.059-0.979; P = .047). No significant relationship was found between complete concentric velum collapse and MMA response. There was no statistically significant association between effect of jaw thrust maneuver during DISE on upper airway patency and treatment outcome of MMA., Conclusions: This study indicates that DISE is a promising tool to identify patients who will or will not respond to MMA for treating OSA. Patients with complete anteroposterior epiglottic collapse may be less suitable candidates for MMA., Citation: Zhou N, Ho J-PTF, de Vries N, Bosschieter PFN, Ravesloot MJL, de Lange J. Evaluation of drug-induced sleep endoscopy as a tool for selecting patients with obstructive sleep apnea for maxillomandibular advancement. J Clin Sleep Med . 2022;18(4):1073-1081., (© 2022 American Academy of Sleep Medicine.)

Local anesthesia is indispensable in dentistry. Worldwide, millions of local anesthetic injections are administered annually, and are generally considered safe invasive procedures. However, adverse effects are possible, of which dentists should be aware of. This scoping review aimed to provide an extensive overview of the reported literature on the adverse effects of dental local anesthesia. The types of papers, what is reported, and how they are reported were reviewed. Additionally, the incidence and duration of adverse effects and factors influencing their occurrence were also reviewed. An electronic search for relevant articles was performed in PubMed and Embase databases from inception to January 2, 2020. The titles and abstracts were independently screened by two reviewers. The analysis was narrative, and no meta-analysis was performed. This study included 78 articles. Ocular and neurological adverse effects, allergies, hematomas, needle breakage, tissue necrosis, blanching, jaw ankylosis, osteomyelitis, and isolated atrial fibrillation have been described. Multiple adverse effects of dental local anesthesia have been reported in the literature. The results were heterogeneous, and detailed descriptions of the related procedures were lacking. Vital information concerning adverse effects, such as the dosage or type of anesthetic solution, or the type of needle used, was frequently missing. Therefore, high-quality research on this topic is needed. Finally, the adverse effects that are rarely encountered in real-world general practice are overrepresented in the literature., Competing Interests: DECLARATION OF INTEREST: The authors have no conflicts of interest to declare., (Copyright © 2021 Journal of Dental Anesthesia and Pain Medicine.)

The aims of this study were (1) to quantify the intra-individual variation in the upper airway measurements on supine computed tomography (CT) scans at two different time points; and (2) to identify the most stable parameters of the upper airway measurements over time. Ten subjects with paired CT datasets (3-6 months interval) were studied, using computer software to segment and measure the upper airway. The minimum cross-sectional area of the total airway and all its segments (velopharynx, oropharynx, tongue base, and epiglottis) generally had the largest variation, while the length of the total airway had the lowest variation. Sphericity was the only parameter that was stable over time (relative difference <15%), both in the total airway and each subregion. There was considerable intra-individual variation in CT measurements of the upper airway, with the same patient instruction protocol for image acquisitions. The length of the total airway, and the sphericity of the total upper airway and each segment were stable over time. Hence, such intra-individual variation should be taken into account when interpreting and comparing upper airway evaluation parameters on CT in order to quantify treatment results or disease progress., Competing Interests: The authors have declared that no competing interests exist.