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Background: The Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) is a validated patient-reported outcome measure that evaluates subjective cosmetic and functional complaints. The goa...

Background: Dorsal preservation rhinoplasty (DPR) has recently received significant academic attention in part due to theoretical benefits over excisional surgical methods. The purpose of this study was to assess the global practice patterns regarding this technique. Materials and Methods: An 11-item questionnaire was electronically distributed to regional academies/societies representing rhinoplasty surgeons worldwide. Respondent exposure to and use of DPR were assessed based on geographic location. Results: Eight hundred thirty-six responses were received. Despite early publications on DPR originating largely from Western Europe and the United States, Turkey and Mexico have the greatest use of DPR techniques currently. The familiarity across many regions with preservation techniques appear to be secondary to courses and conferences rather than incorporation into training. Mexico demonstrates the greatest exposure to DPR during training. One hundred twenty-five respondents had previously used but abandoned dorsal preservation techniques. Poor results, less predictability, and complications (largely hump recurrence) are cited as common reasons for this. Conclusion: There is variability in the global practice of DPR across regions and this will likely continue to evolve.

Objective: LVADs are surgically implanted mechanical pumps that improve survival rates of individuals with advanced heart failure. LVAD therapy is associated with high morbidity, which can be partially attributed to challenges with detecting LVAD complications before adverse events occur. Current methods used to monitor for complications with LVAD support require frequent clinical assessments at specialized LVAD centers. Analysis of recorded precordial sounds may enable real-time, remote monitoring of device and cardiac function for early detection of LVAD complications. The dominance of LVAD sounds in the precordium limits the utility of routine cardiac auscultation of LVAD recipients. In this work, we develop a signal processing pipeline to mitigate sounds generated by the LVAD. Methods: We collected in vivo precordial sounds from 17 LVAD recipients, and contemporaneous echocardiograms from 12 of these individuals, to validate heart valve closure timings. Results: We characterized various acoustic signatures of heart sounds extracted from in vivo recordings, and report preliminary findings linking fundamental heart sound characteristics and level of LVAD support. Conclusion: Mitigation of LVAD sounds from precordial sound recordings of LVAD recipients enables analysis of intrinsic heart sounds. Significance: These findings provide proof-of-concept evidence of the clinical utility of heart sound analysis for bedside and remote monitoring of LVAD recipients.

Background Left ventricular assist devices (LVAD) are increasingly used for durable mechanical circulatory support in advanced heart failure. While LVAD therapy provides substantial improvement in mortality and quality of life, long-term therapy confers increased risk for device complications. We evaluated if cardiac computed tomography (CCT) improves the detection of cardiomechanical complications among patients with LVAD and suspected device malfunction. Methods In this study, we compared the diagnostic performance of CCT and transthoracic echocardiography (TTE) for the identification of cardiomechanical LVAD complications, including thrombus or neointimal hyperplasia, inflow cannula malposition with dynamic obstruction, fixed outflow obstruction, device infection, and severe aortic regurgitation. Complications were confirmed with surgical evaluation, pathologic assessment, or response to therapeutic intervention. Results Among 58 LVAD patients, who underwent CCT and TTE for suspected LVAD dysfunction, there were 49 confirmed cardiomechanical LVAD complications among 43 (74.1%) patients. The most common LVAD complication was thrombus or neointimal hyperplasia (65.3%), followed by dynamic obstruction (26.5%). Individually, CCT identified 29 of the 49 (59.2%) confirmed LVAD cardiomechanical complications, whereas TTE alone identified a complication in 11 cases (22.4%). However, diagnostic performance was greatest when the two modalities were used in combination, yielding a sensitivity of 67%, specificity of 93%, PPV of 97%, NPV of 47% and diagnostic accuracy of 73%. Conclusion The novel and complementary use of CCT with TTE for the evaluation of suspected device malfunction improves the accurate identification of cardiomechanical LVAD complication compared to either modality alone.

Preservation rhinoplasty may refer to preserving several anatomic components including: the nasal bones, upper lateral cartilages, the keystone area and/or ligaments of the nose. Preserving the osseocartilaginous framework or "dorsal preservation" minimizes or completely avoids violation of the dorsal aesthetic lines' architecture. Conventional hump reduction in open rhinoplasty disrupts these lines; however, it also provides versatility to reshape the entire dorsum. Surgical success with either technique requires a thorough understanding of the underlying nasal anatomy.

There has been particular recent interest in dorsal preservation rhinoplasty techniques because of claims of superior functional and aesthetic results relative to conventional hump reductions. The septum in dorsal preservation rhinoplasty is managed in a variety of ways with differences largely based on the location of septal excision (subdorsal resection, midseptal resection, and inferior septal resection). The technical considerations of a modified subdorsal strip method using a structural preservation technique are described. This technique maintains a subdorsal and caudal strut of cartilage. Patient-reported measures demonstrate significantly improved functional and aesthetic outcomes postoperatively with this procedure.

Classic Joseph hump reduction techniques have been a hallmark of current rhinoplasty practice and teaching. Recently, there has been a renewed global interest in preservation rhinoplasty techniques, although these techniques are not new. The work and techniques of innovative surgeons including Goodale, Lothrop, and Cottle describing preservation concepts from the late nineteenth century and early twentieth century were not as prevalently adopted as open structural approaches. As such, there has been a relative paucity in both research and teaching of preservation techniques—particularly in the United States. A survey of members of the American Academy of Facial Plastic and Reconstructive Surgery and The Rhinoplasty Society (145 respondents) demonstrates that while 15 (10%) of surgeons are not at all familiar with dorsal preservation surgery, 130 (90%) were. In the group that was familiar with dorsal preservation, the majority were only somewhat familiar (84, 65%) with these techniques. Only 11 respondents received any formal training in dorsal preservation techniques during residency or fellowship. 61 (42%) had attended a course or conference in which dorsal preservation techniques were discussed. One-hundred twenty-two survey respondents (84.1%) do not currently implement preservation techniques into their rhinoplasty practice. Twelve (8%) respondents implement it in 50% of cases. As research and formal training in preservation rhinoplasty grow, familiarity and implementation of these techniques will likely also grow in the United States.

Background Although prior studies have identified a low risk of venous thromboembolism (VTE) in rhinoplasty, these studies are limited by small samples and associated risk factors remain unknown. Objectives The aim of this study was to discern the incidence of VTE following rhinoplasty in a large patient population through analysis of a nationwide insurance claims database. Methods This study involved a population-based retrospective analysis of insurance claims made by patients who underwent rhinoplasty between 2007 and 2016. Established risk factors for VTE, demographic data, procedural details, and absolute incidence of VTE were collected. Results We identified a total of 55,287 patients who underwent rhinoplasty from 2007 to 2016. Mean age [standard error of the mean] was 38.74 [0.06] years (range, 18-74 years), and 54% were female. The overall incidence of VTE was 111, of which 70 were DVT and 41 were PE. From multivariate regression analysis, previous VTE (odds ratio [OR], 52.8; 95% confidence interval [CI], 35.2-78.6; P Conclusions We demonstrate a low overall incidence of VTE in rhinoplasty patients. Previous VTE, PICC/central line, advancing age, IBD, and intraoperative rib graft harvest were most strongly associated with VTE in this population cohort. Level of Evidence: 4

Reconstructive procedures in the head and neck can be a surgical challenge owing to the complex anatomical and physiological structure. Different locoregional and microvascular flaps are used for various defects to improve both function and cosmesis. Subjective clinical findings have been the mainstay for perfusion monitoring; however, areas of borderline perfusion are much more difficult to assess clinically. Multiple technologies that offer objective perfusion assessment have been developed to improve surgical outcomes. Indocyanine green (ICG) angiography has gained popularity owing to its minimal invasiveness and increased sensitivity and specificity in assessing flap perfusion particularly in the head and neck. It has been extensively used in free flaps, pedicled flaps (including nasal reconstruction), facelift procedures, random flaps, skull base reconstruction, and pharyngocutaneous fistula prediction. Its perioperative use has provided valuable qualitative and quantitative data that aid our understanding of flap hemodynamics. Clinically, this impacted decision-making in flap design, harvest, inset, and precocious salvage interventions. Though increased cost and intraoperative time could be limitations, cost-effectiveness studies have supported its use, particularly in high-risk individuals. Limitations include the lack of standardized dosing and consistent methodology agreement for data analysis. Future studies should involve larger cohorts and multi-institute studies to overcome such limitations.

Machine learning and artificial intelligence are generating significant attention in the scientific community and media. Such algorithms have great potential in medicine for personalizing and improving patient care, including in the diagnosis and management of heart failure. Many physicians are familiar with these terms and the excitement surrounding them, but many are unfamiliar with the basics of these algorithms and how they are applied to medicine. Within heart failure research, current applications of machine learning include creating new approaches to diagnosis, classifying patients into novel phenotypic groups, and improving prediction capabilities. In this paper, we provide an overview of machine learning targeted for the practicing clinician and evaluate current applications of machine learning in the diagnosis, classification, and prediction of heart failure.

Background It would be useful if existing tools or outcomes measures could predict which patients are at greater risk of revision surgery following rhinoplasty. Objectives The authors sought to determine if a single question assessing nasal self-esteem could be utilized to predict which patients are at greatest risk of revision surgery following rhinoplasty. Methods The authors conducted a retrospective chart review of 148 patients who underwent cosmetic rhinoplasty. Results of pre- and postoperative Standardized Cosmesis and Health Nasal Outcomes Survey questionnaires and rates of revision or patient-initiated revision discussions (RD) were collected. Patients were stratified based on answers to Standardized Cosmesis and Health Nasal Outcomes Survey question 5 (SQ5), “Decreased mood and self-esteem due to my nose.” Results Of the 148 patients included in the analysis, 72.9% were women, and the mean age was 30.9 (15-59, standard deviation = 10.3) years. Those patients who selected 4 or 5 on SQ5 had an overall revision rate of 16.7% and 18.8%, respectively, and a RD rate of 27.8% and 31.25%, respectively. Those patients who selected 0 through 3 on SQ5 had an overall revision rate of 0% and an overall RD rate of 10.4%. Only SQ5 was predictive of revision and RD on logistic regression analysis (P = 0.0484 and P = 0.0257) after Bonferroni correction. Conclusions SQ5 appears to offer a useful adjunct to guide surgical management of the cosmetic rhinoplasty patient. Those patients who reported worse nasal self-esteem and associated mood preoperatively were more likely to request and undergo revision. Level of Evidence: 4

Importance: Although conventional hump resections are a hallmark of rhinoplasty, there has been a rekindled interest in dorsal preservation (DP) techniques as a means for addressing the dorsal hump, with claims of superior functional and aesthetic results. As such, an understanding of DP, including technical considerations and outcomes, is imperative. Observations: DP allows for mobilization of the osseocartilaginous nasal vault as a single unit and thereby prevents disruption of the natural keystone area. The osseous nasal vault is managed with a transverse osteotomy and either a bilateral single lateral osteotomy (pushdown procedure) or bilateral bony wedge resections (letdown procedure) to allow for descent of the nasal dorsum. A variety of approaches to the septum exist, each differentiated by the location of cartilage resection: subdorsal, high-septal, midseptal, or inferior septum. These techniques result in pleasing dorsal aesthetic lines but may be limited by a higher rate of dorsal hump recurrence. Patency of the internal nasal valve (INV) is theoretically improved with DP. Robust series with patient-reported outcomes are lacking, although several reports and early experience at our center with a newly described high-septal resection technique do suggest positive functional and cosmetic outcomes with DP. Conclusions and Relevance: With the recent revitalized interest in DP, an understanding of the potential benefits, techniques, and challenges associated with this surgery is helpful. Maintenance of the dorsum as a single unit has implications for maintaining structural integrity at the nasal keystone, pleasing dorsal aesthetic lines, and the patency of the INV. As surgeons continue to develop and employ these techniques, critical assessment of patient-reported outcomes and objective nasal measurements, with an emphasis on comparison with standard hump takedown techniques, will be valuable.

This study evaluates the impact of different hump takedown techniques, namely the conventional hump resection with midvault reconstruction, the push-down (PD) and the let-down (LD) procedures, on the INV dimensions. In this cadaveric study, six heads were divided randomly into either the conventional hump resection technique (Group A; n = 6 sides) or DPR techniques (n = 6 sides). This latter group was subdivided such that initially a PD procedure was performed (Group B; n = 6 sides), followed by a LD procedure on the same heads (Group C; n = 6 sides). A validated radiological method was used to measure the INV angle and cross-sectional area (CSA) in a modified coronal plane both pre- and post-procedurally. Group A did not show significant reduction in the INV angle nor in CSA (p = 0.068 and p = 0.156, respectively). In the push-down group (B), we observed a mean change of 2.05° in the angles and 0.3 cm2 in the CSA (p = 0.0163 and p

Nasal obstruction is a common presenting symptom of patients seen by primary care physicians, otolaryngologists, and facial plastic surgeons. A variety of treatment strategies, both surgical and nonsurgical, have been used with success in improving nasal obstruction and quality of life. In a subset of patients, many of whom have either attempted these common treatment strategies or are intolerant of them, nasal obstruction remains a significant symptom. In these patients, there may be an identifiable problem, but it is simply not repairable or there is no identifiable anatomic issue. The management of these patients is discussed in this article, with an emphasis on a sensitive approach that takes into consideration a patient's mental health. While the need for diagnostic testing is generally not necessary for most cases of nasal obstruction, endoscopy and imaging should be considered in these patients. Validated patient-reported outcome measures are particularly helpful in providing an objective measure to a patient's frustrating symptoms. A variety of medications can be either contributory to the patient's symptoms or therapeutic if used appropriately. A variety of surgical interventions can also result in a functionally crippled nose and diagnoses including nasal valve stenosis, septal perforations, and empty nose syndrome are discussed. Importantly, further surgical interventions may not be appropriate if a deformity is minimal, and a surgeon should resist the temptation to proceed with surgery in those situations.

There has been a resurgence in dorsal preservation rhinoplasty (DPR) caused by theoretic aesthetic and functional advantages compared with conventional hump takedown rhinoplasty. Classically, the push-down and let-down maneuvers have been described for management of the bony nasal vault. There have been a variety of modifications in the septal resection that is a requisite for dorsal lowering in DPR. Partial dorsal preservation techniques, including cartilage-only preservation, have also been described. Although several studies have reported aesthetic and functional success with a variety of techniques, few have used objective or patient-centered subjective measures.

IMPORTANCE: In the last decade, there has been a significant increase in the number of practitioners administering botulinum toxin for facial synkinesis. However, there are few resources available to guide treatment patterns, and little is known about how these patterns are associated with functional outcomes and quality of life. OBJECTIVE: To evaluate botulinum treatment patterns, including the dosing and frequency of muscle targeting, for treatment of facial synkinesis and to quantify patient outcomes. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study of 99 patients treated for facial synkinesis was conducted from January 2016 through December 2018 at the Vanderbilt Bill Wilkerson Center in Nashville, Tennessee, a tertiary referral center. INTERVENTION: Onabotulinum toxin A treatment of facial synkinesis. MAIN OUTCOMES AND MEASURES: Patient-reported outcomes on the Synkinesis Assessment Questionnaire and botulinum treatment patterns, including the dosages and frequency of injection for each facial muscle, were compared at the initiation of treatment and at the end of recorded treatment. RESULTS: In total, 99 patients (80 female patients [81%]) underwent botulinum injections for treatment of facial synkinesis. The median (interquartile range) age was 54.0 (43.5-61.5) years, and the median (interquartile range) follow-up was 27.1 (8.9-59.7) months. Most patients underwent injections after receiving a diagnosis of Bell palsy (41 patients, 41%) or after resection of vestibular schwannoma (36 patients [36%]). The patients received a total of 441 treatment injections, and 369 pretreatment and posttreatment Synkinesis Assessment Questionnaire scores were analyzed. The mean botulinum dose was 2 to 3 U for each facial muscle and 9 to 10 U for the platysma muscle. The dose increased over time for the majority of all muscles, with steady state achieved after a median of 3 treatments (interquartile range, 2-3). Linear regression analysis for cluster data of the mean total questionnaire score difference was −14.2 (95% CI, −17.0 to −11.5; P

Background Although technological advances to pump design have improved survival, left ventricular assist device (LVAD) recipients experience variable improvements in quality of life. Methods for optimizing LVAD support to improve quality of life are needed. We investigated whether acoustic signatures obtained from digital stethoscopes can predict patient‐centered outcomes in LVAD recipients. Methods and Results We followed precordial sounds over 6 months in 24 LVAD recipients (8 HeartWare HVAD™, 16 HeartMate 3 [HM3]). Subjects recorded their precordial sounds with a digital stethoscope and completed a Kansas City Cardiomyopathy Questionnaire weekly. We developed a novel algorithm to filter LVAD sounds from recordings. Unsupervised clustering of LVAD‐mitigated sounds revealed distinct groups of acoustic features. Of 16 HM3 recipients, 6 (38%) had a unique acoustic feature that we have termed the pulse synchronized sound based on its temporal association with the artificial pulse of the HM3. HM3 recipients with the pulse synchronized sound had significantly better Kansas City Cardiomyopathy Questionnaire scores at baseline (median, 89.1 [interquartile range, 86.2–90.4] versus 66.1 [interquartile range, 31.1–73.7]; P =0.03) and over the 6‐month study period (marginal mean, 77.6 [95% CI, 66.3–88.9] versus 59.9 [95% CI, 47.9–70.0]; P Conclusions We have identified a novel acoustic biomarker associated with better quality of life in HM3 LVAD recipients, which may provide a method for assaying optimized LVAD support.

The left ventricular assist device (LVAD) has emerged as a bridge or alternative to heart transplant in individuals with advanced heart failure. However, the LVAD recipient population currently faces high rehospitalization rates. Remote analysis of precordial sounds in LVAD recipients may improve aftercare through early detection of complications. Prior work on analyses of precordial sounds in LVAD recipients focused on identifying pump thrombosis. Here, we focus on analyzing intrinsic precordial sounds to provide insight into intrinsic cardiac function. We analyzed a dataset of patient-acquired recordings of precordial sounds in LVAD recipients. We developed a signal processing pipeline to separate LVAD-generated sounds from other precordial sounds, making heart sound analysis in LVAD recipients feasible. Unsupervised clustering of features extracted from LVAD-mitigated sounds revealed subgroups of subjects possessing heart sounds with distinct frequency characteristics. The results provide preliminary evidence for the potential utility of exploring heart sound analysis in LVAD recipients for remote monitoring.

Background: In Rhinoplasty, understanding patient expectations are pivotal in achieving an optimal surgical outcome. Objective: To understand preoperative expectations and postoperative satisfactio...

Dorsal preservation rhinoplasty requires precise management of the osseocartilaginous vault. Ultrasonic piezo instruments offer several advantages compared with traditional tools such as hand saws, rasps, and osteotomes. As always, an understanding of the dynamics of manipulation of the vault, anatomy, and proper technique are paramount and are reviewed herein.

Introduction: Left ventricular assist device (LVAD) recipients experience variable improvements in quality of life (QoL). Methods for optimizing LVAD support to improve QoL are needed. Hypothesis: We hypothesized that acoustic signatures obtained from digital stethoscopes can predict patient-centered outcomes in LVAD recipients. Methods: Subjects were recruited from the LVAD clinic at Duke University Medical Center. Subjects were trained to use a digital stethoscope and recorded their precordial sounds weekly for 6 months. Subjects also completed a Kansas City Cardiomyopathy Questionnaire (KCCQ) weekly. The primary outcome for this study was QoL, as measured by the KCCQ summary score. Results: Twenty-four subjects, 8 supported by a HeartWare LVAD and 16 supported by a HeartMate3 (HM3) LVAD, were enrolled. We developed a novel algorithm to filter LVAD sounds from recordings. Unsupervised clustering of LVAD-mitigated sounds revealed discrete groups of acoustic features. Six out of 16 [38%] HM3 recipients made up a unique cluster and shared a common acoustic feature that we have termed the pulse synchronized sound (PSS) based on its temporal association to the artificial pulse of the HM3. Subjects with the PSS had significantly better KCCQ scores at baseline (median, 89.1 [IQR, 86.2-90.4] vs 66.1 [IQR, 31.1-73.7], P = 0.03) and over the 6 months of the study (mean = 79.67 [95% CI, 74.55 - 84.78] vs 60.57 [95% CI, 55.58 - 65.55], P < .001). Mechanistically, the PSS shares acoustic features with patient-derived intrinsic sounds. Because the PSS cannot be detected by routine auscultation, we developed a robust machine learning algorithm to detect the PSS in precordial sound recordings (AUC = 0.95 by leave-one-subject out cross-validation). Conclusions: We have identified a novel acoustic feature associated with better QoL in HM3 recipients. This novel biomarker is the first of its kind in LVAD recipients and may provide a method for assaying optimized LVAD support.

Background: Septal extension grafts (SEGs) are used widely in rhinoplasty as a means of controlling tip position. Grafts positioned in a side-to-side configuration may cause nasal airway obstruction. Methods: Retrospective cohort analysis of patients undergoing cosmetic rhinoplasty. Patients undergoing SEG placement were grouped according to completion of the Nasal Obstruction Symptom Evaluation (NOSE) or Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS). The latter has a cosmetic (C) and functional (O) domain. Each group was matched to a cohort that did not undergo SEG placement using criteria: preoperative NOSE or SCHNOS-O score, age, and gender. Patient demographics and outcomes, including NOSE, SCHNOS, and visual analog scale (VAS) scores, were compared between SEG and no-SEG groups using univariate and multivariate analyses. If patients underwent placement of an SEG and complained of obstruction, the laterality of the graft in relation to the complaint was examined. Results: SEGs were placed in 79 patients, of whom 77 completed the NOSE survey and 37 completed the SCHNOS-O both pre- and postoperatively. These patients were matched to patients without SEGs. For both the SCHNOS and NOSE-matched cohorts, functional outcomes (NOSE, SCHNOS-O, and VAS-F) did not significantly differ between SEG and no-SEG groups. These findings were also observed when patients were stratified by cosmetic surgery alone versus combined functional and cosmetic surgery. On multivariate linear regression analysis, when accounting for intraoperative techniques, there was no difference in postoperative NOSE or SCHNOS-O outcomes between the SEG and no-SEG cohorts. Side of postoperative nasal obstruction did not correlate with side of SEG placement. Conclusion: SEGs, when used in a unilateral side-to-side configuration, yield excellent aesthetic results without compromising functional outcomes.

Objectives/hypothesis Deviations of the caudal nasal septum can impact airflow and aesthetics. The anterior septal reconstruction (ASR) technique, a modification of extracorporeal septoplasty, addresses this issue while preserving a segment of the dorsal septum. When ASR is combined with dorsal hump reductions and osteotomies, the keystone may be destabilized. This study evaluates the outcomes of this intervention. Study design Retrospective chart review. Methods This is a retrospective study evaluating the functional and aesthetic outcomes of 58 patients who underwent ASR combined with dorsal hump reductions (with or without osteotomies). The Nasal Obstruction Symptom Evaluation (NOSE) and Standardized Cosmesis and Health Nasal Outcomes Survey Obstructive/Cosmetic (SCHNOS-O, SCHNOS-C) scores were measured and compared pre- and postoperatively. Linear regression analysis was performed to determine the impact of sex, gender, osteotomies, and trauma on outcomes. Results Mean improvement in NOSE, SCHNOS-O, and SCHNOS-C scores within the first 3 months after surgery were -41.8, -32.6, and -51.5 respectively (P 9 months, these improvements were also significant for NOSE and SCHNOS-O scores and approached significance (P = .06) for SCHNOS-C scores. A subanalysis of patients who underwent osteotomies yielded functional and aesthetic improvements across all follow-up periods, all of which were significant with the exception of SCHNOS-O scores at >9 months (P = .1). In a multiple linear regression analysis, osteotomies contributed significantly to change in SCHNOS-C scores (β = -64.09, P = .001) at 3- to 9-month follow-up. Conclusions The combination of ASR, hump take down, and osteotomies is safe and efficacious with implications for patients who seek correction of caudal septal deviations in conjunction with changes in external contour deformities. Level of evidence 3 Laryngoscope, 2020.

Facial plastic surgeons must understand nasal aesthetics in the context of race, ethnicity, and culture. The lack of aesthetic norms and ideal standards in non-Caucasian patients and the variation in nasal anatomy and morphology among races can create a challenge in approaching ethnic rhinoplasty. Preoperative assessment of nasal and facial features that contribute to a nose that is unpleasing for a non-Caucasian patient cannot be based on neoclassical canons. This article describes the concepts of facial aesthetics important to approaching ethnic rhinoplasty. Understanding these features will allow the surgeon to achieve nasal symmetry and improved definition without effacing ethnicity.

Background Botulinum resistance poses significant treatment challenges for both patients and healthcare practitioners. We first present a case highlighting botulinum resistance in a patient who failed to respond to alternative formulations but who responded remarkably to incobotulinum toxinA, an identical toxin free of complexing proteins. Secondly, we provide a treatment algorithm and a review of the literature detailing clinical and immunochemical botulinum resistance. Results Patients with botulinum resistance show a predisposition to failure on subsequent injections and possess a propensity toward neutralizing and nonneutralizing antibody development. The mechanisms of resistance are not entirely understood but thought to be secondary to an immunologic response. Risk factors for resistance include higher botulinum doses, more frequent injections, and high total lifetime dosage. Patients may still respond to other botulinum formulations or subtypes; however, this effect may be temporary. Conclusion This case report describes a patient who responded to incobotulinum toxinA after failing treatment with the identical toxin compounded with buffer proteins, ultimately supporting the possibility of immune-mediated resistance to the surrounding proteins and not the toxin itself. Often, impending treatment resistance is preceded by a poor or limited clinical response. Antibody testing is not indicated because it is neither sensitive nor specific and does not change clinical practice. Initially, higher doses of botulinum may overcome resistance without increasing treatment frequency, and side effects are far less common in those with clinical resistance. If higher dosages fail to produce a response, alternative botulinum formulations or subtypes can be considered. Laryngoscope, 129:2269-2273, 2019.

OBJECTIVE To compare presenting characteristics of patients with adductor spasmodic dysphonia (ADSD), ADSD with laryngeal tremor (ADSD + LT), and laryngeal tremor without ADSD (LT). DESIGN Cross-sectional analysis. METHODS Patients treated for laryngeal movement disorders (1990-2016) were included. Analysis of variance and chi square tests measured differences in patient characteristics across the three disease groups. Using ADSD as the referent, multivariable logistic regression models were used to determine whether potential risk factors including patient demographics, family history, presence of potential inciting events prior to disease onset, and coprevalent movement disorders were associated with ADSD + LT or LT. RESULTS In all, 652 patients with ADSD (n = 377), ADSD + LT (n = 98), and LT (n = 177) were included. ADSD patients were significantly younger than those with ADSD + LT and LT (52.5 ± 13.4, 63.9 ± 11.3, and 69.3 ± 10.5 years, respectively; P

Objective To identify and clarify current evidence supporting and disputing the effectiveness of perioperative antibiotic use for common otolaryngology procedures. Data Sources PubMed, Embase (OVID), and CINAHL (EBSCO). Review Methods English-language, original research (systematic reviews/meta-analyses, randomized control trials, prospective or retrospective cohort studies, case-control studies, or case series) studies that evaluated the role of perioperative antibiotic use in common otolaryngology surgeries were systematically extracted using standardized search criteria by 2 investigators independently. Conclusions Current evidence does not support routine antibiotic prophylaxis for tonsillectomy, simple septorhinoplasty, endoscopic sinus surgery, clean otologic surgery (tympanostomy with tube placement, tympanoplasty, stapedectomy, and mastoidectomy), and clean head and neck surgeries (eg, thyroidectomy, parathyroidectomy, salivary gland excisions). Antibiotic prophylaxis is recommended for complex septorhinoplasty, skull base surgery (anterior and lateral), clean-contaminated otologic surgery (cholesteatoma, purulent otorrhea), and clean-contaminated head and neck surgery (violation of aerodigestive tract, free flaps). In these cases, antibiotic use for 24 to 48 hours postoperatively has shown equal benefit to longer duration of prophylaxis. Despite lack of high-quality evidence, the US Food and Drug Administration suggests antibiotic prophylaxis for cochlear implantation due to the devastating consequence of infection. Data are inconclusive regarding postoperative prophylaxis for nasal packing/splints after sinonasal surgery. Implications for Practice Evidence does not support the use of perioperative antibiotics for most otolaryngologic procedures. Antibiotic overuse and variability among providers may be due to lack of formal practice guidelines. This review can help otolaryngologists understand current evidence so they can make informed decisions about perioperative antibiotic usage.

Study Design Comparison, in terms of insertion accuracy and biomechanical performance, between an increased cortical purchase and straightforward pedicle screw trajectory. Objective This study aims to compare a trajectory with increased cortical purchase to the more common straightforward trajectory in terms of strength and insertion accuracy using real-time navigation. Summary of Background Data In previous studies, it was suggested that pedicle screw pullout strength is strongly correlated with bone mineral density, and using a more cortical tract allows a greater portion of the denser bone, the cortex, to be in contact with the screw. In light of this advantage, an insertion technique has been proposed more recently, to increase the cortical purchase to maximize screw thread contact with cortical bone. It is performed inserting the screw with reduced transverse inclination and results in cortical bone purchase in the lateral portion of the pedicle. Methods Eight T1 and eight T3 vertebra models were reconstructed in Mimics Suite (Materialise, Leuven, Belgium) using CT data obtained with a Medtronic O-arm. Using a previously developed computer algorithm, we calculated all achievable safe trajectories for pedicle screw placement ensuring a minimal distance of 0.5 mm between screw and pedicle edges. For both vertebrae, among these, the straightest and the most convergent trajectories with the calculated insertion region greater than 15% of the total were selected to safely instrument the vertebrae, respectively, as ICP and straightforward techniques. The straightforward technique was planned with a transverse angle of 22.50° in both vertebrae whereas the ICP was planned with a transverse angle of 12.50° for T1 and 2.5° for T3. The screws were implanted by a surgeon experienced in straightforward insertion, and other independent investigators measured placement accuracy and mechanical performance. Results The transverse screw angles for T1 and T3 with straightforward technique had average values of 24.93° ± 2.96° and 23.53° ± 2.70°, respectively. For the ICP technique, the average values were 15.60° ± 2.95° for T1 and 2.29° ± 1.55° for T3. The resultant errors associated with screw placement for T1 and T3 were not significantly different (p > .05). The pullout failure loads with straightforward techniques ranged from 756 ± 164 N in T1 to 703 ± 74 N in T3 and were not significantly different (p > .05) from the values of 699 ± 84 N for T1 and of 732 ± 113 N measured for the ICP. Conclusions For the upper thoracic vertebrae tested, despite the use of shorter screws, the insertion technique with increased cortical purchase, in biomechanical terms, is comparable with the straightforward trajectory. Using guidance, the proposed ICP technique was performed with the same accuracy as the popular straightforward technique. Level of Evidence Level V.

More than 2,400 continuous-flow left ventricular assist devices (LVADs) are implanted each year in the United States alone. Both the number of patients living with LVADs and the life expectancy of these patients are increasing. As a result, patients with LVADs are increasingly encountered by non-LVAD specialists who do not have training in managing advanced heart failure for general medical care, cardiovascular procedures, and other subspecialty care. An understanding of the initial evaluation and management of patients with LVADs is now an essential skill for many health care providers. In this State-of-the-Art Review, we discuss current LVAD technology, summarize our clinical experience with LVADs, and review the current data for the medical management of patients living with LVADs.

An elderly male presented for emergent repair of a ruptured abdominal aortic aneurysm. For anticipated volume resuscitation, vasopressor administration, and hemodynamic monitoring, a large-bore central venous catheter was placed in the left internal jugular vein under ultrasound guidance before surgical incision. Initially, there were no readily apparent signs of venous perforation. However, a massive left hemothorax developed because of perforation of the brachiocephalic vein and violation of the pleural space. This case report discusses both prevention and management of such a complication.

AIMS Worsening heart failure (HF) is associated with shorter left ventricular systolic ejection time (SET), but there are limited data describing the relationship between SET and clinical outcomes. Thus, the objective was to describe the association between SET and clinical outcomes in an ambulatory HF population irrespective of ejection fraction (EF). METHODS AND RESULTS We identified ambulatory patients with HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) who had an outpatient transthoracic echocardiogram performed between August 2008 and July 2010 at a tertiary referral centre. Multivariable logistic regression was used to evaluate the association between SET and 1-year outcomes. A total of 545 HF patients (171 HFrEF, 374 HFpEF) met eligibility criteria. Compared with HFpEF, HFrEF patients were younger [median age 60 years (25th-75th percentiles 50-69) vs. 64 years (25th-75th percentiles 53-74], with fewer females (30% vs. 56%) and a similar percentage of African Americans (36% vs. 35%). Median (25th-75th percentiles) EF with HFrEF was 30% (25-35%) and with HFpEF was 54% (48-58%). Median SET was shorter (280 ms vs. 315 ms, P

Postoperative pulmonary complications (PPCs) are common following major surgical procedures. Risk stratification tools have been developed to identify patients at risk for PPCs. While otolaryngology cases were included in the development of common predictive tools, they comprised small percentages in each tool. It is unclear how these tools perform in patients undergoing major head and neck surgery with free flap reconstruction. This retrospective review studied all free flap reconstructions in head and neck surgery over a 12-year period at a single institution in the southeastern US. Baseline demographic and medical information were included for each case. All cases were reviewed for development of major PPCs, including pneumonia and respiratory failure. The cohort underwent risk stratification using the ARISCAT and Gupta pulmonary risk indices. Performance of these predictive models for head and neck surgery was determined through receiver-operator curve comparison. 794 patients were identified with a median age of 62 years (IQR 41–83). Sixty-five percent were male. Forty-three (5.4%) developed pneumonia, 23 patients developed respiratory failure (2.9%), and 38 patients developed both (4.8%), resulting in a total PPC proportion of 13.1% (n = 104). Both ARISCAT and Gupta pulmonary risk indices demonstrated low discrimination to predict PPCs in head and neck free flap reconstruction, with areas under the curve of 0.60 and 0.65, respectively. Two major indices for prediction of postoperative pulmonary complications do not accurately identify risk in patients undergoing major head and neck surgery. Further studies are needed to develop predictive tools for PPCs in this high-risk population.

Introduction Heart failure (HF) is the number one discharge diagnosis at most hospitals in America. The impact of newly added heart failure providers on the care of heart failure patients is unclear. We reviewed the impact of creating a new HF practice on clinical care and readmissions at a large, tertiary care health system. Methods In December 2017, a new heart failure practice was established at a large, 3 hospital system. The practice included 1.5 physicians and 1 advanced practice provider and developed both an inpatient consultative service and an outpatient practice including availability of same day IV diuretic therapy. We reviewed the 2018-2019 readmission rate of patients seen versus not seen by the HF practice in either the inpatient or outpatient setting. Results A total of 2597 patients were discharged with a primary diagnosis of HF and 372 (14.3%) were readmitted within 1 month. Table 1 shows quarterly clinic volumes. Due to challenges with referral volumes, guidelines for referral were developed and included patients with new diagnosis of heart failure, readmissions within 6 months, or BNP > 1000. Readmission rates by provider type are shown in Table 2. There was a substantial reduction in readmissions when the HF team was involved in care. Additionally, 30 patients were referred for heart transplantation and 21 for LVAD therapy. Conclusion Establishing a HF practice is associated with a reduction in readmissions for patients managed by the HF practice, but not for the overall hospital. Careful consideration of appropriate referrals and strategies to increase “patient touches” should be performed when establishing a new heart failure practice.

Left ventricular assist devices (LVADs) are life-saving, surgically implanted mechanical heart pumps used to treat patients with advanced heart failure (HF). While life-saving, LVAD support is associated with a high incidence of complications, making early recognition and management of LVAD complications a critical need. Blood clot formation within the LVAD, known as LVAD thrombosis, is a catastrophic complication of LVAD therapy that often requires LVAD exchange due to delayed diagnosis and treatment. Using digital stethoscopes, we identified differences in acoustic spectra from two patients presenting with LVAD thrombosis compared with normally functioning LVAD pumps within the same patient. Importantly, these acoustic changes were present even in the absence of typical signs of HF that are often present in LVAD thrombosis patients. Our work suggests that acoustic spectral analysis of digital stethoscope signals could be used for early detection and mitigation of LVAD complications.

To assess current management strategies for advanced heart failure in adults with congenital heart disease, including heart transplantation and mechanical circulatory support. Current data demonstrate that adults with CHD generally experience higher short-term mortality after heart transplantation and MCS implantation, but enjoy superior long-term survival. Such patients are nonetheless less likely to receive a transplant than non-ACHD peers due to a variety of factors, including lack of applicability of current listing criteria to HF in ACHD. MCS is underutilized in ACHD, but provides similar quality of life benefits for ACHD and non-ACHD patients alike. Heart failure in ACHD is complex and difficult to treat, and both heart transplantation and mechanical circulatory support are often challenging to implement in this patient population. However, long-term results are encouraging, and existing data supports increasing use of MCS and transplant earlier in their disease course. Multidisciplinary care is critical to success in these complex patients.

Objective To determine if immediate postoperative uncuffed tracheostomy placement following oral cavity or oropharyngeal head and neck free flap reconstruction is associated with shorter hospital length of stay and higher inpatient decannulation rates without an increase in respiratory complications, as compared with immediate placement of cuffed tracheostomy. Study Design Retrospective cohort. Setting Tertiary referral center. Subjects and Methods Patients were included if they underwent free flap reconstruction for oral cavity or oropharyngeal squamous cell carcinoma and had an intraoperative tracheostomy placed between 2005 and 2016. In 2012, head and neck surgeons changed from routine placement of cuffed to uncuffed tracheostomy tubes immediately after free flap reconstruction. This study compares length of hospital stay, inpatient decannulation rates, and respiratory complications between patients who had cuffed and uncuffed tracheostomies. Analysis of variance and chi-square test were used to examine continuous and categorical variables, respectively. Multivariable regression analyses were performed to determine whether cuff status was independently associated with primary outcomes of length of hospital stay, decannulation, and respiratory complications. Results Of 752 patients who underwent free flap reconstruction, 493 patients met inclusion criteria (cuffed, n = 366; uncuffed, n = 127). Patient variables (ie, age, sex, body mass index, prior chemoradiation) and tumor characteristics (ie, location, stage) did not differ significantly between groups. Adjusted analysis showed that an uncuffed tracheostomy (vs a cuffed tracheostomy) was associated with shorter length of stay (7.7 vs 9.7 days, P < .001) and did not increase the rate of respiratory complications. Conclusion Immediate placement of a uncuffed tracheostomy after oral cavity or oropharyngeal free flap reconstruction is associated with shorter hospital stays without an increase in respiratory complications.

Objective To determine the factors associated with intra- and postoperative cerebrospinal fluid (CSF) leaks in setting of endoscopic transsphenoidal sellar surgery. Study Design Retrospective cohort. Setting Tertiary referral center. Subjects and Methods This study included 806 patients who underwent endoscopic transsphenoidal sellar surgery between 2004 and 2016. The associations between CSF leaks (intra- and postoperative) and patient demographics, medical history, tumor characteristics, and intraoperative repair techniques were analyzed. Results In sum, 205 (25.4%) patients had a CSF leak: 188 (23.3%) intraoperative leaks and 38 (4.7%) postoperative leaks. Twenty-one (2.6%) patients had postoperative leaks after having repair of an intraoperative leak; 55% of patients with a postoperative leak had an intraoperative leak repaired. On multivariate analysis, body mass index (BMI), hydrocephalus, suprasellar extension, and craniopharyngioma significantly predicted intraoperative CSF leaks, while only BMI and hydrocephalus predicted postoperative CSF leaks. Patients having septal flap repairs of CSF leaks had a higher postoperative leak rate relative to other repair techniques (odds ratio, 6.37; P = .013). Rigid reconstruction did not correlate with leaks. Conclusion For this large cohort of patients undergoing endoscopic transsphenoidal sellar surgery, BMI and hydrocephalus were identified as predictors of postoperative CSF leaks, including those occurring after repair of intraoperative leak. These variables may put stress on the surgical repair of sellar defects, and consideration of these risk factors may help counsel patients and guide perioperative decision making in regard to repair strategies and CSF diversion techniques.

Background While there have been multiple studies published that have stressed the importance of restoring various different radiographic parameters to improve functional outcome scores, there is no consensus on the parameter that correlates most with patients’ functional outcomes. We hypothesize that obtaining near anatomical reduction of the palmar lunate facet is critical to improving functional outcome scores. The purpose of this study is to determine the effects of reduction and stabilization of the palmar lunate facet on functional outcomes in patients with intra-articular distal radius fracture. Materials and methods We prospectively collected clinical examination data, radiographic measurements, and functional outcome scores on 157 patients who were treated operatively for multifragmentary intra-articular fractures of the distal radius (AO Type C3) between 1996 and 2006. Prospective data were acquired at 3, 6 months, and 1 year postsurgical intervention in clinical follow-up. Based on radiographic measurements, patients were designated into a nondisplaced palmar lunate facet group and a displaced palmar lunate facet group. Clinical and functional outcomes were then compared between the groups. Results Patients without displacement had a significantly higher value of wrist extension and forearm supination when compared with the patients with displacement. In addition, the Gartland and Werley score was significantly higher in patients with displacement of the palmar lunate facet. Conclusion This study demonstrates that patients with near anatomical reduction of the palmar lunate facet after surgical treatment of an intra-articular distal radius fracture had improved range of motion and better functional outcome scores compared with patients with residual displacement of the palmar lunate facet. Richard MJ, Lampley AJ, Patel PD, Nomides REK, Mithani SK, Leversedge FJ, Ruch DS. The Importance of the Palmar Lunate Facet in the Treatment of Distal Radius Fractures. The Duke Orthop J 2016;6(1):56-60.

Background— Novel oral anticoagulants (NOACs) have been shown to be at least as good as warfarin for preventing stroke or transient ischemic attack in patients with atrial fibrillation, yet diffusion of these therapies and patterns of use among atrial fibrillation patients with ischemic stroke and transient ischemic attack have not been well characterized. Methods and Results— Using data from Get With The Guidelines-Stroke, we identified a cohort of 61 655 atrial fibrillation patients with ischemic stroke or transient ischemic attack hospitalized between October 2010 and September 2012 and discharged on warfarin or NOAC (either dabigatran or rivaroxaban). Multivariable logistic regression was used to identify factors associated with NOAC versus warfarin therapy. In our study population, warfarin was prescribed to 88.9%, dabigatran to 9.6%, and rivaroxaban to 1.5%. NOAC use increased from 0.04% to a 16% to 17% plateau during the study period, although anticoagulation rates among eligible patients did not change appreciably (93.7% versus 94.1% from first quarter 2011 to second quarter 2012), suggesting a trend of switching from warfarin to NOACs rather than increased rates of anticoagulation among eligible patients. Several bleeding risk factors and CHA 2 DS 2 -VASc scores were lower among those discharged on NOAC versus warfarin therapy (47.9% versus 40.9% with CHA 2 DS 2 -VASc ≤5, P 2 DS 2 -VASc). Conclusions— NOACs have had modest but growing uptake over time among atrial fibrillation patients hospitalized with stroke or transient ischemic attack and are prescribed to patients with lower stroke risk compared with warfarin.

Nasopharyngeal carcinoma (NPC) is a rare malignancy of epidermoid origin, one that is especially uncommon in children in low risk areas such as the United States. The relative rarity in children makes the diagnosis of this malignancy difficult, and therefore childhood nasopharyngeal carcinoma is associated with advanced locoregional disease and higher prevalence of distant metastasis. A case of pediatric nasopharyngeal carcinoma is described here to highlight a possible presentation of this uncommon pediatric disease and reasons for delayed diagnosis. This is followed by a brief discussion of epidemiology, diagnosis, treatment, and outcomes for this malignancy in children.

The buccinator, despite being a prominent midface muscle, has been previously overlooked as a target in the treatment of facial synkinesis with botulinum toxin.To evaluate outcomes of patients treated with botulinum toxin to the buccinator muscle in the setting of facial synkinesis.Prospective cohort study of patients who underwent treatment for facial synkinesis with botulinum toxin over multiple treatment cycles during a 1-year period was carried out in a tertiary referral center.Botulinum toxin treatment of facial musculature, including treatment cycles with and without buccinator injections.Subjective outcomes were evaluated using the Synkinesis Assessment Questionnaire (SAQ) prior to injection of botulinum toxin and 2 weeks after treatment. Outcomes of SAQ preinjection and postinjection scores were compared in patients who had at least 1 treatment cycle with and without buccinator injections. Subanalysis was performed on SAQ questions specific to buccinator function (facial tightness and lip movement).Of 84 patients who received botulinum toxin injections for facial synkinesis, 33 received injections into the buccinator muscle. Of the 33, 23 met inclusion criteria (19 [82.6%] women; mean [SD] age, 46 [10] years). These patients presented for 82 treatment visits, of which 44 (53.6%) involved buccinator injections and 38 (46.4%) were without buccinator injections. The most common etiology of facial paralysis included vestibular schwannoma (10 [43.5%] participants) and Bell Palsy (9 [39.1%] participants). All patients had improved posttreatment SAQ scores compared with prebotulinum scores regardless of buccinator treatment. Compared with treatment cycles in which the buccinator was not addressed, buccinator injections resulted in lower total postinjection SAQ scores (45.9; 95% CI, 38.8-46.8; vs 42.8; 95% CI, 41.3-50.4; P = .43) and greater differences in prebotox and postbotox injection outcomes (18; 95% CI, 16.2-21.8; vs 19; 95% CI, 14.2-21.8; P = .73). Subanalysis of buccinator-specific scores revealed significantly improved postbotox injection scores with the addition of buccinator injections (5.7; 95% CI, 5.0-6.4; vs 4.1; 95% CI, 3.7-4.6; P = .004) and this corresponded to greater differences between prebotulinum and postbotulinum injection scores (3.3; 95% CI, 2.7-3.9; vs 2.0; 95% CI, 1.4-2.6; P = .02). The duration of botulinum toxin effect was similar both with and without buccinator treatment (66.8; 95% CI, 61.7-69.6; vs 65.7; 95% CI, 62.5-71.1; P = .72).The buccinator is a symptomatic muscle in the facial synkinesis population. Treatment with botulinum toxin is safe, effective and significantly improves patient symptoms.3.

To report on the post-tonsillectomy bleeding outcomes and factors associated with hemorrhage among children with pre- or post-operatively diagnosed bleeding disorders treated with an institutional protocol.Retrospective cohort study of patients with hematologic disorders who underwent tonsillectomy between 2003 and 2016 and were treated with perioperative desmopressin or factor replacement and/or aminocaproic acid. Postoperative outcomes were compared to controls matched for age, sex, and indication for surgery. Analysis of factors associated with hemorrhage was performed in patients with bleeding disorders using Mann-Whitney U or chi-squared tests.45 patients with hematologic disorders met inclusion criteria. Platelet dysfunction, including von Willebrand Disease (vWD), was the most common diagnosis (77.8%). Most patients had a preoperative diagnosis of a bleeding disorder and received perioperative hematologic medications (86.7%). Compared to matched controls, patients with hematologic disorders experienced more postoperative bleeding (15.5%; 12 bleeds, 7 patients vs. 1.7%; 1 bleed, 1 patient, p = 0.05) and had longer postoperative stays (1.3 days vs. 0.4 days, p 0.001). Among the patients with hematologic disorders, patients who experienced a postoperative bleed were significantly more likely to have a factor deficiency (e.g. Hemophilia over vWD) and have a postoperative diagnosis (compared to preoperative diagnosis) for which they did not receive perioperative hematologic medication. Of patients with a postoperative bleed, all those diagnosed postoperatively required at least one surgical intervention to control bleeding compared to 33% of patients with a preoperative diagnosis. A history of post-surgical bleeding, male sex, age at surgery, and pharyngitis as surgical indication were not associated with higher hemorrhage rates in this group.This study suggests a clinically important magnitude of increased bleeding risk in patients with hematologic disease. This risk appears to decrease with the use of an institutional protocol consisting of desmopressin or factor replacement and an antifibrinolytic agent extending through postoperative day 10.

Adenoid Cystic Carcinoma (ACC) is a salivary gland malignancy with unpredictable growth and poorly understood prognostic factors. A database search of patients treated at a single institution was used to identify patients with histologically confirmed ACC. Patient, tumor, and treatment characteristics were examined via review of medical records. Statistical analyses were performed to assess outcomes and associated prognostic factors. A total of 70 patients were identified with a median follow up of 3.5 years. Overall survival at 5, 10, and 15 years was 80.4%, 61.3%, and 29.4%, respectively. Disease recurrence was seen in 31.9%; of these, 72.7% developed distant metastasis. Older age, higher stage, skull base involvement, positive margins, and metastatic disease, but not local recurrence, predicted a worse overall survival. Higher stage and skull base disease were associated with shorter disease free survival. Higher T stage and perineural disease were associated with distant failure, whereas skull base involvement predicted higher local recurrence. While lung metastasis was the most common, vertebral metastasis was associated with poorer survival. In conclusion, disease stage, positive margins, skull base involvement, perineural invasion, time to recurrence, and location of metastasis, but not nodal involvement, could serve as poor prognostic factors in ACC.

Anaplastic thyroid cancer (ATC) is characterized by very aggressive growth with undifferentiated features. Recently, it has been reported that the Notch1 signaling pathway, which affects thyrocyte proliferation and differentiation, is inactivated in ATC. However, it remains largely unknown whether using Notch1 activating compounds can be an effective therapeutic strategy in ATC. Therefore, in this study, we aimed to evaluate the drug effects of a potential Notch activator hesperetin on ATC cell. A unique ATC cell line HTh7 was used to evaluate the drug effects of hesperetin. The Notch1 activating function and cell proliferation were evaluated. The mechanism of growth regulation was investigated by the detection of apoptotic markers. The expression levels of thyrocyte-specific genes were quantified for ATC redifferentiation. Upregulated expression of Notch1 and its downstream effectors hairy and enhancer of split 1 (Hes1) and Hes1 related with YRPW motif was observed in hesperetin-treated ATC cells. The enhanced luciferase signal also confirmed the functional activity of hesperetin-induced Notch1 signaling. Hesperetin led to a time- and dose-dependent decrease in ATC cell proliferation. The cell-growth inhibition was mainly caused by apoptosis as evidenced by increased levels of cleaved poly ADP ribose polymerase and cleaved caspase-3 as well as decreased survivin. Additionally, hesperetin induced the expression levels of thyrocyte-specific genes including thyroid transcription factor 1 (TTF1), TTF2, paired box gene 8, thyroid stimulating hormone receptor, and sodium/iodide symporter. Hesperetin activates the Notch1 signaling cascade and suppresses ATC cell proliferation mainly via apoptosis. Hesperetin also induces cell redifferentiation of ATC, which could be useful clinically.

The seed storage glycoprotein Arachis hypogaea (Ara h) 1 is a major allergen found in peanuts. The biochemical resistance of food proteins to protease digestion contributes to their allergenicity. The rapid proteolysis of Ara h 1 under gastric conditions challenges this model. Biophysical and in vitro digestion experiments were carried out to identify how Ara h 1 epitopes might survive digestion, despite their facile degradation. The bicupin core of Ara h 1 can be unfolded at low pH and reversibly folded at higher pH. Additionally, peptide fragments from simulated gastric digestion predominantly form noncovalent aggregates when transferred to base. Disulfide cross-links within these aggregates occur as intermediates in relatively low amounts only at early times and play no role in shielding peptides from degradation. It is proposed that peptide fragments which survive gastric conditions form large aggregates in basic environments such as the small intestine, making epitopes available for triggering an allergic response.