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Summary: Recurrent respiratory papillomatosis (RRP) is characterized by benign exophytic lesions of the respiratory tract caused by the human papillomavirus (HPV), in particular low‐risk HPV6 and HPV11. Aggressiveness varies greatly among patients. Surgical excision is the current standard of care for RRP, with adjuvant therapy used when surgery cannot control disease recurrence. Numerous adjuvant therapies have been used to control RRP with some success, but none are curative. Current literature supports a polarization of the adaptive immune response to a T helper type 2 (Th2)‐like or T regulatory phenotype, driven by a complex interplay between innate immunity, adaptive immunity and HPV6/11 proteins. Additionally, certain immunogenetic polymorphisms can predispose individuals to an HPV6/11‐tolerant microenvironment. As a result, immunomodulatory efforts are being made to restore the host immune system to a more balanced T cell phenotype and clear viral infection. Literature has shown exciting evidence for the role of HPV vaccination with Gardasil or Gardasil‐9 as both primary prevention, by decreasing incidence through childhood vaccinations, and secondary prevention, by treating active RRP disease. Multi‐institution randomized clinical trials are needed to better assess their efficacy as treatment for active disease. Interestingly, a DNA vaccine has recently shown in‐vitro success in generating a more robust CD8+ T cell response. Furthermore, clinical trials for programmed death 1 (PD‐1) inhibitors are under investigation for RRP management. Molecular insights into RRP, in particular the interplay between RRP and the immune system, are needed to advance our understanding of this disease and may lead to the identification of immunomodulatory agents to better manage RRP. [ABSTRACT FROM AUTHOR]

Objective: To identify characteristics of patients who have poor improvement in symptoms following surgical management of Zenker Diverticulum (ZD)., Methods: Prospective, multicenter cohort study of all individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative who underwent surgical repair of ZD between August 2017 and January 2024. Patient demographics, esophagrams, and the 10-item Eating Assessment Tool (EAT-10) pre- and post-procedure were obtained from a REDCap database. t-tests, Wilcoxon rank sum tests, Chi-square or Fisher's exact tests were used to compare the characteristics. Patients with <50% improvement in their EAT-10 scores were deemed surgical nonresponders (SNRs). Those with ≥50% improvement in their EAT-10 scores were deemed surgical responders (SRs)., Results: A total of 184 patients were prospectively followed after undergoing either open or endoscopic surgical management. Twenty-two patients (12%) were deemed SNRs. Preoperative presence of a hiatal hernia was statistically significant characteristic between the SNRs (63.6%) and SRs (32.1%) (p = 0.004). Size of the ZD and history of previous ZD surgery was not a significant characteristic. The length of stay and complication rate were not statistically different between the groups., Conclusion: Coexistent esophageal pathology may lead to poor symptomatic improvement following ZD surgery. Preoperative workup of other esophageal disorders is recommended to detect likely SNRs. For SNRs, further esophageal workup may be necessary to evaluate for other esophageal causes related to poor symptomatic improvement following ZD surgery., Level of Evidence: Level 3 Laryngoscope, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Aims: The purpose of this systematic review and meta-analysis was to investigate the effects of family-based health promotion interventions on child-level risk factors for type 2 diabetes in vulnerable families., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for systematic reviews formed the methodological framework. CINAHL, Embase, MEDLINE, PsycINFO, and Web of Science were searched on January 12, 2024. The NTP-OHAT Risk of Bias Assessment Tool was used to assess the risk of bias in the individual studies, and meta-analyses were performed., Results: The 4723 studies were identified, and 55 studies met the inclusion criteria. Results showed significant effects on children's body mass index (mean difference [MD], -0.18, 95% CI [-0.33 to -0.03], p = 0.02), body fat percentage (MD, -2.00, 95% CI [-3.31 to -0.69], p = 0.003), daily activity (standardized mean difference [SMD], 0.23, 95% CI [0.01; 0.44], p = 0.04), physical activity self-efficacy (SMD, 0.73, 95% CI [0.36 to 1.10], p < 0.01), intake of snacks (MD, -0.10, 95% CI [-0.17 to -0.04], p = 0.002), and sugar-sweetened beverages (SMD, -0.21, 95% CI [-0.42 to -0.01], p = 0.04). Subgroup analyses suggested that interventions aiming to change child and parent behavior simultaneously have larger effect on fasting glucose and nutrition consumption, and that interventions longer than 26 weeks have larger effects on body composition and physical activity behavior than shorter interventions., (© 2024 World Obesity Federation.)

Objectives: The aim of the study was to identify trends in postoperative management of persons undergoing surgery for Zenker diverticula (ZD) by evaluating length of stay (LOS), diet on discharge, and imaging with or without surgical complication., Methods: Prospectively enrolled adult patients with cricopharyngeal muscle dysfunction with diverticula undergoing surgery from August 1, 2017 to February 1, 2023 were included. Data were extracted from a multi-institutional REDCap database, summarizing means, medians, percentages, and frequencies. Fisher's exact or chi squared analyses were utilized, as appropriate, to compare subsets of data. Descriptive analysis assessed differences in clinical course and the relationship to postoperative management., Results: There were 298 patients with a mean (standard deviation) age of 71.8 (11.2) years and 60% male. Endoscopic surgery was performed in 79.5% (237/298) of patients versus 20.5% (61/298) open surgery. Sixty patients (20.1%) received postoperative imaging, with four leaks identified. Complications were identified in 9.4% of cases (n = 29 complications in 28 patients), more commonly in open surgery. Most (81.2%) patients were discharged within 23 h. About half of patients (49%) were discharged from the hospital on a pureed/liquid diet; 36% had been advanced to a soft diet. In patients without complications, LOS was significantly longer following open cases (p = 0.002); postoperative diet was not different between open and endoscopic (p = 0.26)., Conclusions: Overall, most patients are discharged within 23 h without imaging. However, LOS was affected by surgical approach. Postoperative complications are different in endoscopic versus open surgery. Complications with either approach were associated with prolonged LOS, need for imaging, and diet restriction., Level of Evidence: Level III Laryngoscope, 134:2678-2683, 2024., (© 2023 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Recurrent respiratory papillomatosis is a benign manifestation of human papillomavirus types 6 and 11 in the respiratory tract. Disease is recurrent, and factors predicting these recurrences and severity of disease are incompletely characterised. This retrospective cohort study examined the relationship of immunosuppression with recurrent respiratory papillomatosis morbidity., Methods: A retrospective cohort of 97 adult patients with recurrent respiratory papillomatosis treated at a tertiary referral centre from 2005 to 2020 was conducted. Measures assessed included inter-surgical interval, Voice Handicap Index ('VHI-10') and anatomical Derkay scores., Results: Bivariate analyses comparing average inter-surgical interval, Voice Handicap Index and Derkay scores in immunosuppressed and healthy patients were insignificant. When controlling for diabetes mellitus and comparing immunosuppressed to healthy patients, inter-surgical interval and Voice Handicap Index change were insignificant ( p = 0.458 and p = 0.465, respectively)., Conclusion: Recurrent respiratory papillomatosis morbidity for immunosuppressed patients did not significantly differ from that of immunocompetent patients.

Objective: To compare improvement in patient-reported outcomes (PROM) in persons undergoing endoscopic and open surgical management of Zenker diverticula (ZD)., Methodology: Prospective, multicenter cohort study of all individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative who underwent surgery for ZD. Patient survey, radiography reports, and the 10-item Eating Assessment Tool (EAT-10) pre- and post-procedure were abstracted from a REDCap database, which summarized means, medians, percentages, and frequencies of. Outcome based on operative intervention (endoscopic vs. open) was compared using t-test, Wilcoxon rank sum test or chi-square test, as appropriate., Results: One hundred and forty-seven persons were prospectively followed. The mean age (SD) of the cohort was 68.7 (11.0). Overall, 66% of patients reported 100% improvement in EAT-10; 81% of patients had greater than 75% improvement; and 88% had greater than 50% improvement. Endoscopic was used for n = 109 patients, and open surgical intervention was used for n = 38. The median [interquartile range, IQR] EAT-10 percent improvement for endoscopic treatment was 93.3% [72, 100], and open was 100% [92.3, 100] (p = 0.05). The incidence of intraoperative complications was 3.7% for endoscopic and 7.9% for open surgical management. The median [IQR] in follow-up was 86 and 97.5 days, respectively., Conclusion: Both endoscopic and open surgical management of ZD provide significant improvement in patient-reported outcomes. The data suggest that open diverticulectomy may provide a modest advantage in symptomatic improvement compared to endoscopic management. The data suggest that the postoperative complication rate is higher in the open surgical group., Level of Evidence: 3 Laryngoscope, 134:97-102, 2024., (© 2023 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Introduction: Recurrent respiratory papillomatosis (RRP) is a chronic disease of the upper respiratory tract caused by human papillomavirus types 6 and 11. The disease course is characteristically unpredictable, ranging from spontaneous remission to aggressive, recurrent disease. Thus, management is often challenging and requires unique approaches tailored to each individual patient. While recent literature has described risk factors for more aggressive disease, few sources have investigated the impact of smoking on RRP disease course and risk for malignant transformation., Methods: A retrospective chart review was conducted for adult RRP patients evaluated at an academic tertiary care center between 2005 and 2020. A total of 188 patients were identified. Demographic and clinical data were collected, including smoking and alcohol history, HPV subtype, history of dysplasia and/or carcinoma, voice handicap index scores, Derkay scores, debulkings (in office and operating room), and days to papilloma recurrence., Results: Malignant degeneration in RRP occurred in 16.3% of smokers and 3.6% of nonsmokers. Smokers who developed carcinoma had less debulkings per years of evaluation than those not developing carcinoma (0.21 vs 0.92, P  = .004). Additionally, patients that either presented with or developed carcinoma during their course had a higher pack-year smoking history (18.0 vs 12.21, P  = .0002). No difference in days to recurrence or inter-surgical interval was demonstrated between smokers and nonsmokers., Conclusions: The report demonstrates that smoking can increase the risk of malignant transformation in RRP patients.

Objective: Neurogenic cough related to hypersensitivity of the internal branch of the superior laryngeal nerve (SLN) is often treated with neuromodulating medications, which can cause considerable side effects. An alternative therapy is steroid and local anesthetic injection of the SLN ("SLN block"), initially proposed to benefit those with lateralizing symptoms (tenderness over the thyrohyoid membrane or unilateral cough source). Our objectives are to determine if SLN block produces subjective symptomatic improvements and if repeat injections further improve symptoms, and evaluate clinical factors potentially predictive of response., Methods: Retrospective chart review of 54 patients receiving SLN blocks at a tertiary medical academic center from January 2010 to June 2020. Medical history and anticipated predictors of positive response, including stigmata of laryngeal hypersensitivity, were recorded. Outcomes included symptomatic response, number of injections required, and side effects. Response was defined subjectively by asking patients whether the injection was beneficial and objectively by using CSI scores., Results: Fifty-four patients met the inclusion criteria. Thirty-eight patients (70.4%) endorsed improvement. No variables were identified as positive predictors of response. Thirty-two of the 38 (84.2%) endorsed improvement after one injection. Six of 15 (40%) patients who failed the first injection had positive response to the second. No significant side effects were reported., Conclusion: No localizing symptoms, specific cough features, or aspects of the medical history helped predict response, suggesting that a broader range of patients may be offered the intervention. The majority of patients reported symptomatic improvement and repeat injections may benefit patients with initial nonresponse., Level of Evidence: 4 Laryngoscope, 133:2647-2653, 2023., (© 2023 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To assess barium esophagram (BAS) as a diagnostic marker for patients with Killian Jamieson diverticula (KJD)., Methods: Prospective, multicenter cohort study of individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative. Patient demographics, comorbidities, radiographic imaging reports, laryngoscopy findings, patient-reported outcome measures (PROM), and operative reporting were abstracted from a REDCap database and summarized using means, medians, percentages, frequencies. Paired t-tests and Wilcoxon Signed Rank test were used to test pre- to post-operative differences in RSI, EAT-10, and VHI-10 scores. Diagnostic test evaluation including sensitivity, specificity, positive, and negative predictive value with 95% confidence intervals were calculated comparing BAS findings to operative report., Results: A total of 287 persons were enrolled; 13 (4%) patients were identified with confirmed KJD on operative reports. 100% underwent open transcervical excision. BAS has a 46.2% (95% confidence interval [CI]: 23.2, 70.9) sensitivity and 97.8% (95% CI: 95.3, 99.0) specificity in detecting a KJD and 50% (95% CI: 25.4, 74.6) positive predictive value but 97.4% (95%CI: 94.8, 98.7) negative predictive value. Preoperatively, patients reported mean (SD) RSI and EAT-10 of 19.4 (9) and 8.3 (7.5) accordingly. Postoperatively, patients reported mean (SD) RSI and EAT-10 as 5.4 (6.2) and 2.3 (3.3). Both changes in RSI and EAT-10 were statistically significant (p = 0.008, p = 0.03)., Conclusion: KJD are rare and represent <5% of hypopharyngeal diverticula undergoing surgical intervention. Open transcervical surgery significantly improves symptoms of dysphagia. BAS has high specificity but low sensitivity in detecting KJD., Level of Evidence: 4 Laryngoscope, 133:2110-2115, 2023., (© 2022 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Biologic therapies for psoriasis can cause paradoxical eczema. The role of genetic factors in its pathogenesis is unknown. To identify risk variants, we conducted a GWAS of 3,212 patients with psoriasis, of whom 88 developed paradoxical eczema. Two lead SNPs reached genome-wide significance (P ≤ 5 × 10 -8 ) for association with paradoxical eczema: rs192705221 (near UNC5B, P = 9.52 × 10 -10 ) and rs72925168 (within SLC1A2, P = 1.66 × 10 -9 ). Genome-wide significant SNPs from published GWAS were used to generate polygenic risk scores (PRSs) for atopic eczema, general atopic disease, or a combination, which were tested for association with paradoxical eczema. Improvement over a clinical risk model was assessed by the area under the curve. All three atopy polygenic risk scores were associated with paradoxical eczema (P < 0.05); polygenic risk score for a combination of atopic eczema and general atopic disease had the strongest association (OR = 1.83, 95% CI = 1.17-2.84, P = 0.0078). Including atopic polygenic risk scores in the multivariable model, which included age, sex, atopic background, and psoriatic arthritis history, increased the area under the curve from 0.671 to 0.681-0.686. Atopic genetic burden is associated with paradoxical eczema occurring in biologic-treated patients with psoriasis, indicating shared underlying mechanisms. Incorporating genetic risk may improve treatment outcome prediction models for psoriasis., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To describe demographics and imaging and compare findings and symptoms at presentation in a large cohort of persons with cricopharyngeus muscle dysfunction (CPMD) with and without hypopharyngeal diverticula., Methodology: Prospective, multicenter cohort study of all individuals enrolled in the Prospective OUtcomes of Cricopharyngeal Hypertonicity (POUCH) Collaborative. Patient survey, comorbidities, radiography, laryngoscopy findings, and patient-reported outcome measures (e.g., Eating Assessment Tool [EAT-10]) data were abstracted from a REDCap database and summarized using means, medians, percentages, and frequencies. Diagnostic categories were compared using analysis of variance., Results: A total of 250 persons were included. The mean age (standard deviation [SD]) of the cohort was 69.0 (11.2). Forty-two percent identified as female. Zenker diverticula (ZD) was diagnosed in 85.2%, 9.2% with CPMD without diverticula, 4.4% with a Killian Jamieson diverticula (KJD), and 1.2% traction-type diverticula. There were no differences between diagnostic categories in regard to age, gender, and duration of symptoms (p = 0.25, 0.19, 0.45). The mean (SD) EAT-10 score for each group was 17.1 (10.1) for ZD, 20.2 (9.3) for CPMD, and 10.3 (9.4) for KJD. Patients with isolated CPMD had significantly greater EAT-10 scores compared to the other diagnostic groups (p = 0.03)., Conclusion: ZD is the most common, followed by CPMD without diverticula, KJD, and traction-type. Patients with isolated obstructing CPMD may be more symptomatic than persons with ZD or KJD., Level of Evidence: 4 Laryngoscope, 133:1349-1355, 2023., (© 2022 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Generation Health (GH) is a 10-week family-based lifestyle program designed to promote a healthy lifestyle for families with children who are off the healthy weight trajectory in British Columbia, Canada. GH uses a blended delivery format that involves 10 weekly in-person sessions, and self-guided lessons and activities on a web portal. The blended program was adapted to be delivered virtually due to the COVID-19 pandemic. Currently, the effectiveness of the virtual GH program compared with that of the blended GH program remains unclear., Objective: We aimed to (1) compare the effectiveness of the virtual GH program delivered during the COVID-19 pandemic with that of the blended GH program delivered prior to the pandemic for changing child physical activity, sedentary and dietary behaviors, screen time, and parental support-related behaviors for child physical activity and healthy eating, and (2) explore virtual GH program engagement and satisfaction., Methods: This study used a single-arm pre-post design. The blended GH program (n=102) was delivered from January 2019 to February 2020, and the virtual GH program (n=90) was delivered during the COVID-19 pandemic from April 2020 to March 2021. Families with children aged 8-12 years and considered overweight or obese (BMI ≥85th percentile according to age and sex) were recruited. Participants completed preintervention and postintervention questionnaires to assess the children's physical activity, dietary and sedentary behaviors, and screen time, and the parent's support behaviors. Intervention feedback was obtained by interviews. Repeated measures ANOVA was used to evaluate the difference between the virtual and blended GH programs over time. Qualitative interviews were analyzed using thematic analyses., Results: Both the virtual and blended GH programs improved children's moderate-to-vigorous physical activity (F 1,380 =18.37; P<.001; ηp 2 =0.07) and reduced screen time (F 1,380 =9.17; P=.003; ηp 2 =0.06). However, vegetable intake was significantly greater in the virtual GH group than in the blended GH group at the 10-week follow-up (F 1,380 =15.19; P<.001; ηp 2 =0.004). Parents in both groups showed significant improvements in support behaviors for children's physical activity (F 1,380 =5.55; P=.02; ηp 2 =0.002) and healthy eating (F 1,380 =3.91; P<.001; ηp 2 =0.01), as well as self-regulation of parental support for children's physical activity (F 1,380 =49.20; P<.001; ηp 2 =0.16) and healthy eating (F 1,380 =91.13; P<.001; ηp 2 =0.28). Families in both groups were satisfied with program delivery. There were no significant differences in attendance for the weekly in-person or group video chat sessions; however, portal usage was significantly greater in the virtual GH group (mean 50, SD 55.82 minutes) than in the blended GH group (mean 17, SD 15.3 minutes; P<.001)., Conclusions: The study findings suggested that the virtual GH program was as effective as the blended program for improving child lifestyle behaviors and parental support-related behaviors. The virtual program has the potential to improve the flexibility and scalability of family-based childhood obesity management interventions., (©Kayla Nuss, Rebecca Coulter, Bianca DeSilva, Jeann Buenafe, Ronak Sheikhi, Patti-Jean Naylor, Sam Liu. Originally published in JMIR Pediatrics and Parenting (https://pediatrics.jmir.org), 03.11.2022.)

Decades of discussion and publication have gone into the guidance from the scientific community and the regulatory agencies on the use and validation of pharmacokinetic and toxicokinetic assays by chromatographic and ligand binding assays for the measurement of drugs and metabolites. These assay validations are well described in the FDA Guidance on Bioanalytical Methods Validation (BMV, 2018). While the BMV included biomarker assay validation, the focus was on understanding the challenges posed in validating biomarker assays and the importance of having reliable biomarker assays when used for regulatory submissions, rather than definition of the appropriate experiments to be performed. Different from PK bioanalysis, analysis of biomarkers can be challenging due to the presence of target analyte(s) in the control matrices used for calibrator and quality control sample preparation, and greater difficulty in procuring appropriate reference standards representative of the endogenous molecule. Several papers have been published offering recommendations for biomarker assay validation. The situational nature of biomarker applications necessitates fit-for-purpose (FFP) assay validation. A unifying theme for FFP analysis is that method validation requirements be consistent with the proposed context of use (COU) for any given biomarker. This communication provides specific recommendations for biomarker assay validation (BAV) by LC-MS, for both small and large molecule biomarkers. The consensus recommendations include creation of a validation plan that contains definition of the COU of the assay, use of the PK assay validation elements that support the COU, and definition of assay validation elements adapted to fit biomarker assays and the acceptance criteria for both., (© 2022. The Author(s).)

Objectives/hypothesis: To identify the incidence and nature of positive findings on imaging studies ordered for evaluation of unilateral vocal fold paralysis (UVFP) of unknown etiology, to analyze these findings based on laterality, and to examine the use of the expanded-field computed tomography (CT) neck protocol in this evaluation., Study Design: Retrospective review., Methods: A total of 145 patients from 2000 to 2018 with UVFP of unknown etiology were studied. Data on imaging studies ordered, laterality of paralysis, and significant positive results were studied. An expanded-field CT neck protocol that included the entire course of the vagus and recurrent laryngeal nerves was instituted during the study period., Results: A total of 20.7% of patients had an etiology for paralysis identified on imaging. Malignancies comprised the majority of findings overall (19/30), whether in the chest (12/18) or the neck (7/12). Etiology was more often found in the chest for left-sided paralysis (15/21) and in the neck for right-sided paralysis (6/9). In 26 patients who underwent both expanded-field CT neck and CT chest, no findings related to the UVFP were seen on CT chest that were not captured by expanded-field CT neck., Conclusions: This is one of the largest retrospective studies examining the incidence of positive findings on imaging studies for evaluation of UVFP of unknown etiology. Imaging in one of five patients with UVFP of unknown etiology will reveal a causative lesion, most often malignant. Left-sided paralysis tends to localize to the chest, and right-sided paralysis to the neck. Expanded-field CT neck may allow practitioners to forego dedicated CT chest in evaluation of UVFP., Level of Evidence: 4 Laryngoscope, 131:1840-1844, 2021., (@ 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives/hypotheses: The primary objective of this study was to determine whether the diagnosis and treatment of pediatric Paradoxical Vocal Fold Motion Disorder (PVFMD) leads to decreased asthma medication use. Our secondary objective was to determine dyspnea outcomes following diagnosis and treatment for PVFMD., Study Design: Prospective observational study., Methods: Patients with newly diagnosed PVFMD between the ages of 11 and 17 were recruited at a single pediatric institution. A medication questionnaire and Dyspnea Index (DI) were completed at the initial visit, at the first return visit, and at greater than 6 months post-diagnosis and therapy. Laryngeal Control Therapy (LCT) consisted of teaching breathing techniques and identifying emotional, physical, and environmental contributing factors and strategies to reduce them., Results: Twenty-six patients were recruited to the study. There were 19/26 (73%) patients diagnosed with asthma prior to a diagnosis of PVFMD, and 26/26 (100%) patients were using an inhaler prior to the enrollment visit. Twenty-two (85%) patients completed follow-up questionnaires. Five patients participated in no therapy, seven patients in partial therapy, and 14 patients in full therapy. Significant reduction in asthma medication use was seen in the full therapy group (P < .05) and in those with exercise as their only trigger (P < .05). Furthermore, symptoms as scored by the DI decreased overall from 25.5 to 18.8 (P < .001)., Conclusions: Diagnosis and treatment of pediatric PVFMD leads to a decline in asthma medication use in those patients who participate in at least two LCT sessions and in those with exercise-induced PVFMD. LCT for pediatric PVFMD leads to a significant decrease in symptoms as measured by the DI., Level of Evidence: 4 Laryngoscope, 131:1639-1646, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Patient transitions from inpatient to home care are an important area of focus for reducing costly unplanned hospital readmissions. In rural settings, the challenge of reducing unplanned readmissions is amplified by limited access to both ambulatory and acute care as well as high levels of social disadvantage. In addition, there is a scarcity of evidence regarding strategies that have been proven to improve care transitions and related patient outcomes in this setting. This paper describes the process for implementation and results of a telephone-based transitional care management (TCM) program designed to reduce readmissions for patients with diabetes in a rural hospital in Scotland County, North Carolina. Data were collected from July 2016 to January 2019 using billing records to identify adult patients with high or very high risk of readmission based on length of stay, acuity, comorbidity, and emergency department visits (LACE) scores. Care managers contacted eligible patients by phone after discharge to review discharge instructions, assess need for home health services and transportation assistance, and schedule primary care follow-up visits. Overall, 13.8% of 15,271 discharges were targeted for TCM; 68.2% of these involved a patient with diabetes. The post-intervention 30-day readmission rate was 18.0% among patients identified as high or very high risk versus 8.8% among the overall population and did not differ significantly between TCM participants with diabetes and those without (22.9% vs.18.8%; P  = 0.525). Findings highlight challenges with implementing transition of care interventions in rural settings, which include staffing, patient volume, and accessing data from out-of-network providers.

Objective: To evaluate voice outcomes of medialization laryngoplasty in the elderly population (65 years and older) and to identify swallow outcomes, complication rates, and predictors of voice outcomes., Study Design: Case series with chart review., Setting: Two tertiary academic medical centers., Subjects and Methods: We retrospectively reviewed charts of 136 patients age 65 years and older undergoing medialization laryngoplasty between January 2008 and May 2016 at 2 tertiary academic institutions. Primary outcome was assessed using Voice Handicap Index 10 (VHI-10) score and Grade, Roughness, Breathiness, Asthenia, and Strain (GRBAS) score. Secondary outcomes were assessed using the Eating Assessment Tool 10 (EAT-10) when dysphagia was present, stroboscopic analysis of glottic closure, and complication rates. A logistic regression analysis assessed predictors of voice improvement after medialization laryngoplasty., Results: Total GRBAS and VHI-10 scores showed a significant improvement postoperatively ( P < .05). A ≥20% improvement was seen in 81.6% of patients, and a ≥50% improvement was seen in 53.7%. No patient had major complications. Minor complications occurred in 5.9% of patients. Multivariable logistic regression identified preoperative injection augmentation as an independent predictor of less improvement in VHI-10 score ( P = .015). Voice therapy prior to medialization did not affect voice outcomes ( P = .640)., Conclusion: Patient- and provider-perceived voice quality are significantly improved after medialization laryngoplasty in the elderly, and the procedure is associated with a low complication rate even in an elderly cohort. Improvement in patient-perceived voice outcomes after medialization laryngoplasty was diminished in patients with preoperative injection augmentation.

In September 2018, the American Association of Pharmaceutical Scientists (AAPS) conducted an Annual Guidance Forum on the considerations related to immunogenicity testing for therapeutic protein products. In addition to a broad representation by the pharmaceutical industry, the event included strong representation by leading scientists from the US Food and Drug Administration (FDA). The agency and industry perspectives and updates to the guidance were presented. Specific topics that were discussed included the strategies of anti-drug antibody (ADA) assay cut-point assessments, the selection of ADA-positive controls (PCs), and the evaluation of PC performance. Assessment strategies and relevance of ADA assay attributes were also discussed, including assay drug tolerance and ADA assay sensitivity. The following is a summary of the discussion.

Objective: Demonstrate efficacy of vocal fold botulinum toxin injection for treatment of refractory paradoxical vocal fold motion disorder (PVFMD)., Methods: A retrospective review was completed of patients diagnosed with PVFMD who underwent vocal fold botulinum toxin injection for dyspnea symptoms that persisted despite laryngeal control therapy, medical management, and biofeedback therapy. Outcomes measured included overall improvement and resolution of dyspnea symptoms, number of botulinum toxin injections and dose range, change in dyspnea severity index (DSI) scores, and adverse effects of injection therapy., Results: Thirteen patients (9 female/4 male) underwent vocal fold botulinum toxin injection for refractory PVFMD. The average dose was 2.55 units per vocal fold (range 1.75-5.5 units). The average number of injections was 3.85 (range 1-12 injections). Eleven of 13 (84.6%) patients experienced improvement in dyspnea symptoms, with two of 11 (18.2%) having complete resolution of symptoms. There was a statistically significant improvement in DSI scores because the mean preinjection DSI was 30.43 and improved to 17.43 postinjection (P = 0.017). Temporary breathy voice quality was experienced by all patients with no other adverse side effects., Conclusion: Vocal fold botulinum toxin injection is a safe and effective treatment option for PVFMD and should be considered in patients with refractory dyspnea symptoms following appropriate medical therapy and respiratory retraining protocols., Level of Evidence: 4 Laryngoscope, 129:808-811, 2019., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective To determine the incidence of posttracheostomy tracheal stenosis and to investigate variables related to the patient, hospitalization, or operation that may affect stenosis rates. Study Design A combined retrospective cohort and case-control study. Setting Tertiary care academic medical center. Subjects and Methods A total of 1656 patients who underwent tracheostomy at a tertiary care medical center from January 2011 to November 2016 were reviewed for evidence of subsequent tracheal stenosis on airway endoscopy or computed tomography. Forty-three confirmed cases of posttracheostomy tracheal stenosis (PTTS) were compared with a subgroup of 319 controls. Factors including medical comorbidity, type and setting of tracheostomy, and hospitalization details were analyzed. Results Five-year incidence of PTTS was 2.6%. Obesity was the sole demographic factor associated with stenosis. Hospitalization-related variables associated with stenosis included tracheostomy after 10 days of orotracheal intubation and endotracheal tube cuff pressure ≥30 mm H 2 O. The surgical variables associated with higher rates of stenosis included percutaneous technique and insertion of an initial tracheostomy tube size >6. Bjork flap creation was negatively associated with stenosis. In multivariable analysis, obesity and insertion of tracheostomy tube size >6 were identified as risk factors. Conclusion Greater than 10 days of orotracheal intubation prior to tracheostomy and endotracheal tube cuff pressure ≥30 mm H 2 O were associated with greater rates of subsequent tracheal stenosis. The only patient-related factor associated with tracheal stenosis was obesity. Surgical variables associated with increased rates of subsequent stenosis included placement of a tracheostomy tube size >6, use of percutaneous technique, and failure to create a Bjork flap.

Objectives/hypothesis: To assess the feasibility of jet ventilation in obese patients and to compare complications of jet ventilation in obese and nonobese patients., Study Design: Retrospective review of medical records., Methods: We reviewed 46 patient charts (70 procedures) with the diagnosis of tracheal or subglottic stenosis who underwent endoscopic surgery with jet ventilation between March 2014 and January 2017. Adequacy of jet ventilation was assessed by chest rise, avoidance of endotracheal intubation, and length of case and ventilation. Records were reviewed for demographic details, anesthesia records, and complications., Results: In 29/70 (41.4%) of cases, patients were obese; in 9/29 (31.0%) of these cases, patients were morbidly obese. Jet ventilation was successful in 28/29 (97%) of obese cases. In 1/29 (3.4%) of cases, the patient required alternative airway management. There were no significant differences between obese and nonobese patients in chest rise, need for endotracheal intubation, and length of surgery or ventilation (P > .05). There were 2/29 (6.9%) cases of intra- and postoperative complications including laryngospasm (1/29, 3.4%) and tachycardia (1/29, 3.4%). Rate of complications did not differ between obese and nonobese patients (P = .178)., Conclusions: Jet ventilation in obese patients can be done successfully, and complications are similar between obese patients and nonobese patients., Level of Evidence: 4. Laryngoscope, 1887-1892, 2018., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

Ligand-binding assay (LBA) performance depends on quality reagents. Strategic reagent screening and characterization is critical to LBA development, optimization and validation. Application of advanced technologies expedites the reagent screening and assay development process. By evaluating surface plasmon resonance technology that offers high-throughput kinetic information, this article aims to provide perspectives on applying the surface plasmon resonance technology to strategic LBA critical reagent screening and characterization supported by a number of case studies from multiple biotherapeutic programs.

Objectives: Recurrent respiratory papillomatosis (RRP) is a chronic disease of the respiratory tract that occurs in both children and adults. It is caused by the human papillomavirus (HPV), in particular low-risk HPV6 and HPV11, and aggressiveness varies among patients. RRP remains a chronic disease that is difficult to manage. This review provides perspectives on current and future management of RRP., Results: The current standard of care is surgical excision, with adjuvant therapies as needed. Surgical management of RRP has evolved with the introduction of microdebriders and photoangiolytic lasers; the latter can now be used in the office setting. Numerous adjuvant pharmacologic therapies have been utilized with some success. Also, exciting preliminary data show that HPV vaccines may prolong the time to recurrence in the RRP population. There is also optimism that wide-spread HPV vaccination could reduce RRP incidence indirectly by preventing vertical HPV transmission to newborns., Conclusion: To date, the biology of RRP is not well understood, although it has been noted to become more aggressive in the setting of immune suppression. Additional research is needed to better understand immune system dysfunction in RRP such that immunomodulatory approaches may be developed for RRP management., Level of Evidence: 4.

The 2017 11th Workshop on Recent Issues in Bioanalysis took place in Los Angeles/Universal City, California, on 3-7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule analysis involving LC-MS, hybrid ligand-binding assay (LBA)/LC-MS and LBA approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations for large-molecule bioanalysis, biomarkers and immunogenicity using LBA. Part 1 (LC-MS for small molecules, peptides and small molecule biomarkers) and Part 2 (hybrid LBA/LC-MS for biotherapeutics and regulatory agencies' inputs) are published in volume 9 of Bioanalysis, issues 22 and 23 (2017), respectively.

Objectives/hypothesis: To determine whether diagnosis and treatment of paradoxical vocal fold movement disorder (PVFMD) leads to decreased asthma medication use. Secondary objectives include determining initial rate of asthma medication use, characterizing symptom improvement, and correlating with pulmonary function testing (PFT)., Study Design: Prospective observational study., Methods: Patients newly diagnosed with PVFMD at a single institution were recruited to participate. Medication questionnaires were completed at the initial visit, at the first return visit for therapy, and at 6 months. PFTs were reviewed when available., Results: Sixty-six patients were recruited; the study was closed early because findings reached significance. Fifty-six patients (85%) were taking asthma medication at presentation. Forty-four patients presented with PFTs, and two-thirds were normal. Forty-two patients completed follow-up questionnaires; 79% decreased asthma medication use (P < .001), and 82% reported symptom improvement. Seventy-seven percent of patients participated in therapy and 23% did not, with equal rates of decrease in asthma medication use between these groups. Outcomes did not vary based on PFT pattern (i.e., obstructive vs. nonobstructive, P = .75)., Conclusions: Diagnosis and treatment of PVFMD lead to a decline in asthma medication use. This decrease occurred alongside symptom improvement and irrespective of PFT findings. Use of asthma medication in this patient population is high, at 85%., Level of Evidence: 4. Laryngoscope, 127:1531-1537, 2017., (© 2016 The American Laryngological, Rhinological and Otological Society, Inc.)

The Gyrolab™ xP is a microfluidic platform for conducting ligand binding assays (LBAs) and is recognized for its utility in discovery bioanalysis. However, few reports have focused on the technology for regulated bioanalysis. This technology has the advantage of low reagent consumption, low sample volume, and automated ligand binding methods. To improve bioanalysis testing timelines and increase the speed at which biotherapeutics are delivered to patients, we evaluated the technology for its potential to deliver high-quality data at reduced testing timelines for regulated bioanalysis. Six LBA methods were validated to support bioanalysis for GLP toxicokinetic or clinical pharmacokinetic studies. Validation, sample analysis, and method transfer are described. In total, approximately 4000 samples have been tested for regulated bioanalysis to support 6 GLP toxicology studies and approximately 1000 samples to support 2 clinical studies. Gyrolab™ xP had high run pass rates (≥83%) and high incurred sample reanalysis (ISR) pass rates (>94%). The maximum total error observed across all QC levels for a given assay was <30% for all six LBAs. High instrument response precision (CV ≤5%) was observed across compact discs (CDs), and methods were validated to use a single standard curve across multiple CDs within a Gyrolab™ xP run. Reduced bioanalysis timelines were achieved compared to standard manual plate-based methods, and methods were successfully transferred across testing labs, paving the way for this platform for use in late-stage clinical development.

Aim: Ligand-binding assay (LBA) reagent labeling may change the binding characteristics of the reagent to its target and degrade its performance in LBAs., Results: A surface plasmon resonance (SPR) biosensor was used to evaluate the impact of the biotin labeling process on reagent-binding kinetics and affinity for a specific target. The SPR results demonstrate that the biotin molar challenge ratio affects both association and dissociation rates for the labeled reagent binding to its target. The SPR results also predict the labeled reagent performance in LBAs., Conclusion: The methodology used in this study provides an example of using an SPR biosensor as an efficient way to analytically and functionally characterize critical reagents and to understand their performance postmodification in LBAs.

The chairs of each of the 8 Special Interest Groups of the Board of Pharmaceutical Sciences of the International Pharmaceutical Federation have compiled opinions with regard to major challenges for the pharmaceutical sciences over the next 5-10 years. Areas covered are drug design and discovery, natural products, formulation design and pharmaceutical technology, pharmacokinetics/pharmacodynamics and systems pharmacology, translational and personalized medicine, biotechnology, analytical sciences and quality control, and regulatory science., (Copyright © 2016. Published by Elsevier Inc.)

Background: Antibody-drug conjugates (ADCs) are complex drug constructs with multiple species in the heterogeneous mixture that contribute to their efficacy and toxicity. The bioanalysis of ADCs involves multiple assays and analytical platforms., Methods: A series of ligand binding and LC-MS/MS (LB-LC-MS/MS) hybrid assays, through different combinations of anti-idiotype (anti-Id), anti-payload, or generic capture reagents, and cathepsin-B or trypsin enzyme digestion, were developed and evaluated for the analysis of conjugated-payload as well as for species traditionally measured by ligand-binding assays, total-antibody and conjugated-antibody., Results & Conclusion: Hybrid assays are complementary or viable alternatives to ligand-binding assay for ADC bioanalysis and PK/PD modeling. The fit-for-purpose choice of analytes, assays and platforms and an integrated strategy from Discovery to Development for ADC PK and bioanalysis are recommended.

Background: The bioanalytical strategy for antibody-drug conjugates (ADC) includes multiple integrated measurements of pharmacologically relevant ADC., Methods & Results: Three ligand-binding assays were validated for the measurement of total antibody, active ADC and total ADC. Accuracy and precision demonstrate %bias from -8 to 14%, %CV from 3 to 11% and total error from 3 to 21%, with >98% samples meeting incurred sample reanalysis criteria. Each assay met stability, selectivity, dilutional integrity, carry over and specificity criteria with no interference from associated metabolite/impurity. Given the active ADC assay sensitivity to payload, active ADC was used to assess drug to antibody ratio., Discussion & Conclusion: Implementation of a microfluidic automated platform enabled high throughput sample analysis of multiple analytes with minimal sample processing.

Immunogenicity testing for PEGylated biotherapeutics should include methods to detect both anti-protein and anti-PEG antibodies (anti-PEG). Although some methods have been published for the detection of anti-PEG antibodies, the information is incomplete and, in some cases, reagents used (such as Tween-20) are known to interfere with detection. This rapid communication describes the use of BioScale's Acoustic Membrane MicroParticle (AMMP®) technology using the ViBE® Workstation to measure anti-PEG antibodies in human serum samples. Briefly, a sample spiked with monoclonal human IgG anti-PEG antibody is diluted in buffer and incubated with paramagnetic beads coated with linear chain mPEG to capture anti-PEG antibodies. The complex is then captured on an acoustic membrane coated with Protein A. The change in mass on the membrane caused by the binding of the complex to the membrane results in a signal proportional to the mass of anti-PEG antibodies. The data indicate that an assay with a sensitivity of less than 1000 ng/mL for IgG is achievable. This level of sensitivity is better than current published reports on IgG anti-PEG antibody detection.

Objectives/hypothesis: The objectives of this study were to evaluate safety and patient tolerance of intraoral ultrasound and to evaluate efficacy of intraoral ultrasound in the diagnosis of peritonsillar infections., Study Design: Prospective single-cohort study involving adult patients (age>18 years) with evaluation consistent with possible peritonsillar abscess., Methods: Twenty-four patients were evaluated in the emergency department for peritonsillar infection. Signs and symptoms were recorded including uvular deviation, trismus, and fluctuance. Intraoral ultrasound was performed, and presence or absence of abscess was recorded. Eight patients had a computed tomography (CT) scan. Needle aspiration was performed by the otolaryngology physician in appropriate patients. Presence of purulence confirmed peritonsillar abscess., Results: Intraoral ultrasound was successfully performed on 87.5% (21/24) of patients. The probe could not access the peritonsillar space in 12.5% (3/24) of patients due to trismus. The positive predictive value of ultrasound in diagnosing abscess was 78.6% (11/14). The negative predictive value was 100% (7/7). The specificity was 70% (7/10), and the sensitivity was 100% (11/11). CT scan of the neck was obtained in 8/24 patients and found to be 100% sensitive and specific in diagnosing abscess., Conclusions: Intraoral ultrasound is a sensitive imaging modality at our institution, making it a strong initial imaging choice in patients with peritonsillar infections. Ultrasound can reliably rule out the presence of abscess and make CT of the neck unnecessary in most patients. Although ultrasound is generally well tolerated, diagnosis in patients with severe trismus can be made clinically or with CT scan. Intraoral ultrasound is a useful tool in diagnosing and treating peritonsillar infections when imaging is required., Level of Evidence: 4., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Programmed death-1 (PD-1) protein is a co-inhibitory receptor which negatively regulates immune cell activation and permits tumors to evade normal immune defense. Anti-PD-1 antibodies have been shown to restore immune cell activation and effector function-an exciting breakthrough in cancer immunotherapy. Recent reports have documented a soluble form of PD-1 (sPD-1) in the circulation of normal and disease state individuals. A clinical assay to quantify sPD-1 would contribute to the understanding of sPD-1-function and facilitate the development of anti-PD-1 drugs. Here, we report the development and validation of a sPD-1 protein assay. The assay validation followed the framework for full validation of a biotherapeutic pharmacokinetic assay. A purified recombinant human PD-1 protein was characterized extensively and was identified as the assay reference material which mimics the endogenous analyte in structure and function. The lower limit of quantitation (LLOQ) was determined to be 100 pg/mL, with a dynamic range spanning three logs to 10,000 pg/mL. The intra- and inter-assay imprecision were ≤15%, and the assay bias (percent deviation) was ≤10%. Potential matrix effects were investigated in sera from both normal healthy volunteers and selected cancer patients. Bulk-prepared frozen standards and pre-coated Streptavidin plates were used in the assay to ensure consistency in assay performance over time. This assay appears to specifically measure total sPD-1 protein since the human anti-PD-1 antibody, nivolumab, and the endogenous ligands of PD-1 protein, PDL-1 and PDL-2, do not interfere with the assay.

A novel format was introduced at the recent AAPS NBC Workshop on Method Development, Validation and Troubleshooting in San Diego on 18th May 2014. The workshop format was initiated by Binodh De Silva; Marie Rock and Sherri Dudal joined the initiative to develop and chair the workshop. Questions were solicited by a variety of avenues, including a Linked-In Discussion Group. Once collated and clarified, the topics covered assay development, validation, and analysis of PK, Immunogenicity, and Biomarkers with an additional topic on alternative bioanalytical technologies. A panel of experts (workshop report co-authors) was assigned to each topic to bring forward thought-provoking aspects of each topic. The format of the workshop was developed to target the needs of bioanalytical scientists with intermediate to advanced experience in the field ranging to enable robust discussion and to delve deeper into the current bioanalytical hot topics. While the new format allowed for an interactive session with the topical discussion driven by the audience members, it did not foster equal discussion time for all of the proposed topics, especially Biomarkers and alternative LBA technologies.

Bioanalytical data from early human studies conducted in normal volunteers are often used for building pharmacokinetic/pharmacodynamic models that can predict outcomes of future studies in diseased patients. Thus, it is important to develop and validate reliable and accurate bioanalytical assays that instill confidence that the intended therapeutic species (total or free) are being measured. Assays quantifying the free therapeutic species, the partially bound (for multivalent therapeutics) and unbound species, require much more characterization than assays that quantify the total therapeutic species. We have developed an immunoassay to measure free BMS-962476, an Adnectin protein therapeutic against soluble proprotein convertase subtilisin kexin (PCSK)-9, and performed an in-depth characterization of the accuracy of this assay with the assistance of modeling. The experimental data correlates with modeled data within 15% at all clinically relevant levels of PCSK9 in normal and diseased populations., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In September 2013, the FDA released a draft revision of the Bioanalytical Method Validation (BMV) Guidance, which included a number of changes to the expectations for bioanalysis, most notably the inclusion of biomarker assays and data. To provide a forum for an open, inclusive discussion of the revised draft BMV Guidance, the AAPS and FDA once again collaborated to convene a two-and-a-half day workshop during early December 2013 in Baltimore, MD, USA. The resulting format embodied extensive open discussion and each thematic session included only brief, concise descriptions by Agency and industry representatives prior to opening the floor discussion. The Workshop was built around four thematic sessions (Common Topics, Chromatographic, Ligand-Binding Assays, and Biomarkers) and a final session with international regulators, concluding with a review of the outcomes and recommendations from the thematic sessions. This Workshop report summarizes the outcomes and includes topics of agreement, those where the FDA will consider the Industry's perspective, and those where the workshop provided a first open dialogue. This article will be available to the bioanalytical community at http://www.aaps.org/BMV13 .