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The targeting of natural tolerogenic liver sinusoidal endothelial cells (LSEC) by nanoparticles (NPs), decorated with a stabilin receptor ligand, is capable of generating regulatory T-cells (Tregs), which can suppress antigen-specific immune responses, including to ovalbumin (OVA), a possible food allergen. In this regard, we have previously demonstrated that OVA-encapsulating poly(lactic-co-glycolic acid) (PLGA) nanoparticles eliminate allergic airway inflammation in OVA-sensitized mice, prophylactically and therapeutically. A competing approach is a nanocarrier platform that incorporates pharmaceutical agents interfering in mTOR (rapamycin) or NF-κB (curcumin) pathways, with the ability to induce a tolerogenic state in nontargeted antigen-presenting cells system-wide. First, we compared OVA-encapsulating, LSEC-targeting tolerogenic nanoparticles (TNPs) with nontargeted NPs incorporating curcumin and rapamycin (Rapa) in a murine eosinophilic airway inflammation model, which is Treg-sensitive. This demonstrated roughly similar tolerogenic effects on allergic airway inflammation by stabilin-targeting NPOVA versus nontargeted NPs delivering OVA plus Rapa. Reduction in eosinophilic inflammation and TH2-mediated immune responses in the lung was accompanied by increased Foxp3+ Treg recruitment and TGF-β production in both platforms. As OVA incorporates IgE-binding as well as non-IgE-binding epitopes, the next experiment explored the possibility of obtaining immune tolerance by non-anaphylactic T-cell epitopes. This was accomplished by incorporating OVA323-339 and OVA257-264 epitopes in liver-targeting NPs to assess the prophylactic and therapeutic impact on allergic inflammation in transgenic OT-II mice. Importantly, we demonstrated that the major histocompatibility complex (MHC)-II binding (former) but not the MHC-I binding (latter) epitope interfered in allergic airway inflammation, improving TNPOVA efficacy. The epitope-specific effect was transduced by TGF-β-producing Tregs. In the final phase of experimentation, we used an OVA-induced anaphylaxis model to demonstrate that targeted delivery of OVA and its MHC-II epitope could significantly suppress the anaphylaxis symptom score, mast cell release, and the late-phase inflammatory response. In summary, these results demonstrate comparable efficacy of LSEC-targeting versus pharmaceutical PLGA nanoparticles, as well as the ability of T-cell epitopes to achieve response outcomes similar to those of the intact allergens.

Nanoparticles (NPs) can be used to accomplish antigen-specific immune tolerance in allergic and autoimmune disease. The available options for custom-designing tolerogenic NPs include the use of nanocarriers that introduce antigens into natural tolerogenic environments, such as the liver, where antigen presentation promotes tolerance to self- or foreign antigens. Here, we demonstrate the engineering of a biodegradable polymeric poly(lactic- co-glycolic acid) (PLGA) nanocarrier for the selective delivery of the murine allergen, ovalbumin (OVA), to the liver. This was accomplished by developing a series of NPs in the 200-300 nm size range as well as decorating particle surfaces with ligands that target scavenger and mannose receptors on liver sinusoidal endothelial cells (LSECs). LSECs represent a major antigen-presenting cell type in the liver capable of generating regulatory T-cells (Tregs).  In vitro exposure of LSECs to NPOVA induced abundant TGF-β, IL-4, and IL-10 production, which was further increased by surface ligands. Animal experiments showed that, in the chosen size range, NPOVA was almost exclusively delivered to the liver, where the colocalization of fluorescent-labeled particles with LSECs could be seen to increase by surface ligand decoration. Moreover, prophylactic treatment with NPOVA in OVA-sensitized and challenged animals (aerosolized inhalation) could be seen to significantly suppress anti-OVA IgE responses, airway eosinophilia, and TH2 cytokine production in the bronchoalveolar lavage fluid. The suppression of allergic airway inflammation was further enhanced by attachment of surface ligands, particularly for particles decorated with the ApoB peptide, which induced high levels of TGF-β production in the lung along with the appearance of Foxp3+ Tregs. The ApoB-peptide-coated NPs could also interfere in allergic airway inflammation when delivered postsensitization. The significance of these findings is that liver and LSEC targeting PLGA NPs could be used for therapy of allergic airway disease, in addition to the potential of using their tolerogenic effects for other disease applications.

Introduction: Laryngeal sensory function in healthy adults was assessed through the delivery of tactile stimuli using Cheung–Bearelly monofilaments. Methods: 37 healthy adults were recruited with 340 tactile stimuli analyzed. Four calibrated tactile stimuli were delivered to three laryngeal sites: false vocal fold (FVF), aryepiglottic fold (AEF), and lateral pyriform sinus (LPS). Primary outcome was the elicitation of laryngeal adductor reflex (LAR). Secondary outcomes were gag, patient‐reported laryngeal sensation (PRLS), and perceptual strength. Analysis was performed with mixed effects logistic regression modeling. Results: Positive LAR was observed in 35.7%, 70.2%, and 91.2% of stimuli at LPS, AEF, and FVF respectively. LAR rates were significantly associated with laryngopharyngeal subsite (p < 0.001), tactile force (p = 0.001), age (p = 0.022) and sex (p = 0.022). LAR, gag, PRLS, and perceptual strength significantly increased as a more medial laryngeal subsite was stimulated and as stimulus force increased. Each of the ten years of age increase was associated with 19% reduction in odds of LAR (aOR = 0.81, 95% CI [0.68, 0.97]; p = 0.022). Male gender was associated with a 55% reduction in odds of LAR (aOR = 0.45, 95% CI [0.23, 0.89]; p = 0.022). Conclusion: LAR elicitation capability decreases in the male gender, aging, and a more lateral subsite. This study provides insight into the pathophysiology of hypo‐ and hyper‐sensitive laryngeal disorders and is paramount to making accurate diagnostic assessments and finding novel treatment options for various laryngological disorders. Laryngoscope, 133:2525–2532, 2023 [ABSTRACT FROM AUTHOR]

Background/Objectives: Laryngeal sensory abnormality has been implicated as a component of adductor laryngeal dystonia (AdLD). The study objective was to assess laryngopharyngeal sensation in AdLD utilizing a calibrated, tactile aesthesiometer to deliver differential stimuli to lateral pyriform sinus (LPS), aryepiglottic fold (AEF), and false vocal fold (FVF). Methods: Patients with known Botox‐responsive AdLD underwent sensory testing using a previously‐validated methodology involving calibrated tactile stimuli (6–0, 5–0, 4.5–0, 4–0 nylon monofilaments). Laryngeal adductor reflex (LAR) and participant‐rated perceptual strength of stimulI were evaluated. Responses were compared to normative controls (n = 33). Two‐samples, Mann–Whitney and Fisher exact tests compared mean strength ratings and LAR between AdLD and control groups. Mixed‐effects logistic regression and linear models assessed association of filament size, stimulus site, age, sex, and LD status on LAR and perceptual strength rating respectively. Results: Thirteen AdLD patients (nine women, mean age 60+/−15 years) completed testing. Average LAR response rates were higher amongst all filament sizes in AdLD versus controls at LPS (56.3% vs. 35.7%) and AEF (96.1% vs. 70.2%) with comparable rates at FVF (90.2% vs. 91.7%). AdLD had 3.3 times the odds of observed LAR compared to controls (p = 0.005), but differences in subjective detection of stimuli, perceptual strength ratings, and cough/gag rates were insignificant on multivariate modeling (p > 0.05). Conclusions: This is the first study to objectively assess laryngopharyngeal sensation in AdLD. Findings demonstrated increased laryngopharyngeal sensation in AdLD compared to controls. The identification of increased laryngeal hypersensitivity in these patients may improve understanding of AdLD pathophysiology and identify future targets for intervention. Level of Evidence: 2 Laryngoscope, 133:2271–2278, 2023 [ABSTRACT FROM AUTHOR]

Background/Objective: Cheung–Bearelly aesthesiometers can deliver buckling‐force stimuli to the laryngopharynx and objectively evaluate sensation. Ambiguity surrounds the transformation of stimuli in the laryngopharyngeal environment. This study aims to evaluate the effect of aesthesiometer size, saliva, successive compressions, and angles of tissue contact on stimulus force delivered. Methods: An ex vivo stimulus delivery device was constructed to measure the buckling force of aesthesiometers. Dry and saliva‐saturated aesthesiometers (6–0, 5–0, 4.5–0, and 4–0) were each compressed six times on cadaveric buccal mucosa on an electronic balance. The force for each compression was recorded at 0, 15, 30, 45, and 60° from the vertical plane. 240 compressions were analyzed utilizing a mixed‐effects statistical model. Results: The mean force delivered by the 6–0, 5–0, 4.5–0, and 4–0 aesthesiometers were 0.017, 0.082, 0.120, and 0.268 g respectively (p < 0.001). Mean force significantly reduced for the 4–0 aesthesiometer at 30° (p = 0.003) and 60° (p = 0.001). Force decreased by the 4th compression for the 5–0 aesthesiometer (p = 0.004) and after one compression for the 4.5–0 (p = 0.004) and 4–0 (p < 0.001) aesthesiometer. By the 4th compression, the 4.5–0 aesthesiometer was indistinguishable (p > 0.05) from the 5–0 aesthesiometer. The effect of saliva was insignificant (p = 0.83). Conclusion: Aesthesiometers can deliver discrete buckling‐force stimuli to evaluate laryngopharynx sensory function. Up to 60° (15° for 4–0 aesthesiometer) deviation from orthogonal tissue contact and salivary forces do not significantly alter force delivered. 4.5–0 aesthesiometers should be exchanged after three compressions. For all other aesthesiometers, force reduction after six compressions is likely clinically insignificant given current laryngopharyngeal sensory testing protocols. Level of Evidence: N/A Ex Vivo Laboratory Design Laryngoscope, 133:1933–1937, 2023 [ABSTRACT FROM AUTHOR]

Background: Despite many available patient‐reported outcome measures (PROMs) for laryngeal movement disorders, there is a lack of patient input regarding which PROM most accurately and conveniently captures aspects related to their vocal disease. This study aimed to assess patients' preferences among a selection of voice‐related PROMs (Voice Handicap Index‐10 [VHI‐10], OMNI‐Vocal Effort Scale [OMNI‐VES], Communicative Participation Item Bank‐General Short Form [CPIB‐10], and Visual Analog Scales [VAS]) within the laryngeal movement disorder population and investigate associations between selected instruments. Methods: Prior to botulinum toxin A injection, patients with laryngeal dystonia and/or essential tremor of the vocal tract were administered the VHI‐10, OMNI‐VES, CPIB‐10, and three novel VAS questions in a randomized order. Patients rank ordered the four PROMs based on the PROMs' reflection of their voice problems. Pearson's correlation coefficients evaluated pairwise associations among PROM scores. Fisher's exact test compared the preferred PROM rankings. Results: Seventy patients (53 female, mean age = 60.7 years) participated. The VHI‐10 and CPIB‐10 were most preferred at 33.9% and 27.4% respectively. The OMNI‐VES and VAS scales were less favored (19.4%, each). When analyzed by age ≥60 years, the CPIB‐10 was most favored (33.3%), but for age <60 years, VHI‐10 was most preferred (42.3%). There was a strong correlation between scores of all administered PROMs (strongest correlation between OMNI‐VES and VAS, r = 0.8, p < 0.001; the weakest correlation between OMNI‐VES and VHI‐10, r = 0.6, p < 0.001). Conclusions: With an increasing trend in PROMs usage and a strong correlation between all evaluated outcome instruments, insight regarding patients' PROM preferences is an area for further consideration. Level of Evidence: NA Laryngoscope, 133:1448–1454, 2023 For patients with laryngeal dystonia (formally called spasmodic dysphonia) and vocal tremors, there is no universally accepted outcome metric to assess and compare disease severity or response to treatment. Our study looks to determine which of the currently used tools/questionnaires are most preferred by patients themselves. [ABSTRACT FROM AUTHOR]

Background/Objective: Quantitative swallowing displacement kinematics evolve in patients treated for oropharyngeal squamous cell carcinoma (OPSCC). We aimed to longitudinally assess these measurements and correlate them with functional swallowing outcomes. Method: A retrospective review was conducted on patients with OPSCC treated with definitive (chemo)radiation ([C]RT) or surgery with adjuvant (chemo)radiation (S‐[C]RT) who completed at least two videofluoroscopic swallow studies (VFSS). Longitudinal analysis was accomplished via mixed‐effects logistic regression for the Functional Oral Intake Scale (FOIS), and Penetration Aspiration Scale (PAS), and mixed‐effects linear regression for kinematic measures. Spearman's correlation was conducted between changes in FOIS/PAS and kinematic measures. Results: Ninety‐seven patients (76 males; mean age 61) completed 245 VFSS studies. A total of 94% had human papillomavirus (HPV)/p16 positive OPSCC and 74% were T0–T2. Sixty‐four patients underwent [C]RT while 33 patients underwent S‐[C]RT. After treatment, posterior pharyngeal wall at hold (PPWhold) increased 3.2 standard deviation (SD) between 0 and 6 months (p < 0.001), then decreased 2.2 SD between 6 and 12 months (p < 0.001) and did not return to baseline. Hyoid‐to‐larynx (HL) (p = 0.046) and maximal hyoid displacement (Hmax) + HL (p = 0.042) increased between 6 and 12 months. Hmax (p = 0.020) and Hmax + HL (p < 0.001) decreased between 12–24 months beyond baseline values. The decrease in HL and increase in PPWhold (p < 0.05) correlated with an increase in PAS. From baseline, increased pharyngeal constriction ratio correlated with decreased FOIS and PPWhold (p < 0.05). Conclusions: Quantitative swallowing kinematic measures can effectively track changes in swallowing physiology. Increased PPWhold and restricted hyolaryngeal movement were seen in patients with OPSCC after treatment and correlated with a change in swallowing outcome, emphasizing the need for serial VFSS monitoring and targeted intervention. Level of Evidence: 3 Laryngoscope, 133:1339–1348, 2023 [ABSTRACT FROM AUTHOR]

Objective: Airway stenosis—particularly multi‐level—presents complex management challenges. This study assessed rates of tracheostomy, decannulation, and the number of surgeries required in patients with posterior glottic stenosis (PGS), multi‐level airway stenosis (MLAS), and bilateral vocal fold paralysis (BVFP). Methods: Airway stenosis patients treated between 2016 and 2021 at three tertiary medical centers were identified. Demographics, etiology of stenosis, medical comorbidities, and patient‐reported outcome measures (PROMs) were collected. Results: 158 patients (84 women, mean age 56.98 ± 15.5 years) were identified (54 PGS, 38 MLAS, and 66 BVFP). 72.3% required tracheostomy, including 72.2%, 86.8%, and 63.6% in these groups, respectively. Decannulation rates were 43.6%, 21.2%, and 32.5% in these groups, respectively. Patients with MLAS had higher rates of tracheostomy than BVFP (p < 0.05). However, decannulation rates were not different between groups (p > 0.05). MLAS required more surgeries (mean 4.0 ± 3.9) than PGS (2.4 ± 2.2, p = 0.02) or BVFP (1.0 ± 1.8, p < 0.0001). Mean PROMs scores at the latest follow‐up were abnormal: 15.4 ± 12.2 (Dyspnea Index), 19.9 ± 12.2 (Voice Handicap Index‐10), and 9.67 ± 11.1 (Eating Assessment Tool‐10). Co‐morbidities present included body mass index >30 (41.4%), diabetes (31.8%), pulmonary disease (50.7%), gastroesophageal reflux disease (39.4%), autoimmune disease (22.9%), and tobacco use history (55.2%). Conclusions: Airway stenosis is a challenging clinical problem that negatively impacts patients' quality of life and often requires numerous surgeries. PGS more frequently requires tracheostomy compared to BVFP, but patients can often decannulate successfully. Patients with multi‐level stenosis have lower decannulation rates and require more surgeries than glottic stenosis alone; these patients may benefit from earlier and/or more aggressive intervention. Level of Evidence: 4 Laryngoscope, 133:528–534, 2023 [ABSTRACT FROM AUTHOR]

Importance: The gold-standard treatment for laryngeal dystonia (LD) and essential tremor of the vocal tract (ETVT) is botulinum toxin (BoNT) chemodenervation. Although safe and effective, it is not curative, and periodic injections are required. Some medical insurance companies only cover injections at a 3-month interval, though some patients benefit from injections more frequently., Objective: To determine the proportion and characteristics of patients who receive BoNT chemodenervation treatment in intervals shorter than 90 days., Design, Setting, and Participants: This retrospective cohort study across 3 quaternary care neurolaryngology specialty practices in Washington and California recruited patients who underwent at least 4 consecutive laryngeal BoNT injections for LD and/or ETVT in the past 5 years. Data were collected from March through June 2022 and analyzed from June through December 2022., Exposure: Laryngeal BoNT treatment., Main Outcomes and Measures: Biodemographic and clinical variables, injection characteristics, evolution during the 3 interinjection intervals, and lifetime laryngeal BoNT treatment data were collected from patient medical records. Logistic regression was used to assess association to the short-interval outcome, defined as an average injection interval shorter than 90 days., Results: Of 255 patients included from the 3 institutions, 189 (74.1%) were female, and the mean (SD) age was 62.7 (14.3) years. The predominant diagnosis was adductor LD (n = 199 [78.0%]), followed by adductor dystonic voice tremor (n = 26 [10.2%]) and ETVT (n = 13 [5.1%]). Seventy patients (27.5%) received short-interval injections (<90 days). The short-interval group was younger than the long-interval group (≥90 days), with a mean (SD) age of 58.6 (15.5) years and 64.2 (13.5) years, respectively, and a mean difference of -5.7 years (95% CI, -9.6 to -1.8 years). There were no patient-related differences between the short- and long-interval groups in terms of sex, employment status, or diagnosis., Conclusions and Relevance: This cohort study demonstrated that while insurance companies often mandate a 3-month or greater interval for BoNT chemodenervation financial coverage, there is a considerable subset of patients with LD and ETVT who receive short-interval treatment to optimize their vocal function. Short-interval chemodenervation injections demonstrate a similar adverse effect profile and do not appear to predispose to resistance through antibody formation.