Severe Type 2 Inflammation Leads to High Platelet-Activating-Factor-Associated Pathology in Chronic Rhinosinusitis with Nasal Polyps-A Hierarchical Cluster Analysis Using Bulk RNA Barcoding and Sequencing.

Platelet-activating factor (PAF) is a phospholipid-derived inflammatory mediator that triggers various inflammatory conditions, including eosinophil activation and recruitment. This study aimed to evaluate the expressions of PAF-metabolism-associated genes, namely genes coding the enzymes involved in PAF synthesis (LPCAT1, LPCAT2, LPCAT3, and LPCAT4), PAF degradation (PAFAH1B2, PAFAH1B3, and PAFAH2), and the gene for the PAF receptor (PTAFR) in subtypes of CRSwNP classified by clinical- or hierarchal-analysis-based classifications. Transcriptomic analysis using bulk RNA barcoding and sequencing (BRB-seq) was performed with CRSwNP, including eosinophilic CRS (ECRS) (n = 9), nonECRS (n = 8), ECRS with aspirin-exacerbated respiratory disease (Asp) (n = 3), and controls with a normal uncinate process mucosa (n = 6). PTAFR was only upregulated in ECRS and nonECRS. In the hierarchical cluster analysis with clusters 1 and 2 reflecting patients with low-to-moderate and high levels of type 2 inflammation, respectively, cluster 1 exhibited a significant downregulation of LPCAT2 and an upregulation of PTAFR expression, while cluster 2 showed an upregulation of LPCAT1, PAFAH1B2, and PTAFR and downregulation of PAFAH2 expression. Understanding this strong PAF-associated pathophysiology in the severe type 2 inflammation group could provide valuable insights into the treatment and management of CRSwNP.

Swallowing Exercise Evaluated Using High-Density Surface Electromyography in Patients with Head and Neck Cancer: Supplementary Analysis of an Exploratory Phase II Trial.

Background and Objectives: Muscle strength evaluation using high-density surface electromyography (HD-sEMG) was recently developed for the detailed analysis of the motor unit (MU). Detection of the spatial distribution of sEMG can detect changes in MU recruitment patterns resulting from muscle-strengthening exercises. We conducted a prospective study in 2022 to evaluate the safety and feasibility of transcutaneous electrical sensory stimulation (TESS) therapy using an interferential current device (IFCD) in patients with head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy (CRT), and reported the safety and feasibility of TESS. We evaluated the efficacy of swallowing exercises in patients with HNSCC undergoing CRT and determined the significance of sEMG in evaluating swallowing function. Materials and Methods: In this supplementary study, the patients performed muscle-strengthening exercises five days a week. The association of the effects of the exercises with body mass index, skeletal muscle mass index, HD-sEMG, tongue muscle strength, and tongue pressure were evaluated. Results: We found significant correlations between the rate of weight loss and skeletal muscle mass index reduction and the rate of change in the recruitment of the MU of the suprahyoid muscle group measured using HD-sEMG. Conclusions: We believe that nutritional supplementation is necessary in addition to muscle strengthening during CRT.

Exhaled Nitric Oxide and Olfactory Dysfunction in Patients with Asthma: Association with Chronic Rhinosinusitis.

Objectives: Olfactory dysfunction is a clinical sign that is important to detect with coexistent upper airway comorbidities in patients with asthma. This study aimed to investigate the etiology of olfactory dysfunction in patients with asthma and the relationship between fractional exhaled nitric oxide (FeNO) levels. Materials and Methods: This study included 47 asthma patients who were evaluated for olfactory dysfunction at Hiroshima University Hospital between 2012 and 2020. The etiologies of olfactory dysfunction were evaluated, and they were classified according to the FeNO levels of patients with asthma. Results: Olfactory dysfunction was observed in 30 patients with asthma, with chronic rhinosinusitis (77%) being the most prevalent etiology. Eosinophilic chronic rhinosinusitis (ECRS) was the most prevalent etiology of olfactory dysfunction in asthma patients with high FeNO levels (≥25 ppb), while non-eosinophilic chronic rhinosinusitis (NCRS) was the most prevalent etiology in asthma patients with low FeNO levels (<25 ppb). Additionally, the prevalence of ECRS was significantly higher in asthma patients with olfactory dysfunction and high FeNO levels (74%) than in those with either high FeNO levels or olfactory dysfunction and those with low FeNO levels and no olfactory dysfunction (12% and 9%, respectively). Conclusions: We found that ECRS was the predominant cause of olfactory dysfunction in patients with high FeNO levels, while NCRS was more common in those with low FeNO levels. The present study showed that both ECRS and NCRS are common etiologies of olfactory dysfunction in patients with asthma. Additionally, this study supports the link between upper and lower airway inflammation in patients with asthma complicated with olfactory dysfunction.

Evaluation of the Safety of Percutaneous Sensory Nerve Stimulation in Patients with Head and Neck Cancer Receiving Chemoradiotherapy.

Chemoradiotherapy (CRT) is the standard treatment for locally advanced head and neck cancer; however, CRT may cause post-treatment dysphagia. Transcutaneous electrical sensory stimulation (TESS), developed in recent years for swallowing rehabilitation, is used at many medical facilities. Although TESS has been used for dysphagia in several fields, its safety and efficacy in patients with head and neck cancer remain to be clarified. Therefore, this study evaluated the safety of TESS in ten patients with head and neck cancers undergoing CRT. Swallowing rehabilitation intervention and TESS implementation were performed for all patients during CRT. Non-blood-toxicity adverse events (AEs), such as dermatitis and mucositis, occurred during CRT; however, the severity was less than grade 3. No patient experienced pain due to TESS. As survival time analysis using the Kaplan-Meier method for interferential current device implementation rates revealed a feasibility of 100% for up to 60 Gy and a feasibility of 78% for up to 70 Gy, TESS may be feasible until 70 Gy. This study confirmed the feasibility and safety of TESS in the head and neck region during CRT. Although the precise mechanism of TESS on dysphagia remains unclear, its continued use has great potential for improving sensory disturbance.

Effectiveness of Expanded Instantaneous Input Dynamic Range Adjustment on Speech Perception.

Instantaneous input dynamic range (IIDR), as defined by Cochlear Ltd. (Sydney, Australia), refers to the acoustic level of short-term input dynamic range (IDR). Our aim was to evaluate the efficacy of expanding IIDR to improve speech understanding. We enrolled 11 unilateral Cochlear Ltd. patients with post-lingual hearing loss. The two types of IIDR settings (T-SPL/C-SPL of 25/65 dB (default IIDR) and 25/80 dB (wide IIDR)) were blindly assigned, and only one IIDR setting selected according to their preference was used for at least three months. Each IIDR group was evaluated with both default and wide IIDR conditions using the recorded word and sentence test materials of the Japanese CD speech discrimination scoring system (CI-2004 test) in quiet and noise with a signal-to-noise ratio (SNR) of +10 dB, presented at 65/80 dB SPL. Wide IIDR significantly improved speech perception in all tests, except for sentences in quiet conditions at a presentation level of 65 dB. Improvements during loud conversations in noisy environments were obtained without any adaptation period. Wide IIDR should become a new individual configuration setting method in Cochlear Ltd. devices to improve hearing in loud conversations and noisy environments.

Deep Association between Transglutaminase 1 and Tissue Eosinophil Infiltration Leading to Nasal Polyp Formation and/or Maintenance with Fibrin Polymerization in Chronic Rhinosinusitis with Nasal Polyps.

Transglutaminase (TGM) isoform catalyze the cross-linking reaction of identical or different substrate proteins. Eosinophil has been recognized in chronic rhinosinusitis with nasal polyps (CRSwNP) forming tissue eosinophil in nasal polyp (NP), and TGM isoforms are suggested to be associated with a critical role in asthma and other allergic conditions. The aim of this study was to reveal the association of specific TGM isoform with both the tissue eosinophil infiltration deeply concerning with the intractable severity of CRSwNP and the fibrin polymerization ability of TGM isoform associated with the tissue eosinophil infiltration, which lead to NP formation and/or maintenance in CRSwNP. NP tissues (CRSwNP group) and uncinate process (UP) (control group) were collected from patients with CRSwNP and control subjects. We examined: (1) the expression level of TGM isoforms by using a real-time polymerase chain reaction (PCR) and the comparison to the issue eosinophil count in the CRSwNP group, (2) the location of specific TGM isoform in the mucosal tissue using immunohistochemistry, (3) the inflammatory cell showing the colocalization of specific TGM isoform in Laser Scanning Confocal Microscopy (LSCM) imaging, and (4) the fibrin polymerase activity of specific TGM isoform using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). A certain level of TGM 1, 2, 3, 5 expression was present in both the CRSwNP group and the control group. Only TGM 1 expression showed a positive significant correlation with the tissue eosinophil count in the CRSwNP group. The localization of TGM 1 in NP (CRSwNP) laid mainly in a submucosal layer as inflammatory cells and was at the cytoplasm in the tissue eosinophil. Fibrin polymerase activity of TGM 1 showed the same polymerase ability of factor XIIIA. TGM 1 might influence the NP formation and/or maintenance in CRSwNP related to the tissue eosinophil infiltration, which formed fibrin mesh composing NP stroma.

Distinct Gene Set Enrichment Profiles in Eosinophilic and Non-Eosinophilic Chronic Rhinosinusitis with Nasal Polyps by Bulk RNA Barcoding and Sequencing.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease with a high symptom burden, including nasal congestion and smell disorders. This study performed a detailed transcriptomic analysis in CRSwNP classified as eosinophilic CRS (ECRS), nonECRS according to the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) criteria, and a group of ECRS with comorbid aspirin intolerant asthma (Asp). Gene expression profiles of nasal polyps and the uncinate process in CRSwNP patients and normal subjects (controls) were generated by bulk RNA barcoding and sequencing (BRB-seq). A differentially expressed genes (DEGs) analysis was performed using DESeq2 software in iDEP to clarify any relationship between gene expression and disease backgrounds. A total of 3004 genes were identified by DEGs analysis to be associated with ECRS vs control, nonECRS vs control, and Asp vs control. A pathway analysis showed distinct profiles between the groups. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed distinct phenotype-specific pathways of expressed genes. In the specific pathway of "cytokine-cytokine receptor interaction", the differentially expressed genes were widely distributed. This study indicates that transcriptome analysis using BRB-seq may be a valuable tool to explore the pathogenesis of type 2 inflammation in CRSwNP.

Co-Expression and Localization of Angiotensin-Converting Enzyme-2 (ACE2) and the Transmembrane Serine Protease 2 (TMPRSS2) in Paranasal Ciliated Epithelium of Patients with Chronic Rhinosinusitis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme-2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) as a primary receptor for invasion. Cell entry by the virus requires the co-expression of these molecules in the host cells. OBJECTIVE: We investigated ACE2 and TMPRSS2 expression and localization in paranasal epithelium of eosinophilic chronic rhinosinusitis (ECRS) patients (n = 38), non-ECRS (n = 31), and healthy controls (n = 25). CRS inflammatory patterns are characterized by the type of cytokines; we investigated whether inflammatory endotypes are associated with cell-entry molecules, as this could be linked to susceptibility to SARS-CoV-2 infection. METHODS: The ACE2, TMPRSS2, and other inflammatory cytokine mRNA levels were assessed by quantitative RT-PCR. The localizations of ACE2- and TMPRSS2-positive cells were examined with immunofluorescent double-staining using laser scanning confocal microscopy (LSCM). RESULTS: The non-ECRS patients showed significantly increased ACE2 and TMPRSS2 mRNA expressions compared to the ECRS patients. The CRS patients' ACE2 and TMPRSS2 mRNA levels were positively correlated with IFN-γ (r = 0.3227 and r = 0.3264, respectively) and TNF-α (r = 0.4008, r = 0.3962, respectively). ACE2 and TMPRSS2 were negatively correlated with tissue eosinophils (r = -0.3308, r = -0.3112, respectively), but not with IL-13. ACE2 mRNA levels were positively correlated with TMPRSS2 (r = 0.7478). ACE2 and TMPRSS2 immunoreactivities were localized mainly in the epithelial ciliated cells, as confirmed by co-staining with TMPRSS2 and acetylated α-tubulin, a cilia organelle marker. Using LSCM imaging, we observed higher expressions of these molecules in the non-ECRS patients versus the ECRS patients. CONCLUSION: ECRS patients with type 2 inflammation showed decreased ACE2 and TMPRSS2 expressions in their sinus mucosa. ACE2 and TMPRSS2 regulation seems to be positively related to IFN-γ and TNF-α production in CRS patients; ACE2 and TMPRSS2 were co-expressed in the ciliated epithelium of their paranasal mucosa, implicating the paranasal epithelium as a portal for initial infection and transmission.

Vocal cord dysfunction detected by a three-dimensional image of dynamic change in respiratory resistance in a patient with difficult-to-treat asthma: a case report.

INTRODUCTION: Vocal cord dysfunction (VCD) often coexists with asthma and exacerbates respiratory symptoms. A noninvasive method could be considered beneficial for the detection and follow-up of VCD complicated by asthma. Here, we report a case of VCD complicated by asthma, highlighting the effectiveness of colored three-dimensional (3-D) imaging of respiratory impedance using a broadband frequency forced oscillation technique (MostGraph). CASE STUDY: A 74-year-old woman with difficult-to-treat asthma, in whom mepolizumab treatment was ineffective, was referred to our hospital. Stridulous sounds were loudest over the anterior neck. Pulmonary function tests' results were normal; however, a flattening of the inspiratory flow-volume curve was detected. RESULTS: Remarkably, prominent spikes were observed in the inspiratory phase in the colored 3-D imaging of respiratory resistance, which was superimposed on increased respiratory resistance in the expiratory phase. Flexible laryngoscopy revealed the adduction of vocal cords on inspiration. The patient was diagnosed with asthma complicated by VCD. After successful treatment of VCD by speech therapy, inspiratory spikes of respiratory resistance disappeared, and normal vocal cord movement was observed on laryngoscopy. CONCLUSION: The present case report indicates the effectiveness of forced oscillometry in evaluating dynamic changes in respiratory resistance for detecting and monitoring VCD complicated by asthma.

Effect of Body Mass Index on Posttonsillectomy Hemorrhage.

OBJECTIVE: Obesity affects adverse outcomes in patients undergoing various surgeries. Tonsillectomy is one of the most common surgical procedures and posttonsillectomy hemorrhage (PTH) is the major complication in patients with tonsillectomy. However, the effect of body mass index (BMI) on posttonsillectomy bleeding episodes is not well known. This study aimed to assess the clinical association between obesity and PTH. METHODS: A total of 98 tonsillectomies were retrospectively reviewed. Patient charts were analyzed regarding demographic data and the indication for surgery. Patients with PTH were compared with uneventful cases. Patients were divided into three groups based on BMI: normal weight (BMI < 25 kg/m2), overweight (BMI ≥ 25 and <30 kg/m2), and obese (≥30 kg/m2). RESULTS: PTH occurred in 13% of patients with normal weight, in 23.5% of patients with overweight, and in 50% patients with obesity. The occurrence of PTH was significantly higher in patients with obesity than in those with normal weight and overweight (p = 0.008). Multivariate analysis showed that obesity was a significant factor affecting the incidence of PTH after adjusting for confounding factors. CONCLUSIONS: Our findings suggest that the obese condition is independently associated with the incidence of PTH.

Efficacy of the red blood cell distribution width for predicting the prognosis of Bell palsy: a pilot study.

The aim of this study was to investigate the association between RDW values and the prognosis of patients with Bell palsy in an effort to find a prognostic biomarker that predicts recovery from Bell palsy. We measured RDW and evaluated facial movement in 61 patients with Bell palsy aged 50 years and less. All patients were treated with a steroid plus an antiviral agent. Seven patients underwent surgery for facial nerve decompression. During the post-treatment period, patients with a Yanagihara grading score of 36 or more were regarded as having a satisfactory recovery. Patients were divided into two groups (recovered and unrecovered) according to their response to treatment, and several parameters, including the RDW, were measured for further analysis. RDW values were significantly higher in the unrecovered group than in the recovered group (13.5 ± 1.7 vs. 12.7 ± 0.7%, p = 0.046). In the multiple logistic regression model, RDW was the only factor associated with recovery from Bell palsy (odds ratio 1.93, 95% confidence interval 1.02-4.65, p = 0.042). Our preliminary study provides the first evidence that the red cell distribution width (RDW) can predict recovery from Bell palsy in patients aged 50 years and less. Further studies are necessary to elucidate the potential pathophysiological mechanisms for our findings.

Outcomes of endoscopic endonasal dacryocystorhinostomy for intractable lacrimal dacryostenosis and associated factors.

AIM: To examine the effects of patient age, canalicular obstruction, mode of anesthesia, and duration of nasolacrimal intubation on the outcomes of endoscopic endonasal dacryocystorhinostomy (DCR). METHODS: Totally 56 eyes of 46 patients with prolonged epiphora underwent minimally invasive endoscopic endonasal DCR. A successful surgical outcome was defined as a significant improvement in symptoms, adequate water passage from the puncta to the nasal cavity, and patency of the DCR ostium. All outcomes were assessed at least 6mo after extubation. Fisher's exact test was used to discuss the factors, and then the logistic regression analysis was made by SAS 9.4 software. RESULTS: The overall success rate was 75.0%, and complete resolution was observed in 27 eyes. The success rate was higher for patients with ≥6mo intubation than for those with <6mo intubation. However, there were no significant differences in outcomes between groups stratified by age (<65 or ≥65y), presence or absence of canalicular obstruction, mode of anesthesia (local or general), and use or nonuse of a radiowave unit. One patient developed subcutaneous emphysema around the eye and nose and one developed subcutaneous hemorrhage after surgery. CONCLUSION: Endoscopic endonasal DCR can be considered safe and minimally invasive with reasonable success rates, particularly when the duration of nasolacrimal intubation is ≥6mo.

Red blood cell distribution width predicts prognosis in idiopathic sudden sensorineural hearing loss.

CONCLUSION: Red cell distribution width (RDW) can predict outcome in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). Further studies are required to clarify the potential pathophysiological explanations for these findings. OBJECTIVES: RDW is one of the parameters reported in a complete blood count, and is elevated in direct proportion to variation in red cell size (anisocytosis). High RDW values are strongly associated with poor clinical outcomes in various diseases, including inflammatory and thrombotic diseases. To identify a prognostic biomarker that better predicts outcomes after ISSNHL, the association between RDW values at hospitalization and prognosis in patients with ISSNHL was assessed. METHOD: This study measured RDW and performed hearing assessments in 89 consecutive patients with ISSNHL. Patients were then divided into two groups ('recovered' and 'unrecovered'), according to their response to the treatment, and further analysis undertaken. RESULTS: Mean RDW was significantly higher in the unrecovered group (13.2% ± 1.0% compared with 12.7% ± 0.7% in the recovered group, p = 0.031). After adjusting for potentially confounding factors in a binary logistic regression model, only RDW was associated with recovery from ISSNHL (odds ratio = 2.33, 95% confidence interval = 1.20-4.51, p = 0.012).

Investigation of the ototoxicity of gadoteridol (ProHance) and gadodiamide (Omniscan) in mice.

CONCLUSION: In the mouse, when a tympanic perforation is present, gadoteridol does not seem to cause ototoxicity. Gadodiamide may cause mild ototoxicity other than toxicity to the outer hair cells of the cochlea. OBJECTIVES: Endolymphatic hydrops have been visualized through intra-tympanic injection of gadolinium-based contrast agents (GBCAs) and three-dimensional fluid-attenuated inversion recovery (3-D FLAIR) magnetic resonance imaging. However, reports on the safety of GBCAs are limited. This study aimed to assess ototoxicity of gadoteridol and gadodiamide. METHOD: In a prospective, randomized, controlled trial, myringotomies in the left ear were performed in 20 male C57 BL/6 mice. After testing the baseline auditory brainstem response (ABR) (range = 8-32 kHz), the test solution (gadoteridol, gadodiamide, saline, or cisplatin) was injected into the left ear. ABR testing was repeated 14 days after test solution application. In morphological experiments, images of post-mortem surface preparations were assessed for cochlear hair cell status. RESULTS: At 14 days following gadoteridol application, there was no significant change in ABR thresholds at 8, 16, or 32 kHz. Gadodiamide application caused a significant change in the ABR threshold at 8 kHz. Apparent cochlear hair cell loss was not observed in the surface preparation after gadoteridol or gadodiamide application.

Soybean ß-Conglycinin Prevents Age-Related Hearing Impairment.

Obesity-related complications are associated with the development of age-related hearing impairment. ß-Conglycinin (ß-CG), one of the main storage proteins in soy, offers multiple health benefits, including anti-obesity and anti-atherosclerotic effects. Here, to elucidate the potential therapeutic application of ß-CG, we investigated the effect of ß-CG on age-related hearing impairment. Male wild-type mice (age 6 months) were randomly divided into ß-CG-fed and control groups. Six months later, the body weight was significantly lower in ß-CG-fed mice than in the controls. Consumption of ß-CG rescued the hearing impairment observed in control mice. Cochlear blood flow also increased in ß-CG-fed mice, as did the expression of eNOS in the stria vascularis (SV), which protects vasculature. ß-CG consumption also ameliorated oxidative status as assessed by 4-HNE staining. In the SV, lipofuscin granules of marginal cells and vacuolar degeneration of microvascular pericytes were decreased in ß-CG-fed mice, as shown by transmission electron microscopy. ß-CG consumption prevented loss of spiral ganglion cells and reduced the frequencies of lipofuscin granules, nuclear invaginations, and myelin vacuolation. Our observations indicate that ß-CG ameliorates age-related hearing impairment by preserving cochlear blood flow and suppressing oxidative stress.