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Objective: To assess the efficacy, safety, and tissue penetration of solithromycin for the treatment of otorhinolaryngological infections, we conducted three studies: a tissue penetration study with patients scheduled to undergo otorhinolaryngological tissue removal, an open-label study comprising patients with otitis media, pharyngitis, laryngitis, and tonsillitis, and a non-inferiority study compared with high-dose cefcapene-pivoxil (CFPN-PI)., Methods: Tissue penetration study; 17 patients with chronic rhinosinusitis, chronic otitis media, chronic tonsillitis, or palatine tonsillar hypertrophy, who required resection or removal of their tissue, were enrolled. Solithromycin was administered orally, and otorhinolaryngological tissues were collected 3.5-6 h after drug administration; blood was collected within 15 min before and after drug administration. The collected tissues and blood concentrations were measured at a central laboratory. Open-label study; 55 patients who were diagnosed with acute otitis media, laryngopharyngitis, or tonsillitis were enrolled. Solithromycin was administered orally 800 mg on Day 1, while on days 2-7, 400 mg of the drug was administered once daily. The primary endpoint is the clinical response at Test-of-Cure (TOC: 5-10 days after completion) Non-inferiority study; 283 patients with acute rhinosinusitis or acute exacerbation of chronic rhinosinusitis were randomized into either the solithromycin group or CFPN-PI group. Solithromycin was administered 800 mg once daily on Day 1 and 400 mg once daily while on Days 2-7 in solithromycin group, and CFPN-PI was administered 150 mg three times a day while on Days 1-7 in CFPN-PI group. The primary endpoint is the clinical response at TOC., Results: In the tissue penetration study, the tissue concentration ratios (tissue concentration/plasma concentration) of solithromycin were 4.19 in the sinonasal mucosa, 1.33 in the middle ear mucosa, and 6.12 in the palatine tonsil tissue. In the open-label study, the efficacy rates at the TOC were 97.0 % for acute otitis media, 100 % for laryngopharyngitis, and 81.8 % for tonsillitis. In the non-inferiority study comprising patients with rhinosinusitis, the efficacy rate at the TOC was 87.7 % for solithromycin and 89.7 % for CFPN-PI. The difference in the efficacy rate (95 % confidence interval) was -2.0 % (-9.4 % to 5.4 %), verifying the non-inferiority of solithromycin to CFPN-PI. The most common adverse events in patients administered solithromycin were diarrhea (20.7 %), nausea and nasopharyngitis (3.6 %,), pharyngitis and elevated hepatic function test results (3.1 %), and abnormal hepatic function (2.1 %)., Conclusion: Based on the findings, it is suggested that solithromycin is useful for the treatment of otorhinolaryngological infections., Competing Interests: Declaration of Competing Interest Yuichi Kurono has received financial support for the present manuscript and consulting fees as coordinating investigator from FUJIFILM Toyama Chemical Co., Ltd. Fumiyo Kudo has received financial support for the present manuscript and consulting fees as coordinating investigator from FUJIFILM Toyama Chemical Co., Ltd. Akira Watanabe has received financial support for the present manuscript and consulting fees as medical expert from FUJIFILM Toyama Chemical Co., Ltd. Kenji Suzuki has received financial support for the present manuscript and consulting fees as medical expert from FUJIFILM Toyama Chemical Co., Ltd., KYORIN Pharmaceutical Co., Ltd. and CEOLIA Pharma Co., Ltd. Takahiro Yamatake and Satoshi Shimada are employee of FUJIFILM Toyama Chemical Co., Ltd., (Copyright © 2023. Published by Elsevier B.V.)

Objective: A phosphorylcholine (PC)-derivative with high binding ability (PCDB) was intranasally administered to mice with ovalbumin (OVA), and immune responses were investigated to determine whether PCDB has antigenicity and adjuvanticity., Methods: BALB/c mice were intranasally immunized with PCDB coupled with OVA, unbound PCDB plus OVA, cholera toxin (CT) plus OVA, OVA alone, and PCDB alone. Then, the production of OVA- and PC-specific antibodies in external secretions and serum, and the secretion of cytokines such as IL-4 and IFN-γ from splenic mononuclear cells by stimulation with PCDB and OVA were examined. Furthermore, the secretion of IL-12p40 from CD11c + cells following stimulation with PCDB was observed to clarify the adjuvant effect of PCDB through TLR4., Results: Intranasal immunization with PCDB plus OVA increased OVA- and PC-specific IgA in external secretions and OVA- and PC-specific antibodies in the serum. The analysis of IgG subclasses specific to OVA and PC showed a higher production of IgG1 than IgG2, and the secretion of both IL-4 and IFN-γ was enhanced. However, IL-12p40 secretion from CD11c + cells was increased and OVA-specific IgE production was not promoted by PCDB stimulation., Conclusion: Intranasal administration of the protein antigen with PCDB enhanced immune responses specific to the mixed antigen and PC. Although PCDB acted to bias the immune response toward the Th2-type, antigen-specific IgE production did not increase. These findings suggest that PCDB has the potential to be a mucosal vaccine with both adjuvanticity and antigenicity without causing side effects due to type I allergy., (Copyright © 2023. Published by Elsevier B.V.)

The purpose of this study was to examine clinical dysphonia in patients with polymyositis (PM)/dermatomyositis (DM). The subjects were 21 Japanese patients with PM/DM (11 females, 10 males; mean age ± SD, 61.4 ± 16.2 years) who visited our department between April 2009 and March 2020. Dysphonia was evaluated by laryngoscopy and histopathological examination. Eight (38.1%) patients were aware of dysphonia. These patients included one with PM and 7 with DM, 5 were male and 3 were female, and the mean age at diagnosis was 62.0 (range 48 to 72) years. White lesions on the vocal cords were found in 7 of the patients with dysphonia. The patient without these white lesions had regurgitation into the nasal cavity. Histopathological examination revealed inflammation of lamina propria in the laryngeal white lesions. White lesions on the vocal cords were found in patients with dysphonia in patients with polymyositis (PM)/dermatomyositis (DM). Histopathological examination revealed fiber necrosis and inflammatory cell infiltration in lamina propria of the laryngeal lesions. White lesions on the vocal cords were relieved by treatment. Level of Evidence 2b (Individual retrospective cohort study)., Competing Interests: Conflict of interestThere are no conflicts of interest to declare., (© Association of Otolaryngologists of India 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

The Practical Guideline for the Management of Allergic Rhinitis, the fist guideline for allergic rhinitis in Japan, was prepared after a symposium held by the Japanese Society of Allergology in 1993. The current 9th edition was published in 2020 and is widely used today. The most recent collection of evidence from the literature was supplemented to the revised guideline to incorporate evidence-based medicine. The revised guideline includes updated epidemiology of allergic rhinitis in Japan, a figure representing the mechanisms of allergic rhinitis in both the onset and sensitization phases with the introduction of regulatory T cells and type 2 innate lymphoid cells, practical assessment for diagnosis, new pharmacotherapy agents such as anti-IgE mAb and a new drug delivery system for antihistamines, sublingual immunotherapy for children, dual sublingual immunotherapy for house dust mites and Japanese cedar pollen extract, new classification for surgery for allergic rhinitis, and treatment and prescriptions for older adults. An evidence-based step-by-step strategy for treatment is also described., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Objective: The purpose of this report to determine sudden death following operation, radiotherapy (RT) or chemoradiotherapy (CRT) for head and neck cancer., Study Design: Retrospective, observational, single-center., Methods: Data from 729 consecutive patients diagnosed with head and neck cancer (confirmed using multiple modalities) who underwent operation, RT or CRT at Kagoshima University Hospital between April 2011, and March 2020 were analyzed. A total of 199 patients underwent operation, 223 patients underwent RT and 307 underwent CRT. 175 patients who received operation, 118 patients who received RT and 190 who received CRT had a complete response., Results: There were 13 cases of sudden death reported in 10 years. 12 were male and one was female.Sudden death occurred in 3/175 patients (1.7%) who received operation, in 4/118 patients (3.4%) who had received RT and in 6/190 (3.1%) who had received CRT., Conclusions: We present the first report on cases of sudden death after operation, RT and CRT for head and neck cancer. Otolaryngologists should still follow these patients carefully after such treatment given that sudden death does occur in some patients.

Objectives: Although many studies have shown that acupuncture can improve sleep quality, there is no clear evidence by objective physiological measures. The authors investigated the effects of acupuncture on the autonomic indices of heart rate variability (HRV) during sleep. Design: The authors applied true acupuncture and sham-site stimulations in 10 healthy adult males (mean ± standard deviation age, 40 ± 9 years) and compared autonomic nerve indices of HRV during each sleep stage in a crossover design. The sleep stages were estimated by the combined analysis of an HRV maker of non-rapid eye movement (REM) sleep (HRV sleep index [Hsi]) and actigraphic body movement. Results: Heart rate was lower (true vs. sham acupuncture, mean ± standard error of the mean, 60.9 ± 1.8 vs. 61.7 ± 1.7 bpm, p  < 0.0001) and the power of low-frequency and high-frequency components of HRV was higher (35.6 ± 2.0 vs. 34.7 ± 2.0 msec, p  = 0.04 and 26.7 ± 3.2 vs. 25.8 ± 3.2 msec, p  < 0.0001, respectively) after the true acupuncture compared with the sham-site stimulation throughout sleep. During non-REM sleep, heart rate was lower (59.6 ± 1.8 vs. 60.1 ± 1.8 bpm, p  = 0.0004) and the power of low-frequency and high-frequency components were higher (27.7 ± 1.8 vs. 26.1 ± 1.8 msec p  = 0.0004 and 28.4 ± 3.5 vs. 27.7 ± 3.5 msec, p  = 0.004) after the true acupuncture than the sham-site stimulation. Whereas during REM sleep, there was no significant difference in either HRV indices between them, while heart rate was lower after the true acupuncture than the sham-site stimulation (60.8 ± 1.6 vs. 61.7 ± 1.6 bpm, p  < 0.0001). Conclusions: Acupuncture increases parasympathetic HRV indices during sleep, especially during the non-REM stage.

Nontypeable Haemophilus influenzae (NTHi) strains form a major group of pathogenic bacteria that colonizes the nasopharynx and causes otitis media in young children. At present, there is no licensed vaccine for NTHi. Because NTHi colonizes the upper respiratory tract and forms biofilms that cause subsequent infectious events, a nasal vaccine that induces NTHi-specific secretory IgA capable of preventing biofilm formation in the respiratory tract is desirable. Here, we developed a cationic cholesteryl pullulan-based (cCHP nanogel) nasal vaccine containing the NTHi surface antigen P6 (cCHP-P6) as a universal vaccine antigen, because P6 expression is conserved among 90% of NTHi strains. Nasal immunization of mice with cCHP-P6 effectively induced P6-specific IgA in mucosal fluids, including nasal and middle ear washes. The vaccine-induced P6-specific IgA showed direct binding to the NTHi via the surface P6 proteins, resulting in the inhibition of NTHi biofilm formation. cCHP-P6 nasal vaccine thus protected mice from intranasal NTHi challenge by reducing NTHi colonization of nasal tissues and eventually eliminated the bacteria. In addition, the vaccine-induced IgA bound to different NTHi clinical isolates from patients with otitis media and inhibited NTHi attachment in a three-dimensional in vitro model of the human nasal epithelial surface. Therefore, the cCHP-P6 nanogel nasal vaccine induced effective protection in the airway mucosa, making it a strong vaccine candidate for preventing NTHi-induced infectious diseases, such as otitis media, sinusitis, and pneumonia., Competing Interests: YY and HK are directors and founders of HanaVax Inc. RN-O, S-IS, KA, and YK are scientific advisors of HanaVax Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nakahashi-Ouchida, Mori, Yuki, Umemoto, Hirano, Uchida, Machita, Yamanoue, Sawada, Suzuki, Fujihashi, Akiyoshi, Kurono and Kiyono.)

Objective: Nebulizer therapy is an effective and safe topical treatment for rhinosinusitis and is frequently used by otolaryngologists in Japan. However, treatment methods used vary among regions and according to doctors' preferences. In this study, we aimed to investigate the use of nebulizer therapy for rhinosinusitis. Administration of nebulizer therapy has been affected by the coronavirus disease 2019 (COVID-19) pandemic. Thus, we also investigated the difference in the prevalence of nebulizer use before and during the pandemic., Methods: Between February and September 2016 and in January 2021, we administered questionnaire surveys on nebulizer treatment for rhinosinusitis to otorhinolaryngologists, who were members of the Oto-Rhino-Laryngological Society of Japan, in Aomori, Saitama, Mie, Fukui, Shiga, Okayama, and Kagoshima prefectures., Results: More than 90% of the otorhinolaryngologists performed nebulizer treatment for rhinosinusitis in 2016. In April 2020 (the first wave of the COVID-19 pandemic), the use rate decreased to 20%, but in January 2021, the use rate increased to 60%. Jet nebulizers were the most frequently used type. One-third of the otolaryngologists enlarged the natural opening of the paranasal sinuses in more than half of their patients by using vasoconstrictors. Cefmenoxime and betamethasone were the most commonly used antibiotics and steroids, respectively., Conclusion: Because it is important to perform nasal pretreatment and strict disinfection of nebulizer equipment, it is clear that education of otorhinolaryngologists as well as paramedical personnel is required to ensure safe and effective use of nebulizer therapy in Japan., Competing Interests: Conflict of interest The authors have no conflict of interest to declare., (Copyright © 2021. Published by Elsevier B.V.)

The mucosal immune system prevents microorganism invasion through mucosal surfaces and consists of inductive and effector sites. Nasopharynx-associated lymphoid tissue (NALT) functions as an inductive site, inducing mucosal immune responses in the upper respiratory tract. It follows that intranasal vaccines may prevent upper respiratory infections. To induce and enhance the immune response by administering inactivated antigens intranasally, mucosal adjuvants have been developed, including mutant cholera toxin and cationic cholesteryl pullulan nanogel, which do not accumulate in the central nervous system. Moreover, multivalent pneumococcal polysaccharide conjugate vaccines are used to prevent invasive pneumococcal infections and otitis media, although they only provide moderate protection against acute otitis media because non-vaccine serotypes of Streptococcus pneumoniae and Haemophilus influenzae also cause this infection. To address this problem, pneumococcal surface protein A of S. pneumoniae and P6 of H. influenzae are used as broad-spectrum vaccine antigens. Alternatively, phosphorylcholine (PC) is present in the cell walls of both gram-positive and gram-negative bacteria and induces immune responses through antigenic activity. The significant effects of PC as a mucosal vaccine have been demonstrated through intranasal and sublingual immunization in mice. Furthermore, intranasal administration of PC reverses increases in IgE levels and prevents allergic rhinitis. After immunization with pneumococcal polysaccharide conjugate vaccine, intranasal immunization with PC boosts immune responses to vaccine strains and to PC itself. Thus, PC may be useful as a mucosal vaccine to prevent upper respiratory infections and allergic rhinitis, and it could be used as a booster to the currently used pneumococcal vaccine as it protects against non-vaccine strains., (Copyright © 2021. Published by Elsevier B.V.)