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Objectives: Vitamin D deficiency as a risk factor of tinnitus has not been well known. We tried to evaluate the association between the serum 25-(OH) vitamin D levels and tinnitus among the Korean population to propose the possible role of serum vitamin D in patients with tinnitus. Methods: This cross-sectional study investigated the potential risk factors of tinnitus in relation to serum 25(OH)D levels within the Korean population. It encompassed a health interview, nutrition assessment, and a health examination. Data was sourced from the KNHANES V (2010-2012), conducted by the Division of Health and Nutritional Survey under the Korean Centers for Disease Control and Prevention (KCDCP). Participants were chosen from various sampling units categorized by geography, gender, and age group. The selection was facilitated through household registries using a stratified, multistage, clustered probability sampling approach. Results: Data of 16 408 subjects were collected in this study. There were significant differences in gender, economic status, educational level, and sun exposure duration between the tinnitus and non-tinnitus groups. Serum 25(OH) vitamin D level between hearing loss and normal hearing was also significantly different. The logistic regression models with serum 25(OH) vitamin D quartile and tinnitus as the dependent variable, which were controlled for age, sex, smoking status, BMI, diabetes, hypertension, sun exposure, regular exercise, income, and education, eventually demonstrated that serum vitamin D deficiency and low sun exposure duration significantly increased the risk of tinnitus development. Conclusion: This study demonstrated a significant association between serum vitamin D levels and tinnitus, driven by large epidemiological data. The results of our study provide baseline data for further research to investigate the role of vitamin D in the pathogenesis and management of tinnitus. [ABSTRACT FROM AUTHOR]

Despite the remarkable progress in the development of sweat sensors, self‐powered sweat‐responsive sensing displays that detect sweat in electric signals with simultaneous and direct visualization of the sweat is rarely demonstrated. Here, a self‐powered sweat‐responsive structural color (SC) display enabled by ionomer‐doped block copolymer (BCP) photonic crystals (PCs) is presented. The sweat‐responsive BCP PC is developed by employing a cross‐linking single‐mobile ionomer (SMI) with mobile anions anchored to immobile polycations to a 1‐D BCP PC. The hydrophobic SMI‐doped BCP PC is mechanically robust as well as water and temperature‐resistive, exhibiting ionomer concentration‐dependent full visible SCs. Moreover, the mobile anions periodically confined in the SMI‐doped BCP PC harvest triboelectric energy, giving rise to a high‐power density of ≈0.774 Mw cm−2. Cation‐sensitive SC variation is observed in the SMI‐doped BCP PC, allowing the visualization of sweat containing various cations. A skin‐patchable self‐powered sweat‐responsive display is demonstrated in which kirigami‐patterned SMI‐doped BCP PC incorporated in the display can withstand up to 50% strain during exercise. Sweat from the exercise is visualized via SC display and measured using both ionic resistance changes and triboelectric signals. In addition, the integration of sweat sensing membrane into SMI‐doped BCP PC enables the quantification of sweat. [ABSTRACT FROM AUTHOR]

Liquid-free ionic conductors, known as ionoelastomers, are of great interest because of their potential for developing reliable and resilient ionic devices with elastic mechanical properties. This study presents an intrinsically stretchable diode consisting of a highly stretchable ionoelastomer bilayer vertically stacked with liquid metal electrodes. The bilayer contains two types of ionoelastomer networks: one containing fixed anions with mobile cations and one containing fixed cations with mobile anions. Both ionoelastomers use 2-hydroxyethyl acrylate to provide high stretchability. The junction between the two ionoelastomers creates a diode with excellent non-Faradaic ionic current rectification. The voltage-dependent modulation of the ionic double layer at the interface between the two ionoelastomers provides the rectification. The elastic diode works under cyclic loading to a uniaxial stretch ratio of 6 (strain of 500%), allowing the development of a highly stretchable ionic OR logic gate. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to investigate current perception and expected price of personal sound amplification products (PSAPs) and to analyze influencing factors through multi-center hospital-based surveys of outpatients, caregivers, and hearing experts. Methods: A multi-center exploratory cross-sectional study was conducted in two groups of respondents with two separate surveys: 1) a perception survey of patients and caregivers who visited an otorhinolaryngology outpatient clinic in 5 general hospitals and 2) an opinion survey of hearing specialists about the expected price of PSAPs. A total of 197 outpatient visitors responded to the perception survey, and 42 hearing specialists responded to the opinion survey. Results: Overall perception score (18 questions) was 3.04 (95% CI, 3.00–3.09). When 5 categories of perception (knowledge, needs, cost, expectation, and information categories) were analyzed, cost and expectation showed the highest scores of 3.33 (95% CI, 3.21–3.44) and 3.33 (95% CI, 3.27–3.40), respectively, and needs showed the lowest score of 2.23 (95% CI, 1.97–2.49). The ≥ 60-year-old group showed significantly higher perception of PSAPs (P = 0.002), and the individuals with greater severity of subjective hearing loss showed significantly higher perception of PSAPs (P = 0.002). The expected price of PSAPs of the outpatient visitors was 933.9 USD (95% CI, 811.9–1056.0) per ear. Mean expected price of PSAPs of hearing specialists was 291.3 USD (95% CI, 238.2–344.3) per ear. Conclusion: The perception rate of PSAPs was very low, and there was a discrepancy in the expected price of PSAPs between patients/caregivers and hearing experts. Hearing specialists should make effort to improve perception of PSAPs. [ABSTRACT FROM AUTHOR]

5‐Aryl‐substituted (piperdin‐4‐yl)pyrimidine‐2,4‐diamine derivatives were synthesized and their inhibitory activities were evaluated against TAM kinase (Tyro3, Axl, Mer), respectively. Detailed SAR studies on the fifth position of pyrimidine could lead to the discovery of potent and selective TAM kinase inhibitor. Compounds 6f, 7b, and 7f exhibited potent inhibitory activity and excellent selectivity toward Axl, Tyro3 and Mer kinases. Molecular docking studies corroborated that slight changes of substituents induced dramatic structural change of Met596, 623, 674 backbone carbonyl and amide in the hinge region of Axl, Tyro3, Mer, and resulted in different binding poses of 6f, 7b, and 7f, respectively. It was identified as a strong possibility to control selectivity by structural modification of phenyl substituents of pyrimidine as a new class of TAM kinase inhibitors. [ABSTRACT FROM AUTHOR]

Objective: We assessed the diagnostic accuracy of sentinel lymph node biopsy (SLNB) for detecting neck nodal metastasis in early oral squamous cell carcinoma (OSCC) as an alternative to elective neck dissection.Study Design: A systematic search for relevant literature was conducted in the PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases.Methods: Two reviewers individually searched the five databases up to November 2019. For studies that met inclusion criteria, data on patient diagnoses were pooled, including true positives, true negatives, false positives, and false negatives. Methodological quality was checked with the Quality Assessment of Diagnostic Accuracy Studies (version 2) tool.Results: In total, 98 observational or retrospective studies were included. The diagnostic odds ratio of SLNB was 326.165 (95% confidence interval [CI]: 231.477-459.587; I2  = 0%). The area under the summary receiver operating characteristic curve was 0.982. Sensitivity was 0.827 (95% CI: 0.804-0.848), and specificity was 0.981 (95% CI: 0.975-0.986). The correlation between sensitivity and the false positive rate was -0.076, which indicates that heterogeneity did not exist. Subgroup analyses were performed with the subgroups reference test type, publication year, and study type. No significant difference was found within the reference test type subgroup. However, differences within the publication year and study type subgroups were significant, where the retrospective study subgroup was significantly more sensitive and specific than the prospective study subgroup.Conclusion: Results of this meta-analysis imply that the high specificity of SLNB supports its role as a diagnostic tool for patients with clinical tumor stage (CT)1-2 clinically negative (N0) OSCC. More studies should be done to further verify the results of this study.Level Of Evidence: 2a Laryngoscope, 131:E459-E465, 2021. [ABSTRACT FROM AUTHOR]

We evaluated the diagnostic accuracy of narrowband imaging (NBI) in terms of detecting laryngeal cancer compared to that of white light endoscopy (WLE). Two reviewers individually searched the six databases for studies published between the first record date and December 31, 2019. We recorded the numbers of true positives, true negatives, false positives, and false negatives. Quality Assessment of Diagnostic Accuracy Studies ver. 2 software was used to assess the studies. The extent of the inter‐rater agreement was also measured. The diagnostic odds ratio (OR) associated with NBI was 87.463 (95% confidence interval [CI]: 46.968, 160.873). The area under the summary receiver operating characteristic curve was 0.954. NBI was more diagnostically accurate than WLE, which was associated with a diagnostic OR of 13.750. NBI affords high diagnostic accuracy, thus supporting a role for NBI in the diagnostic work‐up of laryngeal cancer. [ABSTRACT FROM AUTHOR]

Objective: To examine the effect of xylitol nasal irrigation in a large sample size of patients who had undergone nasal surgery.Study Design: Double-blinded randomized controlled crossover study.Setting: Tertiary referral center.Methods: The study included 100 patients with sinonasal disease who underwent endoscopic sinus surgery (ESS), septoplasty, or both concurrently. To identify patients with allergic sensitization, serum-specific immunoglobulin E levels were measured. Nasal symptoms were evaluated with the NOSE (Nasal Obstruction Symptoms Evaluation) and SNOT-20 (Sino-Nasal Outcome Test-20) and via visual analog scale (VAS) scores.Results: In the ESS group (n = 34), the general nasal symptom score evaluated by the SNOT-20 showed significantly greater improvement in the xylitol group versus the saline group ( P = .022). VAS symptom scores for sneezing ( P = .003), headache ( P = .02), and facial pain ( P = .037) were also more improved in the xylitol group. In the septoplasty group (n = 39), the VAS score for nasal stuffiness showed a significantly greater improvement in the xylitol group when compared with the saline irrigation group ( P = .001). Among the patients with allergic sensitization (n = 31), rhinorrhea symptoms improved significantly more in the xylitol group than in the saline group ( P = .024). The preference survey showed that more than half of the patients in each surgical group preferred xylitol irrigation.Conclusion: We found that xylitol nasal irrigation was useful in postoperative ESS and septoplasty care. For patients with allergic sensitization, rhinorrhea showed greater improvement in the xylitol group than in the saline group. [ABSTRACT FROM AUTHOR]

Due to high demand but limited supply, there has been an increase in the need to replace autologous bone grafts with alternatives that fulfill osteogenic requirements. In this study, two different types of bone grafts were tested for their drug carrying abilities along with their osteogenic properties. Two different types of alendronate-loaded bone grafts, Bio-Oss (bovine bone graft) and InRoad (biphasic synthetic bone graft) were observed to see how different concentrations of alendronate would affect the sustained release to enhance osteogenesis. In this study, defected ovariectomize-induced osteoporotic rat calvarias were observed for 28 days with three different concentrations of alendronate (0 mg, 1 mg, 5 mg) for both Bio-Oss and InRoad. A higher concentration (5 mg) allowed for a more controlled and sustained release throughout the 28-day comparison to those of lower concentrations (0 mg, 1 mg). When comparing Bio-Oss and InRoad through histology and Micro-CT, InRoad showed higher enhancement in osteogenesis. Through this study, it was observed that alendronate not only brings out robust osteogenesis with InRoad bone grafts, but also enhances bone regeneration in an alendronate-concentration-dependent manner. The combination of higher concentration of alendronate and multiple porous bone graft containing internal micro-channel structure of InRoad resulted in higher osteogenesis with a sustained release of alendronate. [ABSTRACT FROM AUTHOR]

In this paper, we studied the mechanism of the triglyceride (TG)‐lowering effect of kaempferol in vitro and in vivo. Kaempferol showed LXR agonistic activities without inducing TGs or the expression of several lipogenic genes in cultured cells. A luciferase and qPCR analysis showed that kaempferol increased the transactivation of PPARα and PPARδ and stimulated gene expression associated with fatty acid oxidation and uptake in hepatocytes. More importantly, kaempferol inhibited protein kinase B (Akt) activity and suppressed SREBP‐1 activation via multiple mechanisms, including through increasing Insig‐2a expression, reducing SREBP‐1 phosphorylation, and increasing GSK‐3 phosphorylation. Collectively, these actions inhibited the SREBP‐1 activation process. Furthermore, as an Akt/mTOR pathway inhibitor, kaempferol led to the induction of hepatic autophagy and resulted in a decrease in lipid droplet formation in the mouse liver. These findings demonstrate that kaempferol exerts its TG‐lowering effect via Akt inhibition and activation of PPARα and PPARδ. Practical applications: Kaempferol is a major dietary flavonoid in various plant‐based foods, and it is used as a valuable ingredient in functional foods, with numerous beneficial properties such as anticancer, antioxidant, and anti‐atherosclerotic activities. Kaempferol exerts its TG‐lowering effect via Akt inhibition and activation of PPARα and PPARδ. Currently, the number of people with hyperlipidemia is rapidly growing in both developed and developing societies; thus, we propose that kaempferol could be used for therapeutic interventions aimed at the treatment of these individuals. [ABSTRACT FROM AUTHOR]

Olfactory receptors (ORs) comprise the largest G protein-coupled receptor gene superfamily. Recent studies indicate that ORs are also expressed in non-olfactory organs, including metabolically active tissues, although their biological functions in these tissues are largely unknown. In this study, OR1A1 expression was detected in HepG2 liver cells. OR1A1 activation by (−)-carvone, a known OR1A1 ligand, increased the cyclic adenosine monophosphate (cAMP), but not intracellular Ca 2+ concentration, thereby inducing protein kinase A (PKA) activity with subsequent phosphorylation of cAMP response element-binding protein (CREB) and upregulation of the CREB-responsive gene hairy and enhancer of split (HES)-1, a corepressor of peroxisome proliferator-activated receptor-γ (PPAR-γ) in hepatocytes. In (−)-carvone-stimulated cells, the repression of PPAR-γ reduced the expression of the target gene, mitochondrial glycerol-3-phosphate acyltransferase, which encodes a key enzyme involved in triglyceride synthesis. Intracellular triglyceride level and lipid accumulation were reduced in cells stimulated with (−)-carvone, effects that were diminished following the loss of OR1A1 function. These results indicate that OR1A1 may function as a non-redundant receptor in hepatocytes that regulates the PKA-CREB-HES-1 signaling axis and thereby modulates hepatic triglyceride metabolism. [ABSTRACT FROM AUTHOR]

Background: Hearing rehabilitation with auditory training (AT) is necessary to improve speech perception ability in patients with hearing loss. However, face-to-face AT has not been widely implemented due to its high cost and personnel requirements. Therefore, there is a need for the development of a patient-friendly, mobile-based AT program., Objective: In this study, we evaluated the effectiveness of hearing rehabilitation with our chat-based mobile AT (CMAT) program for speech perception performance among experienced hearing aid (HA) users., Methods: A total of 42 adult patients with hearing loss who had worn bilateral HAs for more than 3 months were enrolled and randomly allocated to the AT or control group. In the AT group, CMAT was performed for 30 minutes a day for 2 months, while no intervention was provided in the control group. During the study, 2 patients from the AT group and 1 patient from the control group dropped out. At 0-, 1- and 2-month visits, results of hearing tests and speech perception tests, compliance, and questionnaires were prospectively collected and compared in the 2 groups., Results: The AT group (n=19) showed better improvement in word and sentence perception tests compared to the control group (n=20; P=.04 and P=.03, respectively), while no significant difference was observed in phoneme and consonant perception tests (both P>.05). All participants were able to use CMAT without any difficulties, and 85% (17/20) of the AT group completed required training sessions. There were no changes in time or completion rate between the first and the second month of AT. No significant difference was observed between the 2 groups in questionnaire surveys., Conclusions: After using the CMAT program, word and sentence perception performance was significantly improved in experienced HA users. In addition, CMAT showed high compliance and adherence over the 2-month study period. Further investigations are needed to validate long-term efficacy in a larger population., Trial Registration: Clinical Research Information Service (CRiS) KCT0006509; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=22110&search_page=L., (© Jae Sang Han, Ji Hyung Lim, Yeonji Kim, Aynur Aliyeva, Jae-Hyun Seo, Jaehyuk Lee, Shi Nae Park. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org).)

Backgruound: The preventative effect of melatonin on the development of obesity and the progression of fatty liver under a high-fat diet (HFD) has been well elucidated through previous studies. We investigated the mechanism behind this effect regarding cholesterol biosynthesis and regulation of cholesterol levels., Methods: Mice were divided into three groups: normal chow diet (NCD); HFD; and HFD and melatonin administration group (HFD+M). We assessed the serum lipid profile, mRNA expression levels of proteins involved in cholesterol synthesis and reabsorption in the liver and nutrient transporters in the intestines, and cytokine levels. Additionally, an in vitro experiment using HepG2 cells was performed., Results: Expression of hepatic sterol regulatory element-binding protein 2 (SREBP-2), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), and low-density lipoprotein receptor (LDLR) demonstrated that melatonin administration significantly reduces hepatic cholesterol synthesis in mice fed an HFD. Expression of intestinal sodium-glucose transporter 1 (SGLT1), glucose transporter 2 (GLUT2), GLUT5, and Niemann-pick C1-like 1 (NPC1L1) demonstrated that melatonin administration significantly reduces intestinal carbohydrate and lipid absorption in mice fed an HFD. There were no differences in local and circulatory inflammatory cytokine levels among the NCD, HFD, and HFD+M group. HepG2 cells stimulated with palmitate showed reduced levels of SREBP, LDLR, and HMGCR indicating these results are due to the direct mechanistic effect of melatonin on hepatocytes., Conclusion: Collectively, these data indicate the mechanism behind the protective effects of melatonin from weight gain and liver steatosis under HFD is through a reduction in intestinal caloric absorption and hepatic cholesterol synthesis highlighting its potential in the treatment of obesity and fatty liver disease.

African swine fever (ASF), a highly contagious and severe hemorrhagic viral disease in swine, is emerging as a major threat not only in Korea but also worldwide. The first confirmed case of ASF in Korea was reported in 2019. Despite the occurrence of ASF in Korea, only a few studies have genetically characterized the causative ASF virus (ASFV). In this study, we aimed to genetically characterize the ASFV responsible for the 2019 outbreak in Korea. The genome of the ASFV isolated during the first outbreak in Korea was analyzed. The Korea/YC1/2019 strain has 188,950 base pairs, with a GC content of 38.4%. The complete genome sequence was compared with other ASFV genomes annotated in the NCBI database. The Korea/YC1/2019 strain shared the highest similarity with Georgia 2007, Belgium 2018/1, and ASFV-wbBS01 strains. This study expands our knowledge of the genetic diversity of ASFV, providing valuable information for epidemiology, diagnostics, therapies, and vaccine development., Competing Interests: The 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 © 2023 Kim, Park, Kim, Kim, Kim, Kim and Jheong.)

Background: Immunological contexture differs across malignancies, and understanding it in the tumor microenvironment (TME) is essential for development of new anticancer agents in order to achieve synergistic effects with anti-programmed cell death protein-1 (PD-1) therapy. TYRO3, AXL, and MERTK receptors are bi-expressed in both cancer and immune cells, and thus emerge as promising targets for therapeutic intervention. Whereas AXL and MERTK have been extensively studied, the role of TYRO3, in the TME, is still undetermined., Methods: Here, we screened the TYRO3-focused chemical library consisting of 208 compounds and presented a potent and highly selective TYRO3 inhibitor, KRCT87. We explored the role of TYRO3 using mouse engrafting MC38 or 4T1 tumors. We validated the results using flow cytometry, RNA sequencing analysis, gene knockdown or overexpression, ex vivo immune cells isolation from mouse models, immunoblotting and quantitative PCR. Flow cytometry was used for the quantification of cell populations and immunophenotyping of macrophages and T cells. Co-cultures of macrophages and T cells were performed to verify the role of CCN1 in the tumors., Results: TYRO3 blockade boosts antitumor immune responses in both the tumor-draining lymph nodes and tumors in MC38-syngeneic mice models. Moreover, the combination of KRCT87 and anti-PD-1 therapy exerts significant synergistic antitumor effects in anti-PD-1-non-responsive 4T1-syngeneic model. Mechanistically, we demonstrated that inhibition of TYRO3-driven CCN1 secretion fosters macrophages into M1-skewing phenotypes, thereby triggering antitumor T-cell responses. CCN1 overexpression in MC38 tumors diminishes responsiveness to anti-PD-1 therapy., Conclusions: The activated TYRO3-CCN1 axis in cancer could dampen anti-PD-1 therapy responses. These findings highlight the potential of TYRO3 blockade to improve the clinical outcomes of anti-PD-1 therapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Liquid mobility is ubiquitous in nature, with droplets emerging at all size scales, and artificial surfaces have been designed to mimic such mobility over the past few decades. Meanwhile, millimeter-sized droplets are frequently used for wettability characterization, even with facial mask applications, although these applications have a droplet-size target range that spans from millimeters to aerosols measuring less than a few micrometers. Unlike large droplets, microdroplets can interact sensitively with the fibers they contact with and are prone to evaporation. However, wetting behaviors at the single-microfiber level remain poorly understood. Herein, we characterized the wettability of fibrous layers, which revealed that a multiscale landscape of droplets ranged from the millimeter to the micrometer scale. The contact angle (CA) values of small droplets on pristine fibrous media showed sudden decrements, especially on a single microfiber, owing to the lack of air cushions for the tiny droplets. Moreover, droplets easily adhered to the pristine layer during droplet impact tests and then yielding widespread areas of contamination on the microfibers. To resolve this, we carved nanowalls on the pristine fibers by plasma etching, which effectively suppressed such wetting phenomena. Significantly, the resulting topographies of the microfibers managed the dynamic wettability of droplets at the multiscale, which reduced the probability of contamination with impact droplets and suppressed the wetting transition upon evaporation. These findings for the dynamic wettability of fibrous media will be useful in the fight against infectious droplets.

Alpha-lipoic acid (ALA) is an antioxidant with oto-protective effects. In the present study, the safety and effectiveness of ALA therapy after noise-induced hearing loss was confirmed based on the administration method. The safety of intratympanic ALA (IT-ALA) was evaluated with oto-endoscopy and middle ear mucosa morphologic study. Perilymph ALA concentrations according to the administration routes were compared, and the efficacy of ALA was investigated through hearing tests and cochlear histological studies. The middle ear mucosa was swollen 1 week after IT-ALA but completely recovered within 3 weeks. ALA concentration in the perilymph was significantly higher in the IT-ALA group. Recovery of organ of Corti morphology and hearing levels were predominant in the IT-ALA group compared with the intraperitoneal injection group (IP-ALA) and showed similar rescue effects in the IT-dexamethasone group (IT-DEX). Interleukin-1 beta and nuclear factor-kappa B expression was significantly downregulated in the IT-ALA group. IT-ALA showed better cochlear recovery from acoustic trauma with higher inner ear penetration rate than IP-ALA. The rescue effect of IT-ALA after noise-induced hearing loss was similar to IT-DEX; however, the ALA and DEX mechanisms are different. IT-ALA appears to be another safe and effective treatment modality after acoustic trauma and comparable to IT-DEX.

Objectives: Despite sufficient hearing gains, many patients with hearing loss have difficulty using hearing aids due to poor word recognition ability. This study was performed to introduce our hearing rehabilitation therapy (HRT) program for hearing aid users and to evaluate its effect on hearing improvement., Methods: In this prospective randomized case-control study, 37 participants with moderate or moderate-severe sensorineural hearing loss who had used bilateral hearing aids for more than 3 months with sufficient functional hearing gain were enrolled in this study. Nineteen participants were randomly assigned to the control group (CG) and 18 patients were assigned to participate in our HRT program once a week for 8 consecutive weeks (hearing rehabilitation therapy group [HRTG]). Their hearing results and questionnaire scores for hearing handicap and hearing aid outcomes were prospectively collected and compared between the two groups., Results: After completing 8 weeks of the HRT program, the HRTG showed a significantly greater improvement in scores for consonant-only and consonant-vowel sound perception than the CG (P<0.05). In addition, the HRTG showed a significant improvement in hearing ability as measured by two questionnaires (p<0.05), while no differences were observed in the CG. However, word and sentence recognition test results did not show significant differences between the two groups., Conclusion: Even after short-term HRT, patients had subjectively better hearing outcomes and improved phoneme perception ability; this provides scientific evidence regarding a possible positive role for HRT programs in hearing aid users. Further validation in a larger population through a long-term follow-up study is needed.

Extracellular vesicles (EV) in the tumor microenvironment have emerged as crucial mediators that promote proliferation, metastasis, and chemoresistance. However, the role of circulating small EVs (csEV) in cancer progression remains poorly understood. In this study, we report that csEV facilitate cancer progression and determine its molecular mechanism. csEVs strongly promoted the migration of cancer cells via interaction with phosphatidylserine of csEVs. Among the three TAM receptors, TYRO3, AXL, and MerTK, TYRO3 mainly interacted with csEVs. csEV-mediated TYRO3 activation promoted migration and metastasis via the epithelial-mesenchymal transition and stimulation of RhoA in invasive cancer cells. Additionally, csEV-TYRO3 interaction induced YAP activation, which led to increased cell proliferation and chemoresistance. Combination treatment with gefitinib and KRCT-6j, a selective TYRO3 inhibitor, significantly reduced tumor volume in xenografts implanted with gefitinib-resistant non-small cell lung cancer cells. The results of this study show that TYRO3 activation by csEVs facilitates cancer cell migration and chemoresistance by activation of RhoA or YAP, indicating that the csEV/TYRO3 interaction may serve as a potential therapeutic target for aggressive cancers in the clinic. SIGNIFICANCE: These findings demonstrate that circulating extracellular vesicles are a novel driver in migration and survival of aggressive cancer cells via TYRO3 activation. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/13/3539/F1.large.jpg., (©2021 American Association for Cancer Research.)

Endoscopic sinus and skull base surgeries are minimally invasive surgical techniques that reduce postoperative symptoms and complications and enhance patients' quality of life. However, to ensure excellent surgical outcomes after such interventions, intimate familiarity with important landmarks and high-level endoscope manipulation skills are essential. Cadaver training is one possible option, but cadavers are expensive, scarce, and nonreusable and cadaver work requires specialized equipment and staff. In addition, it is difficult to mimic specific diseases using cadavers. Virtual reality simulators can create a computerized environment in which the patient's anatomy is reproduced and interaction with endoscopic handling and realistic haptic feedback is possible. Moreover, they can be used to present scenarios that improve trainees' skills and confidence. Therefore, virtual simulator training can be implemented at all levels of surgical education. This review introduces the current literature on virtual reality training for endoscopic sinus and skull base surgeons, and discusses the direction of future developments.