Background Cisplatin-induced ototoxicity represents a major dose-limiting adverse effect of chemotherapy, leading to irreversible sensorineural hearing loss. Astragaloside IV (AS-IV), a bioactive saponin derived from Astragalus membranaceus, exhibits potent antioxidant and cytoprotective properties in various pathological settings. This study aimed to elucidate the protective effects and underlying mechanisms of AS-IV in cisplatin-induced cochlear injury. Methods In vitro, HEI-OC1 cells, cochlear basilar membrane explants, and spiral ganglion neurons were treated with cisplatin in the presence or absence of AS-IV pretreatment. Cell viability, ATP production, ROS accumulation, mitochondrial membrane potential, and apoptosis were assessed using CCK-8, EdU incorporation, flow cytometry, immunofluorescence, and TUNEL staining. Mitochondrial DNA (mtDNA) copy number was quantified by qPCR, and exogenous mitochondrial transplantation was performed to confirm functional relevance. The potential involvement of the Nrf2 pathway was predicted by network pharmacology and validated by qPCR, Western blotting, and pharmacological inhibition. Results AS-IV markedly improved cell viability without influencing proliferation, and effectively preserved cochlear hair cells and spiral ganglion neurons against cisplatin-induced injury. Mechanistically, AS-IV attenuated mitochondrial dysfunction by reducing ROS overproduction, maintaining mitochondrial membrane potential, and restoring ATP synthesis. Importantly, AS-IV activated the Nrf2/HO-1/NQO1 signaling axis, whereas pharmacological inhibition of Nrf2 abrogated its protective effects. Conclusion Our in vitro data demonstrate that AS-IV protects cochlear cells and neurites against cisplatin-induced damage by maintaining mitochondrial integrity and activating the Nrf2-dependent antioxidant pathway. These findings highlight AS-IV as a potential therapeutic candidate for preventing chemotherapy-related hearing loss and provide novel mechanistic insight into mitochondrial preservation as a strategy for otoprotection.

Schizantherin B (SNB), a key bioactive ingredient of the Chinese traditional medicine Schisandra chinensis, possesses anti-inflammatory and antioxidant properties. Cisplatin (CDDP) is typically used to treat various malignant tumors, however, its clinical utility is often limited by significant off-target toxicities, most notably irreversible hearing loss. Various strategies have been explored to mitigate this side effect. In this study, we investigated the protective effects of SNB against cisplatin-induced hearing loss(CIHL) as a potential preclinical therapeutic strategy. Firstly, in the ex-vivo basilar membrane, we found that SNB alleviated CDDP-induced loss of hair cells, cochlear spiral ganglion cells, and ribbon synapses. Secondly, in vivo experiments showed that SNB protected animals against CHL, returning their response close to normal level. Thirdly, in multiple tumor cell lines, we found SNB did not interfere with CDDP’s anti-tumor effects. Consistently, in a mouse model for breast cancer, we found that SNB did not obtrude CDDP’s effects in reducing tumor mass. Finally, in examining the molecular mechanisms, we found that SNB reduced both oxidative stress and cell apoptosis in the auditory cell line of HEI-OC1 during CDDP treatment, likely through the Bcl-2/Bax/cleaved-Caspase-3 signal pathways. Collectively, our study demonstrated that SNB mitigates CIHL without interfering with its therapeutic effects in treating cancer, suggesting that SNB is a potential drug candidate for preventing CIHL in cancer patients.

Cycloastragenol protects cochlear hair cells against cisplatin-induced ototoxicity by preserving mitochondrial function, suppressing apoptosis, and activating the PI3K/Akt/mTOR signaling pathway. These findings highlight the potential of CAG as a therapeutic candidate for preventing cisplatin-induced hearing loss. CAG significantly improved cell viability and reduced cisplatin-induced apoptosis in cochlear hair cells, as demonstrated by decreased TUNEL positivity, reduced apoptotic rates, and modulation of apoptosis-related proteins. CAG also preserved hair-cell marker expression and maintained cochlear hair-cell morphology. Furthermore, CAG restored mitochondrial function by increasing ATP production, maintaining ΔΨm, reducing ROS accumulation, and enhancing respiratory chain complex activities, while preventing mitochondrial fragmentation. In vivo, CAG markedly attenuated cisplatin-induced hearing loss, as indicated by improved ABR thresholds. Mechanistically, CAG activated the PI3K/Akt/mTOR signaling pathway, and inhibition of this pathway abolished its protective effects. Cisplatin-induced ototoxicity, a major adverse effect of chemotherapy, results in irreversible sensorineural hearing loss primarily due to apoptotic loss of cochlear sensory hair cells. Cycloastragenol (CAG), a naturally occurring triterpenoid saponin derived from Astragalus, possesses antioxidant and anti-apoptotic properties. However, its potential protective effects against cisplatin-induced cochlear injury and the underlying mechanisms remain unclear. HEI-OC1 cells, cochlear explant cultures (including the ex vivo cochlear explant model), and a mouse model were used to evaluate the protective effects of CAG against cisplatin-induced ototoxicity. Cell viability was assessed using the CCK-8 assay, while apoptosis was evaluated by TUNEL staining, flow cytometry, and Western blotting of apoptosis-related proteins. Hair-cell markers (Myo7a and Prestin) and cochlear hair-cell morphology were examined by immunofluorescence staining. Mitochondrial function was assessed by measuring ATP levels, mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS), and respiratory chain complex activities, along with mitochondrial morphology analysis using immunofluorescence and transmission electron microscopy. Auditory function in mice was evaluated by auditory brainstem response (ABR) measurements. The involvement of the PI3K/Akt/mTOR pathway was analyzed by Western blotting and inhibition assays using the PI3K inhibitor LY294002.

Background Accurate preoperative identification of pathologic extranodal extension (ENE) at CT is essential for precise treatment decisions in laryngeal and hypopharyngeal squamous cell cancer (LHSCC). However, human interpretation of ENE is neither reliable nor reproducible. Purpose To develop and evaluate the diagnostic performance of a new deep learning tool, DeepENE, in detecting metastatic and ENE lymph nodes on preoperative CT scans in patients with LHSCC in a multicenter cohort. Materials and Methods In this retrospective study, patients with LHSCC from Zhongshan Hospital, Fudan University (April 2011-August 2022), were included in training, validation, and internal test sets to develop DeepENE. For the reference standard, lymph nodes were segmented on CT scans and labeled for metastasis and ENE status based on pathologic findings. DeepENE was tested using three external cohorts of patients with LHSCC (external test sets 1-3) and one external cohort of patients with oral squamous cell carcinoma. The primary diagnostic metric was the area under the receiver operating characteristic curve (AUC). The performance of DeepENE was compared with that of five board-certified head and neck cancer specialists using the DeLong method. Results Overall, 289 patients with LHSCC with 1954 pathologically confirmed lymph nodes were evaluated. DeepENE achieved an AUC of 0.93 for ENE diagnosis in the internal test set under fivefold cross-validation, and AUCs of 0.96, 0.87, and 0.90 in external test sets 1, 2, and 3, respectively. DeepENE outperformed the five experts, especially in early-stage ENE detection in external test set 2 (AUC of 0.87 for DeepENE vs mean AUC of 0.66 for readers; P < .001). In external test set 1, DeepENE maintained a high sensitivity of 97% at specificity of 90%, compared with experts' mean sensitivity of 77% (P = .003). In external test sets 2 and 3, DeepENE had sensitivity of 78% and 80%, compared with experts' mean sensitivity of 36% (P < .001) and 46% (P < .001), respectively. Conclusion DeepENE accurately detected ENE on preoperative CT scans in patients with LHSCC and outperformed head and neck cancer specialists. © RSNA, 2026 Supplemental material is available for this article.

Background: Cisplatin-induced ototoxicity (CIO) causes irreversible sensorineural hearing loss in 40–80% of treated patients, yet no FDA-approved otoprotectant currently exists to prevent this dose-limiting toxicity. Mitoxyperilysis—mitochondrial oxidative membrane rupture governed by BAX, BAK1, BID, and mTORC2 (Wang et al., Cell 2025)—is a novel, mechanistically distinct form of regulated cell death whose role in cochlear injury has not previously been characterised. Methods: Three GEO datasets (GSE136196, GSE165662, GSE281324) comprising 9,678 stria vascularis (SV) cells across four experimental conditions (adult chronic cisplatin/control; P6 acute cisplatin/control) were integrated employing Harmony batch-effect correction and UMAP dimensionality reduction. Mitoxyperilysis pathway scores were computed per cell. Differential expression analysis, followed by LASSO-regularised logistic regression, Random Forest classification (n_estimators=500; 5-fold cross-validation), and WGCNA co-expression network analysis, were subsequently applied to identify 20 SV hub genes. Network pharmacology queries against DrugBank v5.1.11 and STITCH v5.0 prioritised otoprotective candidates. Structural validation of the dominant hub gene was conducted via 100 ns all-atom molecular dynamics (MD) simulation (CHARMM36m force field; POPC/POPE bilayer) and AutoDock Vina 2026 molecular docking. Results: The integrated SV atlas comprised 9,678 cells annotated into four subpopulations: Marginal Cells (n=3,064), Intermediate Cells (n=2,055), Basal Cells (n=2,308), and Fibrocytes (n=2,251). Adult SV Mitoxyperilysis scores declined from Ctrl_Chronic (0.447) to Cis_Chronic (0.266), reflecting survivor-bias depletion of pathway-executing cells. mt-Nd4l ranked first in Random Forest feature importance (importance=0.0731), and the prognostic model achieved AUC=0.938 (Random Forest) and AUC=0.921 (LASSO-LR). Marginal Cells exhibited the highest median cisplatin risk score (~0.65). Network pharmacology prioritised Rifampicin, Rapamycin, and Idebenone as otoprotective candidates; Idebenone provided dual targeting of MT-ND4L and COX20. MD simulation confirmed transmembrane helical stability (backbone RMSD=6.42±0.83 Å; Rg=23.76±0.75 Å). Idebenone docking demonstrated binding at the Complex I/ND4L membrane interface (ΔG=−4.007 kcal/mol). Conclusions: This study presents the first computational application of Mitoxyperilysis to CIO, integrating multi-dataset single-cell transcriptomics with machine learning, network pharmacology, and structural biology. Collectively, the findings provide a mechanistic framework centred on mt-Nd4l and the respiratory chain for otoprotective drug development, with Rifampicin, Rapamycin, and Idebenone identified as prioritised candidates warranting experimental validation.

Background: Endoscopic submucosal dissection (ESD) has recently been reported as an alternative to open surgery for superficial hypopharyngeal cancer. This retrospective analysis compared outcomes between patients treated with ESD and those undergoing open surgery, with a particular focus on long-term efficacy. Methods: This was a single-center retrospective cohort study. Patients who underwent ESD or partial/total laryngectomy for hypopharyngeal squamous cell carcinoma between April 2015 and December 2020 were retrospectively analyzed. Long-term outcomes were compared between the two groups. Results: A total of 49 patients with hypopharyngeal cancer, with a median follow-up of 61 months (range 52-82), were included. Twenty patients underwent ESD, and 29 underwent open surgery. Inverse probability of treatment weighting (IPTW) based on propensity scores was used to equilibrate T stages across both cohorts. After IPTW adjustment, the R0 resection rates were 75.9% in the ESD group and 90.0% in the surgery group (P = 0.249). Compared with surgery, ESD was associated with a significantly shorter hospitalization (median 4 vs. 18 days, P < 0.001), as well as lower incidences of tracheal fistula and vocal cord dysfunction. The 5-year progression-free survival rate was identical in both groups at 65.5% (P = 0.916). Conclusion: ESD represents a viable therapeutic alternative for superficial hypopharyngeal cancers, offering superior quality-of-life outcomes compared with conventional surgery, without compromising long-term survival. Copyright (c) 2025, Society of Gastrointestinal Intervention.

Objective To investigate the value of artificial intelligence-assisted compressed sensing(ACS)technology for intravenous gadolinium contrast-enhanced magnetic resonance imaging of the inner ear using three-dimensional fluid-attenuated inversion recovery(3D-FLAIR)sequence.Methods The patients received gadolinium contrast-enhanced magnetic resonance imaging using ACS and united compressed sensing(uCS)3D-FLAIR at Zhongshan Hospital,Fudan University from January to November 2024 were prospectively enrolled.The repetition time was 16000 ms,and acquisition time was 6 min 40 s and 10 min 24 s in ACS 3D-FLAIR and uCS 3D-FLAIR,respectively.The images on the two sequences were evaluated independently by two radiologists.The image quality of the two sequences was subjectively evaluated and compared.The signal-to-noise ratio(SNR)and contrast-to-noise ratio(CNR)were compared between the two sequences.The grading consistencies using two sequences and between the two doctors were analyzed.Results There was no statistically difference in subjective score of image quality between the two sequences.SNR and CNR of the ACS 3D-FLAIR sequence were significantly higher than those of the uCS 3D-FLAIR sequence(P<0.001).The kappa values of grades of cochlear and vestibular endolymphatic hydrops were 0.942 and 0.888 using two sequences(P<0.001).The kappa values of grades of cochlear and vestibular endolymphatic hydrops using the ACS 3D-FLAIR sequence between the two doctors were 0.784 and 0.831,respectively(P<0.001);the kappa values of grades of cochlear and vestibular endolymphatic hydrops using uCS 3D-FLAIR sequence between the two doctors were 0.725 and 0.756,respectively(P<0.001).Conclusions ACS 3D-FLAIR could provide higher SNR and CNR than uCS 3D-FLAIR,and is more suitable for intravenous gadolinium contrast-enhanced magnetic resonance imaging of the inner ear;the endolymphatic hydrops grades using ACS 3D-FLAIR is similar to use uCS 3D-FLAIR.

OBJECTIVE:This study aimed to elucidate the role of P2X3 receptors on type II spiral ganglion neurons (SGNs) in mediating the enhancement of the medial olivocochlear (MOC) reflex following long-term noise exposure. METHODS:We utilized four groups of male CBA/Ca mice: control, ouabain, ouabain noise, and ouabain noise + AF-353. The ouabain group received local cochlear application of ouabain to selectively induce apoptosis of type I SGNs. The ouabain noise group was then exposed to moderate noise [80 dB sound pressure level (SPL)] for 6 h daily over 4 weeks, while the ouabain noise + AF-353 group received the P2X3 receptor blocker AF-353 before noise sessions. Auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were measured to assess hearing. The MOC reflex was evaluated via contralateral and ipsilateral suppression of DPOAEs. Immunofluorescence visualized P2X3 receptor expression. RESULTS:Ouabain-treated mice exposed to noise displayed a significantly enhanced MOC reflex, which was attenuated by AF-353. ABR thresholds were elevated and wave I amplitude was reduced, suggesting hearing impairment, whereas DPOAE thresholds were unchanged. Immunofluorescence indicated a marked upregulation of P2X3 receptors in the cochlea's middle turn after noise exposure, an effect decreased by AF-353. CONCLUSION:The enhanced MOC reflex induced by long-term moderate noise exposure is mediated by the upregulation of P2X3 receptors on type II SGNs. The selective ablation of type I SGNs confirms the pivotal role of type II SGNs in this adaptive neural plasticity.

ObjectiveTo evaluate the value of an optimized three-dimensional inversion-recovery with real reconstruction (3D-real IR) sequence with a longer repetition time (TR, 16 000 ms) based on modulated flip angle technique in refocused imaging with extended echo train (MATRIX) in the endolymphatic hydrops (EH) imaging after intratympanic gadolinium (Gd) administration, and to compare it with a conventional 3D-real IR based on the turbo spin echo (TSE) sequence. MethodsFrom July 2021 to November 2022, twenty-seven patients received both the conventional and optimized 3D-real IR sequences after bilateral intratympanic Gd administration. Images of the two sequences were qualitativly evaluated and compared. Contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR), and area ratio of endolymph against the total lymphatic space from the two sequences were measured and compared. Results14(25.9%) ears with insufficient contrast for the EH diagnosis on the conventional sequence were clearly displayed on the optimized sequence. Image score, CNR and SNR of the optimized sequence were significantly higher than those of the conventional sequence (P ＜ 0.001). The scanning time of two sequences was similar. The area ratio of endolymph against the total lymphatic space in the cochlear was significantly higher on the conventional 3D-real IR than that on the optimized 3D-real IR (P ＜ 0.001); there was no statistical difference in the vestibule between the two sequences. ConclusionsCompared with conventional sequence, optimized 3D-real IR sequence with a longer TR may be better for evaluation of EH after intratympanic Gd administration.

Objective To establish a high-fidelity finite element method (FEM) model of the human inner ear and explore the biomechanical effects of superior semicircular canal dehiscence (SCD) on both cochlear and vestibular function. Methods A detailed FEM model of the entire human ear was reconstructed from high-resolution computed tomography (CT) data. The model was validated through comparison with established experimental data, including basilar membrane (BM) displacement patterns, cochlear tonotopy, inner ear impedance, and middle-ear transfer function. After validation, the model was adapted to simulate SCD. Results The simulated outcomes were consistent with published in-vitro and in-vivo findings, indicating the accuracy of the model. The introduction of SCD resulted in attenuated BM displacement, a marked reduction in cochlear impedance, and an increase in vestibular sensitivity to air-conducted stimuli. Conclusion This study developed and validated a whole-ear FEM model demonstrating that SCD produces low-frequency conductive hearing loss and enhances vestibular sound responses. These findings provide explanations for clinical symptoms and VEMP findings, while also revealing the influence of intracranial pressure. Collectively, this model serves as a valuable tool for advancing pathophysiological and diagnostic research.

BACKGROUND:This study developed a foundation model-based analytical framework for the analysis of postoperative endoscopic images in chronic rhinosinusitis (CRS). The framework leverages the standardized identification and reproducible results enabled by artificial intelligence algorithms, combined with the strengths of pre-trained foundation models in developing downstream applications. This approach effectively addresses the inherent challenge of strong subjectivity in conventional postoperative endoscopic evaluation for CRS. METHODS:The postoperative sinus cavity status in CRS was classified into three states: "polyp", "edema", and "smooth", to establish an endoscopic image dataset. Using transfer learning based on pre-trained large models for endoscopic images, we developed an analytical model for postoperative outcome evaluation in CRS. Comparative studies with various traditional training methods were conducted to evaluate this approach, demonstrating that it can achieve satisfactory model performance even with limited datasets. RESULTS:The endoscopic image-based pre-trained transfer learning model proposed in this study demonstrates significant advantages over conventional methods in diagnostic performance. In the precision evaluation for distinguishing smooth mucosa from rest conditions (edema and polyps), our model achieved mean accuracy and AUC values of 91.17% and 0.97, respectively, with specificity reaching 86.35% and sensitivity attaining 91.85%. This represents an approximate 4% improvement in mean accuracy compared to traditional algorithms. Notably, in the differential diagnosis between polyps and rest conditions (smooth mucosa and edema), the proposed algorithm attained mean accuracy and AUC values of 81.87% and 0.90, respectively, demonstrating specificity of 80.53% and sensitivity of 81.04%. This configuration shows a substantial 15% enhancement in mean accuracy relative to conventional diagnostic approaches. CONCLUSION:The transfer learning algorithm model based on pre-trained foundation models can provide accurate and reproducible analysis of postoperative outcomes in CRS, effectively addressing the issue of high subjectivity in postoperative evaluation. With limited data, our model can achieve better generalization performance compared to traditional algorithms.

Background:Tinnitus is a common and often debilitating auditory condition with limited treatment options. While sound therapy is widely used, robust evidence from long-term randomised trials is scarce. We aimed to evaluate the 9-month efficacy and 3-month posttreatment durability of four sound therapies for adults with chronic subjective tinnitus and identify predictors of response. Methods:In this multicentre, double-blind, randomised controlled clinical trial, participants (aged 18-80 years) with chronic subjective tinnitus from three academic hospitals in China were included. Participants were randomly 1:1:1:1 assigned to receive one of four daily 2-h interventions: unmodified music (UM), UM plus pitch-centered narrowband noise (UM + NBN), high-frequency-enhanced music (HFEM), or digital frequency-customised relieving sound (DFCRS). Primary outcome was tinnitus severity assessed by Tinnitus Handicap Inventory (THI). Assessments occurred at baseline, 1, 2, 3, 6, and 9 months, with a 3-month posttreatment follow-up. Two prespecified primary endpoints were defined: (a) complete remission, operationalised as a THI score of 0 at any follow-up visit within the 9-month period. Participants achieving this endpoint were considered clinically cured, and sound therapy was discontinued; or (b) if complete remission was not achieved by the end of 9 months, the magnitude of improvement was defined as the change in THI score from baseline to the 9-month endpoint. The primary analysis followed the intention-to-treat (ITT) principle, This trial is registered with the Chinese Clinical Trial Registry, ChiCTR2000039007. Findings:Between May 14, 2021, and November 30, 2022, 440 participants (median age 45 years [IQR, 35-56]; 222/440 [50·5%] male; median tinnitus duration 13 months [IQR, 7-36]) were enrolled and randomly assigned (UM, n = 111; UM + NBN, n = 110; HFEM, n = 108; DFCRS, n = 111). Baseline characteristics were balanced between the groups. Only one participant in the HFEM group achieved complete remission, with a THI score of 0 at the 6-month follow-up. THI scores significantly decreased over time in all groups (median 50·00 [IQR 36·00-62·00]) at baseline to 9-month follow-up (35·00 [24·00-48·00]; p < 0·0001), with effects sustained posttreatment. Significant group × time interactions occurred (UM: F(5, 618) = 11·45; UM + NBN: F(5, 605) = 7·17; HFEM: F(5, 599) = 8·3; DFCRS: F(5, 619) = 12·65; all p < 0·0001) in all arms. DFCRS demonstrated superior efficacy (parameter estimate -4·37, 95% CI -6·25 to -2·48; p < 0·0001), when compared to UM as reference. No adverse events were reported in any group. Interpretation:In this exploratory trial, personalised acoustic therapy may provide promising efficacy for chronic tinnitus. Although interpretation is tempered by the absence of a blank control arm and objective adherence monitoring, these limitations highlight opportunities for future studies to refine methods and validate treatment benefits more robustly. Funding:The Ministry of Science and Technology, the Shanghai Shenkang Development Centre, the Shanghai Science and Technology Committee, and the National Natural Science Foundation of China.

BACKGROUND:Ménière's disease (MD) remains a heterogeneous disorder with unclear pathogenesis. While immune dysregulation has been implicated, the specific role of CD4+ T cell subsets and their clinical correlations in MD are poorly understood. METHODS:We performed comprehensive immune profiling of 30 MD patients and 27 healthy controls using flow cytometry to analyze six CD4+ T cell subsets (Th1, Th2, Th17, Treg, TGF-β+, TNF-α+) and multiplex cytokine analysis of 16 inflammatory mediators plus IgE. Unsupervised hierarchical clustering identified distinct immune phenotypes, and cox regression analysis determined biomarkers of disease activity. RESULTS:Three distinct immunophenotypes were identified: Autoinflammatory (35.7 %, elevated Th1/TNF-α + cells), inactive (28.6 %, balanced profiles), and type 2-skewed (35.7 %, increased Treg/TGF-β + cells). MD patients showed significantly altered Th1/Th2/Th17 balance with elevated TGF-β + cells (p < 0.001) and decreased serum IFN-γ, IL-1β, and IL-17 a levels, while CCL3/CCL4 chemokines were increased. Cluster-specific immune-clinical correlations revealed distinct pathophysiological patterns. IL-2Rα (HR = 0.18, p = 0.007) and IFN-γ (HR = 0.26, p = 0.046) may represent biomarkers of disease activity. CONCLUSION:MD exhibits significant immunological heterogeneity with three distinct CD4+ T cell-defined phenotypes. These findings support the development of personalized treatment approaches and suggest potential biomarkers of disease activity, advancing our understanding of MD pathogenesis through comprehensive immune profiling.

Background: Sharp esophageal foreign body (SEFB) impaction can cause varying degrees of damage to the esophagus. There are few studies analyzing the postoperative fasting time in SEFB patients. Methods: We retrospectively collected 835 SEFB patients. According to the fasting time after the endoscopic removal (ER) of SEFBs, the patients were divided into two groups: short fasting time (SFT, fasted <= 24 h) and long fasting time (LFT, fasted >24 h). Results: There were 216 and 619 patients in the SFT and LFT group, respectively. The average age of the SFT group (52.97 years) was younger than that of the LFT group (55.96 years) (p = 0.025). The LFT group had lower proportion of duration of impaction (DOI) within 12 hours (14.2% vs 22.2%, p = 0.006) and erosion rates (89.0% vs 94.0%, p = 0.034) as well as higher proportion of esophageal perforation (19.5 vs 6.5%, p = 0.010) and patients who got intravenous anesthesia (63.78% vs 31.9%, p = 0.000) than the SFT group. The longest diameter of the foreign body (Lmax) in the LFT group (2.60 +/- 1.01 cm) was greater than that in the SFT group (2.41 +/- 0.83 cm; p = 0.01). Multivariate regression analysis found that age (OR = 1.726[1.208-2.465], p = 0.003), DOI (OR = 1.793[1.175-2.737], p = 0.007), Lmax (OR = 1.477[1.033-2.111], p = 0.032), perforation (OR = 3.698[2.038-6.710]; p < 0.01) and intravenous anesthesia (OR = 3.734[2.642-5.278]; p < 0.01) were the independent factors that prolonged fasting time in patients with SEFBs, while esophageal mucosal erosion (OR = 0.433[0.229-0.820]; p = 0.01) was the influencing factor leading to shortened fasting time. Conclusion: For the first time, we analyzed factors influencing the fasting time after ER in SEFB patients. Age, DOI, Lmax, perforation and intravenous anesthesia were risk factors for a prolonged postoperative fasting time

Cisplatin (CDDP) is extensively utilized in the management of diverse types of cancers, but its ototoxicity cannot be ignored, and clinical interventions are not ideal. Histidine decarboxylase (HDC) is the exclusive enzyme for histamine synthesis. Anti-histamine receptor drugs are ubiquitously employed in the therapeutics of allergies and gastrointestinal diseases. Yet, the specific role of histamine and its signaling in the inner ear is not fully understood. This study utilized cisplatin treated mice and HEI-OC1 auditory hair cell line to establish a cisplatin-induced ototoxicity (CIO) model. Histidine decarboxylase knockout (HDC-/-) mice and histamine receptor 1 (H1R) antagonist were utilized to investigate the influence of HDC/histamine/H1R signaling on ototoxicity. The results identified HDC and H1R expression in mouse hair cells. Transcriptomics indicated that the expression levels of oxidative stress-related genes in the cochlea of HDC-/- mice increased. Furthermore, histamine deficiency or suppression of H1R signaling accelerated HC ferroptosis, a pivotal factor underlying the aggravation of CIO in vivo and in vitro, conversely, the supplementation of exogenous histamine reversed these deleterious effects. Mechanistically, this study revealed that the malfunction of HDC/histamine/H1R signaling induced upregulation of NRF2 expression, accompanied by the upregulation of ACSL4 and downregulation of GPX4 expression, which are major regulatory factors of ferroptosis. In summary, histamine deficiency may induce hair cell death by regulating the H1R pathway and exacerbate CIO. Our findings have indicated a potential therapeutic target for CIO.

Electromagnetic middle ear implants (MEIs), which use the mechanical vibration of their implanted transducers to treat hearing loss, have emerged to overcome the limitations of conventional hearing aids. Several reports have indicated that the electromagnetic MEI's performance changed with different stimulation sites of the transducer. The aim of this study was to analyze the influence of the transducers' stimulation sites on the electromagnetic MEIs' performance. To aid this investigation, a human ear finite-element model was developed from micro-CT images of an adult's right ear. The validity of the model was confirmed by comparing the model-derived results with experimental data. Then, stimulation forces, which simulate ideal electromagnetic transducers, were respectively applied at five typical coupling sites: the umbo, incus body, incus long process, the round window, and the stapes. The stimulation sites' influence on the electromagnetic MEI's performance was studied by analyzing their corresponding basilar membrane displacements. The results show that stimulation of the round window with a force produces more cochlear stimulation than equal force stimulation of the umbo, incus body, incus long process and the stapes, though the superiority of the round window depends on its smaller area compared to the stapes footplate. Among the forward stimulation, the stapes is the optimal stimulation site for the electromagnetic transducer regarding its hearing compensation's efficiency. The performance of the umbo stimulation is comparable to that of the incus-long-process stimulation. Driving the incus body is less efficient than stimulating the other forward driving sites. Additional, using the stapes response to evaluate the forward stimulation gives results similar to those deduced by the basilar membrane response; in contrast, for the round-window stimulation, the evaluation result based on the stapes response is prominently less than the one calculated by the basilar membrane response, especially in the mid-high frequency range.

Background The stria vascularis (SV), located in the lateral wall of the cochlea, maintains cochlear fluid homeostasis and mechanoelectrical transduction (MET) activity required for sound wave conduction. The pathogenesis of a number of human inheritable deafness syndromes, age related hearing loss, drug-induced ototoxicity and noise-induced hearing loss results from the morphological changes and functional impairments in the development of the SV. In this study, we investigate the implications of intercellular communication within the SV in the pathogenesis of sensorineural hearing loss (SNHL). We aim to identify commonly regulated signaling pathways using publicly available single-cell transcriptomic sequencing (scRNA-seq) datasets. Methods We analyzed scRNA-seq data, which was derived from studying the cochlear SV in mice with SNHL compared to normal adult mice. After quality control and filtering, we obtained the major cellular components of the mouse cochlear SV and integrated the data. Using Seurat's FindAllMarkers and FindMarkers packages, we searched for novel conservative genes and differential genes. We employed KEGG and GSEA to identify molecular pathways that are commonly altered among different types of SNHL. We utilized pySCENIC to discover new specific regulatory factors in SV subpopulation cells. With the help of CellChat, we identified changes in subpopulation cells showing similar trends across different SNHL types and their alterations in intercellular communication pathways. Results Through the analysis of the integrated data, we discovered new conserved genes to SV specific cells and identified common downregulated pathways in three types of SNHL. The enriched genes for these pathways showing similar trends are primarily associated with the Electron Transport Chain, related to mitochondrial energy metabolism. Using the CellChat package, we further found that there are shared pathways in the incoming signaling of specific intermediate cells in SNHL, and these pathways have common upstream regulatory transcription factor of Nfe2l2. Combining the results from pySCENIC and CellChat, we predicted the transcription factor Nfe2l2 as an upstream regulatory factor for multiple shared cellular pathways in IC. Additionally, it serves as an upstream factor for several genes within the Electron Transport Chain. Conclusion Our bioinformatics analysis has revealed that downregulation of the mitochondrial electron transport chain have been observed in various conditions of SNHL. E2f1, Esrrb, Runx1, Yy1, and Gata2 could serve as novel important common TFs regulating the electron transport chain. Adm has emerged as a potential new marker gene for intermediate cells, while Itgb5 and Tesc show promise as potential new marker genes for marginal cells in the SV. These findings offer a new perspective on SV lesions in SNHL and provide additional theoretical evidence for the same drug treatment and prevention of different pathologies of SNHL.

Objective: This study aimed to investigate the optimal head position (OHP) following intratympanic injection, a critical intervention in treating inner ear disorders. Identifying OHP is essential to maximize drug retention in the middle ear, thereby significantly enhancing the therapeutic efficacy by mitigating the significant issue of injectate leakage through the eustachian tube (ET). Exploratory various positions of ET orifice and round window (RW) were investigated and associated with head movements. Methods: Twenty-two (10 males and 12 females) anonymized high-resolution computed tomography (HRCT) datasets of patients without structural ear disease were selected from January 2022 to December 2022 in the study. The subjects were categorized into two groups: children (≤18 years) and adult group (>18 years). The reconstruction of the ET orifice and RW from HRCT were analyzed using Mimics software and the distances from the center point of ET orifice or the center point of RW to the reference plane were defined as distance of ET orifice (DET) and distance of RW (DRW). Results: In the supine position, the OHP for intratympanic injection was 23°of pronation and 24° of posterior extension, and the maximum distance between the ET orifice and RW (DET-RW) was 9.29 ± 2.13 mm. As the head position extended posteriorly beyond 43°, DET was relatively high compared with DRW, resulting in the OHP a fully posteriorly extended 90° of the head being the optimal position with DET-RW of 2.13 ± 1.60 mm in the supine position, however, it is not realized in human beings. Moreover, the OHP had no obvious relevance corresponding to age following intratympanic injections. Conclusion: Our study suggested that OHP after intratympanic injections treatment consists of supine position, along with a slight pronation and posterior extension.

BACKGROUND:Immunotherapy for colorectal cancer (CRC) with microsatellite stability (MSS) and mismatch repair proficiency (pMMR) has shown limited success in clinical trials. The combination of immunomodulators and immune checkpoint inhibitors (ICIs) is a potential strategy for treating CRC. METHODS:Histone deacetylase (HDAC) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in CRC tissues and adjacent normal tissues was analyzed via database analysis, immunohistochemistry, and western blotting. A nanodrug designated as NP-I/P was subsequently formulated, encapsulating an IDO1 inhibitor (IDO1i; namely, epacadostat) and an immunomodulatory HDAC inhibitor (HDACi; namely, panobinostat). The antitumor efficacy of the nanoparticles and their effects on tumor microenvironment features were evaluated via in vitro and in vivo experiments. RESULTS:In the present study, we found that HDAC overexpression and IDO1 expression were attenuated in MSS/pMMR CRC. Thus, a nanodrug designated as NP-I/P was formulated to encapsulate epacadostat and panobinostat. In vitro, NP-I/P treatment promoted the apoptosis of tumor cells and induced the release of damage-associated molecular patterns, thereby leading to cell death-associated immune activation. The in vivo results revealed that NP-I/P treatment reversed the immunosuppressive phenotype of the microenvironment by inducing tumor immunogenic cell death (ICD), promoting CD8+ T cell infiltration, and reducing the numbers of Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells. Finally, the results of the patient-derived xenograft and patient-derived organoid models demonstrated that NP-I/P treatment triggered tumor cell death and modulated the immune microenvironment in human CRC. CONCLUSION:The combination of IDO1 and HDAC inhibitors represents a promising strategy for CRC treatment, and NP-I/P is a candidate for clinical trials.