miR-409-3p Regulates IFNG and p16 Signaling in the Human Blood of Aging-Related Hearing Loss.

Presbycusis, also referred to as age-related hearing loss (ARHL), is a multifaceted condition caused by the natural aging process affecting the auditory system. Genome-wide association studies (GWAS) in human populations can identify potential genes linked to ARHL. Despite this, our knowledge of the biochemical and molecular mechanisms behind the condition remains incomplete. This study aims to evaluate a potential protective tool for ARHL treatment by comparing human blood-based target gene-miRNA associations regulated in ARHL. To identify promising target genes for ARHL, we utilized an mRNA assay. To determine the role of miRNA in ARHL, we investigated the expression profile of miRNA in whole blood in ARHL patients with real-time polymerase chain reaction (RT-qPCR). A reporter gene assay was performed to confirm the regulation of candidate genes by microRNA. Through RT-qPCR validation analysis, we finally confirmed the relationship between ARHL and the role of the interferon-gamma (IFNG) gene. This gene can be regarded as an age-related gene. Through gene ontology (GO) analysis, it has been found that these genes are enriched in pathways related to apoptosis. Among them, IFNG induces an inflammatory response, apoptotic cell death, and cellular senescence. We found that miR-409-3p downregulates the expression of the IFNG in vitro. In addition, the downregulation of the IFNG by miRNA 409-3p promoted cell apoptosis and suppressed proliferation. In conclusion, our study produced gene signatures and associated microRNA regulation that could be a protective key for ARHL patients. IFNG genes and miR-409-3p should be investigated for their usefulness as a new biomarker for treatment modality.

Latent stem cell-stimulating radially aligned electrospun nanofibrous patches for chronic tympanic membrane perforation therapy.

Chronic tympanic membrane (TM) perforation is a tubotympanic disease caused by either traumatic injury or inflammation. A recent study demonstrated significant progress in promoting the regeneration of chronic TM perforations through the application of nanofibers with radially aligned nanostructures and controlled release of growth factors. However, radially aligned nanostructures with stem cell-stimulating factors have never been used. In this study, insulin-like growth factor binding factor 2 (IGFBP2)-incorporated radially aligned nanofibrous patches (IRA-NFPs) were developed and applied to regenerate chronic TM perforations. The IRA-NFPs were prepared by electrospinning 8 wt% polycaprolactone in trifluoroethanol and acetic acid (9:1). Random nanofibers (RFs) and aligned nanofibers (AFs) were successfully fabricated using a flat plate and a custom-designed circular collector, respectively. The presence of IGFBP2 was confirmed via Fourier transform infrared spectroscopy and the release of IGFBP2 was sustained for up to 20 days. In vitro studies revealed enhanced cellular proliferation and migration on AFs compared to RFs, and the incorporation of IGFBP2 further promoted these effects. Quantitative real-time PCR revealed mRNA downregulation, correlating with accelerated migration and increased cell confluency. In vivo studies showed IGFBP2-loaded RF and AF patches increased regeneration success rates by 1.59-fold and 2.23-fold, respectively, while also reducing healing time by 2.5-fold compared to the control. Furthermore, IGFBP2-incorporated AFs demonstrated superior efficacy in healing larger perforations with enhanced histological similarity to native TMs. This study, combining stem cell stimulating factors and aligned nanostructures, proposes a novel approach potentially replacing conventional surgical methods for chronic TM perforation regeneration. STATEMENT OF SIGNIFICANCE: Chronic otitis media (COM) affects approximately 200 million people worldwide due to inflammation, inadequate blood supply, and lack of growth factors. Current surgical treatments have limitations like high costs and anesthetic risks. Recent research explored the use of nanofibers with radially aligned nanostructures and controlled release of growth factors to treat chronic tympanic membrane (TM) perforations. In this study, insulin-like growth factor binding protein 2 (IGFBP2)-incorporated radially aligned nanofibrous patches (IRA-NFPs) were developed and applied to regenerate chronic TM perforations. We assessed their properties and efficacy through in vitro and in vivo studies. IRA-NFPs showed promising healing capabilities with chronic TM perforation models. This innovative approach has the potential to improve COM management, reduce surgery costs, and enhance patient safety.

Tinnitus reduction after active bone-conduction implantation in patients with single-sided deafness: a prospective multicenter study.

PURPOSE: Single-sided deafness (SSD) presents significant challenges for patients, including compromised sound localization, reduced speech recognition, and often, tinnitus. These issues are typically addressed using interventions such as cochlear implantation (CI) and bone conduction implant (BCI). However, evidence regarding the efficacy of BCI in reducing tinnitus in SSD patients remains limited. This study explored the ability of a novel active transcutaneous BCI (Bonebridge BCI602) to alleviate tinnitus in SSD patients. STUDY DESIGN: Prospective cohort multicenter study. SETTING: Tertiary referral hospitals. METHODS: A prospective multicenter study of 30 SSD patients was conducted. The patients were divided into two groups: those with (n = 19) and without (n = 11) tinnitus. Audiometric assessments, subjective questionnaires including the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Bern Benefit in Single-Sided Deafness (BBSS), and tinnitus evaluations with the Tinnitus Handicap Inventory (THI) and tinnitogram were conducted before and after BCI surgery. RESULTS: THI scores after surgery were significantly reduced in SSD patients with tinnitus. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups; however, the former group exhibited a significantly greater improvement in the APHAB questionnaire score. According to tinnitograms, the loudness of tinnitus decreased, particularly in patients with ipsilateral tinnitus. Patients with residual hearing had greater reductions in their THI scores. However, three patients without residual hearing had a relative worsening of tinnitus after surgery. CONCLUSION: The Bonebridge BCI602 effectively reduced tinnitus in SSD patients, particularly in those with residual hearing. Subjective satisfaction improved in both the tinnitus and non-tinnitus groups. These findings demonstrate the therapeutic potential of BCI for managing SSD and associated tinnitus.

Sialyllactose preserves residual hearing after cochlear implantation.

In individuals with hearing loss, protection of residual hearing is essential following cochlear implantation to facilitate acoustic and electric hearing. Hearing preservation requires slow insertion, atraumatic electrode and delivery of the optimal quantity of a pharmacological agent. Several studies have reported variable hearing outcomes with osmotic pump-mediated steroid delivery. New drugs, such as sialyllactose (SL) which have anti-inflammatory effect in many body parts, can prevent tissue overgrowth. In the present study, the positive effects of the pharmacological agent SL against insults were evaluated in vitro using HEI-OC1 cells. An animal model to simulate the damage due to electrode insertion during cochlear implantation was used. SL was delivered using osmotic pumps to prevent loss of the residual hearing in this animal model. Hearing deterioration, tissue fibrosis and ossification were confirmed in this animal model. Increased gene expressions of inflammatory cytokines were identified in the cochleae following dummy electrode insertion. Following the administration of SL, insertion led to a decrease in hearing threshold shifts, tissue reactions, and inflammatory markers. These results emphasize the possible role of SL in hearing preservation and improve our understanding of the mechanism underlying hearing loss after cochlear implantation.

The Suppression of Ubiquitin C-Terminal Hydrolase L1 Promotes the Transdifferentiation of Auditory Supporting Cells into Hair Cells by Regulating the mTOR Pathway.

In mammals, hearing loss is irreversible due to the lack of the regenerative capacity of the auditory epithelium. However, stem/progenitor cells in mammalian cochleae may be a therapeutic target for hearing regeneration. The ubiquitin proteasome system plays an important role in cochlear development and maintenance. In this study, we investigated the role of ubiquitin C-terminal hydrolase L1 (UCHL1) in the process of the transdifferentiation of auditory supporting cells (SCs) into hair cells (HCs). The expression of UCHL1 gradually decreased as HCs developed and was restricted to inner pillar cells and third-row Deiters' cells between P2 and P7, suggesting that UCHL1-expressing cells are similar to the cells with Lgr5-positive progenitors. UCHL1 expression was decreased even under conditions in which supernumerary HCs were generated with a γ-secretase inhibitor and Wnt agonist. Moreover, the inhibition of UCHL1 by LDN-57444 led to an increase in HC numbers. Mechanistically, LDN-57444 increased mTOR complex 1 activity and allowed SCs to transdifferentiate into HCs. The suppression of UCHL1 induces the transdifferentiation of auditory SCs and progenitors into HCs by regulating the mTOR pathway.

Factors Predicting Subjective Satisfaction for Successful Hearing Aid Adaptation.

(1) Background: For successful hearing aid (HA) use during daily life, an objective parameter reflecting the subjective satisfaction is required. We explored the aided hearing status, hearing in noise test (HINT) scores, and subjective outcomes to predict performance improvements in everyday living. (2) Methods: A total of 406 patients with hearing loss (HL) who were prescribed HAs were included and were divided into two groups according to the symmetricity of HL. The relationship between audiometric data and subjective questionnaires under unaided and aided (3 months) conditions were investigated. (3) Results: Patients with symmetric HL showed a significant HINT signal-to-noise ratio (SNR) change and significant increase in their subjective satisfaction questionnaire score under the bilateral HA condition. On the other hand, the HINT SNR change and subjective questionnaire score showed various significances according to the side of HA (better or worse hearing) in asymmetric HL HINT SNR and was significantly correlated with the subjective questionnaire score in symmetric HL patients and AHL patients with unilateral HA in their better ear. (4) Conclusions: The HINT SNR improvement after long-term HA use could be an effective tool for predicting the subjective satisfaction of HA use and HA validation.

Objective and subjective efficacy of hearing aids in patients with mild-to-moderate unilateral hearing loss: a prospective study.

PURPOSE: In patients with unilateral sensorineural hearing loss (USNHL), we explored both objective functional audiological gains and subjective satisfaction, indicating when a unilateral hearing aid is valuable. METHODS: Thirty-seven patients with mild-to-moderate USNHL (mean pure-tone thresholds between 25 and 70 dB) were prescribed unilateral hearing aids. Functional gain, the aided speech discrimination score (SDS), the Hearing in Noise Test (HINT) score, and the sound localization test score were collected, and a questionnaire (the Hearing Handicap Inventory for the Elderly, HHIE) completed after 1, 2, and 3 months of hearing aid use. We classified the participants as having 'no handicap' (HHIE < 17), 'mild-to-moderate handicap' (17-42), and 'significant handicap' (> 42). RESULTS: The decrease in handicap afforded by unilateral hearing aids was largest in the 'significant handicap' group (the HHIE total score fell from 59.1 to 37.2; P = 0.007). There were no between-group differences in either functional gain or the aided SDS. Only the 'significant handicap' group evidenced an improved HINT score; the composite signal-to-noise ratio (SNR) fell from - 1.5 to - 2.2 dB [S/N] (P = 0.023). The HHIE usefully indicated when a hearing aid alleviated the discomfort of USNHL; patients with unaided HHIE scores ≥ 20 evidenced significant decreases in the composite SNR (- 1.7 to - 2.0 dB [S/N]; P = 0.045). CONCLUSIONS: When considering whether to prescribe a unilateral hearing aid for patients with mild-to-moderate USNHL, it is helpful to use the HHIE to evaluate discomfort. If the total score is ≥ 20, a hearing aid is appropriate.

Efficacy of the Bonebridge BCI602 for Adult Patients with Single-sided Deafness: A Prospective Multicenter Study.

OBJECTIVE: To investigate the safety and efficacy of a novel active transcutaneous bone conduction implant (BCI) device for patients with single-sided deafness (SSD). STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral hospitals. METHODS: This prospective multicenter study was conducted at 15 institutions nationwide. Thirty adult (aged ≥19 years) SSD patients were recruited. They underwent implantation of an active transcutaneous BCI device (Bonebridge BCI602). Objective outcomes included aided pure-tone thresholds, aided speech discrimination scores (SDSs), and the Hearing in Noise Test (HINT) and sound localization test results. The Bern Benefit in Single-Sided Deafness (BBSS) questionnaire, the Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire, and the Tinnitus Handicap Inventory (THI) were used to measure subjective benefits. RESULTS: The mean aided pure-tone threshold was 34.2 (11.3), mean (SD), dB HL at 500 to 4000 Hz. The mean total BBSS score was 27.5 (13.8). All APHAB questionnaire domain scores showed significant improvements: ease of communication, 33.6 (23.2) versus 22.6 (21.3), P = .025; reverberation, 44.8 (16.6) versus 32.8 (15.9), P = .002; background noise, 55.5 (23.6) versus 35.2 (18.1), P < .001; and aversiveness, 36.7 (22.8) versus 25.8 (21.4), P = .028. Moreover, the THI scores were significantly reduced [47.4 (30.1) versus 31.1 (27.0), P = .003]. Congenital SSD was a significant factor of subjective benefit (-11.643; 95% confidence interval: -21.946 to -1.340). CONCLUSION: The BCI602 active transcutaneous BCI device can provide functional hearing gain without any adverse effects and is a feasible option for acquired SSD patients with long-term deafness.

Mechanism underlying and prevention of electrode migration in cochlear implants.

PURPOSE: We investigate the clinical manifestations, mechanisms, and methods of preventing electrode migration in Cochlear Implantation (CI) patients, based on our practical experience with this problem. STUDY DESIGN: This is a retrospective study in a single center. METHODS: We retrospectively reviewed electrode migration in 4 (0.75%) of 532 patients who underwent CI at our tertiary institution from January 2002 to December 2022. Pre- and post-operative pure-tone audiometry, word recognition score, aided functional gain test, and sound field speech intelligibility test were evaluated. RESULTS: All four patients underwent CIs with the straight electrode type. The following events or symptoms were observed in the patients before confirming electrode migration: an increase in high-frequency thresholds during the post-operative aided functional gain test and a decline in scores on the sound field speech intelligibility test. Electrode migration was confirmed through transocular view X-ray or temporal bone computer tomography. Two patients showed coiled electrodes within the mastoid cavity; while in the others, the electrodes were observed to be floating inside the cavity. To prevent migration of electrodes due to these issues, we mixed bone paste collected during the drilling of the mastoid cavity with glue and used it to secure the electrodes in place. CONCLUSION: Electrode migration can result in a decrease in hearing ability and may necessitate a revision surgery to adjust the electrode placement. The main factors affecting electrode placement include the position of electrode within the mastoid cavity and the elasticity of straight electrodes. It is important for surgeons to recognize the factors that increase the risk of electrode migration and to take preventative measures to reduce this risk.

Abnormal Cholesterol Metabolism and Lysosomal Dysfunction Induce Age-Related Hearing Loss by Inhibiting mTORC1-TFEB-Dependent Autophagy.

Cholesterol is a risk factor for age-related hearing loss (ARHL). However, the effect of cholesterol on the organ of Corti during the onset of ARHL is unclear. We established a mouse model for the ARHL group (24 months, n = 12) and a young group (6 months, n = 12). Auditory thresholds were measured in both groups using auditory brainstem response (ABR) at frequencies of 8, 16, and 32 kHz. Subsequently, mice were sacrificed and subjected to histological analyses, including transmission electron microscopy (TEM), H&E, Sudan Black B (SBB), and Filipin staining, as well as biochemical assays such as IHC, enzymatic analysis, and immunoblotting. Additionally, mRNA extracted from both young and aged cochlea underwent RNA sequencing. To identify the mechanism, in vitro studies utilizing HEI-OC1 cells were also performed. RNA sequencing showed a positive correlation with increased expression of genes related to metabolic diseases, cholesterol homeostasis, and target of rapamycin complex 1 (mTORC1) signaling in the ARHL group as compared to the younger group. In addition, ARHL tissues exhibited increased cholesterol and lipofuscin aggregates in the organ of Corti, lateral walls, and spiral ganglion neurons. Autophagic flux was inhibited by the accumulation of damaged lysosomes and autolysosomes. Subsequently, we observed a decrease in the level of transcription factor EB (TFEB) protein, which regulates lysosomal biosynthesis and autophagy, together with increased mTORC1 activity in ARHL tissues. These changes in TFEB and mTORC1 expression were observed in a cholesterol-dependent manner. Treatment of ARHL mice with atorvastatin, a cholesterol synthesis inhibitor, delayed hearing loss by reducing the cholesterol level and maintaining lysosomal function and autophagy by inhibiting mTORC1 and activating TFEB. The above findings were confirmed using stress-induced premature senescent House Ear Institute organ of Corti 1 (HEI-OC1) cells. The findings implicate cholesterol in the pathogenesis of ARHL. We propose that atorvastatin could prevent ARHL by maintaining lysosomal function and autophagy by inhibiting mTORC1 and activating TFEB during the aging process.

Determination of Tympanostomy Tube Types for Otitis Media with Effusion in Patients with Cleft Palate: Comparison between Paparella Type 1 and Type 2 Tubes.

This study examined the effects of different types of tympanostomy tubes in pediatric patients undergoing cleft palate (CP) surgery in order to provide guidance for the proper insertion of tympanostomy tubes in the management of otitis media with effusion (OME). A total of 101 ears with middle ear effusion in 51 patients with CP were included in this study. Patients underwent palatoplasty and tympanostomy tube surgery at the same time. The type of tube inserted (Paparella type 1 or 2), the severity of CP, and types of palatoplasty surgeries were investigated. All patients were followed up for at least 6 months, and recurrence rates, complications, and reinsertion surgery were evaluated. The rate of OME recurrence after spontaneous tube extrusion was significantly higher in the type 1 group than in the type 2 group (44.3% vs. 19.4%, respectively, p = 0.016). Persistent eardrum perforation was more common in the type 2 group than in the type 1 group (41.9% vs. 12.9%, respectively, p = 0.001). The tube reinsertion rate was higher in the type 1 group than in the type 2 group (22.9% vs. 3.2%, respectively, p = 0.015). The tube reinsertion rate decreased to 8.6% in cases of palatoplasty with Sommerlad's technique, even with type 1 tube insertion, which was not significantly different from the reinsertion rate in the type 2 group (3.7%, p = 0.439). The Paparella type 1 tube would be a better choice in cases of palatoplasty performed using Sommerlad's technique, particularly considering the higher rate of persistent eardrum perforation after extrusion associated with the Paparella type 2 tube. Alternatively, a larger size type 2 tube may be considered in other surgeries to decrease the frequency of recurrence and tube reinsertion.

Pearls & Oy-sters: Familial Verbal Auditory Agnosia Due to C9orf72 Repeat Expansion.

Chromosome 9 open reading frame 72 (C9orf72) gene pathogenic variants have been typically associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), but recent studies suggest their involvement in other disorders. This report describes a family with an autosomal dominant pattern of inheritance of progressive verbal auditory agnosia due to GGGGCC repeat expansion in C9orf72. A 60-year-old right-handed male truck driver presented with slowly progressive poor speech perception for 8 years, which became most troublesome when receiving verbal orders over the phone. He had difficulty recognizing single-syllable spoken words beyond his hearing loss but had no problem understanding complex written language. He had a heterozygous pathogenic variant carrying 160 hexanucleotide repeats in the C9orf72 gene. His family history included his deceased mother with similar symptoms that had progressed over 30 years, as well as his older brother and youngest sister who experienced speech perception difficulty beginning in their early fifties. His asymptomatic younger brother had a heterozygous 2 repeat in the C9orf72 gene, while his symptomatic youngest sister had a heterozygous 159 repeat. The patient and his sister exhibited more pronounced cortical thinning in the frontotemporoparietal areas. The discrepancy observed between the distribution of atrophy and the presentation of symptoms in patients with C9orf72 pathogenic repeat expansion may be attributable to the slow progression of their clinical course over time. The variable symptom presentation of C9orf72 pathogenic repeat expansion highlights the importance of considering this pathogenic variant as a potential cause of autosomal dominant degenerative brain diseases beyond FTD and ALS.

Relationship Between Facial Bone Fractures and the Risk of Posttraumatic Complications: A Hypothesis on the Cushion Effect of the Facial Skeletons in Temporal Bone Fractures.

BACKGROUND: This study investigated whether concomitant facial bone (FB) fractures reduce temporal bone (TB) injuries, such as posttraumatic facial palsy and vertigo, through an impact absorbing effect, so-called "cushion effect," in severe trauma patients. METHODS: A total of 134 patients with a TB fracture were included. They were divided into two groups according to their concomitant facial fractures: group I (no FB fracture) and group II (FB fracture). We compared clinical characteristics, such as brain injury, trauma severity, and complications of TB fracture, between the two groups. RESULTS: In group II, immediate facial palsy was more frequent (11.6% vs. 1.5% in group I), and the Injury Severity Score was higher (19.0 ± 5.9 vs. 16.7 ± 7.3, P = 0.020). Delayed facial palsy (12.3% in group I vs. 4.3% in group II) and posttraumatic vertigo (24.6% vs. 7.2%) occurred more often in group I. FB fractures significantly decreased the incidence of posttraumatic vertigo (odds ratio [OR], 0.276; 95% confidence interval [CI], 0.083-0.914). Intraventricular hemorrhage (OR, 20.958; 95% CI, 2.075-211.677), facial nerve canal injury (OR, 12.229; 95% CI, 2.465-60.670), and FB fractures (OR, 16.420; 95% CI, 1.298-207.738) increased the risk of immediate facial palsy. CONCLUSION: Concomitant FB fractures reduced the risk of the occurrence of delayed facial palsy and posttraumatic vertigo in injured patients with TB fracture. Particularly, an anterior force may be reduced by the cushion effect of the bony fracture.

Probing the Ion Transport Properties of Ultrashort Carbon Nanotubes Integrated with Supported Lipid Bilayers via Electrochemical Analysis.

Supported lipid bilayers (SLBs) are commonly used to investigate interactions between cell membranes and their environment. These model platforms can be formed on electrode surfaces and analyzed using electrochemical methods for bioapplications. Carbon nanotube porins (CNTPs) integrated with SLBs have emerged as promising artificial ion channel platforms. In this study, we present the integration and ion transport characterization of CNTPs in in vivo environments. We combine experimental and simulation data obtained from electrochemical analysis to analyze the membrane resistance of the equivalent circuits. Our results show that carrying CNTPs on a gold electrode results in high conductance for monovalent cations (K+ and Na+) and low conductance for divalent cations (Ca2+).

Graphene Hybrid Inner Ear Organoid with Enhanced Maturity.

Inner ear organoids (IEOs) are 3D structures grown in vitro, which can mimic the complex cellular structure and function of the inner ear. IEOs are potential solutions to problems related to inner ear development, disease modeling, and drug delivery. However, current approaches in generating IEOs using chemical factors have a few limitations, resulting in unpredictable outcomes. In this study, we propose the use of nanomaterial-based approaches, specifically by using graphene oxide (GO). GO's unique properties promote cell-extracellular matrix interactions and cell-cell gap junctions, thereby enhancing hair cell formation, which is an essential part of IEO development. We also investigated the potential applications for drug testing. Our findings suggest that GO is a promising candidate for enhancing the functionality of IEOs and advancing our understanding of the problems underlying inner ear development. The use of nanomaterial-based approaches may provide a more reliable and effective method for building better IEOs in the future.

Efficacy and Safety of Co-Administered St. John's Wort and Ginkgo biloba Extracts in Patients with Subjective Tinnitus: A Preliminary Prospective Randomized Controlled Trial.

It is widely accepted that extracts of St. John's wort (Hypericum perforatum) improve depressive symptoms, and tinnitus patients commonly presented with either mild depression or anxiety. We investigated whether co-administration of St. John's wort and Ginkgo biloba extracts can suppress tinnitus. Participants with subjective tinnitus aged 30-70 years were randomly assigned to the experimental (co-administration of St. John's wort and Ginkgo biloba extract; n = 20) or control (Ginkgo biloba extract only; n = 26) group for 12 weeks. Participants were blinded to the group assignments. After 12 weeks of treatment, no significant change in the minimum masking level on the tinnitogram was observed in either group. In the co-administration group, the Tinnitus Handicap Inventory (THI) score decreased from 34.7 (SD, 15.9) to 29.6 (16.0) (p = 0.102). However, the control group showed a significant decrease in THI score, from 30.5 (16.7) to 25.6 (17.1) (p = 0.046). Regarding the Short Form-36 Health Survey (SF-36), only the "Social Functioning" domain score changed significantly after extract co-administration, from 74.5 (21.5) to 83.9 (20.5) (p = 0.047). Co-administration of St. John's wort and Ginkgo biloba extracts did not improve the symptoms of subjective tinnitus compared to administration of Ginkgo biloba extract alone.

What is the most important factor to preserve hearing in lateral semicircular canal fistula surgeries, fistula size or bony structure?

PURPOSE: Cholesteatoma on lateral semicircular canal (LSCC) fistula > 2 mm in size is likely to be unmanipulated due to the risk of sensorineural hearing loss. However, the matrix can be successfully removed without hearing loss when it is > 2 mm. The purpose of the study was to evaluate surgical experience over the past 10 years and to suggest the important factor for the hearing preservation in LSCC fistula surgeries. METHODS: According to the fistula size and symptoms, 63 patients with LSCC fistula were grouped as follows: Type I (fistula < 2 mm), Type II (≥ 2 mm and < 4 mm without vertigo), Type III (≥ 2 mm and < 4 mm with vertigo), Type IV (≥ 4 mm), and Type V (any size fistula but with deafness at the initial visit). The cholesteatoma matrix was meticulously manipulated and removed by experienced surgeons. RESULTS: Only two patients completely lost their hearing after surgery (4.5%). However, the loss was inevitable because their cholesteatomas were highly invasive and there was also facial nerve canal involvement; thus, the bony structure of the LSCC was already destroyed by the cholesteatoma. Unlike these two Type IV patients, Type I-III patients, and those with a fistula size < 4 mm, did not lose their sensorineural hearing. If the structure of the LSCC was maintained, hearing loss did not occur even if the fistula size ≥ 4 mm. CONCLUSIONS: The preservation of the labyrinthine structure is more important than the defect size of the LSCC fistula. If the structure is intact, cholesteatoma matrices lying on the defect can be safely removed, even though the size of bony defect is large.

SMO-CRISPR-mediated apoptosis in CD133-targeted cancer stem cells and tumor growth inhibition.

Cancer stem cells (CSCs) possess the ability to indefinitely proliferate and resist therapy, leading to cancer relapse and metastasis. To address this, we aimed to develop a CSC-inclusive therapy that targets both CSCs and non-CSC glioblastoma (GBM) cells. We accomplished this by using a smoothened (SMO) CRISPR/Cas9 plasmid to suppress the hedgehog pathway in CSCs, in combination with inhibiting the serine hydroxymethyl transferase 1 (SHMT1)-driven thymidylate biosynthesis pathway in non-CSC GBM cells using SHMT1 siRNA (siSHMT1). We targeted CSCs using a CD133 peptide attached to an osmotically active vitamin B6-coupled polydixylitol vector (VPX-CD133) by a photoactivatable heterobifunctional linker. VPX-CD133 nanocomplexes in comparison to VPX complexes remarkably targeted and transfected CSCs both in vitro and in subcutaneous tumor. The VPX-CD133-mediated targeted delivery of SMO CRISPR in CSCs led to SMO suppression that negatively affected its growth. Next, we performed comprehensive therapy in xenograft mice using VPX-CD133, which delivered SMO-CRISPR to CSCs, and VPX, which delivered siSHMT1 to non-CSC GBM cells. The combined treatment induced apoptosis in a large number of cells, reduced tumor volume by up to 81%, and improved the health of treated mice significantly. By eliminating CSCs together with the non-CSC GBM cells, the combined study paves the way for developing CSC-inclusive therapies for GBM.

Which is Better for Ossiculoplasty Following Tympanomastoidectomy: Polycel® or Titanium?

OBJECTIVES: The purpose of this study was to compare the surgical outcomes of Polycel® and titanium in ossiculoplasty following tympanomastoidectomy (TM). METHODS: A total of 221 patients underwent ossiculoplasty following TM by a single surgeon using either Polycel® or titanium as prosthesis. Hearing was tested preoperatively and postoperatively at 6 months by pure-tone audiometry. Successful surgery was defined if postoperative air-bone gap (ABG) was <20 dB, the gain in air conduction (AC) hearing was >15 dB HL, or postoperative AC was <30 dB HL. Multiple linear regression was conducted to identify the factors associated with the surgical outcomes. RESULTS: In canal wall up mastoidectomy (CWUM), both Polycel® and titanium showed favorable successful rates if partial ossicular replacement prosthesis (PORP) was used (64.3% of Polycel® and 67.6% in titanium). If total ossicular replacement prosthesis (TORP) was used, both represented similar outcomes (54.5% of Polycel® and 75.0% in titanium). In canal wall down mastoidectomy (CWDM), significant ABG reductions were observed only in the titanium group (5.2 ± 14.7 dB of Polycel® [P = .083] and 7.0 ± 14.2 dB of titanium [P = .002] in PORP; 4.6 ± 13.5 dB of Polycel® [P = .097] and 9.5 ± 11.2 dB of titanium [P < .001] in TORP). In multivariate analysis, titanium had a positive effect on the reduction of postoperative AC thresholds (B: -4.772; 95% CI: -8.706--0.838). CONCLUSIONS: Both Polycel® and titanium showed favorable surgical outcomes for ossiculoplasty following CWUM. Titanium prosthesis is recommended for surgery after CWDM.