A novel frameshift variant of LMX1A that leads to autosomal dominant non-syndromic sensorineural hearing loss: functional characterization of the C-terminal domain in LMX1A.

Non-syndromic sensorineural hearing loss (NSHL) is a group of genetically heterogeneous conditions with broad phenotypic heterogeneity. There is, at present, no curative treatment for genetic hearing loss (HL). Early molecular diagnosis of progressive disorders and elucidation of the causes and pathomechanisms are essential for developing therapeutic strategies. Here, we identified a novel rare frameshift variant of LMX1A (c.915dup), which resulted in the C-terminal-altered and -truncated LMX1A (p.Val306Cysfs*32). This C-terminal frameshift mutation co-segregated with autosomal dominant (AD) NSHL in a four-generation Chinese family, suggesting that the LMX1A non-missense mutation is also contributed to ADNSHL. In this family, the affected individuals exhibited the variable auditory phenotypes ranging from profound congenital deafness at birth or to mild/moderate HL in adulthood. We also found that the embryonic cells carrying with the heterozygous variant significantly expressed several upregulated HL-associated genes at transcriptional level. In vitro splicing assay suggested that the LMX1A mRNA with c.915dup did not cause nonsense-mediated decay and was translated into a truncated LMX1A. In addition, electrophoresis mobility shift assay and luciferase assays have shown that the highly conserved C-terminal domain (amino acid 306-382) of the LMX1A was required for regulating the protein-DNA interaction and transactivation in vitro. Furthermore, apoptosis assays suggested that the C-terminal domain of the LMX1A was important for mediating apoptosis in the cochlear hair cells. Our work provided the multiline of the evidence to support that non-missense mutation of LMX1A leads to ADNSHL and the C-terminal domain of LMX1A is important for mediating transcriptional activity and associated with promoting apoptosis in the cells.

Shikonin potentiates skin wound healing in Sprague-Dawley rats by stimulating fibroblast and endothelial cell proliferation and angiogenesis.

BACKGROUND: Shikonin, a major component of Lithospermum erythrorhizon, exerts anti-inflammatory and antibacterial effects and expedites wound healing. This study aims to evaluate the anti-inflammatory and antioxidant activities of shikonin in a Sprague-Dawley rat model and cell models using fibroblast and endothelial cells. METHODS: The impact of shikonin on the activity of endothelial cells and fibroblasts was examined by cell counting kit 8 and wound-healing assays. A diabetic rat model was constructed, followed by wound creation for treatment with shikonin. Hematoxylin-eosin staining was used to assess pathological changes, and Masson's trichrome method to detect collagen deposition. Immunohistochemistry using antibodies against proliferating cell nuclear antigen and CD31 was conducted to detect proliferation and vascular density. Enzyme-linked immunosorbent assay and immunohistochemistry were carried out to assess pro-inflammatory and anti-inflammatory factor concentrations. Western blot and immunofluorescence were implemented to analyze oxidative stress-related protein expression. RESULTS: Shikonin induced the activity of both fibroblasts and endothelial cells. Shikonin treatment contributed to facilitated wound healing and higher healing rates in rats. It also resulted in faster lesion debulking in tissues, reduced inflammatory infiltration, increased collagen deposition, and enhanced angiogenesis. Detection of markers at the wounds showed that shikonin accelerated cell proliferation, enhanced tissue remodeling, and inhibited oxidative stress. CONCLUSION: Shikonin stimulates the proliferation and migration of fibroblasts and endothelial cells to promote angiogenesis and tissue remodeling, resulting in faster wound healing.

A Questionnaire-Based Ensemble Learning Model to Predict the Diagnosis of Vertigo: Model Development and Validation Study.

BACKGROUND: Questionnaires have been used in the past 2 decades to predict the diagnosis of vertigo and assist clinical decision-making. A questionnaire-based machine learning model is expected to improve the efficiency of diagnosis of vestibular disorders. OBJECTIVE: This study aims to develop and validate a questionnaire-based machine learning model that predicts the diagnosis of vertigo. METHODS: In this multicenter prospective study, patients presenting with vertigo entered a consecutive cohort at their first visit to the ENT and vertigo clinics of 7 tertiary referral centers from August 2019 to March 2021, with a follow-up period of 2 months. All participants completed a diagnostic questionnaire after eligibility screening. Patients who received only 1 final diagnosis by their treating specialists for their primary complaint were included in model development and validation. The data of patients enrolled before February 1, 2021 were used for modeling and cross-validation, while patients enrolled afterward entered external validation. RESULTS: A total of 1693 patients were enrolled, with a response rate of 96.2% (1693/1760). The median age was 51 (IQR 38-61) years, with 991 (58.5%) females; 1041 (61.5%) patients received the final diagnosis during the study period. Among them, 928 (54.8%) patients were included in model development and validation, and 113 (6.7%) patients who enrolled later were used as a test set for external validation. They were classified into 5 diagnostic categories. We compared 9 candidate machine learning methods, and the recalibrated model of light gradient boosting machine achieved the best performance, with an area under the curve of 0.937 (95% CI 0.917-0.962) in cross-validation and 0.954 (95% CI 0.944-0.967) in external validation. CONCLUSIONS: The questionnaire-based light gradient boosting machine was able to predict common vestibular disorders and assist decision-making in ENT and vertigo clinics. Further studies with a larger sample size and the participation of neurologists will help assess the generalization and robustness of this machine learning method.

Salvianolic acid B inhibits ototoxic drug-induced ototoxicity by suppression of the mitochondrial apoptosis pathway.

It has been claimed that salvianolic acid B (Sal B), a natural bioactive antioxidant, exerts protective effects in various types of cells. This study aims to evaluate the antioxidant and anti-apoptosis effects of Sal B in a cultured HEI-OC1 cell line and in transgenic zebrafish (Brn3C: EGFP). A CCK-8 assay, Annexin V Apoptosis Detection Kit, TUNEL and caspase-3/7 staining, respectively, examined apoptosis and cell viability. The levels of reactive oxygen species (ROS) were evaluated by CellROX and MitoSOX Red staining. JC-1 staining was employed to detect the mitochondrial membrane potential (ΔΨm). Western blotting was used to assess expressions of Bax and Bcl-2. The expression pattern of p-PI3K and p-Akt was determined by immunofluorescent staining. We found that Sal B protected against neomycin- and cisplatin-induced apoptotic features, enhanced cell viability and accompanied with decreased caspase-3 activity in the HEI-OC1 cells. Supplementary experiments determined that Sal B reduced ROS production (increased ΔΨm), promoted Bcl-2 expression and down-regulated the expression of Bax, as well as activated PI3K/AKT signalling pathways in neomycin- and cisplatin-injured HEI-OC1 cells. Moreover, Sal B markedly decreased the TUNEL signal and protected against neomycin- and cisplatin-induced neuromast HC loss in the transgenic zebrafish. These results unravel a novel role for Sal B as an otoprotective agent against ototoxic drug-induced HC apoptosis, offering a potential use in the treatment of hearing loss.

Toxic Effects of 3,3'-Iminodipropionitrile on Vestibular System in Adult C57BL/6J Mice In Vivo.

The utricle is one of the five sensory organs in the mammalian vestibular system, and while the utricle has a limited ability to repair itself, this is not sufficient for the recovery of vestibular function after hair cell (HC) loss induced by ototoxic drugs. In order to further explore the possible self-recovery mechanism of the adult mouse vestibular system, we established a reliable utricle epithelium injury model for studying the regeneration of HCs and examined the toxic effects of 3,3'-iminodiproprionitrile (IDPN) on the utricle in vivo in C57BL/6J mice, which is one of the most commonly used strains in inner ear research. This work focused on the epithelial cell loss, vestibular dysfunction, and spontaneous cell regeneration after IDPN administration. HC loss and supporting cell (SC) loss after IDPN treatment was dose-dependent and resulted in dysfunction of the vestibular system, as indicated by the swim test and the rotating vestibular ocular reflex (VOR) test. EdU-positive SCs were observed only in severely injured utricles wherein above 47% SCs were dead. No EdU-positive HCs were observed in either control or injured utricles. RT-qPCR showed transient upregulation of Hes5 and Hey1 and fluctuating upregulation of Axin2 and ß-catenin after IDPN administration. We conclude that a single intraperitoneal injection of IDPN is a practical way to establish an injured utricle model in adult C57BL/6J mice in vivo. We observed activation of Notch and Wnt signaling during the limited spontaneous HC regeneration after vestibular sensory epithelium damage, and such signaling might act as the promoting factors for tissue self-repair in the inner ear.

Formononetin ameliorates cisplatin-induced hair cell death via activation of the PI3K/AKT-Nrf2 signaling pathway.

Cisplatin (CDDP) stands as a highly effective chemotherapeutic agent; however, its ototoxicity remains a perplexing challenge in the field. Formononetin (FMNT), a potent flavonoid isolated from Astragalus membranaceus, displays a diverse range of promising pharmacological activities, encompassing antioxidant, anti-apoptotic, and anti-inflammatory effects. Nonetheless, the advantageous effects of FMNT on cisplatin-induced cochlear hair cell injury demand further investigation. This study aimed to assess the protective properties of FMNT against cisplatin-induced hair cell damage by conducting in vitro assays on explant-cultured cochlear hair cells. The findings revealed that FMNT exhibited a notable reduction in cisplatin-induced hair cell apoptosis. Also, FMNT effectively mitigated the accumulation of reactive oxygen species and mitochondrial damage in cochlear explants exposed to cisplatin, while also restoring the turnover of the reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio. Furthermore, our study demonstrated that FMNT protects hair cells against CDDP injury through the activation of the PI3K/AKT-Nrf2 signaling pathway. Consequently, formononetin emerges as a potential therapeutic agent for the treatment of cisplatin-induced ototoxicity.

Mendelian Randomization Reveals: Triglycerides and Sensorineural Hearing Loss.

BACKGROUND: Sensorineural hearing loss (SNHL) is a multifactorial disorder with potential links to various physiological systems, including the cardiovascular system via blood lipid levels such as triglycerides (TG). This study investigates the causal relationship between TG levels and SNHL using Mendelian randomization (MR), which offers a method to reduce confounding and reverse causality by using genetic variants as instrumental variables. METHODS: Utilizing publicly available genome-wide association study (GWAS) data, we performed a two-sample MR analysis. The initial analysis unveiled a causal relationship between TG (GWAS ID: ebi-a-GCST90018975) and SNHL (GWAS ID: finn b-H8_HL_SEN-NAS). Subsequent analysis validated this through MR with a larger sample size for TG (GWAS ID: ieu-b-111) and SNHL. To conduct the MR analysis, we utilized several methods including inverse-variance weighted (IVW), MR Egger, weighted median, and weighted mode. We also employed Cochrane's Q test to identify any heterogeneity in the MR results. To detect horizontal pleiotropy, we conducted the MR-Egger intercept test and MR pleiotropy residual sum and outliers (MR-PRESSO) test. We performed a leave-one-out analysis to assess the sensitivity of this association. Finally, a meta-analysis of the MR results was undertaken. RESULTS: Our study found a significant positive correlation between TG and SNHL, with OR values of 1.14 (95% CI: 1.07-1.23, p < 0.001) in the IVW analysis and 1.09 (95% CI: 1.03-1.16, p < 0.006) in the replicate analysis. We also found no evidence of horizontal pleiotropy or heterogeneity between the genetic variants (p > 0.05), and a leave-one-out test confirmed the stability and robustness of this association. The meta-analysis combining the initial and replicate analyses showed a significant causal effect with OR values of 1.11 (95% CI: 1.06-1.16, p = 0.01). CONCLUSION: These findings indicate TG as a risk factor for SNHL, suggesting potential pathways for prevention and intervention in populations at risk. This conclusion underscores the importance of managing TG levels as a strategy to mitigate the risk of developing SNHL.

Giant condyloma acuminata of Buschke-Lowenstein: successful treatment mainly by an innovative surgical method.

Many remedies can be applied to condyloma acuminatum. However, it is the most difficult to treat giant condyloma acuminatum because of bleeding, recurrence, intolerance of patients, etc. After careful physical examination, the present authors found the giant tumor was composed of many smaller cauliflower-like warts with long and thin pedicles. So the present authors successfully excised the giant tumor mainly by clamping and cutting the pedicles with the best effects, the least damage to the perineal and perianal areas and lower recurrence. After 2 months, the patient recovered very well and remained free of recurrence at a 2-year follow-up.

PORP vs. TORP: a meta-analysis.

After the surgical procedure of ossicular chain reconstruction, the effectiveness and/or stability of partial ossicular replacement prosthesis (PORP) or total ossicular replacement prosthesis (TORP) were systematically compared and evaluated using meta-analysis. A total of 40 eligible investigations with 4,311 subjects were included in our study. There was a significant difference in the effectiveness of the reconstruction of the ossicular chain between PORP and TORP; the data showed a combined risk ratio (RR) of 1.28 (95 % CI 1.17-1.41, p < 0.00001), but no notable difference was obtained in staged procedures subgroup and cholesteatoma subgroup, with a combined RR of 1.13 (95 % CI 0.60-2.11, p = 0.70) in staged procedures subgroup and RR of 2.60 (95 % CI 0.20-36.21, p = 0.59 in cholesteatoma subgroup). There was a statistically significant difference in the stability of the prostheses in long-term follow-up, with a combined RR of 0.37 (95 % CI 0.16-0.85, p = 0.02), but no significant difference was observed in the total sample, with a combined RR of 0.64 (95 % CI 0.40-1.03, p = 0.06). Our overall results suggest that the effectiveness of PORP was higher than TORP, except within staged procedures subgroup and cholesteatoma subgroup. In addition, the stability of PORP was significantly superior to TORP in long-term follow-ups, but no significant effect was detected in the general study.

Social distancing cut down the prevalence of acute otitis media in children.

Objectives: To evaluate the additional, unintended benefits of social distancing in cutting down the prevalence of acute otitis media (AOM) in children, especially during coronavirus disease 2019 (COVID-19) periods. Methods: The daily outpatient attendance of AOM for childhood (from 6 months to 12 years) was compared in the tertiary hospital in Shanghai during pre-COVID-19 and COVID-19 year. Results: A total of 24,543 AOM cases were included from 2015 to 2020. When age was taken into account, children in kindergarten (aged 4-6) constitute 66.2% (16,236/24,543) of all case, followed by primary school students (6,441/24,543, 26.2%) and preschoolers <3 years old (1,866/24,543, 7.6%). There was an estimated 63.6% (54.32-70.36%) reduction in the daily outpatient attendance of AOM associated with the introduction of social distancing in 2020 (COVID-19 year). The epidemic trend of AOM in 2015-2019 was characterized by seasonal fluctuations, with highest incidence in December (18.8 ± 0.5%) and lower in February (4.5 ± 0.2%), June (3.7 ± 0.7%) and August (3.5 ± 0.5%). And distribution characteristics of different ages in COVID-19 period broadly in line with that in non-pandemic period. Conclusion: Seasonal fluctuation in the prevalence of AOM was observed in pre-COVID-19 period (2015-2019), with a peak in winter and a nadir in summer. The >50% drop of outpatient attendance of AOM in 2020 (COVID-19 year) suggest that social distancing, mask effects and good hand hygiene can significantly reduce the incidence of AOM, which provides a preventive and therapeutic point of view for AOM.

Prognosis of vestibular dysfunction in idiopathic sudden sensorineural hearing loss with vertigo: a prospective cohort study.

BACKGROUND: Approximately 28%-57% of patients with idiopathic sudden sensorineural hearing loss (ISSNHL) have an acute vertigo attack and probable vestibular dysfunction; however, the prognosis of vestibular function in these patients remains unclear. METHODS: A prospective cohort study of patients with ISSNHL and vertigo was conducted to evaluate the prognosis of vestibular function, especially the roles of peripheral vestibular restoration and central compensation, in patients with ISSNHL and vertigo. Clinical data were recorded at baseline and at 60 days from onset in participants with unilateral ISSNHL with vertigo. Enrolment occurred from May 1, 2019 to May 1, 2022 in the outpatient clinics and inpatient departments of the Eye and ENT Hospital of Fudan University in Shanghai. The primary outcome measure was the recovery rate of vestibular function 60 days after onset as assessed by vestibular function tests, including caloric tests, cervical and ocular vestibular-evoked myogenic potential tests (cVEMP, oVEMP), video head impulse tests (vHIT), and sensory organization tests (SOT). The secondary outcome measure was the recovery of subjective evaluations in vestibular dysfunction (the dizziness handicap inventory [DHI], and the visual analogue scale for vertigo [VAS-V]) and hearing assessments (pure-tone audiometry [PTA]). RESULTS: Overall, 86 patients were recruited, with an average duration of disease of 11.7 days and follow-up time of 60.7 days. Vestibular function was significantly improved (p < 0.05) after 60 days. The recovery rates were 100% for anterior semicircular canal (ASC), 56% for posterior semicircular canal (PSC), 41% for horizontal semicircular canal (HSC), 28% for saccule, and 23% for utricle. The recovery of vestibular function was not significantly related to changes in DHI (p = 0.245), VAS-V score (p = 0.509), or hearing outcome (p = 0.390). CONCLUSIONS: Restoration of peripheral vestibular sensory input and central vestibular compensation can occur during the course of ISSNHL with vertigo. The otolith organs are at a higher risk of being affected and have worse recovery than the semicircular canals. Incomplete and in-process restoration of vestibular dysfunction may perturb and delay the establishment of central compensation for balance. Neither hearing outcomes nor subjective vestibular symptoms are related to recovery from vestibular dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov (identifier NCT03951584).

The clinical effects of modified tinnitus relieving sound (MTRS) for chronic tinnitus: protocol for a randomized controlled trial.

INTRODUCTION: Chronic subjective tinnitus has become an increasingly serious hazard that affects the health-related quality of life for millions of people. Due to the lack of curative treatment strategies, this study aims to introduce a novel acoustic therapy named the modified tinnitus relieving sound (MTRS) for tinnitus and to evaluate the efficacy of MTRS in comparison with unmodified music (UM) which served as a control. METHODS AND ANALYSIS: A randomized, double-blinded, controlled, clinical trial will be carried out. Sixty-eight patients with subjective tinnitus will be recruited and randomly allocated into two groups in 1:1 ratio. The primary outcome is Tinnitus Handicapped Inventory (THI); the secondary outcomes are the Hospital Anxiety and Distress Scale (HADS; HADS subscales for Anxiety (HADS-A) and Depression (HADS-D)), Athens Insomnia Scale (AIS), the visual analog scale (VAS) for tinnitus, and tinnitus loudness matched by sensation level (SL). Assessment will be performed at baseline and at 1, 3, 9, and 12 months post-randomization. The sound stimulus will be persistent until 9 months after randomization, and be interdictory in the last three months. Data collected during the intervention process will be analyzed and compared to baseline. ETHICS AND DISSEMINATION: This trial received ethical approval from the Institutional Review Board (IRB) of Eye & ENT Hospital of Fudan University (No. 2017048). The study results will be disseminated via academic journals and conferences. FUNDING: This study is supported by the Shanghai Shenkang Development Program (SHDC12019119), the Excellent Doctors-Excellent Clinical Researchers Program (SYB202008), the Shanghai Rising-Star Program (23QC1401200), the Shanghai Rising Stars of Medical Talent Youth Development Program (2021-99), the National Natural Science Foundation of China (81800912), and the National Natural Science Foundation of Shanghai (21ZR1411800). TRIAL REGISTRATION: ClinicalTrials.gov NCT04026932. Registered on 18 July 2019.

Association between severe preoperative hearing impairment and postoperative emergence agitation among elderly patients undergoing middle ear surgery.

BACKGROUND: Hearing impairment is an established independent risk factor for delirium.Whether preoperative hearing impairment is associated with postoperative emergence agitation (POEA) in elderly patients remains unknown. This study aimed to investigate the association between preoperative hearing impairment and POEA in elderly patients undergoing ear surgery. METHODS: This prospective observational study was carried out at an otologic centre in a tertiary hospital between July 15, 2020, and February 28, 2021. Data of 417 elderly patients who underwent microscopic and endoscopic middle ear surgery were analyzed. Pure tone average was used to assess preoperative hearing function, with a PTA ≥ 50 dB indicating severe hearing impairment. POEA was measured using the Richmond Agitation-Sedation Scale. Multiple logistic regression was used to determine the association between preoperative hearing function and POEA. RESULTS: Of the 417 participants, 45.8% were men, and the median age was 64 (interquartile range: 62-67) years old. Severe preoperative hearing impairment was present in 113 patients (27.1%), and POEA occurred in 42 patients (10.1%). Multiple logistic regression analysis indicated that severe preoperative hearing impairment was associated with an increased risk of POEA (odds ratio: 2.031; 95% confidence interval: 1.044-3.954, P = 0.037). CONCLUSION: Pending confirmative studies, these findings suggest that severe preoperative hearing impairment could serve as an independent predictor of POEA in older patients undergoing middle ear surgery. These results highlight the need for further research to better understand the biomarker and pathogenesis of POEA, leading to identification of targeted interventions of POEA and improvement of postoperative outcomes in patients.

Novel cis compound heterozygous variants in MYO6 causes early onset of non-syndromic hearing loss in a Chinese family.

Background: Mutations in the MYO6 gene have been associated with both autosomal dominant non-syndromic hearing loss (ADNSHL) and autosomal recessive non-syndromic hearing loss (ARNSHL), with a cumulative identification of 125 pathogenic variants. To investigate the underlying genetic factor within a Chinese family affected with heriditary hearing loss, prompted the utilization of high-throughput sequencing. Method: A detailed clinical investigation was performed. Genetic testing was performed by using target panel sequencing, and Sanger sequencing. Targeted sequencing identified the variants and Sanger sequencing was employed to validate segregation of the identified variants within family. Additionally, bioinformatics analysis was performed to strengthen our findings. Results: Clinical investigation revealed the family members were affected by progressive and sensorineural hearing loss with an onset around 8-10 years old. Furthermore, genetic testing identified novel MYO6 variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn], positioned in a cis pattern, as plausible pathogenic contributors to early-onset hearing loss characterized by a severe and progressive course. Moreover, bioinformatics analysis showd disruptin in hydrogen bonding of mutant amino acids with interactive amino acids. Conclusion: Our research uncovered a relationship between mutations in the MYO6 gene and non-syndromic hearing loss. We identified two variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn] in MYO6 as strong candidates responsible for the observed progressive hereditary hearing loss. This study not only adds to our knowledge about hearing problems related to MYO6 but also reveals the presence of monogenic compound heterozygosity. Our study will provide a new sight for genetic diagnosis in such patients and their management for future use.

GWAS of Chronic Spontaneous Urticaria Reveals Genetic Overlap with Autoimmune Diseases, Not Atopic Diseases.

Although chronic spontaneous urticaria (CSU) is a common disease, GWASs of CSU are lacking. We aimed to identify susceptibility SNPs by performing a GWAS in Chinese Han adults with CSU. The discovery cohort included 430 CSU cases and 482 healthy controls. The GWAS findings were validated in 800 CSU cases and 900 healthy controls. Genetic, functional enrichment, and bioinformatic analyses of genome-wide significant SNPs were performed to assess the association between CSU and autoimmunity or atopy. Five genome-wide significant SNPs were identified: rs434124/LILRA3, rs61986182/IGHG1/2, rs73075571/TDGF1, rs9378141/HLA-G, and rs3789612/PTPN22. The first four SNPs were in linkage disequilibrium with autoimmune-related diseases‒associated SNPs and were cis-expression quantitative trait loci in immune cells. The five SNPs-annotated genes were significantly enriched in immune processes. Higher polygenic risk scores and allele frequencies of rs3789612∗T, rs9378141∗C, and rs73075571∗G were significantly associated with autoimmune-related CSU phenotypes, including positive antithyroglobulin IgG, positive anti-FcεRIα IgG, total IgE <40 IU/ml, and positive antithyroid peroxidase IgG but not with atopic or allergic sensitized CSU phenotypes. This GWAS of CSU identifies five risk loci and reveals that CSU shares genetic overlap with autoimmune diseases and that genetic factors predisposing to CSU mainly manifest through associations with autoimmune traits.

Effects of intratympanic gentamicin and intratympanic glucocorticoids in Ménière's disease: a network meta-analysis.

OBJECTIVE: Intratympanic therapies, usually including glucocorticoid and gentamicin, are becoming worldwide used in clinical practice of Ménière's disease today. However, clinical efficacy and safety of these two therapies are still in controversial. DATA SOURCES: Electronic searches in PubMed, CENTRAL, Web of Science, EMBASE, CINAHL, ClinicalTrials.gov and the European Union Clinical Trials Register were conducted from inception until September 2020. REVIEW METHODS: The pre-specified protocol of this systematic review and meta-analysis has been registered and published in November 2018 (PROSPERO Identifier: CRD42018114389). All randomized controlled trials of intratympanic gentamicin or glucocorticoids for Ménière's disease, compared with each other or placebo, were considered for this review. RESULTS: Ten studies with 455 patients met the inclusion criteria. Pooled results indicated significant advantage of intratympanic gentamicin and glucocorticoids over placebo treatments in vertigo control (gentamicin vs placebo: risk rate, RR, 2.56; 95% CI 1.18-5.54; glucocorticoids vs placebo: RR, 3.02; 95% CI 1.36-6.73). There was no significant difference between gentamicin and glucocorticoids in vertigo control (gentamicin vs placebo: RR, 1.18; 95% CI 0.97-1.45). Intratympanic glucocorticoids showed better hearing protective results than gentamicin (change of pure tone audiometric, PTA, mean difference, MD, - 6.48 dB; 95% CI - 11.84 to - 1.13 dB; change of speech discrimination scale, SDS, MD 7.69%; 95% CI 0.83-14.55%). CONCLUSIONS: Intratympanic gentamicin and glucocorticoids are two effective approaches to control vertigo symptoms for Ménière's disease. Glucocorticoids showed a potentially better hearing protective role over gentamicin.

Clinical Phenotypic Variability and Significance of Pneumolabyrinth After Tympanum-Penetrating Injury.

OBJECTIVES: This study aimed to investigate the clinical manifestations, treatment, and prognosis of traumatic pneumolabyrinth caused by tympanic membrane (TM) perforation. METHODS: Clinical data were collected from 3 cases of traumatic pneumolabyrinth occurring between 2015 and 2021 and 22 cases were identified from 20 articles in PubMed database that reported pneumolabyrinth due to tympanum-penetrating injury. INTERVENTION: Nonoperative treatment was performed in Cases 1 and 3. Middle ear inspection was performed 1 year after the injury due to worsening vertigo upon head movement in Case 2. MAIN OUTCOME MEASURES: Hearing outcomes and vestibular evaluations were presented for the 3 cases, and all comparable cases in the literature were reviewed. RESULTS: All 25 patients had a history of traumatic TM perforation, with perforations mostly located in the posterior or posterior superior quadrant (16 cases). Air signs were observed in the vestibule in all 25 patients, 15 of whom revealed stapes luxation into the vestibule. Conservative treatments were performed in 8 cases, and exploratory surgery in 17 cases. Most patients were free of vertigo (23/25). There were no significant hearing improvements in 15 cases, while hearing recovery or improvement was observed in 9 cases. CONCLUSIONS: The clinical manifestations of pneumolabyrinth due to tympanum-penetrating injuries vary widely. Importantly, the degree of hearing loss is not directly related to the subjectively perceived vertigo but to the location and extent of pneumolabyrinth.

Case Report: Successful Treatment of Alopecia Universalis With Tofacitinib and Increased Cytokine Levels: Normal Therapeutic Reaction or Danger Signal?

Alopecia universalis (AU) is an autoimmune disorder characterized by non-scarring hair loss in the scalp, eyebrows, beard, and nearly the entire body, negatively affecting patient prognosis. Available treatments are usually unsatisfactory. The autoimmune attacks of hair follicles induced by CD8+ T cells and the collapse of hair follicle immune privilege are believed to be the leading causes of AU. Additionally, interferon (IFN)-γ plays an important role in triggering the collapse of hair follicle immune privilege and impairing hair follicle stem cells. Furthermore, the upregulation of Janus kinase (JAK)3 and phospho-signal transducer and activator of transcription (pSTAT)3/STAT1 in alopecia areata patients suggest that JAK inhibitors can be a potentially promising choice for AU patients for the reason that JAK inhibitors can interfere with JAK-STAT signaling pathways and inhibit IFN-γ. Herein, we report a case of AU successfully treated with tofacitinib. However, this beneficial response in the patient was accompanied by a remarkable increase in peripheral blood cytokine levels during tofacitinib treatment.

Phenotypic Profiling of People With Subjective Tinnitus and Without a Clinical Hearing Loss.

Our objective was to study the characteristics of patients with subjective tinnitus and normal hearing and to investigate whether the features correlated to different shapes on audiograms. In this retrospective study, 313 patients with subjective tinnitus and clinically normal hearing were enrolled from the tinnitus outpatient department of the Eye and ENT Hospital of Fudan University. The following phenotypic variables were collected: age, dominant tinnitus pitch (TP), tinnitus loudness, tinnitus duration, tinnitus severity, sex, education, hearing thresholds, tinnitus position, and tinnitus condition. The dominant TPs of patients with normal hearing were mostly high-pitched, with a mean of 4866.8 ± 2579.6 Hz; thus, we speculated that the condition is related to high-frequency hearing threshold elevations. We further divided the patients into four subgroups based on the matched TP: (i) TP ≤ 500 Hz (n = 34), (ii) 500 Hz < TP ≤ 3,000 Hz (n = 15), (iii) 3,000 Hz < TP ≤ 8,000 Hz (n = 259), and (iv) TP > 8,000 Hz (n = 5). We studied the phenotypic profiling of different audiograms and found that the group with TP of ≤500 Hz had an average "inverted-U" shaped audiogram, and the group with TP between 500 and 3,000 Hz had a slowly ascending slope audiogram below 2,000 Hz, followed by a drastically descending slope audiogram ranging from 2,000 to 8,000 Hz; further, the high-frequency (3,000-8,000 Hz) and ultra-high-frequency (>8,000 Hz) groups had flat curves below 2,000 Hz and steeper slope audiograms over 2,000 Hz. Our findings confirmed a consistency ratio between the distributions of dominant TPs and the frequencies of maximum hearing thresholds in both ears. The dominant TP was positively correlated with the maximum hearing threshold elevation frequency (left ear: r = 0.277, p < 0.05; right ear: r = 0.367, p < 0.001). Hearing threshold elevations, especially in high frequency, might explain the appearance of dominant high-frequency TP in patients without clinically defined hearing loss. This is consistent with the causal role of high-frequency coding in the generation of tinnitus.

Droughts across China: Drought factors, prediction and impacts.

Drought is a complicated and costly natural hazard and identification of critical drought factors is critical for modeling and forecasting of droughts and hence development of drought mitigation measures (the Standardized Precipitation-Evapotranspiration Index) in both space and time. Here we quantified relationships between drought and 23 drought factors using remote sensing data during the period of 2002-2016. Based on the Gradient Boosting Algorithm (GBM), we found that precipitation and soil moisture had relatively large contributions to droughts. During the growing season, the relative importance of Normalized Difference Water Index (NDWI-7) for SPEI3, SPEI6, SPEI9, and SPEI12 reached as high as 50%. However, during the non-growing season, the Snow Cover Fraction (SCF) had larger fractional relative importance for short-term droughts in the Inner Mongolia and the Loess Plateau which can reach as high as 10%. We also compared Extremely Randomized Trees (ERT), H2O-based Deep Learning (Model developed by H2O.deep learning in R H2O.DL), and Extreme Learning Machine (ELM) for drought prediction at various time scales, and found that the ERT model had the highest prediction performance with R2 > 0.72. Based on the Meta-Gaussian model, we quantified the probability of maize yield reduction in the North China Plain under different compound dry-hot conditions. Due to extreme drought and hot conditions, Shandong Province in North China had the highest probability of >80% of the maize yield reduction; due to the extreme hot conditions, Jiangsu Province in East China had the largest probability of >86% of the maize yield reduction.