Hearing Features and Cochlear Implantation Outcomes in Patients With Pathogenic MYO15A Variants: a Multicenter Observational Study.

OBJECTIVES: Recessive variants in the MYO15A gene constitute an important cause of sensorineural hearing impairment (SNHI). However, the clinical features of MYO15A-related SNHI have not been systemically investigated. This study aimed to delineate the hearing features and outcomes in patients with pathogenic MYO15A variants. DESIGN: This study recruited 40 patients with biallelic MYO15A variants from 31 unrelated families. The patients were grouped based on the presence of N-terminal domain variants (N variants). The longitudinal audiological data and for those undergoing cochlear implantation, the auditory and speech performance with cochlear implants, were ascertained and compared between patients with different genotypes. RESULTS: At the first audiometric examination, 32 patients (80.0%) presented with severe to profound SNHI. Patients with at least one allele of the N variant exhibited significantly better hearing levels than those with biallelic non-N variants (78.2 ± 23.9 dBHL and 94.7 ± 22.8 dBHL, respectively) (p = 0.033). Progressive SNHI was observed in 82.4% of patients with non-profound SNHI, in whom the average progression rate of hearing loss was 6.3 ± 4.8 dBHL/year irrespective of the genotypes. Most of the 25 patients who underwent cochlear implantation exhibited favorable auditory and speech performances post-implantation. CONCLUSIONS: The hearing features of patients with biallelic pathogenic MYO15A variants are characterized by severe to profound SNHI, rapid hearing progression, and favorable outcomes with cochlear implants. Periodic auditory monitoring is warranted for these patients to enable early intervention.

The Efficacy of Pulsed Dye Laser Treatment for Acne Vulgaris: A Systemic Review and Meta-Analysis.

BACKGROUND: Previous reports have shown that pulsed dye laser (PDL) is promising for the treatment of acne; however, results provide conflicting evidence. OBJECTIVE: To determine the efficacy of PDL in treating acne vulgaris. METHODS: A systematic review and meta-analysis of studies published before March 31, 2020 was conducted. Randomized controlled trials and case series were analyzed. The meta-analysis estimated the standardized mean difference (SMD) in acne severity score changes in patients treated by PDL versus control and also the SMD of the acne severity scores and comedone counts changes before and after PDL treatment. RESULTS: Eleven studies were included in this systematic review. Six studies were included in the meta-analysis. Pulsed dye laser treatment was not found to be superior to the control group in treating acne vulgaris (SMD: -0.285; 95% confidence interval [CI], -0.886 to 0.317). However, single-arm studies revealed a significantly improved acne severity score after PDL therapy (SMD, -1.321; 95% CI, -2.057 to -0.586), especially when a multiple-session treatment and a longer pulse duration were employed. The comedone counts were significantly decreased after PDL therapy (SMD, -0.596; 95% CI, -1.137 to -0.054). CONCLUSION: When treatment consisted of 4 or more sessions or longer pulse duration, PDL could significantly decrease the acne severity score.

Therapeutic Effect of Icaritin on Cerebral Ischemia-Reperfusion-Induced Senescence and Apoptosis in an Acute Ischemic Stroke Mouse Model.

An ischemic stroke is brain damage caused by interruption of blood supply to the brain that can cause death and long-term disability. New medical strategies or therapies are urgently needed for ischemic stroke. Icaritin (ICT) is a metabolite of icariin (ICA), which are two active flavonoid components extracted from Herba epimedii and considered neuroprotective agents in animal models of Alzheimer's disease and ischemic stroke. The therapeutic effect of ICT on ischemic still remains to be clarified. The aim of this study was to investigate the therapeutic effect of ICT on cerebral ischemia-reperfusion-associated senescence and apoptosis in a middle cerebral artery occlusion (MCAO) mouse model (ischemia for 50 min and reperfusion for 24 h). Administration of ICT after ischemia significantly reduced MCAO-induced neurological damage, infarct volume, and histopathological changes in the brain of acute ischemic stroke mice. ICT treatment could also reduce neuronal apoptosis and senescence and reversed the expression of apoptosis- and senescence-related signaling proteins. These findings suggest that ICT may have therapeutic potential to ameliorate acute ischemic stroke.

Serum Homocysteine, Folate, and Vitamin B12 Levels in Patients with Systemic Lupus Erythematosus: A Meta-Analysis and Meta-Regression.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) have elevated cardiovascular risk. Hyperhomocysteinemia may be one of the contributing factors to this phenomenon. This study therefore aimed to compare the serum homocysteine levels and the levels of folate and vitamin B12, cofactors for homocysteine metabolism, between individuals with and without SLE. METHODS: A literature search was performed in PubMed, Embase, and the Cochrane library (from inception to March 31, 2019). Studies comparing serum homocysteine, folate or vitamin B12 levels between individuals with and without SLE were selected. Of the 1040 screened studies, 50 studies met the inclusion criteria. RESULTS: A total of 50 studies involving 4396 patients with SLE were included. Patients with SLE had a significantly higher serum level of homocysteine (standardized mean difference [SMD], 1.134; 95% CI, 0.795-1.474) and lower level of vitamin B12 (SMD, -0.359; 95% CI, -0.638 to -0.080) than controls. The folate level didn't differ markedly between SLE patients and the control group (SMD, -0.276; 95% CI, -0.674-0.123). Subgroup analysis showed consistent results in adult SLE patients. A random effects meta-regression analysis revealed a significantly inverse correlation between the SMD of homocysteine levels and C3 levels (coefficient, -0.0356, 95% CI, -0.054 to -0.0171; P < .001) and C4 levels (coefficient, -0.0876, 95% CI, -0.1407 to -0.0345; P = .0012). CONCLUSIONS: Serum homocysteine levels were higher and vitamin B12 levels were lower among individuals with SLE than those without SLE. Physicians are encouraged to monitor these parameters and offer timely interventions for patients with SLE.

Small molecule inhibitors and biologics in treating nail psoriasis: A systematic review and network meta-analysis.

BACKGROUND: Various systemic immunomodulating therapies have been investigated to treat nail psoriasis, but the efficacy remains unclear. OBJECTIVE: To perform a systematic review and network meta-analysis to evaluate the efficacy of small molecule inhibitors and biologics in treating nail psoriasis. METHODS: Eligible studies in online databases were identified until March 10, 2020. To assess the efficacy of small molecule inhibitors and biologics, network meta-analyses with surface under the cumulative ranking curve of improvement in nail score at 10 to 16 and at 24 to 26 weeks, as well as 100% improvement of Nail Psoriasis Severity Index (NAPSI), were performed. RESULTS: Thirty-nine studies with a total of 13 treatment arms involving 15,673 patients with nail psoriasis were included. An network meta-analysis showed that tofacitinib (weighted mean difference, 56.67; 95% confidence interval [CI], 35.87-77.48) and ixekizumab (weighted mean difference, 59.40; 95% CI, 45.87-72.93) presented the most improvement of nail score at 10 to 16 weeks and 24 to 26 weeks, respectively. For 100% improvement of the Nail Psoriasis Severity Index, ixekizumab showed the best efficacy among all treatments (odds ratio, 2.98; 95% CI, 1.74-5.10). LIMITATIONS: Insufficiency of eligible data and no long-term follow-up data. CONCLUSION: Tofacitinib and ixekizumab presented the best efficacy for treating nail psoriasis in 10 to 16 weeks and 24 to 26 weeks, respectively.

Toward the Pathogenicity of the SLC26A4 p.C565Y Variant Using a Genetically Driven Mouse Model.

Recessive variants of the SLC26A4 gene are globally a common cause of hearing impairment. In the past, cell lines and transgenic mice were widely used to investigate the pathogenicity associated with SLC26A4 variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some SLC26A4 variants. For instance, the p.C565Y variant, which was reported to be pathogenic in humans, did not exhibit functional pathogenic consequences in cell lines. To address the pathogenicity of p.C565Y, we used a genotype-based approach in which we generated knock-in mice that were heterozygous (Slc26a4+/C565Y), homozygous (Slc26a4C565Y/C565Y), and compound heterozygous (Slc26a4919-2A>G/C565Y) for this variant. Subsequent phenotypic characterization revealed that mice with these genotypes demonstrated normal auditory and vestibular functions, and normal inner-ear morphology and pendrin expression. These findings indicate that the p.C565Y variant is nonpathogenic for mice, and that a single p.C565Y allele is sufficient to maintain normal inner-ear physiology in mice. Our results highlight the differences in pathogenicity associated with certain SLC26A4 variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for SLC26A4-related deafness.

Prediction Model for Audiological Outcomes in Patients With GJB2 Mutations.

OBJECTIVES: Recessive mutations in GJB2 are the most common genetic cause of sensorineural hearing impairment (SNHI) in humans. SNHI related to GJB2 mutations demonstrates a wide variation in audiological features, and there has been no reliable prediction model for hearing outcomes until now. The objectives of this study were to clarify the predominant factors determining hearing outcome and to establish a predictive model for SNHI in patients with GJB2 mutations. DESIGN: A total of 434 patients confirmed to have biallelic GJB2 mutations were enrolled and divided into three groups according to their GJB2 genotypes. Audiological data, including hearing levels and audiogram configurations, were compared between patients with different genotypes. Univariate and multivariate generalized estimating equation (GEE) analyses were performed to analyze longitudinal data of patients with multiple audiological records. RESULTS: Of the 434 patients, 346 (79.7%) were homozygous for the GJB2 p.V37I mutation, 55 (12.7%) were compound heterozygous for p.V37I and another GJB2 mutation, and 33 (7.6%) had biallelic GJB2 mutations other than p.V37I. There was a significant difference in hearing level and the distribution of audiogram configurations between the three groups. Multivariate GEE analyses on 707 audiological records of 227 patients revealed that the baseline hearing level and the duration of follow-up were the predominant predictors of hearing outcome, and that hearing levels in patients with GJB2 mutations could be estimated based on these two parameters: (Predicted Hearing Level [dBHL]) = 3.78 + 0.96 × (Baseline Hearing Level [dBHL]) + 0.55 × (Duration of Follow-Up [y]). CONCLUSION: The baseline hearing level and the duration of follow-up are the main prognostic factors for outcome of GJB2-related SNHI. These findings may have important clinical implications in guiding follow-up protocols and designing treatment plans in patients with GJB2 mutations.

Efficacy of Nail Braces for Acute and Chronic Ingrown Toenails: A Prospective Study.

BACKGROUND: Nail braces are an alternative treatment for ingrown toenails. OBJECTIVE: This study aimed to prospectively examine the efficacy of nail braces for treatment of acute inflamed (AI)-type and chronic dystrophic-type ingrown toenails. MATERIALS AND METHODS: The authors conducted a prospective study of patients with ingrown toenails treated at Wan Fang Hospital between January 1, 2017, and July 31, 2018. Evaluation using physician global assessment scores and patient satisfaction questionnaires was performed at 1, 3, and 6 months after the start of treatment and during the final visit. Patient demographics, treatment courses, and outcomes were compared between the 2 types of ingrown toenails. RESULTS: Chronic dystrophic-type and AI-type ingrown toenails were observed in 25 (61 sides) and 28 patients (35 sides), respectively. Of the affected sides, 80.9%, 94.9%, and 100% achieved an excellent or fair result at 1, 3, and 6 months, respectively. Treatment duration and follow-up period were 179.2 ± 96.8 days and 281.6 ± 120.9, respectively. The recurrence rate was 7.4%. The treatment course and response were different between the 2 types of ingrown toenails. CONCLUSION: Ingrown toenails could be effectively treated with nail braces with excellent outcomes, favorable patient satisfaction, and low recurrence rates.

Eradicating Otomycosis with Terbinafine Solution: Basic and Clinical Investigation.

BACKGROUND: Otomycosis still remains intractable in clinical practice, likely because topical antifungal agents lack efficacy or are potentially toxic to the inner ear end organs. OBJECTIVES: The aim of this study was to investigate whether terbinafine solution is a potential candidate for treating intractable otomycosis in humans. In addition, the toxic effect on the inner ear was also assessed by animal models treated with terbinafine. METHODS: Guinea pigs were instilled with 0.1 mL terbinafine (10 and 25 mg/mL) in the left round window membrane. At 2 weeks after treatment, all animals underwent an inner ear test battery and were then sacrificed for morphological study. Clinically, 20 patients with otomycosis were treated with terbinafine solution at a dosage of 0.4 mg. RESULTS: All terbinafine-treated animals showed intact inner ear function when total dosage of terbinafine was <2.5 mg, which was further confirmed by morphological study. Subsidence of otomycosis was achieved in all 20 patients 1 week after treatment with terbinafine (0.4 mg) without untoward effect. No evidence of recurrence was noted 1 year after treatment. CONCLUSION: The paucity of inner ear toxicity of terbinafine even at a dosage of 2.5 mg was identified in guinea pig models morphologically and physiologically. Topical application of terbinafine solution at a dosage of 0.4 mg may be a potential treatment for otomycosis in humans.

Low Intensity Pulsed Ultrasound Prevents Recurrent Ischemic Stroke in a Cerebral Ischemia/Reperfusion Injury Mouse Model via Brain-derived Neurotrophic Factor Induction.

The incidence of stroke recurrence is still higher despite the advanced progression of therapeutic treatment and medical technology. Low intensity pulsed ultrasound (LIPUS) has been demonstrated to possess therapeutic effects on neuronal diseases and stroke via brain-derived neurotrophic factor (BDNF) induction. In this study, we hypothesized that LIPUS treatment possessed therapeutic benefits for the improvement of stroke recurrence. Adult male C57BL/6J mice were subjected to a middle cerebral artery occlusion (MCAO) surgery and then followed to secondary MCAO surgery as a stroke recurrence occurred after nine days from the first MCAO. LIPUS was administered continuously for nine days before secondary MCAO. LIPUS treatment not only decreased the mortality but also significantly moderated neuronal function injury including neurological score, motor activity, and brain pathological score in the recurrent stroke mice. Furthermore, the administration of LIPUS attenuated the apoptotic neuronal cells and increased Bax/Bcl-2 protein expression ratio and accelerated the expression of BDNF in the brain of the recurrent stroke mice. Taken together, these results demonstrate for the first time that LIPUS treatment arouses the expression of BDNF and possesses a therapeutic benefit for the improvement of stroke recurrence in a mouse model. The neuroprotective potential of LIPUS may provide a useful strategy for the prevention of a recurrent stroke.

Advanced glycation end-products induce skeletal muscle atrophy and dysfunction in diabetic mice via a RAGE-mediated, AMPK-down-regulated, Akt pathway.

Diabetic myopathy, a less studied complication of diabetes, exhibits the clinical observations characterized by a less muscle mass, muscle weakness and a reduced physical functional capacity. Accumulation of advanced glycation end-products (AGEs), known to play a role in diabetic complications, has been identified in ageing human skeletal muscles. However, the role of AGEs in diabetic myopathy remains unclear. Here, we investigated the effects of AGEs on myogenic differentiation and muscle atrophy in vivo and in vitro. We also evaluated the therapeutic potential of alagebrium chloride (Ala-Cl), an inhibitor of AGEs. Muscle fibre atrophy and immunoreactivity for AGEs, Atrogin-1 (a muscle atrophy marker) and phosphorylated AMP-activated protein kinase (AMPK) expressions were markedly increased in human skeletal muscles from patients with diabetes as compared with control subjects. Moreover, in diabetic mice we found increased blood AGEs, less muscle mass, lower muscular endurance, atrophic muscle size and poor regenerative capacity, and increased levels of muscle AGE and receptor for AGE (RAGE), Atrogin-1 and phosphorylated AMPK, which could be significantly ameliorated by Ala-Cl. Furthermore, in vitro, AGEs (in a dose-dependent manner) reduced myotube diameters (myotube atrophy) and induced Atrogin-1 protein expression in myotubes differentiated from both mouse myoblasts and primary human skeletal muscle-derived progenitor cells. AGEs exerted a negative regulation of myogenesis of mouse and human myoblasts. Ala-Cl significantly inhibited the effects of AGEs on myotube atrophy and myogenesis. We further demonstrated that AGEs induced muscle atrophy/myogenesis impairment via a RAGE-mediated AMPK-down-regulation of the Akt signalling pathway. Our findings support that AGEs play an important role in diabetic myopathy, and that an inhibitor of AGEs may offer a therapeutic strategy for managing the dysfunction of muscle due to diabetes or ageing.

Machine learning-based longitudinal prediction for GJB2-related sensorineural hearing loss.

BACKGROUND: Recessive GJB2 variants, the most common genetic cause of hearing loss, may contribute to progressive sensorineural hearing loss (SNHL). The aim of this study is to build a realistic predictive model for GJB2-related SNHL using machine learning to enable personalized medical planning for timely intervention. METHOD: Patients with SNHL with confirmed biallelic GJB2 variants in a nationwide cohort between 2005 and 2022 were included. Different data preprocessing protocols and computational algorithms were combined to construct a prediction model. We randomly divided the dataset into training, validation, and test sets at a ratio of 72:8:20, and repeated this process ten times to obtain an average result. The performance of the models was evaluated using the mean absolute error (MAE), which refers to the discrepancy between the predicted and actual hearing thresholds. RESULTS: We enrolled 449 patients with 2184 audiograms available for deep learning analysis. SNHL progression was identified in all models and was independent of age, sex, and genotype. The average hearing progression rate was 0.61 dB HL per year. The best MAE for linear regression, multilayer perceptron, long short-term memory, and attention model were 4.42, 4.38, 4.34, and 4.76 dB HL, respectively. The long short-term memory model performed best with an average MAE of 4.34 dB HL and acceptable accuracy for up to 4 years. CONCLUSIONS: We have developed a prognostic model that uses machine learning to approximate realistic hearing progression in GJB2-related SNHL, allowing for the design of individualized medical plans, such as recommending the optimal follow-up interval for this population.

Revisiting Genetic Epidemiology with a Refined Targeted Gene Panel for Hereditary Hearing Impairment in the Taiwanese Population.

Hearing impairment is one of the most common sensory disorders in children, and targeted next-generation sequencing (NGS)-based genetic examinations can assist in its prognostication and management. In 2020, we developed a simplified 30-gene NGS panel from the original 214-gene NGS version based on Taiwanese genetic epidemiology data to increase the accessibility of NGS-based examinations. In this study, we evaluated the diagnostic performance of the 30-gene NGS panel and compared it with that of the original 214-gene NGS panel in patient subgroups with different clinical features. Data on the clinical features, genetic etiologies, audiological profiles, and outcomes were collected from 350 patients who underwent NGS-based genetic examinations for idiopathic bilateral sensorineural hearing impairment between 2020 and 2022. The overall diagnostic yield was 52%, with slight differences in genetic etiology between patients with different degrees of hearing impairment and ages of onset. No significant difference was found in the diagnostic yields between the two panels, regardless of clinical features, except for a lower detection rate of the 30-gene panel in the late-onset group. For patients with negative genetic results, where the causative variant is undetectable on current NGS-based methods, part of the negative results may be due to genes not covered by the panel or yet to be identified. In such cases, the hearing prognosis varies and may decline over time, necessitating appropriate follow-up and consultation. In conclusion, genetic etiologies can serve as references for refining targeted NGS panels with satisfactory diagnostic performance.

Cochlear Implantation Outcomes in Patients with Auditory Neuropathy Spectrum Disorder of Genetic and Non-Genetic Etiologies: A Multicenter Study.

With diverse etiologies and clinical features, the management of pediatric auditory neuropathy spectrum disorder (ANSD) is often challenging, and the outcomes of cochlear implants (CIs) are variable. This study aimed to investigate CI outcomes in pediatric patients with ANSD of different etiologies. Thirty-six children with ANSD who underwent cochlear implantation between 2001 and 2021 were included. Comprehensive etiological analyses were conducted, including a history review, next-generation sequencing-based genetic examinations, and imaging studies using high-resolution computed tomography and magnetic resonance imaging. Serial behavioral and speech audiometry were performed before and after surgery, and the outcomes with CI were evaluated using the Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR) scores. By etiology, 18, 1, 1, and 10 patients had OTOF-related, WFS1-related, OPA1-related, and cochlear nerve deficiency (CND)-related ANSD, respectively. Six patients had no definite etiology. The average CI-aided behavioral threshold was 28.3 ± 7.8 dBHL, and those with CND-related ANSD were significantly worse than OTOF-related ANSD. The patients' median CAP and SIR scores were 6 and 4, respectively. Favorable CI outcomes were observed in patients with certain etiologies of ANSD, particularly those with OTOF (CAP/SIR scores 5-7/2-5), WFS1 (CAP/SIR score 6/5), and OPA1 variants (CAP/SIR score 7/5). Patients with CND had suboptimal CI outcomes (CAP/SIR scores 2-6/1-3). Identifying the etiologies in ANSD patients is crucial before surgery and can aid in predicting prognoses.

Detection and genotyping of Giardia duodenalis from cattle and pigs in Hualien country, Eastern Taiwan.

BACKGROUND: Giardia duodenalis is a zoonotic protozoan parasite causing diarrhea through waterborne or fecal-oral infection. The cysts can live in the drinking water and cause pandemic diseases. In Taiwan, very little information is available regarding the epidemiology of G. duodenalis in domestic animals. METHODS: Fecal samples were collected from cattle (n = 156) and pigs (n = 141) in Hualien country, eastern Taiwan. Detection and genotyping were done by microscopy examination of fecal samples and amplification of the ß-giardin gene using nested PCR. RESULTS: The prevalence of G. duodenalis infection was 19.87% for cattle (31/156) and 4.26% for pigs (6/141). Using nested PCR, 30 infected samples found in cattle belonged to Assemblage E, and one sample belonged to Assemblage D. For pigs, four samples belonged to Assemblage E, one belonged to Assemblage D, and another one belonged to Assemblage A. In addition, these results showed that G. duodenalis Assemblage A was detected in pigs and may cause zoonotic transmission. CONCLUSION: This is the first epidemiological investigation of G. duodenalis infection in animals in Hualien, Taiwan. These results could provide epidemiological information for disease control and public health protection.

Heat-killed Propionibacterium acnes augment the protective effect of 28-kDa glutathione S-transferases antigen against Schistosoma mansoni infection.

Sm28GST is one of the candidate antigens for Schistosoma mansoni vaccine. Already Sm28GST vaccine formulations have shown to be protective against S. mansoni infection. Currently, efforts have been put into finding an adjuvant to enhance the immunity induced by Sm28GST. In the present work, we investigated whether heat-killed Propionibacterium acnes can be served as a potential adjuvant for recombinant Sm28GST (rSm28GST) antigen. As the results showed, P. acnes successfully modulated the Th1 humoral immune response induced by rSm28GST. Stronger Th1 cytokines responses were also observed in mice immunized with P. acnes-adjuvanted rSm28GST. Immunization of mice with P. acnes-adjuvanted rSm28GST was able to reduce worm burden and hepatic egg burden by 54.20 and 73.61%. Reduced granuloma size and count, as well as improved liver histology, were seen in P. acnes-adjuvanted rSm28GST immunized mice. These data suggest that P. acnes may evoke a stronger rSm28GST-induced immune response, higher resistance to S. mansoni infection, and more profound protection against S. mansoni-induced liver damages.