Ivacaftor attenuates gentamicin-induced ototoxicity through the CFTR-Nrf2-HO1/NQO1 pathway.

OBJECTIVES: Gentamicin is one of the most common ototoxic drugs that can lower patients' quality of life. Oxidative stress is a key factors inducing sensory hair cell death during gentamicin administration. So far, there are no effective drugs to prevent or treat gentamicin- induced hearing loss. A recent study found cystic fibrosis transmembrane conductance regulator (CFTR) as a new target to modulate cellular oxidative balance. The objective of this study was to estimate the effect of the CFTR activator ivacaftor on gentamicin-induced ototoxicity and determine its mechanism. METHODS: The hair cell count was analyzed by Myosin 7a staining. Apoptosis was analyzed by TUNEL Apoptosis Kit. Cellular reactive oxygen species (ROS) level was detected by DCFH-DA probes. The Nrf2 related proteins expression levels were analyzed by western blot. RESULTS: An in vitro cochlear explant model showed that gentamicin caused ROS accumulation in sensory hair cells and induced apoptosis, and this effect was alleviated by pretreatment with ivacaftor. Western blotting showed that ivacaftor administration markedly increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The protective effect of ivacaftor was abolished by the Nrf2 inhibitor ML385. DISCUSSION: Our results indicate the protective role of the CFTR-Nrf2-HO1/NQO1 pathway in gentamicin-induced ototoxicity. Ivacaftor may be repositioned or repurposed towards aminoglycosides-induced hearing loss.

Cochlear implantation in patients with Streptococcus suis meningitis: clinical characteristics and postoperative evaluation.

BACKGROUND: Hearing loss is a common sequala of Streptococcus suis (S. suis) meningitis, but few have addressed cochlear implantation (CI) candidates with S. suis meningitis. OBJECTIVES: To assess the clinical characteristics and CI postoperative outcomes in S. suis meningitis patients. MATERIAL AND METHODS: Eight S. suis meningitis patients underwent CI at Sun Yat-sen Memorial Hospital between 2020 and 2023. Control groups included (1) non-Suis meningitis patients (n = 12) and (2) non-meningitis patients (n = 35). Electrode impedances and neural response telemetry (NRT) thresholds were recorded at one month after surgery. The auditory performance-II (CAP) and speech intelligibility rating (SIR) were recorded at the last visit. RESULTS: CAP scores of S. suis meningitis patients were significantly lower than those of non-Suis meningitis and non-meningitis patients (p = .019; p<.001). And NRT thresholds of S. suis meningitis patients were higher than those of non-Suis meningitis and non-meningitis patients (p = .006; p = .027). CONCLUSIONS AND SIGNIFICANCE: It is recommended for S. suis meningitis CI candidates to undergo CI promptly after controlling infection, preferably within four to six weeks. CI users with S. suis meningitis tend to exhibit suboptimal hearing rehabilitation outcomes, possibly associated with the more severe damage on spiral ganglion cells after S. suis meningitis.

Selective Nitrate Electroreduction to Ammonia on CNT Electrodes with Controllable Interfacial Wettability.

The development of electrocatalysts that can efficiently reduce nitrate (NO3-) to ammonia (NH3) has garnered increasing attention due to their potential to reduce carbon emissions and promote environmental protection. Intensive efforts have focused on catalyst development, but a thorough understanding of the effect of the microenvironment around the reactive sites of the catalyst is also crucial to maximize the performance of the electrocatalysts. This study explored an electrocatalytic system that utilized quaternary ammonium surfactants with a range of alkyl chain lengths to modify an electrode made of carbon nanotubes (CNT), with the goal of regulating interfacial wettability toward NO3- reduction. Trimethyltetradecylammonium bromide with a moderate alkyl chain length created a very hydrophobic interface, which led to a high selectivity in the production of NH3 (∼87%). Detailed mechanistic investigations that used operando Fourier-transform infrared (FTIR) spectroscopy and online differential electrochemical mass spectrometry (DEMS) revealed that the construction of a hydrophobic modified CNT played a synergistic role in suppressing a side reaction involving the generation of hydrogen, which would compete with the reduction of NO3-. This electrocatalytic system led to a favorable process for the reduction of NO3- to NH3 through a direct electron transfer pathway. Our findings underscore the significance of controlling the hydrophobic surface of electrocatalysts as an effective means to enhance electrochemical performance in aqueous media.

Endoplasmic reticulum stress-induced necroptosis promotes cochlear inflammation: Implications for age-related hearing loss.

Age-related hearing loss (ARHL) is the most common sensory disorder associated with human aging. Chronic inflammation is supposed to be an important contributor to ARHL. Yet, the underlying mechanisms of developing cochlear inflammation are still not well understood. In this study, we found that the inflammation, endoplasmic reticulum (ER) stress and necroptosis signalings are activated in the cochlea of aged C57BL/6 mice. ER stress activator tunicamycin (TM) induced necroptosis in cochlear HEI-OC1 cells and cochlear explants, while necroptosis inhibitors protected cochlear cells from ER stress-induced cell death. The antioxidants inhibited necroptosis and protected HEI-OC1 cells from TM insults. Necroptotic HEI-OC1 cells promoted the activation of the co-cultured macrophages via Myd88 signaling. Moreover, necroptosis inhibitor protected from TM-induced hearing loss, and inhibited inflammation in C57BL/6 mice. These findings suggest that ER stress-induced necroptosis promotes cochlear inflammation and hearing loss. Targeting necroptosis serves as a potential approach for the treatment of cochlear inflammation and ARHL.

Reactive Oxygen Species-Related Disruptions to Cochlear Hair Cell and Stria Vascularis Consequently Leading to Radiation-Induced Sensorineural Hearing Loss.

Aims: Radiation-induced sensorineural hearing loss (RISNHL) is one of the major side effects of radiotherapy for head and neck cancers. At present, no effective clinical treatment or prevention is available for RISNHL. This study thus aimed to investigate the cochlear pathology so that the underlying mechanisms of RISNHL may be elucidated, consequently paving the way for potential protective strategies to be developed. Results: Functional and morphological impairment in the stria vascularis (SV) was observed after irradiation (IR), as indicated by endocochlear potential (EP) reduction, hyperpermeability, and SV atrophy. The expression of zonulae occludins-1 was found to have decreased after IR. The loss of outer hair cells (OHCs) occurred later than SV damage. The disruption to the SV and OHCs could be attributed to reactive oxygen species (ROS)-related damage. In addition, EP shifts and the loss of OHCs were reduced when ROS was reduced by N-acetylcysteine (NAC) in C57BL/6 mice, attenuating auditory threshold shifts. Innovation: The damage to the SV was found to occur before OHC loss. ROS-related damage accounted for SV damage and OHC loss. The incidences of SV damage and OHC loss were decreased through ROS modulation by NAC, subsequently preventing RISNHL, suggesting the possible role of NAC as a possible protective agent against RISNHL. Conclusion: The findings from this study suggest oxidative stress-induced early SV injury and late OHC loss to be the key factors leading to RISNHL. NAC prevents IR-induced OHC loss, and attenuates auditory brainstem response and EP shifts by regulating the level of oxidative stress. Antioxid. Redox Signal. 40, 470-491.

Re-evaluation for systematic reviews of traditional Chinese medicine in the treatment of chronic bronchitis.

BACKGROUND: Chronic bronchitis (CB) is a common clinical chronic respiratory disease, which has a high incidence in the middle aged and elderly population. With the development of the disease, the number of acute attacks becomes more and more frequent, which leads to the continuous decrease of lung function. If not treated in time, it will lead to a variety of complications and seriously affect the quality of life of patients. Traditional Chinese medicine (TCM) or TCM combined with western medicine is highly effective in the treatment of CB disease. In recent years, there are many systematic reviews on the use of TCM therapy in the treatment of CB, and the efficacy and safety of TCM in the treatment of CB diseases are evaluated. The aim of this study was to re-evaluate the Meta analysis/Systematic reviews (MAs/SRs) of TCM for the treatment of CB, aiming to provide a clinical basis for the treatment of CB by TCM. METHODS: Retrieval among Chinese and English databases such as China National Knowledge Infrastructure, Wanfang database, China Scientific Journals Database, SinoMed, PubMed, Web of Science, The Cochrane Library and EMbase, etc. were conducted within the duration from database establish Tion date to March 2023.The included research was independently conducted by 2 researchers for literature screening, data extraction, and quality evaluation. The AMSTAR 2 scale was used to evaluate the quality of the report, the PRISMA 2020 statement evaluated the quality of the report, the ROBIS tool evaluated the risk of bias, and the GRADE quality evaluation tool evaluated the quality of the evidence. RESULTS: Fifteen MAs/SRs were included, for a total of 224 studies involving 20,710 patients with CB. The 15 studies included in AMSTAR 2 are of very low quality. The ROBIS evaluation results showed that 8 MAs/SRs were considered to have high risk and 7 with low risk. The PRISMA 2020 report quality showed evaluation results of the included studies scores between 24 and 30, among them 13 with high quality and 2 with low quality. The GRADE system results showed that, within 70 outcome indicators, only 14 of them have moderate quality for evidence, with 31 for low quality, 25 for very low quality, and none for high quality. CONCLUSION: The MAs/SRs methodological quality of using TCM for treatment CB is generally poor, the quality of reports as well as evidence are generally low, and the risk of bias is high, therefore we should treat these results with caution.

Exploring the alternative virulence determinants PB2 S155N and PA S49Y/D347G that promote mammalian adaptation of the H9N2 avian influenza virus in mice.

The occurrence of human infections caused by avian H9N2 influenza viruses has raised concerns regarding the potential for human epidemics and pandemics. The molecular basis of viral adaptation to a new host needs to be further studied. Here, the bases of nucleotides 627 and 701 of PB2 were changed according to the uncoverable purine-to-pyrimidine transversion to block the development of PB2 627K and 701N mutations during serial passaging in mice. The purpose of this experiment was to identify key adaptive mutations in polymerase and NP genes that were obscured by the widely known host range determinants PB2 627K and 701N. Mouse-adapted H9N2 variants were obtained via twelve serial lung-to-lung passages. Sequence analysis showed that the mouse-adapted viruses acquired several mutations within the seven gene segments (PB2, PB1, PA, NP, HA, NA, and NS). One variant isolate with the highest polymerase activity possessed three substitutions, PB2 S155N, PA S49Y and D347G, which contributed to the highly virulent and mouse-adaptative phenotype. Further studies demonstrated that these three mutations resulted in increased polymerase activity, viral transcription and replication in mammalian cells, severe interstitial pneumonia, excessive inflammatory cellular infiltration and increased growth rates in mice. Our results suggest that the substitution of these three amino acid mutations may be an alternative strategy for H9N2 avian influenza viruses to adapt to mammalian hosts. The continued surveillance of zoonotic H9N2 influenza viruses should also include these mammalian adaptation markers as part of our pandemic preparedness efforts.

CFTR potentiator ivacaftor protects against noise-induced hair cell loss by increasing Nrf2 and reducing oxidative stress.

Over-production of reactive oxygen species (ROS) in the inner ear can be triggered by a variety of pathological events identified in animal models after traumatic noise exposure. Our previous research found that inhibition of the AMP-activated protein kinase alpha subunit (AMPKα) protects against noise-induced cochlear hair cell loss and hearing loss by reducing ROS accumulation. However, the molecular pathway through which AMPKα exerts its antioxidative effect is still unclear. In this study, we have investigated a potential target of AMPKα and ROS, cystic fibrosis transmembrane conductance regulator (CFTR), and the protective effect against noise-induced hair cell loss of an FDA-approved CFTR potentiator, ivacaftor, in FVB/NJ mice, mouse explant cultures, and HEI-OC1 cells. We found that noise exposure increases phosphorylation of CFTR at serine 737 (p-CFTR, S737), which reduces wildtype CFTR function, resulting in oxidative stress in cochlear sensory hair cells. Pretreatment with a single dose of ivacaftor maintains CFTR function by preventing noise-increased p-CFTR (S737). Furthermore, ivacaftor treatment increases nuclear factor E2-related factor 2 (Nrf2) expression, diminishes ROS formation, and attenuates noise-induced hair cell loss and hearing loss. Additionally, inhibition of noise-induced AMPKα activation by compound C also diminishes p-CFTR (S737) expression. In line with these in-vivo results, administration of hydrogen peroxide to cochlear explants or HEI-OC1 cells increases p-CFTR (S737) expression and induces sensory hair cell or HEI-OC1 cell damage, while application of ivacaftor halts these effects. Although ivacaftor increases Nrf2 expression and reduces ROS accumulation, cotreatment with ML385, an Nrf2 inhibitor, abolishes the protective effects of ivacaftor against hydrogen-peroxide-induced HEI-OC1 cell death. Our results indicate that noise-induced sensory hair cell damage is associated with p-CFTR. Ivacaftor has potential for treatment of noise-induced hearing loss by maintaining CFTR function and increasing Nrf2 expression for support of redox homeostasis in sensory hair cells.

Rational design of electrocatalytic system to selective transform nitrate to nitrogen.

Nitrate (NO3-) is one of the most common pollutants in natural bodies of water and as such threatens both human health and the safety of aquatic environment. There are efficient electrochemical techniques to directly remove NO3-, but inexpensive, selective and electrocatalytic strategies to eliminate NO3- by converting it into benign nitrogen (N2) remain challenging. This work studied Cu particles that were formed directly on a Ni foam (Cu-NF) and evaluated their electrocatalytic NO3- reduction performance. The use of carbon nanotubes (CNT) functionalized with titanium suboxides (TiSO) as the anode facilitated the generation of active chlorine species that had a key role in the removal of NH4+. An electrochemical system that integrated a Cu-NF cathode with a TiSO-CNT anode could remove 88.5% of NO3- with a >99% N2 selectivity when operated over 6 h (4.1 × 10-4 h-1) at a potential of -1.2 V vs Ag/AgCl. Because the chloride ions are very common in natural sources of water, this technique offers a sustainable and environmentally friendly approach for the removal of NO3- from contaminated water sources.

Abnormal Functional Connectivity Within Default Mode Network and Salience Network Related to Tinnitus Severity.

BACKGROUND: Previous studies have demonstrated that tinnitus is associated with neural changes in the cerebral cortex. This study is aimed at investigating the central nervous characteristics of tinnitus patients with different severity by using a rs-EEG. PARTICIPANTS AND METHODS: rs-EEG was recorded in fifty-seven patients with chronic tinnitus and twenty-seven healthy controls. Tinnitus patients were divided into moderate-to-severe tinnitus group and slight-to-mild tinnitus group based on their Tinnitus Handicap Inventory (THI) scores. Source localization and functional connectivity analyses were used to measure the changes in central levels and examine the altered network patterns. The correlation between functional connectivity and tinnitus severity was analyzed. RESULT: Compared to the healthy controls, all tinnitus patients showed significant activation in the auditory cortex (middle temporal lobe, BA 21), while moderate-to-severe tinnitus group showed enhanced connectivity between the parahippocampus and posterior cingulate gyrus. Moreover, the moderate-to-severe tinnitus group had enhanced functional connectivity between auditory cortex and insula compared to the slight-to-mild tinnitus group. The connections between the insula and the parahippocampal and posterior cingulate gyrus were positively correlated with THI scores. CONCLUSION: The current study reveals that patients with moderate-to-severe tinnitus demonstrate greater changes in the central brain areas, including the auditory cortex, insula, parahippocampus and posterior cingulate gyrus. In addition, enhanced connections were found between the insula and the auditory cortex, as well as the posterior cingulate gyrus and the parahippocampus, which suggests abnormality in the auditory network, salience network, and default mode network. Specifically, the insula is the core region of the neural pathway that is composed of the auditory cortex, insula, and parahippocampus/posterior cingulate gyrus. This suggests that the severity of tinnitus is affected by multiple brain regions.

Cognitive reserve disorder in age-related hearing loss: cognitive cortical compensatory to auditory perceptual processing.

The aim of this study is to ascertain the mechanisms of cognitive reserve disorder in age-related hearing loss (ARHL), to study the correlation between ARHL and cognitive decline via EEG, and to reverse the adverse remodeling of auditory-cognitive connectivity with hearing aids (HAs). In this study, 32 participants were enrolled, including 12 with ARHLs, 9 with HAs, and 11 healthy controls (HCs), to undergo EEG, Pure Tone Average (PTA), Montreal Cognitive Assessment (MoCA), and other general cognitive tests. There were the lowest MoCA in the ARHL group (P = 0.001), especially in language and abstraction. In the ARHL group, power spectral density of the gamma in right middle temporal gyrus was significantly higher than HC and HA groups, while functional connectivity between superior frontal gyrus and cingulate gyrus was weaker than HC group (P = 0.036) and HA group (P = 0.021). In the HA group, superior temporal gyrus and cuneus had higher connectivity than in the HC group (P = 0.036). In the ARHL group, DeltaTM_DTA (P = 0.042) and CTB (P = 0.011) were more frequent than in the HC group, while there was less DeltaTM_CTA (P = 0.029). PTA was found to be associated with MoCA (r = -0.580) and language (r = -0.572), DeltaTM_CTB had a likewise correlation with MoCA (r = 0.483) and language (r = 0.493), while DeltaTM_DTA was related to abstraction (r = -0.458). Cognitive cortexes compensate for worse auditory perceptual processing in ARHL, which relates to cognitive decline. The impaired functional connectivity between auditory and cognitive cortexes can be remodeled by HAs. DeltaTM may serve as a biomarker for early cognitive decline and decreased auditory speech perception in ARHL.

Analysis of Clinical Efficacy and Influencing Factors of Nerve Growth Factor (NGF) Treatment for Sudden Sensorineural Hearing Loss.

Objective: This study aims to examine the clinical efficacy and prognostic factors associated with nerve growth factor (NGF) treatment for sudden sensorineural hearing loss (SSHL). Materials and methods: A retrospective analysis was conducted on the clinical data of 101 patients with moderate or more severe SSHL who underwent secondary treatment at Sun Yat-sen Memorial Hospital of Sun Yat-sen University between January 2019 and July 2020. Prior to treatment, all patients were assessed using Pure Tone Audiometry (PTA), auditory brainstem response, otoacoustic emission, temporal bone computed tomography, or inner ear magnetic resonance imaging. Fifty-seven patients received conventional systemic treatment and served as the control group, while 44 patients received NGF in conjunction with conventional systemic treatment, forming the experimental group. PTA results were compared between the two groups before treatment and at 1 week, 2 weeks, and 1 month post-treatment. Additionally, the impact of age, sex, affected side, hypertension, and other factors on patient prognosis was analyzed. Results: Both groups demonstrated significant PTA improvements following treatment, with a statistically significant difference (P < .05). The hearing recovery effective rate in the control group was 42.1%, while that of the experimental group reached 70.5%, with a statistically significant difference between the groups (P < .05). Most patients experienced notable hearing improvements 1 week after treatment, with some patients still showing progress 2 weeks post-treatment. Multifactor analysis revealed that hypertension and onset days were associated with treatment outcomes. Conclusion: Secondary treatment remains clinically significant for patients with SSHL who have not achieved a satisfactory response or show no clear improvement following initial treatment. The presence of hypertension and delayed treatment are negative factors related to treatment efficacy.

[Reliability and validity of the Chinese version of URICA-Voice scale].

Objective:To translate the University of Rhode Island Change Assessment of voice scale（URICA-Voice） into Chinese and test its reliability and validity. Methods:The URICA-Voice scale was converted into Chinese by literal translation, cultural adjustment, expert consultation, pre-investigation, and back translation. Convenience sampling was used to recruit patients at four speech therapy centers from February to May 2022. Then the Chinese version of the scale was distributed to them, and the reliability and validity of the scale were tested after data collection. Cronbach ɑ was used to evaluate the reliability. The critical ratio method and Pearson correlation coefficient were used for item analysis. Item-level content validity, scale-level content validity, and confirmatory factor analysis were used to test the validity of the scale. Results:A total of 247 valid questionnaires were collected. ①Item analysis: the critical ratios between a high-score and low-score groups of 32 items were all statistically significant（P<0.01） and all the critical ratios were above 3.00. The Pearson correlation between 32 items and the total score was significant（P<0.01）. ②Validity analysis: I-CVI=1.00, S-CVI/Ave=1.00, χ²/df=2.30, RMSEA=0.07. Except for item 9 and 23, the standardized factor loading coefficients of other items were all above 0.50. AVE of the four dimensions of the scale was all above 0.50, and the combined reliability of the four dimensions was all above 0.70. The correlation coefficients between dimensions were less than the square root of the AVE of the dimension itself. ③Reliability analysis: the Cronbach ɑ of the whole scale was 0.94, and the Cronbach ɑ of the four dimensions were 0.88, 0.92, 0.94, and 0.88 respectively. Conclusion:The Chinese version of URICA-Voice has good reliability and validity, and can be used as a specific measurement tool for evaluating the compliance of voice training in China.

Cross-Subject Tinnitus Diagnosis Based on Multi-Band EEG Contrastive Representation Learning.

Electroencephalogram (EEG) is an important technology to explore the central nervous mechanism of tinnitus. However, it is hard to obtain consistent results in many previous studies for the high heterogeneity of tinnitus. In order to identify tinnitus and provide theoretical guidance for the diagnosis and treatment, we propose a robust, data-efficient multi-task learning framework called Multi-band EEG Contrastive Representation Learning (MECRL). In this study, we collect resting-state EEG data from 187 tinnitus patients and 80 healthy subjects to generate a high-quality large-scale EEG dataset on tinnitus diagnosis, and then apply the MECRL framework on the generated dataset to obtain a deep neural network model which can distinguish tinnitus patients from the healthy controls accurately. Subject-independent tinnitus diagnosis experiments are conducted and the result shows that the proposed MECRL method is significantly superior to other state-of-the-art baselines and can be well generalized to unseen topics. Meanwhile, visual experiments on key parameters of the model indicate that the high-classification weight electrodes of tinnitus' EEG signals are mainly distributed in the frontal, parietal and temporal regions. In conclusion, this study facilitates our understanding of the relationship between electrophysiology and pathophysiology changes of tinnitus and provides a new deep learning method (MECRL) to identify the neuronal biomarkers in tinnitus.

Comprehensive analysis of the key amino acid substitutions in the polymerase and NP of avian influenza virus that enhance polymerase activity and affect adaptation to mammalian hosts.

Accumulation of adaptive mutations in the polymerase and NP genes is crucial for the adaptation of avian influenza A viruses (IAV) to a new host. Here, we identified residues in the polymerase and NP proteins for which the percentages were substantially different between avian and human influenza viruses, to screen for key mammalian adaptive markers. The top 10 human virus-like residues in each gene segment were then selected for analysis of polymerase activity. Our research revealed that the PA-M311I and PA-A343S mutations increased the polymerase activity among the 40 individual mutations that augmented viral transcription and genomic replication, leading to increased virus yields, pro-inflammatory cytokine/chemokine levels and pathogenicity in mice. We also investigated the accumulative mutations in multiple polymerase genes and discovered that a combination of PB2-E120D/V227I, PB1-K52R/L212V/R486K/V709I, PA-R204K/M311I, and NP-E18D/R65K (hereafter referred to as the ten-sites joint mutations) has been identified to generate the highest polymerase activity, which can to some extent make up for the highest polymerase activity caused by the PB2-627 K mutation. When the ten-sites joint mutations co-occur with 627 K, the polymerase activity was further enhanced, potentially resulting in a virus with an improved phenotype that can infect a broader range of hosts, including mammals. This could lead to a greater public health concern than the current epidemic, highlighting that continuous surveillance of the variations of these sites is utmost important.

Risk factors of significant relapse and appropriate maintenance therapy strategy in SLE-associated immune thrombocytopenia.

Background: Systemic lupus erythematosus-associated immune thrombocytopenia (SLE-ITP) is characterized by relapse. The risk factors of relapse and appropriate maintenance therapy strategy deserve further exploration. Objectives: To determine the risk factors for relapse and appropriate maintenance therapy in significant SLE-ITP patients (a platelet count ⩽30 × 109/l) after the first complete response. Design: Retrospective cohort study using the medical records of 105 patients diagnosed as significant SLE-ITP in Fujian Medical University Union Hospital during December 2012 to March 2021. Patients were followed through a call for observations in January 2022. Methods: Data including demographics, initial clinical feature, induction and maintenance therapy, and outcome at the end of follow-up were analyzed. Risk factors for significant relapse were analyzed using multivariate logistic regression models. The cumulative hazard of significant relapse and the duration of response were estimated, and the differences in outcome between groups were compared using the Cox regression analysis. Results: A total of 65 significant SLE-ITP patients were eligible for the final analysis. Median [interquartile range (IQR)] follow-up duration and median [IQR] duration of response were 62.2 [41.0-79.6] months and 43.4 [20.3-68.7] months, respectively. After the first complete response, 19/65 (29.2%) had a significant relapse. Compared with sustained clinical remission (SCR) + sustained response (SR) group, significant relapse group had a higher proportion of discontinued patients (47.4% versus 8.7%, p = 0.001). Among the 13 discontinued patients, the duration of maintenance therapy of the patients in significant relapse group was significantly shorter than that of the patients in SCR + SR group (months, median [IQR], 43.1 [32.0-62.4] versus 12.0 [5.1-22.0], p = 0.009). Multivariate logistic regression analysis showed that drug withdrawal was an independent risk factor for significant relapse [odds ratio (OR) = 10.4, confidence interval (CI) 95% 2.2-47.8, p = 0.003]. There was no significant difference between glucocorticoids (GCs) + hydroxychloroquine (HCQ) group and GCs + HCQ + immunosuppressive agents (ISAs) group in significant relapse rate (26.7% versus 22.2%, p > 0.05). The two SR curves of GCs + HCQ and GCs + HCQ+ ISA group basically coincided by the Cox regression analysis, demonstrating comparable long-term outcomes (p > 0.05). Conclusion: Drug withdrawal, especially abrupt withdrawal with insufficient duration of maintenance therapy, is an independent risk factor for significant relapse of SLE-ITP. HCQ combined with GCs is expected to be the first choice of the maintenance therapy for SLE-ITP patients.

Age-related hearing loss accelerates the decline in fast speech comprehension and the decompensation of cortical network connections.

Patients with age-related hearing loss face hearing difficulties in daily life. The causes of age-related hearing loss are complex and include changes in peripheral hearing, central processing, and cognitive-related abilities. Furthermore, the factors by which aging relates to hearing loss via changes in auditory processing ability are still unclear. In this cross-sectional study, we evaluated 27 older adults (over 60 years old) with age-related hearing loss, 21 older adults (over 60 years old) with normal hearing, and 30 younger subjects (18-30 years old) with normal hearing. We used the outcome of the upper-threshold test, including the time-compressed threshold and the speech recognition threshold in noisy conditions, as a behavioral indicator of auditory processing ability. We also used electroencephalography to identify presbycusis-related abnormalities in the brain while the participants were in a spontaneous resting state. The time-compressed threshold and speech recognition threshold data indicated significant differences among the groups. In patients with age-related hearing loss, information masking (babble noise) had a greater effect than energy masking (speech-shaped noise) on processing difficulties. In terms of resting-state electroencephalography signals, we observed enhanced frontal lobe (Brodmann's area, BA11) activation in the older adults with normal hearing compared with the younger participants with normal hearing, and greater activation in the parietal (BA7) and occipital (BA19) lobes in the individuals with age-related hearing loss compared with the younger adults. Our functional connection analysis suggested that compared with younger people, the older adults with normal hearing exhibited enhanced connections among networks, including the default mode network, sensorimotor network, cingulo-opercular network, occipital network, and frontoparietal network. These results suggest that both normal aging and the development of age-related hearing loss have a negative effect on advanced auditory processing capabilities and that hearing loss accelerates the decline in speech comprehension, especially in speech competition situations. Older adults with normal hearing may have increased compensatory attentional resource recruitment represented by the top-down active listening mechanism, while those with age-related hearing loss exhibit decompensation of network connections involving multisensory integration.

Promoting TFEB nuclear localization with curcumin analog C1 attenuates sensory hair cell injury and delays age-related hearing loss in C57BL/6 mice.

Sensory hair cell (HC) injuries, especially outer hair cell (OHC) loss, are well-documented to be the primary pathology of age-related hearing loss (AHL). Recent studies have demonstrated that autophagy plays an important role in HC injury in the inner ear. In our previous works, a decline in autophagy levels and HC loss were found to occur simultaneously in the inner ears of aged C57BL/6 mice, and the administration of rapamycin promoted autophagy levels, which reduced OHC loss and delayed AHL, but the underlying mechanism of autophagy in AHL has not been well elucidated. Transcription factor EB (TFEB), an autophagy regulator and the downstream target of mammalian target of rapamycin (mTOR), is involved in the pathological development of neurodegenerative disease. This study would address the link between autophagy and TFEB in aged C57BL/6 mouse cochleae and clarify the effect of the TFEB activator curcumin analog C1 (C1) in aged cochleae. Decreased TFEB nuclear localization (p = 0.0371) and autophagy dysfunction (p = 0.0273) were observed in the cochleae of aged C57BL/6 mice that exhibited AHL, HCs loss and HCs senescence. Treatment with C1 promoted TFEB nuclear localization and restored autophagy, subsequently alleviating HC injury and delaying AHL. The protective effect of C1 on HEI-OC1 cells against autophagy disorder and aging induced by D-galactose was abolished by chloroquine, which is one of the commonly used autophagy inhibitors. Overall, our results demonstrated that the capacity to perform autophagy is mediated by the nuclear localization of TFEB in aged C57BL/6 mouse cochleae. C1 promotes the nuclear localization of TFEB, subsequently alleviating HC injury and delaying AHL by restoring the impaired autophagy function. TFEB may serve as a new therapeutic target for AHL treatment.

Skeletal standardized uptake values obtained using quantitative SPECT/CT for the detection of bone metastases in patients with lung adenocarcinoma.

Purpose: To assess the utility of skeletal standardized uptake values (SUVs) obtained using quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) in differentiating bone metastases from benign lesions, particularly in patients with lung adenocarcinoma. Methods: Patients with lung adenocarcinoma who had undergone whole-body Tc-99m methyl-diphosphonate (99mTc-MDP) bone scans and received late phase SPECT/CT were retrospectively analyzed in this study. The maximum SUV (SUVmax); Hounsfield units (HUs); and volumes of osteoblastic, osteolytic, mixed, CT-negative metastatic and benign bone lesions, and normal vertebrae were compared. Receiver operating characteristic curves were used to determine the optimal cutoff SUVmax between metastatic and benign lesions as well as the cutoff SUVmax between CT-negative metastatic lesions and normal vertebrae. The linear correlation between SUVmax and HUs of metastatic lesions as well as that between SUVmax and the volume of all bone lesions were investigated. Results: A total of 252 bone metastatic lesions, 140 benign bone lesions, and 199 normal vertebrae from 115 patients with lung adenocarcinoma were studied (48 males, 67 females, median age: 59 years). Metastatic lesions had a significantly higher SUVmax (23.85 ± 14.34) than benign lesions (9.67 ± 7.47) and normal vertebrae (6.19 ± 1.46; P < 0.0001). The SPECT/CT hotspot of patients with bone metastases could be distinguished from benign lesions using a cutoff SUVmax of 11.10, with a sensitivity of 87.70% and a specificity of 80.71%. The SUVmax of osteoblastic (29.16 ± 16.63) and mixed (26.62 ± 14.97) lesions was significantly greater than that of osteolytic (15.79 ± 5.57) and CT-negative (16.51 ± 6.93) lesions (P < 0.0001, P = 0.0003, and 0.002). SUVmax at the cutoff value of 8.135 could distinguish CT-negative bone metastases from normal vertebrae, with a sensitivity of 100.00% and a specificity of 91.96%. SUVmax showed a weak positive linear correlation with HUs in all bone metastases and the volume of all bone lesions. Conclusion: SUVmax of quantitative SPECT/CT is a useful index for distinguishing benign bone lesions from bone metastases in patients with lung adenocarcinoma, particularly in the diagnosis of CT-negative bone metastases, but other factors that may affect SUVmax should be considered.