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.

Efficacy of Tailor-Made Notched Music Training Versus Tinnitus Retraining Therapy in Adults With Chronic Subjective Tinnitus: A Randomized Controlled Clinical Trial.

OBJECTIVES: Chronic subjective tinnitus can have a serious effect on daily life, even causing serious psychological disorders. Currently there are no specific effective solutions or cures. Tailor-made notched music training (TMNMT) is a recently proposed sound therapy that has simpler processes and a higher compliance rate than tinnitus retraining therapy (TRT), a widely used treatment for chronic subjective tinnitus. This study explores the therapeutic effect of TMNMT in comparison to TRT to highlight its clinical value. DESIGN: The study was a randomized controlled, single-blinded clinical trial. One hundred twenty eligible participants were randomly assigned to receive TMNMT (n = 60) or TRT (n = 60) for 3 mo with concurrent follow-up. It should be noted that the duration of sound treatment in TRT was modified to 2 hr per day for better feasibility in practice. The primary outcome was mean change in tinnitus handicap inventory (THI) measured at baseline ( T0 ), 1 mo ( T1 ) and 3 mo ( T2 ) after intervention. Change in visual analog scale (VAS) was measured as a secondary outcome. A comparison of therapeutic effectiveness between TMNMT and TRT was evaluated by repeated measure analysis of variance. RESULTS: One hundred and twelve (93%) of participants took part in the study, of which 64 were men and 48 women. Mean (SD) age was 42.80 (12.91) years. Fifty-eight were allocated to receive TMNMT and 54 to receive TRT. The between-group difference in primary outcome was -6.90 points (95% confidence interval [CI], -13.53 to -0.27) at T1 and -6.17 points (95% CI, -13.04 to 0.71) at T2 . These results closely reached to clinical significance of tinnitus-related effective relief. For the secondary outcome, the mean value in the TMNMT group was 0.83 points (95% CI, 0.12 to 1.54), significantly lower than the mean value of the TRT group. The differences in THI and VAS between the two groups were statistically significant after intervention. Further analysis showed that age and baseline THI and VAS scores were associated with change in THI and VAS scores after interventions. CONCLUSIONS: Both TMNMT and TRT were able to alleviate chronic subjective tinnitus effectively after a 3 month intervention. When the two forms of therapy were compared TMNMT appeared to be more effective and consequently potentially superior to TRT for reducing tinnitus loudness and functional and emotional disturbance associated with chronic subjective tinnitus.

Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma.

BACKGROUND: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy showed remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). This phase 1 dose-escalation and expansion study developed C-CAR088, a novel second-generation humanized anti-BCMA CAR T-cell therapy, and assessed the safety and efficacy of three dosages of C-CAR088 in patients with RRMM. METHODS: Patients received lymphodepletion with three doses of cyclophosphamide (300 mg/m2) and three doses of fludarabine (30 mg/m2) on days -5, -4, and -3, followed by an infusion of C-CAR088 on day 0. Doses of 1.0×106, 3.0×106, and 6.0×106 CAR T cells/kg (±20%) were tested in the dose-escalation cohorts and expansion cohorts. The primary endpoint was treatment safety, including the rate of treatment-emergent adverse events after cell infusion. Secondary endpoints were the overall response rate and progression-free survival. The exploratory endpoints were the quantification of C-CAR088 CAR T cells, selection of cytokines and chemokines in blood, and measurement of tumor BCMA expression. RESULTS: As of July 2, 2021, 31 patients had been infused with C-CAR088. Any grade cytokine release syndrome (CRS) occurred in 29 patients (93.5%), and grade 3 CRS occurred in 3 patients (9.7%). One patient from the high-dose group (4.5-6.0×106 CAR T cells/kg) developed grade 1 neurotoxicity. No dose-limiting toxicities were observed in any dose group, and all adverse events were reversible after proper management. The overall response, stringent complete response, complete response (CR), and very good partial response rates were 96.4%, 46.4%, 10.7%, and 32.1%, respectively. The CR rate in the medium-dose (3.0×106 CAR T cells/kg) and high-dose (4.5-6.0×106 CAR T cells/kg) groups was 54.5% and 71.4%, respectively. In the CR group, 15 (93.7%) patients achieved minimal residual disease (MRD) negativity (test sensitivity >1/10-5). All seven patients with double-hit or triple-hit multiple myeloma achieved MRD-negative CR. CONCLUSIONS: The present study demonstrated that C-CAR088 had a good safety profile and high antitumor activity in patients with RRMM, constituting a promising treatment option for RRMM. TRIAL REGISTRATION NUMBER: NCT03815383, NCT03751293, NCT04295018, and NCT04322292.

Aberrant Modulations of Neurocognitive Network Dynamics in Migraine Comorbid With Tinnitus.

Purpose: The possible relationship between migraine and tinnitus still remains elusive although migraine is often accompanied by chronic tinnitus. Several neuroimaging studies have reinforced the cognitive network abnormality in migraine and probably as well as tinnitus. The present work aims to investigate the dynamic neurocognitive network alterations of migraine comorbid with tinnitus. Materials and Methods: Participants included migraine patients (n = 32), tinnitus patients (n = 20), migraine with tinnitus (n = 27), and healthy controls (n = 47), matched for age and gender. Resting-state functional magnetic resonance imaging (rs-fMRI) with independent component analysis (ICA), sliding window cross-correlation, and clustering state analysis was used to detect the dynamic functional network connectivity (dFNC) of each group. Correlation analyses illustrated the association between clinical symptoms and abnormal dFNC in migraine as well as tinnitus. Results: Compared with healthy controls, migraine patients exhibited decreased cerebellar network and visual network (CN-VN) connectivity in State 2; migraine with tinnitus patients showed not only decreased CN-VN connectivity in State 2 but also decreased cerebellar network and executive control network (CN-ECN) connectivity in State 2 and increased cerebellar network and somatomotor network (SMN-VN) connectivity in State 1. The abnormal cerebellum dFNC with the executive control network (CN-ECN) was negatively correlated with headache frequency of migraine (rho = -0.776, p = 0.005). Conclusion: Brain network characteristics of migraine with tinnitus patients may indicate different mechanisms for migraine and tinnitus. Our results demonstrated a transient pathologic state with atypical cerebellar-cortical connectivity in migraine with tinnitus patients, which might be used to identify the neuro-pathophysiological mechanisms in migraine accompanied by tinnitus.

Tinnitus Affects Endogenous But Not Exogenous Auditory Attention Orienting.

PURPOSE: Previous studies have demonstrated that people with tinnitus show attention dysfunctions. In this study, we investigated the influence of tinnitus on attention orienting, especially whether the ability of attention orienting could be modulated by the degree of tinnitus. METHOD: Fifty-nine and 54 unilateral tinnitus participants were included in Experiment 1 and Experiment 2, respectively. All participants reported subjective tinnitus for at least 3 months and were divided into a mild tinnitus group (Tinnitus Handicap Inventory [THI] < 37) or a moderate to severe tinnitus group (THI ≥ 37) according to the THI score. An auditory exogenous attention task and an auditory endogenous attention task were adopted. In the exogenous task, a target sound following a cue sound was presented on either the left or right side. Participants were required to discriminate whether the target was pure tone or white noise. In the endogenous task, participants were required to pay attention to the stimuli on one side and judge the pitch of a target sound. Mixed-design analyses of variance were conducted for the mean reaction times and accuracy across the experimental conditions. RESULTS: Our results showed that in the endogenous attention task, compared with the mild tinnitus group, moderate to severe tinnitus participants had better performance for stimuli presented on the tinnitus side but not on the nontinnitus side. In contrast, in the exogenous attention task, no differences were found between mild and moderate to severe tinnitus groups. CONCLUSION: The results suggest that the degree of tinnitus influences the performance of auditory endogenous attention but not auditory exogenous attention orienting.

Specific brain network predictors of interventions with different mechanisms for tinnitus patients.

BACKGROUND: The aberrant brain network that gives rise to the phantom sound of tinnitus is believed to determine the effectiveness of tinnitus therapies involving neuromodulation with repetitive transcranial magnetic stimulation (rTMS) and sound therapy utilizing tailor-made notch music training (TMNMT). To test this hypothesis, we determined how effective rTMS or TMNMT were in ameliorating tinnitus in patients with different functional brain networks. METHODS: Resting-state functional MRI was used to construct brain functional networks in patients with tinnitus (41 males/45 females, mean age 49.53±11.19 years) and gender-matched healthy controls (22 males/35 females, mean age 46.23±10.23 years) with independent component analysis (ICA). A 2 × 2 analysis of variance with treatment outcomes (Effective group, EG/Ineffective group, IG) and treatment types (rTMS/TMNMT) was used to test the interaction between outcomes and treatment types associated with functional network connections (FNCs). FINDINGS: The optimal neuroimaging indicator for responding to rTMS (AUC 0.804, sensitivity 0.700, specificity 0.913) was FNCs in the salience network-right frontoparietal network (SN-RFPN) while for responding to TMNMT (AUC 0.764, sensitivity 0.864, specificity 0.667) was the combination of FNCs in the auditory network- salience network (AUN-SN) and auditory network-cerebellar network (AUN-CN). INTERPRETATION: Tinnitus patients with higher FNCs in the SN-RFPN is associated with a recommendation for rTMS whereas patients with lower FNCs in the AUN-SN and AUN-CN would suggest TMNMT as the better choice. These results indicate that brain network-based measures aid in the selection of the optimal form of treatment for a patient contributing to advances in precision medicine. FUNDING: Yuexin Cai is supported by Key R&D Program of Guangdong Province, China (Grant No. 2018B030339001), National Natural Science Foundation of China (82071062), Natural Science Foundation of Guangdong province (2021A1515012038), the Fundamental Research Funds for the Central Universities (20ykpy91), and Sun Yat-Sen Clinical Research Cultivating Program (SYS-Q-201903). Yu-Chen Chen is supported by Medical Science and Technology Development Foundation of Nanjing Department of Health (No. ZKX20037), and Natural Science Foundation of Jiangsu Province (No. BK20211008).

Topological features of limbic dysfunction in chronicity of tinnitus with intact hearing: New hypothesis for 'noise-cancellation' mechanism.

PURPOSE: The reorganization of the limbic regions extend to general cognitive network is believed to exist in the chronicity of tinnitus with particular 'hubs' contributing to a 'noise-cancellation' mechanism. To test this hypothesis, we investigated the topological brain network of tinnitus in different periods. METHODS: Resting-state functional magnetic resonance imaging were obtained from 32 patients with acute tinnitus, 41 patients with chronic tinnitus and 60 age- and gender- matched healthy controls (HC). The topological features of their brain networks were explored using graph theory analysis. RESULTS: Common small-world attributes were compared between the three groups, all showed a significantly increased values in Cp, Lp, λ (all p < 0.05). Significantly increased nodal centralities in the left superior frontal gyrus and the right precuneus, significantly decreased nodal centralities in the right inferior temporal gyrus were observed for acute tinnitus patients compared to HC. While for chronic tinnitus patients, there were significant increased nodal centralities in the left hippocampus, amygdala, and temporal pole, but decreased nodal centralities in the right inferior temporal gyrus. Additionally, significant higher nodal centralities were found in bilateral medial superior frontal gyrus for acute tinnitus patients compared to chronic tinnitus patients. Besides, alterations in rich-club organization were found in acute tinnitus patients and chronic tinnitus patients compared with HC, with increased functional connections among rich-club nodes and peripheral nodes in patients with tinnitus. CONCLUSIONS: Brain network topological properties altered across prefrontal-limbic-subcortical regions in tinnitus. The existed hubs in tinnitus might indicate an emotional and cognitive burden in 'noise-cancellation' mechanism.

Reduced Functional Connectivity in Children With Congenital Cataracts Using Resting-State Electroencephalography Measurement.

OBJECTIVES: Numerous task-based functional magnetic resonance imaging studies indicate the presence of compensatory functional improvement in patients with congenital cataracts. However, there is neuroimaging evidence that shows decreased sensory perception or cognition information processing related to visual dysfunction, which favors a general loss hypothesis. This study explored the functional connectivity between visual and other networks in children with congenital cataracts using resting state electroencephalography. METHODS: Twenty-one children with congenital cataracts (age: 8.02 ± 2.03 years) and thirty-five sex- and age-matched normal sighted controls were enrolled to investigate functional connectivity between the visual cortex and the default mode network, the salience network, and the cerebellum network during resting state electroencephalography (eyes closed) recordings. RESULT: The congenital cataract group was less active, than the control group, in the occipital, temporal, frontal and limbic lobes in the theta, alpha, beta1 and beta2 frequency bands. Additionally, there was reduced alpha-band connectivity between the visual and somatosensory cortices and between regions of the frontal and parietal cortices associated with cognitive and attentive control. CONCLUSION: The results indicate abnormalities in sensory, cognition, motion and execution functional connectivity across the developing brains of children with congenital cataracts when compared with normal controls. Reduced frontal alpha activity and alpha-band connectivity between the visual cortex and salience network might reflect attenuated inhibitory information flow, leading to higher attentional states, which could contribute to adaptation of environmental change in this group of patients.

Investigating the use of a two-stage attention-aware convolutional neural network for the automated diagnosis of otitis media from tympanic membrane images: a prediction model development and validation study.

OBJECTIVES: This study investigated the usefulness and performance of a two-stage attention-aware convolutional neural network (CNN) for the automated diagnosis of otitis media from tympanic membrane (TM) images. DESIGN: A classification model development and validation study in ears with otitis media based on otoscopic TM images. Two commonly used CNNs were trained and evaluated on the dataset. On the basis of a Class Activation Map (CAM), a two-stage classification pipeline was developed to improve accuracy and reliability, and simulate an expert reading the TM images. SETTING AND PARTICIPANTS: This is a retrospective study using otoendoscopic images obtained from the Department of Otorhinolaryngology in China. A dataset was generated with 6066 otoscopic images from 2022 participants comprising four kinds of TM images, that is, normal eardrum, otitis media with effusion (OME) and two stages of chronic suppurative otitis media (CSOM). RESULTS: The proposed method achieved an overall accuracy of 93.4% using ResNet50 as the backbone network in a threefold cross-validation. The F1 Score of classification for normal images was 94.3%, and 96.8% for OME. There was a small difference between the active and inactive status of CSOM, achieving 91.7% and 82.4% F1 scores, respectively. The results demonstrate a classification performance equivalent to the diagnosis level of an associate professor in otolaryngology. CONCLUSIONS: CNNs provide a useful and effective tool for the automated classification of TM images. In addition, having a weakly supervised method such as CAM can help the network focus on discriminative parts of the image and improve performance with a relatively small database. This two-stage method is beneficial to improve the accuracy of diagnosis of otitis media for junior otolaryngologists and physicians in other disciplines.

Alterations of brain activity and functional connectivity in transition from acute to chronic tinnitus.

The objective of this study was to investigate alterations to brain activity and functional connectivity in patients with tinnitus, exploring neural features in the transition from acute to chronic phantom perception. Twenty-four patients with acute tinnitus, 23 patients with chronic tinnitus, and 32 healthy controls were recruited. High-density electroencephalography (EEG) was used to explore changes in brain areas and functional connectivity in different groups. When compared with healthy subjects, acute tinnitus patients had a significant reduction in superior frontal cortex activity across all frequency bands, whereas chronic tinnitus patients had a significant reduction in the superior frontal cortex at beta 3 and gamma frequency bands as well as a significant increase in the inferior frontal cortex at delta-band and superior temporal cortex at alpha 1 frequency band. When compared to the chronic tinnitus group, the acute tinnitus group activity was significantly increased in the middle frontal and parietal gyrus at the gamma-band. Functional connectivity analysis showed that the chronic tinnitus group had increased connections between the parahippocampus gyrus, posterior cingulate cortex, and precuneus when compared with the healthy group. Alterations of local brain activity and connections between the parahippocampus gyrus and other nonauditory areas appeared in the transition from acute to chronic tinnitus. This indicates that the appearance and development of tinnitus is a dynamic process involving aberrant local neural activity and abnormal connectivity in multifunctional brain networks.

Study on Rh(I)/Ru(III) Bimetallic Catalyst Catalyzed Carbonylation of Methanol to Acetic Acid.

In this study, a Rh(I)/Ru(III) catalyst with a bimetallic space structure was designed and synthesized. The interaction between the metals of the bimetallic catalyst and the structure of the bridged dimer can effectively reduce the steric hindrance effect and help speed up the reaction rate while ensuring the stability of the catalyst. X-ray photoelectron spectroscopy (XPS) results show that rhodium accepts electrons from chlorine, thereby increasing the electron-rich nature of rhodium and improving the catalytic activity. This promotes the nucleophilic reaction of the catalyst with methyl iodide and reduces the reaction energy barrier. The methanol carbonylation performance of the Rh/Ru catalyst was evaluated, and the results show that the conversion rate of methyl acetate and the yield of acetic acid are 96.0% under certain conditions. Furthermore, during the catalysis, no precipitate is formed and the amount of water is greatly reduced. It can be seen that the catalyst has good stability and activity.

Aberrant Functional and Causal Connectivity in Acute Tinnitus With Sensorineural Hearing Loss.

PURPOSE: The neural bases in acute tinnitus remains largely undetected. The objective of this study was to identify the alteration of the brain network involved in patients with acute tinnitus and hearing loss. METHODS: Acute tinnitus patients (n = 24) with hearing loss and age-, sex-, education-matched healthy controls (n = 21) participated in the current study and underwent resting-state functional magnetic resonance imaging (fMRI) scanning. Regional homogeneity and amplitude of low-frequency fluctuation were used to investigate the local spontaneous neural activity and functional connectivity (FC), and Granger causality analysis (GCA) was used to analyze the undirected and directed connectivity of brain regions. RESULTS: Compared with healthy subjects, acute tinnitus patients had a general reduction in FC between auditory and non-auditory brain regions. Based on FC analysis, the superior temporal gyrus (STG) revealed reduced undirected connectivity with non-auditory brain regions including the amygdala (AMYG), nucleus accumbens (NAc), the cerebellum, and postcentral gyrus (PoCG). Using the GCA algorithm, increased effective connectivity from the right AMYG to the right STG, and reduced connectivity from the right PoCG to the left NAc was observed in acute tinnitus patients with hearing loss. The pure-tone threshold was positively correlated with FC between the AMYG and STG, and negatively correlated with FC between the left NAc and the right PoCG. In addition, a negative association between the GCA value from the right PoCG to the left NAc and the THI scores was observed. CONCLUSION: Acute tinnitus patients have aberrant FC strength and causal connectivity in both the auditory and non-auditory cortex, especially in the STG, AMYG, and NAc. The current findings will provide a new perspective for understanding the neuropathophysiological mechanism in acute tinnitus.

Lycorine inhibits breast cancer growth and metastasis via inducing apoptosis and blocking Src/FAK-involved pathway.

Breast cancer is the most commonly diagnosed cancer type worldwide among women and more than 90% of patients die from tumor metastasis. Lycorine, a natural alkaloid, has been widely reported possessing potential efficacy against cancer proliferation and metastasis. In our study, the anti-tumor potency on breast cancer was evaluated in vitro and in vivo for the first time. Our results indicated that lycorine inhibited breast cancer cells growth, migration and invasion as well as induced their apoptosis. In in vivo study, lycorine not only suppressed breast tumor growth in xenograft models and inhibited breast tumor metastasis in MDA-MB-231 tail vein model. More importantly, we found lycorine had less toxicity than first-line chemotherapy drug paclitaxel at the same effective dose in vivo. Furthermore, on mechanism, lycorine inhibited tumor cell migration and invasion via blocking the Src/FAK (focal adhesion kinase)-involved pathway. In conclusion, our study implied lycorine was a potential candidate for the treatment of breast cancer by inhibition of tumor growth and metastasis.

A novel synthetic small molecule YF-452 inhibits tumor growth through antiangiogenesis by suppressing VEGF receptor 2 signaling.

Tumor angiogenesis is characterized by abnormal vessel morphology, endowing tumor with highly hypoxia and unresponsive toward treatment. To date, mounting angiogenic factors have been discovered as therapeutic targets in antiangiogenic drug development. Among them, vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors exerts potent antiangiogenic activity in tumor therapy. Therefore, it may provide a valid strategy for cancer treatment through targeting the tumor angiogenesis via VEGFR2 pathway. In this study, we established a high-profile compounds library and certificated a novel compound named N-(N-pyrrolidylacetyl)-9-(4-bromobenzyl)-1,3,4,9-tetrahydro-ß-carboline (YF-452), which remarkably inhibited the migration, invasion and tube-like structure formation of human umbilical vein endothelial cells (HUVECs) with little toxicity invitro. Rat thoracic aorta ring assay indicated that YF-452 significantly blocked the formation of microvascular exvivo. In addition, YF-452 inhibited angiogenesis in chick chorioallantoic membrane (CAM) and mouse corneal micropocket assays. Moreover, YF-452 remarkably suppressed tumor growth in xenografts mice model. Furthermore, investigation of molecular mechanism revealed that YF-452 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal regulated kinase (ERK), focal adhesion kinase (FAK) and Src. These results indicate that YF-452 inhibits angiogenesis and may be a potential antiangiogenic drug candidate for cancer therapy.

Dynamic changes in amino acid concentration profiles in patients with sepsis.

OBJECTIVES: The goal of this work was to explore the dynamic concentration profiles of 42 amino acids and the significance of these profiles in relation to sepsis, with the aim of providing guidance for clinical therapies. METHODS: Thirty-five critically ill patients with sepsis were included. These patients were further divided into sepsis (12 cases) and severe sepsis (23 cases) groups or survivor (20 cases) and non-survivor (15 cases) groups. Serum samples from the patients were collected on days 1, 3, 5, 7, 10, and 14 following intensive care unit (ICU) admission, and the serum concentrations of 42 amino acids were measured. RESULTS: The metabolic spectrum of the amino acids changed dramatically in patients with sepsis. As the disease progressed further or with poor prognosis, the levels of the different amino acids gradually increased, decreased, or fluctuated over time. The concentrations of sulfur-containing amino acids (SAAs), especially taurine, decreased significantly as the severity of sepsis worsened or with poor prognosis of the patient. The serum concentrations of SAAs, especially taurine, exhibited weak negative correlations with the Sequential Organ Failure Assessment (SOFA) (r=-0.319) and Acute Physiology and Chronic Health Evaluation (APACHE) II (r=-0.325) scores. The areas under the receiver operating characteristic curves of cystine, taurine, and SAA levels and the SOFA and APACHE II scores, which denoted disease prognosis, were 0.623, 0.674, 0.678, 0.86, and 0.857, respectively. CONCLUSIONS: Critically ill patients with disorders of amino acid metabolism, especially of SAAs such as cystine and taurine, may provide an indicator of the need for the nutritional support of sepsis in the clinic. TRIAL REGISTRATION: ClinicalTrial.gov identifier NCT01818830.