Hearing loss is the most prevalent disabling disease. Cochlear implantation（CI） serves as the primary intervention for severe to profound hearing loss. This consensus systematically explores the value of genetic diagnosis in the pre-operative assessment and efficacy prognosis for CI. Drawing upon domestic and international research and clinical experience, it proposes an evidence-based medicine three-tiered prognostic classification system（Favorable, Marginal, Poor）. The consensus focuses on common hereditary non-syndromic hearing loss（such as that caused by mutations in genes like GJB2, SLC26A4, OTOF, LOXHD1） and syndromic hereditary hearing loss（such as Jervell & Lange-Nielsen syndrome and Waardenburg syndrome）, which are closely associated with congenital hearing loss, analyzing the impact of their pathological mechanisms on CI outcomes. The consensus provides recommendations based on multiple round of expert discussion and voting. It emphasizes that genetic diagnosis can optimize patient selection, predict prognosis, guide post-operative rehabilitation, offer stratified management strategies for patients with different genotypes, and advance the application of precision medicine in the field of CI.
Humans ; Cochlear Implantation ; Prognosis ; Hearing Loss/surgery* ; Consensus ; Connexin 26 ; Mutation ; Sulfate Transporters ; Connexins/genetics*

Reactive astrocytes, which exhibit a correlation with the degeneration of dopaminergic neurons, are present in a considerable number during the progression of Parkinson's disease (PD). However, the underlying factors shaping astrocyte reactivity and neuroinflammation in PD remain inadequately elucidated. Here, we demonstrate that fibroblast growth factor 7 (FGF7)/FGF receptor 2 (FGFR2) autocrine signaling intensifies astrocyte reactivity and inflammation. Genetic deletion of Arrb2, β-Arrestin2 encoding gene, led to escalated astrocyte reactivity in MPTP-treated mice, which was further substantiated in astrocyte-specific Arrb2 knockdown mice. RNA sequencing profiling of Arrb2 knockout astrocytes identified Fgf7 as a critical effector of astrocyte reactivity. Subsequently, conditional knockdown of Fgf7 and its receptor Fgfr2 in astrocytes elicited advantageous effects for MPTP-treated mice by restraining the inflammatory phenotypic transition of reactive astrocytes. Furthermore, deletion of astrocytic Fgf7 mitigated MPTP-induced pathology in Arrb2 knockout mice. Mechanistically, STAT1 was distinguished as the transcription factor suppressing Fgf7 expression, while β-Arrestin2 counteracted the proteasomal degradation of STAT1 by binding to RNF220, an E3 ubiquitin ligase for STAT1. More importantly, selectively engaging dopamine D2 receptor (Drd2)/β-Arrestin2-biased signaling using the agonist UNC9995 exhibited therapeutic potential in MPTP-treated mice via moderation of astrocytic FGF7 production, thereby restoring balance in astrocyte reactivity. Collectively, our study bridges a crucial knowledge gap by elucidating the novel functions of FGF family members within the central nervous system, particularly within the context of PD. The autocrine signaling of FGF7/FGFR2 represents a novel mechanism and a potential druggable target for modulating astrocyte-derived inflammation.

Instrument separation is a critical complication during root canal therapy, impacting treatment success and long-term tooth preservation. The etiology of instrument separation is multifactorial, involving the intricate anatomy of the root canal system, instrument-related factors, and instrumentation techniques. Instrument separation can hinder thorough cleaning, shaping, and obturation of the root canal, posing challenges to successful treatment outcomes. Although retrieval of separated instrument is often feasible, it carries risks including perforation, excessive removal of tooth structure and root fractures. Effective management of separated instruments requires a comprehensive understanding of the contributing factors, meticulous preoperative assessment, and precise evaluation of the retrieval difficulty. The application of appropriate retrieval techniques is essential to minimize complications and optimize clinical outcomes. The current manuscript provides a framework for understanding the causes, risk factors, and clinical management principles of instrument separation. By integrating effective strategies, endodontists can enhance decision-making, improve endodontic treatment success and ensure the preservation of natural dentition.
Humans ; Root Canal Therapy/adverse effects* ; Consensus ; Root Canal Preparation/adverse effects*

Computational approaches for predicting drug-target interactions (DTIs) are pivotal in advancing drug discovery. Current methodologies leveraging heterogeneous networks often fall short in fully integrating both local and global network information. To comprehensively consider network information, we propose DHGT-DTI, a novel deep learning-based approach for DTI prediction. Specifically, we capture the local and global structural information of the network from both neighborhood and meta-path perspectives. In the neighborhood perspective, we employ a heterogeneous graph neural network (HGNN), which extends Graph Sample and Aggregate (GraphSAGE) to handle diverse node and edge types, effectively learning local network structures. In the meta-path perspective, we introduce a Graph Transformer with residual connections to model higher-order relationships defined by meta-paths, such as "drug-disease-drug", and use an attention mechanism to fuse information across multiple meta-paths. The learned features from these dual perspectives are synergistically integrated for DTI prediction via a matrix decomposition method. Furthermore, DHGT-DTI reconstructs not only the DTI network but also auxiliary networks to bolster prediction accuracy. Comprehensive experiments on two benchmark datasets validate the superiority of DHGT-DTI over existing baseline methods. Additionally, case studies on six drugs used to treat Parkinson's disease not only validate the practical utility of DHGT-DTI but also highlight its broader potential in accelerating drug discovery for other diseases.

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

Objective To investigate the characteristics and differences of congenital endowment in senile dementia population based on the theory of five circuits and six qi.Methods Based on the cross-sectional data of China Health and Retirement Longitudinal Survey(CHARLS)in 2018,the dementia status of the population aged 60 and above in China was evaluated by using the Mini-Mental State Examination(MMSE),and the five-circuit and six-qi features at birth in the senile dementia population were analyzed by descriptive statistics and Chi-square goodness-of-fit test.Results A total of 854 patients with senile dementia were included.The five-circuit and six-qi features at birth in the senile dementia population were as follows:most of them were born at the heavenly stem of Bing while the least at the heavenly stem of Ji and Geng(P＜0.001),most of them were born at the earthly branch of Wei while the least at the earthly branch of Zi(P＜0.001),most of them were born at the yearly circuit of excessive water circuit while the least at the yearly circuit of excessive gold circuit and deficient earth circuit(P＜0.001),and most of the patients were born at sitan of taiyin damp-earth and zaiquan of taiyang cold-water while the least at sitan of jueyin wind-wood and zaiquan of shaoyang ministerial fire;no statistically significant differences were found in the dominant qi and guest qi(P＞0.05);most of the patients were born in the year of combination of circuit and qi being Shunhua while the least in the year of combination of circuit and qi being same celestial correspondence(P＜0.001),and the patients born in the year of Shunhua usually were frequently distributed in heavenly-stem and earthly-branch year of Jiawu(P＜0.001).Conclusion There is a certain relationship between the congenital endowment at birth and the incidence of senile dementia in the population of senile dementia.The circuit-qi features at birth for the prevalence of senile dementia are the yearly circuit of excessive water circuit,sitan of taiyin damp-earth and zaiquan of taiyang cold-water,and the year of the combination of circuit and qi being Shunhua.The population born at the time with the above circuit-qi features are prone to suffer the injury of the kidneys,the heart,and the spleen,and then result into illness.