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Objective: To study the clinical effect of group cognitive behavioral therapy to one-on-one treatment on patients with early-onset schizophrenia. Methods: Totally,133 patients with early-onset schizophrenia admitted to the Department of Psychiatry of our hospital from September 2020 to September 2023 were selected and divided into a control group and an observation group according to whether group behavioral cognitive therapy was performed. The general demographic data of the patients were collected, and the propensity score matching method was used to balance the baseline data of the 2 groups. The Positive and negative syndrome scale, Personal and Social Performance Scale, severity of illness (SI), and efficacy index (EI) were compared between the 2 groups after matching. Results: After matching, 72 patients were included in our study. Compared to the control group, observation group PANSS score were decreased including after intervention (P > .05). Both groups showed a decrease between before and after treatments. Positive and Negative Syndrome Scale reduction rate after treatment and total response rate were increased in the observation group (P <.001). Personal and Social Performance Scale of the Clinical Global Impression (CGI) scores were higher than those of the control group. In the CGI scores, there is a significant difference that SI scores were lower in the observation group (P = .002), while EI scores were higher (P <.001). Conclusion: Group cognitive behavioral therapy is beneficial to the improvement of mental symptoms and disease severity, social function, and curative effect, which is advocated and popularized.
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As a natural renewable biomacromolecule, lignin has some inherently interesting properties such as fluorescence, antioxidation, and antibacterial performance. However, the unsatisfactory fluorescence and biological activities have greatly limited their value-added and large-scale applications. In this work, lignin nanoparticles (LNPs) grafted with vitamin B1 hybrid nanoparticles (LEVs) were obtained by using ethylenediamine and different contents of vitamin B1 through a simple hydrothermal method. The chemical structure, fluorescence properties, and bioactivity were characterized to assess the effects of ethylenediamine and vitamin B1 on the properties of LEVs. It was found that the fluorescence performance of synthesized LEV particles was improved with the increase in the amount of vitamin B1. The free radical scavenging rate (RSA, %) increased to 97.8%, while the antibacterial rates reached up to 99.9%. The antibacterial activity of LEV involved multiple combined mechanisms. The introduction of imine, amide groups, and positively charged VB1 of LEV will make it easier to interact with the negatively charged bacterial phospholipid membranes and cause bacterial lysis and death. Then, the PVA/LEV hydrogel composites were prepared by the freezing-thawing method, and the results showed that PVA/LEV hydrogels had more comprehensive performance such as improved mechanical properties and antioxidant and antibacterial activities, resulting in its great potential to be used as an efficient biomedical material.
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Antibacterianos , Lignina , Antibacterianos/farmacologia , Antibacterianos/química , Lignina/química , Lignina/farmacologia , Nanopartículas/química , Tiamina/química , Tiamina/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Fluorescência , Escherichia coli/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Hidrogéis/química , Hidrogéis/farmacologiaRESUMO
The effective reconstruction of osteochondral biomimetic structures is a key factor in guiding the regeneration of full-thickness osteochondral defects. Due to the avascular nature of hyaline cartilage, the greatest challenge in constructing this scaffold lies in both utilizing the biomimetic structure to promote vascular differentiation for nutrient delivery to hyaline cartilage, thereby enhancing the efficiency of osteochondral reconstruction, and effectively blocking vascular ingrowth into the cartilage layer to prevent cartilage mineralization. However, the intrinsic relationship between the planning of the microporous pipe network and the flow resistance in the biomimetic structure, and the mechanism of promoting cell adhesion to achieve vascular differentiation and inhibiting cell adhesion to block the growth of blood vessels are still unclear. Inspired by the structure of tree trunks, this study designed a biomimetic tree-like tubular network structure for osteochondral scaffolds based on Murray's law. Utilizing computational fluid dynamics, the study investigated the influence of the branching angle of micro-pores on the flow velocity, pressure distribution, and scaffold permeability within the scaffold. The results indicate that when the differentiation angle exceeds 50 degrees, the highest flow velocity occurs at the confluence of tributaries at the ninth fractal position, forming a barrier layer. This structure effectively guides vascular growth, enhances nutrient transport capacity, increases flow velocity to promote cell adhesion, and inhibits cell infiltration into the cartilage layer.
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CaWRKY40 coordinately activates pepper immunity against Ralstonia solanacearum infection (RSI) and high temperature stress (HTS), forms positive feedback loops with other positive regulators and is promoted by CaWRKY27b/CaWRKY28 through physical interactions; however, whether and how it is regulated by negative regulators to function appropriately remain unclear. Herein, we provide evidence that CaWRKY40 is repressed by a SALT TOLERANCE HOMOLOG2 in pepper (CaSTH2). Our data from gene silencing and transient overexpression in pepper and epoptic overexpression in Nicotiana benthamiana plants showed that CaSTH2 acted as negative regulator in immunity against RSI and thermotolerance. Our data from BiFC, CoIP, pull down, and MST indicate that CaSTH2 interacted with CaWRKY40, by which CaWRKY40 was prevented from activating immunity or thermotolerance-related genes. It was also found that CaSTH2 repressed CaWRKY40 at least partially through blocking interaction of CaWRKY40 with CaWRKY27b/CaWRKY28, but not through directly repressing binding of CaWRKY40 to its target genes. The results of study provide new insight into the mechanisms underlying the coordination of pepper immunity and thermotolerance.
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The aim of this study was to examine the parenting characteristics of young patients with bipolar disorder (BD) and explore the sex differences. The parental rearing pattern of young patients with BD was measured and compared with the healthy control of young adults. The EMBU scale was used to assess parental rearing patterns. Patients with BD reported significantly higher scores in the punishment and severity index, as well as of the rejection and denial index, but lower scores in the warmth & affectionate index in the paternal rearing pattern, compared with healthy controls. In addition, patients scored higher on the punishment and severity index and rejection and patterns index in maternal rearing patterns. More importantly, we found significant sex differences in maternal rearing patterns (pBonferroni < 0.05). Specifically, in the maternal rearing patterns, male patients had higher scores on the favoring index than male controls, whereas female patients had lower scores on the warmth & affectionate index than female controls. This study shows significant differences in parental rearing patterns between patients and control subjects. Male patients were overprotective by their mothers and female patients were overlooked by their mothers during upbringing.
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Transtorno Bipolar , Criança , Humanos , Masculino , Feminino , Adulto Jovem , Educação Infantil , Caracteres Sexuais , Relações Pais-Filho , Pais , Poder FamiliarRESUMO
Owing to their unique advantages, single-electrode triboelectric nanogenerators (SETENGs) have gained wide attention and have been applied in myriad areas, especially in the burgeoning flexible/wearable electronics. However, there is still a lack of a clear understanding of SETENGs. For example, previous simulation models generally put the reference electrode perpendicularly below the working part, but in practice, the reference electrode is designed in various scenarios and noticeable differences in outputs often occur when the reference electrode changes. With SETENGs developing towards wearability and portability, its reference electrode is often required to be constructed inside the device. Consequently, to achieve optimum performance, it is essential to understand the reference electrode's influence on the outputs. Here, the influence of the reference electrode on the performance of SETENGs is systematically investigated and the targeted optimization strategies are thoroughly revealed. First, theoretical simulations are conducted to investigate the reference electrode's effect on the performance of SETENGs with different structures and in various working modes. Secondly, the theoretical results are certified through corresponding experiments. Based on the results, the targeted optimization strategies for SETENGs are comprehensively demonstrated. This work provides fundamental guidance for the development of TENGs and the design and fabrication of new electronic devices.
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Backgrounds: The widespread coronavirus disease 2019 (COVID-19) outbreak impacted the mental health of infected patients admitted to Fangcang shelter hospital a large-scale, temporary structure converted from existing public venues to isolate patients with mild or moderate symptoms of COVID-19 infection. Objective: This study aimed to investigate the risk factors of the infected patients from a new pharmacological perspective based on psychiatric drug consumption rather than questionnaires for the first time. Methods: We summarised the medical information and analysed the prevalence proportion, characteristics, and the related risk factors of omicron variants infected patients in the Fangcang Shelter Hospital of the National Exhibition and Convention Center (Shanghai) from 9 April 2022 to 31 May 2022. Results: In this study, 6,218 individuals at 3.57% of all admitted patients in the Fangcang shelter were collected suffering from mental health problems in severe conditions including schizophrenia, depression, insomnia, and anxiety who needed psychiatric drug intervention. In the group, 97.44% experienced their first prescription of psychiatric drugs and had no diagnosed historical psychiatric diseases. Further analysis indicated that female sex, no vaccination, older age, longer hospitalization time, and more comorbidities were independent risk factors for the drug-intervened patients. Conclusion: This is the first study to analyse the mental health problems of omicron variants infected patients hospitalised in Fangcang shelter hospitals. The research demonstrated the necessity of potential mental and psychological service development in Fangcang shelters during the COVID-19 pandemic and other public emergency responses.
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Long noncoding RNAs (lncRNAs) have been reported to be involved in the development and progression of various human malignancies. However, the role of lncRNA CASC2 in hepatocellular carcinoma (HCC) remains mostly unknown. The aim of this study was to investigate the potential roles and underlying mechanisms of CASC2 in HCC progression. We found that CASC2 expressions were downregulated in HCC tissue samples and cell lines. The clinical assays revealed that lower levels of CASC2 were associated with the TNM stage, lymph node metastasis, and a poorer prognosis specific to HCC patients. Overexpression of CASC2 inhibited the proliferating, migratory, and invasion capacity of HCC cells. Bioinformatics analysis and the luciferase reporter assay revealed that CASC2 worked as a molecular sponge for miR-155. And CASC2 could upregulate SOCS1 expression by inhibiting miR-155 expression in HCC cells. Furthermore, SOCS1 inhibition partially inverses the suppression effect of cell proliferation, migration, and invasion regulated by CASC2 in Huh7 and HepG2 cells. Taken together, our findings identified CASC2 as a tumor suppressor to inhibit HCC development by regulating the miR-155/SOCS1 axis, and CASC2 might be a potential therapeutic target of HCC for future clinical treatment.
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Silver nanowires (AgNWs) have received much attention and application in transparent electrodes, wearable electronic devices, and sensors. The hope is for these nanowires to eventually replace the most commonly used transparent electrode material-indium tin oxide (ITO). However, electrospinning used for the preparation of AgNWs on a large scale is limited by its low productivity and high electric field, while the alcohol-thermal method is limited to mixing by-product silver nanoparticles in silver nanowires. We demonstrate a novel and simple centrifugal spinning approach in order to successfully fabricate ultra-long silver microfibers based on AgNO3 and polyvinyl pyrrolidone (PVP). The centrifugal-spun precursor fiber and silver fiber can be prepared to as thin as 390 and 310 nm, respectively. Annealed fibers show typical nanostructures with grains down to a minimum size of 51 nm. Combinations of different parameters, including concentrations of PVP, needle size, and annealing temperature are also investigated, in order to optimize the spinning process of ultra-long silver microfibers. The feasibility of preparing silver microfibers by centrifugal spinning is preliminarily verified, examining prospects for mass production. Furthermore, numerous strategies related to assisting the creation of silver nanofibers using centrifugal spinning are presented as possibilities in future development.
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MXenes have shown great potential for supercapacitor electrodes due to their unique characteristics, but simultaneously achieving high capacitance, rate capability, and cyclic stability along with good mechanical flexibility is exceptionally challenging. Here, highly enhanced capacitance, rate capability, and cyclic stability, as well as good mechanical flexibility for T3C2Tx MXene-based supercapacitor electrodes are simultaneously obtained by engineering the electrode structure, modifying the surface chemistry, and optimizing the fabrication process via an optimized integration approach. This approach combines and more importantly optimizes three methods that all require a calcination process: carbonizing in situ grown polymer ("Cpolymer") on the MXene, alkali treatment ("A"), and template sacrificing ("P"); and the optimized processes lead to more abundant active sites, faster ion accessibility, better chemical stability, and good mechanical flexibility. The obtained P-MXene/Cpolymer-A electrodes are binder-free and self-supporting and not only have good mechanical flexibility but also demonstrate much larger capacitances and better rate performance than the pristine MXene electrode. Specifically, the P-MXene/CPAQ-A electrode (PAQ: quinone-amine polymer) achieves a high capacitance of 532.9 F g-1 at 5 mV s-1, together with superior rate performance and improved cyclic stability (97.1% capacitance retention after 40â¯000 cycles at 20 A g-1) compared with the pristine MXene (79.6% retention) and P-MXene-A (77.3% retention) electrodes. In addition, it is discovered that carbonizing in situ grown polymers can variously remove the -F group and the removal effect can be accumulated with that by the alkali treatment.
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Photodynamic therapy (PDT) utilizes the photogeneration of reactive oxygen species (ROS) with high cytotoxicity to kill cancer cells, holding great promise for cancer treatment. Fractionated delivery of singlet oxygen (1O2) is a wise approach to relieving hypoxia, thus enhancing the therapeutic efficacy. In this article, an anthracene-functionalized semiconducting compound (DPPA) has been designed and synthesized. With irradiation, the compound is able to undergo efficient intersystem crossing (ISC) and non-radioactive decay for photodynamic/photothermal synergistic therapy. In addition, the anthracene module is able to capture and release 1O2 reversibly with or without irradiation. DPPA nanoparticles (NPs) obtained by nanoprecipitation with DSPE-PEG exhibit considerable high phototoxicity on human kidney cancer cells (A498), and the half maximum inhibitory concentration (IC50) is 15.8 µg/ml. Furthermore, an in vivo study demonstrates that complete tumor suppression was observed when the mice were administered DPPA NPs with the help of laser, compared with the control and dark groups. The H&E analysis of the normal tissues (the heart, liver, spleen, lungs, and kidney) indicates that such NPs cause no side effects, indicating the biosafety of DPPA NPs. The results provide a strategy to design a heavy-atom-free photosensitizer for photothermal and fractionated PDT against kidney tumors.
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The resource utilization of biological solid waste is crucial for practical environmental remediation. By comprehensively utilizing LiBr treatment and dopamine chemistry, herein the cow dung waste was successfully converted into the composite biomass material for efficient heavy metal ions removal. A selective etching mechanism of cellulose was discovered in the LiBr treatment process, achieving the large-scale preparation of coralline-like porous biomass material with hundred times increased specific surface. Benefiting from the co-deposition of polyethyleneimine and Fe3O4, the fabricated material showed significantly higher adsorption capacity (183.82 and 231.48 mg·g-1 for Cu2+ and Cd2+) than that of raw cow dung (0.95 and 1.25 mg·g-1 for Cu2+ and Cd2+). Furthermore, this composite biomass adsorbent also exhibited rapid adsorption equilibrium, magnetic separation capability, monolayer chemisorption feature and feasible recycling use. Collectively, this work contributes to both the resource utilization of husbandry solid waste and the development of advanced biomass adsorbent.
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Metais Pesados , Poluentes Químicos da Água , Adsorção , Biomassa , Íons , Cinética , PolietilenoiminaRESUMO
Flexible temperature sensors can be attached to the surface of human skin or curved surfaces directly for continuous and stable data measurements, and have attracted extensive attention in myriad areas. Carbon nanomaterials possess great potential for temperature sensing, and flexible temperature sensors based on carbon nanomaterials have demonstrated unique advantages such as high sensitivity, fast response, good mechanical adaptability, low-cost fabrication processes, high cycling stability and reliability. In this review, the working mechanisms, device structures, material compositions, fabrication technologies, temperature sensing properties, the crucial roles of carbon nanomaterials, specific advantages and existing limitations of different types of flexible temperature sensors based on carbon nanomaterials are comprehensively elaborated and discussed. Based on recent advances, conclusions are made and challenges as well as future perspectives are systematically outlined and discussed.
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Carbono/química , Fenômenos Mecânicos , Nanoestruturas , Nanotecnologia/instrumentação , Temperatura , HumanosRESUMO
Using silk fibroin as the base material, the drug-loaded microspheres are prepared by an emulsification method. In order to determine the drug-loading and drug-release performance parameters of the microspheres, the central composite design method is used to design and investigate the effects of the parameters of the microsphere preparation process, such as the oil-water ratio, stirring temperature, and stirring rate, on the microsphere particle size, drug-loading rate, and drug release rate. The "overall desirability" is taken as a comprehensive evaluation index, and the response surface method (RSM) and genetic algorithm-backpropagation (GA-BP) neural network GA-BP model are used to predict and evaluate the parameters of the drug-loaded microsphere preparation process. The root-mean-square error values obtained from the RSM and BP-GA model experiments are 0.000325 and 0.00022, respectively. The results show that the BP-GA model has better prediction accuracy and optimization ability than the RSM. The optimal microsphere preparation process conditions were determined to be as follows: a water-oil ratio of 10:1, at a temperature of 45°C with stirring at a speed of 400 rpm, the particle size of the microspheres is 1.392 µm, the drug-loading rate is 3.218%, and the drug release rate is 51.991%. The results of this study indicate that this approach is an effective method for the optimization of the parameters of the drug-loaded microsphere preparation process.
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Portadores de Fármacos/química , Fibroínas/química , Isoniazida/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Técnicas In Vitro , Isoniazida/farmacologia , Microesferas , Modelos Químicos , Redes Neurais de Computação , Tamanho da Partícula , TemperaturaRESUMO
Design and preparation of photosensitizers (PSs) play an important role in photodynamic therapy (PDT). PDT mainly relies on the production of toxic reactive oxygen species (ROS) of the PSs. Conventional fluorophores, however, often suffer from aggregation caused quenching (ACQ), which limits the potential of PSs as fluorescent imaging agents. Molecules with aggregation-induced emission (AIE) properties maintain high fluorescence and dispersity in aqueous solutions, overcoming the ACQ effect. Ruthenium (II)-based AIE compounds are highly biocompatible molecules and can be used for response cell imaging. In the current study, two novel Ru(II)-based AIE compounds with main ligands 1,3-di(2H-tetrazol-5-yl)benzene (Hphbtz) by changing auxiliary ligand 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen) have been successfully synthesized and characterized, [Ru(Hphbtz)(bipy)2][PF6] (1) and [Ru(Hphbtz)(phen)2][PF6] (2). The NPs show strong intra-cellular fluorescence and also simultaneously exhibited potent cytotoxic activity. These compounds can self-assemble to form nanoparticles (NPs) by nanoprecipitation. The compounds are found to exhibit a high AIE property with emission maxima at 353 nm and 380 nm, respectively. And the compounds have the low IC50 (half maximal inhibitory concentration) of only 15 µg/mL (1.94 µM) and 13 µg/mL (1.58 µM) on HeLa cells, respectively. Meanwhile, negligible dark toxicity has been also observed for these NPs. The results show that [Ru(Hphbtz)(bipy)2][PF6] (1) and [Ru(Hphbtz)(phen)2][PF6] (2) NPs can inhibit cell proliferation in vitro, and may be potential candidates for photodynamic therapy.
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Complexos de Coordenação/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Compostos de Rutênio/farmacologia , Antineoplásicos/farmacologia , Células HeLa , HumanosRESUMO
Boosting the photosensitization type I process will enhance the phototherapy efficacy because the superoxide radicals (O2-) generated during type I process are more toxic than the singlet oxygen (1O2) in type II process. Herein, [Ru(Hdtza)(phen)2][PF6] (1) and [Ru(pytz)(phen)2][PF6] (2) (phen = 1,10-phenanthroline) based on two nitrogen-rich tetrazole ligands, di(2H-tetrazol-5-yl) amine (H2dtza) and 5-(2-pyridyl)tetrazole (Hpytz) have been developed for photodynamic therapy (PDT) against lung cancer, respectively. Nanoprecipitation was used to prepare the nanoparticles (NPs) of both compounds. [Ru(Hdtza)(phen)2][PF6] NPs mainly undergo an electron transfer process to generate O2- while [Ru(pytz)(phen)2][PF6] the direct energy transfer to produce 1O2, which is responsible for the higher phototoxicity of [Ru(Hdtza)(phen)2][PF6] NPs (IC50 ~ 4.8 µg/mL) than that of [Ru(pytz)(phen)2][PF6] NPs (IC50 ~ 13.6 µg/mL) on human lung cancer cells (A549). Furthermore, in vivo study indicates that the tumor proliferation of nude mice can be effectively inhibited with the help of laser when the mice were injected with [Ru(pytz)(phen)2][PF6] NPs. This work may provide a simple strategy to design type I photosensitizers for enhanced photodynamic therapy.
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Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Rutênio/química , Tetrazóis/química , Animais , Antineoplásicos/química , Humanos , Ligantes , Camundongos , Estrutura Molecular , Fotoquimioterapia , Compostos de Rutênio/farmacologiaRESUMO
Plant-derived materials as environmentally friendly biosorbents to remove heavy metals from wastewater have been extensively studied. However, the chemical oxygen demand (COD) increase caused by the plant-derived biosorbent has not been considered previously. In this study, water hyacinth was used as biosorbent to remove Cd(II) from wastewater. About 66% of Cd(II) was removed by the biosorbent with a maximum biosorption capacity (qmax) of 21.6 mg g-1. However, the COD of the filtrate increased from 0 to 292 mg L-1 during this process. Subsequently, endophytes, microalgae and the microalgae-endophyte symbiotic system (MESS) were assessed for the simultaneous Cd(II) and COD removal. Among these three systems, the MESS achieved the best performance. After 3 d of inoculation, the extent of total Cd(II) removal increased to 99.2% while COD decreased to 77 mg L-1. This study provides a new insight into the application of a plant-derived biosorbent in combination with microalgae and endophytes for the effective treatment of heavy metal-bearing wastewater.
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Metais Pesados , Microalgas , Poluentes Químicos da Água/análise , Adsorção , Biomassa , Cádmio , EndófitosRESUMO
In order to combine the drug with the tissue-engineered bone scaffold and make the drugs on the scaffolds stable to achieve sustained-release stepwise function, a new method for preparing coaxial drug-loaded tissue engineering bone scaffolds using coaxial three-dimensional printing technology is proposed, in which inner layer material can carry drugs and the outer material can adjust the drug sustained-release rate. The coupling mechanism of both shape control and property control in the process of coaxial three-dimensional printing micro-structural unit is presented. Design-Expert software is introduced for experimental design. The influences of extrusion speed, filling speed, and delamination height on the forming quality are analyzed, and a coaxial gradient composite scaffold model with controllable micro-structure is established. The macro-structure, mechanical properties, in vitro degradation rate, and drug release rate of the scaffolds were analyzed. The experimental results show that the proposed forming technology and process parameter optimization can effectively improve the forming quality of the coaxial scaffold. At the same time, this design of the coaxial structure can effectively slow down the degradation rate of the scaffold and enables stable and long-time drug release. Furthermore, the presented method provides a new technical approach for the further implementation of implantable drug delivery systems for the effective treatment of bone tuberculosis.
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Osso e Ossos/citologia , Sistemas de Liberação de Medicamentos/métodos , Impressão Tridimensional , Engenharia Tecidual , Alicerces Teciduais/química , Propriedades de Superfície , ViscosidadeRESUMO
OBJECTIVE: To research advanced glycation end-product receptors (RAGE), NF-kappaB, p21 expressions in C57BL/6j mice cochlea spiral ganglion cells(SGC) ,and then to investigate the presbycusis pathogenesis. METHOD: To take C57BL/6J mice:2 month 25,and 10 month 25. Histological sections were observed the SGC. RAGE, NF-kappaB, p21 were immunohistochemical in the SGC,with IPP6 to IOD. RESULT: (1) The count SGCs of 10 month-old was obviously decreased comparing to 2 month-old, the count of 2 month SGC is 39 +/- 5, 10 month group is 20 +/- 6, P < 0.01; (2) RAGE, NF-kappaB, p21 expressed in spiral ganglion cell,different place with different age,and the means optical density in the 10 month are higher than the 2 month, respectively. The IOD of RAGE expression in 2 month SGC: 0.179 +/- 0.025, 10 month IOD: 0.308 +/- 0.050; The IOD of NF-kappaB expression in 2 month SGC: 0.181 +/- 0.045, 10 month IOD: 0.335 +/- 0.120; The IOD of p21 expression in 2 month SGC: 0.160 +/- 0.023, 10 month IOD: 0.365 +/- 0.031, compare with 2 group, respectively, P < 0.05, and the difference has statistics sense. CONCLUSION: RAGE,NF-kappaB, p21 expressions are in SGCs and increases with the aging of SGCs, suppose RAGE, NF-kappaB, p21 may participate in the process of presbycusis pathogenesis.