Objective To evaluate the role of distortion product otoacoustic emissions (DPOAE) testing in evaluating early hearing loss among noise-exposed workers. Methods A total of 174 noise-exposed workers in a metal shipbuilding enterprise were selected as the research subjects by the convenience sampling method. Pure tone audiometry (PTA), DPOAE and the level of noise exposure were conducted on the workers. The rank correlation analysis was used to analyze the correlation between DPOAE amplitude and PTA threshold. The multilevel model was used to analyze the effects of gender, age, noise exposure intensity, cumulative noise exposure (CNE), hearing loss classification and PTA threshold on DPOAE results. Results At the frequencies of 0.50, 1.00, 2.00, 3.00, 4.00, 6.00 and 8.00 kHz, the DPOAE amplitude was negatively correlated with the PTA threshold (rank correlation coefficients were -0.12, -0.48, -0.47, -0.18, -0.23, -0.44, -0.19, respectively, all P<0.01). At the most frequencies, DPOAE amplitude was negatively correlated with age and CNE (all P<0.05). The results of multilevel model analysis showed that there were significant differences in DPOAE amplitudes at certain frequencies across gender, age, noise intensity, CNE, and hearing loss classification (all P<0.05). Significant differences in DPOAE responses were found among different CNE and hearing loss groups (all P<0.01). Conclusion DPOAE testing can objectively reflect the hearing status of noise-exposed workers and could be considered for inclusion in routine hearing monitoring to facilitate early detection of noise-induced hearing loss.

BACKGROUND: Peripheral helper T (T PH ) cells are uniquely positioned within pathologically inflamed non-lymphoid tissues to stimulate B-cell responses and antibody production. However, the phenotype, function, and clinical relevance of T PH cells in hepatocellular carcinoma (HCC) are currently unknown. METHODS: Blood, tumor, and peritumoral liver tissue samples from 39 HCC patients (Sep 2016-Aug 2017) and 101 HCC patients (Sep 2011-Dec 2012) at the Third Affiliated Hospital of Sun Yat-sen University were used. Flow cytometry was used to quantify the expression, phenotype, and function of T PH cells. Log-rank tests were performed to evaluate disease-free survival and overall survival in samples from 39 patients and 101 patients with HCC. T PH cells, CD19 + B cells, and T follicular helper (T FH ) cells were cultured separately in vitro or isolated from C57/B6L mice in vivo for functional assays. RESULTS: T PH cells highly infiltrated tumor tissues, which was correlated with tumor size, early recurrence, and shorter survival time. The tumor-infiltrated T PH cells showed a unique ICOS hi CXCL13 + IL-21 - MAF + BCL-6 - phenotype and triggered naïve B-cell differentiation into regulatory B cells. Triggering programmed cell death protein 1 (PD-1) induced the production of C-X-C motif chemokine ligand 13 (CXCL13) by T PH cells, which then suppressed tumor-specific immunity and promoted disease progression. CONCLUSION Our study reveals a novel regulatory mechanism of T PH cell-regulatory B-cell-mediated immunosuppression and provides an important perspective for determining the balance between the differentiation of protumorigenic T PH cells and that of antitumorigenic T FH cells in the HCC microenvironment.
Carcinoma, Hepatocellular/metabolism* ; Liver Neoplasms/metabolism* ; Humans ; T-Lymphocytes, Helper-Inducer/metabolism* ; Animals ; Mice ; Male ; Female ; Mice, Inbred C57BL ; Middle Aged ; B-Lymphocytes, Regulatory/metabolism* ; Flow Cytometry ; Interleukin-21 ; Aged ; Chemokine CXCL13/metabolism*

Negative logarithm of the acid dissociation constant (pK _a) significantly influences the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of molecules and is a crucial indicator in drug research. Given the rapid and accurate characteristics of computational methods, their role in predicting drug properties is increasingly important. Although many pK _a prediction models currently exist, they often focus on enhancing model precision while neglecting interpretability. In this study, we present GraFpK _a, a pK _a prediction model using graph neural networks (GNNs) and molecular fingerprints. The results show that our acidic and basic models achieved mean absolute errors (MAEs) of 0.621 and 0.402, respectively, on the test set, demonstrating good predictive performance. Notably, to improve interpretability, GraFpK _a also incorporates Integrated Gradients (IGs), providing a clearer visual description of the atoms significantly affecting the pK _a values. The high reliability and interpretability of GraFpK _a ensure accurate pK _a predictions while also facilitating a deeper understanding of the relationship between molecular structure and pK _a values, making it a valuable tool in the field of pK _a prediction.

Objective To investigate the factors influencing the prognosis of complex intracranial aneurysms treated with pipeline flow-directed device(PED)and to develop a nomogram prediction model.Methods The clinical data of a total of 98 patients with complex intracranial aneurysm,who were admitted to the Anyue County People's Hospital or the Second Affiliated Hospital of Guilin Medical College of China from January 2021 to April 2023 to receive PED treatment,were retrospectively analyzed.The influencing factors that might affect the prognosis of patients with complex intracranial aneurysm were collected.According to the modified Rankin Scale(mRS)score,the patients were divided into good prognosis group(being defined as mRS ≤2 points)and poor prognosis group(being defined as mRS＞2 points).The clinical data were compared between the two groups,and a nomogram model was established and validated.Results In the 98 patients,poor prognosis was seen in 10(10.20％).The differences in age,history of hypertension,history of diabetes mellitus,clopidogrel resistance,Fisher classification,repeated aneurysm rupture,aneurysm location,aneurysm size,aneurysm neck,multiple lesions,and Hunt-Hess grade on admission between good prognosis group and poor prognosis group were statistically significant(all P＜0.05).Multivariate analysis revealed that history of hypertension,clopidogrel resistance,repeated aneurysm rupture,aneurysm location,multiple lesions,and Hunt-Hess grade were the independent factors influencing the prognosis of patients with complex intracranial aneurysm after receiving PED treatment.The AUC of the nomogram model in predicting the prognosis of PED for complex intracranial aneurysms was 0.849(95％CI=0.758-0.939).The predicted curves of the model group and validation group were basically fitted to the standard curves.The results of the decision curve analysis showed that the net benefit to patients was greater than 0 when the probability threshold of the nomogram model for predicting a poor prognosis of PED for complex intracranial aneurysms was 0.10-0.90.Conclusion The factors causing poor prognosis of PED for complex intracranial aneurysms mainly include history of hypertension,clopidogrel resistance,repeated aneurysm rupture,etc.The nomogram model established in this study can predict the risk of poor prognosis in patients with complicated intracranial aneurysm after receiving PED treatment.

Objective To analyze the changes of liver and kidney function, blood glucose and lipid metabolism at different follow-up time points of different treatment regimens, and to provide reference for clinical optimization and adjustment of medication in HIV/AIDS patients. Methods The changes of liver and kidney function, blood glucose and lipid metabolism at seven follow-up time points were analyzed retrospectively. The baseline blood collection time of HIV /AIDS patients was set as the starting point, and the final follow-up time was set as the end point. The seven follow-up points were 0, 3, 6, 9, 12, 18 and 24 months respectively. Results There were statistically significant differences in the distribution of sex, age, education, marital status, WHO staging, infection route, and baseline CD4+T lymphocyte count among 605 enrolled patients based on different treatment regimens. Liver function: The level of T-Bil in group E was higher than that of baseline at 9M, 12M, 18M and 24M after treatment (P<0.01); In group F, the level of T-Bil was higher than that of baseline at 9M after treatment (P=0.001); The levels of ALT in group C at the six follow-up points after treatment were higher than the baseline (P<0.001); The level of AST in group C was higher than that of baseline after 3M and 6M treatment (P<0.05). Renal function: The level of UREA in group C was higher than that in baseline after 6M treatment (P=0.007); The level of UREA in group F was higher than that in the baseline after 12M treatment (P<0.001); The level of UA in group F was higher than that of baseline after 3M, 6M and 12M treatment (P<0.05). Blood lipid and blood glucose: The levels of Glu at some follow-up points after ART treatment in group A and group C were higher than that at baseline (P<0.05); The levels of TG at some follow-up points in group A, group E and group F after ART treatment were higher than those at baseline (P<0.05); The levels of TC at some follow-up points in group A, group B, group C, group E and group F after ART treatment were all higher than the baseline (P<0.05). Conclusion Regular monitoring of changes in laboratory indicators of different treatment regimens during ART is of great importance to the prognosis of patients. Different laboratory indicators should be monitored according to different treatment regimens to effectively prevent adverse reactions caused by different treatment regimens.

OBJECTIVE:The rabbit model of steroid-induced osteonecrosis of femoral head is the most commonly used animal model of femoral head necrosis.The pathological changes of the femoral head are close to clinical practice,however,the conditions,methods and evaluation standards of animal models reported in and outside China are not uniform,which leads to the low scientific value of animal models and is difficult to popularize.This study aimed to clarify the influence of different mold-making conditions on the establishment of steroid-induced osteonecrosis of femoral head rabbit model and analyze the appropriate conditions for the successful model establishment. METHODS:We searched the CNKI,WanFang,VIP,CBM,WoS,PubMed and EMbsae databases for the literature on the modeling of steroid-induced osteonecrosis of femoral head rabbits up to April 1,2022,completed the screening of the literature according to the inclusion and exclusion criteria and literature quality evaluation,and extracted the outcome index data in the literature.RevMan Stata and ADDIS statistical software were used to conduct a meta-analysis of the included data. RESULTS:(1)A total of 82 articles with 1 366 rabbits were included in the study.The steroid-induced osteonecrosis of femoral head modeling methods were divided into three types:steroid-alone method,steroid combined lipopolysaccharide method and steroid combined serum method.Among these,33 articles used steroid-alone method;20 articles used steroid combined lipopolysaccharide method;29 articles used steroid combined serum method.(2)Meta-analysis results showed that the three modeling methods significantly increased the rate of empty bone lacunae in the femoral head of steroid-induced osteonecrosis of femoral head rabbits(P<0.001),and significantly decreased the ratio of the trabecular bone area in the femoral head of steroid-induced osteonecrosis of femoral head rabbits(P<0.001).The order of empty bone lacunae rate of each modeling method was:steroid combined with lipopolysaccharide method>steroid-alone method>steroid combined with serum method>normal group,and the order of trabecular bone area rate of each modeling method was:normal group>steroid combined with serum method>steroid-alone method>steroid combined with lipopolysaccharide method.(3)The results of subgroup analysis suggested that the rate of empty bone lacunae in the rabbit model induced by steroid alone might be related to the rabbit variety and the type of steroid used for modeling(difference between groups P<0.05),in which the combined effect amount of New Zealand white rabbits was higher than that of Chinese white rabbits(P<0.05)and Japanese white rabbits,and the combined effect amount of dexamethasone was higher than that of other steroids.The rate of empty bone lacunae induced by steroid combined with lipopolysaccharide was related to the administration mode of lipopolysaccharide and the type of steroid(P<0.05),among which the combined effect of methylprednisolone sodium succinate was significantly higher than that of other steroids(P<0.05),and the combined effect of prednisolone was significantly lower than that of other steroids(P<0.05).The combined effect of lipopolysaccharide 100 μg/kg×twice was significantly lower than 10 μg/kg×twice and 50 μg/kg×twice(P<0.05).The rate of empty bone lacunae in the model induced by steroid combined with serum was related to serum dose and steroid type(P<0.05),among which the combined effect amount of dexamethasone sodium phosphate was significantly higher than other steroid types(P<0.05),and the combined effect amount of dexamethasone was significantly lower than other steroid types(P<0.05);the combined effect amount of serum"10 mL/kg+6 mL/kg"combined dose was lower than other serum doses(P<0.05). CONCLUSION:(1)With the rate of empty bone lacunae and the ratio of trabecular bone area as the judgment standard for the successful establishment of the model,the three modeling methods can successfully construct the rabbit steroid-induced osteonecrosis of femoral head model,of which the steroid combined with lipopolysaccharide method is the best.(2)New Zealand white rabbits and dexamethasone are recommended when selecting the steroid-alone method.Methylprednisolone sodium succinate and low-dose lipopolysaccharide are recommended when selecting the steroid combined with lipopolysaccharide method.Dexamethasone sodium phosphate is recommended when selecting the steroid combined with serum modeling method.

ObjectiveTo investigate the protective effect of Jianpi Huogu prescription （JPHGP） on the functional injury of vascular endothelial cells caused by alcohol and explore its mechanism based on protein kinase B/c-Jun amino-terminal kinase/p38 MAPK （Akt/JNK/p38 MAPK） signaling pathway. MethodThrough chick embryo allantoic membrane， thoracic aortic ring， and migration， invasion， adhesion， and lumen formation of human umbilical vein endothelial cells （HUVEC）， the effect of JPHGP with different concentrations （8， 16 and 32 μg·L^-1） on angiogenesis was observed in the presence or absence of alcohol. The expression levels of phosphorylation of Akt， JNK， and p38 MAPK were determined by Western blot. ResultAs compared with the normal group， the number and length of capillaries around the arterial ring in the model group were decreased， and the migration， invasion， and lumen formation capacity of HUVEC were decreased （P<0.05， P<0.01）. After treatment with 16 and 32 μg·L^-1 JPHGP， the length of neovascularization in chick embryo allantoic membrane was significantly increased （P<0.05， P<0.01）. Compared with the model group， the 8， 16， and 32 μg·L^-1 JPHGP groups increased the number of capillaries around the thoracic aortic ring in a concentration-dependent manner （P<0.05， P<0.01）， and the 32 μg·L^-1 JPHGP group increased the length of capillaries around the thoracic aortic ring （P<0.05）. The 16 and 32 μg·L^-1 JPHGP groups enhanced the migration， invasion， and lumen formation capacity of HUVEC. The results of Western blot showed that， as compared with the normal group， the protein expression levels of p-JNK/JNK， p-p38 MAPK/p38 MAPK， and p-Akt/Akt were significantly decreased in the model group （P<0.01）， and as compared with the model group， the protein expression levels of p-p38 MAPK/p38 MAPK and p-Akt/Akt were significantly increased in the 8， 16， and 32 μg·L^-1 JPHGP groups （P<0.01） and the protein expression level of p-JNK/JNK was increased significantly in the 16 and 32 μg·L^-1 JPHGP groups （P<0.01）. ConclusionJPHGP has a protective effect on the functional injury of vascular endothelial cells caused by alcohol， and its mechanism may be related to the activation of Akt/JNK/p38 MAPK signaling pathway. Relevant research results will provide certain scientific basis for clarifying the effect of JPHGP on 'invigorating spleen and promoting blood circulation'.

ObjectiveTo clarify the intervention effect of Osteoking （OK） in rats with myofascial pain syndrome （MPS） and preliminarily explore the pharmacological mechanism of OK in relieving chronic pain from the perspective of anti-inflammatory disease. MethodThe 60 SD rats were divided into normal group， model group， low， medium， and high dose OK groups （0.66， 1.31， 2.63 mL·kg^-1）， and positive celecoxib group （21 mg·kg^-1）. The MPS rat model was established by beating combined with the centrifugal exercise method， and the OK and celecoxib were given at the same time. SMALGO paw pressure pain manometer detected the shock pain point tenderness threshold of rats， and the Von-Frey needle and acetone stimulation method detected the mechanical hyperalgesia threshold and cold hyperalgesia stimulation response respectively. Eight weeks and 10 weeks after modeling， the spontaneous discharge state and convulsion response of MPS rats were determined by electromyograph （EMG） instrument. The gait changes of MPS rats were detected using a CatWalk gait analyzer. The expression levels of interleukin-1 β （IL-1β）， tumor necrosis factor-α （TNF-α）， substance P （SP）， and bradykinin （BK） were measured by enzyme-linked immunosorbent assay （ELISA）. The protein expression levels of nuclear transcription factor-κB （NF-κB） inhibiting protein α （IκBα）， phosphorylates （p）- IκBα， NF-κB p65， and p-NF-κB p65 were detected in MPS rats by Western blot. The positive expression of p-NF-κB p65 was detected by immunofluorescence. ResultCompared with the normal group， the model group shows 100% positive rates for EMG signal and local convulsions response at both the 8th and 10th weeks. The tenderness threshold and mechanical hyperalgesia threshold are significantly reduced. Cold hyperalgesia score is significantly increased， and gait is abnormal. The expression levels of serum and trigger points IL-1β， TNF-α， SP， BK， p-IκBα， and p-NF-κB p65， as well as the positive expression intensity of p-NF-κB p65 are significantly increased （P<0.01）. Compared with the model group， the positive rate of EMG detection and local convulsion response is significantly reduced in the medium and high dose OK groups （P<0.05）. The tenderness threshold and mechanical hyperalgesia threshold increase significantly in the medium and high dose OK groups， and the cold hyperalgesia score is significantly reduced in the high dose OK group （P<0.01）. The standing time， swing time， and walking period are significantly increased. The swing speed， maximum contact area， and maximum contact intensity are significantly decreased in the high dose OK group （P<0.05）. Moreover， the protein expression levels of p-IκBα/IκBα and p-NF-κB p65/NF-κB p65 are significantly reduced in the medium and high dose OK groups （P<0.05，P<0.01）. The positive expression intensity of p-NF-κB p65 is significantly decreased in the high dose OK group （P<0.01）. ConclusionThe mechanism of OK in relieving the pain in trigger points of MPS and improving gait abnormalities is related to the downregulation of the NF-κB p65 inflammatory signaling pathway to reduce the expression of inflammatory factors and pain mediators in blood and trigger point tissue.

ObjectiveFrom the perspective of energy metabolism， the mechanism of Osteoking （OK） in the treatment of myofascial pain syndrome （MPS） was revealed through systems biology prediction combined with holistic animal experimental validation methods. MethodFirstly， the key targets of MPS and their related molecular mechanisms were predicted by the systems biology method， and the core network targets were screened. Then， the network-predicted targets were verified by animal experiments. Specifically， 60 SD rats were randomly divided into normal group， model group， low， medium， and high dose OK groups （0.66， 1.31， 2.63 mL·kg^-1）， and positive celecoxib group （21 mg·kg^-1）. The MPS model was established by beating combined with a centrifugal exercise method for eight weeks. Except for two days after modeling， the intervention of OK or celecoxib was performed. After the completion of the model， the drug was administered for two weeks. The histopathological changes of trigger point muscle tissue were observed by hematoxylin-eosin staining. The content/activity of Na-K-ATP enzyme （Na⁺-K⁺-ATPase）， Ca²⁺ pump （Ca²⁺ATPase）， Ca²⁺， lactate dehydrogenase （LDH）， glutathione （GSH）， malondialal （MDA）， superoxide dismutase （SOD）， cyclic adenosine phosphate （cAMP）， and protein kinase A （PKA） in serum and/or trigger point muscle tissue in MPS rats was detected by enzyme-linked immunosorbent assay. Protein expression levels of PKA and the peroxisome proliferator-activated receptor γ coactivator 1α （PGC1α） in MPS rats were detected by immunohistochemistry. The protein expression levels of PKA， PGC1α， and mitochondrial transcription factor A （TFAM） in MPS rats were detected by Western blot. ResultThe network prediction results suggest that OK acts on the key target of energy metabolism related to the occurrence and development of MPS and may participate in the activation of the cAMP/PKA/PGC1α signaling pathway. The experimental validation results show that compared with the normal group， contracture nodules and disordered arrangement of muscle fibers appear in the trigger point muscle tissue of MPS rats. Na⁺-K⁺-ATPase， Ca²⁺ATPase， SOD activity， Ca²⁺， and GSH contents in serum and/or trigger point muscle tissue are significantly decreased （P<0.01）. Both LDH activity and MDA contents are significantly increased （P<0.01）， and the protein expression levels of cAMP， PKA， PGC1α， and TFAM are significantly decreased （P<0.01）. Compared with the model group， OK improves the histopathological morphology of trigger point muscle fibers in MPS rats， and after the intervention of OK， Na⁺-K⁺-ATPase， Ca²⁺ATPase， SOD activity， Ca²⁺， and GSH contents in serum and/or trigger point muscle tissue in MPS rats are significantly increased （P<0.05， P<0.01）. LDH activity and MDA contents are significantly reduced （P<0.05， P<0.01）. The protein expression levels of cAMP， PKA， PGC1α， and TFAM are significantly increased （P<0.05， P<0.01）. ConclusionThe mechanism of OK's intervention in MPS rats may be related to its effective activation of the cAMP/PKA/PGC1α signaling pathway， thus promoting mitochondrial energy metabolism and trigger point muscle fiber damage repair in muscle cells.

Objective: To evaluate the association of smoking with the risk of ankylosing spondylitis (AS) using a Mendelian randomization (MR) approach. Methods: A total of 16 383 186 AS-associated single nucleotide polymorphisms (SNPs), 378 smoking initiation associated SNPs and 126 lifetime smoking score-associated SNPs were collected from three large-scale genome-wide association studies (GWAS). The association of smoking phenotypes with the risk of AS was examined using inverse-variance weighted (IVW) with AS as a outcome variable, smoking initiation and lifetime smoking score as exposure factors and SNPs with strong associations with smoking as instrumental variables, and sensitivity analyses were performed with maximum likelihood-based method, MR pleiotropy residual sum and outlier (MR-PRESSO) test and MR-Egger regression analysis. Results: A 33.5% increased risk of AS was found among genetically predicted smokers relative to non-smokers (OR=1.335, 95%CI: 1.059-1.682), and an increase in predicted lifetime smoking by per standard deviation resulted in a 101.4% increased risk of AS (OR=2.014, 95%CI: 1.341-3.024). The maximum likelihood-based method and MR-PRESSO test showed consistent correlated effect estimations and MR-Egger regression analysis identified no evidence of pleiotropy. Conclusion It is genetically predicted that smoking is associated with an increased risk of AS.