ObjectiveTo evaluate the impact of yang-reinforcing and blood-activating therapy on the long-term prognosis for patients with dilated cardiomyopathy （DCM） of yang deficiency and blood stasis syndrome. MethodsA retrospective cohort study was conducted involving 371 DCM patients with yang deficiency and blood stasis syndrome. The yang-reinforcing and blood-activating therapy was defined as the exposure factor. Patients were categorized into exposure group （186 cases） and non-exposure group （185 cases） according to whether they received yang-reinforcing and blood-activating therapy combined with conventional western medicine for 6 months or longer. The follow-up period was set at 48 months， and the Kaplan-Meier survival analysis was used to assess the cumulative incidence of major adverse cardiovascular events （MACE） in both groups. Cox regression analysis was used to explore the impact of yang-reinforcing and blood-activating therapy on the risk of MACE， and subgroup analysis was performed. Changes in traditional Chinese medicine （TCM） syndrome score， left ventricular ejection fraction （LVEF）， left ventricular fractional shortening （LVFS）， left ventricular end-diastolic diameter （LVEDD）， and Minnesota Living with Heart Failure Questionnaire （MLHFQ） score were compared between groups at the time of first combined use of yang-reinforcing and blood-activating therapy （before treatment） and 1 year after receiving the therapy （after treatment）. ResultsMACE occurred in 31 cases （16.67%） in the exposure group and 47 cases （25.41%） in the non-exposure group. The cumulative incidence of MACE in the exposure group was significantly lower than that in the non-exposure group ［HR=0.559， 95%CI（0.361，0.895）， P=0.014］. Cox regression analysis showed that yang-reinforcing and blood-activating therapy was an independent factor for reducing the risk of MACE in DCM patients ［HR=0.623， 95%CI（0.396，0.980）， P=0.041］， and consistent results were observed in different subgroups. Compared with pre-treatment， the exposure group showed decreased TCM syndrome score and MLHFQ score， reduced LVEDD， and increased LVEF and LVFS after treatment （P＜0.05）； in the non-exposure group， TCM syndrome score decreased， LVEF and LVFS increased， and LVEDD reduced after treatment （P＜0.05）. After treatment， the exposure group had higher LVEF and LVFS， smaller LVEDD， and lower TCM syndrome score and MLHFQ score compared with the non-exposure group （P＜0.05）. ConclusionCombining yang-reinforcing and blood-activating therapy with conventional western medicine can reduce the risk of MACE in DCM patients with yang deficiency and blood stasis syndrome， meanwhile improving their clinical symptoms， cardiac function， and quality of life.

ObjectiveMigraine is a leading neurological disorder and the fourth most common cause of years lived with disability worldwide, affecting nearly 116 million individuals. Although pharmacological treatments are available, their efficacy is often limited by side effects and variable response rates. Repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) offers a safe, non-invasive alternative for migraine management. However, the neurophysiological mechanisms, particularly how rTMS modulates local cortical excitability and distributed pain-related circuits, remain poorly understood. Elucidating these mechanisms is essential for optimizing treatment protocols and improving clinical outcomes. MethodsThis study employed concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to investigate neuroplastic and neurocircuitry mechanisms of DLPFC-rTMS in migraine. Study 1 compared 30 migraineurs and 28 healthy controls to identify abnormalities in TMS-evoked potentials (TEPs) and significant current density (SCD) within sensory-discriminative regions including the primary somatosensory cortex (S1) and posterior insula (pINS), cognitive-affective regions including the anterior insula (aINS) and midcingulate cortex (MCC), and a descending modulatory region, the periaqueductal gray (PAG). Study 2 used a single-blind, crossover, sham-controlled design in 34 healthy participants. Each participant received both active (10 Hz, 80% RMT, 1 500 pulses) and sham DLPFC-rTMS in counterbalanced order. TMS-EEG and cold pain tolerance were assessed before and after each session. ResultsIn Study 1, migraineurs showed a significantly less negative N120 amplitude compared to healthy controls (P=0.027, Cohen’s d=0.60), indicating local intracortical disinhibition. No group differences were observed for N40, P60, or P180 components. At the source level, migraineurs exhibited significantly higher SCD in the S1, pINS, aINS, and MCC (allQ<0.05), but not in the ventroposterior thalamus (vpTHAL), mediodorsal thalamus (mdTHAL), or PAG. In Study 2, active rTMS significantly reduced SCD from pre- to post-stimulation in the S1, aINS, and MCC (all Q<0.05). Sham stimulation also reduced SCD in the S1 (Q<0.05) but not in the aINS or MCC. Although no significant group-level analgesic effect was observed between active and sham conditions (P=0.107), correlation analyses revealed that greater SCD reductions in the S1 and MCC were significantly associated with higher post-rTMS pain tolerance (R=-0.487 and -0.495, both Q<0.01) and larger improvements in pain tolerance(R=-0.487 and -0.451, both Q<0.05). No such correlations were found following sham stimulation, suggesting that the behavioural relevance of neural changes is specific to active rTMS. ConclusionThis study provides novel evidence that migraineurs exhibit both local neuroplastic abnormalities (reduced N120 amplitude) and hyperactivity in key pain-processing regions (S1, pINS, aINS, MCC). A single session of DLPFC-rTMS reduced hyperactivity in the aINS, MCC, and S1. Notably, greater reductions in the S1 and MCC were associated with improved pain tolerance. These findings identify distinct cortical circuitries, particularly within the cognitive-affective pain network, that may serve as potential biomarkers for optimizing rTMS treatment in migraine and other chronic pain conditions. Future studies should validate these results in patient populations experiencing spontaneous migraine attacks and explore multi-session or accelerated rTMS protocols.

Serine protease inhibitor Kazal-type (SPINK) is a skin keratinizing protease inhibitor, which was initially found in animal serum and is widely present in plants, animals, bacteria, and viruses, and they act as key regulators of skin keratinizing proteases and are involved in the regulation of keratinocyte proliferation and inflammation, primarily through the inhibition of deregulated tissue kinin-releasing enzymes (KLKs) in skin response. This process plays a crucial role in alleviating various skin problems caused by hyperkeratinization and inflammation, and can greatly improve the overall condition of the skin. Specifically, the different members of the SPINK family, such as SPINK5, SPINK6, SPINK7, and SPINK9, each have unique biological functions and mechanisms of action. The existence of these members demonstrates the diversity and complexity of skin health and disease. First, SPINK5 mutations are closely associated with the development of various skin diseases, such as Netherton’s syndrome and atopic dermatitis, and SPINK5 is able to inhibit the activation of the STAT3 signaling pathway, thereby effectively preventing the metastasis of melanoma cells, which is important in preventing the invasion and migration of malignant tumors. Secondly, SPINK6 is mainly distributed in the epidermis and contains lysine and glutamate residues, which can act as a substrate for epidermal transglutaminase to maintain the normal structure and function of the skin. In addition, SPINK6 can activate the intracellular ERK1/2 and AKT signaling pathways through the activation of epidermal growth factor receptor and protease receptor-2 (EphA2), which can promote the migration of melanoma cells, and SPINK6 further deepens its role in stimulating the migration of malignant tumor cells by inhibiting the activation of STAT3 signaling pathway. This process further deepens its potential impact in stimulating tumor invasive migration. Furthermore, SPINK7 plays a role in the pathology of some inflammatory skin diseases, and is likely to be an important factor contributing to the exacerbation of skin diseases by promoting aberrant proliferation of keratinocytes and local inflammatory responses. Finally, SPINK9 can induce cell migration and promote skin wound healing by activating purinergic receptor 2 (P2R) to induce phosphorylation of epidermal growth factor and further activating the downstream ERK1/2 signaling pathway. In addition, SPINK9 also plays an antimicrobial role, preventing the interference of some pathogenic microorganisms. Taken as a whole, some members of the SPINK family may be potential targets for the treatment of dermatological disorders by regulating multiple biological processes such as keratinization metabolism and immuno-inflammatory processes in the skin. The development of drugs such as small molecule inhibitors and monoclonal antibodies has great potential for the treatment of dermatologic diseases, and future research on SPINK will help to gain a deeper understanding of the physiopathologic processes of the skin. Through its functions and regulatory mechanisms, the formation and maintenance of the skin barrier and the occurrence and development of inflammatory responses can be better understood, which will provide novel ideas and methods for the prevention and treatment of skin diseases.

Objective:To explore the predictive value of neutrophil-to-lymphocyte ratio (NLR) and tumor necrosis factor -α (TNF-α) level on the therapeutic effect of transcatheter arterial chemoembolization (TACE) combined with microwave ablation in patients with massive liver cancer.Methods:The medical records of 106 patients with massive liver cancer who underwent TACE combined with microwave ablation treatment in the Affiliated Hospital of Weifang Medical University from February 2020 to February 2023 were retrospectively analyzed. The efficacy was evaluated 6 weeks after surgery, and the patients were divided into remission group and non-remission group according to the therapeutic effect. The levels of NLR and TNF-α in the two groups were detected before surgery, 3 days after surgery and 7 days after surgery. Point two column correlation was used to analyze the relationship between the levels of NLR and TNF-α in different time periods and the therapeutic effect of TACE combined with microwave ablation in patients with massive liver cancer. The receiver operator characteristic (ROC) curve was drawn to analyze the predictive value of NLR and TNF-α levels in different time periods for the therapeutic effect of TACE combined with microwave ablation in patients with massive liver cancer.Results:Six weeks after surgery, out of 106 patients with massive liver cancer, 13 achieved complete remission, 48 achieved partial remission, 20 experienced disease progression, and 25 remained stable. The overall remission rate was 57.55% (61/106). Before surgery, the levels of NLR [ (2.26±0.13) vs. (2.43±0.12), t=6.87, P<0.001] and TNF-α [ (36.20±4.38) pg/ml vs. (42.74±5.74) pg/ml, t=6.66, P<0.001] in the remission group ( n=61) were lower than those in the non-remission group ( n=45), with statistically significant differences. At 3 days after surgery, there were no statistically significant difference in the levels of NLR [ (6.16±3.22) vs. (6.22±3.30), t=0.09, P=0.925] or TNF-α [ (48.84±7.22) pg/ml vs. (49.13±7.34) pg/ml, t=0.20, P=0.840] between the remission group and the non-remission group. At 7 days after surgery, the levels of NLR [ (2.60±0.18) vs. (2.82±0.26), t=5.15, P<0.001] and TNF-α [ (38.20±6.30) pg/ml vs. (45.57±5.79) pg/ml, t=6.16, P<0.001] in the remission group were lower than those in the non-remission group, with statistically significant differences. There were statistically significant differences in NLR and TNF-α levels before surgery, 3 days and 7 days after surgery between the remission group and the non-remission group ( F=82.43, P<0.001; F=54.45, P<0.001; F=76.23, P<0.001; F=15.61, P<0.001). Further pair-to-pair comparison showed that the levels of NLR and TNF-α were higher in both groups 3 and 7 days after surgery than before surgery, but the levels of NLR and TNF-α were lower in both groups 7 days after surgery than 3 days after surgery, with statistically significant differences (all P<0.005). Point two column correlation analysis showed that NLR level, TNF-α level and the efficacy of TACE combined with microwave ablation in patients with massive liver cancer were significantly positively correlated before and 7 days after surgery ( r=0.42, P<0.001; r=0.49, P<0.001; r=0.43, P<0.001; r=0.46, P<0.001). ROC curve showed that the area under the curve (AUC) of NLR and TNF-α alone in predicting the efficacy of TACE combined with microwave ablation in patients with massive liver cancer before and 7 days after surgery was 0.750 (95% CI: 0.656-0.844), 0.788 (95% CI: 0.699-0.877), 0.751 (95% CI: 0.652-0.850), 0.788 (95% CI: 0.700-0.876), respectively. The AUC of combined prediction of NLR and TNF-α before and 7 days after surgery were 0.818 (95% CI: 0.736-0.900) and 0.813 (95% CI: 0.730-0.897), respectively. There were no statistically significant differences in the AUC values of NLR and TNF-α alone or in combination for predicting the therapeutic effect of TACE combined with microwave ablation in patients with massive liver cancer before and 7 days after surgery (all P>0.05) . Conclusions:The levels of NLR and TNF-α before and 7 days after surgery are related to the effect of TACE combined with microwave ablation in patients with massive liver cancer, and the combination of NLR and TNF-α levels before and 7 days after surgery has certain value in predicting the effect of TACE combined with microwave ablation in patients with massive liver cancer.

Objective To investigate the neuroprotective effects and mechanisms of abscisic acid(ABA)in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced Parkinson's disease(PD)mouse models.Methods Eight-week-old C57BL/6J mice were randomly divided into three groups,control group(Ctrl),MPTP group,and MPTP+ABA group,12 mice in each group.Except for the control group,mice in the other groups were intraperitoneally injected with MPTP 25 mg/kg daily for 8 consecutive days to establish a subacute PD model.The MPTP+ABA group received intraperitoneal injections of ABA 25 mg/kg daily for 11 consecutive days,starting 3 days prior to MPTP administration.Behavioral tests were performed 24 hours after the last administration.On day 3,the expression of tyrosine hydroxylase(TH)and glial fibrillary acidic protein(GFAP)in the substantia nigra pars compacta(SNc)and striatum(STR)was analyzed by Western blotting,and mRNA levels of inflammatory factors were measured by Real-time PCR.Immunofluorescent staining was used to detect the expression of TH,GFAP,and ionized calcium-binding adapter molecule 1(Iba1).Results Compared with the control group,MPTP-treated mice exhibited impaired motor function,a reduced number of TH-positive dopaminergic neurons in the SNc,down-regulated TH protein expression in both the SNc and striatum,up-regulated GFAP protein expression,increased numbers of GFAP-and Iba1-positive cells,and elevated levels of pro-inflammatory factors.In contrast,the MPTP+ABA group showed improved motor function,increased TH-positive neurons in the SNc,up-regulated TH protein expression,down-regulated GFAP protein expression,reduced numbers of GFAP-and Iba1-positive cells,and decreased pro-inflammatory factor levels compared to the MPTP group.Conclusion ABA ameliorates motor dysfunction in MPTP-induced PD model mice,reduces degeneration and death of dopaminergic neurons in the SNc,suppresses the proliferation and activation of astrocytes and microglia in the SNc and striatum,and alleviates neuroinflammation.These results suggest that ABA exerts neuroprotective effects in MPTP-induced PD model mice.

Objective To identify the core constitutions and prodromal symptoms of relapse in schizophrenia patients using network analysis,and to analyze their relationships as well as gender differences.Methods Schizophrenia patients hospitalized in the psychiatry department of Hunan Brain Hospital in Hunan Province between October 2022 and December 2023 were selected as survey participants.A general information questionnaire,a Traditional Chinese Medicine Constitution Scale,and a Schizophrenia Prodromal Symptoms of Relapse Scale were used for investigation.Network anal-ysis was conducted using R language.Results The core constitutions of schizophrenia patients were qi deficiency constitution[Expected Influence(EI)=1.08]and dampness-heat constitution(EI=1.00),and the core prodromal symptoms of relapse were depression/withdrawal(EI=0.84)and ini-tial psychotic manifestations(EI=0.81).There were statistically significant differences in constitutions of traditional Chinese medicine and prodromal symptoms of relapse between patients of different genders(P＜0.05).Females mainly exhibited qi deficiency constitution(EI=1.20)with anxiety as the core prodromal symptom(EI=0.98),while males mainly exhibited yin deficiency constitution(EI=1.05)with depression/withdrawal as the core prodromal symptom(EI=1.00).Conclusion Healthcare professionals can early identify core prodromal symptoms of relapse by core imbalanced constitutions of schizophrenia patients,and develop precise intervention strategies,thereby promoting changes in their network structure,preventing disease relapse,and improving patients'quality of life.

Objective:To explore the potential advantages and application prospects of cardiopulmonary resuscitation ventilation mode (CPRV) for ventilation during CPR, through comparing of the resuscitation effect of CPRV, intermittent positive pressure ventilation (IPPV) and impedance threshold device (ITD) during advanced cardiovascular life support (ACLS).Methods:30 miniature landrace pigs [weighing (31.7±4.5) kg] were randomly divided into three groups: CPRV group, IPPV group and ITD group (10 pigs in each group). Each animal received 5 min of chest compressions only CPR after 3 min of untreated ventricular fibrillation. Then in the ACLS stage, chest compressions and mechanical ventilation (tidal volume of 7 mL/kg, respiratory rate 10 times/min) were performed according to the divided groups. Defibrillation was delivered after 16 min of ACLS, and intravenous epinephrine was administered for the pigs without return of spontaneous circulation (ROSC). A second defibrillation was delivered after 2 more minutes of CPR. Blood gases, respiratory parameters, and hemodynamic parameters were collected at baseline, ACLS 8 min and ACLS 16 min. ROSC after defibrillation was also recorded.Results:At ACLS 8 min and 16 min, intrathoracic high pressure and intrathoracic pressure variability of CPRV group were significantly higher than those of IPPV and ITD group, while the absolute value of intrathoracic negative pressure in CPRV group was higher than that in IPPV group (all P <0.01), but no difference was found between CPRV group and ITD group. The levels of arterial pH, PaO 2 and venous oxygen saturation in CPRV group were significantly higher than those in IPPV group and ITD group during ACLS, while PaCO 2 was significantly lower in CPRV group than in IPPV group and ITD group (all P <0.05). Aortic blood pressure, coronary perfusion pressure and carotid blood flow during ACLS in CPRV group were significantly higher than those in IPPV group, and right atrial pressure of CPRV group was significantly lower than that of IPPV group (all P <0.05). Coronary perfusion pressure of CPRV group was significantly higher than that of ITD group at ACLS 16 min but not ACLS 8 min, and there were no differences of aortic blood pressure and carotid blood flow between CPRV group and ITD group. The total ROSC rate in the CPRV group (90%) was significantly higher than that in the IPPV group (30%) and the ITD group (40%) (P <0.05). Conclusion:Ventilation with CPRV during ACLS showed better ventilation, oxygenation, hemodynamic effects and higher ROSC than IPPV and ITD, and the use of CPRV during CPR shows a certain application prospect.

Objective To explore the risk signals of niraparib and provide references for rational and safe clinical medication.Methods Niraparib-related adverse drug events(ADEs)reports from Q1 2017 to Q2 2023 were extracted from the US FDA Adverse Event Reporting System(FAERS)database.Risk signals were identified using the reporting odds ratio(ROR),proportional reporting ratio(PRR),Bayesian confidence propagation neural network(BCPNN),and multi-item gamma Poisson shrinker(MGPS)methods.The Risk signals were described and classified by preferred system organ classes(SOCs)and preferred terms(PTs)from the Medical Dictionary for Regulatory Activities(MedDRA)version 26.1,and the occurrence of niraparib-related ADEs was also analyzed.Results A total of 16,961 ADE reports with niraparib as the primary suspected drug were extracted.Through screening and analysis,32 PTs were identified involving 11 SOCs,which were largely consistent with the information in the drug label.However,suspicious signals not mentioned in the label,including neuropathy peripheral,decreased red blood cell count,reduced hematocrit,dehydration,and hot flashes,require further attention.The median occurrence time was 22 days(IQR 2-98 days),and the Weibull distribution test indicated an early failure-type curve.Conclusion When using niraparib,particularly in early stages of treatment,it is essential to monitor not only the ADEs mentioned in the drug instructions,such as decreased platelet count,nausea and fatigue,but also to pay close attention to the ADEs not included in the instructions,such as peripheral neuropathy and decreased red blood cell count,which exhibit strong signal values,to ensure patient medication safety.

Objective:To elucidate the regulatory role of matrix metallopeptidase 14 (MMP14) in the migration of chondrogenic precursor cells, thereby providing data support for investigating the pathogenesis of microtia.Methods:An in vitro differentiation model was established using human induced pluripotent stem cells (iPSCs) sequentially induced into neural crest cells (iNCCs) and subsequently into chondrogenic precursor cells (iCPCs), combined with lentivirus-mediated knockdown of MMP14, to investigate the effects of MMP14 on the biological characteristics of iCPCs, including proliferation, differentiation, and migration. Collective cell migration was assessed using scratch wound healing and Transwell migration assays; directional migration was characterized via high-content live-cell imaging; single-cell adhesion force was measured using a micromanipulation system. Collagen degradation was evaluated through hydroxyproline digestion assays. Cell proliferation was analyzed using the CCK-8 assay, and the expression of osteogenic/chondrogenic-related genes (SOX5/6/9, COL1A1, COL2A1, RUNX2, TWIST1) were quantified by real-time quantitative PCR. Immunofluorescence staining was used to assess the expression of F-actin and CD44 proteins. Additionally, transcriptomic sequencing was performed on iCPCs before and after MMP14 knockdown. Results:iPSC→iNCC→iCPC differentiation model was established in vitro. The resulting iCPCs expressed osteo/chondrogenic marker genes, including SOX5, SOX6, SOX9, COL1A1, COL2A1, RUNX2, and TWIST1, and exhibited positive expression of mesenchymal stem cell markers CD90, CD105, and CD73. Upon further induction, functional cartilage spheroids were formed. Compared with normal auricular chondrocytes, auricular chondrocytes from microtia patients showed reduced expression of MMP14 at both mRNA and protein levels. Lentivirus-mediated shRNA knockdown of MMP14 in iCPCs resulted in a marked decrease in its mRNA and protein expression. MMP14 knockdown significantly impaired collective migration of iCPCs, as evidenced by reduced wound closure rates in scratch assays and decreased numbers of migrated cells in Transwell assays. High-content live-cell imaging revealed that MMP14-deficient iCPCs displayed more erratic migration trajectories and a lower straight-line migration ratio. Single-cell adhesion assays showed extracellular matrix (ECM)-dependent alterations: cell adhesion was enhanced on matrigel-coated surfaces but weakened under uncoated conditions. MMP14 knockdown also led to reduced proliferation, decreased collagen degradation, diminished F-actin expression, fewer peripheral adhesion sites, and downregulation of CD44 protein expression, without significantly affecting the expression of chondrogenic genes such as SOX6, SOX9, COL1A1, COL2A1, RUNX2, and TWIST1. Transcriptomic analysis further revealed that MMP14 knockdown significantly downregulated genes involved in extracellular matrix organization, cell adhesion, migration, and tissue development, with enrichment in pathways including ECM-receptor interaction, focal adhesion, and MAPK signaling. Conclusion:MMP14 plays a critical role in the directional migration of chondrogenic precursor cells by regulating ECM remodeling, adhesion signaling, and cytoskeletal proteins.

Objective:To explore the path way of self-acceptance and implicit attitude on perceived stress and body image disorder among patients with thyroid associated ophthalmopathy, and provide a basis for clinical medical staff to develop intervention measures to reduce patients′ body image impairment.Methods:A cross-sectional survey was conducted using convenience sampling from October 2018 to October 2023 on patients with thyroid associated ophthalmopathy who visited the Huazhong University of Science and Technology Tongji Medical College Affiliated Union Hospital. The survey included the General Information Questionnaire, Perceived Stress Scale, Self-Acceptance Questionnaire, Implicit Association Test, and Body Image Scale.Results:Finally, 310 questionnaires were distributed in total, 303 valid questionnaires were recovered, with an effective recovery rate of 97.7%. Among the 303 patients, there were 87 males and 216 females, aged 25-78 (44.07 ± 4.76) years. The scores for body image impairment, perceived stress, self-acceptance, and implicit attitude in patients with thyroid associated ophthalmopathy were (16.51 ± 4.19), (38.36 ± 6.74), (33.49 ± 10.07), and (0.45 ± 0.11) points, respectively; there was a perceived stress positively correlated with body image disorder and implicit attitude ( r=0.829, 0.636, both P<0.05), perceived stress also negative correlated with self-acceptance ( r=-0.807, P<0.05). The mediating model showed that perceived stress not only had a significant direct effect on body image disorder ( β=0.409, P<0.05), but also indirectly affected body image disorder through three paths, including the independent mediating effect of self-acceptance ( β=0.125, P<0.05), and implicit attitude ( β=0.195, P<0.05), as well as the chain mediating effect of self-acceptance and implicit attitude ( β=0.022, P<0.05), which accounting for 45.5% of the total effect. Conclusions:Self-acceptance and implicit attitude play mediating role in the relationship between perceived stress and body image disorder in patients with thyroid associated ophthalmopathy, medical staff can promote self-acceptance by enhance self-compassion, correct negative implicit attitude, decrease the effect of perceived stress on body image disorder in patients with thyroid associated ophthalmopathy.