Chronic pain is a complex condition shaped by long-standing alterations in both physiological and psychological processes. Rather than representing a simple continuation of acute nociceptive signaling, chronic pain is increasingly understood as the outcome of progressive dysregulation within distributed neural systems that govern sensation, affect, motivation, and cognitive control. Neuroimaging and electrophysiological studies indicate that this state is accompanied by extensive plastic changes in deep brain structures and large-scale networks. Beyond well-described central sensitization processes, chronic pain is characterized by disrupted oscillatory rhythms and altered connectivity within large-scale brain networks, including thalamo-cortical circuits and prefrontal-limbic-reward networks. These findings support a conceptual shift from viewing chronic pain as a focal, lesion-driven phenomenon toward recognizing it as a disorder of distributed network pathology. Pharmacological treatments remain central to clinical practice, yet their long-term efficacy is often limited and frequently accompanied by substantial side effects. The ongoing concerns about opioid-related risks and the inadequate therapeutic response in a subset of patients highlight the need for safe, non-pharmacological approaches that can address not only pain but also comorbid disturbances in mood, sleep, and social functioning. Neuromodulation provides a promising path toward mechanism-based and non-pharmacological management of chronic pain by employing physical or chemical stimulation to alter the excitability and synchrony of specific neural populations within central, peripheral, and autonomic systems. While invasive deep brain stimulation demonstrates that targeting deep brain structures can be effective, its clinical application is restricted by surgical risks and cost, highlighting the importance of non-invasive techniques capable of reaching deep targets. Current non-invasive approaches, such as transcranial electric stimulation, are constrained by limited penetration depth and insufficient spatial precision. These limitations hinder reliable engagement of deep regions implicated in pain, including the thalamus and nucleus accumbens, and tend to produce broad, non-specific modulation of cross-network oscillatory activity. Temporal interference (TI) stimulation has emerged as a means of overcoming these obstacles. By delivering interacting high-frequency currents that generate a low-frequency envelope within the head, TI enables focal stimulation of deep targets while minimizing superficial current delivery. Recent multiscale modeling and animal studies indicate that TI exploits the nonlinear rectification properties of neuronal membranes in response to high-frequency carriers, as well as their phase-locked responses to low-frequency envelopes, to generate “peak-focused” electric fields in deep regions under relatively low superficial current loads. Moreover, TI appears to exhibit potential advantages in terms of cell-type selectivity and rhythm-specific engagement, including differential responses across neuronal subtypes and distinct coupling to θ-, β-, and γ-band oscillations. These features suggest a promising avenue for correcting abnormal rhythms and network dynamics that contribute to chronic pain. This review summarizes current knowledge of the neural mechanisms underlying chronic pain and recent advances in TI research. It examines functional disturbances across key pain-related regions and networks, outlines the principles and technical characteristics of TI, and discusses potential deep-brain targets and stimulation strategies relevant to chronic pain. Evidence to date indicates that TI, with its non-invasiveness, tolerability, and capacity for precise deep brain modulation, holds great promise for the management of treatment-resistant chronic pain and may evolve into a new generation of precise and efficient non-pharmacological analgesic strategies.

Chronic pain is a complex condition shaped by long-standing alterations in both physiological and psychological processes. Rather than representing a simple continuation of acute nociceptive signaling, chronic pain is increasingly understood as the outcome of progressive dysregulation within distributed neural systems that govern sensation, affect, motivation, and cognitive control. Neuroimaging and electrophysiological studies indicate that this state is accompanied by extensive plastic changes in deep brain structures and large-scale networks. Beyond well-described central sensitization processes, chronic pain is characterized by disrupted oscillatory rhythms and altered connectivity within large-scale brain networks, including thalamo-cortical circuits and prefrontal-limbic-reward networks. These findings support a conceptual shift from viewing chronic pain as a focal, lesion-driven phenomenon toward recognizing it as a disorder of distributed network pathology. Pharmacological treatments remain central to clinical practice, yet their long-term efficacy is often limited and frequently accompanied by substantial side effects. The ongoing concerns about opioid-related risks and the inadequate therapeutic response in a subset of patients highlight the need for safe, non-pharmacological approaches that can address not only pain but also comorbid disturbances in mood, sleep, and social functioning. Neuromodulation provides a promising path toward mechanism-based and non-pharmacological management of chronic pain by employing physical or chemical stimulation to alter the excitability and synchrony of specific neural populations within central, peripheral, and autonomic systems. While invasive deep brain stimulation demonstrates that targeting deep brain structures can be effective, its clinical application is restricted by surgical risks and cost, highlighting the importance of non-invasive techniques capable of reaching deep targets. Current non-invasive approaches, such as transcranial electric stimulation, are constrained by limited penetration depth and insufficient spatial precision. These limitations hinder reliable engagement of deep regions implicated in pain, including the thalamus and nucleus accumbens, and tend to produce broad, non-specific modulation of cross-network oscillatory activity. Temporal interference (TI) stimulation has emerged as a means of overcoming these obstacles. By delivering interacting high-frequency currents that generate a low-frequency envelope within the head, TI enables focal stimulation of deep targets while minimizing superficial current delivery. Recent multiscale modeling and animal studies indicate that TI exploits the nonlinear rectification properties of neuronal membranes in response to high-frequency carriers, as well as their phase-locked responses to low-frequency envelopes, to generate “peak-focused” electric fields in deep regions under relatively low superficial current loads. Moreover, TI appears to exhibit potential advantages in terms of cell-type selectivity and rhythm-specific engagement, including differential responses across neuronal subtypes and distinct coupling to θ-, β-, and γ-band oscillations. These features suggest a promising avenue for correcting abnormal rhythms and network dynamics that contribute to chronic pain. This review summarizes current knowledge of the neural mechanisms underlying chronic pain and recent advances in TI research. It examines functional disturbances across key pain-related regions and networks, outlines the principles and technical characteristics of TI, and discusses potential deep-brain targets and stimulation strategies relevant to chronic pain. Evidence to date indicates that TI, with its non-invasiveness, tolerability, and capacity for precise deep brain modulation, holds great promise for the management of treatment-resistant chronic pain and may evolve into a new generation of precise and efficient non-pharmacological analgesic strategies.

Background: High-mobility group box protein 1 (HMGB1) is a chromatin-binding protein involved in arthritis, ischemia, sepsis, atherosclerosis, neurodegenerative disorders, meningitis, and cancer. HMGB1 exhibits dual roles in cancer, acting as either a tumor suppressor or oncoprotein depending on context. Objective: This research aimed to elucidate HMGB1’s functional significance in cutaneous squamous cell carcinoma (cSCC). Methods: We overexpressed HMGB1 in cSCC cell lines using recombinant adenovirus and examined its effects on cell proliferation, colony formation, and cell migration. Results: Immunohistochemical analysis revealed elevated HMGB1 expression levels in cSCC tissue relative to normal epidermis. To assess the influence of HMGB1, we employed recombinant adenoviruses expressing HMGB1 to transduce SCC cell lines (SCC12 and SCC13). Enhanced HMGB1 expression significantly promoted cellular proliferation and colony formation capacity.Notably, HMGB1 overexpression elevated the levels of proliferation regulators, including P63, SOX2, CDK4 and CDK6. Furthermore, HMGB1 overexpression substantially enhanced tumor invasiveness, accompanied by upregulation of epithelial-mesenchymal transition (EMT) biomarkers. Mechanistically, overexpression of HMGB1 enhanced transforming growth factor-β signaling by increasing phosphorylation of SMAD2/3, the key mediators of EMT. Conclusion These data imply that HMGB1 acts as a tumor-promoting factor in cSCC.

Aim To explore the mechanism by which the compound Chaijin Jieyu formula(CCJJY)regulates the TLR4/NLRP3 signaling pathway to inhibit central oxidative stress and improve hippocampal synaptic plasticity damage in depression.Methods SD rats were randomly divided into the control group,chronic unpredictable mild stress group,sleep deprivation group,chronic unpredictable mild stress combined with sleep deprivation group,positive drug group(venlafax-ine+melatonin),low-dose group of CCJJY,medium dose group of CCJJY,and high-dose group of CCJJY,with nine rats in each group.Except for the control group,a rat model of depression complicated with in-somnia was established using chronic unpredictable mild stress combined with sleep deprivation.Depres-sion-like and sleep behaviors in rats were evaluated through weight,food intake,water maze,and pento-barbital sodium tests.ELisa was used to detect ROS,AANAT,and HPLC-EC was used to detect 5-HT con-tent,while Western blot/RT-PCR was used to detect the expression of IL-1β,TLR4,NLRP3,PSD-95,and SYN related proteins and mRNA.HE and Golgic stai-ning were used to observe the pathological changes in the third ventricle,hippocampus,and neuronal synap-ses.Results Compared with the control group,the depression-like behaviors of the model group rats were significant.The expression of IL-1β,TLR4,and NL-RP3 in the hippocampus increased,while the expres-sion of PSD-95 and SYN decreased.Activation of NL-RP3 inflammasomes led to "sleeve like" pathological changes in the third ventricle,with hippocampal neu-rons undergoing apoptosis and significant damage to neuronal synaptic plasticity.Compared with the model group,after intervention with CCJJY,the expression of ROS,IL-1β,TLR4,and NLRP3 decreased,while the expression of AANAT,5-HT,PSD-95,and SYN in-creased.Pathological damage to the third ventricle and hippocampal neurons was repaired.Conclusion The CCJJY improves hippocampal synaptic plasticity dam-age in depression by regulating the TLR4/NLRP3 sig-naling pathway to inhibit central oxidative stress.

Objective To observe the association between afterschool physical exercise and sleep quality among preschool children,and to explore the proper afterschool physical exercise model for better sleep quality.Methods A cross-sectional study was conducted.From Apr to Jun 2024,a total of 1 430 children from three public kindergartens in Minhang district were enrolled to participate in the survey.Parents were invited to complete the basic sociodemographic information,afterschool physical exercise information and the Children's Sleep Habits Questionnaire.One-way ANOVA and linear mixed effects models were used to explore the relationship between afterschool exercise and sleep quality.Results A total of 1 430 questionnaires were sent out and 1 384 were recovered with a recovery rate of 96.78%.Among them 1 366 were valid,with an effective rate of 95.52%.The average age of the children was(5.19±0.87)years old with gender ration of 1.07∶1(male:female).The prevalence of poor sleep quality was 80.60%(regarding a CSHQ total score>41 as cutoff).A one-way ANOVA indicated that time on afterschool physical exercise was significantly associated with sleep duration,Night waking,and sleep onset delay(P<0.05).After adjusting for age,gender,the only child or not,main caregiver,and parental education and occupation,linear mixed effects models showed that engaging in afterschool physical activity for at least 180 mins per week has a statistically significant predictive effect on sleep duration scores(β=-0.50,z=-4.52,95%CI:-0.72,-0.28,P<0.001),night waking scores(β=-0.16,z=-2.34,95%CI:-0.29,-0.02,P=0.020),and sleep onset delay scores(β=-0.14,z=-2.35,95%CI:-0.26,-0.02,P=0.019).Conclusion Afterschool exercise was significantly associated with sleep quality among preschool children in Minhang district of Shanghai.The time≥180 min on afterschool exercise per week in preschool children was significantly positively associated with maintaining sleep duration,reducing night wakings and shortening the latency to fall asleep.The habit of afterschool exercise and the time on afterschool exercise should be emphasized by parents and the society to improve sleep quality among preschool children.

AIM:To observe the changes of atrial fibrillation susceptibility,and the remodeling of atrial myo-cyte action potential,ultrarapid activation delayed rectifier potassium current(IKur)and transient outward potassium cur-rent(Ito)in elderly mice,and to explore the mechanism of atrial fibrillation from the single cell electrophysiological level.METHODS:The C57BL/6J mice were divided into old group(20 months old)and young group(4 months old).Atrial fi-brillation was induced by esophageal atrial pacing.The atrial myocytes were isolated,and action potential and ion currents were recorded with patch-clamp technique.The associated proteins were detected by Western blot technique.RE-SULTS:(1)Compared with young mice,the total incidence of atrial fibrillation was significantly increased in old mice(20.0%at 4 months old vs 60.0%at 20 months old,P<0.01).(2)The action potential duration of atrial myocytes in aged mice was shortened,and more significantly after stimulation.(3)The density of Ito and IKur in atrial myocytes of aged mice increased significantly,from(12.6±1.4)pA/pF to(21.7±1.1)pA/pF,and from(7.5±1.5)pA/pF to(13.3±2.1)pA/pF,respectively(P<0.01).After stimulation,the current increased more significantly,especially in older atrial cells.Compared with the young mice,the steady-state activation curve of Ito in the atrial myocytes of the aged mice shifted towards the depolarization,suggesting that activation of Ito channels in the aged mice increased at the same voltage stimula-tion.(4)Compared with young group,the expression of KV4.2(generating Ito)and KV1.5(generating IKur)proteins in the atrial tissue of the mice in old group was significantly increased,and the expression of caveolin-3 and end-binding protein 1(EB1)was up-regulated,suggesting that the increases in KV4.2 and KV1.5 total channel proteins and effective proteins in the cell membrane might contribute to the increase in the remodeling of potassium currents in the elderly atrial myo-cytes.CONCLUSION:The incidence of atrial fibrillation in elderly mice is significantly augmented,which may be related to the increases in Ito and IKur in atrial myocytes.The remodeling of potassium currents in elderly atrial myocytes is one of the electrophysiological bases leading to the shortening of action potential duration and the occurrence of atrial fibrillation.

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

Objective:To explore the risk factors for recurrence of thyroid cancer after radical resection via areola endoscopy,and to construct a visual risk prediction model.Methods:The clinical data of 350 thyroid cancer patients who underwent radical surgery via areola endoscopy in our hospital from January 2016 to October 2018 were retro-spectively analyzed,and they were randomly divided into the modeling group(233 cases)and the internal validation group(117 cases)in a 2:1 ratio.All patients were followed up for 3 years after surgery,and the patients of modeling group were further divided into recurrent group(51)and non recurrent group(182)according to whether they with or not recurrence.Another 163 patients with thyroid cancer who underwent laparoscopic radical mastectomy at our hos-pital from January 2019 to May 2020 were selected as the external validation group.The risk factors for recurrence of thyroid cancer after radical surgery via areola endoscopy was analyzed by using Cox regression method,and a risk prediction nomogram model was established based on this.Internal validation of the nomogram model was conducted by using the Bootstrap method,and the calibration,predictive efficacy and clinical net benefit of the nomogram model were evaluated by the calibration curve,receiver operating characteristic(ROC)curve and decision curve analysis(DCA).The external validation group data was used for external validation.Results:The recurrence rate of thyroid cancer patients after 5 years of radical surgery via areola endoscopy was 21.64％(111/513).The proportions of multiple le-sions,preoperative lymph node metastasis,TNM stages Ⅲ-Ⅳ and maximum tumor diameter,the levels of thyro-globulin(TG),triiodothyronine(T3),thyroxine(T4),free triiodothyronine(FT3),free thyroxine(FT4)and thyroid stimulating hormone(TSH)in the recurrence group were higher than those in the non recurrence group(P<0.05).The Cox regres-sion analysis results showed that the maximum tumor diameter,multiple lesions,preoperative lymph node metasta-sis,TNM stage Ⅲ-Ⅳ and TG,T3,T4,FT3,FT4 and TSH levels were all risk factors for recurrence of thyroid cancer after radical surgery via areola endoscopy(P<0.05).The risk prediction nomogram model of recurrence of thyroid cancer af-ter radical surgery under areola endoscopy was constructed based on the above influencing factors.After internal and external validation,the consistency indices of the modeling group,internal verification group and external verification group were 0.832,0.825 and 0.41 respectively,and the calibration curves of three groups were close to the standard curve.The ROC curve analysis and verification showed that the area under the curve predicted by the nomogram model of the modeling group,internal verification group and external verification group were 0.859,0.847 and 0.853 respectively.The DCA curve showed that the nomogram model had good clinical net benefits when the threshold probability of the modeling group,internal verification group and external verification group were 0.03-0.82,0.02-0.78 and 0.06-0.88 respectively.Conclusion:The maximum tumor diameter,multiple lesions,preoperative lymph node metastasis,TNM staging stage Ⅲ-Ⅳ and levels of TG,T3,T4,FT3,FT4 and TSH are all risk factors for recurrence of thy-roid cancer after radical surgery via areola endoscopy,and the risk prediction visualization nomogram model con-structed based on this is helpful for clinical screening of high-risk patients to guide early intervention and reduce the risk of recurrence.

The glymphatic system(GS)is a unique toxic sub-stance clearance system in brain,which is very important for maintaining the microenvironment stability of the central nervous system.The polarization distribution of aquaporin 4(AQP4)lo-cated in the terminal foot of astrocytes affects the function of GS and participates in the pathological progress of many neurodegen-erative diseases,but the detailed regulation mechanism of AQP4 polarization distribution has not been systematically summarized.Therefore,this paper systematically combs the mechanism of reg-ulating the polarization distribution of AQP4 from the perspective of the composition integrity of dystrophin-glycoprotein complex(DGC)and basement membrane foot complex,and summarizes the potential drug and non-drug therapies for targeted regulation of AQP4 polarization distribution at present,aiming at providing new target reference and theoretical basis for targeted regulation of AQP4 polarization to prevent and treat neurodegenerative dis-eases.

Objective To investigate the risk factors of hemodynamic instability after carotid artery stenting by meta-analysis.Methods Ten databases were searched:PubMed,ProQuest,ScienceDirect,Embase,Cochrane Library,Web of Science,China Knowledge Network,Wanfang Data,VIP Information Database,and China Biomedical Database.The search date was from inception until 2 February 2024,and meta-analysis was performed using Stata 16.0 statistical software.Results A total of 27 studies with 4199 subjects and 22 influencing factors were included.The studies showed a 37.4％(95％CI 30.3％-44.8％)incidence of haemodynamic instability after carotid stenting,Meta-analysis determined that age＞60 years(P＜0.001),hypertension(P＜0.001),calcified plaque(P＜0.001),stenosis＞70％(P=0.008),eccentric plaque(P=0.002),distance from the largest stenosis to the carotid bifurcation≤ 10 mm(P＜0.001),stenosis involvement of the balloon or bifurcation(P＜0.001),balloon post-dilation(P=0.003),open-loop stenting(P＜0.001),dilated balloon diameter≥5 mm(P=0.002),repeat balloon dilation(P=0.011)and balloon dilation pressure≥8 atm(P＜0.001)are risk factors for intraoperative and postoperative haemodynamic instability in patients undergoing carotid artery stenting surgery.Statin use was a protective factor(P＜0.001).Conclusions Medical staff working in the clinic should assess the patient's condition preoperatively,identify risk factors that may lead to haemodynamic instability,and avoid unnecessary intraoperative stimulation of patients who are already in a high-risk state.Reduce postoperative clinical complications in patients with carotid artery stenosis and improve patient recovery.