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.

Cancer stem cells (CSCs) represent a distinct subpopulation of cells characterized by self-renewal capacity, differentiation potential, and critical roles in driving tumor progression, therapeutic resistance, recurrence, and maintenance of the tumor microenvironment. Targeting CSCs has emerged as a pivotal direction in cancer research, offering novel strategies to overcome drug resistance and prevent metastasis and relapse. Lysosomes, traditionally recognized as central organelles for intracellular degradation and recycling, are indispensable for cellular homeostasis. Dysregulation of lysosomal function is intimately linked to various diseases, including cancer. In tumors, aberrant lysosomal activity can promote malignant progression through mechanisms such as altering metabolic pathways, enhancing lysosomal exocytosis, modulating drug resistance, and interfering with autophagy-lysosomal pathways. Recent studies have underscored the involvement of lysosomes in regulating CSC properties. This review synthesizes findings on lysosomal regulation of CSCs through the following aspects. (1) Lysosomes exert complex and critical bidirectional control over CSC stemness maintenance through three degradation pathways that are dependent on their degradative function. (i) The lysophagy pathway. This pathway exhibits dual roles. Activation can sustain CSC functions; for instance, in glioblastoma, hypoxia upregulates Gal-8 via the STAT3/HIF1α signaling axis to induce autophagy, supporting stem cell survival. In head and neck squamous cell carcinoma, degradation of GSK3β activates the Wnt pathway, enhancing stemness. Conversely, this pathway can suppress stemness by degrading stemness-related proteins such as BMI-1 and OCT4A, thereby impairing CSC self-renewal capacity. (ii) Mitophagy pathway. In non-small cell lung cancer stem cells, mitophagy-related mechanisms, such as the accumulation of mitochondrial DNA (mtDNA) activating the TLR9-Notch1-AMPK signaling axis, have been shown to promote CSC proliferation. (iii) Autophagosome-dependent lysosomal degradation pathway. This pathway directly regulates stemness-related proteins in a bidirectional manner. Enhanced degradative function can promote CSC properties, exemplified by the degradation of NUMB to activate Notch signaling. Conversely, attenuated degradative function can also enhance stemness by stabilizing oncoproteins (e.g., protecting Frizzled-1 from degradation to sustain Wnt signaling) or preventing the degradation of tumor suppressors (e.g., inhibiting Notch degradation). (2) Constituent proteins of lysosomes, including membrane proteins and luminal acid hydrolases, participate in regulating CSC stemness. Regarding membrane proteins, LAMP2A facilitates chaperone-mediated autophagy to maintain stemness in glioblastoma and ovarian cancer. V-ATPase, by maintaining an acidic luminal environment, promotes proliferation and drug resistance in glioma stem cells. Among hydrolases, cathepsins B and L are highly expressed in pancreatic and ovarian cancers and correlate with poor prognosis. Furthermore, targeting lysosomes to induce lysosomal membrane permeabilization (LMP) triggers lysosome-mediated cell death, presenting a potential therapeutic strategy for eradicating CSCs.(3) The acidic luminal environment, single-membrane structure, and the presence of transmembrane transporters (e.g., ABCA3) enable lysosomes to passively trap or actively uptake and sequester chemotherapeutic drugs. Subsequent drug extrusion via exocytosis confers drug resistance. In CSCs, this lysosome-mediated drug sequestration, often cooperating with autophagy, establishes multimodal drug resistance. Therefore, targeting lysosomal function represents a potential strategy to overcome therapy resistance. The central role of lysosomes in regulating CSC stemness and resistance positions them as highly promising therapeutic targets. Strategies aimed at disrupting lysosomal function to selectively eliminate CSCs include: inhibiting the lysosome-autophagy system using agents like IITZ or lovastatin; inducing lysosomal membrane permeabilization (LMP) with compounds such as hexamethylene amiloride to compromise membrane stability; and disrupting the acidic luminal environment using drugs like siramesine or the K/H transport compound 2. In conclusion, lysosomes critically regulate CSC stemness maintenance and drug resistance through degradative pathways, membrane protein functions, luminal hydrolase activities, and drug sequestration mechanisms. This redefines the lysosome from a traditional “waste disposal unit” to a “signal integration center” in CSCs. The duality and context-dependency of lysosomal function in CSCs offer novel insights into the heterogeneity observed across different tumors. Targeting lysosomal vulnerabilities—such as inducing LMP, disrupting acidity, or blocking autophagic flux—provides a strategy to bypass canonical CSC resistance mechanisms and directly trigger cell death. This establishes the lysosome as a key target to overcome CSC-mediated therapy resistance, paving the way for developing diverse candidate drugs and innovative combination therapies in oncology.

OBJECTIVE To formulate Guidelines for the standardized implementation of pharmacist-managed clinics （ 2026 edition ） in response to the challenges faced by such clinics in China， including uneven development， large discrepancies in service specifications， insufficient patient awareness， and limited medical insurance coverage. METHODS Led by the Pharmaceutical Affairs Professional Committee of the Chinese Hospital Association， the Evidence-based Pharmacy Professional Committee of the Chinese Pharmaceutical Association， and the Hospital Pharmacy Professional Committee of the Cross-strait Medical and Health Exchange Association， a total of 19 domestic hospital pharmacy experts were organized. Through a systematic review of national policies and literature research， current practical experience was summarized. Consensus on the contents of the guidelines was reached after in-depth discussions. RESULTS &CONCLUSIONS The guidelines covered five sections： definition and connotation of pharmacist-managed clinics， establishment requirements， implementation and management， post competency， and practical research. Firstly， the definition and connotation included three operational forms of pharmacist-managed clinics （independent mode， physician-pharmacist joint mode， and online pharmacist-managed clinic mode） and classified service modes （specialty-specific， drug-specific， and disease-specific pharmacist-managed clinics）. The establishment requirements were further refined， covering system construction （pharmaceutical service management system， quality control and assessment mechanism）， personnel qualifications （professional credentials， continuing education and professional training， etc）， service recipients， as well as service venues and facilities. Subsequently， the implementation and management of pharmacist-managed clinics were proposed， involving service procedures， intervention measures， documentation and records， patient education and follow-up， humanistic care， as well as risk management and quality control. Finally， post competency encompassed the competency requirements for pharmacists providing services in pharmacist-managed clinics， as well as the suggestions on teaching methods； practical research encouraged the conduct of high-quality pharmaceutical practice in the setting of pharmacist-managed clinics. The guidelines provide valuable guidance for the standardized implementation of pharmacist-managed clinics in China in terms of establishment， management， teaching， and research， fill the guideline gap in this field， and can promote the high-quality development of pharmacist-managed clinics.

OBJECTIVE To provide standardized guidance for the rational clinical use of antibody-based drugs for the treatment of myasthenia gravis， and to enhance the evidence-based system of guidelines and consensus in this field. METHODS The consensus expert team consisted of 71 multidisciplinary experts from 28 provinces/autonomous regions/municipalities directly under the Central Government. Evidence was systematically retrieved through multiple databases， drug package inserts， and official websites of international and national health administrative authorities， drug regulatory agencies， healthcare security departments， and related industry associations， up to April 30， 2025. Evidence was graded according to the 2014 version of JBI pre-grading system for evidence from intervention studies. Based on full consideration of the current best evidence and multidisciplinary expert experience， the expert consensus recommendations were formulated using a modified Delphi method. RESULTS The Evidence-based expert consensus on the clinical application and pharmaceutical management of antibody-based drugs for the treatment of myasthenia gravis standardized the key points of whole-process pharmaceutical management for four antibody-based drugs approved for marketing in the mainland of China for the treatment of myasthenia gravis （efgartigimod alfa， efgartigimod alfa/hyaluronidase， eculizumab， and rozanolixizumab）. It formulated 37 expert consensus recommendations covering nine pharmaceutical management aspects： drug suitability selection， medication in special populations， administration methods， drug storage， therapeutic drug monitoring and pharmacogenetic testing， immunization management， drug interactions， pharmaceutical care， and off-label drug use. CONCLUSIONS Based on the current best evidence and multidisciplinary expert experience， this consensus establishes a whole-process management framework for antibody-based drugs for the treatment of myasthenia gravis， from clinical application to pharmaceutical management. It provides a scientific basis for the rational and precise use of these drugs in clinical practice， effectively promotes the enhancement of pharmaceutical management efficiency， and helps improve the overall therapeutic benefits for patients.

Objective:To explore the efficacy and safety of combining targeted therapy and immunotherapy with standard chemotherapy in patients with advanced pancreatic cancer.Methods:This is a single-center retrospective cohort study. A total of 123 patients with advanced pancreatic cancer who received first-line systemic treatment at the Second Hospital of Hebei Medical University between January 2022 and December 2024 were retrospectively enrolled. There were 65 males and 58 females,with a mean age of (65.1±10.1) years (range:22 to 88 years). According to whether targeted therapy combined with immunotherapy was added to chemotherapy,patients were divided into a triplet group ( n=46) and a standard chemotherapy group ( n=77). The primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included radiological efficacy indicators (objective response rate (ORR), disease control rate (DCR),clinical benefit rate,etc.) and treatment-related adverse events. Propensity score matching (PSM,caliper=0.2) was used to balance baseline characteristics between groups. Kaplan-Meier curves were used to estimate survival,and Cox regression models were applied to analyze factors influencing OS and PFS. Results:In the original cohort,the median OS was 11 months in the triplet group and 8 months in the chemotherapy group,with no statistically significant difference ( P=0.056). The median PFS was 5 months in the triplet group and 3 months in the chemotherapy group,also without statistical significance ( P>0.05). Multivariate Cox regression analysis indicated that the triplet regimen was an independent prognostic factor for both OS and PFS ( P<0.05). After PSM,baseline balance between groups was good. The median OS was 10.0 months in the triplet group and 7.0 months in the chemotherapy group, with no significant difference ( P=0.094). In terms of efficacy, the ORR was 26.1% (12/46) in the triplet group versus 7.8% (6/77) in the chemotherapy group,with a statistically significant difference ( χ2=6.320, P=0.012). The DCR was 54.3% (25/46) in the triplet group and 33.8% (26/77) in the chemotherapy group,also statistically significant ( χ2=4.214, P=0.037). The incidence of adverse events was similar between groups,mostly grade 1 to 2. Conclusions:The triplet regimen of chemotherapy,targeted therapy,and immunotherapy shows potential in improving efficacy and prolonging survival with acceptable safety in patients with advanced pancreatic cancer. However, its definitive benefits require further investigation.

Objective:To explore the efficacy and safety of combining targeted therapy and immunotherapy with standard chemotherapy in patients with advanced pancreatic cancer.Methods:This is a single-center retrospective cohort study. A total of 123 patients with advanced pancreatic cancer who received first-line systemic treatment at the Second Hospital of Hebei Medical University between January 2022 and December 2024 were retrospectively enrolled. There were 65 males and 58 females,with a mean age of (65.1±10.1) years (range:22 to 88 years). According to whether targeted therapy combined with immunotherapy was added to chemotherapy,patients were divided into a triplet group ( n=46) and a standard chemotherapy group ( n=77). The primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included radiological efficacy indicators (objective response rate (ORR), disease control rate (DCR),clinical benefit rate,etc.) and treatment-related adverse events. Propensity score matching (PSM,caliper=0.2) was used to balance baseline characteristics between groups. Kaplan-Meier curves were used to estimate survival,and Cox regression models were applied to analyze factors influencing OS and PFS. Results:In the original cohort,the median OS was 11 months in the triplet group and 8 months in the chemotherapy group,with no statistically significant difference ( P=0.056). The median PFS was 5 months in the triplet group and 3 months in the chemotherapy group,also without statistical significance ( P>0.05). Multivariate Cox regression analysis indicated that the triplet regimen was an independent prognostic factor for both OS and PFS ( P<0.05). After PSM,baseline balance between groups was good. The median OS was 10.0 months in the triplet group and 7.0 months in the chemotherapy group, with no significant difference ( P=0.094). In terms of efficacy, the ORR was 26.1% (12/46) in the triplet group versus 7.8% (6/77) in the chemotherapy group,with a statistically significant difference ( χ2=6.320, P=0.012). The DCR was 54.3% (25/46) in the triplet group and 33.8% (26/77) in the chemotherapy group,also statistically significant ( χ2=4.214, P=0.037). The incidence of adverse events was similar between groups,mostly grade 1 to 2. Conclusions:The triplet regimen of chemotherapy,targeted therapy,and immunotherapy shows potential in improving efficacy and prolonging survival with acceptable safety in patients with advanced pancreatic cancer. However, its definitive benefits require further investigation.

ObjectiveTo investigate the effects of hand-arm bimanual intensive training （HABIT） based on the FITT-CORRECT principles on upper limb function and functional independence in children with spastic hemiplegic cerebral palsy. MethodsA total of 87 children with spastic hemiplegia were enrolled and randomly divided into an observation group （n=44）， which received HABIT based on the FITT-CORRECT principles， and a control group （n=43）， which received conventional HABIT. Both groups received intervention for 6 weeks. The quality of upper extremity skills test （QUEST）， peabody developmental motor scales-fine motor （PDMS-FM）， and the functional independence measure for children （WeeFIM） were administered before and after treatment. The root mean square （RMS） values of the biceps and triceps brachii during maximum isometric contraction of elbow flexion and extension on the affected side were also measured. ResultsBefore treatment， there were no significant differences between the two groups in QUEST， PDMS-FM， WeeFIM scores， or RMS values of the biceps and triceps during maximum isometric contraction of the affected elbow （P>0.05）. After 6 weeks of treatment， no significant change was observed in the RMS values of the triceps during elbow flexion in either group （P>0.05）. All other outcome measures improved significantly in both groups （P<0.05）. The observation group showed significantly greater improvements in dissociated movement and grasp scores of QUEST， grasp and visual-motor integration scores of PDMS-FM， WeeFIM scores， as well as RMS values of the biceps during elbow flexion and both the biceps and triceps during elbow extension on the affected side （P<0.05）. ConclusionCompared with conventional HABIT， HABIT based on the FITT-CORRECT principles is more effective in improving upper limb function and functional independence in children with spastic hemiplegia.

ObjectiveTo observe the clinical efficacy and safety of Tianmeng Lingjiao Formula（天礞羚角方， TLF） as an adjunctive therapy for paroxysmal atrial fibrillation （PAF） with phlegm-heat harassing the interior syndrome. MethodsNinety patients with PAF and phlegm-heat harassing the interior syndrome were enrolled and randomly assigned in a 2∶1 ratio to test group （60 cases） and control group （30 cases）. The control group received conventional western medicine， while the test group received TLF in addition to the conventional treatment， with one dose administered daily. The treatment course for both groups was 4 weeks. The efficacy of traditional Chinese medicine （TCM） syndrome and the rate of atrial fibrillation （AF） conversion were compared between groups. Assessments included AF burden， frequency and duration of AF episodes， TCM syndrome scores， and European Heart Rhythm Association （EHRA） AF symptom classification before and after treatment. Safety indicators such as blood routine， urine routine， stool routine， liver function， kidney function， and electrolytes were also monitored. Adverse events were recorded. ResultsA total of 82 patients completed the study （54 in the test group and 28 in the control group）. After treatment， AF burden， the frequency and duration of AF episodes， and TCM syndrome scores were significantly reduced in both groups， and the test group showed lower indicators than the control group （P＜0.01 or P＜0.05）. The AF conversion rate was 25.93% （14/54） in the test group， significantly higher than 3.57% （1/28） in the control group （P＜0.05）. The total effective rate for TCM syndrome efficacy was 83.33% （45/54） in the test group， which was significantly higher than 67.86% （19/28） in the control group （P＜0.05）. After treatment， the EHRA atrial fibrillation symptom severity in the test group showed significant improvement， and the improvement in atrial fibrillation symptoms was superior to that in the control group （P＜0.01or P＜0.05）. No significant abnormalities were observed in safety indicators， and no adverse events occurred during the trial. ConclusionTLF as an adjunctive therapy can reduce AF burden， enhance the conversion rate of AF， decrease the frequency and duration of episodes， and improve clinical symptoms in patients with paroxysmal atrial fibrillation presenting with phlegm-heat harassing the interior syndrome， with a favorable safety profile.

Objective:To observe the effects of Yiyuan moxibustion on bladder function and antioxidant level of spinal cord tissues in rats with urinary retention after spinal cord injury (SCI); To explore the mechanism of inhibition of ferroptosis in spinal cord neurons after SCI by Yiyuan moxibustion.Methods:Wistar female rats were divided into sham-operation group, model group, and Yiyuan moxibustion group according to random number table method, with 12 rats in each group. The modified Allen′s vertical percussion method was used to construct the model of urinary retention after SCI in T10 segment. The rats in the Yiyuan moxibustion group were moxibued at the Zhongji acupoint, Guanyuan acupoint, and Shenque acupoint for 20 min per day, and the intervention was continued for 2 weeks. Urodynamic test was used to observe the degree of urinary retention in rats; HE staining was used to observe the morphological changes of the injured spinal cord tissues; transmission electron microscopy was used to observe the mitochondrial ultrastructure of the spinal cord tissues; ferric ion kit was used to detect the ferric ion content of the spinal cord tissues; ELISA was used to detect the GSH and MDA contents of the spinal cord tissues of the rats; Western blot was used to measure the relative expressions of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) proteins in rat spinal cord tissue.Results:Compared with the model group, the basal and leakage point pressures of the bladder, and bladder compliance were significantly reduced in the Yiyuan moxibustion group ( P<0.05); the spinal cord tissue structure was restored and mitochondrial morphology improved; the levels of iron ions and MDA in spinal cord tissue decreased ( P<0.05), while the level of GSH increased ( P<0.05), and the relative expressions of GPX4 and SLC7A11 proteins increased ( P<0.05). Conclusion:Yiyuan moxibustion can improve bladder function in rats with urinary retention after SCI, and the mechanism may involve the initiation of antioxidant defense and reduction of lipid peroxidation in spinal cord neuronal cells, thus preventing the occurrence of ferroptosis and achieving the protection of neuronal cells.