Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

Background/Aims: Anti-reflux mucosal ablation (ARMA) is a promising endoscopic intervention for proton pump inhibitor (PPI)-dependent gastroesophageal reflux disease (GERD). However, the effect of ARMA on esophageal motility remains unclear. Methods: Twenty patients with PPI-dependent GERD receiving ARMA were prospectively enrolled. Comprehensive self-report symptom questionnaires, endoscopy, 24-hour impedance-pH monitoring, and high-resolution impedance manometry were performed and analyzed before and 3 months after ARMA. Results: All ARMA procedures were performed successfully. Symptom scores, including GerdQ (11.16 ± 2.67 to 9.11 ± 2.64, P = 0.026) and reflux symptom index (11.63 ± 5.62 to 6.11 ± 3.86, P = 0.001), improved significantly, while 13 patients (65%) reported discontinuation of PPI. Total acid exposure time (5.84 ± 4.63% to 2.83 ± 3.41%, P = 0.024) and number of reflux episodes (73.05 ± 19.34 to 37.55 ± 22.71, P < 0.001) decreased significantly after ARMA. Improved esophagogastric junction (EGJ) barrier function, including increased lower esophageal sphincter resting pressure (13.89 ± 10.78 mmHg to 21.68 ± 11.5 mmHg, P = 0.034), 4-second integrated relaxation pressure (5.75 ± 6.42 mmHg to 9.99 ± 5.89 mmHg, P = 0.020), and EGJ-contractile integral(16.42 ± 16.93 mmHg · cm to 31.95 ± 21.25 mmHg · cm, P = 0.016), were observed. Esophageal body contractility also increased significantly (distal contractile integral, 966.85 ± 845.84 mmHg · s · cm to 1198.8 ± 811.74 mmHg · s · cm, P = 0.023). Patients with symptom improvement had better pre-AMRA esophageal body contractility. Conclusions ARMA effectively improves symptoms and reflux burden, EGJ barrier function, and esophageal body contractility in patients with PPIdependent GERD during short-term evaluation. Longer follow-up to clarify the sustainability of ARMA is needed.

Chronic kidney disease(CKD)is a chronic disease characterized by renal structural damage and dysfunction.At present,there is still a lack of effective therapeutic drugs and prevention and treatment methods for CKD in clinical practice.More and more studies have shown that necroptosis,as a new type of programmed cell death,plays a vital role in the onset and progression of CKD.Targeting key molecules in the necroptosis pathway,such as RIPK1,RIPK3 and MLKL,the development of small molecule inhibitors has become an emerging strategy for the treatment of CKD,and has shown significant potential to pro-tect the kidneys and alleviate renal fibrosis in a variety of in vitro and in vivo models.Therefore,this article summarizes the re-search progress of the mechanism of necroptosis in recent years,and focuses on the potential role of necroptosis in the pathogene-sis of CKD and the therapeutic potential of targeting this path-way,providing a new perspective and research direction for the prevention and treatment of CKD in the future.

AIM To study the chemical constituents from Inula japonica Thunb.and their anti-asthmatic activity.METHODS Separation and purification were performed using silica gel and Sephadex LH-20,then the structures of obtained compounds were identified by physicochemical properties and spectral data.The effect of compounds on the release rate of β-Hex was evaluated by substrate coloration method.RESULTS Twenty-three compounds were isolated and identified as dehydrodontic acid(1),vitexin(2),alternariol(3),globuxanthone(4),1,3,6,7-tetrahydroxyxanthone(5),hydroxyhydrolapachol(6),isoscopoletin(7),elephanmollen(8),benzoylcholine(9),hoconobiflavone(10),clovandiol(11),hydroxydihydrobovolide(12),5,7-dihydroxycoumarin(13),scopoletin(14),orlichenol glucoside(15),urolignoside(16),9-angeloyloxythymol(17),6,3′,4′-trihydroxyaurone(18),flufuran(19),sweroside(20),guajadial(21),5,7,4′-trimethoxy-4-phenylcoumarin(22),dibutylphthalate(23).After intervention with compounds 9 and 16,the release rates of β-Hex were(56.64±2.37)％and(58.07±2.29)％,respectively.CONCLUSION Compounds 1-23 are isolated from Ⅰ.japonica for the first time.Compounds 9 and 16 have anti-asthmatic activity.

Objective:To analyze the distribution of causes of death among residents in Chuzhou City of Anhui Province from 2019 to 2022,in order to provide evidence for formulating disease prevention and control strategies.Methods:The death data of residents in Chuzhou City from 2019 to 2022 were obtained from the cause of death surveillance system of Chuzhou Center for Disease Control and Prevention in Anhui Province.The crude death rate,composition ratio of cause of death and the rank of cause of death were analyzed.The annual percent change(APC)of mortality was calculated by using the Joinpoint regression model to describe the average annual change of mortality.Results:From 2019 to 2022,the average annual crude mortality of permanent residents in Chuzhou City was 668.80/100 000,and the crude mortality rate(/100 000)was 640.58,652.10,659.32,and 723.46,respectively(APC=3.10%,P=0.356).The annual crude mortality of males(735.93/100 000)was higher than that of females(598.52/100 000)(χ2=1 148.724,P＜0.01).The top three causes of death were malignant tumor,cerebrovascular disease,and cardiovascular disease.The mortality of malignant tumors showed a decreasing trend(APC=-1.51%,P＜0.01),and the top three causes of death of malignant tumors were lung cancer,gastric cancer and liver cancer.Among the age groups,congenital malformations and deformations,chromosomal abnormalities,and certain conditions originating in the perinatal period were the leading causes of death among residents aged 0 to 4 years old.Accidental injuries were the first cause of death among residents aged 5 to 14 years old.The leading cause of death among residents in the 15-44 and 45-64 age groups was malignant tumor.Cerebrovascular disease was the leading cause of death in≥65 years old.The mortality of accidental injuries showed an increasing trend(APC=1.64%,P＜0.01),and the specific types of death causes of accidental injuries were different among different age groups.Conclusion:Chronic non-communicable diseases,especially cancer and cardiovascular and cerebrovascular diseases,are the main health threats to the residents of Chuzhou City of Anhui Province,and feasible prevention and control measures should be formulated.

Objective Metabolomics combined with machine learning algorithms was used to systematically study the preoperative serum metabolites of patients with early postoperative cognitive dysfunction(POCD)after heart valve replacement,so as to screen biomarkers that may predict early POCD after heart valve replacement and explore the corresponding metabolic regulatory mechanisms.Methods A total of 60 patients underwent heart valve replacement under extracorporeal circulation were selected and divided into early-POCD group(group P)and non-POCD group(group N)according to whether POCD occurred or not.Metabolomic analysis was performed on preoperative serum samples of patients in group P and group N to screen the differential metabolites and metabolic pathways.The biomarkers related to early POCD were identified by random forest algorithm.Results A total of 532 differential metabolites were detected by metabonomics analysis,and 5 biomarkers were screened by random forest algorithm,namely quinoline,3'-sialyllactose,sphingomyelin(d18∶1/20∶0),lysophosphatidylcholine[P-18∶1(9Z)]and 25-hydroxycholesterol.Among them,the main metabolic pathways were phenylalanine metabolism,primary bile acid biosynthesis,ascorbic acid and aldonate metabolism,pentose and glucuronate interconversion,tryptophan metabolism,drug metabolism-cytochrome P450,porphyrin and chlorophyll metabolism.Conclusion Many metabolic pathways in patients with early POCD after heart valve replacement under extracorporeal circulation have changed before operation,which may lead to the occurrence of early POCD.Quinoline,3'-sialyllactose,sphingomyelin(d18∶1/20∶0),lysophosphatidylcholine[P-18∶1(9Z)]and 25-hydroxycholesterol may be biomarkers for predicting early POCD.

Chronic kidney disease(CKD)is a chronic disease characterized by renal structural damage and dysfunction.At present,there is still a lack of effective therapeutic drugs and prevention and treatment methods for CKD in clinical practice.More and more studies have shown that necroptosis,as a new type of programmed cell death,plays a vital role in the onset and progression of CKD.Targeting key molecules in the necroptosis pathway,such as RIPK1,RIPK3 and MLKL,the development of small molecule inhibitors has become an emerging strategy for the treatment of CKD,and has shown significant potential to pro-tect the kidneys and alleviate renal fibrosis in a variety of in vitro and in vivo models.Therefore,this article summarizes the re-search progress of the mechanism of necroptosis in recent years,and focuses on the potential role of necroptosis in the pathogene-sis of CKD and the therapeutic potential of targeting this path-way,providing a new perspective and research direction for the prevention and treatment of CKD in the future.

Objective Metabolomics combined with machine learning algorithms was used to systematically study the preoperative serum metabolites of patients with early postoperative cognitive dysfunction(POCD)after heart valve replacement,so as to screen biomarkers that may predict early POCD after heart valve replacement and explore the corresponding metabolic regulatory mechanisms.Methods A total of 60 patients underwent heart valve replacement under extracorporeal circulation were selected and divided into early-POCD group(group P)and non-POCD group(group N)according to whether POCD occurred or not.Metabolomic analysis was performed on preoperative serum samples of patients in group P and group N to screen the differential metabolites and metabolic pathways.The biomarkers related to early POCD were identified by random forest algorithm.Results A total of 532 differential metabolites were detected by metabonomics analysis,and 5 biomarkers were screened by random forest algorithm,namely quinoline,3'-sialyllactose,sphingomyelin(d18∶1/20∶0),lysophosphatidylcholine[P-18∶1(9Z)]and 25-hydroxycholesterol.Among them,the main metabolic pathways were phenylalanine metabolism,primary bile acid biosynthesis,ascorbic acid and aldonate metabolism,pentose and glucuronate interconversion,tryptophan metabolism,drug metabolism-cytochrome P450,porphyrin and chlorophyll metabolism.Conclusion Many metabolic pathways in patients with early POCD after heart valve replacement under extracorporeal circulation have changed before operation,which may lead to the occurrence of early POCD.Quinoline,3'-sialyllactose,sphingomyelin(d18∶1/20∶0),lysophosphatidylcholine[P-18∶1(9Z)]and 25-hydroxycholesterol may be biomarkers for predicting early POCD.