OBJECTIVE To investigate the influence of CYP2C19 gene polymorphism on platelet function and inflammatory cytokines in elderly patients with ischemic stroke， and to analyze potential factors associated with poor prognosis. METHODS A retrospective study was conducted on elderly patients with ischemic stroke admitted to our hospital from June 2024 to June 2025， wh o underwent CYP2C19 genotype testing and received antiplatelet therapy with clopidogrel. The levels of platelet function indicators and inflammatory cytokines before and after treatment were compared among patients with different metabolic phenotypes. Based on the prognosis at 6 months post-treatment， patients were divided into poor prognosis group and good prognosis group. Univariate analysis was performed on general data， metabolic phenotype， the levels of platelet function indicators and inflammatory cytokines. Variables with P ＜0.05 and the levels of inflammatory cytokines before treatment were included in a multivariate Logistic regression analysis to identify independent risk factors for poor prognosis. Multiple linear regression was used to further analyze the relationship between metabolic phenotypes and inflammatory cytokines. RESULTS A total of 448 elderly patients with ischemic stroke were included； among them， 162 cases were normal metabolic phenotype， 218 were intermediate metabolic phenotype， and 68 were poor metabolic phenotype. No rapid or ultrarapid metabolic phenotypes were observed. After treatment， platelet aggregation rate， the levels of P-selectin and platelet activated complex-1 （PAC-1）， high-sensitivity C-reactive Protein （hs-CRP）， interleukin-1β （IL-1β）， IL-6 and tumor necrosis factor-α （TNF-α） in the normal metabolic phenotype group， intermediate metabolic phenotype group， and poor metabolic phenotype group （except for platelet aggregation rate， and the levels of P-selectin and PAC-1 in the poor metabolic phenotype group） were significantly lower than those before treatment in the same group. Moreover， the above indicators in the normal metabolic phenotype group were significantly lower than those in the intermediate and poor metabolic phenotype groups at the corresponding time， and the levels of platelet function indicators in the intermediate metabolic phenotype group were significantly lower than those in the poor metabol ic phenotype group at the corresponding time （ P ＜0.05）. Univariate and multivariate Logistic regression analyses showed that combined with hypertension， combined with diabetes mellitus， and intermediate or poor metabolic genotypes were independent risk factors for poor prognosis in elderly patients with ischemic stroke （ P ＜0.05）. Multiple linear regression analysis showed that serum levels of hs-CRP， IL-1β， IL-6 and TNF-α before treatment were significantly higher in patients with intermediate and poor metabolic genotypes compared to those with normal metabolic genotype （ P ＜0.05）， with a greater magnitude of increase in inflammatory cytokines observed in the patients with poor metabolic genotype. CONCLUSIONS The elderly ischemic stroke patients with CYP2C19 intermediate and poor metabolic genotypes have poor inhibition effect on platelet and higher levels of inflammatory cytokines than normal metabolic genotype； CYP2C19 gene polymorphism， and in combination with hypertension and diabetes， can be used as independent predictors of poor prognosis.

Background/Aims: Reflux symptoms frequently present in patients diagnosed with functional dyspepsia (FD). This investigation sought to elucidate the contribution of gastroesophageal reflux in the overlap relationship. Methods: Consecutive patients presenting with reflux symptoms and/or FD symptoms were prospectively included. Comprehensive assessments, including symptoms evaluation, endoscopy, esophageal functional examinations (high-resolution manometry and reflux monitoring), and proton pump inhibitor (PPI) treatment efficacy evaluation, were conducted in these patients. Results: The study enrolled 315 patients, 43.2% of which had concurrent FD symptoms and overlapping reflux symptoms. Notably, a mere 28.7% of patients in the overlap symptoms group had objective gastroesophageal reflux disease evidences (the grade of esophagitis≥ B or the acid exposure time ≥ 4.2%). Functional heartburn was demonstrated to be the main cause of overlapping reflux symptoms(55.1%). Reflux parameters analysis revealed that the reflux burden in the overlap symptoms group paralleled that of the FD symptoms group, with both registering lower levels than the reflux symptoms group (P < 0.05). Furthermore, PPI response rates were notably diminished in the overlap symptoms group (P < 0.001), even for those with objective gastroesophageal reflux disease evidences. Conclusions The study illuminated that overlapping reflux symptoms in FD was common. Strikingly, these symptoms primarily diverged from reflux etiology and exhibited suboptimal responses to PPI intervention. These findings challenge prevailing paradigms and accentuate the imperative for nuanced therapeutic approaches tailored to the distinctive characteristics of overlapping reflux symptoms in the context of FD.

Background::B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T (CAR-T) therapy yield remarkable responses in patients with relapsed/refractory multiple myeloma (R/RMM). Circulating tumor DNA (ctDNA) reportedly exhibits distinct advantages in addressing the challenges posed by tumor heterogeneity in the distribution and genetic variations in R/RMM.Methods::Herein, the ctDNA of 108 peripheral blood plasma samples from patients with R/RMM at the First Affiliated Hospital, School of Medicine, Zhejiang University was thoroughly investigated before administration of anti-BCMA CAR-T therapy to establish its predictive potential. Flow cytometry is used primarily to detect subgroups of T cells or CAR-T cells.Results::In this study, several tumor and T cell effector-mediated factors were considered to be related to treatment failure by an integrat analysis, including higher percentages of multiple myeloma (MM) cells in the bone marrow ( P = 0.0125), lower percentages of CAR-T cells in the peripheral blood at peak ( P = 0.0375), and higher percentages of CD8 + T cells ( P = 0.0340). Furthermore, there is a substantial correlation between high ctDNA level (>143 ng/mL) and shorter progression-free survival (PFS) ( P = 0.007). Multivariate Cox regression analysis showed that high levels of ctDNA (>143 ng/mL), MM-driven high-risk mutations (including IGLL5 [ P = 0.004], IRF4 [ P = 0.024], and CREBBP [ P = 0.041]), number of multisite mutations, and resistance-related mutation ( ERBB4, P = 0.040) were independent risk factors for PFS. Conclusion::Finally, a ctDNA-based risk model was built based on the above independent risk factors, which serves as an adjunct non-invasive measure of substantial tumor burden and a prognostic genetic feature that can assist in predicting the response to anti-BCMA CAR-T therapy.

OBJECTIVE: To explore the clinical phenotype and genetic characteristics of a patient with Progressive pseudorheumatoid dysplasia (PPRD) due to compound heterozygous variants of CCN6 gene. METHODS: A patient who was admitted to Qilu Hospital of Shandong University due to "bilateral finger joint deformity, bilateral hip and knee joint movement limitation for 19 years" was selected as the study subject. Clinical data of the patient were retrospectively collected. Peripheral blood samples were collected from the patient and her parents and subjected to whole exome sequencing (WES). Long-read sequencing (LRS) and Sanger sequencing were used to verify the candidate variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the pathogenicity of candidate variants was classified. This study was approved by the Medical Ethics Committee of Qilu Hospital of Shandong University (Ethics No.: KYLL-202502 061). RESULTS: The patient, a 23-year-old female, presented with progressive polyarticular deformity, limited movement and abnormal growth and development since childhood. She was initially misdiagnosed as Ankylosing spondylitis and had poor response to sulphasalazine and etoricoxib treatment. WES revealed that she has harbored two heterozygous variants of the CCN6 gene (NM_198239.2), namely c.348C>A and c.676G>C. LRS confirmed that the two variants are located on two homologous chromosomes and constitute compound heterozygous variants. Based on the ACMG guidelines, both variants were rated as pathogenic (PVS1+PM2_Supporting+PM3; PM1+PM2_Supporting+PM3_Supporting+PM5+PP3_Strong). The c.676G>C variant has not been recorded by the HGMD and ClinVar databases. CONCLUSION The c.348C>A and c.676G>C compound heterozygous variants of the CCN6 gene probably underlay the pathogenesis of PPRD in this patient. Above finding has enriched the mutational spectrum of PPRD and provided a basis for the clinical diagnosis and genetic counseling.
Humans ; Female ; CCN Intercellular Signaling Proteins/genetics* ; Phenotype ; Heterozygote ; Young Adult ; Mutation ; Exome Sequencing ; Joint Diseases/congenital*

Objective:To investigate the predictive value of machine learning-based CT radiomics model for radioresistance in patients with esophageal squamous cell carcinoma (ESCC).Methods:Clinical data of 185 patients with ESCC treated with radical radiotherapy in the First Affiliated Hospital of Anhui Medical University from December 2015 to July 2022 were retrospectively analyzed, and all patients were randomly divided into a training set ( n=129) and a validation set ( n=56) at a ratio of 7 : 3. The radiomics parameters of the primary lesion of esophageal cancer and the surrounding 5 cm region in the patients' CT arterial phase images were extracted, and 6 machine learning methods were used to screen the optimal radiomics model to obtain the optimal radiomics score (Radscore). Independent prognostic predictors of radioresistance in ESCC were obtained by univariate and multivariate logistic regression analyses, which was used as the basis for constructing the nomogram. The predictive performance of different models was compared by the area under the receiver operating characteristic (ROC) curve (AUC). The predictive efficacy and clinical value of the combined model were evaluated using calibration curve, decision curve analysis and clinical impact curve, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Results:The combined intratumoral and peritumoral radiomics model based on naive Bayesian classifier yielded the optimal prediction performance, with AUC of 0.859 and 0.936 in the training set and validation set, respectively. Multivariate logistic regression analysis showed that Radscore and T stage were the independent prognostic predictors of radioresistance in ESCC patients, and the AUC of the combined model constructed based on these predictors in the training and validation sets were 0.942 and 0.959, respectively. Calibration curve, decision curve analysis and clinical impact curve, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) all indicated higher clinical benefit and more consistent predictive efficacy of the combined model.Conclusions:Machine learning-based CT radiomics model is useful for the prediction of radioresistance in ESCC. The nomogram of radiomics and clinical parameters can further improve the prediction accuracy and provide novel reference for individualized treatment of patients with ESCC.

Objective:To investigate the current level of awareness among Chinese gastroenterologists regarding small intestinal bacterial overgrowth (SIBO).Methods:From March 7th to April 14th, 2024, an online survey questionnaire was sent to qualified clinical physicians specializing in gastroenterology in various levels of general hospitals across the country through the official channels of national academic organizations such as the Gastroenterology Branch of the Chinese Medical Association, the Gastrointestinal Motility Group of the Gastroenterology Branch of the Chinese Medical Association, and the Functional Gastrointestinal Disorders Collaborative Group of the Gastroenterology Branch of the Chinese Medical Association, as well as through the national medical continuing education project cooperation platform. The questionnaire content includes basic information, awareness of consensus guidelines on functional gastrointestinal disorders (FGID) and SIBO, understanding of SIBO and its diagnosis and treatment strategies, et al. The influencing factors of physicians′ cognitive level regarding SIBO were analyzed based on the questionnaire results. Statistical methods employed descriptive statistical method and partial correlation analysis.Results:A total of 511 valid questionnaires were collected, among them, 78.1% (399/511) of the respondents practiced in tertiary hospitals, and 90.2% (461/511) of the respondents were aware of the definition of SIBO. However, only 9.0% (46/511) could accurately identify all the key points of the relevant consensus guidelines. Educational background (undergraduate and master′s degree vs. doctor degree, OR=0.265, 0.528, 95% confidence interval(95% CI): 0.155 to 0.454, 0.322 to 0.865), professional title (junior title vs. senior title, OR=0.577, 95% CI: 0.344 to 0.968), and the number of SIBO cases handled per year (less than 50 cases vs. more than 200 cases, OR=0.144, 95% CI: 0.043 to 0.479) were independent influencing factors that affect the cognitive level of specialist physicians regarding SIBO and the guidelines (all P<0.05). The results of hydrogen and methane breath test (HMBT) was the main reference indicator for diagnosing SIBO in the respondents (79.8%, 408/511), but only 8.4%(43/511) of the specialists were familiar with the principle of HMBT, and 65.9% (337/511) were not clear about the differences in diagnostic thresholds among different consensus or guidelines. Rifaximin was the most commonly used therapy (87.5%, 447/511), but there was significant heterogeneity in the selection of dosage and treatment course. According to the survey, 17.6% (90/511) of the clinicians believed that comprehensive assessment of the patient′s clinical condition was not necessary for the diagnosis and treatment of FGID. Conclusion:Gastroenterologists are familiar with the basic concepts of SIBO, but their understanding of the diagnostic criteria application and the latest research progress is limited.

One female patient with cancer pain due to bone metastasis from breast cancer was initially treated with Xinhuang tablets,diclofenac sodium double-release enteric-soluble capsules,paracetamol dihydrocodeine tablets and paracetamol oxycodone tablets,before being switched to controlled-release oxycodone hydrochloride tablets.She regularly took oxycodone hydrochloride sustained-release tablets 20 mg,q12h,no abnormalities were observed,and the dosage was increased to 40 mg,q12h due to poor pain control.The patient was diagnosed with 5-hydroxytryptamine syndrome after 1 d of intermittent recurrent tremor,myotonia,scalp sweating,restlessness and elevated blood pressure.When oxycodone hydrochloride sustained release tablet was adjusted to 20 mg,q12h and gabapentin capsule was added to 0.1 g,tid,the frequency of tremor and myotonia attacks slightly decreased,and sweating and agitation symptoms were not relieved.After 14 days,oxycodone hydrochloride sustained release tablets were stopped and morphine sulfate sustained release tablets 60 mg,q12h were replaced.Three days later,the patient's symptoms disappeared.During 5-month follow-up,the patient's pain was well-contrdled,with no change in the dose of morphine sulfate sustained-release tablets,and no adverse drug reactions observed.Using the Naranjo's Assessment Scale,the association between the patient's serotonin syndrome and the suspected drug oxycodone hydrochloride sustained-release tablets was evaluated as"probable".Thiscase highlights the importance for clinicians to closely monitor adverse reactions induced by rapid opioid dose escalation to ensure medication safety in patients.

Objective:To discuss the effects of bone marrow-derived mesenchymal stem cells(BMSCs)transplantation on mitophagy in the vascular dementia(VaD)rats through reactive oxygen species(ROS)/nuclear factor erythroid 2-related factor 2(Nrf2)signaling,and to clarify its mechanism.Methods:Forty-five male adult SD rats were randomly divided into sham operation group,model group,unloaded group,BMSCs group,and MSCs+ML385(Nrf2 inhibitor)group(combination group),and there were 9 rats in each group.After intraperitoneal anesthesia,the VaD models were established in all groups except sham operation group.Morris water maze test was used to detect the learning and memory abilities of the rats in various groups;HE staining was used to observe the histopathological morphology of brain tissue of the rats in various groups;Nissl staining was used to observe the changes of Nissl bodies in hippocampus region of brain tissue of the rats in various groups;transmission electron microscope was used to observe the ultrastructure of hippocampus region of the rats in various groups;fluorescence probe method was used to detect the ROS levels in hippocampus neurons in various groups;Western blotting method was used to detect the expression levels of Nrf2,heme oxygenase-1(HO-1),PTEN-induced putative kinase 1(PINK1),parkin RBR E3 ubiquitin protein ligase(Parkin),Beclin-1,ubiquitin-binding protein p62(P62),and microtubule-associated protein 1A/1B-light chain 3(LC3-Ⅱ/LC3-Ⅰ)ratio in brain tissue of the rats in various groups.Results:The Morris water maze results showed that compared with sham operation group,the escape latency of the rats in model group was significantly increased(P<0.01),while the number of crossing time and residence time were significantly decreased(P<0.01).Compared with model group,the escape latency of the rats in BMSCs group was significantly decreased(P<0.01),while the number of crossing time and residence time were significantly increased(P<0.01).Compared with BMSCs group,the escape latency of the rats in combination group was significantly increased(P<0.01),while the number of crossing time and residence time were significantly decreased(P<0.01).The HE staining results showed that hippocampus neurons of the rats in sham operation group were normal in quantity and morphology,with uniform staining and clear structure.Compared with sham operation group,the hippocampus tissue of the rats in model group showed sparse arrangement,disordered structure,reduced neuronal quantity,varied morphology,uneven staining,nuclear pyknosis,and partial neuronal necrosis.Compared with model group,the neuronal damage of the rats in hippocampus regio in BMSCs group was alleviated,with restored morphology and improved neuronal loss.Compared with BMSCs group,the neurons of the rats in hippocampus region in combination group showed irregular morphology,disordered structure,unclear cell boundaries,uneven staining,and nuclear pyknosis.The Nissl staining results showed that the hippocampal neurons in sham operation group were tightly arranged with intact morphology,obvious nucleoli,and abundant darkly stained Nissl bodies.Compared with sham operation group,the neurons in hippocampus region of the rats in model group showed pyknosis,vacuolization,and sparse Nissl bodies.Compared with model group,the BMSCs group showed reduced neuronal pyknosis,relatively intact morphology,and increased Nissl bodies.Compared with BMSCs group,the combination group showed neuronal pyknosis,loss of morphological integrity,and fragmented Nissl bodies.The transmission electron microscope results showed that mitochondria in sham operation group exhibited oval shape with intact double-membrane structure and cristae.Compared with sham operation group,the mitochondria in model group showed swelling,disrupted membranes,broken cristae,and numerous autophagosomes.Compared with model group,the BMSCs group showed improved mitochondrial structure and reduced autophagosomes.Compared with BMSCs group,the combination group showed swollen mitochondria,disrupted membranes,broken cristae,and visible autophagosomes.The fluorescence probe results showed that compared with sham operation group,the ROS levels in the hippocampus neurons in brain tissue of the rats in model group were significantly increased(P<0.01);compared with model group,the ROS levels in hippocampus neurons in brain tissue of the rats in BMSCs group were significantly decreased(P<0.01);compared with BMSCs group,the ROS levels in hippocampus neurons in brain tissue of the rats in combination group were significantly increased(P<0.01).The Western blotting results showed that compared with sham operation group,the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in model group were significantly decreased(P<0.01);compared with model group,the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in BMSCs group were significantly increased(P<0.01);compared with BMSCs group,the expression levels of Nrf2 and HO-1 proteins in brain tissue of the rats in combination group were significantly decreased(P<0.01);compared with sham operation group,the expression levels of Parkin,PINK1,and Beclin-1 proteins,and LC3-Ⅱ/LC3-Ⅰ ratio of the rats in model group were significantly increased(P<0.01),while the expression level of P62 protein was significantly decreased(P<0.01);compared with model group,the expression levels of Parkin,PINK1,and Beclin-1 proteins,as well as the LC3-Ⅱ/LC3-Ⅰ ratio,of the rats in BMSCs group were significantly decreased(P<0.01),while the expression level of P62 protein was significantly increased(P<0.01);compared with BMSCs group,the expression levels of Parkin,PINK1,and Beclin-1 proteins,as well as the LC3-Ⅱ/LC3-Ⅰ ratio,of the rats in combination group were significantly increased(P<0.01),while the expression level of P62 protein was significantly decreased(P<0.01).Conclusion:BMSCs can alleviate the hippocampal neuronal pathological changes and improve cognitive function in the VaD rats,and its mechanism may be related to the regulation of ROS/Nrf2 signaling pathway to inhibit mitophagy.

Lipid rafts are microdomains in the cell membrane that are involved in cell signal transduction,metabolism,and intercellu-lar interactions.In recent years,studies have shown that lipid rafts play an important role in the pathogenesis of diabetes.Cholesterol and sphingolipids are the main lipid components in lipid rafts,and the protein components in lipid rafts include caveolin,flotillin,pal-mitoylated proteins,and glycosylphosphatidylinositol-anchored proteins.Changes in these components affect the structure and function of lipid rafts,which in turn may affect insulin signal transduction,leading to the occurrence of diabetes-related diseases.Lipid rafts are closely related to the occurrence and development of diabetes in different tissues.Pancreatic lipid rafts are closely related to insulin se-cretion,and their structural changes affect insulin synthesis and release.Changes in lipid rafts in adipose tissue are related to insulin resistance and disorders of glycolipid metabolism.Changes in lipid rafts in the liver can affect gluconeogenesis and glycogen synthesis.Lipid rafts in the kidney play a regulatory role in the progression of diabetic nephropathy.This article aims to provide a comprehensive overview of the role of lipid rafts in the pathogenesis of diabetes,offering insights into the identification of new targets for the prevention and treatment of diabetes in the future,as well as presenting a new perspective for the development of therapeutic agents for diabetes.

Objective:To investigate the long-term outcome of deep brain stimulation (DBS) in patients with KMT2B gene-related dystonia. Methods:Seven patients with KMT2B gene-related dystonia who were treated at Peking Union Medical College Hospital from April 2018 to December 2020 were enrolled. Whole-exome sequencing was used to detect genetic variations, and clinical phenotypes were summarized. All patients underwent DBS surgery and were followed up at 6 months, 3 years, and 5 years post-surgery. The therapeutic effects of DBS were evaluated by Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), including BFMDRS Motor Subscale (BFMDRS-M) and Disability Subscale (BFMDRS-D). Results:The preoperative BFMDRS-M and BFMDRS-D scores were 60.43±27.12 and 17.00±6.24, respectively. The most significant improvements were observed at 6 months post-surgery, with the BFMDRS-M and BFMDRS-D scores being 20.64±5.50 and 9.57±1.72, reflecting improvements of 65.8% and 43.7%, respectively, both with statistically significant differences ( t=4.342, P=0.005; t=2.828, P=0.030). At 3 years post-surgery, the BFMDRS-M and BFMDRS-D scores were 26.20±8.68 and 10.50±2.74, representing improvements of 56.7% ( t=3.045, P=0.029) and 38.2% ( t=2.012, P=0.100), respectively. At 5 years post-surgery, the BFMDRS-M and BFMDRS-D scores were 27.80±14.87 and 11.00±2.83, with improvements of 54.0% ( t=1.824, P=0.142) and 35.3% ( t=1.933, P=0.125), respectively. At the 5-year postoperative follow-up, the patients′ cervical dystonia improved by 78.9%, while the upper limbs, lower limbs, and trunk dystonia improved by 57.8%, 56.6%, and 58.0%, respectively. However, only 1 patient showed significant improvement in the language function. Conclusions:DBS showed good therapeutic effects on KMT2B gene-related dystonia, but the efficacy declined over time. Significant improvements were observed in patients′ cervical, limb and trunk dystonia, but the improvement in language function was not significant.