Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)mode...Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)models were established by colorectal distention in newborn rats aged 8 to 14 days,and visceral hypersensitivity was assessed using electromyogram(EMG).Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats.The protein expressions of oxytocin receptor(OTR),γ-aminobutyric acid type B1 receptor(GABAB1),and transient receptor potential vanilloid 1(TRPV1)in the lumbosacral spinal cord regions were measured.IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression.Intrathecal oxytocin treatment not only normalized these molecular alterations(increasing GABAB1 while decreasing TRPV1)but also ameliorated visceral pain behaviors.Crucially,this therapeutic effect was fully reversed by GABAB1 inhibition,establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia.Collectively,these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.展开更多
Severe acute pancreatitis(SAP)can induce acute respiratory distress syndrome(ARDS)and abdominal compartment syndrome(ACS).Although prone position ventilation(PPV)can improve outcomes in patients with ARDS,there is sig...Severe acute pancreatitis(SAP)can induce acute respiratory distress syndrome(ARDS)and abdominal compartment syndrome(ACS).Although prone position ventilation(PPV)can improve outcomes in patients with ARDS,there is significant controversy regarding its concurrent use with ACS owing to concerns of increased risk of intra-abdominal pressure(IAP).[1]We present a case of successful PPV application without adverse eff ects.展开更多
AIM:To evaluate the efficacy of the total computer vision syndrome questionnaire(CVS-Q)score as a predictive tool for identifying individuals with symptomatic binocular vision anomalies and refractive errors.METHODS:A...AIM:To evaluate the efficacy of the total computer vision syndrome questionnaire(CVS-Q)score as a predictive tool for identifying individuals with symptomatic binocular vision anomalies and refractive errors.METHODS:A total of 141 healthy computer users underwent comprehensive clinical visual function assessments,including evaluations of refractive errors,accommodation(amplitude of accommodation,positive relative accommodation,negative relative accommodation,accommodative accuracy,and accommodative facility),and vergence(phoria,positive and negative fusional vergence,near point of convergence,and vergence facility).Total CVS-Q scores were recorded to explore potential associations between symptom scores and the aforementioned clinical visual function parameters.RESULTS:The cohort included 54 males(38.3%)with a mean age of 23.9±0.58y and 87 age-matched females(61.7%)with a mean age of 23.9±0.53y.The multiple regression model was statistically significant[R²=0.60,F=13.28,degrees of freedom(DF=17122,P<0.001].This indicates that 60%of the variance in total CVS-Q scores(reflecting reported symptoms)could be explained by four clinical measurements:amplitude of accommodation,positive relative accommodation,exophoria at distance and near,and positive fusional vergence at near.CONCLUSION:The total CVS-Q score is a valid and reliable tool for predicting the presence of various nonstrabismic binocular vision anomalies and refractive errors in symptomatic computer users.展开更多
Objective:To investigate the clinical efficacy of electrophysiological therapy under different parameter modes in chronic pelvic pain syndrome(CPPS).Methods:A total of 95patients with CPPS from the Department of Urolo...Objective:To investigate the clinical efficacy of electrophysiological therapy under different parameter modes in chronic pelvic pain syndrome(CPPS).Methods:A total of 95patients with CPPS from the Department of Urology,First Affiliated Hospital of Jinan University,were selected and treated with electrophysiological therapy.They were randomly divided into three groups:the fixed-parameter AA7 treatment group,the P2+P4 treatment group,and the precision treatment group(individualized parameter treatment).Pain scores of patients in each group were compared before and after treatment,with a pain score of 0 indicating cure.The cure rate of each group was observed.Results:The average ages of the AA7 group,P2+P4 group,and precision treatment group were 34±14.17 years,35.58±12.57 years,and 35.5±11.27 years,respectively.There was no significant difference in age among the three groups(p>0.05).Before treatment,the pain scores of the AA7 group,P2+P4 group,and precision treatment group were 4.14±1.74,4.64±1.72,and 3.50±1.89,respectively,with no significant differences among the groups(p>0.05).After treatment,the pain scores were 0.71±0.99 for the AA7 group(cure rate:57%),0.49±0.79 for the P2+P4 group(cure rate:67%),and 0.50±0.77 for the precision treatment group(cure rate:64%),with no significant differences among the groups(p>0.05).The cure rates for different pain locations were as follows:83%for lower abdominal pain,74%for perineal pain,62%for dysuria,49%for testicular pain,and 75%for inguinal pain.Conclusion:The pathogenesis of CPPS is complex and diverse,with numerous treatment options and uncertain efficacy,posing significant challenges to clinical practice.This study showed that electrophysiological therapy under different parameter modes significantly reduced pain scores before and after treatment,indicating significant therapeutic effects on CPPS.All three modes demonstrated good cure rates.Individualized precision treatment and fixed-mode P2+P4 or AA7 treatment were safe and effective in CPPS treatment and are worth promoting.Fixed-mode P2+P4 and AA7,due to their easier standardization of parameters and patch modes,reduced the learning curve and had better potential for widespread application.展开更多
Objective To evaluate the therapeutic potential and underlying mechanism of Latakaranja vati(LV)in dehydroepiandrosterone(DHEA)-induced polycystic ovarian syndrome(PCOS)in female Wistar rats through integrated network...Objective To evaluate the therapeutic potential and underlying mechanism of Latakaranja vati(LV)in dehydroepiandrosterone(DHEA)-induced polycystic ovarian syndrome(PCOS)in female Wistar rats through integrated network pharmacology,molecular docking,and experimental validation.Methods Bioactive constituents in LV tablets were identified using liquid chromatographymass spectrometry(LC-MS).Network pharmacology analysis was performed to predict LVrelated targets and PCOS-associated genes using BindingDB,Super-PRED,GeneCards,and DisGeNET databases.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were conducted to clarify biological processes and signaling pathways.Molecular docking simulations evaluated binding affinities between LV phytoconstituents and key predicted targets.For in vivo validation,PCOS was induced in 36 female Wistar rats by daily subcutaneous administration of DHEA(60 mg/kg)for 21 d,and after successful model establishment,rats were randomly divided into DHEA,metformin(MET),clomiphene citrate(CC),and LV low-dose(LV-L,51.5 mg/kg),medium-dose(LV-M,103 mg/kg),and high-dose(LV-H,206 mg/kg)groups(n=6 each),which were orally administered for 21 d,respectively.Additional 6 rats were kept as normal control(NC)group,which did not receive any DHEA treatment.Estrous cyclicity,body weight,ovarian weight and diameter,fasting blood glucose(FBG),serum hormones[testosterone,progesterone,estrogen,follicle-stimulating hormone(FSH),luteinizing hormone(LH),and anti-Müllerian hormone(AMH)],insulin resistance[homeostatic model assessment for insulin resistance(HOMAIR)],lipid profile[total cholesterol(TC),triglycerides(TG),high-density lipoprotein(HDL),and low-density lipoprotein(LDL)],inflammatory cytokines[tumor necrosis factor(TNF)-αand interleukin(IL)-6],oxidative stress markers[superoxide dismutase(SOD),catalase(CAT),glutathione peroxidase(GPx),malondialdehyde(MDA),and nitric oxide(NO)],myeloperoxidase(MPO),and ovarian histopathology were evaluated.Results LC-MS analysis identified eight major phytoconstituents in LV:sitosterol,citrulline,bonducellin,oleic acid,δ-caesalpin,heptocosane,palmitic acid,and stearic acid.Network pharmacology revealed 36 overlapping targets between LV and PCOS,with key targets including estrogen receptor 1(ESR1),nuclear receptor subfamily 3 group C member 1(NR3C1),signal transducer and activator of transcription 3(STAT3),and epidermal growth factor receptor(EGFR).GO and KEGG enrichment analyses indicated involvement in lipid metabolism regulation,steroid hormone receptor activity,prolactin signaling pathway,hypoxia-inducible factor(HIF)-1 signaling pathway,and insulin resistance pathways.Molecular docking demonstrated strong binding affinities between LV phytoconstituents and predicted targets,with sitosterol showing the strongest binding to EGFR(−9.9 kcal/mol)and ESR1(−8.3 kcal/mol).In vivo experiments confirmed that LV treatment restored normal estrous cyclicity and significantly reduced body weight,ovarian weight,and ovarian diameter compared with DHEA group(P<0.05,P<0.01,or P<0.001).LV dose-dependently restored FBG,insulin,and HOMA-IR levels(P<0.01 or P<0.001),and improved lipid profile,including reduced TC,TG,and LDL,and increased HDL(P<0.05,P<0.01,or P<0.001).Hormonal abnormalities were corrected with testosterone,LH,and AMH decreased and progesterone,estrogen,and FSH increased(P<0.05,P<0.01,or P<0.001).Furthermore,LV enhanced activities of antioxidant enzymes(SOD,CAT,and GPx),and reduced oxidative stress markers(MDA and NO)(P<0.05,P<0.01,or P<0.001).Pro-inflammatory cytokines TNF-αand IL-6 were significantly suppressed,and MPO activity decreased compared with DHEA group(P<0.05,P<0.01,or P<0.001).Histopathological examination showed that after LV treatment,ovarian morphology recovered with cystic follicles decreased and corpus luteum increased.Among the three LV-treated groups,LV-H group exhibited the most pronounced improvements across all parameters,indicating a clear dose-dependent therapeutic effects.Conclusion LV showed protective effects against DHEA-induced pcos by restoring endocrine balance and mitigating metabolic,oxidative,and inflammatory disturbances.The involvement of key regulatory targets,including ESR1,NR3C1,STAT3,and EGFR,supports its multi-target therapeutic potential.These findings highlight LV as a promising herbal candidate for polycystic ovarian syndrome management.展开更多
Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.Ho...Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.展开更多
AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyse...AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.展开更多
BACKGROUND:This study aims to develop and validate a machine learning-based in-hospital mortality predictive model for acute aortic syndrome(AAS)in the emergency department(ED)and to derive a simplifi ed version suita...BACKGROUND:This study aims to develop and validate a machine learning-based in-hospital mortality predictive model for acute aortic syndrome(AAS)in the emergency department(ED)and to derive a simplifi ed version suitable for rapid clinical application.METHODS:In this multi-center retrospective cohort study,AAS patient data from three hospitals were analyzed.The modeling cohort included data from the First Affiliated Hospital of Zhengzhou University and the People’s Hospital of Xinjiang Uygur Autonomous Region,with Peking University Third Hospital data serving as the external test set.Four machine learning algorithms—logistic regression(LR),multilayer perceptron(MLP),Gaussian naive Bayes(GNB),and random forest(RF)—were used to develop predictive models based on 34 early-accessible clinical variables.A simplifi ed model was then derived based on fi ve key variables(Stanford type,pericardial eff usion,asymmetric peripheral arterial pulsation,decreased bowel sounds,and dyspnea)via Least Absolute Shrinkage and Selection Operator(LASSO)regression to improve ED applicability.RESULTS:A total of 929 patients were included in the modeling cohort,and 210 were included in the external test set.Four machine learning models based on 34 clinical variables were developed,achieving internal and external validation AUCs of 0.85-0.90 and 0.73-0.85,respectively.The simplifi ed model incorporating fi ve key variables demonstrated internal and external validation AUCs of 0.71-0.86 and 0.75-0.78,respectively.Both models showed robust calibration and predictive stability across datasets.CONCLUSION:Both kinds of models were built based on machine learning tools,and proved to have certain prediction performance and extrapolation.展开更多
Background:“Qi deficiency”(a pathological state where the body’s vital energy(Qi)is insufficient or weakened,impairing physiological functions and diminishing the body’s ability to perform daily activities,defend ...Background:“Qi deficiency”(a pathological state where the body’s vital energy(Qi)is insufficient or weakened,impairing physiological functions and diminishing the body’s ability to perform daily activities,defend against illness,and maintain homeostasis)syndrome is considered a critical syndrome in traditional Chinese medicine(TCM)and is associated with poor prognosis in heart failure(HF).This study investigates the clinical,metabolic,and transcriptomic differences between heart failure patients with and without Qi deficiency syndrome.Methods:56 heart failure patients were evaluated using a Qi deficiency syndrome scale and divided into Qi deficiency syndrome(QD)and non-Qi deficiency(non-QD)groups based on the median score.Clinical characteristics,including baseline N-terminal pro-B-type natriuretic peptide(NT-proBNP),left ventricular ejection fraction(LVEF),total diuretic use during hospitalization,and 90-day rehospitalization rates,were compared between the groups.Differentially expressed genes(DEGs)and differential metabolites were identified,followed by enrichment analyses and validation using qPCR and Western blot in AC16 cardiomyocytes.Results:QD patients exhibited significantly higher NT-proBNP levels,lower LVEF,and increased 90-day rehospitalization rates.Metabolomic profiling revealed lipid metabolism disruptions,notably in linoleic acid and phospholipid pathways.Transcriptomic analysis highlighted 17 DEGs,including CISD2,a critical mitochondrial regulator,which was downregulated in QD patients.Correlation analysis identified significant associations between DEGs(e.g.,CISD2,BPGM)and lipid metabolites such as PC(16:0/P-16:0).Functional knockdown of CISD2 in AC16 cells led to upregulation of lipid oxidation enzymes ALOX15 and CYP1A2,linking CISD2 dysfunction to lipid metabolic dysregulation.Conclusion:Qi deficiency is associated with more severe heart failure symptoms,worse prognosis,and distinct metabolic and transcriptomic profiles,particularly in lipid metabolism.CISD2 emerges as a potential therapeutic target,offering new avenues for integrating molecular insights with TCM approaches to optimize HF management.展开更多
Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chron...Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).展开更多
Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genoty...Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS(MEARDS),the Molecular Epidemiology of Sepsis in the ICU(MESSI),and the Molecular Diagnosis and Risk Stratification of Sepsis(MARS)cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls.First,we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression(GReX).Second,we examined the association of the confirmed gene(interferon regulatory factor 1,IRF1)with ARDS risk and survival and conducted a mediation analysis.Through discovery and validation,we found that the GReX of IRF1 was associated with ARDS risk(odds ratio[OR_(MEARDS)]=0.84,P=0.008;OR_(MESSI)=0.83,P=0.034).Furthermore,individual-level measured IRF1 expression was associated with reduced ARDS risk(OR=0.58,P=8.67×10^(-4)),and improved overall survival in ARDS patients(hazard ratio[HR_(28-day)]=0.49,P=0.009)and sepsis patients(HR_(28-day)=0.76,P=0.008).Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex,including HLA-F,which mediated more than 70%of protective effects of IRF1 on ARDS.The findings were validated by in vitro biological experiments including time-series infection dynamics,overexpression,knockout,and chromatin immunoprecipitation sequencing.Early prophylactic interventions to activate IRF1 in sepsis patients,thereby regulating HLA-F,may reduce the risk of ARDS and mortality,especially in severely ill patients.展开更多
BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to th...BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to the Hungarian population.METHODS This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP(aFAP).Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes.To identify larger deletions and insertions,a multiplex amplifiable probe hybridization technique was used.The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines.RESULTS A total of 26 index patients with clinically suspected FAP(n=21)and aFAP(n=5)were enrolled.APC gene alterations were confirmed in 92.31%of the cases(region 1B deletion,n=2;whole-gene deletion,n=4;frameshift mutation,n=2;nonsense mutation,n=5,and splice mutation,n=1),with the remaining two cases having CHEK2 and MSH3 gene alterations.According to pathogenicity,21 cases had pathogenic mutations,6 cases had likely pathogenic mutations,and 16 cases had variants of unknown significance(VUS).The most frequent of the latter were the POLE(n=5)and PIEZO1(n=4)gene variants.CONCLUSION Germline mutations in the APC gene were confirmed in more than 90%of Hungarian patients with clinically suspected FAP.Although the role of VUS genes is unclear,they are highly likely to play a role in the development of CRC.展开更多
Objective To address the dual challenges of long-tail distribution and feature sparsity in traditional Chinese medicine(TCM)syndrome differentiation within real clinical settings,we propose a data-efficient learning f...Objective To address the dual challenges of long-tail distribution and feature sparsity in traditional Chinese medicine(TCM)syndrome differentiation within real clinical settings,we propose a data-efficient learning framework enhanced by knowledge graphs.Methods We developed Agent-GNN,a three-stage decoupled learning framework,and validated it on the Traditional Chinese Medicine Syndrome Diagnosis(TCM-SD)dataset containing 54152 clinical records across 148 syndrome categories.First,we constructed a comprehensive medical knowledge graph encoding the complete TCM reasoning system.Second,we proposed a Functional Patient Profiling(FPP)method that utilizes large language models(LLMs)combined with Graph Retrieval-Augmented Generation(RAG)to extract structured symptom-etiology-pathogenesis subgraphs from medical records.Third,we employed heterogeneous graph neural networks to learn structured combination patterns explicitly.We compared our method against multiple baselines including BERT,ZY-BERT,ZY-BERT+Know,GAT,and GPT-4 Few-shot,using macro-F1 score as the primary evaluation metric.Additionally,ablation experiments were conducted to validate the contribution of each key component to model performance.Results Agent-GNN achieved an overall macro-F1 score of 72.4%,representing an 8.7 percentage points improvement over ZY-BERT+Know(63.7%),the strongest baseline among traditional methods.For long-tail syndromes with fewer than 10 samples,Agent-GNN reached a macro-F1 score of 58.6%,compared with 39.3%for ZY-BERT+Know and 41.2%for GPT-4 Few-shot,representing relative improvements of 49.2%and 42.2%,respectively.Ablation experiments confirmed that the explicit modeling of etiology-pathogenesis nodes contributed 12.4 percentage points to this enhanced long-tail syndrome performance.Conclusion This study proposes Agent-GNN,a knowledge graph-enhanced framework that effectively addresses the long-tail distribution challenge in TCM syndrome differentiation.By explicitly modeling manifestation-mechanism-essence patterns through structured knowledge graphs,our approach achieves superior performance in data-scarce scenarios while providing interpretable reasoning paths for TCM intelligent diagnosis.展开更多
BACKGROUND:Individualized positive end-expiratory pressure(PEEP)titration is a crucial technique in mechanical ventilation therapy for acute respiratory distress syndrome(ARDS)patients with intra-abdominal hypertensio...BACKGROUND:Individualized positive end-expiratory pressure(PEEP)titration is a crucial technique in mechanical ventilation therapy for acute respiratory distress syndrome(ARDS)patients with intra-abdominal hypertension(IAH).This study aimed to evaluate the eff ectiveness of electrical impedance tomography(EIT)-guided PEEP titration in this population.METHODS:This prospective study enrolled 36 ARDS patients,including 22 patients with IAH and 14 without IAH.All the patients underwent EIT-guided PEEP titration at the intersection point between alveolar overdistension and collapse during a decremental PEEP trial.The changes in pulmonary ventilation distribution,respiratory mechanics and hemodynamics during the titration process were observed.RESULTS:After EIT-guided PEEP titration was performed,the PEEP,peak inspiratory pressure and plateau pressure increased significantly(P<0.05).Furthermore,no significant differences were observed in respiratory system compliance,tidal volume,driving pressure,or the 4*DP+RR index between the two groups(P>0.05).The mechanical power increased in the non-IAH(NIAH)group after PEEP titration(P<0.05).Ventilation in gravity-dependent lung regions significantly increased(P<0.05),and the oxygenation index(PaO2/FiO2)improved signifi cantly(P<0.05)in both groups.However,blood pressure,heart rate,respiratory rate,central venous pressure,and lactate levels did not signifi cantly change.In the IAH group,the PaO2/FiO2 ratio improved less than that in the NIAH group did(P<0.05).CONCLUSION:In our study,individualized PEEP titration guided by EIT improved oxygenation in ARDS patients with concomitant IAH without signifi cantly aff ecting hemodynamics.The presence of IAH may limit the improvement of oxygenation during EIT-guided PEEP titration.展开更多
Objective Patients with atherosclerotic cardiovascular disease(ASCVD)following percutaneous coronary intervention(PCI)are classified as very-high-risk individuals in cardiovascular disease(CVD)risk stratification.The ...Objective Patients with atherosclerotic cardiovascular disease(ASCVD)following percutaneous coronary intervention(PCI)are classified as very-high-risk individuals in cardiovascular disease(CVD)risk stratification.The distribution pattern of traditional Chinese medicine(TCM)syndromes in this patient population,as well as its association with blood lipid profiles and clinical prognosis,remains unclear.The present prospective cohort study aims to investigate these correlations,thereby providing insights to enrich the research fields.Methods We enrolled consecutive patients with ASCVD who underwent PCI at the Integrated Cardiology Unit of China-Japan Friendship Hospital between September 1,2020 and December 31,2022.Demographics and clinical characteristics,signs and symptoms defining each TCM syndrome,and fasting venous blood samples were collected at baseline and follow up or upon major adverse cardiovascular events(MACEs).We analyzed the correlation between TCM syndromes,blood lipid profiles,and MACEs,and developed a new joint prognostic model incorporating both TCM syndromes and blood lipids using logistic regression.The analyses were based on detailed baseline and one-year follow-up data.Results A per-protocol analysis was performed on 586 patients with complete data ultimately.During the one-year follow-up,174 patients(29.69%)experienced a MACE.We performed statistical analyses on comorbidities,medication,and biochemical indicators across groups defined by TCM syndrome differentiation.When comparing different TCM syndromes,no significant differences were found in age,body mass index(BMI),history of revascularization,comorbidities,family history of CVD,smoking or drinking,or statin intensity(P>0.05).Patients with intertwined phlegm and blood stasis syndrome exhibited significantly higher levels of total cholesterol(TC,5.27±1.18 mmol/L,P<0.001),triglyceride(TG,1.96±1.33 mmol/L,P=0.008),low-density lipoprotein cholesterol(LDL-C,3.35±0.79 mmol/L,P<0.001),and high-density lipoprotein cholesterol(HDL-C,1.24±0.81 mmol/L,P<0.001)compared with those with other TCM syndromes combined.A multivariable logistic regression model was constructed to predict MACEs.The model included TCM syndrome type[with intertwined phlegm and blood stasis as a predictor,adjusted odds ratio(OR)=1.413,95%confidence interval(CI):0.517–3.864,P=0.501],age(adjusted OR=0.97,95%CI:0.955–1.001,P=0.057),male gender(adjusted OR=0.698,95%CI:0.416–1.170,P=0.173),TC(adjusted OR=1.004,95%CI:0.513–1.965,P=0.990),and LDL-C(adjusted OR=5.825,95%CI:2.214–15.326,P<0.001).This model demonstrated good discriminatory ability for MACEs in post-PCI ASCVD patients[the area under the receiver operating characteristic(ROC)curve(AUC)=0.865,95%CI:0.816–0.914].Conclusion The intertwined phlegm and blood stasis TCM syndrome is associated with a distinct atherogenic lipid profile characterized by elevated levels of TC and LDL-C.The prognostic model that incorporates this TCM syndrome type along with conventional lipid parameters(TC and LDL-C)shows good discriminatory ability for predicting MACEs in ASCVD patients after PCI,underscoring the potential clinical utility of integrating TCM syndrome differentiation into CVD risk assessment.展开更多
Background:Humanized mouse models are essential for studying the human immune response and antibody development.However,conventional models show limited B cell maturation and antigen-specific humoral responses.To over...Background:Humanized mouse models are essential for studying the human immune response and antibody development.However,conventional models show limited B cell maturation and antigen-specific humoral responses.To overcome these limitations,we used the NOG-EXL mice expressing human interleukin 3(IL-3)and granulocyte-macrophage colony-stimulating factor(GM-CSF)to enhance myeloid and B-cell lineage differentiation.Methods:Human CD34^(+)hematopoietic stem cells(HSC)were transplanted into NOG-EXL mice to produce humanized immune systems.After immune cell reconstitution was confirmed across 12 weeks,the mice were immunized twice with inactivated severe fever with thrombocytopenia syndrome virus(SFTSV)antigens.Peripheral blood mononuclear cells and splenocytes were analyzed using multicolor flow cytometry to assess human immune cell subsets.Antigen-specific immunoglobulin G(IgG)production was quantified using enzyme-linked immunosorbent assay(ELISA),and virus-specific B cells were isolated using antigen-labeled recombinant protein probes.Results:Twelve weeks after transplantation of HSCs into NOG-EXL mice,they exhibited robust engraftment of human leukocytes,including T,B,and dendritic cells,compared to NOG mice.Unlike NOG mice,humanized NOG-EXL mice exhibited an increase in human IgG levels,indicating the production of human antibody responses to antigens.Humanized NOG-EXL mice were immunized twice every 2 weeks with inactivated SFTSV,and antigen-specific human antibodies against the virus were detected in the mouse sera by ELISA.Sera from SFTSV-immunized humanized mice demonstrated neutralizing activity against SFTSV,confirming the induction of functional virus-specific neutralizing antibodies.Antigen-binding IgG-positive human B cells were isolated from mouse splenocytes using recombinant protein probes.Conclusion:This model provides a valuable platform for evaluating humoral immunity and isolating B cells using high-affinity human monoclonal antibodies without genetic engineering.展开更多
It is challenging to diagnose isolated hyperbilirubinemia with rare and complex etiologies under the constraints of traditional testing conditions.Herein,we present a rare case of coexisting Gilbert syndrome(GS)and er...It is challenging to diagnose isolated hyperbilirubinemia with rare and complex etiologies under the constraints of traditional testing conditions.Herein,we present a rare case of coexisting Gilbert syndrome(GS)and erythropoietic protoporphyria(EPP),which has not been previously documented.CASE SUMMARY We present a rare case of coexisting GS and EPP in a 23-year-old Chinese male with a long history of jaundice and recently found splenomegaly.Serial nonspecific hemolysis screening tests yielded inconsistent results,and investigations for common hemolytic etiologies were negative.However,Levitt’s carbon monoxide breath test,which measures erythrocyte lifespan(the gold-standard marker of hemolysis),demonstrated significant hemolysis,revealing a markedly shortened erythrocyte lifespan of 11 days(normal average 120 days).Genetic testing subsequently confirmed EPP with a homozygous ferrochelatase gene mutation and GS with a heterozygous uridine diphosphate glucuronosyl trans-ferase 1A1 gene mutation.CONCLUSION The rapid,non-invasive Levitt’s carbon monoxide breath test resolved the diagnostic challenge posed by a rare and complex cause of hyperbilirubinemia.展开更多
Background:Panacis Quinquefolii Radix(PQR)is known for its ability to nourish“Qi”(it serves as the driving force for the functional activities of the body’s organs and meridians,promoting and regulating various phy...Background:Panacis Quinquefolii Radix(PQR)is known for its ability to nourish“Qi”(it serves as the driving force for the functional activities of the body’s organs and meridians,promoting and regulating various physiological functions)and“Yin”(it represents the material foundation of the human body.It plays a role in nourishing,moistening,and cooling the body).Notoginseng Radix et Rhizoma(NRR)is recognized for its properties of resolving blood stasis(it refers to a pathological condition characterized by impaired or stagnant blood circulation within the body).Changes in the compatibility ratio of these herbs often lead to variations in their chemical composition and efficacy.However,the specific alterations in chemical composition and efficacy resulting from compatibility adjustments remain unclear.We aimed to compare the material basis and their effects of different compatibility ratios of PQR and NRR on“Qi”deficiency and blood stasis syndrome(QBS).Methods:This study employed UPLC-Q/TOF-MS to identify effective compounds in the compatibility of PQR and NRR and utilized UPLC-TQ-MS/MS to analyze the dissolution of 16 saponins in PQR and NRR at 9 different ratios.A rat model of QBS was established,and the efficacy of PQR and NRR in treating this syndrome was assessed using hemorheology and coagulation analyses.Results:The study results show that PQR and NRR exhibit significant efficacy,effectively reducing blood viscosity induced by platelet aggregation and lowering inflammatory markers such as IL-6,IL-10,TXB2 and ET associated with vascular injury.Moreover,this combination regulates ATP and ADP levels,enhances energy metabolism,and promotes overall health.A total of 104 compounds in the compatibility of PQR and NRR were identified.The ratios of 1:2 and 1:3 showed the highest total saponin content,but the ratio of 1:1 demonstrated a superior pharmacological effect for the treatment of QBS.Conclusion:In summary,the compatibility of PQR and NRR not only shows the complex interactions between traditional Chinese medicinal materials,but also provides a new idea and method for the treatment of QBS.展开更多
Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal ce...Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.展开更多
BACKGROUND Phelan-McDermid syndrome(PMS)is a rare genetic disorder characterized by intellectual disability,delayed language development,autism spectrum disorders,motor tone abnormalities,and a high risk of psychiatri...BACKGROUND Phelan-McDermid syndrome(PMS)is a rare genetic disorder characterized by intellectual disability,delayed language development,autism spectrum disorders,motor tone abnormalities,and a high risk of psychiatric symptoms,including bipolar disorder.CASE SUMMARY This report presented an 18-year clinical history of a 36-year-old woman with PMS,marked by intellectual disabilities,social withdrawal,and stereotyped behaviors.Diagnosed with bipolar disorder at the age of 18 years old,she encountered significant treatment challenges,including severe adverse reactions to antipsychotic medications in 2022,which led to speech and functional regression.Through rehabilitation and comprehensive therapy,her condition gradually improved.In 2024,after further treatment,her symptoms stabilized,highlighting the complexities and successes of long-term management.CONCLUSION Effective management of PMS requires a thorough clinical history,genetic testing,and long-term supportive care.展开更多
基金supported by the National Natural Science Foundation of China(No.82471229)Science and Technology Collaborative Innovation Fund of Fujian Province(No.2021Y9172)the Natural Science Foundation of Fujian Province,China(No.2023J01169)。
文摘Oxytocin has been found to modulate and improve pain in humans,but the mechanisms underlying these antinociceptive properties,especially in visceral hypersensitivity,are still unclear.Irritable bowel syndrome(IBS)models were established by colorectal distention in newborn rats aged 8 to 14 days,and visceral hypersensitivity was assessed using electromyogram(EMG).Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats.The protein expressions of oxytocin receptor(OTR),γ-aminobutyric acid type B1 receptor(GABAB1),and transient receptor potential vanilloid 1(TRPV1)in the lumbosacral spinal cord regions were measured.IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression.Intrathecal oxytocin treatment not only normalized these molecular alterations(increasing GABAB1 while decreasing TRPV1)but also ameliorated visceral pain behaviors.Crucially,this therapeutic effect was fully reversed by GABAB1 inhibition,establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia.Collectively,these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.
文摘Severe acute pancreatitis(SAP)can induce acute respiratory distress syndrome(ARDS)and abdominal compartment syndrome(ACS).Although prone position ventilation(PPV)can improve outcomes in patients with ARDS,there is significant controversy regarding its concurrent use with ACS owing to concerns of increased risk of intra-abdominal pressure(IAP).[1]We present a case of successful PPV application without adverse eff ects.
基金Supported by Ongoing Research Funding Program(ORFFT-2025-054-1),King Saud University,Riyadh,Saudi Arabia.
文摘AIM:To evaluate the efficacy of the total computer vision syndrome questionnaire(CVS-Q)score as a predictive tool for identifying individuals with symptomatic binocular vision anomalies and refractive errors.METHODS:A total of 141 healthy computer users underwent comprehensive clinical visual function assessments,including evaluations of refractive errors,accommodation(amplitude of accommodation,positive relative accommodation,negative relative accommodation,accommodative accuracy,and accommodative facility),and vergence(phoria,positive and negative fusional vergence,near point of convergence,and vergence facility).Total CVS-Q scores were recorded to explore potential associations between symptom scores and the aforementioned clinical visual function parameters.RESULTS:The cohort included 54 males(38.3%)with a mean age of 23.9±0.58y and 87 age-matched females(61.7%)with a mean age of 23.9±0.53y.The multiple regression model was statistically significant[R²=0.60,F=13.28,degrees of freedom(DF=17122,P<0.001].This indicates that 60%of the variance in total CVS-Q scores(reflecting reported symptoms)could be explained by four clinical measurements:amplitude of accommodation,positive relative accommodation,exophoria at distance and near,and positive fusional vergence at near.CONCLUSION:The total CVS-Q score is a valid and reliable tool for predicting the presence of various nonstrabismic binocular vision anomalies and refractive errors in symptomatic computer users.
文摘Objective:To investigate the clinical efficacy of electrophysiological therapy under different parameter modes in chronic pelvic pain syndrome(CPPS).Methods:A total of 95patients with CPPS from the Department of Urology,First Affiliated Hospital of Jinan University,were selected and treated with electrophysiological therapy.They were randomly divided into three groups:the fixed-parameter AA7 treatment group,the P2+P4 treatment group,and the precision treatment group(individualized parameter treatment).Pain scores of patients in each group were compared before and after treatment,with a pain score of 0 indicating cure.The cure rate of each group was observed.Results:The average ages of the AA7 group,P2+P4 group,and precision treatment group were 34±14.17 years,35.58±12.57 years,and 35.5±11.27 years,respectively.There was no significant difference in age among the three groups(p>0.05).Before treatment,the pain scores of the AA7 group,P2+P4 group,and precision treatment group were 4.14±1.74,4.64±1.72,and 3.50±1.89,respectively,with no significant differences among the groups(p>0.05).After treatment,the pain scores were 0.71±0.99 for the AA7 group(cure rate:57%),0.49±0.79 for the P2+P4 group(cure rate:67%),and 0.50±0.77 for the precision treatment group(cure rate:64%),with no significant differences among the groups(p>0.05).The cure rates for different pain locations were as follows:83%for lower abdominal pain,74%for perineal pain,62%for dysuria,49%for testicular pain,and 75%for inguinal pain.Conclusion:The pathogenesis of CPPS is complex and diverse,with numerous treatment options and uncertain efficacy,posing significant challenges to clinical practice.This study showed that electrophysiological therapy under different parameter modes significantly reduced pain scores before and after treatment,indicating significant therapeutic effects on CPPS.All three modes demonstrated good cure rates.Individualized precision treatment and fixed-mode P2+P4 or AA7 treatment were safe and effective in CPPS treatment and are worth promoting.Fixed-mode P2+P4 and AA7,due to their easier standardization of parameters and patch modes,reduced the learning curve and had better potential for widespread application.
文摘Objective To evaluate the therapeutic potential and underlying mechanism of Latakaranja vati(LV)in dehydroepiandrosterone(DHEA)-induced polycystic ovarian syndrome(PCOS)in female Wistar rats through integrated network pharmacology,molecular docking,and experimental validation.Methods Bioactive constituents in LV tablets were identified using liquid chromatographymass spectrometry(LC-MS).Network pharmacology analysis was performed to predict LVrelated targets and PCOS-associated genes using BindingDB,Super-PRED,GeneCards,and DisGeNET databases.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses were conducted to clarify biological processes and signaling pathways.Molecular docking simulations evaluated binding affinities between LV phytoconstituents and key predicted targets.For in vivo validation,PCOS was induced in 36 female Wistar rats by daily subcutaneous administration of DHEA(60 mg/kg)for 21 d,and after successful model establishment,rats were randomly divided into DHEA,metformin(MET),clomiphene citrate(CC),and LV low-dose(LV-L,51.5 mg/kg),medium-dose(LV-M,103 mg/kg),and high-dose(LV-H,206 mg/kg)groups(n=6 each),which were orally administered for 21 d,respectively.Additional 6 rats were kept as normal control(NC)group,which did not receive any DHEA treatment.Estrous cyclicity,body weight,ovarian weight and diameter,fasting blood glucose(FBG),serum hormones[testosterone,progesterone,estrogen,follicle-stimulating hormone(FSH),luteinizing hormone(LH),and anti-Müllerian hormone(AMH)],insulin resistance[homeostatic model assessment for insulin resistance(HOMAIR)],lipid profile[total cholesterol(TC),triglycerides(TG),high-density lipoprotein(HDL),and low-density lipoprotein(LDL)],inflammatory cytokines[tumor necrosis factor(TNF)-αand interleukin(IL)-6],oxidative stress markers[superoxide dismutase(SOD),catalase(CAT),glutathione peroxidase(GPx),malondialdehyde(MDA),and nitric oxide(NO)],myeloperoxidase(MPO),and ovarian histopathology were evaluated.Results LC-MS analysis identified eight major phytoconstituents in LV:sitosterol,citrulline,bonducellin,oleic acid,δ-caesalpin,heptocosane,palmitic acid,and stearic acid.Network pharmacology revealed 36 overlapping targets between LV and PCOS,with key targets including estrogen receptor 1(ESR1),nuclear receptor subfamily 3 group C member 1(NR3C1),signal transducer and activator of transcription 3(STAT3),and epidermal growth factor receptor(EGFR).GO and KEGG enrichment analyses indicated involvement in lipid metabolism regulation,steroid hormone receptor activity,prolactin signaling pathway,hypoxia-inducible factor(HIF)-1 signaling pathway,and insulin resistance pathways.Molecular docking demonstrated strong binding affinities between LV phytoconstituents and predicted targets,with sitosterol showing the strongest binding to EGFR(−9.9 kcal/mol)and ESR1(−8.3 kcal/mol).In vivo experiments confirmed that LV treatment restored normal estrous cyclicity and significantly reduced body weight,ovarian weight,and ovarian diameter compared with DHEA group(P<0.05,P<0.01,or P<0.001).LV dose-dependently restored FBG,insulin,and HOMA-IR levels(P<0.01 or P<0.001),and improved lipid profile,including reduced TC,TG,and LDL,and increased HDL(P<0.05,P<0.01,or P<0.001).Hormonal abnormalities were corrected with testosterone,LH,and AMH decreased and progesterone,estrogen,and FSH increased(P<0.05,P<0.01,or P<0.001).Furthermore,LV enhanced activities of antioxidant enzymes(SOD,CAT,and GPx),and reduced oxidative stress markers(MDA and NO)(P<0.05,P<0.01,or P<0.001).Pro-inflammatory cytokines TNF-αand IL-6 were significantly suppressed,and MPO activity decreased compared with DHEA group(P<0.05,P<0.01,or P<0.001).Histopathological examination showed that after LV treatment,ovarian morphology recovered with cystic follicles decreased and corpus luteum increased.Among the three LV-treated groups,LV-H group exhibited the most pronounced improvements across all parameters,indicating a clear dose-dependent therapeutic effects.Conclusion LV showed protective effects against DHEA-induced pcos by restoring endocrine balance and mitigating metabolic,oxidative,and inflammatory disturbances.The involvement of key regulatory targets,including ESR1,NR3C1,STAT3,and EGFR,supports its multi-target therapeutic potential.These findings highlight LV as a promising herbal candidate for polycystic ovarian syndrome management.
基金supported by the Fundamental Research Funds for the Central Universities(226-2022-00035)the National Natural Science Foundation of China(81600986).
文摘Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.
文摘AIM:To investigate the genetic basis of Weill-Marchesani syndrome(WMS)in a Chinese family and clarify the pathogenic mechanism of novel ADAMTS17 mutations.METHODS:Comprehensive clinical assessments and genetic analyses were performed on a Chinese family with two affected siblings.Whole-exome sequencing(WES)was conducted for the proband and other family members.Bioinformatics tools were used to evaluate the conservation,predicted pathogenicity,and structural effects of the identified ADAMTS17 variants.In addition,protein structure modeling was applied to assess the functional impacts of the mutations.RESULTS:The proband(a 32-year-old male)and his elder sister(42y)presented typical clinical features of WMS,including short stature,brachydactyly,high myopia,ectopia lentis,and secondary glaucoma.WES identified a novel compound heterozygous mutation in ADAMTS17:a splicing mutation(c.451-2A>G)inherited from the father and a missense mutation(c.1043G>A;p.C348Y)inherited from the mother.The splicing mutation disrupted normal mRNA splicing and processing,leading to premature translation termination.The missense mutation,which is located in the metalloprotease catalytic domain,was predicted to abolish a critical disulfide bond,thereby impairing protein stability.Both mutations exhibited high evolutionary conservation and were predicted to be pathogenic by multiple bioinformatics algorithms.CONCLUSION:A novel compound heterozygous mutation in ADAMTS17 is identified in this WMS-affected Chinese family,and its pathogenicity is verified via bioinformatics analysis and protein structural modeling.These findings are expected to facilitate the genetic diagnosis of WMS and deepen the understanding of its molecular pathogenesis.
基金supported by the special fund of the National Clinical Key Specialty Construction Program[(2022)301-2305].
文摘BACKGROUND:This study aims to develop and validate a machine learning-based in-hospital mortality predictive model for acute aortic syndrome(AAS)in the emergency department(ED)and to derive a simplifi ed version suitable for rapid clinical application.METHODS:In this multi-center retrospective cohort study,AAS patient data from three hospitals were analyzed.The modeling cohort included data from the First Affiliated Hospital of Zhengzhou University and the People’s Hospital of Xinjiang Uygur Autonomous Region,with Peking University Third Hospital data serving as the external test set.Four machine learning algorithms—logistic regression(LR),multilayer perceptron(MLP),Gaussian naive Bayes(GNB),and random forest(RF)—were used to develop predictive models based on 34 early-accessible clinical variables.A simplifi ed model was then derived based on fi ve key variables(Stanford type,pericardial eff usion,asymmetric peripheral arterial pulsation,decreased bowel sounds,and dyspnea)via Least Absolute Shrinkage and Selection Operator(LASSO)regression to improve ED applicability.RESULTS:A total of 929 patients were included in the modeling cohort,and 210 were included in the external test set.Four machine learning models based on 34 clinical variables were developed,achieving internal and external validation AUCs of 0.85-0.90 and 0.73-0.85,respectively.The simplifi ed model incorporating fi ve key variables demonstrated internal and external validation AUCs of 0.71-0.86 and 0.75-0.78,respectively.Both models showed robust calibration and predictive stability across datasets.CONCLUSION:Both kinds of models were built based on machine learning tools,and proved to have certain prediction performance and extrapolation.
基金supported by the Sanming Project of Medicine in Shenzhen[SZZYSM202206001]National Natural Science Foundation of China[82004320 and 82374383]+3 种基金Natural Science Foundation of Guangdong Province of China[2022A1515011710 and 2022A1515010679]Shenzhen Science and Technology Innovation Committee[JCYJ20220530141407017 and JCYJ20240813153619026]2024 High-quality Development Research Project of Shenzhen Bao’an Public Hospital[YNXM2024078]and Shenzhen Bao’an Chinese Medicine Hospital Research Program[BAZYY20220702].
文摘Background:“Qi deficiency”(a pathological state where the body’s vital energy(Qi)is insufficient or weakened,impairing physiological functions and diminishing the body’s ability to perform daily activities,defend against illness,and maintain homeostasis)syndrome is considered a critical syndrome in traditional Chinese medicine(TCM)and is associated with poor prognosis in heart failure(HF).This study investigates the clinical,metabolic,and transcriptomic differences between heart failure patients with and without Qi deficiency syndrome.Methods:56 heart failure patients were evaluated using a Qi deficiency syndrome scale and divided into Qi deficiency syndrome(QD)and non-Qi deficiency(non-QD)groups based on the median score.Clinical characteristics,including baseline N-terminal pro-B-type natriuretic peptide(NT-proBNP),left ventricular ejection fraction(LVEF),total diuretic use during hospitalization,and 90-day rehospitalization rates,were compared between the groups.Differentially expressed genes(DEGs)and differential metabolites were identified,followed by enrichment analyses and validation using qPCR and Western blot in AC16 cardiomyocytes.Results:QD patients exhibited significantly higher NT-proBNP levels,lower LVEF,and increased 90-day rehospitalization rates.Metabolomic profiling revealed lipid metabolism disruptions,notably in linoleic acid and phospholipid pathways.Transcriptomic analysis highlighted 17 DEGs,including CISD2,a critical mitochondrial regulator,which was downregulated in QD patients.Correlation analysis identified significant associations between DEGs(e.g.,CISD2,BPGM)and lipid metabolites such as PC(16:0/P-16:0).Functional knockdown of CISD2 in AC16 cells led to upregulation of lipid oxidation enzymes ALOX15 and CYP1A2,linking CISD2 dysfunction to lipid metabolic dysregulation.Conclusion:Qi deficiency is associated with more severe heart failure symptoms,worse prognosis,and distinct metabolic and transcriptomic profiles,particularly in lipid metabolism.CISD2 emerges as a potential therapeutic target,offering new avenues for integrating molecular insights with TCM approaches to optimize HF management.
基金supported by the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program(#Mason2210)to JX。
文摘Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).
基金supported by the National Natural Science Foundation of China(Grant No.82220108002 to F.C.and Grant No.82273737 to R.Z.)the U.S.National Institutes of Health(Grant Nos.CA209414,HL060710,and ES000002 to D.C.C.,Grant Nos.CA209414 and CA249096 to Y.L.)+1 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)supported by the Qing Lan Project of the Higher Education Institutions of Jiangsu Province and the Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University.
文摘Interferon-related genes are involved in antiviral responses,inflammation,and immunity,which are closely related to sepsis-associated acute respiratory distress syndrome(ARDS).We analyzed 1972 participants with genotype data and 681 participants with gene expression data from the Molecular Epidemiology of ARDS(MEARDS),the Molecular Epidemiology of Sepsis in the ICU(MESSI),and the Molecular Diagnosis and Risk Stratification of Sepsis(MARS)cohorts in a three-step study focusing on sepsis-associated ARDS and sepsis-only controls.First,we identified and validated interferon-related genes associated with sepsis-associated ARDS risk using genetically regulated gene expression(GReX).Second,we examined the association of the confirmed gene(interferon regulatory factor 1,IRF1)with ARDS risk and survival and conducted a mediation analysis.Through discovery and validation,we found that the GReX of IRF1 was associated with ARDS risk(odds ratio[OR_(MEARDS)]=0.84,P=0.008;OR_(MESSI)=0.83,P=0.034).Furthermore,individual-level measured IRF1 expression was associated with reduced ARDS risk(OR=0.58,P=8.67×10^(-4)),and improved overall survival in ARDS patients(hazard ratio[HR_(28-day)]=0.49,P=0.009)and sepsis patients(HR_(28-day)=0.76,P=0.008).Mediation analysis revealed that IRF1 may enhance immune function by regulating the major histocompatibility complex,including HLA-F,which mediated more than 70%of protective effects of IRF1 on ARDS.The findings were validated by in vitro biological experiments including time-series infection dynamics,overexpression,knockout,and chromatin immunoprecipitation sequencing.Early prophylactic interventions to activate IRF1 in sepsis patients,thereby regulating HLA-F,may reduce the risk of ARDS and mortality,especially in severely ill patients.
基金Supported by the Research Grants of the National Research,Development and Innovation Office,No.K125377,No.K134863 and No.K143549New National Excellence Program of the Ministry of Human Capacities,No.UNKP-20-5-SZTE-161,No.UNKP-22-3-SZTE-233,No.UNKP-23-5-SZTE-719,No.UNKP-22-4-SZTE-296 and No.UNKP-22-3-SZTE-278+1 种基金Janos Bolyai Research Grant,No.BO/00723/22the Géza Hetényi Research Grant by Albert Szent-Györgyi Medical School,University of Szeged.
文摘BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to the Hungarian population.METHODS This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP(aFAP).Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes.To identify larger deletions and insertions,a multiplex amplifiable probe hybridization technique was used.The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines.RESULTS A total of 26 index patients with clinically suspected FAP(n=21)and aFAP(n=5)were enrolled.APC gene alterations were confirmed in 92.31%of the cases(region 1B deletion,n=2;whole-gene deletion,n=4;frameshift mutation,n=2;nonsense mutation,n=5,and splice mutation,n=1),with the remaining two cases having CHEK2 and MSH3 gene alterations.According to pathogenicity,21 cases had pathogenic mutations,6 cases had likely pathogenic mutations,and 16 cases had variants of unknown significance(VUS).The most frequent of the latter were the POLE(n=5)and PIEZO1(n=4)gene variants.CONCLUSION Germline mutations in the APC gene were confirmed in more than 90%of Hungarian patients with clinically suspected FAP.Although the role of VUS genes is unclear,they are highly likely to play a role in the development of CRC.
基金Sichuan TCM Culture Coordinated Development Research Center Project(2023XT131)National Key Science and Technology Project of China(2023ZD0509405)National Natural Science Foundation of China(82174236).
文摘Objective To address the dual challenges of long-tail distribution and feature sparsity in traditional Chinese medicine(TCM)syndrome differentiation within real clinical settings,we propose a data-efficient learning framework enhanced by knowledge graphs.Methods We developed Agent-GNN,a three-stage decoupled learning framework,and validated it on the Traditional Chinese Medicine Syndrome Diagnosis(TCM-SD)dataset containing 54152 clinical records across 148 syndrome categories.First,we constructed a comprehensive medical knowledge graph encoding the complete TCM reasoning system.Second,we proposed a Functional Patient Profiling(FPP)method that utilizes large language models(LLMs)combined with Graph Retrieval-Augmented Generation(RAG)to extract structured symptom-etiology-pathogenesis subgraphs from medical records.Third,we employed heterogeneous graph neural networks to learn structured combination patterns explicitly.We compared our method against multiple baselines including BERT,ZY-BERT,ZY-BERT+Know,GAT,and GPT-4 Few-shot,using macro-F1 score as the primary evaluation metric.Additionally,ablation experiments were conducted to validate the contribution of each key component to model performance.Results Agent-GNN achieved an overall macro-F1 score of 72.4%,representing an 8.7 percentage points improvement over ZY-BERT+Know(63.7%),the strongest baseline among traditional methods.For long-tail syndromes with fewer than 10 samples,Agent-GNN reached a macro-F1 score of 58.6%,compared with 39.3%for ZY-BERT+Know and 41.2%for GPT-4 Few-shot,representing relative improvements of 49.2%and 42.2%,respectively.Ablation experiments confirmed that the explicit modeling of etiology-pathogenesis nodes contributed 12.4 percentage points to this enhanced long-tail syndrome performance.Conclusion This study proposes Agent-GNN,a knowledge graph-enhanced framework that effectively addresses the long-tail distribution challenge in TCM syndrome differentiation.By explicitly modeling manifestation-mechanism-essence patterns through structured knowledge graphs,our approach achieves superior performance in data-scarce scenarios while providing interpretable reasoning paths for TCM intelligent diagnosis.
基金PEEP titration in ARDS patients using EIT combined with lung ultrasound,Key Laboratory of Emergency Trauma Research,Ministry of Education (KLET-202201)airway clearance protocol in ICU mechanically ventilated patients based on electrical impedance imaging technology,Natural Science Foundation of Hunan Province (2024JJ9148)effects of end expiratory positive pressure on lung re-expansion in patients with ARDS and intra-abdominal hypertension monitored using lung ultrasound,Natural Science Foundation of Hunan Province (2023JJ60308)
文摘BACKGROUND:Individualized positive end-expiratory pressure(PEEP)titration is a crucial technique in mechanical ventilation therapy for acute respiratory distress syndrome(ARDS)patients with intra-abdominal hypertension(IAH).This study aimed to evaluate the eff ectiveness of electrical impedance tomography(EIT)-guided PEEP titration in this population.METHODS:This prospective study enrolled 36 ARDS patients,including 22 patients with IAH and 14 without IAH.All the patients underwent EIT-guided PEEP titration at the intersection point between alveolar overdistension and collapse during a decremental PEEP trial.The changes in pulmonary ventilation distribution,respiratory mechanics and hemodynamics during the titration process were observed.RESULTS:After EIT-guided PEEP titration was performed,the PEEP,peak inspiratory pressure and plateau pressure increased significantly(P<0.05).Furthermore,no significant differences were observed in respiratory system compliance,tidal volume,driving pressure,or the 4*DP+RR index between the two groups(P>0.05).The mechanical power increased in the non-IAH(NIAH)group after PEEP titration(P<0.05).Ventilation in gravity-dependent lung regions significantly increased(P<0.05),and the oxygenation index(PaO2/FiO2)improved signifi cantly(P<0.05)in both groups.However,blood pressure,heart rate,respiratory rate,central venous pressure,and lactate levels did not signifi cantly change.In the IAH group,the PaO2/FiO2 ratio improved less than that in the NIAH group did(P<0.05).CONCLUSION:In our study,individualized PEEP titration guided by EIT improved oxygenation in ARDS patients with concomitant IAH without signifi cantly aff ecting hemodynamics.The presence of IAH may limit the improvement of oxygenation during EIT-guided PEEP titration.
基金Capital Health Development Scientific Research Project(2020-2-4064)National Key Research and Development Program of China(2018YFC2002502).
文摘Objective Patients with atherosclerotic cardiovascular disease(ASCVD)following percutaneous coronary intervention(PCI)are classified as very-high-risk individuals in cardiovascular disease(CVD)risk stratification.The distribution pattern of traditional Chinese medicine(TCM)syndromes in this patient population,as well as its association with blood lipid profiles and clinical prognosis,remains unclear.The present prospective cohort study aims to investigate these correlations,thereby providing insights to enrich the research fields.Methods We enrolled consecutive patients with ASCVD who underwent PCI at the Integrated Cardiology Unit of China-Japan Friendship Hospital between September 1,2020 and December 31,2022.Demographics and clinical characteristics,signs and symptoms defining each TCM syndrome,and fasting venous blood samples were collected at baseline and follow up or upon major adverse cardiovascular events(MACEs).We analyzed the correlation between TCM syndromes,blood lipid profiles,and MACEs,and developed a new joint prognostic model incorporating both TCM syndromes and blood lipids using logistic regression.The analyses were based on detailed baseline and one-year follow-up data.Results A per-protocol analysis was performed on 586 patients with complete data ultimately.During the one-year follow-up,174 patients(29.69%)experienced a MACE.We performed statistical analyses on comorbidities,medication,and biochemical indicators across groups defined by TCM syndrome differentiation.When comparing different TCM syndromes,no significant differences were found in age,body mass index(BMI),history of revascularization,comorbidities,family history of CVD,smoking or drinking,or statin intensity(P>0.05).Patients with intertwined phlegm and blood stasis syndrome exhibited significantly higher levels of total cholesterol(TC,5.27±1.18 mmol/L,P<0.001),triglyceride(TG,1.96±1.33 mmol/L,P=0.008),low-density lipoprotein cholesterol(LDL-C,3.35±0.79 mmol/L,P<0.001),and high-density lipoprotein cholesterol(HDL-C,1.24±0.81 mmol/L,P<0.001)compared with those with other TCM syndromes combined.A multivariable logistic regression model was constructed to predict MACEs.The model included TCM syndrome type[with intertwined phlegm and blood stasis as a predictor,adjusted odds ratio(OR)=1.413,95%confidence interval(CI):0.517–3.864,P=0.501],age(adjusted OR=0.97,95%CI:0.955–1.001,P=0.057),male gender(adjusted OR=0.698,95%CI:0.416–1.170,P=0.173),TC(adjusted OR=1.004,95%CI:0.513–1.965,P=0.990),and LDL-C(adjusted OR=5.825,95%CI:2.214–15.326,P<0.001).This model demonstrated good discriminatory ability for MACEs in post-PCI ASCVD patients[the area under the receiver operating characteristic(ROC)curve(AUC)=0.865,95%CI:0.816–0.914].Conclusion The intertwined phlegm and blood stasis TCM syndrome is associated with a distinct atherogenic lipid profile characterized by elevated levels of TC and LDL-C.The prognostic model that incorporates this TCM syndrome type along with conventional lipid parameters(TC and LDL-C)shows good discriminatory ability for predicting MACEs in ASCVD patients after PCI,underscoring the potential clinical utility of integrating TCM syndrome differentiation into CVD risk assessment.
基金The Korea Centers for Disease Control and Prevention,Grant/Award Number:2022-ER1701-00,2022-NI-041-02,2024-ER1702-00 and 2025-NI-014-00。
文摘Background:Humanized mouse models are essential for studying the human immune response and antibody development.However,conventional models show limited B cell maturation and antigen-specific humoral responses.To overcome these limitations,we used the NOG-EXL mice expressing human interleukin 3(IL-3)and granulocyte-macrophage colony-stimulating factor(GM-CSF)to enhance myeloid and B-cell lineage differentiation.Methods:Human CD34^(+)hematopoietic stem cells(HSC)were transplanted into NOG-EXL mice to produce humanized immune systems.After immune cell reconstitution was confirmed across 12 weeks,the mice were immunized twice with inactivated severe fever with thrombocytopenia syndrome virus(SFTSV)antigens.Peripheral blood mononuclear cells and splenocytes were analyzed using multicolor flow cytometry to assess human immune cell subsets.Antigen-specific immunoglobulin G(IgG)production was quantified using enzyme-linked immunosorbent assay(ELISA),and virus-specific B cells were isolated using antigen-labeled recombinant protein probes.Results:Twelve weeks after transplantation of HSCs into NOG-EXL mice,they exhibited robust engraftment of human leukocytes,including T,B,and dendritic cells,compared to NOG mice.Unlike NOG mice,humanized NOG-EXL mice exhibited an increase in human IgG levels,indicating the production of human antibody responses to antigens.Humanized NOG-EXL mice were immunized twice every 2 weeks with inactivated SFTSV,and antigen-specific human antibodies against the virus were detected in the mouse sera by ELISA.Sera from SFTSV-immunized humanized mice demonstrated neutralizing activity against SFTSV,confirming the induction of functional virus-specific neutralizing antibodies.Antigen-binding IgG-positive human B cells were isolated from mouse splenocytes using recombinant protein probes.Conclusion:This model provides a valuable platform for evaluating humoral immunity and isolating B cells using high-affinity human monoclonal antibodies without genetic engineering.
文摘It is challenging to diagnose isolated hyperbilirubinemia with rare and complex etiologies under the constraints of traditional testing conditions.Herein,we present a rare case of coexisting Gilbert syndrome(GS)and erythropoietic protoporphyria(EPP),which has not been previously documented.CASE SUMMARY We present a rare case of coexisting GS and EPP in a 23-year-old Chinese male with a long history of jaundice and recently found splenomegaly.Serial nonspecific hemolysis screening tests yielded inconsistent results,and investigations for common hemolytic etiologies were negative.However,Levitt’s carbon monoxide breath test,which measures erythrocyte lifespan(the gold-standard marker of hemolysis),demonstrated significant hemolysis,revealing a markedly shortened erythrocyte lifespan of 11 days(normal average 120 days).Genetic testing subsequently confirmed EPP with a homozygous ferrochelatase gene mutation and GS with a heterozygous uridine diphosphate glucuronosyl trans-ferase 1A1 gene mutation.CONCLUSION The rapid,non-invasive Levitt’s carbon monoxide breath test resolved the diagnostic challenge posed by a rare and complex cause of hyperbilirubinemia.
基金funded by the Entrusted service project of Shaanxi Administration of Traditional Chinese Medicine(ZYJXG-L23001)2023 Sanqin Talent Special Support Program Innovation and Entrepreneurship Team Project,and Sci-Tech Innovation Talent System Construction Program of Shaanxi University of Chinese Medicine(2023).
文摘Background:Panacis Quinquefolii Radix(PQR)is known for its ability to nourish“Qi”(it serves as the driving force for the functional activities of the body’s organs and meridians,promoting and regulating various physiological functions)and“Yin”(it represents the material foundation of the human body.It plays a role in nourishing,moistening,and cooling the body).Notoginseng Radix et Rhizoma(NRR)is recognized for its properties of resolving blood stasis(it refers to a pathological condition characterized by impaired or stagnant blood circulation within the body).Changes in the compatibility ratio of these herbs often lead to variations in their chemical composition and efficacy.However,the specific alterations in chemical composition and efficacy resulting from compatibility adjustments remain unclear.We aimed to compare the material basis and their effects of different compatibility ratios of PQR and NRR on“Qi”deficiency and blood stasis syndrome(QBS).Methods:This study employed UPLC-Q/TOF-MS to identify effective compounds in the compatibility of PQR and NRR and utilized UPLC-TQ-MS/MS to analyze the dissolution of 16 saponins in PQR and NRR at 9 different ratios.A rat model of QBS was established,and the efficacy of PQR and NRR in treating this syndrome was assessed using hemorheology and coagulation analyses.Results:The study results show that PQR and NRR exhibit significant efficacy,effectively reducing blood viscosity induced by platelet aggregation and lowering inflammatory markers such as IL-6,IL-10,TXB2 and ET associated with vascular injury.Moreover,this combination regulates ATP and ADP levels,enhances energy metabolism,and promotes overall health.A total of 104 compounds in the compatibility of PQR and NRR were identified.The ratios of 1:2 and 1:3 showed the highest total saponin content,but the ratio of 1:1 demonstrated a superior pharmacological effect for the treatment of QBS.Conclusion:In summary,the compatibility of PQR and NRR not only shows the complex interactions between traditional Chinese medicinal materials,but also provides a new idea and method for the treatment of QBS.
基金the Scientific and Technological Research Council of Türkiye(TÜBİTAK)Under the International Postdoctoral Research Fellowship Program(2219),No.1059B192400980the National Postdoctoral Research Fellowship Program(2218),No.122C158.
文摘Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.
基金Supported by the Zhejiang Province Medicine and Health Science and Technology Program,No.2023KY980Hangzhou Municipal Health and Family Planning Commission,No.A20220133.
文摘BACKGROUND Phelan-McDermid syndrome(PMS)is a rare genetic disorder characterized by intellectual disability,delayed language development,autism spectrum disorders,motor tone abnormalities,and a high risk of psychiatric symptoms,including bipolar disorder.CASE SUMMARY This report presented an 18-year clinical history of a 36-year-old woman with PMS,marked by intellectual disabilities,social withdrawal,and stereotyped behaviors.Diagnosed with bipolar disorder at the age of 18 years old,she encountered significant treatment challenges,including severe adverse reactions to antipsychotic medications in 2022,which led to speech and functional regression.Through rehabilitation and comprehensive therapy,her condition gradually improved.In 2024,after further treatment,her symptoms stabilized,highlighting the complexities and successes of long-term management.CONCLUSION Effective management of PMS requires a thorough clinical history,genetic testing,and long-term supportive care.
