This study aims to understand the biological characteristics of Streptococcus dysgalacti-ae of yak origin.Bacterial isolation and identification,drug susceptibility test,virulence gene test and pathogenicity test were carried out on milk samples of yaks from Naqu City to evaluate the bi-ological characteristics of the isolated strains.Meanwhile,molecular biological information such as virulence factors and drug resistance genes were analyzed by whole genome sequencing,and viru-lence genes were verified by PCR.The results showed that a strain of Streptococcus dysgalactiae was isolated from the milk of yak,and its colony morphology was pinpoint size,smooth edge and milky white.This strain is sensitive to many antibiotics(penicillin G,cephalosporin,ciprofloxacin,tetracycline,erythromycin,etc.).Virulence gene test results showed that the strain carries six key virulence genes(cyl,eno,scpB,bca,bac and napr),which may be closely related to its pathoge-nicity.In the pathogenicity test,the mice were listless and less active after infection,but no death occurred during the observation period.The pathological changes of spleen,kidney,liver and lung tissue were found,suggesting that the strain had certain pathogenic potential but not high lethali-ty.Whole genome sequencing data showed that the gene length of this strain was 4 079 280 bp,the GC content was 39.41％,3 964 coding genes were predicted,604 of which were annotated as viru-lence factors,and another 28 gene mutations may enhance its pathogenic ability.Through annota-tion of CARD database,two Pat A resistance genes and two lmrp resistance genes were found,re-vealing their potential resistance mechanism.Through whole genome sequencing technology and bioinformatics analysis method,this study revealed the genomic characteristics,drug resistance and pathogenicity mechanism of Streptococcus dysgalactiae of yak origin.The findings provide impor-tant scientific evidence for further exploration of the pathogenicity,drug resistance mechanisms,and molecular evolution of yak-derived Streptococcus agalactiae.

This study aims to understand the biological characteristics of Streptococcus dysgalacti-ae of yak origin.Bacterial isolation and identification,drug susceptibility test,virulence gene test and pathogenicity test were carried out on milk samples of yaks from Naqu City to evaluate the bi-ological characteristics of the isolated strains.Meanwhile,molecular biological information such as virulence factors and drug resistance genes were analyzed by whole genome sequencing,and viru-lence genes were verified by PCR.The results showed that a strain of Streptococcus dysgalactiae was isolated from the milk of yak,and its colony morphology was pinpoint size,smooth edge and milky white.This strain is sensitive to many antibiotics(penicillin G,cephalosporin,ciprofloxacin,tetracycline,erythromycin,etc.).Virulence gene test results showed that the strain carries six key virulence genes(cyl,eno,scpB,bca,bac and napr),which may be closely related to its pathoge-nicity.In the pathogenicity test,the mice were listless and less active after infection,but no death occurred during the observation period.The pathological changes of spleen,kidney,liver and lung tissue were found,suggesting that the strain had certain pathogenic potential but not high lethali-ty.Whole genome sequencing data showed that the gene length of this strain was 4 079 280 bp,the GC content was 39.41％,3 964 coding genes were predicted,604 of which were annotated as viru-lence factors,and another 28 gene mutations may enhance its pathogenic ability.Through annota-tion of CARD database,two Pat A resistance genes and two lmrp resistance genes were found,re-vealing their potential resistance mechanism.Through whole genome sequencing technology and bioinformatics analysis method,this study revealed the genomic characteristics,drug resistance and pathogenicity mechanism of Streptococcus dysgalactiae of yak origin.The findings provide impor-tant scientific evidence for further exploration of the pathogenicity,drug resistance mechanisms,and molecular evolution of yak-derived Streptococcus agalactiae.

OBJECTIVE:To assess the efficacy and safety of transcranial magnetic stimulation in the treatment of refractory depression and to compare the differences in efficacy between various transcranial magnetic stimulation treatment protocols in refractory depression,thereby providing a theoretical basis for the clinical selection of transcranial magnetic stimulation treatment protocols.METHODS:A comprehensive search was conducted across multiple databases,including PubMed,Embase,Cochrane Library,Web of Science,CNKI,WanFang Data,CBM and VIP.The search terms were"transcranial magnetic stimulation,treatment-resistant depression,randomized controlled trial"in Chinese,and"depressive disorder,treatment-resistant,transcranial magnetic stimulation,randomized controlled trial"in English.The objective was to identify randomized controlled trials on the treatment of patients with refractory depression published from the establishment of the databases to September 2024.The quality of the included studies was evaluated using the Cochrane risk of bias assessment tool,version 5.1.0,and the Physiotherapy Evidence Database scale.Meta-analysis of the outcome indicators was conducted using the Review Manager 5.4 and Stata 18.0 software.RESULTS:(1)Following a comprehensive review,20 randomized controlled trials were included in the analysis.All of the trials were assessed to be of high or very high quality according to the Physiotherapy Evidence Database scale.(2)Meta-analysis results showed that,compared with the sham stimulation group,high-frequency repetitive transcranial magnetic stimulation could significantly reduce the scores of Hamilton Depression Rating Scale[mean difference(MD)=-3.89,95％confidence interval(CI):-6.14 to-1.65,P＜0.05)or the Montgomery Depression Rating Scale(MD=-3.97,95％CI:-6.57 to-1.36,P＜0.05).(3)The probability ranking results of the network Meta-analysis showed that,in terms of the Hamilton Depression Rating Scale score,the probability ranking results were as follows:high-frequency repetitive transcranial magnetic stimulation(69.9％)＞intermittent theta burst stimulation(62.8％)＞bilateral theta pulse stimulation(57.5％)＞low-frequency repetitive transcranial magnetic stimulation(54.9％)＞bilateral sequential transcranial magnetic stimulation(49.0％)＞transcranial pulsed electromagnetic field(37.0％)＞sham stimulation(18.9％).And in terms of the Montgomery Depression Rating Scale score,the probability ranking results were as follows:high-frequency repetitive transcranial magnetic stimulation(93.3％)＞bilateral theta pulse stimulation(50.3％)＞sham stimulation(45.9％)＞low-frequency repetitive transcranial magnetic stimulation(32.1％)＞bilateral sequential transcranial magnetic stimulation(28.4％).CONCLUSION:Transcranial magnetic stimulations can improve the depressive symptoms of patients with treatment-resistant depression.Among them,the high-frequency repetitive transcranial magnetic stimulation mode has the best effect on improving the depressive symptoms of patients with treatment-resistant depression,followed by the intermittent θ burst stimulation mode.

OBJECTIVE:To assess the efficacy and safety of transcranial magnetic stimulation in the treatment of refractory depression and to compare the differences in efficacy between various transcranial magnetic stimulation treatment protocols in refractory depression,thereby providing a theoretical basis for the clinical selection of transcranial magnetic stimulation treatment protocols.METHODS:A comprehensive search was conducted across multiple databases,including PubMed,Embase,Cochrane Library,Web of Science,CNKI,WanFang Data,CBM and VIP.The search terms were"transcranial magnetic stimulation,treatment-resistant depression,randomized controlled trial"in Chinese,and"depressive disorder,treatment-resistant,transcranial magnetic stimulation,randomized controlled trial"in English.The objective was to identify randomized controlled trials on the treatment of patients with refractory depression published from the establishment of the databases to September 2024.The quality of the included studies was evaluated using the Cochrane risk of bias assessment tool,version 5.1.0,and the Physiotherapy Evidence Database scale.Meta-analysis of the outcome indicators was conducted using the Review Manager 5.4 and Stata 18.0 software.RESULTS:(1)Following a comprehensive review,20 randomized controlled trials were included in the analysis.All of the trials were assessed to be of high or very high quality according to the Physiotherapy Evidence Database scale.(2)Meta-analysis results showed that,compared with the sham stimulation group,high-frequency repetitive transcranial magnetic stimulation could significantly reduce the scores of Hamilton Depression Rating Scale[mean difference(MD)=-3.89,95％confidence interval(CI):-6.14 to-1.65,P＜0.05)or the Montgomery Depression Rating Scale(MD=-3.97,95％CI:-6.57 to-1.36,P＜0.05).(3)The probability ranking results of the network Meta-analysis showed that,in terms of the Hamilton Depression Rating Scale score,the probability ranking results were as follows:high-frequency repetitive transcranial magnetic stimulation(69.9％)＞intermittent theta burst stimulation(62.8％)＞bilateral theta pulse stimulation(57.5％)＞low-frequency repetitive transcranial magnetic stimulation(54.9％)＞bilateral sequential transcranial magnetic stimulation(49.0％)＞transcranial pulsed electromagnetic field(37.0％)＞sham stimulation(18.9％).And in terms of the Montgomery Depression Rating Scale score,the probability ranking results were as follows:high-frequency repetitive transcranial magnetic stimulation(93.3％)＞bilateral theta pulse stimulation(50.3％)＞sham stimulation(45.9％)＞low-frequency repetitive transcranial magnetic stimulation(32.1％)＞bilateral sequential transcranial magnetic stimulation(28.4％).CONCLUSION:Transcranial magnetic stimulations can improve the depressive symptoms of patients with treatment-resistant depression.Among them,the high-frequency repetitive transcranial magnetic stimulation mode has the best effect on improving the depressive symptoms of patients with treatment-resistant depression,followed by the intermittent θ burst stimulation mode.

Objective·To investigate the effects and molecular mechanisms of phosphatidylethanolamine(PE)on macrophage senescence and its senescence-associated secretory phenotype(SASP),as well as its pathophysiological role in liver injury.Methods·A macrophage senescence model was established using doxorubicin(DOX),followed by PE treatment.A mouse liver injury model was generated via intraperitoneal co-administration of PE and lipopolysaccharide(LPS)to investigate the effects of PE on liver injury.Senescence markers and SASP factors,including senescence-associated β-galactosidase(SA-β-gal),cell cycle inhibitor p21,tumor necrosis factor-α(TNF-α),and interleukin-6(IL-6),were evaluated using SA-β-gal staining,quantitative real-time PCR,and Western blotting.RNA sequencing(RNA-seq)was performed,followed by Gene Ontology(GO)cellular component enrichment analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis,Gene Set Variation Analysis(GSVA),and Gene Set Enrichment Analysis(GSEA),to explore the molecular mechanisms and signaling pathways by which PE promotes macrophage senescence.The expression of endoplasmic reticulum(ER)stress-related proteins,including inositol-requiring enzyme 1 α(IRE1α),spliced X-box binding protein 1(XBP1s),activating transcription factor 6(ATF6),ATF4,and C/EBP homologous protein(CHOP),was analyzed through in vivo and in vitro experiments.Results·PE significantly promoted the expression of senescence markers SA-β-gal,p21,p16 and SASP factors.RNA-seq analysis revealed that ER stress was involved in PE-induced promotion of SASP.Further experiments demonstrated that PE activated the ER stress signaling pathway,promoting macrophage senescence and the expression of SASP factors.In vivo experiments further confirmed that PE exacerbated LPS-induced liver injury in mice through ER stress.Conclusion·PE promotes macrophage senescence and the expression of SASP factors by activating ER stress signaling pathway,thereby aggravating LPS-induced liver injury.

Objective:To investigate the characteristics of clinical manifestations and parameters of 24 hour multichannel intraluminal impedance and pH monitoring (24 h MII-pH) in patients with low mean nocturnal baseline impedance (MNBI) of proximal esophagus.Methods:From November 4, 2014 to February 18, 2024, 308 patients who underwent 24 h MII-pH at Peking University First Hospital due to typical gastroesophageal reflux disease symptoms and(or) extra-esophageal symptoms were retrospectively enrolled. MNBI at 17 or 15 cm above the lower esophageal sphincter (LES) < 2 292 Ω was defined as low proximal esophageal impedance (LPEI), both MNBI at 17 and 15 cm above the LES ≥ 2 292 Ω was defined as normal proximal esophageal impedance (NPEI). The 24 h MII-pH parameters were compared between patients with LPEI and patients with NPEI, as well as the incidence of extra-esophageal symptoms. And the 24 h MII-pH parameters were compared between patients with and without extra-esophageal symptoms. Independent sample t-test, Mann-Whitney U test and chi-square test were used for statistical analysis. Results:Among the 308 patients, 71 patients with LPEI, 236 patients with NPEI, and 1 patient was excluded due to missing the 24 h MII-pH data; and there were 215 patients with extra-esophageal symptoms and 93 without extra-esophageal symptoms. The proportion of extra-esophageal symptoms in the LPEI patients was higher than that in the NPEI patients(81.7% (58/71) vs. 66.1% (156/236)), the times of postprandial total reflux, postprandial acid reflux detected by impedance, proximal total reflux, and proximal acid reflux in the LPEI patients were more than those in the NPEI patients (22.5 (22.8) vs. 17.0 (19.0), 10.5 (13.3) vs. 7.0 (13.0), 9.0 (12.0) vs. 5.0 (11.0), 5.0 (10.0) vs. 3.0 (7.0)), and the differences were statistically significant( χ2=6.28, Z=-1.99, -2.06, -2.26 and -2.44; all P<0.05). The times of weak acidic reflux at supine position, proximal total reflux, proximal acid reflux, and proximal non-acid reflux of the patients with extra-esophageal symptoms were more than those in patients without extra-esophageal symptoms (2.0(5.0) vs. 1.0(4.0), 6.0(13.0) vs. 4.0(10.0), 4.0(10.0) vs. 3.0(7.0), 2.0(4.0) vs. 1.0(3.0)), the MNBI at 15 cm above the LES in patients with extra-esophageal symptoms was lower than that in patients without extra-esophageal symptoms ((3 222.4±1 018.7) Ω vs. (3 512.3±1 032.1) Ω), and the differences were statistically significant ( Z=-2.32, -2.25, -2.00 and -2.13, t=-2.28; all P<0.05). Conclusions:LPEI patients have higher proportion of extra-esophageal symptoms, more times of proximal and postprandial acidic reflux. The proximal esophageal impedance and proximal reflux parameters should be emphasized in the diagnosis and treatment of patients with extra-esophageal symptoms.

Objective·To investigate the effects and molecular mechanisms of phosphatidylethanolamine(PE)on macrophage senescence and its senescence-associated secretory phenotype(SASP),as well as its pathophysiological role in liver injury.Methods·A macrophage senescence model was established using doxorubicin(DOX),followed by PE treatment.A mouse liver injury model was generated via intraperitoneal co-administration of PE and lipopolysaccharide(LPS)to investigate the effects of PE on liver injury.Senescence markers and SASP factors,including senescence-associated β-galactosidase(SA-β-gal),cell cycle inhibitor p21,tumor necrosis factor-α(TNF-α),and interleukin-6(IL-6),were evaluated using SA-β-gal staining,quantitative real-time PCR,and Western blotting.RNA sequencing(RNA-seq)was performed,followed by Gene Ontology(GO)cellular component enrichment analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis,Gene Set Variation Analysis(GSVA),and Gene Set Enrichment Analysis(GSEA),to explore the molecular mechanisms and signaling pathways by which PE promotes macrophage senescence.The expression of endoplasmic reticulum(ER)stress-related proteins,including inositol-requiring enzyme 1 α(IRE1α),spliced X-box binding protein 1(XBP1s),activating transcription factor 6(ATF6),ATF4,and C/EBP homologous protein(CHOP),was analyzed through in vivo and in vitro experiments.Results·PE significantly promoted the expression of senescence markers SA-β-gal,p21,p16 and SASP factors.RNA-seq analysis revealed that ER stress was involved in PE-induced promotion of SASP.Further experiments demonstrated that PE activated the ER stress signaling pathway,promoting macrophage senescence and the expression of SASP factors.In vivo experiments further confirmed that PE exacerbated LPS-induced liver injury in mice through ER stress.Conclusion·PE promotes macrophage senescence and the expression of SASP factors by activating ER stress signaling pathway,thereby aggravating LPS-induced liver injury.

Objective:To investigate the characteristics of clinical manifestations and parameters of 24 hour multichannel intraluminal impedance and pH monitoring (24 h MII-pH) in patients with low mean nocturnal baseline impedance (MNBI) of proximal esophagus.Methods:From November 4, 2014 to February 18, 2024, 308 patients who underwent 24 h MII-pH at Peking University First Hospital due to typical gastroesophageal reflux disease symptoms and(or) extra-esophageal symptoms were retrospectively enrolled. MNBI at 17 or 15 cm above the lower esophageal sphincter (LES) < 2 292 Ω was defined as low proximal esophageal impedance (LPEI), both MNBI at 17 and 15 cm above the LES ≥ 2 292 Ω was defined as normal proximal esophageal impedance (NPEI). The 24 h MII-pH parameters were compared between patients with LPEI and patients with NPEI, as well as the incidence of extra-esophageal symptoms. And the 24 h MII-pH parameters were compared between patients with and without extra-esophageal symptoms. Independent sample t-test, Mann-Whitney U test and chi-square test were used for statistical analysis. Results:Among the 308 patients, 71 patients with LPEI, 236 patients with NPEI, and 1 patient was excluded due to missing the 24 h MII-pH data; and there were 215 patients with extra-esophageal symptoms and 93 without extra-esophageal symptoms. The proportion of extra-esophageal symptoms in the LPEI patients was higher than that in the NPEI patients(81.7% (58/71) vs. 66.1% (156/236)), the times of postprandial total reflux, postprandial acid reflux detected by impedance, proximal total reflux, and proximal acid reflux in the LPEI patients were more than those in the NPEI patients (22.5 (22.8) vs. 17.0 (19.0), 10.5 (13.3) vs. 7.0 (13.0), 9.0 (12.0) vs. 5.0 (11.0), 5.0 (10.0) vs. 3.0 (7.0)), and the differences were statistically significant( χ2=6.28, Z=-1.99, -2.06, -2.26 and -2.44; all P<0.05). The times of weak acidic reflux at supine position, proximal total reflux, proximal acid reflux, and proximal non-acid reflux of the patients with extra-esophageal symptoms were more than those in patients without extra-esophageal symptoms (2.0(5.0) vs. 1.0(4.0), 6.0(13.0) vs. 4.0(10.0), 4.0(10.0) vs. 3.0(7.0), 2.0(4.0) vs. 1.0(3.0)), the MNBI at 15 cm above the LES in patients with extra-esophageal symptoms was lower than that in patients without extra-esophageal symptoms ((3 222.4±1 018.7) Ω vs. (3 512.3±1 032.1) Ω), and the differences were statistically significant ( Z=-2.32, -2.25, -2.00 and -2.13, t=-2.28; all P<0.05). Conclusions:LPEI patients have higher proportion of extra-esophageal symptoms, more times of proximal and postprandial acidic reflux. The proximal esophageal impedance and proximal reflux parameters should be emphasized in the diagnosis and treatment of patients with extra-esophageal symptoms.

Objective:To study the changes of immunoglobulins(IgG,IgA,IgM)and helper T cell Th9 subset,and their cor-relation with insulin-like growth factor-1(IGF-1)and S-100B protein in patients with Parkinson's disease(PD).Methods:A total of 108 patients with PD confirmed in Hebei Hospital of Traditional Chinese Medicine were enrolled as study group between December 2020 and December 2022.According to disease severity,they were divided into mild group(35 cases),moderate group(44 cases)and severe group(29 cases);a total of 108 healthy adults were enrolled as control group.Levels of immunoglobulins and Th9 subset were compared between study group and control group,and levels of immunoglobulins,Th9 subset,IGF-1 and S-100B protein were compared among mild group,moderate group and severe group.Correlation between immunoglobulins,Th9 subset and IGF-1,S-100B proteins were analyzed by Pearson correlation analysis.Correlation between disease severity and all differential indexes in PD patients were analyzed by Spearman correlation analysis.Results:IgM level in study group was lower than that in control group,and which was the lowest in severe group,followed by moderate group and mild group(P<0.05).Levels of IgG,IgA,IL-9 and Th9 subset in study group were higher than those in control group,and which were the highest in severe group,followed by moderate group and mild group(P<0.05).IGF-1 level was the lowest in severe group,followed by moderate group and mild group,while level of S-100B protein was on the contrary(P<0.05).Results of Pearson correlation analysis showed that IgM level was positively correlated with IGF-1 level,while negatively correlated with level of S-100B protein.Levels of IgG,IgA,IL-9 and Th9 subset were negatively correlated with IGF-1 level,while positively correlated with level of S-100B protein(P<0.05).Results of Spearman correlation analysis showed that the disease severity was negatively correlated with IgM and IGF-1 levels,while positively correlated with levels of S-100B protein,IgG,IgA,IL-9 and Th9 subset(P<0.05).Conclusion:IgM level is decreased,while levels of IgG,IgA and Th9 subset are increased in PD patients.Changes of the above indexes are significantly correlated with IGF-1 and S-100B,which can be applied to evaluate dis-ease severity.

Narrative medicine emphasizes the cultivation of narrative ability,providing an important pathway to promote clinical discipline teaching and guide the transformation of medical students into the role of doctors.Based on the theory of narrative medicine,the Warm Medicine course is designed with a two-layer advanced practical teaching system covering the entire life cycle of"birth,aging,illness,and death".It can train the ability of medical students to absorb,interpret,and respond to patients'stories and difficulties in actual medical scenarios.Taking the"birth"theme practice as an example,the paper presentes the specific implementation and development of the course.The practical teaching of the"birth"theme enhanced students'understanding of medical themes and their perception of the essence of life,as well as promoting the establishment of the subjectivity of doctor-patient relationships and the formation of medical students'holistic medical diagnosis and treatment thinking.