This study aims to explore the effects of Buzhong Yiqi Decoction(BYD) on the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING) signaling pathway in the mouse model of autoimmune thyroiditis(AIT) and the mechanism of BYD in alleviating the immune injury. Forty-eight NOD.H-2~(h4) mice were assigned into normal, model, low-, medium-, and high-dose BYD, and selenium yeast tablets groups(n=8). Mice of 8 weeks old were treated with 0.05% sodium iodide solution for 8 weeks for the modeling of AIT and then administrated with corresponding drugs by gavage for 8 weeks before sampling. High performance liquid chromatography was employed to measure the astragaloside Ⅳ content in BYD. Hematoxylin-eosin staining was employed to observe the pathological changes in the mouse thyroid tissue. Enzyme-linked immunosorbent assay was employed to measure the serum levels of thyroid peroxidase antibody(TPO-Ab), thyroglobulin antibody(TgAb), and interferon-γ(IFN-γ). Flow cytometry was employed to detect the distribution of T cell subsets in the spleen. The immunohistochemical method was used to detect the expression of cGAS, STING, TANK-binding kinase 1(TBK1), and interferon regulatory factor 3(IRF3). Real-time PCR and Western blot were employed to determine the mRNA and protein levels, respectively, of markers related to the cGAS-STING signaling pathway in the thyroid tissue. The results showed that the content of astragaloside Ⅳ in BYD was(7.06±0.08) mg·mL~(-1). Compared with the normal group, the model group showed disrupted structures of thyroid follicular epithelial cells, massive infiltration of lymphocytes, and elevated levels of TgAb and TPO-Ab. Compared with the model group, the four treatment groups showed intact epithelial cells, reduced lymphocyte infiltration, and lowered levels of TgAb and TPO-Ab. Compared with the normal group, the model group showed increases in the proportions of Th1 and Th17 cells, a decrease in the proportion of Th2 cells, and an increase in the IFN-γ level. Compared with the model group, the four treatment groups presented decreased proportions of Th1 and Th17 cells and lowered levels of IFN-γ, and the medium-dose BYD group showed an increase in the proportion of Th2 cells. Compared with the normal group, the modeling up-regulated the mRNA levels of cGAS, STING, TBK1, and IRF3 and the protein levels of cGAS, p-STING, p-TBK1, and p-IRF3. Compared with the model group, the four treatment groups showed reduced levels of cGAS, STING, TBK1, and IRF3-positive products, down-regulated mRNA levels of cGAS, STING, and TBK1, and down-regulated protein levels of cGAS and p-STING. The high-dose BYD group showed down-regulations in the mRNA level of IRF3 and the protein levels of p-TBK1 and p-IRF3. The above results indicate that BYD can repair the imbalance of T cell subsets, alleviate immune injury, and reduce thyroid lymphocyte infiltration in AIT mice by inhibiting the cGAS-STING signaling pathway.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Signal Transduction/drug effects* ; Thyroiditis, Autoimmune/metabolism* ; Mice ; Membrane Proteins/metabolism* ; Mice, Inbred NOD ; Humans ; Female ; Nucleotidyltransferases/metabolism* ; Male ; Disease Models, Animal

BACKGROUND: Previous evidence showed that ambient air pollution and cardiovascular mortality are related. However, there is a lack of evidence towards the modification effect of long-term lifestyle on the association between short-term ambient air pollution and death from cardiovascular events. METHOD: A total of 14,609 death from major adverse cardiovascular events (MACE) were identified among the China Kadoorie Biobank participants from 2013 to 2018. Ambient air pollution exposure including particulate matter 2.5 (PM_2.5), SO₂, NO₂, CO, and O₃ from the same period were obtained from space-time model reconstructions based on remote sensing data. Case-crossover design and conditional logistic regression was applied to estimate the effect of short-term exposure to air pollutants on MACE mortality. RESULTS: We found MACE mortality was significantly associated with PM_2.5 (relative percent increase 2.91% per 10 µg/m³ increase, 95% CI 1.32-4.53), NO₂ (5.37% per 10 µg/m³ increase, 95% CI 1.56-9.33), SO₂ (6.82% per 10 µg/m³ increase, 95% CI 2.99-10.80), and CO (2.24% per 0.1 mg/m³ increase, 95% CI 1.02-3.48). Stratified analyses indicated that drinking was associated with elevated risk of MACE mortality with NO₂ and SO₂ exposure; physical inactivity was associated with higher risk of death from MACE when exposed to PM_2.5; and people who had balanced diet had lower risk of MACE mortality when exposed to CO and NO₂. CONCLUSIONS The study results showed that short-term exposure to ambient PM_2.5, NO₂, SO₂, and CO would aggravate the risk of cardiovascular mortality, yet healthy lifestyle conduct might mitigate such negative impact to some extent.
Humans ; Cardiovascular Diseases/epidemiology* ; China/epidemiology* ; Male ; Female ; Air Pollution/adverse effects* ; Middle Aged ; Air Pollutants/analysis* ; Particulate Matter/analysis* ; Environmental Exposure/adverse effects* ; Life Style ; Aged ; Adult ; Risk Factors ; Cross-Over Studies ; East Asian People

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Objective To understand the epidemiological and clinical characteristics of healthcare-associated infec-tion(HAI)in neonates with different gestational ages and birth weights,and provide guidance for personalized cli-nical diagnosis and treatment.Methods According to the inclusion and exclusion criteria,240 neonates with HAI in the neonatal intensive care unit(NICU)of a hospital in Handan City from January 2018 to December 2022 were selected as the study group,720 neonates without HAI were selected as the control group based on systematic sam-pling method with a ratio of 1∶3.The incidence of HAI,distribution characteristics of infection site,pathogenic features of HAI,as well as the effect of different delivery modes on HAI in neonates with different gestational ages and birth weights were analyzed.Results Neonates with gestational age＜28 weeks and birth weight＜1 000 g had the highest incidence of HAI,which were 19.48％and 20.41％,respectively.Among neonates with gestational age＜28 weeks,unidentified site infection were the most(37.50％),while in all gestational age groups within 28-36+6 weeks,bloodstream infection(BSI)and respiratory system infection were predominant.For neonates with gestational age ≥37 weeks,BSI and unidentified site infection occurred frequently.Among neonates in all weight groups,BSI was the most frequent,followed by respiratory system infection.Pathogens from different sites of in-fections in neonates with different gestational ages and birth weights varied.Among neonates with gestational age of 28-31+6 weeks and birth weight of 1 000-1 499 g,the constituent of birth modes showed statistically significant difference between neonates with and without HAI(both P＜0.05).Conclusion Epidemiological and clinical chara-cteristics of HAI in neonates with different gestational ages and birth weights are different.For the prevention and control of HAI,individualized diagnosis and treatment plans should be developed to achieve precise prevention and control,reduce the incidence of HAI,and improve the overall treatment level of neonates.

Objective To verify the safety and efficacy of a new portable extracorporeal membrane oxygenation(ECMO)system(Xijing Advanced Life Support System JC-Ⅲ)in large animals.Methods A total of 10 healthy small fat-tail sheep underwent veno-arterial extracorporeal membrane oxygenation(VA-ECMO)support by carotid arterial-jugular catheterization to evaluate the performance of the JC-Ⅲ ECMO system.Systemic anticoagulation was achieved by continuous infusion of heparin.Active coagulation time(ACT)was recorded every 2 hours during the experiment,and the ACT was maintained between 200-250 s.Centrifugal pump speed is set at 3 000-3 500 r/min.The changes of hemoglobin,blood cell counts,hematocrit,liver and kidney function were monitored before and 24 h after ECMO initiation,respectively.After the experiment,the pump and oxygenator were dissected to probe the thrombosis.Results The success rate of VA-ECMO operation was 100％,and there was no hemolysis,pump thrombosis and oxygenator thrombosis after 24 h of ECMO.Before and after the operation,there were no significant changes in indicators such as hemoglobin content,white blood cell counts,platelet counts,alanine aminotransferase concentration,aspartate aminotransferase concentration,urea,creatinine,high-sensitivity troponin Ⅰ,and N-terminal pro-brain natriuretic peptide(all P＞0.05).Conclusions This in vivo study confirms that Xijing Advanced Life support System JC-Ⅲ is safe and effective.

Major depressive disorder(MDD)is a prevalent con-dition associated with substantial impairment and low remission rates.Traditional antidepressants demonstrate delayed effects,low cure rate,and inadequate therapeutic effectiveness for man-aging treatment-resistant depression(TRD).Several studies have shown that ketamine,a non-selective N-methyl-D-aspartate receptor(NMDAR)antagonist,can produce rapid and sustained antidepressant effects.Ketamine has demonstrated efficacy for reducing suicidality in TRD patients.However,the pharmaco-logical mechanism for ketamine's antidepressant effects remains incompletely understood.Previous research suggests that the an-tidepressant effects of ketamine may involve the monoaminergic,glutamatergic and dopaminergic systems.This paper provides an overview of the pharmacological mechanism for ketamine's anti-depressant effects and discuss the potential directions for future research.

Glutamate,norepinephrine,and their receptors com-prise the glutamatergic and norepinephrine systems,which mu-tually affect each other and play essential roles in mediating vari-ous neuropsychiatric diseases.This paper reviews the functions of N-methyl-D-aspartate receptor(NMDA-R)and α2-adrenergic receptor(α2-AR)and their functional crosstalk at the molecular level in brain in common neuropsychiatric diseases,which would benefit our understanding of neuropathophysiology of psychiatric diseases,drug development and optimization of clinical neuro-psychopharmacology.

For the treatment of atrial fibrillation,Professor WU Wei innovatively put forward the theory of heart-blood-vessels trinity and the theory of stasis-toxin causing palpitation.It is believed that atrial fibrillation is caused by stasis and toxin,and affects the heart,blood and vessels.The core pathogenesis of atrial fibrillation is due to qi stagnation,blood stasis and toxin.The treatment for atrial fibrillation should be closely based on the pathogenesis,the therapeutic principles of treating from the perspective of stasis and together by removing toxin gradually is advocated.And the therapy of regulating qi,activating blood and removing stasis is also the way to remove toxin.The medication is based on the modified Taoren Honghua Decoction,which is mainly composed of Persicae Semen,Carthami Flos,Chuanxiong Rhizoma,Corydalis Rhizoma,Rehmanniae Radix,Paeoniae Radix Rubra,Salviae Miltiorrhizae Radix et Rhizoma,Jujubae Fructus,Puerariae Lobatae Radix,Nardostachyos Radix et Rhizoma,Ostreae Concha,Poria,and Polygonati Odorati Rhizoma.According to the characteristics of Lingnan climate and atrial fibrillation mostly being easy to affect the emotions,the pungent drugs in the prescription are usually removed,and the specific herbal pair of Puerariae Lobatae Radix-Nardostachyos Radix et Rhizoma is added to remove toxin according to the differentiation of disease.Moreover,for the treatment of atrial fibrillation,Professor WU Wei also adopts traditional Chinese medicine(TCM)external treatment such as foot bath,acupuncture and moxibustion,and physical-breathing exercise as well as health-care methods for comprehensive regulation,relieving the toxin and restoring the original qi.During the treatment atrial fibrillation,Professor WU Wei follows the principle of precise intervention and comprehensive regulation with Chinese medicine,so as to achieve the purpose of eliminating symptoms,restoring sinus rhythm and improving physical constitution.The thoughts of Professor WU Wei for the syndrome differentiation and treatment of atrial fibrillation will provide reference for the treatment of atrial fibrillation with TCM.

Objective:To investigate the effect of the number of positive preoperative serological tumor markers on the surgical approach and prognosis of patients with intrahepatic cholangiocarcinoma.Methods:This is a retrospective case-series study. Data from 548 patients with intrahepatic cholangiocarcinoma after radical resection from October 2010 to April 2019 were retrospectively collected in 10 hospitals of China. There were 277 males and 271 females with an age of (57.8±10.2)years(range:23 to 84 years). Four hundred and twenty-six patients(77.7%) had at least one positive preoperative serum tumor marker. The data collection included the results of 4 preoperative serological tumor markers,other preoperative indicators(5 prodromal symptoms, 6 medical history,8 preoperative serological indicators,5 preoperative imaging indicators,and 14 preoperative pathological examination indicators),baseline data (gender and age),surgical methods,and prognostic follow-up data. Four preoperative results of serologic tumor marker and surgical procedure were converted into categorical variables. The number of positive preoperative serum tumor markers was used as the treatment variable,the surgical method was used as the mediating variable,and the survival time was used as the outcome variable. Univariate and multivariate analysis were used to screen for other preoperative indicators which were independent factors that influenced the surgical procedure and the prognosis of patients as covariates to analyze the mediating effect.Results:Of the 548 patients included in the study, 176 patients (32.1%) underwent partial hepatectomy,151 patients(27.5%) underwent hemihepatectomy, and 221 patients(40.3%) underwent partial hepatectomy or hemihepatectomy combined with other treatments. The results of the univariate and multivariate analysis showed that the number of positive serum tumor markers,intrahepatic bile duct dilatation,portal vein invasion,pathological differentiation,pathological type,vascular invasion,T stage,N stage and maximum tumor diameter were independent factors influencing the surgical procedure(all P<0.05). Intrahepatic bile duct dilatation,pathological differentiation and T stage were independent prognostic factors for patients with intrahepatic cholangiocarcinoma(all P<0.05). Intrahepatic bile duct dilatation,differentiation and T stage were included as covariates in the mediation effect model. The results showed that the number of positive serum tumor markers before surgery had a negative predictive effect on the survival time of patients with intrahepatic cholangiocarcinoma ( β=-0.092, P=0.039),and had a positive predictive effect on the surgical method ( β=0.244, P<0.01). The number of positive serum tumor markers had a negative predictive effect on the survival time of patients with intrahepatic cholangiocarcinoma ( β=-0.151, P=0.002). Direct and indirect effects accounted for 71.3% and 28.7% of total effects,respectively. Conclusions:The higher the positive number of preoperative tumor markers,the worse the prognosis of patients with intrahepatic cholangiocarcinoma. The number of positive cells not only directly affects the prognosis of patients,but also indirectly affects the prognosis of patients by affecting the surgical method.

The post-translational modification of proteins is a key mechanism that imparts physiological functions to proteins,among which reversible phosphorylation modifications play a pivotal role in many biological processes.Aberrant changes in phosphorylation are often closely associated with various major disease processes.In recent years,with the aid of proteomic technologies and methods,high-throughput,high-precision qualitative and quantitative approaches for phosphorylated proteins have rapidly advanced.This article reviews the research progress of phosphorylated protein quantification and chemical proteomics analysis methods based on the"bottom-up"strategy,including phosphopeptide enrichment methods,mass spectrometry fragmentation methods,quantification analysis methods and phosphorylation site stoichiometry,and discusses the development trend of quantification and stoichiometric analysis methods for phosphorylated proteins.