ObjectiveHepatocyte nuclear factor 4-alpha (HNF4A) is a critical transcription factor in the liver and pancreas. Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1 (MODY1). Notably, MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels, but the mechanisms remain unclear. This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways. MethodsA stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A. RNA sequencing (RNA-seq) was performed to analyze transcriptional differences. Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes. ResultsRNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5 (TM4SF5) mRNA in HNF4A-overexpressing cells. Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter. Finally, we confirmed that the DR1 site in the -57 to -48 region of the TM4SF5 promoter is the key binding motif for HNF4A. ConclusionThis study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation. Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion, which closely aligns with phenotypes observed in MODY1 patients, our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.

OBJECTIVE: This study aimed to identify high-risk areas for type 2 diabetes mellitus (T2DM) mortality to provide relevant evidence for interventions in emerging economies. METHODS: Empirical Bayesian Kriging and a discrete Poisson space-time scan statistic were applied to identify the spatiotemporal clusters of T2DM mortality. The relationships between economic factors, air pollutants, and the mortality risk of T2DM were assessed using regression analysis and the Poisson Log-linear Model. RESULTS: A coastal district in East Guangdong, China, had the highest risk (Relative Risk [RR] = 4.58, P < 0.01), followed by the 10 coastal districts/counties in West Guangdong, China (RR = 2.88, P < 0.01). The coastal county in the Pearl River Delta, China (RR = 2.24, P < 0.01), had the third-highest risk. The remaining risk areas were two coastal counties in East Guangdong, 16 districts/counties in the Pearl River Delta, and two counties in North Guangdong, China. Mortality due to T2DM was associated with gross domestic product per capita (GDP per capita). In pilot assessments, T2DM mortality was significantly associated with carbon monoxide. CONCLUSION High mortality from T2DM occurred in the coastal areas of East and West Guangdong, especially where the economy was progressing towards the upper middle-income level.
Diabetes Mellitus, Type 2/epidemiology* ; China/epidemiology* ; Humans ; Risk Factors ; Spatio-Temporal Analysis ; Air Pollutants/analysis* ; Socioeconomic Factors ; Bayes Theorem ; Female ; Male ; Middle Aged

Objectives:To investigate the association between cardiac magnetic resonance(CMR)structural parameters and myocardial fibrosis in patients with hypertrophic cardiomyopathy(HCM),and to assess their predictive value for major adverse cardiovascular events(MACE).Methods:A total of 120 patients with HCM who underwent CMR examination at Affiliated Hospital of Guangdong Medical University between December 2021 and December 2023 were retrospectively enrolled.Patients were divided into the MACE group and the non-MACE group.MACE included acute myocardial infarction,angina pectoris,stroke,heart failure,severe arrhythmia.The CMR parameters were compared between the two groups.The correlation between CMR structural parameters and the myocardial fibrosis index(number of myocardial fibrotic segments/total segment number×100%)was evaluated using the locally weighted scatterplot smoothing method(LOWESS).Multivariate Cox regression was performed to identify the influencing factors of MACE.Threshold effect analysis of CMR structural parameters was conducted,and receiver operating characteristic(ROC)curves were generated to evaluate the diagnostic performance of CMR structural parameters for MACE.Results:During a follow-up period of 12(5,30)months,a total of 78(65.0%)patients developed MACE(the MACE group),and the remaining 42(35.0%)patients were assigned to the non-MACE group.Compared with the non-MACE group,patients in the MACE group had significantly larger left atrial diameter,left ventricular end-diastolic maximum diameter,maximal interventricular septal thickness,maximal left ventricular wall thickness,and higher myocardial fibrosis index(all P<0.05).The LOWESS analysis showed significant positive correlations between the above CMR structural parameters and the myocardial fibrosis index(all Poverall<0.05).The multivariate Cox regression showed that the echocardiographic interventricular septal thickness OR=2.622,95%CI:1.537-3.033),left ventricular posterior wall thickness(OR=1.597,95%CI:1.353-2.420),as well as CMR-derived left atrial diameter(OR=1.623,95%CI:1.314-2.595),left ventricular end-diastolic maximum diameter(OR=1.927,95%CI:1.594-2.981),maximal interventricular septal thickness(OR=2.085,95%CI:1.426-2.563),and maximal left ventricular wall thickness(OR=2.306,95%CI:1.760-2.805)were independent predictors of MACE(all P<0.05).The threshold effect analysis revealed that the left atrial diameter,left ventricular end-diastolic maximum diameter,maximal interventricular septal thickness,and maximal left ventricular wall thickness were all positively associated with the risk of MACE(all Poverall<0.05).The ROC curve analysis demonstrated that among individual CMR parameters,maximal interventricular septal thickness had the highest predictive performance(AUC=0.86,95%CI:0.74-0.95;sensitivity was 83.67%,specificity was 78.87%).Combined structural parameters(left atrial diameter,left ventricular end-diastolic maximum diameter,maximal interventricular septal thickness,and maximal left ventricular wall thickness)provided superior predictive accuracy(AUC=0.91,95%CI:0.84-0.99;sensitivity was 86.22%,specificity was 76.26%).Conclusions:HCM patients with MACE exhibit distinct clinical and imaging features compared with those without MACE.CMR structural parameters,including left atrial diameter,left ventricular end-diastolic maximum diameter,maximal interventricular septal thickness,and maximal left ventricular wall thickness,are closely related to myocardial fibrosis and strongly associated with MACE risk.A composite index integrating these parameters shows high predictive value for MACE.

Objectives:To investigate the association between cardiac magnetic resonance(CMR)structural parameters and myocardial fibrosis in patients with hypertrophic cardiomyopathy(HCM),and to assess their predictive value for major adverse cardiovascular events(MACE).Methods:A total of 120 patients with HCM who underwent CMR examination at Affiliated Hospital of Guangdong Medical University between December 2021 and December 2023 were retrospectively enrolled.Patients were divided into the MACE group and the non-MACE group.MACE included acute myocardial infarction,angina pectoris,stroke,heart failure,severe arrhythmia.The CMR parameters were compared between the two groups.The correlation between CMR structural parameters and the myocardial fibrosis index(number of myocardial fibrotic segments/total segment number×100%)was evaluated using the locally weighted scatterplot smoothing method(LOWESS).Multivariate Cox regression was performed to identify the influencing factors of MACE.Threshold effect analysis of CMR structural parameters was conducted,and receiver operating characteristic(ROC)curves were generated to evaluate the diagnostic performance of CMR structural parameters for MACE.Results:During a follow-up period of 12(5,30)months,a total of 78(65.0%)patients developed MACE(the MACE group),and the remaining 42(35.0%)patients were assigned to the non-MACE group.Compared with the non-MACE group,patients in the MACE group had significantly larger left atrial diameter,left ventricular end-diastolic maximum diameter,maximal interventricular septal thickness,maximal left ventricular wall thickness,and higher myocardial fibrosis index(all P<0.05).The LOWESS analysis showed significant positive correlations between the above CMR structural parameters and the myocardial fibrosis index(all Poverall<0.05).The multivariate Cox regression showed that the echocardiographic interventricular septal thickness OR=2.622,95%CI:1.537-3.033),left ventricular posterior wall thickness(OR=1.597,95%CI:1.353-2.420),as well as CMR-derived left atrial diameter(OR=1.623,95%CI:1.314-2.595),left ventricular end-diastolic maximum diameter(OR=1.927,95%CI:1.594-2.981),maximal interventricular septal thickness(OR=2.085,95%CI:1.426-2.563),and maximal left ventricular wall thickness(OR=2.306,95%CI:1.760-2.805)were independent predictors of MACE(all P<0.05).The threshold effect analysis revealed that the left atrial diameter,left ventricular end-diastolic maximum diameter,maximal interventricular septal thickness,and maximal left ventricular wall thickness were all positively associated with the risk of MACE(all Poverall<0.05).The ROC curve analysis demonstrated that among individual CMR parameters,maximal interventricular septal thickness had the highest predictive performance(AUC=0.86,95%CI:0.74-0.95;sensitivity was 83.67%,specificity was 78.87%).Combined structural parameters(left atrial diameter,left ventricular end-diastolic maximum diameter,maximal interventricular septal thickness,and maximal left ventricular wall thickness)provided superior predictive accuracy(AUC=0.91,95%CI:0.84-0.99;sensitivity was 86.22%,specificity was 76.26%).Conclusions:HCM patients with MACE exhibit distinct clinical and imaging features compared with those without MACE.CMR structural parameters,including left atrial diameter,left ventricular end-diastolic maximum diameter,maximal interventricular septal thickness,and maximal left ventricular wall thickness,are closely related to myocardial fibrosis and strongly associated with MACE risk.A composite index integrating these parameters shows high predictive value for MACE.

Objective To investigate the toxicokinetic differences of 3,4-methylenedioxy-N-methylamphetamine(MDMA)and its metabolite 4,5-methylene dioxy amphetamine(MDA)in rats af-ter single and continuous administration of MDMA,providing reference data for the forensic identifica-tion of MDMA.Methods A total of 24 rats in the single administration group were randomly divided into 5,10 and 20 mg/kg experimental groups and the control group,with 6 rats in each group.The ex-perimental group was given intraperitoneal injection of MDMA,and the control group was given intraperi-toneal injection of the same volume of normal saline as the experimental group.The amount of 0.5 mL blood was collected from the medial canthus 5 min,30 min,1 h,1.5 h,2 h,4 h,6 h,8 h,10 h,12 h after administration.In the continuous administration group,24 rats were randomly divided into the experi-mental group(18 rats)and the control group(6 rats).The experimental group was given MDMA 7 d by continuous intraperitoneal injection in increments of 5,7,9,11,13,15,17 mg/kg per day,respectively,while the control group was given the same volume of normal saline as the experimental group by in-traperitoneal injection.On the eighth day,the experimental rats were randomly divided into 5,10 and 20 mg/kg dose groups,with 6 rats in each group.MDMA was injected intraperitoneally,and the con-trol group was injected intraperitoneally with the same volume of normal saline as the experimental group.On the eighth day,0.5 mL of blood was taken from the medial canthus 5 min,30 min,1 h,1.5 h,2 h,4 h,6 h,8 h,10 h,12 h after administration.Liquid chromatography-triple quadrupole tandem mass spectrometry was used to detect MDMA and MDA levels,and statistical software was employed for data analysis.Results In the single-administration group,peak concentrations of MDMA and MDA were reached at 5 min and 1 h after administration,respectively,with the largest detection time limit of 12 h.In the continuous administration group,peak concentrations were reached at 30 min and 1.5 h af-ter administration,respectively,with the largest detection time limit of 10 h.Nonlinear fitting equations for the concentration ratio of MDMA and MDA in plasma and administration time in the single-administration group and continuous administration group were as follows:T=10.362C-1.183,R2=0.974 6;T=7.397 3C-0.694,R2=0.961 5(T:injection time;C:concentration ratio of MDMA to MDA in plasma).Conclusions The toxicokinetic data of MDMA and its metabolite MDA in rats,obtained through single and continuous administration,including peak concentration,peak time,detection time limit,and the relationship between concentration ratio and administration time,provide a theoretical and data foundation for relevant forensic identification.

Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.

Objective:To investigate the mechanism of polygonatum and astragalus compound(PA)in inhibiting the progression of lung adenocarcinoma. Methods:CCK-8 assay was used to assess the inhibitory rate of proliferation in A549 and H1299 cells treated with PA at different concentrations and to calculate the half maximal inhibitory concentration(IC50).C57BL/6 mice(KRASG12D/+;TP53flox/flox)were treated with adenovirus carrying Cre enzyme via nasal inhalation to establish a mouse model of primary lung adenocarcinoma.The model mice were fed with PA-containing diet to directly observe the effect of PA on the lung adenocarcinoma tissue.Immunohistochemical staining was used to examine the pathological status of the lung tissue.Bioinformatics analysis indicated that PA affects the progression of lung adenocarcinoma through the apelin-peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α)-mitochondrial brown fat uncoupling protein 1(UCP1).Real-time quantitative PCR and Western blotting analysis were used to study the effect of PA on the mRNA and protein expression levels of apelin-PGC1α-UCP1 signaling pathway related genes.An ATP detection kit and flow cytometry were used to evaluate the effect of PA on the ATP and mitochondrial ROS production,respectively,in A549 and H1299 cells.siUCP1 was used to silent the expression of UCP1 while Z160 was used to induce UCP1 overexpression in A549 and H1299 cells,and the changes in ATP and mitochondrial ROS production were examined to further investigate whether PA acts on apelin-PGC1α-UCP1 signaling pathway to affect the progression of lung adenocarcinoma. Results:PA could obviously inhibit the proliferation of A549 and H1299 cells with the IC50 values of 10.66 mg/mL for A549 cells and 9.66 mg/mL for H1299 cells.In the mouse primary lung adenocarcinoma model,PA could effectively inhibit the growth of tumor,downregulate apelin-PGC1α-UCP1 signaling pathway and inhibit the expression of lung adenocarcinoma-promoting gene UCP1.In A549 and H1299 cells,PA could significantly inhibit the expression of apelin,PGC1α and UCP1(P＜0.05),promote the production of ATP(P＜0.000 1)and ROS,restore mitochondrial oxidative phosphorylation,and inhibit aerobic glycolysis(P＜0.01).UCP1 silencing could increase the production of ATP(P＜0.01)and mitochondrial ROS and decrease the expression of key glycolysis enzymes hexokinase 2(HK2)and pyruvate kinase isozyme type M2(PKM2)(P＜0.05).Increasing the expression of UCP1 could reduce the ATP production(P＜0.01)and mitochondrial ROS generation in cells while increase the expression of HK2 and PKM2(P＜0.05).Treating cells with PA and Z160 simultaneously(PA+Z160)could reverse the inhibitory effect of PA on the ATP production and glycolysis of tumor cells(P＜0.05). Conclusion:PA can downregulate the apelin-PGC1α-UCP1 signaling pathway,inhibit mitochondrial uncoupling,restore mitochondrial oxidative phosphorylation,inhibit aerobic glycolysis,reverse the Warburg effect,and thus inhibit lung adenocarcinoma progression.

Objective To compare the efficacies of retrograde tibial nailing(RTN)versus minimally invasive percutaneous plate osteosynthesis(MIPPO)in the treatment of distal tibial fractures.Methods A retrospective analysis was conducted on the clinical data of 55 patients with distal tibial fractures who underwent surgery in our hospital.Patients were divided into two groups based on the different surgical methods,patients in the RTN group(n=25)were treated with RTN,and patients in the MIPPO group(n=30)were treated with MIPPO.The surgical parameters(operation time,intraoperative blood loss,intraoperative fluoroscopy times,and success rate of closed reduction),fracture healing time,ankle dorsiflexion range of motion and American Orthopaedic Foot and Ankle Society(AOFAS)ankle-hindfoot scores 6 months after operation and at the last follow-up,and the incidence of complications during perioperative period and follow-up were compared between the two groups.Results The operation time,intraoperative blood loss,and intraoperative fluoroscopy times in the RTN group were significantly shorter/less than those in the MIPPO group(P＜0.05).The ankle dorsiflexion range of motion and AOFAS ankle-hindfoot score 6 months after operation in the RTN group were significantly greater/higher than those in the MIPPO group(P＜0.05).There was no statistically significant difference in the fracture healing time,or ankle dorsiflexion range of motion and AOFAS ankle-hindfoot score at the last follow-up between the two groups(P＞0.05).The success rate of closed reduction in the RTN group was 72.00％,which was lower than that of 96.67％in the MIPPO group(P＜0.05).The incidence of soft tissue-related complications in the RTN group was signifi-cantly lower than that in the MIPPO group(P＜0.05),while there was no statistically significant difference in the overall incidence of complica-tions between the two groups(P＞0.05).Conclusion RTN is an effective minimally invasive surgical technique for the treatment of distal tibial fractures,characterized by minimal trauma,low incidence of soft tissue complications,and fast recovery of joint function compared with MIPPO.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

【Subjects】 To investigate the clinical application value of myocardial contrast echocardiography （MCE） in selecting CTO-PCI patients. MethodsFrom February 2019 to March 2020， a total of 50 patients with chronic coronary artery occlusion were consecutively selected as the research subjects. MCE and two-dimensional speck-tracking echocardiography were completed before and 12 months after interventional therapy. The primary end point was major adverse cardiovascular events. Patients were divided into groups according to the preoperative myocardial perfusion level of MCE. The improvement of left ventricular function was evaluated by two-dimensional echocardiography and left ventricular global longitudinal strain. ResultsCompared with the abnormal perfusion group， the improvement of GLS in the normal perfusion group was greater （P=0.028）. The wall motion score index （WMSI） of the abnormal perfusion group before PCI was higher than that of the normal perfusion group （P=0.002）. WMSI in the abnormal perfusion group was higher than that in the normal perfusion group one year after PCI （P<0.001）. The left ventricular GLS（P=0.008）.WMSI（P=0.016） and left ventricular end-diastolic volume（P=0.032） in the normal perfusion group were improved compared with those before operation； The postoperative perfusion score of patients with abnormal perfusion was significantly improved （ P=0.032）. ConclusionMCE has clinical application value in optimizing the selection of CTO-PCI patients. CTO patients with different myocardial perfusion types have different benefits after PCI.