ObjectiveTo investigate the expression changes of the Endophilin A1 （EPA1）-reactive oxygen species （ROS）-NLR family pyrin domain containing 1 （NLRP1） signaling pathway in chronic unpredictable mild stress （CUMS）-induced depression model mice. Methods50 C57BL/6 mice were randomly divided into control group and CUMS model group（n=25）. The model mice received 42 days of CUMS stress exposure， after which behavioral changes were assessed through monitoring body weight， sucrose preference test， forced swim test， tail suspension test， open field test， and elevated plus-maze test. Hematoxylin-Eosin and Nissl staining were used to observe neuronal damage in hippocampal CA1 and CA3 regions. Calcium ion （Ca²⁺） assay kit was used to detect Ca²⁺ levels in the hippocampus. Immunofluorescence was used to detect colocalization of EPA1 and NLRP1 as well as ROS changes in the hippocampus. Transmission electron microscopy was used to observe mitochondrial structure in hippocampal neurons. The expression levels of calcium-activated neutral protease 1 （Calpain-1）， nicotinamide adenine dinucleotide phosphate oxidase 2 （NOX2）， NLRP1 inflammasome， downstream inflammatory proteins， and synapse-associated proteins in the hippocampus of mice was detected by using Western blot. ResultsCompared with the control group， mice in the CUMS model group exhibited depressive-like behavior and hippocampal neuronal damage. The levels of NLRP1 and EPA1 significantly increased in the hippocampus， and both were co-expressed in the cytoplasm and membrane of hippocampal neurons in the CUMS group mice（P<0.01）. Ca²⁺ concentration was elevated（P<0.01）， and the protein levels of Calpain 1 and NOX2 were upregulated（P<0.01）. The average fluorescence intensity of ROS significantly increased， accompanied by structural damage to neuronal mitochondria（P<0.01）. The levels of NLRP1 and its downstream inflammatory proteins significantly increased （P<0.01）， while the expression levels of synapse-associated proteins significantly decreased （P<0.01）. ConclusionEPA1 exhibits abnormal expression changes in CUMS-induced depression model mice， which may be closely associated with ROS generation， NLRP1 inflammasome activation， and the regulation of synaptic protein expression.

Objective:To investigate the value of machine learning models based on CT radiomics for predicting the outcome of neoadjuvant chemotherapy (NAC) in patients with locally advanced gastric cancer (LAGC).Methods:A retrospective case series study was conducted. A total of 279 LAGC patients receiving NAC before surgery in Shanxi Province Cancer Hospital from January 2018 to November 2020 were included. According to a ratio of 7∶3, all patients were randomly divided into the training set (196 cases) and the validation set (83 cases). According to the tumor regression grade (TRG), the pathological grade was divided into the good response of NAC (GR) group (TRG 0-1, 55 cases) and the poor response of NAC (PR) group (TRG 2-3, 224 cases). The clinicopathological data of patients were collected, such as age, gender, differentiation degree, clinical T and N staging, carcinoembryonic antigen (CEA), and carbohydrate antigen 199 (CA199) level. Radiomics features were extracted from the enhanced CT images in the vein phase, and the features were screened by 3-step dimensionality reduction. And then 5 machine learning algorithms including logistic regression (LR), naive bayes (NB), random forest (RF), support vector machine (SVM) and extreme gradient boosting (XGB) were applied to build prediction models based on the CT radiomics. The receiver operating characteristic (ROC) curve and the decision analysis (DCA) curve were drawn to evaluate the predictive performance and clinical benefit of each model on the outcome of NAC in patients with LAGC.Results:Among 196 patients in the training set, there were 39 cases in GR group and 157 cases in PR group; among 83 patients in the validation set, there were 16 cases in GR group and 67 cases in PR group. There were no statistically significant differences in clinicopathological data of patients between the training and validation sets, or between GR and PR groups in the training and validation sets (all P > 0.05). A total of 102 radiomics features were extracted from region of interest of CT images in the vein phase, and 6 key features were finally selected including original_firstorder_10Percentile, original_firstorder_RoubustMeanAbsoluteDeviation, original_glcm_Idmn, original_glcm_MCC, original_ngtdm_Busyness, original_ngtdm_Contrast; and there were statistically significant differences in 6 features between the GR and PR groups (all P < 0.05). LR, NB, RF, SVM and XGB machine learning algorithms were used to construct 5 prediction models based on the CT radiomics. The area under ROC curve for NAC prediction in the training set was 0.553, 0.709, 0.668, 0.772 and 0.790, respectively; in the validation set was 0.662, 0.622, 0.683, 0.752 and 0.784, respectively. The model constructed by XGB showed the best comprehensive performance, and its accuracy, sensitivity and specificity was 0.771, 0.562 and 0.821, respectively. In the DCA of 5 machine learning models in the training set, XGB-based model provided a higher net benefit. Conclusions:Machine learning models based on enhanced CT radiomics in the vein phase have a high predictive efficacy in the outcome of NAC in LAGC patients before surgery and it helps make clinical personalized treatment decisions.

Objective:To evaluate the prevalence, potential risk factors, and correlation between coronary and peripheral microvascular dysfunction in heart failure with non-reduced ejection fraction (nHFrEF) patients.Methods:This was a prospective registry study. nHFrEF patients admitted to Zhongshan Hospital affiliated with Fudan University from December 2021 to December 2023 were enrolled. According to coronary flow reserve (CFR) or reactive congestion index (RHI), enrolled patients were divided into coronary microvascular endothelial dysfunction (CMD) group (CFR<2.5) and no CMD group (CFR≥2.5) or peripheral microvascular endothelial dysfunction (MED) group (RHI<1.67) and no MED group (RHI≥1.67). Patients′ general information, laboratory and auxiliary examination data were collected. Univariate and multivariate logistic regression were used to analyze the influencing factors of CMD and MED in nHFrEF patients, and Spearman correlation analysis was used to evaluate the correlation between MED and CMD.Results:A total of 142 nHFrEF patients were enrolled, aged 69.0 (59.0, 74.0) years, with a male proportion of 66.9% (95/142). The grouping results were as follows: (1) According to CFR, there were 73 cases in the CMD group and 69 cases in the no CMD group; (2) According to RHI, there were 57 cases in the MED group and 85 cases in the no MED group. The prevalence of CMD and MED in this study was 51.4% (73/142) and 40.1% (57/142), respectively. Univariate logistic regression analysis showed that increased heart rate, chronic kidney disease, atrial fibrillation, elevated N-terminal pro-B type natriuretic peptide levels, and increased urinary albumin/creatinine ratio were risk factors for CMD, while increased RHI was a protective factor for CMD; Atrial fibrillation is a risk factor for MED, while increased CFR is a protective factor for MED. Incorporating clinically significant variables from univariate analysis into multivariate analysis, the results showed that increased heart rate and elevated RHI remained risk and protective factors for CMD, respectively; increased CFR remains a protective factor for MED. Spearman correlation analysis showed that CFR was negatively correlated with lg urinary albumin/creatinine ratio, lg cardiac troponin T, lg N-terminal pro-B type natriuretic peptide, and heart rate; RHI is positively correlated with CFR.Conclusions:The prevalence of CMD and MED in nHFrEF patients is high, and the two have a certain positive correlation. Increased heart rate and RHI are risk and protective factors for CMD, respectively, while increased CFR is a protective factor for MED. MED may be a potential therapeutic target for nHFrEF patients.

Objective:To report the nationwide surveillance results of pathogenic profiles and antimicrobial resistance patterns of Gram-positive bloodstream infections in China in 2023.Methods:The clinical isolates of Gram-posttive bacteria from blood cultures were collected in member hospitals of National Bloodstream Infection Bacterial Resistant Investigation Collaborative System（BRICS）during January to December 2023. Antimicrobial susceptibility testing was performed using the dilution method recommended by the Clinical and Laboratory Standards Institute（CLSI）. Statistical analyses were conducted using WHONET 5.6 and SPSS 25.0 software.Results:A total of 4 385 Gram-positive bacterial isolates were obtained from 60 participating center. The top five pathogens were Staphylococcus aureus（ n=1 544，35.2%），coagulase-negative Staphylococci（ n=1 441，32.9%）， Enterococcus faecium（ n=574，13.1%）， Enterococcus faecalis（ n=385，8.8%），and α-hemolytic Streptococci（ n=187，4.3%）. The prevalence of methicillin-resistant Staphylococcus aureus（MRSA）and methicillin-resistant coagulase-negative Staphylococci（MRCNS）was 26.2%（405/1 544）and 69.8%（1 006/1 441），respectively. Notably，all Staphylococci remained susceptible to glycopeptide or daptomycin. Staphylococcus aureus demonstrated excellent susceptibility（>97.0%）to cephalobiol，rifampicin，trimethoprim-sulfamethoxazole，linezolid，minocycline，tigecycline，and eravacycline. No Enterococcus exhibiting resistance to linezolid were detected. Glycopeptide resistance was uncommon but more frequent in Enterococcus faecium（resistance to vancomycin and teicoplanin：both 1.7%）compared to Enterococcus faecalis（both 0.3%）. The detection rates of MRSA and MRCNS exhibited significant regional variations across the country（ χ2=17.674 and 148.650，respectively，both P<0.001）. No vancomycin-resistant Enterococci were detected in central China. Institutional comparison demonstrated higher prevalence of MRSA（ χ2=14.111， P<0.001）and MRCNS（ χ2=4.828， P=0.028）in provincial hospitals than that in municipal hospitals. Socioeconomic analysis identified elevated detection rates of both MRSA（ χ2=18.986， P<0.001）and MRCNS（ χ2=4.477， P=0.034）in less developed regions（per capita GDP

Objective:To report the results of bacterial resistant investigation collaborative system（BRICS）on the distribution and antimicrobial resistance profile of clinical Gram-negative bacteria isolates from bloodstream infections in China in 2023，and provide reference for clinical tretment of bloodstream infections and prevention and control of bacterial resistance.Methods:The clinical isolates of Gram-negative bacteria from blood cultures in member hospitals of BRICS were collected during January 2023 to December 2023. Antibiotic susceptibility tests were conducted by agar dilution or broth dilution methods recommended by Clinical and Laboratory Standards Institute（CLSI）. WHONET 5.6 and SPSS 25.0 were used to analyze the data.Results:During the study period，11 492 strains of Gram-negative bacteria were collected from 60 hospitals，of which 10 098（87.9%）were Enterobacterales and 1 394（12.1%）were non-fermentative bacteria. The top 5 bacterial species were Escherichia coli（50.0%）， Klebsiella pneumoniae（26.1%）， Pseudomonas aeruginosa（5.1%）， Acinetobacter baumannii complex（5.0%）and Enterobacter cloacae complex（4.1%）. The ESBL-producing rates in Escherichia coli， Klebsiella pneumoniae and Proteus mirablilis were 46.8%（2 685/5 741），18.3%（549/2 999）and 44.0%（77/175），respectively. The prevalence of carbapenem-resistant Escherichia coli（CREC）and carbapenem-resistant Klebsiella pneumoniae（CRKP）were 1.3%（76/5 741）and 15.0%（450/2 999）；32.9%（25/76）and 78.0%（351/450）of CREC and CRKP were sensitive to ceftazidime/avibactam combination，respectively. 94.7%（72/76）and 90.2%（406/450）of CREC and CRKP were sensitive to aztreonam/avibactam combination. Furthermore，57.9%（44/76）and 79.1%（356/450）were sensitive to imipenem/relebactam combination. The prevalence of carbapenem-resistant Acinetobacter baumannii（CRAB）complex was 64.6%（370/573），while more than 80.0% of CRAB complex was sensitive to tigecycline，eravacycline and polymyxin B. The prevalence of carbapenem-resistant Pseudomonas aeruginosa（CRPA）was 17.0%（99/581）. There were differences in the composition ratio of Gram-negative bacteria in bloodstream infections and the prevalence of important Gram-negative bacteria resistance among different regions in China，with statistically significant differences in the prevalence of CREC，CRKP，CRPA and CRAB complex（ χ2=10.6，28.6，10.8 and 19.3， P<0.05）. The prevalence of ESBL-producing Escherichia coli， CREC，CRAB complex and CRKP were higher in provincial hospitals than those in municipal hospitals（ χ2=12.5，9.8，12.7 and 57.8，all P<0.01）. Conclusions:Gram-negative bacteria are the main pathogens causing bloodstream infections in China，and Escherichia coli is ranked in the top，while the trend of Klebsiella pneumoniae increases continuously with time. CRKP infection shows a slow upward trend，CREC infecton maintains a low prevalence level，and CRAB complex infection continues to exhibit a high prevalence rate. The composition and resistance patterns of pathogens causing bloodstream infections vary to some extent across different regions and levels of hospitals in China.

AIM: To analyze the current status and influencing factors for insufficient hyperopia reserve in preschool children from Changzhi City, Shanxi Province, and to provide reference and basis for myopia prevention and control in this district.METHODS: A stratified cluster random sampling strategy was used to select 2 854 preschool children(5 708 eyes)from 29 child-care centers in Changzhi City between January and May 2024. Hyperopia reserve was assessed through measurements and questionnaire surveys. Totally 2 820 cases(5 640 eyes)were finally included, with 34 cases excluded(32 cases of uncooperativeness and 2 cases of distractibility). The univariate analysis and multivariate Logistic regression were performed to analyze the associated influencing factors of insufficient hyperopia reserve.RESULTS: A total of 580 preschool children with insufficient hyperopia reserve were detected, with an incidence of 20.57%. Logistic regression analysis revealed that male(OR=1.723, 95% CI: 1.419-2.093), maternal myopia(OR=2.210, 95% CI: 1.681-2.906), paternal myopia(OR=1.426, 95% CI: 1.059-1.921), myopia in both parents(OR=2.761, 95% CI: 2.110-3.612), preterm infants(OR=1.740, 95% CI: 1.294-2.342), the mean daily sleep duration <10 h(OR=1.272, 95% CI: 1.024-1.579), and the mean daily outdoor activity time <2 h(OR=1.222, 95% CI: 1.005-1.485)were risk factors for insufficient hyperopia reserve(all P<0.05). Conversely, using blackout curtains during the day and turning off lights at night(OR=0.598, 95% CI: 0.405-0.883)were identified to be protective factors(P<0.05).CONCLUSION: Sex, genetics, gestational age, sleep duration and environmental conditions, and outdoor activity time are potentially associated with insufficient hyperopia reserve in preschool children. Caregivers should prioritize the management of these risk factors to prevent the occurrence of myopia.

BACKGROUND: The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation. METHODS: We conducted a kidney xenotransplantation in a brain-dead human recipient using a porcine kidney with five gene edits (5GE) on March 25, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22 days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation. RESULTS: The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24 h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient. CONCLUSIONS 5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.
Transplantation, Heterologous/methods* ; Kidney Transplantation/methods* ; Heterografts/pathology* ; Immunoglobulins, Intravenous/administration & dosage* ; Graft Survival/immunology* ; Humans ; Animals ; Sus scrofa ; Graft Rejection/prevention & control* ; Kidney/pathology* ; Gene Editing ; Species Specificity ; Immunosuppression Therapy/methods* ; Plasma Exchange ; Brain Death ; Biopsy ; Male ; Aged

Objective:To investigate the effect and mechanism of Jianpi Qinghua granule in improving skeletal muscle insulin resistance induced by long-term low-dose cadmium exposure in rats.Methods:A total of 24 SPF-grade healthy 2-month-old Sprague-Dawley rats were assigned to normal control(NC) group, cadmium exposure(Cd) group, and Jianpi Qinghua granule protection(Cd+ JPQHG) group. After 24 weeks, fasting blood glucose and insulin levels were measured, and HOMA-IR was calculated. The intraperitoneal glucose tolerance test and insulin tolerance test were conducted to assess insulin sensitivity. Skeletal muscle tissues were extracted for Western blot analysis to detect levels of insulin signaling pathway-related proteins. Immunofluorescence was used to assess the translocation of glucose transporter 4(GLUT4), and oxidative stress markers were measured.Results:Compared to the NC group, the Cd group showed significant increases in fasting plasma glucose, fasting insulin levels, and HOMA-IR after 24-week exposure. Abnormal glucose and insulin tolerance were also observed in the Cd group. The 12-week intervention with Jianpi Qinghua granule significantly improved glucose metabolism and alleviated the abnormalities in glucose and insulin tolerance. Western blot results indicated that the phosphorylation levels of PI3K and Akt in the skeletal muscle of the Cd group were significantly reduced compared to the NC group, while these levels were significantly elevated in the Cd+ JPQHG group, along with increased translocation of GLUT4 to the cell membrane. Additionally, cadmium exposure significantly increased H 2O 2 and malondialdehyde levels while decreased antioxidant enzyme activity. These oxidative stress indicators improved significantly after Jianpi Qinghua granule intervention( P<0.05). Conclusion:Jianpi Qinghua granule may improve skeletal muscle insulin resistance and glucose metabolism disorders due to long-term low-dose cadmium exposure by reducing oxidative stress, regulating the phosphorylation levels of key proteins in the insulin signaling pathway, and promoting GLUT4 translocation to the cell membrane.

Objective:To investigate the assoication of amino acid metabolism levels with severity of diabetic peripheral neuropathy(DPN) in patients with type 2 diabetes mellitus.Methods:A retrospective analysis was conducted on 118 patients with type 2 diabetes mellitus who were admitted to Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from January to April 2021. Patients were divided into groups according to the Toronto Clinical Scoring System(TCSS), and amino acid profiling was performed. General demographics and biochemical indicators of each group were collected to analyze the relationship between DPN severity and amino acid metabolism.Results:As TCSS scores increased, patients were older and had a longer duration of diabetes. Statistically significant differences in leucine, isoleucine, tryptophan, and phenylalanine levels were observed among the four groups. After adjusting for confounding variables using covariance analysis, when the TCSS score was≥13, the serum phenylalanine level was significantly elevated, and the difference was statistically significant( P<0.05). Multivariate linear regression analysis indicated that TCSS score was an influencing factor for phenylalanine levels( P=0.010). Multivariate logistic regression analysis demonstrated that higher serum phenylalanine levels correlated with higher TCSS scores( OR=1.047, 95% CI 1.011-1.083, P=0.010). Receiver operating characteristic(ROC) curve analysis revealed that serum phenylalanine and the difference between phenylalanine and tryptophan had diagnostic value for severe DPN patients, with areas under the ROC curve of 0.673(95% CI 0.553-0.793, P=0.006) and 0.746(95% CI 0.641-0.852, P<0.001) respectively. Conclusions:The levels of phenylalanine and tryptophan in the serum of patients with type 2 diabetes mellitus are correlated with the severity of DPN. These findings suggest that serum phenylalanine, tryptophan, or their metabolic products may be involved in the pathogenesis and progression of DPN.

Objective:To investigate the clinical manifestations, treatment, and outcomes of Barth syndrome (BTHS).Methods:A retrospective analysis was conducted on 21 pediatric patients diagnosed with BTHS between January 2010 and December 2023 at Beijing Children′s Hospital, Beijing Anzhen Hospital, and Beijing JingDu Children′s Hospital. Clinical data including gender, age at onset, initial symptoms, clinical manifestations, personal history, family genetic history, and laboratory tests (neutrophil count, echocardiography, electrocardiogram and genetic testing) were reviewed.Results:All the 21 patients were male, with the age of onset at 4.1 (1.1, 9.3) months. Main clinical manifestations included heart failure (18 cases), neutropenia (16 cases), respiratory symptoms (15 cases), 3-methylpentenediuria (7 cases),develop retardation (8 cases), gastrointestinal symptoms (7 cases), fatigue and anorexia (6 cases), and recurrent infection (2 cases). Electrocardiogram abnormalities included ST changes (18 cases), flattened T wave and low voltage of limb leads (2 cases), and abnormal Q waves in lead Ⅰ and avL (1 case). Echocardiographic features showed increased trabeculation, interventricular septum and left ventricular wall thickening, and left ventricular enlargement with reduced ejection fraction. Genetic testing identified TAZ gene variations in all 21 patients: 11 missense mutations, 2 nonsense mutations, 2 frameshift mutations, 2 whole code mutations, 2 exon deletions, 1 splicing mutation, and 1 synonymous mutation. Fifteen mutations were maternally inherited, 2 were de novo, and 4 lacked verified variant origin.In terms of treatment, all 18 patients with heart failure received routine heart failure treatment, of whom 11 patients also received intravenous immunoglobulin and corticosteroids. After the follow-up of 91.0 (75.5, 109.5) months, 15 of the 18 patients showed restoration of cardiac function after 4.5 (3.0, 9.8) months of treatment, with one case of significant improvement, while 2 cases suddenly died.Conclusions:BTHS predominantly affects males with early onset, mainly characterized by abnormal cardiac structure and function, along with clinical features including fatigue, delayed growth and development, and neutropenia. Early diagnosis and intervention, including heart failure treatment, intravenous immunoglobulin, and corticosteroids, can lead to significant improvement in cardiac function, though sudden death remains a risk.