OBJECTIVES: To investigate the genomic characteristics and prognostic factors of juvenile myelomonocytic leukemia (JMML) with RAS mutations. METHODS: A retrospective analysis was conducted on the clinical data of JMML children with RAS mutations treated at the Hematology Hospital of Chinese Academy of Medical Sciences, from January 2008 to November 2022. RESULTS: A total of 34 children were included, with 17 cases (50%) having isolated NRAS mutations, 9 cases (27%) having isolated KRAS mutations, and 8 cases (24%) having compound mutations. Compared to children with isolated NRAS mutations, those with NRAS compound mutations showed statistically significant differences in age at onset, platelet count, and fetal hemoglobin proportion (P<0.05). Cox proportional hazards regression model analysis revealed that hematopoietic stem cell transplantation (HSCT) and hepatomegaly (≥2 cm below the costal margin) were factors affecting the survival rate of JMML children with RAS mutations (P<0.05); hepatomegaly was a factor affecting survival in the non-HSCT group (P<0.05). CONCLUSIONS Children with NRAS compound mutations have a later onset age compared to those with isolated NRAS mutations. At initial diagnosis, children with NRAS compound mutations have poorer peripheral platelet and fetal hemoglobin levels than those with isolated NRAS mutations. Liver size at initial diagnosis is related to the prognosis of JMML children with RAS mutations. HSCT can improve the prognosis of JMML children with RAS mutations.
Humans ; Leukemia, Myelomonocytic, Juvenile/therapy* ; Mutation ; Male ; Female ; Child, Preschool ; Retrospective Studies ; Child ; Infant ; GTP Phosphohydrolases/genetics* ; Membrane Proteins/genetics* ; Adolescent ; Hematopoietic Stem Cell Transplantation ; Proportional Hazards Models ; Proto-Oncogene Proteins p21(ras)/genetics* ; Prognosis

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia in the elderly. This study aimed to evaluate urban-rural disparities in its prevalence and management in elderly Chinese. METHODS: Consecutive participants aged ≥ 65 years attending outpatient clinics were enrolled for AF screening using handheld single-lead electrocardiogram (ECG) from April 2017 to December 2022. Each ECG rhythm strip was reviewed from the research team. AF or uninterpretable single-lead ECGs were referred for 12-lead ECG. Primary study outcome comparison was between rural and urban areas for the prevalence of AF. The Student's t-test was used to compare mean values of clinical characteristics between rural and urban participants, while the Pearson's chi-square test was used to compare between-group proportions. Multivariate stepwise logistic regression analysis was performed to estimate the association between AF and various patient characteristics. RESULTS: The 29,166 study participants included 13,253 men (45.4%) and had a mean age of 72.2 years. The 7073 rural participants differed significantly (P ≤ 0.02) from the 22,093 urban participants in several major characteristics, such as older age, greater body mass index, and so on. The overall prevalence of AF was 4.6% (n = 1347). AF was more prevalent in 7073 rural participants than 22,093 urban participants (5.6% vs. 4.3%, P < 0.01), before and after adjustment for age, body mass index, blood pressure, pulse rate, cigarette smoking, alcohol consumption and prior medical history. Multivariate logistic regression analysis identified overweight/obesity (OR = 1.35, 95% CI: 1.17-1.54) in urban areas and cigarette smoking (OR = 1.62, 95% CI: 1.20-2.17) and alcohol consumption (OR = 1.42, 95% CI: 1.04-1.93) in rural areas as specific risk factors for prevalent AF. In patients with known AF in urban areas (n = 781) and rural areas (n = 338), 60.6% and 45.9%, respectively, received AF treatment (P < 0.01), and only 22.4% and 17.2%, respectively, received anticoagulation therapy (P = 0.05). CONCLUSIONS In China, there are urban-rural disparities in AF in the elderly, with a higher prevalence and worse management in rural areas than urban areas. Our study findings provide insight for health policymakers to consider urban-rural disparity in the prevention and treatment of AF.

OBJECTIVE: To explore the relationship between serum chloride levels and prognosis in patients with hepatic coma in the intensive care unit (ICU). METHODS: We analyzed 545 patients with hepatic coma in the ICU from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Associations between serum chloride levels and 28-day and 1-year mortality rates were assessed using restricted cubic splines (RCSs), Kaplan-Meier (KM) curves, and Cox regression. Subgroup analyses, external validation, and mechanistic studies were also performed. RESULTS: A total of 545 patients were included in the study. RCS analysis revealed a U-shaped association between serum chloride levels and mortality in patients with hepatic coma. The KM curves indicated lower survival rates among patients with low chloride levels (< 103 mmol/L). Low chloride levels were independently linked to increased 28-day and 1-year all-cause mortality rates. In the multivariate models, the hazard ratio ( HR) for 28-day mortality in the low-chloride group was 1.424 (95% confidence interval [ CI]: 1.041-1.949), while the adjusted hazard ratio for 1-year mortality was 1.313 (95% CI: 1.026-1.679). Subgroup analyses and external validation supported these findings. Cytological experiments suggested that low chloride levels may activate the phosphorylation of the NF-κB signaling pathway, promote the expression of pro-inflammatory cytokines, and reduce neuronal cell viability. CONCLUSION Low serum chloride levels are independently associated with increased mortality in patients with hepatic coma.
Humans ; Male ; Female ; Middle Aged ; Intensive Care Units ; Prognosis ; Chlorides/blood* ; Aged ; Coma/blood* ; Adult

ObjectiveExosomes are microvesicles which could be secreted by all cell types with diameters between 30 and 150 nm. It was widely distributed in body fluids including blood, urine, and breast milk. Exosomes are considered as potential biomarkers and drug carriers by reason of containing nucleic acids, lipids, proteins and other bioactive molecules. Milk-derived exosomes have been widely used as drug delivery carriers to treat targeted diseases with a lower cost, higher biocompatibility and lower immunogenicity. Until now, there is no research about the milk-derived exosomes phosphorylation to reveal the difference of protein phosphorylation in different species of milk. To investigate the pathways and proteins with specific functions, phosphorylated proteomic analysis of milk-derived exosomes from different species is performed, and provide new ideas for exploring diversified treatments of disease. MethodsWhey and exosomes derived from bovine, porcine and caprine milk were performed for proteomics and phosphoproteomics analysis. The relationship between milk exosome proteins from different species and signaling pathways were analyzed using bioinformatics tools. ResultsA total of 4 191 global proteins, 1 640 phosphoproteins and 4 064 phosphosites were identified from 3 species of milk-derived exosomes, and the exosome proteins and phosphoproteins from different species were significantly higher than those of whey. Meanwhile, some special pathways were enriched like Fcγ-mediated phagocytosis from bovine exosomes, pathways related with neural and immune system from caprine exosomes, positive and negative regulation of multiple activities from porcine exosomes. ConclusionIn this study, the proteomic and phosphoproteomic analyses of exosomes and whey from bovine, porcine and caprine milk were carried out to reveal the difference of composition and related signaling pathways of milk exosome from different species. These results provided powerful support for the application of exosomes from different milk sources in the field of disease treatment.

Connectomics, a research field in neuroscience studying the synaptic connectivity patterns between neurons across different brain regions, is crucial for understanding neural computations underlying complex functions such as emotion, learning, and cognition. Specifically, micrometer-resolution mesoscale connectomics has become the most widely used technology in rodent neuroscience due to its unique advantages, and it also has the potential to transform brain research in non-human primates. Traditional mesoscale connectome techniques typically use fluorescence labeling and optical imaging to perform anterograde or retrograde tracing of neural circuits. To achieve single-cell resolution, methods for sparse labeling of neurons have been developed. However, it remains challenging to trace neurons in high throughput in individual animals and integrate multi-omics data across modalities. In the past decade, high-throughput mesoscale connectome technologies based on DNA barcoding have made significant progress. These technologies have provided novel tools to map single cell connectome, with higher throughput, lower cost, and multi-omics compatibility. Here we review several mature mesoscale connectome technologies based on DNA barcoding, discussing their principles, applications, advantages and disadvantages. We also propose future directions for barcoding-based connectomics.

Aim To compare the pharmacokinetics of pemirolast potassium tablets in healthy subjects in Chi-na under single fasting and postprandial conditions,and to evaluate the bioequivalence of the test prepara-tion(T)and the reference preparation(R).Methods A randomized,open-ended,single-dose,two-cycle,double-cross bioequivalence trial design was adopted,and 26 and 30 subjects were enrolled in the fasting group and the postprandial group,respectively,and 10 mg of the test preparation and the reference preparation were taken in the fasting or postprandial state each cy-cle,and venous blood was collected at the designed time points before and after the administration cycle.The concentration of pemirolast potassium in plasma was determined by LC-MS/MS method,and the phar-macokinetic parameters were calculated with PhoenixTM WinNonlin ?(8.3)software,and the bioequivalence analysis of the two preparations was performed.Re-sults The t1/2 of the test preparation and the reference preparation was(4.44±0.91)h and(4.49±0.93)h,respectively;the median tmax was(1.96±1.29)h and(2.18±1.25)h,respectively;the Cmax was(867.12±205.56)μg·L-1 and(863.35±172.03)μg·L-1,respectively;the AUC0-t was(5 513.23±1463.67)h·μg·L-1 and(5 661.32±1 628.65)h·μg·L-1,respectively;AUC0_∞ was(5 699.81±1477.68)h·μg·L-1 and(5 849.44±1 644.75)h·μg·L-1,respectively.The statistical results of the 90％confidence intervals of the main pharmacokinetic parameters Cmax,AUC0-t,and AUC0-∞ was 92.49％～107.53％,94.71％～100.67％and 95.28％～100.27％,respectively,all of which were within the range of 80.00％～125.00％,and the safety of the tested preparation and the reference preparation was good when taken orally on an empty stomach.The t1/2 of single oral administration after prandial administra-tion of the tested preparation and the reference prepara-tion was(4.46±0.78)and(4.51±0.84)h,respec-tively;the median tmax was(3.08±1.36)h and(3.28±1.28)h,respectively;the Cmax was(683.83±111.87)μg·L-1 and(689.77±110.24)μg·L-1,respectively;the AUC0-t was(5 695.99±1566.05)h·μg·L-1 and(5 773.60±1 551.04)h·μg·L-1,respectively;the AUC0-∞ was(5 914.06±1 551.86)h·μg·L-1 and(5 967.30±1552.89)h·μg·L-1,respectively.The 90％confi-dence interval of Cmax,AUC0-t,and AUC0-∞ was 93.56％～104.69％,96.43％～100.83％,and 97.29％～101.14％,respectively,which was in the range of 80.00％～125.00％,and the safety of the tested preparation and the reference preparation was good after meals.Conclusion In the state of fasting and postprandial single oral administration,the two kinds of pemirolast potassium tablets have good bio-equivalence.

Objective To explore the mechanism of tumor-associated fibroblasts(CAFs)for regulating proliferation and migration of prostate cancer(PCa)cells.Methods We conducted a bioinformatics analysis to identify miRNAs with high expression in PCa.The proliferation,migration and hsa-miR-18b-5p expression levels were observed in PCa cells co-cultured with CAFs.We further examined hsa-miR-18b-5p expression level in 20 pairs of PCa and adjacent tissue samples and in different PCa cell lines and normal epithelial cells using RT-qPCR.In PCa cell lines C4-2 and LNCAPNC,the effects of transfection with a hsa-miR-18b-5p inhibitor on cell proliferation,migration,invasion,drug resistance,apoptosis and cell cycle were evaluated,and the effects of has-miR-18b-5p knockdown on C4-2 cell xenograft growth and mouse survival were observed in nude mice.Dual luciferase reporter gene assay was used to validate the targeting relationship between hsa-miR-18b-5p and its target genes,whose expressions were detected in PCa cells using RT-qPCR and Western blotting.Results The expression of hsa-miR-18b-5p was significantly increased in the co-culture of CAFs and PCa cell lines,which exhibited significantly enhanced proliferation and migration abilities.Transfection with has-miR-18b-5p inhibitor strongly attenuated the effect of CAFs for promoting proliferation and migration of PCa cells,and in C4-2 and LNCAP cells cultured alone,inhibition of hsa-miR-18b-5p obviously suppressed cell proliferation,migration,invasion,and drug resistance.In the tumor-bearing mice,hsa-miR-18b-5p knockdown in the transplanted cells significantly inhibited xenograft growth and increased the survival time of the mice.Target gene prediction suggested that FBXL3 was a potential target of hsa-miR-18b-5p,and dual luciferase reporter gene confirmed a binding site between them.In C4-2 and LNCAP cells,hsa-miR-18b-5p knockdown resulted in significantly increased expression levels of FBXL3.Conclusion CAFs promotes proliferation and migration of PCa cells by up-regulating hsa-miR-18b-5p to suppress FBXL3 expression.

Objective:To explore the potential causal relationship between gut microbiota and teratozoospermia.Methods:We searched the database of Genome-Wide Association Study(GWAS)for gut microbiota-and teratozoospermia-related data.We used gut microbiota as an exposure factor,determined the instrumental variables according to the GWAS data on 18 340 participants released by the MiBioGen Alliance,and derived the outcome variables from the European data on teratozoospermia,with a sample size of 85 716,including 915 cases and 209 006 controls.Using inverse-variance weighting(IVW),MR-Egger regression and the weighted median estimator(WME),we performed two-sample Mendelian randomization(MR)analysis on the retrieved data,and estimated the causal relationship between gut microbiota and teratozoospermia based on the β value.Results:Two-sample MR analysis indicated that the class Erysipelotrichia,family Erysipelotrichaceae,family Streptococcaceae,genus Coprococcusl,genus Ruminococcaceae UCG009,genus Streptococcus,order Clostridialesm and order Erysipelotrichales were causally related with the increased risk,while the family Porphyromonadaceae with the decreased risk of teratozoospermia.Conclusion:The class Erysipelotrichia,family Erysipe-lotrichaceae,family Streptococcaceae,genus Coprococcusl,genus Ruminococcaceae UCG009,genus Streptococcus,order Clostridia-lesm and order Erysipelotrichales are one of the causes of teratozoospermia,related to the increased risk of the condition,while the family Porphyromonadaceae has a protective effect on sperm morphology,reducing the risk of teratozoospermia.

Objective To investigate the clinical characteristics and prognosis of pneumococcal meningitis(PM),and drug sensitivity of Streptococcus pneumoniae(SP)isolates in Chinese children.Methods A retrospective analysis was conducted on clinical information,laboratory data,and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country.Results Among the 160 children with PM,there were 103 males and 57 females.The age ranged from 15 days to 15 years,with 109 cases(68.1% )aged 3 months to under 3 years.SP strains were isolated from 95 cases(59.4% )in cerebrospinal fluid cultures and from 57 cases(35.6% )in blood cultures.The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87)and 27% (21/78),respectively.Fifty-five cases(34.4% )had one or more risk factors for purulent meningitis,113 cases(70.6% )had one or more extra-cranial infectious foci,and 18 cases(11.3% )had underlying diseases.The most common clinical symptoms were fever(147 cases,91.9% ),followed by lethargy(98 cases,61.3% )and vomiting(61 cases,38.1% ).Sixty-nine cases(43.1% )experienced intracranial complications during hospitalization,with subdural effusion and/or empyema being the most common complication[43 cases(26.9% )],followed by hydrocephalus in 24 cases(15.0% ),brain abscess in 23 cases(14.4% ),and cerebral hemorrhage in 8 cases(5.0% ).Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old,with rates of 91% (39/43)and 83% (20/24),respectively.SP strains exhibited complete sensitivity to vancomycin(100% ,75/75),linezolid(100% ,56/56),and meropenem(100% ,6/6).High sensitivity rates were also observed for levofloxacin(81% ,22/27),moxifloxacin(82% ,14/17),rifampicin(96% ,25/26),and chloramphenicol(91% ,21/23).However,low sensitivity rates were found for penicillin(16% ,11/68)and clindamycin(6% ,1/17),and SP strains were completely resistant to erythromycin(100% ,31/31).The rates of discharge with cure and improvement were 22.5% (36/160)and 66.2% (106/160),respectively,while 18 cases(11.3% )had adverse outcomes.Conclusions Pediatric PM is more common in children aged 3 months to under 3 years.Intracranial complications are more frequently observed in children under 1 year old.Fever is the most common clinical manifestation of PM,and subdural effusion/emphysema and hydrocephalus are the most frequent complications.Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates.Adverse outcomes can be noted in more than 10% of PM cases.SP strains are high sensitivity to vancomycin,linezolid,meropenem,levofloxacin,moxifloxacin,rifampicin,and chloramphenicol.[Chinese Journal of Contemporary Pediatrics,2024,26(2):131-138]

Objective To explore the efficiency of artificial intelligence and radiomics-assisted X-ray in diagnosis of lumbar osteoporotic vertebral compression fractures(OVCF).Methods The clinical data of 455 patients diagnosed as lumbar OVCF by MRI in our hospital were selected.The patients were divided into the training group(n=364)and the validation group(n=91),X-ray films were extracted,the image delineation,feature extraction and data analysis were carried out,and the artificial intelligence radiomics deep learning was applied to establish a diagnostic model for OVCF.After verifying the effectiveness of the model by receiver operating characteristic(ROC)curve,area under the curve(AUC),calibration curve,and decision curve analysis(DCA),the efficiencies of manual reading,model reading,and model-assisted manual reading of X-ray in the early diagnosis of OVCF were compared.Results The ROC curve,AUC and calibration curve proved that the model had good discrimination and calibration,and excellent diagnostic performance.DCA demonstrated that the model had a higher clinical net benefit.The diagnostic efficiency of the manual reading group:the accuracy rate was 0.89,the recall rate was 0.62.The diagnostic efficiency of the model reading group:the accuracy rate was 0.93,the recall rate was 0.86,the model diagnosis showed good predictive performance,which was significantly better than the manual reading group.The diagnostic efficiency of the model-assisted manual reading group:the accuracy rate was 0.92,the recall rate was 0.72,and the recall rate of the model-assisted manual reading group was higher than that of the manual reading group,but lower than that of the model reading group,indicating the superiority of the model diagnosis.Conclusion The diagnostic model established based on artificial intelligence and radiomics in this study has reached an ideal level of efficacy,with better diagnostic efficacy compared with manual reading,and can be used to assist X-ray in the early diagnosis of OVCF.