OBJECTIVES: To investigate the clinical sub-phenotype (SP) of pediatric acute kidney injury (AKI) and their association with clinical outcomes. METHODS: General status and initial values of laboratory markers within 24 hours after admission to the pediatric intensive care unit (PICU) were recorded for children with AKI in the derivation cohort (n=650) and the validation cohort (n=177). In the derivation cohort, a least absolute shrinkage and selection operator (LASSO) regression analysis was used to identify death-related indicators, and a two-step cluster analysis was employed to obtain the clinical SP of AKI. A logistic regression analysis was used to develop a parsimonious classifier model with simplified metrics, and the area under the curve (AUC) was used to assess the value of this model. This model was then applied to the validation cohort and the combined derivation and validation cohort. The association between SPs and clinical outcomes was analyzed with all children with AKI as subjects. RESULTS: In the derivation cohort, two clinical SPs of AKI (SP1 and SP2) were identified by the two-step cluster analysis using the 20 variables screened by LASSO regression, namely SP_d1 group (n=536) and SP_d2 group (n=114). The simplified classifier model containing eight variables (P<0.05) had an AUC of 0.965 in identifying the two clinical SPs of AKI (P<0.001). The validation cohort was clustered into SP_v1 group (n=156) and SP_v2 group (n=21), and the combined derivation and validation cohort was clustered into SP1 group (n=694) and SP2 group (n=133). After adjustment for confounding factors, compared with the SP1 group, the SP2 group had significantly higher incidence rates of multiple organ dysfunction syndrome and death during the PICU stay (P<0.001), and SP2 was significantly associated with the risk of death within 28 days after admission to the PICU (P<0.001). CONCLUSIONS This study establishes a parsimonious classifier model and identifies two clinical SPs of AKI with different clinical features and outcomes.The SP2 group has more severe disease and worse clinical prognosis.
Humans ; Acute Kidney Injury/diagnosis* ; Prognosis ; Male ; Female ; Child ; Child, Preschool ; Phenotype ; Infant ; Logistic Models ; Adolescent

OBJECTIVE: To investigate the effect of zedoarondiol on neovascularization of atherosclerotic (AS) plaque by exosomes experiment. METHODS: ApoE^-/- mice were fed with high-fat diet to establish AS model and treated with high- and low-dose (10, 5 mg/kg daily) of zedoarondiol, respectively. After 14 weeks, the expressions of anti-angiogenic protein thrombospondin 1 (THBS-1) and its receptor CD36 in plaques, as well as platelet activation rate and exosome-derived miR-let-7a were detected. Then, zedoarondiol was used to intervene in platelets in vitro, and miR-let-7a was detected in platelet-derived exosomes (Pexo). Finally, human umbilical vein endothelial cells (HUVECs) were transfected with miR-let-7a mimics and treated with Pexo to observe the effect of miR-let-7a in Pexo on tube formation. RESULTS: Animal experiments showed that after treating with zedoarondiol, the neovascularization density in plaques of AS mice was significantly reduced, THBS-1 and CD36 increased, the platelet activation rate was markedly reduced, and the miR-let-7a level in Pexo was reduced (P<0.01). In vitro experiments, the platelet activation rate and miR-let-7a levels in Pexo were significantly reduced after zedoarondiol's intervention. Cell experiments showed that after Pexo's intervention, the tube length increased, and the transfection of miR-let-7a minics further increased the tube length of cells, while reducing the expressions of THBS-1 and CD36. CONCLUSION Zedoarondiol has the effect of inhibiting neovascularization within plaque in AS mice, and its mechanism may be potentially related to inhibiting platelet activation and reducing the Pexo-derived miRNA-let-7a level.
Animals ; MicroRNAs/genetics* ; Exosomes/drug effects* ; Plaque, Atherosclerotic/genetics* ; Neovascularization, Pathologic/genetics* ; Human Umbilical Vein Endothelial Cells/metabolism* ; Humans ; Blood Platelets/drug effects* ; Apolipoproteins E/deficiency* ; Thrombospondin 1/metabolism* ; CD36 Antigens/metabolism* ; Platelet Activation/drug effects* ; Male ; Mice ; Mice, Inbred C57BL

Age-related macular degeneration (AMD) is a disease that affects the vision of elderly individuals worldwide. Although current therapeutics have shown effectiveness against AMD, some patients may remain unresponsive and continue to experience disease progression. Therefore, in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment. Recently, studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species (ROS) and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) innate immunity pathways, ultimately resulting in sterile inflammation and cell death in various cells, such as cardiomyocytes and macrophages. Therefore, combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management. Notably, emerging evidence indicates that natural products targeting mitochondrial quality control (MQC) and the cGAS/STING innate immunity pathways exhibit promise in treating AMD. Here, we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways, as well as their interconnected mediators, which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses, thereby hoping to offer new insights into therapeutic interventions for AMD treatment.

Objective This study aims at establishing a teaching catalog and content for breast rare dis-eases and developing the syllabus for the breast rare disease using integrated multimodality of case-/problem-/resource-based learning(CBL+PBL+RBL).Methods By conducting bibliometrics co-occurrence analysis,we collected 6291 articles on breast rare disease published from January,1975 to June,2024.Additionally,we re-trieved the Textbook on Rare Diseases,the Catalog of Chinese Rare Disease,and Second Batch of Rare Dis-ease Catalog and then decided the teaching content.Results From 16,387 keywords,1000(6.1％)keywords were identified through co-occurrence analysis,including 50(0.3％)candidate diseases.These were classified into three categories:rare primary breast diseases,rare genetic mutation-related diseases associated with breast cancer,and rare systemic multi-system diseases involving the breast.From the candidate list,20(0.1％)rare primary breast diseases were further selected for their notable clinical teaching significance,and significant multi-systemic diseases affecting the breast,whether related to gene mutations or not.Teaching plans were draf-ted using a diversified parallel teaching approaches,taking into account the characteristics of different diseases and the focus of different teaching methods.Conclusions This study initiated the development of the teaching content for breast rare diseases and developed the teaching syllabus using the CBL+PBL+RBL integrated multi teaching model and targeting each rare breast disease for the critical point for teaching.

BACKGROUND: The benefits of healthy lifestyles are well recognized. However, the extent to which improving unhealthy lifestyles reduces cardiovascular disease (CVD) risk needs to be discussed. We evaluated the impact of lifestyle improvement on CVD incidence using data from the China-PAR project (Prediction for Atherosclerotic Cardiovascular Disease Risk in China). METHODS: A total of 12,588 participants free of CVD were followed up for three visits after the baseline examination. Changes in four lifestyle factors (LFs) (smoking, diet, physical activity, and alcohol consumption) were assessed through questionnaires from the baseline to the first follow-up visit. Cox proportional hazard models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). The risk advancement periods (RAPs: the age difference between exposed and unexposed participants reaching the same incident CVD risk) and population-attributable risk percentage (PAR%) were also calculated. RESULTS: A total of 909 incident CVD cases occurred over a median follow-up of 11.14 years. Compared with maintaining 0-1 healthy LFs, maintaining 3-4 healthy LFs was associated with a 40% risk reduction of incident CVD (HR = 0.60, 95% CI: 0.45-0.79) and delayed CVD risk by 6.31 years (RAP: -6.31 [-9.92, -2.70] years). The PAR% of maintaining 3-4 unhealthy LFs was 22.0% compared to maintaining 0-1 unhealthy LFs. Besides, compared with maintaining two healthy LFs, improving healthy LFs from 2 to 3-4 was associated with a 23% lower risk of CVD (HR = 0.77, 95% CI: 0.60-0.98). CONCLUSIONS Long-term sustenance of healthy lifestyles or improving unhealthy lifestyles can reduce and delay CVD risk.

Humans ; Stroke, Lacunar ; Mendelian Randomization Analysis ; Leukocytes ; Telomere/genetics* ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide

The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62⁺ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62⁺ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.

Objective: To examine the clinical efficacy of 3 anti-reflux methods of digestive tract reconstruction after proximal gastrectomy for gastric cancer. Methods: The clinical data and follow-up data of gastric cancer patients who underwent anti-reflux reconstruction after proximal gastrectomy in 11 medical centers of China from September 2016 to August 2021 were retrospectively collected, including 273 males and 65 females, aging of (63±10) years (range: 28 to 91 years). Among them, 159 cases were performed with gastric tube anastomosis (GTA), 107 cases with double tract reconstruction (DTR), and 72 cases with double-flap technique (DFT), respectively. The duration of operation, length of postoperative hospital stay and early postoperative complications (referring to Clavien-Dindo classification) of different anti-reflux reconstruction methods were assessed. Body mass index, hemoglobin and albumin were used to reflect postoperative nutritional status. Reflux esophagitis was graded according to Los Angeles criteria based on the routinely gastroscopy within 12 months after surgery. The postoperative quality of life (QoL) was evaluated by Visick score system. The ANOVA analysis, Kruskal-Wallis rank sum test, χ² test and Fisher's exact test were used for comparison between multiple groups, and further comparison among groups were performed with LSD, Tamhane's test or Bonferroni corrected χ² test. The mixed effect model was used to compare the trends of Body mass index, hemoglobin and albumin over time among different groups. Results: The operation time of DFT was significantly longer than that of GTA and DTR ((352±63) minutes vs. (221±66) minutes, (352±63) minutes vs. (234±61) minutes, both P<0.01). The incidence of early complications with Clavien-Dindo grade Ⅱ to Ⅴ in GTA, DFT and DTR groups was 17.0% (27/159), 9.7% (7/72) and 10.3% (11/107), respectively, without significant difference among these three groups (χ²=3.51, P=0.173). Body mass index decreased more significantly in GTA than DFT group at 6 and 12 months after surgery (mean difference=1.721 kg/m², P<0.01; mean difference=2.429 kg/m², P<0.01). body mass index decreased significantly in DTR compared with DFT at 12 months after surgery (mean difference=1.319 kg/m², P=0.027). There was no significant difference in hemoglobin or albumin fluctuation between different reconstruction methods perioperative. The incidence of reflux esophagitis one year after surgery in DTR group was 12.9% (4/31), which was lower than that in DFT (45.9% (17/37), χ²=8.63, P=0.003). Follow-up of postoperative quality of life showed the incidence of Visick grade 2 to 4 in DFT group was lower than that in GTA group (10.4% (7/67) vs. 34.6% (27/78), χ²=11.70, P=0.018), while there was no significant difference between DFT and DTR group (10.4% (7/67) vs. 22.2% (8/36, P>0.05). Conclusions: Compared with GTA and DTR, DFT is more time-consuming, but there is no significant difference in early complications among three methods. DFT reconstruction is more conducive to maintain postoperative nutritional status and improve QoL, especially compared with GTA. The risk of reflux esophagitis after DTR reconstruction is lower than that of DFT.
Aged ; Albumins ; Esophagitis, Peptic/surgery* ; Female ; Gastrectomy/methods* ; Hemoglobins ; Humans ; Male ; Middle Aged ; Quality of Life ; Retrospective Studies ; Stomach Neoplasms/surgery*

Background: The association of serum retinol-binding protein (RBP) levels with nonalcoholic fatty liver disease (NAFLD) remains controversial. Furthermore, few studies have investigated their relationship in type 2 diabetes mellitus (T2DM) patients. Therefore, the aim of the present study was to explore the association between serum RBP levels and NAFLD in Chinese inpatients with T2DM. Methods: This cross-sectional, real-world study included 2,263 Chinese T2DM inpatients. NAFLD was diagnosed by abdominal ultrasonography. The subjects were divided into four groups based on RBP quartiles, and clinical characteristics were compared among the four groups. The associations of both RBP levels and quartiles with the presence of NAFLD were also analyzed. Results: After adjustment for sex, age, and diabetes duration, there was a significant increase in the prevalence of NAFLD from the lowest to the highest RBP quartiles (30.4%, 40.0%, 42.4%, and 44.7% for the first, second, third, and fourth quartiles, respectively, P<0.001 for trend). Fully adjusted multiple logistic regression analysis revealed that both increased RBP levels (odds ratio, 1.155; 95% confidence interval, 1.012 to 1.318; P=0.033) and quartiles (P=0.014 for trend) were independently associated with the presence of NAFLD in T2DM patients. Conclusion Increased serum RBP levels were independently associated with the presence of NAFLD in Chinese T2DM inpatients. Serum RBP levels may be used as one of the indicators to assess the risk of NAFLD in T2DM patients.

OBJECTIVE: To investigate the treatment and prognosis of multiple primary malignant neoplasms (MPMN) complicated with renal cell carcinoma (RCC), and to make risk stratification. METHODS: A retrospective study of 27 cases of MPMN with RCC in two centers, including the different tumors of MPMN, specific treatment methods, and the interval between primary cancers. At the same time, the survival conditions, including recurrence, metastasis and survival, were followed up for statistical analysis. The interval between the two kinds of primary cancer within 6 months was simultaneous MPMNs, and more than 6 months was metachronous MPMNs. For simple risk stratification of cases, as long as one of the MPMNs had a stage Ⅲ or higher malignancy, which was defined as high risk. RESULTS: Among the 27 patients, 20 were male and 7 were female, with age at the time of diagnosis was 42-82 years, with an average age of (61.3±11.7) years. The age at the diagnosis of renal cancer was 43-87 years, with an average age of (66.0±11.3) years. There were 21 cases with duplex primary malignant neoplasms, 4 cases with triple primary malignant neoplasms, and 2 cases with quadruple primary malignant neoplasms. The interval between first cancer and second cancer was 0-360 months, with a median of 18 months. There were 17 cases of metachronous multiple primary malignant neoplasms and 10 cases of simultaneous multiple primary malignant neoplasms. The most common system of MPMN with comorbid RCC involved urologic system, digestive system and respiratory system. The most common locations of MPMN with comorbid RCC were bladder cancer, lung cancer and colon cancer. Follow-up time calcu- lated from the last cancer was 2-156 months, with a median of 32 months. And 14 cases survived and 13 cases died, with 11 cases being tumor related. Tumor stage was the risk factor of prognosis. Any kind of tumor stage in stage Ⅲ or above had a relatively poor prognosis. CONCLUSION MPMN complicated with RCC is relatively rare. Standard treatment should be used for each cancer type during the treatment process. The prognosis mainly depends on the highest stage of each tumor. Simple risk stratification shows that the prognosis of the high-risk group is worse. This simple stratification method may be helpful to predict the prognosis.
Aged ; Carcinoma, Renal Cell/therapy* ; Female ; Humans ; Kidney Neoplasms/therapy* ; Male ; Middle Aged ; Neoplasms, Multiple Primary/therapy* ; Prognosis ; Retrospective Studies