Background::Substantial metabolic heterogeneity exists prior to the development of diabetes, creating opportunities for earlier and more precise intervention. This study aimed to analyze common clinical indicators in a diabetes-free population using innovative clustering methods to identify characteristic subgroups and evaluate their utility in stratified prediction of diabetes risk and related complications.Methods::This analysis included 13,829 adults without diabetes from the Kunshan Aging Research with E-health (KARE) cohort, a population-based longitudinal cohort of 51,400 community-dwelling residents from both urban and rural areas of Kunshan City, China, who have received annual health examinations between January 2014 and December 2023. A novel subtype classification method based on complication clustering and weighted naive Bayes classification was applied to select the most informative variables and categorize individuals into distinct diabetes subtypes. We then assessed 3-year risks of diabetes and complications, including cardiovascular disease (CVD), fatty liver disease (FLD), and stroke. To evaluate the influence of genetic factors, polygenic risk scores (PRS) were compared across all participants. External validation was performed using data from 6209 diabetes-free individuals in a cohort of 22,630 people who have been followed since 2014 at Beijing Jiuhua Hospital.Results::Thirteen clinically relevant variables were identified: sex, age, body mass index (BMI), waist circumference, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), uric acid (UA), blood urea nitrogen (BUN), fasting blood glucose (FBG), systolic blood pressure (SBP), and heart rate. Three clusters were identified in the Kunshan cohort. Cluster 1 ( n = 6751) had favorable indicators and the lowest risks of diabetes (2.04%, 138/6751) and complications, including CVD (4.52%, 305/6751), FLD (15.30%, 1033/6751), and stroke (9.07%, 612/6751). Cluster 2 ( n = 4622) had the poorest glucose and lipid control, with the highest 3-year cumulative incidence of diabetes (9.95%, 460/4622) and FLD (52.14%, 2410/4622). Cluster 3 ( n = 2456) was characterized by the oldest age, highest SBP, BMI, and waist circumference, with intermediate diabetes risk (3.05%, 75/2456) and the highest risks of CVD (8.47%, 208/2456) and stroke (14.13%, 347/2456). In Cox survival analysis for FLD (adjusted), using Cluster 1 as reference, the hazard ratio (HR) was 2.357 (95% confidence interval [CI]: 2.161-2.571, P <0.001) for Cluster 2, and was 1.903 (95% CI: 1.718-2.108, P <0.001) for Cluster 3. In Cox survival analysis for CVD, HRs were 1.193 (95% CI: 0.975-1.459, P = 0.087) for Cluster 2 and 1.295 (95% CI: 1.041-1.611, P = 0.02) for Cluster 3. In stroke analysis, HRs were 1.058 (95% CI: 0.911-1.23, P = 0.46) for Cluster 2 and 1.212 (95% CI: 1.029-1.428, P = 0.021) for Cluster 3. The risks of diabetes and CVD predicted by PRS were consistent with those identified by clinical clustering. The findings were independently confirmed in the Beijing Jiuhua Hospital cohort. Conclusions::Phenotypes derived from clinical characteristic analysis using the new clustering method effectively identify and stratify the risk of diabetes and related complications, such as CVD, FLD, and stroke, in two large cohorts of diabetes-free Chinese adults, supporting the development of more precise and individualized prevention strategies.

In forensic genetics, Y-chromosomal short tandem repeats (Y-STRs) and single nucleotide polymorphisms (Y-SNPs) are indispensable for paternal lineage identification and population genetic research. While Y-STRs enable short-term familial linkage, their high mutation rates complicate precise lineage determinations. Conversely, Y-SNPs provide stable deep phylogenetic resolution, complementing Y-STRs by resolving mutation-induced ambiguities and enhancing forensic accuracy. However, existing methods lack a combined detection system tailored to Chinese populations that integrates Y-STRs (with varied mutation rates) and Y-SNPs optimized for diverse forensic scenarios. To address this gap, we developed a 365-plex next-generation sequencing (NGS) panel optimized for Chinese populations. The panel integrates 57 Y-STRs (13 rapidly mutating, 44 moderate-to-slow) and 308 Y-SNPs (68% targeting O subclades), with short amplicons designed for degraded DNA. Validation following SWGDAM guidelines confirmed its reliability. It has a genotyping sensitivity of 125pg input DNA, 100% repeatability, and can resolve male-male mixtures up to 1:4 and male-female mixtures up to 1:10 and no cross-reactivity in non-target samples. Among 326 Shandong Han Chinese males, the panel achieved perfect Y-STR haplotype diversity (HD=1.0000) and discrimination capacity (DC=1.0000). Remarkably, 13 rapidly mutating Y-STRs exhibited discriminatory power comparable to 44 moderate-to-slow loci, effectively distinguishing close relatives. Y-SNP analysis identified 137 terminal haplogroups with a haplogroup diversity of 0.9910, confirming high resolution for Chinese populations. By simultaneously analyzing recent familial relationships and deep phylogenetic lineages, this panel resolves Y-STR mutation ambiguities, offering a robust tool for paternal lineage and ancestry analysis in Chinese forensic applications.

Age estimation is a critical area of research in forensic medicine. Accurate age assessments provide vital insights for criminal investigations and play a significant role in shaping case characteristics, as well as influencing conviction and sentencing outcomes. In previous studies, skeletal and dental morphology was the most commonly employed method for age estimation. However, these techniques have notable limitations, including insufficient accuracy, significant subjectivity, and challenges in application to trace evidence. Consequently, the search for new molecular markers for age inference has emerged as a prominent research focus. Recently, mitochondrial DNA (mtDNA) has attracted attention due to its close association with development and aging processes.However, mtDNA has not been applied in forensic age estimation. In this study, the relative quantity of mitochondrial DNA to nuclear DNA, i.e., the mitochondrial DNA copy number(mtDNAcn), was determined using real-time quantitative PCR and used as an indicator for assessing mitochondrial copy number. The correlation between mtDNA and age was further investigated. A model for estimating age from mtDNAcn in blood was constructed through machine learning techniques. Of the various methods evaluated, the k-nearest neighbors (kNN) algorithm demonstrated the best performance, achieving a mean absolute error (MAE) of 4.938 years and an R² value of 0.758. This framework offers a novel approach for age estimation from trace forensic evidence and significantly expands the potential applications of mtDNA in the field of forensic science.

Unexplained recurrent spontaneous abortion (URSA) is a distressing pregnancy complication that seriously threat to women's reproductive health. Trophoblast pyroptosis was involved in the occurrence of URSA, but the potential mechanism remains unclear. In this work, we found CASP1 transcription and the level of pyroptosis were significantly elevated in the villous tissues of URSA patients. Suppression of cell pyroptosis by Gasdermin-D (GSDMD) or Caspase-1 inhibitors can reduce embryo resorption rate of URSA mice, while Caspase-1 over-expression in normal pregnant (NP) mice can aggravate embryo resorption. Meanwhile, a pronounced decline in the expression of microRNA-126-5p (miR-126-5p) was found in URSA patients, which was inversely related to CASP1 expression. Over-expression of miR-126-5p restrained trophoblast pyroptosis via inhibiting Caspase-1/GSDMD signaling pathway by direct binding to 3'-UTR of CASP1. Moreover, experiments in vivo substantiated that up-regulation of miR-126-5p effectively suppressed Caspase-1-mediated pyroptosis in placental tissue and significantly reduced embryo resorption rate. Collectively, these results underscored that diminished miR-126-5p expression plays a crucial role in URSA by enhancing trophoblast pyroptosis through activating Caspase-1/GSDMD signaling pathway. As a result, miR-126-5p shows significant promise as a possible biomarker for diagnosis and treatment of URSA.

Age estimation can offer additional information to inform an investigation. The determination can assist in directing investigators towards putative victims and narrowing the scope of the investigation. Age-related skeletal development and epigenetic clocks have been broadly applied in forensic age estimation. However, challenges in age estimation include the requirement for high-quality samples and cumbersome detection methods. Small noncoding RNAs have attracted the interest of forensic researchers owing to their low molecular weight and high stability. Transfer RNA-derived small RNA (tsRNA) is a newly discovered small RNA. Increasing evidence indicates that tsRNA has the potential as a biomarker for age estimation. In this study, 16 age-related tsRNAs recovered from blood were identified using massive parallel sequencing technology. Four tsRNAs were verified by real-time fluorescence quantitative polymerase chain reaction, and three age-related tsRNAs were used to establish age estimation models. The support vector machine regression model performed best with a mean absolute error of 6.38 years (R2 = 0.36) in the participants with an age range from 19 to 53. This study provides the first evidence that age can be estimated using tsRNA biomarkers. The use of small noncoding RNAs as biomarkers is a promising approach for age estimation in forensic samples.

Objective: This study aims to explore plasma exosomal piRNAs (Piwi-interacting RNAs) associated with acute myocardial infarction (AMI) progression, particularly those capable of interacting with PIWI proteins. Furthermore, we preliminarily investigate the correlation between these piRNAs and AMI to evaluate their potential as diagnostic biomarkers for AMI. Methods: A total of 12 male Wistar rats aged 6-8 weeks, weighing 210-310 g, were selected to establish AMI models with varying infarction time points by ligating the left anterior descending branch of the coronary artery (LAD). The rats were divided into two groups: Sham group and AMI group, with 6 rats in each group. Blood samples were subsequently collected from each group, and plasma was isolated. Exosomes and their contained RNA were further extracted from the plasma. We employed massively parallel sequencing (MPS) technology to compare the two groups and validated the differentially expressed piRNAs in rat plasma exosomes by real-time quantitative PCR (qPCR). Based on the piRBase database, further target gene analysis of the identified piRNAs was conducted. Results: MPS detected a total of 39,930 piRNAs. Compared to the Sham group, the expression profiles of piRNAs in the AMI group showed significant changes, with 15,777 piRNAs upregulated and 9,695 piRNAs downregulated. Validation by qPCR confirmed that the expression changes of piR-rno-1287165, piR-rno-568508, piR-rno-2058103, piR-rno-2375534, piR-rno-863759, and piR-rno-2096428 were consistent with the sequencing results, showing increased expression levels following AMI. Target gene analysis of the differentially expressed piRNAs was performed. The results revealed that piR-rno-568508 has 2 target genes (Wwp, Mir140), piR-rno-2096428 has 2 target genes (Gene symbol: AABR07015057.1, AABR07015081.2), and piR-rno-2058103 has 3 target genes (Gene symbol: AABR07015067.1, AABR07015081.2, AABR07063425.3). Conclusion: During AMI progression, six plasma exosomal piRNAs (piR-rno-1287165, piR-rno-568508, piR-rno- 2058103, piR-rno-2375534, piR-rno-863759, and piR-rno-2096428) showed significant expression changes, suggesting their potential as biomarkers for early differential diagnosis of AMI. The identification and functional analysis of these piRNA target genes offer valuable insights for the clinical diagnosis, treatment, and prognosis of AMI. Moreover, this finding provides a novel approach for early differential diagnosis of AMI in forensic medicine, advancing diagnostic technologies in this field.

High-grade serous ovarian cancer (HGSOC) exhibits poor prognosis due to late diagnosis, chemoresistance, and limited responses to immune checkpoint inhibitors. Although tumor‐infiltrating CD8+ T cells correlate with improved survival, current prognostic models remain inadequate. Thus, robust biomarkers linked to CD8+ T cell activation are urgently needed to guide clinical management. Transcriptomic and clinical profiles from 874 late-stage HGSOC patients were analyzed via single-sample gene set enrichment analysis for immune infiltration and weighted gene co-expression network analysis to identify CD8+ T cell-associated genes. An integrative machine learning approach was employed to develop a CD8⁺ T cell-associated immune prognostic signature (CIPS), which was then validated across multiple independent cohorts and benchmarked against 56 published models. CIPS was further characterized using single-cell RNA-seq analysis. The resulting 10-gene signature independently predicted overall survival in all cohorts and consistently surpassed most clinicopathological variables and comparator models. Low-risk patients exhibited significantly enhanced CD8+ T cell and cytotoxic gene scores, correlating with better responses to chemotherapy and immunotherapy. CIPS inversely correlated with tumor-mutation burden, BRCA1/2 mutations and homologous-recombination deficiency. Single-cell analysis localized signature genes to T lymphocyte and myeloid compartments and linked elevated CIPS activity to augmented intercellular communication in platinum-resistant tumors. CIPS captures a CD8+ T cell activation program that powerfully stratifies late-stage HGSOC, forecasts therapeutic benefit and offers a practicable biomarker for personalized immuno-oncology strategies.

OBJECT:The differentiation of acute myocardial infarction (AMI) has long been a challenging problem in clinical diagnosis and forensic identification. Recent studies have shown that microRNAs (miRNAs) in exosomes are involved in the development and progression of AMI. results indicated that plasma exosomal miRNAs can be considered as novel biomarkers for early AMI recognition. METHOD:In this study, exosomal miRNAs in plasma associated with the pathogenesis of AMI was explored and AMI identification model based on these miRNAs were established using machine learning technology. RESULT:Following the analysis of differentially expressed miRNAs in plasma-derived exosomes, the expression levels of 36 miRNAs increase with the passage of time, including miR-3473, miR-504, miR-490-5p, miR-218a-2-3p, and miR-760-3p, showed an increasing trend over time in the plasma exosomes of AMI rats. Based on machine learning techniques, miR-3473, miR-504, miR-490-5p, miR-218a-2-3p were used to construct a model for recognizing early AMI. The precision of the AMI identification model reached 0.955. CONCLUSION:The results indicated that plasma exosomal miRNAs can be considered as novel biomarkers for early AMI recognition.

BACKGROUND:Deep vein thrombosis (DVT) is a prevalent peripheral vascular disorder associated with abnormal epigenetic processes and altered gene expression in endothelial cells. Accumulating evidence has demonstrated that NAT10 (N-acetyltransferase 10)-mediated N4-acetylcytidine modification exerts unique roles in ferroptosis, but its roles are still elusive in DVT. METHODS:To explore the potential mechanism of NAT10 and ferroptosis on thrombogenesis, we used NAT10 and GPX4 (glutathione peroxidase 4) knockout mice as an in vivo model, and utilized techniques, such as RNA immunoprecipitation, acRIP-qPCR (acetylated RNA immunoprecipitation-quantitative PCR), N4-acetylcytidine Dot Blotting assay, and Western blotting, for detailed molecular analysis. RESULTS:GPX4 is a pivotal gene that suppresses ferroptosis. Utilizing endothelial cell-specific GPX4 conditional knockout mice (GPX4fl/flCdh5-Cre+), we proved that ferroptosis in endothelial cells promotes the formation of thrombosis. Previous evidence indicates that NAT10 overexpression induces ferroptosis and downregulates GPX4 expression. Here, we found that NAT10 expression was elevated in DVT mice, and silencing of NAT10 markedly attenuated ferroptosis both in vitro and in vivo. Furthermore, endothelial cell-specific knockout of NAT10 (NAT10fl/flCdh5-Cre+) demonstrated a reduction in endothelial ferroptosis, thereby inhibiting both the formation and progression of DVT. Mechanistic studies indicated that NAT10 facilitated the N4-acetylcytidine modification of HMOX1 (heme oxygenase 1), which enhanced its mRNA stability, leading to the accumulation of ferrous ions, and exacerbating endothelial dysfunction in DVT. CONCLUSIONS:Collectively, our data elucidate that downregulation of NAT10 mitigates endothelial ferroptosis and prevents DVT formation and progression by modulating HMOX1 expression, which offers a potential novel strategy for the prevention and treatment of thrombosis in DVT.

With the aging of population, the proportion of elderly patients with diabetes is gradually increasing, which poses challenges in the management and treatment of diabetes in this population. The aim of the study was to investigate the temporal changes in the treatment regimens and medical expenditures in older patients with diabetes in Beijing, China. Data of patients with diabetes from the Beijing Medical Insurance Database with medical records from 2016 to 2018 were retrospectively analyzed. Primary and secondary outcomes included the number of medications, comorbidities, diabetes-related complications, the estimated annual drug cost, the treatment strategies for elderly diabetic patients, and the classes of drugs prescribed. Data of 598,440 patients with diabetes in 2018 revealed that 49.8% of the recruited patients were female among elderly patients (>65 years old). The most common comorbidity was hypertension (87.6%). Over the 3 years, about 4.51 medications, including 1.88 antiglycemic drugs and 2.63 non-antiglycemic drugs were prescribed in elderly patients. The mean total annual medication cost was ¥12,186 ($1,676), including ¥6,116 ($841) for antiglycemic drugs and ¥6,070 ($835) for non-antiglycemic drugs. Hypertension (cost ¥4,658, $640, mean medications 2.12 for elderly patients), dyslipidemia (¥5,044, $693, 1.70), and coronary heart disease (¥4,004, $550, 1.40) were the top three diseases that caused the increase in the cost and medications. Over the 3 years, more than 94% of elderly diabetic patients received at least one type of antiglycemic drugs, and the α-glucosidase inhibitors and premixed insulin are the most commonly prescribed hypoglycemic drugs and insulin, respectively. Diabetes management in older patients faces challenges due to extensive variability. Medication analysis in this study found that the current situation of comprehensive control of diabetes in elderly patients is worrying, and the complexity of their medication is still on the increasing trend. It is important to select more appropriate antiglycemic drugs to economically benefit the patients and to control the progression of complications.

BackgroundDeep vein thrombosis (DVT) is associated with aberrant gene expression that is a common peripheral vascular disease. Here, we aimed to elucidate that the epigenetic modification of forkhead box protein 3 (FOXP3) at the post-transcriptional level, which might be the key trigger leading to the down-regulation of FOXP3 expression in DVT.MethodsIn order to explore the relationship between microRNAs (miRNAs) and FOXP3, mRNA and microRNA microarray analysis were performed. Dual luciferase reporter assay was used to verify the upstream miRNAs of FOXP3. Quantitative real-time polymerase chain reaction, flow cytometry and Western blot were used to detect the relative expression of miR-6132 and FOXP3. Additionally, DVT models were established to investigate the role of miR-6132 by Murine Doppler Ultrasound and Hematoxylin-Eosin staining.ResultsMicroarray and flow cytometry results showed that the FOXP3 expression was decreased while miR-6132 level was increased substantially in DVT, and there was significant negative correlation between miR-6132 and FOXP3. Moreover, we discovered that overexpressed miR-6132 reduced FOXP3 expression and aggravated DVT formation, while miR-6132 knockdown increased FOXP3 expression and alleviated DVT formation. Dual luciferase reporter assay validated the direct binding of miR-6132 to FOXP3.ConclusionCollectively, our data elucidate a new avenue through which up-regulated miR-6132 contributes to the formation and progression of DVT by inhibiting FOXP3 expression.

ObjectiveThe study aimed to screen key genes in early diabetic kidney disease (DKD) and predict their biological functions and signaling pathways using bioinformatics analysis of gene chips interrelated to early DKD in the Gene Expression Omnibus database.MethodsGene chip data for early DKD was obtained from the Gene Expression Omnibus expression profile database. We analyzed differentially expressed genes (DEGs) between patients with early DKD and healthy controls using the R language. For the screened DEGs, we predicted the biological functions and relevant signaling pathways by enrichment analysis of Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Using the STRING database and Cytoscape software, we constructed a protein interaction network to screen hub pathogenic genes. Finally, we performed immunohistochemistry on kidney specimens from the Beijing Hospital to verify the above findings.ResultsA total of 267 differential genes were obtained using GSE142025, namely, 176 upregulated and 91 downregulated genes. GO functional annotation enrichment analysis indicated that the DEGs were mainly involved in immune inflammatory response and cytokine effects. KEGG pathway analysis indicated that C-C receptor interactions and the IL-17 signaling pathway are essential for early DKD. We identified FOS, EGR1, ATF3, and JUN as hub sites of protein interactions using a protein–protein interaction network and module analysis. We performed immunohistochemistry (IHC) on five samples of early DKD and three normal samples from the Beijing Hospital to label the proteins. This demonstrated that FOS, EGR1, ATF3, and JUN in the early DKD group were significantly downregulated.ConclusionThe four hub genes FOS, EGR1, ATF3, and JUN were strongly associated with the infiltration of monocytes, M2 macrophages, and T regulatory cells in early DKD samples. We revealed that the expression of immune response or inflammatory genes was suppressed in early DKD. Meanwhile, the FOS group of low-expression genes showed that the activated biological functions included mRNA methylation, insulin receptor binding, and protein kinase A binding. These genes and pathways may serve as potential targets for treating early DKD.

High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecological cancer. Genetic studies have revealed gene copy number alterations (CNAs) frequently occurred in HGSOC pathogenesis, however the function and mechanism of CNAs for microRNAs are still not fully understood. Here, we show the dependence on gene copy number amplification of MIR937 that enhances cell autophagy and dictates HGSOC proliferative activity. Data mining of TCGA database revealed MIR937 amplification is correlated with increased MIR937 expression and cell proliferation of HGSOC. Deletion of MIR937 in HGSOC cells led to impaired autophagy and retarded cell proliferation, and the extent for its inhibitory effects scaled with the degree of MIR937 copy loss. Rescue assay confirmed miR-937-5p, a mature product of MIR937, was sufficient to restore its oncogenic function. Mechanistically, MIR937 amplification raised the expression of miR-937-5p, enhanced its binding to 3' UTR of FBXO16 transcript, and thereby restricting FBXO16 degradative effects on ULK1. Our results demonstrate that MIR937 amplification augments cell autophagy and proliferation, and suggest an alternative strategy of MIR937/FBXO16/ULK1 targeting for HGSOC treatment.

AIM:To establish an innovative clustering method for predicting variable categories of diabetic complications in Chinese ≥ 65 with diabetes. MATERIALS AND METHODS:We selected and extracted data from elderly patients with diabetes (n = 4980) from a medical examination group of 51,400 people followed up annually from 2014 to date in Kunshan, China. A deep contrast clustering approach was used to cluster and predict diabetic complications. The clustering approach was further validated using data from elderly patients with diabetes (n = 397) from one medical examination cohort of 20,000 people followed up yearly from 2014 to date in Beijing Jiuhua Hospital. RESULTS:The patients were clustered into 6 categories by analysing 20 indicators. Cluster 1-Heavy smoking and a high cardiovascular disease (CVD) risk; Cluster 2-High alcohol consumption, high aminotransferase levels, the highest risk of stroke complications, and a high fatty liver disease (FLD) risk; Cluster 3-High blood lipid levels and a risk of FLD and stroke complications; Cluster 4-Good health indicators and a low risk of FLD, stroke, and CVD complications; Cluster 5-Older age, higher uric acid concentration and creatinine level, and the highest risk of CVD complications; Cluster 6-Large waist circumference, high BMI, high blood pressure, and the highest risk of FLD complications. The gene for nonalcoholic fatty liver disease in cluster 2 had the highest risk coefficient. This was consistent with cluster 2, which had a higher FLD prevalence. CONCLUSIONS:A new clustering method was developed from two large Chinese cohorts of older patients with diabetes, which may effectively predict complications by clustering into different categories.

BACKGROUND AND AIMS:To assess the cost-effectiveness of utilizing IDegLira in comparison to other treatment regimens ( liraglutide and degludec) in managing type 2 diabetes, taking into account the Chinese healthcare system's perspective.METHODS:The clinical data were obtained from the randomized controlled trials (RCTs) of the DUAL I and DUAL II evidence studies that took place in China. To estimate the lifetime quality-adjusted life-years (QALYs) and direct medical costs of patients receiving different treatment strategies from a long-term perspective, the IQVIA CORE Diabetes Model version 9.0 (IQVIA, Basel, Switzerland) was utilized. The costs were evaluated from the perspective of the China National Health System. Future costs and clinical benefits were discounted annually at 5%, and sensitivity analyses were conducted.RESULTS:IDegLira was projected to reduce the incidence of diabetes-related complications and improve quality-adjusted life expectancy (QALE) versus liraglutide and degludec. A survival benefit was observed with IDegLira over Liraglutide (0.073 years). Lifetime costs were lower by Chinese yuan (CNY) 27,945 on IDegLira than on Liraglutide therapy. A similar survival benefit was observed with IDegLira over degludec (0.068 years). Lifetime costs were lower by CNY 1196 on IDegLira than on degludec therapy. Therefore, IDegLira was found to be cost-effective versus liraglutide and degludec with incremental cost-effectiveness ratios of Dominant per QALY gained, respectively, under the threshold of three times the gross domestic product (GDP) per capita in China.CONCLUSION:IDegLira is a cost-effective hypoglycemic treatment option that delivers positive clinical outcomes while also reducing costs for Chinese patients living with type 2 diabetes.

Background:Renal hemodynamic changes in early diabetes occur before the onset of significant structural abnormalities or clinical manifestations, and timely detection of these changes has clinical significance. This study aimed to evaluate renal elasticity and perfusion changes in an early-stage diabetic rat model by shear wave elastography (SWE) and contrast-enhanced ultrasound (CEUS), and to explore the potential correlations between renal elasticity and perfusion parameters.Methods:A total of 18 male Sprague-Dawley rats were randomly divided into three groups: a control group (group 1, n=6), a diabetic group (group 2, n=6), and a diabetic group receiving drug therapy (group 3, n=6). An intraperitoneal injection of streptozotocin (STZ) for 2 days combined with a high-fat diet (HFD) was used as the early-stage diabetic rat model. The diabetic rats in group 3 were treated with canagliflozin and losartan for 6 weeks, whereas the rats in groups 1 and 2 were given equal amounts of purified water. Renal stiffness on SWE and perfusion parameters on CEUS were measured and compared among the three groups, then the rats were sacrificed, and serum, urine, and renal histopathology were evaluated to confirm the development of early diabetes.Results:The early-stage diabetic rats without significant pathological changes exhibited bigger kidneys and higher blood glucose (all P<0.05). Among the CEUS parameters, peak enhancement (PE), wash-in area under the curve (WiAUC), wash-in perfusion index (WiPI), wash-out AUC (WoAUC), wash-in and wash-out AUC (WiWoAUC), rise time (RT), and time to peak (TTP) of diabetic rats in group 2 were significantly increased (all P<0.05), and the hyperperfusion ameliorated significantly after drug treatment. The renal elasticity measured by SWE varied in accordance with certain perfusion parameters, and was strongly positively correlated with WiAUC (r=0.701, P<0.001), WoAUC (r=0.647, P<0.001), and WiWoAUC (r=0.655, P<0.001), and moderately positively correlated with PE (r=0.539, P=0.001), WiPI (r=0.555, P<0.001), RT (r=0.425, P=0.010), and TTP (r=0.439, P=0.007).Conclusions:Renal elasticity and perfusion changes in the early stage of diabetes, and renal elasticity was positively associated with delayed and increased perfusion.

OBJECTIVE:The risk of metabolic disease in adulthood is not only attributed to an unhealthy lifestyle after birth but also to famine exposure during the foetal period. This systematic review and meta-analysis aimed to evaluate the effects of foetal exposure to famine as a risk factor for developing nonalcoholic fatty liver disease (NAFLD) in adulthood.METHODS:Studies were retrieved from PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang databases to evaluate the effect of foetal exposure to famine on the risk of nonalcoholic fatty liver disease in adulthood.RESULTS:Six studies involving 90,582 subjects were included in this meta-analysis. Foetal exposure to famine was associated with an increased risk of NAFLD(RR = 1.17, 95% CI: 1.08-1.27, P < 0.0001). Exposure to famine during the foetal period significantly increased the incidence of NAFLD in women (RR = 1.27, 95% CI: 1.16-1.40, P <0.00001), while similar results were not observed in the male subgroup (RR =0.99, 95% CI: 0.89-1.11, P = 0.88). Foetal exposure to famine was associated with the risk of mild NAFLD (RR = 1.17, 95% CI: 1.02-1.33, P = 0.02) and moderate to severe NAFLD (RR = 1.51, 95% CI: 1.16-1.98, P = 0.002).CONCLUSIONS:Foetal exposure to famine is associated with an increased risk of NAFLD in adulthood. Women with NAFLD and moderate to severe NAFLD have a more robust association with foetal exposure to famine.

PROBLEM:Postmenopausal osteoporosis (PMO) is a common osteoporosis. Hyperoside (Hyp), a natural flavonoid compound, has anti-osteoporotic effects, but the underlying mechanisms remain poorly understood. Inflammatory cytokine IL-17A is upregulated in PMO and plays vital roles in bone loss, but the upstream regulatory factors and mechanisms are still unknown.METHOD OF STUDY:Twenty PMO patients and 20 healthy control subjects were included to analyze IL-17A expression changes and screen dys-regulated miRNAs in the peripheral blood of PMO patients. miR-19a-5p mimics and inhibitor were transfected into RAW264.7 osteoclasts, and injected into bilateral ovariectomized (OVX) mice to explore the regulatory effect of miR-19a-5p on IL-17A. OVX mice were randomly grouped and treated with different doses of Hyp to uncover the effective targets for the medicine in PMO disease.RESULTS:MiR-19a-5p was downregulated in PMO patients and the expression level was negatively correlated with that of IL-17A. miR-19a-5p could directly bind to the 3'UTR of IL-17A and regulate its expression. Both in vitro and in vivo studies demonstrated that miR-19a-5p mimics decreased the expression of IL-17A, RANK and Cathepsin K, while miR-19a-5p inhibitor significantly increased the expression of IL-17A, RANK, and Cathepsin K. Importantly, the Hyp could improve bone structure of OVX mice by enhancing miR-19a-5p-mediated IL-17A downregulation.CONCLUSION:Overall, these data demonstrated that miR-19a-5p/IL-17A axis might serve as novel therapeutic candidate for PMO. Hyp could relieve bone resorption by targeting the miR-19a-5p/IL-17A axis in OVX mice and exhibited prospective for the treatment of PMO.

Background: To subgroup Chinese patients with newly diagnosed type 2 diabetes (T2D) by K-means cluster analysis on clinical indicators, and to explore whether these subgroups represent different genetic features and calculated cardiovascular risks.Methods: The K-means clustering analysis was performed on two cohorts (n = 590 and 392), both consisting of Chinese participants with newly diagnosed T2D. To assess genetic risks, multiple polygenic risk scores (PRSs) and mitochondrial DNA copy numbers (mtDNA-CN) were calculated for all participants. Furthermore, Framingham risk scores (FRS) of cardiovascular diseases in two cohorts were also calculated to verify the genetic risks.Results: Four clusters were identified including the mild age-related diabetes (MARD)(35.08%), mild obesity -related diabetes (MOD) (34.41%), severe autoimmune diabetes (SAID) 19.15%, and severe insulin-resistant diabetes (SIRD) 11.36% subgroups in the MARCH (metformin, and acarbose in Chinese patients as the initial hypoglycemic treatment) cohort. There was a significant difference in PRS for cardiovascular diseases (CVD) across four subgroups in the MARCH cohort (p < 0.05). Compared with the SIDD and SIRD subgroups, patients in the MOD subgroup had a relatively lower PRS for CVD (p < 0.05) in the MARCH cohort. Females had a higher PRS compared to males, with no significant difference in FRS across the four clusters. The MOD subgroup had a significantly lower FRS which was consistent with the results of PRS. Similar results of PRS and FRS were also replicated in the CONFIDENCE (comparison of glycemic control and b-cell function among newly diagnosed patients with type 2 diabetes treated with exenatide, insulin or pioglitazone) cohort.Conclusion: There are different CVD risks in diabetic subgroups based on clinical and genetic evidence which may promote precision medicine.

OBJECTIVE:This study aimed to evaluate the effects of Glucagon-like peptide-1 receptor agonist (GLP-1RA) on prediabetes with overweight/obesity.METHODS:A search of PubMed, Embase, Cochrane Library, and Web of Science databases was performed to identify randomised controlled trials (up to 4 July 2022) which evaluated the effect of GLP-1RA on prediabetes with overweight/obesity.RESULTS:Eight hundred and nine articles were retrieved (80 from PubMed, 481 from Embase, 137 from Cochrane library, and 111 from Web of Science) and a total of 5 articles were included in this meta-analysis. More individuals in GLP-1RAs group regressed from prediabetes to normoglycemia than individuals in the placebo group (OR = 4.56, 95% CI:3.58, 5.80, P = 0.004); fewer individuals in GLP-1RAs group were diagnosed with diabetes than those in the placebo group (OR = 0.31, 95% CI:0.12,0.81, P = 0.017). Results from five studies showed that GLP-1RAs significantly reduced fasting glucose (mean difference = -0.41 mmol/L, 95% CI: -0.58, -0.25, P < 0.00001), with an acceptable heterogeneity (I2  = 42%).CONCLUSIONS:The present meta-analysis suggested that GLP-1RA significantly improves glucose metabolism, reduces systolic blood pressure and body weight in prediabetes with overweight/obesity. It could also prevent the development of diabetes and reverse abnormal glucose metabolism.