BackgroundEctopic Cushing’s syndrome (ECS) secondary to medullary thyroid carcinoma (MTC) is a rare endocrine manifestation associated with aggressive disease and considerable morbidity from severe hypercortisolism.MethodsWe conducted a systematic review of PubMed and Web of Science from inception to January 25, 2026, in accordance with PRISMA guidelines, to identify all published cases of ECS due to MTC. Data were extracted on clinical presentation, RET mutational status, treatments, outcomes, and causes of death. In addition, we described four previously unreported patients from “C. I. Parhon” National Institute in Bucharest, Romania, analyzed independently from the systematic review dataset.ResultsThe systematic review identified 99 published cases of ECS caused by MTC. The mean age at diagnosis was 46.3 years (range 12–84), with male predominance (69.7%). Among cases with available genetic data, most were sporadic 32/43 cases (74.4%), frequently harboring somatic RET M918T mutation. MTC stage at diagnosis was available in 90 cases, of which 48 patients (53.3%) presented with distant metastases. ECS and MTC were diagnosed concomitantly in 45/89 patients (50.6%), while MTC preceded ECS in 43/89 patients (48.3%), with a median delay of 42 months. Hypercortisolism manifestations predominated and often masked locoregional thyroid disease. Thyroid surgery was the initial therapeutic approach in 62/77 cases (80.5%). Hypercortisolism was difficult to control and often refractory to multiple treatment strategies. Bilateral adrenalectomy was required in 33 patients, including 12 in whom it served as rescue treatment following failure of medical therapy. Selective RET inhibitors, particularly selpercatinib, have recently emerged as a promising treatment option, with all five reported cases demonstrating rapid biochemical improvement and radiologic responses. Among cases with available outcome data, mortality was primarily driven by complications of uncontrolled hypercortisolism and progressive metastatic MTC. Complementing the systematic review, regarding the four cases from our center, we have observed substantial disease burden, with thyroid surgery performed in every patient. Two cases received vandetanib producing favorable biochemical (calcitonin) and radiologic responses. Hypercortisolism proved challenging to manage, with three patients failing to achieve remission despite multimodal therapy, including surgery, targeted therapy, adrenalectomy, or medical treatment.ConclusionECS secondary to MTC is an exceptionally rare and highly morbid manifestation that occurs predominantly in metastatic sporadic MTC. Management of both tumor burden and hypercortisolism is complex and often requires multimodal therapy. Emerging data suggests that selective RET inhibitors may lead to simultaneous control of both tumor progression and cortisol excess in RET-mutated disease, although current data remain limited to case reports. The four institutional cases offer additional real-world clinical context and are presented separately from the systematic review to maintain methodological rigor.
BackgroundSodium-glucose co-transporter 2 inhibitors (SGLT2i) are associated with a rare but serious risk of diabetic ketoacidosis (S-DKA). This study aimed to identify risk factors for S-DKA, develop a tool for its early detection, and assess the associated in-hospital severity.MethodsA retrospective, multicenter cohort study was conducted across four hospitals from September 2019 to June 2024. After screening 35,633 SGLT2i-prescribed inpatients, a 1:3 propensity score matching was applied. The study included 432 patients in the development cohort (2019-2023) and 128 in a validation cohort (2023-2024). Lasso regression and logistic regression were used to identify S-DKA risk factors and construct a nomogram. The primary endpoint for severity was the need for intensive care.ResultsSix independent predictive factors for S-DKA were identified: female, indications with diabetes, high HbA1c levels, fasting, infection and low BMI. The prediction nomogram demonstrated excellent discrimination, with an area under the curve (AUC) of 0.920(95% CI: 0.888 -0.952) in the development cohort and 0.735 (95% CI: 0.644 -0.826) upon validation. The model was well-calibrated. Furthermore, patients with S-DKA required intensive care at a significantly higher rate compared to those without.ConclusionS-DKA is associated with greater in-hospital severity, necessitating early identification. The developed nomogram provides a clinically valuable tool for predicting S-DKA risk, potentially aiding physicians in proactive patient management and improving outcomes.
BackgroundGestational diabetes mellitus (GDM) is closely related to maternal adiposity and insulin resistance. The rate of body fat percentage (BFP) change in early pregnancy may describe estimated BFP gain before routine glucose screening. The Single-Point Insulin Sensitivity Estimator (SPISE) offers a fasting estimate of insulin sensitivity without insulin testing. It is still uncertain whether SPISE explains the link between early BFP change and later GDM.MethodsWe analyzed public, de-identified data from a prospective Korean cohort of singleton pregnancies. BFP was estimated from age and body mass index. Early-pregnancy estimated BFP change rate was defined as BFP at 10–14 weeks minus pre-pregnancy BFP, divided by gestational week at assessment, and rescaled to per mille units. SPISE was calculated from fasting triglycerides, high-density lipoprotein cholesterol, and body mass index. GDM was assessed at 24–28 weeks with a two-step diagnostic approach. The analyses used restricted cubic splines, segmented regression, mediation models, and propensity score matching.ResultsAmong 586 women in the analytic cohort, 37 (6.3%) developed GDM. Higher estimated BFP change rate was linked to greater GDM risk (P overall = 0.006; P non-linearity = 0.140). SPISE showed a non-linear inverse association with GDM (P overall < 0.001; P non-linearity = 0.003), with an estimated threshold of 7.089. Below this threshold, each one-unit increase in SPISE was linked to lower GDM odds (OR 0.127, 95% CI 0.049-0.328; P < 0.001). Above the threshold, the association was weaker and not significant. estimated BFP change rate was also inversely associated with SPISE. In mediation analysis, the model-based estimated proportion mediated was 43.65%. After propensity score matching, available-case outcomes showed more GDM events in the low-SPISE group than in the high-SPISE group (14.5% vs 0.0%; P = 0.003).ConclusionsFaster estimated BFP change in early pregnancy was linked to higher later GDM risk, and lower SPISE explained part of this relationship in statistical mediation models. The proposed SPISE threshold and mediation pattern need validation in independent cohorts before clinical use.
IntroductionObesity is a global health challenge, and fecal microbiota transplantation (FMT) is considered a potential intervention; however, its long-term ecological impact remains unclear.MethodsIn this 182-day longitudinal cohort of adolescents with obesity (378 samples), metagenomic sequencing was used to assess FMT-induced remodeling of the multi-kingdom gut ecosystem through species composition, diversity, microbial networks, and machine learning analyses.ResultsFMT induced only transient shifts in community structure, with limited donor strain engraftment and strong resilience of recipient core taxa. Bacteria were the primary responders, the virome showed short-term perturbation, and network restoration was partial and donor-dependent.DiscussionFMT exerts limited, donor-dependent ecological effects in obese adolescents. Optimizing donor selection and personalized matching may be essential for improving long-term efficacy.
IntroductionWhile early growth and current weight individually affect cardiometabolic health, their combined effects are poorly understood. This study examines the integrated impact of birth weight and current weight status on the clustering of cardiometabolic risk factors (CMRFs) in children and adolescents.MethodsThis study analyzed data from 15,910 children and adolescents aged 6 to 18 years from a multistage cross-sectional survey. Participants were categorized into six combined exposure groups based on birth weight (normal/low/high) and current weight status (non-overweight/overweight/obese). Multivariable logistic regression models assessed the associations of these categories with CMRF clustering (defined as the presence of 2 or more of the following: elevated blood pressure, impaired fasting glucose, elevated triglycerides, and low high-density lipoprotein cholesterol). Additive interaction was evaluated using the relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (SI). Statistical mediation analysis decomposed the association of birth weight with CMRF clustering into indirect (current BMI) and direct pathways.ResultsOf 15,910 participants, 6.30% had CMRF clustering. In fully adjusted models, compared with the normal birth weight/non-overweight group, the low birth weight/overweight-obese group had the highest odds of CMRF clustering (OR = 6.11, 95% CI: 3.32 to 10.53, P < 0.001). No statistically significant additive interaction was observed between low birth weight and current overweight/obesity (RERI = 1.57, P = 0.193; AP = 0.26, P = 0.127; SI = 1.44, P = 0.158). Mediation analysis revealed a competitive mediation pattern: birth weight had a significant positive indirect effect on CMRF clustering through current BMI (β = 0.0091, P < 0.001) and a significant negative direct effect (β = −0.0144, P = 0.002), while the total effect was not statistically significant (β = −0.0052, P = 0.326).ConclusionAlthough the combination of LBW and current overweight/obesity conferred the greatest risk for CMRF clustering, this was driven primarily by current weight status rather than a synergistic effect. However, LBW remained independently associated with metabolic risk after BMI adjustment, indicating distinct pathophysiological pathways. Thus, preventing excessive weight gain in low birth weight children is critical for reducing cardiometabolic risk.
BackgroundThe prevalence of Type 2 Diabetes (T2D) has increased over the years. However, the current diagnostic markers such as fasting blood glucose and HbA1c come with certain limitations. Hence, there is a need for a more robust minimally invasive biomarker. This study aimed to identify sets of dysregulated miRNAs in plasma small extracellular vesicles (sEVs) as biomarkers for T2D diagnosis.MethodsThis study was part of the Rice Intervention for Chronic Health (RICH) trial. Plasma sEVs were isolated from T2D and control subjects and characterized. The sEVs-miRNAs expressions were compared using next generation sequencing and validated using digital PCR. Bioinformatic analyses were performed to study the roles of dysregulated miRNAs. Plasma proteins were profiled to study the systemically dysregulated T2D pathways.ResultsThe levels of miR-142-3p and miR-454-3p were increased in plasma sEVs of T2D subjects. Among a subgroup of T2D subjects in whom glycemic control improved (n = 13), these two upregulated miRNAs also decreased. The combination of sEVs-miR-142-3p, waist circumference, and BMI demonstrated high diagnostic values (AUC-ROC=0.985, p < 0.001) to distinguish between T2D and control subjects. The integrated results from miRNA bioinformatics analysis and plasma proteomics profiling suggested association between the predicted targets of miRNA and systemic dysregulated pathways in T2D.ConclusionThis study identified the potential of sEV-miR-142-3p as biomarkers for T2D diagnosis when used in combination with waist circumference and BMI. This study provided preliminary evidence of sEVs-miRNAs in future clinical use for T2D management.
BackgroundIdiopathic male infertility (IMI) accounts for 30%–40% of male infertility cases, yet the molecular networks associated with seminal plasma dysfunction and non-invasive biomarkers remain largely unclear. This study aimed to preliminarily explore the transcriptomic and metabolomic alterations in IMI seminal plasma through cross-omics integration, and to screen for exploratory candidate discriminators among the metabolites.MethodsA total of 30 IMI patients and 30 normozoospermic controls were recruited for untargeted UHPLC-MS/MS metabolomics of seminal plasma. Candidate differential metabolites were screened and subjected to KEGG and Gene Set Enrichment Analysis (GSEA); ROC analysis with bootstrap internal validation was conducted on candidate differential metabolites to explore candidate discriminators. For miRNA sequencing, 10 subjects were randomly selected from each group to isolate and identify seminal plasma small extracellular vesicles (sp-sEVs) following International Society for Extracellular Vesicles (ISEV) standards. Subsequent bioinformatic analyses included miRNA differential expression screening, target gene prediction, GO/KEGG enrichment, protein–protein interaction (PPI) network construction, and pairwise Pearson correlation analysis between dysregulated miRNAs and differential metabolites within the nested subgroup.ResultsWe identified 68 and 152 candidate differential metabolites under negative and positive electrospray ionization modes, respectively. Metabolite perturbations were predominantly enriched in unsaturated fatty acid biosynthesis, whereas the arginine and proline metabolism pathway was globally suppressed in IMI patients. The phosphatidic acid derivative PA(i‑15:0/18:1(12Z)‑2OH(9,10)) showed the best discriminatory potential among all screened metabolites, with a AUC of 0.822 (95% CI: 0.716–0.929). miRNA sequencing uncovered 128 differentially expressed miRNAs (62 upregulated, 66 downregulated) in IMI sp-sEVs. Functional enrichment of miRNA target genes highlighted perturbed protein phosphorylation and intracellular signal transduction, with the phospholipase D (PLD) signaling pathway as the most statistically significant pathway; PIK3CA, PIK3R1, and AKT1 were suggested to be core hub genes within the PLD network. Correlation analysis suggested that upregulated miRNAs (hsa-miR-141-5p, hsa-miR-28-5p) were positively correlated with up-regulated N-cis-11,14-eicosadienoyl ethanolamine in seminal plasma.ConclusionCoordinated alterations between sp-sEV miRNAs and seminal plasma metabolites were observed in IMI. Several candidate metabolites showed discriminatory value in this single cohort, but require validation. The PLD pathway may be involved, though causality remains unconfirmed.
BackgroundThis network meta-analysis (NMA) intends to fully assess the value of contrast-enhanced ultrasound (CEUS) combined with other imaging techniques in the diagnosis of thyroid nodules (TNs), and provide clinical guidance.MethodsWe systematically searched PubMed, Web of Science, Embase, and Cochrane up to October 15, 2025, and assessed study quality by the QUADAS-2 tool. The combination of CEUS and CEUS with other techniques was assessed for accuracy by R4.5.1 and ANOVA-based NMA.ResultsTwenty-six original studies were included, encompassing 5022 TNs from 4484 patients. CEUS-ultrasound elastography (UE) demonstrated favorable diagnostic performance in differentiating benign and malignant TNs (superiority index [SI]: 3.47, 95%CI 0.2–7). The pooled sensitivity (SE) and specificity (SP) of CEUS-UE were 0.92 (95%CI 0.88–0.95, SUCRA 80.0%) and 0.83 (95%CI 0.75–0.89, SUCRA 60.7%), respectively. CEUS-artificial intelligence (AI) was generally effective in identifying high-risk TNs (SI: 3.81, 95%CI 0.33–9), with pooled SE and SP of 0.95 (95%CI 0.91–0.98, SUCRA 90.0%) and 0.81 (95%CI 0.68–0.91, SUCRA 49.6%), respectively. CEUS-conventional ultrasound (US) showed favorable diagnostic performance in identifying non-risk-stratified TNs (SI: 5.29, 95%CI 0.33–9), with pooled SE and SP of 0.89 (95% CI 0.74–0.97, SUCRA 61.4%) and 0.88 (95%CI 0.69–0.97, SUCRA 76.9%), respectively.ConclusionCEUS-UE demonstrates favorable overall diagnostic performance in differentiating benign and malignant TNs. CEUS-AI may offer additional value in identifying high-risk TNs with multiple suspicious features. CEUS-US is effective in identifying non-risk-stratified TNs. However, these subgroup findings require further validation in larger, diverse external cohorts.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/myprospero, identifier CRD420251169562.
BackgroundPituitary apoplexy is a clinical emergency resulting from hemorrhage or infarction of a pituitary adenoma, which leads to a sudden increase in tumor volume, acute neuroendocrine dysfunction, and local compressive symptoms. In severe cases, it may be life-threatening. The diagnosis of this condition remains challenging, especially in patients without a prior history of pituitary disease, and reliable serum biomarkers are currently lacking. Metabolomics enables the systematic identification of metabolic alterations under physiological and pathological conditions, thereby providing a powerful tool for elucidating disease mechanisms and discovering diagnostic biomarkers.MethodsIn this study, untargeted metabolomics analysis using UPLC-MS/MS was performed on serum samples collected from 39 patients with nonapoplectic pituitary adenoma and 11 patients with pituitary apoplexy. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were applied to assess differences in metabolic profiles between the two groups. Differential metabolites were identified based on variable importance in projection (VIP > 1) and an independent-samples t-test (p < 0.05). The diagnostic potential of these metabolites was further evaluated using receiver operating characteristic (ROC) curves.ResultsCompared with the nonapoplectic pituitary adenoma group, the pituitary apoplexy group showed distinct serum metabolic profiles, with 92 metabolites upregulated and 310 metabolites downregulated. Further analysis revealed two key differential metabolites—glycerol-3-phosphate (G-3-P) and N-acetyl-d-galactosamine (GalNAc)—as potential diagnostic biomarkers for pituitary apoplexy.ConclusionsThis study reveals distinct serum metabolic profiles between the pituitary apoplexy group and the nonapoplectic pituitary adenoma group, offering novel metabolic insights into the pathogenesis of pituitary apoplexy.
BackgroundThis study aimed to develop and validate a clinical nomogram to predict the risk of central lymph node metastasis (CLNM) in patients with clinically low-risk papillary thyroid microcarcinoma (PTMC).MethodsPatients with clinically low-risk PTMC were enrolled in this retrospective cohort study. Potential predictive factors include sex, age, tumor size, tumor location, and Hashimoto’s thyroiditis (HT). Independent predictive factors were identified using multivariate logistic regression and a nomogram was developed using the finalized model. The performance of the model was evaluated using receiver operating characteristic (ROC) curve analysis, calibration plots, and decision curve analysis (DCA).ResultsThis study included 4,201 patients with clinically low-risk unifocal PTMC, of whom 1,553 (37.0%) presented with CLNM. Multivariate logistic regression analysis revealed four independent predictive factors: sex, age, tumor size, and tumor location. The constructed nomogram demonstrated moderate predictive performance, with an area under the ROC curve (AUC) of 0.700 (95% confidence interval [CI]: 0.680–0.719) in the training cohort and 0.697 (95% CI: 0.667–0.727) in the validation cohort. Furthermore, the fit of the calibration curves was good, and the DCA results suggest potential clinical utility for patient benefit.ConclusionA clinical nomogram incorporating sex, age, tumor size, and tumor location was developed and internally validated. This tool achieved moderate predictive accuracy for estimating the risk of CLNM in patients with clinically low-risk unifocal PTMC. This screening-level model may provide auxiliary clinical value for outpatient consultation. It can aid clinicians in patient counselling and facilitate preliminary risk stratification and clinician–patient communication for this patient population.
BackgroundThe liver-bone axis plays a key role in lipid metabolism and endocrine regulation. However, the relationship between fatty liver disease and both the level and longitudinal changes of bone mineral density (BMD) remains inconclusive. This study aimed to explore the correlation of liver fat with lumbar BMD and bone marrow fat in postmenopausal women.MethodsIn this cross-sectional study, conducted between May 2023 and December 2025, 118 postmenopausal women were included and stratified into 2 groups based on their BMI. All participants underwent quantitative computed tomography (QCT) to assess lumbar BMD and liver fat fraction, and underwent MRI using the mDixon-Quant sequence to assess lumbar proton density fat fraction (PDFF). Correlation analysis, linear regression, and mediation analysis were performed to evaluate the relationships among liver fat, lumbar PDFF, and BMD. Logistic regression analysis was used to assess the impact of liver fat on osteoporosis.ResultsIn the normal-BMI group, the liver fat fraction was correlated negatively with BMD [β = -0.368, 95% confidence interval (CI): –0.605 to –0.131, P = 0.003] and positively with lumbar PDFF (β = 0.335, 95% CI: 0.064 to 0.607, P = 0.016) after adjusting for age BMI, and visceral fat area. The liver fat fraction was also identified as an associated factor for osteoporosis [odds ratio (OR) = 1.345, 95% CI: 1.065 to 1.699, P = 0.013] in the normal-BMI group. Mediation analysis demonstrated that lumbar PDFF played a crucial intermediary role (38.6%) in the relationship between liver fat fraction and BMD. However, in the higher BMI group, no correlation was found between liver fat and BMD or lumbar PDFF.ConclusionLiver fat fraction is independently associated with lower lumbar BMD in normal-BMI postmenopausal women, partially mediated by bone marrow fat, suggesting it may serve as a potential extra-osseous imaging biomarker for osteoporosis risk.
Adipose tissue dysfunction is at the interphase between obesity and impaired metabolic health. Increased lipid spillover is a key mechanism by which adipose tissue dysfunction contributes to systemic metabolic dysregulation. This, in turn, leads to the accumulation of lipotoxic lipid species, such as ceramides, within metabolically active tissue not suited for lipid storage tissues thereby fueling insulin resistance. However, the buildup of ceramides also occurs in the adipose tissue of individuals with obesity where these sphingolipids may disrupt energy metabolism, insulin sensitivity and affect adipose tissue secretome, compromising systemic metabolic health. This review will provide an updated overview on the contribution of ceramides to adipose tissue dysfunction, with a particular focus on the onset of insulin resistance. Additionally, this manuscript will focus on the involvement of ceramides in modulating extracellular vesicle (EVs) secretion from the white adipose tissue and their role as bioactive components of EV lipidome able to discern individuals based on their metabolic status.
Preeclampsia (PE) is characterized by placental hypoxia, metabolic stress, trophoblast dysfunction, and impaired spiral artery remodeling, but the mechanisms linking these abnormalities remain incompletely understood. Cuproptosis, a recently identified form of regulated cell death driven by copper-dependent aggregation of lipoylated tricarboxylic acid cycle proteins, may provide a mechanistic link between placental metabolic stress and trophoblast injury. Here, we propose a hypothesis in which hypoxia-induced glycolytic reprogramming and lactate accumulation promote histone H3K18 lactylation, activate GRHL2, and increase SLC31A1/CTR1-mediated copper uptake. Subsequent FDX1-dependent copper reduction, DLAT aggregation, Fe-S cluster loss, and mitochondrial proteotoxic stress may preferentially affect mitochondria-rich villous syncytiotrophoblasts, while also impairing EVT function. Cuproptosis may interact with ferroptosis and oxidative stress through shared metal-redox and mitochondrial vulnerabilities. Although current evidence does not establish cuproptosis as an initiating cause of PE, it may amplify placental dysfunction. Targeting copper transport, mitochondrial stress, or pathway-specific biomarkers warrants further investigation.
IntroductionMaternal obesity is associated with altered maternal–fetal adipokine profiles and adverse early neonatal outcomes. This study aimed to characterize maternal and fetal adipokine patterns across obesity severity groups and to evaluate their associations with macrosomia and neonatal intensive care unit (NICU) requirement.MethodsIn this prospective study, 126 singleton pregnancies were stratified into normal-weight, class I obesity, and class II–III obesity groups (n=42 each). Maternal venous and fetal cord blood adiponectin, leptin, asprosin, fetuin-A, retinol-binding protein-4 (RBP-4), adipsin, and glucose transporter-1 (GLUT-1) were assessed at delivery. Macrosomia and NICU requirement were evaluated using group comparisons, receiver operating characteristic (ROC) analyses, and multivariable logistic regression models.ResultsMaternal and fetal adipokine profiles differed significantly across obesity severity groups. Maternal fetuin-A, RBP-4, and adipsin levels, along with fetal leptin, fetuin-A, RBP-4, adipsin, and GLUT-1 levels, increased significantly with increasing obesity severity. In ROC analyses, fetal adipsin showed the highest discrimination for macrosomia (AUC=0.951), whereas fetal RBP-4 showed the highest discrimination for NICU requirement (AUC=0.781). In exploratory adjusted analyses, fetal adipsin remained associated with macrosomia (adjusted OR=5.43, 95% CI 2.14–13.77), whereas fetal RBP-4 remained statistically associated with NICU requirement (adjusted OR=3.31, 95% CI 1.87–5.86).DiscussionMaternal obesity is accompanied by distinct maternal and fetal adipokine remodeling at delivery, with fetal adipsin and RBP-4 showing outcome-specific associations with neonatal macrosomia and NICU requirement, respectively. The compartment-specific biomarker patterns further suggest that the fetal metabolic response to increasing maternal adiposity is not simply a reflection of maternal circulating profiles. These exploratory findings warrant validation in larger, independent cohorts.
IntroductionThe physiological burden of chronic stress, quantified as allostatic load (AL), is implicated in cancer development and outcomes. However, a synthesis of evidence regarding its role in female-specific cancers is lacking.ObjectiveThis systematic review aimed to synthesize existing evidence on the application of AL in female cancer patients, covering both its predictive value for cancer risk in healthy populations and its prognostic significance for outcomes and quality of life in cancer patients.MethodsFollowing PRISMA guidelines, we systematically searched PubMed, Web of Science, Springer Link, and Wiley Online Library from inception to June 2025. Studies investigating AL in patients with common female cancers (e.g., breast, endometrial, ovarian) were included. Study quality was assessed using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Data on study characteristics, AL assessment methods, associated factors, and key findings were extracted.Results17 studies (14 on breast cancer, 2 on endometrial cancer, and 1 on ovarian cancer) were included. AL levels were influenced by sociodemographic, lifestyle, and structural factors. Higher AL was associated with an increased risk of female cancers (particularly breast cancer) incidence, poorer health-related quality of life, a higher incidence of postoperative complications (e.g., lymphedema), and increased all-cause mortality. And existing studies exhibit heterogeneity in biomarker selection and scoring thresholds.ConclusionsAL is a promising composite marker associated with the risk, prognosis, and quality of life in female cancer patients, primarily breast cancer. Current evidence is concentrated on breast cancer with limited evidence available for other types of female cancers. Future research requires standardized AL assessment and investigations across diverse female cancer populations.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251080672.
BackgroundNon-alcoholic fatty liver disease (NAFLD) and diabetic retinopathy (DR) are common clinical complications of metabolic syndrome in different organ systems. However, the relationship between NAFLD and DR remains controversial, and more high-level evidence is needed to clarify the causal link between them. We aimed to investigate the causal relationship between NAFLD and DR across its progression stages, and to identify circulating proteins may mediate this association.Materials and methodsBased on genetic tools, a multi-stage network MR framework was constructed, integrating NAFLD/DR genome-wide association study data and three blood proteome-wide datasets. Causal effects of NAFLD on DR were assessed using inverse-variance weighted regression and multimodal models. Proteome-wide MR identified DR-associated proteins. Bidirectional two-sample MR and mediation models quantified regulatory weights in NAFLD-protein-DR pathways. In addition, the transcriptional expression levels of the identified mediator proteins in the liver were verified through single-cell transcriptome sequencing. The levels of the mediator protein in the serum samples of clinical patients were detected by ELISA. The levels of mediator proteins in the aqueous humor and vitreous humor samples of clinical patients were detected by Luminex liquid-phase protein chip.ResultsNAFLD increased DR risk (OR = 1.04, 95% CI: 1.01-1.08) and specifically promoted non-proliferative DR (NPDR) progression (OR = 1.26, 95% CI: 1.05-1.52). Four proteins were identified as candidate mediators of NAFLD-DR association, among them, LTB (lymphotoxin-β, a TNF superfamily member involved in immune regulation and inflammatory responses) showed the strongest effect. In the liver of NAFLD model mice, the expression of the LTB gene was mainly elevated in T cells and B cells. The levels of LTB protein in the aqueous humor, vitreous humor and serum of NAFLD patients with DR were all higher than those of NAFLD patients without DR.ConclusionsNAFLD is causally associated with an increased risk of DR development, particularly during early NPDR stages. LTB may mediate the biological process by which NAFLD promotes DR. T cells and B cells in the liver of patients with NAFLD produce higher levels of LTB protein. In NAFLD patients with DR, LTB protein levels were elevated in serum, aqueous humor, and vitreous humor compared to NAFLD patients without DR, suggesting that LTB may play a role in the link between these two conditions.
BackgroundThe regulation and secretion of hormones in the endocrine system change with aging. While these changes may influence age-related disease risks, the role of hypothalamic-pituitary-thyroid (HPT) axis sensitivity in metabolic and cardiovascular health remains unclear.MethodsThis study enrolled 13,646 participants (6,221 males, 7,425 females). Metabolic (BMI, SUA, FPG, lipoproteins) and cardiovascular (ECG, CK-MB, NT-proBNP) indices were measured. Multivariable logistic regression adjusted for age (per 10-year increment), sex, and outcome-specific confounders. Nonlinear relationships between age and TFQI were analyzed using restricted cubic splines (RCS).ResultRCS analysis revealed a significant age-dependent decline in TFQI-fT3 values, with an inflection point at 48 years (p<0.001); TFQI-fT4 showed a similar but attenuated trend. For metabolic outcomes, increased fT3 sensitivity (TFQI-fT3 Q1) was associated with lower MetS risk in older adults (>48 years) (OR 0.79, 95% CI 0.65-0.97, p=0.023), whereas no significant association was observed in younger adults (≤48 years) (all p>0.05). For cardiovascular outcomes, higher fT3 sensitivity was associated with reduced risk of abnormal ST segments in both age groups (younger: OR 0.57, 95% CI 0.32-0.97, p=0.046; older: OR 0.68, 95% CI 0.48-0.95, p=0.027). Conversely, decreased fT4 sensitivity (TFQI-fT4 Q4) specifically increased abnormal ST-segment risk in older adults (OR 1.43, 95% CI 1.04-1.96, p=0.025), with no significant effect in younger adults (OR 1.11, 95% CI 0.65-1.82, p=0.693).ConclusionEnhanced HPT axis sensitivity to fT3 increased with age (inflection point at 48 years in this study) and was associated with a lower prevalence of metabolic syndrome (in >48-year-olds) and ST-segment abnormalities (all adults).
ObjectiveThe predictive value of the Visceral Adiposity Index (VAI) for diabetic kidney disease (DKD) is unclear. This study systematically reviews the association of elevated VAI with DKD, as well as its predictive performance.MethodsPubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang, VIP, and CBM were searched until December 1, 2025, for studies investigating VAI and DKD. The pooled outcomes and effect measures included odds ratio (OR), hazard ratio (HR), area under the curve (AUC), sensitivity (SEN), specificity (SPEC), and diagnostic 2×2 tables. Additional analyses encompassed sensitivity analysis, heterogeneity assessment, and publication bias evaluation. Statistical analyses were enabled by Stata MP 15.1.ResultsNineteen studies on 58,312 participants were encompassed. Meta-analysis demonstrated that rising VAI was significantly associated with an elevated DKD risk (OR = 1.23, 95% CI: 1.14-1.33; HR = 1.12, 95% CI: 1.09-1.16). The pooled diagnostic performance of VAI for predicting DKD showed an AUC of 0.74 (95% CI: 0.70-0.77), with a SEN of 0.64 (95% CI: 0.55-0.73) and a SPEC of 0.72 (95% CI: 0.63-0.79).ConclusionsAn increased VAI is associated with an elevated DKD risk and serves as an independent predictor. However, its predictive accuracy remains moderate. It cannot yet replace existing standards (such as urinary albumin-to-creatinine ratio (UACR) and the estimated glomerular filtration rate (eGFR)), but may serve as a complementary tool in resource-limited settings. Future research should explore whether combining VAI with other relevant indicators enhances the prediction of DKD risk.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024587271.
ObjectiveTo compare cardiovascular and renal benefits and safety of GLP-1RAs, SGLT2is, and nsMRAs in T2D-CKD using network meta-analysis.MethodsRCTs published through 7 August 2026 were systematically identified. A frequentist random-effects network meta-analysis was performed. Evidence certainty was assessed with CINeMA.ResultsA total of 21 RCTs involving 51,899 patients were included. Compared with placebo, nsMRAs were associated with lower risks of the major kidney composite outcome and hospitalization for heart failure (HHF), whereas SGLT2is were associated with lower risks of major adverse cardiovascular events (MACE), the major kidney composite outcome, and HHF. GLP-1RAs were associated with lower risks of MACE, the major kidney composite outcome, HHF, all-cause mortality, and cardiovascular death. Between-class indirect comparisons suggested a lower estimated risk of the major kidney composite outcome with SGLT2is than with GLP-1RAs (RR 0.77, 95% CI 0.64–0.91) or nsMRAs (nsMRAs versus SGLT2is: RR 1.28, 95% CI 1.10–1.50). The estimated risk of HHF was also lower with SGLT2is than with nsMRAs (nsMRAs versus SGLT2is: RR 1.28, 95% CI 1.01–1.63). For cardiovascular death, the indirect estimate suggested a lower risk with GLP-1RAs than with SGLT2is (SGLT2is versus GLP-1RAs: RR 1.28, 95% CI 1.03–1.58), whereas the comparison between nsMRAs and GLP-1RAs did not reach statistical significance (RR 1.24, 95% CI 0.99–1.56). No statistically significant between-class differences were identified for MACE or all-cause mortality. All between-class comparisons were based exclusively on indirect evidence. Safety analyses showed higher risks of hyperkalemia with nsMRAs and genital infections with SGLT2is than with placebo. Sensitivity analyses broadly supported the main findings. Confidence in the evidence was mostly low to moderate, primarily because of indirectness.ConclusionIn patients with T2D-CKD, all three drug classes reduced several cardiorenal outcomes versus placebo. Between-class indirect comparisons suggested more favorable relative-effect estimates for SGLT2is on major kidney outcomes and HHF in selected comparisons, and for GLP-1RAs on cardiovascular death. No clear between-class difference was observed for MACE. Because the network lacked head-to-head comparisons between active drug classes, these findings and treatment rankings should be interpreted cautiously. Direct comparative and combination-therapy trials are needed to guide individualized treatment selection.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251150683, identifier CRD420251150683.
Diabetes-associated cognitive dysfunction (DACD) arises from interacting metabolic, vascular, inflammatory, and neuronal insults, but evidence for Panax-derived interventions is often overgeneralized across chemically non-equivalent materials. This critical narrative review evaluated whether defined Panax-derived saponins support a coherent mechanism of DACD and identified the evidence needed for translation. A structured multilingual search of eight bibliographic databases, supplemented by a targeted search of Cochrane CENTRAL, followed by deduplication and full-text reassessment, yielded 59 records: 16 A1 in vivo studies relevant to DACD (direct or near-direct), six neural-cell studies, 17 auxiliary Panax/barrier/formulation studies, and 20 contextual records. Purified monomers, the active metabolite compound K, saponin fractions, extracts, formulations, and combination interventions were appraised as non-interchangeable exposures. The most consistent signal was improved learning or memory accompanied by hippocampal or cortical tissue protection. Mechanistic findings converged on three connected but partly parallel processes: impaired brain insulin signaling and neuronal glucose handling; advanced glycation end product/methylglyoxal-associated oxidative and organelle stress; and glial-inflammasome amplification. Causal support was uneven, and brain exposure or central target engagement was rarely demonstrated. Most animal studies used young or adult animals of one sex and preventive or early-treatment designs, while several risk-of-bias domains were insufficiently reported. Panax-derived saponins should therefore be regarded as preclinical modulators of hippocampal metabolic-inflammatory-neuronal injury, not established DACD treatments. Translation requires defined interventions, parent/metabolite profiling, quantitative brain exposure, target-engagement assays, delayed-treatment and reversal designs, and clinically aligned biomarkers.
