This prospective observational study investigated whether systolic blood pressure variability (SBPV) during the transitional care period predicts long-term outcomes after coronary artery bypass grafting (CABG). We enrolled 120 consecutive patients undergoing isolated CABG between 2020 and 2024 in a structured Transitional Care Service System. Office blood pressure was measured at scheduled visits. SBPV was quantified using the coefficient of variation (CV), and patients were stratified by median SBP-CV (8.4%) into low- and high-variability groups. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE). During a median follow-up of 46 months (corresponding to 34 months post-landmark), 19 MACCE events occurred in the landmark cohort of 116 patients (4 early events were excluded). The high-variability group experienced significantly more events than the low-variability group (26.3% vs. 6.8%, p = 0.005), with markedly reduced event-free survival (log-rank p = 0.005). After multivariable adjustment for age, diabetes mellitus, number of measurements, and mean systolic blood pressure, high SBPV remained an independent predictor of MACCE (hazard ratio 2.85, 95% confidence interval 1.12-7.24, p = 0.028). Sensitivity analyses using alternative metrics confirmed these findings, whereas mean systolic blood pressure was not predictive. In conclusion, high visit-to-visit SBPV during postoperative transitional care independently predicts long-term cardiovascular events after CABG. Monitoring blood pressure stability may enhance risk stratification in this high-risk population.

Insulin-producing cells (IPCs) derived from human amniotic epithelial stem cells (hAECs) represent a promising strategy for cell replacement therapy for diabetes. However, poor graft survival and immune rejection remain major obstacles to clinical application. Our previous work established that METTL3 overexpression enhances IPCs induction efficiency and maturation, yet whether it improves in vivo transplantation efficacy and the associated mechanisms remain unexplored. WT-IPCs and Mettl3-OE-IPCs were transplanted beneath the renal capsule of streptozotocin-induced type 1 diabetic mice. Blood glucose, serum C-peptide, in vivo GFP fluorescence imaging, and histology were used to assess graft survival. Untargeted metabolomics of intestinal contents identified differential metabolites. Western blot, RT-qPCR, immunofluorescence, and ELISA examined associations among METTL3, IDO1, and kynurenine (Kyn) in vitro. A four-group rescue experiment (WT-IPCs, WT-IPCs+Kyn, Mettl3-OE-IPCs, Mettl3-OE-IPCs+1-MT) evaluated the causal contribution of Kyn. Immunofluorescence and immunohistochemistry assessed endogenous islet apoptosis and local immune infiltration. Mettl3-OE-IPCs transplantation significantly improved glycemic control and prolonged graft survival compared with the WT-IPCs group. Endogenous islets in the Mettl3-OE-IPCs group showed elevated insulin expression, reduced BAX, and increased Bcl-2. Serum C-peptide levels were also higher in this group. Untargeted metabolomics identified Kyn as the significantly enriched metabolite in the intestinal contents of the Mettl3-OE-IPCs group. Serum Kyn levels were markedly elevated (p < 0.0001). In vitro, METTL3 overexpression was associated with IDO1 upregulation at mRNA and protein levels and increased Kyn secretion. Rescue experiments showed that Kyn supplementation conferred comparable glycemic benefits and islet apoptosis suppression to the Mettl3-OE-IPCs group; IDO1 inhibition with 1-MT substantially attenuated these advantages (IPGTT AUC, p < 0.0001). Immune profiling revealed splenic CD25⁺CD4⁺ T cell expansion and reduced transplant side renal CD8+ T cell infiltration in Kyn-treated and the Mettl3-OE-IPCs group; both effects were abrogated by 1-MT. This study shows that METTL3 overexpression is associated with IDO1 upregulation and elevated systemic Kyn levels. These changes are accompanied by improved graft survival and reduced endogenous islet apoptosis. Rescue experiments show that Kyn is both sufficient and necessary for these effects. These findings suggest that the METTL3-IDO1-Kyn pathway may be a potential target for improving cell replacement therapy for diabetes.

Based on multicenter clinical data, this study aimed to develop and validate a predictive model for chronic low back pain (CLBP) after lumbar decompression surgery in patients with diabetes mellitus and lumbar disc herniation. The model integrated metabolic indicators and imaging-derived features of the paraspinal muscles.

This study was designed as a multicenter retrospective cohort study. A total of 2776 patients with diabetes mellitus and lumbar disc herniation were included. All patients underwent unilateral biportal endoscopic (UBE) decompression between January 2021 and December 2024 across six medical centers. Postoperative CLBP was defined as persistent or recurrent low back or lumbosacral pain lasting more than six months after surgery. A visual analogue scale (VAS) score greater than 4 was used as the threshold for outcome assessment. Patients were excluded if postoperative pain could be attributed to structural complications or recurrent pathology. Patients with severe psychiatric or psychosocial conditions that might impair the reliability of pain assessment were also excluded. Data from four centers were used for model development and internal validation, while the remaining two centers served as independent external validation cohorts. Clinical variables, laboratory findings, and imaging parameters were integrated to develop multiple machine learning-based predictive models. Model performance was evaluated based on discrimination, calibration, and clinical net benefit. In addition, restricted cubic spline (RCS) analysis was performed to assess potential nonlinear relationships between key continuous variables and postoperative CLBP risk. Shapley additive explanations (SHAP) and local interpretable model-agnostic explanations (LIME) were used to interpret model predictions at both global and individual levels.

Among individual models, the ExtraTrees algorithm achieved the highest discriminative performance in the validation cohort (AUC = 0.855) and showed stable performance across the two external validation cohorts. However, its sensitivity (0.413) and F1 score (0.531) remained relatively low. After comprehensive evaluation of discrimination, classification performance, and calibration, a stacking ensemble model combining XGBoost, artificial neural networks (ANN), and linear discriminant analysis (LDA) was selected as the final model due to its more balanced overall performance. In the validation cohort, this model achieved an AUC of 0.838, which was slightly lower than that of ExtraTrees. However, it demonstrated substantial improvements in sensitivity, F1 score, and accuracy by 43.8%, 24.7%, and 4.9%, respectively, along with improved calibration performance (Brier score = 0.146). Decision curve analysis demonstrated stable clinical net benefit across the validation cohort and both external validation cohorts. RCS analysis revealed significant nonlinear associations between postoperative CLBP risk and age, admission blood glucose, glycated hemoglobin, psoas muscle index, multifidus fat infiltration, albumin, alkaline phosphatase, and serum calcium. SHAP and LIME analyses identified intervertebral disc degeneration grade, age, psoas muscle index, admission blood glucose, and paraspinal muscle fat infiltration as the most important predictors in the model.

This multicenter study developed and externally validated a predictive model for postoperative CLBP using integrated clinical and imaging data. The model demonstrated good discriminative ability and interpretability. It may be useful for estimating the risk of CLBP after lumbar decompression surgery in patients with diabetes mellitus. Metabolic abnormalities and paraspinal muscle degeneration-related features contributed substantially to model predictions, suggesting a statistical association with postoperative chronic pain development. The model may support individualized risk stratification, postoperative follow-up, and rehabilitation planning. However, given its limited sensitivity, further validation in prospective studies is required before clinical application.

Sarcopenic obesity, defined by reduced muscle mass and strength with excess adiposity, is poorly characterized in Japanese individuals with type 2 diabetes (T2D). This post hoc analysis assessed its prevalence and associations with physical quality of life (QOL), walking ability, and falls.

This post hoc cross-sectional analysis used sub-cohort data from the Impact of Diabetes Mellitus on Dynapenia (iDIAMOND) study, conducted across seven medical centers. The study included 930 individuals aged 40-75 years (527 with T2D and 403 without diabetes [non-D]). Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia criteria, defined as low grip strength and/or slow gait speed with low skeletal muscle mass index. Sarcopenic obesity was diagnosed using the Japanese Working Group on Sarcopenic Obesity criteria, defined as high body mass index (BMI) or waist circumference combined with low grip strength, low skeletal muscle mass relative to BMI, and high body fat percentage. Participants meeting neither criterion were classified as robust.

Among participants aged 40-75 years, sarcopenic obesity was observed in 4.9% of those with T2D and 0.5% of non-D individuals (P < 0.001). In the T2D group, sarcopenic obesity was associated with lower physical QOL, reduced physical activity, slow gait speed, and a high incidence of falls compared with the robust group. Multivariate logistic regression identified advanced age, high BMI, and reduced physical activity as independent correlates of sarcopenic obesity.

Sarcopenic obesity is more prevalent in individuals with T2D and is associated with impaired physical QOL, reduced walking ability, and increased falls.

Combined renal and islet xenotransplantation could provide a durable treatment for end-stage diabetic nephropathy. In this feasibility-focused study, we evaluated two complementary approaches for clinical translation: (1) pre-vascularized composite islet-kidney (I-K) grafts and (2) sequential islet-after-kidney xenotransplantation with vascularized thymic lobe (VTL) co-transplantation as an adjunct immune tolerance strategy.

Composite I-K grafts were generated in nine MHC-matched, minor-antigen-mismatched miniature swine pairs by implanting adult porcine islets beneath the renal capsule of juvenile kidney donors followed by pre-vascularization under tacrolimus-based immunosuppression. Separately, three baboons underwent GalTKO.hCD55 kidney and VTL xenotransplantation, followed by streptozocin-induced diabetes and intraportal adult porcine islet infusion from a separate donor. Renal/metabolic function, porcine C-peptide, histology, and immune profiling were assessed.

Composite I-K grafts demonstrated limited islet survival with peri-islet inflammation on histology at the graft preparation stage and were not advanced to pig-to-NHP xenotransplantation in this study. Sequential islet-after-kidney transplantation restored insulin-independent euglycemia in all recipients. Porcine C-peptide was detectable in the long-term survivor with intrahepatic insulin-positive islets at necropsy. Infection-associated thrombotic microangiopathy limited survival in two animals; in the 180-day survivor, anti-porcine hypo-responsiveness and evidence of thymopoiesis within the VTL graft were observed.

In this limited series, sequential islet-after-kidney xenotransplantation restored metabolic control and represents a promising translational strategy for diabetic nephropathy.

Triplet therapy with androgen deprivation therapy (ADT), docetaxel, and androgen receptor pathway inhibitors (ARPIs), either darolutamide or abiraterone, is one of the standard treatments for metastatic hormone-sensitive prostate cancer (mHSPC); however, no randomized trial has directly compared both ARPIs within this regimen. Given practical and financial constraints, a head-to-head randomized trial directly comparing these ARPIs may be unlikely.

To compare the real-world effectiveness of darolutamide- versus abiraterone-based triplet therapy in patients with mHSPC.

Retrospective cohort study using a multinational electronic health record network.

We conducted a retrospective cohort study using the TriNetX research network. Patients with mHSPC treated with darolutamide- or abiraterone-based triplet therapy were identified and balanced using propensity-score matching. The primary outcome was overall survival (OS), and the secondary outcome was time to next treatment (TTNT), defined by treatment switch. Prespecified subgroup analyses focused on age, cardiometabolic comorbidities, and polypharmacy-related medication use.

Among 1607 eligible patients, 1252 were included after propensity score matching (626 per group). Darolutamide-based triplet therapy was associated with longer OS compared with abiraterone (hazard ratio (HR) 0.42). A favorable difference in TTNT was also observed (HR 0.66). These associations were consistent across clinically relevant subgroups, including patients aged ⩾65 years and those with ischemic heart disease or diabetes mellitus. In polypharmacy-enriched subgroups, darolutamide-based therapy was consistently associated with more favorable OS and TTNT.

In this large real-world analysis, darolutamide-based triplet therapy was associated with longer OS and TTNT compared with abiraterone-based triplet therapy in patients with mHSPC, particularly among older individuals and those with comorbidities. These findings are hypothesis-generating, suggesting that ARPI selection within triplet therapy may have clinically relevant implications, supporting the need for prospective studies.

The American Gastroenterological Association (AGA) Clinical Care Pathway provides a tiered, noninvasive algorithm for fibrosis risk stratification in populations at high risk for metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed the 2-year longitudinal performance of the AGA pathway using magnetic resonance elastography (MRE) as the reference.

This prospective cohort study enrolled adults aged 50-79 years with type 2 diabetes mellitus from ambulatory care clinics between the dates of February 2016 and February 2025. Participants underwent a standardized clinical research visit with Fibrosis-4 index (FIB-4), vibration-controlled transient elastography (VCTE), and MRE at baseline and at a 2-year interval at the UCSD MASLD Research Center.

Of 626 participants with a baseline assessment, 209 had longitudinal follow-up assessment and were included in the study. The prevalence of MASLD was 69.9%, and 19.0% had significant fibrosis at baseline (MRE ≥3.30 kPa). Applying the AGA pathway of FIB-4 and VCTE, the false negative rate (low risk by pathway with MRE ≥3.30 kPa) at baseline was 7% with 17.6% of participants qualifying for specialty referral. At 2-year follow-up, the false negative rate decreased to 3% and an additional 7%, respectively qualified for specialty referral. Applying a FIB-4 cut point of 1.0 decreased the false negative rate to 0%; however, the number of patients requiring VCTE increased by 54% over 2-years.

Longitudinal reassessment of patients initially classified as low risk by the AGA Clinical Care Pathway substantially reduced misclassification of significant fibrosis, while maintaining a low rate of specialty referral. These findings support serial re-evaluation as a key component of noninvasive fibrosis risk stratification in at-risk populations.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have progressed from the initial discovery of endogenous GLP-1 biology in 1986 to widely used therapies for type 2 diabetes and obesity, with expanding indications driven by pleiotropic metabolic and cardiovascular benefits. Although no randomized controlled trials have evaluated GLP-1RA as inflammatory bowel disease (IBD)-directed therapy, retrospective observational studies in IBD populations prescribed GLP-1RA for metabolic indications provide emerging real-world evidence regarding weight loss efficacy, IBD-related outcomes, and adverse events. This narrative review summarizes GLP-1RA pharmacology, mechanistic rationale, and the current clinical evidence base in IBD, with emphasis on safety considerations and priorities for prospective trials.

Diabetic retinopathy (DR), a leading cause of blindness, is driven by hyperglycemia-induced neurovascular damage. Emerging evidence indicates that PANoptosis, an integrated inflammatory programmed cell death modality encompassing apoptosis, pyroptosis, and necroptosis, participates in the progression of diabetic retinal damage; however, the supporting evidence varies substantially across clinical specimens, diabetic animal models, high-glucose cultured retinal cells, and non-DR inflammatory disease models. This review systematically summarizes the latest advances in PANoptosis-associated mechanisms underlying DR pathogenesis, focusing on PANoptosome signaling networks, non-coding RNA-mediated regulation, and immune-metabolic crosstalk. We outline promising candidate biomarkers including PANoptosis-related gene signatures and inflammatory cell death molecules, and critically evaluate multiple translational therapeutic strategies covering small-molecule inhibitors, gene intervention, and nanomedicine delivery. Importantly, we further address context-dependent dual roles of PANoptosis, potential safety risks of non-selective PANoptosis blockade, challenges in blood-retinal barrier penetration, systemic immune side effects, and pathological heterogeneity among DR subtypes and disease stages. Since PANoptosis also fundamentally contributes to host defense and retinal innate immune homeostasis, DR therapeutic strategies should prioritize biomarker-guided, local ocular delivery, time-dependent stage intervention, and cell-type-specific fine tuning, rather than generalized systemic suppression. By reconciling mechanistic progress with unresolved translational bottlenecks, this review proposes that PANoptosis serves as a dynamic and evolving conceptual framework for interpreting inflammatory neurovascular degeneration in DR, instead of an entirely confirmed clinical therapeutic target. We emphasize the urgent need for DR-specific mechanistic verification, longitudinal biomarker cohort studies, and well-designed multicenter clinical trials to advance safe and precise targeted interventions.

Obesity drives chronic diseases such as cardiovascular disease and diabetes. Danlou tablet (DLT), a traditional Chinese medicine formula, is used to treat coronary heart disease by regulating lipid metabolism, suggesting potential for addressing obesity-related metabolic dysfunction. However, its role in obesity and insulin resistance remains unexplored.

We investigated the efficacy and mechanisms of DLT against high-fat diet (HFD)-induced obesity and insulin resistance.

C57BL/6N mice were fed an HFD for 22 weeks and treated with DLT. A comprehensive phenotypic assessment was conducted, including body weight, glucose tolerance, insulin sensitivity, serum biochemistry, and histopathology of key tissues. To elucidate the therapeutic mechanism, we integrated 16S rRNA gene sequencing of gut microbiota, serum metabolomics (UPLC-Q-TOF-MS), and hepatic transcriptomics.

DLT treatment counteracted HFD-induced metabolic dysfunction, reducing body weight, adiposity, dyslipidemia, and insulin resistance, while ameliorating hepatic steatosis, inflammation, and oxidative stress. At the microbial level, DLT restored gut microbial diversity, corrected the Firmicutes/Bacteroidota ratio, and modulated key genera. Metabolomics linked these changes to restored fatty acid β-oxidation. In the liver, transcriptomics showed that DLT reversed HFD-induced gene expression, suppressed inflammatory pathways and enhanced fatty acid oxidation and xenobiotic metabolism. Integrated multi-omics analysis revealed a strong correlative relationship that DLT's therapeutic benefits are associated with the modulation of the gut-liver axis, where remodeling of the gut microbiome is closely linked to the reprogramming of hepatic metabolic pathways.

DLT counteracts HFD-induced obesity and insulin resistance via a multi-level regulatory mechanism that is closely associated with the modulation of the gut-liver axis, which involves suppressing pathogenic gut microbes, restoring fatty acid metabolism, and enhancing hepatic lipid catabolism and antioxidant defense. This comprehensive preclinical evidence supports the clinical translation of DLT as a novel therapeutic option for obesity and type 2 diabetes mellitus.