Yang Yang

Background: Hyperuricemia (HUA) frequently coexists with glucolipid metabolic disturbances characterized by insulin resistance, dyslipidemia, and adipose tissue dysfunction. However, the association between insulin resistance (IR)-related indices and cardiovascular disease (CVD) incidence/mortality in HUA patients remains not yet fully established. Methods: Data from the UK Biobank (UKBB) and Shanghai Pudong cohort were analyzed, enrolling 35,853 and 12,680 HUA patients, respectively. Associations between seven IR-related indices and adverse cardiovascular events were assessed using multivariate Cox proportional hazards models, restricted cubic spline analyses, time-dependent receiver operating characteristic, random forest modeling, and Mendelian randomization. Mediation analyses evaluated the role of phenotypic aging biomarkers and inflammatory markers in these relationships. Results: All seven IR indices exhibited significant associations with CVD events and mortality in HUA patients from two cohorts. TyG-WHTR showed comparable 10-year CVD mortality predictive performance to SCORE2 in UKBB (AUC, 0.733). Elevated TyG-WHTR correlated with increased CVD mortality [T3 vs. T1: HR, 1.76 (95%CI: 1.48–2.11)], while higher CMI predicted myocardial infarction [HR, 1.52 (1.31–1.76)]. C-reactive protein (mediation ratio: 1.3–13.3%) and accelerated aging (4.5–34.4%) partially mediated these associations. Genetically predicted TyG index elevation was linked to myocardial infarction risk [OR, 1.79 (1.48–2.16)]. Conclusion: IR-related indices serve as clinically valuable tools for CVD risk stratification in HUA, with inflammatory activation and accelerated aging constituting key mechanistic pathways. These findings provide novel insights for early identification and targeted prevention of cardiovascular complications in HUA patients.

While insulin resistance (IR) and frailty are mechanistically intertwined via shared pathways of chronic inflammation and metabolic dysregulation, their synergistic impact on cardiovascular risk has yet to be fully elucidated. We aimed to evaluate the joint association of IR and frailty index (FI) with the risk of incident atherosclerotic cardiovascular disease (ASCVD) and major adverse cardiovascular events (MACE) in individuals with Cardiovascular-Kidney-Metabolic (CKM) syndrome stages 0-3. This study enrolled 259,714 and 2632 CKM syndrome stages 0-3 from the UK Biobank (UKB), and China Health and Retirement Longitudinal Study (CHARLS). Three IR-related indices, namely the triglyceride-glucose index (TyG), metabolic score for IR (METS-IR), and estimated glucose disposal rate (eGDR), were each combined with two frailty assessments, the FI and physical FI (PFI), yielding six composite IR-FI indices for analysis. In the UKB, MACE and ASCVD were the co-primary outcomes, with heart disease and stroke as secondary outcomes. In the CHARLS, the outcomes included CVD, heart disease, and stroke. Multivariate Cox proportional hazards models, restricted cubic spline analyses, Kaplan-Meier analyses and time-dependent receiver operating characteristic curves were employed to assess associations. Mediation analysis and functional proteomic enrichment provided a framework for exploring the potential biological mechanisms. In the UKB, elevated levels of the IR-FI were associated with increased risks of ASCVD and MACE, with consistent findings observed for CVD, heart disease, and stroke in the CHARLS. Significant positive nonlinear relationships were established for the METS-IR-FI and eGDR-FI regarding cardiovascular outcomes. Mediation analysis revealed that Creactive protein, neutrophils, and leucocyte partially mediated these associations (ratio range: 1.5-12%). Proteomic analyses identified Cytokine-cytokine receptor interaction as a primary regulatory hub, while leukocyte migration, chemotaxis, and neutrophil degranulation were characterized as the central pathological execution mechanisms in this process. The IR-FI are significantly associated with the incidence of cardiovascular events, an association that appears to be mediated through systemic inflammatory pathways. These novel integrated indices represent promising biomarkers for early screening and targeted clinical intervention among individuals with CKM syndrome stages 0-3.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and non-alcoholic fatty liver disease (NAFLD) are closely linked to insulin resistance and elevated cardiovascular risk, triglyceride-glucose (TyG)-related indices, the atherogenic index of plasma (AIP), and the cardiometabolic index (CMI) have emerged as practical surrogate markers for cardiometabolic risk assessment in these populations. However, it remains unclear whether the associations of these indices with adverse cardiovascular events remain consistent when transitioning from the NAFLD to the newly defined MASLD framework, and a comprehensive comparison of these indices across both diagnostic criteria is lacking. This study included 4693/3266, 74,173/67,864, and 7823/10,576 individuals with MASLD/NAFLD from the National Health and Nutrition Examination Survey (NHANES), UK Biobank (UKB), and China Pudong cohort, respectively. Multivariate Cox proportional hazards models, restricted cubic spline analyses, and time-dependent receiver operating characteristic curves were employed to assess associations. Linear regression models evaluated relationships between TyG-related indices and cortical/subcortical structural volumes. Mediation analyses examined the role of oxidative stress, phenotypic aging, and inflammatory markers. Most IR-related indices demonstrated nonlinear, predominantly J-shaped associations with cardiovascular disease (CVD) and related mortality, especially within the UKB. TyG-WC optimally predicted 3-year CVD mortality in MASLD/NAFLD across UKB and NHANES, as well as ischemic stroke (IS) in UKB-MASLD. TyG-WHTR was the strongest predictor for CVD mortality in the Pudong cohort and myocardial infarction (MI) in UKB-MASLD. Notably, elevated TyG-WHTR was consistently associated with heightened risks across all endpoints: CVD mortality (NAFLD: UKB: HR 1.60, 95%CI 1.38-1.84, NHANES: 1.90, 1.34-2.70, Pudong: 1.24, 1.10-1.40; MASLD: UKB: 1.59, 1.38-1.82, NHANES: 1.86, 1.36-2.54, Pudong: 1.70, 1.43-2.03), MI (NAFLD: 1.20, 1.09-1.33; MASLD: 1.22, 1.11-1.34), and IS (NAFLD: 1.41, 1.24-1.61; MASLD: 1.39, 1.23-1.57). Structural neuroimaging analyses revealed significant negative correlations between TyG-WC/TyG-WHTR and subcortical volumes (P < 1 × 10^-4). Mediation analyses indicated that oxidative stress, phenotypic aging, and inflammatory markers collectively accounted for 1.4-27% of the observed associations. Insulin Resistance-Related Indices demonstrate robust clinical utility in predicting CVD and mortality in NAFLD/MASLD across three distinct cohorts, with oxidative stress, inflammatory activation, and accelerated aging serving as potential mechanistic pathways.

Zhou X, et al. J Periodontal Implant Sci. 2026 ;56:e29. https://doi.org/10.5051/jpis.2500240012

Both fatty liver/fibrosis and insulin resistance (IR) contribute to the development of Cardiovascular-Kidney-Metabolic (CKM) syndrome and elevate cardiovascular risk. This study aimed to investigate the joint associations of IR and fatty liver/fibrosis indices with major adverse cardiovascular events (MACE) and mortality in individuals with CKM syndrome stages 0–3. This study enrolled 259,699 and 6808 CKM syndrome stages 0–3 from the UK Biobank (UKB) and the National Health and Nutrition Examination Survey (NHANES). Two IR-related indices (triglyceride-glucose index, TyG; cardiometabolic index, CMI), fatty liver indices (Fatty Liver Index, FLI; Hepatic Steatosis Index, HSI), and liver fibrosis score (LiverRisk score, LRS) were calculated to construct composite indices. Multivariable Cox proportional hazards models, restricted cubic splines, Kaplan–Meier analyses, and time-dependent receiver operating characteristic curves were employed to assess prognostic associations. Mediation modeling and proteomic enrichment analyses provided a robust framework for exploring the potential pathophysiological pathways. In the UKB, elevated levels of the IR-FLI/HSI/LRS indices were significantly associated with increased risks of MACE and mortality, with consistent findings observed for all-cause and CVD mortality in the NHANES. Significant positive nonlinear relationships were established between the CMI-FLI/HSI/LRS indices and the risk of MACE. Furthermore, these composite indices demonstrated superior 10-year predictive performance compared to individual IR-related indices, and the combination of CMI and LRS showed the best performance for predicting cardiovascular mortality in both cohorts, with AUCs of 0.755 in the UKB and 0.847 in the NHANES. Mediation analysis revealed that C-reactive protein, neutrophils, and leukocytes partially mediated these associations (ratio 5.3%–14.8%). Proteomic analyses identified cytokine–cytokine receptor interactions as a primary regulatory hub, while leukocyte migration, chemotaxis, and neutrophil degranulation emerged as potential effector mechanisms implicated in this process. IR–fatty liver/fibrosis indices are significantly associated with MACE and mortality and may serve as promising biomarkers for early screening and targeted intervention in CKM stages 0–3.

Adequate keratinized mucosa around implants is crucial for maintaining peri-implant hard and soft tissue health. Concentrated growth factor (CGF), a novel platelet concentrate, has been widely applied to promote tissue regeneration and wound healing, which could also be effective in peri-implant keratinized mucosa augmentation. This prospective case series aimed to present the clinical outcomes of apically repositioned flap (ARF) combined with CGF and to provide histological evidence. Patients with insufficient keratinized mucosa (< 2 mm) were included. ARF combined with CGF was performed to augment the keratinized mucosa. Changes in the keratinized mucosa width (KMW) and vestibular depth (VD) from surgery to 12 months were documented. The secondary endpoints included the mucosal thickness (MT), marginal bone loss (MBL), modified plaque index (mPI), bleeding on probing (BOP), and probing depth (PD). Additionally, two biopsy samples were collected to analyze their tissue morphology and keratin expression. Thirty patients with a mean age of 46.0 ± 13.4 years and a total of 48 implant sites were recruited for the study. The KMW increased significantly from 1.44 ± 0.54 mm to 5.04 ± 1.64 mm at 2 weeks and stabilized at 2.48 ± 0.80 mm over 1 year (p < 0.001). The VD improved from 4.46 ± 2.38 mm to 5.32 ± 1.93 mm at 1-year post-ARF (p < 0.001). The MT increased from 1.48 ± 0.48 mm to 2.45 ± 0.70 mm (p < 0.001). After 1 year, the mPI and BOP were 0.47 ± 0.93 and 0.17 ± 0.39, respectively. The PD and MBL were 2.39 ± 0.59 mm and 0.36 ± 0.24 mm, respectively. Histological evaluation confirmed a typical keratinized mucosal structure with appropriate expression of keratin 5 and 10. Within the limitations of this case series, our findings suggested that the use of ARF combined with CGF could be a reliable approach for keratinized mucosal augmentation and vestibular deepening. KMW achieved the clinically ideal value of more than 2 mm one year after surgery. Histological analysis revealed the formation of keratinized mucosa around the implants.

It has been reported that elderly individuals exhibit reduced scarring during the wound healing process compared to younger adults. However, the underlying mechanisms responsible for this phenomenon remain poorly understood. Here, we revealed that aged mice exhibited more pronounced regenerative outcomes compared to young mice, characterized by increased hair follicle numbers and collagen fiber features closer to normal skin. Single-cell sequencing identified a reparative fibroblast subpopulation (Prss35 ⁺ Fib) enriched in the aged group, which promotes regeneration through communication with epithelial cells, macrophages, and T cell subpopulations via PTN and EREG signaling. Spatial transcriptomics validated this communication pattern by elucidating cell proximity and locating the regenerative niche in the upper dermis. Finally, EREG treatment significantly enhanced regenerative outcomes in young mice, while the small wound model of aged mice, lacking the reparative fibroblast and EREG signaling, failed to achieve regeneration. Collectively, our findings advance the understanding of regenerative plasticity in aging and provide new insights for designing scarless therapeutic strategies.