BACKGROUND: Carotid angioplasty and stenting (CAS) has increasingly been used as an alternative to carotid endarterectomy (CEA) in the treatment of carotid artery disease. However, neurological complications following carotid angiography or CAS remain a clinical concern. This study aimed to evaluate whether naturally occurring ABO blood group antigens and hematological parameters are associated with cerebrovascular complications after diagnostic or therapeutic carotid angiography. METHODS: In this single-center retrospective study, patients were classified as blood group O or non-O (A, B, or AB). Cerebrovascular complications were defined as in-hospital amaurosis fugax, transient ischemic attack (TIA), or stroke occurring after carotid angiography or carotid artery stenting (CAS). RESULTS: A total of 316 patients who underwent carotid angiography were included; 106 (33.5%) had blood group O and 210 (66.5%) had non-O blood groups. Cerebrovascular events were significantly more frequent in patients with non-O blood groups. Stroke occurred in 13.8% of patients with non-O blood groups compared with 1.9% in those with blood group O (p < 0.001), while TIA was also more common in the non-O group (11.0% vs. 3.8%, p = 0.033). When stratified by procedure type, this association was predominantly observed in patients undergoing CAS, whereas cerebrovascular event rates were low and comparable between groups in patients undergoing diagnostic angiography alone. In univariable analysis, diabetes mellitus was associated with stroke (OR = 2.392, p = 0.024), while blood group O was associated with lower odds of stroke (OR = 0.120, p = 0.004). In multivariable analysis, blood group O (OR = 0.127, p = 0.007) and contrast volume (OR per 10 mL increase: 1.218, p < 0.001) remained independently associated with stroke, whereas diabetes mellitus was no longer statistically significant. CONCLUSION: Non-O blood groups were associated with a higher risk of stroke and TIA following carotid angiography, particularly in patients undergoing CAS, whereas blood group O was associated with a lower risk of stroke. These findings should be interpreted with caution due to the observational design and potential residual confounding.

IMPORTANCE: The effects of orforglipron, an oral, nonpeptide glucagon-like peptide 1 receptor agonist, added to insulin glargine for treatment of type 2 diabetes have not been described. OBJECTIVE: To assess efficacy and safety of orforglipron added to titrated insulin glargine in adults with type 2 diabetes and inadequate glycemic control. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, phase 3 study conducted at 72 sites across the US, Brazil, China, Japan, and Romania between November 10, 2023, and September 15, 2025, in adults with type 2 diabetes taking insulin glargine with or without metformin and/or sodium-glucose cotransporter 2 inhibitors over 40 weeks. INTERVENTIONS: Participants were randomized (1:1:1:1) to receive once-daily 3-mg (n = 137), 12-mg (n = 132), or 36-mg (n = 136) dosages of orforglipron or placebo (n = 141), in addition to titrated insulin glargine. MAIN OUTCOMES AND MEASURES: The primary outcome was mean hemoglobin A1c (HbA1c) change from baseline to week 40 (for the 12-mg once daily and 36-mg once daily dosages of orforglipron). Key secondary outcomes were mean HbA1c change from baseline (for the 3-mg once daily dosage of orforglipron), proportion of participants achieving HbA1c targets of lower than 7.0% and 6.5% or lower, and mean body weight change and percentage change from baseline to week 40. RESULTS: Among 546 randomized participants (median age, 61.0 [IQR, 26-95] years; 52.9% male; median duration of type 2 diabetes, 14.6 [IQR, 0.1-40.7] years; mean HbA1c, 8.50% [SD, 0.95%]; mean body mass index, 30.8 [SD, 6.1]), 507 (92.9%) completed the trial. At week 40, the mean changes from baseline in HbA1c were -1.58%, -1.88%, and -1.82% with orforglipron, 3 mg, 12 mg, and 36 mg once daily, respectively, vs -0.79% with placebo. Each dosage of orforglipron was superior to placebo (estimated treatment differences: 3 mg once daily, -0.78% [95% CI, -1.02% to -0.55%]; 12 mg once daily, -1.08% [95% CI, -1.33% to -0.83%]; 36 mg once daily, -1.03% [95% CI, -1.28% to -0.77%]; P < .001 for all). All key secondary outcomes demonstrated statistically significant differences in favor of orforglipron compared with placebo. Mean percentage body weight change from baseline was -2.6%, -4.8%, and -5.4% with orforglipron, 3 mg once daily, 12 mg once daily, and 36 mg once daily, respectively, vs 0.2% with placebo. The most frequent adverse events with orforglipron were gastrointestinal (mild to moderate). Orforglipron did not increase the risk of clinically significant hypoglycemia vs placebo. CONCLUSIONS AND RELEVANCE: In participants with type 2 diabetes inadequately controlled by insulin glargine, addition of oral orforglipron significantly improved glycemic control and body weight, without increasing hypoglycemia risk, compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06109311.

OBJECTIVE: We evaluated whether early pregnancy oral glucose tolerance testing (OGTT) or continuous glucose monitoring (CGM) improves gestational diabetes mellitus (GDM) or large for gestational age (LGA) birth prediction over clinical factors alone. RESEARCH DESIGN AND METHODS: In the Glycemic Observation and Metabolic Outcomes in Mothers and Offspring (GO MOMs) study, a prospective observational study at nine U.S. sites (2021-2025), participants with singleton gestation and without preexisting diabetes underwent blinded 75-g OGTT and CGM at 10-14 weeks' gestation. Predictive models for GDM at 24-28 weeks' and LGA were developed using these data and clinical factors (maternal age, BMI, GDM or macrosomia history). New glycemic criteria maximized the area under the receiver operating characteristic curve in training data from four sites and were validated in five. Models incorporating OGTT or CGM criteria versus clinical factors alone compared positive predictive value (PPV) at a prespecified negative predictive value (NPV) at a reported 8.3% national GDM prevalence and 10% for LGA. RESULTS: Of 2,178 participants, 93.3% who were pregnant at 24-28 weeks completed OGTTs (15.4% GDM), and 98.1% with live births had data to determine LGA (11.2% LGA). At NPV ≥96% and 8.3% GDM prevalence, PPV for GDM was 12.2% (95% CI 11.0-13.3%) for clinical factors alone, 26.5% (23.1-30.3%) for OGTT plus clinical factors, and 19.8% (17.2-22.5%) for CGM plus clinical factors. For LGA, neither glycemic model improved PPV. Validation confirmed findings. CONCLUSIONS: In a U.S.-representative population, adding 10-14-week OGTT or CGM criteria to clinical factors improved GDM but not LGA prediction. Future studies should determine whether predicting GDM in the first trimester facilitates interventions that improve GDM-related pregnancy outcomes.

BACKGROUND: HTD1801 is an anti-inflammatory metabolic modulator being developed to treat type 2 diabetes (T2D). The safety and efficacy of HTD1801 as an add-on to metformin among patients with T2D with inadequate glycemic control despite stable metformin use have not been well evaluated. METHODS: This phase 3 double-blind trial included patients with T2D, glycated hemoglobin (HbA1c) 7.0% to 10.5%, fasting glucose levels of 250.5 mg/dl or lower, and stable use of metformin for 8 weeks or more. Patients were randomly assigned 2:1 to receive either HTD1801 1000 mg orally twice daily (n=365) or placebo (n=184) in addition to their prior metformin treatment. The primary end point was change in HbA1c from baseline to week 24. Data on adverse events were collected during this 24-week time frame. RESULTS: The mean HbA1c was 8.6% at baseline and 7.4% at 24 weeks in the HTD1801 group (mean change, -1.2 percentage points; 95% confidence interval [CI], -1.3 to -1.1). The mean HbA1c was 8.5% at baseline and 7.8% at 24 weeks in the placebo group (mean change, -0.7 percentage point; 95% CI, -0.8 to -0.6). The adjusted least-squares mean difference between groups for the change in HbA1c from baseline to week 24 was -0.5 (95% CI, -0.7 to -0.4; P<0.0001). Diarrhea was the most common adverse event (HTD1801, 23.8%; placebo, 1.1%), with three cases in the HTD1801 group graded as severe, and all the other cases being mild to moderate in severity. No patients experienced severe hypoglycemia. CONCLUSIONS: After 24 weeks, HbA1c reduction was significantly greater among patients with T2D taking metformin and randomly assigned to receive HTD1801 versus placebo. A higher proportion of patients in the HTD1801 group experienced mild to moderate diarrhea compared with the placebo group. (Funded by Shenzhen HighTide Biopharmaceutical; ClinicalTrials.gov number, NCT06353347.).

IMPORTANCE: Obesity is a worldwide problem and a major public health issue in China. OBJECTIVE: To evaluate the efficacy and safety of mazdutide (a once-weekly glucagon and glucagon-like peptide-1 receptor dual agonist) in Chinese adults with obesity (defined as a body mass index of ≥30). DESIGN, SETTING, AND PARTICIPANTS: A double-blind, placebo-controlled, phase 3, randomized clinical trial including Chinese adults with or without type 2 diabetes that was conducted at 27 hospitals from December 2023 to November 2025. INTERVENTIONS: Participants were randomized in a 2:1 ratio to receive a once weekly, 9-mg dose of mazdutide administered subcutaneously (n = 308) or placebo (n = 154) as an adjunct to a reduced calorie diet and increased physical activity for 60 weeks. MAIN OUTCOMES AND MEASURES: The coprimary outcomes were the percentage change in body weight from baseline and a weight reduction of at least 5% at week 60. The efficacy and safety analyses were performed in participants who received at least 1 dose of the study treatment. RESULTS: A total of 461 participants (295 [64.0%] female; 16.1% with type 2 diabetes; mean age, 33.9 [SD, 8.4] years; body weight, 94.0 [SD, 13.8] kg; BMI, 34.3 [SD, 3.2]) received the study treatment (307 in the mazdutide group and 154 in the placebo group) and were included in the analyses. At week 60, the mean percentage change in body weight from baseline was -16.65% (95% CI, -18.19% to -15.12%) in the mazdutide group compared with -1.50% (95% CI, -3.43% to 0.43%) in the placebo group (between-group difference, -15.15% [95% CI, -17.22% to -13.09%]; P < .001). At week 60, 84.3% of participants in the mazdutide group had a body weight reduction of 5% or greater compared with 33.1% in the placebo group (between-group difference, 51.6% [95% CI, 43.0% to 60.1%]; P < .001). Adverse events leading to study treatment discontinuation were reported in 2.9% of participants in the mazdutide group compared with 0% in the placebo group. The most common adverse events were vomiting (53.1% in the mazdutide group vs 1.3% in the placebo group), nausea (46.9% vs 3.2%, respectively), and diarrhea (39.4% vs 6.5%); most of the adverse events were mild to moderate in severity. CONCLUSIONS AND RELEVANCE: Mazdutide provided clinically meaningful weight reduction in Chinese adults with moderate to severe obesity compared with placebo, but participants receiving the drug experienced gastrointestinal adverse reactions compared with those receiving placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06164873.

Although oral antidiabetic agents are widely prescribed for management of type 2 diabetes mellitus (T2DM), their long-term mutagenic and carcinogenic safety remains insufficiently characterized. The aim of this study was to examine the genotoxic potential of empagliflozin, linagliptin, pioglitazone, and the fixed-dose combination (empagliflozin/linagliptin) using Somatic Mutation and Recombination Test (SMART) in . Third-instar larvae from standard (ST) and high-bioactivation (HB) crosses, differing in cytochrome P450 enzyme activity, were chronically exposed to increasing concentrations of selected drugs. Empagliflozin, linagliptin, and their combination did not induce significant alterations in mutant clone frequency across all tested doses in either cross. In contrast, the highest concentration of pioglitazone (72 mg/ml) significantly elevated DNA damage, with lesions originating from both mutation and recombination in the ST cross, but almost exclusively from mutational events in the HB cross. These findings suggest that while empagliflozin and linagliptin present no apparent detectable genotoxic hazard under these tested conditions, pioglitazone displays a dose-dependent genotoxic effect. Data indicate the importance of systematic genotoxicity assessment in widely used antidiabetic medications to ensure patient safety.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly prescribed for type 2 diabetes mellitus (T2DM), yet the perioperative safety profile in hand/wrist surgery remains incompletely defined. This study evaluated the association between preoperative GLP-1 RA exposure and postoperative complications and healthcare use following operative fixation of distal radius fractures in adults with T2DM. METHODS: A retrospective cohort study was performed using the TriNetX Network (2018-2024). Adults with T2DM undergoing open surgical fixation of a distal radius fracture were categorized by active GLP-1 RA use within 180 days preoperatively. Propensity score matching (1:1) balanced demographics, fracture complexity, metabolic factors, diabetes severity, and medication use. Outcomes included 90-day medical complications, 180-day surgical complications, and healthcare use through 180 days. Odds ratios with 95% confidence intervals were estimated by logistic regression. RESULTS: After matching, 1080 patients (540 per cohort) were included. Glucagon-like peptide-1 receptor agonist use was not associated with significant differences in composite 90-day medical complications or composite 180-day surgical complications. Individual adverse events were uncommon and did not differ between groups. Notably, GLP-1 RA use was associated with lower odds of emergency department visit and/or inpatient hospital readmission at 180 days, while use at 30 and 90 days was similar between cohorts. CONCLUSIONS: Among adults with T2DM undergoing operative fixation of distal radius fractures, preoperative GLP-1 RA exposure was not associated with increased medical or surgical complications and was associated with reduced 180-day healthcare use. These findings support the perioperative safety of GLP-1 RAs in this setting and warrant prospective validation.

BACKGROUND: De-implementation-reducing low-value or harmful care-is critical but difficult in clinical practice. Clinical decision support (CDS) "nudges" in electronic health records (EHRs) aim to promote guideline-concordant deprescribing, but effects are inconsistent. In a pragmatic randomized controlled trial across a large health system, we tested a suite of EHR-based CDS nudges to support Choosing Wisely-aligned deprescribing of glycemic medications in older adults with type 2 diabetes. Although a prior pilot showed modest improvement in guideline concordance (5.1%), the full trial found no significant changes in prescribing; this process evaluation examines clinicians' comments on alerts to explain why. METHODS: We conducted a mixed-methods process evaluation of comments within EHR-based alerts from a null-result RCT that promoted Choosing Wisely deprescribing for older adults with type 2 diabetes. Among 66,634 alerts firing across EHR encounters (December 2016-July 2023), providers commented on 764 (1.2%). Two researchers independently coded comments using reflexive thematic analysis, identifying four themes (three negative). Exploratory logistic and multinomial regressions examined predictors of commenting, valence, and themes among acknowledged firings, adjusting for patient, provider, and encounter factors. RESULTS: Thematic analysis of comments revealed three barriers to deprescribing: (1) disagreement with Choosing Wisely guidelines (308 comments, e.g., perceived low overtreatment risk); (2) workflow misalignment (203 comments, e.g., wrong provider responsibility); and (3) patient preferences (69 comments). Logistic regression showed multiple concurrent OPAs reduced action odds by 31.6% (OR 0.684, 95% CI 0.560-0.835); comments were 2.57 times more likely to be negative than positive (OR 2.565, 95% CI 1.637-4.018). Disparities in engagement were found, with female providers, patients, and socially vulnerable individuals less likely to comment. CONCLUSION: This process evaluation demonstrates scalable real-time feedback for clinical decision support refinement in de-implementation, with regressions identifying context-specific predictors. Provider disagreement, alert firings misaligned to workflows, and patient resistance hinder effectiveness. Future work should refine clinical decision support design to address complexity, enhance guideline explainability to build provider concordance, align with provider roles and workflows, and include patient-centered approaches. TRIAL REGISTRATION: The NYU School of Medicine Institutional Review Board (i17-01308) approved the trial, which has the clinicaltrials.gov ID NCT04181307 (https://clinicaltrials.gov/study/NCT04181307), with a first record date of November 26, 2019.

BACKGROUND: Ensuring equitable access to essential medicines is fundamental to universal health coverage, yet disparities in availability, pricing, and affordability persist in many low- and middle-income countries. OBJECTIVES: This study assessed the availability, prices, and affordability of essential cardiovascular and antidiabetic medicines across public and private healthcare sectors in Pakistan using the WHO/Health Action International (WHO/HAI) methodology. METHODS: A cross-sectional survey of 32 essential medicines was conducted across selected study areas (Rawalpindi, Muzaffargarh, Vehari, Gujranwala, Islamabad, and Azad Jammu & Kashmir). Medicine availability was measured as the percentage of facilities stocking medicines on the survey day. Prices were analyzed using median price ratios (MPRs) against international reference prices, and affordability was calculated as the number of days' wages required by the lowest-paid unskilled government worker to purchase a standard 30-day treatment. Sectoral and regional differences were evaluated using chi-square tests. RESULTS: The availability of the 32 cardiovascular and antidiabetic medications was generally poor, especially in government facilities; originator brands (OBs) and lowest-priced generics (LPGs) were consistently more readily available in private pharmacies (χ²=180.6, p < 0.001). There were notable geographical differences, with rural areas exhibiting very poor access (χ²=202.8, p < 0.001) and Gujranwala exhibiting the greatest availability. While certain OBs, particularly insulin analogs, were noticeably more expensive than LPGs, prices and affordability favored LPGs across all medications. Public and private sectors continued to have insufficient supplies of insulin and emergency medications, falling short of WHO objectives. CONCLUSION: This study reveals persistent inequities in the availability and affordability of essential medicines across the selected districts in Pakistan. While these findings specifically reflect the studied regions, they provide actionable evidence to strengthen Pakistan's public-sector supply systems, promote generic medicines, and inform national access policies.

Diabetes mellitus (DM) is frequently complicated by refractory oral ulcers, which are characterized by persistent inflammation and impaired healing. We first identified that diabetic oral ulcer tissues exhibit significant selenium deficiency, downregulated SELENBP1 expression, and substantial mitochondrial damage - key factors contributing to the pathogenesis. To address this pathological condition, we developed a sericin-selenium nanoparticle-loaded microneedle patch (Ser-SeNPs@MN) for efficient selenium delivery and targeted therapy of diabetic oral ulcers. The Ser-SeNPs were synthesized using a green sericin-based method, demonstrating enhanced stability and biosafety. The Ser-SeNPs@MN enabled mucosal adhesion and sustained release of Ser-SeNPs, significantly improving selenium bioavailability. In vitro experiments revealed that Ser-SeNPs@MN promoted the expression of SELENBP1 and key selenoproteins (GPX1, GPX2, TXNRD1, TXNRD2), activated PINK1/Parkin-mediated mitophagy, and restored mitochondrial function. Consequently, it suppressed pro-inflammatory responses and facilitated M2 macrophage polarization. In both diabetic oral ulcer and skin wound rat models, Ser-SeNPs@MN accelerated wound closure, enhanced collagen deposition, and promoted angiogenesis. These findings underscore the therapeutic potential of Ser-SeNPs@MN as a multifunctional platform for diabetic wound management through selenium-mediated mitochondrial recovery and immune modulation.

BACKGROUND: Insulin resistance (IR) is a multifactorial metabolic condition influenced by lifestyle, body composition, and behavioral factors. Regular physical activity is known to improve insulin sensitivity, yet its associations with anthropometric and socio-demographic variables remain incompletely understood, particularly among young women. METHODS: A total of 443 women aged 18-35 years participated in this cross-sectional study, including 301 with medically confirmed IR and 142 metabolically healthy controls. Anthropometric indices, Body Mass Index (BMI), Waist-Hip Ratio (WHR), Abdominal Volume Index (AVI), and Body Adiposity Index (BAI), were self-measured using standardized procedures. Physical activity was assessed via the Global Physical Activity Questionnaire (GPAQ), with total energy expenditure expressed as Metabolic Equivalent of Task (MET). Group comparisons were performed using Mann-Whitney U tests and Generalized Linear Models (GENLIN) with robust covariance estimation. RESULTS: Women with IR exhibited significantly higher BMI, WHR, AVI, and BAI values (all p < 0.001) and lower total physical activity (2,615 vs. 3,679 MET; p = 0.01) compared with controls. Sedentary behavior was more prevalent among IR participants (449 vs. 363 MET; p < 0.001). The observed differences were independent of anthropometric covariates. Socio-demographic factors showed nonlinear associations: lower and higher income levels, as well as rural residence, were linked to reduced activity in the IR group. Sleep duration showed no significant effect. CONCLUSIONS: Physical activity, independent of body composition, is a key determinant of metabolic health in women. The results highlight the need for targeted behavioral interventions promoting movement as a core therapeutic and preventive strategy in insulin resistance management.

INTRODUCTION: The prevalence of diabetes in Belgium has steadily increased since 2001, reaching 6.9% in 2024, with type 2 diabetes (T2D) accounting for approximately 90% of cases. Diabetes-related healthcare expenditures were estimated at €2 billion in 2022. The European Care4Diabetes Joint Action aimed to transfer and adapt the evidence-based Dutch lifestyle program Reverse Diabetes2 Now to 12 European countries. This study evaluated the transferability and potential effectiveness of the Care4Diabetes lifestyle intervention on metabolic, behavioral, and subjective health outcomes among Belgian adults with T2D in primary care. RESEARCH DESIGN: This quasi-experimental implementation study was conducted in two primary care centers in Wallonia. Forty-three participants initiated the program and 37 completed the 12-month follow-up. The intervention included a 6-month intensive phase with five thematic group sessions and one individual check-up, followed by an additional check-up and a refresher session at Month 12. Primary outcomes were changes in HbA1c and T2D medication use. Secondary outcomes included anthropometric measures, lipid profile, behavioral outcomes, and subjective health indicators. Linear mixed models were used to assess changes over time, accounting for repeated measures. RESULTS: At Month 12, 46% of participants had no change in T2D medication, 43% underwent medication de-intensification, and 11% required intensification. After adjustment for T2D medication changes, HbA1c decreased significantly from baseline to Month 6 by 5.4 mmol/mol (0.49%; p = 0.002), but the reduction was attenuated at Month 12 to 2.8 mmol/mol (0.26%; p = 0.06). Sensitivity analyses restricted to participants without T2D medication changes showed significant decreases in HbA1c at Month 6 and Month 12. Body weight decreased significantly (- 3.6 kg at Month 12, p < 0.001). Improvements were also observed in dietary behaviors and perceived general health, and satisfaction among participants and healthcare providers was high. CONCLUSIONS: The Care4Diabetes program demonstrated good transferability and promising effectiveness in primary care in Wallonia. Larger studies across Belgium are needed to further assess clinical effectiveness and potential economic benefits.

BACKGROUND: Screening and referral for type 2 diabetes mellitus (T2DM) during dental care visits has the potential for expanding preventive care. Using the consolidated framework for implementation research (CFIR) and the theoretical domains framework (TDF), we examined the barriers and facilitators at pre-implementation of a community-driven T2DM screening program in an urban dental clinic serving Alaska Native and American Indian (AN/AI) adults. METHODS: This convergent mixed-methods parallel study was informed by the updated CFIR. Data were collected in 2023 through a 13-item survey of adult AN/AI potential recipients of the T2DM screening innovation/intervention, and individual in-person interviews with dental and primary care providers, staff, and operational leaders who were from the population of potential innovation deliverers. Univariate statistics and differences between strata were analyzed using R software. Interview transcripts were coded onto CFIR and TDF domains using template analysis then thematically analyzed. A convergent analysis identified areas of convergence, divergence, or complementarity. RESULTS: Two hundred and fifty potential innovation recipients provided survey responses. The majority of survey respondents agreed that the dental clinic is a good place to get T2DM screening, thought screening would be helpful, and had no concerns about the setting. Some respondents had concerns about T2DM screening in the dental setting or by dental staff due to T2DM screening not usually occurring in a dental visit. However, most survey respondents thought the dental clinic as a good place to get screened for diabetes and had low levels of concern about T2DM screening in dental settings. Primary care providers did not see the need for T2DM screening in dental settings; however, about half of potential innovation recipients thought the T2DM screening information would be helpful for their doctor and would be a good way to find if they were at risk for or currently had T2DM. CONCLUSIONS: Using CFIR and TDF, we identified barriers and facilitators to inform the design of a pilot process, development of pilot materials, and selection of innovation deliverers.

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome represents a composite disease state driven by glucose and lipid metabolic dysregulation. The Cholesterol, High-density lipoprotein, and Glucose (CHG) index reflects the composite burden of these metabolic factors. However, its impact on the onset, stage-wise progression, and prognosis of CKM syndrome remains unclear. METHODS: This study utilized data from two large-scale prospective cohorts. In the UK Biobank (UKB) cohort, Fine-Gray proportional subdistribution hazards models were employed to investigate associations between CHG levels and the risk of incident cardiovascular disease (CVD), chronic kidney disease (CKD), and type 2 diabetes mellitus (T2DM), as well as the risk of progression from CKM Stage 0-1 to 2-3 and Stage 1-3 to 4. In the Beijing Anzhen Hospital cohort, Cox regression models assessed the impact of CHG on major adverse cardiovascular and cerebrovascular events (MACCE) in patients with CKM Stage 4 (established coronary artery disease). A causal forest algorithm was used to identify high-value subpopulations, and restricted cubic splines (RCS) characterized dose-response relationships. Sensitivity analyses were conducted to verify result robustness. RESULTS: The study included 370,916 participants free of CKM diseases from UKB (median follow-up: 16.5 years) and 8,494 patients with CKM Stage 4 from Beijing Anzhen Hospital (median follow-up: 645 days). In the general population, each 1-SD increase in the CHG index was significantly associated with an increased risk of incident T2DM (HR: 1.47; 95% CI: 1.40-1.53), CVD (HR: 1.07; 1.06-1.09), and CKD (HR: 1.07; 1.04-1.10). Furthermore, elevated CHG significantly accelerated CKM progression from Stage 0-1 to 2-3 (HR: 1.16; 1.11-1.23) and from Stage 1-3 to 4 (HR: 1.06; 1.05-1.08) per 1-SD increase. In patients with established CAD (Stage 4), a 1-SD increase in CHG was associated with a higher risk of MACCE (HR: 1.12; 1.05-1.19). Machine learning analysis revealed that this prognostic impact was particularly pronounced in patients with low systemic inflammation and elevated HbA1c. CONCLUSIONS: The CHG index demonstrates significant predictive value for the onset of component diseases, stage-wise progression, and adverse prognosis across the entire CKM syndrome continuum.

Sotagliflozin is a dual SGLT-1 and SGLT-2 inhibitor approved by the FDA in 2023 which has emerged as a novel therapeutic agent for the management of type 2 diabetes mellitus. In this study robust and sensitive LC-MS/MS method was developed and validated for quantification of sotagliflozin in rabbit plasma as rabbit is commonly used non-rodent model for preclinical research. Sample preparation involved protein precipitation for efficient analyte extraction from rabbit plasma. Chromatographic separation was performed utilizing on BDS Hypersil C18 column (100 mm x 4.6 mm, 5 μm) using mobile phase composed of methanol (85%) and 5 mM ammonium acetate in milli-Q water (15%) and rolipram as internal standard. The method employed flow rate of 0.7 mL/min with a total runtime of 4 min and an injection volume of 10 µL. Method validation was carried out in accordance with ICH M10 guidelines, covering precision, accuracy, selectivity, recovery, and stability at different storage conditions. The method was found to be linear over the concentration range of 10-1280 ng/mL with sensitivity of 10.20 ng/mL (LLOQ) in rabbit plasma. Recovery of analyte from the rabbit plasma was found to be > 92% with stability > 99% at different storage conditions (viz., room temperature, autosampler, freeze-thaw and frozen). Overall, the developed LC-MS/MS method offers a simple, precise and reproducible approach for the quantification of sotagliflozin in rabbit plasma and is well-suited for application in pharmacokinetic and other preclinical studies.

BACKGROUND AND OBJECTIVE: The atherogenic index of plasma (AIP) reflects atherogenic dyslipidemia and insulin resistance, whereas the frailty index (FI) quantifies cumulative physiological deficits across multiple organ systems. Although both the AIP and FI are independently associated with cardiometabolic multimorbidity (CMM), the joint impact of the atherogenic index of plasma-frailty index (AIPFI) on the risk of CMM remains unclear. In this study, the associations between baseline levels, cumulative AIPFI and longitudinal changes of AIPFI and the incidence of CMM were evaluated. METHODS: Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS). A total of 7995 participants were included in the baseline analysis, and 4,483 participants with repeated biomarker measurements in 2012 and 2015 were included in the longitudinal analysis. AIPFI was calculated via the following formula: AIPFI = AIP × FI. Multivariate Cox proportional hazards models and restricted cubic splines were applied to evaluate the associations of AIPFI with the incidence of CMM. K-means clustering characterized longitudinal AIPFI patterns. The clinical prediction model was performed in both the training and validation cohorts, as validated by receiver operating characteristic curve analysis, calibration curve analysis, and decision curve analysis. The shapley additive explanations (SHAP) method was employed to provide further explanation. RESULTS: A total of 7995 participants were included and followed for a median of 9.0 years, during which 747 (9.3%) incident CMMs occurred. Across quartiles of the AIPFI, the risk of CMM increased progressively, with adjusted HR of 2.46 (95% CI 1.77-3.43) for Q4 compared with those for Q1. In longitudinal analyses (n = 4,483), participants in cluster 2, with persistently high and increasing AIPFI values, presented increased risks of CMM (HR 1.54, 95% CI 1.19-2.01). An elevated cumulative AIPFI was associated with an increased incidence of CMM (HR 1.01, 95% CI 1.01-1.01). The RCS revealed a significant positive nonlinear relationship between the baseline AIPFI and cumulative AIPFI with the risk of CMM (all P < 0.05, and all P for nonlinear values < 0.05). SHAP model analysis revealed hypertension, heart disease, and AIPFI as the most influential predictors. CONCLUSIONS: Both baseline and longitudinal changes in the AIPFI were independently associated with the risk of CMM. The incorporation of longitudinal monitoring of the AIPFI into routine health evaluations may enhance population-level CMM risk prediction and support more effective prevention strategies.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is increasingly recognized as a systemic inflammatory condition closely linked to metabolic dysfunction. While traditional obesity metrics often fail to capture visceral adiposity and insulin resistance simultaneously, the Triglyceride-glucose body shape index (TyG-ABSI) has emerged as a composite marker of cardiometabolic risk. This study aimed to evaluate the association between TyG-ABSI and COPD risk and to assess its predictive utility using machine learning algorithms. METHODS: Data were analyzed from two large-scale distinct cohorts: the China Health and Retirement Longitudinal Study (CHARLS, N = 2,771) and the National Health and Nutrition Examination Survey (NHANES, N = 1,925 pre-diabetic participants). The relationship between TyG-ABSI and COPD was assessed using multivariable logistic regression, subgroup analyses, and Restricted Cubic Splines (RCS). Furthermore, five machine learning models (XGBoost, LightGBM, CatBoost, Random Forest, and KNN) were developed to predict COPD risk. Model interpretability was achieved using SHapley Additive exPlanations (SHAP). RESULTS: In both cohorts, elevated TyG-ABSI levels were significantly associated with an increased risk of COPD. Fully adjusted regression models revealed a linear dose-response relationship, with the highest quartile of TyG-ABSI showing a 59% increased risk in CHARLS (OR: 1.591) and a four-fold risk increase in NHANES (OR: 4.017) compared to the lowest quartile. Tree-based machine learning models, particularly XGBoost and LightGBM, demonstrated superior discriminative performance with AUCs exceeding 0.96 in the CHARLS dataset. SHAP analysis consistently identified TyG-ABSI as a high-priority feature contributing to disease prediction, irrespective of demographic variations. CONCLUSIONS: The TyG-ABSI index serves as a robust, independent risk factor for COPD across Chinese and American populations. Its integration into screening protocols, augmented by explainable machine learning, offers a valuable tool for early identification of high-risk individuals, highlighting the critical intersection of metabolic health and respiratory function.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus is a multifactorial disease marked by progressive beta cell dysfunction; however, no reliable, easily measurable circulating biomarkers are currently available to track this decline. As microRNAs (miRNAs) tightly regulate beta cell physiology and are secreted and found in blood, we investigated whether specific circulating miRNAs reflect in vivo beta cell function in living donors. METHODS: We conducted a cross-sectional study on two independent cohorts: a discovery cohort comprising 78 individuals with different levels of glucose tolerance [23 with normal glucose tolerance (NGT), 22 with impaired glucose tolerance (IGT) and 33 with type 2 diabetes] and a validation cohort comprising 158 individuals (71 non-diabetic individuals and 87 with type 2 diabetes) who were administered an oral glucose tolerance test (OGTT) and/or a mixed meal test (MMT) with measurement of glucose, insulin and C-peptide. We profiled plasma RNA by small RNA sequencing, and analysed differences between glucose tolerance groups using DESeq2. We used linear regression analyses to determine the association between miRNA abundance and clinical and metabolic measures. We validated selected miRNAs using droplet digital PCR (ddPCR). Finally, we specified a set of features that were used as an input for a LASSO model to select a biomarker signature that was able to estimate beta cell rate sensitivity (RS) values as a measure of beta cell function. RESULTS: We identified 11 miRNAs that were differentially expressed across the three glucose tolerance groups of the discovery cohort. Integrated analyses pinpointed a three-miRNA signature (miR-34a-5p, miR-1306-5p and miR-335-5p) that correlated with beta cell RS, which is an early indicator of insulin secretory impairment. We incorporated this panel of selected miRNAs with age and 1 h post-load glucose into a LASSO regression model that enabled discrimination of RS values (Spearman's ρ=0.43, p<0.05). We also confirmed model performance in an additional cohort of 71 non-diabetic individuals and 87 individuals with type 2 diabetes (Spearman's ρ=0.23, p<0.05). To provide proof of concept for potential clinical use, we substituted basal glucose for 1 h post-load glucose while retaining miRNA levels and age; this adaptation preserved the significance of the model in the discovery cohort (Spearman's ρ=0.46, p<0.05), and showed an interesting, but not significant, association in the validation cohort (Spearman's ρ=0.15, p=0.061). CONCLUSIONS/INTERPRETATION: This three-miRNA signature combined with simple clinical parameters constitutes a promising biomarker for early beta cell dysfunction and type 2 diabetes progression that deserves further validation in additional cohorts.

AIMS/HYPOTHESIS: Time-restricted eating (TRE) consolidates daily energy intake to a consistent 6-10 h window. The aim was to assess whether TRE is non-inferior to individualised dietetic guidance (IDG) in changing HbA at 4 months in adults at risk of type 2 diabetes. METHODS: In a two-arm, parallel-group, multi-centre randomised, non-inferiority clinical trial at two Australian clinical research institutes, adults at risk of type 2 diabetes (i.e. with overweight or obesity and a score of ≥15 on the Australian type 2 diabetes risk assessment tool) were recruited. Participants were randomly assigned using an electronic system (1:1) to TRE (9 h, self-selected eating window, last eating occasion by 19:00 hours) or IDG. Staff conducting assessments and analyses were blinded to allocation; participants and dietitians were unblinded. Both groups received five personalised telehealth consultations between 0 and 3 months (3 h total), specific to their allocated group. The primary outcome was the between-group difference for change in HbA at 4 months assessed via covariate linear regression using multiple imputation with a non-inferiority margin set at 1.1 mmol/mol (0.10%). Secondary outcomes were change in HbA at 12 months and changes in fasting glucose, insulin, HOMA-IR and nocturnal glucose AUC. Exploratory outcomes included changes in cardiometabolic outcomes and body mass and composition. Adverse events were tracked for 12 months. RESULTS: One hundred and twenty four participants were randomised to TRE and 123 to IDG (mean ± SD HbA: 40 ± 3 mmol/mol [5.8 ± 0.3%]). At 4 months, TRE was non-inferior but not superior to IDG for HbA (mean [95% CI]: -0.22 [-0.72, 0.30] mmol/mol; -0.02 [-0.07, 0.03]%; p=0.40). At 12 months, the upper bound of the difference between groups was larger than the non-inferiority margin (0.10%) meaning that non-inferiority could no longer be concluded (mean [95% CI]: 0.47 [-0.19, 1.23] mmol/mol; 0.05 [-0.02, 0.11]%; p=0.14). However, the absolute changes in HbA were small and not clinically meaningful in either group at either time point. Adverse events were minor and not different between interventions. CONCLUSIONS/INTERPRETATION: TRE may offer a pragmatic and practical short-term alternative when access to dietetic support is limited, or if the approach is preferred by an individual. TRIAL REGISTRATION: ClinicalTrials.gov; NCT04762251 FUNDING: This research was funded by the Australian Government Medical Research Future Fund (MRFF 1200555).

Childhood obesity is associated with insulin resistance and early cardiometabolic risk. Lipocalin-2 (LCN2), a biomarker linked to inflammation, metabolic regulation, and renal tubular stress, has been proposed as a potential indicator of obesity-related complications. However, data regarding urinary LCN2 in pediatric obesity remain limited. This study aimed to evaluate 24-h urinary LCN2 levels and their associations with metabolic parameters in children with obesity. This cross-sectional study included 43 children with obesity and 32 age-matched healthy controls aged 11-16 years. Anthropometric and biochemical assessments included fasting glucose, insulin, lipid profile, and renal-related urinary markers. Insulin resistance was assessed using HOMA-IR. Twenty-four-hour urinary LCN2 was measured by ELISA and normalized to urinary creatinine. Group comparisons and exploratory multivariable analyses were performed using appropriate statistical tests. The urinary LCN2/creatinine ratio was significantly higher in children with obesity than in controls. Absolute urinary LCN2 concentrations did not significantly differ between groups. Within the obesity group, urinary LCN2 concentrations were higher in participants classified as insulin resistant. Creatinine-normalized urinary LCN2 differed between children with obesity and controls and showed associations with insulin resistance status. These findings suggest that urinary LCN2 may reflect early metabolic or renal-related alterations in pediatric obesity. Larger prospective multicenter studies are needed to determine its clinical utility.

Atherosclerosis is a chronic disease which can lead to peripheral vascular occlusion causing cardiovascular, cerebrovascular, and peripheral artery diseases (PAD). Key contributors to PAD include ageing, classical cardiovascular risk factors, diabetes mellitus, and hypertension. For decades, these factors have also been related to arterial tortuosity, potentially indicating vascular fragility or arteriopathies. We aimed to evaluate the association between abdominal aortic tortuosity (AAT) and arteriopathies from other vascular beds and to assess its potential role as a subclinical marker of peripheral vascular disease. Atherosclerosis is a chronic disease which can lead to peripheral vascular occlusion causing cardiovascular, cerebrovascular, and peripheral artery diseases (PAD). Key contributors to PAD include ageing, classical cardiovascular risk factors, diabetes mellitus, and hypertension. For decades, these factors have also been related to arterial tortuosity, potentially indicating vascular fragility or arteriopathies. We aimed to evaluate the association between abdominal aortic tortuosity (AAT) and arteriopathies from other vascular beds and to assess its potential role as a subclinical marker of peripheral vascular disease. We included individuals aged ≥ 50 years and excluded those with dorsolumbar scoliosis. We built a multivariate log-linear regression model to identify factors associated with AAT. The model was adjusted by carotid calcification, stiffness, and stenosis as well as individual clinical characteristics and previously registered vascular diseases. A total of 490 individuals (mean age, 66.92 years; range, 50-98 years; 44.29% of women) from the Ageing Imageomics Study were included in this analysis. We observed that the AAT index was strongly dependent on age and also with diastolic blood pressure and estimated glomerular filtration rate (eGFR), but to a lesser extent. In contrast, other classical cardiovascular risk factors like diabetes mellitus, hypertension, smoking, aortic stiffness, and calcification did not play a significant role. Our results do not support the AAT index as a subclinical marker of cardiac, cerebrovascular, or peripheral vascular disease. AAT was not associated with classical cardiovascular risk factors and comorbidities.

BACKGROUND: Heart failure (HF) and type 2 diabetes (T2DM) are significant public health concerns. This study evaluated a 6-month home-based telemedicine program for older patients with combined HF and T2DM. The primary outcome was exercise tolerance evaluated at the 6-minute walk test (6MWT). Secondary outcomes included improvements in the physical activity profile (PASE), quality of life, clinical parameters, and biomarkers. METHODS: Patients were randomized into an Intervention (IG) or a Control (CG) Group. The IG received teleassistance from a nurse case manager, including telemonitoring and an app for medication adherence and symptom reporting. The CG received the usual care. RESULTS: 163 patients (84% male) were included 82 (71 ± 9 years) in the IG and 81 (74 ± 8 years) in the CG. After six months, the IG showed a mean increase of 12.4 meters (95% CI [1.7, 23.1]; p = 0.0168) in the distance walked at 6MWT, while the CG experienced a decrease of -22.4 meters (95% CI [-36, -8.9]; p = 0.0029), with a significant difference between groups of p = 0.0001. The PASE scores in the IG revealed a slight increase (p = 0.2914). Conversely, the CG significantly decreased their PASE scores (p = 0.0242), indicating a meaningful difference (p = 0.0164). No significant changes were observed in the quality-of-life questionnaires. Positive results were obtained on clinical parameters. CONCLUSIONS: The study proposed a home-based Phase III telerehabilitation program to help patients with HF and T2DM to maintain a healthy lifestyle. While technology can be complex for the elderly, its acceptance improves when seen as beneficial.

The United States has not produced a national noise health burden estimate using disability-adjusted life year methodology. We quantified the population health burden of transportation noise across the contiguous United States and examined its distribution across states and socially vulnerable communities. We applied comparative risk assessment to census-tract noise exposure data from the National Transportation Noise Exposure Map for 324.4 million residents. We estimated attributable ischemic heart disease, ischemic stroke, cardiomyopathy, type 2 diabetes, cardiovascular mortality, high annoyance, and high sleep disturbance using exposure-response functions from WHO systematic reviews. We calculated disability-adjusted life years with WHO 2024 noise-specific disability weights, stratified by state and CDC Social Vulnerability Index quintile, with 12-parameter Monte Carlo uncertainty analysis. An estimated 94.5 million people were exposed to transportation noise at or above 45 dB LAeq. We attributed 272,600 DALYs annually (84 per 100,000; 95% UI: 45-121), including 6,330 premature cardiovascular deaths, 11,400 ischemic heart disease cases, 13,600 type 2 diabetes cases, 12.3 million highly annoyed, and 3.3 million with high sleep disturbance. State burden varied six-fold, from 25 to 149 DALYs per 100,000. Communities in the highest social vulnerability quintile bore 2.29 times the burden of the least vulnerable. This is the first US noise burden estimate using WHO DALY methodology with social vulnerability stratification. The equity disparity identifies target populations for noise reduction. Disability weights for annoyance (30%) and road noise fraction (32%) are the two largest contributors to DALY variance, followed by sleep disturbance disability weight (14%) and the LAeq-to-Lden offset (11%), pointing to source-specific noise mapping, larger valuation studies, and standardized metric conversion as priorities.