Bailey, Kent R.

BACKGROUND: In the Myocardial Infarction Genes clinical trial (URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01936675), participants at intermediate risk of coronary heart disease (CHD) were randomized to receive a Framingham risk score (Framingham risk score group, n=103) or an integrated risk score (integrated risk score group [IRS g ], n=104) that additionally included a polygenic risk score. After 6 months, IRS g participants had higher statin initiation and lower low-density lipoprotein cholesterol. We conducted a post hoc 10-year follow-up analysis to investigate whether disclosure of a polygenic risk score for CHD was associated with a reduction in major adverse cardiovascular events (MACE). METHODS: Participants were followed from randomization in October 2013 to September 2023 to ascertain MACE, testing for CHD, and changes in risk factors. The primary outcome was time to first MACE, defined as cardiovascular death, nonfatal myocardial infarction, coronary revascularization, and nonfatal stroke. Statistical analyses included Cox proportional hazards regression and linear mixed-effects models. RESULTS: We followed all participants who completed the trial, 100 in Framingham risk score group and 103 in IRS g (mean age at the end of follow-up, 68.2±5.2; 48% male). During a median follow-up of 9.5 years, 9 MACEs occurred in Framingham risk score group and 2 in IRS g (hazard ratio, 0.20 [95% CI, 0.04–0.94]; P =0.042). In Framingham risk score group, 47 (47%) underwent at least 1 diagnostic test for CHD, compared with 30 (29%) in IRS g (hazard ratio, 0.51 [95% CI, 0.32–0.81]; P =0.004). A higher proportion of IRS g participants were on statin therapy during the first 4 years postrandomization and had a greater reduction in low-density lipoprotein cholesterol for up to 3 years postrandomization. No significant differences were observed between 2 groups in other traditional cardiovascular risk factors during follow-up. CONCLUSIONS: Disclosure of an integrated risk score that included a polygenic risk score to individuals at intermediate risk for CHD was associated with lower MACE incidence after 10 years, likely due to higher statin initiation, leading to lower low-density lipoprotein cholesterol levels.

ABSTRACTBackgroundThe carbon‐13 spirulina gastric emptying breath test (GEBT) is approved to identify delayed, but not accelerated, gastric emptying (GE). We compared the utility of the GEBT to scintigraphy for diagnosing abnormal GE in patients with diabetes mellitus.MethodsTwenty‐eight patients with diabetes ate a 230‐kcal test meal labeled with technetium 99 m and 13C‐spirulina, after which 10 scintigraphic images and breath samples (baseline, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 min) were collected on 2 occasions 1 week apart. We assessed the accuracy of 13C‐spirulina GEBT excretion rate (percent dose multiplied by 1000 [kPCD] min−1) values to predict scintigraphic half‐life and distinguish between normal, delayed, and accelerated GE and the intraindividual reproducibility of the GEBT.Key ResultsScintigraphy revealed normal, delayed, and accelerated GE, respectively, in 17 (30%), 29 (52%), and 10 (18%) test results. GE T½ values measured with scintigraphy and GEBT were highly concordant within individuals; the intraindividual reproducibility was 34% (scintigraphy) and 15% (GEBT). Compared to current criteria, the kPCD150 (150 min) and kPCD180 values provided equally sensitive (90%) and more specific (81% vs. 67%) approach for distinguishing between delayed versus normal/accelerated GE. A new metric (kPCD60–kPCD15 min) was 90% sensitive and 83% specific for distinguishing between accelerated versus normal/delayed GE. These findings were used to create nomograms and an algorithm for interpreting GEBT results.Conclusions and InferencesAmong patients with poorly controlled diabetes, the 13C‐spirulina GEBT can accurately and precisely assess GE and effectively distinguish between normal, delayed, and accelerated GE.

ImportanceUnderstanding the interplay between diabetes risk factors and diabetes development is important to develop individual, practice, and population-level prevention strategies.ObjectiveTo evaluate the progression from normal and impaired fasting glucose levels to diabetes among adults.Design, Setting, and ParticipantsThis retrospective community-based cohort study used data from the Rochester Epidemiology Project, in Olmsted County, Minnesota, on 44 992 individuals with at least 2 fasting plasma glucose (FPG) measurements from January 1, 2005, to December 31, 2017. People who met criteria for diabetes on or before their first FPG measurement were excluded. Data were electronically retrieved in December 2019 with analyses finalized in November 2024.ExposuresThe exposure was baseline FPG level, with covariates including the following measures that are consistently recorded in the electronic health record: body mass index (BMI), age, and sex.Main Outcomes and MeasuresThe cumulative probability of freedom from diabetes was estimated and presented graphically using a Kaplan-Meier curve. Multivariable Cox proportional hazards regression modeling was used to estimate the partial hazard ratios (HRs) for variables of interest. Diabetes was defined as an FPG level greater than 125 mg/dL.ResultsA total of 44 992 individuals (mean [SD] age at baseline, 43.7 [11.8] years; 26 025 women [57.8%]) were included. The baseline mean (SD) BMI was 28.9 (6.6). Over a median follow-up of 6.8 years (IQR, 3.6-9.7 years), 3879 individuals (8.6%) developed diabetes. The Kaplan-Meier 10-year cumulative risk of incident diabetes was 12.8% (95% CI, 12.4%-13.2%). All initial FPG levels outside a range of 80 to 94 mg/dL were associated with increased risk for diabetes (ie, FPG <70 mg/dL: HR, 3.49 [95% CI, 2.19-5.57]; FPG 120-125 mg/dL: HR, 12.47 [10.84-14.34]). Other independent risk factors were male sex (HR, 1.31 [95% CI, 1.22-1.40]), older age (≥60 years: HR, 1.97 [95% CI, 1.71-2.28]), and any abnormal category of BMI, including underweight (BMI <18.5: HR, 2.42 [95% CI, 1.77-3.29]; BMI ≥40: HR, 4.03 [95% CI, 3.56-4.56]). There was a significant additive association of variables, particularly FPG level and BMI. For instance, a woman aged 55 to 59 years with a BMI of 18.5 to 24.9 and an FPG level of 95 to 99 mg/dL had an estimated 10-year diabetes risk of 7.0%. However, an almost doubling of risk to 13.0% was observed if the BMI was 30.0 to 34.9, and risk more than doubled again to 28.0% if FPG level also increased to 105 to 109 mg/dL. A nomogram was generated to facilitate individual classification into one of four 10-year risk categories.Conclusions and RelevanceThis retrospective cohort study of 44 992 individuals suggests that FPG level, age, BMI, and male sex were all associated with development of diabetes, with significant interaction between these variables. These data contribute to understanding the clinical course of diabetes and highlight the substantial individual variation in diabetes risk according to commonly measured clinical variables. The findings facilitate lifestyle and pharmacologic interventions to treat those at highest risk of diabetes to reduce future morbidity and mortality. Further work is needed to validate this risk categorization tool for different populations.

Abstract Context Defects in insulin secretion and action contribute to the progression of prediabetes to diabetes. However, the contribution of α-cell dysfunction to this process has been unclear. Objective This work aimed to understand the relative contributions of α-cell and β-cell dysfunction to declining glucose tolerance. Methods A longitudinal, community-based observational study was conducted at a clinical research unit at an academic medical center. We studied 96 individuals without diabetes (age 55 ± 1 years; body mass index 27.7 ± 0.4) on 2 occasions, 3 years apart using an oral 75-g glucose challenge. Indices for insulin secretion and action were estimated using the oral minimal model. Glucagon secretion rate (GSR) was estimated by deconvolution from peripheral glucagon concentrations. Main outcome measures included glucose tolerance status (categorical variable) and then symmetrical percentage change in peak and 120-minute glucose (post oral glucose tolerance test) concentrations (continuous variables). Results A total of 32 individuals progressed from normal to impaired glucose tolerance (IGT) or from IGT to type 2 diabetes. The disposition index (DI) declined in the progressors (568 ± 98 vs 403 ± 65 10−4 dL/kg/min per μU/mL, baseline vs 3 years; P = .04). α-Cell suppression by glucose (δGSR/δglucose) did not change in the nonprogressors (1.5 ± 0.1 vs 1.3 ± 0.1 nmol/min/L; P = .37) but decreased (1.0 ± 0.2 vs 0.8 ± 0.2 nmol/min/L; P < .01) in those who progressed. Analysis of the entire cohort showed that DI and δGSR/δglucose were independently and inversely correlated with an increase in glycemic excursion. Conclusion These data show that α-cell dysfunction accompanies a decline in β-cell function as IGT or overt type 2 diabetes develops.

ABSTRACT Background: Neutrophil extracellular traps (NETs), and its formation and release, known as NETosis, may play a role in the initiation of thrombin generation (TG) in trauma. The objective of this study was to assess whether trauma patients, who develop symptomatic venous thromboembolism (VTE), have increased levels of plasma citrullinated histone H3 (CitH3) and accelerated TG kinetics. Methods: Patients presenting to a level I trauma center as trauma activations had samples collected within 12 h of time of injury, alongside healthy volunteers (HV). CitH3 was measured by enzyme-linked immunosorbent assay, and TG data were measured using a TG analyzer, comparing results between patients developing symptomatic VTE versus those who did not, within 90 days of injury. Data were expressed as median and quartiles (Q1, Q3), and tested using Wilcoxon rank-sum or Fisher’s exact test, or 1-sample test of Spearman’s correlation, P < 0.05 considered significant. Results: 39 trauma patient samples were analyzed (10 with and 29 without VTE), and compared to 15 HV samples. CitH3 levels in patients who developed VTE were significantly greater as compared to those who did not (12.8 ng/mL [7.1, 30.8]; 3.0 ng/mL [1.8,6.8], P = 0.024), with levels in both groups greater compared to HV (1.2 [0.3, 4.1], P = 0.003, P = 0.012), respectively. TG profiles were accelerated in patients developing VTE, with differences in peak height (337.6 nM [304.4, 356.0]; 231.8 nM [180.2, 281.8], P = 0.008), endogenous thrombin potential (1718.5 nM*min [1,500, 1794]; 1208.5 nM*min [1,072, 1,417], P = 0.003) and velocity index (213.2 nM/min [162.3, 260.5]; 124.3 nM/min [93.2, 223.1], P = 0.03), respectively. Conclusion: Trauma patients developing VTE exhibit increased NETosis, measured by increased CitH3 levels and accelerated TG early after injury, outlining an area for further understanding VTE after trauma.

Abstract Objective To assess the association of systolic and diastolic blood pressure (SBP and DBP) in recently menopausal women with white matter hyperintensity (WMH) volume later in life and determine whether short-term menopausal hormone therapy (mHT) modifies these associations. Methods Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, randomized, double-blinded, placebo-controlled 4-year mHT trial (oral conjugated equine estrogens or transdermal 17β-estradiol). KEEPS continuation was an observational follow-up of the participants 10 years after the end of mHT. The associations between KEEPS baseline blood pressure (BP) with KEEPS continuation WMH volume were examined adjusting for covariates in model 1 (age, total intracranial volume, study site, mHT type) and model 2 (additionally conventional CVD risk factors). Interaction terms (BP × mHT type) were added into the linear regression models. Results The mean ± SD ages of participants were 53 (±2) years at KEEPS baseline and 67 (±2) years at KEEPS continuation. Elevated BP at KEEPS baseline was associated with greater WMH volume measured 14 years later (model 1: SBP: β = 0.01 [95% CI, 0.001‐0.01] and DBP: β = 0.01 [95% CI, 0.003‐0.03]) and after additionally adjusting for CVD risk factors (model 2). We did not find any evidence that mHT versus placebo modified these associations. Topographically, higher BP was associated with greater periventricular WMH in the frontal and parietal lobes. Conclusion Our findings suggest the importance of maintaining normal BP in recently postmenopausal women with low CVD risk, irrespective of short-term mHT usage, to potentially reduce the risk of WMH later in life.

Abstract INTRODUCTION Premenopausal bilateral oophorectomy (PBO) before the age of 46 years is associated with an increased risk of dementia. We investigated the long‐term effects of PBO performed before age 50 years on amyloid beta (Aβ), tau, and neurodegeneration imaging biomarkers of Alzheimer's disease (AD). METHODS Mayo Clinic Cohort Study of Oophorectomy and Aging‐2 participants were divided into early PBO (< 46 years; n = 61), and late PBO (46–49 years; n = 51) groups and were compared to referent women who did not undergo PBO ( n = 119). RESULTS Early PBO was associated with thinner entorhinal cortex ( p = 0.014), higher tau load at higher levels of Aβ load ( Pp = 0.005), higher Aβ load ( p = 0.026), and smaller temporal lobe cortical thickness ( p = 0.022), only at older ages compared to the referent group. DISCUSSION PBO before the age of 46 years is associated with entorhinal cortex thinning, elevated tau at higher Aβ levels, along with an AD‐like pattern of atrophy at older ages. CLINICAL TRIALS REGISTRATION NCT03821857 sex‐specific effects of endocrine disruption on aging and AD. Highlights Premenopausal bilateral oophorectomy (PBO) before the ages of 46 (early PBO) years and ages 46 to 49 (late PBO) years was studied. Early PBO was associated with reduced entorhinal cortex thickness later in life. Early PBO was associated with greater amyloid beta (Aβ) load at older ages. Early PBO was associated with greater Alzheimer's disease pattern of atrophy at older ages. Early PBO was associated with higher tau load at higher Aβ levels.

Trauma-induced coagulopathy (TIC) is common after injury and reliable quantification of its severity is lacking. The objective of this study was to evaluate whether thrombin generation would be significantly altered if whole blood samples from trauma patients were collected without (citrate-only) and with corn trypsin inhibitor (CTI+). In a prospective cohort study, 36 trauma pts presenting to a Level I Trauma Center within 12 hours of injury, had whole blood collected simultaneously in citrate-only (3.2%) and citrated plus CTI (CTI+ [final 25 ug/mL]), and processed to platelet free plasma by double centrifugation (3000g, 15 minutes). Samples were stored at -80C with no thawing until analysis. Thrombin generation profiles were measured using the ST Genesia assay (Diagnostica STAGO SAS) and parameters included endogenous thrombin potential (ETP), lag time (LT), peak height, start of tail, velocity index, and time to peak (ttPeak) were analyzed for trauma pts. Data presented as median [IQR] or n (%), with paired t-test and Spearman's correlation analysis were performed between citrated non-CTI and citrated CTI spiked blood samples, with p-value &lt;0.05 statistically significant. Pts presented with significant injury ISS 13 [5, 21], age 45 [29, 59] years, 80.6% male, BMI 26.9 [25.4, 28.3], 94.4% blunt trauma, 22.3% had surgery by day 1 of admission. Significant differences were found between the citrated-only and CTI +tubes in several thrombin generation parameters: ETP (1339 Nm*min [1172.5,1417], 1124.5 [925.4,1285], p&lt;0.001), peak height (222.3 Nm [186.0, 275.6], 160.6 [132.7,208.3], p&lt;0.001), ttPeak (5.64 min [4.86,6.63], 6.19 [5.36, 7.34], p&lt;0.001), start of tail (19.4 min [17.6,21.3], 21.6 [18.9, 23.6], p=0.014), and velocity index (117.6 Nm/min [77.9, 163.1], 71.9 [54.9,106.0], p&lt;0.001). However, LT (3.14 min [2.74, 3.90], 3.08 [2.84, 3.96], p=0.665) did not show a statistically significant difference. Spearman's correlation analysis showed high correlation between citrate-only and CTI+ citrated plasma samples, with Spearman's rank correlation coefficients for LT (0.941), peak height (0.760), ttPeak (0.928), ETP (0.770), start of tail (0.869), and velocity index (0.766) respectively. The results suggest that use of CTI+ decrease thrombin generation kinetics from blood samples obtained from trauma patients. These findings underscore the need for careful consideration of sample collection and processing for use of thrombin generation assays in clinical setting. However, there is very strong correlation of the thrombin parameters obtained from citrated-only plasma to CTI+ plasma samples, suggesting they capture similar information. CTI-spiked citrated tubes appear to reduce contact activation with respect to thrombin generation profiles compared to standard citrated only tubes. This should be a consideration for platform-based lab processing of thrombin generation assays for assessment of coagulopathy after injury; however, given the cost of CTI, citrated-only tubes can be an option for characterization of thrombin generation profile in clinical samples.

Abstract Introduction Vulnerable populations experience a higher burden of cardiovascular disease.(1) However, the incidence of cardiovascular risk factors, such as diabetes, within these populations, is incompletely characterized. Recently, the United States Centers for Disease Control and Prevention (US CDC) developed the Social Vulnerability Index (SVI) to categorize counties that may be vulnerable to worse health outcomes. The SVI is composed of 4 themes: socioeconomic status (Theme 1), household composition & disability (Theme 2), minority status & language (Theme 3), and housing type & transportation (Theme 4).(2) We sought to evaluate the association of the 4 SVI themes with county incidence of diagnosed diabetes. Method We used CDC data (2004-2019; reported for 94% of US counties), on county incidence of diagnosed diabetes. The SVI themes were scored from 0 to 1 (low to high vulnerability) based on national percentile ranking. We used weighted least squares regression with restricted cubic splines to model the relationship between SVI themes and incidence of diagnosed diabetes (median data 2004−2019), adjusting for median age, sex ratio, state, percent uninsured, food environment index, healthcare providers, and rurality.(3) The partial effects of SVI themes and diabetes incidence were reported as F-statistics (P-values) and diabetes incidence rate ratios (IRR [95% confidence interval]), which were plotted for all values compared with the 50th percentile (SVI 0.5). For each theme, we also present the IRR for a 0.5-point increase when moving over the lower (SVI score 0.5 vs. 0.0) and the upper (1.0 vs. 0.5) half of the SVI score distribution. Results The 4 SVI theme rank scores were significantly associated with diabetes incidence (all, P&lt;.001). However, Theme 1 and 2 scores showed stronger associations with IRR than Theme 3 and 4 (Figure). For Theme 1, SVI score 0.5 vs. 0.0 was associated with a 15% higher incidence (IRR 1.15 [1.13–1.18]) and score 1.0 vs. 0.5 was associated with a 13% higher incidence (IRR 1.13 [1.11–1.16]). For Theme 2, SVI score 0.5 vs. 0.0 was associated with a 16% higher incidence (IRR 1.16 [1.14–1.18]), but there was no difference between rates for SVI score 1.0 vs. 0.5 (IRR 1.01 [0.99–1.03]). For Theme 3, there was no difference between SVI score 0.5 vs. 0.0 (IRR 0.98 [0.96–1.00]), but rates were 8% lower for SVI score 1.0 vs. 0.5 (IRR 0.92 [0.90–0.94]). For Theme 4, SVI score 0.5 vs. 0.0 was associated with a 3% lower incidence (IRR 0.97 [0.96–0.99]) and score 1.0 vs. 0.5 was associated with a 2% higher incidence (IRR 1.02 [1.01–1.04]). Conclusion In US counties, the strength and directionality of the association between SVI themes and diabetes incidence differed by theme and level of SVI scores. These themes, particularly socioeconomic status and household composition & disability may be leveraged to identify high-risk counties for primary prevention of diabetes, with implications for reduction in cardiovascular risk.