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Importance US rural vs nonrural populations have striking disparities in diabetes care. Whether rurality contributes to disparities in diabetes mortality is unknown. Objective To examine rates and trends in diabetes mortality based on county urbanization. Design, Setting, and Participants In this observational, cross-sectional study, the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database was searched from January 1, 1999, to December 31, 2018, for diabetes as a multiple cause and the underlying cause of death among residents aged 25 years or older in US counties. County urbanization was categorized as metro, medium-small, and rural. Weighted multiple linear regression models and jackknife resampling, with a 3-segment time component, were used. The models included exposures with up to 3-way interactions and were age standardized to the 2009-2010 population. The analyses were conducted from July 1, 2020, to February 1, 2022. Exposures County urbanization (metro, medium-small, or rural), gender (men or women), age group (25-54, 55-74, or ≥75 years), and region (Midwest, Northeast, South, or West). Main Outcomes and Measures Annual diabetes mortality rate per 100 000 people. Results From 1999-2018, based on 4 022 238 309 person-years, diabetes was a multiple cause of death for 4 735 849 adults aged 25 years or older. As a multiple cause, diabetes mortality rates in 2017-2018 vs 1999-2000 were highest and unchanged in rural counties (157.2 [95% CI, 150.7-163.7] vs 154.1 [95% CI, 148.2-160.1]; P = .49) but lower in medium-small counties (123.6 [95% CI, 119.6-127.6] vs 133.6 [95% CI, 128.4-138.8]; P = .003) and urban counties (92.9 [95% CI, 90.5-95.3] vs 109.7 [95% CI, 105.2-114.1]; P < .001). In 2017-2018 vs 1999-2000, mortality rates were higher in rural men (+18.2; 95% CI, 14.3-22.1) but lower in rural women (−14.0; 95% CI, −17.7 to −10.3) ( P < .001 for both). In the 25- to 54-year age group, mortality rates in 2017-2018 vs 1999-2000 showed a greater increase in rural counties (+9.4; 95% CI, 8.6-10.2) compared with medium-small counties (+4.5; 95% CI, 4.0-5.0) and metro counties (+0.9; 95% CI, 0.4-1.4) ( P < .001 for all). Of all regions and urbanization levels, the mortality rate in 2017-2018 vs 1999-2000 was higher only in the rural South (+13.8; 95% CI, 7.6-20.0; P < .001). Conclusions and Relevance In this cross-sectional study, US rural counties had the highest overall diabetes mortality rate. The determinants of persistent rural disparities, in particular for rural men and for adults in the rural South, require investigation.

ABSTRACT Introduction: Neutrophil extracellular traps (NETs) trigger thrombin generation. We aimed to characterize the effects of deoxyribonuclease (DNAse) on NET components (cell-free DNA [cfDNA] and histones) and thrombin generation after trauma. Methods: Citrated plasma samples were collected from trauma patients and healthy volunteers. Thrombin generation (calibrated automated thrombogram) was measured as lag time (LT, in minutes), peak height (in nM), and time to peak thrombin generation (in minutes). Citrullinated histone 3 (CitH3) and 4 (CitH4) were measured by enzyme-linked immunosorbent assay; cfDNA by PicoGreen (all in nanograms per milliliter). Samples analyzed +/− DNAse (1,000 U/mL). Results expressed as median and quartiles [Q1, Q3], Wilcoxon testing, P < 0.05 significant. Results: We enrolled 46 patients (age, 48 [31, 67] years; 67% male) and 21 volunteers (age, 45 [28, 53] years; 43% male). Deoxyribonuclease treatment of trauma plasma led to shorter LT (3.11 [2.67, 3.52] min; 2.93 [2.67, 3.19] min), shorter time to peak thrombin generation (6.00 [5.30, 6.67] min; 5.48 [5.00, 6.00] min), greater peak height (273.7 [230.7, 300.5] nM; 288.7 [257.6, 319.2] nM), decreased cfDNA (576.9 [503.3, 803.1] ng/mL; 456.0 [393.5, 626.7] ng/mL), decreased CitH3 (4.54 [2.23, 10.01] ng/mL; 3.59 [1.93, 7.98] ng/mL), and increased H4 (1.30 [0.64, 6.36] ng/mL; 1.75 [0.83, 9.67] ng/mL), all P < 0.001. The effect of DNAse was greater on trauma patients as compared with volunteers for LT (ΔLT, −0.21 vs. −0.02 min, P = 0.007), cfDNA (ΔcfDNA −133.4 vs. −84.9 ng/mL, P < 0.001), and CitH3 (ΔCitH3, –0.65 vs. −0.11 ng/mL, P = 0.004). Conclusion: Deoxyribonuclease treatment accelerates thrombin generation kinetics in trauma patient samples as compared with healthy volunteers. These findings suggest that NETs may contribute to the hypercoagulable state observed in trauma patients.

AbstractBackgroundThe optimal methods for measuring and analyzing anal resting and squeeze pressure with high‐resolution manometry (HRM) are unclear.MethodsAnal resting and squeeze pressures were measured with HRM in 90 healthy women, 35 women with defecatory disorders (DD), and 85 with fecal incontinence (FI). Pressures were analyzed with Manoview™ software and a customized approach. Resting pressures measured for 20, 60, and 300 s were compared. During the squeeze period, (3 maneuvers, 20 s each), the squeeze increment, which was averaged over 5, 10, 15, and 20 s, and squeeze duration were evaluated.ResultsCompared to healthy women, the anal resting pressure, squeeze pressure increment, and squeeze duration were lower in FI (p ≤ 0.04) but not in DD. The 20, 60, and 300 s resting pressures were strongly correlated (concordance correlation coefficients = 0.96–0.99) in healthy and DD women. The 5 s squeeze increment was the greatest; 10, 15, and 20 s values were progressively lower (p < 0.001). The squeeze pressure increment and duration differed (p < 0.01) among the three maneuvers in healthy and DD women but not in FI women. The upper 95th percentile limit for squeeze duration was 19.5 s in controls, 19.9 s in DD, and 19.3 s in FI. Adjusted for age, resting pressure, and squeeze duration, a greater squeeze increment was associated with a lower risk of FI versus health (OR, 0.96; 95% CI, 0.94–0.97).ConclusionsThese findings suggest that anal resting and squeeze pressures can be accurately measured over 20 s. In most patients, one squeeze maneuver is probably sufficient.

Introduction: The cardiac hormone atrial natriuretic peptide (ANP) plays a key role in blood pressure (BP) and metabolic homeostasis through guanylyl cyclase receptor-A. While the role of ANP in cardiovascular disease (CVD) has been extensively investigated, its role in metabolic regulation has only recently emerged. A genetic variant of the ANP gene (rs5068), which increases production of ANP and NT-proANP, is associated with lower blood pressure (BP), reduced risk for hypertension and a decreased prevalence of obesity and metabolic syndrome. Hypothesis: We hypothesized that sex differences in ANP may have an important role in cardiometabolic disease together with cardiovascular (CV) morbidity and mortality. Methods: We studied 1176 subjects (age > 45 years) in the general population from Olmsted County MN. Plasma ANP molecular forms were quantified. Metabolic and cardiorenal parameters, and detailed medical records were reviewed. The cardiometabolic protective action of the ANP gene variant rs5068 was also assessed. Subjects were followed for all-cause mortality and morbidity for 12 years. Results: Plasma ANP molecular forms were significantly lower in males compared to females. Males had higher BMI and greater incidence of myocardial infarction (MI), coronary artery disease and heart failure (HF). Males also had lower EF and HDL cholesterol and higher LA volume and LV mass, serum glucose, insulin and diastolic pressure. The presence of the rs5068 minor allele improved the cardiometabolic phenotype including BP and widespread metabolic parameters in males but not females. After adjustment by age, males had increased risk of all-cause mortality, HF, MI, and stroke. Conclusions: Males are characterized by a relative ANP deficiency compared to females and widespread prevalence of cardiometabolic disease and increased CV morbidity and mortality in the general population. We demonstrate that the cardiometabolic protective action of the ANP gene variant rs5068 minor allele is sex dependent and protective in males. These findings have diagnostic and therapeutic implications, particularly in males.

Background: Whether VTE risk can be further stratified among patients with neurologic disease and leg paresis is unknown. Objective: To identify independent risk factors for deep vein thrombosis (DVT) and pulmonary embolism (PE) among patients with neurologic disease and leg paresis. Methods: Using the population-based resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with incident DVT or PE over the 45-year period, 1966 to 2010. We performed a case-control study nested within the Olmsted County population with incident VTE associated with neurologic disease and leg paresis over the 18-year period, 1988-2010 (n=192). For each VTE case, we identified 1 Olmsted County resident with neurologic disease, leg paresis and no VTE (control) matched to each case on sex, date of birth (+/- 5 years), calendar year (+/- 1 year) and duration of medical records. Using conditional logistic regression, we tested duration of paresis (index-3 months, 3-12 months, and > 12 months), paresis etiology, and degree of immobility as potential risk factors for VTE after adjusting for other known VTE risk factors, including hospitalization for major surgery or acute medical illness, trauma/fracture, and active cancer. Results: In univariate analyses of the 192 pairs, trauma/fracture, hospitalization for major surgery or for acute medical illness, active cancer, duration of paresis, and degree of immobility were associated with VTE. In the multivariable analysis, hospitalization for acute medical illness, active cancer, degree of immobility (ambulatory without/with assistance, function from a wheelchair base, bed bound; OR: 2.60; 95%Cl: 1.65-4.11); p=<0.0001) were independent predictors of VTE. Conclusion: Among patients with neurologic disease and leg paresis, VTE risk can be further stratified by hospitalization for acute medical illness, active cancer and degree of immobility; these patients should be considered for VTE prophylaxis.

AbstractBackgroundElevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) are risk factors for white matter (WM) injury associated with cognitive decline and dementia. White matter hyperintensities (WMH) on MRI, markers of WM injury, increase with aging and are more common in women than in men after the age of 60. We examined SBP and DBP in relation to WMH volume and diffusion MRI measures of WM integrity in postmenopausal women.MethodWomen (n=144) with median age of 67 (range 58‐72) and of good cardiovascular health who were previously enrolled in the multi‐site randomized clinical trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP, DBP, and MRI data were collected approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions. WM integrity was assessed with WMH volume measurements (log transformed) on structural MRI and with measures of WM microstructure on diffusion MRI. Multiple linear regression analyses, adjusted for age, were used to test for associations of SBP and DBP with MRI measures.ResultThe median SBP was 128 (range 86‐180) and DBP was 77 (range 47‐106). Higher SBP (r=0.332;p=0.015) and DBP (r=0.346;p=0.007) were associated with higher WMH volumes. Among the WM tracts, higher SBP was associated with lower fractional anisotropy (FA) in lateral orbitofrontal gyrus WM (r=0.198;p=0.039) and sagittal stratum (r=0.226;p=0.043), and higher DBP was associated with lower FA in the superior occipital gyrus WM (r=0.370;p=0.045). Higher SBP and DBP were associated with higher mean diffusivity (MD) in the external capsule [(r=0.311;p=0.007);(r=375;p<0.001)] and the fronto‐occipital fasciculus [(r=0.286;p=0.016); (r=0.303;p=0.008)]. Furthermore, higher DBP was associated with higher MD in the anterior corona radiata (r=0.233;p=0.039), internal capsule (r=0.303;p=0.042), and the middle (r=0.275; p=0.03) and superior frontal gyrus (r=0.269;p=0.03) WM.ConclusionElevated SBP and DBP measurements are associated with greater WM injury in postmenopausal women. In particular, the frontal lobe WM and its connecting tracts may be more vulnerable to elevation in SBP and DBP. Whether BP control reduces the risk for WM injury, a risk factor for dementia, in post‐menopausal women warrants study.