Bailey, Kent R.

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

Introduction: The MI-GENES randomized clinical trial (NCT01936675) assessed the effect of disclosing a polygenic risk score (PRS) for coronary heart disease (CHD), in addition to a clinical risk based on Framingham risk score (FRS), on LDL-C levels. The trial enrolled participants from Olmsted County, Minnesota, without cardiovascular disease, at intermediate CHD risk (10-y risk: 5-20%), and not on statins. There was a significant LDL-C reduction in the integrated risk score group (IRS g ; received PRS information in addition to the FRS) compared to the FRS group (FRS g ; received their risk based on FRS), due to more frequent statin initiation. Research Question: Does disclosure of an IRS for CHD lead to a lower rate of major adverse cardiovascular events (MACE)? Methods: Participants were followed from randomization beginning in October 2013 until September 2023 to ascertain cardiovascular events, testing for CHD, and risk factor changes, by blinded review of electronic health records. The primary outcome was time from randomization to the first MACE— defined as cardiovascular death, nonfatal MI, coronary revascularization, and nonfatal stroke. Analyses were done using Cox and linear mixed-effects models. Results: We followed all 203 participants, who completed the MI-GENES trial, 100 in FRS g and 103 in IRS g (mean age at the end of follow-up 68.2±5.2 years, 48% male). During a median follow-up of 9.5 years, 9 MACE occurred in FRS g and 2 in IRS g (HR, 0.20; 95% CI, 0.04 to 0.94; P =0.042, Figure 1A). In FRS g , 47 (47%) underwent at least one test for CHD, compared to 30 (29%) in IRS g (HR, 0.51; 95% CI, 0.32 to 0.81; P =0.004, Figure 1B). IRS g participants had a longer duration of statin therapy during the first four years post-randomization (Figure 1C) and a greater reduction in LDL-C for up to 3 years post-randomization (Figure 1D). No significant differences between the two groups were observed for hemoglobin A1C, blood pressure, weight, and smoking cessation rate during follow-up. Conclusion: The disclosure of 10-year CHD risk that included a PRS to those at intermediate risk was associated with lower incidence of MACE after a decade, likely due to more frequent and prolonged statin use, leading to lower LDL-C levels.

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.

Introduction: Triple oral antithrombotic therapy (TOAT) (aspirin, clopidogrel, and warfarin) is associated with an increased risk of bleeding. Despite this, the optimal management of patients with indications for warfarin following percutaneous coronary intervention (PCI) has not been established. We sought to compare long-term clinical outcomes between patients receiving TOAT with those receiving dual antiplatelet therapy (DAPT) (aspirin and clopidogrel) after PCI. Hypothesis: Patients with clinical indications for warfarin have higher baseline risk which is largely responsible for the observed differences in outcomes between patients receiving TOAT vs. DAPT. Methods: Retrospective analysis of prospectively collected data from 9,009 patients. The primary outcome was a composite of all-cause mortality, ischemic or embolic events (myocardial infarction or stroke), or bleeding. Secondary outcomes were death plus ischemic or embolic events, death plus bleeding, death, MI, stroke, and bleeding. A 2:1 propensity matched analysis was also performed. Results: In 9,009 patients, 812 received TOAT and 8,197 received DAPT. Median follow-up was 61 months. The primary end point occurred in 2,749 patients. At 1 year, 22% of patients treated with TOAT had the primary endpoint versus 11% of DAPT patients (p<0.001). At 1 year, secondary end points of death or ischemic or embolic events (19% vs. 10%, p<0.001), and death or bleeding events (15% vs. 5%, p<0.001) also occurred with a higher frequency with TOAT. After propensity matched analysis the above differences were no longer significant with 1 year primary endpoint rates of 19% vs. 17% respectively (HR 1.95%, CI 0.88, 1.47; p = 0.33). Following propensity matching the only significant difference between TOAT and DAPT groups was minor bleeding (5% vs. 2%; HR 2.65, 95% CI 1.39, 5.03; p=0.003). Conclusions: In a large single center registry with comprehensive follow up, patients treated with TOAT had higher rates of ischemic and bleeding events. However, when baseline risks are accounted for event rates are similar, other than minor bleeding, indicating patient risk characteristics are largely responsible for the observed differences in outcomes.

Background Break down of the blood brain barrier and activation of brain cells are implicated in progression of deposition of β‐amyloid that is associated with the pathophysiology of Alzheimer's disease. A previous study from our group indicated that deposition of β‐amyloid may be reduced in the brains of menopausal women treated with transdermal 17β‐estradiol. This study aimed to determine the association of peripheral microvesicles carrying markers of cells of the neurovascular unit with β‐amyloid in the brains of menopausal women and if the association was affected by prior menopausal hormone treatments (MHT). Methods Menopausal women previously enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic underwent β‐amyloid positron emission tomography (PET) imaging of their brains 3 years following treatment with either placebo (PL, n=29), transdermal 17β‐estradiol (tE2; n=21), or oral conjugated equine estrogen (oCEE; n=17) for 4 years. Microvesicles (MV) were isolated from peripheral venous blood by differential centrifugation and analyzed by flow cytometry using fluorophore conjugated antibodies directed toward total tau, β‐amyloid 1‐42 (Ab1‐42), neuron specific class III β‐tubulin (Tuj1), microglia ionized calcium adaptor molecule 1(Iab‐1), glial fibrillar acid protein (GFAP), and low density lipoprotein receptor‐related protein 1. Principal components analysis was used to reduce the dimensionality of the 6 brain markers to 2 principal components (PCs). Proportional odds ordinal logistic regression analysis was used to regress deposition of β‐amyloid on the 2 PCs with and without adjustment for MHT group. Results Number of blood MV positive for Ab1‐42 differed significantly among MHT groups (median [IQR]: 6.06 [2.11, 12.55] in the PL; 2.49 [0.73, 3.59] in the tE2 and 4.96 [0.83, 10.31] in the oCEE; P=0.036). The first 2 PCs explain 58% of the variance of the 6 markers. PC#1 represented a contrast between MV‐Iab‐1 and the MV‐GFAP and MV‐Tuj1. In multivariable models, brain β‐amyloid load positively associated with the first PC after adjustment for MHT (P= 0.006). Conclusion MV derived from cells of the neurovascular unit can be detected in peripheral blood, and, when combined into summary scores, showed an association with deposition of β‐amyloid in the brain that is independent of MHT. Support or Funding Information Supported by grants from NIH P50 AG044170 and the Mayo Foundation This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Anderson, Paul J., Christina M. Wood-Wentz, Kent R. Bailey, and Bruce D. Johnson. Objective versus self-reported sleep quality at high altitude. High Alt Med Biol . 24:144–148, 2023. Background: Previous studies have found little relationship between polysomnography and a diagnosis of acute mountain sickness (AMS) using the Lake Louise Symptom Questionnaire (LLSQ). The correlation between sleep question responses on the LLSQ and polysomnography results has not been explored. We compared LLSQ sleep responses and polysomnography data from our previous study of workers rapidly transported to the South Pole. Methods: Sixty-three subjects completed a 3-hour flight from sea level to the South Pole (3200 m, 9800 ft). Participants completed limited overnight polysomnography on their first night and completed LLSQ upon awakening. We compared polysomnography results at the South Pole with sleep question responses on the LLSQ to assess their degree of correspondence. Results: Twenty-two (30%) individuals reported no sleep problems whereas 20 (32%) reported some problems and 20 (33%) individuals reported poor sleep and 1 reported no sleep ( n = 1). Median sleep efficiency was (94%) among response groups and mean overnight oxygen saturation was 81%. Median apnea hypopnea index (AHI; events/hour) was 10.2 in those who reported no problems sleeping, 5.1 in those reporting some problems sleeping, and 13.7 in those who reported poor sleep. These differences were not statistically significant. Conclusion: Self-reported sleep quality varied but there were no associated significant differences in sleep efficiency, overnight oxygen saturation, nor AHI. Studies that explore the role of objective sleep quality in the development of AMS should remove the sleep question on the LLSQ from AMS scoring algorithms.

BackgroundMitral valve repair has been suggested as providing a better postoperative outcome than valve replacement for mitral regurgitation, but this impression has been obscured by differences in baseline characteristics and has not been confirmed in multivariate analyses.Methods and ResultsThe outcomes in 195 patients with valve repair and 214 with replacement for organic mitral regurgitation were compared using multivariate analysis. All patients had preoperative echocardiographic assessment of left ventricular function. Before surgery, patients with valve repair were less symptomatic than those with replacement (42% in New York Heart Association functional class I or II versus 24%, respectively;P=.001), had less atrial fibrillation (41% versus 53%;P=.017), and had a better ejection fraction (63±9% versus 60±12%,P=.016). After valve repair, compared with valve replacement, overall survival at 10 years was 68±6% versus 52±4% (P=.0004), overall operative mortality was 2.6% versus 10.3% (P=.002), operative mortality in patients under age 75 was 1.3% versus 5.7% (P=.036), and late survival (in operative survivors) at 10 years was 69±6% versus 58±5% (P=.018). Late survival after valve repair was not different from expected survival. After surgery, ejection fraction decreased significantly in both groups but was higher after valve repair (P=.001). Multivariate analysis indicated an independent beneficial effect of valve repair on overall survival (hazard ratio, 0.39;P=.00001), operative mortality (odds ratio, 0.27;P=.026), late survival (hazard ratio, 0.44;P=.001), and postoperative ejection fraction (P=.001).ConclusionsValve repair significantly improves postoperative outcome in patients with mitral regurgitation and should be the preferred mode of surgical correction. The low operative mortality is an incentive for early surgery before ventricular dysfunction occurs.

Abstract Venous stasis syndrome may complicate deep vein thrombosis (DVT; i.e. post-phlebitic syndrome), but, in most cases, venous stasis syndrome is not post-phlebitic. The objective of this study was to determine the risk factors (including prior DVT) for venous stasis syndrome, and to assess venous outflow obstruction and venous valvular incompetence as possible mechanisms for venous stasis syndrome. This was a case–control study nested within a population-based inception cohort. The study population consisted of 232 Olmsted County, MN residents with a first lifetime venous thromboembolism (VTE) and 133 residents without VTE. Measurements included a questionnaire and physical examination for venous stasis syndrome; strain gauge outflow plethysmography, venous continuous wave Doppler ultrasonography and passive venous drainage and refill testing for venous outflow obstruction and venous valvular incompetence. Altogether, 161 (44%), 43 (12%), and 136 (38%) subjects respectively, had venous stasis syndrome, venous outflow obstruction and venous valvular incompetence. Independent risk factors for venous stasis syndrome included increasing patient age and body mass index (BMI), prior DVT, longer time interval since DVT, and varicose veins. Both venous outflow obstruction ( p = 0.003) and venous valvular incompetence ( p < 0.0001) were strongly associated with venous stasis syndrome. Increasing age and prior DVT were significantly associated with venous outflow obstruction, while prior DVT, varicose veins and venous stasis syndrome diagnosed prior to the incident DVT were significantly associated with venous valvular incompetence. The risks of venous outflow obstruction, venous valvular incompetence and venous stasis syndrome were higher with left leg DVT. In conclusion, increasing patient age and BMI, prior DVT (particularly left leg DVT), longer time interval since DVT and varicose veins are independent risk factors for venous stasis syndrome. Venous stasis syndrome related to DVT is due to venous outflow obstruction and venous valvular incompetence, while venous stasis syndrome related to older age and to varicose veins is due to venous outflow obstruction and to venous valvular incompetence, respectively.