Takahashi, Paul Y.

Background: Larger within-patient variability of lipid levels has been associated with an increased risk of cardiovascular disease (CVD). However, measures of lipid variability are not currently used clinically. We investigated the feasibility of calculating lipid variability within a large electronic health record (EHR)-based population cohort and assessed associations with incident CVD. Methods: We identified all individuals ≥40 years of age who resided in Olmsted County, MN on 1/1/2006 (index date) without prior CVD. CVD was defined as myocardial infarction, coronary artery bypass graft surgery, percutaneous coronary intervention or stroke. Patients with ≥3 measurements of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and/or triglycerides during the 5 years before the index date were retained in the analyses. Lipid variability was calculated using variability independent of the mean (VIM). Patients were followed through 9/30/2017 for incident CVD (including CVD death). Cox regression was used to investigate the association between quintiles of lipid VIMs and incident CVD. Results: We identified 18,642 individuals (mean age 60; 55% female) who were free of CVD at baseline and VIM calculated for at least one lipid measurement. After adjustment, those in the highest VIM quintiles of total cholesterol had a 25% increased risk of CVD (Q5 vs. Q1 HR: 1.25, 95% CI: 1.08-1.45; Table). We observed similar results for LDL-C (Q5 vs. Q1 HR: 1.20, 95% CI: 1.04-1.39) and HDL-C (Q5 vs. Q1 HR: 1.25, 95% CI: 1.09-1.43). There was no association between triglyceride variability quintiles and CVD risk. Conclusion: In a large EHR-based population cohort, high variability in total cholesterol, HDL-C and LDL-C was associated with an increased risk of CVD, independently of traditional risk factors, suggesting it may be a target for intervention. Lipid variability can be calculated in the EHR environment but more research is needed to determine its clinical utility.

Abstract Background Residents of nursing homes and long‐term care facilities are at increased risk for severe coronavirus disease‐19 (COVID‐19) but may not be able to access monoclonal antibody therapies offered at outpatient infusion centers due to frailty and logistical issues. We describe a mobile monoclonal antibody infusion program for patients with COVID‐19 in skilled nursing facilities and provide descriptive data on its outcomes. Design Retrospective cohort study. Setting Collaboration between Mayo Clinic and skilled nursing facilities in Southeast Minnesota was developed to administer anti‐spike monoclonal antibodies under the FDA Emergency Use Authorization. Participants Seventy five residents of skilled nursing facilities at high risk of COVID‐19 complications. Exposure Emergency use treatment with bamlanivimab and casirivimab–imdevimab. Measurements Hospitalization and medically attended visits. Results The mobile infusion unit, staffed by Mayo Clinic Infusion Therapy registered nurses and supported by the skilled nursing facility staff, infused anti‐spike monoclonal antibodies to 45 of 75 patients (average age, 77.8 years) in December 2020. The infusions occurred at an average of 4.3 days after COVID‐19 diagnosis. Fourteen days after infusion, there were no deaths, two emergency department visits, and three hospitalizations, for a combined event rate of 11.1%. There was one reported adverse event. Conclusion The implementation of a mobile infusion unit embedded in a collaborative process resulted in rapid infusion of monoclonal antibodies to high‐risk COVID‐19 patients in skilled nursing facilities, who would otherwise be unable to access the novel therapies. The therapies were well tolerated and appear beneficial. Further study is warranted to explore the scalability and efficacy of this program.

Abstract Background Older adults with severe aortic stenosis (AS) are at high risk of mortality unless surgical or transcatheter aortic valve replacement (AVR) is performed. Risk stratification often becomes complicated in frail elders with multi-morbidity, and time constraints limit thorough evaluation of geriatric comorbidities in the outpatient clinic setting. Purpose Utilization of an automated administratively-derived electronic health record (EHR) tool may aid in risk stratification of AS patients undergoing AVR. Methods We reviewed patients with severe AS undergoing AVR at our hospital program and cross-referenced with the Elder Risk Assessment (ERA) score. The ERA score is an administratively abstracted score derived on adults >60 years old followed by general medicine clinic. It contains the following variables: marital status, age, hospitalized days in preceding 2 years, diabetes, coronary disease, heart failure, stroke, pulmonary disease, cancer, and dementia; higher scores indicate greater risk for adverse outcomes. Kaplan-Meier method was used to estimate survival by ERA score tertile. Cox regression was used to test the association of ERA with survival. Results There were 97 patients with severe AS undergoing AVR with ERA scores. Mean age was 80.6 (±6.6) years, 37% were female, average Society of Thoracic Surgery (STS) score was 3.6% (± 2.6), and 7% had transcatheter AVR. Co-morbidities were prevalent and included atrial fibrillation (41%), chronic renal failure (16%), stroke (14%), and diabetes (35%). Over a mean follow-up of 68 months (± 37.9 months), there were 62 deaths. Elevated ERA score was associated with worse long term survival (p=0.016 by log-rank) (Figure 1), with only 49% surviving at 5 years in the highest ERA tertile vs 68% in the lowest ERA tertile. Cox regression demonstrated that the relative risk of death per 6 unit increase in ERA score was 1.54 (95% CI 1.21–1.96, P<0.001) in single variable analysis and 1.43 (95% CI 1.11–1.84, P=0.006) after adjusting for STS score. Conclusions Patients undergoing AVR for severe AS are often co-morbid older adults. An automated EHR derived ERA score was independently associated with survival after accounting for STS score and may streamline and improve risk assessment in these patients. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Mayo Clinic

AbstractIntroductionMany evidence‐based programs (EBPs) have been determined in randomized controlled trials to be effective, but few studies explore the real‐world effectiveness of EBPs implemented in the natural community setting. Our study evaluated whether a novel linked infrastructure would enable such insights and continuous improvement as part of a learning healthcare‐community bridged “wellcare” ecosystem.MethodsWe created a secure, web‐based data entry and storage platform with a network of Minnesota community‐based organizations to record EBP participants' demographics and attendance, and program details. We then linked participant's information to their Rochester Epidemiology Project (REP) medical records. With this infrastructure, we conducted a proof of concept, retrospective cohort study by matching EBP participants to REP controls and comparing medical record‐documented outcomes over 1 year follow‐up.ResultsWe successfully linked EBP participant records with medical records in 77.6% of cases, and the infrastructure proved feasible and scalable. Still, key challenges remain in obtaining participant consent for data sharing. Upfront resource investments and the availability of REP‐like warehouses limit generalizability. Optimal learning will be improved by enhancements that better track program fidelity. Our pilot study established a proof‐of‐concept, but sample sizes (n = 99 for falls prevention and n = 97 chronic disease/pain management EBP completers) were too small to detect significant differences in hospital admittance as compared to matched controls for either EBP group, (OR = 0.66[0.36, 1.19]) and (OR = 0.81[0.43, 1.54]), respectively. Events were too rare to gather meaningful information about effects on fall rates.ConclusionsOur pilot demonstrates the feasibility of developing an online infrastructure that connects information from community leaders with medical record documented health outcomes, bridging the knowledge gap between community programs and the health care system. Insights gleaned from our infrastructure can be used to continuously shape community program delivery to reduce the need for formal health care services.

Background: Interleukin-2 (IL-2), one of the proinflammatory cytokines, is used in the treatment of certain malignancies. In some studies, transient increases in cortisol and ACTH secretion occurred. Thus, this agent may be used as an experimental probe of adrenal cortisol secretion. Objective: This study quantifies the effects of low and moderate doses of IL-2 on cortisol secretion and assesses the modulation by age, dose and body composition. Site: Mayo Clinical Translational Research Unit. Subjects: Study comprised 35 healthy men, 17 young and 18 older. Methods: Randomized prospective double-blind saline-controlled study of IL-2 administration in two doses with concurrent 10-min blood sampling for 24 h. Outcome measures: Deconvolution analysis and approximate entropy of cortisol secretion. Results: Low-dose IL-2 administration increased nocturnal pulsatile cortisol secretion from 1460 ± 160 to 2120 ± 220 nmol/L/8 h in young subjects and from 1680 ± 105 to 1960 ± 125 nmol/L/8 h (treatment P < 0.0001, but more in young than older, P = 0.02). Comparable results were obtained for total cortisol secretion ( P treatment <0.0001, age effect P = 0.005). The higher IL-2 dose caused a large increase in young ( P < 0.0001), but not in older ( P = 0.90) subjects. This dose also increased approximate entropy from 0.877 ± 0.041 to 1.024 ± 0.049 ( P = 0.008), pointing to reduced secretory orderliness. Incremental cortisol (nocturnal) secretion correlated negatively with visceral fat mass ( R = −0.41, P = 0.019). Conclusion: In healthy men, IL-2 injection drives pulsatile cortisol secretion in a dose-dependent way in young, but not older, individuals and erodes cortisol secretory orderliness at a higher dose in young subjects. Cortisol responses are diminished with increasing abdominal visceral fat mass.

Abstract Introduction: In young men, sleep restriction decreases testosterone and increases afternoon cortisol, leading to anabolic-catabolic imbalance, insulin resistance and metabolic, neurocognitive, reproductive, and other adverse effects. Age-related differences in the hypothalamo-pituitary-testicular/adrenal response to sleep restriction could expose older individuals to greater or lesser risk, but this possibility has not been previously studied. Subjects and Methods: Thirty-five healthy young and older men aged 18-30y (n=17) and 60-80y (n=18), underwent blood sampling in the Mayo Clinic Center for Clinical and Translational Science every 10 minutes for 24 hours from 6PM-6PM under two conditions in random order spaced at least 3 weeks apart: awake (no sleep) or sleep (from 10PM to 6AM). Blood was assayed for LH, testosterone (T) and cortisol (F), and then analyzed by automated mathematical deconvolution and with cross approximate entropy statistics to determine hormone secretion and hormone synchrony, respectively. Statistical significance was construed by repeated measures ANOVA using a full factorial model that included age, sleep and the interaction. Results: Sleep deprivation had multiple effects on 24-hour (6PM-6PM) Te secretion with significant reductions in mean concentrations, basal, total and pulsatile secretion, and pulse frequency (each P&lt;0.05), in the absence of detectable changes in LH. These effects were most apparent in older men and differed according to age for some parameters: pulsatile Te secretion (P=0.03) and T pulse frequency (P=0.02). Time-of-day analyses revealed that sleep restriction significantly reduced Te in the morning (6AM-9AM) and afternoon (3PM-6PM), reduced LH in the morning, and increased F in the afternoon, particularly in older men. Cross-approximate entropy statistics showed that sleep restriction enforced greater LH-Te and Te-LH joint synchrony in the morning (P&lt;0.05 for each), but not in the afternoon. Conclusion: Sleep restriction decreases morning LH secretion, morning and afternoon Te secretion, and increases afternoon F secretion, especially in older men. This combination of findings could plausibly cause metabolic and reproductive ill-health when accumulated over decades of life, and may explain how chronic sleep loss contributes to metabolic and reproductive diseases that are more prevalent in older men. These preliminary data also suggest a time-of-day dependent uncoupling of the regulatory control of the testicular axis, and of cortisol secretion. Direct verification by interventions that manipulate hormones during the morning and late afternoon in appropriately matched cohorts of young and older men are now required.

Abstract Context. Interleukin-2 (IL2), a proinflammatory cytokine, is used for treatment of malignancies. Increased cortisol and ACTH were noted, but not investigated in detail. This is the first study in healthy men which uses moderate high IL2 doses as used in cancer treatment. Objective. The goal of this study was to quantify cortisol secretion after a single sc injection of IL2 at 1900 h in young and older healthy men in relation to dose, age and body composition. Design. This was a placebo-controlled, blinded, prospectively randomized cross-over study in 17 young subjects (mean age 24.1 yr, range 19–30 yr) and 18 older subjects (mean age 63.9 yr, range 60–75 yr). The subjects underwent 24 h of blood sampling at 10-min intervals, starting at 1800 h. At 2000 h IL2 (3 or 6 million units per m2 body surface) or saline was injected sc. Lights were off between 2300 and 0700 h. Setting. The study was performed in a Clinical Translational Research Unit. Outcome measures. Mean concentrations of cortisol, deconvolution analysis, and approximate entropy. Abdominal visceral fat (AVF) and total abdominal fat (TAF) were calculated from single slice CT. Results. Cortisol concentrations started to rise at 2300 h. The AUC’s during the lights-on periods were unchanged by IL2. Therefore, most analyses were restricted to the 8 h lights-off period. In young volunteers pulsatile cortisol secretion increased from 52.9±5.8 to 77.0±8.0 µg/L/8h and in older subjects from 60.6±3.8 to 70.6±4.6 µg/L/8h (GLM: treatment P &lt;0.0001, treatment x age: P=0.02, mean ± SEM). Thus, the effect was smaller in older subjects. Increasing the IL2 dose increased cortisol secretion in young subjects (P= 0.001), but not in older subjects (P=0.90). In addition, the slopes (mean ± SE) of the linear part of the concentration curves after IL-2 were steeper than after placebo, pointing to accelerated release (young 1.40±0.13 to 3.76±0.11, P&lt;0.0001, in older 1.27±0.04 to 3.28±0.15, P&lt;0.0001).The incremental nocturnal pulsatile cortisol secretion after IL2 was negatively related to body composition (AVF: R= ̶ 0.41, P=0.019; TAF R= ̶ 0.41, P=0.043). Nocturnal ApEn-cortisol did not increase after low dose IL2 (0.981± 0.099 to 0.991±0.046, P=0.92). After high-dose, ApEn increased from 0.877±0.041 to 1.024±0.049, P=0.008, not correlated with body composition, nor with age. The ApEn increase points to decreased secretory regularity imposed by enhanced CRF signaling, rather than diminished cortisol feedback, which leads to greater secretory regularity. Conclusion. Il2, a paradigm for inflammation, increased pulsatile cortisol secretion, more in young than in older subjects. Higher IL2 doses in young subjects amplified cortisol secretion, but not in older subjects. Cortisol secretion exhibited an advance (earlier) time shift, accompanied by accelerated secretion. Incremental nocturnal cortisol secretion was negatively related to fat mass.

Abstract Context. Aging is associated with diminished testosterone (Te) secretion, which could be attributed to Leydig cell dysfunction, decreased pituitary stimulation and altered Te feedback. Objective. The goal was to quantify all three regulatory nodes of the GnRH-LH-Leydig cell- axis in the same cohort of healthy men, by measuring (1) indirectly the strength of the endogenous GnRH signal on the gonadotrope, (2) the strength of Te feedback on LH by ketoconazole (KTCZ), and (3) the effect of LH infusions on Te secretion, in relation to age and body composition. Design. This was a placebo-controlled, blinded, prospectively randomized cross-over study in 40 men, age 19–73 yr, BMI 20–34.3 kg/m2. A submaximal dose of ganirelix (GnRH antagonist) was used to assess outflow of GnRH, by calculating the difference between LH output during the control and ganirelix arm. Ketoconazole (steroidogenic inhibitor) was used to estimate feedback, by the difference in LH output during ketoconazole and control arm. High-dose ganirelix and repeated 6-min LH (18.75 IU) infusions were used to measure testicular responsivity. Blood sampling was at 10-min intervals. The 4 sessions were concluded with, a single submaximally GnRH stimulus to assess the responsiveness of the gonadotrope during ganirelix inhibition. Setting. The study was performed in a Clinical Translational Research Unit. Interventions. In 3 of the 4 experiments subjects underwent 5 h of blood sampling at 10-min intervals, starting at 0800 h. At 1100 h GnRH was injected and sampling was continued for another 2 h. Admission was at 1700 h the day before. At 2000 h they received KTCZ, dexamethasone or ganirelix and/or placebo. KTCZ and dexamethasone (or placebo) were administered again at 0700 when the IV catheter was placed. High-dose ganirelix was used to test the testicular responsiveness, and 7 LH pulses (90 min intervals) were given., with blood sampling from 1500 till 1300 h next day. Outcome measures. Mean concentrations of LH and (bio)Te, deconvolution analysis, endogenous dose-response LH-bioTe relation, and approximate entropy. Abdominal visceral fat (AVF) was calculated from single slice CT. Results. There were age-, but not body composition-related decreases in estimated endogenous GnRH secretion, Te’s feedback strength on LH, and Leydig cell responsivity to LH, accompanied by changes in approximate entropy. Bioavailable Te levels were negatively related to both age and AVF, without interaction between these variables. The LH response to a submaximal dose of GnRH was independent of age and AVF. Conclusion. Advancing age is associated with 1) attenuated bioavailable Te secretion caused by diminished GnRH outflow and not by decreased GnRH responsivity of the gonadotrope, 2) diminished testicular responsivity to infused LH pulses, and 3) partial compensation by diminished Te feedback on central gonadotropic regulation.

Background: Current cardiovascular disease (CVD) risk scores are derived from research cohorts and are particularly inaccurate in women, older adults, and those with missing data. To overcome these limitations, we aimed to develop a cohort to capitalize on the depth and breadth of clinical data within electronic health record (EHR) systems in order to develop next-generation sex-specific risk prediction scores for incident CVD. Methods: All individuals 30 years of age or older residing in Olmsted County, Minnesota on 1/1/2006 were identified. We developed and validated algorithms to define a variety of risk factors, thus building a comprehensive risk profile for each patient. Outcomes including myocardial infarction (MI), percutaneous intervention (PCI), coronary artery bypass graft (CABG), and CVD death were ascertained through 9/30/2017. Results: We identified 73,069 individuals without CVD (Table). We retrieved a total of 14,962,762 lab results; 14,534,466 diagnoses; 17,062,601 services/procedures; 1,236,998 outpatient prescriptions; 1,079,065 heart rate measurements; and 1,320,115 blood pressure measurements. The median number of blood pressure and heart rate measurements ascertained per individuals were 11 and 9, respectively. The five most prevalent conditions were: hypertension, hyperlipidemia, arthritis, depression, and cardiac arrhythmias. During follow-up 1,455 MIs, 1,581 PCI, 652 CABG, and 2,161 CVD-related deaths occurred. Conclusions: We developed a cohort with comprehensive risk profiles and follow-up for each patient. Using sophisticated machine learning approaches, this electronic cohort will be utilized to develop next-generation sex-specific CVD risk prediction scores. These approaches will allow us to address several challenges with use of EHR data including the ability to 1) deal with missing values, 2) assess and utilize a large number of variables without over-fitting, 3) allow non-linear relationships, and 4) use time-to-event data.

Abstract Study Objectives In young men, sleep restriction decreases testosterone (Te) and increases afternoon cortisol (F), leading to anabolic–catabolic imbalance, insulin resistance, and other andrological health consequences. Age-related differences in the hypothalamo–pituitary–testicular/adrenal response to sleep restriction could expose older individuals to greater or lesser risk. We aimed to evaluate and compare the 24-h and time-of-day effect of sleep restriction on F, luteinizing hormone (LH), and Te in young and older men. Methods Thirty-five healthy men, aged 18–30 (n = 17) and 60–80 (n =18) years, underwent overnight sleep deprivation (complete nighttime wakefulness) or nighttime sleep (10 pm to 6 am) with concurrent 10-min blood sampling in a prospectively randomized crossover study. F, LH, and Te secretion were calculated by deconvolution analysis. Results Sleep deprivation had multiple effects on 24-h Te secretion with significant reductions in mean concentrations, basal, total and pulsatile secretion, and pulse frequency (each p &lt; 0.05), in the absence of detectable changes in LH. These effects were most apparent in older men and differed according to age for some parameters: pulsatile Te secretion (p = 0.03) and Te pulse frequency (p = 0.02). Time-of-day analyses revealed that sleep restriction significantly reduced Te in the morning and afternoon, reduced LH in the morning in both age groups, and increased F in the afternoon in older men. Conclusions These data suggest a time-of-day dependent uncoupling of the regulatory control of the testicular axis and of F secretion. Future studies will need to directly verify these regulatory possibilities specifically and separately in young and older men. Clinical Trial Not applicable.