Takahashi, Paul

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.

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.

Background and Purpose— We aimed at providing estimates of mortality associated with cardiometabolic comorbidity and incident readmission from cardiometabolic as compared with noncardiometabolic conditions after a first transient ischemic attack. Methods— Between 2000 and 2015, patients hospitalized for a first transient ischemic attack were examined for cardiometabolic comorbidities (diabetes mellitus, coronary artery disease, heart failure, and atrial fibrillation), 5-year incident hospitalization, and time to death. Results— Of 251 patients with transient ischemic attack, 134 (53%) had at least 1 and 55 (22%) had at least 2 cardiometabolic conditions. By 5 years, 491 readmissions (134 [27%] cardiometabolic and 357 [73%] noncardiometabolic) and 75 deaths (27 [36%] cardiometabolic and 47 [64%] noncardiometabolic) were observed. Mortality was increased with any concurrent cardiometabolic comorbidity (hazard ratio, 1.89; 95% confidence interval, 1.17–3.03; P =0.0089) with multiplicative mortality risk from a combination of coronary artery disease and heart failure. Each hospitalization was associated with a 1.5-fold risk of death (95% confidence interval, 1.37–1.64; P <0.0001). Risk of cardiometabolic and noncardiometabolic mortality was correlated with the corresponding category-specific readmission. Conclusions— Among patients hospitalized for first transient ischemic attack, 5-year mortality is associated with concurrent cardiometabolic comorbidity and rates of subsequent hospitalization.

AbstractBackgroundThe implications of early readmission on long‐term mortality after transient ischemic attack (TIA) are not known. We aimed at examining the effect of 180‐day readmission on subsequent long‐term mortality after index hospitalization for TIA.MethodsA retrospective study of patients hospitalized for first‐ever TIA at Mayo Clinic from 2000 through 2017. Patients readmitted within 180 days postdischarge were compared with those not readmitted in long‐term risk of death.ResultsOf 251 TIA patients aged 73 ± 15 years with 1509 person‐years of follow‐up, 65 (26%) were readmitted within 180 days of discharge and 125 died during a median follow‐up of 5.7 years. The mortality was 10 vs. 7 deaths per 100 person‐years in patients who were readmitted compared to those who were not readmitted with hazard ratio (HR) 1.73 (95% confidence interval [CI] 1.13–2.66). Other competing predictors of mortality were age ≥65 years (HR 5.70, 95% CI 2.72–11.96), cancer (HR 1.65, 95% CI 1.03–3.38), chronic obstructive pulmonary disease (HR 1.90, 95% CI 1.07–3.38), heart failure (HR 3.03, 95% CI 1.82–5.06), dementia (HR 5.87, 95% CI 3.27–10.52), creatinine ≥1.4 mg/dl (HR 1.89, 95% CI 1.17–3.06), and hemoglobin level <10 g/dl (HR 2.80, 95% CI 1.20–6.66).ConclusionsHospital readmission within 180 days of discharge from index TIA was associated with increased risk of death several years after initial readmission. Older age and several comorbidities identified during index hospitalization also confer increased risk for long‐term mortality.

Context Studies on 24-h cortisol secretion are rare. The impact of sex, age and adiposity on cortisol levels, often restricted to one or a few samples, are well recognized, but conflicting. Objective To investigate cortisol dynamics in 143 healthy men and women, spanning 7 decades and with a 2-fold body mass index (BMI) range with different analytic tools. Setting Clinical Research Unit. Design Cortisol concentrations in 10-min samples collected for 24 h. Outcomes were mean levels, deconvolution parameters, approximate entropy (ApEn, regularity statistic) and 24-h rhythms. Results Total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. Mean 24-h cortisol concentrations were lower in premenopausal women than those in men of comparable age (176 ± 8.2 vs 217 ± 9.4 nmol/L, P = 0.02), but not in subjects older than 50 years. This was due to lower daytime levels in women, albeit similar in the quiescent overnight period. Aging increased mean cortisol by 10 nmol/L per decade during the quiescent secretory phase and advanced the acrophase of the diurnal rhythm by 24 min/decade. However, total 24-h cortisol secretion rates estimated by deconvolution analysis were sex, age and BMI independent. ApEn of 24-h profiles was higher (more random) in premenopausal women than those in men (1.048 ± 0.025 vs 0.933 ± 0.023, P = 0.001), but not in subjects older than 50 years. ApEn peaked during the daytime. Conclusion Sex and age jointly determine the 24-h cortisol secretory profile. Sex effects are largely restricted to age <50 years, whereas age effects elevate concentrations in the late evening and early night and advance the timing of the peak diurnal rhythm.

Background: Systemic concentrations of T, estradiol (E2), GH, IGF-1, and IGF binding protein-3 decline in healthy aging individuals. Conversely, T and E2 stimulate GH and IGF-1 production in hypogonadal patients. Hypothesis: Because E2 stimulates GH secretion, putatively via the nuclear estrogen receptor-α and E2 and GH fall with menopause, we postulated that diminished endogenous E2 contributes to low GH output in older women. Location: The study was conducted at the Mayo Center for Clinical and Translational Science. Study Design: This was a randomized, double-blind, controlled study in 60 healthy postmenopausal women treated with the following: 1) double placebo; 2) anastrozole, a potent inhibitor of aromatase-enzyme activity, which mediates E2 synthesis from T; and/or 3) fulvestrant, a selective estrogen receptor-α antagonist. Methods: GH pulse generation was quantified by frequent GH sampling before and after short-term iv somatostatin infusion, thought to induce hypothalamic GHRH-mediated rebound-like GH secretion. Results: On anastrozole, E2 fell from 3.1 ± 0.35 pg/mL to 0.36 ± 0.04 pg/mL, and estrone from 13 ± 1.4 pg/mL to 1.9 ± 0.01 pg/mL (P &lt; .001) by mass spectrometry. Estrogen values were unchanged by fulvestrant. T concentrations did not change. One-hour peak GH rebound after somatostatin infusion declined markedly during both estrogen-deprivation schedules (P &lt; .001). Mean (150 min) maximal GH rebound decreased comparably (P &lt; .001). Measures of GH rebound correlated negatively with computed tomography-estimated abdominal visceral fat (all P &lt; .05). Conclusion: These data suggest a previously unrecognized dependence of hypothalamo-pituitary GH regulation on low levels of endogenous estrogen after menopause.