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BACKGROUND Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and brief. Whether the occurrence of AHREs in patients without atrial fibrillation (as documented on a conventional electrocardiogram [ECG]) justifies the initiation of anticoagulants is not known. METHODS We conducted an event-driven, double-blind, double-dummy, randomized trial involving patients 65 years of age or older who had AHREs lasting for at least 6 minutes and who had at least one additional risk factor for stroke. Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding. RESULTS The analysis population consisted of 2536 patients (1270 in the edoxaban group and 1266 in the placebo group). The mean age was 78 years, 37.4% were women, and the median duration of AHREs was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed. A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.60 to 1.08; P = 0.15). The incidence of stroke was approximately 1% per patient-year in both groups. A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02 to 1.67; P = 0.03). ECG-diagnosed atrial fibrillation developed in 462 of 2536 patients (18.2% total, 8.7% per patient-y

The management of atrial fibrillation (AF), the most common sustained arrhythmia, impacts healthcare resource utilization (HCRU). This study aims to estimate global resource use in AF patients, using the GARFIELD-AF registry. A prospective cohort study was conducted to characterize HCRU in AF patients enrolled in sequential cohorts from 2012 to 2016 in 35 countries. Components of HCRU studied were hospital admissions, outpatient care visits, and diagnostic and interventional procedures occurring during follow-up. AF-related HCRU was reported as the percentage of patients demonstrating at least one event and was quantified as rate-per-patient-per-year (PPPY) over time. A total of 49,574 patients was analyzed, having an overall median follow-up of 719 days. Almost all patients (99.5%) had at least one outpatient care visit, while hospital admissions were the second most frequent medical contact, with similar proportions in North America (37.5%) and Europe (37.2%), and slightly higher in the other GARFIELD-AF countries (42.0%; namely Australia, Egypt, and South Africa). Asia and Latin America showed lower percentages of hospitalizations, outpatient care visits, and diagnostic and interventional procedures. Analyses of GARFIELD-AF highlighted the vast AF-related HCRU, underlying significant geographical differences in the type, quantity, and frequency of AF-related HCRU. These differences were likely attributable to health service availability and differing models of care.

Growth and maturation of the fetal gastrointestinal tract near term prepares the offspring for the onset of enteral nutrition at birth. Structural and functional changes are regulated by the prepartum rise in cortisol in the fetal circulation, although the role of the coincident rise in plasma tri-iodothyronine (T3) is unknown. This study examined the effect of hypothyroidism on the structural development of the gastrointestinal tract and the activity of brush-border digestive enzymes in the ovine fetus near term. In intact fetuses studied between 100 and 144 days of gestation (dGA; term ∼145 days), plasma concentrations of T3, cortisol and gastrin; the mucosal thickness in the abomasum, duodenum, jejunum and ileum; and intestinal villus height and crypt depth increased with gestational age. Removal of the fetal thyroid gland at 105–110 dGA suppressed plasma thyroxine (T4) and T3 concentrations to the limit of assay detection in fetuses studied at 130 and 144 dGA, and decreased plasma cortisol and gastrin near term, compared to age-matched intact fetuses. Hypothyroidism was associated with reductions in the relative weights of the stomach compartments and small intestines, the outer perimeter of the intestines, the thickness of the gastric and intestinal mucosa, villus height and width, and crypt depth. The thickness of the mucosal epithelial cell layer and muscularis propria in the small intestines were not affected by gestational age or treatment. Activities of the brush border enzymes varied with gestational age in a manner that depended on the enzyme and region of the small intestines studied. In the ileum, maltase and dipeptidyl peptidase IV (DPPIV) activities were lower, and aminopeptidase N (ApN) were higher, in the hypothyroid compared to intact fetuses near term. These findings highlight the importance of thyroid hormones in the structural and functional development of the gastrointestinal tract near term, and indicate how hypothyroidism in utero may imp

In adults, glucocorticoids are stress hormones that act, partly, through actions on mitochondrial oxidative phosphorylation (OXPHOS) to increase energy availability. Before birth, glucocorticoids are primarily maturational signals that prepare the fetus for new postnatal challenges. However, the role of the normal prepartum glucocorticoid rise in preparing mitochondria for the increased postnatal energy demands remains largely unknown. This study examined the effect of physiological increases in the fetal cortisol concentration on cerebral mitochondrial OXPHOS capacity near term (~130 days gestation, term ~145 days gestation). Fetal sheep were infused with saline or cortisol for 5 days at ~0.8 of gestation before the mitochondrial content, respiratory rates, abundance of the electron transfer system proteins and OXPHOS efficiency were measured in their cortex and cerebellum. Cerebral morphology was assessed by immunohistochemistry and stereology. Cortisol treatment increased the mitochondrial content, while decreasing Complex I-linked respiration in the cerebellum. There was no effect on the cortical mitochondrial OXPHOS capacity. Cortisol infusion had regional effects on cerebral morphology, with increased myelination in the cerebrum. The findings demonstrate the importance of cortisol in regulating the cerebral mitochondrial OXPHOS capacity prenatally and have implications for infants born preterm or after glucocorticoid overexposure due to pregnancy complications or clinical treatment.

Prenatal glucocorticoid overexposure causes adult metabolic dysfunction in several species but its effects on adult mitochondrial function remain largely unknown. Using respirometry, this study examined mitochondrial substrate metabolism of fetal and adult ovine biceps femoris (BF) and semitendinosus (ST) muscles after cortisol infusion before birth. Physiological Increases in fetal cortisol concentrations pre-term induced muscle- and substrate-specific changes in mitochondrial oxidative phosphorylation capacity in adulthood. These changes were accompanied by muscle-specific alterations in protein content, fibre composition and abundance of the mitochondrial electron transfer system (ETS) complexes. In adult ST, respiration using palmitoyl-carnitine and malate was increased after fetal cortisol treatment but not with other substrate combinations. There were also significant increases in protein content and reductions in the abundance of all four ETS complexes, but not ATP synthase, in the ST of adults receiving cortisol prenatally. In adult BF, intrauterine cortisol treatment had no effect on protein content, respiratory rates, ETS complex abundances or ATP synthase. Activity of citrate synthase, a marker of mitochondrial content, was unaffected by intrauterine treatment in both adult muscles. In the ST but not BF, respiratory rates using all substrate combinations were significantly lower in the adults than fetuses, predominantly in the saline-infused controls. The ontogenic and cortisol-induced changes in mitochondrial function were, therefore, more pronounced in the ST than BF muscle. Collectively, the results show that fetal cortisol overexposure programs mitochondrial substrate metabolism in specific adult muscles with potential consequences for adult metabolism and energetics.