AimsPatient‐reported quality of life (QOL) is a highly prognostic and clinically relevant endpoint in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The relationships between QOL and different markers of HF severity remain unclear, particularly as they relate to functional capacity and directly measured activity levels. We hypothesized that QOL would demonstrate a stronger relationship with measures of exercise capacity and adiposity compared to other disease measures.Methods and resultsThis is a secondary analysis of the National Heart, Lung, and Blood Institute‐sponsored RELAX, NEAT‐HFpEF and INDIE‐HFpEF trials to determine the relationships between QOL (assessed by the Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire) and different domains reflecting HF severity, including maximal aerobic capacity (peak oxygen consumption), submaximal exercise capacity (6‐min walk distance), volume of daily activity (accelerometry), physician‐estimated functional class, resting echocardiography, and plasma natriuretic peptide levels. A total of 408 unique patients with chronic HFpEF were split into tertiles of QOL scores defined as QOLworst, QOLintermediate, QOLbest. The QOLworst HFpEF group was youngest, with a higher body mass index, greater prevalence of class II obesity and diabetes, and the lowest N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels. After adjustment for age, sex and body mass index, poorer QOL was associated with worse physical capacity and activity levels, assessed by peak oxygen consumption, 6‐min walk distance and actigraphy, but was not associated with NT‐proBNP or indices from resting echocardiography. QOL was similarly reduced in patients with and without prior HF hospitalization.ConclusionsQuality of life in HFpEF is poorest in patients who are young, obese and have diabetes, and is more robustly tied to measures reflecting functional capacity and daily activity levels rather than elevations in NT‐proBNP or prior HF hospitalization. These findings have major implications for the understanding of QOL in HFpEF and for the design of future clinical trials targeting symptom improvement in HFpEF.Clinical Trial Registration: RELAX, NCT00763867; NEAT‐HFpEF, NCT02053493; INDIE‐HFpEF, NCT02742129.

Background and Objective While one in five children in the USA are now obese, and more than three-quarters receive at least one drug during childhood, there is limited dosing guidance for this vulnerable patient population. Physiologically based pharmacokinetic modeling can bridge the gap in the understanding of how pharmacokinetics, including drug distribution and clearance, changes with obesity by incorporating known obesity-related physiological changes in children. The objective of this study was to develop a virtual population of children with obesity to enable physiologically based pharmacokinetic modeling, then use the novel virtual population in conjunction with previously developed models of clindamycin and trimethoprim/sulfamethoxazole to better understand dosing of these drugs in children with obesity. Methods To enable physiologically based pharmacokinetic modeling, a virtual population of children with obesity was developed using national survey, electronic health record, and clinical trial data, as well as data extracted from the literature. The virtual population accounts for key obesity-related changes in physiology relevant to pharmacokinetics, including increased body size, body composition, organ size and blood flow, plasma protein concentrations, and glomerular filtration rate. The virtual population was then used to predict the pharmacokinetics of clindamycin and trimethoprim/sulfamethoxazole in children with obesity using previously developed physiologically based pharmacokinetic models. Results Model simulations predicted observed concentrations well, with an overall average fold error of 1.09, 1.24, and 1.53 for clindamycin, trimethoprim, and sulfamethoxazole, respectively. Relative to children without obesity, children with obesity experienced decreased clindamycin and trimethoprim/sulfamethoxazole weight-normalized clearance and volume of distribution, and higher absolute doses under recommended pediatric weight-based dosing regimens. Conclusions Model simulations support current recommended weight-based dosing in children with obesity for clindamycin and trimethoprim/sulfamethoxazole, as they met target exposure despite these changes in clearance and volume of distribution.The members of "on behalf of the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee" is present in the Acknowledgements section.

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Objectives: To characterize the course of decongestion among patients hospitalized for acute heart failure (AHF) by history of atrial fibrillation/atrial flutter (AF/AFL). Background: AF/AFL and chronic heart failure (HF) commonly coexist. Little is known regarding impact of AF/AFL on relief of congestion among patients who develop acute heart failure (AHF). Methods: We pooled patients from 3 randomized trials of AHF conducted within the Heart Failure Network (the Diuretic Optimization Strategies trial, the Renal Optimization Strategies Trial, and the Cardiorenal Rescue Study in Acute Decompensated Heart Failure). The association between AF/AFL history and in-hospital changes in various metrics of congestion was assessed using covariate-adjusted linear and ordinal logistic regression models. Results: Of 750 unique patients, 418 (56%) had a history of AF/AFL. Left ventricular ejection fraction was higher (35% vs. 27% P<0.001) and N-terminal pro-brain natriuretic peptide (NTproBNP) levels were non-significantly lower at baseline (4210 pg/mL vs. 5037 pg/mL, P=0.27) in AF/AFL. After covariate adjustment, history of AF/AFL was associated with less substantial loss of weight (−5.7% vs. −6.5%, P=0.02) and decrease in NT-proBNP levels (−18.7% vs. −31.3%, P= 0.003) by 72 or 96 hours. History of AF/AFL was also associated with a blunted increase in global sense of well-being at 72/96 hours (P=0.04). There was no association between AF/AFL history and change in orthodema congestion score (P=0.67) or the 60-day composite clinical endpoint (all-cause mortality or any rehospitalization) (hazard ratio 1.21, 95% confidence interval 0.92–1.59, P=0.17). Conclusion: More than half of patients admitted with AHF had a history of AF/AFL. History of AF/AFL was independently associated with a blunted course of in-hospital decongestion. Further research is required to understand the utility of specific therapies targeting AF/AFL during hospitalization for AHF.

Objective:The objective of this study was to describe treatment preferences and perceived quality of existing outcome measures among children and adolescents with migraine and their caregivers. Background: Across disciplines, there is increasing recognition of the value of direct input from stakeholders. Little empirical work has been done to determine what outcomes matter most to pediatric patients with migraine and their caregivers. Methods: In this qualitative study, we recruited participants from the multicenter, prospective Pediatric Migraine Registry. We used stratified purposive sampling to recruit children and adolescents of varied ages and headache frequency. Patients with migraine and their caregivers completed semistructured interviews targeting treatment preferences and perceived quality of existing outcome measures. Emergent themes and subthemes were identified using conventional content analysis. Results: Thirty dyads of children/adolescents and their caregivers were enrolled and completed 59 interviews (n = 29 children/adolescent interviews and n = 30 caregiver interviews). Three themes emerged. (1) Symptom relief: Looking beyond headache resolution: Participants described the value of outcomes in addition to pain relief, including a reduction in migraine intensity and improvement in non-pain symptoms. (2) Tradeoffs between side effects and relief: Participants described cost-benefit analyses that can occur with headache treatment and acknowledged the impact of drug side effects on daily life and medication adherence. (3) Child-centered treatment: Participants described medication attributes salient to the pediatric context, including ageappropriate routes of administration and adequate safety data. Conclusions: Children, adolescents, and caregivers impacted by migraine value outcomes in addition to traditionally studied migraine endpoints. Participants valued decreased pain severity, even in the absence of pain resolution. Participants also prioritized the absence of side effects and key medication attributes, including fast onset and age-appropriate routes of administration. These results highlight an opportunity to design patient-centered clinical trials, develop drugs, and support product labeling How to cite this article: