Author Correction: Consistency of HFrEF treatment effect in underrepresented groups in randomized clinical trials
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Consistency of HFrEF treatment effect in underrepresented groups in randomized clinical trials
Despite the established efficacy of heart failure (HF) guideline-directed medical therapies, implementation varies across demographic groups, including Black, Indigenous, and people of color, older adults, females, and those who are socioeconomically deprived. This review synthesizes the representativeness of trial participants and describes subgroup analyses from pivotal trials in HF with reduced ejection fraction (HFrEF). It reviews the largely consistent treatment effect of medical therapies across the demographic groups represented in trials. It makes arguments for broad implementation of therapies based on these data, while calling for more representative trials to improve research and health equity in HF.
Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes
Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.
Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia
X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX gene, which is predominantly expressed in osteoblasts, osteocytes and odontoblasts. XLH is characterized by increased synthesis of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23), which results in renal phosphate wasting with consecutive hypophosphataemia, rickets, osteomalacia, disproportionate short stature, oral manifestations, pseudofractures, craniosynostosis, enthesopathies and osteoarthritis. Patients with XLH should be provided with multidisciplinary care organized by a metabolic bone expert. Historically, these patients were treated with frequent doses of oral phosphate supplements and active vitamin D, which was of limited efficiency and associated with adverse effects. However, the management of XLH has evolved in the past few years owing to the availability of burosumab, a fully humanized monoclonal antibody that neutralizes circulating FGF23. Here, we provide updated clinical practice recommendations for the diagnosis and management of XLH to improve outcomes and quality of life in these patients.
Human neural dynamics of real-world and imagined navigation
The ability to form episodic memories and later imagine them is integral to the human experience, influencing our recollection of the past and envisioning of the future. While rodent studies suggest the medial temporal lobe, especially the hippocampus, is involved in these functions, its role in human imagination remains uncertain. In human participants, imaginations can be explicitly instructed and reported. Here we investigate hippocampal theta oscillations during real-world and imagined navigation using motion capture and intracranial electroencephalographic recordings from individuals with chronically implanted medial temporal lobe electrodes. Our results revealed intermittent theta dynamics, particularly within the hippocampus, encoding spatial information and partitioning navigational routes into linear segments during real-world navigation. During imagined navigation, theta dynamics exhibited similar patterns despite the absence of external cues. A statistical model successfully reconstructed real-world and imagined positions, providing insights into the neural mechanisms underlying human navigation and imagination, with implications for understanding memory in real-world settings.
Prediction of individual treatment allocation between electroconvulsive therapy or ketamine using the Personalized Advantage Index
Electroconvulsive therapy (ECT) and ketamine are effective treatments for depression; however, evidence-based guidelines are needed to inform individual treatment selection. We adapted the Personalized Advantage Index (PAI) using machine learning to predict optimal treatment assignment to ECT or ketamine using EHR data on 2506 ECT and 196 ketamine patients. Depressive symptoms were evaluated using the Quick Inventory of Depressive Symptomatology (QIDS) before and during acute treatment. Propensity score matching across treatments was used to address confounding by indication, yielding a sample of 392 patients (n = 196 per treatment). Models predicted differential minimum QIDS scores (min-QIDS) over acute treatment using pretreatment EHR measures and SHAP values identified prescriptive predictors. Patients with large PAI scores who received a predicted optimal had significantly lower min-QIDS compared to the non-optimal treatment group (mean difference = 1.19 [95% CI: 0.32, ∞], t = 2.25, q < 0.05, d = 0.26). Our model identified candidate pretreatment factors to provide actionable, effective antidepressant treatment selection guidelines.
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