Natural History of MYH7-Related Dilated Cardiomyopathy

BACKGROUND Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 +/- 19.2 years) recruited from 29 international centers. RESULTS At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% +/- 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of <= 35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

Fellow-brethren and compeers : Montaigne’s rapprochement between man and animal

Anthropology is a notoriously polysemous term. Within a continental European academic context, it is usually employed in the sense of philosophical anthropology , and mainly concerned with exploring concepts of a universal human nature. By contrast, Anglo-American scholarship almost exclusively associates anthropology with the investigation of cultural and ethnic differences ( cultural anthropology ). How these two main traditions (and their 'derivations' such as literary anthropology, historical anthropology, ethnology, ethnography, intercultural studies) relate to each other is a matter of debate. Both, however, have their roots in the path-breaking changes that occurred within sixteenth and early seventeenth-century culture and scientific discourse. It was in fact during this period that the term anthropology first acquired the meanings on which its current usage is based. The Renaissance did not 'invent' the human. But the period that gave rise to 'humanism' witnessed an unprecedented diversification of the concept that was at its very core. The question of what defines the human became increasingly contested as new developments like the emergence of the natural sciences, religious pluralisation, as well as colonial expansion, were undermining old certainties. The proliferation of doctrines of the human in the early modern age bears out the assumption that anthropology is a discipline of crisis, seeking to establish sets of common values and discursive norms in situations when authority finds itself under pressure

Structured, Harmonized, and Interoperable Integration of Clinical Routine Data to Compute Heart Failure Risk Scores

Risk prediction in patients with heart failure (HF) is essential to improve the tailoring of preventive, diagnostic, and therapeutic strategies for the individual patient, and effectively use health care resources. Risk scores derived from controlled clinical studies can be used to calculate the risk of mortality and HF hospitalizations. However, these scores are poorly implemented into routine care, predominantly because their calculation requires considerable efforts in practice and necessary data often are not available in an interoperable format. In this work, we demonstrate the feasibility of a multi-site solution to derive and calculate two exemplary HF scores from clinical routine data (MAGGIC score with six continuous and eight categorical variables; Barcelona Bio-HF score with five continuous and six categorical variables). Within HiGHmed, a German Medical Informatics Initiative consortium, we implemented an interoperable solution, collecting a harmonized HF-phenotypic core data set (CDS) within the openEHR framework. Our approach minimizes the need for manual data entry by automatically retrieving data from primary systems. We show, across five participating medical centers, that the implemented structures to execute dedicated data queries, followed by harmonized data processing and score calculation, work well in practice. In summary, we demonstrated the feasibility of clinical routine data usage across multiple partner sites to compute HF risk scores. This solution can be extended to a large spectrum of applications in clinical care

&#946;-estradiol rescues &#916;-F508CFTR functional expression in human cystic fibrosis airway CFBE41o^- cells through the up-regulation of NHERF1

Background information Cystic fibrosis (CF) is a disease caused by mutations within the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The most common mutation, &#916;F508, results in a protein that is defective in folding and trafficking to the cell surface but is functional if properly localized in the plasma membrane. We have recently demonstrated that over-expression of the PDZ protein NHERF1 in (Na+/H+-exchanger regulatory factor 1) CF airway cells induced both a redistribution of &#916;F508CFTR from the cytoplasm to the apical membrane and the PKA-dependent activation of &#916;F508CFTR-dependent chloride secretion. In view of the potential importance of the targeted up-regulation of NHERF1 in a therapeutic context and since it has been demonstrated that estrogen treatment increases endogenous NHERF1 expression, we tested the hypothesis that the estrogen treatment can increase NHERF1 expression in a human bronchiolar epithelial CF cell line, CFBE41o-, with a subsequent rescue of apical &#916;F508CFTR chloride transport activity. Results: We found that CFBE41o- cells do express estrogen receptors in the nuclear fraction and that &#946;-estradiol treatment was able to significantly rescue the &#916;F508CFTR-dependent chloride secretion in CFBE41o- cell monolayers, demonstrating that the &#916;F508CFTR translocated to the apical membrane can function as a cAMP-responsive channel. Importantly, knock-down of NHERF1 expression by transfection with siRNA for NHERF1 inhibited the &#946;-estradiol-dependent increase of &#916;F508CFTR protein expression levels and completely prevented the &#946;-estradiol-dependent rescue of &#916;F508CFTR transport activity. Conclusions. These results demonstrate that &#946;-estradiol-dependent up-regulation of NHERF1 significantly increases &#916;F508CFTR functional expression in CFBE41o- cells