Marfan syndrome (MFS) is an autosomal-dominant disorder of the fibrous connective tissue that is typically caused by mutations in the gene coding for fibrillin-1 (FBN1), a major component of extracellular microfibrils. The clinical spectrum of MFS is highly variable and includes involvement of the cardiovascular, skeletal, ocular, and other organ systems; however, the genotype-phenotype correlations have not been well developed. Various screening methods have led to the identification of about 600 different mutations (FBN1-UMD database; www.umd.be). In this study we performed SSCP and/or direct sequencing to analyze all 65 exons of the FBN1 gene in 116 patients presenting with classic MFS or related phenotypes. Twenty-nine novel and nine recurrent mutations were identified in 38 of the analyzed patients. The mutations comprised 18 missense (47%), eight nonsense (21%), and five splice site (13%) mutations. Seven further mutations (18%) resulted from deletion, insertion, or duplication events, six of which led to a frameshift and subsequent premature termination. Additionally, we describe new polymorphisms and sequence variants. On the basis of the data presented here and in a previous study, we were able to establish highly significant correlations between the FBN1 mutation type and the MFS phenotype in a group of 76 mutation-positive patients for whom comprehensive clinical data were available. Most strikingly, there was a significantly lower incidence of ectopia lentis in patients who carried a mutation that led to a premature termination codon (PTC) or a missense mutation without cysteine involvement in FBN1, as compared to patients whose mutations involved a cysteine substitution or splice site alteration.

Myocarditis represents an important cause for acute heart failure. MYKKE, a prospective multicenter registry of pediatric patients with myocarditis, aims to gain knowledge on courses, diagnostics, and therapy of pediatric myocarditis. The role of mechanical circulatory support (MCS) in children with severe heart failure and myocarditis is unclear. The aim of this study was to determine characteristics and outcome of patients with severe heart failure requiring MCS and/or heart transplantation. The MYKKE cohort between September 2013 and 2016 was analyzed. A total of 195 patients were prospectively enrolled by 17 German hospitals. Twenty‐eight patients (14%) received MCS (median 1.5 years), more frequently in the youngest age group (0‐2 years) than in the older groups (P < 0.001; 2‐12 and 13‐18 years). In the MCS group, 50% received a VAD, 36% ECMO, and 14% both, with a survival rate of 79%. The weaning rate was 43% (12/28). Nine (32%) patients were transplanted, one had ongoing support, and six (21%) died. Histology was positive for myocarditis in 63% of the MCS group. Patients within the whole cohort with age <2 years and/or ejection fraction <30% had a significantly worse survival with high risk for MCS, transplantation, and death (P < 0.001). Myocarditis represents a life‐threatening disease with an overall mortality of 4.6% in this cohort. The fulminant form more often affected the youngest, leading to significantly higher rate of MCS, transplantation, and mortality. MCS represents an important and life‐saving therapeutic option in children with myocarditis with a weaning rate of 43%.

Several activity interventions in preschool settings exist, but little attention has been paid to effects on hemodynamic factors. The study aimed to assess the effectiveness of an exercise program on health-related outcomes including blood pressure (BP) and markers of vascular function in preschoolers, with focus on socioeconomic background. This study is a cluster-randomized controlled trial, with preschool as unit of randomization and children as unit of analysis. Preschools with 3-to 6-year-old children, stratified by social area, were randomly allocated to: intervention (three clusters, n = 92) including 2 d·wk −1 /45 min (6 months) exercise lessons or control (two clusters, n = 43). In total, 135 children (4.8 ± 0.8 y) had minimum one outcome measurement at baseline and follow-up. Primary outcome: peripheral BP. Secondary outcomes: central BP, pulse wave velocity (PWV), BMI, waist circumference, physical activity measures, motor skills. Maternal education was used as an indicator of socioeconomic status. Mixed models were applied to evaluate differences in mean change. Group allocation had no effect on primary or secondary outcomes. However, the intervention was effective in reducing increases in peripheral systolic BP (−3.4 mm Hg; 95% CI: −6.6; −0.2; P = 0.037), central systolic BP (−3.8 mm Hg; −6.4; −1.1; P = 0.006), and PWV (−0.1 m/s; −0.2; −0.0; P = 0.045) among children whose mothers had the lowest educational level. We found no evidence for effectiveness of a 6-months preschool-based exercise program on hemodynamics, anthropometrics, activity, or motor skills, but lack of process evaluations and poor fidelity preclude interpretation of the causal relation. However, the results indicate that children from lower social backgrounds could benefit from early exercise-promoting interventions. K E Y W O R D Sarterial stiffness, blood pressure, children, intervention, physical activity, preschool, social background

To assess the incidence and prognostic significance of cardiac dysrhythmias in children with idiopathic dilated or hypertrophic cardiomyopathy, the clinical course of 59 patients was retrospectively reviewed over a period of 27 years. Dilated cardiomyopathy (DCM) was diagnosed in 28 patients and hypertrophic cardiomyopathy (HCM) in 31 patients. The mean age at the time of diagnosis was 2.8 +/- 0.7 years in DCM patients and 6.7 +/- 0.8 years in HCM patients. Mean follow-up time after diagnosis of cardiomyopathy was 4.1 +/- 1.0 years in DCM patients and 6.6 +/- 0.8 years in HCM patients. Clinically significant cardiac dysrhythmias were found in 17 of 59 patients (29%): 7 of 28 patients (25%) with DCM and 10 of 31 patients (32%) with HCM. The initial diagnosis of a cardiac dysrhythmia was made by standard electrocardiography in 12 of 17 patients (71%) and by 24-hour Holter monitoring in 5 of 17 patients (29%). Ventricular dysrhythmias were present in 5 of 7 patients with dilated cardiomyopathy and in 5 of 10 patients with hypertrophic cardiomyopathy. During the followup time, death occurred in 18 of 59 patients (31%): 8 of 59 patients (14%) died from congestive heart failure and 10 of 59 patients (17%) died suddenly. Among the sudden deaths were 4 of 28 patients (14%) with dilated cardiomyopathy and 6 of 31 patients (19%) with hypertrophic cardiomyopathy. Cardiac dysrhythmias had been documented in 6 of the 10 patients dying suddenly (3 of 4 patients with DCM and 3 of 6 patients with HCM).(ABSTRACT TRUNCATED AT 250 WORDS)

Currently, no reliable genotype–phenotype correlation is available for pediatric Marfan patients in everyday clinical practice. We investigated correlations of FBN1 variants with the prevalence and age of onset of Marfan manifestations in childhood and differentiated three groups: missense/in-frame, splice, and nonsense/frameshift variants. In addition, we differentiated missense variants destroying or generating a cysteine (cys-missense) and alterations not affecting cysteine. We categorized 105 FBN1-positive pediatric patients. Patients with cys-missense more frequently developed aortic dilatation (p = 0.03) requiring medication (p = 0.003), tricuspid valve prolapse (p = 0.03), and earlier onset of myopia (p = 0.02) than those with other missense variants. Missense variants correlated with a higher prevalence of ectopia lentis (p = 0.002) and earlier onset of pulmonary artery dilatation (p = 0.03) than nonsense/frameshift, and dural ectasia was more common in the latter (p = 0.005). Pectus excavatum (p = 0.007) appeared more often in patients with splice compared with missense/in-frame variants, while hernia (p = 0.04) appeared earlier in the latter. Findings on genotype–phenotype correlations in Marfan-affected children can improve interdisciplinary therapy. In patients with cys-missense variants, early medical treatment of aortic dilatation seems reasonable and early regular ophthalmologic follow-up essential. Patients with nonsense/frameshift and splice variants require early involvement of orthopedic specialists to support the growing child.

No abstract

Objective This study presents data from the admission trial to show the feasibility, safety and effectiveness of the Nit-Occlud® Lê VSD in the treatment of perimembranous ventricular septal defects with an aneurysmal configuration and a diameter up to 8 mm. Background The majority of ventricular septal defects (VSD) are still closed surgically, while a less invasive transcatheter treatment by closure devices is available. Device-based closure is reported to be associated with the risk of complete atrio-ventricular block, especially with double-disc devices in perimembranous defects. Methods In six tertiary centers in Germany and Israel, an interventional closure of a periembranous VSD was attempted in 88 patients using the Nit-Occlud® Lê VSD. Results The interventional VSD closure was performed in 85 patients. Patients had a median age of 8.0 (2–65) years and a median body weight of 26.7 (10–109) kg. A complete closure of the defects was achieved in 85.4% 2 weeks after device implantation, in 88.9% after three months and in 98.6% at the 5-year follow-up. There was no incidence of death during the study nor did any patient suffer of permanent atrio-ventricular block of higher degree. Serious adverse events, by definition, are potentially life-threatening or require surgery to correct, while major serious events require medical or transcatheter intervention to correct. The study results exhibit a serious adverse event rate of 3.5% (3/85 patients) and a major adverse event rate of 5.9% (5/85 patients). Conclusion The Nit-Occlud® Lê VSD coil offers the possibility of an effective and safe approach in patients with aneurysmal perimembranous ventricular septal defects.

This article studies the return effects seen on listed private equity funds, which are the result of exit events of portfolio companies. It shows that private equity as an asset class has long been connected to sophisticated investors, including high-net-worth institutions or individuals. It then hypothesizes that exit announcements cause significantly positive share price reactions and provides data that was gathered from all exit announcements made by firms. This article determines that the hypothesis is true, and that it is due to the fact that a better price may be achieved in an IPO.