The MEDEA childhood asthma study design for mitigation of desert dust health effects: implementation of novel methods for assessment of air pollution exposure and lessons learned

Background: Desert dust events in Mediterranean countries, originating mostly from the Sahara and Arabian deserts, have been linked to climate change and are associated with significant increase in mortality and hospital admissions from respiratory causes. The MEDEA clinical intervention study in children with asthma is funded by EU LIFE+ program to evaluate the efficacy of recommendations aiming to reduce exposure to desert dust and related health effects. Methods: This paper describes the design, methods, and challenges of the MEDEA childhood asthma study, which is performed in two highly exposed regions of the Eastern Mediterranean: Cyprus and Greece-Crete. Eligible children are recruited using screening surveys performed at primary schools and are randomized to three parallel intervention groups: a) no intervention for desert dust events, b) interventions for outdoor exposure reduction, and c) interventions for both outdoor and indoor exposure reduction. At baseline visits, participants are enrolled on MEDena® Health-Hub, which communicates, alerts and provides exposure reduction recommendations in anticipation of desert dust events. MEDEA employs novel environmental epidemiology and telemedicine methods including wearable GPS, actigraphy, health parameters sensors as well as indoor and outdoor air pollution samplers to assess study participants’ compliance to recommendations, air pollutant exposures in homes and schools, and disease related clinical outcomes. Discussion: The MEDEA study evaluates, for the first time, interventions aiming to reduce desert dust exposure and implement novel telemedicine methods in assessing clinical outcomes and personal compliance to recommendations. In Cyprus and Crete, during the first study period (February–May 2019), a total of 91 children participated in the trial while for the second study period (February–May 2020), another 120 children completed data collection. Recruitment for the third study period (February–May 2021) is underway. In this paper, we also present the unique challenges faced during the implementation of novel methodologies to reduce air pollution exposure in children. Engagement of families of asthmatic children, schools and local communities, is critical. Successful study completion will provide the knowledge for informed decision-making both at national and international level for mitigating the health effects of desert dust events in South-Eastern Europe. Trial registration: ClinicalTrials.gov: NCT03503812, April 20, 2018

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome.

BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. OBJECTIVES: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. METHODS: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. RESULTS: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10(-5)). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. CONCLUSIONS: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation

Genetics of Heritable Thoracic Aortic Disease

Genetic testing plays an increasing diagnostic and prognostic role in the management of patients with heritable thoracic aortic disease (HTAD). The identification of a specific variant can establish or confirm the diagnosis of syndromic HTAD, dictate extensive evaluation of the arterial tree in HTAD with known distal vasculature involvement and justify closer follow-up and earlier surgical intervention in HTAD with high risk of dissection of minimal or normal aortic size. Evolving phenotype–genotype correlations lead us towards more precise and individualized management and treatment of patients with HTAD. In this review, we present the latest evidence regarding the role of genetics in patients with HTAD

Genetics of Heritable Thoracic Aortic Disease

Genetic testing plays an increasing diagnostic and prognostic role in the management of patients with heritable thoracic aortic disease (HTAD). The identification of a specific variant can establish or confirm the diagnosis of syndromic HTAD, dictate extensive evaluation of the arterial tree in HTAD with known distal vasculature involvement and justify closer follow-up and earlier surgical intervention in HTAD with high risk of dissection of minimal or normal aortic size. Evolving phenotype–genotype correlations lead us towards more precise and individualized management and treatment of patients with HTAD. In this review, we present the latest evidence regarding the role of genetics in patients with HTAD

A truncating variant altering the extreme C-terminal region of desmoplakin (DSP) suggests the crucial functional role of the region: a case report study

Abstract Background Homozygous truncating mutations located in the C-terminal region of the desmoplakin gene (DSP) are known to mainly cause Carvajal syndrome, an autosomal recessive syndromic form of arrhythmogenic cardiomyopathy with an extra-cardiac cutaneous phenotype. Case presentation Here we describe a female proband with a documented arrhythmogenic left ventricular cardiomyopathy and a syncopal episode at the age of 13, who was found homozygous for the novel DSP variant: NM_004415.4:c.8586delC, p.(Ser2863Hisfs*20) at the extreme C-terminal region of the protein, just 8 amino acids upstream the stop codon. She did not have any of the typical dermatological symptoms that characterize Carvajal syndrome. Her brother had died suddenly at the age of 18 during exercise and was found homozygous for the same variant at the post-mortem, while their parents were heterozygous. The region of origin of both parents was the same geographic area of Greece, but they were not aware of any common ancestor. Detailed clinical examination revealed that the mother displayed a mild arrhythmic phenotype, while the father was asymptomatic. Conclusion These observations pinpoint to a significant functional role of the extreme C-terminal tail of the protein

Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration

Dickkopf-1 is an inhibitor of Wnt signaling, which is crucial for osteoblast differentiation. This study shows that serum levels of Dicckopf-1 are increased in patients with thalassemia and osteoporosis. Interestingly, in a placebo-controlled, randomized therapeutic trial a 12-months treatment with zoledronic acid reduced serum Dickkopf-1 levels and increased bone mineral density in these patients

Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration

Dickkopf-1 is an inhibitor of Wnt signaling, which is crucial for osteoblast differentiation. We evaluated serum levels of Dickkopf-1 in 66 patients with thalassemia-induced osteoporosis who received therapy with zoledronic acid in a placebo-controlled, randomized trial. At baseline, thalassemia patients had increased serum levels of Dickkopf-1 that correlated with reduced bone mineral density of the lumbar spine and the distal radius. High Dickkopf-1 also correlated with increased bone resorption and reduced bone formation markets. Zoledronic acid produced a reduction in serum Dickkopf-1, which was associated with bone mineral density increase after 12 months of therapy. On the contrary, placebo group showed a borderline increase of Dickkopf-1, which was higher in patients who showed deterioration in pain scores. These results suggest that Dickkopf-1 is implicated in the pathogenesis of osteoporosis in thalassemia and reveal Dickkopf-1 as a possible target for the development of novel agents for the management of thalassemia-induced osteoporosis (ClinicalTrials. got., Identifier: NCT00346242)