Proarrhythmia assessment in treatment with hydroxychloroquine and azithromycin hospitalized elderly COVID-19 patients - our experience

The aim of our study was to characterize the repolarization disorders propensity induced by drug-drug interaction. In this observational retrospective study, we report our experience on all elderly patients with ascertained diagnosis of coronavirus disease 2019 through nasopharyngeal swab with real time-polymerase chain reaction at our Pugliese-Ciaccio hospital in Catanzaro, who received hydroxychloroquine (HCQ), with or without azithromycin (AZY). 33 hospitalized patients were examined. We calculated QT value, cQT, QT dispersion, and cQT dispersion and examined possible progression on the basal electrocardiogram (T0) and after the insertion of the drug (T1). The QT value is increased by T0 vs T1 (370±40.74 vs 420±36.91 ms; P=0.000), as well as the cQT value (408±25.40 vs 451.54±58.81; P=0.003), the QT dispersion (QTd: 36.36±14.53 vs 50.90±13.12 ms; P=0.000); the dispersion of cQTc (cQTd 46.27±18.72 vs 63.18±21.93 ms; P=0.001). The ΔQT was 37.44±44.09 while the ΔcQT was 32.01±56.47). The main determinant of QTc prolongation is the number of drug at risk of prolongation of the QT that could influence the ventricular repolarization phase. The use of HCQ in combination with AZY, in patients suffering from severe acute respiratory syndrome-related coronavirus-2, can favor the onset of serious side effects, even potentially fatal. Finally, the measures of QTd and cQTd confirmed additional electrocardiographic parameters useful in identifying patients being treated with drugs at risk of potential adverse arrhythmic events following drug interaction

Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD

Introduction: Despite the progress made in the study of Facioscapulohumeral Dystrophy (FSHD), the wide heterogeneity of disease complicates its diagnosis and the genotype-phenotype correlation among patients and within families. In this context, the present work employed Whole Exome Sequencing (WES) to investigate known and unknown genetic contributors that may be involved in FSHD and may represent potential disease modifiers, even in presence of a D4Z4 Reduced Allele (DRA).Methods: A cohort of 126 patients with clinical signs of FSHD were included in the study, which were characterized by D4Z4 sizing, methylation analysis and WES. Specific protocols were employed for D4Z4 sizing and methylation analysis, whereas the Illumina® Next-Seq 550 system was utilized for WES. The study included both patients with a DRA compatible with FSHD diagnosis and patients with longer D4Z4 alleles. In case of patients harboring relevant variants from WES, the molecular analysis was extended to the family members.Results: The WES data analysis highlighted 20 relevant variants, among which 14 were located in known genetic modifiers (SMCHD1, DNMT3B and LRIF1) and 6 in candidate genes (CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1). Most of them were found together with a permissive short (4–7 RU) or borderline/long DRA (8–20 RU), supporting the possibility that different genes can contribute to disease heterogeneity in presence of a FSHD permissive background. The segregation and methylation analysis among family members, together with clinical findings, provided a more comprehensive picture of patients.Discussion: Our results support FSHD pathomechanism being complex with a multigenic contribution by several known (SMCHD1, DNMT3B, LRIF1) and possibly other candidate genes (CTCF, DNMT1, DNMT3A, EZH2, SUV39H1) to disease penetrance and expressivity. Our results further emphasize the importance of extending the analysis of molecular findings within the proband’s family, with the purpose of providing a broader framework for understanding single cases and allowing finer genotype-phenotype correlations in FSHD-affected families