Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.1668F is a founder variant among Ashkenazi Jews (allele frequency of -.2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.Genetics of disease, diagnosis and treatmen

Decrease of antibiotic consumption in children with upper respiratory tract infections after implementation of an intervention program in cyprus

To assess the impact of intervention on antibiotic misuse in children, parents' and pediatricians' knowledge, attitudes, and practices (KAP) concerning antibiotic use were evaluated pre- and postintervention in Larnaca (Cyprus) and Limassol (Cyprus). Concurrently, pediatricians documented upper respiratory tract infection (URTI) visits and pharmacists provided antibiotic consumption data. Intervention was implemented for parents and pediatricians residing in Larnaca. The consumption/URTI incidence index was significantly reduced in Larnaca but not in Limassol. Parental responses to a KAP questionnaire remained unchanged; therefore, antibiotic consumption reduction is attributable to pediatricians' education. Copyright © 2012, American Society for Microbiology. All Rights Reserved

Decrease of Antibiotic Consumption in Children with Upper Respiratory Tract Infections after Implementation of an Intervention Program in Cyprus

To assess the impact of intervention on antibiotic misuse in children, parents' and pediatricians' knowledge, attitudes, and practices (KAP) concerning antibiotic use were evaluated pre- and postintervention in Larnaca (Cyprus) and Limassol (Cyprus). Concurrently, pediatricians documented upper respiratory tract infection (URTI) visits and pharmacists provided antibiotic consumption data. Intervention was implemented for parents and pediatricians residing in Larnaca. The consumption/URTI incidence index was significantly reduced in Larnaca but not in Limassol. Parental responses to a KAP questionnaire remained unchanged; therefore, antibiotic consumption reduction is attributable to pediatricians' education