A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity

Cross-border differences in the prevalence and risk factors for carriage of antimicrobial resistance in children attending daycare centers: a point prevalence study in the Netherlands and Belgium

Background: Day care centres (DCCs) are ideal settings for drug-resistant bacteria to emerge. Prevalence numbers of faecal carriage of antimicrobial resistant bacteria in these settings are rare. We aimed to determine the prevalence of faecal antimicrobial resistant bacteria carriage in children attending DCCs and to assess and identify infection risk factors within DCCs in The Netherlands and Belgium. Methods: A point-prevalence study was conducted in 28 Dutch (499 children) and 18 Belgian (448 children) DCCs. Stool samples were taken from the children’s diapers and a questionnaire was filled in by their parents. Hygiene related to stool and toilet use, hygiene related to food, environmental contamination, hand hygiene and hygiene guidelines were assessed conform a standardized questionnaire by the infection prevention and control expert visiting the DCC. Multilevel logistical regression analyses were used to define which characteristics predicted the presence of extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E), carbapenemase-producing Enterobacterales (CPE), vancomycin-resistant enterococci (VRE), and ciprofloxacin-resistant Enterobacterales (CipR-E). Results: The ESBL-E prevalence was 16% (n = 71) in Belgium and 6% (n = 30) in the Netherlands. The CipR-E prevalence was 17% (n = 78) in Belgium and 8% (n = 38) in the Netherlands. Antimicrobial use (RR: 0.30; 95% CI: 0.33–0.48) and hospital admissions (RR: 0.37; 95% CI: 0.25–0.54) were lower in the Netherlands. Children travelling to Asia were at higher risk of being an ESBL-E carrier. Children using antimicrobials were at higher risk of being a CipR-E carrier. Cleaning the changing mat after each use was found as a protective factor for CipR-E carriage. Conclusions: We established a significant difference in ESBL-E and CipR-E carriage and antimicrobial use and hospital admissions between the Netherlands and Belgium among children attending DCCs. The differences between both countries should be further studied to improve the policy on anti-microbial use and hospital admissions in children