7,12-Dimethylbenz-[a]anthracene (DMBA) is an environmental carcinogen which has a potent ovotoxic affect on rat and mouse ovaries, causing complete follicular depletion resulting in premature ovarian failure. Although the overall effects of DMBA on ovarian folliculogenesis are well known, little is known about the exact molecular mechanisms behind its ovotoxicity. In this study, we characterized the mechanisms behind DMBA-induced ovotoxicity in immature follicles. Microarray analysis of neonatal mouse ovaries exposed to DMBA in vitro revealed a multilayered mechanism of DMBA-induced neonatal ovotoxicity involving a distinct cohort of genes and ovarian signaling pathways primarily associated with follicular atresia, tumorigenesis, and follicular growth. Histomorphological and immunohistological analysis supported the microarray data, showing evidence of primordial follicle activation and preantral follicle atresia both in vitro and in vivo. Further immunohistological analysis identified increased Akt1 phosphorylation, mTOR activation, and decreased FOXO3a expression in DMBA-treated primordial oocytes. Our results reveal a novel mechanism of DMBA-induced preantral ovotoxicity involving selective immature follicle destruction and primordial follicle activation involving downstream members of the PI3K/Akt and mTOR signaling pathways.

The global spread of multidrug-resistant organisms has led to an increase in urinary tract infections (UTIs) in children that are difficult to treat. This review explores the current literature regarding multidrug-resistant UTIs in childhood and proposes an approach to management. Multidrug-resistant organisms include a wide range of potential urinary tract pathogens and, while most literature on drug resistance in UTIs during childhood has focused on extended-spectrum beta-lactamase producing organisms, in this review, we have included a discussion of multidrug resistance including and beyond beta-lactamase production. We provide definitions for multidrug-resistant organisms in line with current consensus guidelines and summarise clinically relevant mechanisms of resistance. Additionally, in this review, we outline the global epidemiology of multidrug-resistant UTIs in children, summarising published prevalence rates, which range from 5 to 90% in different settings. Finally, we also critically review the evidence on risk factors for colonisation and infection of the urinary tract with multidrug-resistant organisms, including prior antibiotic use, hospitalisation and underlying urological malformations. We also highlight multidrug-resistant UTI occurring in children without any identifiable risk factors, reflecting an increasing prevalence of colonisation with these organisms in the general community. Taken as a whole, this emphasises a need for careful and evidence-based use of antibiotics when treating UTIs in children and, to aide clinicians, we have outlined here potential management strategies for when infection with a multidrug-resistant organism is suspected or confirmed.

Background: Infective endocarditis (IE) is a rare entity in children associated with significant morbidity and mortality. To optimize management, it is important to understand local epidemiology, risk factors, clinical features and outcome. These are investigated in this retrospective 10-year study of endocarditis in children in Queensland. Methods: Children <18 years with IE were identified from the statewide pediatric cardiology center (Mater Children's Hospital, 2009 Queensland Children's Hospital, 2014 through International Classification of Diseases codes and local cardiology database. Clinical records were assessed by a clinician and echocardiograms by a cardiologist. Incidence was calculated using Australian Bureau of Statistics Queensland Estimated Resident Population data, 2019.Results: Fifty-one children were identified, with an overall estimated incidence of 0.84 per 100,000 per year; 0.69 per 100,000 in 2009-2013 and 0.99 per 100,000 in 2014-2018, respectively. Twenty-four (47.1%) children were male and 10 (19.6%) were identified as Aboriginal or Torres Strait Islander peoples. Underlying cardiac conditions were present in 29 (56.9%): 25 congenital heart disease, 3 rheumatic heart disease and 1 cardiomyopathy. A causative pathogen was identified in 46 (90.2%) children with Staphylococcus aureus most common. Thirty-six (70.6%) met criteria for "Definite IE" as per modified Duke criteria, with the remainder "Possible IE." Surgery was required in 26 (51%). Median duration of antibiotics was 42 (interquartile range = 32-51) days and hospitalization 49 (interquartile range = 34-75) days. One child died due to IE. Conclusions: IE in children in Queensland is increasing in incidence and is higher than the reported incidence in New Zealand and the United States. Congenital heart disease is the most common risk factor and S. aureus is the commonest responsible organism. Aboriginal or Torres Strait Islander children are over-represented. Mortality remains low.

Children in hospital are frequently prescribed intravenous antibiotics for longer than needed. Programmes to optimise timely intravenous-to-oral antibiotic switch may limit excessive in-hospital antibiotic use, minimise complications of intravenous therapy and allow children to go home faster. Here, we describe a quality improvement approach to implement a guideline, with team-based education, audit and feedback, for timely, safe switch from intravenous-to-oral antibiotics in hospitalised children. Eligibility for switch was based on evidence-based guidelines and supported by education and feedback. The project was conducted over 12 months in a tertiary paediatric hospital. Primary outcomes assessed were the proportion of eligible children admitted under paediatric and surgical teams switched within 24 hours, and switch timing prior to and after guideline launch. Secondary outcomes were hospital length of stay, recommencement of intravenous therapy or readmission. The percentage of children switched within 24 hours of eligibility significantly increased from 32/50 (64%) at baseline to 203/249 (82%) post-implementation (p=0.006). The median time to switch fell from 15 hours 42 min to 4 hours 20 min (p=0.0006). In addition, there was a 14-hour median reduction in hospital length of stay (p=0.008). Readmission to hospital and recommencement of intravenous therapy did not significantly change postimplementation. This education, audit and feedback approach improved timely intravenous-to-oral switch in children and also allowed for more timely discharge from hospital. The study demonstrates proof of concept for this implementation with a methodology that can be readily adapted to other paediatric inpatient settings.