Abstract Background Diagnosing urinary tract infections (UTIs) in children in the emergency department (ED) is challenging due to the variable clinical presentations and difficulties in obtaining a urine sample free from contamination. Clinicians need to weigh a range of observations to make timely diagnostic and management decisions, a difficult task to achieve without support due to the complex interactions among relevant factors. Directed acyclic graphs (DAG) and causal Bayesian networks (BN) offer a way to explicitly outline the underlying disease, contamination and diagnostic processes, and to further make quantitative inference on the event of interest thus serving as a tool for decision support. Methods We prospectively collected data on children present to ED with suspected UTIs. Through knowledge elicitation workshops and one-on-one meetings, a DAG was co-developed with domain experts (the Expert DAG) to describe the causal relationships among variables relevant to paediatric UTIs. The Expert DAG was combined with prospective data and further domain knowledge to inform the development of an application-oriented BN (the Applied BN), designed to support the diagnosis of UTI. We assessed the performance of the Applied BN using quantitative and qualitative methods. Results We summarised patient background, clinical and laboratory characteristics of 431 episodes of suspected UTIs enrolled from May 2019 to November 2020. The Expert DAG was presented with a narrative description, elucidating how infection, specimen contamination and management pathways causally interact to form the complex picture of paediatric UTIs. Parameterised using prospective data and expert-elicited parameters, the Applied BN achieved an excellent and stable performance in predicting E.coli culture results, with a mean AUROC of 0.86 and a mean log loss of 0.48 based on 10-fold cross-validation. The BN predictions were reviewed via a validation workshop, and we illustrate how they can be presented for decision support using three hypothetical clinical scenarios. Conclusion Causal BNs created from both expert knowledge and data can integrate case-specific information to provide individual decision support during the diagnosis of paediatric UTIs in ED. The model aids the interpretation of culture results and the diagnosis of UTIs, promising the prospect of improved patient care and judicious use of antibiotics.
Staphylococcus aureus is a common cause of community and health care–associated bacteremia, with authors of recent studies estimating the incidence of S aureus bacteremia (SAB) in high-income countries between 8 and 26 per 100 000 children per year. Despite this, <300 children worldwide have ever been randomly assigned into clinical trials to assess the efficacy of treatment of SAB. A panel of infectious diseases physicians with clinical and research interests in pediatric SAB identified 7 key clinical questions. The available literature is systematically appraised, summarizing SAB management in children in relation to these priority clinical questions. The management of neonates, children, and adolescents with SAB is predominantly based on clinical experience and trial data extrapolated from adult studies, with limited high-quality evidence available to guide management. The optimal, comprehensive management strategies for SAB in children will remain unknown until the questions outlined are answered through prospective observational cohorts and inclusion of children with SAB in clinical trials.
Aim To explore immunisation rates and catch‐up delivery to children admitted to hospital before and after an immunisation service was commenced. Methods This pre‐ and post‐intervention study examined 300 admissions prior to (cohort 1) and 300 following (cohort 2) the introduction of an immunisation service. Immunisation rates, documentation, catch‐up delivery and accuracy of the Australian Immunisation Register (AIR) were examined. Results On admission, 75% (cohort 1) and 89% (cohort 2) were up‐to‐date with immunisations. Immunisation history was documented in the medical record in 78% and requirement for catch‐up documented in 10%. AIR was incorrect in one‐third of cases. By 3 months following discharge, 28% (cohort 1) and 64% (cohort 2) of patients were immunised. Conclusions Children admitted to hospital have lower immunisation rates than the national average. Documentation was poor, opportunities for catch‐up were missed and AIR is error‐prone. Catch‐up rates increased following the introduction of an immunisation service.
Abstract Introduction: Estrogen receptor 1 (ER/ESR1) mutations have arisen as key biomarkers for endocrine therapy resistance in ER positive (ER+) breast cancer (BC) patients: detecting these mutations is key to guiding researchers to better understand acquired resistance during treatment. Ongoing clinical trials, which explore the prevalence of ESR1 mutations under various treatments, commonly use next-generation sequencing (NGS)-based assays. However, the NGS panels available are costly, can have long turnaround times and require specialist equipment and software. Research use only digital PCR assays are also available but have similar drawbacks to NGS. A targeted qPCR-based assay is more time and cost effective, and does not require specialist equipment. Here, we demonstrate the APIS ESR1 Mutations Kit, a targeted, sensitive, and robust qualitative qPCR assay able to detect eleven ESR1 mutations across ESR1 exons 5 (E380Q), 7 (S463P) and 8 (P535H, L536R, L536Q, L536H, L536P, Y537C, Y537S, Y537N and D538G). The assay is designed to assess circulating-free DNA (cfDNA) samples, reducing the need for invasive procedures in clinical settings and can make use of standard cfDNA extraction kits. Therefore, the APIS ESR1 Mutations Kit provides the flexibility for researchers in any conventional molecular biology laboratory to explore ESR1 mutations with high sensitivity and specificity. Methods: The APIS ESR1 Mutations Kit provides all components and controls required to assess samples. For kit development, mutation-specific DNA fragments were spiked into wildtype background DNA (either cfDNA extracted from pooled healthy donor plasma, human genomic DNA, or DNA fragments); the Limit of Blank (LoB) and Limit of Detection (LoD) were determined using these samples. To determine linearity, a dilution series of DNA fragments ranging from 5 to 10,000 copies per reaction was assessed. All PCR runs were performed using a QuantStudio™5 Dx (ThermoFisher) instrument. Results: The performance studies showed the APIS ESR1 Mutations Kit can detect D538G at 0.4 % mutant allele frequency (MAF) and Y537S at 0.06 % MAF. All other mutations can be detected at ≤ 1.0 % MAF. By using clamp and blocking technologies, each design is mutation specific, enabling identification of specific amino acid mutations. In addition, the assays can perform in high wild-type backgrounds, enabling lower limit of blanks with ≥95% confidence and threshold cut-offs to enhance the sensitivity of the assay. The linearity of each target is within 90-110% from 50 to 10,000 copies per reaction. Conclusions: The ESR1 Mutations Kit demonstrated high sensitivity and performance as a qualitative qPCR assay to detect eleven ESR1 mutations. Table. Mutations detected with the APIS ESR1 Mutations Kit Citation Format: Anna Gasior, Colette Whitfield, Anita Campbell, Christine Hoy, Sally Holdsworth, Jesse Mukose, Ryan Nana, Sahar Shammakhi, Benjamin Scales, Joanna Gorniak. Design and Development of the APIS ESR1 Mutations Kit to Detect Eleven Mutations Relevant to Acquired Endocrine Therapy Resistance [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-08.
Staphylococcus aureus bacteraemia (SAB) causes considerable morbidity and mortality in children. Despite this, its epidemiology and risk factors are poorly understood, with minimal paediatric clinical trial data available to guide clinicians in management. We conducted a pilot study to characterise SAB and validate a severity classification for use in future clinical trials. Patients with SAB were prospectively identified at Princess Margaret Hospital for Children (Perth, Western Australia) from May 2011 to December 2013. Retrospective data were collected from clinical and laboratory records. Cases were classified based on a priori defined criteria as simple (single or contiguous, peripheral site focus) or complex (multi-site, deep tissue, no focus or sepsis) and tested against risk factors and markers of severity of infection. There were 49 cases of SAB (median age 7.7 years), with classification as simple (n = 30, 61%) and complex (n = 19, 39%) respectively. There were no deaths or relapses in our cohort. Only 10% of isolates were methicillin resistant S. aureus (MRSA), and none of these were healthcare-associated. Age, gender, Indigenous status, MRSA and healthcare-associated infections were not predictive of complex infection. Pre-existing malignancy was a risk factor for complex infection (p = 0.02). Complex infections were associated with a higher median maximum C reactive protein (216 mg/L vs 50 mg/L, p = < 0.001), longer median length of stay (42 vs 10 days, p = < 0.001) and longer duration of antibiotic therapy (43 vs 34 days, p = 0.03). This is the first attempt to categorise paediatric SAB as simple versus complex, to guide clinicians in decision making. There is a wide spectrum of disease severity in paediatric SAB, with maximum CRP, length of stay, and duration of therapy greater in those with complex disease. Distinct cohorts with simple and complex courses which may be a target for future clinical trials have been described.
Skin scar formation following Bacille Calmette-Guérin (BCG) or smallpox (Vaccinia) vaccination is an established marker of successful vaccination and 'vaccine take'. Potent pathogen-specific (tuberculosis; smallpox) and pathogen-agnostic (protection from diseases unrelated to the intentionally targeted pathogen) effects of BCG and smallpox vaccines hold significant translational potential. Yet despite their use for centuries, how scar formation occurs and how local skin-based events relate to systemic effects that allow these two vaccines to deliver powerful health promoting effects has not yet been determined. We review here what is known about the events occurring in the skin and place this knowledge in the context of the overall impact of these two vaccines on human health with a particular focus on maternal-child health.
Aim To describe the clinical epidemiology of children receiving cochlear implants, as well as the management and outcomes of cochlear implant infections and adherence to infection prevention measures. Methods A retrospective observational study was conducted in children ≤18 years who received cochlear implants in Western Australia's tertiary paediatric hospital. Information was obtained from medical and laboratory records regarding demographics, indication for implant, implant infection and preoperative Staphylococcus aureus screening/decolonisation. Immunisation history was examined using the Australian Immunisation Register. Results Overall, 118 children received cochlear implants, with 158 devices inserted (599 cochlear implant insertion‐years). An implant infection rate of 3.8% (6/158) was identified during the study period (four pneumococcal and two community‐acquired methicillin resistant S. aureus infections). All required surgical management, with an overall median duration of antibiotic therapy of 37 days (interquartile range (IQR) 29–48) and median length of stay of 8 days (IQR 8–9.5). All devices were retained and there were no relapses or deaths. Half of the children who developed cochlear implant infections (50%, 3/6) were up‐to‐date with additional pneumococcal vaccinations and no children (0%, 0/118) received S. aureus screening/decolonisation before implant insertion. Conclusions Favourable outcomes were achieved with cochlear implant retention; however, the treatment was burdensome for families. We demonstrate significant scope to improve adherence to existing infection prevention strategies and provide direction for optimising preventative measures in the future. These include ensuring parental education, additional pneumococcal vaccinations and S. aureus decolonisation which are delivered as an infection prevention bundle to the growing population of infants receiving cochlear implants.
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