Paediatrics (RCH) - Research Publications
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ItemHigher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children(Rockefeller University Press, 2024-01-04)We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-α2 in 10 patients: IFN-α2 only in three, IFN-α2 plus IFN-ω in five, and IFN-α2, IFN-ω plus IFN-β in two; IFN-ω only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-α2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-ω in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-α2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-ω only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-ω and/or IFN-α2.
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ItemDevelopment of tuberculosis treatment decision algorithms in children below 5 years hospitalised with severe acute malnutrition in Zambia and Uganda: a prospective diagnostic cohort study(Elsevier, 2024-07-01)Background: In children with severe acute malnutrition (SAM) tuberculosis is common, challenging to diagnose, and often fatal. We developed tuberculosis treatment decision algorithms (TDAs) for children under the age of 5 years with SAM. Methods: In this prospective diagnostic study, we enrolled and followed up children aged <60 months hospitalised with SAM at three tertiary hospitals in Zambia and Uganda from 4 November 2019 to 20 June 2022. We included children aged 2–59 months with SAM as defined by WHO and hospitalised following the WHO clinical criteria. We excluded children with current or history of antituberculosis treatment within the preceding 3 months. They underwent tuberculosis symptom screening, clinical assessment, chest X-ray, abdominal ultrasound, Xpert MTB/RIF Ultra (Ultra) and culture on respiratory and stool samples with 6 months follow-up. Tuberculosis was retrospectively defined using the 2015 standard case definition for childhood tuberculosis. We used logistic regression to develop diagnostic prediction models for a one-step diagnosis and a two-step screening and diagnostic approaches. We derived scores from models using WHO-recommended thresholds for sensitivity and proposed TDAs. This study is registered with ClinicalTrials.gov, NCT04240990. Findings: Of 1906 children hospitalised with SAM during the study period, 1230 were screened, 1152 were eligible and 603 were enrolled. Of the 603 children enrolled–median age 15 (inter-quartile range (IQR): 11–20) months and 65 (11.0%) living with HIV–114 (18.9%) were diagnosed with tuberculosis, including 51 (8.5%) with microbiological confirmation and 104 (17.2%) initiated treatment at a median of 6(IQR: 2–10) days after inclusion. 108 children were retrospectively classified as having tuberculosis resulting in a prevalence of 17.9% (95% confidence intervals (CI): 15.1; 21.2). 75 (69.4%) children with tuberculosis reported cough of any duration, 32 (29.6%) cough ≥2 weeks and 11 (10.2%) tuberculosis contact history. 535 children had complete data and were included in the diagnostic prediction model. The one-step diagnostic model had 15 predictors, including Ultra, clinical, radiographic, and abdominal features, an area under the receiving operating curve (AUROC) of 0.910, and derived TDA sensitivity of 86.14% (95% CI: 78.07–91.56) and specificity of 80.88% (95% CI: 76.91–84.30). The two-step model had AUROCs of 0.750 and 0.912 for screening and diagnosis, respectively, and derived combined TDA sensitivity of 79.21% (95% CI: 70.30–85.98) and a specificity of 83.64% (95% CI: 79.87–86.82). Interpretation: Tuberculosis prevalence was high among hospitalised children with SAM, with atypical clinical features. TDAs achieved satisfactory diagnostic accuracy and could be used to improve diagnosis in this vulnerable group.
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ItemSatisfaction, disappointment and regret surrounding fertility preservation decisions in the paediatric and adolescent cancer population(SPRINGER/PLENUM PUBLISHERS, 2019-09)PURPOSE: With over 80% of paediatric and adolescent cancer patients surviving into adulthood, quality-of-life issues such as future fertility are increasingly important. However, little is known about regret around decisions to pursue or forgo fertility preservation (FP). We investigated the risk of decision regret in families involved in making a FP decision and explored contributive factors. METHODS: Parents and patients ≥ 15 years were invited to participate. Participants completed a 10-item survey, including a validated Decision Regret Scale. Scores ≥ 30 indicated high regret. Free-text response items allowed participants to provide reasons for satisfaction or regret. RESULTS: A total of 108 parents and 30 patients participated. Most (81.4%) reported low regret (mean score 13.7). On multivariate analysis, predictors of low regret included having a FP procedure and a fertility discussion pre-treatment. Most participants believed that FP offers hope for future fertility. Some reported dissatisfaction with the process of decision-making. CONCLUSION: Overall levels of regret in the study population were low, with factors associated with quality, timely discussion and belief in the success of FP technology being predictors of low regret. However, dissatisfaction with the decision-making process itself revealed that refinements to the programme are required to meet families' needs.
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ItemPredicting successful sperm retrieval in transfeminine adolescents after testicular biopsy(SPRINGER/PLENUM PUBLISHERS, 2021-10)PURPOSE: Increasing numbers of transgender adolescents are receiving gender-affirming treatments (GAT). Given GAT can impair reproductive function, clinical guidelines advise prior counselling regarding fertility preservation (FP). For transgender adults assigned male at birth, FP is usually achieved via a masturbatory sample and sperm cryopreservation. This is less straightforward in transgender adolescents, since they may not be developmentally ready to masturbate and/or masturbation may cause unacceptable gender dysphoria. Testicular biopsy represents an alternative method for sperm retrieval in these adolescents, but for those in early/mid puberty, it is difficult to predict whether sperm will be found. The purpose of this study was therefore to identify factors that predict successful sperm retrieval for cryopreservation via testicular biopsy. METHODS: A retrospective cohort study was undertaken at a tertiary-referral pediatric gender service. Subjects were included if they'd received a testicular biopsy in association with the commencement of GAT between 2010 and 2019. The primary outcome measure was successful sperm retrieval, and potential predictors included age, testicular volume and serum testosterone, LH and FSH levels. RESULTS: Of 25 subjects who received a biopsy prior to starting any GAT, 17 had successful sperm retrieval. While age, testosterone, LH and FSH levels showed minimal differences, testicular volume was significantly higher in those with successful sperm retrieval, and a threshold of ≥ 10 mL showed 92% sensitivity and 71% specificity in predicting successful retrieval. An additional 6 patients received a biopsy after starting puberty suppression and before commencement of oestrogen, and one of these individuals had sperm successfully retrieved despite > 2 years of regular puberty suppression. CONCLUSION: These findings suggest that testicular volume is most useful in predicting successful sperm retrieval following testicular biopsy in transgender adolescents and are likely to be of relevance to other young people undertaking FP, including those with cancer.
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ItemThe Australian New Zealand Consortium in Children, Adolescents, and Young Adults Oncofertility action plan(WILEY, 2024-07)International and national oncofertility networks, including the US-led Oncofertility Consortium, FertiProtekt, and the Danish Network, have played pivotal roles in advancing the discipline of oncofertility over the last decade. Many other countries lack a shared approach to pediatric oncofertility health service delivery. This study aims to describe baseline oncofertility practices at Australian New Zealand Children's Haematology/Oncology Group centers in 2019-2021, describe binational priorities for care, and propose a 5-year action plan for best practice to be implemented by the newly formed Australian New Zealand Consortium in Children, Adolescents, and Young Adults (CAYA) Oncofertility (ANZCO).
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ItemPediatric Tuberculosis: A Review of Evidence-Based Best Practices for Clinicians and Health Care Providers(MDPI AG, 2024)Advances in pediatric TB care are promising, the result of decades of advocacy, operational and clinical trials research, and political will by national and local TB programs in high-burden countries. However, implementation challenges remain in linking policy to practice and scaling up innovations for prevention, diagnosis, and treatment of TB in children, especially in resource-limited settings. There is both need and opportunity to strengthen clinician confidence in making a TB diagnosis and managing the various manifestations of TB in children, which can facilitate the translation of evidence to action and expand access to new tools and strategies to address TB in this population. This review aims to summarize existing guidance and best practices for clinicians and health care providers in low-resource, TB-endemic settings and identify resources with more detailed and actionable information for decision-making along the clinical cascade to prevent, find, and cure TB in children.
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ItemNon-communicable disease mortality in young people with a history of contact with the youth justice system in Queensland, Australia: a retrospective, population-based cohort study(ELSEVIER SCI LTD, 2023-08)BACKGROUND: Young people who have had contact with the criminal justice system are at increased risk of early death, especially from injuries. However, deaths due to non-communicable diseases (NCDs) in this population remain poorly described. We aimed to estimate mortality due to NCDs in people with a history of involvement with the youth justice system, compare NCD mortality rates in this population with those in the general population, and characterise demographic and justice-related factors associated with deaths caused by NCDs in people with a history of contact with the youth justice system. METHODS: In this retrospective, population-based cohort study (the Youth Justice Mortality [YJ-Mort] study), we included all people aged 10-18 years (at baseline) charged with a criminal offence in Queensland, Australia, between June 30, 1993, and July 1, 2014. We probabilistically linked youth justice records with adult correctional records and national death records up to Jan 31, 2017. Indigenous status was ascertained from youth justice and adult correctional records, with individuals identified as Indigenous in either source classified as Indigenous in the final dataset. We estimated crude mortality rates and standardised mortality ratios (SMRs) for comparisons with data from the Australian general population. We identified risk factors for NCD deaths using competing-risks regression. FINDINGS: Of 48 670 individuals aged 10-18 years (at baseline) charged with a criminal offence in Queensland, Australia, between June 30, 1993, and July 1, 2014, 11 897 (24·4%) individuals were female, 36 773 (75·6%) were male, and 13 250 (27·2%) were identified as identified as Indigenous. The median age at first contact with the youth justice system was 15 years (IQR 14-16), the median follow-up time was 13·4 years (8·4-18·4), and the median age at the end of the study was 28·6 years (23·6-33·6). Of 1431 deaths, 932 (65·1%) had a known and attributed cause, and 121 (13·0%) of these were caused by an NCD. The crude mortality rate from NCDs was 18·5 (95% CI 15·5-22·1) per 100 000 person-years among individuals with a history of involvement with the youth justice system, which was higher than among the age-matched and sex-matched Australian general population (SMR 1·67 [1·39-1·99]). Two or more admissions to adult custody (compared with none; adjusted sub-distribution hazard ratio 2·09 [1·36-3·22]), and up to 52 weeks in adult custody (compared with none; 1·98 [1·18-3·32]) was associated with NCD death. INTERPRETATION: Young people with a history of contact with the justice system are at increased risk of death from NCDs compared with age-matched and sex-matched peers in the general Australian population. Reducing youth incarceration and providing young people's rights to access clinical, preventive, and restorative services should be a priority. FUNDING: National Health and Medical Research Council.
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ItemPatient experiences and perceived value of genetic testing in inherited retinal diseases: a cross-sectional survey(NATURE PORTFOLIO, 2024-03-05)This study evaluated patient experiences with genetic testing for inherited retinal diseases (IRDs) and the association between underlying knowledge, testing outcomes, and the perceived value of the results. An online survey was distributed to adults with IRDs and parents/guardians of dependents with IRDs who had had genetic testing. Data included details of genetic testing, pre- and post- test perceptions, Decision Regret Scale, perceived value of results, and knowledge of gene therapy. Of 135 responses (85% from adults with IRDs), genetic testing was primarily conducted at no charge through public hospitals (49%) or in a research setting (30%). Key motivations for genetic testing were to confirm IRD diagnosis and to contribute towards research. Those who had received a genetic diagnosis (odds ratio: 6.71; p < 0.001) and those self-reported to have good knowledge of gene therapy (odds ratio: 2.69; p = 0.018) were more likely to have gained confidence in managing their clinical care. For over 80% of respondents, knowing the causative gene empowered them to learn more about their IRD and explore opportunities regarding clinical trials. Key genetic counselling information needs include resources for family communications, structured information provision, and ongoing genetic support, particularly in the context of emerging ocular therapies, to enhance consistency in information uptake.
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ItemEliciting parental preferences and values for the return of additional findings from genomic sequencing(NATURE PORTFOLIO, 2024-02-14)Health economic evidence is needed to inform the design of high-value and cost-effective processes for returning genomic results from analyses for additional findings (AF). This study reports the results of a discrete-choice experiment designed to elicit preferences for the process of returning AF results from the perspective of parents of children with rare conditions and to estimate the value placed on AF analysis. Overall, 94 parents recruited within the Australian Genomics and Melbourne Genomics programmes participated in the survey, providing preferences in a total of 1128 choice scenarios. Statistically significant preferences were identified for the opportunity to change the choices made about AF; receiving positive AF in person from a genetic counsellor; timely access to a medical specialist and high-quality online resources; receiving automatic updates through a secure online portal if new information becomes available; and lower costs. For AF uptake rates ranging between 50-95%, the mean per person value from AF analysis was estimated at AU$450-$1700 (US$300-$1140). The findings enable the design of a value-maximising process of analysis for AF in rare-disease genomic sequencing.
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ItemInter-species gene flow drives ongoing evolution of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis(NATURE PORTFOLIO, 2024-03-13)Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection with invasive disease incidence and clinical manifestations comparable to the closely related species, Streptococcus pyogenes. Through systematic genomic analyses of 501 disseminated SDSE strains, we demonstrate extensive overlap between the genomes of SDSE and S. pyogenes. More than 75% of core genes are shared between the two species with one third demonstrating evidence of cross-species recombination. Twenty-five percent of mobile genetic element (MGE) clusters and 16 of 55 SDSE MGE insertion regions were shared across species. Assessing potential cross-protection from leading S. pyogenes vaccine candidates on SDSE, 12/34 preclinical vaccine antigen genes were shown to be present in >99% of isolates of both species. Relevant to possible vaccine evasion, six vaccine candidate genes demonstrated evidence of inter-species recombination. These findings demonstrate previously unappreciated levels of genomic overlap between these closely related pathogens with implications for streptococcal pathobiology, disease surveillance and prevention.