Paediatrics (RCH) - Research Publications

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    Methodological optimisation of thymocyte isolation and cryopreservation of human thymus samples.
    Hagen, RR ; Xu, C ; Koay, H-F ; Konstantinov, IE ; Berzins, SP ; Kedzierska, K ; van de Sandt, CE (Elsevier BV, 2024-05)
    Premature lymphocytes develop into non-autoreactive, mature naïve CD4+ or CD8+ T cells in the thymus before entering the circulation. However, in-depth characterization of human thymocyte development remains challenging due to limited availability of human thymus samples and the fragile nature of thymocyte populations. Thymocytes often do not survive cryopreservation and thawing procedures, especially the fragile CD4+CD8+ double positive population. It is generally recommended to use fresh human thymus tissue on the day of excision to avoid any biases in thymocyte composition. This hampers the possibility to perform multiple experiments on the same thymus sample. To establish how the thymocyte viability and composition can be maintained, we compared two thymocyte isolation methods used for human and/or mice thymi, three cryopreservation methods in combination with our most gentle thawing technique. Based on our findings we established that fresh human thymi remain viable in cold storage for up to two days post-surgery without compromising thymocyte composition. Thymocytes can be cryopreserved if required, although the CD4+CD8+ double positive populations may be reduced. Our study provides thoroughly optimized methods to study human thymocyte development over a considerable time-frame post-surgery.
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    Cardiometabolic health markers among Aboriginal adolescents from the Next Generation Youth Wellbeing Cohort Study.
    McKay, CD ; Gubhaju, L ; Gibberd, AJ ; McNamara, BJ ; Banks, E ; Azzopardi, P ; Williams, R ; Eades, S (Elsevier BV, 2024-04)
    OBJECTIVE: The objective of this study was to investigate cardiometabolic health markers among Aboriginal adolescents aged 10-24 years and relationships with age, gender, and body composition. METHODS: Baseline data (2018-2020) from the Next Generation Youth Wellbeing Cohort Study (Western Australia, New South Wales, and Central Australia) on clinically assessed body mass index, waist/height ratio, blood pressure, glycated haemoglobin (HbA1c), total and high-density lipoprotein cholesterol, total/high-density lipoprotein cholesterol ratio, and triglycerides were analysed. RESULTS: Among 1100 participants, the proportion with individual health markers within the ideal range ranged from 59% for total cholesterol to 91% for HbA1c. Four percent had high blood pressure, which was more common with increasing age and among males; 1% had HbA1c indicative of diabetes. Healthier body composition (body mass index and waist/height ratio) was associated with having individual health markers in the ideal range and with an ideal cardiometabolic profile. CONCLUSIONS: Most Aboriginal adolescents in this study had cardiometabolic markers within the ideal range, though markers of high risk were present from early adolescence. Ideal health markers were more prevalent among those with healthy body composition. IMPLICATIONS FOR PUBLIC HEALTH: Specific screening and management guidelines for Aboriginal adolescents and population health initiatives that support maintenance of healthy body composition could help improve cardiometabolic health in this population.
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    Understanding cannabis use and mental health difficulties in context with women's experiences of stressful events and social health issues in pregnancy: The Aboriginal Families Study.
    Mensah, FK ; Glover, K ; Leane, C ; Gartland, D ; Nikolof, A ; Clark, Y ; Gee, G ; Brown, SJ (Elsevier BV, 2024-05)
    BACKGROUND: Few population-based data sources fully recognise the intersections between stressful events, social health issues, and cannabis use in pregnancy, and little is known about sequelae for women's mental health. METHODS: We draw on two waves of population-based data for 344 families participating in the Aboriginal Families Study longitudinal cohort. We examine women's mental health in the first year postpartum and when children were aged 5-9 years in context with life experiences and use of cannabis in pregnancy. OUTCOMES: One in five women (19·5%) used cannabis during pregnancy (with or without co-use of tobacco). Within this group of women, 88·3% experienced 3 or more (3+) stressful events or social health issues. Psychological distress (Kessler-5 scale, K-5) in the year postpartum was substantially higher amongst women who had used cannabis or experienced 3+ stressful events or social health issues. High proportions of women met criteria for support and referral for depression and/or anxiety (52·5% of women who had used cannabis compared to 20·9% amongst women who had neither used cannabis nor tobacco; 43·2% of women who had experienced 3+ stressful events or social health issues compared to 15·6% amongst women who had not indicated these experiences). Similar patterns of psychological distress, depressive (9-item adapted Personal Health Questionnaire, aPHQ-9) and anxiety symptoms (7-item Generalised Anxiety Disorder score, GAD-7) were evident when the study children were aged 5-9 years. INTERPRETATION: Amongst women who had used cannabis in pregnancy, a high burden of psychological distress, depression, and anxiety is evident in the postpartum period and as their children turn 5-9 years. The overlay of stressful events and social health issues and the high proportion of women meeting criteria for referral for mental health assessment and support indicate an urgent need to offer women opportunities for safe disclosure of cannabis use and opportunities to access sustained holistic services. Reducing the harms of cannabis use on Aboriginal and Torres Strait Islander families must be coupled with culturally safe ways of addressing the social, historical, and structural determinants of mental health distress and harmful use of substances.
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    Rapid and Accurate Diagnosis of Pediatric Tuberculosis Disease: A Diagnostic Accuracy Study for Pediatric Tuberculosis.
    Olbrich, L ; Nliwasa, M ; Sabi, I ; Ntinginya, NE ; Khosa, C ; Banze, D ; Corbett, EL ; Semphere, R ; Verghese, VP ; Michael, JS ; Graham, SM ; Egere, U ; Schaaf, HS ; Morrison, J ; McHugh, TD ; Song, R ; Nabeta, P ; Trollip, A ; Geldmacher, C ; Hoelscher, M ; Zar, HJ ; Heinrich, N ; RaPaed-AIDA-TB Consortium, (Ovid Technologies (Wolters Kluwer Health), 2023-05-01)
    INTRODUCTION: An estimated 1.2 million children develop tuberculosis (TB) every year with 240,000 dying because of missed diagnosis. Existing tools suffer from lack of accuracy and are often unavailable. Here, we describe the scientific and clinical methodology applied in RaPaed-TB, a diagnostic accuracy study. METHODS: This prospective diagnostic accuracy study evaluating several candidate tests for TB was set out to recruit 1000 children <15 years with presumptive TB in 5 countries (Malawi, Mozambique, South Africa, Tanzania, India). Assessments at baseline included documentation of TB signs and symptoms, TB history, radiography, tuberculin skin test, HIV testing and spirometry. Respiratory samples for reference standard testing (culture, Xpert Ultra) included sputum (induced/spontaneous) or gastric aspirate, and nasopharyngeal aspirate (if <5 years). For novel tests, blood, urine and stool were collected. All participants were followed up at months 1 and 3, and month 6 if on TB treatment or unwell. The primary endpoint followed NIH-consensus statements on categorization of TB disease status for each participant. The study was approved by the sponsor's and all relevant local ethics committees. DISCUSSION: As a diagnostic accuracy study for a disease with an imperfect reference standard, Rapid and Accurate Diagnosis of Pediatric Tuberculosis Disease (RaPaed-TB) was designed following a rigorous and complex methodology. This allows for the determination of diagnostic accuracy of novel assays and combination of testing strategies for optimal care for children, including high-risk groups (ie, very young, malnourished, children living with HIV). Being one of the largest of its kind, RaPaed-TB will inform the development of improved diagnostic approaches to increase case detection in pediatric TB.
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    Championing Health at Hope Street
    Hargreaves, J ; Heerde, J (Council to Homeless Persons, 2024-04-17)
    Prevention and early intervention are vital to reducing homelessness among children and young people. For people under 25 experiencing homelessness and their children, access to timely healthcare is vital to wellbeing. These young people need to be supported through wrap-around service-delivery models that are child and youth specific and tailored to address their health needs. The largest cohort of homeless people in Australia are children and young people (0 to 24 years), making up 37.4 per cent of the homeless.
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    Clinical outcomes in children living with HIV treated for non-severe tuberculosis in the SHINE Trial
    Chabala, C ; Wobudeya, E ; van der Zalm, MM ; Kapasa, M ; Raichur, P ; Mboizi, R ; Palmer, M ; Kinikar, A ; Hissar, S ; Mulenga, V ; Mave, V ; Musoke, P ; Hesseling, AC ; McIlleron, H ; Gibb, D ; Crook, A ; Turkova, A ; SHINE trial team, (Oxford University Press, 2024-04-09)
    BACKGROUND: Children living with HIV(CLWH) are at high risk of tuberculosis(TB) and face poor outcomes, despite antiretroviral treatment(ART). We evaluated outcomes in CLWH and HIV-uninfected children treated for non-severe TB in the SHINE trial. METHODS: SHINE was a randomized trial that enrolled children aged <16 years with smear-negative, non-severe TB who were randomized to receive 4 vs 6 months of TB treatment and followed for 72 weeks. We assessed TB relapse/recurrence, mortality, hospitalizations, grade ≥3 adverse events by HIV status, and HIV virological suppression in CLWH. RESULTS: Of 1204 enrolled, 127(11%) were CLWH, of similar age (median(IQR) 3.6(1.2, 10.3) vs. 3.5(1.5, 6.9)years, p= 0.07), but more underweight (WAZ; -2.3(-3.3, -0.8) vs -1.0(-1.8, -0.2), p<0.01) and anemic (hemoglobin 9.5(8.7, 10.9) vs 11.5(10.4, 12.3)g/dl, p<0.01) compared to HIV-uninfected children. 68(54%) CLWH were ART-naïve; baseline median CD4 count 719(241-1134) cells/mm3, CD4% 16(10-26)%). CLWH were more likely to be hospitalized (aOR=2.4(1.3-4.6)) and die (aHR(95%CI) 2.6(1.2,5.8)). HIV status, age <3 years (aHR 6.3(1.5,27.3)), malnutrition (aHR 6.2(2.4,15.9)) and hemoglobin <7g/dl(aHR 3.8(1.3,11.5) independently predicted mortality. Among children with available VL, 45% and 61% CLWH had VL<1000copies/ml at weeks 24 and 48, respectively. There was no difference in the effect of randomized treatment duration (4 vs 6 months) on TB treatment outcomes by HIV status (p for interaction=0.42). CONCLUSIONS: We found no evidence of a difference in TB outcomes between 4 and 6 months of treatment for CLWH treated for non-severe TB. Irrespective of TB treatment duration, CLWH had higher rates of mortality and hospitalization than HIV-uninfected counterparts.
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    Adverse experiences in early intimate relationships and next-generation infant-mother attachment: findings from the ATP Generation 3 Study
    Opie, J ; Mcintosh, J ; Olsson, CM ; Greenwood, CJ ; Letcher, P ; Tan, E ; Opie, JE ; Booth, A ; Mcintosh, J ; Olsson, CA (WILEY, 2023-12)
    Abstract Chronic insecurities that emerge from adverse experiences in early intimate partner relationships in adolescence and emerging adulthood can have profound impacts on mental health and well‐being. Less clear is the extent to which these experiences for parents impact subsequent relationships within and across generations. We examine the extent to which secure, dismissing, pre‐occupied, and fearful intimate partner relationships in adolescence and emerging adulthood, well before becoming a parent, are associated with next‐generation patterns of attachment between mothers and infant offspring. Data were drawn from a nested study of infant–mother attachment (n = 220) within the Australian Temperament Project Generation 3 Study (N = 1167, est. 1983). Intimate partner relationships in adolescence and young adulthood were assessed by self‐report at 23–24 years of age. Over a decade later, infant–mother attachment security was assessed at 12 months post‐partum. Young adult intimate partner relationships defined by high levels of fearful, pre‐occupied, and dismissing attachment styles were reported in 11%, 17%, and 38% of young mothers, respectively. Increases in fear of intimacy in relationships were associated with an increase in the odds, by around 50%, of infant–mother insecure attachments (vs secure; OR = 1.56, 95% CI = 1.07, 2.28) and disorganised attachments (vs organised; OR = 1.49, 95% CI = 1.00, 2.22). A mother's self‐reported history of fear of intimacy within young adult relationships predicts later insecure and disorganised mother–infant attachments. Guidance and greater support for young people navigating their earliest intimate relationships may not only prevent adverse relational experiences at the time but also on becoming a parent. Findings have relevance for family and infant mental health therapies. Translating these findings into supported conversations may help prevent infant–mother attachment difficulties, or later repair them, through validation of the lingering effects of early fear of intimacy and empowerment of parents to prevent next‐generation infant experiences of distrust.
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    Endophenotyping social cognition in the broader autism phenotype
    Pua, EPK ; Desai, T ; Green, C ; Trevis, K ; Brown, N ; Delatycki, M ; Scheffer, I ; Wilson, S (WILEY, 2023-11-30)
    Relatives of individuals with autism spectrum disorder (ASD) may display milder social traits of the broader autism phenotype (BAP) providing potential endophenotypic markers of genetic risk for ASD. We performed a case-control comparison to quantify social cognition and pragmatic language difficulties in the BAP (n = 25 cases; n = 33 controls) using the Faux Pas test (FPT) and the Goldman-Eisler Cartoon task. Using deep phenotyping we then examined patterns of inheritance of social cognition in two large multiplex families and the spectrum of performance in 32 additional families (159 members; n = 51 ASD, n = 87 BAP, n = 21 unaffected). BAP individuals showed significantly poorer FPT performance and reduced verbal fluency with the absence of a compression effect in social discourse compared to controls. In multiplex families, we observed reduced FPT performance in 89% of autistic family members, 63% of BAP relatives and 50% of unaffected relatives. Across all affected families, there was a graded spectrum of difficulties, with ASD individuals showing the most severe FPT difficulties, followed by the BAP and unaffected relatives compared to community controls. We conclude that relatives of probands show an inherited pattern of graded difficulties in social cognition with atypical faux pas detection in social discourse providing a novel candidate endophenotype for ASD.
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    A novel MYB::PAIP1 oncogenic fusion in pediatric blastic plasmacytoid dendritic cell neoplasm (BPDCN) is dependent on BCL2 expression and is sensitive to venetoclax
    Kosasih, HJ ; Healey, G ; Brennan, MS ; Bjelosevic, S ; Sadras, T ; Jalud, FB ; Ibnat, T ; Ng, AP ; Mayoh, C ; Mao, J ; Tax, G ; Ludlow, LEA ; Johnstone, RW ; Herold, MJ ; Khaw, SL ; de Bock, CE ; Ekert, PG (WILEY, 2024-02)
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    Genetic architecture of childhood speech disorder: a review
    Morgan, AT ; Amor, DJ ; St John, MD ; Scheffer, IE ; Hildebrand, MS (SPRINGERNATURE, 2024-02-16)
    Severe speech disorders lead to poor literacy, reduced academic attainment and negative psychosocial outcomes. As early as the 1950s, the familial nature of speech disorders was recognized, implying a genetic basis; but the molecular genetic basis remained unknown. In 2001, investigation of a large three generational family with severe speech disorder, known as childhood apraxia of speech (CAS), revealed the first causative gene; FOXP2. A long hiatus then followed for CAS candidate genes, but in the past three years, genetic analysis of cohorts ascertained for CAS have revealed over 30 causative genes. A total of 36 pathogenic variants have been identified from 122 cases across 3 cohorts in this nascent field. All genes identified have been in coding regions to date, with no apparent benefit at this stage for WGS over WES in identifying monogenic conditions associated with CAS. Hence current findings suggest a remarkable one in three children have a genetic variant that explains their CAS, with significant genetic heterogeneity emerging. Around half of the candidate genes identified are currently supported by medium (6 genes) to strong (9 genes) evidence supporting the association between the gene and CAS. Despite genetic heterogeneity; many implicated proteins functionally converge on pathways involved in chromatin modification or transcriptional regulation, opening the door to precision diagnosis and therapies. Most of the new candidate genes for CAS are associated with previously described neurodevelopmental conditions that include intellectual disability, autism and epilepsy; broadening the phenotypic spectrum to a distinctly milder presentation defined by primary speech disorder in the setting of normal intellect. Insights into the genetic bases of CAS, a severe, rare speech disorder, are yet to translate to understanding the heritability of more common, typically milder forms of speech or language impairment such as stuttering or phonological disorder. These disorders likely follow complex inheritance with polygenic contributions in many cases, rather than the monogenic patterns that underly one-third of patients with CAS. Clinical genetic testing for should now be implemented for individuals with CAS, given its high diagnostic rate, which parallels many other neurodevelopmental disorders where this testing is already standard of care. The shared mechanisms implicated by gene discovery for CAS highlight potential new targets for future precision therapies.