Paediatrics (RCH) - Research Publications

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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.
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    Psychometric Performance Comparison of the Adapted versus Original Versions of the EQ-5D-Y-3L and -Y-5L in Proxy Respondents for 2-to 4-Year-Olds
    van Heusden, A ; Rivero-Arias, O ; Herdman, M ; Hiscock, H ; Devlin, N ; Dalziel, K (ADIS INT LTD, 2024-01-18)
    INTRODUCTION: Few preference-weighted instruments are available to measure health-related quality of life in young children (2-4 years of age). The EQ-5D-Y-3L and EQ-5D-Y-5L were recently modified for this purpose. OBJECTIVE: The aim of this study was to test the psychometric properties of these adapted versions for use with parent proxies of children aged 2-4 years and to compare their performance with the original versions. It was hypothesised that the adapted instrument wording would result in improved psychometric performance. METHODS: Survey data of children aged 2-4 years were obtained from the Australian Paediatric Multi-Instrument Comparison study. Distributional and psychometric properties tested included feasibility, convergence, distribution of level scores, ceiling effects, known-group validity (Cohen's D effect sizes for prespecified groups defined by the presence/absence of special healthcare needs [SHCNs]), test-retest reliability (intraclass correlation coefficients [ICCs]), and responsiveness (standardised response mean [SRM] effect sizes for changes in health). Level sum scores were used to provide summary outcomes. Supplementary analysis using utility scores (from the Swedish EQ-5D-Y-3L value set) were conducted for the adapted and original EQ-5D-Y-3L, and no value sets were available for the EQ-5D-Y-5L. RESULTS: A total of 842 parents of children aged 2-4 years completed the survey. All instruments were easy to complete. There was strong convergence between the adapted and original EQ-5D-Y-3L and EQ-5D-Y-5L. The adapted EQ-5D-Y-3L and adapted EQ-5D-Y-5L showed more responses in the severe levels of the five EQ-5D-Y dimensions, particularly in the usual activity and mobility dimensions (EQ-5D-Y-5L: mobility level 1: adapted n = 478 [83%], original n = 253 [94%]; mobility level 4/5: adapted n = 17 [2.9%], original n = 4 [1.5%)]). The difference in the distribution of responses was more evident in children with SHCNs. Assessment of known-group validity showed a greater effect size for the adapted EQ-5D-Y-3L and adapted EQ-5D-Y-5L compared with the original instruments (EQ-5D-Y-5L: adapted Cohen's D = 1.01, original Cohen's D = 0.83) between children with and without SHCNs. The adapted EQ-5D-Y-3L and adapted EQ-5D-Y-5L showed improved reliability at 4-week follow-up, with improved ICCs (EQ-5D-Y-5L: adapted ICC = 0.83, original ICC = 0.44). The responsiveness of all instruments moved in the hypothesised direction for better or worse health at follow-up. Probability of superiority analysis showed little/no differences between the adapted and original EQ-5D-Y-3L and EQ-5D-Y-5L. Supplementary psychometric analysis of the adapted and original EQ-5D-Y-3L using utilities showed comparable findings with analyses using level sum scores. CONCLUSIONS: The findings suggest improved psychometric performance of the adapted version of the EQ-5D-Y-3L and EQ-5D-Y-5L in children aged 2-4 years compared with the original versions.
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    Confounding-adjustment methods for the causal difference in medians
    Shepherd, DA ; Baer, BR ; Moreno-Betancur, M (BMC, 2023-12-07)
    BACKGROUND: With continuous outcomes, the average causal effect is typically defined using a contrast of expected potential outcomes. However, in the presence of skewed outcome data, the expectation (population mean) may no longer be meaningful. In practice the typical approach is to continue defining the estimand this way or transform the outcome to obtain a more symmetric distribution, although neither approach may be entirely satisfactory. Alternatively the causal effect can be redefined as a contrast of median potential outcomes, yet discussion of confounding-adjustment methods to estimate the causal difference in medians is limited. In this study we described and compared confounding-adjustment methods to address this gap. METHODS: The methods considered were multivariable quantile regression, an inverse probability weighted (IPW) estimator, weighted quantile regression (another form of IPW) and two little-known implementations of g-computation for this problem. Methods were evaluated within a simulation study under varying degrees of skewness in the outcome and applied to an empirical study using data from the Longitudinal Study of Australian Children. RESULTS: Simulation results indicated the IPW estimator, weighted quantile regression and g-computation implementations minimised bias across all settings when the relevant models were correctly specified, with g-computation additionally minimising the variance. Multivariable quantile regression, which relies on a constant-effect assumption, consistently yielded biased results. Application to the empirical study illustrated the practical value of these methods. CONCLUSION: The presented methods provide appealing avenues for estimating the causal difference in medians.
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    On the use of multiple imputation to address data missing by design as well as unintended missing data in case-cohort studies with a binary endpoint
    Middleton, M ; Nguyen, C ; Carlin, JB ; Moreno-Betancur, M ; Lee, KJ (BMC, 2023-12-07)
    BACKGROUND: Case-cohort studies are conducted within cohort studies, with the defining feature that collection of exposure data is limited to a subset of the cohort, leading to a large proportion of missing data by design. Standard analysis uses inverse probability weighting (IPW) to address this intended missing data, but little research has been conducted into how best to perform analysis when there is also unintended missingness. Multiple imputation (MI) has become a default standard for handling unintended missingness and is typically used in combination with IPW to handle the intended missingness due to the case-control sampling. Alternatively, MI could be used to handle both the intended and unintended missingness. While the performance of an MI-only approach has been investigated in the context of a case-cohort study with a time-to-event outcome, it is unclear how this approach performs with a binary outcome. METHODS: We conducted a simulation study to assess and compare the performance of approaches using only MI, only IPW, and a combination of MI and IPW, for handling intended and unintended missingness in the case-cohort setting. We also applied the approaches to a case study. RESULTS: Our results show that the combined approach is approximately unbiased for estimation of the exposure effect when the sample size is large, and was the least biased with small sample sizes, while MI-only and IPW-only exhibited larger biases in both sample size settings. CONCLUSIONS: These findings suggest that a combined MI/IPW approach should be preferred to handle intended and unintended missing data in case-cohort studies with binary outcomes.
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    Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis
    Albers, FEM ; Lou, MWC ; Dashti, SG ; Swain, CTV ; Rinaldi, S ; Viallon, V ; Karahalios, A ; Brown, KA ; Gunter, MJ ; Milne, RL ; English, DR ; Lynch, BM (SPRINGER, 2024-02-16)
    PURPOSE: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. METHODS: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. RESULTS: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). CONCLUSION: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.
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    Changing climates, compounding challenges: a participatory study on how disasters affect the sexual and reproductive health and rights of young people in Fiji.
    Murphy, N ; Rarama, T ; Atama, A ; Kauyaca, I ; Batibasaga, K ; Azzopardi, P ; Bowen, KJ ; Bohren, MA (BMJ, 2023-12-16)
    Pacific youth are at the forefront of the climate crisis, which has important implications for their health and rights. Youth in Fiji currently bear a disproportionate burden of poor experiences and outcomes related to their sexual and reproductive health and rights (SRHR). There is limited information about how the increasing climate impacts may affect their SRHR, and what the implications may be for climate action and disaster risk reduction. We aimed to explore the experiences of 21 Fijian youth in fulfilling their SRHR when living through multiple natural hazards. We conducted 2 workshops and 18 individual semistructured interviews using visual and storytelling methods. Irrespective of the type of hazard or context of disasters, participants identified limited agency as the main challenge that increased SRHR risks. Through reflexive thematic analysis, we identified four themes centred around 'youth SRHR agency'; (1) information and knowledge, (2) community and belonging, (3) needs and resources, and (4) collective risks. These themes encompassed multiple factors that limited youth agency and increased their SRHR risks. Participants highlighted how existing challenges to their SRHR, such as access to SRHR information being controlled by community gatekeepers, and discrimination of sexual and gender diverse youth, were exacerbated in disasters. In disaster contexts, immediate priorities such as water, food and financial insecurity increased risks of transactional early marriage and transactional sex to access these resources. Daily SRHR risks related to normalisation of sexual and gender-based violence and taboos limited youth agency and influenced their perceptions of disasters and SRHR risks. Findings offer important insights into factors that limited youth SRHR agency before, during and after disasters. We underscore the urgency for addressing existing social and health inequities in climate and disaster governance. We highlight four key implications for reducing youth SRHR risks through whole-of-society approaches at multiple (sociocultural, institutional, governance) levels.
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    Kidney organoids reveal redundancy in viral entry pathways during ACE2-dependent SARS-CoV-2 infection
    Vanslambrouck, JM ; Neil, JA ; Rudraraju, R ; Mah, S ; Tan, KS ; Groenewegen, E ; Forbes, TA ; Karavendzas, K ; Elliott, DA ; Porrello, ER ; Subbarao, K ; Little, MH ; Liu, S-L (AMER SOC MICROBIOLOGY, 2024-03-19)
    UNLABELLED: With a high incidence of acute kidney injury among hospitalized COVID-19 patients, considerable attention has been focussed on whether SARS-CoV-2 specifically targets kidney cells to directly impact renal function, or whether renal damage is primarily an indirect outcome. To date, several studies have utilized kidney organoids to understand the pathogenesis of COVID-19, revealing the ability for SARS-CoV-2 to predominantly infect cells of the proximal tubule (PT), with reduced infectivity following administration of soluble ACE2. However, the immaturity of standard human kidney organoids represents a significant hurdle, leaving the preferred SARS-CoV-2 processing pathway, existence of alternate viral receptors, and the effect of common hypertensive medications on the expression of ACE2 in the context of SARS-CoV-2 exposure incompletely understood. Utilizing a novel kidney organoid model with enhanced PT maturity, genetic- and drug-mediated inhibition of viral entry and processing factors confirmed the requirement for ACE2 for SARS-CoV-2 entry but showed that the virus can utilize dual viral spike protein processing pathways downstream of ACE2 receptor binding. These include TMPRSS- and CTSL/CTSB-mediated non-endosomal and endocytic pathways, with TMPRSS10 likely playing a more significant role in the non-endosomal pathway in renal cells than TMPRSS2. Finally, treatment with the antihypertensive ACE inhibitor, lisinopril, showed negligible impact on receptor expression or susceptibility of renal cells to infection. This study represents the first in-depth characterization of viral entry in stem cell-derived human kidney organoids with enhanced PTs, providing deeper insight into the renal implications of the ongoing COVID-19 pandemic. IMPORTANCE: Utilizing a human iPSC-derived kidney organoid model with improved proximal tubule (PT) maturity, we identified the mechanism of SARS-CoV-2 entry in renal cells, confirming ACE2 as the sole receptor and revealing redundancy in downstream cell surface TMPRSS- and endocytic Cathepsin-mediated pathways. In addition, these data address the implications of SARS-CoV-2 exposure in the setting of the commonly prescribed ACE-inhibitor, lisinopril, confirming its negligible impact on infection of kidney cells. Taken together, these results provide valuable insight into the mechanism of viral infection in the human kidney.