Paediatrics (RCH) - Research Publications

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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.
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    Trusting relationships and learning together: A rapid review of Indigenous reference groups in Australian Indigenous health research
    D'Aprano, A ; Lloyd-Johnsen, C ; Cameron, D ; Wunungmurra, A ; Hull, C ; Boyle, C ; Naylon, M ; Brunette, R ; Campbell, J ; Matthews, V (ELSEVIER SCIENCE INC, 2023-06)
    OBJECTIVE: This rapid review aims to identify how Indigenous research governance is conceptualised, implemented and documented within Australian Indigenous health research studies. METHODS: We searched for peer-reviewed English-language articles in two databases and for web-based grey literature published from database inception to November 2021. Reference lists were searched to identify additional articles. Data relating to research governance were extracted and analysed thematically. RESULTS: A total of 1120 records were screened, and 27 articles were included. Most articles providing detailed description of Indigenous research governance activities were qualitative studies (n=15, 55.6%). Key themes included members are experts; respectful relationships; flexibility; and key logistic considerations (nuts 'n' bolts). CONCLUSIONS: Although Indigenous research governance is recognised as an essential part of ethical research, activities and contributions made by Indigenous reference group (IRG) members are underreported. This important work needs greater visibility in the published literature to share best practice in Indigenous research governance that foregrounds Indigenous expert knowledge, perspectives, and experiences. IMPLICATIONS FOR PUBLIC HEALTH: The study provides a synthesis of factors to consider when establishing and facilitating an IRG for research with Indigenous communities. This has implications for researchers who can adapt and apply the findings to their practice.
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    Expanding the phenotype of Kleefstra syndrome: speech, language and cognition in 103 individuals
    Morison, LD ; Kennis, MGP ; Rots, D ; Bouman, A ; Kummeling, J ; Palmer, E ; Vogel, AP ; Liegeois, F ; Brignell, A ; Srivastava, S ; Frazier, Z ; Milnes, D ; Goel, H ; Amor, DJ ; Scheffer, IE ; Kleefstra, T ; Morgan, AT (BMJ PUBLISHING GROUP, 2024-01-30)
    OBJECTIVES: Speech and language impairments are core features of the neurodevelopmental genetic condition Kleefstra syndrome. Communication has not been systematically examined to guide intervention recommendations. We define the speech, language and cognitive phenotypic spectrum in a large cohort of individuals with Kleefstra syndrome. METHOD: 103 individuals with Kleefstra syndrome (40 males, median age 9.5 years, range 1-43 years) with pathogenic variants (52 9q34.3 deletions, 50 intragenic variants, 1 balanced translocation) were included. Speech, language and non-verbal communication were assessed. Cognitive, health and neurodevelopmental data were obtained. RESULTS: The cognitive spectrum ranged from average intelligence (12/79, 15%) to severe intellectual disability (12/79, 15%). Language ability also ranged from average intelligence (10/90, 11%) to severe intellectual disability (53/90, 59%). Speech disorders occurred in 48/49 (98%) verbal individuals and even occurred alongside average language and cognition. Developmental regression occurred in 11/80 (14%) individuals across motor, language and psychosocial domains. Communication aids, such as sign and speech-generating devices, were crucial for 61/103 (59%) individuals including those who were minimally verbal, had a speech disorder or following regression. CONCLUSIONS: The speech, language and cognitive profile of Kleefstra syndrome is broad, ranging from severe impairment to average ability. Genotype and age do not explain the phenotypic variability. Early access to communication aids may improve communication and quality of life.
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    Stuttering associated with a pathogenic variant in the chaperone protein cyclophilin 40
    Morgan, AT ; Scerri, TS ; Vogel, AP ; Reid, CA ; Quach, M ; Jackson, VE ; McKenzie, C ; Burrows, EL ; Bennett, MF ; Turner, SJ ; Reilly, S ; Horton, SE ; Block, S ; Kefalianos, E ; Frigerio-Domingues, C ; Sainz, E ; Rigbye, KA ; Featherby, TJ ; Richards, KL ; Kueh, A ; Herold, MJ ; Corbett, MA ; Gecz, J ; Helbig, I ; Thompson-Lake, DGY ; Liegeois, FJ ; Morell, RJ ; Hung, A ; Drayna, D ; Scheffer, IE ; Wright, DK ; Bahlo, M ; Hildebrand, MS (OXFORD UNIV PRESS, 2023-12-01)
    Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.
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    Parental Mental Health and Parenting Behaviors Following Very Preterm Birth: Associations in Mothers and Fathers and Implications for Child Cognitive Outcome.
    McMahon, GE ; Treyvaud, K ; Spittle, AJ ; Giallo, R ; Lee, KJ ; Cheong, JL ; Doyle, LW ; Spencer-Smith, MM ; Anderson, PJ (Oxford University Press (OUP), 2023-03-20)
    OBJECTIVES: To investigate the longitudinal associations between parental mental health symptoms within 4 weeks of birth, parenting behaviors at 1 year, and child general cognitive ability at 4.5-5 years in a sample of children born very preterm (VP). This study also examined whether these associations differed based on level of family social risk. METHODS: Participants were 143 children born <30 weeks' gestation and their parents. Within 4 weeks of birth, mothers' and fathers' depressive and anxiety symptoms were assessed using the Center for Epidemiologic Studies Depression Scale and Hospital Anxiety Depression Scale-Anxiety Subscale. Parents' sensitive and structuring parenting behaviors were assessed at 1 year using the Emotional Availability Scales. Child general cognitive ability was assessed at 4.5-5 years using the Wechsler Preschool & Primary Scale of Intelligence-Fourth Edition. RESULTS: Higher maternal depressive symptoms were associated with lower levels of sensitive and structuring parenting behavior, while higher maternal anxiety symptoms were associated with higher levels of structuring parenting behavior. There was weak evidence for positive associations between mothers' sensitive parenting behavior and fathers' structuring parenting behavior and child general cognitive ability. There was also weak evidence for stronger associations between mothers' mental health symptoms, parenting behaviors, and child general cognitive ability, in families of higher compared with lower social risk. CONCLUSIONS: Depressive and anxiety symptoms experienced by mothers in the initial weeks following VP birth can have long-term effects on their parenting behaviors. Enquiring about parents' mental health during their child's hospitalization in the neonatal intensive care unit is crucial.
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    Association of maternal air pollution exposure and infant lung function is modified by genetic propensity to oxidative stress.
    Vilcins, D ; Lee, WR ; Pham, C ; Tanner, S ; Knibbs, LD ; Burgner, D ; Blake, TL ; Mansell, T ; Ponsonby, A-L ; Sly, PD ; Barwon Infant Study Investigator group, (Cold Spring Harbor Laboratory, 2023-10-13)
    INTRODUCTION: The association between air pollution and poor respiratory health outcomes is well established, however less is known about the biological mechanisms, especially in early life. Children are particularly at risk from air pollution, especially during the prenatal period as their organs and systems are still undergoing crucial development. Therefore, our study aims to investigate if maternal exposure to air pollution during pregnancy is associated with oxidative stress (OS) and inflammation in pregnancy or infant lung function at 4 weeks of age, and the extent to which the association is modified by an infant's genetic risk of OS. METHODS: The Barwon Infant Study (BIS) is a longitudinal study of Australian children from the region of Geelong, Victoria. A total of 314 infants had available lung function and maternal OS markers. Exposure to annual air pollutants (NO 2 and PM 2.5 ) were estimated using validated, satellite-based, land-use regression models. Infant lung function was measured by multiple-breath washout, and the ratio of peak tidal expiratory flow over expiratory time was calculated at 4 weeks of age. An inflammation biomarker, glycoprotein acetyls (GlycA), was measured in maternal (36 weeks) and cord blood, and oxidative stress (OS) biomarkers, 8-hydroxyguanine (8-OHGua) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured in maternal urine at 28 weeks. A genetic pathway score for OS (gPFS ox ) was calculated for each infant participant in the BIS cohort, and high risk defined as score >8. Linear regression was used to explore the association of maternal air pollution exposure with infant lung function, and potential modification by OS genotype was tested through use of interaction terms and other methods. RESULTS: There was no evidence of a relationship between maternal exposure to air pollution and infant lung function in the whole population. We did not find an association between air pollution and GlycA or OS during pregnancy. We found evidence of an association between NO 2 and lower in functional residual capacity (FRC) for children with a high genetic risk of OS (β=-5.3 mls, 95% CI (-9.3, -1.3), p=0.01). We also found that when NO 2 was considered in tertiles, the highest tertile of NO 2 was associated with increase in lung clearance index (LCI) (β=0.46 turnovers, (95% CI 0.10, 0.82), p=0.01) in children with a genetic propensity to OS. CONCLUSION: Our study found that high prenatal levels of exposure to ambient NO 2 levels is associated with lower FRC and higher LCI in infants with a genetic propensity to oxidative stress. There was no relationship between maternal exposure to air pollution with maternal and cord blood inflammation or OS biomarkers.
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    Youth Participatory Research Needed to Keep Time Ticking Forward
    Sawyer, SM ; Begun, S (ELSEVIER SCIENCE INC, 2023-12)
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    Household income supplements in early childhood to reduce inequities in children's development
    Goldfeld, S ; Downes, M ; Gray, S ; Pham, C ; Guo, S ; O'Connor, E ; Redmond, G ; Azpitarte, F ; Badland, H ; Woolfenden, S ; Williams, K ; Priest, N ; O'Connor, M ; Moreno-Betancur, M (PERGAMON-ELSEVIER SCIENCE LTD, 2024-01)
    BACKGROUND: Early childhood interventions have the potential to reduce children's developmental inequities. We aimed to estimate the extent to which household income supplements for lower-income families in early childhood could close the gap in children's developmental outcomes and parental mental health. METHODS: Data were drawn from a nationally representative birth cohort, the Longitudinal Study of Australian Children (N = 5107), which commenced in 2004 and conducted follow-ups every two years. Exposure was annual household income (0-1 year). Outcomes were children's developmental outcomes, specifically social-emotional, physical functioning, and learning (bottom 15% versus top 85%) at 4-5 years, and an intermediate outcome, parental mental health (poor versus good) at 2-3 years. We modelled hypothetical interventions that provided a fixed-income supplement to lower-income families with a child aged 0-1 year. Considering varying eligibility scenarios and amounts motivated by actual policies in the Australian context, we estimated the risk of poor outcomes for eligible families under no intervention and the hypothetical intervention using marginal structural models. The reduction in risk under intervention relative to no intervention was estimated. RESULTS: A single hypothetical supplement of AU$26,000 (equivalent to ∼USD$17,350) provided to lower-income families (below AU$56,137 (∼USD$37,915) per annum) in a child's first year of life demonstrated an absolute reduction of 2.7%, 1.9% and 2.6% in the risk of poor social-emotional, physical functioning and learning outcomes in children, respectively (equivalent to relative reductions of 12%, 10% and 11%, respectively). The absolute reduction in risk of poor mental health in eligible parents was 1.0%, equivalent to a relative reduction of 7%. Benefits were similar across other income thresholds used to assess eligibility (range, AU$73,329-$99,864). CONCLUSIONS: Household income supplements provided to lower-income families may benefit children's development and parental mental health. This intervention should be considered within a social-ecological approach by stacking complementary interventions to eliminate developmental inequities.
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    Higher versus lower nasal continuous positive airway pressure for extubation of extremely preterm infants in Australia (ÉCLAT): a multicentre, randomised, superiority trial
    Kidman, AM ; Manley, BJ ; Boland, RA ; Malhotra, A ; Donath, SM ; Beker, F ; Davis, PG ; Bhatia, R (ELSEVIER SCI LTD, 2023-12)
    BACKGROUND: Extremely preterm infants often require invasive mechanical ventilation, and clinicians aim to extubate these infants as soon as possible. However, extubation failure occurs in up to 60% of extremely preterm infants and is associated with increased mortality and morbidity. Nasal continuous positive airway pressure (nCPAP) is the most common post-extubation respiratory support, but there is no consensus on the optimal nCPAP level to safely avoid extubation failure in extremely preterm infants. We aimed to determine if higher nCPAP levels compared with standard nCPAP levels would decrease rates of extubation failure in extremely preterm infants within 7 days of their first extubation. METHODS: In this multicentre, randomised, open-label controlled trial done at three tertiary perinatal centres in Australia, we assigned extremely preterm infants to extubation to either higher nCPAP (10 cmH2O) or standard nCPAP (7 cmH2O). Infants were eligible if they were born at less than 28 weeks' gestation, were receiving mechanical ventilation via an endotracheal tube, and were being extubated for the first time to nCPAP. Eligible infants must have received previous treatment with exogenous surfactant and caffeine. Infants were ineligible if they were planned to be extubated to a mode of respiratory support other than nCPAP, if they had a known major congenital anomaly that might affect breathing, or if ongoing intensive care was not being provided. Parents or guardians provided prospective, written, informed consent. Infants were maintained within an assigned nCPAP range for a minimum of 24 h after extubation (higher nCPAP group 9-11 cmH2O and standard nCPAP group 6-8 cmH2O). Randomisation was stratified by both gestation (22-25 completed weeks or 26-27 completed weeks) and recruiting centre. The primary outcome was extubation failure within 7 days and analysis was by intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12618001638224. FINDINGS: Between March 3, 2019, and July 31, 2022, 483 infants were born at less than 28 weeks and admitted to the recruiting centres. 92 infants were not eligible, 172 were not approached, 65 families declined to participate, and 15 consented but were not randomly assigned. 139 infants were enrolled and randomly assigned, 70 to the higher nCPAP group and 69 to the standard nCPAP group. One infant in the higher nCPAP group was excluded from the analysis because consent was withdrawn after randomisation. 104 (75%) of 138 mothers were White. The mean gestation was 25·7 weeks (SD 1·3) and the mean birthweight was 777 grams (201). 70 (51%) of 138 infants were female. Extubation failure occurred in 24 (35%) of 69 infants in the higher nCPAP group and in 39 (57%) of 69 infants in the standard nCPAP group (risk difference -21·7%, 95% CI -38·5% to -3·7%). There were no significant differences in rates of adverse events between groups during the primary outcome period. Three patients died (two in the higher nCPAP group and one in the standard nCPAP group), pneumothorax occurred in one patient from each group, spontaneous intestinal perforation in three patients (two in the higher nCPAP group and one in the standard nCPAP group) and there were no events of pulmonary interstitial emphysema. INTERPRETATION: Extubation of extremely preterm infants to higher nCPAP significantly reduced extubation failure compared with extubation to standard nCPAP, without increasing rates of adverse effects. Future larger trials are essential to confirm these findings in terms of both efficacy and safety. FUNDING: National Health and Medical Research Council Centre for Research Excellence in Newborn Medicine, number 1153176.
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    A gene therapy targeting medium-chain acyl-CoA dehydrogenase (MCAD) did not protect against diabetes-induced cardiac pathology
    Weeks, KL ; Kiriazis, H ; Wadley, GD ; Masterman, EI ; Sergienko, NM ; Raaijmakers, AJA ; Trewin, AJ ; Harmawan, CA ; Yildiz, GS ; Liu, Y ; Drew, BG ; Gregorevic, P ; Delbridge, LMD ; McMullen, JR ; Bernardo, BC (SPRINGER HEIDELBERG, 2024-01)
    Diabetic cardiomyopathy describes heart disease in patients with diabetes who have no other cardiac conditions but have a higher risk of developing heart failure. Specific therapies to treat the diabetic heart are limited. A key mechanism involved in the progression of diabetic cardiomyopathy is dysregulation of cardiac energy metabolism. The aim of this study was to determine if increasing the expression of medium-chain acyl-coenzyme A dehydrogenase (MCAD; encoded by Acadm), a key regulator of fatty acid oxidation, could improve the function of the diabetic heart. Male mice were administered streptozotocin to induce diabetes, which led to diastolic dysfunction 8 weeks post-injection. Mice then received cardiac-selective adeno-associated viral vectors encoding MCAD (rAAV6:MCAD) or control AAV and were followed for 8 weeks. In the non-diabetic heart, rAAV6:MCAD increased MCAD expression (mRNA and protein) and increased Acadl and Acadvl, but an increase in MCAD enzyme activity was not detectable. rAAV6:MCAD delivery in the diabetic heart increased MCAD mRNA expression but did not significantly increase protein, activity, or improve diabetes-induced cardiac pathology or molecular metabolic and lipid markers. The uptake of AAV viral vectors was reduced in the diabetic versus non-diabetic heart, which may have implications for the translation of AAV therapies into the clinic. KEY MESSAGES: The effects of increasing MCAD in the diabetic heart are unknown. Delivery of rAAV6:MCAD increased MCAD mRNA and protein, but not enzyme activity, in the non-diabetic heart. Independent of MCAD enzyme activity, rAAV6:MCAD increased Acadl and Acadvl in the non-diabetic heart. Increasing MCAD cardiac gene expression alone was not sufficient to protect against diabetes-induced cardiac pathology. AAV transduction efficiency was reduced in the diabetic heart, which has clinical implications.