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Item Metadata only Non-invasive, label-free optical analysis to detect aneuploidy within the inner cell mass of the preimplantation embryo(Oxford University Press (OUP), 2021) Tan, C.Y.; Mahbub, S.B.; Campugan, C.A.; Campbell, J.; Habibalahi, A.; Chow, D.J.X.; Mustafa, S.; Goldys, E.M.; Dunning, K.R.; 37th Annual Meeting of the European Society of Human Reproduction and Embryology (26 Jun 2021 - 1 Jul 2021 : virtual online)Abstract not availableItem Open Access Mechanics of Small-Scale Spherical Inclusions Using Nonlocal Poroelasticity Integrated with Light Gradient Boosting Machine(MDPI AG, 2024) Farajpour, A.; Ingman, W.V.Detecting inclusions in materials at small scales is of high importance to ensure the quality, structural integrity and performance efficiency of microelectromechanical machines and products. Ultrasound waves are commonly used as a non-destructive method to find inclusions or structural flaws in a material. Mathematical continuum models can be used to enable ultrasound techniques to provide quantitative information about the change in the mechanical properties due to the presence of inclusions. In this paper, a nonlocal size-dependent poroelasticity model integrated with machine learning is developed for the description of the mechanical behaviour of spherical inclusions under uniform radial compression. The scale effects on fluid pressure and radial displacement are captured using Eringen’s theory of nonlocality. The conservation of mass law is utilised for both the solid matrix and fluid content of the poroelastic material to derive the storage equation. The governing differential equations are derived by decoupling the equilibrium equation and effective stress–strain relations in the spherical coordinate system. An accurate numerical solution is obtained using the Galerkin discretisation technique and a precise integration method. A Dormand–Prince solution is also developed for comparison purposes. A light gradient boosting machine learning model in conjunction with the nonlocal model is used to extract the pattern of changes in the mechanical response of the poroelastic inclusion. The optimised hyperparameters are calculated by a grid search cross validation. The modelling estimation power is enhanced by considering nonlocal effects and applying machine learning processes, facilitating the detection of ultrasmall inclusions within a poroelastic medium at micro/nanoscales.Item Open Access Dynamic regulation of semaphorin 7A and adhesion receptors in ovarian follicle remodeling and ovulation(Frontiers Media S.A., 2023) Emery, A.; Dunning, K.R.; Dinh, D.T.; Akison, L.K.; Robker, R.L.; Russell, D.L.The ovarian follicle is a complex structure that protects and helps in the maturation of the oocyte, and then releases it through the controlled molecular and structural remodeling process of ovulation. The progesterone receptor (PGR) has been shown to be essential in regulating ovulation-related gene expression changes. In this study, we found disrupted expression of the cellular adhesion receptor gene Sema7A in the granulosa cells of PGR-/- mice during ovulation. We subsequently found that expression of Sema7A in preovulatory follicles is promoted by gonadotropins and hypoxia, establishing an asymmetrical pattern with the SEMA7A protein enriched at the apex of large antral follicles. Sema7A expression was downregulated through a PGR-dependent mechanism in the periovulatory period, the abundance of SEMA7A protein was reduced, and the asymmetric pattern became more homogeneous after an ovulatory stimulus. Receptors for Sema7A can either repel or promote intercellular adhesion. During ovulation, striking inverse regulation of repulsive Plxnc1 and adhesive Itga5/Itgb1 receptors likely contributes to dramatic tissue remodeling. The adhesive receptor Itga5 was significantly increased in periovulatory granulosa cells and cumulus-oocyte complexes (COCs), and functional assays showed that periovulatory granulosa cells and COCs acquire increased adhesive phenotypes, while Sema7A repels granulosa cell contact. These findings suggest that the regulation of Sema7A and its associated receptors, along with the modulation of integrin α5, may be critical in establishing the multilaminar ovarian follicle structure and facilitating the remodeling and apical release of the cumulus-oocyte complex during ovulation.Item Open Access UVA Hyperspectral Light-Sheet Microscopy for Volumetric Metabolic Imaging: Application to Preimplantation Embryo Development(American Chemical Society, 2023) Morizet, J.; Chow, D.; Wijesinghe, P.; Schartner, E.; Dwapanyin, G.; Dubost, N.; Bruce, G.D.; Anckaert, E.; Dunning, K.; Dholakia, K.Cellular metabolism is a key regulator of energetics, cell growth, regeneration, and homeostasis. Spatially mapping the heterogeneity of cellular metabolic activity is of great importance for unraveling the overall cell and tissue health. In this regard, imaging the endogenous metabolic cofactors, nicotinamide adenine dinucleotide (phosphate) (NAD- (P)H) and flavin adenine dinucleotide (FAD), with subcellular resolution and in a noninvasive manner would be useful to determine tissue and cell viability in a clinical environment, but practical use is limited by current imaging techniques. In this paper, we demonstrate the use of phasor-based hyperspectral light-sheet (HS-LS) microscopy using a single UVA excitation wavelength as a route to mapping metabolism in three dimensions. We show that excitation solely at a UVA wavelength of 375 nm can simultaneously excite NAD(P)H and FAD autofluorescence, while their relative contributions can be readily quantified using a hardware-based spectral phasor analysis. We demonstrate the potential of our HS-LS system by capturing dynamic changes in metabolic activity during preimplantation embryo development. To validate our approach, we delineate metabolic changes during preimplantation embryo development from volumetric maps of metabolic activity. Importantly, our approach overcomes the need for multiple excitation wavelengths, two-photon imaging, or significant postprocessing of data, paving the way toward clinical translation, such as in situ, noninvasive assessment of embryo viability.Item Open Access Compromised transcription-mRNA export factor THOC2 causes R-loop accumulation, DNA damage and adverse neurodevelopment(Nature, 2024) Bhattacharjee, R.; Jolly, L.A.; Corbett, M.A.; Wee, I.C.; Rao, S.R.; Gardner, A.E.; Ritchie, T.; van Hugte, E.J.H.; Ciptasari, U.; Piltz, S.; Noll, J.E.; Nazri, N.; van Eyk, C.L.; White, M.; Fornarino, D.; Poulton, C.; Baynam, G.; Collins-Praino, L.E.; Snel, M.F.; Nadif Kasri, N.; et al.We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37–38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37–38 deletion male (Thoc2Δ/Y) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.Item Metadata only Bi-allelic variants in the neuronal cell adhesion molecule NRCAM lead to a novel neurodevelopmental disorder characterized by developmental delay, hypotonia, peripheral neuropathy or spasticity(Springer, 2023) Kurolap, A.; Kreuder, F.; Gonzaga-Jauregui, C.; Duvdevani, M.P.; Harel, T.; Tammer, L.; Xin, B.; Bakhtiari, S.; Rice, J.; van Eyk, C.; Gecz, J.; Mah, J.K.; Atkinson, D.; Cope, H.; Sullivan, J.A.; Douek, A.M.; Colquhoun, D.; Henry, J.; Wlodkowic, D.; Parman, Y.; et al.; 55th European Society of Human Genetics Conference (ESHG) (11 Jun 2022 - 14 Jun 2022 : Vienna, Austria & virtual online)Item Open Access Anxiety and Depression in Early Gestation and the Association with Subsequent Gestational Diabetes Mellitus in a Disadvantaged Population(Springer, 2023) Pathirana, M.M.; Andraweera, P.H.; Leemaqz, S.; Aldridge, E.; Arstall, M.A.; Dekker, G.A.; Roberts, C.T.Objectives: Evaluate the association between poor mental health and risk of developing gestational diabetes mellitus (GDM) in a cohort of women from a socioeconomically disadvantaged community. Methods: A total of 1363 nulliparous women with singleton pregnancies recruited to the Screening Tests to Predict Poor Outcomes of Pregnancy study in Adelaide, Australia. Women were assessed for mental health in the first trimester, including likelihood of depression, high functioning anxiety, perceived stress and risk of developing a mental health disorder. GDM was diagnosed based on the International Association of Diabetes in Pregnancy Study Group (IADPSG) criteria. Socioeconomic status was measured using the New Zealand Socioeconomic Index (NZSEI). Results: Complete mental health data was available for 1281 participants. There was no statistically significant difference in SEI, depression, risk of mental health issues, high functioning anxiety and perceived stress between women who developed GDM and those who did not. There was no difference in history of depression nor risk of developing a high mental health disorder in first trimester after adjusting for SEI, BMI in first trimester, smoking status in first trimester and maternal age between women with a GDM pregnancy and those who did not. Conclusions for Practice: There was no difference in markers of poor mental health in early pregnancy between women who subsequently did or did not develop GDM. Cohort participants were socioeconomically disadvantaged, potentially contributing to the lack of apparent differences in depression observed between groups. Socioeconomically disadvantaged women should be targeted in pre-conception planning to reduce risk of GDM.Item Open Access Agreement of Clinician-Administered and Modified Parent-Administered House-Brackmann Scales in Children with Bell's Palsy(SAGE Publishing, 2023) Babl, F.E.; Eapen, N.; Herd, D.; Borland, M.L.; Kochar, A.; Zhang, M.; Oakley, E.; Hopper, S.M.; Berkowitz, R.G.; Wilson, C.L.; Williams, A.; Mackay, M.T.; Lee, K.J.; Hearps, S.Objective. Currently there is no parent administered scale for facial nerve function in children. We set out to assess the agreement between a newly developed parent-administered modified version of the House-Brackmann (HB) scale and the standard clinician-administered HB scale in children with Bell's palsy. Study Design. Secondary analysis of a triple-blind, randomized, placebo-controlled trial of corticosteroids to treat idiopathic facial paralysis (Bell's palsy) in children (6 months to <18 years). Setting. Multicenter study at pediatric hospitals with recruitment in emergency departments. Methods. Children were recruited within 72 hours of symptom onset and assessed using the clinicianadministered and the parent-administered modified HB scales at baseline, and at 1, 3, and 6 months until recovered. Agreement between the 2 scales was assessed using intraclass coefficient (ICC) and a Bland-Altman plot. Results. Data were available for 174 of the 187 children randomized from at least 1 study time point. The mean ICC between clinician and parent HB scores across all time points was 0.88 (95% confidence interval, CI: 0.86, 0.90). The ICC for the data collected at baseline was 0.53 (95% CI: 0.43, 0.64), at 1 month was 0.88 (95% CI: 0.84, 0.91), at 3 months was 0.80 (95% CI: 0.71, 0.87) and at 6 months was 0.73 (95% CI: 0.47, 0.89). A Bland-Altman plot indicated a mean difference between the 2 scores (clinician-reported minus parent-reported) of only −0.07 (95% limits of agreement −1.37 to 1.23). Conclusion. There was good agreement between the modified parent-administered and the clinician-administered HB scales.Item Open Access A Quality Improvement Initiative to Reduce Blood Culture Contamination in the Neonatal Unit(Wolters Kluwer, 2021) Allen, E.; Cavallaro, A.; Keir, A.K.Introduction: Peripheral blood culture contamination (BCC) can lead to an initiation of unnecessary antimicrobial treatment, further laboratory tests, increased length of stay, and increased costs. This study describes a 12-month quality improvement (QI) program to reduce the BCC rate in a neonatal unit by 50%. Methods: The QI team focused on standardizing processes to align with best practices using process mapping and cause and effect diagrams. Plan-Do-Study-Act (PDSA) 1: inoculation of blood culture bottles with the introduction of transfer device; PDSA 2: preparation of the skin for peripheral intravenous cannula insertion; PDSA 3: aseptic technique education package; and PDSA 4: optimizing blood volume of blood collected for culture. The team used statistical process control methodology to detect special cause variation. Results: Compliance with the standard processes as part of PSDA 1 improved from a mean level of 50% to 100% and for PDSA 2 improved from a mean level of 50% to 95%. After implementation of PDSA 3, scores on a relevant knowledge test increased from a mean of 39% (pretraining test; n = 10) to 92% (posttraining test; n = 10) (P < 0.001). Postimplementation of the processes for PDSA 4, a minimum of 1 mL was collected in 94% of blood culture collection events (n = 450) (mean 1.1 mL; range 0.5–3.5 mL). Special cause variation occurred after the implementation of the PDSA cycles. During the baseline period, the BCC rate was 2.0% and decreased to 1.0% postinterventions implementation. Conclusions: Interventions focused on standardizing practices around collection of blood cultures in neonates were associated with fewer contaminants. This study is reported according to the SQUIRE 2.0 guidelines.Item Open Access Iron-fortified foods are needed to meet the Estimated Average Requirement for iron in Australian infants 6-12 months(Oxford University Press (OUP), 2023) Moumin, N.A.; Grieger, J.A.; Netting, M.J.; Makrides, M.; Green, T.J.Background: Meeting iron intake recommendations is challenging for infants 6–12 mo, especially breastfed infants. Three-quarters of Australian infants 6–12 mo have iron intakes below the estimated average requirement (7 mg), placing them at risk of iron deficiency. After 6 mo, breastmilk is no longer sufficient to meet the increased demand for iron, and iron-rich complementary foods are recommended. Ironfortified foods may be a means of improving iron intake in infants, particularly those that are breastfed. Objectives: The aims of the study were as follows: 1) to examine the effect of milk-type and fortified foods on iron intake and the prevalence of inadequacy in infants 6–12 mo; 2) to model the effect of fixed amounts of iron-fortified infant cereal (IFIC) at 6 levels of iron fortification on total iron intake and the prevalence of inadequacy; and 3) to assess the effect IFIC on the intake of other nutrients in the diet. Design: Secondary analysis of cross-sectional dietary intake data of infants 6–12 mo (n ¼ 286) participating in the Australian Feeding Infants and Toddlers Study (OzFITS) 2021. Results: Median (interquartile range) iron intake was 8.9 (7.5, 10.3); 6.3 (4.5, 8.2); and 2.7 (1.5, 4.4) mg/d in formula-fed, combinationfed, and breastfed infants, respectively. The corresponding prevalence of inadequacy was 19%, 67%, and 96%. Infants who consumed fortified foods had higher median iron intakes than those who did not, 6.2 compared with 1.9 mg/d. Dietary modeling showed that consuming 18 g (300 kJ) of IFIC, fortified at 35 mg/100 g dry weight, reduces the prevalence of inadequacy for iron from 75% to 5% for all infants. Conclusions: Iron intakes are low in Australian infants, especially for breastfed infants in the second half of infancy. Modeling shows that 300 kJ of IFIC, the current manufacturer-recommended serving, fortified at 35 mg/100 g dry weight, added to infant diets would be an effective means to reduce the prevalence of inadequacy for iron.Item Open Access The collective burden of childhood dementia: a scoping review(Oxford University Press (OUP), 2023) Elvidge, K.L.; Christodoulou, J.; Farrar, M.A.; Tilden, D.; Maack, M.; Valeri, M.; Ellis, M.; Smith, N.J.C.; Childhood, D.W.G.Childhood dementia is a devastating and under-recognised group of disorders with a high level of unmet need. Typically monogenic in origin, this collective of individual neurodegenerative conditions are defined by a progressive impairment of neurocognitive function, presenting in childhood and adolescence. This scoping review aims to clarify definitions and conceptual boundaries of childhood dementia and quantify the collective disease burden. A literature review identified conditions that met the case definition. An expert clinical working group reviewed and ratified inclusion. Epidemiological data were extracted from published literature and collective burden modelled. One hundred and seventy genetic childhood dementia disorders were identified. Of these, 25 were analysed separately as treatable conditions. Collectively, currently untreatable childhood dementia was estimated to have an incidence of 34.5 per 100,000 (1 in 2,900 births), median life expectancy of 9 years and prevalence of 5.3 per 100,000 persons. The estimated number of premature deaths per year is similar to childhood cancer (0-14 years) and approximately 70% of those deaths will be prior to adulthood. An additional 49.8 per 100,000 births are attributable to treatable conditions that would cause childhood dementia if not diagnosed early and stringently treated. A relational database of the childhood dementia disorders has been created and will be continually updated as new disorders are identified (https://knowledgebase.childhooddementia.org/). We present the first comprehensive overview of monogenic childhood dementia conditions and their collective epidemiology. Unifying these conditions, with consistent language and definitions, reinforces motivation to advance therapeutic development and health service supports for this significantly disadvantaged group of children and their families.Item Open Access Neuroimaging Findings in Axenfeld-Rieger Syndrome: A Case Series(American Society of Neuroradiology, 2023) White, S.; Taranath, A.; Hanagandi, P.; Taranath, D.A.; To, M.-S.; Souzeau, E.; Siggs, O.M.; Craig, J.E.Axenfeld-Rieger syndrome is an autosomal dominant condition associated with multisystemic features including developmental anomalies of the anterior segment of the eye. Single nucleotide and copy number variants in the paired-like homeodomain transcription factor 2 (PITX2) and forkhead box C1 (FOXC1) genes are associated with Axenfeld-Rieger syndrome as well as other CNS malformations. We determined the association between Axenfeld-Rieger syndrome and specific brain MR imaging neuroradiologic anomalies in cases with or without a genetic diagnosis. This case series included 8 individuals with pathogenic variants in FOXC1; 2, in PITX2; and 2 without a genetic diagnosis. The most common observation was vertebrobasilar artery dolichoectasia, with 46% prevalence. Other prevalent abnormalities included WM hyperintensities, cerebellar hypoplasia, and ventriculomegaly. Vertebrobasilar artery dolichoectasia and absent/hypoplastic olfactory bulbs were reported in >50% of individuals with FOXC1 variants compared with 0% of PITX2 variants. Notwithstanding the small sample size, neuroimaging abnormalities were more prevalent in individuals with FOXC1 variants compared those with PITX2 variants.Item Metadata only Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers(Massachusetts Medical Society, 2023) Pittet, L.F.; Messina, N.L.; Orsini, F.; Moore, C.L.; Abruzzo, V.; Barry, S.; Bonnici, R.; Bonten, M.; Campbell, J.; Croda, J.; Dalcolmo, M.; Gardiner, K.; Gell, G.; Germano, S.; Gomes-Silva, A.; Goodall, C.; Gwee, A.; Jamieson, T.; Jardim, B.; Kollmann, T.R.; et al.BACKGROUND: The bacille Calmette–Guérin (BCG) vaccine has immunomodulatory “off-target” effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], −0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, −1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.)Item Metadata only Reply(Elsevier, 2018) Palmer, D.; Prescott, S.; Makrides, M.Item Metadata only Association of reaction symptoms and eliciting dose with health-related quality of life in children with peanut allergy(Elsevier, 2023) Hu, A.; Lloyd, M.; Loke, P.; Chebar Lozinsky, A.; O'Sullivan, M.; Quinn, P.; Gold, M.; Tang, M.L.BACKGROUND: Food allergy adversely affects the healthrelated quality of life (HRQoL) of patients. It is unclear whether factors such as the reaction eliciting dose (ED) and the nature of allergic reaction symptoms affect HRQoL. OBJECTIVE: To explore associations between reaction ED or the nature of allergic symptoms and HRQoL among children with peanut allergy. METHODS: This study was a secondary analysis of baseline data from the PPOIT-003 randomized trial in 212 children aged 1 to 10 years with challenge-confirmed peanut allergy. Children’s past reaction symptoms were collected by clinicians during screening. Associations between variables of interest and parentreported child-proxy HRQoL were examined by univariable and multivariable linear regression. RESULTS: Mean age of study participants was 5.9 years; 63.2% were male. Children with a low reaction ED of 80 mg peanut protein had significantly poorer HRQoL (b [ e0.81; 95% CI, e1.61 to e0.00; P [ .049) compared with children with a high ED of 2,500 mg peanut protein. Gastrointestinal symptoms (b [ 0.45; 95% CI, 0.03-0.87; P [ .037), lower airway symptoms (b [ 0.46; 95% CI, 0.05-0.87; P [ .030), multisystem involvement (b [ 0.71; 95% CI, 0.25-1.16; P ¼ .003), or anaphylaxis (b ¼ 0.46; 95% CI, 0.04-0.87; P ¼ .031) during a previous reaction were associated with worse HRQoL. CONCLUSIONS: Peanut-allergic children with a lower allergen reaction threshold experienced a greater negative HRQoL impact compared with children with higher reaction thresholds. In addition, specific past allergic reaction symptoms were associated with comparatively worse HRQoL. Children experiencing these symptoms and those with lower reaction ED require increased clinical support to manage the food allergy and are likely to benefit from interventions that can improve HRQoL.Item Metadata only Patterns in the provision of government-subsidised hormonal postpartum contraception in Queensland, Australia between 2012 and 2018: a population-based cohort study(BMJ Journals, 2024) Carrandi, A.; Bull, C.; Hu, Y.; Grzeskowiak, L.E.; Teede, H.; Black, K.; Callander, E.Background: Short birth intervals and unintended pregnancy are associated with poorer maternal and infant outcomes. There is a risk of pregnancy during the immediate postpartum period unless contraception is initiated. This retrospective cohort study aimed to capture the current patterns of hormonal contraceptive provision within 12 months postpartum in a high-income country. Methods: We used a linked administrative dataset comprising all women who gave birth in Queensland, Australia between 1 July 2012 and 30 June 2018 (n=339 265 pregnancies). We described our cohort by whether they were provided with government-subsidised hormonal contraception within 12 months postpartum. The associations between hormonal postpartum contraceptive provision and demographic and clinical characteristics were examined using univariate and multivariate logistic regression and presented in terms of crude and adjusted odds ratios with 95% confidence intervals. Results: A majority of women (60.2%) were not provided with government-subsidised hormonal postpartum contraception within 12 months postpartum. Women who were younger (<25 years), were overweight or obese, smoked, were born in Australia, were non-Indigenous, gave birth in a public hospital, or were in the lowest socioeconomic status group were more likely to be provided with postpartum contraception after adjusting for other covariates, compared with their counterparts. Conclusions: Strategies to increase the provision and uptake of contraception in the immediate postpartum period are needed to prevent short birth intervals and unintended pregnancy and ensure women’s fertility intentions are enacted. Ongoing research is needed to examine the factors influencing women’s access to contraceptive services and, further, the types of contraception provided.Item Open Access Prenatal iodine supplementation and early childhood neurodevelopment: the PoppiE trial - study protocol for a multicentre randomised controlled trial(BMJ Journals, 2023) Best, K.P.; Gould, J.F.; Makrides, M.; Sullivan, T.; Cheong, J.; Zhou, S.J.; Kane, S.; Safa, H.; Sparks, A.; Doyle, L.W.; McPhee, A.J.; Nippita, T.A.C.; Afzali, H.H.A.; Grivell, R.; Mackerras, D.; Knight, E.; Wood, S.; Green, T.INTRODUCTION: Observational studies suggest both low and high iodine intakes in pregnancy are associated with poorer neurodevelopmental outcomes in children. This raises concern that current universal iodine supplement recommendations for pregnant women in populations considered to be iodine sufficient may negatively impact child neurodevelopment. We aim to determine the effect of reducing iodine intake from supplements for women who have adequate iodine intake from food on the cognitive development of children at 24 months of age. METHODS AND ANALYSIS: A multicentre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. Using a hybrid decentralised clinical trial model, 754 women (377 per group) less than 13 weeks' gestation with an iodine intake of ≥165 µg/day from food will be randomised to receive either a low iodine (20 µg/day) multivitamin and mineral supplement or an identical supplement containing 200) µg/day (amount commonly used in prenatal supplements in Australia), from enrolment until delivery. The primary outcome is the developmental quotient of infants at 24 months of age assessed with the Cognitive Scale of the Bayley Scales of Infant Development, fourth edition. Secondary outcomes include infant language and motor development; behavioural and emotional development; maternal and infant clinical outcomes and health service utilisation of children. Cognitive scores will be compared between groups using linear regression, with adjustment for location of enrolment and the treatment effect described as a mean difference with 95% CI. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Research Ethics Committee (HREC/17/WCHN/187). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04586348.Item Metadata only Prenatal Nutritional Strategies to Reduce the Risk of Preterm Birth(Karger Publishers, 2021) Best, K.; Gomersall, J.; Makrides, M.Abstract not availableItem Open Access Transnasal Humidified Rapid Insufflation Ventilatory Exchange in children requiring emergent intubation (Kids THRIVE): a statistical analysis plan for a randomised controlled trial(Springer, 2023) George, S.; Gibbons, K.; Williams, T.; Humphreys, S.; Gelbart, B.; Le Marsney, R.; Craig, S.; Tingay, D.; Chavan, A.; Schibler, A.; Cronin, J.; Pearson, K.; Rasmussen, K.; Acworth, J.; Hickey, L.; Delzoppo, C.; Perkins, E.; Oberender, F.; Waghorn, J.; McCahill, C.; et al.The placement of an endotracheal tube for children with acute or critical illness is a low-frequency and high-risk procedure, associated with high rates of first-attempt failure and adverse events, including hypoxaemia. To reduce the frequency of these adverse events, the provision of oxygen to the patient during the apnoeic phase of intubation has been proposed as a method to prolong the time available for the operator to insert the endotracheal tube, prior to the onset of hypoxaemia. However, there are limited data from randomised controlled trials to validate the efficacy of this technique in children. The technique known as transnasal humidified rapid insufflation ventilatory exchange (THRIVE) uses high oxygen flow rates (approximately 2 L/kg/min) delivered through nasal cannulae during apnoea. It has been shown to at least double the amount of time available for safe intubation in healthy children undergoing elective surgery. The technique and its application in real time have not previously been studied in acutely ill or injured children presenting to the emergency department or admitted to an intensive care unit. The Kids THRIVE trial is a multicentre, international, randomised controlled trial (RCT) in children less than 16 years old undergoing emergent intubation in either the intensive care unit or emergency department of participating hospitals. Participants will be randomised to receive either the THRIVE intervention or standard care (no apnoeic oxygenation) during their intubation. The primary objective of the trial is to determine if the use of THRIVE reduces the frequency of oxygen desaturation and increases the frequency of first-attempt success without hypoxaemia in emergent intubation of children compared with standard practice. The secondary objectives of the study are to assess the impact of the use of THRIVE on the rate of adverse events, length of mechanical ventilation and length of stay in intensive care. In this paper, we describe the detailed statistical analysis plan as an update of the previously published protocol.Item Open Access Pharmacological emergency management of agitation in children and young people: protocol for a randomised controlled trial of oral medication (PEAChY-O)(BMJ Journals, 2023) Bourke, E.M.; Borland, M.L.; Kochar, A.; George, S.; Shellshear, D.; Jani, S.; Perkins, K.; Tham, D.; Gordon, M.S.; Klein, K.; Prakash, C.; Lee, K.; Davidson, A.; Knott, J.C.; Craig, S.; Babl, F.E.Introduction: Acute severe behavioural disturbance (ASBD) is a condition seen with increasing frequency in emergency departments (EDs) in adults and young people. Despite the increasing number of presentations and significant associated risks to patients, families and caregivers, there is limited evidence to guide the most effective pharmacological management in children and adolescents. The aim of this study is to determine whether a single dose of oral olanzapine is more effective than a dose of oral diazepam at successfully sedating young people with ASBD. Methods and analysis: This study is a multicentre, open-label, superiority randomised controlled trial. Young people aged between 9 years and 17 years and 364 days presenting to an ED with ASBD who are deemed to require medication for behavioural containment will be recruited to the study. Participants will be randomised in a 1:1 allocation between a single weight-based dose of oral olanzapine and oral diazepam. The primary outcome is the proportion of participants who achieve successful sedation at 1-hour post randomisation without the need for additional sedation. Secondary outcomes will include assessing for adverse events, additional medications provided in the ED, further episodes of ASBD, length of stay in the ED and hospital and satisfaction with management. Effectiveness will be determined using an intention-to-treat analysis, with medication efficacy determined as part of the secondary outcomes using a per-protocol analysis. The primary outcome of successful sedation at 1 hour will be presented as a percentage within each treatment group, with comparisons presented as a risk difference with its 95% CIs. Ethics and dissemination: Ethics approval was received from the Royal Children’s Hospital Human Research Ethics Committee (HREC/66478/RCHM-2020). This incorporated a waiver of informed consent for the study. The findings will be disseminated in a peer-reviewed journal and at academic conferences. Trial registration number: ACTRN12621001236886.