Scott W. White

Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease

Genetic factors account for a significant proportion of the phenotypic variance of nonalcoholic fatty liver disease (NAFLD); however, very few predisposing genes have been identified. We aimed to (1) identify novel genetic associations with NAFLD by performing a genome‐wide association study (GWAS), and (2) examine the biological expression of the strongest genetic associations in a separate cohort. We performed GWAS of a population‐based cohort (Raine Study) of 928 adolescents assessed for NAFLD by ultrasound at age 17. Expression of genes with single nucleotide polymorphisms (SNPs) that were associated with NAFLD at a significance level of P < 10−5 was examined in adults with NAFLD and controls by quantifying hepatic messenger RNA (mRNA) expression and serum levels of protein. After adjustment for sex and degree of adiposity, SNPs in two genes expressed in liver were associated with NAFLD adolescents: group‐specific component (GC) (odds ratio [OR], 2.54; P = 1.20 × 10−6) and lymphocyte cytosolic protein‐1 (LCP1) (OR, 3.29; P = 2.96 × 10−6). SNPs in two genes expressed in neurons were also associated with NAFLD: lipid phosphate phosphatase‐related protein type 4 (LPPR4) (OR, 2.30; P = 4.82 × 10−6) and solute carrier family 38 member 8 (SLC38A8) (OR, 3.14; P = 1.86 × 10−6). Hepatic GC mRNA was significantly reduced (by 83%) and LCP1 mRNA was increased (by 300%) in liver biopsy samples from patients with NAFLD compared to controls (P < 0.05). Mean serum levels of GC protein were significantly lower in patients with NAFLD than controls (250 ± 90 versus 298 ± 90, respectively; P = 0.004); GC protein levels decreased with increasing severity of hepatic steatosis (P < 0.01). Conclusion: The association between GC and LCP1 SNPs and NAFLD as well as altered biological expression implicate these genes in the pathogenesis of NAFLD. (HEPATOLOGY 2013;)

Impact of the new IADPSG gestational diabetes diagnostic criteria on pregnancy outcomes in Western Australia.

There is debate as to the most appropriate diagnostic criteria to diagnose gestational diabetes mellitus (GDM). The proposed International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria have recently been endorsed by various bodies, but there remains no national consensus.

Cohort Profile: The Western Australian Pregnancy Cohort (Raine) Study-Generation 2

Cohort Profile: The Western Australian Pregnancy Cohort (Raine) Study–Generation 2 Leon Straker,* Jenny Mountain, Angela Jacques, Scott White, Anne Smith, Louis Landau, Fiona Stanley, John Newnham, Craig Pennell and Peter Eastwood School of Physiotherapy and Exercise Science, Curtin University, Perth, WA, Australia, School of Population Health, University of Western Australia, Perth, WA, Australia, Maternal Fetal Medicine Service, King Edward Memorial Hospital, Perth, WA, Australia, School of Medicine and Pharmacology, University of Western Australia, and Department of Health, Government of Western Australia, Perth, WA, Australia, Telethon Kids Institute, Perth, WA, Australia, School of Women’s and Infant’s Health and Centre for Sleep Science, School of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, WA, Australia.

Reducing preterm birth by a statewide multifaceted program: an implementation study

BACKGROUND: A comprehensive preterm birth prevention program was introduced in the state of Western Australia encompassing new clinical guidelines, an outreach program for health care practitioners, a public health program for women and their families based on print and social media, and a new clinic at the state’s sole tertiary level perinatal center for referral of those pregnant women at highest risk. The initiative had the single aim of safely lowering the rate of preterm birth. OBJECTIVE: The objective of the study was to evaluate the outcomes of the initiative on the rates of preterm birth both statewide and in the single tertiary level perinatal referral center. STUDY DESIGN: This was a prospective population‐based cohort study of perinatal outcomes before and after 1 full year of implementation of the preterm birth prevention program. RESULTS: In the state overall, the rate of singleton preterm birth was reduced by 7.6% and was lower than in any of the preceding 6 years. This reduction amounted to 196 cases relative to the year before the introduction of the initiative and the effect extended from the 28–31 week gestational age group onward. Within the tertiary level center, the rate of preterm birth in 2015 was also significantly lower than in the preceding years. CONCLUSION: A comprehensive and multifaceted preterm birth prevention program aimed at both health care practitioners and the general public, operating within the environment of a government‐funded universal health care system can significantly lower the rate of early birth. Further research is now required to increase the effect and to determine the relative contributions of each of the interventions.

Intrauterine Candida albicans Infection Causes Systemic Fetal Candidiasis with Progressive Cardiac Dysfunction in a Sheep Model of Early Pregnancy

Introduction: Several recent studies have identified a potential role for intrauterine Candida albicans in adverse pregnancy outcomes, including preterm birth. There is, however, a limited understanding of the impact of intrauterine candida infection on fetal well-being in early pregnancy. Using a sheep model of early pregnancy, the aims of this study were to determine (1) the ability of experimentally induced intrauterine C albicans to infect the fetus and (2) whether C albicans exposure in early pregnancy is associated with alterations in fetal cardiac function, as measured by spectral tissue Doppler imaging analysis of fetal cardiac function. Methods: Merino ewes carrying singleton pregnancies at 89 days’ gestation (term is ∼150 days) received C albicans (n = 8) via ultrasound-guided intra-amniotic injection. Saline-exposed fetuses served as controls (n = 6). Spectral tissue Doppler imaging echocardiography and amniotic fluid collection were performed at baseline and 24 and 72 hours after intrauterine C albicans injection. Fetal tissues were collected at postmortem for analysis of infection and inflammation. Results: Relative to saline control, intrauterine C albicans infection resulted in pronounced increases in amniotic fluid tumor necrosis factor α (TNF-α; P < .05) and cytokine/chemokine messenger RNA (interleukin [IL] 1β, IL-6, TNF-α, and monocyte chemoattractant protein 1; P < .05) in the fetal myocardium, lung, skin, and liver at 72 and 96 hours postinfection. Spectral tissue Doppler imaging showed diastolic dysfunction at 24 hours and severe biventricular diastolic dysfunction 72 hours postinfection. Conclusion: Intrauterine C albicans infection in a sheep model of early pregnancy causes systemic fetal candidiasis, which is associated with a robust systemic inflammatory response and progressive cardiac dysfunction detectable by spectral tissue Doppler imaging.

Improving customized fetal biometry by longitudinal modelling

Abstract Objective: To develop customized biometric charts to better define abnormal fetal growth. Methods: A total of 1056 singleton fetuses from the Raine Study underwent serial ultrasound biometry (abdominal circumference [AC], head circumference, and femur length) at 18, 24, 28, 34, and 38 weeks’ gestation. Customized biometry trajectories were developed adjusting for epidemiological influences upon fetal biometry using covariates available at 18 weeks gestation. Prediction accuracy (areas under the receiver operating characteristic curve [AUC] and 95% confidence interval [95%CI]) was evaluated by repeated random sub-sampling cross-validation methodology. Results: The model for derived estimated fetal weight (EFW) performed well for EFW less than 10th predicted percentile (AUC = 0.695, 95%CI, 0.692–0.699) and EFW greater than 90th predicted percentile (AUC = 0.705, 95%CI, 0.702–0.708). Fetal AC was also well predicted for growth restriction (AUC = 0.789, 95%CI, 0.784–0.794) and macrosomia (AUC = 0.796, 95%CI, 0.793–0.799). Population-derived, sex-specific charts misclassified 7.9% of small fetuses and 10.7% of large fetuses as normal. Conversely, 9.2% of those classified as abnormally grown by population-derived charts were considered normal by customized charts, potentially leading to complications of unnecessary intervention. Conclusions: Customized fetal biometric charts may offer improved ability for clinicians to detect deviations from optimal fetal growth and influence pregnancy management.

Applying Precision Public Health to Prevent Preterm Birth

Preterm birth (PTB) is one of the major health-care challenges of our time. Being born too early is associated with major risks to the child with potential for serious consequences in terms of life-long disability and health-care costs. Discovering how to prevent PTB needs to be one of our greatest priorities. Recent advances have provided hope that a percentage of cases known to be related to risk factors may be amenable to prevention; but the majority of cases remain of unknown cause, and there is little chance of prevention. Applying the principle of precision public health may offer opportunities previously unavailable. Presented in this article are ideas that may improve our abilities in the fields of studying the effects of migration and of populations in transition, public health programs, tobacco control, routine measurement of length of the cervix in mid-pregnancy by ultrasound imaging, prevention of non-medically indicated late PTB, identification of pregnant women for whom treatment of vaginal infection may be of benefit, and screening by genetics and other “omics.” Opening new research in these fields, and viewing these clinical problems through a prism of precision public health, may produce benefits that will affect the lives of large numbers of people.

Contemporary prenatal aneuploidy screening practice in Australia: Frequently asked questions in the cell‐free DNA era

Cell‐free DNA screening has quickly become established in Australia as an accurate – albeit costly – prenatal screening test for trisomy 21, 18 and 13. It is also commonly used for the detection of sex chromosome abnormalities. The increasing number of prenatal screening pathways available to women has increased the complexity of pretest counselling. Concurrent advances in diagnostic testing with the widespread use of chromosomal microarrays create further challenges for the continuing education of clinicians and health consumers. This article aims to answer common clinical questions in this rapidly evolving field and complements the recently updated Royal Australian and New Zealand College of Obstetricians and Gynaecologists Statement on Prenatal Screening for Fetal Chromosome and Genetic Conditions.

Is it possible to safely prevent late preterm and early term births

Late preterm and early term birth is associated with adverse short- and long-term consequences, particularly for neurodevelopment. A clear reduction in these births can be achieved by avoidance of non-medically indicated births prior to 39 weeks gestation, as shown following the introduction of prohibitive policies in the USA. However, clinicians and policy-makers must always consider the potential for unintended adverse consequences of such action, such as a potential for an increase in term stillbirth. Finding the balance between optimising long-term neurological outcomes and avoiding rare but devastating term stillbirths is one of the challenges of modern maternity care. In this article we review the current evidence for whether this balance can be found, where early births can be safely prevented, and what remains to be addressed to optimise this balance safely.

A prospective study of fetal head growth, autistic traits and autism spectrum disorder

Altered trajectories of brain growth are often reported in Autism Spectrum Disorder (ASD), particularly during the first year of life. However, less is known about prenatal head growth trajectories, and no study has examined the relation with postnatal autistic symptom severity. The current study prospectively examined the association between fetal head growth and the spectrum of autistic symptom severity in two large population‐based cohorts, including a sample of individuals with clinically diagnosed ASD. This study included 3,820 children from two longitudinal prenatal cohorts in The Netherlands and Australia, comprising 60 individuals with a confirmed diagnosis of ASD. Latent growth curve models were used to examine the relationship between fetal head circumference measured at three different time points and autistic traits measured in postnatal life using either the Social Responsiveness Scale or the Autism‐Spectrum Quotient. While lower initial prenatal HC was weakly associated with increasing autistic traits in the Dutch cohort, this relationship was not observed in the Australian cohort, nor when the two cohorts were analysed together. No differences in prenatal head growth were found between individuals with ASD and controls. This large population‐based study identified no consistent association across two cohorts between prenatal head growth and postnatal autistic traits. Our mixed findings suggest that further research in this area is needed. Autism Res 2018, 11: 602–612.