Fetal alcohol spectrum disorder and attention deficit hyperactivity disorder stimulant trial in children: an N-of-1 pilot trial to compare stimulant to placebo (FASST): protocol.

INTRODUCTION: Fetal alcohol spectrum disorder (FASD) is a neurodevelopmental disorder caused by alcohol exposure during pregnancy. FASD is associated with neurodevelopmental deviations, and 50%-94% of children with FASD meet the Diagnostic and Statistical Manual of Mental Disorders-fifth edition diagnostic criteria for attention deficit hyperactivity disorder (ADHD). There is a paucity of evidence around medication efficacy for ADHD symptoms in children with FASD. This series of N-of-1 trials aims to provide pilot data on the feasibility of conducting N-of-1 trials in children with FASD and ADHD. METHODS AND ANALYSIS: A pilot N-of-1 randomised trial design with 20 cycles of stimulant and placebo (four cycles of 2-week duration) for each child will be conducted (n=20) in Melbourne, Australia.Feasibility and tolerability will be assessed using recruitment and retention rates, protocol adherence, adverse events and parent ratings of side effects. Each child's treatment effect will be determined by analysing teacher ADHD ratings across stimulant and placebo conditions (Wilcoxon rank). N-of-1 data will be aggregated to provide an estimate of the cohort treatment effect as well as individual-level treatment effects. We will assess the sample size and number of cycles required for a future trial. Potential mediating factors will be explored to identify variables that might be associated with treatment response variability. ETHICS AND DISSEMINATION: The study was approved by the Hospital and Health Service Human Research Ethics Committee (HREC/74678/MonH-2021-269029), Monash (protocol V6, 25 June 2023).Individual outcome data will be summarised and provided to participating carers and practitioners to enhance care. Group-level findings will be presented at a local workshop to engage stakeholders. Findings will be presented at national and international conferences and published in peer-reviewed journals. All results will be reported so that they can be used to inform prior information for future trials. TRIAL REGISTRATION NUMBER: NCT04968522.

Carer-reported sleep disturbance and carer- and teacher-rated executive functioning in children with prenatal alcohol exposure and Fetal Alcohol Spectrum Disorder.

Children with prenatal alcohol exposure (PAE) and Fetal Alcohol Spectrum Disorder (FASD) have high rates of sleep disturbance and marked difficulties with executive functioning (EF). Sleep disturbance has been associated with poorer EF across development in typically developing children. The contribution of insomnia symptoms and nightmares to EF difficulties in children with PAE and FASD is unclear. The current study examined whether caregiver-reported insomnia symptoms and nightmares predicted difficulties with EF in children with PAE who were assessed at FASD diagnostic clinics. Archival data on 116 children with PAE assessed at FASD diagnostic clinics were extracted from databases. Children were assigned to a preschool-age group (3.1 to 5.9 years, n = 40) and a school-age group (5.9 to 10.9 years, n = 76). Insomnia symptoms and nightmares were measured using items extracted from the Child Behavior Checklist (CBCL) while EF was measured using the caregiver and teacher Behavior Rating Inventory of Executive Function (BRIEF) rating forms. Bootstrapped regression models were used examine the effects of insomnia symptoms and nightmares on domains of EF in each group while adjusting for potential confounds. For preschool children, insomnia symptoms were associated with greater daytime tiredness while nightmares were associated with greater difficulties with Emergent Metacognition according to their teachers. For school-age children, insomnia symptoms predicted greater EF difficulties across most domains according to their caregivers but not teachers. Sleep disturbance may compound EF impairments in children with PAE and should be screened for as part of FASD diagnostic assessment.

Diagnostic Accuracy and economic value of a Tiered Assessment for Fetal Alcohol Spectrum Disorder (DATAforFASD): Protocol.

INTRODUCTION: Australian practices for diagnosing fetal alcohol spectrum disorder (FASD) are lengthy and require specialist expertise. Specialist teams are based in urban locations; they are expensive and have prolonged waitlists. Innovative, flexible solutions are needed to ensure First Nations children living in rural/remote communities have culturally appropriate and equitable access to timely diagnosis and support. This study compares the accuracy of rapid assessments (index tests) that can be administered by a range of primary healthcare practitioners to specialist standardised FASD assessments (reference tests). The cost-efficiency of index tests will be compared with reference tests. METHODS AND ANALYSIS: At least 200 children aged 6-16 years at-risk of FASD will be recruited across at least seven study sites. Following standards for reporting diagnostic accuracy study (STARD) guidelines, all children will complete index and reference tests. Diagnostic accuracy statistics (including receiver operating curves, sensitivity, specificity, positive and negative predictive values and likelihood ratios) will identify whether rapid assessments can accurately identify: (1) the presence of an FASD diagnosis and (2) impairment in each neurodevelopmental domain, compared to comprehensive assessments. Direct and indirect healthcare costs for index tests compared to reference tests will be collected in primary healthcare and specialist settings. ETHICS AND DISSEMINATION OF RESULTS: Children's Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC/20/QCHQ/63173); Griffith University Human Research Ethics Committee (2020/743). Results will assist in validating the use of index tests as part of a tiered neurodevelopmental assessment process that was co-designed with First Nations community and primary healthcare practitioners. Outcomes will be summarised and provided to participating practitioners and sites, and disseminated to community health services and consumers. Findings will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12622000498796.

Exploring resource implications and models of care for assessment and diagnosis of fetal alcohol spectrum disorder: A scoping review.

Previous reviews have examined annual mean costs of care for individuals with fetal alcohol spectrum disorder (FASD), costs of the health burden, costs to the justice system, productivity losses for caregivers, and both the monetary and nonmonetary costs of reduced quality of life. However, because there have been no published reviews focused on understanding the resource implications and specific service features for the assessment and diagnostic process for FASD, the current scoping review investigated the available evidence on these topics. Eligible studies were identified through a systematic search of six databases and included if they contained information on the potential costs or models of care associated with undertaking an assessment for FASD. Data were charted, underwent content analysis, and were reported according to the PRISMA extension for scoping reviews. Eleven studies were included in the final qualitative synthesis. The primary patient costs were attributed to the lengthy time required for diagnosis (up to 47 h). The primary service costs were attributed to costs of clinicians and support personnel and the involvement of multidisciplinary teams in the assessment process. Estimates of the specific dollar values of diagnostic costs were limited and varied between studies. Several models of care were explored, primarily in Canadian clinics, which aimed to capitalize on available services to improve accessibility and patient care and reduce service costs. This study provides important preliminary insights into the resource implications and models of care involved in the diagnostic assessment of FASD. However, the low number of available studies and variability in available data highlight the need for formal costing studies and detailed information gathering on available models of care to inform future clinical practice and policy development.

Desiderosmia: a manifestation of iron deficiency in pregnancy.

A pregnant woman in her 20s presented with an excessive desire to smell a specific household cleaning product. She was found to have severe iron deficiency anaemia and her symptoms resolved following intravenous iron supplementation. She described symptoms of fatigue, shortness of breath and olfactory cravings. The specific scent could not be replicated with other smells and the woman had to significantly modify her lifestyle to accommodate the excessive desire. She had a similar experience during her prior pregnancy which resolved after the correction of severe iron deficiency anaemia. This unique symptom has been described as desiderosmia: iron deficiency manifesting as olfactory cravings. This underappreciated but useful symptom is defined as a separate entity to pica, as there is an absence of desire to ingest the product. Desiderosmia can harm mother and baby through inhalation of potentially harmful fumes; hence, women who describe this symptom should be assessed for iron deficiency anaemia.

Polygenic Adaptation and Clonal Interference Enable Sustained Diversity in Experimental Pseudomonas aeruginosa Populations.

How biodiversity arises and can be maintained in asexual microbial populations growing on a single resource remains unclear. Many models presume that beneficial genotypes will outgrow others and purge variation via selective sweeps. Environmental structure like that found in biofilms, which are associated with persistence during infection and other stressful conditions, may oppose this process and preserve variation. We tested this hypothesis by evolving Pseudomonas aeruginosa populations in biofilm-promoting arginine media for 3 months, using both a bead model of the biofilm life cycle and planktonic serial transfer. Surprisingly, adaptation and diversification were mostly uninterrupted by fixation events that eliminate diversity, with hundreds of mutations maintained at intermediate frequencies. The exceptions included genotypes with mutator alleles that also accelerated genetic diversification. Despite the rarity of hard sweeps, a remarkable 40 genes acquired parallel mutations in both treatments and often among competing genotypes within a population. These incomplete soft sweeps include several transporters (including pitA, pntB, nosD, and pchF) suggesting adaptation to the growth media that becomes highly alkaline during growth. Further, genes involved in signal transduction (including gacS, aer2, bdlA, and PA14_71750) reflect likely adaptations to biofilm-inducing conditions. Contrary to evolution experiments that select mutations in a few genes, these results suggest that some environments may expose a larger fraction of the genome and select for many adaptations at once. Thus, even growth on a sole carbon source can lead to persistent genetic and phenotypic variation despite strong selection that would normally purge diversity.

The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project design and methodologies: a dimensional approach to understanding neurobiological and genetic aetiology.

BACKGROUND: ASD and ADHD are prevalent neurodevelopmental disorders that frequently co-occur and have strong evidence for a degree of shared genetic aetiology. Behavioural and neurocognitive heterogeneity in ASD and ADHD has hampered attempts to map the underlying genetics and neurobiology, predict intervention response, and improve diagnostic accuracy. Moving away from categorical conceptualisations of psychopathology to a dimensional approach is anticipated to facilitate discovery of data-driven clusters and enhance our understanding of the neurobiological and genetic aetiology of these conditions. The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project is one of the first large-scale, family-based studies to take a truly transdiagnostic approach to ASD and ADHD. Using a comprehensive phenotyping protocol capturing dimensional traits central to ASD and ADHD, the MAGNET project aims to identify data-driven clusters across ADHD-ASD spectra using deep phenotyping of symptoms and behaviours; investigate the degree of familiality for different dimensional ASD-ADHD phenotypes and clusters; and map the neurocognitive, brain imaging, and genetic correlates of these data-driven symptom-based clusters. METHODS: The MAGNET project will recruit 1,200 families with children who are either typically developing, or who display elevated ASD, ADHD, or ASD-ADHD traits, in addition to affected and unaffected biological siblings of probands, and parents. All children will be comprehensively phenotyped for behavioural symptoms, comorbidities, neurocognitive and neuroimaging traits and genetics. CONCLUSION: The MAGNET project will be the first large-scale family study to take a transdiagnostic approach to ASD-ADHD, utilising deep phenotyping across behavioural, neurocognitive, brain imaging and genetic measures.

Challenging the definition of hypertension in pregnancy: a retrospective cohort study.

BACKGROUND: In routine antenatal care, blood pressure is used as a screening tool for preeclampsia and its associated adverse outcomes. As such women with a blood pressure greater than 140/90 mm Hg undergo further investigation and closer follow-up, whereas those with lower blood pressures receive no additional care. In the nonpregnant setting, the American College of Cardiology now endorses lower hypertensive thresholds and it remains unclear whether these lower thresholds should also be considered in pregnancy. OBJECTIVE: (1) To examine the association between lower blood pressure thresholds (as per the American College of Cardiology guidelines) and pregnancy outcomes and (2) to determine whether there is a continuous relationship between blood pressure and pregnancy outcomes and identify the point of a change at which blood pressure is associated with an increased risk of such outcomes. STUDY DESIGN: This was a retrospective study of singleton pregnancies at Monash Health, Australia. Data were obtained with regards to maternal characteristics and blood pressure measurements at varying gestational ages. Blood pressures were then categorized as (1) mean arterial pressure and (2) normal, elevated, stage 1 and stage 2 hypertension, as per the American College of Cardiology guidelines. Multivariable regression analysis was performed to identify associations between blood pressure categories and pregnancy outcomes. RESULTS: This study included 18,243 singleton pregnancies. We demonstrated a positive dose-response relationship between mean arterial pressure and the development of preeclampsia in later pregnancy. Across all gestational ages, the risk of preeclampsia was greater in those with "elevated blood pressure" and "stage 1 hypertension" in comparison with the normotensive group (adjusted risk ratio; 2.45, 95% confidence interval, 1.74-3.44 and adjusted risk ratio, 6.60; 95% confidence interval, 4.98-8.73 respectively, at 34-36 weeks' gestation). There was also an association between stage 1 hypertension, preterm birth, and adverse perinatal outcomes. CONCLUSION: This study demonstrated that preeclampsia and the associated adverse outcomes are not exclusive to those with blood pressures greater than 140/90 mm Hg. As such, those with prehypertensive blood pressures may also benefit from closer monitoring. Further research is essential to determine whether lowering the blood pressure threshold in pregnancy would improve detection and outcomes.

Negative frequency-dependent selection maintains coexisting genotypes during fluctuating selection.

Natural environments are rarely static; rather selection can fluctuate on timescales ranging from hours to centuries. However, it is unclear how adaptation to fluctuating environments differs from adaptation to constant environments at the genetic level. For bacteria, one key axis of environmental variation is selection for planktonic or biofilm modes of growth. We conducted an evolution experiment with Burkholderia cenocepacia, comparing the evolutionary dynamics of populations evolving under constant selection for either biofilm formation or planktonic growth with populations in which selection fluctuated between the two environments on a weekly basis. Populations evolved in the fluctuating environment shared many of the same genetic targets of selection as those evolved in constant biofilm selection, but were genetically distinct from the constant planktonic populations. In the fluctuating environment, mutations in the biofilm-regulating genes wspA and rpfR rose to high frequency in all replicate populations. A mutation in wspA first rose rapidly and nearly fixed during the initial biofilm phase but was subsequently displaced by a collection of rpfR mutants upon the shift to the planktonic phase. The wspA and rpfR genotypes coexisted via negative frequency-dependent selection around an equilibrium frequency that shifted between the environments. The maintenance of coexisting genotypes in the fluctuating environment was unexpected. Under temporally fluctuating environments, coexistence of two genotypes is only predicted under a narrow range of conditions, but the frequency-dependent interactions we observed provide a mechanism that can increase the likelihood of coexistence in fluctuating environments.

Online referral and immediate appointment selection system empowers families and improves access to public community paediatric clinics.

AIM: We aimed to introduce a low-cost combined online referral and immediate appointment selection system (CORIAS) to empower referrers and parents by allowing them to schedule an appointment at a time and location of their choosing in conjunction with the referrer at the time of referral. This was because an unacceptably high rate of reported lost referrals, combined with a high rate of failure to attend initial appointments (FTAs), was noted at a six-site community paediatric clinic service. We aimed to analyse the impact of CORIAS on important outcomes including timely appointment scheduling, attendance, loss of referrals, user acceptance, overall cost and administrative burden. METHODS: For 3-month periods before and after the implementation of CORIAS, data were collected regarding all new referrals received and initial appointments scheduled, as well as reports of lost referrals. The number of attended initial appointments, FTAs, failures in successfully scheduling appointments, referrer background, CORIAS cost and qualitative feedback received from relevant parties was collated and analysed. RESULTS: The proportion of referrals reported lost was 6% following the implementation of the combined online system in comparison to 17% pre-implementation. The FTA rate for scheduled initial appointments pre-implementation was 16%; post-implementation, the FTA rate was 9%. Qualitative benefits included a decrease in the administrative burden associated with appointment scheduling and increased service access for culturally and linguistically diverse families. CONCLUSION: Appropriately designed and implemented novel online systems may improve timely and equitable access to health care by providing secure, reliable pathways for referrers and by empowering and improving communication with patients and families.

Comparison of psychosocial correlates in primary school age children with attention deficit/ hyperactivity disorder- combined type, with and without dysthymic disorder.

In this study, standardized assessments of maternal psychopathology, family functioning and marital adjustment were compared between 115 medication naïve, clinically referred primary school age children with Attention Deficit Hyperactivity Disorder combined type (ADHD-CT) alone and 29 children with comorbid dysthymic disorder (DD) and ADHD-CT. The mothers of children with ADHD-CT and DD reported higher rates of anxiety and depression than those of children with ADHD-CT alone. These results reinforce the need for early recognition of comorbid DD when working with children with ADHD-CT. Increased rates of maternal anxiety and depression in children with ADHD-CT and DD may contribute to the children's symptoms, require specific psychological and/or medication treatments and careful ongoing monitoring of these specific treatments.

Garlic attenuates hypercholesterolemic risk factors in olive oil fed rats and high cholesterol fed rats.

This study was undertaken to compare the effects of garlic (G) on hypercholesterolemic risk factors in rats fed with corn oil (C) or olive oil (O) with and without cholesterol (Ch) enrichment in the diet. Male Sprague-Dawley rats (n=6 per group) were fed semi-purified diets containing 5% oil with or without cholesterol (Ch) or garlic (G) for 21 days. In the C fed rats, addition of dietary Ch, there was a redistribution of Ch from HDL to LDL class. In contrast, 1% Ch added to O diets produced a 4-fold increase in serum Ch compared with levels in rats fed O without Ch. This was associated with a 14-fold increase in LDL Ch and a 7-fold decrease in HDL Ch levels. Addition of 2% G had no effect on the distribution of serum Ch between HDL and LDL Ch in C+Ch fed rats, but in O+Ch fed rats, G halved the increase in serum Ch and LDL and attenuated the decrease in serum HDL by 23%. The results suggest that the dietary O regulated the levels of serum in Ch loaded rats. G attenuated serum Ch in O fed rats and decreased serum risk factors, both total Ch and LDL-C ratio and LDL-Ch/HDL-Ch ratio.

Which anxiety disorders may differentiate attention deficit hyperactivity disorder, combined type with dysthymic disorder from attention deficit hyperactivity disorder, combined type alone?

OBJECTIVE: Attention deficit hyperactivity disorder, combined type (ADHD-CT), dysthymic disorder, and anxiety disorders frequently co-occur in primary school age children, although there have been no published data describing their association. We investigated the association of anxiety, defined from a parent or child perspective, with primary school-age children with ADHD-CT with and without dysthymic disorder. METHOD: One hundred and forty-six medication naïve children with ADHD-CT were studied. Two groups with and without dysthymic disorder were formed to compare parent and child reports of anxiety, using categorical and continuous measures of anxiety, using logistic regression. RESULTS: Separation anxiety disorder and social phobia were associated with primary school-age children with ADHD-CT and dysthymic disorder, compared to children with ADHD-CT without dysthymic disorder. CONCLUSIONS: The recognition of dysthymic disorder and anxiety disorders and their management in primary school-age children with ADHD-CT is generally poorly understood. The identification and elucidation of composite anxiety and depressive phenomena that may be systematically investigated through longitudinal studies of epidemiologically derived samples is needed in this particular group of children.