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The unintended modulation of nuclear receptor (NR) activity by drugs can lead to toxicities amongst the endocrine, gastrointestinal, hepatic cardiovascular, and central nervous systems. While secondary pharmacology screening assays include NRs, safety risks due to unintended interactions of small molecule drugs with NRs remain poorly understood. To identify potential nonclinical and clinical safety effects resulting from functional interactions with 44 of the 48 human-expressed NRs, we conducted a systematic narrative review of the scientific literature, tissue expression data, and used curated databases (OFF-X™) (Off-X, Clarivate) to organize reported toxicities linked to the functional modulation of NRs in a tabular and machine-readable format. The top five NRs associated with the highest number of safety alerts from peer-reviewed journals, regulatory agency communications, congresses/conferences, clinical trial registries, and company communications were the Glucocorticoid Receptor (GR, 18,328), Androgen Receptor (AR, 18,219), Estrogen Receptor (ER, 12,028), Retinoic acid receptors (RAR, 10,450), and Pregnane X receptor (PXR, 8044). Toxicities associated with NR modulation include hepatotoxicity, cardiotoxicity, endocrine disruption, carcinogenicity, metabolic disorders, and neurotoxicity. These toxicities often arise from the dysregulation of receptors like Peroxisome proliferator-activated receptors (PPARα, PPARγ), the ER, PXR, AR, and GR. This dysregulation leads to various health issues, including liver enlargement, hepatocellular carcinoma, heart-related problems, hormonal imbalances, tumor growth, metabolic syndromes, and brain function impairment. Gene expression analysis using heatmaps for human and rat tissues complemented the functional modulation of NRs associated with the reported toxicities. Interestingly, certain NRs showed ubiquitous expression in tissues not previously linked to toxicities, suggesting the potential utilization of organ-specific NR interactions for therapeutic purposes.

The process of discovering small molecule drugs involves screening numerous compounds and optimizing the most promising ones, both in vitro and in vivo. However, approximately 90% of these optimized candidates fail during trials due to unexpected toxicity or insufficient efficacy. Current concepts with respect to drug–protein interactions suggest that each small molecule interacts with an average of 6–11 targets. This implies that approved drugs and even discontinued compounds could be repurposed by leveraging their interactions with unintended targets. Therefore, we developed a computational repurposing framework for small molecules, which combines artificial intelligence/machine learning (AI/ML)-based and chemical similarity-based target prediction methods with cross-species transcriptomics information. This repurposing methodology incorporates eight distinct target prediction methods, including three machine learning methods. By using multiple orthogonal methods for a “dataset” composed of 2766 FDA-approved drugs targeting multiple therapeutic target classes, we identified 27,371 off-target interactions involving 2013 protein targets (i.e., an average of around 10 interactions per drug). Relative to the drugs in the dataset, we identified 150,620 structurally similar compounds. The highest number of predicted interactions were for drugs targeting G protein-coupled receptors (GPCRs), enzymes, and kinases with 10,648, 4081, and 3678 interactions, respectively. Notably, 17,283 (63%) of the off-target interactions have been confirmed in vitro. Approximately 4000 interactions had an IC50 of 50 of

One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2–19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajectories. In this Mini Review, we summarize findings to date from the APP cohort and describe progress made toward identifying meaningful subgroups of autism.

This paper describes a Saribas Iban rite of healing called the Sugi sakit. What distinguished this rite from other forms of Saribas Iban healing was that it incorporated within its performance a long narrative epic concerned with the adventures and love affairs of an Iban culture hero named Bujang Sugi. Here I explore the language used by Iban priest bards both in telling the Sugi epic and in performing the larger ritual drama in which it was set, and look, in particular, at how the Sugi epic, which was otherwise told for entertainment, was integrated into this drama and recast by the priest bards as they performed the ritual, so that it not only entertained their listeners, but also served as a serious instrument of healing.

OBJECTIVE: To determine whether the clinical efficacy and safety of infliximab in diverse clinical referral practices was similar to that seen in the randomized, controlled clinical trials.

WALKER, ANTHONY R. (ed.). Pika-Pika: The Flashing Firefly. Essays to Honour and Celebrate the Life of Pauline Hetland Walker (1938–2005). New Delhi: Hindustan Publishing Corporation, 2009. Pp. xv + 489. ISBN: 81-7075-087-3.

Abstract Background There is a need for an adherence measure, to monitor adherence services in clinical practice, which can distinguish between different types of non-adherence and measure changes over time. In order to be inclusive of all patients it needs to be able to be administered to both patients and carers and to be suitable for patients taking multiple medications for a range of clinical conditions. A systematic review found that no adherence measure met all these criteria. We therefore wished to develop a theory based adherence scale (the DAMS) and establish its content, face and preliminary construct validity in a primary care population. Methods The DAMS (consisting of 6 questions) was developed from theory by a multidisciplinary team and the questions were initially tested in small patient populations. Further to this, patients were recruited when attending a General Practice and interviewed using the DAMS and two other validated self-reported adherence measures, theMorisky-8 and Lu questionnaires. A semi-structured interview was used to explore acceptability and reasons for differences in responses between the DAMS and the other measures. Descriptive data were generated and Spearman rank correlation tests were used to identify associations between the DAMS and the other adherence measures. Results One hundred patients completed the DAMS in an average of 1 minute 28 seconds and reported finding it straightforward to complete. An adherence score could not be calculated for the 4(4%) patients only taking ‘when required’ medication. Thirty six(37.5%) of the remaining patients reported some non-adherence. Adherence ratings of the DAMS were significantly associated with levels of self reported adherence on all other measures Spearman Rho 0.348-0.719, (p Conclusion The DAMS has been developed for routine monitoring of adherence in clinical practice. It was acceptable to patients taking single or multiple medication and valid when tested against other adherence measures. However, ‘when required’ medication needs to be excluded. Further tests of the DAMS against objective measures such as MEMS are in progress and reliability needs to be established. Further investigation of the carers’ version of the DAMS is required.

Abstract Background There is a recognised need to build primary care medication adherence services which are tailored to patients' needs. Continuous quality improvement of such services requires a regular working method of measuring adherence in order to monitor effectiveness. Self report has been considered the method of choice for clinical use; it is cheap, relatively unobtrusive and able to distinguish between intentional and unintentional non-adherence, which have different underlying causes and therefore require different interventions. A self report adherence measure used in routine clinical practice would ideally be brief, acceptable to patients, valid, reliable, have the ability to distinguish between different types of non-adherence and be able to be completed by or in conjunction with carers where necessary. Methods We systematically reviewed the literature in order to identify self report adherence measures currently available which are suitable for primary care and evaluate the extent to which they met the criteria described above. We searched the databases Medline, Embase, International Pharmaceutical Abstracts, Pharmline, CINAHL, PsycINFO and HaPI to identify studies reporting the development, validation or reliability of generic adherence measures. One reviewer screened all abstracts and assessed all relevant full text articles obtained and a second reviewer screened/assessed 10% to check reliability. Results Fifty eight measures were identified. While validation data were presented in support of the vast majority of self reported measures (54/58), data for a relatively small number of measures was presented for reliability (16/58) and time to complete (3/58). Few were designed to have the ability to be completed by or in conjunction with carers and few were able to distinguish between different types of non-adherence, which limited their ability be used effectively in the continuous improvement of targeted adherence enhancing interventions. The data available suggested that patients find it easier to estimate general adherence than to report a specific number of doses missed. Visual analogue scales can be easier for patients than other types of scale but are not suitable for telephone administration. Conclusions There is a need for a measure which can be used in the routine continual quality monitoring of adherence services.

Abstract Background Quantitative prospective methods are widely used to evaluate the impact of new technologies such as electronic prescribing (eP) on medication errors. However, they are labour-intensive and it is not always feasible to obtain pre-intervention data. Our objective was to compare the eP medication error picture obtained with retrospective quantitative and qualitative methods. Methods The study was carried out at one English district general hospital approximately two years after implementation of an integrated electronic prescribing, administration and records system. Quantitative: A structured retrospective analysis was carried out of clinical records and medication orders for 75 randomly selected patients admitted to three wards (medicine, surgery and paediatrics) six months after eP implementation. Qualitative: Eight doctors, 6 nurses, 8 pharmacy staff and 4 other staff at senior, middle and junior grades, and 19 adult patients on acute surgical and medical wards were interviewed. Staff interviews explored experiences of developing and working with the system; patient interviews focused on experiences of medicine prescribing and administration on the ward. Interview transcripts were searched systematically for accounts of medication incidents. A classification scheme was developed and applied to the errors identified in the records review. Results The two approaches produced similar pictures of the drug use process. Interviews identified types of error identified in the retrospective notes review plus two eP-specific errors which were not detected by record review. Interview data took less time to collect than record review, and provided rich data on the prescribing process, and reasons for delays or non-administration of medicines, including "once only" orders and "as required" medicines. Conclusions The qualitative approach provided more understanding of processes, and some insights into why medication errors can happen. The method is cost-effective and could be used to supplement information from anonymous error reporting schemes.

COVID-19 pandemic continues to evolve and new variants like Delta and Omicron have been discovered. REGEN-COV is a recombinant human monoclonal antibody to the spike protein of SARS-CoV-2 which received emergency use authorisation for treatment and post-exposure prophylaxis in patients with high risk of progression to severe disease. We review our experience with use of REGEN-COV in paediatric heart transplant patients.

We systematically evaluated randomized-controlled trials (RCTs) for Staphylococcus aureus bacteremia (SAB). There was intertrial heterogeneity in cohort characteristics, including bacteremia source, complicated SAB, and comorbidities. Reporting of cohort characteristics was itself variable, including bacteremia source and illness severity. Selection bias was introduced by exclusion criteria relating to comorbidities, illness severity, infection types, and source control. Mortality was lower in RCT control arms compared with observational cohorts. Differences in outcome definitions impedes meta-analysis. These issues complicate the interpretation and application of SAB RCT results. The value of these trials should be maximized by a standardized approach to recruitment, definitions, and reporting., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background/objectives: This study analysed the relationship between early childhood socioeconomic status (SES) measured by maternal education and household income and the subsequent development of childhood overweight and obesity., Subjects/methods: Data from seven population-representative prospective child cohorts in six high-income countries: United Kingdom, Australia, the Netherlands, Canada (one national cohort and one from the province of Quebec), USA, Sweden. Children were included at birth or within the first 2 years of life. Pooled estimates relate to a total of N = 26,565 included children. Overweight and obesity were defined using International Obesity Task Force (IOTF) cut-offs and measured in late childhood (8-11 years). Risk ratios (RRs) and pooled risk estimates were adjusted for potential confounders (maternal age, ethnicity, child sex). Slope Indexes of Inequality (SII) were estimated to quantify absolute inequality for maternal education and household income., Results: Prevalence ranged from 15.0% overweight and 2.4% obese in the Swedish cohort to 37.6% overweight and 15.8% obese in the US cohort. Overall, across cohorts, social gradients were observed for risk of obesity for both low maternal education (pooled RR: 2.99, 95% CI: 2.07, 4.31) and low household income (pooled RR: 2.69, 95% CI: 1.68, 4.30); between-cohort heterogeneity ranged from negligible to moderate (p: 0.300 to < 0.001). The association between RRs of obesity by income was lowest in Sweden than in other cohorts., Conclusions: There was a social gradient by maternal education on the risk of childhood obesity in all included cohorts. The SES associations measured by income were more heterogeneous and differed between Sweden versus the other national cohorts; these findings may be attributable to policy differences, including preschool policies, maternity leave, a ban on advertising to children, and universal free school meals., (© 2022. The Author(s).)

Background/objectives: Modelling genetic pre-disposition may identify children at risk of obesity. However, most polygenic scores (PGSs) have been derived in adults, and lack validation during childhood. This study compared the utility of existing large-scale adult-derived PGSs to predict common anthropometric traits (body mass index (BMI), waist circumference, and body fat) in children and adults, and examined whether childhood BMI prediction could be improved by combining PGSs and non-genetic factors (maternal and earlier child BMI)., Subjects/methods: Participants (n = 1365 children, and n = 2094 adults made up of their parents) were drawn from the Longitudinal Study of Australian Children. Children were weighed and measured every two years from 0-1 to 12-13 years, and adults were measured or self-reported measurements were obtained concurrently (average analysed). Participants were genotyped from blood or oral samples, and PGSs were derived based on published genome-wide association studies. We used linear regression to compare the relative utility of these PGSs to predict their respective traits at different ages., Results: BMI PGSs explained up to 12% of child BMI z-score variance in 10-13 year olds, compared with up to 15% in adults. PGSs for waist circumference and body fat explained less variance (up to 8%). An interaction between BMI PGSs and puberty (p = 0.001-0.002) suggests the effect of some variants may differ across the life course. Individual BMI measures across childhood predicted 10-60% of the variance in BMI at 12-13 years, and maternal BMI and BMI PGS each added 1-9% above this., Conclusion: Adult-derived PGSs for BMI, particularly those derived by modelling between-variant interactions, may be useful for predicting BMI during adolescence with similar accuracy to that obtained in adulthood. The level of precision presented here to predict BMI during childhood may be relevant to public health, but is likely to be less useful for individual clinical purposes., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: This study aimed to examine social gradients in ADHD during late childhood (age 9-11 years) using absolute and relative relationships with socioeconomic status exposure (household income, maternal education) during early childhood (<5 years) in seven cohorts from six industrialised countries (UK, Australia, Canada, The Netherlands, USA, Sweden)., Methods: Secondary analyses were conducted for each birth cohort. Risk ratios, pooled risk estimates, and absolute inequality, measured by the Slope Index of Inequality (SII), were estimated to quantify social gradients in ADHD during late childhood by household income and maternal education measured during early childhood. Estimates were adjusted for child sex, mother age at birth, mother ethnicity, and multiple births., Findings: All cohorts demonstrated social gradients by household income and maternal education in early childhood, except for maternal education in Quebec. Pooled risk estimates, relating to 44,925 children, yielded expected gradients (income: low 1.83(CI 1.38,2.41), middle 1.42(1.13,1.79), high (reference); maternal education: low 2.13(1.39,3.25), middle 1.42(1.13,1.79)). Estimates of absolute inequality using SII showed that the largest differences in ADHD prevalence between the highest and lowest levels of maternal education were observed in Australia (4% lower) and Sweden (3% lower); for household income, the largest differences were observed in Quebec (6% lower) and Canada (all provinces: 5% lower)., Conclusion: Findings indicate that children in families with high household income or maternal education are less likely to have ADHD at age 9-11. Absolute inequality, in combination with relative inequality, provides a more complete account of the socioeconomic status and ADHD relationship in different high-income countries. While the study design precludes causal inference, the linear relation between early childhood social circumstances and later ADHD suggests a potential role for policies that promote high levels of education, especially among women, and adequate levels of household income over children's early years in reducing risk of later ADHD., Competing Interests: The authors have declared that no competing interests exist.

Medication non-adherence causes poor outcomes in paediatric organ transplantation. COVID-19 pandemic has led to an exponential use of mobile health approaches for patient care. Herein, we describe a pilot intervention study using mobile video directly observed therapy building on emerging trends in research and clinical practice pertaining to medication adherence in paediatric organ transplantation.

Objective: To investigate associations between early-life diet trajectories and preclinical cardiovascular phenotypes and metabolic risk by age 12 years., Methods: Participants were 1861 children (51% male) from the Longitudinal Study of Australian Children. At five biennial waves from 2-3 to 10-11 years: Every 2 years from 2006 to 2014, diet quality scores were collected from brief 24-h parent/self-reported dietary recalls and then classified using group-based trajectory modeling as 'never healthy' (7%), 'becoming less healthy' (17%), 'moderately healthy' (21%), and 'always healthy' (56%). At 11-12 years: During children's physical health Child Health CheckPoint (2015-2016), we measured cardiovascular functional (resting heart rate, blood pressure, pulse wave velocity, carotid elasticity/distensibility) and structural (carotid intima-media thickness, retinal microvasculature) phenotypes, and metabolic risk score (composite of body mass index z-score, systolic blood pressure, high-density lipoproteins cholesterol, triglycerides, and glucose). Associations were estimated using linear regression models (n = 1100-1800) adjusted for age, sex, and socioeconomic position., Results: Compared to 'always healthy', the 'never healthy' trajectory had higher resting heart rate (2.6 bpm, 95% CI 0.4, 4.7) and metabolic risk score (0.23, 95% CI 0.01, 0.45), and lower arterial elasticity (-0.3% per 10 mmHg, 95% CI -0.6, -0.1) and distensibility (-1.2%, 95% CI -1.9, -0.5) (all effect sizes 0.3-0.4). Heart rate, distensibility, and diastolic blood pressure were progressively poorer for less healthy diet trajectories (linear trends p ≤ 0.02). Effects for systolic blood pressure, pulse wave velocity, and structural phenotypes were less evident., Conclusions: Children following the least healthy diet trajectory had poorer functional cardiovascular phenotypes and metabolic syndrome risk, including higher resting heart rate, one of the strongest precursors of all-cause mortality. Structural phenotypes were not associated with diet trajectories, suggesting the window to prevent permanent changes remains open to at least late childhood.

Background: Many current research needs can only be addressed using very large cohorts. In such studies, traditional one-on-one phone, face-to-face, or paper-based engagement may not be feasible. The only realistic mechanism for maintaining engagement and participation at this scale is via digital methods. Given the substantial investment being made into very large birth cohort studies, evidence for optimal methods of participant engagement, participation, and retention over sustained periods without in-person contact from researchers is paramount., Objective: This study aims to provide an overview of systematic reviews and meta-analyses evaluating alternative strategies for maximizing participant engagement and retention rates in large-scale studies using digital methods., Methods: We used a rapid review method by searching PubMed and Ovid MEDLINE databases from January 2012 to December 2019. Studies evaluating at least 1 e-engagement, participation, or retention strategy were eligible. Articles were screened for relevance based on preset inclusion and exclusion criteria. The methodological quality of the included reviews was assessed using the AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews 2) measurement tool, and a narrative synthesis of the data was conducted., Results: The literature search yielded 19 eligible reviews. Overall, 63% (n=12) of these reviews reported on the effectiveness of e-engagement or participation promotion strategies. These evaluations were generally not conducted within very large observational digital cohorts. Most of the contributing reviews included multipurpose cohort studies (with both observational and interventional elements) conducted in clinical and research settings. Email or SMS text message reminders, SMS text messages or voice notifications, and incentives were the most commonly used design features to engage and retain participants. For parental outcomes, engagement-facilitation interventions influenced uptake and behavior change, including video feedback, goal setting, and intensive human facilitation and support. Participant-stated preferences for content included new knowledge, reminders, solutions, and suggestions about health issues presented in a clear, short, and personalized way. Perinatal and postpartum women valued self-monitoring and personalized feedback. Digital reminders and multiple SMS text messages were specific strategies that were found to increase adherence to medication and clinic attendance, respectively., Conclusions: This review adds to the growing literature evaluating methods to optimize engagement and participation that may apply to large-scale studies using digital methods; it is promising that most e-engagement and participation promotion strategies appear to be effective. However, these reviews canvassed relatively few strategies, suggesting that few alternative strategies have been experimentally evaluated. The reviews also revealed a dearth of experimental evidence generated within very large observational digital cohort studies, which may reflect the small number of such studies worldwide. Thus, very large studies may need to proactively build in experimental opportunities to test engagement and retention approaches to enhance the success of their own and other large digital contact studies., (©Joanna Nkyekyer, Susan A Clifford, Fiona K Mensah, Yichao Wang, Lauren Chiu, Melissa Wake. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 14.05.2021.)

Amino acid (AA) concentrations are influenced by both exogenous (e.g. diet, lifestyle) and endogenous factors (e.g. genetic, transcriptomic, epigenetic, and metabolomic). Fasting plasma AA profiles in adulthood are predictive of diabetes risk over periods of up to 12 years. Data on AA profiles in cross-generational cohorts, including individuals from shared gene-environment settings are scarce, but would allow the identification of the contribution of heritable and environmental factors characterising the levels of circulating AAs. This study aimed to investigate parent-child (familial dyad) concordance, absolute differences between generations- (children versus adults), age- (in adults: 28-71 years), and sex-dependent differences in plasma AA concentrations. Plasma AA concentrations were measured by UHPLC/MS-MS in 1166 children [mean (SD) age 11 (0.5) years, 51% female] and 1324 of their parents [44 (5.1) years, 87% female]. AA concentrations were variably concordant between parents and their children (5-41% of variability explained). Most AA concentrations were higher in adults than children, except for the non-essential AAs arginine, aspartic acid, glutamine, hydroxy-proline, proline, and serine. Male adults and children typically had higher AA concentrations than females. The exceptions were alanine, glutamine, glycine, hydroxy-proline, serine, and threonine in girls; and glycine and serine in women. Age, sex, and shared familial factors are important determinants of plasma AA concentrations.

Study Objectives: To examine longitudinal, bidirectional associations among behavioral sleep problems, internalizing and externalizing symptoms, and domains of health-related quality of life (HRQoL) from early childhood to adolescence in a population sample of Australian children., Method: Data were drawn from the Longitudinal Study of Australian Children, a national prospective cohort study with 4983 children participating in the Kindergarten cohort. Data were collected when children were aged 4-5, 6-7, 8-9, 10-11, and 12-13 years. At each study wave, the primary parent (97% mothers) reported on behavioral child sleep problems, internalizing and externalizing symptoms, and HRQoL domains (psychosocial and physical). Cross-lagged structural equation models were used to evaluate bidirectional associations., Results: At nearly every age, behavioral sleep problems were associated with worse subsequent psychosocial and physical HRQoL. Despite bidirectional associations between mental health and HRQoL at many waves, HRQoL domains more strongly predicted later internalizing symptoms, while externalizing symptoms more strongly predicted later HRQoL. Many of the bidirectional associations among sleep, mental health, and HRQoL were found earlier in childhood., Conclusions: Behavioral sleep problems may forecast later HRQoL psychosocial and physical impairments. Attending to both sleep problems and HRQoL could prevent the progression of internalizing conditions, while a focus on externalizing concerns could prevent the worsening of these symptoms, sleep problems, and HRQoL, particularly during the transition to school., (© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Background: Trimethylamine N-oxide (TMAO) is a diet- and microbiome-derived metabolite and a proposed biomarker of adverse cardiometabolic outcomes. TMAO studies have mainly been conducted in individuals with cardiometabolic disease, and studies in population-derived samples are limited., Objective: We aimed to investigate the associations between plasma TMAO concentrations and its precursors [carnitine, choline, betaine, and dimethylglycine (DMG)] with metabolic syndrome (MetS) scores, preclinical cardiovascular phenotypes, and inflammatory biomarkers (i.e. high-sensitivity C-reactive protein and serum glycoprotein acetyls) in a population-derived cohort of children and their parents., Methods: The concentrations of TMAO and its precursors were quantified using UHPLC coupled with tandem MS (UHPLC/MS-MS) in 1166 children (mean age 11 y ± 0.5 y, 51% female) and 1324 adults (44 y ± 5.1 y, 87% female) participating in The Growing Up in Australia's Child Health CheckPoint Study. We developed multivariable fractional polynomial models to analyze associations between TMAO, its precursors, MetS (adjusted for sex and age), and cardiovascular phenotypes (adjusted for sex, age, BMI, household income, and the urinary albumin to creatinine ratio). Pearson's correlations were computed to identify associations between TMAO, its precursors, and inflammatory biomarkers., Results: The concentrations of TMAO precursors, but not TMAO itself, were associated with MetS, cardiovascular phenotypes, and inflammatory biomarkers in children and adults., Conclusions: TMAO precursors, but not TMAO itself, were associated with adverse cardiometabolic and inflammatory phenotypes in children and adults. TMAO precursor concentrations may better reflect cardiovascular health and inflammatory status within the wider population. Replication in other population settings and mechanistic studies are warranted., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objectives: To examine how overweight and obesity at specific ages and overall BMI growth patterns throughout childhood predict cardiometabolic phenotypes at 11 to 12 years., Methods: In a population-based sample of 5107 infants, BMI was measured every 2 years between ages 2 to 3 and 10 to 11 years. We identified 5 BMI trajectories using growth curve models. At ages 11 to 12 years, 1811 children completed assessments for metabolic syndrome risk scores, carotid-femoral pulse wave velocity, and carotid intima-media thickness. Multivariable regression models were used to estimate associations, adjusted for potential confounders (eg, age, sex, smoking exposure, and small for gestational age)., Results: Overweight and obesity from early childhood onward were strongly associated with higher cardiometabolic risk at 11 to 12 years of age. At age 6 to 7 years, compared with those with a healthy weight, children with overweight had higher metabolic syndrome risk scores by 0.23 SD units (95% confidence interval 0.05 to 0.41) and with obesity by 0.76 SD units (0.51-1.01), with associations almost doubling by age 10 to 11 years. Obese (but not overweight) children had higher outcome pulse wave velocity (0.64-0.73 SD units) from ages 6 to 7 years and slightly higher outcome carotid intima-media thickness (0.20-0.30 SD units) at all ages. Cumulative exposure to high BMI from 2 to 3 years of age carried the greatest cardiometabolic risk, with a gradient of risk across trajectories., Conclusions: High early-childhood BMI is already silently associated with the development of cardiometabolic risk by 11 to 12 years, highlighting the urgent need for effective action to reduce overweight and obesity in early childhood., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Background: Trimethylamine N-oxide (TMAO) is a microbiome- and diet-derived metabolite implicated in adverse cardiovascular outcomes. To date, studies of plasma TMAO concentrations have largely focused on individuals with metabolic disease. As such, data on TMAO concentrations in population settings and parent-child dyads are lacking., Objectives: This study aimed to investigate parent-child concordance, age, and sex effects on plasma concentrations of TMAO and its precursors [l-carnitine, choline, betaine, and dimethylglycine (DMG)]. Associations between concentrations of TMAO and its precursors and self-reported dietary intakes of animal protein (i.e., red meat, meat products, chicken, fish, milk products, and cheese) and fast-food meals were also investigated., Methods: A total of 1166 children (mean ± SD age: 11 ± 0.5 y, 51% female) and 1324 parents (mean ± SD age: 44 ± 5.1 y, 87% female) had a biomedical assessment as part of Growing Up in Australia's Child Health Checkpoint. Plasma TMAO and precursor concentrations were quantified using ultra-high-pressure LC coupled with tandem MS., Results: Familial dyads significantly contributed to plasma TMAO and precursor concentrations ( P  < 0.0001), explaining 37% of variance for TMAO concentrations. Least-square mean ± SE plasma TMAO was lower in children (0.79 ± 0.02 µM on the log-scale) than in adults (1.22 ± 0.02 µM). By contrast, children's betaine (40.30 ± 0.34 µM) and DMG concentrations (1.02 ± 0.01 µM on the log-scale) were higher than adults' betaine (37.50 ± 0.32 µM) and DMG concentrations (0.80 ± 0.01 µM) ( P  < 0.0001). Mean values of all metabolites, except adult TMAO, were higher in males than in females ( P  < 0.001). Greater reported intake of red meat and fish was associated with higher TMAO concentrations in both children [estimates (95% CIs) for red meat: 0.06 (0.01, 0.10); fish: 0.11 (0.06, 0.17)] and adults [red meat: 0.13 (0.08, 0.17); meat products: 0.07 (0.03, 0.12); and fish: 0.09 (0.04, 0.14)]., Conclusions: Age, sex, and shared family factors, including diet, contribute to variation in plasma concentrations of TMAO and its precursors., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Objectives: Snacks contribute to overconsumption of energy-dense foods and thence obesity. Previous studies in this area are limited by self-reported data and small samples. In a large population-based cohort of parent-child dyads, we investigated how modification of pre-packaged snack food, i.e. (a) item quantity and variety, and (b) dishware (boxed container) size affected intake., Methods: Design: Randomized trial nested within the cross-sectional Child Health CheckPoint of the Longitudinal Study of Australian Children, clustered by day of visit., Sample: 1299 11-12 year olds, 1274 parents., Exposure: 2 × 2 manipulation of snack box container size and item quantity/variety: (1) small box, few items, (2) large box, few items, (3) small box, more items, (4) large box, more items., Procedure: Participants received a snack box during a 15 min break within their 3.5 h visit; any snacks remaining were weighed., Outcomes: Consumed quantity (grams) and energy intake (kilojoules)., Analyses: Unadjusted linear regression., Results: Children who were offered a greater quantity and variety of snack items consumed considerably more energy and a slightly higher food mass (main effect for energy intake: 349 kJ, 95% CI 282-416, standardized mean difference (effect size) 0.66; main effect for mass: 10 g, 95% CI 3-17, effect size 0.17). In contrast, manipulating box size had little effect on child consumption, and neither box size nor quantity/variety of items consistently affected adults' consumption., Conclusion: In children, reducing the number and variety of snack food items available may be a more fruitful intervention than focusing on container or dishware size. Effects observed among adults were small, although we could not exclude social desirability bias in adults aware of observation.

Objectives: To describe the distribution of health-related quality of life (HRQL) in a national sample of Australian children aged 11-12 years and their parents, and examine associations within parent-child dyads., Design: The Child Health CheckPoint, a population-based cross-sectional study nested between waves 6 and 7 of the Longitudinal Study of Australian Children (LSAC)., Setting: Assessment centres in seven Australian cities and eight regional towns, or home visit; February 2015 to March 2016., Participants: Of all participating CheckPoint families (n=1874), 1853 children (49.0% girls) and 1863 parents (87.7% mothers) with HRQL data were included (1786 pairs)., Outcome Measures: HRQL was self-reported using preference-based (Child Health Utility 9Dimension, CHU9D) and non-preference-based (Pediatric Quality of Life, PedsQL V.4.0) measures for children and preference-based measures for parents (CHU9D; Assessment of Quality of Life 8 Dimension, AQoL-8D). Utility scores from preference-based measures were calculated using existing Australian algorithms to present a score on a 0-1 scale, where 1 represents full health. Parent-child concordance was assessed using Pearson's correlation coefficients and adjusted linear regression models. Survey weights and methods were applied to account for LSAC's complex sample design, stratification and clustering within postcodes., Results: Children's means and SD were 0.81 (SD 0.16) for CHU9D and 78.3 (SD 13.03) for PedsQL. In adults, mean HRQL for AQoL-8D and CHU9D were 0.78 (SD 0.16) and 0.89 (SD 0.10), respectively. Mean HRQL was similar for boys and girls, but slightly higher for fathers than mothers. The Pearson correlation coefficient for parent-child CHU9D values was 0.13 (95% CI 0.09 to 0.18). Percentiles and concordance are presented for both samples for males and females separately and together., Conclusions: We provide Australian paediatric population values for HRQL measures, and the first national CHU9D values for mid-life adults. At age 11-12 years in this relatively healthy sample, parent-child concordance in HRQL was small., Competing Interests: Competing interests: MW received support from Sandoz to present at a symposium outside the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To describe the epidemiology and parent-child concordance of hearing, speech reception, vocabulary and language in Australian parent-child dyads at child age 11 to 12 years., Design: Population-based cross-sectional study (Child Health CheckPoint) nested within the Longitudinal Study of Australian Children., Setting: Assessment centres in seven Australian cities and eight regional towns or home visits around Australia, February 2015 to March 2016., Participants: Of all participating CheckPoint families (n=1874), 1516 children (50% female) and 1520 parents (87% mothers, mean age 43.8 years) undertook at least one of four measurements of hearing and language., Outcome Measures: Hearing threshold (better ear mean of 1, 2 and 4 kHz) from pure-tone audiometry, speech reception threshold, receptive vocabulary, expressive and receptive languages using a sentence repetition task. Parent-child concordance was examined using Pearson's correlation coefficients and adjusted linear regression models. Survey weights and methods accounted for Longitudinal Study of Australian Children's complex sampling and stratification., Results: Children had a similar speech reception threshold to parents (children mean -14.3, SD 2.4; parents -14.9, SD 3.2 dB) but better hearing acuity (children 8.3, SD 6.3; parents 13.4, SD 7.0 decibels hearing level). Standardised sentence repetition scores were similar (children 9.8, SD 2.9; parents 9.1, SD 3.3) but, as expected, parents had superior receptive vocabularies. Parent-child correlations were higher for the cognitively-based language measures (vocabulary 0.31, 95% CI 0.26 to 0.36; sentence repetition 0.29, 95% CI 0.24 to 0.34) than the auditory measures (hearing 0.18, 95% CI 0.13 to 0.23; speech reception threshold 0.18, 95% CI 0.13 to 0.22). Mother-child and father-child concordances were similar for all measures., Conclusions: We provide population reference values for multiple measures spanning auditory and verbal communication systems in children and mid-life adults. Concordance values aligned with previous twin studies and offspring studies in adults, in keeping with polygenic heritability that is modest for audition but around 60% for language by late childhood., Competing Interests: Competing interests: MW received support from Sandoz to present at a symposium outside the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study investigates how dietary patterns and scores are associated with subsequent BMI and waist:height ratio (WHtR), and how BMI and WHtR are associated with subsequent dietary patterns or scores, from 2-3 to 10-11 and 4-5 to 14-15 years of age. In the Longitudinal Study of Australian Children, height, weight and waist circumference were measured biennially in children, yielding BMI z-score and WHtR. Parents, latterly children, reported frequency of child consumption of 12-16 food/drink items during the previous 24 h. At each wave, we empirically derived dietary patterns using factor analyses, and dietary scores based on the 2013 Australian Dietary Guidelines. We used structural-equation modelling to investigate cross-lagged associations (n 1972-2882) between diet and body composition measures in univariable and multivariable analyses. Dietary scores/patterns did not consistently predict WHtR and BMI z-score in the next wave, nor did BMI z-score and WHtR consistently predict diet in the next wave. The few associations seen were weak and often in the opposite direction to that hypothesised. The largest effect, associated with each standard deviation increase in BMI in wave 5 of the K cohort (age 12-13 years), was a 0·06 standard deviation estimated mean increase in dietary score (higher quality diet) in the subsequent wave (95 % CI 0·02, 0·11, P=0·003). Associations between dietary patterns/scores and body composition were not strongly evident in either direction. Better quantitative childhood dietary tools feasible for large-scale administration are needed to quantify how dietary patterns, energy intake and anthropometry co-develop.

Objective: To determine which parental health behaviours early in childhood most strongly predict whole-of-childhood dietary trajectories., Design: Population-based Longitudinal Study of Australian Children (LSAC, waves 1-6; 2004-2014). Exposures were parents' fruit/vegetable consumption, alcohol, smoking and physical activity at child age 0-1 years (B Cohort) or 4-5 years (K Cohort). Outcomes, from repeated biennial short diet diaries, were group-based trajectories of (i) dietary scores and empirically derived patterns of (ii) healthful and (iii) unhealthful foods consumed, spanning ages 2-3 to 10-11 years (B Cohort) and 4-5 to 14-15 years (K Cohort). We investigated associations of baseline parental health behaviours with child dietary trajectories using multinomial logistic regression., Setting: Australian homes., Subjects: Of children, 4443 (87·0 %) from the B Cohort and 4620 (92·7 %) from the K Cohort were included in all trajectories. Multivariable analyses included 2719 to 2905 children and both parents., Results: Children whose primary caregiver reported the lowest fruit/vegetable consumption had markedly higher odds of belonging to the least healthy score and pattern trajectories (K Cohort: OR=8·7, 95 % CI 5·0, 15·1 and OR=8·4, 95 % CI 4·8, 14·7, respectively); associations were weaker (K Cohort: OR=2·3, 95 % CI 1·0, 5·2) for the unhealthiest pattern trajectory. Secondary caregiver fruit/vegetable associations were smaller and inconsistent. Parental alcohol, smoking and physical activity were not predictive in multivariable analyses. Results were largely replicated for the B Cohort., Conclusions: Low primary caregiver fruit/vegetable consumption increased nearly ninefold the odds of children being in the lowest intake of healthy, but only weakly predicted unhealthy, food trajectories. Healthy and unhealthy food intake may have different determinants.