Impact of Distinct Anti-Androgen Exposures on the Plasma Metabolome in Feminizing Gender-Affirming Hormone Therapy.

CONTEXT: The plasma metabolome is a functional readout of metabolic activity and is associated with phenotypes exhibiting sexual dimorphism, such as cardiovascular disease. Sex hormones are thought to play a key role in driving sexual dimorphism. OBJECTIVE: Gender-affirming hormone therapy (GAHT) is a cornerstone of transgender care, but longitudinal changes in the plasma metabolome with feminizing GAHT have not been described. METHODS: Blood samples were collected at baseline and after three and six months of GAHT from transgender women (n = 53). Participants were randomized to different anti-androgens, cyproterone acetate or spironolactone. NMR-based metabolomics was used to measure 249 metabolic biomarkers in plasma. Additionally, we used metabolic biomarker data from an unrelated cohort of children and their parents (n = 3,748) to identify sex- and age-related metabolite patterns. RESULTS: We identified 43 metabolic biomarkers altered after six months in both anti-androgen groups, most belonging to the very low- or low-density lipoprotein subclasses, with all but one showing a decrease. We observed a cyproterone acetate-specific decrease in glutamine, glycine, and alanine levels. Notably, of the metabolic biomarkers exhibiting the most abundant 'sex- and age-related' pattern (higher in assigned female children and lower in assigned female adults, relative to assigned males), 80% were significantly lowered after GAHT, reflecting a shift toward the adult female profile. CONCLUSION: Our results suggest an anti-atherogenic signature in the plasma metabolome after the first six months of feminizing GAHT, with cyproterone acetate also reducing specific plasma amino acids. This study provides novel insight into the metabolic changes occurring across feminizing GAHT.

Cord blood lipid correlation network profiles are associated with subsequent attention-deficit/hyperactivity disorder and autism spectrum disorder symptoms at 2 years: a prospective birth cohort study.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions with early life origins. Alterations in blood lipids have been linked to ADHD and ASD; however, prospective early life data are limited. This study examined (i) associations between the cord blood lipidome and ADHD/ASD symptoms at 2 years of age, (ii) associations between prenatal and perinatal predictors of ADHD/ASD symptoms and cord blood lipidome, and (iii) mediation by the cord blood lipidome. METHODS: From the Barwon Infant Study cohort (1074 mother-child pairs, 52.3% male children), child circulating lipid levels at birth were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. These were clustered into lipid network modules via Weighted Gene Correlation Network Analysis. Associations between lipid modules and ADHD/ASD symptoms at 2 years, assessed with the Child Behavior Checklist, were explored via linear regression analyses. Mediation analysis identified indirect effects of prenatal and perinatal risk factors on ADHD/ASD symptoms through lipid modules. FINDINGS: The acylcarnitine lipid module is associated with both ADHD and ASD symptoms at 2 years of age. Risk factors of these outcomes such as low income, Apgar score, and maternal inflammation were partly mediated by higher birth acylcarnitine levels. Other cord blood lipid profiles were also associated with ADHD and ASD symptoms. INTERPRETATION: This study highlights that elevated cord blood birth acylcarnitine levels, either directly or as a possible marker of disrupted cell energy metabolism, are on the causal pathway of prenatal and perinatal risk factors for ADHD and ASD symptoms in early life. FUNDING: The foundational work and infrastructure for the BIS was sponsored by the Murdoch Children's Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the Minderoo Foundation, the European Union's Horizon 2020 research and innovation programme (ENDpoiNTs: No 825759), National Health and Medical Research Council of Australia (NHMRC) and Agency for Science, Technology and Research Singapore [APP1149047], The William and Vera Ellen Houston Memorial Trust Fund (via HOMER Hack), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, Geelong Medical and Hospital Benefits Association, Vanguard Investments Australia Ltd, the Percy Baxter Charitable Trust, and Perpetual Trustees.

Comparison of the stability of glycoprotein acetyls and high sensitivity C-reactive protein as markers of chronic inflammation.

It has been suggested that glycoprotein acetyls (GlycA) better reflects chronic inflammation than high sensitivity C-reactive protein (hsCRP), but paediatric/life-course data are sparse. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK Biobank, we compared short- (over weeks) and long-term (over years) correlations of GlycA and hsCRP, cross-sectional correlations between GlycA and hsCRP, and associations of pro-inflammatory risk factors with GlycA and hsCRP across the life-course. GlycA showed high short-term (weeks) stability at 15 years (r = 0.75; 95% CI = 0.56, 0.94), 18 years (r = 0.74; 0.64, 0.85), 24 years (r = 0.74; 0.51, 0.98) and 48 years (r = 0.82 0.76, 0.86) and this was comparable to the short-term stability of hsCRP at 24 years. GlycA stability was moderate over the long-term, for example between 15 and 18 years r = 0.52; 0.47, 0.56 and between 15 and 24 years r = 0.37; 0.31, 0.44. These were larger than equivalent correlations of hsCRP. GlycA and concurrently measured hsCRP were moderately correlated at all ages, for example at 15 years (r = 0.44; 0.40, 0.48) and at 18 years (r = 0.55; 0.51, 0.59). We found similar associations of known proinflammatory factors and inflammatory diseases with GlycA and hsCRP. For example, BMI was positively associated with GlycA (mean difference in GlycA per standard deviation change in BMI = 0.08; 95% CI = 0.07, 0.10) and hsCRP (0.10; 0.08, 0.11). This study showed that GlycA has greater long-term stability than hsCRP, however associations of proinflammatory factors with GlycA and hsCRP were broadly similar.

Caries Detection in Primary Teeth Using Intraoral Scanners Featuring Fluorescence: Protocol for a Diagnostic Agreement Study.

BACKGROUND: Digital methods that enable early caries identification can streamline data collection in research and optimize dental examinations for young children. Intraoral scanners are devices used for creating 3D models of teeth in dentistry and are being rapidly adopted into clinical workflows. Integrating fluorescence technology into scanner hardware can support early caries detection. However, the performance of caries detection methods using 3D models featuring color and fluorescence in primary teeth is unknown. OBJECTIVE: This study aims to assess the diagnostic agreement between visual examination (VE), on-screen assessment of 3D models in approximate natural colors with and without fluorescence, and application of an automated caries scoring system to the 3D models with fluorescence for caries detection in primary teeth. METHODS: The study sample will be drawn from eligible participants in a randomized controlled trial at the Royal Children's Hospital, Melbourne, Australia, where a dental assessment was conducted, including VE using the International Caries Detection and Assessment System (ICDAS) and intraoral scan using the TRIOS 4 (3Shape TRIOS A/S). Participant clinical records will be collected, and all records meeting eligibility criteria will be subject to an on-screen assessment of 3D models by 4 dental practitioners. First, all primary tooth surfaces will be examined for caries based on 3D geometry and color, using a merged ICDAS index. Second, the on-screen assessment of 3D models will include fluorescence, where caries will be classified using a merged ICDAS index that has been modified to incorporate fluorescence criteria. After 4 weeks, all examiners will repeat the on-screen assessment for all 3D models. Finally, an automated caries scoring system will be used to classify caries on primary occlusal surfaces. The agreement in the total number of caries detected per person between methods will be assessed using a Bland-Altman analysis and intraclass correlation coefficients. At a tooth surface level, agreement between methods will be estimated using multilevel models to account for the clustering of dental data. RESULTS: Automated caries scoring of 3D models was completed as of October 2023, with the publication of results expected by July 2024. On-screen assessment has commenced, with the expected completion of scoring and data analysis by March 2024. Results will be disseminated by the end of 2024. CONCLUSIONS: The study outcomes may inform new practices that use digital models to facilitate dental assessments. Novel approaches that enable remote dental examination without compromising the accuracy of VE have wide applications in the research environment, clinical practice, and the provision of teledentistry. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12622001237774; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384632. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51578.

Effects of prenatal alcohol exposure on infant lung function, wheeze, and respiratory infections in Australian children.

BACKGROUND: Prenatal alcohol exposure (PAE) is a known risk factor for a range of adverse outcomes, such as facial dysmorphism, adverse birth outcomes, and neurodevelopmental changes. Preclinical research shows that PAE also inhibits lung development, lowers surfactant protein expression, has detrimental effects on alveolar macrophages, and decreases both T and B cell numbers. However, clinical evidence of respiratory impacts from PAE is limited. This study explored whether lung function, wheeze, and incidence of respiratory infections differ in children with PAE compared with unexposed children. METHODS: Data from the Barwon Infant Study (n = 1074) were examined. PAE data were extracted from maternal questionnaires at trimesters 1 and 2 (combined), and trimester 3, and included as "total standard drinks" during each trimester and total pregnancy intake, a binary yes/no for PAE, and binge drinking (>5 standard drinks in one session). Respiratory outcomes were parent-reported wheeze, lung function (measured by multiple breath washout), and parent report and medical record indicators of health service attendances for respiratory conditions. Linear and logistic regressions were performed to quantify relationships between PAE and respiratory outcomes, controlling for socioeconomic status, birthweight, sex, gestational age, and maternal smoking. RESULTS: Binge drinking was associated with increased health service attendance for respiratory condition(s) in the first 12 months of life (OR = 5.0, 95% CI (1.7, 20.7), p = 0.008). We did not find a relationship between binary PAE and binge drinking with lung function at 4 weeks of age or wheeze at 12 months. The number of standard drinks consumed in trimester two was associated with a lower lung clearance index (ß = -0.011 turnovers, 95% CI (-0.0200, -0.0013), p = 0.03), and a small increase in functional residual capacity (ß = 0.34 mL, 95% CI (0.02, 0.66), p = 0.04). CONCLUSIONS: We found an association between binge drinking and health service utilization for respiratory conditions in infancy, but no evidence that low-level PAE was associated with adverse respiratory outcomes.

Maternal glycemic status during pregnancy and mid-childhood plasma amino acid profiles: findings from a multi-ethnic Asian birth cohort.

BACKGROUND: Increasing maternal glycaemia across the continuum during pregnancy may predispose offspring to subsequent cardiometabolic risk later in life. However, evidence of long-term impacts of maternal glycemic status on offspring amino acid (AA) profiles is scarce. We aimed to investigate the association between maternal antenatal glycaemia and offspring mid-childhood amino acid (AA) profiles, which are emerging cardiometabolic biomarkers. METHODS: Data were drawn from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) study, a multi-ethnic Asian birth cohort. A subset of 422 mother-child dyads from the GUSTO study, who was followed from early pregnancy to mid-childhood, was included. Mothers underwent an oral glucose tolerance test (OGTT) at 26-28 weeks gestation, with fasting and 2-h plasma glucose concentrations measured and gestational diabetes mellitus (GDM) diagnosed per WHO 1999 guidelines. Offspring fasting plasma samples were collected at mean age 6.1 years, from which AA profiles of nine AAs, alanine, glutamine, glycine, histidine, isoleucine, leucine, valine, phenylalanine, and tyrosine were measured. Total branched-chain amino acids (BCAAs) were calculated as the sum of isoleucine, leucine, and valine concentrations. Multi-variable linear regression was used to estimate the association of maternal glycemic status and offspring mid-childhood AA profiles adjusting for maternal age, ethnicity, maternal education, parity, family history of diabetes, ppBMI, child sex, age and BMI z-scores. RESULTS: Approximately 20% of mothers were diagnosed with GDM. Increasing maternal fasting glucose was significantly associated with higher offspring plasma valine and total BCAAs, whereas higher 2-h glucose was significantly associated with higher histidine, isoleucine, valine, and total BCAAs. Offspring born to mothers with GDM had higher valine (standardized mean difference 0.27 SD; 95% CI: 0.01, 0.52), leucine (0.28 SD; 0.02, 0.53), and total BCAAs (0.26 SD; 0.01, 0.52) than their counterparts. Inconsistent associations were found between maternal GDM and other amino acids among offspring during mid-childhood. CONCLUSIONS: Increasing maternal fasting and post-OGTT glucose concentrations at 26-28 weeks gestation were significantly associated with mid-childhood individual and total BCAAs concentrations. The findings suggest that elevated maternal glycaemia throughout pregnancy, especially GDM, may have persistent programming effects on offspring AA metabolism which were strongly associated with adverse cardiometabolic profiles at mid-childhood.

Polygenic Risk Scores and the Risk of Childhood Overweight/Obesity in Association With the Consumption of Sweetened Beverages: A Population-Based Cohort Study.

Background: Sugar-sweetened beverage (SSB) and non-nutritive sweetened beverage (NNSB) consumption is associated with obesity and are targets for population-level dietary interventions. In children (<16 years), we evaluate whether SSB or NNSB consumption is associated with subsequent (2 years later) overweight and/or obesity, and the effect of consumption on subsequent overweight/obesity differs by BMI polygenic risk score (BMI-PRS). Methods: The nationally representative Longitudinal-Study-of-Australian-Children had biennial data collection from birth (n = 5107) until age 14/15 years (n = 3127). At age 11/12 years, a comprehensive biomedical assessment, including PRS assessment, was undertaken (n = 1422). Parent- or self-reported beverage consumption (SSBs: soft drinks, energy drinks, and/or juice; NNSBs: diet drinks) was measured as any/none over previous 24 hours. BMI-PRS was derived using published results (high PRS ≥75th percentile). At ages 4/5-14/15 children were classified as having obesity, overweight/obesity, or not having overweight/obesity using BMI z-score (CDC cut points). Results: SSB consumption had limited association with subsequent overweight/obesity. NNSB consumption was associated with ∼8% more children with subsequent overweight/obesity at most ages. In older children with high BMI-PRS, associations between NNSB consumption and subsequent overweight/obesity strengthened with age [at age 14-15 for high BMI-PRS, difference in proportion with overweight/obesity among NNSB consumers vs. nonconsumers = 0.38 (95% confidence interval: 0.22 to 0.55, p ≤ 0.001)]. There was limited association between SSB consumption and BMI-PRS. Conclusion: NNSB consumption was associated with increased risk of overweight/obesity for children with greater genetic risk at older ages (12-15 years). Focused intervention among children with high genetic risk could target NNSB consumption; however, reverse causality (children with genetic risk and/or high BMI consume more NNSBs) cannot be excluded.

Maternal oxidative stress during pregnancy associated with emotional and behavioural problems in early childhood: implications for foetal programming.

Childhood mental disorders, including emotional and behavioural problems (EBP) are increasingly prevalent. Higher maternal oxidative stress (OS) during pregnancy (matOSpreg) is linked to offspring mental disorders. Environmental factors contribute to matOSpreg. However, the role of matOSpreg in childhood EBP is unclear. We investigated the associations between (i) matOSpreg and offspring EBP; (ii) social and prenatal environmental factors and matOSpreg; and (iii) social and prenatal factors and childhood EBP and evaluated whether matOSpreg mediated these associations. Maternal urinary OS biomarkers, 8-hydroxyguanosine (8-OHGua; an oxidative RNA damage marker) and 8-hydroxy-2'-deoxyguanosine (8-OHdG; an oxidative DNA damage marker), at 36 weeks of pregnancy were quantified by liquid chromatography-mass spectrometry in a population-derived birth cohort, Barwon Infant Study (n = 1074 mother-infant pairs). Social and prenatal environmental factors were collected by mother-reported questionnaires. Offspring total EBP was measured by Child Behavior Checklist Total Problems T-scores at age two (n = 675) and Strengths and Difficulties Questionnaire Total Difficulties score at age four (n = 791). Prospective associations were examined by multivariable regression analyses adjusted for covariates. Mediation effects were evaluated using counterfactual-based mediation analysis. Higher maternal urinary 8-OHGua at 36 weeks (mat8-OHGua36w) was associated with greater offspring total EBP at age four (ß = 0.38, 95% CI (0.07, 0.69), P = 0.02) and age two (ß = 0.62, 95% CI (-0.06, 1.30), P = 0.07). Weaker evidence of association was detected for 8-OHdG. Five early-life factors were associated with both mat8-OHGua36w and childhood EBP (P-range < 0.001-0.05), including lower maternal education, socioeconomic disadvantage and prenatal tobacco smoking. These risk factor-childhood EBP associations were partly mediated by higher mat8-OHGua36w (P-range = 0.01-0.05). Higher matOSpreg, particularly oxidant RNA damage, is associated with later offspring EBP. Effects of some social and prenatal lifestyle factors on childhood EBP were partly mediated by matOSpreg. Future studies are warranted to further elucidate the role of early-life oxidant damage in childhood EBP.

Live vaccines following intravenous immunoglobulin for Kawasaki disease: Are we vaccinating appropriately?

AIM: Australian and New Zealand guidelines recommend that live vaccines be postponed for 11 months after treatment of Kawasaki disease (KD) with intravenous immunoglobulin (IVIG). We aimed to describe patterns of live-vaccine administration after KD treatment, focusing on the measles-mumps-rubella/measles-mumps-rubella-varicella (MMR/MMRV) vaccines, and to compare real-world practice with current recommendations. METHODS: We combined data from inpatient Electronic Health Records and the Australian Immunisation Register for all children who received IVIG for the treatment of KD under the age of 5 years at two Australian tertiary children's hospitals over a 12-year period. Children who received IVIG <11 months before a scheduled MMR/MMRV were deemed 'at risk' of breaching the guidelines, and those whose subsequent vaccination occurred <11 months after the IVIG were deemed to have 'breached' the guidelines. RESULTS: Of those at risk, three-quarters (76%) breached the guidelines for their first MMR/MMRV. Findings were similar (50%-80%) for the second MMR/MMRV dose. CONCLUSIONS: The majority of Australian children treated for KD with IVIG may not be optimally protected by MMRV vaccination. Immunisation systems should address this avoidable risk.

Defining the lipid profiles of human milk, infant formula, and animal milk: implications for infant feeding.

Background: Breastfed infants have lower disease risk compared to formula-fed infants, however, the mechanisms behind this protection are unknown. Human milk has a complex lipidome which may have many critical roles in health and disease risk. However, human milk lipidomics is challenging, and research is still required to fully understand the lipidome and to interpret and translate findings. This study aimed to address key human milk lipidome knowledge gaps and discuss possible implications for early life health. Methods: Human milk samples from two birth cohorts, the Barwon Infant Study (n = 312) and University of Western Australia birth cohort (n = 342), were analysed using four liquid chromatography-mass spectrometry (LC-MS) methods (lipidome, triacylglycerol, total fatty acid, alkylglycerol). Bovine, goat, and soy-based infant formula, and bovine and goat milk were analysed for comparison. Composition was explored as concentrations, relative abundance, and infant lipid intake. Statistical analyses included principal component analysis, mixed effects modelling, and correlation, with false discovery rate correction, to explore human milk lipidome longitudinal trends and inter and intra-individual variation, differences between sample types, lipid intakes, and correlations between infant plasma and human milk lipids. Results: Lipidomics analysis identified 979 lipids. The human milk lipidome was distinct from that of infant formula and animal milk. Ether lipids were of particular interest, as they were significantly higher, in concentration and relative abundance, in human milk than in formula and animal milk, if present in the latter samples at all. Many ether lipids were highest in colostrum, and some changed significantly through lactation. Significant correlations were identified between human milk and infant circulating lipids (40% of which were ether lipids), and specific ether lipid intake by exclusively breastfed infants was 200-fold higher than that of an exclusively formula-fed infant. Conclusion: There are marked differences between the lipidomes of human milk, infant formula, and animal milk, with notable distinctions between ether lipids that are reflected in the infant plasma lipidome. These findings have potential implications for early life health, and may reveal why breast and formula-fed infants are not afforded the same protections. Comprehensive lipidomics studies with outcomes are required to understand the impacts on infant health and tailor translation.

Childhood infection burden, recent antibiotic exposure and vascular phenotypes in preschool children.

BACKGROUND: Severe childhood infection has a dose-dependent association with adult cardiovascular events and with adverse cardiometabolic phenotypes. The relationship between cardiovascular outcomes and less severe childhood infections is unclear. AIM: To investigate the relationship between common, non-hospitalised infections, antibiotic exposure, and preclinical vascular phenotypes in young children. DESIGN: A Dutch prospective population-derived birth cohort study. METHODS: Participants were from the Wheezing-Illnesses-Study-Leidsche-Rijn (WHISTLER) birth cohort. We collected data from birth to 5 years on antibiotic prescriptions, general practitioner (GP)-diagnosed infections, and monthly parent-reported febrile illnesses (0-1 years). At 5 years, carotid intima-media thickness (CIMT), carotid artery distensibility, and blood pressure (BP) were measured. General linear regression models were adjusted for age, sex, smoke exposure, birth weight z-score, body mass index, and socioeconomic status. RESULTS: Recent antibiotic exposure was associated with adverse cardiovascular phenotypes; each antibiotic prescription in the 3 and 6 months prior to vascular assessment was associated with an 18.1 µm (95% confidence interval, 4.5-31.6, p = 0.01) and 10.7 µm (0.8-20.5, p = 0.03) increase in CIMT, respectively. Each additional antibiotic prescription in the preceding 6 months was associated with an 8.3 mPa-1 decrease in carotid distensibility (-15.6- -1.1, p = 0.02). Any parent-reported febrile episode (compared to none) showed weak evidence of association with diastolic BP (1.6 mmHg increase, 0.04-3.1, p = 0.04). GP-diagnosed infections were not associated with vascular phenotypes. CONCLUSIONS: Recent antibiotics are associated with adverse vascular phenotypes in early childhood. Mechanistic studies may differentiate antibiotic-related from infection-related effects and inform preventative strategies.

BNT162b2 COVID-19 vaccination in children alters cytokine responses to heterologous pathogens and Toll-like receptor agonists.

Background: Vaccines can have beneficial off-target (heterologous) effects that alter immune responses to, and protect against, unrelated infections. The heterologous effects of COVID-19 vaccines have not been investigated in children. Aim: To investigate heterologous and specific immunological effects of BNT162b2 COVID-19 vaccination in children. Methods: A whole blood stimulation assay was used to investigate in vitro cytokine responses to heterologous stimulants (killed pathogens, Toll-like receptor ligands) and SARS-CoV-2 antigens. Samples from 29 children, aged 5-11 years, before and 28 days after a second BNT162b2 vaccination were analysed (V2 + 28). Samples from eight children were analysed six months after BNT162b2 vaccination. Results: At V2 + 28, interferon-γ and monocyte chemoattractant protein-1 responses to S. aureus, E. coli, L. monocytogenes, BCG vaccine, H. influenzae, hepatitis B antigen, poly(I:C) and R848 stimulations were decreased compared to pre-vaccination. For most of these heterologous stimulants, IL-6, IL-15 and IL-17 responses were also decreased. There were sustained decreases in cytokine responses to viral, but not bacterial, stimulants six months after BNT162b2 vaccination. Cytokine responses to irradiated SARS-CoV-2, and spike glycoprotein subunits (S1 and S2) were increased at V2 + 28 for most cytokines and remained higher than pre-vaccination responses 6 months after BNT162b2 vaccination for irradiated SARS-CoV-2 and S1. There was no correlation between BNT162b2 vaccination-induced anti-SARS-CoV2-receptor binding domain IgG antibody titre at V2 + 28 and cytokine responses. Conclusions: BNT162b2 vaccination in children alters cytokine responses to heterologous stimulants, particularly one month after vaccination. This study is the first to report the immunological heterologous effects of COVID-19 vaccination in children.

Change in adiposity is associated with change in glycoprotein acetyls but not hsCRP in adolescents with severe obesity.

BACKGROUND: Obesity-associated chronic inflammation mediates the development of adverse cardiometabolic outcomes. There are sparse data on associations between severe obesity and inflammatory biomarkers in adolescence; most are cross-sectional and limited to acute phase reactants. Here, we investigate associations between adiposity measures and inflammatory biomarkers in children and adolescents with severe obesity both cross-sectionally and longitudinally. METHODS: From the Childhood Overweight Biorepository of Australia (COBRA) study, a total of n = 262 participants, mean age 11.5 years (SD 3.5) with obesity had measures of adiposity (body mass index, BMI; % above the 95th BMI-centile, %>95th BMI-centile; waist circumference, WC; waist/height ratio, WtH; % total body fat, %BF; % truncal body fat, %TF) and inflammation biomarkers (glycoprotein acetyls, GlycA; high-sensitivity C-Reactive Protein, hsCRP; white blood cell count, WBC; and neutrophil/lymphocyte ratio, NLR) assessed at baseline. Ninety-eight individuals at mean age of 15.9 years (3.7) participated in a follow-up study 5.6 (2.1) years later. Sixty-two individuals had longitudinal data. Linear regression models, adjusted for age and sex for cross-sectional analyses were applied. To estimate longitudinal associations between change in adiposity measures with inflammation biomarkers, models were adjusted for baseline measures of adiposity and inflammation. RESULTS: All adiposity measures were cross-sectionally associated with GlycA, hsCRP and WBC at both time points. Change in BMI, %>95th BMI-centile, WC, WtH and %TF were associated with concomitant change in GlycA and WBC, but not in hsCRP and NLR. CONCLUSION: GlycA and WBC but not hsCRP and NLR may be useful in assessing adiposity-related severity of chronic inflammation over time.

International Pediatric COVID-19 Severity Over the Course of the Pandemic.

Importance: Multiple SARS-CoV-2 variants have emerged over the COVID-19 pandemic. The implications for COVID-19 severity in children worldwide are unclear. Objective: To determine whether the dominant circulating SARS-CoV-2 variants of concern (VOCs) were associated with differences in COVID-19 severity among hospitalized children. Design, Setting, and Participants: Clinical data from hospitalized children and adolescents (younger than 18 years) who were SARS-CoV-2 positive were obtained from 9 countries (Australia, Brazil, Italy, Portugal, South Africa, Switzerland, Thailand, UK, and the US) during 3 different time frames. Time frames 1 (T1), 2 (T2), and 3 (T3) were defined to represent periods of dominance by the ancestral virus, pre-Omicron VOCs, and Omicron, respectively. Age groups for analysis were younger than 6 months, 6 months to younger than 5 years, and 5 to younger than 18 years. Children with an incidental positive test result for SARS-CoV-2 were excluded. Exposures: SARS-CoV-2 hospitalization during the stipulated time frame. Main Outcomes and Measures: The severity of disease was assessed by admission to intensive care unit (ICU), the need for ventilatory support, or oxygen therapy. Results: Among 31 785 hospitalized children and adolescents, the median age was 4 (IQR 1-12) years and 16 639 were male (52.3%). In children younger than 5 years, across successive SARS-CoV-2 waves, there was a reduction in ICU admission (T3 vs T1: risk ratio [RR], 0.56; 95% CI, 0.42-0.75 [younger than 6 months]; RR, 0.61, 95% CI; 0.47-0.79 [6 months to younger than 5 years]), but not ventilatory support or oxygen therapy. In contrast, ICU admission (T3 vs T1: RR, 0.39, 95% CI, 0.32-0.48), ventilatory support (T3 vs T1: RR, 0.37; 95% CI, 0.27-0.51), and oxygen therapy (T3 vs T1: RR, 0.47; 95% CI, 0.32-0.70) decreased across SARS-CoV-2 waves in children 5 years to younger than 18 years old. The results were consistent when data were restricted to unvaccinated children. Conclusions and Relevance: This study provides valuable insights into the impact of SARS-CoV-2 VOCs on the severity of COVID-19 in hospitalized children across different age groups and countries, suggesting that while ICU admissions decreased across the pandemic in all age groups, ventilatory and oxygen support generally did not decrease over time in children aged younger than 5 years. These findings highlight the importance of considering different pediatric age groups when assessing disease severity in COVID-19.

The potential of intervening on childhood adversity to reduce socioeconomic inequities in body mass index and inflammation among Australian and UK children: A causal mediation analysis.

BACKGROUND: Lower maternal education is associated with higher body mass index (BMI) and higher chronic inflammation in offspring. Childhood adversity potentially mediates these associations. We examined the extent to which addressing childhood adversity could reduce socioeconomic inequities in these outcomes. METHODS: We analysed data from two early-life longitudinal cohorts: the Longitudinal Study of Australian Children (LSAC; n=1873) and the UK Avon Longitudinal Study of Parents and Children (ALSPAC; n=7085). EXPOSURE: low/medium (below university degree) versus high maternal education, as a key indicator of family socioeconomic position (0-1 year). OUTCOMES: BMI and log-transformed glycoprotein acetyls (GlycA) (LSAC: 11-12 years; ALSPAC: 15.5 years). Mediator: multiple adversities (≥2/<2) indicated by family violence, mental illness, substance abuse and harsh parenting (LSAC: 2-11 years; ALSPAC: 1-12 years). A causal mediation analysis was conducted. RESULTS: Low/medium maternal education was associated with up to 1.03 kg/m2 higher BMI (95% CI: 0.95 to 1.10) and up to 1.69% higher GlycA (95% CI: 1.68 to 1.71) compared with high maternal education, adjusting for confounders. Causal mediation analysis estimated that decreasing the levels of multiple adversities in children with low/medium maternal education to be like their high maternal education peers could reduce BMI inequalities by up to 1.8% and up to 3.3% in GlycA. CONCLUSIONS: Our findings in both cohorts suggest that slight reductions in socioeconomic inequities in children's BMI and inflammation could be achieved by addressing childhood adversities. Public health and social policy efforts should help those affected by childhood adversity, but also consider underlying socioeconomic conditions that drive health inequities.

Rising Kawasaki disease incidence in New Zealand: analysis of national population incidence and outcomes 2000-2017.

OBJECTIVE: The recent epidemiology of Kawasaki disease (KD) in New Zealand (NZ) is unknown. Our aim was to describe the incidence, seasonal variation, long-term outcomes and mortality for KD in NZ. DESIGN: Retrospective national database analysis. SETTING: New Zealand. PATIENTS: First hospitalisation and deaths diagnosed with KD. MAIN OUTCOME MEASURES: Data were extracted for all hospital admissions in NZ coded as KD (International Classification of Diseases (ICD)-9 and ICD-10) from the National Minimum Dataset 1 January 2000 to 31 December 2017. Age, sex, ethnicity and associated diagnoses were available to review. Intervention rates for immunoglobulin administration were also analysed. RESULTS: Over the study period, there were 1008 children with initial hospitalisation for KD. The mean age was 39.8 months (SD 37) and 592 (59%) were boys. The annual incidence rate of KD has increased from 12.2 to 19.5 per 100 000 children <5 years old (0.46 case increase per year; 95% CI 0.09 to 0.83). Children of Asian and Pacific Island ethnicities had the highest incidence (51.2 and 26.1/100 000, respectively). The highest growth in incidence was among East Asian children. The case mortality rate was low (12 of 1008, 1.2%); however, Maori were over-represented (6 of 12 deaths). CONCLUSIONS: There is evidence of increasing KD hospitalisation in NZ, similar to recent studies from Northeast Asia and Australia. KD incidence data were available for retrospective review from a national database, but data on complications and outcomes were incomplete. Notification for KD and an active national surveillance system are recommended to improve care. Future work should focus on factors contributing to poorer outcomes in Maori.

Pre-pregnancy obesity is associated with greater systemic inflammation and increased risk of antenatal depression.

BACKGROUND: Pre-pregnancy obesity is an emerging risk factor for perinatal depression. However, the underlying mechanisms remain unclear. We investigated the association between pre-pregnancy body mass index (BMI) and perinatal depressive symptoms in a large population-based pre-birth cohort, the Barwon Infant Study. We also assessed whether the levels of circulating inflammatory markers during pregnancy mediated this relationship. METHODS: Depressive symptoms were assessed in 883 women using the Edinburgh Postnatal Depression Scale (EPDS) and psychological stress using the Perceived Stress Scale (PSS) at 28 weeks gestation and 4 weeks postpartum. Glycoprotein acetyls (GlycA), high-sensitivity C-reactive protein (hsCRP) and cytokines were assessed at 28 weeks gestation. We performed regression analyses, adjusted for potential confounders, and investigated mediation using nested counterfactual models. RESULTS: The estimated effect of pre-pregnancy obesity (BMI ≥ 30 kg/m2) on antenatal EPDS scores was 1.05 points per kg/m2 increase in BMI (95% CI: 0.20, 1.90; p = 0.02). GlycA, hsCRP, interleukin (IL) -1ra and IL-6 were higher in women with obesity, compared to healthy weight women, while eotaxin and IL-4 were lower. Higher GlycA was associated with higher EPDS and PSS scores and partially mediated the association between pre-pregnancy obesity and EPDS/PSS scores in unadjusted models, but this association attenuated upon adjustment for socioeconomic adversity. IL-6 and eotaxin were negatively associated with EPDS/PSS scores, however there was no evidence for mediation. CONCLUSIONS: Pre-pregnancy obesity increases the risk of antenatal depressive symptoms and is also associated with systemic inflammation during pregnancy. While discrete inflammatory markers are associated with antenatal depressive symptoms and perceived stress, their role in mediating the effects of pre-pregnancy obesity on antenatal depression requires further investigation.

Corrigendum to "Lower risk of multi-system Inflammatory Syndrome in Children (MIS-C) with the Omicron variant" [The Lancet Regional Health - Western Pacific 27 (2022) 100604].

[This corrects the article DOI: 10.1016/j.lanwpc.2022.100604.].

The distribution of dietary choline intake and serum choline levels in Australian women during pregnancy and associated early life factors.

BACKGROUND: Maternal dietary choline has a central role in foetal brain development and may be associated with later cognitive function. However, many countries are reporting lower than recommended intake of choline during pregnancy. METHODS: Dietary choline was estimated using food frequency questionnaires in pregnant women participating in population-derived birth cohort, the Barwon Infant Study (BIS). Dietary choline is reported as the sum of all choline-containing moieties. Serum total choline-containing compounds (choline-c), phosphatidylcholine and sphingomyelin were measured using nuclear magnetic resonance metabolomics in the third trimester. The main form of analysis was multivariable linear regression. RESULTS: The mean daily dietary choline during pregnancy was 372 (standard deviation (SD) 104) mg/day. A total of 236 women (23%) had adequate choline intake (440 mg/day) based on the Australian and New Zealand guidelines, and 27 women (2.6%) took supplemental choline ([Formula: see text] 50 mg/dose) daily during pregnancy. The mean serum choline-c in pregnant women was 3.27 (SD 0.44) mmol/l. Ingested choline and serum choline-c were not correlated (R2) = - 0.005, p = 0.880. Maternal age, maternal weight gain in pregnancy, and a pregnancy with more than one infant were associated with higher serum choline-c, whereas gestational diabetes and environmental tobacco smoke during preconception and pregnancy were associated with lower serum choline-c. Nutrients or dietary patterns were not associated with variation in serum choline-c. CONCLUSION: In this cohort, approximately one-quarter of women met daily choline recommendations during pregnancy. Future studies are needed to understand the potential impact of low dietary choline intake during pregnancy on infant cognition and metabolic intermediaries.