Sex Hormone Treatment for Female Children and young Adults with Disorders Affecting Hypothalamic Pituitary and Ovarian Function.

BACKGROUND: Normal hypothalamic-pituitary-ovarian (HPO) endocrine function is essential for female pubertal and psychosocial development and for ongoing adult physical, sexual and psychosocial health. Girls with hypogonadism, any endocrine disorder causing abnormal uterine bleeding (AUB) or with contraception needs may require sex hormone treatment. Challenges include evolving needs of a young girl through the course of sexual maturation, potential health risks related to the use of sex hormones for pubertal induction, hormone replacement therapy (HRT), menstrual management and/or contraception. SUMMARY: To ensure optimal sex hormone treatment, both a comprehensive understanding of the underlying disorder affecting HPO endocrine function and a professional communication with the patient and physicians involved are warranted. In this narrative mini-review, we discuss pubertal induction and HRT for girls with hypogonadism and the management of AUB and contraception for young women up to age 30 years. Additionally, we provide advice on management of AUB and contraception in young women with common conditions including polycystic ovary syndrome, congenital adrenal hyperplasia and others. A PubMed-literature search including articles published over the last 20 years, together with clinical experience of the authors was integrated to provide treatment recommendations. KEY MESSAGE: Sex hormone treatment, where needed, requires comprehensive understanding of a range of available options. When tailored to individual needs, with flexibility to accommodate changing circumstance in young women it is safe, well tolerated and provides both physical and psychosocial health.

Increased innate immune responses in adolescents with obesity and its relation to subclinical cardiovascular measures: An exploratory study.

Cardiometabolic risk accrues across the life course and childhood and adolescence are key periods for effective prevention. Obesity is associated with inflammation in adults, but pediatric data are scarce. In a cross-sectional and longitudinal study, we investigated immune cell composition and activation in 31 adolescents with obesity (41.9% male, BMIz>2.5, 14.4 years) and 22 controls with healthy weight (45.1% male, -1.5

DEXA-based Fat Mass with the Risk of Worsening Insulin Resistance in Adolescents: A 9-Year Temporal and Mediation Study.

CONTEXT: Surrogate measures of childhood and adolescent obesity have impaired the understanding of body composition's relationship with insulin resistance in the young population. OBJECTIVES: We aim to examine the longitudinal associations of directly measured total fat mass, trunk fat mass, and lean mass with the risk of hyperglycaemia, hyperinsulinemia, and insulin resistance from ages 15-24 years, the mediation path through which lipids and inflammation influence insulin resistance and whether increased fat mass temporally precede insulin resistance. METHODS: We studied 3160 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, who had complete dual-energy Xray absorptiometry measure and fasting blood samples at age 15 years and repeated measures at ages 17- and 24-years clinic visit. Fasting glucose >6.1 mmol/L, insulin >11.78 mU/L, and homeostatic model assessment for insulin resistance (HOMA-IR) ≥75th percentile were categorized as hyperglycaemia, hyperinsulinemia, and high insulin resistance, respectively. Longitudinal associations were examined with generalized logit-mixed effect models, whilst mediation and temporal path analyses were examined using structural equation models, adjusting for cardiometabolic and other lifestyle factors. RESULTS: Among 3160 participants (51% female), fat mass and lean mass increased linearly in both males and females while glucose, insulin, and HOMA-IR had a U-shaped course from age 15 through 24 years. After full adjustment, each 1 kg cumulative increase in total fat mass [odds ratio 1.12 (95% confidence interval 1.11-1.13)] and trunk fat mass [1.21 (1.19-1.23)] from ages 15 through 24 years were associated with a progressively worsening risk of high insulin resistance as well as hyperglycaemia and hyperinsulinemia. The association of increased total fat mass with increased insulin resistance was partly mediated by triglycerides (9% mediation). In the temporal path analysis, higher total fat mass at age 15 years was associated with higher insulin resistance at 17 years, but not vice versa. Higher total fat mass at 17 years was bi-directionally associated with higher insulin resistance at 24 years. CONCLUSION: Mid-adolescence may be an optimal time for interrupting the worsening fat mass-insulin resistance pathologic cycle and attenuating the risk of progressively worsening metabolic dysfunction before young adulthood.

Evidence for the protein leverage hypothesis in preschool children prone to obesity.

BACKGROUND & AIMS: The protein leverage hypothesis (PLH) proposed that strict regulation of protein intake drives energy overconsumption and obesity when diets are diluted by fat and/or carbohydrates. Evidence about the PLH has been found in adults, while studies in children are limited. Thus, we aimed to test the PLH by assessing the role of dietary protein on macronutrients, energy intake, and obesity risk using data from preschool children followed for 1.3 years. METHODS: 553 preschool children aged 2-6 years from the 'Healthy Start' project were included. EXPOSURES: The proportion of energy intake from protein, fat, and carbohydrates collected from a 4-day dietary record. OUTCOMES: Energy intake, BMI z-score, fat mass (FM) %, waist- (WHtR) and hip-height ratio (HHtR). Power function analysis was used to test the leverage of protein on energy intake. Mixture models were used to explore interactive associations of macronutrient composition on all these outcomes, with results visualized as response surfaces on the nutritional geometry. RESULTS: Evidence for the PLH was confirmed in preschool children. The distribution of protein intake (% of MJ, IQR: 3.2) varied substantially less than for carbohydrate (IQR: 5.7) or fat (IQR: 6.3) intakes, suggesting protein intake is most tightly regulated. Absolute energy intake varied inversely with dietary percentage energy from protein (L = -0.14, 95% CI: -0.25, -0.04). Compared to children with high fat or carbohydrate intakes, children with high dietary protein intake (>20% of MJ) had a greater decrease in WHtR and HHtR over the 1.3-year follow-up, offering evidence for the PLH in prospective analysis. But no association was observed between macronutrient distribution and changes in BMI z-score or FM%. CONCLUSIONS: In this study in preschool children, protein intake was the most tightly regulated macronutrient, and energy intake was an inverse function of dietary protein concentration, indicating the evidence for protein leverage. Increases in WHtR and HHtR were principally associated with the dietary protein dilution, supporting the PLH. These findings highlight the importance of protein in children's diets, which seems to have significant implications for childhood obesity risk and overall health.

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.

Evidence for protein leverage in a general population sample of children and adolescents.

BACKGROUND/OBJECTIVES: The strong regulation of protein intake can lead to overconsumption of total energy on diets with a low proportion of energy from protein, a process referred to as protein leverage. The protein leverage hypothesis posits that protein leverage explains variation in energy intake and potentially obesity in ecological settings. Here, we tested for protein leverage and the protein leverage hypothesis in children and adolescents. SUBJECTS/METHODS: A population sample of children, mean (SD) age 7.6 (0.4) years (n = 422), followed up at age 9.8 (0.4) years (n = 387) and at age 15.8 (0.4) years (n = 229), participating for the Physical Activity and Nutrition in Children (PANIC) study. EXPOSURES: 4-day food records-related proportional energy intake of proteins, fats, and carbohydrates. OUTCOMES: energy intake, body mass index (BMI) z-score and dual-energy X-ray absorptiometry-related energy expenditure. RESULTS: Proportional energy intake of proteins was inversely associated with energy intake following power functions at all 3 ages (mean [95%CI] strength of leverage of L = -0.36 [-0.47 to -0.25]; L = -0.26 [-0.37 to -0.15]; L = -0.25 [-0.38 to -0.13]; all P < 0.001). Mixture analysis indicated that variance in energy intake was associated primarily with the proportional intake of energy from proteins, not with either fats or carbohydrates. At all 3 ages, energy intake was not associated with BMI z-score but positively associated with energy expenditure (all P < 0.001). CONCLUSIONS: This study provides evidence consistent with protein leverage in a population sample of children and adolescents. Increased energy intake on diets with lower protein content was counterbalanced by increased energy expenditure and therefore did not translate into increased adiposity.

Decreasing severity of obesity from early to late adolescence and young adulthood associates with longitudinal metabolomic changes implicated in lower cardiometabolic disease risk.

BACKGROUND: Obesity in childhood is associated with metabolic dysfunction, adverse subclinical cardiovascular phenotypes and adult cardiovascular disease. Longitudinal studies of youth with obesity investigating changes in severity of obesity with metabolomic profiles are sparse. We investigated associations between (i) baseline body mass index (BMI) and follow-up metabolomic profiles; (ii) change in BMI with follow-up metabolomic profiles; and (iii) change in BMI with change in metabolomic profiles (mean interval 5.5 years). METHODS: Participants (n = 98, 52% males) were recruited from the Childhood Overweight Biorepository of Australia study. At baseline and follow-up, BMI and the % >95th BMI-centile (percentage above the age-, and sex-specific 95th BMI-centile) indicate severity of obesity, and nuclear magnetic resonance spectroscopy profiling of 72 metabolites/ratios, log-transformed and scaled to standard deviations (SD), was performed in fasting serum. Fully adjusted linear regression analyses were performed. RESULTS: Mean (SD) age and % >95th BMI-centile were 10.3 (SD 3.5) years and 134.6% (19.0) at baseline, 15.8 (3.7) years and 130.7% (26.2) at follow-up. Change in BMI over time, but not baseline BMI, was associated with metabolites at follow-up. Each unit (kg/m2) decrease in sex- and age-adjusted BMI was associated with change (SD; 95% CI; p value) in metabolites of: alanine (-0.07; -0.11 to -0.04; p < 0.001), phenylalanine (-0.07; -0.10 to -0.04; p < 0.001), tyrosine (-0.07; -0.10 to -0.04; p < 0.001), glycoprotein acetyls (-0.06; -0.09 to -0.04; p < 0.001), degree of fatty acid unsaturation (0.06; 0.02 to 0.10; p = 0.003), monounsaturated fatty acids (-0.04; -0.07 to -0.01; p = 0.004), ratio of ApoB/ApoA1 (-0.05; -0.07 to -0.02; p = 0.001), VLDL-cholesterol (-0.04; -0.06 to -0.01; p = 0.01), HDL cholesterol (0.05; 0.08 to 0.1; p = 0.01), pyruvate (-0.08; -0.11 to -0.04; p < 0.001), acetoacetate (0.07; 0.02 to 0.11; p = 0.005) and 3-hydroxybuturate (0.07; 0.02 to 0.11; p = 0.01). Results using the % >95th BMI-centile were largely consistent with age- and sex-adjusted BMI measures. CONCLUSIONS: In children and young adults with obesity, decreasing the severity of obesity was associated with changes in metabolomic profiles consistent with lower cardiovascular and metabolic disease risk in adults.

Impact of Type 1 Diabetes Mellitus on Bone Health in Children.

This paper gives an overview of the impact of type 1 diabetes on bone health in children and adolescents. Firstly, we analyse studies using dual X-ray absorptiometry to assess bone mineral content and bone mineral density. Then, we discuss modern, non-invasive techniques including peripheral quantitative computer tomography (pQCT) and high-resolution pQCT for the detailed assessment of bone health aspects including bone mass, bone geometry, bone microarchitecture, and bone strength. Thereafter, we explore some of the mechanisms that are responsible for diabetic bone disease in children, like low bone turnover and high sclerostin levels. Finally, we summarize some of the evidence for the importance of microvascular disease in the pathophysiology of diabetic bone disease.

The international Perinatal Outcomes in the Pandemic (iPOP) study: protocol.

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread "natural experiment" of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic.

Modest decrease in severity of obesity in adolescence associates with low arterial stiffness.

BACKGROUND AND AIMS: Childhood obesity is associated with cardiovascular risk factors (CVRF), subclinical cardiovascular phenotypes (carotid intima-media thickness, cIMT; pulse-wave velocity, PWV; and carotid elasticity), and adult cardiovascular disease (CVD) mortality. In youth with obesity (body mass index, BMI ≥95th centile), we investigated associations between changes in adiposity and CVRF in early adolescence and subclinical cardiovascular phenotypes in late adolescence. METHODS: Participants had adiposity measures (the severity of obesity in percentage >95th BMI-centile (%>95th BMI-centile)), waist circumference (WC), percentage total body fat (%BF) and CVRF (systolic blood pressure, SBP; glycoprotein acetyls, GlycA; and low-density lipoprotein cholesterol) assessed in early (mean age 10.2 ± 3.5y) and late (15.7 ± 3.7y) adolescence. Subclinical cardiovascular phenotypes were assessed in late adolescence. Multivariable regression analysis was performed. RESULTS: Decreasing the %>95th BMI-centile was associated with carotid elasticity (0.945%/10 mmHg, p = 0.002) in females, and with PWV in males (-0.75 m/s, p < 0.001). Changes in all adiposity measures (per 1-unit increase) were associated with carotid elasticity (-0.020 to -0.063%/10 mmHg, p < 0.005), and PWV (0.011-0.045 m/s, p < 0.005). Changes in GlycA (per 50µmol-increase) were associated with elasticity (-0.162%/10 mmHg, p = 0.042), and changes in SBP (per 10 mmHg-increase) were associated with PWV (0.260 m/s, p < 0.001). Adjusted for change in BMI, the coefficient for GlycA was reduced by 46% and for SBP by 12%. Only male sex was associated with cIMT (+34 µm, p = 0.006). CONCLUSIONS: In youth with obesity, decreasing or maintaining the severity of obesity, and decreasing the levels of SBP and GlycA from early to late adolescence was associated with low arterial stiffness.

Diabetes and Overweight/Obesity Are Independent, Nonadditive Risk Factors for In-Hospital Severity of COVID-19: An International, Multicenter Retrospective Meta-analysis.

OBJECTIVE: Obesity is an established risk factor for severe coronavirus disease 2019 (COVID-19), but the contribution of overweight and/or diabetes remains unclear. In a multicenter, international study, we investigated if overweight, obesity, and diabetes were independently associated with COVID-19 severity and whether the BMI-associated risk was increased among those with diabetes. RESEARCH DESIGN AND METHODS: We retrospectively extracted data from health care records and regional databases of hospitalized adult patients with COVID-19 from 18 sites in 11 countries. We used standardized definitions and analyses to generate site-specific estimates, modeling the odds of each outcome (supplemental oxygen/noninvasive ventilatory support, invasive mechanical ventilatory support, and in-hospital mortality) by BMI category (reference, overweight, obese), adjusting for age, sex, and prespecified comorbidities. Subgroup analysis was performed on patients with preexisting diabetes. Site-specific estimates were combined in a meta-analysis. RESULTS: Among 7,244 patients (65.6% overweight/obese), those with overweight were more likely to require oxygen/noninvasive ventilatory support (random effects adjusted odds ratio [aOR], 1.44; 95% CI 1.15-1.80) and invasive mechanical ventilatory support (aOR, 1.22; 95% CI 1.03-1.46). There was no association between overweight and in-hospital mortality (aOR, 0.88; 95% CI 0.74-1.04). Similar effects were observed in patients with obesity or diabetes. In the subgroup analysis, the aOR for any outcome was not additionally increased in those with diabetes and overweight or obesity. CONCLUSIONS: In adults hospitalized with COVID-19, overweight, obesity, and diabetes were associated with increased odds of requiring respiratory support but were not associated with death. In patients with diabetes, the odds of severe COVID-19 were not increased above the BMI-associated risk.

Lower grip strength in youth with obesity identifies those with increased cardiometabolic risk.

BACKGROUND: We examined whether grip strength differentiates youth with obesity with increased cardiometabolic risk. METHODS: The sample comprised 43 youth with severe obesity (mean age 14.8, standard deviation 3.0 years) enrolled in the Childhood Overweight BioRepository of Australia. Grip strength was normalized to body mass and categorized as low and moderate/high. RESULTS: Youth with low grip strength had higher systolic blood pressure (mean difference 13mmHg), low-density lipoprotein cholesterol (0.26mmol/l), continuous metabolic syndrome score (0.36), and carotid intima-media thickness (0.05mm) compared with those with moderate/high grip strength. CONCLUSIONS: Low grip strength may differentiate youth with obesity with increased cardiometabolic risk.

Trained Immunity: Linking Obesity and Cardiovascular Disease across the Life-Course?

Obesity, a chronic inflammatory disease, is the most prevalent modifiable risk factor for cardiovascular disease. The mechanisms underlying inflammation in obesity are incompletely understood. Recent developments have challenged the dogma of immunological memory occurring exclusively in the adaptive immune system and show that the innate immune system has potential to be reprogrammed. This innate immune memory (trained immunity) is characterized by epigenetic and metabolic reprogramming of myeloid cells following endogenous or exogenous stimulation, resulting in enhanced inflammation to subsequent stimuli. Trained immunity phenotypes have now been reported for other immune and non-immune cells. Here, we provide a novel perspective on the putative role of trained immunity in mediating the adverse cardiovascular effects of obesity and highlight potential translational pathways.

Evidence for Protein Leverage in Children and Adolescents with Obesity.

OBJECTIVE: The aim of this study was to test the protein leverage hypothesis in a cohort of youth with obesity. METHODS: A retrospective study was conducted in a cohort of youth with obesity attending a tertiary weight management service. Validated food questionnaires revealed total energy intake (TEI) and percentage of energy intake from carbohydrates (%EC), fats (%EF), and proteins (%EP). Individuals with a Goldberg cutoff ≥ 1.2 of the ratio of reported TEI to basal metabolic rate from fat-free mass were included. A subgroup had accelerometer data. Statistics included modeling of percentage of energy from macronutrients and TEI, compositional data analysis to predict TEI from macronutrient ratios, and mixture models for sensitivity testing. RESULTS: A total of 137 of 203 participants were included (mean [SD] age 11.3 [2.7] years, 68 females, BMI z score 2.47 [0.27]). Mean TEI was 10,330 (2,728) kJ, mean %EC was 50.6% (6.1%), mean %EF was 31.6% (4.9%), and mean %EP was 18.4% (3.1%). The relationship between %EP and TEI followed a power function (L coefficient -0.48; P < 0.001). TEI was inversely associated with increasing %EP. In the subgroup with < 60 min/d of moderate to vigorous physical activity (n = 48), lower BMI z scores were associated with higher %EP and moderate %EC. CONCLUSIONS: In youth with obesity, protein dilution by either carbohydrates or fats increases TEI. Assessment of dietary protein may be useful to assist in reducing TEI and BMI in youth with obesity.

Neighbourhood socioeconomic circumstances, adiposity and cardiometabolic risk measures in children with severe obesity.

BACKGROUND: It has recently been shown that neighbourhood socioeconomic disadvantage in childhood is associated with obesity, hypertension, fatty liver, and type 2 diabetes in adulthood. However, it is largely unknown whether neighbourhood socioeconomic circumstances are important predictors of adiposity and associated measures in children, especially in those with severe obesity. Therefore, we evaluated the associations between neighbourhood socioeconomic factors with the severity of obesity, and related cardiometabolic risk factors in a cohort of obese children. METHODS: The Childhood Overweight BioRepository of Australia (COBRA) cohort study comprises 444 children (mean age 11.1years, mean BMI z-score 2.5). Neighbourhood socioeconomic advantage/disadvantage was evaluated based on postcode information by the national Australian Socio-Economic Indexes for Areas (SEIFA) scores. Participants/parents also completed self-administered questionnaires on neighbourhood related facilities, family education and family income. RESULTS: In analyses adjusted for age, sex and pubertal status, SEIFA indicating neighbourhood education/occupation was negatively associated with BMI, waist circumference and body fat%. Higher family education was associated with lower BMI. Neighbourhood walkability was related to lower waist circumference. Good shopping facilities in the neighbourhood were associated with increased risk of dyslipidemia and fatty liver, and the existence of parks and playgrounds nearby was related to dyslipidemia. CONCLUSIONS: The present data suggest that neighbourhood-related issues are associated with less severe adiposity among children with established obesity. Concerning cardiometabolic risk factors, shopping facilities were related to dyslipidemia and fatty liver. These findings suggest that increased awareness and efforts are needed to diminish socioeconomic inequalities between neighbourhoods.

Sex and puberty-related differences in metabolomic profiles associated with adiposity measures in youth with obesity.

BACKGROUND: Specific patterns of metabolomic profiles relating to cardiometabolic disease are associated with increased weight in adults. In youth with obesity, metabolomic data are sparse and associations with adiposity measures unknown. OBJECTIVES: Primary, to determine associations between adiposity measures and metabolomic profiles with increased cardiometabolic risks in youth with obesity. Secondary, to stratify associations by sex and puberty. METHODS: Participants were from COBRA (Childhood Overweight BioRepository of Australia; a paediatric cohort with obesity). Adiposity measures (BMI, BMI z-score, %truncal and %whole body fat, waist circumference and waist/height ratio), puberty staging and NMR metabolomic profiles from serum were assessed. Statistics included multivariate analysis (principal component analysis, PCA) and multiple linear regression models with false discovery rate adjustment. RESULTS: 214 participants had metabolomic profiles analyzed, mean age 11.9 years (SD ± 3.1), mean BMI z-score 2.49 (SD ± 0.24), 53% females. Unsupervised PCA identified no separable clusters of individuals. Positive associations included BMI z-score and phenylalanine, total body fat % and lipids in medium HDL, and waist circumference and tyrosine; negative associations included total body fat % and the ratio of docosahexaenoic acid/total fatty acids and histidine. Stratifying by sex and puberty, patterns of associations with BMI z-score in post-pubertal males included positive associations with lipid-, cholesterol- and triglyceride-content in VLDL lipoproteins; total fatty acids; total triglycerides; isoleucine, leucine and glycoprotein acetyls. CONCLUSION: In a paediatric cohort with obesity, increased adiposity measures, especially in post-pubertal males, were associated with distinct patterns in metabolomic profiles.

Circadian and ultradian cardiovascular rhythmicity in obese children.

UNLABELLED: Altered circadian and ultradian blood pressure (BP) and heart rate (HR) rhythmicity have been described in diseases with increased cardiovascular risk. We analyzed cardiovascular rhythmicity in obese children. BP and HR rhythmicity was assessed with Fourier analysis from 24-h ambulatory BP measurements in 75 obese children and compared with an age- and gender-matched, lean healthy reference group of 150 subjects. Multivariate regression analysis was applied to identify significant independent factors explaining variability of rhythmicity. Prevalence of 24- and 6-h BP rhythmicity in the obese group was lower (p = 0.03 and p = 0.02), whereas the prevalence of HR rhythmicity was comparable in both groups. Excluding hypertensive participants, the results remained similar. Twenty-four-hour BP and HR acrophase were delayed in obese children (p = 0.004, p < 0.0001), 24-h BP amplitude did not differ (p = 0.07), and 24-h HR amplitude was blunted (p = < 0.0001). BP Mesor in the obese group was higher (p = 0.02); HR Mesor did not differ (p = 0.1). Multivariate regression analysis failed to identify a single anthropometric or blood pressure parameter explaining the variability of BP and HR rhythmicity. CONCLUSION: Prevalence and parameters of circadian and ultradian BP and HR rhythmicity in obese children are altered compared to a healthy reference group, independent of preexisting hypertension. WHAT IS KNOWN: • Altered cardiovascular rhythmicity has been described in children with different diseases such as primary hypertension or chronic renal failure. What is New: • This study reveals altered cardiovascular rhythmicity in obese children compared to an age and gender-matched healthy reference group independent from preexisting hypertension.

Increased ambulatory arterial stiffness index in obese children.

OBJECTIVE: Altered arterial stiffness is a recognized risk factor of poor cardiovascular health. Ambulatory arterial stiffness index (AASI, defined as one minus the regression slope of diastolic on systolic blood pressure values derived from a 24 h arterial blood pressure monitoring, ABPM) is an upcoming and readily available marker of arterial stiffness. Our hypothesis was that AASI is increased in obese children compared to age- and gender matched healthy subjects. METHODS: AASI was calculated from ABPM in 101 obese children (BMI ≥ 1.88 SDS according to age- and sex-specific BMI charts), 45% girls, median BMI SDS 2.8 (interquartile range (IQR) 2.5-3.4), median age 11.5 years (9.1-13.4) and compared with an age and gender matched healthy control group of 71 subjects with median BMI SDS 0.0 (-0.8-0.5). Multivariate regression analysis was applied to identify significant independent factors explaining AASI variability in this population. RESULTS: AASI was significantly higher in obese children compared to controls (0.388 (0.254-0.499) versus 0.190 (0.070-0.320), p < 0.0001), but blood pressure values were similar. In a multivariate analysis including obese children only, AASI was independently predicted by 24-h systolic blood pressure SDS (p = 0.012); in a multivariate analysis including obese children and controls BMI SDS and pulse pressure independently influenced AASI (p < 0.001). CONCLUSIONS: This study shows that AASI, a surrogate marker of arterial stiffness, is increased in obese children. AASI seems to be influenced by BMI and pulse pressure independently of systolic and diastolic blood pressure values, suggesting that other factors are involved in increased arterial stiffness in obese children.

Long-term cardiovascular and non-cardiovascular mortality in women and men with type 1 and type 2 diabetes mellitus: a 30-year follow-up in Switzerland.

BACKGROUND: While studies from other countries have shown an excess mortality in diabetic individuals when compared with the general population, comparable long-term data is not available for Switzerland. AIMS: To assess gender-specific cardiovascular and non-cardiovascular mortality of patients with type 1 and type 2 diabetes compared with the general Swiss population between 1974 and 2005. DESIGN: 533 patients (225 type 1, 308 type 2 diabetes, 52.2% men) were followed for 30 years (10349 person-years). RESULTS: Diabetic patients had an increased all-cause mortality compared with the general population (SMR [95% CI] 3.8 [3.5-4.3]). Standardised mortality ratio (SMR) was higher for type 1 compared with type 2 diabetic patients (4.5 [3.8-5.3] vs 3.5 [3.1-4.0], p = 0.032). For cardiovascular and non-cardiovascular deaths SMRs were 5.6 (95% CI 4.8-6.6) and 2.7 (2.3-3.1) and did not differ according to type of diabetes. SMRs for all-cause and cardiovascular mortality were significantly higher in women compared with men in type 1 (p <0.05 and p <0.01) and type 2 diabetes (p <0.001 and p <0.01). In both types of diabetes, SMRs significantly decreased during the last two decades (p for trend 0.004 and 0.002). CONCLUSIONS: Patients with type 1 and type 2 diabetes had an increased long-term mortality compared with the general Swiss population. Excess mortality was higher in type 1 compared with type 2 diabetes and in women compared with men for both types of diabetes, but steadily decreased over the last two decades.