Sources of Variation in Food-Related Metabolites during Pregnancy.

The extent to which variation in food-related metabolites are attributable to non-dietary factors remains unclear, which may explain inconsistent food-metabolite associations observed in population studies. This study examined the association between non-dietary factors and the serum concentrations of food-related biomarkers and quantified the amount of variability in metabolite concentrations explained by non-dietary factors. Pregnant women (n = 600) from two Canadian birth cohorts completed a validated semi-quantitative food frequency questionnaire, and serum metabolites were measured by multisegment injection-capillary electrophoresis-mass spectrometry. Hierarchical linear modelling and principal component partial R-square (PC-PR2) were used for data analysis. For proline betaine and DHA (mainly exogenous), citrus foods and fish/fish oil intake, respectively, explained the highest proportion of variability relative to non-dietary factors. The unique contribution of dietary factors was similar (15:0, 17:0, hippuric acid, TMAO) or lower (14:0, tryptophan betaine, 3-methylhistidine, carnitine) compared to non-dietary factors (i.e., ethnicity, maternal age, gestational age, pre-pregnancy BMI, physical activity, and smoking) for metabolites that can either be produced endogenously, biotransformed by gut microbiota, and/or derived from multiple food sources. The results emphasize the importance of adjusting for non-dietary factors in future analyses to improve the accuracy and precision of the measures of food intake and their associations with health and disease.

Serum metabolomic signatures of gestational diabetes in South Asian and white European women.

INTRODUCTION: This study aimed to identify serum metabolomic signatures associated with gestational diabetes mellitus (GDM), and to examine if ethnic-specific differences exist between South Asian and white European women. RESEARCH DESIGN AND METHODS: Prospective cohort study with a nested case-control analysis of 600 pregnant women from two Canadian birth cohorts; using an untargeted approach, 63 fasting serum metabolites were measured and analyzed using multisegment injection-capillary electrophoresis-mass spectrometry. Multivariate logistic regression modeling was conducted overall and by cohort. RESULTS: The proportion of women with GDM was higher in South Asians (27.1%) compared with white Europeans (17.9%). Several amino acid, carbohydrate, and lipid pathways related to GDM were common to South Asian and white European women. Elevated circulating concentrations of glutamic acid, propionylcarnitine, tryptophan, arginine, 2-hydroxybutyric acid, 3-hydroxybutyric acid, and 3-methyl-2-oxovaleric acid were associated with higher odds of GDM, while higher glutamine, ornithine, oxoproline, cystine, glycine with lower odds of GDM. Per SD increase in glucose concentration, the odds of GDM increased (OR=2.07, 95% CI 1.58 to 2.71), similarly for metabolite ratios: glucose to glutamine (OR=2.15, 95% CI 1.65 to 2.80), glucose to creatinine (OR=1.79, 95% CI 1.39 to 2.32), and glutamic acid to glutamine (OR=1.46, 95% CI 1.16 to 1.83). South Asians had higher circulating ratios of glucose to glutamine, glucose to creatinine, arginine to ornithine, and citrulline to ornithine, compared with white Europeans. CONCLUSIONS: We identified a panel of serum metabolites implicated in GDM pathophysiology, consistent in South Asian and white European women. The metabolic alterations leading to larger ratios of glucose to glutamine, glucose to creatinine, arginine to ornithine, and citrulline to ornithine in South Asians likely reflect the greater burden of GDM among South Asians compared with white Europeans.

How Do Health Schemas Inform Healthy Behaviours During Pregnancy? Qualitative Findings from the Be Healthy in Pregnancy (BHIP) Study.

OBJECTIVE: Excess gestational weight gain (GWG) is associated with adverse long and short-term outcomes for both woman and child, yet evidence demonstrates pregnant women are frequently not engaging in healthy behaviours linked to appropriate weight gain. The purpose of the current study was to explore women's values and beliefs related to weight, nutrition and physical activity during pregnancy and to describe how these beliefs influence their behaviours. METHODS: As part of a larger randomized controlled trial, we conducted 20 focus groups with 66 pregnant women between 16 and 24-weeks gestation using a semi-structured interview guide. Focus groups were recorded and transcribed verbatim and analyzed using a grounded theory approach. RESULTS: Three personal health schemas emerged from the findings which illustrated women's diverging beliefs about their health behaviours in pregnancy. 'Interconnected health' described beliefs regarding the impact their health had on that of their growing baby and awareness of risks associated with inappropriate weight gain. 'Gestational weight gain as an indicator of health' illustrated perceptions regarding how GWG impacted health and the utility of guidelines. Finally, 'Control in pregnancy' described the sense of agency over one's body and health. CONCLUSIONS FOR PRACTICE: Our results showed that health-related behaviours in pregnancy are driven by personal health schemas which are often discordant with clinical evidence. Interventions and health care provider advice aimed at behaviour modification would benefit from first understanding and addressing these schemas. Tackling the conflict between beliefs and behaviour may improve health outcomes associated with appropriate weight gain in pregnancy.

A Validated Risk Prediction Model for Bone Fragility in Children With Acute Lymphoblastic Leukemia.

Although bone fragility may already be present at diagnosis of pediatric acute lymphoblastic leukemia (ALL), routine performance of dual-energy X-ray absorptiometry (DXA) in every child is not universally feasible. The aim of this study was to develop and validate a risk prediction model for low lumbar spine bone mineral density (LS BMD Z-score ≤ -2.0) at diagnosis, as an important indicator for fracture risk and further treatment-related BMD aggravation. Children with ALL (4-18 years), treated according to the Dutch Childhood Oncology Group protocol (DCOG-ALL9; model development; n = 249) and children from the Canadian Steroid-Associated Osteoporosis in the Pediatric Population cohort (STOPP; validation; n = 99) were included in this study. Multivariable logistic regression analyses were used to develop the prediction model and to confirm the association of low LS BMD at diagnosis with symptomatic fractures during and shortly after cessation of ALL treatment. The area under the receiver operating characteristic curve (AUC) was used to assess model performance. The prediction model for low LS BMD at diagnosis using weight (ß = -0.70) and age (ß = -0.10) at diagnosis revealed an AUC of 0.71 (95% CI, 0.63-0.78) in DCOG-ALL9 and 0.74 (95% CI, 0.63-0.84) in STOPP, and resulted in correct identification of 71% of the patients with low LS BMD. We confirmed that low LS BMD at diagnosis is associated with LS BMD at treatment cessation (OR 5.9; 95% CI, 3.2-10.9) and with symptomatic fractures (OR 1.7; 95% CI, 1.3-2.4) that occurred between diagnosis and 12 months following treatment cessation. In meta-analysis, LS BMD at diagnosis (OR 1.6; 95% CI, 1.1-2.4) and the 6-month cumulative glucocorticoid dose (OR 1.9; 95% CI, 1.1-3.2) were associated with fractures that occurred in the first year of treatment. In summary, a prediction model for identifying pediatric ALL patients with low LS BMD at diagnosis, as an important indicator for bone fragility, was successfully developed and validated. This can facilitate identification of future bone fragility in individual pediatric ALL patients. © 2021 American Society for Bone and Mineral Research (ASBMR).

Vitamin D's role in health and disease: How does the present inform our understanding of the past?

While the role of vitamin D in supporting bone homeostasis during growth and maintenance is well substantiated, emerging evidence from ecological and observational studies suggests that a deficiency of vitamin D is associated with some cancers, immune disorders, cardiovascular disease, abnormal glucose metabolism, and neurodegenerative diseases. Biological plausibility for extraskeletal functions originated with the discovery of the vitamin D receptor in many body tissues and knowledge that the conversion of 25-hydroxyvitamin D (25(OH)D) to its active metabolite 1,25(OH)2D occurs in many cell types in addition to the kidney. The association of vitamin D status in humans as an etiological factor in developmental programming of bone, in some chronic diseases, and in all-cause mortality, in addition to skeletal morbidity, is supported by some but not all observational studies and randomized controlled trials. These clinical observations have implications for paleopathology, both in terms of specific comorbidities and the potential role of vitamin D in individuals who display no evidence for skeletal disease. This paper outlines recent clinical research on vitamin D metabolism and its novel biological roles, and explores the possible relevance to paleopathological research designs, theoretical models, and interpretations of disease experience.

Bone Morbidity and Recovery in Children With Acute Lymphoblastic Leukemia: Results of a Six-Year Prospective Cohort Study.

Osteoporotic fractures are a significant cause of morbidity in acute lymphoblastic leukemia (ALL). Our objective was to determine the incidence and predictors of fractures and recovery from osteoporosis in pediatric ALL over 6 years following glucocorticoid initiation. Vertebral fractures (VF) and vertebral body reshaping were assessed on annual spine radiographs, low-trauma non-VF were recorded at regular intervals and spine bone mineral density (BMD) was captured every 6 months for 4 years and then annually. A total of 186 children with ALL were enrolled (median age 5.3 years; range, 1.3 to 17.0 years). The cumulative fracture incidence was 32.5% for VF and 23.0% for non-VF; 39.0% of children with VF were asymptomatic. No fractures occurred in the sixth year and 71.3% of incident fractures occurred in the first 2 years. Baseline VF, cumulative glucocorticoid dose, and baseline lumbar spine (LS) BMD Z-score predicted both VF and non-VF. Vertebral body reshaping following VF was incomplete or absent in 22.7% of children. Those with residual vertebral deformity following VF were older compared to those without (median age 8.0 years at baseline [interquartile range {IQR}, 5.5 to 9.4] versus 4.8 years [IQR, 3.6 to 6.2], p = 0.04) and had more severe vertebral collapse (median maximum spinal deformity index 3.5 [IQR, 1.0 to 8.0] versus 0.5 [IQR, 0.0 to 1.0], p = 0.01). VF and low LS BMD Z-score at baseline as well as glucocorticoid exposure predicted incident VF and non-VF. Nearly 25% of children had persistent vertebral deformity following VF, more frequent in older children, and in those with more severe collapse. These results suggest the need for trials addressing interventions in the first 2 years of chemotherapy, targeting older children and children with more severe vertebral collapse, because these children are at greatest risk for incident VF and subsequent residual vertebral deformity. © 2018 American Society for Bone and Mineral Research.

Harmonization of Food-Frequency Questionnaires and Dietary Pattern Analysis in 4 Ethnically Diverse Birth Cohorts.

BACKGROUND: Canada is an ethnically diverse nation, which introduces challenges for health care providers tasked with providing evidence-based dietary advice. OBJECTIVES: We aimed to harmonize food-frequency questionnaires (FFQs) across 4 birth cohorts of ethnically diverse pregnant women to derive robust dietary patterns to investigate maternal and newborn outcomes. METHODS: The NutriGen Alliance comprises 4 prospective birth cohorts and includes 4880 Canadian mother-infant pairs of predominantly white European [CHILD (Canadian Healthy Infant Longitudinal Development) and FAMILY (Family Atherosclerosis Monitoring In earLY life)], South Asian [START (SouTh Asian birth cohoRT)-Canada], or Aboriginal [ABC (Aboriginal Birth Cohort)] origins. CHILD used a multiethnic FFQ based on a previously validated instrument designed by the Fred Hutchinson Cancer Research Center, whereas FAMILY, START, and ABC used questionnaires specifically designed for use in white European, South Asian, and Aboriginal people, respectively. The serving sizes and consumption frequencies of individual food items within the 4 FFQs were harmonized and aggregated into 36 common food groups. Principal components analysis was used to identify dietary patterns that were internally validated against self-reported vegetarian status and externally validated against a modified Alternative Healthy Eating Index (mAHEI). RESULTS: Three maternal dietary patterns were identified-"plant-based," "Western," and "health-conscious"-which collectively explained 29% of the total variability in eating habits observed in the NutriGen Alliance. These patterns were strongly associated with self-reported vegetarian status (OR: 3.85; 95% CI: 3.47, 4.29; r2 = 0.30, P < 0.001; for a plant-based diet), and average adherence to the plant-based diet was higher in participants in the fourth quartile of the mAHEI than in the first quartile (mean difference: 46.1%; r2 = 0.81, P < 0.001). CONCLUSION: Dietary data collected by using FFQs from ethnically diverse pregnant women can be harmonized to identify common dietary patterns to investigate associations between maternal dietary intake and health outcomes.

Effects of Short-Term Exercise Training With and Without Milk Intake on Cardiometabolic and Inflammatory Adaptations in Obese Adolescents.

There is some evidence that a combination of factors can reduce inflammation and associated metabolic risk factors. We studied the early cardiometabolic and inflammatory adaptations to a short-term exercise intervention with and without milk in obese adolescents. Fifty-four adolescents were randomized to consume milk post exercise (MILK) or a carbohydrate beverage (CONT) during one-week of daily exercise. Insulin levels were not different between the groups post training. Glucose was reduced over time in both groups (-9 ± 13 mg/ dl MILK and -6 ± 14 mg/dl CONT, p < .05) but not different between groups. There was a greater decrease in mean arterial pressure (MAP) in the MILK group (-3 ± 6 mmHg MILK vs. 2 ± 7 mmHg CONT, p < .04). Milk provided postexercise did not affect C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6). The exercise intervention led to an increase in TNF-α in both groups (0.27 ± 0.7 pg/ml MILK and 0.48 ± 0.6 pg/ml CONT, p < .001). The early adaptations to a short-term exercise intervention in obese adolescents include a reduction in MAP and an increase in some inflammatory markers.

Maternal and pregnancy related predictors of cardiometabolic traits in newborns.

BACKGROUND: The influence of multiple maternal and pregnancy characteristics on offspring cardiometabolic traits at birth is not well understood and was evaluated in this study. METHODS AND FINDINGS: The Family Atherosclerosis Monitoring In earLY life (FAMILY) Study prospectively evaluated 11 cardiometabolic traits in 901 babies born to 857 mothers. The influence of maternal age, health (pre-pregnancy weight, blood pressure, glycemic status, lipids), health behaviors (diet, activity, smoking) and pregnancy characteristics (gestational age at birth, gestational weight gain and placental-fetal ratio) were examined. Greater gestational age influenced multiple newborn cardiometabolic traits including cord blood lipids, glucose and insulin, body fat and blood pressure. In a subset of 442 singleton mother/infant pairs, principal component analysis grouped 11 newborn cardiometabolic traits into 5 components (anthropometry/insulin, 2 lipid components, blood pressure and glycemia), accounting for 74% of the variance of the 11 outcome variables. Determinants of these components, corrected for sex and gestational age, were examined. Baby anthropometry/insulin was independently predicted by higher maternal pre-pregnancy weight (standardized estimate 0.30) and gestational weight gain (0.30; both p<0.0001) and was inversely related to smoking during pregnancy (-0.144; p = 0.01) and maternal polyunsaturated to saturated fat intake (-0.135;p = 0.01). Component 2 (HDL-C/Apo Apolipoprotein1) was inversely associated with maternal age. Component 3 (blood pressure) was not clustered with any other newborn cardiometabolic trait and no associations with maternal pregnancy characteristics were identified. Component 4 (triglycerides) was positively associated with maternal hypertension and triglycerides, and inversely associated with maternal HDL and age. Component 5 (glycemia) was inversely associated with placental/fetal ratio (-0.141; p = 0.005). LDL-C was a bridging variable between the lipid factors and glycemia. CONCLUSIONS: Maternal health, health behaviours and placenta to fetal weight ratio are associated with newborn cardiometabolic traits over and above gestational age. Future investigations are needed to determine if these factors remain important determinants of cardiometabolic health throughout childhood.

Screening for dysglycemia in overweight youth presenting for weight management.

OBJECTIVE: To examine the performance of current screening recommendations for detecting dysglycemia in children and adolescents with obesity. RESEARCH DESIGN AND METHODS: In a cross-sectional study, an oral glucose tolerance test and demographic (age, sex, family history of diabetes, and ethnicity), clinical (BMI z score, waist circumference, and pubertal stage), and laboratory variables used in current pediatric screening criteria for type 2 diabetes mellitus were measured in 259 overweight or obese youth aged 5-17 years. Glycemic status was based on American Diabetes Association (ADA) thresholds. The performance (sensitivity and specificity) of current screening criteria and newly developed models to identify isolated IGT were compared. RESULTS: Dysglycemia was present in 20.8% of the cohort. Of the 54 participants with dysglycemia, 68% had a normal fasting glucose and were identified with the 2-h glucose test. Current ADA criteria had low sensitivity (41.7% [95% CI 25.6-57.8]) and moderate specificity (69.5% [63.5-75.6]) to identify IGT. In receiver operating characteristic (ROC) analysis, the addition of hemoglobin A(1c) (HbA(1c)) or FPG did not improve the ROC area under the curve (AUC) (HbA(1c): 0.64 vs. 0.63; P = 0.54; HbA(1c) + FPG: 0.66; P = 0.42), but adding triglyceride level did (AUC 0.72 vs. 0.63; P = 0.03). A simple model with fasting triglyceride level >1.17 mmol/L improved AUC compared with ADA screening criteria (0.68 vs. 0.57; P = 0.04). CONCLUSIONS: The prevalence of IGT is high among obese children and youth. Current screening criteria have low sensitivity to detect isolated IGT. Although adding nonfasting laboratory values to history and physical measures does not improve diagnostic accuracy, adding fasting lipid profile improves predictive value.

Incident vertebral fractures among children with rheumatic disorders 12 months after glucocorticoid initiation: a national observational study.

OBJECTIVE: To determine the frequency of incident vertebral fractures (IVF) 12 months after glucocorticoid (GC) initiation in children with rheumatic diseases and to identify children at higher risk. METHODS: Children with rheumatic diseases initiating GC were enrolled in a prospective observational study. Annual spine radiographs were evaluated using the Genant semiquantitative method. Spine areal bone mineral density (aBMD) was measured every 6 months. Clinical features, including cumulative GC dose, back pain, disease and physical activity, calcium and vitamin D intake, and spine aBMD Z scores, were analyzed for association with IVF. RESULTS: Seven (6%) of 118 children (95% confidence interval 2.9-11.7%) had IVF. Their diagnoses were: juvenile dermatomyositis (n = 2), systemic lupus erythematosus (n = 3), systemic vasculitis (n = 1), and mixed connective tissue disease (n = 1). One child was omitted from the analyses after 4 months because of osteoporosis treatment for symptomatic IVF. Children with IVF received on average 50% more GC than those without (P = 0.030), had a greater increase in body mass index (BMI) at 6 months (P = 0.010), and had greater decrements in spine aBMD Z scores in the first 6 months (P = 0.048). Four (67%) of 6 children with IVF and data to 12 months had spine aBMD Z scores less than -2.0 at 12 months compared to 16% of children without IVF (P = 0.011). CONCLUSION: The incidence of VF 12 months following GC initiation was 6%; most children were asymptomatic. Children with IVF received more GC, had greater increases in BMI, and had greater declines in spine aBMD Z scores in the first 6 months.

Vitamin D status and bone biomarkers in childhood cancer.

Early detection of abnormalities in bone turnover may be facilitated by assessing biomarkers of bone metabolism including vitamin D status. In many children with cancer, biomarkers of bone formation (osteocalcin, bone specific alkaline phosphatase and carboxy-(or N terminal) propeptide of type 1 procollagen) were observed to be suppressed, while bone resorption was elevated as measured by serum cross-linked (or C-terminal) telopeptide of type 1 collagen. Insulin-like growth factor 1, which stimulates bone formation, may be suppressed indirectly indicating a growth hormone insufficiency. Leptin may also play a role in bone remodeling as hyperleptinemia has been observed in association with acute lymphoblastic leukemia. Evaluation of bone status using such biomarkers is complicated by the lack of universally accepted reference values and the variation by age, gender, or pubertal status. Etiologic factors contributing to the observed skeletal morbidities include disease process, chemotherapy (drugs such as glucocorticoids and methotrexate) and radiotherapy. Other factors common to children with cancer, such as chronic inflammation, dietary changes and physical inactivity, must also be taken into account. The current evidence for abnormalities in biomarkers of vitamin D status and bone turnover will be the focus of this review of published studies.

Early life factors predict abnormal growth and bone accretion at prepuberty in former premature infants with/without neonatal dexamethasone exposure.

Growth, bone, and body composition were studied at prepuberty in former very low birth weight (VLBW) infants who received dexamethasone (DEX) for bronchopulmonary dysplasia (BPD) compared with VLBW infants without DEX and term-born infants (TERM) to identify early life risk factors for later low bone mass. Children (56 girls/63 boys, 5-10 y) previously studied in neonatal life were recruited into three groups: VLBW + DEX, VLBW - DEX, and TERM children. Anthropometry and whole body bone, fat, and lean mass were measured. At prepuberty, the average height and weight for VLBW + DEX group were significantly lower than that for VLBW - DEX and TERM. Both VLBW groups had lower bone mass even adjusted for height and lean mass than TERM children and lower lean mass both total and adjusted for height. Z-scores for whole body bone mineral content below -1.5 occurred in 27.9% of VLBW + DEX children. The key factors for low bone mass were earlier gestational age and having BPD with DEX in neonatal life. In former VLBW infants, growth and bone mass attainment before puberty can be predicted from early life variables. VLBW + DEX children may be protected from overweight, but are at risk for short stature and low bone mass.

Hypomagnesemia associated with chemotherapy in patients treated for acute lymphoblastic leukemia: possible mechanisms.

Body weight, height and lumbar spine bone mineral density (BMD) were measured in 40 children (27 male, 13 female, aged 0.3-17.0 years) with acute lymphoblastic leukemia (ALL) at diagnosis and 6 months after initiation of chemotherapy, and in 40 age- and sex-matched local healthy children. Serum and urinary biochemical indices of mineral metabolism were measured in the children with ALL at both time points. From diagnosis to 6 months, a reduction in the fractional excretion of magnesium was found. Serum osteocalcin was low at diagnosis and increased during chemotherapy, whereas 24-h urinary type I collagen cross-linked N-telopeptide was unchanged. The Z-scores for lumbar spine BMD increased and were correlated with the serum osteocalcin at 6 months. The change in serum magnesium was correlated negatively with the change in lumbar spine BMD, and with the lumbar spine BMD Z-score at 6 months. After initiation of treatment for ALL, rapid recovery in bone formation, which results in the movement of extracellular magnesium into the skeleton through bone formation, may be an important contributor to hypomagnesemia.

Osteopenia in survivors of Wilms tumor.

Diminished bone mass (osteopenia) is recognized increasingly as a consequence of therapy in survivors of cancer in childhood. It has been reported in two small series of survivors of Wilms tumor. The objectives of this study were to explore, in a larger sample of such subjects, the prevalence of osteopenia and a possible relationship between osteopenia of the lumbar spine and abdominal irradiation. All survivors of Wilms tumor (n=49) in a single institution were considered eligible for study. Thirty-one agreed to participate; the non-participants were not notably different in their demographic characteristics and diseases/treatment experience. Information was obtained about prior treatment, and usual diet, sun exposure and physical activity. Bone mineral content was measured by dual energy X-ray absorptiometry, and biochemical markers of bone turnover, calciotropic hormones and minerals were assessed in a single blood sample. By Z-scores of whole body bone mineral content, 8 subjects were osteopenic. This was unrelated to milk intake or sun exposure and was not more common in the lumbar spine of those who had been irradiated (15/31 subjects). Physical activity correlated positively with bone mineral density Z-scores (p<0.005). Normal bone formation was reflected in normal blood levels of osteocalcin. C-telopeptide levels, reflecting bone resorption, were high but approximately correlated inversely with maturity. Low serum magnesium and parathyroid hormone levels were detected in a minority of subjects. Osteopenia is present in a large minority (27%) of survivors of Wilms tumor, and an imbalance of bone turnover (with excessive resorption) may be common. Irradiation does not appear to play a causal role. It is possible that a subtle renal tubular defect exists in these individuals; a prospect worthy of further exploration.