Bile salt hydrolase catalyses formation of amine-conjugated bile acids.

Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1-6; however, the bacterial gene(s) responsible for their production remain unknown. Herein, we report that bile salt hydrolase (BSH) possesses dual functions in bile acid metabolism. Specifically, we identified a previously unknown role for BSH as an amine N-acyltransferase that conjugates amines to bile acids, thus forming bacterial bile acid amidates (BBAAs). To characterize this amine N-acyltransferase BSH activity, we used pharmacological inhibition of BSH, heterologous expression of bsh and mutants in Escherichia coli and bsh knockout and complementation in Bacteroides fragilis to demonstrate that BSH generates BBAAs. We further show in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria. Lastly, we report that in cell culture models, BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor. These findings enhance our understanding of how gut bacteria, through the promiscuous actions of BSH, have a significant role in regulating the bile acid metabolic network.

The stepwise assembly of the neonatal virome is modulated by breastfeeding.

The gut of healthy human neonates is usually devoid of viruses at birth, but quickly becomes colonized, which-in some cases-leads to gastrointestinal disorders1-4. Here we show that the assembly of the viral community in neonates takes place in distinct steps. Fluorescent staining of virus-like particles purified from infant meconium or early stool samples shows few or no particles, but by one month of life particle numbers increase to 109 per gram, and these numbers seem to persist throughout life5-7. We investigated the origin of these viral populations using shotgun metagenomic sequencing of virus-enriched preparations and whole microbial communities, followed by targeted microbiological analyses. Results indicate that, early after birth, pioneer bacteria colonize the infant gut and by one month prophages induced from these bacteria provide the predominant population of virus-like particles. By four months of life, identifiable viruses that replicate in human cells become more prominent. Multiple human viruses were more abundant in stool samples from babies who were exclusively fed on formula milk compared with those fed partially or fully on breast milk, paralleling reports that breast milk can be protective against viral infections8-10. Bacteriophage populations also differed depending on whether or not the infant was breastfed. We show that the colonization of the infant gut is stepwise, first mainly by temperate bacteriophages induced from pioneer bacteria, and later by viruses that replicate in human cells; this second phase is modulated by breastfeeding.

The Cross-Sectional Relation of Body Mass Index to Adiposity among 8- to 19-Year-Olds within Several Races and Ethnicities.

OBJECTIVE: To assess the screening ability of a high body mass index (BMI) for high adiposity among 8- to 19-year-olds. STUDY DESIGN: This cross-sectional study included 6454 National Health and Nutrition Survey participants from 2011 through 2018. Fat and lean mass were measured with dual-energy X-ray absorptiometry (DXA). We expressed adiposity as fat mass index (FMI, kg ÷ m2) and %fat. RESULTS: Based on the Centers for Disease Control and Prevention 95th percentile, a high BMI correctly classified a high FMI for about 95% of participants in each racial and ethnic group. About 81% (Blacks) to 90% (Hispanics) of participants with a high BMI also had a high FMI. Further, children with a high BMI were 17 (Hispanics) to 46 (Blacks) times more likely to have a high FMI than those with a "normal" BMI. The screening ability of high BMI for high %fat was weaker because levels of %fat are influenced by both fat mass (numerator) and lean mass (denominator). CONCLUSIONS: Despite differences in body composition, a high BMI is a very good screening tool for identifying high FMI not only among White 8- to 19-year-olds but also among Asians, Blacks, and Hispanics. Compared with %fat, FMI is likely a better adiposity metric among children and adolescents.

Alendronate preserves bone mineral density in adults with sickle cell disease and osteoporosis.

Low bone mineral density is highly prevalent in sickle cell disease (SCD); whether bisphosphonates can safely preserve or increase bone mass in SCD adults remains unknown. In this study, lumbar spine bone density remained stable with alendronate use, and treatment-related side effects were mostly mild and self-limited. PURPOSE: To describe the effects of alendronate in adults with sickle cell disease (SCD) and osteoporosis. METHODS: We reviewed retrospective clinical data from adults with SCD and osteoporosis treated with alendronate at a single center in Brazil (2009-2019). Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck, and total hip. We analyzed BMD changes by alendronate treatment duration (months), stratified by sex, skeletal site, and SCD genotype. RESULTS: Sixty-four SCD adults with osteoporosis (69% females, 73% HbSS, mean age ± standard deviation 42.4 ± 10.9 years) received alendronate for a median (interquartile range) of 48 (29, 73) months. Compared with males, females had significantly lower baseline BMD (g/cm2) at the femoral neck (0.72 vs 0.85, p = < 0.001) and total hip (0.79 vs 0.88, p = 0.009). The between-sex differences in BMD changes were insignificant. Mean lumbar spine BMD significantly changed by 0.0357 g/cm2 (p = 0.028) in those on alendronate for > 5 years. Four adults (6.3%) reported mild therapy-related side effects. An atypical femoral diaphysis fracture, attributed to alendronate, was incidentally noted in a 37-year-old man on treatment for 4 years. CONCLUSION: In this retrospective cohort of adults with SCD and osteoporosis on alendronate for a median of 48 months, we found no significant interactions between sex and changes in lumbar spine, femoral neck, or total hip BMD with alendronate. Lumbar spine BMD was stable in those on alendronate for < 5 years. Side effects of alendronate were mild, though one patient developed an atypical femoral fracture.

Relative leg-to-arm skeletal strength proportions in orangutans by species and sex.

Among extant great apes, orangutans climb most frequently. However, Bornean orangutans (Pongo pygmaeus) exhibit higher frequencies of terrestrial locomotion than do Sumatran orangutans (Pongo abelii). Variation in long bone cross-sectional geometry is known to reflect differential loading of the limbs. Thus, Bornean orangutans should show greater relative leg-to-arm strength than their Sumatran counterparts. Using skeletal specimens from museum collections, we measured two cross-sectional geometric measures of bone strength: the polar section modulus (Zpol) and the ratio of maximum to minimum area moments of inertia (Imax/Imin), at the midshaft of long bones in Bornean (n = 19) and Sumatran adult orangutans (n = 12) using medical CT and peripheral quantitative CT scans, and compared results to published data of other great apes. Relative leg-to-arm strength was quantified using ratios of femur and tibia over humerus, radius, and ulna, respectively. Differences between orangutan species and between sexes in median ratios were assessed using Wilcoxon rank sum tests. The tibia of Bornean orangutans was stronger relative to the humerus and the ulna than in Sumatran orangutans (p = 0.008 and 0.025, respectively), consistent with behavioral studies that indicate higher frequencies of terrestrial locomotion in the former. In three Zpol ratios, adult female orangutans showed greater leg-to-arm bone strength compared to flanged males, which may relate to females using their legs more during arboreal locomotion than in adult flanged males. A greater amount of habitat discontinuity on Borneo compared to Sumatra has been posited as a possible explanation for observed interspecific differences in locomotor behaviors, but recent camera trap studies has called this into question. Alternatively, greater frequencies of terrestriality in Pongo pygmaeus may be due to the absence of tigers on Borneo. The results of this study are consistent with the latter explanation given that habitat continuity was greater a century ago when our study sample was collected.

Fluoxetine and Sertraline Inhibit Height Growth and Growth Hormone Signaling During Puberty.

PURPOSE: The aim of this study was to examine the effect of fluoxetine and sertraline on height growth and insulin-like growth factor-1 (IGF-1) during puberty. METHODS: In this 6-month cohort study, electronic medical records were used to identify 8- to 15-year-old participants, within 1 month of starting fluoxetine (n = 39) or sertraline (n = 27), and sexual maturation stages 2 to 4 were confirmed. Conditions that interfere with height growth led to exclusion. Participants underwent anthropometric assessments and phlebotomy. Healthy, unmedicated children (n = 36) also provided anthropometric data. RESULTS: After the baseline height Z-score, sex, Tanner stage, daily selective serotonin reuptake inhibitor (SSRI) dose, and time were accounted for, the interaction effect of dose by time was inversely associated with height Z-score in SSRI-treated participants (ß = -0.18; 95% confidence interval [CI]: -0.35, -0.02). Sertraline and fluoxetine did not differ in their effect on height growth. Compared with being unmedicated, SSRI treatment was associated with a smaller growth in height (time × dose 2-way interaction effect ß = -1.30; 95% CI: -2.52, -0.09). The interaction effect of dose by time was significant for body mass index Z-score (ß = 0.35; 95% CI: 0.06, 0.64) but not weight Z-score (ß = 0.24; 95% CI: -0.01, 0.49). Body mass index Z-score increased more with sertraline compared with fluoxetine (time × dose × SSRI type 3-way interaction effect P < 0.05). SSRI dose was inversely associated with IGF-1 (ß = -63.5; 95% CI: -112.2, -14.7) but not insulin growth factor binding protein-3 concentration (ß = -207.3; 95% CI: -536.2, 121.5). CONCLUSIONS: Fluoxetine and sertraline reduce height gain and IGF-1 concentration, in a dose-dependent manner. Longer-term studies are necessary.

Trajectory of body mass index and obesity in children with Crohn's disease compared to healthy children.

BACKGROUND: There is increasing recognition that children with Crohn's Disease (CD) can develop obesity. METHODS: Using the RISK Study, an inception cohort of pediatric CD participants, and Bone Mineral Density in Childhood Study (BMDCS), a longitudinal cohort of healthy children, multivariable linear mixed effects, generalized linear mixed effects, and logistic regression models were used to evaluate factors associated with change in body mass index z-score (BMIZ), obesity, and excessive weight gain, respectively. RESULTS: 1029 CD participants (625 exposed to antitumor necrosis factor (anti-TNF) therapy) and 1880 healthy children were included. Change in BMIZ was higher in CD exposed to anti-TNF as compared to CD unexposed to anti-TNF and the healthy reference group. Sex, age, baseline BMIZ, C-reactive protein, anti-TNF, and steroids were associated with changes in BMIZ in CD. CD exposed (odds ratio [OR] 4.81, confidence interval [CI] 4.00-5.78) and unexposed (OR 3.14, CI 2.62-3.76) had a greater likelihood of becoming obese versus the healthy reference group. While the prevalence of obesity was higher at baseline in the healthy reference group (21.3%) versus CD participants (8.5% exposed vs. 11.1% unexposed), rates of obesity were similar by the end of follow-up (21.4% healthy vs. 20.3% exposed vs. 22.5% unexposed). Anti-TNF therapy was an independent risk factor for the development of obesity and excessive weight gain in CD participants. CONCLUSIONS: Patients with CD have dynamic changes in BMIZ over time, and while for most, this is restorative, for some, this can lead to obesity and excessive weight gain. It is important to understand the factors that may lead to these changes, including anti-TNF therapy. Counseling of patients and early lifestyle intervention may be necessary.

Paediatric dominant and non-dominant handgrip reference curves and the association with body composition.

BACKGROUND: Lack of paediatric reference data limits the utility of handgrip strength as a measure of fitness and well-being. AIM: To develop paediatric handgrip reference curves and evaluate associations with body size and composition and race/ethnicity group. SUBJECTS AND METHODS: Handgrip, body size and composition data were obtained from National Health and Nutrition Examination Survey 2011-2014 participants aged 6-20 years. Densitometry-derived fat and appendicular lean soft tissue mass index Z-scores (FMIZ, ALSTMIZ) were generated in participants >8 years. Dominant and non-dominant handgrip reference curves were created using the LMS method. Analyses included sample weights to produce nationally representative estimates. RESULTS: Differences in handgrip strength according to hand dominance increased with age. Handgrip strength was associated with height and arm length Z-scores (R = 0.42 to 0.47) and ALSTMIZ (R = 0.54). Handgrip strength was higher in the non-Hispanic Black group and lower in the Mexican American compared to non-Hispanic White group. Group differences were attenuated when adjusted for height, arm length or ALSTMIZ. CONCLUSION: Paediatric handgrip reference curves were generated from which individual Z-scores can be calculated separately for dominant versus non-dominant hand and adjusted for body size. Association with ALSTMIZ suggests handgrip Z-score may be used as a measure of functional body composition.

Cardiometabolic risk in young adults with Down syndrome.

Studies regarding cardiometabolic risk (CMR) for individuals with Down syndrome (DS) conflict. Our previous research in youth with DS, aged 10-20 years, found increased prevalence of dyslipidemia and prediabetes compared to matched peers without DS. Herein, we compare CMR in young adults with DS, aged 18-35 years, to a similar population-based sample from the 2001-2018 National Health and Nutrition Examination Survey (NHANES). The group with DS had higher NonHDL-C (mean DS 131.9 mg/dL; NHANES 126.1 p < 0.001), lower HDL-C (DS 47.5 mg/dL; NHANES 52.2 p < 0.001), higher LDL-C (DS 109.3 mg/dL; NHANES 105.4 p < 0.001), higher triglycerides (DS 102.9 mg/dL; NHANES 86.9 p < 0.001), but lower fasting glucose (DS 85.8 mg/dL; NHANES 95.2 p < 0.0001), lower HOMA-IR (DS 2.17; NHANES 2.24 p = 0.0006), lower systolic (DS 109.7 mmHg; NHANES 114.6 p < 0.0001) and lower diastolic (DS 60.9 mmHg; NHANES 67.8 p < 0.0001) blood pressures. There was relationship of higher HDL-C, triglycerides, glucose, systolic, and diastolic blood pressure with increasing BMI in the NHANES cohort which was dampened in the group with DS. These results indicate that more information is needed to guide clinicians in screening for CMR in individuals with DS.

Bone health in children with recurrent and chronic pancreatitis: A multi-center cross sectional analysis.

BACKGROUND/OBJECTIVES: Bone health of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) is not well studied. METHODS: This retrospective study was performed at three sites and included data from INSPPIRE-2. RESULTS: Of the 87 children in the study: 46 had ARP (53%), 41 had CP (47%). Mean age was 13.6 ± 3.9 years at last DXA scan. The prevalence of low height-for-age (Z-score < -2) (13%, 10/78) and low bone mineral density (BMD) adjusted for height (Z-score < -2) (6.4%, 5/78) were higher than a healthy reference sample (2.5%, p < 0.0001 and p = 0.03, respectively). CONCLUSION: Children with ARP or CP have lower height and BMD than healthy peers. Attention to deficits in growth and bone mineral accrual in children with pancreatic disease is warranted.

Associations of body mass index (BMI) and BMI change with progression of chronic kidney disease in children.

BACKGROUND: Obesity is prevalent among children with chronic kidney disease (CKD) and is associated with cardiovascular disease and reduced quality of life. Its relationship with pediatric CKD progression has not been described. METHODS: We evaluated relationships between both body mass index (BMI) category (normal, overweight, obese) and BMI z-score (BMIz) change on CKD progression among participants of the Chronic Kidney Disease in Children study. Kaplan-Meier survival curves and multivariable parametric failure time models depict the association of baseline BMI category on time to kidney replacement therapy (KRT). Additionally, the annualized percentage change in estimated glomerular filtration rate (eGFR) was modeled against concurrent change in BMIz using multivariable linear regression with generalized estimating equations which allowed for quantification of the effect of BMIz change on annualized eGFR change. RESULTS: Participants had median age of 10.9 years [IQR: 6.5, 14.6], median eGFR of 50 ml/1.73 m2 [IQR: 37, 64] and 63% were male. 160 (27%) of 600 children with non-glomerular and 77 (31%) of 247 children with glomerular CKD progressed to KRT over a median of 5 years [IQR: 2, 8]. Times to KRT were not significantly associated with baseline BMI category. Children with non-glomerular CKD who were obese experienced significant improvement in eGFR (+ 0.62%; 95% CI: + 0.17%, + 1.08%) for every 0.1 standard deviation concurrent decrease in BMI. In participants with glomerular CKD who were obese, BMIz change was not significantly associated with annualized eGFR change. CONCLUSION: Obesity may represent a target of intervention to improve kidney function in children with non-glomerular CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

African American mothers' perceptions of infant body size are prospectively associated with infant growth and BMI.

OBJECTIVES: The effect of mothers' perceptions of infant body size on infant growth and later BMI is poorly understood. We aimed to assess whether maternal perceptions were associated with infant BMI and weight gain and to identify factors that may influence maternal perceptions. METHODS: We analyzed data from a prospective, longitudinal study of pregnant African American women living with healthy weight (BMI < 25 kg/m2 ) or obesity (BMI ≥ 30 kg/m2 ). We collected sociodemographic, feeding mode, perceived stress, depression, and food insecurity information. The African American Infant Body Habitus Scale assessed maternal perceptions of infant body size at age 6 months. A "maternal satisfaction with infant body size" score was derived. Infant BMI z-scores (BMIZ) were calculated at 6 and 24 months. RESULTS: Maternal perception and satisfaction scores did not differ between obese (n = 148) and healthy weight (n = 132) groups. Perception of infant size at 6 months was positively associated with infant BMIZ at 6 and 24 months. A positive association of maternal satisfaction scores with change in infant BMIZ from 6 to 24 months indicated that BMIZ changed less for infants whose mothers preferred them to be smaller at 6 months. Perception and satisfaction scores were not associated with feeding variables, maternal stress, depression, socioeconomic status, or food security status. CONCLUSION: Mothers' perceptions of and satisfaction with infant size correlated with current and later infant BMI. However, mother's perceptions were not associated with maternal weight status or other factors explored for their potential to impact maternal perceptions. Further work is needed to elucidate factors linking maternal perception/satisfaction and infant growth.

Assessment of fluid removal using ultrasound, bioimpedance and anthropometry in pediatric dialysis: a pilot study.

BACKGROUND: Fluid overload is associated with morbidity and mortality in children receiving dialysis. Accurate clinical assessment is difficult, and using deuterium oxide (D2O) to measure total body water (TBW) is impractical. We investigated the use of ultrasound (US), bioimpedance spectroscopy (BIS), and anthropometry to assess fluid removal in children receiving maintenance hemodialysis (HD). METHODS: Participants completed US, BIS, and anthropometry immediately before and 1-2 h after HD for up to five sessions. US measured inferior vena cava (IVC) diameter, lung B-lines, muscle elastography, and dermal thickness. BIS measured the volume of extracellular (ECF) and intracellular (ICF) fluid. Anthropometry included mid-upper arm, calf and ankle circumferences, and triceps skinfold thickness. D2O was performed once pre-HD. We assessed the change in study measures pre- versus post-HD, and the correlation of change in study measures with percent change in body weight (%∆BW). We also assessed the agreement between TBW measured by BIS and D2O. RESULTS: Eight participants aged 3.4-18.5 years were enrolled. Comparison of pre- and post-HD measures showed significant decrease in IVC diameters, lung B-lines, dermal thickness, BIS %ECF, mid-upper arm circumference, ankle, and calf circumference. Repeated measures correlation showed significant relationships between %∆BW and changes in BIS ECF (rrm =0.51, 95% CI 0.04, 0.80) and calf circumference (rrm=0.80, 95% CI 0.51, 0.92). BIS TBW correlated with D2O TBW but overestimated TBW by 2.2 L (95% LOA, -4.75 to 0.42). CONCLUSION: BIS and calf circumference may be helpful to assess changes in fluid status in children receiving maintenance HD. IVC diameter, lung B-lines and dermal thickness are potential candidates for future studies.

From growth charts to growth status: how concepts of optimal growth and tempo influence the interpretation of growth measurements.

Growth measurements are largely uninterpretable without comparison to a growth chart. Consequently, the characteristics of a growth chart become an integral component of the interpretation of growth measurements. The concepts of optimal growth and tempo are well recognised by auxologists, yet their implications for interpretation of growth measurements remain problematic. This narrative review discusses the concept of optimal growth and how it serves as a guiding principle in the development and use of growth charts. The challenges of operationalising tempo for growth assessment are also discussed. Illustrative examples highlight the importance of these two central concepts in the use and interpretation of growth measurements.

Sarcopenic obesity in rheumatoid arthritis: prevalence and impact on physical functioning.

OBJECTIVE: We determined the prevalence of sarcopenic obesity in patients with RA using multiple methods and assessed associations with physical functioning. METHODS: This study evaluated data from three RA cohorts. Whole-body dual-energy absorptiometry (DXA) measures of appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI) were converted to age, sex and race-specific Z-Scores and categorized using a recently validated method and compared it to a widely-used existing method. The prevalence of body composition abnormalities in RA was compared with two reference populations. In the RA cohorts, associations between body composition and change in the HAQ and the Short Physical Performance Battery (SPPB) in follow-up were assessed using linear and logistic regression, adjusting for age, sex, race and study. RESULTS: The prevalence of low lean mass and sarcopenic obesity was higher in patients with RA (14.2; 12.6%, respectively) compared with the reference population cohorts (7-10%; 4-4.5%, respectively, all P <0.05). There was only moderate agreement among methods of sarcopenic obesity categorization (Kappa 0.45). The recently validated method categorized fewer subjects as obese, and many of these were categorized as low lean mass only. Low lean mass, obesity and sarcopenic obesity were each associated with higher HAQ and lower SPPB at baseline and numerically greater worsening. CONCLUSION: RA patients had higher rates of low lean mass and sarcopenic obesity than the general population. The recently validated methods characterized body composition changes differently from traditional methods and were more strongly associated with physical function.

Using linear and natural cubic splines, SITAR, and latent trajectory models to characterise nonlinear longitudinal growth trajectories in cohort studies.

BACKGROUND: Longitudinal data analysis can improve our understanding of the influences on health trajectories across the life-course. There are a variety of statistical models which can be used, and their fitting and interpretation can be complex, particularly where there is a nonlinear trajectory. Our aim was to provide an accessible guide along with applied examples to using four sophisticated modelling procedures for describing nonlinear growth trajectories. METHODS: This expository paper provides an illustrative guide to summarising nonlinear growth trajectories for repeatedly measured continuous outcomes using (i) linear spline and (ii) natural cubic spline linear mixed-effects (LME) models, (iii) Super Imposition by Translation and Rotation (SITAR) nonlinear mixed effects models, and (iv) latent trajectory models. The underlying model for each approach, their similarities and differences, and their advantages and disadvantages are described. Their application and correct interpretation of their results is illustrated by analysing repeated bone mass measures to characterise bone growth patterns and their sex differences in three cohort studies from the UK, USA, and Canada comprising 8500 individuals and 37,000 measurements from ages 5-40 years. Recommendations for choosing a modelling approach are provided along with a discussion and signposting on further modelling extensions for analysing trajectory exposures and outcomes, and multiple cohorts. RESULTS: Linear and natural cubic spline LME models and SITAR provided similar summary of the mean bone growth trajectory and growth velocity, and the sex differences in growth patterns. Growth velocity (in grams/year) peaked during adolescence, and peaked earlier in females than males e.g., mean age at peak bone mineral content accrual from multicohort SITAR models was 12.2 years in females and 13.9 years in males. Latent trajectory models (with trajectory shapes estimated using a natural cubic spline) identified up to four subgroups of individuals with distinct trajectories throughout adolescence. CONCLUSIONS: LME models with linear and natural cubic splines, SITAR, and latent trajectory models are useful for describing nonlinear growth trajectories, and these methods can be adapted for other complex traits. Choice of method depends on the research aims, complexity of the trajectory, and available data. Scripts and synthetic datasets are provided for readers to replicate trajectory modelling and visualisation using the R statistical computing software.

Lower dietary intake of magnesium is associated with more callous-unemotional traits in children.

BACKGROUND: Although researchers increasingly recognize the role of nutrition in mental health, little research has examined specific micronutrient intake in relation to antisocial behavior and callous-unemotional (CU) traits in children. Vitamin B6 and magnesium are involved in neurochemical processes implicated in modulating antisocial behavior and CU traits. The current study examined dietary intakes of magnesium and vitamin B6 in relation to antisocial behavior and CU traits. METHOD: : We enrolled 11-12 year old children (n = 446, mean age = 11.9 years) participating in the Healthy Brains and Behavior Study. Magnesium and vitamin B6 dietary intake were assessed with three 24-hour dietary recall interviews in children. CU traits and antisocial behavior were assessed by caregiver-reported questionnaires. We controlled for age, sex, race, total energy intake, body mass index, social adversity, ADHD or learning disability diagnosis, and internalizing behavior in all regression analyses. RESULTS: Children with lower magnesium intake had higher levels of CU traits, controlling for covariates (ß = -0.18, B = -0.0066, SE = 0.0027, p < 0.05). Vitamin B6 intake was not significantly associated with CU traits (ß = 0.061, B = 0.19, SE = 0.20, p > 0.05). Neither magnesium (ß = 0.014, B = 0.0020, SE = 0.0093, p > 0.05) nor vitamin B6 (ß = 0.025, B = 0.33, SE = 0.70, p > 0.05) were significantly associated with antisocial behavior. CONCLUSIONS: Findings suggest that low dietary intake of magnesium may play a role in the etiology of CU traits but not general antisocial behavior. More studies are needed to determine if magnesium supplementation or diets higher in magnesium could improve CU traits in children.

Glycemic Control and Bone in Diabetes.

PURPOSE OF REVIEW: This review summarizes recent developments on the effects of glycemic control and diabetes on bone health. We discuss the foundational cellular mechanisms through which diabetes and impaired glucose control impact bone biology, and how these processes contribute to bone fragility in diabetes. RECENT FINDINGS: Glucose is important for osteoblast differentiation and energy consumption of mature osteoblasts. The role of insulin is less clear, but insulin receptor deletion in mouse osteoblasts reduces bone formation. Epidemiologically, type 1 (T1D) and type 2 diabetes (T2D) associate with increased fracture risk, which is greater among people with T1D. Accumulation of cortical bone micro-pores, micro-vascular complications, and AGEs likely contribute to diabetes-related bone fragility. The effects of youth-onset T2D on peak bone mass attainment and subsequent skeletal fragility are of particular concern. Further research is needed to understand the effects of hyperglycemia on skeletal health through the lifecycle, including the related factors of inflammation and microvascular damage.

Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Deficits in the Functional Muscle-Bone Unit in Youths with Fontan Physiology.

OBJECTIVE: To determine whether dual energy X-ray absorptiometry (DXA), a clinically available tool, mirrors the magnitude of deficits in trabecular and cortical bone mineral density (BMD) demonstrated on peripheral quantitative computed tomography in youth with Fontan physiology. STUDY DESIGN: We aimed to describe DXA-derived BMD at multiple sites and to investigate the relationship between BMD and leg lean mass, a surrogate for skeletal muscle loading. Subjects with Fontan (n = 46; aged 5-20 years) underwent DXA in a cross-sectional study of growth and bone and muscle health as described previously. Data from the Bone Mineral Density in Childhood Study were used to calculate age-, sex-, and race-specific BMD z-scores of the whole body, lumbar spine, hip, femoral neck, distal one-third radius, ultradistal radius, and leg lean mass z-score (LLMZ). RESULTS: Fontan BMD z-scores were significantly lower than reference at all sites-whole body, -0.34 ± 0.85 (P = .01); spine, -0.41 ± 0.96 (P = .008); hip, -0.75 ± 1.1 (P < .001); femoral neck, -0.73 ± 1.0 (P < .001); distal one-third radius, -0.87 ± 1.1 (P < .001); and ultradistal radius. -0.92 ± 1.03 (P < .001)-as was LLMZ (-0.93 ± 1.1; P < .001). Lower LLMZ was associated with lower BMD of the whole body (R2 = 0.40; P < .001), lumbar spine (R2 = 0.16; P = .005), total hip (R2 = 0.32; P < .001), femoral neck (R2 = 0.47; P < .001), and ultradistal radius (R2 = 0.35; P < .001). CONCLUSIONS: Patients with Fontan have marked deficits in both cortical (hip, distal one-third radius) and trabecular (lumbar spine, femoral neck, ultradistal radius) BMD. Lower LLMZ is associated with lower BMD and may reflect inadequate skeletal muscle loading. Interventions to increase muscle mass may improve bone accrual.