Mead Johnson Nutrition Research Articles

Decreased Vitamin C Intake from Food and Supplements in the US Pregnant and Non-Pregnant Population: From NHANES 1999–2018

ObjectivesTo examine how vitamin C intake among women of reproductive age changed from 1999 to 2018 using data from 10 cycles of the National Health and Nutrition Examination Survey (NHANES) from 1999–2000 to 2017–2018.MethodsUsual vitamin C intake and prevalence of inadequate intake were estimated among pregnant and non-pregnant women 20–44 y who participated in NHANES 1999–2018 (n = 11,129), using the National Cancer Institute Method. Covariates included dietary recall sequence, intake day of the week, and dietary supplement use. Regression models were used to test for trends in vitamin c intake from foods, supplements, foods and supplements combined, and prevalence of inadequate vitamin C intake over 10 cycles of NHANES.Results1,392 were pregnant at the time of the exam. Vitamin C intake from foods alone in pregnant women decreased from 125 ± 6.7 mg in 1999–2000 to 103 ± 5.3 mg in 2017–2018 (p for trend = .0003). Supplemental vitamin c intake among pregnant women decreased from 140 ± 2.8 mg in 1999–2000 to 56 ± 0.9 mg in 2009–2010, followed by an apparent plateau between 2011–2018 (p for trend = .02). Consequently, intake foods and supplements combined decreased from 265 ± 31.9 mg in 1999–2000 to 158 ± 16.7 mg in 2017–2018 (p for trend = .0001). Inadequate intake (% < EAR) increased from 10.5 ± 2.2% in 2001–2002 to 17.2 ± 3.1% in 2017–2018 (p for trend = .015). Vitamin C intake from foods alone in non-pregnant women (n = 9,737) decreased from 84 ± 3.9 mg in 1999–2000 to 71 ± 2.5 mg in 2017–2018 (p for trend < .0001). Supplemental vitamin C intake among non-pregnant women decreased from 101 ± 1.3 mg in 1999–2000 to 41 ± 0.5 mg in 2009–2010 followed by an increase to 86 ± 2.7 mg in 2017–2018 (p for trend = .0075). Consequently, intake from foods and supplements combined decreased from 186 ± 15.4 mg in 1999–2000 to 119 ± 5.9 mg in 2009–2010 followed by an increase to 157 ± 28.4 mg in 2017–2018 (p for trend = .0045). Inadequate intake increased from 27.5 ± 2.5% in 1999–2000 to 38.6 ± 2.4% in 2017–2018 (p for trend < .0001).ConclusionsOver the past 2 decades, decreases in vitamin C intake from foods has outpaced the more recent increases in supplemental vitamin C intake among women 20–44 y. Pregnant women's vitamin C intake from both foods and supplements decreased during this time, which may result in an increased risk of infections, premature birth, and eclampsia.Funding SourcesFunded by the Reckitt|Mead Johnson Nutrition.

Risk Assessment on Use of Lactobacillus rhamnosus (LGG) as an Ingredient in Infant Formula and Baby Foods (II)

On 10. March 2006 , The Norwegian Food Safety Authority (Mattilsynet) decided that, on the basis of VKM’s previous risk assessment (2005), Nutramigen 1 with Lactobacillus rhamnosus GG (LGG) could not be marketed in Norway as medical foods for infants (0-4 months). In addition, The Norwegian Food Safety Authority (Mattilsynet) decided (08. November 2006) to withdraw permission for marketing of Nutramigen 2 with LGG, which is a milk supplement for infants aged between 4 and 6 months, with cow’s milk and soy protein allergy. On 13. December 2006, Mead Johnson Nutritionals appealed against this decision from The Norwegian Food Safety Authority (Mattilsynet). The Norwegian Food Safety Authority forwarded the appeal from the companies, asked the VKM Panel on biological hazards and the VKM Panel on nutrition, dietetic products, novel food and allergy, for a new risk assessment including the new data provided in the appeal.&#x0D; LGG is one of the most studied probiotic strains. Lactic acid produced by LGG in the human gut results in a decrease in faecal pH, which in turn inhibits colonisation by potentially pathogenic bacteria. Short-term beneficial effects from administration of LGG to infants and young children with infectious diarrhoea have been reported in a number of studies, but a prophylactic effect on diarrhoea has not been documented. Furthermore, whilst some studies have reported a prophylactic, or even a curative, effect of LGG on atopic eczema in young children, more recent studies do not report such effects. Some even suggest an increased incidence of allergic sensitization in children receiving LGG supplemented formula at an early age. There are no published data that demonstrate long-term clinical benefits of infant formula supplemented with LGG for children between 4 months and 3 years, although no immediate deleterious effects of LGG have been found. Possible long-term effects of LGG on intestinal colonisation, and its effects on long-term gastrointestinal and immune functions, are not known.&#x0D; LGG, as an ingredient in infant formula and baby foods, is intended for daily use in the target group, and not for short-term, specific treatment. Furthermore, the targeted consumer group includes children below the age of twelve months. These two aspects demand particular consideration with regard to the unknown effects of long-term treatment with large doses of live bacteria on the ecology of the microbiota of the gastrointestinal tract and on the immune system. Neither of these systems is fully matured in infants and small children, and therefore may be particularly susceptible.&#x0D; There is no documented prophylactic effect of LGG on any disease in children. The effect of treatment with LGG-supplemented formula in small children is questionable, except for a documented short-term effect on infectious diarrhoea. Panel on Biological Hazards and Panel on nutrition, dietetic products, novel food and allergy at the Norwegian Scientific Committee for Food Safety find that the data available are not sufficient to support the suggested beneficial effects, or the safety, of LGG in infant formula and baby foods for children aged between 4 months and 3 years, when the products are intended for daily use.

Micronutrient and Glucose-Related Biomarkers Until 24 Mo of Age in Infants Receiving Formula With Added Bovine Milk Fat Globule Membrane Through the First Year of Life: An RCT

ObjectivesBovine milk fat globule membrane (bMFGM) added in routine infant formula supports normal growth and safety through 24 mo of age in term infants. The impact on micronutrients and glucose-related biomarkers is assessed here. MethodsIn this double-blind, randomized, controlled trial, formula-fed infants were enrolled (<120 days of age) and randomized to receive a standard cow’s milk-based infant formula (SF, n = 174) or a similar formula with added whey protein-lipid concentrate (5 g/L; bMFGM; EF n = 173); exclusively breastfed infants were enrolled as a reference (HM, n = 235). In 50% of infants (chosen at random), parents agreed to blood collection (2–4 h fasting) at baseline, 6, 12, and 24 mo of age. Serum micronutrients (zinc, iron, ferritin, transferrin receptor) and glucose-related biomarkers (glucose, insulin, HOMA-IR [Homeostatic Model Assessment-Insulin Resistance], IGF-1) were analyzed. ResultsAt baseline, significant differences in markers of iron status (serum iron, ferritin) and glucose-related biomarkers (glucose, HOMA-IR, and IGF-1) were detected between HM and study formula groups. At 6 and 12 mo, no differences in any measure were detected between study formula groups. Serum iron and ferritin at 12 mo as well as glucose-related biomarkers at 6 mo (insulin, HOMA-IR, IGF-1) and 12 mo (IGF-1 only) were lower in the HM vs study formula groups. By 24 mo, micronutrients and glucose-related biomarkers were similar between study formula groups (with the exception of significantly lower serum iron in the SF group); for HM vs study formula groups, differences included significantly lower zinc and IGF-1. ConclusionsPatterns of micronutrients and glucose-related biomarkers were similar through two years of age in infants who received formula through one year. This study add to the body of data available for glucose-related biomarkers in children at two years of age and younger. Funding SourcesThe study was funded by Mead Johnson Nutrition (MJN). TMP, SSW, and JLW are currently, and CLB was previously employed by MJN.

769-P: Effect on Insulin Secretion Six Months after the Use of CFTR Modulators in Cystic Fibrosis Patients with or without Glucose Metabolism Abnormalities

Objective: To investigate the effect of 6m CFTR modulators treatment on insulin secretion in CF patients.Methods: 21 CF patients (17 Phe.508del hom) were included in a prospective, observational study. After 6m of lumacaftor/tezacaftor+ivacaftor, AUC of glucose, insulin and C peptide were evaluated by using 5-point OGTT. GLM repeated measures test performed.Results: 21 patients initially participated, 3 were excluded: 1 had no basal OTTG, and 2 had drug intolerance. Median age 14,7yr (ICR 8,5-26,0); 57% ≥13 yr and 57% male. Initially: 8 had normal glucose metabolism (N), 1 indeterminate (IND), 2 abnormal glucose tolerance (AGT), 2 IND+AGT, and 5 CFRD. After 6m: in the N group: 5 (62,5%; 100% <18yr) worsened their glucose tolerance status and 3 (37,5%) had no group change; in the abnormal glucose group: 2 (20%) worsened their glucose tolerance status (100% <18 yr), 3 (30%) improved (66,6% adults) and 5 (50%) remained similar (60% adults). Significant increase in AUC of glucose, insulin and C-peptide were observed after 6m in the whole group, without differences after adjustment for glucose tolerance status subgroup in AUC of insulin and C-peptide (Table 1).Conclusion: Increase in AUC of insulin and C-peptide were observed after 6m with CFTR modulators, suggesting a potential role in improving insulin secretion. AUC of glucose should be analyzed prospectively.View largeDownload slideView largeDownload slide DisclosureE. Lecumberri: None. R. Y. Yelmo: None. M. Garriga: None. A. F. Lamas: None. S. Vicente: Consultant; Self; Abbott, Fresenius Medical Care, Mead Johnson Nutrition. M. Martin-frias: None. L. Nattero-chávez: None. V. Martínez-vaello: None. L. Maiz: None. C. Sánchez rodríguez: None. M. Lorenzo: None. B. Dorado avendaño: None.

Inflammation Associated Gene Expression in the Mammary Gland of Lactating Mothers Who Delivered Preterm and Were Randomly Assigned to a Standard vs Increased DHA Supplement

ObjectivesOur objective was to characterize the mRNA-seq transcriptome of the mammary gland of lactating mothers who delivered preterm and were enrolled in a randomized control trial (RCT) of standard versus increased DHA supplementation. We hypothesized that inflammation associated gene expression would be attenuated in the increased DHA group versus the standard dose group. MethodsThe RCT was completed by 8 participants randomized to standard of care DHA supplements (200 mg/day, STD group) and 10 randomized to increased DHA supplements (1000 mg/day, EXP group). High quality extracellular mammary epithelial cell mRNA was isolated from fresh milk fat and submitted to RNA-sequencing in n = 4 STD and n = 6 EXP DHA samples. Aligned and quantified reads were examined for differentially expressed genes using t-tests (DEG, p < 0.05 after false discovery rate adjustment). The resulting DEG list was intersected with the Broad Institute list of hallmark inflammation genes. Ontological analysis of DEGs was performed with Toppcluster. ResultsThere were 409 DEGs overall, including 9 hallmark inflammation genes. In the EXP group, up-regulation of inflammation-inhibiting genes included NFKBIA (FC = 4.0) and IL18BP (FC = 3.6); and down-regulation of pro-inflammatory genes included IL7R (FC = –3.6) and IL1RL1 (FC = –3.9). Ontological analysis revealed 5 clusters of up-regulated gene sets in the EXP group, including immune regulation and management of oxidative stress associated clusters. Strong up-regulation was also seen in the major milk proteins LALBA (3.8-fold increase) and CSN2 (3.4-fold increase). ConclusionsThese findings reveal that increased DHA supplementation during lactation can modulate the expression of inflammation-associated genes within the mammary gland and support improved mammary gland function. These effects may have important clinical implications towards producing milk with a more optimal inflammasome profile and improving overall mammary gland health and function in lactating mothers who deliver preterm, with an overall benefit of reducing inflammation-driven morbidity in their premature infants. Future research with a larger RCT and greater interrogation of milk composition and volume is warranted. Funding SourcesNIH, Mead Johnson Nutrition.

Developing a Reference Framework for Typical Development in the Young Pig

Abstract Objectives The majority of infants in the US do not receive exclusive breastfeeding in the first six months of age, highlighting the necessity of infant formula. The artificially reared piglet is a common model utilized to support substantiation of novel bioactive components in milk or infant formula. However, it is currently unclear to what extent maternal and environmental rearing confounders affect growth outcomes in early life nutrition piglet studies. The objective of the present work is to use historical data to begin to chart typical development of the pig and to develop healthy reference value ranges for the purpose of assessing the safety of bioactive components in infant formula. Methods 8 piglet studies conducted at the University of Illinois Urbana-Champaign over the past ten years were compiled to create and model reference values for body and organ weights in artificially-reared and sow reared pigs. Metadata were organized to include milk replacer sources, bioactive components, sex, breed, source of herd, feeding rates, rearing styles, and health status. A combination of statistical models including simple linear regression, polynomial regression, and generalized additive models were used to analyze how such parameters influence typical growth. The diet of the 18 studies were blinded during data modeling phase. Results Over 13,000 data points from over 500 animals were identified to be suitable for data mining. Minimal differences in the growth of artificially or sow reared pigs were observed in the first 30 days of life (P &amp;gt; 0.05). Similarly, male and female bodyweight growth were nearly identical (P &amp;gt; 0.05). Development outcomes such as brain, liver, and intestinal organ weights were classified as typical for developing pigs. A subset of the data containing subjects with poor growth was identified to model growth under deficient or sub-optimal conditions. Conclusions The use of artificial rearing had no impact on body weight, nor did sex contribute to differences in growth during early life. Ultimately, these data can be used to create preliminary weight-for-age charts in the pig model to better interpret whether bioactive ingredients tested in the pig model affect animal growth within typical reference values. Funding Sources Funding was provided by Mead Johnson Nutrition, LLC, a Reckitt Benckiser LLC company.

930-P: Efficacy of Oral Semaglutide According to Race: An Exploratory Subgroup Analysis of the PIONEER Trial Program

The global PIONEER program investigated the efficacy and safety of oral semaglutide, a glucagon-like peptide-1 receptor agonist. Patients with type 2 diabetes were randomized to once-daily oral semaglutide (3, 7 or 14 mg, or flexibly dosed [flex]), placebo, or active comparator (empagliflozin 25 mg, sitagliptin 100 mg or liraglutide 1.8 mg). This exploratory subgroup analysis evaluated the effect of race on glycated hemoglobin (HbA1c) and body weight (BW) reductions at the end of treatment (week 26, 52 or 78). Data were analyzed from PIONEER 1-5, 7 and 8 by race (White, Asian, Black/African American). Baseline characteristics were generally similar across subgroups except for BW, which was lower in Asian patients. Generally, greater HbA1c reductions were observed with oral semaglutide 14 mg/flex vs. comparators across subgroups (Table). In PIONEER 1, 4 and 8, there was a significant interaction between treatment and race, with greater HbA1c reductions and estimated treatment differences in Asian patients than in other subgroups (Table). Overall, BW reductions were greater for oral semaglutide vs. comparators, regardless of subgroup and without significant interactions between treatment and race. Our findings in this exploratory subgroup analysis suggest that, in some PIONEER trials, Asian patients achieve greater HbA1c reductions than other race groups when treated with oral semaglutide. Disclosure C. Desouza: Consultant; Self; AstraZeneca, Bayer AG, Novo Nordisk A/S. A. Amod: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Sanofi-Aventis, Servier. Consultant; Self; Servier. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk A/S, Sanofi-Aventis, Servier. K. Kallenbach: None. P.J. Lin: Speaker’s Bureau; Self; Abbott, AstraZeneca, Bausch + Lomb, Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Mead Johnson Nutrition, Merck &amp; Co., Inc., Novo Nordisk Inc., Sun Pharmaceutical Industries Ltd. Other Relationship; Self; Elsevier. M. Abildlund Nielsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. R. Sørrig: Employee; Self; Novo Nordisk A/S. E. Montanya: Advisory Panel; Self; Sanofi. Consultant; Self; Novartis Pharmaceuticals Corporation. Employee; Spouse/Partner; Almirall. Speaker’s Bureau; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Funding Novo Nordisk A/S

1188-P: Approaches to and Inertia in Cardiovascular and Renal Risk Management of Type 2 Diabetes Patients in Primary Care: Results from a Global Quantitative Survey

Background: Despite recent recommendations for the use of glucose-lowering therapies with additional cardiovascular (CV) and renal benefits, as demonstrated through CV outcomes trials (CVOTs), many patients (pts) with type 2 diabetes mellitus (T2D) managed in primary care remain on therapeutic regimens now considered suboptimal. This global survey of primary care physicians (PCPs) investigated current approaches to early CV and renal risk management of pts with T2D. Methods: This web-based, global, quantitative panel survey of PCPs and primary care diabetes specialists (PCDSs) constituted 20 demographic, Likert scale, and multiple-choice questions covering the current management of pts with T2D, particularly the use of second/third line therapies (sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors). Results: Globally, 1558 PCPs and 119 PCDSs from 18 countries completed the survey. Respondents saw a mean 132 pts with T2D per month and had treated pts with T2D for 17 years. Overall, 73% of PCPs and 72% of PCDSs were responsible for second/third line treatment initiation. The biggest barrier to second/third line treatment initiation identified by respondents was local healthcare systems/insurance companies restricting access to these therapies. Concerns over safety, pt disinterest, and difficulties in maintaining regular appointments were also identified as significant contributors to treatment inertia. Only 68% of PCPs and 52% of PCDSs were aware of data published from recent CVOTs, while 68% and 58%, respectively, stated they had changed their treatment decisions based on these trials. Conclusions: Significant barriers still prevent optimization of T2D pt care in the primary setting, including limited familiarity of PCPs and PCDSs with new CVOT data, treatment inertia, and access restrictions for second/third line treatments. Disclosure S. Brunton: Advisory Panel; Self; Abbott, Bayer U.S., Merck &amp; Co., Inc., Xeris Pharmaceuticals, Inc. Speaker’s Bureau; Self; Lilly Diabetes. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. F. Cos: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Sanofi. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk A/S, Sanofi. G.F. Deed: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk Inc., Sanofi-Aventis. N. Kanumilli: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Novartis AG, Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim International GmbH, Sanofi-Aventis. Speaker’s Bureau; Self; Napp Pharmaceuticals. P.R. Kushner: Advisory Panel; Self; Abbott, AstraZeneca, Bayer U.S., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Speaker’s Bureau; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. P.J. Lin: Speaker’s Bureau; Self; Abbott, AstraZeneca, Bausch + Lomb, Bayer Inc., Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Mead Johnson Nutrition, Merck &amp; Co., Inc., Novo Nordisk Inc., Sun Pharmaceutical Industries Ltd. Other Relationship; Self; Elsevier. J. Nolte: Advisory Panel; Self; AstraZeneca. Funding AstraZeneca

Growth Through 24 Months of Age in Infants Receiving Formulas with or Without Added Bovine Milk Fat Globule Membrane (MFGM) or Human Milk Through the First Year of Life: An RCT

Abstract Objectives To evaluate growth through 24 months of age in infants receiving added bovine milk fat globule membrane (MFGM) in infant formula through 12 months of age. Concentration of MFGM from bovine milk fractions and incorporation in infant formula may better approximate the composition of complex milk lipids in human milk. Methods In the double-blind, randomized, controlled Chilean Infant Nutrition Trial (ChiNuT; NCT0262613), term infants whose mothers chose to initiate exclusive infant formula feeding before 4 months of age were randomized to receive: a standard cow's milk-based infant formula (SF, n = 174) or a similar formula with added whey protein-lipid concentrate (5 g/L; source of bovine MFGM) (bMFGM, n = 176). A reference group of infants exclusively receiving human milk (HM, n = 236) was also recruited. Growth through 24 months of age was the primary outcome. Length-for-age (LAZ), weight-for-age (WAZ) and body mass index (BMI)-for-age (BAZ) growth z-scores were analyzed by mixed-effects multiple linear regression models adjusted by sex, age (days), and maternal pregestational BMI (kg/m2). Results No significant group differences in sex, gestational age at birth, birthweight, maternal age and maternal education were detected, with the exception of maternal pregestational BMI (mean(SD)) (HM: 27.0(5.2) lower vs SF: 28.6(6.2) or bMFGM: 28.9(6.1); P = 0.002). Groups were similar at baseline (weight, length, WAZ, BAZ) with the exception of LAZ (lower in the bMFGM compared to HM group; P &amp;lt; 0.05). No significant differences in growth z-scores (absolute at 6, 9, 12, and 24 months of age or change between baseline and each study time point) were detected between SF and MFGM groups. Both randomized study formula groups were associated with higher growth z-score increases from baseline compared to the HM reference group between 6 and 24 months (P less than 0.05). Mean growth z-scores fell within the range of −1 to 1 (16th to 84th percentile) for SF, bMFGM, and HM groups at all study time points. Conclusions Added bovine MFGM in a routine cow's milk-based infant formula through 12 months of age supported normal growth through 24 months of age. Funding Sources The study was funded by Mead Johnson Nutrition (MJN). Teresa Murguia-Peniche, Steven Wu, and Jennifer Wampler are currently employed by MJN. Carol Lynn Berseth was previously employed by MJN.

Milk Osteopontin Promotes Intestinal Development in Early Life by Increasing Expression of Osteopontin Receptors

Abstract Objectives Osteopontin (OPN), a phosphorylated glycoprotein, is abundantly present in both human and mouse milk, making the mouse a good model to study functions of milk OPN. OPN is a pleiotropic protein involved in many biological processes such as cell proliferation and differentiation. OPN initiates signaling pathways to exert its multiple functions by binding to its receptors on the surface of target cells. Since milk OPN is partly resistant to in vitro digestion, the current study aimed to investigate roles of milk OPN on intestinal development in early life. Methods A mouse model established by our group was used. In this model, wild-type (WT) mouse pups were either nursed by WT or OPN knock-out (KO) dams, receiving milk with or without OPN from postnatal days 0 to 21 (P0−P21). Whether milk OPN is resistant to in vivo digestion and effects of milk OPN on intestinal development were examined. Results Milk OPN was resistant to in vivo digestion as indicated by immunoblotting using intestinal contents from P12 pups. Young pups (P4 and P6) nursed by WT dams (OPN + group) exhibited significantly longer small intestines than did pups nursed by OPN KO dams (OPN- group), but older pups had similar lengths in both groups (P8 to P30). Further, OPN + pups had a larger inner surface than did OPN- pups at P10 and P20 as revealed by histological analysis of the ratio of villus height/crypt depth. The activity of an intestinal differentiation marker (alkaline phosphatase) was significantly higher in the OPN + group than the OPN- group at P30. In addition, compared with the OPN- group, the OPN + pups (P30) had better differentiation based on the observation that more goblet cells and Paneth cells appeared in the small intestine.. To determine how milk OPN exerts its functions on the intestine, effects of milk OPN on expression of OPN receptors were then determined. qRT-PCR results showed that milk OPN increased transcription of OPN receptors, including integrin αv, integrin β3, and CD44 in duodenum and jejunum from P4 to P30 mouse pups. Immunoblotting results also indicated that milk OPN increased the protein levels of integrin αv. Conclusions Milk OPN promotes intestinal proliferation and differentiation by up-regulating expression of OPN receptors in early life. Funding Sources This study was in part funded by Mead Johnson Nutrition.

Maternal serum concentrations of bisphenol A and propyl paraben in early pregnancy are associated with male infant genital development.

Are maternal serum phthalate metabolite, phenol and paraben concentrations measured at 10-17weeks of gestation associated with male infant genital developmental outcomes, specifically cryptorchidism, anogenital distance (AGD), penile length and testicular descent distance, at birth and postnatally? Maternal serum bisphenol A (BPA) concentration at 10-17weeks of gestation was positively associated with congenital or postnatally acquired cryptorchidism, and n-propyl paraben (n-PrP) concentration was associated with shorter AGD from birth to 24months of age. Male reproductive disorders are increasing in prevalence, which may reflect environmental influences on foetal testicular development. Animal studies have implicated phthalates, BPA and parabens, to which humans are ubiquitously exposed. However, epidemiological studies have generated conflicting results and have often been limited by small sample size and/or measurement of chemical exposures outside the most relevant developmental window. Case-control study of cryptorchidism nested within a prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at 10-17 postmenstrual weeks of gestation from a single UK maternity unit between 2001 and 2009 and 24months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 330 mothers of 334 male infants (30 with congenital cryptorchidism, 25 with postnatally acquired cryptorchidism and 279 unmatched controls) were included in the present analysis. Maternal blood was collected at enrolment, and serum levels of 16 phthalate metabolites, 9 phenols (including BPA) and 6 parabens were measured using liquid chromatography/tandem mass spectrometry. Logistic regression was used to model the association of cryptorchidism with serum chemical concentrations, adjusting for putative confounders. Additionally, offspring AGD, penile length and testicular descent distance were assessed at 0, 3, 12, 18 and 24months of age, and age-specific Z scores were calculated. Associations between serum chemical levels and these outcomes were tested using linear mixed models. Maternal serum BPA concentration was associated with offspring all-type cryptorchidism both when considered as a continuous exposure (adjusted odds ratio per log10 μg/l: 2.90, 95% CI 1.31-6.43, P = 0.009) and as quartiles (phet = 0.002). Detection of n-PrP in maternal serum was associated with shorter AGD (by 0.242 standard deviations, 95% CI 0.051-0.433, P = 0.01) from birth to 24months of age; this reduction was independent of body size and other putative confounders. We did not find any consistent associations with offspring outcomes for the other phenols, parabens, and phthalate metabolites measured. We cannot discount confounding by other demographic factors or endocrine-disrupting chemicals. There may have been misclassification of chemical exposure due to use of single serum measurements. The cohort was not fully representative of pregnant women in the UK, particularly in terms of smoking prevalence and maternal ethnicity. Our observational findings support experimental evidence that intrauterine exposure to BPA and n-PrP during early gestation may adversely affect male reproductive development. More evidence is required before specific public health recommendations can be made. This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), Newlife the Charity for Disabled Children, the Mothercare Group Foundation, Mead Johnson Nutrition and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. Visiting Fellowship (J.M.): Regional Programme 'Jiménez de la Espada' for Research Mobility, Cooperation and Internationalization, Seneca Foundation-Science and Technology Agency for the Region of Murcia (No. 20136/EE/17). K.O. is supported by the Medical Research Council (UK) (Unit Programme number: MC_UU_12015/2). The authors declare no conflict of interest.

1294-P: Detection and Intervention of Prediabetes in a Large Urban Health System: Systematic Failure or Looming Opportunity?

Efficient early detection of prediabetes is critical in order to intervene and reduce conversion to T2DM since lifestyle interventions and/or metformin are proven to reduce progression. Retrospective data from a nationally-ranked tertiary academic medical center were analyzed to determine diagnosis rates, frequency of lifestyle and prescription interventions, and to assess characteristics of patients who were most likely to be clinically identified or treated. Data from the EpicCare EMR were analyzed using the University of Kansas Medical Center i2b2-based clinical data repository (HERON). Data were collected for 69,781 patients established in academically affiliated primary care clinics between 2015 and 2017. After excluding for previous diabetes/prediabetes diagnoses or use of glucose lowering agents, 46,855 patients remained to assess for incident prediabetes (ADA criteria). Clinical recognition of the prediabetes diagnosis, nutrition or weight management referral, and metformin prescription were assessed. Incident prediabetes occurred in 2,581 patients (5%). Thirty eight percent of those received a charted prediabetes diagnosis, 9% received either a referral to nutrition or weight management, and 4% received a metformin prescription. Females (OR 1.57) or those who had higher BMI (OR 1.02) or A1c values (OR 5.67) had higher odds of receiving clinical recognition (p&amp;lt;0.0001). We conclude that relatively few people with prediabetes are clinically noted and even fewer receive interventions that may reduce the conversion to T2DM. There are gender and weight biases; patients with higher BMI, higher A1c values, and females were more likely to have documentation for diagnosis and treatment for prediabetes. These low rates of recognition and treatment are likely to be similar among health care systems across the country. The low rates of recognizing, documenting, and intervening are opportunities to better utilize the EMR and reduce conversion to T2DM. Disclosure E. Newbold: None. S.E. Carlson: Advisory Panel; Self; DSM. Other Relationship; Self; MeadJohnson Nutrition (RB). D.K. Sullivan: None. D.C. Robbins: None. A. Beltramo: None. M. Lowrance: None. L.R. Waitman: None.

Application of the Indicator Amino Acid Oxidation Method for the Determination of the Metabolic Availability of Lysine from Indian Sorghum Protein in Young Adult Men (P08-069-19)

ObjectivesTo measure the protein quality of cooked sorghum by determining the metabolic availability (MA) of lysine; the first limiting indispensable amino acid. Additionally, we aimed to assess the effect of complementation by combining lentils and sorghum in a mixed meal format. MethodsIn a repeated measures design, the MA of lysine in sorghum was studied using the indicator amino acid oxidation (IAAO) method with L-[1–13C] phenylalanine as the indicator at four levels of lysine: 5, 8, 12, 15 mg. kg−1. d−1 in five healthy adult men. These intakes represent 13, 21, 32 and 40%, respectively, of the lysine requirement (37 mg. kg−1. d−1) for adult men. Each subject participated in 8 experimental diets: 4 lysine intakes as L-lysine from crystalline amino acid, 3 intakes of lysine from sorghum prepared by moist cooking and 1 experiment to discern the effects of complementation with lentils. The principles of slope-ratio were applied to calculate the MA of lysine in sorghum by comparing the IAAO response to varying intakes of lysine in cooked sorghum relative to the IAAO response to free crystalline lysine in the reference protein which was modelled after egg protein. ResultsThe MA of lysine from cooked sorghum was found to be 94%. Upon complementation with lentils, there was a decline in the oxidation of L-[1–13C] phenylalanine, reflecting an increased uptake of lysine for the synthesis of protein. ConclusionsThe findings demonstrate that most of the lysine in cooked sorghum, the fifth most commonly consumed cereal grain, is available for protein synthesis despite being of limiting concentration. Upon complementation with lentils, there was a decrease in oxidation which highlights the effectiveness of complementation. A combination of sorghum and lentil protein in a 2:1 ratio is a viable strategy to improve the protein quality for individuals consuming a plant-based sorghum and lentil diet. Funding SourcesSupported by the Canadian Institutes for Health Research. Pfizer Consumer Healthcare (Mississauga, Ontario) donated the multivitamins. Mead Johnson Nutritionals donated the protein-free powder for experimental diets.

Probiotics, Prebiotics, and Synbiotics for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis of Randomized Trials

Background: Bacteriotherapy and modulation of intestinal microbiome by administering probiotics, prebiotics, or both have long been suggested to prevent morbidity and mortality in premature infants. Our objective was to assess the comparative effectiveness of different prophylactic strategies in a network meta-analysis (NMA) of randomized trials. Methods: We searched MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane Central, BIOSIS Previews, and Google Scholar from inception up until December 1, 2018· All-cause mortality, severe necrotizing enterocolitis (NEC - Bell stage II or more), and culture proven sepsis were our a priori primary outcomes. We used a frequentist approach for NMA and assessed the certainty of evidence using the GRADE approach. Findings: We included 79 trials involving 17,655 preterm infants. Multiple-strain probiotics alone proved the only intervention with moderate- or high-quality evidence of reduced all-cause mortality relative to placebo (OR = 0·67; 95% CI: 0·52, 0·87; high certainty; absolute risk reduction = 1·5%). Compared to placebo, multiple-strain probiotics (OR = 0·35; 95% CI: 0·26, 0·47; moderate certainty; absolute risk reduction = 4·1%), and single-strain probiotics alone (OR = 0·63; 95% CI: 0·46, 0·86; moderate certainty; absolute risk reduction = 2·3%) or in combination with lactoferrin (OR = 0·04; 95% CI: 0·01, 0·62; moderate certainty; absolute risk reduction = 6·2%) were among the interventions with moderate- or high-quality evidence that significantly reduced severe NEC. Among the intervention with moderate- or high-quality evidence relative to placebo, single-strain probiotics combined with lactoferrin (OR = 0·27; 95% CI: 0·10, 0·72; moderate certainty; absolute risk reduction = 11·00%) or alone (OR = 0·80; 95% CI: 0·65, 0·99; moderate certainty; absolute risk reduction = 2·6%) and lactoferrin alone (OR = 0·44; 95% CI: 0·27, 0·74; moderate certainty; absolute risk reduction = 5·1%) demonstrated statistically significant reduction in culture proven late-onset sepsis. Interpretation: Moderate-to-high certainty evidence demonstrates the superiority of single and multi-strain probiotics over alternative preventive treatments. Synbiotics (multiple-strain probiotics in combination with prebiotics) provide the largest reduction in morbidity and mortality in preterm infants but this is supported by only low-to-very low certainty evidence; thus, prioritizing synbiotics in future trials may provide important insights. Funding: Mitacs in partnership with Nestle Canada. Declaration of Interest: PMS is the recipient of research support provided by Lallemand Human Nutrition Inc. (Montreal, Quebec, Canada) through a Mitacs Accelerates Internship awarded to Shaiya Robinson, PhD. PMS has received honoraria for CME activities from Nestle Nutrition, Abbott Nutrition, and Mead Johnson Nutrition.

Practical tips for paediatricians: Assessment and management of young children with iron deficiency.

Funding sources: The Pediatric Outcomes Research Team (PORT) is supported by a grant from the Hospital for Sick Children Foundation. Disclosures: PCP received a grant from Canadian Institutes of Health Research (CIHR) for an ongoing trial of iron supplementation in young children with iron deficiency (FRN # 115059). Mead Johnson Nutrition (MJN) supplies Fer-In-Sol® drops in-kind for this investigator-initiated trial. CIHR and MJN had no role in the preparation of this manuscript.

Early Postnatal Diets Affect the Bioregional Small Intestine Microbiome and Ileal Metabolome in Neonatal Pigs

BackgroundBreastfeeding is known to be protective against gastrointestinal disorders and may modify gut development. Although the gut microbiome has been implicated, little is known about how early diet affects the small intestine microbiome. ObjectiveWe hypothesized that disparate early diets would promote unique microbial profiles in the small intestines of neonatal pigs. MethodsMale and female 2-d-old White Dutch Landrace pigs were either sow fed or provided dairy (Similac Advance powder; Ross Products Abbott Laboratories) or soy (Enfamil Prosobee Lipil powder; Mead Johnson Nutritionals) infant formulas until day 21. Bacterial ecology was assessed in the contents of the small intestine through the use of 16S ribosomal RNA sequencing. α-Diversity, β-diversity, and differential abundances of operational taxonomic units were assessed by ANOVA, permutational ANOVA, and negative binomial regression, respectively. Ileum tissue metabolomics were measured by LC-mass spectrometry and assessed by weighted correlation network analysis. ResultsGreater α-diversity was observed in the duodena of sow-fed compared with formula-fed neonatal pigs (P < 0.05). No differences were observed in the ilea. Firmicutes represented the most abundant phylum across all diets in duodena (78.8%, 80.1%, and 53.4% relative abundance in sow, dairy, and soy groups, respectively), followed by Proteobacteria in sow (12.2%) and dairy (12.4%) groups and Cyanobacteria in soy-fed (36.2%) pigs. In contrast to those in the duodenum, Proteobacteria was the dominant phylum in the ileum, with >60% relative abundance in all of the groups. In the duodenum, 77 genera were altered by diet, followed by 48 in the jejunum and 19 in the ileum. Metabolomics analyses revealed associations between ileum tissue metabolites (e.g., acylcarnitines, 3-aminoisobutyric acid) and diet-responsive microbial genera. ConclusionsThese results indicate that the neonatal diet has regional effects on the small intestine microbiome in pigs, with the most pronounced effects occurring in the duodena. Regional effects may be important factors when considering gut tissue metabolism and development in the postnatal period.

Prenatal paracetamol exposure is associated with shorter anogenital distance in male infants

STUDY QUESTIONWhat is the relationship between maternal paracetamol intake during the masculinisation programming window (MPW, 8–14 weeks of gestation) and male infant anogenital distance (AGD), a biomarker for androgen action during the MPW?SUMMARY ANSWERIntrauterine paracetamol exposure during 8–14 weeks of gestation is associated with shorter AGD from birth to 24 months of age.WHAT IS ALREADY KNOWNThe increasing prevalence of male reproductive disorders may reflect environmental influences on foetal testicular development during the MPW. Animal and human xenograft studies have demonstrated that paracetamol reduces foetal testicular testosterone production, consistent with reported epidemiological associations between prenatal paracetamol exposure and cryptorchidism.STUDY DESIGN, SIZE, DURATIONProspective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at ~12 post-menstrual weeks of gestation from a single UK maternity unit between 2001 and 2009, and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 676 delivered male infants and completed a medicine consumption questionnaire.PARTICIPANTS/MATERIALS, SETTING, METHODMothers self-reported medicine consumption during pregnancy by a questionnaire administered during the perinatal period. Infant AGD (measured from 2006 onwards), penile length and testicular descent were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between paracetamol intake during three gestational periods (<8 weeks, 8–14 weeks and >14 weeks) and these outcomes were tested by linear mixed models. Two hundred and twenty-five (33%) of six hundred and eighty-one male infants were exposed to paracetamol during pregnancy, of whom sixty-eight were reported to be exposed during 8–14 weeks. AGD measurements were available for 434 male infants.MAIN RESULTS AND THE ROLE OF CHANCEParacetamol exposure during 8–14 weeks of gestation, but not any other period, was associated with shorter AGD (by 0.27 SD, 95% CI 0.06–0.48, P = 0.014) from birth to 24 months of age. This reduction was independent of body size. Paracetamol exposure was not related to penile length or testicular descent.LIMITATIONS, REASONS FOR CAUTIONConfounding by other drugs or endocrine-disrupting chemicals cannot be discounted. The cohort was not fully representative of pregnant women in the UK, particularly in terms of maternal ethnicity and smoking prevalence. There is likely to have been misclassification of paracetamol exposure due to recall error.WIDER IMPLICATIONS OF THE FINDINGSOur observational findings support experimental evidence that intrauterine paracetamol exposure during the MPW may adversely affect male reproductive development.STUDY FUNDING/COMPETING INTERESTSThis work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), the Newlife Foundation for Disabled Children, the Evelyn Trust, the Mothercare Group Foundation, Mead Johnson Nutrition, and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. The authors declare no conflict of interest.

The Impact of Formula fortified with Milk Fat Globule Membrane on the Neonatal Intestine

BackgroundBreastmilk provides the ideal nutrient source during development. However, in some cases it is not available in adequate amounts, if at all (especially following premature delivery), to the developing infant resulting in a need for formula feeding. As achieving appropriate growth during this early time is essential for proper development and protection from noxious stimuli, there is a need for the composition of formula to mimic that of breastmilk as closely as possible. Fat in breastmilk, a major source of energy for the newborn, contains a unique and very complex triple membrane structure referred to as the Milk Fat Globule Membrane (MFGM) resulting in strikingly large fat molecules (average size of 5μm in human milk). Surprisingly, the fat component in formula is derived from vegetable sources rather than MFGM, which differ greatly in size and composition. Interestingly, although studies in several adult models of infection and inflammation have attributed protective effects to MFGM supplementation, its role in the newborn intestine and its development has not thoroughly been explored.ObjectiveTo examine the effects of Milk Fat Globule Membrane (MFGM) on postnatal development of the small intestine and colon.MethodsRat pups were artificially reared using the pup‐in‐a‐cup model to examine the effects of MFGM (1.2 or 6 mg/mL) supplementation on early intestinal development. Rat pups underwent gastronomy at postnatal day (PD) 5 and were supplemented with formula containing soy (control formula) or MFGM+soy until PD15, at which point they were euthanized along with mother reared littermates, resulting in three groups. Small (jeujunal, ileal) and large intestinal (distal colon) samples were collected for histological assessment and immunohistochemistry (IHC).ResultsAlthough no overt differences were noted in pup weight or overall length of the small or large intestine at PD15 between the three groups, histological assessment revealed significant changes in the epithelial architecture along the length of the intestine (jejunum, ileum and colon). MFGM supplementation resulted in significant dose dependent changes at the intestinal surface, resulting in crypt depths similar to those recorded in mother reared (MR) pups at PD15. IHC analysis of intestinal sections revealed similar positive staining between MFGM and MR pups for major cell types within the epithelium (goblet cells and enterocytes), rates of cell proliferation, and tight junction proteins.ConclusionMFGM normalizes many aspects of intestinal development similar to that observed in mother reared littermates. Its supplementation in formula may be beneficial in neonates who do not have access to breast milk, particularly pre‐term infants to accelerate intestinal development.Support or Funding InformationGanive Bhinder is funded by a Canadian Institutes of Health Research Phd Studentship and University of British Columbia 4 year fellowship.Milk Fat Globule Membrane for this study was provided by Mead Johnson Nutrition.

Soluble Mediators Derived from Lactobacillus rhamnosus GG (LGG) Decrease Visceral Pain Hypersensitivity Induced by Early Life Stress

Maternal separation of rat pups is a robust and reliable model of early life stress that induces long‐term alterations to behavior and brain neurochemistry. These changes are particularly apparent with respect to the microbiota‐gut‐brain axis where probiotic feeding has been shown to ameliorate some of these stress‐induced alterations. It is possible that biologically relevant products of probiotic metabolism are involved in such effects, and therefore could deliver the required benefits without requiring the live organism to be present. In this study the effects of a specific preparation of soluble mediators from the probiotic Lactobacillus rhamnosus GG (LGG) were evaluated. Previously, immunomodulatory properties of this material have been demonstrated both in vitro and in vivo. Production conditions have been standardized with cultivation and downstream processing steps such as desalting, sterile filtration and lyophilization. The maternal separation protocol was conducted as described in O'Mahony et al., 2009. Rats were separated from their mothers for 3 hrs/day from postnatal day (PND) 2 to 12. Starting at weaning (PND 21), both non‐separated (NS) and maternally separated (MS) offspring were randomized into separate experimental groups and were provided drinking water with or without supplementation of LGG soluble mediators. Supplementation of the lyophilized materials was benchmarked to the number of LGG viable cells during cultivation to give a dose equivalent to a range from 1.3×108 to 4.3×108 viable LGG/animal/day throughout the study until PND 85. Visceral hypersensitivity was assessed with the colorectal distension test conducted at PND 79. There were no differences in body weight or water and food intake across groups. MS rats demonstrated visceral hypersensitivity to colorectal distension reflected by a lower pain threshold when compared to NS rats, which was ameliorated by the LGG soluble mediators (p=0.03). There were no differences in the number of observed pain behaviors between treatment groups. Interestingly, the increased pain threshold in rats that received LGG soluble mediators was not observed in animals that received unconditioned culture medium subjected to the same processing steps as the LGG soluble mediators. This indicated the presence of specific bioactives in the culture medium secreted by LGG during growth. In conclusion, administration of LGG soluble mediators in rats reversed the altered visceral pain sensitivity induced by MS. Further studies are needed to elucidate specific mechanism of actions related to gut and brain neurochemistry.Support or Funding InformationSupported by Science Foundation Ireland and Mead Johnson Nutrition.

The Form of Magnesium Fed Early in Life Has Subtle Effects on Open Field Behavior and Acoustic Startle Response, but Does Not Impact Morris Water Maze Performance

Magnesium is an essential mineral that serves as an intracellular cofactor in enzymatic reactions and has an important regulatory role of gating of the N‐methyl‐D‐aspartate receptor (which is involved in learning and memory processing). The purpose of this study was to assess the impact of Magnesium Oxide (MgO) versus Magnesium L‐Threonate (MgT) during normal early postnatal development on anxiety‐related behaviors and cognition in rodents. Newly weaned Sprague‐Dawley rats, postnatal day (PD) 21, were fed a diet that either contained 0.1% MgO or 0.1% MgT. No significant differences were found for body weights or food intake across the study. Open field exploration of PD28 or PD35 rats resulted in a main effect of age (F=2.14, p&lt;0.05) and an age by diet interaction (F=2.45 p&lt;0.05). Rats fed MgO spent less time positioned near the wall at P28 (M 452.5s) than P35 (M 467.5 s) while MgT fed rats spent more time near the apparatus wall at P28 (M 482s) than P35 (M 355s). Percent change in startle response in acoustic startle chamber showed no significant differences between MgO and MgT on PD 28 whereas after two weeks of diet exposure MgT females sensitized to the startle stimulus. In Morris water maze testing, there was a main effect of time (F=22.275 p&lt;0.001) during the training phase on latency to find the hidden platform, but no effect of diet. There was also no effect of diet on latency or % time in target quadrant during the probe trial. Overall, these data suggest the form of dietary magnesium provided early in life caused a subtle shift in development of exploratory behavior and associative learning but did not alter spatial learning or memory.Support or Funding InformationStudy funded by Mead Johnson Nutrition.