International gestational age-specific centiles for blood pressure in pregnancy from the INTERGROWTH-21st Project in 8 countries: A longitudinal cohort study.

BACKGROUND: Gestational hypertensive and acute hypotensive disorders are associated with maternal morbidity and mortality worldwide. However, physiological blood pressure changes in pregnancy are insufficiently defined. We describe blood pressure changes across healthy pregnancies from the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Fetal Growth Longitudinal Study (FGLS) to produce international, gestational age-specific, smoothed centiles (third, 10th, 50th, 90th, and 97th) for blood pressure. METHODS AND FINDINGS: Secondary analysis of a prospective, longitudinal, observational cohort study (2009 to 2016) was conducted across 8 diverse urban areas in Brazil, China, India, Italy, Kenya, Oman, the United Kingdom, and the United States of America. We enrolled healthy women at low risk of pregnancy complications. We measured blood pressure using standardised methodology and validated equipment at enrolment at <14 weeks, then every 5 ± 1 weeks until delivery. We enrolled 4,607 (35%) women of 13,108 screened. The mean maternal age was 28·4 (standard deviation [SD] 3.9) years; 97% (4,204/4,321) of women were married or living with a partner, and 68% (2,955/4,321) were nulliparous. Their mean body mass index (BMI) was 23.3 (SD 3.0) kg/m2. Systolic blood pressure was lowest at 12 weeks: Median was 111.5 (95% CI 111.3 to 111.8) mmHg, rising to a median maximum of 119.6 (95% CI 118.9 to 120.3) mmHg at 40 weeks' gestation, a difference of 8.1 (95% CI 7.4 to 8.8) mmHg. Median diastolic blood pressure decreased from 12 weeks: 69.1 (95% CI 68.9 to 69.3) mmHg to a minimum of 68.5 (95% CI 68.3 to 68.7) mmHg at 19+5 weeks' gestation, a change of -0·6 (95% CI -0.8 to -0.4) mmHg. Diastolic blood pressure subsequently increased to a maximum of 76.3 (95% CI 75.9 to 76.8) mmHg at 40 weeks' gestation. Systolic blood pressure fell by >14 mmHg or diastolic blood pressure by >11 mmHg in fewer than 10% of women at any gestational age. Fewer than 10% of women increased their systolic blood pressure by >24 mmHg or diastolic blood pressure by >18 mmHg at any gestational age. The study's main limitations were the unavailability of prepregnancy blood pressure values and inability to explore circadian effects because time of day was not recorded for the blood pressure measurements. CONCLUSIONS: Our findings provide international, gestational age-specific centiles and limits of acceptable change to facilitate earlier recognition of deteriorating health in pregnant women. These centiles challenge the idea of a clinically significant midpregnancy drop in blood pressure.

Emerging Concepts in Nutrient Needs.

Dietary reference intakes (DRIs) are quantitative, nutrient intake-based standards used for assessing the diets and specific nutrient intakes of healthy individuals and populations and for informing national nutrition policy and nutrition programs. Because nutrition needs vary by age, sex, and physiological state, DRIs are often specified for healthy subgroups within a population. Diet is known to be the leading modifiable risk factor for chronic disease, and the prevalence of chronic disease is growing in all populations globally and across all subgroups, but especially in older adults. It is known that nutrient needs can change in some chronic disease and other clinical states. Disease states and/or disease treatment can cause whole-body or tissue-specific nutrient depletion or excess, resulting in the need for altered nutrient intakes. In other cases, disease-related biochemical dysfunction can result in a requirement for a nonessential nutrient, rendering it as conditionally essential, or result in toxicity for a food component at levels usually tolerated by healthy people, as seen in inborn errors of metabolism. Here we summarize examples from a growing body of literature of disease-altering nutrient requirements, supporting the need to give more consideration to special nutrient requirements in disease states.

The satisfactory growth and development at 2 years of age of the INTERGROWTH-21st Fetal Growth Standards cohort support its appropriateness for constructing international standards.

BACKGROUND: The World Health Organization recommends that human growth should be monitored with the use of international standards. However, in obstetric practice, we continue to monitor fetal growth using numerous local charts or equations that are based on different populations for each body structure. Consistent with World Health Organization recommendations, the INTERGROWTH-21st Project has produced the first set of international standards to date pregnancies; to monitor fetal growth, estimated fetal weight, Doppler measures, and brain structures; to measure uterine growth, maternal nutrition, newborn infant size, and body composition; and to assess the postnatal growth of preterm babies. All these standards are based on the same healthy pregnancy cohort. Recognizing the importance of demonstrating that, postnatally, this cohort still adhered to the World Health Organization prescriptive approach, we followed their growth and development to the key milestone of 2 years of age. OBJECTIVE: The purpose of this study was to determine whether the babies in the INTERGROWTH-21st Project maintained optimal growth and development in childhood. STUDY DESIGN: In the Infant Follow-up Study of the INTERGROWTH-21st Project, we evaluated postnatal growth, nutrition, morbidity, and motor development up to 2 years of age in the children who contributed data to the construction of the international fetal growth, newborn infant size and body composition at birth, and preterm postnatal growth standards. Clinical care, feeding practices, anthropometric measures, and assessment of morbidity were standardized across study sites and documented at 1 and 2 years of age. Weight, length, and head circumference age- and sex-specific z-scores and percentiles and motor development milestones were estimated with the use of the World Health Organization Child Growth Standards and World Health Organization milestone distributions, respectively. For the preterm infants, corrected age was used. Variance components analysis was used to estimate the percentage variability among individuals within a study site compared with that among study sites. RESULTS: There were 3711 eligible singleton live births; 3042 children (82%) were evaluated at 2 years of age. There were no substantive differences between the included group and the lost-to-follow up group. Infant mortality rate was 3 per 1000; neonatal mortality rate was 1.6 per 1000. At the 2-year visit, the children included in the INTERGROWTH-21st Fetal Growth Standards were at the 49th percentile for length, 50th percentile for head circumference, and 58th percentile for weight of the World Health Organization Child Growth Standards. Similar results were seen for the preterm subgroup that was included in the INTERGROWTH-21st Preterm Postnatal Growth Standards. The cohort overlapped between the 3rd and 97th percentiles of the World Health Organization motor development milestones. We estimated that the variance among study sites explains only 5.5% of the total variability in the length of the children between birth and 2 years of age, although the variance among individuals within a study site explains 42.9% (ie, 8 times the amount explained by the variation among sites). An increase of 8.9 cm in adult height over mean parental height is estimated to occur in the cohort from low-middle income countries, provided that children continue to have adequate health, environmental, and nutritional conditions. CONCLUSION: The cohort enrolled in the INTERGROWTH-21st standards remained healthy with adequate growth and motor development up to 2 years of age, which supports its appropriateness for the construction of international fetal and preterm postnatal growth standards.

Successive 1-Month Weight Increments in Infancy Can Be Used to Screen for Faltering Linear Growth.

BACKGROUND: Linear growth faltering in the first 2 y contributes greatly to a high stunting burden, and prevention is hampered by the limited capacity in primary health care for timely screening and intervention. OBJECTIVE: This study aimed to determine an approach to predicting long-term stunting from consecutive 1-mo weight increments in the first year of life. METHODS: By using the reference sample of the WHO velocity standards, the analysis explored patterns of consecutive monthly weight increments among healthy infants. Four candidate screening thresholds of successive increments that could predict stunting were considered, and one was selected for further testing. The selected threshold was applied in a cohort of Bangladeshi infants to assess its predictive value for stunting at ages 12 and 24 mo. RESULTS: Between birth and age 12 mo, 72.6% of infants in the WHO sample tracked within 1 SD of their weight and length. The selected screening criterion ("event") was 2 consecutive monthly increments below the 15th percentile. Bangladeshi infants were born relatively small and, on average, tracked downward from approximately age 6 to <24 mo (51% stunted). The population-attributable risk of stunting associated with the event was 14% at 12 mo and 9% at 24 mo. Assuming the screening strategy is effective, the estimated preventable proportion in the group who experienced the event would be 34% at 12 mo and 24% at 24 mo. CONCLUSIONS: This analysis offers an approach for frontline workers to identify children at risk of stunting, allowing for timely initiation of preventive measures. It opens avenues for further investigation into evidence-informed application of the WHO growth velocity standards.

Complementary feeding and attained linear growth among 6-23-month-old children.

OBJECTIVE: To examine the association between complementary feeding indicators and attained linear growth at 6-23 months. DESIGN: Secondary analysis of Phase V Demographic and Health Surveys data (2003-2008). Country-specific ANOVA models were used to estimate effects of three complementary feeding indicators (minimum meal frequency, minimum dietary diversity and minimum adequate diet) on length-for-age, adjusted for covariates and interactions of interest. SETTING: Twenty-one countries (four Asian, twelve African, four from the Americas and one European). SUBJECTS: Sample sizes ranging from 608 to 13 676. RESULTS: Less than half the countries met minimum meal frequency and minimum dietary diversity, and only Peru had a majority of the sample receiving a minimum adequate diet. Minimum dietary diversity was the indicator most consistently associated with attained length, having significant positive effect estimates (ranging from 0·16 to 1·40 for length-for-age Z-score) in twelve out of twenty-one countries. Length-for-age declined with age in all countries, and the greatest declines in its Z-score were seen in countries (Niger, -1·9; Mali, -1·6; Democratic Republic of Congo, -1·4; Ethiopia, -1·3) where dietary diversity was persistently low or increased very little with age. CONCLUSIONS: There is growing recognition that poor complementary feeding contributes to the characteristic negative growth trends observed in developing countries and therefore needs focused attention and its own tailored interventions. Dietary diversity has the potential to improve linear growth. Using four food groups to define minimum dietary diversity appears to capture enough information in a simplified, standard format for multi-country comparisons of the quality of complementary diets.

Parental height and child growth from birth to 2 years in the WHO Multicentre Growth Reference Study.

Linear growth from birth to 2 years of children enrolled in the World Health Organization Multicentre Growth Reference Study was similar despite substantial parental height differences among the six study sites. Within-site variability in child length attributable to parental height was estimated by repeated measures analysis of variance using generalized linear models. This approach was also used to examine relationships among selected traits (e.g. breastfeeding duration and child morbidity) and linear growth between 6 and 24 months of age. Differences in intergenerational adult heights were evaluated within sites by comparing mid-parental heights (average of the mother's and father's heights) to the children's predicted adult height. Mid-parental height consistently accounted for greater proportions of observed variability in attained child length than did either paternal or maternal height alone. The proportion of variability explained by mid-parental height ranged from 11% in Ghana to 21% in India. The average proportion of between-child variability accounted for by mid-parental height was 16% and the analogous within-child estimate was 6%. In the Norwegian and US samples, no significant differences were observed between mid-parental and children's predicted adult heights. For the other sites, predicted adult heights exceeded mid-parental heights by 6.2-7.8 cm. To the extent that adult height is predicted by height at age 2 years, these results support the expectation that significant community-wide advances in stature are attainable within one generation when care and nutrition approximate international recommendations, notwithstanding adverse conditions likely experienced by the previous generation.

Effect on school attendance and performance of iron and multiple micronutrients as adjunct to drug treatment of Schistosoma-infected anemic schoolchildren.

BACKGROUND: Relationships among Schistosoma haematobium, anemia, and iron deficiency have been documented, and all have been found to be associated with a decline in school attendance and lower performance. OBJECTIVE: To assess the effect of single or combined iron and multiple micronutrients and/or praziquantel on school attendance and achievement in randomly selected 7- to 12-year-old anemic children with documented S. haematobium infection (n = 406) in Mali over a 3-month period. METHODS: Schistosomiasis infection was diagnosed by the presence of schistosome eggs in the urine. Venous blood samples (5 mL) were drawn from an antecubital vein for hemoglobin assessment. Children were randomly assigned to one of four treatment groups: praziquantel alone, praziquantel + iron, praziquantel + multiple micronutrients, and praziquantel + multiple micronutrients + iron. School attendance was defined by the number of days the child was absent from class. Achievement was defined by the child's overall school grades. RESULTS: Changes within treatment groups from baseline to the end of study were found for attendance (p < .001) but not for achievement (p > .05). Significant supplement treatments by age group interactions were found in 7- to 9-year-old children for attendance. Further exploration of treatment effects in this age group showed that only iron treatment's main effect was significant on attendance (p = .049) and was of borderline significance on school grades (p = .08). CONCLUSIONS: Combined praziquantel and iron treatment improved children's school attendance and performance better than praziquantel alone, particularly among younger children.

Post-partum weight change patterns in the WHO Multicentre Growth Reference Study.

The interplay of factors that affect post-partum loss or retention of weight gained during pregnancy is not fully understood. The objective of this paper is to describe patterns of weight change in the six sites of the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS) and explore variables that explain variation in weight change within and between sites. Mothers of 1743 breastfed children enrolled in the MGRS had weights measured at days 7, 14, 28 and 42 post-partum, monthly from 2 to 12 months and bimonthly thereafter until 24 months post-partum. Height, maternal age, parity and employment status were recorded and breastfeeding was monitored throughout the follow-up. Weight change patterns varied significantly among sites. Ghanaian and Omani mothers lost little or gained weight post-partum. In Brazil, India, Norway and USA, mothers on average lost weight during the first year followed by stabilization in the second year. Lactation intensity and duration explained little of the variation in weight change patterns. In most sites, obese mothers tended to lose less weight than normal-weight mothers. In Brazil and Oman, primiparous mothers lost about 1 kg more than multiparous mothers in the first 6 months. In India and Ghana, multiparous mothers lost about 0.6 kg more than primiparas in the second 6 months. Culturally defined mother-care practices probably play a role in weight change patterns among lactating women. This hypothesis should stimulate investigation into gestational weight gain and post-partum losses in different ethnocultural contexts.

Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop.

Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). There is widespread agreement that maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., anemia, birth defects, and cancer). However, there are concerns of potential adverse effects of excess folic acid intake and/or elevated folate status, with the original concern focused on exacerbation of clinical effects of vitamin B-12 deficiency and its role in neurocognitive health. More recently, animal and observational studies have suggested potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk. 1) Does UMFA affect biological pathways leading to adverse health effects? 2) Does elevated folate status resulting from any form of folate intake affect vitamin B-12 function and its roles in sustaining health? 3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B-12 function? This article summarizes the proceedings of an August 2019 NIH expert workshop focused on addressing these research areas.

INTERGROWTH-21st Project international INTER-NDA standards for child development at 2 years of age: an international prospective population-based study.

OBJECTIVES: To describe the construction of the international INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) standards for child development at 2 years by reporting the cognitive, language, motor and behaviour outcomes in optimally healthy and nourished children in the INTERGROWTH-21st Project. DESIGN: Population-based cohort study, the INTERGROWTH-21st Project. SETTING: Brazil, India, Italy, Kenya and the UK. PARTICIPANTS: 1181 children prospectively recruited from early fetal life according to the prescriptive WHO approach, and confirmed to be at low risk of adverse perinatal and postnatal outcomes. PRIMARY MEASURES: Scaled INTER-NDA domain scores for cognition, language, fine and gross motor skills and behaviour; vision outcomes measured on the Cardiff tests; attentional problems and emotional reactivity measured on the respective subscales of the preschool Child Behaviour Checklist; and the age of acquisition of the WHO gross motor milestones. RESULTS: Scaled INTER-NDA domain scores are presented as centiles, which were constructed according to the prescriptive WHO approach and excluded children born preterm and those with significant postnatal/neurological morbidity. For all domains, except negative behaviour, higher scores reflect better outcomes and the threshold for normality was defined as ≥10th centile. For the INTER-NDA's cognitive, fine motor, gross motor, language and positive behaviour domains these are ≥38.5, ≥25.7, ≥51.7, ≥17.8 and ≥51.4, respectively. The threshold for normality for the INTER-NDA's negative behaviour domain is ≤50.0, that is, ≤90th centile. At 22-30 months of age, the cohort overlapped with the WHO motor milestone centiles, showed low postnatal morbidity (<10%), and vision outcomes, attentional problems and emotional reactivity scores within the respective normative ranges. CONCLUSIONS: From this large, healthy and well-nourished, international cohort, we have constructed, using the WHO prescriptive methodology, international INTER-NDA standards for child development at 2 years of age. Standards, rather than references, are recommended for population-level screening and the identification of children at risk of adverse outcomes.

Multiple micronutrients including iron are not more effective than iron alone for improving hemoglobin and iron status of Malian school children.

Iron deficiency and anemia remain among the most important global public health problems facing school children. Helminth infections often peak at school age and aggravate nutritional risks. We conducted a 12-wk randomized controlled trial in 406 Malian anemic schoolchildren infected with Schistosoma hematobium to examine the effects of 2 doses of praziquantel (P) (40 mg/kg body weight), P + 60 mg/d iron (Fe), and/or a multiple micronutrient supplement (MM) that included 18 mg/d Fe. Supplements were administered to the children each school day (5 d/wk) throughout the study. Changes in hemoglobin (Hb), serum ferritin (SF), and serum transferrin receptors (s-TfR) were followed. We also examined interactions between Fe and MM supplements on Hb and SF concentrations and malaria incidence. The effects of Fe on Hb and SF concentrations were greater than the effects of P alone and MM with or without added Fe at 6 and 12 wk (P < 0.001). In all groups, s-TfR decreased at 6 and 12 wk compared with baseline. The decrease was most pronounced in the P + Fe group compared with the other 3 groups at wk 6 (P = 0.05). Fe and MM interacted negatively at wk 6 and 12 to affect Hb (beta = -0.43, 95% CI = -0.77, -0.09; P = 0.01 and beta = -0.47, 95% CI = -0.83, -0.11; P = 0.01, respectively) and SF (beta = -0.42, 95% CI = -25.60, 12.31; P < 0.001, and beta = -0.37, 95% CI = -0.63, -0.12; P = 0.004, respectively). Malaria incidence was higher in the groups treated with added Fe (relative risk: 1.66; 95% CI: 0.75, 3.67). In this context, MM with added iron were not more effective than Fe without MM. Fe supplementation of schoolchildren with 60 mg/d for anemia control should be considered carefully.

Best practices in nutrition science to earn and keep the public's trust.

Public trust in nutrition science is the foundation on which nutrition and health progress is based, including sound public health. An ASN-commissioned, independent Advisory Committee comprehensively reviewed the literature and available public surveys about the public's trust in nutrition science and the factors that influence it and conducted stakeholder outreach regarding publicly available information. The Committee selected 7 overlapping domains projected to significantly influence public trust: 1) conflict of interest and objectivity; 2) public benefit; 3) standards of scientific rigor and reproducibility; 4) transparency; 5) equity; 6) information dissemination (education, communication, and marketing); and 7) accountability. The literature review comprehensively explored current practices and threats to public trust in nutrition science, including gaps that erode trust. Unfortunately, there is a paucity of peer-reviewed material specifically focused on nutrition science. Available material was examined, and its analysis informed the development of priority best practices. The Committee proposed best practices to support public trust, appropriate to ASN and other food and nutrition organizations motivated by the conviction that public trust remains key to the realization of the benefits of past, present, and future scientific advances. The adoption of the best practices by food and nutrition organizations, such as ASN, other stakeholder organizations, researchers, food and nutrition professionals, companies, government officials, and individuals working in the food and nutrition space would strengthen and help ensure earning and keeping the public's continued trust in nutrition science.

Neurodevelopmental milestones and associated behaviours are similar among healthy children across diverse geographical locations.

It is unclear whether early child development is, like skeletal growth, similar across diverse regions with adequate health and nutrition. We prospectively assessed 1307 healthy, well-nourished 2-year-old children of educated mothers, enrolled in early pregnancy from urban areas without major socioeconomic or environmental constraints, in Brazil, India, Italy, Kenya and UK. We used a specially developed psychometric tool, WHO motor milestones and visual tests. Similarities across sites were measured using variance components analysis and standardised site differences (SSD). In 14 of the 16 domains, the percentage of total variance explained by between-site differences ranged from 1.3% (cognitive score) to 9.2% (behaviour score). Of the 80 SSD comparisons, only six were >±0.50 units of the pooled SD for the corresponding item. The sequence and timing of attainment of neurodevelopmental milestones and associated behaviours in early childhood are, therefore, likely innate and universal, as long as nutritional and health needs are met.

Scientific rigor and credibility in the nutrition research landscape.

Scientific progress depends on the quality and credibility of research methods. As discourse on rigor, transparency, and reproducibility joins the cacophony of nutrition information and misinformation in mass media, buttressing the real and perceived reliability of nutrition science is more important than ever. This broad topic was the focus of a 2016 plenary session, "Scientific Rigor and Competing Interests in the Nutrition Research Landscape." This article summarizes and expands on this session in an effort to increase understanding and dialogue with regard to factors that limit the real and perceived reliability of nutrition science and steps that can be taken to mitigate those factors. The end goal is to both earn and merit greater trust in nutrition science by both the scientific community and the general public. The authors offer suggestions in each of the domains of education and training, communications, research conduct, and procedures and policies to help achieve this goal. The authors emphasize the need for adequate funding to support these efforts toward greater rigor and transparency, which will be resource demanding and may require either increased research funding or the recognition that a greater proportion of research funding may need to be allocated to these tasks.

Differential gene expression in intestinal epithelial cells induced by single and mixtures of potato glycoalkaloids.

Alpha-chaconine and alpha-solanine are naturally occurring toxins. They account for 95% of the total glycoalkaloids in potatoes ( Solanum tuberosum L.). At high levels, these glycoalkaloids may be toxic to humans, mainly by disrupting cell membranes of the gastrointestinal tract. Gene-profiling experiments were performed, whereby Caco-2 cells were exposed to equivalent concentrations (10 microM) of pure alpha-chaconine or alpha-solanine or glycoalkaloid mixtures of varying alpha-chaconine/alpha-solanine ratios for 6 h. In addition, lactate dehydrogenase, cell cycle, and apoptosis analyses experiments were also conducted to further elucidate the effects of glycoalkaloids. The main aims of the study were to determine the transcriptional effects of these glycoalkaloid treatments on Caco-2 cells and to investigate DNA microarray utility in conjunction with conventional toxicology in screening for potential toxicities and their severity. Gene expression and pathway analyses identified changes related to cholesterol biosynthesis, growth signaling, lipid and amino acid metabolism, mitogen-activated protein kinase (MAPK) and NF-kappaB cascades, cell cycle, and cell death/apoptosis. To varying extents, DNA microarrays discriminated the severity of the effect among the different glycoalkaloid treatments.

Induction of the cholesterol biosynthesis pathway in differentiated Caco-2 cells by the potato glycoalkaloid alpha-chaconine.

Glycoalkaloids are naturally occurring toxins in potatoes, which at high levels may induce toxic effects in humans, mainly on the gastrointestinal tract by cell membrane disruption. In order to better understand the molecular mechanisms underlying glycoalkaloid toxicity, we examined the effects of alpha-chaconine on gene expression in the Caco-2 intestinal epithelial cell line using DNA microarrays. Caco-2 cells were exposed for 6h to 10 microM alpha-chaconine in three independent experiments (randomized block design). The most prominent finding from our gene expression and pathway analyses was the upregulation of expression of several genes involved in cholesterol biosynthesis. This to some extent is in line with the literature-described mechanism of cell membrane disruption by glycoalkaloids. In addition, various growth factor signaling pathways were found to be significantly upregulated. This study is useful in understanding the mechanism(s) of alpha-chaconine toxicity, which may be extended to other potato glycoalkaloids more generally.

Harmonization of nutrient intake values.

The conceptual framework for the various NIVs is depicted in figure 1 along with the methodological approaches and applications. The NIVs consist of two values derived from a statistical evaluation of data on nutrient requirements, the average nutrient requirement (ANR), or nutrient toxicities, the upper nutrient level (UNL). The individual nutrient levelx (INLx) is derived from the distribution of average nutrient requirements. The percentile chosen is often 98%, which is equivalent to 2 SD above the mean requirement. Concepts underlying the NIVs include criteria for establishing a nutrient requirement, e.g., ferritin stores, nitrogen balance, or serum vitamin C. Once the requirement for the absorbed nutrient is determined, it may be necessary to adjust the value for food sources, i.e., bioavailability, or host factors, such as the effect of infection on nutrient utilization. Other concepts that committees may want to consider when establishing NIVs include the effects of genetic variation on nutrient requirements and the role of the nutrient in preventing long-term disease. Two fundamental uses of NIVs are for assessing the adequacy of nutrient intakes and for planning diets for individuals and populations. Establishing the NIV using the statistical framework proposed in this report improves the efficacy of the values for identifying risks of nutrient deficiency or excess among individuals and populations. NIVs also are applied to a number of aspects of food and nutrition policy. Some examples include regulatory issues and trade, labeling, planning programs for alleviating public health nutrition problems, food fortification, and dietary guidance.

Options for basing Dietary Reference Intakes (DRIs) on chronic disease endpoints: report from a joint US-/Canadian-sponsored working group.

Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met from November 2014 to April 2016 to identify options for addressing key scientific challenges encountered in the use of chronic disease endpoints to establish reference values. The working group focused on 3 key questions: 1) What are the important evidentiary challenges for selecting and using chronic disease endpoints in future DRI reviews, 2) what intake-response models can future DRI committees consider when using chronic disease endpoints, and 3) what are the arguments for and against continuing to include chronic disease endpoints in future DRI reviews? This report outlines the range of options identified by the working group for answering these key questions, as well as the strengths and weaknesses of each option.

New growth standards for the 21st century: a prescriptive approach.

Breast-fed babies have been shown to grow at a substantially different rate from the current international reference curves, with greater growth rates in height but with smaller body weight increases and substantially less variability in the growth patterns of a group. On this basis, the World Health Organization concluded that there was a need to undertake new studies to establish on a global basis the appropriate growth curves for exclusively breast-fed babies, their growth curves then being potentially seen as optimum standard curves rather than an arbitrary set of reference charts. The Multi-Country Growth Reference Study was therefore carried out from July 1997 to December 2003 as a population-based study covering the cities of Davis, California, USA; Muscat, Oman; Oslo, Norway; and Pelotas, Brazil, together with selected affluent neighborhoods of Accra, Ghana and South Delhi, India. These centers were considered conducive to a study of babies and children under optimum breast-feeding and weaning and early feeding conditions. These studies, to be reported shortly, confirm previous observations on breast-fed children, but also show that the greatest differences are within each population group rather than being international differences.

Nutrition and developmental biology--implications for public health.

Recent advances in understanding genome-nutrient and nutrient-network interactions, and the modifying effects of genetic variation on their function, have strengthened interests in acute and long-lasting diet/ nutrition influences on health. Relationships between early and mid-gestational and perinatal conditions (including those related to maternal nutrition) and outcomes, and later-onset chronic diseases have received particular attention. Controlled animal experiments support views that responses with long-lasting effects to nutritional milieus are enabled by epigenetic and other metabolic adjustments during critical windows. Thus, underlying mechanisms are beginning to be understood. For example, chromatin remodeling during development can alter gene expression levels, fix or determine future set points critical to intra- and inter-organ communication networks, alter morphogenesis, initiate remodeling events, etc., all with lifelong consequences. These also may affect DNA mutation rates and thereby influence adult cancer and other risks. There is increasing evidence that nutrient-based strategies will be of value to the prevention or delay of onset of chronic diseases and that these strategies may require initiation during embryonic or fetal stages of development to achieve maximal benefit.