The Evolution of Science and Regulation of Dietary Supplements: Past, Present, and Future.

Dietary supplement use in the United States is widespread and increasing, especially among certain population groups, such as older Americans. The science surrounding dietary supplements has evolved substantially over the last few decades since their formal regulation in 1994. Much has been learned about the mechanisms of action of many dietary supplement ingredients, but the evidence on their health effects is still building. As is true of much nutrition research, there are many studies that point to health effects, but not all are at the level of scientific evidence (e.g., randomized controlled interventions), rigor, or quality needed for definitive statements of efficacy regarding clinical endpoints. New technologies and approaches are being applied to the science of dietary supplements, including nutrigenomics and microbiome analysis, data science, artificial intelligence, and machine learning - all of which can elevate the science behind dietary supplements. Products can contain an array of bioactive compounds derived from foods as well as from medicinal plants, which creates enormous challenges in data collection and management. Clinical applications, particularly those aimed at providing personalized nutrition options for patients, have become more sophisticated as dietary supplements are incorporated increasingly into clinical practice and self-care. The goals of this paper are to provide historical context for the regulation and science of dietary supplements, identify research resources, and suggest some future directions for science in this field.

Dietary Quality and Diet-Related Factors Among U.S. Emerging Adults (18-23y) Are a Cause for Concern, NHANES 2015-2018.

BACKGROUND: Poor dietary quality is a risk factor for diet-related chronic disease and suboptimal nutritional patterns often begin early in the life course. While the dietary intakes of young children, adolescents, and middle-aged and older adults are well established, much less is known about emerging adults, who represent a unique timepoint in life, as they are undergoing significant changes in food environments, autonomy, finances, and caregiver and parental involvement. OBJECTIVE: To examine dietary quality, as assessed via the Healthy Eating Index (HEI), by demographic, socioeconomic, and health-related characteristics among U.S. emerging adults (18-23y) who participated in the 2015-2018 National Health and Nutrition Examination Survey (NHANES). METHODS: NHANES data were collected via a household interview and 2 24-hour dietary recalls (24HR). Usual dietary intakes from the 24HRs were approximated using the multivariate National Cancer Institute Method to compute mean HEI-2015 overall and component scores (range 0-100, higher scores indicating higher dietary quality). RESULTS: Overall dietary quality among U.S. emerging adults [HEI-2015: 50.3±1.3] was significantly lower than other U.S. adults (≥24y) [HEI-2015: 56.3±0.5; p<0.0001], with differences primarily driven by lower intakes of whole fruit, vegetables, and whole grains, and higher intakes of sodium, refined grains, and saturated fat. Few differences in HEI-2015 scores were noted across population subgroups by sex, food security, family income, and food assistance program participation, except for added sugar; intakes of added sugar were significantly higher among women, food insecure, and food assistance program participants as compared to their counterparts, respectively. CONCLUSIONS: Dietary quality is poor among U.S. emerging adults and persists across all population subgroups, suggesting a significant need for tailored public health interventions to improve dietary quality among this population. Future research investigating to what extent emerging adults prioritize healthful behaviors and exploring other indicators for identifying nutritionally vulnerable subgroups may be impactful for identifying disparities among this life stage.

Is adaptation associated with long-term persistence beyond a geographic range limit?

Adaptation to new habitats might facilitate species' range shifts in response to climate change. In 2005, we transplanted experimental populations of coastal dune plant Camissoniopsis cheiranthifolia into four sites within and one site beyond its poleward range limit. Beyond-range transplants had high fitness and often delayed reproduction. To test for adaptation associated with experimental range expansion, we transplanted descendants from beyond and within-range populations after 10 generations in situ into two sites within the range, one at the range edge, and two sites beyond the range. We expected to detect adaptation to beyond-range conditions due to substantial genetic variation within experimental populations and environmental variation among sites. However, individuals from beyond-range experimental populations were not fitter than those from within the range when planted at either beyond-range site, indicating no adaptation to the beyond-range site or beyond-range environments in general. Beyond-range descendants also did not suffer lower fitness within the range. Although reproduction was again delayed beyond the range, late reproduction was not favored more strongly beyond than within the range, and beyond-range descendants did not delay reproduction more than within-range descendants. Persistence in beyond-range environments may not require adaptation, which could allow a rapid response to climate change.

Fighting fair: community perspectives on the fairness of performance enhancement in esports.

Aims: This study aims to explore community perspectives on enhancer usage in competitive gaming and esports, focusing on the perception of fairness and concerns about various potential performance enhancers. Methods: We conducted both qualitative and quantitative surveys to understand the competitive gaming community's opinions on different types of performance enhancers and their potential impact on esports. A thematic analysis was performed to identify key themes in how players rationalize their opinions. Conclusions: The gaming community differentiates between potential performance enhancers based on how problematic they are for the esports scene, with the most concern surrounding hard drugs, pharmaceuticals, and brain stimulation interventions. Participants who are more invested in competitive gaming tend to be more sceptical of enhancers and express greater concerns. Four themes were identified in the thematic analysis: (1) risk, (2) morality, (3) enhancer effects, and (4) regulation. To increase acceptance and perceived legitimacy in decision-making, it is recommended that regulators engage a variety of stakeholders in transparent decision-making processes when forming tournament rules and regulations. This will help address the fragmented regulatory landscape and prevent potential differences in the perception of tournament winners based on the governing body supervising the competition.

Conditionally mutant animal model for investigating the invasive trophoblast cell lineage.

Placental development involves coordinated expansion and differentiation of trophoblast cell lineages possessing specialized functions. Among the differentiated trophoblast cell lineages are invasive trophoblast cells, which exit the placenta and invade the uterus, where they restructure the uterine parenchyma and facilitate remodeling of uterine spiral arteries. The rat exhibits deep intrauterine trophoblast cell invasion, a feature shared with human placentation, and is also amenable to gene manipulation using genome-editing techniques. In this investigation, we generated a conditional rat model targeting the invasive trophoblast cell lineage. Prolactin family 7, subfamily b, member 1 (Prl7b1) is uniquely and abundantly expressed in the rat invasive trophoblast cell lineage. Disruption of Prl7b1 did not adversely affect placental development. We demonstrated that the Prl7b1 locus could be effectively used to drive the expression of Cre recombinase in invasive trophoblast cells. Our rat model represents a new tool for investigating candidate genes contributing to the regulation of invasive trophoblast cells and their roles in trophoblast-guided uterine spiral artery remodeling.

Improvements in dietary intake, behaviors, and psychosocial measures in a community-randomized cardiovascular disease risk reduction intervention: Strong Hearts, Healthy Communities 2.0.

BACKGROUND: Cardiovascular disease (CVD) prevalence has disproportionately risen among midlife and older female adults of rural communities, partly due to poor diet and diet-related behaviors and psychosocial factors that impede healthy eating. OBJECTIVES: This study aimed to evaluate the impact of Strong Hearts Healthy Communities 2.0 (SHHC-2.0) on secondary diet-related outcomes between intervention and control participants that align with the dietary goal and behavioral aims of the SHHC-2.0, a CVD risk reduction program. METHODS: A community-randomized controlled trial was conducted in rural, medically underserved communities. Participants were female adults ≥40 y who were classified as obese or both overweight and sedentary. Communities were randomized to SHHC-2.0 intervention (n = 5 communities; n = 87 participants) or control (with delayed intervention) (n = 6 communities; n = 95 participants). SHHC-2.0 consisted of 24 wk of twice-weekly experiential nutrition education and group-based physical activity classes led by local health educators. Changes between baseline and end point (24 wk) in dietary intake (24-h recalls), dietary behaviors (e.g., Rapid Eating Assessment for Participants-Short Version [REAP-S] scores) and diet-related psychosocial measures (e.g., Three Factor Eating questionnaire) between groups were analyzed using linear mixed-effects multilevel models. RESULTS: At 24 wk, participants from the 5 intervention communities, compared with controls, consumed fewer calories (mean difference [MD]= -211 kcal, 95% CI: -412, -110, P = 0.039), improved overall dietary patterns measured by REAP-S scores (MD: 3.9; 95% CI: 2.26, 5.6; P < 0.001), and improved psychosocial measures (healthy eating attitudes, uncontrolled eating, cognitive restraint, and emotional eating). CONCLUSIONS: SHHC-2.0 has strong potential to improve diet patterns and diet-related psychosocial wellbeing consistent with improved cardiovascular health. This trial was registered at www. CLINICALTRIALS: gov as NCT03059472.

Snack frequency, size, and energy density are associated with diet quality among US adolescents.

OBJECTIVE: To evaluate snacking and diet quality among US adolescents. DESIGN: Cross-sectional analysis examined snack frequency (snacks/day), size (kcal/snack) and energy density (kcal/g/snack) as predictors of diet quality using the mean of two 24-h dietary recalls. Diet quality was assessed using the Healthy Eating Index (HEI-2015, 0-100), a mean adequacy ratio (MAR, 0-100) for under-consumed nutrients (potassium, fibre, Ca, vitamin D) and mean percentage of recommended limits for over-consumed nutrients (added sugar, saturated fat, Na). Linear regression models examined total snacks, food only snacks and beverage only snacks, as predictors of diet quality adjusting for demographic characteristics and estimated energy reporting accuracy. SETTING: 2007-2018 National Health and Nutrition Examination Survey. PARTICIPANTS: Adolescents 12-19 years (n 4985). RESULTS: Snack frequency was associated with higher HEI-2015 (ß = 0·7 (0·3), P < 0·05) but also with higher intake of over-consumed nutrients (ß = 3·0 (0·8), P ≤ 0·001). Snack size was associated with lower HEI (ß = -0·005 (0·001), P ≤ 0·001) and MAR (ß = -0·005 (0·002), P < 0·05) and higher intake of over-consumed nutrients (ß = 0·03 (0·005), P ≤ 0·001). Associations differed for food only and beverage only snacks. Food only snack frequency was associated with higher HEI-2015 (ß = 1·7 (0·03), P ≤ 0·001), while food only snack size (ß = -0·006 (0·0009), P ≤ 0·001) and food only snack energy density (ß = -1·1 (0·2), P ≤ 0·001) were associated with lower HEI-2015. Conversely, beverage only snack frequency (ß = 4·4 (2·1) P < 0·05) and beverage only snack size (ß = 0·03 (0·01), P ≤ 0·001) were associated with higher intake of over-consumed nutrients. CONCLUSIONS: Smaller, frequent, less energy-dense food only snacks are associated with higher diet quality in adolescents; beverages consumed as snacks are associated with greater intake of over-consumed nutrients.

Precision Nutrition: The Hype Is Exceeding the Science and Evidentiary Standards Needed to Inform Public Health Recommendations for Prevention of Chronic Disease.

As dietary guidance for populations shifts from preventing deficiency disorders to chronic disease risk reduction, the biology supporting such guidance becomes more complex due to the multifactorial risk profile of disease and inherent population heterogeneity in the diet-disease relationship. Diet is a primary driver of chronic disease risk, and population-based guidance should account for individual responses. Cascading effects on evidentiary standards for population-based guidance are not straightforward. Precision remains a consideration for dietary guidance to prevent deficiency through the identification of population subgroups with unique nutritional needs. Reducing chronic disease through diet requires greater precision in (a) establishing essential nutrient needs throughout the life cycle in both health and disease; (b) considering effects of nutrients and other food substances on metabolic, immunological, inflammatory, and other physiological responses supporting healthy aging; and (c) considering healthy eating behaviors. Herein we provide a template for guiding population-based eating recommendations for reducing chronic diseases in heterogenous populations.

CONDITIONALLY MUTANT ANIMAL MODEL FOR INVESTIGATING THE INVASIVE TROPHOBLAST CELL LINEAGE.

Placental development involves coordinated expansion and differentiation of trophoblast cell lineages possessing specialized functions. Among the differentiated trophoblast cell lineages are invasive trophoblast cells, which exit the placenta and invade into the uterus where they restructure the uterine parenchyma and facilitate remodeling of uterine spiral arteries. The rat exhibits deep intrauterine trophoblast cell invasion, a feature shared with human placentation, and is also amenable to gene manipulation using genome editing techniques. In this investigation, we generated a conditional rat model targeting the invasive trophoblast cell lineage. Prolactin family 7, subfamily b, member 1 ( Prl7b1 ) is uniquely and abundantly expressed in the rat invasive trophoblast cell lineage. Disruption of Prl7b1 did not adversely affect placental development. We demonstrated that the Prl7b1 locus could be effectively used to drive the expression of Cre recombinase in invasive trophoblast cells. Our rat model represents a new tool for investigating candidate genes contributing to the regulation of invasive trophoblast cells and their contributions to trophoblast-guided uterine spiral artery remodeling.

Neurobiology of eating behavior, nutrition, and health.

Eating behavior and food-related decision making are among the most complex of the motivated behaviors, and understanding the neurobiology of eating behavior, and its developmental dynamics, is critical to advancing the nutritional sciences and public health. Recent advances from both human and animal studies are revealing that individual capacity to make health-promoting food decisions varies based on biological and physiological variation in the signaling pathways that regulate the homeostatic, hedonic, and executive functions; past developmental exposures and current life-stage; the food environment; and complications of chronic disease that reinforce the obese state. Eating rate drives increased calorie intake and represents an important opportunity to lower rates of food consumption and energy intake through product reformulation. Understanding human eating behaviors and nutrition in the context of neuroscience can strengthen the evidence base from which dietary guidelines are derived and can inform policies, practices, and educational programs in a way that increases the likelihood they are adopted and effective for reducing rates of obesity and other diet-related chronic disease.

Usual nutrient intakes and diet quality among United States older adults participating in the Supplemental Nutrition Assistance Program compared with income-eligible nonparticipants.

BACKGROUND: The proportion of older adults with food insecurity at 8% has increased faster than that of the general United States population from 2001 to 2017. Many low-income food-insecure older adults rely on food-assistance programs, such as the Supplemental Nutrition Assistance Program (SNAP), for meeting energy and nutrient needs, whereas others are eligible but do not participate. Neither updated nutrient intake estimates nor potential differences in meeting the Dietary Reference Intakes from foods alone and with dietary supplements (DS) among low-income older adults using or eligible for SNAP are known. OBJECTIVES: This study assessed and compared national estimates of usual nutrient adequacy and dietary quality of United States older adults using SNAP and income-eligible nonparticipants. METHODS: Usual dietary intake was estimated among older adults (≥60 y; n = 2582) in the 2007-2016 NHANES cross-sectional national survey. Data on food-assistance participation and eligibility (poverty-income-ratio ≤130%), DS use, and ≥24-h dietary recalls were used. The NCI method (Markov Chain Monte Carlo approach) was applied to estimate mean usual nutrient intakes, proportion of inadequate nutrient intake, and dietary quality using the 2015 Healthy Eating Index. RESULTS: Neither usual nutrient intake from dietary and total sources nor dietary quality differed between older adult SNAP participants and eligible nonparticipants. Low dietary quality and high percentage of inadequate intake for several nutrients were apparent among both groups, especially from food sources alone, including vitamins A (56%), C (55%), D (97%), E (99%), calcium (73%), and magnesium (74%), but rates were attenuated when DS were also considered (i.e., 36% reduced risk for vitamin D inadequacy). CONCLUSIONS: Diet quality and usual nutrient intake among older adult SNAP participants and eligible nonparticipants were poor, but DS lowered the risk of nutrient inadequacy. Future policies and programs should focus on improving the intake of vitamins A, C, D, E, calcium, and magnesium and dietary quality for all older adults.

Core conserved transcriptional regulatory networks define the invasive trophoblast cell lineage.

The invasive trophoblast cell lineages in rat and human share crucial responsibilities in establishing the uterine-placental interface of the hemochorial placenta. These observations have led to the rat becoming an especially useful animal model for studying hemochorial placentation. However, our understanding of similarities or differences between regulatory mechanisms governing rat and human invasive trophoblast cell populations is limited. In this study, we generated single-nucleus ATAC-seq data from gestation day 15.5 and 19.5 rat uterine-placental interface tissues, and integrated the data with single-cell RNA-seq data generated at the same stages. We determined the chromatin accessibility profiles of invasive trophoblast, natural killer, macrophage, endothelial and smooth muscle cells, and compared invasive trophoblast chromatin accessibility with extravillous trophoblast cell accessibility. In comparing chromatin accessibility profiles between species, we found similarities in patterns of gene regulation and groups of motifs enriched in accessible regions. Finally, we identified a conserved gene regulatory network in invasive trophoblast cells. Our data, findings and analysis will facilitate future studies investigating regulatory mechanisms essential for the invasive trophoblast cell lineage.

Moderate consumption of freeze-dried blueberry powder increased net bone calcium retention compared with no treatment in healthy postmenopausal women: a randomized crossover trial.

BACKGROUND: Preclinical studies suggest that blueberry consumption is associated with improved bone health. OBJECTIVES: We conducted a blueberry dose-response study in ovariectomized (OVX)-rats that informed a study in postmenopausal women using the urinary appearance of calcium (Ca) tracers from prelabeled bone to reflect changes in bone balance. We hypothesized that blueberry consumption would reduce bone loss in a dose-dependent manner compared with no treatment. METHODS: OVX rats were fed 4 doses of blueberry powder (2.5%, 5%, 10%, and 15%) in randomized order to determine bone 45Ca retention. Fourteen healthy, nonosteoporotic women ≥4 y past menopause were dosed with 50 nCi of 41Ca, a long-lived radioisotope, and equilibrated for 5 mo to allow 41Ca deposition in bone. Following a 6-wk baseline period, participants were assigned to a random sequence of 3 6-wk interventions, a low (17.5 g/d), medium (35 g/d), or high (70 g/d) dose of freeze-dried blueberry powder equivalent to 0.75, 1.5, or 3 cups of fresh blueberries incorporated into food and beverage products. Urinary 41Ca:Ca ratio was measured by accelerator mass spectrometry. Serum bone resorption biomarkers and urinary polyphenols were measured at the end of each control and intervention period. Data were analyzed using a linear mixed model and repeated measures analysis of variance. RESULTS: In both OVX rats and postmenopausal women, blueberry interventions benefited net bone calcium balance at lower but not at higher doses. In women, net bone calcium retention increased by 6% with the low (95% CI: 2.50, 8.60; P < 0.01) and 4% with the medium (95% CI: 0.96, 7.90; P < 0.05) dose compared with no treatment. Urinary excretion of hippuric acid increased dose-dependently with blueberry consumption. No significant relationships were found between bone resorption biomarkers, 25-hydroxyvitamin D, and interventions. CONCLUSIONS: Moderate consumption (<1 cup/d) of blueberries may be an effective strategy to attenuate bone loss in healthy postmenopausal women. This trial was registered at clinicaltrials.gov as NCT02630797.

Major Gaps in Understanding Dietary Supplement Use in Health and Disease.

Precise dietary assessment is critical for accurate exposure classification in nutritional research, typically aimed at understanding how diet relates to health. Dietary supplement (DS) use is widespread and represents a considerable source of nutrients. However, few studies have compared the best methods to measure DSs. Our literature review on the relative validity and reproducibility of DS instruments in the United States [e.g., product inventories, questionnaires, and 24-h dietary recalls (24HR)] identified five studies that examined validity (n = 5) and/or reproducibility (n = 4). No gold standard reference method exists for validating DS use; thus, each study's investigators chose the reference instrument used to measure validity. Self-administered questionnaires agreed well with 24HR and inventory methods when comparing the prevalence of commonly used DSs. The inventory method captured nutrient amounts more accurately than the other methods. Reproducibility (over 3 months to 2.4 years) of prevalence of use estimates on the questionnaires was acceptable for common DSs. Given the limited body of research on measurement error in DS assessment, only tentative conclusions on these DS instruments can be drawn at present. Further research is critical to advancing knowledge in DS assessment for research and monitoring purposes.

The autism-associated loss of δ-catenin functions disrupts social behavior.

δ-catenin is expressed in excitatory synapses and functions as an anchor for the glutamatergic AMPA receptor (AMPAR) GluA2 subunit in the postsynaptic density. The glycine 34 to serine (G34S) mutation in the δ-catenin gene has been found in autism spectrum disorder (ASD) patients and results in loss of δ-catenin functions at excitatory synapses, which is presumed to underlie ASD pathogenesis in humans. However, how the G34S mutation causes loss of δ-catenin functions to induce ASD remains unclear. Here, using neuroblastoma cells, we identify that the G34S mutation increases glycogen synthase kinase 3ß (GSK3ß)-dependent δ-catenin degradation to reduce δ-catenin levels, which likely contributes to the loss of δ-catenin functions. Synaptic δ-catenin and GluA2 levels in the cortex are significantly decreased in mice harboring the δ-catenin G34S mutation. The G34S mutation increases glutamatergic activity in cortical excitatory neurons while it is decreased in inhibitory interneurons, indicating changes in cellular excitation and inhibition. δ-catenin G34S mutant mice also exhibit social dysfunction, a common feature of ASD. Most importantly, pharmacological inhibition of GSK3ß activity reverses the G34S-induced loss of δ-catenin function effects in cells and mice. Finally, using δ-catenin knockout mice, we confirm that δ-catenin is required for GSK3ß inhibition-induced restoration of normal social behavior in δ-catenin G34S mutant animals. Taken together, we reveal that the loss of δ-catenin functions arising from the ASD-associated G34S mutation induces social dysfunction via alterations in glutamatergic activity and that GSK3ß inhibition can reverse δ-catenin G34S-induced synaptic and behavioral deficits.

CORE CONSERVED TRANSCRIPTIONAL REGULATORY NETWORKS DEFINE THE INVASIVE TROPHOBLAST CELL LINEAGE.

The invasive trophoblast cell lineage in rat and human share crucial responsibilities in establishing the uterine-placental interface of the hemochorial placenta. These observations have led to the rat becoming an especially useful animal model to study hemochorial placentation. However, our understanding of similarities or differences between regulatory mechanisms governing rat and human invasive trophoblast cell populations is limited. In this study, we generated single-nucleus (sn) ATAC-seq data from gestation day (gd) 15.5 and 19.5 rat uterine-placental interface tissues and integrated the data with single-cell RNA-seq data generated at the same stages. We determined the chromatin accessibility profiles of invasive trophoblast, natural killer, macrophage, endothelial, and smooth muscle cells, and compared invasive trophoblast chromatin accessibility to extravillous trophoblast (EVT) cell accessibility. In comparing chromatin accessibility profiles between species, we found similarities in patterns of gene regulation and groups of motifs enriched in accessible regions. Finally, we identified a conserved gene regulatory network in invasive trophoblast cells. Our data, findings and analysis will facilitate future studies investigating regulatory mechanisms essential for the invasive trophoblast cell lineage.

Selecting a dietary supplement with appropriate dosing for 6 key nutrients in pregnancy.

BACKGROUND: Most pregnant women in the United States (US) are at risk of inadequate intake of key nutrients during pregnancy from foods alone. Current dietary supplement practices reduce risk of inadequacy for only some nutrients and induce excessive intake of other nutrients. OBJECTIVES: Our study aimed to estimate the doses of supplementation needed to help most pregnant women achieve the recommended intake without exceeding upper limits for key prenatal nutrients and to identify US dietary supplements providing these doses. METHODS: We conducted 24-h dietary recalls in 2450 pregnant participants aged 14-50 y from 2007 to 2019. We estimated the usual intake of vitamins A and D, folate, calcium, iron, and ω-3 FAs from foods alone. We calculated the target doses of supplementation needed to shift 90% of participants to consume above the estimated average requirement and keep 90% below the tolerable upper limit. We identified products in the Dietary Supplement Label Database providing these target doses of supplementation. RESULTS: The target dose for supplementation was ≥198 mcg retinol activity equivalents of total vitamin A (with ≤2063 mcg preformed retinol); 7-91 mcg vitamin D; 169-720 mcg dietary folate equivalents of folic acid; 383-943 mg calcium; 13-22 mg iron; and ≥59 mg ω-3 FAs. Out of 20,547 dietary supplements (including 421 prenatal products), 69 products (33 prenatal) contained all 6 nutrients; 7 products (2 prenatal) contained target doses for 5 nutrients. Only 1 product (not a prenatal) contained target doses for all 6 nutrients, but it currently costs ∼USD200/mo and requires 7 tablets per daily serving. CONCLUSIONS: Almost no US dietary supplements provide key nutrients in the doses needed for pregnant women. Affordable and convenient products that fill the gap between food-based intake and estimated requirements of pregnancy without inducing excess intake are needed to support pregnant women and their offspring. Am J Clin Nutr 20XX;xx:xx-xx.