A new generation of standard reference diets (SRDs) is essential to enhance the integrity of research associated with the use of laboratory animal models in the study of human disease. Support for the value of this fundamental facet of experimental methodology is provided via a historical overview, an assessment of current status, and the advancements and opportunities that will be realized through further development and routine use. An outline of the extensive investment in animal nutrition research by National Institutes of Health during the past 30 y is presented with specific reference to rodent animal models and standardization in dietary methodology. Timely recommendations for renewed action that revitalize and expand the use of SRDs in rodents and other models, such as zebrafish, are provided with the aim of achieving more rigor, transparency, replicability, interpretability, and integrity in preclinical and translational animal model-based research. Ultimately, the benefits of these efforts will be fulfilled through expeditious development of prophylactic and therapeutic approaches for human diseases.

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 end points. New technologies and approaches are being applied to the science of dietary supplements, including nutrigenomics and microbiome analysis, data science, artificial intelligence (AI), 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 article 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.

NHANES needs urgent attention to ensure its future, which is facing emerging challenges associated with data collection, stagnant funding that has undercut innovation, and the increased call for granular data for subpopulations and groups at risk. The concerns do not rest merely on securing more funding but focus on the need for a constructive review of the survey to explore new approaches and identify appropriate change. This white paper, developed under the auspices of the ASN's Committee on Advocacy and Science Policy (CASP), is a call to the nutrition community to advocate for and support activities to prepare NHANES for future success in a changing nutrition world. Furthermore, because NHANES is much more than a nutrition survey and serves the needs of many in health fields and even commercial arenas, effective advocacy must be grounded in alliances among the survey's diverse stakeholders so that the full range of expertise and interests can engage. This article highlights the complicated nature of the survey along with key overarching challenges to underscore the importance of a measured, thoughtful, comprehensive, and collaborative approach to considering the future of NHANES. Starting-point questions are identified for the purposes of focusing dialog, discussion forums, and research. In particular, the CASP calls for a National Academies of Sciences, Engi-neering, and Medicine study on NHANES to articulate an actionable framework for NHANES going forward. With a well-informed and integrated set of goals and recommendations that could be provided by such a study, a secure future for NHANES is more readily achievable.

The importance of balanced dietary habits, which include appropriate amounts of antioxidants to maintain the immune system, has become increasingly relevant during the current SARS-CoV-2/COVID-19 pandemic, because viral infections are characterized by high oxidative stress. Furthermore, the measures taken by governments to control the pandemic have led to increased anxiety, stress, and depression, which affect physical and mental health, all of which are influenced by nutritional status, diet, and lifestyle. The Mediterranean diet (MD), Atlantic diet (AD), and the Dietary Guidelines for Americans all provide the essential vitamins, minerals, and phenolic compounds needed to activate enzymatic and nonenzymatic antioxidant responses. However, viral pandemics such as the current COVID-19 crisis entail high oxidative damage caused by both the infection and the resultant social stresses within populations, which increases the probability and severity of infection. Balanced dietary patterns such as the MD and the AD are characterized by the consumption of fruit, vegetables, legumes, olive oil, and whole grains with low intakes of processed foods and red meat. For a healthy lifestyle in young adults, the MD in particular provides the required amount of antioxidants per day for vitamins D (0.3–3.8 μg), E (17.0 mg), C (137.2–269.8 mg), A (1273.3 μg), B-12 (1.5–2.0 μg), and folate (455.1–561.3 μg), the minerals Se (120.0 μg), Zn (11.0 mg), Fe (15.0–18.8 mg), and Mn (5.2–12.5 mg), and polyphenols (1171.00 mg) needed to maintain an active immune response. However, all of these diets are deficient in the recommended amount of vitamin D (20 μg/d). Therefore, vulnerable populations such as elders and obese individuals could benefit from antioxidant supplementation to improve their antioxidant response. Although evidence remains scarce, there is some indication that a healthy diet, along with supplemental antioxidant intake, is beneficial to COVID-19 patients.

BACKGROUND:The US faces remarkable food and nutrition challenges. A new federal effort to strengthen and coordinate nutrition research could rapidly generate the evidence base needed to address these multiple national challenges. However, the relevant characteristics of such an effort have been uncertain.OBJECTIVES:Our aim was to provide an objective, informative summary of 1) the mounting diet-related health burdens facing our nation and corresponding economic, health equity, national security, and sustainability implications; 2) the current federal nutrition research landscape and existing mechanisms for its coordination; 3) the opportunities for and potential impact of new fundamental, clinical, public health, food and agricultural, and translational scientific discoveries; and 4) the various options for further strengthening and coordinating federal nutrition research, including corresponding advantages, disadvantages, and potential executive and legislative considerations.METHODS:We reviewed government and other published documents on federal nutrition research; held various discussions with expert groups, advocacy organizations, and scientific societies; and held in-person or phone meetings with >50 federal staff in executive and legislative roles, as well as with a variety of other stakeholders in academic, industry, and nongovernment organizations.RESULTS:Stark national nutrition challenges were identified. More Americans are sick than are healthy, largely from rising diet-related illnesses. These conditions create tremendous strains on productivity, health care costs, health disparities, government budgets, US economic competitiveness, and military readiness. The coronavirus disease 2019 (COVID-19) outbreak has further laid bare these strains, including food insecurity, major diet-related comorbidities for poor outcomes from COVID-19 such as diabetes, hypertension, and obesity, and insufficient surveillance on and coordination of our food system. More than 10 federal departments and agencies currently invest in critical nutrition research, yet with relatively flat investments over several decades. Coordination also remains suboptimal, documented by multiple governmental reports over 50 years. Greater harmonization and expansion of federal investment in nutrition science, not a silo-ing or rearrangement of existing investments, has tremendous potential to generate new discoveries to improve and sustain the health of all Americans. Two identified key strategies to achieve this were as follows: 1) a new authority for robust cross-governmental coordination of nutrition research and other nutrition-related policy and 2) strengthened authority, investment, and coordination for nutrition research within the NIH. These strategies were found to be complementary, together catalyzing important new science, partnerships, coordination, and returns on investment. Additional complementary actions to accelerate federal nutrition research were identified at the USDA.CONCLUSIONS:The need and opportunities for strengthened federal nutrition research are clear, with specific identified options to help create the new leadership, strategic planning, coordination, and investment the nation requires to address the multiple nutrition-related challenges and grasp the opportunities before us.

Until a decade ago, no dietary supplement (DS) databases with open access for public use existed in the United States. They were needed by researchers, since half of American adults use dietary DSs and, without information on supplement use and composition, exposures could not be estimated. These articles on Challenges and Future Directions for Dietary Supplement Databases describe subsequent progress. They begin by describing why information on DSs is needed by the government and how it is used to ensure the health of the public. Current developments include: application of DS information to meet public health needs; research efforts on DS quality, efficacy, and safety (as conducted by the Office of Dietary Supplements and other federal agencies); enhanced regulatory activities implemented by the FDA Office of Dietary Supplement Programs, the FDA Office of Enforcement, and the Federal Trade Commission; and initiatives for broader development and dissemination of DS databases for commercial and public use. Other contributions in this journal supplement describe the challenges of working with DSs and the progress that has been made. Additional articles describe surveys of DS use among the general US population and also among special groups such as high supplement users, illustrating why there is a need in the United States for information on supplements. Likely directions for the future of DS science are summarized.

Many of the scientific and regulatory challenges that exist in research on the safety, quality and efficacy of dietary supplements are common to all countries as the marketplace for them becomes increasingly global. This article summarizes some of the challenges in supplement science and provides a case study of research at the Office of Dietary Supplements at the National Institutes of Health, USA, along with some resources it has developed that are available to all scientists. It includes examples of some of the regulatory challenges faced and some resources for those who wish to learn more about them.

Due to the extensive use of botanical dietary supplements by consumers in the United States, there is a need for appropriate research and data to support safety assessments. Complexity and variability, both natural and introduced, of botanical dietary supplements make research on these products difficult. Botanical dietary supplements are regulated by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by the 1994 Dietary Supplement Health and Education Act (DSHEA). They are regulated as a category of food, which differs from the regulation of pharmaceutical products. Both manufacturers and the FDA are faced with the challenge of determining the best approaches for evaluating and monitoring the safety of botanical products. High quality botanicals research requires accurate identification and characterization of the material being studied. Inconsistent results in efficacy studies of botanical dietary supplements have led to efforts to improve the rigor and reproducibility of research in the field. Addressing the challenges associated with botanical dietary supplement safety is a global effort requiring coordination between numerous stakeholders, including researchers, suppliers, manufacturers, and regulators, all of whom play a role in ensuring that high quality products are available on the market.

Launched in 2008, the Dietary Supplement Label Database (DSLD) permits the search of any term that appears anywhere on product labels. Since then, the database's search and download features have been periodically improved to enhance use for researchers and consumers. In this review, we describe how to customize searches and identify products and ingredients of interest to users in the DSLD, and provide the limitations of working with information derived from dietary supplement product labels. This article describes how data derived from information printed on product labels are entered and organized in the DSLD. Among the challenges are determining the chemical forms, types of extract, and amounts of dietary ingredients, especially when these are components of proprietary blends. The FDA announced new dietary supplement labeling regulations in May 2016. The 2017 DSLD has been updated to reflect them. These new regulations and examples cited in this article refer to this redesigned version of the DSLD. Search selection characteristics such as for product type and intended user group are as described in FDA guidance and regulations for dietary supplements. For this reason, some age groups (such as teens and seniors) and marketing recommendations for use (e.g., weight loss, performance, and other disease-or condition-specific claims) are not included in the search selections. The DSLD user interface features will be revised periodically to reflect regulatory and technologic developments to enhance user experience. A comprehensive database derived from analytically verified data on composition would be preferable to label data, but is not feasible for technical, logistic, and financial reasons. Therefore, a database derived from information printed on product labels is the only practical option at present for researchers, clinicians, and consumers interested in the composition of these products.

The Office of Dietary Supplements, the National Institute on Minority Health and Health Disparities, the National Institute on Aging, and the National Institute of Diabetes and Digestive and Kidney Diseases, all components of the U.S. National Institutes of Health, co-sponsored an expert panel meeting to discuss the vitamin D paradox in Black Americans. The paradox is that despite markedly low (or “deficient”) measures of vitamin D status in Black Americans, the incidence of falls, fractures, or osteopenia are significantly lower compared to White American counterparts with similar vitamin D status. Six panelists were invited to engage in guided discussions on the state of the science with respect to key knowledge gaps impacting vitamin D status and bone health. They were also asked to reflect on best approaches for advancing the science. A central theme throughout the discussions was that there may be many factors that impact Vitamin D levels in Black Americans and understanding these factors may be key to understanding mechanisms for improving bone health in all populations. Data presented showed that although adiposity, skin pigmentation, vitamin D binding protein polymorphisms, and genetics all contributed to differences in 25(OH)D levels in Black vs. White Americans, no one factor alone could fully explain the vitamin D paradox in Black Americans. However, the panelists did agree that the paradox is significant and warrants further investigation. There was consensus that Black Americans gained no skeletal benefits from high doses of vitamin D supplementation, and that high levels of the biomarker of vitamin D status, serum 25-hydroxyvitamin D or 25(OH)D, in this population are almost certain to result in adverse effects. Some panelists proposed that additional studies are needed so that the Institute of Medicine (IOM) can better define the safe upper limits of vitamin D intake in this and other subpopulations. Others suggested a need for better, more generalizable biomarkers of bone health to advance the science.

It is a special privilege for us to pen this commentary on an article that, although not a particularly old one, has already had a large impact on how we think about nutrient intake in the United States (1). It is also a chance for us to recognize the prescience and insight of our colleagues in the Office of Dietary Supplements at the NIH when they conceived this study. Finally, it is an opportunity for us to recognize and honor one of our most cherished friends,Mary Frances Picciano,who wisely (and sometimes adamantly) encouraged the US Federal nutrition community to address the impact of dietary supplement use on total nutrient intakes in the population. It is now evident that dietary supplement use, as reported by participants in the NHANES and other cohorts, can contribute substantially to the total intake of nutrients by Americans. This is true in other countries as well. There is mounting evidence that dietary supplement use can improve the measured micronutrient status of some people, and this is particularly true for nutrients that may not be readily obtained from the diet for some individuals (e.g., vitamin D). On the other hand, further research from this group and others has served as a reminder that it is possible to get too much, and that the intake of some nutrients from foods and dietary supplements can take people over the Tolerable Upper Intake Level (UL). The NHANES has been collecting data on dietary supplement use by participants since 1971, and a review article describing the prevalence of use covered the periods 1971–1974 and 1976–1980, 1988–1994, and 1999–2000 (2). Over these 30 y, dietary supplement use increased among men and women, decreased among children aged 1–5 y, and did not change for other children and adolescents. These early NHANES cycles queried vitamin or mineral supplement use and whether it was regular or irregular use. Dietary supplement use has been included as a permanent component of the continuous NHANES since 1999. Changes in the continuous survey included asking for vitamin, mineral, or other (herbal or botanical) supplements used during the past month. Some other changes included the following: more accurate documentation of supplements used, having herbal dietary supplements specifically queried, and hand cards given to participants listing supplements other than multivitaminmultimineral (MVMM) products. Information is now also

The National Institute of Standards and Technology (NIST) has developed Standard Reference Material (SRM) 972a Vitamin D Metabolites in Frozen Human Serum as a replacement for SRM 972, which is no longer available. SRM 972a was developed in collaboration with the National Institutes of Health's Office of Dietary Supplements. In contrast to the previous reference material, three of the four levels of SRM 972a are composed of unmodified human serum. This SRM has certified and reference values for the following 25-hydroxyvitamin D [25(OH)D] species: 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3. The value assignment and certification process included three isotope-dilution mass spectrometry approaches, with measurements performed at NIST and at the Centers for Disease Control and Prevention (CDC). The value assignment methods employed have been modified from those utilized for the previous SRM, and all three approaches now incorporate chromatographic resolution of the stereoisomers, 25(OH)D3 and 3-epi-25(OH)D3.

Assay variability has been cited as an obstacle to establishing optimal vitamin D exposure. As part of the Vitamin D Standardization Program (VDSP) effort to standardize the measurement of total 25-hydroxyvitamin D [25(OH)D], the value assignment of total 25(OH)D in 50 single-donor serum samples was performed using two isotope-dilution LC with tandem MS methods. Both methods are recognized as reference measurement procedures (RMPs) by the Joint Committee for Traceability in Laboratory Medicine. These samples and their assigned values serve as the foundation for several aspects of the VDSP. To our knowledge, this is the first time that two RMPs have been used to assign 25(OH)D values to such a large number of serum samples.

We evaluated the impact of standardizing the originally measured serum total 25-hydroxyvitamin D (25(OH)D) values from Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) on the association between 25(OH)D and rate of all-cause mortality. Values were standardized to the gold-standard laboratory method. Follow-up from 1990-2006 consisted of 15,099 participants aged at least 20 years at baseline, among whom there were 3,784 deaths. Relative risk of death was adjusted for age, sex, race/ethnicity, and season using Poisson regression. Results were obtained for eight 25(OH)D (nmol/L) categories: <20 nmol/L, 20-29 nmol/L, 30-39 nmol/L, 40-49 nmol/L, 50-59 nmol/L, 60-74 nmol/L, 75-99 nmol/L (reference), and ≥100 nmol/L. Assay standardization dramatically shifted original 25(OH)D values toward zero. Accordingly, risk ≥120 nmol/L could not be evaluated (i.e., n = 7 and ndeaths = 2). Relative risk (95% confidence interval (CI)) <40 nmol/L remained significant (30-39 nmol/L: relative risk (RR) = 1.4 (95% CI: 1.1, 1.6); 20-29 nmol/L: RR = 1.6 (95% CI: 1.3, 1.9), and <20 nmol/L: RR = 2.1 (95% CI: 1.6, 2.7). However, adjusted relative risk estimates for 25(OH)D levels ≥40 nmol/L were no longer significant (40-49 nmol/L: RR = 1.2 (95% CI: 0.99, 1.4); 50-59 nmol/L: RR = 1.2 (95% CI: 1.04, 1.4); 60-74 nmol/L: RR = 1.1 (95% CI: 0.94, 1.2); 75-99 nmol/L: RR = 1.0 (referent), and ≥100 nmol/L: RR = 1.1 (95% CI: 0.6, 2.1). In summary, after standardization, risk of death from all causes increased with decreasing 25(OH)D <40 nmol/L, while there was no association with values in categories between 40 nmol/L and 120 nmol/L.

Since 2005, the National Institute of Standards and Technology (NIST) has collaborated with the National Institutes of Health (NIH), Office of Dietary Supplements (ODS) to improve the quality of measurements related to human nutritional markers of vitamin D status. In support of the NIH-ODS Vitamin D Initiative, including the Vitamin D Standardization Program (VDSP), NIST efforts have focused on (1) development of validated analytical methods, including reference measurement procedures (RMPs); (2) development of Standard Reference Materials (SRMs); (3) value assignment of critical study samples using NIST RMPs; and (4) development and coordination of laboratory measurement QA programs. As a result of this collaboration, NIST has developed RMPs for 25-hydroxyvitamin D2 [25(OH)D2], 25(OH)D3, and 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3]; disseminated serum-based SRMs with values assigned for 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D3, and 24R,25(OH)2D3; assigned values for critical samples for VDSP studies, including an extensive interlaboratory comparison and reference material commutability study; provided an accuracy basis for the Vitamin D External Quality Assurance Scheme; coordinated the first accuracy-based measurement QA program for the determination of 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 in human serum/plasma; and developed methods and SRMs for the determination of vitamin D and 25(OH)D in food and supplement matrix SRMs. The details of these activities and their benefit and impact to the NIH-ODS Vitamin D Initiative are described.