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We present idealized simulations to explore how the shape of eastern and western continental boundaries along the Atlantic Ocean influences the Atlantic meridional overturning circulation (AMOC). We use a state-of-the art ocean–sea ice model (MOM6 and SIS2) with idealized, zonally symmetric surface forcing and a range of idealized continental configurations with a large, Pacific-like basin and a small, Atlantic-like basin. We perform simulations with five coastline geometries along the Atlantic-like basin that range from coastlines that are straight to coastlines that are shaped like the coasts of the American and African continents. Changing the Atlantic basin coastline shape influences AMOC strength in a manner distinct from simply increasing basin width: widening the basin while maintaining straight coastlines leads to a 10-Sv (1 Sv ≡ 106 m3 s−1) increase in AMOC strength, whereas widening the basin with the geometry of the American and African continents leads to a 6-Sv increase in AMOC strength, despite both cases representing the same average basin-width increase relative to a control case. The structure of AMOC changes are different between these two cases as well: a more realistic basin geometry results in a shoaled AMOC while widening the basin with straight boundaries deepens AMOC. We test the influence of the shape of the both boundaries independently and find that AMOC is more sensitive to the American coastline while the African coastline impacts the abyssal circulation. We also find that AMOC strength and depth scales well with basin-scale meridional density difference, even with different Atlantic basin geometries, illuminating a robust physical link between AMOC and the North Atlantic western boundary density gradient.

The Canadian Earth System Model version 5.0 (CanESM5.0), the most recent major version of the global climate model developed at the Canadian Centre for Climate Modelling and Analysis (CCCma) at Environment and Climate Change Canada (ECCC), has been used extensively in climate research and for providing future climate projections in the context of climate services. Previous studies have shown that CanESM5.0 performs well compared to other models and have revealed several model biases. To address these biases, CCCma has recently initiated the ‘Analysis for Development’ (A4D) activity, a coordinated analysis activity in support of CanESM development. Here we describe the goals and organization of this effort and introduce two variants (``p1'' and ``p2'') of a new CanESM version, CanESM5.1, which features substantial improvements as a result of the A4D activity. These improvements include the elimination of spurious stratospheric temperature spikes and an improved simulation of tropospheric dust. Other climate aspects of the p1 variant of CanESM5.1 are similar to those of CanESM5.0, while the p2 variant of CanESM5.1 features reduced equilibrium climate sensitivity and improved ENSO variability as a result of intentional tuning of the atmospheric component. The A4D activity has also led to the improved understanding of other notable CanESM5.0/5.1 biases, including the overestimation of North Atlantic sea ice, a cold bias over sea ice, biases in the stratospheric circulation and a cold bias over the Himalayas. It provides a potential framework for the broader climate community to contribute to CanESM development, which will facilitate further model improvements and ultimately lead to improved climate change information.

COVID-19 (COronaVIrus Disease of 2019), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an ongoing global health challenge and the deadliest epidemic coronavirus outbreak to date. Early sequencing of the viral genome and knowledge from past coronavirus outbreaks (SARS-CoV-1 and Middle East Respiratory Syndrome, MERS) has led to rapid advances in knowledge of how the virus spreads and infects human hosts. Unfortunately, advancing knowledge has not yet produced a treatment that substantially lowers morbidity or mortality and only recently resulted in the development of a vaccine that prevents severe disease. Mounting evidence supports the notion that dietary supplementation of key essential nutrients may contribute to the body’s defenses against infection as well as bolster the body’s responses to infection. Evidence supporting the potential beneficial roles of vitamin C, vitamin D, zinc, and B3 vitamins is reviewed here, revealing a combination of basic research elucidating underlying mechanisms of action, preclinical studies and human intervention studies has led to the proliferation of registered clinical trials on COVID-19. Overall, the data suggest this collection of nutrients has a promising impact on reducing the risk and/or severity of COVID-19, although firm conclusions await the results of these trials.

The Atlantic meridional overturning circulation (AMOC) is an important part of our climate system, which keeps the North Atlantic relatively warm. It is predicted to weaken under climate change. The AMOC may have a tipping point beyond which recovery is difficult, hence showing quasi-irreversibility (hysteresis). Although hysteresis has been seen in simple models, it has been difficult to demonstrate in comprehensive global climate models.We present initial results from the North Atlantic hosing model intercomparison project, where we applied an idealised forcing of a freshwater flux over the North Atlantic in 9 CMIP6 models. The AMOC weakens in all models from the freshening, but once the freshening ceases, the AMOC recovers in some models, and in others it stays in a weakened state. We discuss how differences in feedbacks affect the AMOC response.

The ocean biogeochemistry components of two new versions of the Canadian Earth System Model (CanESM) are presented and compared to observations and other models. CanESM5 employs the same ocean biology model as CanESM2, whereas CanESM5-CanOE (Canadian Ocean Ecosystem model) is a new, more complex model developed for CMIP6, with multiple food chains, flexible phytoplankton elemental ratios, and a prognostic iron cycle. This new model is described in detail and the outputs (distributions of major tracers such as oxygen, dissolved inorganic carbon, and alkalinity, the iron and nitrogen cycles, plankton biomass, and historical trends in CO2 uptake and export production) compared to CanESM5 and CanESM2, as well as to observations and other CMIP6 models. Both CanESM5 models show gains in skill relative to CanESM2, which are attributed primarily to improvements in ocean circulation. CanESM5-CanOE shows improved skill relative to CanESM5 for most major tracers at most depths. CanESM5-CanOE includes a prognostic iron cycle, and maintains high-nutrient/low-chlorophyll conditions in the expected regions (in CanESM2 and CanESM5, iron limitation is specified as a temporally static “mask”). Surface nitrate concentrations are biased low in the subarctic Pacific and equatorial Pacific, and high in the Southern Ocean, in both CanESM5 and CanESM5-CanOE. Export production in CanESM5-CanOE is among the lowest for CMIP6 models; in CanESM5, it is among the highest, but shows the most rapid decline after about 1980. CanESM5-CanOE shows some ability to simulate aspects of plankton community structure that a single-species model can not (e.g. seasonal dominance of large cells) but is biased towards low concentrations of zooplankton and detritus relative to phytoplankton. Cumulative ocean uptake of anthropogenic carbon dioxide through 2014 is lower in both CanESM5-CanOE (122 PgC) and CanESM5 (132 PgC) than in observation-based estimates (145 PgC) or the model ensemble mean (144 PgC).

We document the configuration and emergent simulation features from the Geophysical Fluid Dynamics Laboratory (GFDL) OM4.0 ocean/sea ice model. OM4 serves as the ocean/sea ice component for the GFDL climate and Earth system models. It is also used for climate science research and is contributing to the Coupled Model Intercomparison Project version 6 Ocean Model Intercomparison Project. The ocean component of OM4 uses version 6 of the Modular Ocean Model and the sea ice component uses version 2 of the Sea Ice Simulator, which have identical horizontal grid layouts (Arakawa C‐grid). We follow the Coordinated Ocean‐sea ice Reference Experiments protocol to assess simulation quality across a broad suite of climate‐relevant features. We present results from two versions differing by horizontal grid spacing and physical parameterizations: OM4p5 has nominal 0.5° spacing and includes mesoscale eddy parameterizations and OM4p25 has nominal 0.25° spacing with no mesoscale eddy parameterization. Modular Ocean Model version 6 makes use of a vertical Lagrangian‐remap algorithm that enables general vertical coordinates. We show that use of a hybrid depth‐isopycnal coordinate reduces the middepth ocean warming drift commonly found in pure z* vertical coordinate ocean models. To test the need for the mesoscale eddy parameterization used in OM4p5, we examine the results from a simulation that removes the eddy parameterization. The water mass structure and model drift are physically degraded relative to OM4p5, thus supporting the key role for a mesoscale closure at this resolution.

Sea levels of different atmosphere–ocean general circulation models (AOGCMs) respond to climate change forcing in different ways, representing a crucial uncertainty in climate change research. We isolate the role of the ocean dynamics in setting the spatial pattern of dynamic sea-level (ζ) change by forcing several AOGCMs with prescribed identical heat, momentum (wind) and freshwater flux perturbations. This method produces a ζ projection spread comparable in magnitude to the spread that results from greenhouse gas forcing, indicating that the differences in ocean model formulation are the cause, rather than diversity in surface flux change. The heat flux change drives most of the global pattern of ζ change, while the momentum and water flux changes cause locally confined features. North Atlantic heat uptake causes large temperature and salinity driven density changes, altering local ocean transport and ζ. The spread between AOGCMs here is caused largely by differences in their regional transport adjustment, which redistributes heat that was already in the ocean prior to perturbation. The geographic details of the ζ change in the North Atlantic are diverse across models, but the underlying dynamic change is similar. In contrast, the heat absorbed by the Southern Ocean does not strongly alter the vertically coherent circulation. The Arctic ζ change is dissimilar across models, owing to differences in passive heat uptake and circulation change. Only the Arctic is strongly affected by nonlinear interactions between the three air-sea flux changes, and these are model specific.

We present a neutral diffusion operator appropriate for an ocean model making use of general vertical coordinates. The diffusion scheme uses polynomial reconstructions in the vertical, along with a horizontally local but vertically nonlocal stencil for estimates of tracer fluxes. These fluxes are calculated on a vertical grid that is the superset of model columns in a neutral density space. Using flux‐limiters, the algorithm dissipates tracer extrema locally, and no new extrema are created. A demonstration using a linear equation of state in an idealized configuration shows that the algorithm is perfectly neutral. When using the nonlinear TEOS‐10 equation of state with a constant reference pressure, the algorithm compares nearly exactly to a case discretized onto isopycnal surfaces and using along‐layer diffusion. The algorithm's cost is comparable to that of tracer advection and can be readily implemented into ocean general circulation models.

A regional Arctic ice ocean model incorporating biogeochemical processes occurring inside the sea ice and water column is used to assess changes to the Arctic Ocean's carbon system, including oceanic carbon uptake and ocean acidification, over the recent period of Arctic sea ice decline (1980–2015). Two novel modifications are the following: (1) incorporation of carbon uptake by sea ice algae and (2) modification of the sea ice carbon pump to allow for vertical transport by brine plumes with high concentrations of dissolved inorganic carbon (DIC) and total alkalinity (TA) to the bottom of the mixed layer. The simulated carbon uptake north of 66.5°N increases by 20%, from 110 to 135 Tg C yr−1 from 1980–2015, and the mean pan‐Arctic sea surface pH decreases from 8.1 to 8.0. There is substantial regional and seasonal variability, highlighting potential problems with interpolating sparse measurements. Two sensitivity studies assess the effects of modifications to the near‐surface carbonate system. First, excluding the sea ice carbon pump results in a marked decrease in seasonal variability of pan‐Arctic‐mean sea surface DIC (∼25% less than the standard run) and TA (∼10% less), suggesting that neglecting the ice carbon pump results in models overestimating the saturation state in summer. Second, neglecting the sea ice algae results in an underestimation of the Arctic Ocean's annual carbon uptake (∼3% per year), indicating that the accumulating year‐on‐year underestimation of annual carbon uptake, as a result of neglecting sea ice algae, would lead to increasing error over multidecadal runs of polar ocean models.

OBJECTIVES: Introduction: Nicotinamide riboside (NR), is a NAD + precursor that is commercially available as a nutritional supplement. NAD + levels have been shown to decline in older adults, thus NR has been identified as a healthy aging nutritional supplement. Clinical and preclinical studies have demonstrated the safety and efficacy of NR supplementation at various doses, however individual responsiveness have been minimally reported. As individuals differ in multiple parameters that may result in variations in response to supplementation, dosing personalization may be a key to NR supplement effectiveness. Objective: Determine if published data of clinical NR supplementation can be used to personalize NR dosing. METHODS: A meta-analysis of published clinical trials of NR supplementation was conducted. Included studies were limited to those that were exclusive to NR supplementation with multiple doses for at least one week. The assessment compared NR dosing, study population demographics, changes in NAD levels, adverse effects, and study outcomes. RESULTS: A total of 11 publications report clinical results from NR supplementation demonstrated in 9 clinical trials (4 RCT), however only five of the studies met our criteria. Most of the studies have been conducted in both males and females with an average age of 45–65 years, with various BMIs. Dosing ranged from 100 mg/day to 2000 mg/day, for a duration of 9 days to 3 months, with no major adverse events reported. When measured, NAD + levels were shown to increase by as much as 139% with 1000 mg/day of NR for 56 days. Measurements for changes in NAD + lacked standardization in collection, analysis, and reporting, thus parallel comparisons could not be made. Additionally, studies did not separate NR responses based upon gender, age, BMI, and health status, preventing personalization of the available data. CONCLUSIONS: To effectively personalize NR dosing, standardization of NAD + analyses and clinical outcomes is gravely needed. Future use of phenotypic flexibility approaches may be beneficial in demonstrating the clinical benefits of NR supplementation. Lastly, it is recommended that future studies include heterogenous response study outcomes to identify responders/non-responders to various endpoints following NR supplementation. FUNDING SOURCES: None.

OBJECTIVES: Introduction: Demonstrating the benefits of nutritional supplements on healthy aging has been challenging, as research has tended to focus on affecting disease rather than health optimization. We propose that by applying the frameworks of intrinsic capacity and the hallmarks of aging, one can more definitively demonstrate measurable benefits of a nutritional supplement. To test the validity of this approach, research previously and actively being conducted on nicotinamide riboside (NR), a precursor to the essential coenzyme nicotinamide adenine dinucleotide (NAD) was evaluated. NAD levels have been shown to decrease with age, thus NR is widely promoted as a nutritional solution for healthy aging. Objective: The goal of this analysis was to determine if the combined frameworks of intrinsic capacity and the hallmarks of aging can be used to demonstrate the benefits of NR supplementation. METHODS: For preliminary assessment, a database of current and past NR research was developed. Each study was categorized as applicable to one or more of the proposed framework categories. The data were graphed by category to demonstrate historical growth in the research categories. RESULTS: Preliminary results indicated that 30.6% of studies in the database could be categorized as including research on one or more of the hallmarks of aging; the most dominant category was that of mitochondrial dysfunction, encompassing 27 preclinical and 7 clinical studies, followed by genomic instability (17,1), altered intercellular communication (9,2), deregulated nutrient sensing (8,3), stem cell exhaustion (11,0), epigenetic alterations (2,0), and telomere attrition (2,0), respectively. More than half of the studies could also be categorized as relating to one or more domains of intrinsic capacity specifically Vitality (50,2) and Locomotion (19,4), followed by Cognition (5,1), Sensory (4,0), and Psychological (1,0), (preclinical, clinical) respectively. CONCLUSIONS: NR research can be applied to multiple categories of the hallmarks of aging as well as intrinsic capacity domains, demonstrating the benefits of NR supplementation Positive results from previous and current research will further validate NR as a multidimensional healthy aging supplement. FUNDING SOURCES: None.

A systematic review of published toxicology and human intervention studies was performed to characterize potential hazards associated with consumption of green tea and its preparations. A review of toxicological evidence from laboratory studies revealed the liver as the target organ and hepatotoxicity as the critical effect, which was strongly associated with certain dosing conditions (e.g. bolus dose via gavage, fasting), and positively correlated with total catechin and epigallocatechingallate (EGCG) content. A review of adverse event (AE) data from 159 human intervention studies yielded findings consistent with toxicological evidence in that a limited range of concentrated, catechin-rich green tea preparations resulted in hepatic AEs in a dose-dependent manner when ingested in large bolus doses, but not when consumed as brewed tea or extracts in beverages or as part of food. Toxico- and pharmacokinetic evidence further suggests internal dose of catechins is a key determinant in the occurrence and severity of hepatotoxicity. A safe intake level of 338 mg EGCG/day for adults was derived from toxicological and human safety data for tea preparations ingested as a solid bolus dose. An Observed Safe Level (OSL) of 704 mg EGCG/day might be considered for tea preparations in beverage form based on human AE data.

Globally, obesity rates remain high and rates of related co-morbidities, e.g., metabolic syndrome and type 2 diabetes, continue to escalate. Poor diet, lifestyle, and an aging population has led to the emergence of “sarcopenic obesity” - characterized by low skeletal muscle mass/strength, combined with excess body fat, much of which is visceral. Surrounding the body's critical organs, visceral fat stimulates systemic inflammation and is an increasingly serious risk factor for cardiovascular disease and diabetes. Nutrition survey data suggest that populations are becoming overfed, yet undernourished, contributing simultaneously to a greater prevalence of sarcopenic obesity and elevated rates of chronic disease and nutrient inadequacy. Nutrition and public health policies need to evolve, including finding an alternative to BMI for assessing healthy body weight, raising awareness of the importance of sustainable physical activity with aging, emphasizing the nutrient density of the diet, and greater consideration of dietary protein and bioactive nutrient intake.

There is increasing interest by consumers, researchers, and regulators into the roles that certain bioactive compounds, derived from plants and other natural sources, can play in health maintenance and promotion, and even prolonging a productive quality of life. Research has rapidly emerged suggesting that a wide range of compounds and mixtures in and from plants (such as fruits and vegetables, tea and cocoa) and animals (such as fish and probiotics) may exert substantial health benefits. There is interest in exploring the possibility of establishing recommended intakes or dietary guidance for certain bioactive substances to help educate consumers. A key aspect of establishing dietary guidance is the assessment of safety/toxicity of these substances. Toxicologists need to be involved in both the development of the safety framework and in the evaluation of the science to establish maximum intake/upper limits.

Many terms for plant-derived food components are commonly used in the literature, but there is a notable lack of standardization and definition of nomenclature. The use of terms is often field-specific, leading to misunderstanding and problems with literature searches and systematic reviews, and results in isolated and divided research; this impacts not only publication quality but also innovation, regulatory compliance, and enforcement. To begin to address this issue, this narrative review describes the current use and definition of terms. The terms are either chemical and/or origin-based, such as phytochemical (chemicals from plants), or function-based, such as phytonutrient, bioactive, or nutraceutical. The ultimate goal is to establish a common harmonized, evidence-based understanding for when to use each term, thereby providing clarity and a specific scientific basis for such nomenclature. Neither the quality nor the quantity of evidence needed to allow the use of functional terms such as phytonutrient or nutraceutical is specifically discussed here; rather, it is simply noted that evidence is needed to apply these terms. The next step would be to define the evidence necessary for a compound to have a functional descriptor. The aim in this article is to establish scientific criteria for definitions that could be applied to clearly define and differentiate commonly used terms and thus ensure their consistent application in the scientific literature.

The Canadian Earth System Model version 5 (CanESM5) is a global model developed to simulate historical climate change and variability, to make centennial scale projections of future climate, and to produce initialized seasonal and decadal predictions. This paper describes the model components and their coupling, as well as various aspects of model development, including tuning, optimization and a reproducibility strategy. We also document the stability of the model using a long control simulation, quantify the model's ability to reproduce large scale features of the historical climate, and evaluate the response of the model to external forcing. CanESM5 is comprised of three dimensional atmosphere (T63 spectral resolution/2.8°) and ocean (nominally 1°) general circulation models, a sea ice model, a land surface scheme, and explicit land and ocean carbon cycle models. The model features relatively coarse resolution and high throughput, which facilitates the production of large ensembles. CanESM5 has a notably higher equilibrium climate sensitivity (5.7 K) than its predecessor CanESM2 (3.8 K), which we briefly discuss, along with simulated changes over the historical period. CanESM5 simulations are contributing to the Coupled Model Intercomparison Project Phase 6 (CMIP6), and will be employed for climate science and service applications in Canada.

OBJECTIVES: Nicotinamide adenine dinucleotide (NAD) is the central catalyst in cells’ energy production and regulates enzymes involved in DNA repair, innate immunity and cell senescence. Metabolic stresses such as poor diet, infection and certain diseases are linked to depletion of cells’ NAD pool, suggesting a role for optimal NAD status in health. However, current dietary recommendations for NAD are based on niacin and avoidance of pellagra, while the tolerable upper intake level (UL) is based on skin flushing, both outdated endpoints. Supplementation with the NAD precursor, nicotinamide riboside (NR), safely raises NAD levels in in humans in a dose-dependent manner suggesting that NR could be a candidate for dietary recommendations to optimize NAD status. The objective was to evaluate the published and ongoing clinical trials with NR to identify data in support of and research gaps related to dietary recommendations. METHODS: Utilizing a database of NR research maintained by the authors, published clinical studies were evaluated for safety, demonstration of clinical benefit, demonstration of an increase in cell/tissue NAD, biomarkers of intake and benefit, study population characteristics and study limitations. Ongoing registered clinical trials were also analyzed to assess potential future relevant outcomes. RESULTS: 12 published clinical studies showed NR supplementation to be safe, with no flushing effect, at a maximum dose of 2000 mg/day for up to 12 weeks; 9 studies demonstrated an elevation in NAD+, however, variation in sampling and testing methods affect the consistency of study results. In addition to elevation of NAD+, muscle acetylcarnitine was identified as a potential biomarker of intake. To date, NR has been evaluated in adults, with variations in gender and race. Ongoing registered and results from published clinical trials suggest NR may benefit inflammation, blood pressure, muscle function, body composition and cognition. Research gaps include the need for a validated biomarker of NAD status and consistent findings on clinical endpoints in different populations. CONCLUSIONS: Though there is early support for dietary recommendations for NR, research gaps, including a validated biomarker of NAD status and a causal link to relevant health outcomes need to be filled to revise the current recommendations. FUNDING SOURCES: None.

OBJECTIVES: Introduction: Many nutrition supplement researchers face hurdles when seeking non-commercially available materials for research. Challenges include difficulty identifying the correct contacts within a company, arranging material transfer agreements (MTAs), and utilizing the products in the most effective manner for success. The ChromaDex External Research Program (CERP) was established to streamline this process for the compound nicotinamide riboside, a healthy-aging nutritional supplement, commercially available as NIAGEN®. Lessons learned from CERP may be beneficial to other companies and academic researchers looking to build mutually beneficial relationships that expand research and product opportunities. Objective: Evaluate the metamorphosis of the MTA program into CERP, as a model for building relationships between nutrition supplement companies and academic investigators. METHODS: The process for obtaining a ChromaDex MTA was critically evaluated by various internal and external stakeholders. Recommendations were implemented and a six-month programmatic assessment was conducted. RESULTS: From 2013 to 2018, ChromaDex issued 175 MTAs to various academic, governmental, and industry researchers, providing preclinical and clinical materials. Evaluation of the program revealed that several MTA requests were missed, agreements were not enforced, and research relationships were not maximized. To improve, the program was re-branded as CERP and multiple changes were implemented. CERP is now comprised of a core team with support from an internal science team (ST). MTA requests now require an application that is reviewed by the ST (35% approval). The ST utilize rubrics and provide protocol recommendations to increase the project's probability of success. Once accepted into the program, investigators are required to communicate regularly with CERP in the form of progress reports. In turn, CERP provides confidential peer-review of manuscripts and intellectual property recommendations to the investigators. Lastly, a CERP webpage and newsletter were established to improve program visibility and accessibility. CONCLUSIONS: CERP is serving as a model in the nutrition supplement industry for fostering academic-industry relationships and advancing science. FUNDING SOURCES: None.

Specific market entry requirements for supplements, nutraceuticals, and functional foods vary from country to country, but most include a form of premarket registration or notification, and several have no specific requirements for entry. However, in recent years countries that embraced the concept of appropriately balancing consumer access with consumer protection have begun to develop market entry requirements. From a global perspective, there has been some convergence from key markets toward the use of a notification-based market entry system for finished products. Although it is too early to know how these shifts have benefited stakeholders, the expectation is that this has reduced the cost and barriers to market entry (for both industry and government) and provided consumers with improved access to products, while not placing consumers at greater risk. Although they have been slightly slower to evolve, most established markets have implemented regulatory frameworks to assess and authorize novel ingredients, an important factor in supporting industry innovation and consumer access to cutting-edge technology. Global convergence toward market entry and novel ingredient regulations that reduce barriers and improve access without sacrificing consumer safety will ultimately lead to an open and vibrant marketplace with highly satisfied customers.

The region of the Southern Ocean that encompasses the Subantarctic Front (SAF) to the north and the Polar Front (PF) to the south contains most of the transport of the Antarctic Circumpolar Current. Here skewness of sea level anomaly (SLA) from 1992 to 2013 is coupled with a meandering Gaussian jetw model to estimate the mean position, meridional width, and the percent variance that each front contributes to total SLA variability. The SAF and PF have comparable widths (85 km) in the circumpolar average, but their widths differ significantly in the East Pacific Basin (85 and 60 km, respectively). Interannual variability in the positions of the SAF and PF are also estimated using annual subsets of the SLA data from 1993 to 2012. The PF position has enhanced variability near strong topographic features such as the Kerguelen Plateau, the Campbell Plateau east of New Zealand, and downstream of Drake Passage. Neither the SAF nor the PF showed a robust meridional trend over the 20 year period. The Southern Annular Mode was significantly correlated with basin-averaged SAF and PF positions in the East Pacific and with the PF south of Australia. A correlation between the PF and the basin-scale wind stress curl anomaly was also found in the western extratropical Pacific but not in other basins.

In the United States, dietary reference intakes describe the relations between nutrient intakes and indicators of adequacy, prevention of disease, and avoidance of excessive intakes among healthy populations for essential nutrients but not dietary bioactive components (DBCs), whose absence from the diet is presumably not deleterious to health (i.e., does not cause a deficiency syndrome). An appropriate framework is needed for establishing recommended intakes for which public health messages and food labeling for DBCs can be derived, because their putative health benefits may not be readily defined in the context of nutritional essentiality. In addition, a myriad of factors make determining their intake and status and investigating their discrete contributions to health particularly challenging. Therefore, the ASN Dietary Bioactive Components Research Interest Section felt it worthwhile to convene a special “hot topic” session at the 2014 Experimental Biology meeting to discuss this issue and serve as a call for future scientific dialogue on establishing a framework for recommended intakes of DBCs. This session summary captures the discussions and presentations that transpired during this session.

This special article seeks to provide balance and clarity to the confusion brought about by the conclusions resulting from a recent study published in Archives of Internal Medicine by Mursu et al. (2011). An examination of three key limitations of the study provides context to why additional research is needed: (a) Nonusers were poorly defined; (b) supplement users were healthier than nonusers; and (c) the number of supplement users increased throughout the study. Although the literature is limited, other similar observational studies have also shown positive effects on the risk mortality for both multivitamins and single-nutrient supplements. Observational trials are an essential component of evidence-based nutrition but do not offer certainty because other data, such as the one generated from randomized controlled trials, are equally important in regard to the totality of evidence. The Senior Scientific Advisory Committee for the Council for Responsible Nutrition, an industry trade group, feels that the conclusions of the study by Mursu et al. (2011) are overstated and suggests that researchers analyze cohort(s) designed to specifically examine vitamin and mineral supplements free of confounding from factors, such as hormone replacement therapy, to better assess their benefits to the general population.

Nutrients can be classified as either “essential” or “non-essential,” the latter are also termed bioactive substances. Whereas the absence of essential nutrients from the diet results in overt deficiency often times with moderate to severe physiological decrements, the absence of bioactive substances from the diet results in suboptimal health. Nutrient reference values are set by Codex Alimentarius and regulatory bodies in many countries, mostly for essential nutrients with recommended daily intakes. The IOM in the United States has defined a set of four DRIs that, when data are appropriate, include an EAR, a RDA that is derived from the EAR, an AI for nutrients without appropriate data to identify an EAR, and an UL. From the RDA, the United States derives a labeling value called the DV, which applies to older children and most adults. In Codex, the equivalents of the DVs are the NRVs to be used in calculating percentage values on food labels. Nothing in the IOM documents specifies that labeling values can be set only for what have been defined to date as essential nutrients. Indeed, the US Food and Drug Administration sets a labeling value for dietary fiber based on the IOM AI for this ingredient. This conference explores the definitions, concepts, and data on two of the best examples of bioactive substances that, perhaps, should have NRVs: lutein and zeaxanthin, and n-3 long-chain polyunsaturated fatty acids.

Market entry requirements for nutraceuticals, functional foods, and supplements vary from country to country. While most essential vitamins and minerals have achieved widespread acceptance, the regulatory acceptability of other bioactive ingredients and ingredients derived from botanicals varies and in many cases is tied to a local country or regional positive and/or negative lists. Most finished products are regulated as a category of food, and as such, the market entry requirements tend to fall under one of three categories: registration, notification, or no entry requirements. There are benefits and drawbacks to all three approaches, although a notification-based approach provides the proper balance between allowing consumer access and choice and protecting public health.

Published by the US Food and Drug Administration in June 2007, current good manufacturing practices (cGMPs) for dietary supplements (21 CFR Part 111) are now mandatory for all firms that manufacture, package, label, or hold dietary supplements for sale in the United States. Ingredient supplier qualification remains one of the most critical, yet least understood, aspects of the regulation. The increasingly global supply chain and multiple instances of supply chain failures that have led to adverse consequences have elevated the need for proper supplier qualification. However, FDA’s expectations for supplier qualification remain unclear, and there is little knowledge of what constitutes industry best practices. Following the precedent set by other FDA-regulated industries, the dietary supplement industry has formed a consortium to address the knowledge and practice gap regarding supplier qualification. The group has developed a series of voluntary guidelines to assist ingredient suppliers and dietary supplement manufacturers with the qualification process. These guidelines, some of which are still under development, are intended to serve as tools or templates on which a firm’s own qualification program or standard operating procedures can be based. It is hoped that these guidelines will serve as the basis for future FDA guidance or rule making, should the need arise.

Taurine, glutamine and arginine are examples of amino acids which have become increasingly popular as ingredients in dietary supplements and functional foods and beverages. Animal and human clinical research suggests that oral supplementation of these amino acids provides additional health and/or performance benefits beyond those observed from normal intake of dietary protein. The increased consumer awareness and use of these amino acids as ingredients in dietary supplements and functional foods warrant a comprehensive review of their safety through quantitative risk assessment, and identification of a potential safe upper level of intake. The absence of a systematic pattern of adverse effects in humans in response to orally administered taurine (Tau), l-glutamine (Gln) and l-arginine (Arg) precluded the selection of a no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL). Therefore, by definition, the usual approach to risk assessment for identification of a tolerable upper level of intake (UL) could not be used. Instead, the newer method described as the Observed Safe Level (OSL) or Highest Observed Intake (HOI) was utilized. The OSL risk assessments indicate that based on the available published human clinical trial data, the evidence for the absence of adverse effects is strong for Tau at supplemental intakes up to 3 g/d, Gln at intakes up to 14 g/d and Arg at intakes up to 20 g/d, and these levels are identified as the respective OSLs for normal healthy adults. Although much higher levels of each of these amino acids have been tested without adverse effects and may be safe, the data for intakes above these levels are not sufficient for a confident conclusion of long-term safety, and therefore these values are not selected as the OSLs.

Carnitine is a conditionally essential amino acid-like compound involved in the transport of long-chain fatty acids into the mitochondria during the beta-oxidation process. Carnitine has become an increasingly popular ingredient in dietary supplements, especially weight loss and some sports nutrition products. A number of clinical trials have been conducted examining the effect of carnitine supplementation on weight loss and energy balance. Regarding safety, systematic evaluation of the research designs and data do not provide a basis for risk assessment and the usual safe upper level of intake (UL) derived from it unless the newer methods described as the observed safe level (OSL) or highest observed intake (HOI) are utilized. The OSL risk assessment method indicates that the evidence of safety is strong at intakes up to 2000mg/day l-carnitine equivalents for chronic supplementation, and this level is identified as the OSL. Although much higher levels have been tested without adverse effects and may be safe, the data for intakes above 2000mg/day are not sufficient for a confident conclusion of long-term safety.

Adverse event (AE) collection and reporting, a form of post-market surveillance is increasingly serving an important role in assuring the safety and quality of supplements and functional foods worldwide. More countries are including mandatory AE reporting as a regulatory requirement. This important activity is critical for the proper monitoring of product quality and safety in the marketplace, and helps to appropriately balance consumer access and protection. A robust globally coordinated AE collection and reporting program can also help manage liability and prepare companies for the rapidly emerging regulatory requirements in this area.

Background Dietary supplements are regularly used by a majority of the American population, and usage by health professionals is also common. There is considerable interest in usage patterns within the population and in the reasons for using dietary supplements. The "Life...supplemented" Healthcare Professionals 2008 Impact Study (HCP Impact Study) surveyed usage of dietary supplements by physicians in three specialties: cardiology, dermatology, and orthopedics. Methods The HCP Impact Study was conducted online by Ipsos Public Affairs for the Council for Responsible Nutrition (CRN), a trade association of the dietary supplement industry. Respondents were 900 physicians, including 300 each from three specialties - cardiology, dermatology, and orthopedics. Results Fifty-seven percent of cardiologists said they use dietary supplements at least occasionally, as did 75% of dermatologists and 73% of orthopedists. The product most commonly reported to be used was a multivitamin, but over 25% in each specialty said they used omega-3 fatty acids and over 20% said they used some botanical supplements. Regular dietary supplement use was reported by 37% of cardiologists, 59% of dermatologists, and 50% of orthopedists. Seventy-two percent of cardiologists, 66% of dermatologists, and 91% of orthopedists reported recommending dietary supplements to their patients. The primary reason given for recommending dietary supplements to patients was for heart health or lowering cholesterol for the cardiologists; benefits for skin, hair and nails for the dermatologists; and bone and joint health for the orthopedists. Conclusions Reported dietary supplement use was relatively common in this sample of physicians, and when they recommended dietary supplements to patients, they tended to do so for reasons related to their specialty.

Creatine has become one of the most popular dietary supplements in the sports nutrition market. The form of creatine that has been most extensively studied and commonly used in dietary supplements is creatine monohydrate (CM). Studies have consistently indicated that CM supplementation increases muscle creatine and phosphocreatine concentrations by approximately 15–40%, enhances anaerobic exercise capacity, and increases training volume leading to greater gains in strength, power, and muscle mass. A number of potential therapeutic benefits have also been suggested in various clinical populations. Studies have indicated that CM is not degraded during normal digestion and that nearly 99% of orally ingested CM is either taken up by muscle or excreted in urine. Further, no medically significant side effects have been reported in literature. Nevertheless, supplement manufacturers have continually introduced newer forms of creatine into the marketplace. These newer forms have been purported to have better physical and chemical properties, bioavailability, efficacy, and/or safety profiles than CM. However, there is little to no evidence that any of the newer forms of creatine are more effective and/or safer than CM whether ingested alone and/or in combination with other nutrients. In addition, whereas the safety, efficacy, and regulatory status of CM is clearly defined in almost all global markets; the safety, efficacy, and regulatory status of other forms of creatine present in today’s marketplace as a dietary or food supplement is less clear.

Current intake recommendations of 200 to 600 IU vitamin D per day may be insufficient for important disease outcomes reduced by vitamin D.This study assessed the benefit of higher-dose and higher achieved 25-hydroxyvitamin D levels [25(OH)D] versus any associated risk.Based on double-blind randomized control trials (RCTs), eight for falls (n = 2426) and 12 for non-vertebral fractures (n = 42,279), there was a significant dose-response relationship between higher-dose and higher achieved 25(OH)D and greater fall and fracture prevention. Optimal benefits were observed at the highest dose tested to date for 700 to 1000 IU vitamin D per day or mean 25(OH)D between 75 and 110 nmol/l (30-44 ng/ml). Prospective cohort data on cardiovascular health and colorectal cancer prevention suggested increased benefits with the highest categories of 25(OH)D evaluated (median between 75 and 110 nmol/l). In 25 RCTs, mean serum calcium levels were not related to oral vitamin D up to 100,000 IU per day or achieved 25(OH)D up to 643 nmol/l. Mean levels of 75 to 110 nmol/l were reached in most RCTs with 1,800 to 4,000 IU vitamin D per day without risk.Our analysis suggests that mean serum 25(OH)D levels of about 75 to 110 nmol/l provide optimal benefits for all investigated endpoints without increasing health risks. These levels can be best obtained with oral doses in the range of 1,800 to 4,000 IU vitamin D per day; further work is needed, including subject and environment factors, to better define the doses that will achieve optimal blood levels in the large majority of the population.