Managing folate deficiency implies filling the gap between laboratory and clinical assessment.

The characterization of folate status in subjects at risk of deficiency and with altered vitamin homeostasis is crucial to endorse preventive intervention health policies, especially in developed countries. Several physiological changes (i.e. pregnancy), clinical situations and diseases have been associated to increased requirement, impaired intake and absorption of folate. However clinical practice guidelines (CPG) endorse folic acid supplementation generally discarding the use of its determination in serum to assess the risk of deficiency and/or its concentration at baseline. Poor confidence on the diagnostic accuracy of serum folate assays still persists in the current CPGs although recent standardization efforts have greatly improved inter-method variability and precision. In this review we critically appraise the methodological issues concerning laboratory folate determination and the evidence on the potential adverse effects of folic acid exposure. The final aim is to build a sound background to promote serum folate-based cost-effective health care policies by optimizing folic acid supplementation in subjects at risk of deficiency and with altered folate homeostasis. Our first result was to adjust in relation to current serum folate assays the thresholds reported by CPGs as index of folate status, defined on the association with metabolic and hematologic indicators. We identify a statistically significant difference between the estimated thresholds and accordingly show that the assessment of folate status actually changes in relation to the assay employed. The use of the method-dependent thresholds here reported may pragmatically endorse the stewardship of folic acid supplementation in clinical practice and increase the cost-effectiveness of health care policies.

Probiotics and the Microbiome-How Can We Help Patients Make Sense of Probiotics?

The notion of probiotics as microbes that confer health benefits has its origins in the speculative ideas that are more than a century old, yet remain largely unsubstantiated by scientific evidence. The recent advances in microbiome science have highlighted the importance of intestinal microbes in human physiology and disease pathogenesis. These developments have provided a boost to the probiotics industry, which continues to experience exponential growth driven mainly by creative marketing. Consumers, patients, and most health care providers are not able to discern the underlying science or differentiate the permitted claims that promise vague health benefits from disease-specific claims reserved for drugs. No probiotic product has been able to satisfy the regulatory requirements to be categorized as a drug, a substance intended to cure, mitigate, or prevent disease. However, patients take probiotic products in the belief that they will help to treat their intestinal or systemic diseases. Thus far, the regulators have failed to create policies that would assist to inform the public in this area. In fact, the existing regulatory regime actually creates formidable barriers to research that could provide evidence for clinical efficacy of probiotic products. We propose a potential solution to this vexing problem, where a committee created through a partnership of academia, professional organizations, and industry, but free of potential conflicts of interest, would be charged with rigorous evaluation of specific probiotic products and the evidence in support of their different claims. Companies that would submit to this process would earn the trust of consumers and healthcare providers, as well as a distinction in the marketplace.

Results from an Epidemiological Follow-Up Survey on Home Artificial Nutrition in Switzerland from 2010 to 2015.

BACKGROUND: Home artificial nutrition (HAN) is an established treatment for malnourished patients. Since July 2012, the costs for oral nutrition supplements (ONS) are covered by the compulsory health insurance providers in Switzerland if the patient has a medical indication based on the Swiss Society for Clinical Nutrition guidelines. Therefore, the purpose of our study was to analyse the development of HAN, including ONS, before and after July 2012. METHODS: We obtained the retrospective and anonymized data from the Swiss association for joint tasks of health insurers (SVK), who registered patients on HAN. Since not all health insurers are working with SVK, this retrospective study recorded nearly 65% of all new patients on HAN in Switzerland from January 1, 2010, to December 31, 2015. RESULTS: A total of 33,410 patients (49.1% men and 50.9% women) with a mean BMI of 21.3 ± 4.5 kg/m2 and mean age of 68.9 ± 17.8 years were recorded. The number of patient cases on ONS increased from 808 cases in 2010 to 18,538 cases in 2015, while patient cases on home enteral nutrition (HEN) and home parenteral nutrition (HPN) remained approximately the same. The relative distribution of type of HAN changed from 26.2% cases on ONS, 68.7% cases on HEN and 5.1% cases on HPN in 2010 to 86.1% cases on ONS, 12.8% cases on HEN, and 1.1% cases on HPN in 2015. Treatment duration decreased for ONS from 698 ± 637 days to 171 ± 274 days, for HEN from 416 ± 553 days to 262 ± 459 days, and for HPN from 96 ± 206 days to 72 ± 123 days. Mean costs per patient decreased for ONS from 1,330 CHF in 2010 to 606 CHF in 2015. Total costs for HAN increased from 16,895,373 CHF in 2010 to 32,868,361 CHF in 2015. CONCLUSION: Our epidemiological follow-up study showed an immense increase in number of patients on HAN in Switzerland after July 2012. Due to shorter therapy duration and reduced mean costs per patient, total costs were only doubled while the number of patients increased 7-fold.

Internet Marketing of Cardioprotective Dietary Supplements.

Objectives: Considering high prevalence of use of dietary supplements and their easy access on the internet, the aim of this research was to examine and assess the prevalence of the internet marketing of heart-protective supplements as the most popular supplements of today, and to investigate the quality and quantity of information that are available to consumers on the sale websites. Design: Three major search engines (Google, Yahoo, and Bing) and keywords "cardiovascular supportive supplements online buy" were used to identify websites that sell cardioprotective dietary supplements. Content of first 50 listed websites in each engine was evaluated for its compliance with regulatory acts while information about supplements' efficacy and safety was compared with the results of the latest scientific research. Results: Of a total of 150 listed websites, 89 selling supplements for the specific indication underwent further analysis. The most commonly registered cardioprotective dietary supplements on the internet were supplements based on omega-3 fatty acids (omega-3) (57 websites, 64.05%). Related to the websites selling omega-3 supplements, risk reduction claims were presented at 23 (40.35%), whereas structure or function claims were present at 50 (87.72%) analyzed websites, but followed with Food and Drug Administration disclaimer only on 68.00% of them. Information about adverse effects were rarely pointed out (1 website, 1.75%) unlike warnings, which were significantly more available to consumers (38, 66.67%). Conclusions: According to obtained results, most of the analyzed websites that sell omega-3 supplements did not contain all important medical information required by Dietary Supplement Health and Education Act. Since use of internet marketing is in expansion and since consumers have no access to relevant medical information about dietary supplements on the selling websites, there is a clear need for better quality control of websites and greater public awareness of these widely used products.

How reliable is dietary supplement labelling?-Experiences from the analysis of ecdysterone supplements.

The present study aimed to design, develop, and optimize an analytical procedure to perform the quantitative determination of ecdysterone in commercially available dietary supplements. The newly developed procedure is based on the extraction of ecdysterone from the supplements and the subsequent analysis by an optimized UHPLC-MS/MS method. Chromatographic separation was performed on an Agilent Eclipse Plus C18 column (2.1 mm x 100 mm, particle size 1.8 µm). The mass spectrometer was operated in positive ionization mode (ESI+) with acquisition in dynamic multiple reaction monitoring (dMRM) mode. Using the protonated molecular ion [M+H]+ ecdysterone (target) and cortisol (internal reference) were detected at m/z 481 and 363, respectively. The assay was fully validated according to ICH guidelines and the method resulted to be fit for purpose in terms of accuracy and precision (CV% and RE% <15). Time-different intermediate precision was found within the reported range according to AOAC guideline for dietary supplements and botanicals. Quantitation has been performed using an external calibration considering the minimal matrix influences, preliminarily assessed following a cross comparison with an elaborate and time consuming standard addition method. The method was successfully applied to 12 different dietary supplements labelled to contain ecdysterone, showing an actual content generally much lower than the labelled one.

The Unregulated Probiotic Market.

BACKGROUND & AIMS: This narrative review provides an overview of the current regulation of probiotics, with a focus on those used for the dietary management of medical conditions (Medical Foods). FINDINGS: The probiotic market has grown rapidly, both for foods and supplements intended to enhance wellness in healthy individuals, and for preparations for the dietary management of disease. Regulation of probiotics varies between regions. Unless they make specific disease-related health claims, probiotics are regulated as food supplements and regulation is focused on the legitimacy of any claims, rather than efficacy, safety and quality. Many properties of probiotics are strain-specific, and safety and efficacy findings associated to specific formulations should not be generalized to other probiotic products. Manufacturing processes, conditions and ingredients are important determinants of product characteristics and changes to manufacturing are likely to give rise to a product not identical to the "original" in efficacy and safety if proper measures and controls are not taken. Current trademark law and the lack of stringent regulation of probiotic manufacturing mean that the trademark owner can commercialize any formulation under the same brand, even if significantly different from the original. These regulatory deficits may have serious consequences for patients where probiotics are used as part of clinical guideline-recommended management of serious conditions such as inflammatory bowel diseases, and may make doctors liable for prescribing a formulation not previously tested for safety and efficacy. CONCLUSIONS: Current regulation of probiotics is inadequate to protect consumers and doctors, especially when probiotics are aimed at the dietary management of serious conditions.

Industry Actions to Address Quality Issues for Dietary Supplements, Botanicals, and Other Natural Products.

The concept of "dietary supplements" is either a blessing for those focused on healthy lifestyles and personal management thereof or a crisis fraught with snake oil and drug analogs that are insidiously poisoning the gullible. Lost in this chatter is the role the ethical, and customer-focused industry takes to drive self-directing/self-governing initiatives to demonstrate unequivocally their position as responsible corporate citizens, meeting the needs of the ever-growing body of wellness-seekers.

Challenges and Opportunities for Improving the Safety Assessment of Botanical Dietary Supplements: A United States Pharmacopeia Perspective.

The United States Pharmacopeia (USP) is an independent, nonprofit, science-based organization whose mission is to improve global health through public quality standards for dietary supplements, medicines, and food ingredients.1 Before developing standards for dietary supplement ingredients, the USP performs an "Admission Evaluation" (Figure 1), which includes an assessment to ascertain that an ingredient does not present a serious health risk.2 This article discusses the challenges encountered during the evaluation of botanicals and proposes possible solutions.

A Tiered Approach for the Evaluation of the Safety of Botanicals Used as Dietary Supplements: An Industry Strategy.

Exposure to botanicals in dietary supplements is increasing across many geographies; with increased expectations from consumers, regulators, and industry stewards centered on quality and safety of these products. We present a tiered approach to assess the safety of botanicals, and an in silico decision tree to address toxicity data gaps. Tier 1 describes a Threshold of Toxicologic Concern (TTC) approach that can be used to assess the safety of conceptual levels of botanicals. Tier 2 is an approach to document a history of safe human use for botanical exposures higher than the TTC. An assessment of botanical-drug interaction (BDI) may also be necessary at this stage. Tier 3 involves botanical chemical constituent identification and safety assessment and the in silico approach as needed. Our novel approaches to identify potential hazards and establish safe human use levels for botanicals is cost and time efficient and minimizes reliance on animal testing.

Dietary Supplements: Regulatory Challenges and Research Resources.

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.

Yellow Oleander Seed, or "Codo de Fraile" (Thevetia spp.): A Review of Its Potential Toxicity as a Purported Weight-Loss Supplement.

The Dietary Supplements and Health Education Act (DSHEA), passed by the United States Congress in October of 1994, defines herbal products as nutritional supplements, not medications. This opened the market for diverse products made from plants, including teas, extracts, essential oils, and syrups. Mexico and the United States share an extensive border, where diverse herbal products are available to the public without a medical prescription. Research undertaken in the neighboring cities of Ciudad Juarez, Mexico, and El Paso, Texas, USA, shows the use of herbs is higher in this border area compared to the rest of the United States. A portion of the population is still under the erroneous impression that "natural" products are completely safe to use and therefore lack side effects. We review the dangers of ingesting the toxic seed of Thevetia spp. (family Apocynaceae), commonly known as "yellow oleander" or "codo de fraile," misleadingly advertised on the Internet as an effective and safe dietary supplement for weight loss. Lack of proper quality control regarding herbs generates a great variability in the quantity and quality of the products' content. Herb-drug interactions occur between some herbal products and certain prescription pharmaceuticals. Certain herbs recently introduced into the U.S. market may not have been previously tested adequately for purity, safety, and efficacy. Due to the lack of reliable clinical data regarding the safe use of various herbal products currently available, the public should be made aware regarding the possible health hazards of using certain herbs for therapeutic purposes. The potentially fatal toxicity of yellow oleander seed is confirmed by cases reported from various countries, while the purported benefits of using it for weight loss have not been evaluated by any known clinical trials. For this reason, the use of yellow oleander seed as a dietary supplement should be avoided.

Variability in Potency Among Commercial Preparations of Berberine.

Berberine is an isoquinoline alkaloid plant extract that is widely available as a dietary supplement in the United States and has demonstrated efficacy in the treatment of type 2 diabetes mellitus and dyslipidemia. Because of its increased use and purported pharmacological properties, potential variations in product quality could pose a barrier to berberine's safety and effectiveness in clinical practice. Thus, this study evaluated the potency of dietary supplements containing berberine available in the U.S. commercial market. Fifteen unique dietary supplements containing berberine were purchased through U.S. dietary supplement vendors. For each product, berberine was extracted from 3 unique capsules and analyzed by ultra-high-performance liquid chromatography tandem mass spectrometry. Percentage content based on the product label claim was determined for each product. The average berberine content across the products was found to be 75% ± 25% of the product label claim, with product potency ranging from 33% to 100%. Nine of the 15 tested products (60%) failed to meet the potency standards of 90% to 110% of labeled content claim, as commonly required of pharmaceutical preparations by the U.S. Pharmacopeial Convention. Evaluation of the relationship between product cost and the measured potency failed to demonstrate an association between quality and cost. Variability in product quality may significantly contribute to inconsistencies in the safety and effectiveness of berberine. In addition, the quality of the berberine product cannot be inferred from its cost.

Situation analysis of procurement and production of multiple micronutrient supplements in 12 lower and upper middle-income countries.

Globally, there are few vitamin and mineral ingredient manufacturers. To support local, in-country or regional procurement and production of multiple micronutrient supplements (MMS), the following production scenarios are possible: (a) straight ingredients of vitamins and minerals forms imported or locally produced that are mixed, tableted, or encapsulated and packaged by a local manufacturer; (b) import or local production of a vitamin and minerals premix that is tableted or encapsulated and packaged locally; (c) import of a bulk, finished product (tablets or capsules) that is packaged and branded; and (d) or import of a branded packaged product. This paper is a situation analysis of the market, manufacturing, and policy factors that are driving the production of MMS in 12 lower and upper middle-income countries. Key informants completed a self-administered structured questionnaire, which examined the local context of products available in the market and their cost, regulations and policies, in Brazil, Colombia, Guatemala, Mexico, Peru, Bangladesh, India, Vietnam, Ghana, Kenya, Nigeria, and South Africa. Our study found that although most countries have the capacity to produce locally MMS, the major barriers observed for sustainable and affordable production include (a) poor technical capacity and policies for ensuring quality along the value chain and (b) lack of policy coherence to incentivize local production and lower the manufacture and retail price of MMS. Also, better guidelines and government oversight will be required because not one country had an MMS formulation that matched the globally recommended formulation of the United Nations Multiple Micronutrient Preparation (UNIMMAP).

The quality of information on the internet relating to top-selling dietary supplements in the Czech Republic.

Background The purchase of dietary supplements (DS) via the Internet is increasing worldwide as well as in the Czech Republic. Objective The aim of the study is to evaluate the quality of information on DS available on the Internet. Setting Czech websites related to dietary supplements. Methods A cross-sectional study was carried out involving the analysis of information placed on the websites related to the 100 top-selling DS in the Czech Republic in 2014, according to IMS Health data. Main outcome measure The following criteria were evaluated: contact for the manufacturer, recommended dosage, information on active substances as well as overall composition, permitted health claims, % of the daily reference intake value (DRIV) for vitamins and minerals, link for online counseling, pregnancy/breastfeeding, allergy information, contraindications, adverse reactions, and supplement-drug interactions (some criteria were evaluated from both points of view). Results A total of 199 web domains and 850 websites were evaluated. From the regulatory point of view, all the criteria were fulfilled by 11.3% of websites. Almost 9% of the websites reported information referring to the treatment, cure, or prevention of a disease. From the clinical point of view, all the criteria were only met by one website. Conclusions The quality of information related to DS available on the Internet in the Czech Republic is quite low. The consumers should consult a specialist when using DS purchased online.

Usefulness of a Risk Assessment Tool to Risk Stratify Dietary Supplements.

BACKGROUND: The use of dietary supplements (DSs) is widespread in the military. Service members use DS for any number of reasons, to include supporting general health, increasing energy levels, enhancing performance, and promoting gains in strength. However, some readily available DS products are potentially unsafe. Therefore, the purpose of this study is to assess the ability of military medical students to use the Operation Supplement Safety DS risk assessment tool. The Operation Supplement Safety risk assessment tool was developed to assist Service members in making decisions about safe DS use. METHODS: Fourth-year medical students used an online assessment tool to risk stratify and evaluate the safety of 12 predesignated DS. The assessment tool consists of seven polar questions (yes/no), with an answer of "yes" given a score of 1 and an answer of "no" given a score of 0. Students recorded responses to each of the seven questions for each of the 12 DSs. The tool then generated a total score for each DS, which was compared to the previously identified correct total score. Students' scores for each individual yes/no question and final conclusion about DS safety were also assessed. FINDINGS: Forty responses for the 12 DSs were examined. Five supplements were expected to receive a score of ≥4, suggesting they were likely safe. The average scores (± standard deviation [SD]) for each DS vs. the correct safety score were fish oil (5.9 ± 1.4 vs. 7.0), iron (4.2 ± 1.4 vs. 4.0), melatonin (4.9 ± 0.8 vs. 5.0), multivitamin/mineral (3.8 ± 1.1 vs. 4.0), multivitamin/mineral for men (4.0 ± 1.0 vs. 5.0), performance-enhancing supplement A (1.5 ± 1.1 vs. 2.0), performance-enhancing supplement B (2.0 ± 1.0 vs. 3.0), performance-enhancing supplement C (0.6 ± 0.5 vs. 1.0), performance-enhancing supplement D (1.8 ± 1.0 vs. 3.0), performance-enhancing supplement E (1.5 ± 1.3 vs. 1.0), sexual enhancement supplement (1.3 ± 0.7 vs. 1.0), and weight loss supplement (1.1 ± 1.1 vs. 1.0). DISCUSSION/IMPACT/RECOMMENDATIONS: The DS risk assessment tool provides consumers a quick way to screen DS for safety and can help consumers make more informed decisions when purchasing DS. Scores had minimal intersubject variability and were comparable to expected risk stratification. Our results suggest the assessment tool may be appropriate for medical students to use when investigating the safety of DS. We recommend additional research to verify whether the findings from this study would be similar for other potential users, as well as assess other psychometric properties.

Pediatric Integrative Medicine.

The American Academy of Pediatrics is dedicated to optimizing the well-being of children and advancing family-centered health care. Related to this mission, the American Academy of Pediatrics recognizes the increasing use of complementary and integrative therapies for children and the subsequent need to provide reliable information and high-quality clinical resources to support pediatricians. This Clinical Report serves as an update to the original 2008 statement on complementary medicine. The range of complementary therapies is both extensive and diverse. Therefore, in-depth discussion of each therapy or product is beyond the scope of this report. Instead, our intentions are to define terms; describe epidemiology of use; outline common types of complementary therapies; review medicolegal, ethical, and research implications; review education and training for select providers of complementary therapies; provide educational resources; and suggest communication strategies for discussing complementary therapies with patients and families.