Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?

BACKGROUND: In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements. OBJECTIVES: The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians. RESULTS: Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency. CONCLUSION: The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.

Plain language titleExcess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?Plain language summaryIt has been known for many decades that high doses of the B vitamin supplement, folic acid, can alleviate the anemia of vitamin B12 deficiency, at least temporarily. However, by alleviating the anemia, such folic acid supplements were said to "mask" the underlying vitamin B12 deficiency, thus allowing neurological damage to continue or possibly be exacerbated. Consequently, treating vitamin B12 deficiency with high dose folic acid was discontinued in the 1970s. The issue of whether folic acid supplements can exacerbate vitamin B12 deficiency reemerged in the 1990s with folic acid fortification of cereals and grains in the United States and Canada (and now in over 80 countries around the world) to prevent spina bifida and other birth defects. This narrative review summarizes the results of studies that have assessed the relationships between folic acid and folate and vitamin B12 status in patients and in populations. A recent hypothesis on how folic acid might exacerbate vitamin B12 deficiency is summarized, and recommendations to clinicians are made for increased vigilance in assessing vitamin B12 status in certain groups at risk of vitamin B12 deficiency, including older adults, people with gastrointestinal issues and other factors that cause vitamin B12 malabsorption, people with unexplained neurological problems, and people who follow vegan or vegetarian diets which are naturally low in vitamin B12.

Challenges and obstacles implementing evidence-based food fortification policy in a high-income country.

The World Health Organization (WHO) recognizes food fortification as one of the most cost-effective and beneficial public health measures available. Mass fortification policies and regulations can reduce health disparities, including in high-income countries, by improving micronutrient intake among food-insecure or high-risk populations without changing their diet or behavior. While international health organizations have traditionally prioritized technical assistance and grants to medium and low-income countries, it is important to recognize that micronutrient deficiencies may also pose an important yet underappreciated public health problem in many high-income countries. Nevertheless, some high-income countries, including Israel, have been slow to adopt fortification, due to a variety of scientific, technological, regulatory, and political barriers. Overcoming these barriers requires an exchange of knowledge and expertise among the all stakeholders to achieve cooperation and broad public acceptance within countries. Similarly, sharing the experience of countries where the matter is in play may help inform efforts to advance fortification globally. Here we share a perspective on progress and barriers to achieve this goal in Israel, to inform efforts made to avoid the regrettable waste of unrealized human potential from prevalent yet preventable nutrient deficiency conditions, in Israel and beyond.

Results of the national biomonitoring program show persistent iodine deficiency in Israel.

BACKGROUND: Adequate iodine intake is essential for human health, for normal thyroid function, and for attainment of full intellectual potential in children. In light of Israel's lack of a mandatory salt fortification policy, heavy reliance on desalination and low iodine intake from dairy products and seafood, there is concern in Israel that the population is iodine deficient. Indeed, the first Israeli National Iodine Survey in 2016 found a median urinary iodine concentration (UIC) of 83 µg/L among school age children, falling below the WHO's adequacy range of 100-299 µg/L for children. METHODS: In the framework of the National Human Biomonitoring Program in Israel, spot urine samples and questionnaire data were collected from 166 healthy children aged 4-12 years in 2020-2021. Urinary iodine concentrations were measured at the Ministry of Health National Biomonitoring Laboratory, using mass spectrometry. An international comparison of median urinary iodine concentrations (UIC) was performed taking into consideration the levels of desalinated water per capita, and fortification policies. RESULTS: The overall median (interquartile range [IQR]) UIC was 80.1 µg/L (44.7-130.8 µg/L) indicating that the population's iodine status has not improved in the five years that have passed since inadequacy was first identified. When comparing 13 countries with population size above 150,000, whose desalinated water per capita was at least 1 m3, Israel and Lebanon were the only countries with median UIC below the WHO adequacy range. CONCLUSIONS: There is an urgent need for mandatory salt fortification in Israel. Based on our international comparison, we conclude that the potential impact of desalination on iodine intake can be compensated for using the implementation of salt fortification policy. This study highlights the critical need for public health surveillance of nutritional and environmental exposures using human biomonitoring, with emphasis on vulnerable populations such as pregnant women and children.

Child food insecurity in the wake of the COVID-19 pandemic: urgent need for policy evaluation and reform in Israel's school feeding programs.

Even in high-income countries like Israel, children have been particularly vulnerable to the surge in food insecurity driven by quarantines, unemployment, and economic hardships of the COVID-19 pandemic. Under normal circumstances, School Feeding Programs (SFPs) can help to ensure child food security. In the wake of the pandemic, policy makers worldwide have been challenged to adapt national SFPs to provide nutritional support to children (and indirectly to their families) during extended school closures. Most national SFPs implemented contingency plans to ensure continued nutritional support for children. In Israel, where SFPs were largely suspended during long periods of mandated school closing, there was a loss of 30-50% of feeding days for the ~ 454,000 children enrolled in the program. The lack of emergency contingency planning and failure to maintain Israeli SFPs during school closures reveals longstanding structural policy flaws that hindered coordination between relevant ministries and authorities and impeded the mobilization of funds and existing programs to meet the emergent need. The school feeding law does not identify child food security as an explicit aim, there are no benchmarks for monitoring and evaluating the program to ensure that the food aid reaches the children most in need, even routinely, and the Ministry of Education had no obligation to maintain the program and to marshal data on the participants that could be acted upon in the emergency. Moreover, because Israeli SFPs are "selective", in other words, implemented according to community risk (low-income, high poverty rate) and geographical factors, attendant stigma and financial burdens can make participation in the program less attractive to families and communities that need them the most. We argue that Israel should make urgent, long-term improvements to the SFPs as follows: First, eliminating childhood food insecurity should be made an explicit goal of legislation in the broader context of national social, health, and nutritional goals, and this includes ensuring SFPs are maintained during emergencies. Second, the government should assume responsibility for the routine assessment and data collection on food insecurity among Israeli children. Third, SFPs should be subjected to rigorous independent program evaluation. Finally, a "universal" SFP providing nutritious diets would likely improve the health of all Israeli children, across all socioeconomic backgrounds. These steps to guarantee that Israeli children have food to realize their full physical and cognitive potential would emphasize Israel's firm commitment to support multiple dimensions of health, educational achievement, and societal values, to combat the complex and long-term consequences of the pandemic, and to prepare for the next one.

Perspective: The High-Folate-Low-Vitamin B-12 Interaction Is a Novel Cause of Vitamin B-12 Depletion with a Specific Etiology-A Hypothesis.

Vitamin B-12 is a water-soluble vitamin that plays important roles in intermediary metabolism. Vitamin B-12 deficiency has many identifiable causes, including autoimmune and other gastrointestinal malabsorption disorders, dietary deficiency, and congenital defects in genes that are involved in vitamin B-12 trafficking and functions. Another putative cause of vitamin B-12 deficiency is the high-folate-low vitamin B-12 interaction, first suspected as the cause for observed relapse and exacerbation of the neurological symptoms in patients with pernicious anemia who were prescribed high oral doses of folic acid. We propose that this interaction is real and represents a novel cause of vitamin B-12 depletion with specific etiology. We hypothesize that excessive intake of folic acid depletes serum holotranscobalamin (holoTC), thereby decreasing active vitamin B-12 in the circulation and limiting its availability for tissues. This effect is specific for holoTC and does not affect holohaptocorrin, the inert form of serum vitamin B-12. Depletion of holoTC by folic acid in individuals with already low vitamin B-12 status further compromises the availability of vitamin B-12 coenzymes to their respective enzymes, and consequently a more pronounced state of biochemical deficiency. This hypothesis is drawn from evidence of observational and intervention studies of vitamin B-12-deficient patients and epidemiological cohorts. The evidence also suggests that, in a depleted state, vitamin B-12 is diverted to the hematopoietic system or the kidney. This most likely reflects a selective response of tissues expressing folate receptors with high affinity for unmetabolized folic acid (UMFA; e.g., hematopoietic progenitors and renal tubules) compared with those tissues (e.g., liver) that only express the reduced folate carrier, which is universally expressed but has poor affinity for UMFA. The biochemical and physiological mechanisms underlying this interaction require elucidation to clarify its potential public health significance.

Effect of Advanced Glycation End Products on Cognition in Older Adults with Type 2 Diabetes: Results from a Pilot Clinical Trial.

BACKGROUND: Dietary advanced glycation end-products (AGEs) are linked to cognitive decline. However, clinical trials have not tested the effect of AGEs on cognition in older adults. OBJECTIVE: The aim of the current pilot trial was to examine the feasibility of an intervention to reduce dietary AGEs on cognition and on cerebral blood flow (CBF). METHODS: The design is a pilot randomized controlled trial of dietary AGEs reduction in older adults with type 2 diabetes. Seventy-five participants were randomized to two arms. The control arm received standard of care (SOC) guidelines for good glycemic control; the intervention arm, in addition to SOC guidelines, were instructed to reduce their dietary AGEs intake. Global cognition and CBF were assessed at baseline and after 6 months of intervention. RESULTS: At baseline, we found a reverse association between AGEs and cognitive functioning, possibly reflecting the long-term toxicity of AGEs on the brain. There was a significant improvement in global cognition at 6 months in both the intervention and SOC groups which was more prominent in participants with mild cognitive impairment. We also found that at baseline, higher AGEs were associated with increased CBF in the left inferior parietal cortex; however, 6 months of the AGEs lowering intervention did not affect CBF levels, despite lowering AGEs exposure in blood. CONCLUSION: The current pilot trial focused on the feasibility and methodology of intervening through diet to reduce AGEs in older adults with type 2 diabetes. Our results suggest that participants with mild cognitive impairment may benefit from an intensive dietary intervention.

Design and Feasibility of a Randomized Controlled Pilot Trial to Reduce Exposure and Cognitive Risk Associated With Advanced Glycation End Products in Older Adults With Type 2 Diabetes.

Introduction: Advanced glycation end products (AGEs) in diet and serum are positively correlated with chronic conditions such as type 2 diabetes and cognitive decline. Dietary reduction of AGEs was shown to reduce their level in serum and to have a beneficial effect on metabolic biomarkers. However, in part due to limitations of feasibility, clinical trials have not tested its effect on cognition in elderly. The current pilot study examines the feasibility of AGE reduction in elderly with diabetes in terms of recruitment and retention. Methods: The design is a randomized controlled pilot trial of dietary AGEs in elderly with type 2 diabetes (clinicaltrials.gov NCT02739971). Recruitment followed two stages: we first recruited participants with mild cognitive impairment (MCI), and after expanding inclusion criteria, we later recruited cognitively normal participants with subjective memory complaints (SMCs). Participants were randomized to two arms. Participants in the control arm received standard of care (SOC) guidelines for good glycemic control; those in the experimental arm, in addition to SOC guidelines, were instructed to lower their dietary AGE intake, primarily by changing their cooking methods. Participants were closely followed for dietary adherence over 6 months and evaluated before and after the intervention for adherence to the assigned diet, blood tests, cognitive performance, and brain MRI. Results: Seventy-five participants (52 with MCI and 23 cognitively normal with SMCs) were recruited primarily through mass mailing and advertising in social media websites. Seventy participants finished the study, and dropout was similar in both groups (7.5% in control vs. 5.7% in intervention, p = 0.757). The majority (57.5%) of participants in the AGEs-lowering arm showed very high adherence with the dietary guidelines. Discussion: Targeting feasible lifestyle modifications in high-risk populations could prevent substantial cases of cognitive decline. Observational evidence supports that AGEs may contribute to cognitive decline; however, the cognitive effect of reducing AGEs exposure has yet to be evaluated in a randomized controlled trial (RCT). The results of our pilot trial delineate a methodology including effective recruitment strategies, population of choice, and ways to assure high adherence during lifestyle modifications, and significantly advance progress toward a definitive and well-powered future RCT.

Long Term Dietary Restriction of Advanced Glycation End-Products (AGEs) in Older Adults with Type 2 Diabetes Is Feasible and Efficacious-Results from a Pilot RCT.

INTRODUCTION: High serum concentrations of advanced glycation end-products (AGEs) in older adults and diabetics are associated with an increased risk of cognitive impairment. The aim of this pilot study was to assess the feasibility of long-term adherence to a dietary intervention designed to decrease intake and exposure to circulating AGEs among older adults with type 2 diabetes. METHODS: Herein, 75 participants were randomized to either a standard of care (SOC) control arm or to an intervention arm receiving instruction on reducing dietary AGEs intake. The primary outcome was a change in serum AGEs at the end of the intervention. Secondary and exploratory outcomes included adherence to diet and its association with circulating AGEs. Cognitive function and brain imaging were also assessed but were out of the scope of this article (ClinicalTrials.gov Identifier: NCT02739971). RESULTS: The intervention resulted in a significant change over time in several serum AGEs compared to the SOC guidelines. Very high adherence (above 80%) to the AGE-lowering diet was associated with a greater reduction in serum AGEs levels. There were no significant differences between the two arms in any other metabolic markers. CONCLUSIONS: A long-term dietary intervention to reduce circulating AGEs is feasible in older adults with type 2 diabetes, especially in those who are highly adherent to the AGE-lowering diet.

CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain.

The Presenilin1 (PSEN1) gene encodes the catalytic peptide of the γ-secretase complex, a key enzyme that cleaves the amyloid-ß protein precursor (AßPP), to generate the amyloid-ß (Aß) peptides, involved in Alzheimer's Disease (AD). Other substrates of the γ-secretase, such as E-cadherin and Notch1, are involved in neurodevelopment and haematopoiesis. Gene-specific DNA methylation influences PSEN1 expression in AD animal models. Here we evaluated canonical and non-canonical cytosine methylation patterns of the PSEN1 5'-flanking during brain development and AD progression, in DNA extracted from the frontal cortex of AD transgenic mice (TgCRND8) and post-mortem human brain. Mapping CpG and non-CpG methylation revealed different methylation profiles in mice and humans. PSEN1 expression only correlated with DNA methylation in adult female mice. However, in post-mortem human brain, lower methylation, both at CpG and non-CpG sites, correlated closely with higher PSEN1 expression during brain development and in disease progression. PSEN1 methylation in blood DNA was significantly lower in AD patients than in controls. The present study is the first to demonstrate a temporal correlation between dynamic changes in PSEN1 CpG and non-CpG methylation patterns and mRNA expression during neurodevelopment and AD neurodegeneration. These observations were made possible by the use of an improved bisulphite methylation assay employing primers that are not biased towards non-CpG methylation. Our findings deepen the understanding of γ-secretase regulation and support the hypothesis that epigenetic changes can promote the pathophysiology of AD. Moreover, they suggest that PSEN1 DNA methylation in peripheral blood may provide a biomarker for AD.

Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine-choline-deficient rats.

Methyl-donor deficiency is a risk factor for neurodegenerative diseases. Dietary deficiency of the methyl-donors methionine and choline [methionine-choline-deficient (MCD) diet] is a well-established model of nonalcoholic steatohepatitis (NASH), yet brain metabolism has not been studied in this model. We hypothesized that supplemental betaine would protect both the liver and brain in this model and that any benefit to the brain would be due to improved liver metabolism because betaine is a methyl-donor in liver methylation but is not metabolically active in the brain. We fed male Sprague-Dawley rats a control diet, MCD diet, or betaine-supplemented MCD (MCD+B) diet for 8 wk and collected blood and tissue. As expected, betaine prevented MCD diet-induced NASH. However, contrary to our prediction, it did not appear to do so by stimulating methylation; the MCD+B diet worsened hyperhomocysteinemia and depressed liver methylation potential 8-fold compared with the MCD diet. Instead, it significantly increased the expression of genes involved in ß-oxidation: fibroblast growth factor 21 and peroxisome proliferator-activated receptor α. In contrast to that of the liver, brain methylation potential was unaffected by diet. Nevertheless, several phospholipid (PL) subclasses involved in stabilizing brain membranes were decreased by the MCD diet, and these improved modestly with betaine. The protective effect of betaine is likely due to the stimulation of ß-oxidation in liver and the effects on PL metabolism in brain.-Abu Ahmad, N., Raizman, M., Weizmann, N., Wasek, B., Arning, E., Bottiglieri, T., Tirosh, O., Troen, A. M. Betaine attenuates pathology by stimulating lipid oxidation in liver and regulating phospholipid metabolism in brain of methionine-choline-deficient rats.

White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Low Iodine Intake from Dairy Foods Despite High Milk Iodine Content in Israel.

BACKGROUND: Milk is a major source of iodine in human nutrition. Because both iodine content and the consumption of milk and dairy vary widely over time and populations, their contribution to iodine intake must be evaluated regularly. A recent national iodine survey found Israel's population to be mildly iodine deficient, possibly due to unmonitored changes in the food content of dietary iodine. Accounting for dairy iodine content can help guide efforts to prevent iodine deficiency. OBJECTIVES: This study aimed to determine the iodine concentration of dairy products typically consumed in the Israeli diet, and to estimate iodine intake from dairy products among Israeli adults. METHODS: Iodine was analyzed in 33 selected dairy products that account for 89% of the total population's dairy intake according to the "MABAT" Israeli National Health and Nutrition survey. Based on these data, the distribution of iodine intake from milk, dairy, and dairy-based foods in the adult population was calculated. RESULTS: Israeli milk is rich in iodine, with a mean concentration of 22 µg/100 g. However, due to low dairy consumption, the mean iodine intake from milk and dairy was only 34 µg/day (median 23 µg/day; range: 0-337 µg/day) or 22% of the recommended daily allowance. Self-reported intake among poor, male, and Arab subgroups was even lower. CONCLUSIONS: Because Israeli milk and dairy products are iodine rich, their contribution to the population's iodine intake would increase if they were consumed in greater amounts, particularly by high-risk groups. Dairy's potential contribution to iodine nutrition should be considered in recommendations for dairy consumption and iodine prophylaxis.

Food-Aid Quality Correlates Positively With Diet Quality of Food Pantry Users in the Leket Israel Food Bank Collaborative.

Introduction: In many affluent countries, including Israel, networks of food banks and pantries have increasing responsibility to alleviate endemic poverty and food insecurity. While they may relieve acute hunger, their long-term influence on health and well-being is poorly understood. Methods: An exploratory cross-sectional telephone survey assessed both adequacy and quality of food aid provided via food pantries in the Leket Israel food bank network, in relation to recipients' dietary needs and health. The quality of food baskets and recipient diets were given a Healthy Portions Score (HPS) to measure compliance with Government guidelines for a "Basic Healthy Food Basket," and a Nutrient Density Score (NDS) to capture how well the food achieved the recommended dietary allowance (RDA) for vital macro and micronutrients. A total of 105 pantry users were surveyed from 16 pantries around the country. Results: The basket HPS correlated positively and highly significantly with dietary quality (individual NDS) after adjusting for gender, marital status and country of birth (standardized ß = 0.22, p = 0.03). Nearly half (46%) reported food insecurity with hunger. Two thirds were overweight or obese, and anemia, cardiovascular and metabolic disease were prevalent. The average food basket provides 30% of energy, 55% of protein, 50% of fiber, but only 33% or less of the household requirement for most minerals and vitamins. Only 60% of participants met their estimated energy requirements, and the intake of many essential micronutrients was well below the RDA. Fruits and vegetable portions contributed by Leket Israel correlated positively with the dietary quality (individual NDS) after adjustment for the same covariates (Standardized ß = 0.20, p = 0.04). Discussion: A structured telephone survey proved a feasible method to study the impact of food-aid quality on the nutrition and health of food pantry users in an affluent country. Food baskets with fruits, vegetables and higher quality nutrition were correlated with healthier diets among the recipients. Data correlating food-aid quality and recipient diet and health is essential to effective policy making.

Effect of Combination Folic Acid, Vitamin B6 , and Vitamin B12 Supplementation on Fracture Risk in Women: A Randomized, Controlled Trial.

Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12 , B6 , and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin B12 (1 mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard = 1.08; 95% confidence interval, 0.88 to 1.34). In a nested case-cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B12 or B6 , or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease. © 2017 American Society for Bone and Mineral Research.

First Israeli National Iodine Survey Demonstrates Iodine Deficiency Among School-Aged Children and Pregnant Women.

BACKGROUND: National data on iodine status in Israel are lacking. Reliance on iodine-depleted desalinated water, the absence of a salt iodization program, and reports of increased use of thyroid medication in Israel suggest that the population's iodine intake is likely inadequate. The aims of this study were therefore to determine the iodine status of Israeli school-age children (SAC) and pregnant women (PW) in a nationally representative sample obtained by a novel approach of using pre-discard urinalysis samples collected from a centralized national laboratory. METHODS: Spot urine samples from 1023 SAC and 1074 PW, representing all regions and major sectors in Israel, were collected during 2016 at the Maccabi Healthcare Services central laboratory. Urinary iodine concentration (UIC) was measured, and the results were analyzed by trimester, sex, region, and sector. RESULTS: SAC were iodine deficient, with a median (interquartile range [IQR]) UIC of 83 µg/L (52-127 µg/L); 62% of SAC UICs were below the World Health Organization adequacy range for SAC (100-199 µg/L). PW were also iodine deficient, with a median (IQR) UIC of 61 µg/L (36-97 µg/L); 85% of PW UICs were below the adequacy range for PW (150-249 µg/L). For both SAC and PW, the median UIC was below the World Health Organization's adequacy range across all sectors, sexes, and districts. Among SAC, the median (IQR) UIC was lower among females (75 µg/L; 48-119 µg/L) than males (92 µg/L; 59-133 µg/L; p < 0.05). Median UIC values of PW correlated significantly with the median UIC for SAC by sub-district (R2 = 0.3, p < 0.05). CONCLUSIONS: Urine sampling via a centralized national laboratory was efficient and cost-saving. Iodine deficiency in Israeli SAC and PW is a serious public-health concern. A national program of salt iodization and iodine supplementation of PW should be urgently considered.

A Technical and Policy Case Study of Large-Scale Rescue and Redistribution of Perishable Foods by the "Leket Israel" Food Bank.

BACKGROUND: Food banks seeking to rescue and redistribute highly nutritious perishable foods to simultaneously alleviate food insecurity and reduce food waste often encounter practical, ethical, and political dilemmas. OBJECTIVES: We present a case study of "Leket Israel," an Israeli food bank that uses an effective large-scale logistical model for the rescue and redistribution of perishable food and discuss the challenges and solutions it offers. RESULTS: The organization operates in a rich country plagued with poverty and inequality, where the government passively encourages nongovernmental organizations to respond to the serious and growing problem of food insecurity. Operating under a business-to-business model, Leket Israel distributes food via intermediary nonprofit organizations (NPOs), enriching the food they provide with fresh produce. Food is obtained through an Agricultural Gleaning project, Self-Growing Farm project, and Meal Rescue project. The partnering NPOs then distribute the food to people in need. Although the rescue and redistribution of highly perishable food is more costly and complex than acquiring, storing, and distributing dried and staple foods and it requires specialized knowledge and infrastructure in order to maintain rigorous safety standards, it improves the nutritional quality of the aid. In 2015, Leket Israel distributed 15 217 389 kg of food, 90% of which was fruit and vegetables, to 180 partnering NPOs nationwide, reaching an estimated 175 000 recipients. CONCLUSION: "Leket Israel" offers a valuable model that can be studied and emulated by international nutrition scientists, practitioners, and policy makers who are seeking to reduce food insecurity and food waste in other countries.

Translational models for vascular cognitive impairment: a review including larger species.

BACKGROUND: Disease models are useful for prospective studies of pathology, identification of molecular and cellular mechanisms, pre-clinical testing of interventions, and validation of clinical biomarkers. Here, we review animal models relevant to vascular cognitive impairment (VCI). A synopsis of each model was initially presented by expert practitioners. Synopses were refined by the authors, and subsequently by the scientific committee of a recent conference (International Conference on Vascular Dementia 2015). Only peer-reviewed sources were cited. METHODS: We included models that mimic VCI-related brain lesions (white matter hypoperfusion injury, focal ischaemia, cerebral amyloid angiopathy) or reproduce VCI risk factors (old age, hypertension, hyperhomocysteinemia, high-salt/high-fat diet) or reproduce genetic causes of VCI (CADASIL-causing Notch3 mutations). CONCLUSIONS: We concluded that (1) translational models may reflect a VCI-relevant pathological process, while not fully replicating a human disease spectrum; (2) rodent models of VCI are limited by paucity of white matter; and (3) further translational models, and improved cognitive testing instruments, are required.

Can desalinated seawater contribute to iodine-deficiency disorders? An observation and hypothesis.

OBJECTIVE: Over 300 million people rely on desalinated seawater and the numbers are growing. Desalination removes iodine from water and could increase the risk of iodine-deficiency disorders (IDD). The present study assessed the relationship between iodine intake and thyroid function in an area reliant on desalination. DESIGN: A case-control study was performed between March 2012 and March 2014. Thyroid function was rigorously assessed by clinical examination, ultrasound and blood tests, including serum thyroglobulin (Tg) and autoimmune antibodies. Iodine intake and the contribution made by unfiltered tap water were estimated by FFQ. The contribution of drinking-water to iodine intake was modelled using three iodine concentrations: likely, worst-case and best-case scenario. SETTING: The setting for the study was a hospital located on the southern Israeli Mediterranean coast. SUBJECTS: Adult volunteers (n 102), 21-80 years old, prospectively recruited. RESULTS: After screening, seventy-four participants met the inclusion criteria. Thirty-seven were euthyroid controls. Among those with thyroid dysfunction, twenty-nine were classified with non-autoimmune thyroid disease (NATD) after excluding eight cases with autoimmunity. Seventy per cent of all participants had iodine intake below the Estimated Average Requirement (EAR) of 95 µg/d. Participants with NATD were significantly more likely to have probable IDD with intake below the EAR (OR=5·2; 95 % CI 1·8, 15·2) and abnormal serum Tg>40 ng/ml (OR=5·8; 95 % CI 1·6, 20·8). CONCLUSIONS: Evidence of prevalent probable IDD in a population reliant on desalinated seawater supports the urgent need to probe the impact of desalinated water on thyroid health in Israel and elsewhere.