Professor Margaret Rayman

This work presents the first systematic comparison of selenium (Se) speciation in plasma from cancer patients treated orally with three Se compounds (sodium selenite, SS; L-selenomethionine, SeMet; or Se-methylselenocysteine, MSC) at 400 µg/day for 28 days. The primary goal was to investigate how these chemical forms of Se affect the plasma Se distribution, aiming to identify the most effective Se compound for optimal selenoprotein expression. This was achieved using methodology based on HPLC-ICP-MS after sample preparation/fractionation approaches. Measurements of total Se in plasma samples collected before and after 4 weeks of treatment showed that median total Se levels increased significantly from 89.6 to 126.4 µg kg-1 Se (p 

© 2012 Springer Science+Business Media, LLC. All rights reserved. There is evidence that selenium affects a number of adverse pregnancy health conditions. While higher selenium status has been associated with a lower risk of miscarriage and preterm birth, the level of evidence is stronger for a benefit of higher selenium intake/status in preeclampsia and autoimmune thyroid disease characterized by raised thyroid peroxidase antibodies. The ability of selenium to reduce oxidative stress, endoplasmic reticulum stress, and inflammation, to protect the endothelium, to control eicosanoid production, to regulate vascular tone, and to reduce infection is likely to be important in the context of these conditions.

Use of selenium enriched foods, supplements and fertilizers has increased markedly in recent years in the US and other Western countries because of the perception that the anti-oxidant properties of selenium could potentially reduce the risk of cancer and other chronic diseases. However, concern has been raised recently about possible adverse cardiometabolic effects of high selenium exposure, including an increased risk of diabetes and hyperlipidemia with high selenium intake. Hence, from a public health perspective, the relationship between selenium status and cardiometabolic health should be clarified in order to help guide consumers in their choices of nutritional supplements and enriched food products. Additional experimental evidence is needed to provide new insights into the role of selenium and of specific selenoproteins in human biology, especially to clarify the underlying mechanisms linking selenium to chronic disease endpoints. Further epidemiological studies and randomized clinical trials across populations with different selenium status should be conducted to determine the causal effect of selenium on cardiovascular disease and risk factors. Nevertheless, at the present time the widespread use of selenium supplements or other strategies that artificially increase selenium status above the level required for optimal selenoprotein activity is not justified and should not be encouraged

Selenium is an essential trace element important for human health. A balanced intake is, however, crucial to maximize the health benefits of selenium. At physiological concentrations, selenium mediates antioxidant, anti‐inflammatory, and pro‐survival actions. However, supra‐nutritional selenium intake was associated with increased diabetes risk leading potentially to endothelial dysfunction, the initiating step in atherosclerosis. High selenium causes apoptosis in cancer cells via endoplasmic reticulum (ER) stress, a mechanism also implicated in endothelial dysfunction. Nonetheless, whether ER stress drives selenium‐induced endothelial dysfunction, remains unknown. Here, we investigated the effects of increasing concentrations of selenium on endothelial cells. High selenite reduced nitric oxide bioavailability and impaired angiogenesis. High selenite also induced ER stress, increased reactive oxygen species (ROS) production, and apoptosis. Pretreatment with the chemical chaperone, 4‐phenylbutyrate, prevented the toxic effects of selenium. Our findings support a model where high selenite leads to endothelial dysfunction through activation of ER stress and increased ROS production. These results highlight the importance of tailoring selenium supplementation to achieve maximal health benefits and suggest that prophylactic use of selenium supplements as antioxidants may entail risk

This work represents the first systematic speciation study of selenium (Se) in plasma from subjects participating in a pilot study for a cancer prevention trial (PRECISE). This involved supplementation of elderly British and Danish individuals with selenised yeast for 6 months and 5 years, respectively, at 100, 200, and 300 μg Se/day or placebo. Speciation data was obtained for male plasma using HPLC-ICP-MS and HPLC-ESI-MS/MS. With the proposed strategy, approximately 1.5 mL of plasma was needed to determine total Se concentration and the fractionation of Se in high molecular weight (HMW) and low molecular weight (LMW) pools, and for quantification and identification of small Se species. For the first time, Se-methyl-selenocysteine (MSC) and methyl-2-acetamido-2deoxy1-seleno-β-D-galactopyranoside (Selenosugar-1) were structurally confirmed in plasma after supplementation with selenised yeast within the studied range. Determination of selenomethionine (SeMet) incorporated non-specifically into albumin (SeALB) was achieved by HPLC-ICP-MS after hydrolysis. By subtracting this SeMet concentration from the total Se in the HMW pool, the concentration of Se incorporated into selenoproteins was calculated. Results from the speciation analysis of the free Se metabolite fraction (5% of total plasma Se) suggest a significant increase in the percentage of Se (as SeMet plus Selenosugar-1) of up to 80% of the total Se in the LMW fraction after 6 months of supplementation. The Se distribution in the HMW fraction reflects a significant increase in SeALB with Se depletion from selenoproteins, which occurs most significantly at doses of over 100 μg Se/day after 5 years. The results of this work will inform future trial design.

© 2015, Shiraz University of Medical Sciences.Background: Preeclampsia is a hypertensive disorder of pregnancy, which is associated with increased maternal and prenatal morbidity and mortality. Oxidative stress associated with preeclampsia may be a consequence of reduced antioxidant defense pathways that might involve inadequate glutathione peroxidase (GPx) levels, perhaps linked to reduced selenium availability. The soluble FMS-like tyrosine kinase-1 (sFlt-1) that contributes to endothelial dysfunction may be partially responsible for the clinical manifestation of preeclampsia. Furthermore, elevated plasminogen activator inhibitor-1 (PAI-1) and decreased plasminogen activator inhibitor-2 (PAI-2) are found in preeclamptic women. Hence, the PAI1: PAI2 ratio maybe a predictor of preeclampsia. Objectives: The objective of this study was to evaluate the efects of selenium supplementation on sFlt-1, GPx activity and PAI1: PAI2 ratio in pregnant women. Materials and Methods: A total of 125 high-risk pregnant women (with a familial history of hypertension, hyperlipidemia and other risk factors for preeclampsia) in the frst trimesters of pregnancy were assigned to either selenium (n = 61) or placebo (n = 64) groups. The selenium group received 100 μg/day of selenium as a selenium-yeast tablet for six months. The placebo group received a placebo yeast tablet for the same period. At the beginning of the trial and at the end, blood samples were collected and the levels of sFlt-1, PAI-1, PAI2 and GPx were measured in blood serum and plasma. Results: Serum selenium concentrations were raised in the selenium group (P < 0.001) from the frst to the third trimester, but was unchanged in the placebo group (P = 0.85). The results showed that sFlt-1 had signifcantly increased in both groups by the end of the gestation period, and selenium supplementation had no signifcant efect on the selenium group (P = 0.51). However, GPx activity was signifcantly increased in the selenium treatment group after supplementation compared to the control group (P < 0.001). The PAI1: PAI2 ratio was not signifcantly diferent between the two groups (P = 0.44). Conclusions: Selenium intake during the second and third trimester of pregnancy increased GPx activity but did not have a

We thank Plat and Mensink for their interest in our letter. They highlight that we focussed on the importance of ensuring nutritional adequacy in older people because of the immune impairments that occur with ageing, which are referred to as immunosenescence. These age-related changes are exaggerated by frailty, by insufficient intake of key micronutrients and, possibly, by gut dysbiosis, each of which occur in many older people. Immunosenescence can result in poorer responses to some vaccines in older people and to increased susceptibility to infection. The context of our letter was the possibility of poorer responses to “COVID-19 vaccines” in older people. Ageing is also associated with heightened low-grade inflammation, a state that is termed inflammaging. Of course, many factors other than ageing influence both the immune response and low-grade inflammation, and Plat and Mensink highlight one of those, obesity. People living with obesity can show immune impairments, have increased susceptibility to some infections, and have poorer outcomes following some vaccinations, perhaps including COVID-19 vaccines. Therefore, we fully agree with Plat and Mensink that a focus on weight management and on nutritional adequacy in those living with overweight and obesity is also important in the context of vaccination programmes.

Urinary iodine-to-creatinine ratio (UI/Creat) reflects recent iodine intake but has limitations for assessing habitual intake. Thyroglobulin (Tg) concentration, which increases with thyroid size, appears to be an indicator of longer-term iodine status in children and adults, however, less is known in pregnancy. This study investigated the determinants of serum-Tg in pregnancy and its use as an iodine-status biomarker in settings of iodine-sufficiency and mild-to-moderate deficiency. Stored blood samples and existing data from pregnant women from the Netherlands-based Generation R (iodine-sufficient) and the Spain-based INMA (mildly-to-moderately iodine-deficient) cohorts were used. Serum-Tg and iodine status (as spot-urine UI/Creat) were measured at median 13 gestational weeks. Using regression models, maternal socio-demographics, diet and iodine-supplement use were investigated as determinants of serum-Tg, as well as the association between UI/Creat and serum-Tg. Median serum-Tg was 11.1 ng/ml in Generation R (n = 3548) and 11.5 ng/ml in INMA (n = 1168). When using 150 µg/g threshold for iodine deficiency, serum-Tg was higher in women with UI/Creat 

Se is an unusual trace element in having its own codon in mRNA that specifies its insertion into selenoproteins as selenocysteine (SeCys), by means of a mechanism requiring a large SeCysinsertion complex. This exacting insertion machinery for selenoprotein production has implications for the Se requirements for cancer prevention. If Se may protect against cancer, an adequate intake of Se is desirable. However, the level of intake in Europe and some parts of the world is not adequate for full expression of protective selenoproteins. The evidence for Se as a cancer preventive agent includes that from geographic, animal, prospective and intervention studies. Newly-published prospective studies on oesophageal, gastric-cardia and lung cancer have reinforced previous evidence, which is particularly strong for prostate cancer. Interventions with Se have shown benefit in reducing the risk of cancer incidence and mortality in all cancers combined, and specifically in liver, prostate, colo-rectal and lung cancers. The effect seems to be strongest in those individuals with the lowest Se status. As the level of Se that appears to be required for optimal effect is higher than that previously understood to be required to maximise the activity of selenoenzymes, the question has been raised as to whether selenoproteins are involved in the anti-cancer process. However, recent evidence showing an association between Se, reduction of DNA damage and oxidative stress together with data showing an effect of selenoprotein genotype on cancer risk implies that selenoproteins are indeed implicated. The likelihood of simultaneous and consecutive effects at different cancer stages still allows an important role for anti-cancer Se metabolites such as methyl selenol formed from g-glutamyl-selenomethyl-SeCys and selenomethyl-SeCys, components identified in certain plants and Se-enriched yeast that have anti-cancer effects. There is some evidence that Se may affect not only cancer risk but also progression and metastasis. Current primary and secondary prevention trials of Se are underway in the USA, including the Selenium and Vitamin E Cancer Prevention Trial (SELECT) relating to prostate cancer, although a large European trial is still desirable given the likelihood of a stronger effect in populations of lower Se status.

Hashimoto’s Thyroiditis (HT) and Graves’ Disease (GD) are examples of autoimmune thyroid disease (AITD), the commonest autoimmune condition. Antibodies to thyroid peroxidase (TPO), the enzyme that catalyses thyroid-hormone production, and antibodies to the receptor for the thyroid-stimulating hormone (TSHR), are characteristic of HT and GD, respectively. It is currently accepted that genetic susceptibility, environmental factors, including nutritional factors, and immune disorders contribute to the development of AITD. Aiming to investigate the effect of iodine, iron and selenium in the risk, pathogenesis and treatment of thyroid disease, PubMed and the Cochrane Library were searched for relevant publications to provide a narrative review. Iodine: Chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly-iodinated thyroglobulin is more immunogenic. Recent introduction of universal salt iodisation can have a similar, though transient, effect. Iron: Iron deficiency impairs thyroid metabolism. TPO is a haem enzyme that becomes active only after binding haem. AITD patients are frequently iron-deficient since autoimmune gastritis, which reduces iron absorption, and coeliac disease which causes iron loss, are frequent co-morbidities. In two-thirds of women with persistent symptoms of hypothyroidism despite appropriate levothyroxine therapy, restoration of serum ferritin above 100 µg/L ameliorated symptoms. Selenium: Selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases remove excessive hydrogen peroxide produced there for the iodination of thyroglobulin to form thyroid hormones. There is evidence from observational studies and randomised controlled trials that selenium, probably as selenoproteins, can reduce TPO-antibody concentration, hypothyroidism and postpartum thyroiditis. Appropriate status of iodine, iron and selenium is crucial to thyroid health.

Background: Severe iodine deficiency during pregnancy can cause intellectual disability, presumably through inadequate placental transfer of maternal thyroid hormone to the fetus. The association between mild-to-moderate iodine deficiency and child neurodevelopmental problems is not well understood. Objective: We investigated the association of maternal iodine status during pregnancy with child attention-deficit hyperactivity disorder (ADHD) and autistic traits. Methods: Collaborative study of three population-based birth cohorts: Generation R (N=1634), INMA (N=1293), and ALSPAC (N=2619). Exclusion criteria were multiple fetuses, fertility treatment, thyroid-interfering medication use, and pre-existing thyroid disease. The mean age of assessment in the cohorts was between 4.4 – 7.7 years for ADHD symptoms and 4.5 – 7.6 years for autistic traits. We studied the association of the urinary iodine-to-creatinine ratio (UI/Creat) < 150 μg/g – in all mother-child pairs, and in those with a urinary-iodine measurement at ≤ 18 weeks and ≤ 14 weeks of gestation – with the risk of ADHD or a high autistic-trait score (≥ 93rd percentile cut-off), using logistic regression. The cohort-specific effect estimates were combined by random effects meta-analyses. We also investigated whether UI/Creat modified the association of maternal free thyroxine (FT4) or thyroid stimulating hormone (TSH) concentrations with ADHD or autistic traits. Results: UI/Creat

OBJECTIVE: Iodine deficiency has recently been found in UK young and pregnant women, which is of concern given the importance of adequate iodine intake in pregnancy for fetal brain development. The WHO recommends that iodine deficiency in a population should be corrected through salt iodisation but there is a lack of UK data on iodised-salt availability, a situation that the present study aimed to address. DESIGN: Availability of iodised salt for household use was determined by a shelf survey in five supermarket chains in each of sixteen UK areas (in Southern England, Wales and Northern Ireland) encompassing a total of seventy-seven supermarkets. All branches of a sixth supermarket chain that had 2·3 % of the market share sold exclusively iodised salt. Weighted iodised-salt availability was calculated taking the market share of supermarkets into account. SETTING: The UK. SUBJECTS: Not applicable. RESULTS: Iodised salt was available in thirty-two of the seventy-seven supermarkets (41·6 %). After accounting for market share and including all six UK supermarket chains, the weighted availability of iodised salt was 21·5 %. The iodine concentration of the major UK brand of iodised salt is low, at 11·5 mg/kg. CONCLUSIONS: In contrast to other countries, iodised household table salt is unlikely to contribute meaningful amounts to UK iodine intake as (i) availability is low, (ii) table salt is only a small percentage of total UK salt intake and (iii) UK public-health campaigns have encouraged reduced salt consumption. As iodine intake in the UK is dependent entirely on food choices, regular monitoring of iodine status is essential.

The human genome contains 25 genes coding for selenocysteine-containing proteins (selenoproteins). These proteins are involved in a variety of functions, most notably redox homeostasis. Selenoprotein enzymes with known functions are designated according to these functions: TXNRD1, TXNRD2, and TXNRD3 (thioredoxin reductases), GPX1, GPX2, GPX3, GPX4 and GPX6 (glutathione peroxidases), DIO1, DIO2, and DIO3 (iodothyronine deiodinases), MSRB1 (methionine-R-sulfoxide reductase 1) and SEPHS2 (selenophosphate synthetase 2). Selenoproteins without known functions have traditionally been denoted by SEL or SEP symbols. However, these symbols are sometimes ambiguous and conflict with the approved nomenclature for several other genes. Therefore, there is a need to implement a rational and coherent nomenclature system for selenoprotein-encoding genes. Our solution is to use the root symbol SELENO followed by a letter. This nomenclature applies to SELENOF (selenoprotein F, the 15 kDa selenoprotein, SEP15), SELENOH (selenoprotein H, SELH, C11orf31), SELENOI (selenoprotein I, SELI, EPT1), SELENOK (selenoprotein K, SELK), SELENOM (selenoprotein M, SELM), SELENON (selenoprotein N, SEPN1, SELN), SELENOO (selenoprotein O, SELO), SELENOP (selenoprotein P, SeP, SEPP1, SELP), SELENOS (selenoprotein S, SELS, SEPS1, VIMP), SELENOT (selenoprotein T, SELT), SELENOV (selenoprotein V, SELV) and SELENOW (selenoprotein W, SELW, SEPW1). This system, approved by the HUGO Gene Nomenclature Committee, also resolves conflicting, missing and ambiguous designations for selenoprotein genes and is applicable to selenoproteins across vertebrates.

In December, 2016, the Iodine Global Network (IGN) published its new map of global iodine nutrition based on median urinary iodine concentration (mUIC) in school-aged children.1 Notably, the status of the UK, which was classified as mildly iodine deficient in 2014–15 (mUIC 50–99 μg/L), had become adequate by 2016 (mUIC 100–299 μg/L).1 The reason for this apparently rapid improvement lies in the different data sources used; data that showed mild deficiency in 2014–15 came from spot-urine samples from 737 girls aged 14–15 years from nine UK centres (mUIC 80·1 μg/L),2 whereas the 2016 data were based on spot-urine samples from 458 boys and girls aged 4–18 years, which were collected in year 6 of the UK National Diet and Nutrition Survey (NDNS).

Iodine deficiency disorders (IDD) represent a global health threat to individuals and societies. IDD prevention programmes have been introduced in many parts of the world. However, challenges remain, particularly in Europe due to fragmentation and diversity of approaches that are not harmonized. Objectives: This review is dedicated to the public-health impact of IDD prevention programmes. It sums up experiences collected by the EUthyroid consortium so far and provides information on stakeholders that should be involved in actions directed to improve the impact of IDD prevention. Methods: A joint European database for combining registry-based outcome and monitoring data as well as tools for harmonizing study methods were established. Methods for analyzing thyroglobulin from a dried blood spot are available for assessing the iodine status in the general population and at-risk groups. Mother-child cohorts are used for in-depth analysis of the potential impact of mild-to-moderate iodine deficiency on the neurocognitive development of the offspring. A decision-analytic model has been developed to evaluate the long-term effectiveness and cost effectiveness of IDD prevention programmes. Results: EUthyroid has produced tools and infrastructure to improve the quality of IDD monitoring and follows a dissemination strategy targeting policymakers and the general public. There are tight connections to major stakeholders in the field of IDD monitoring and prevention. Conclusions: EUthyroid has taken steps towards achieving a euthyroid Europe. Our challenge is to inspire a greater sense of urgency in both policymakers and the wider public to address this remediable deficit caused by IDD.

Iodine and selenium are linked through their effects on thyroid function. Both also have anti-viral properties relevant to SARS-CoV-2 infection. In the form of povidone-iodine solution, iodine is a virucidal agent that has been shown in vitro to kill the coronaviruses SARS-CoV and MERS-CoV implicated in previous coronavirus epidemics. Viral loads of SARS-CoV-2 are high in the nasal cavity, nasopharynx, and oropharynx. Under in-vitro conditions mimicking nasopharyngeal secretions, povidone-iodine solution significantly inactivated SARS-CoV-2

Background: Mild-to-moderate iodine deficiency, particularly in pregnancy, is prevalent; this is of concern as observational studies have shown negative associations with child neurodevelopment. Though neither the benefits nor the safety of iodine supplementation in pregnancy in areas of mild-to-moderate deficiency are well researched, such supplementation is increasingly being recommended by health authorities in a number of countries. Objective: By reviewing the most recent published data on the effects of iodine supplementation in mildly-to-moderately deficient pregnant women on maternal and infant thyroid function and child cognition, we aimed to determine whether the evidence was sufficient to support such recommendations in these areas. Design: A systematic review of randomised controlled trials (RCTs), non-RCT interventions and observational studies was conducted. To identify relevant papers we searched the PubMed and Embase databases. We defined mild-to-moderate iodine deficiency as a baseline, median, urinary iodine-concentration (UIC) of 50-149 µg/L. Eligible studies were included in meta-analyses. Results: In total, 37 publications were included – ten RCTs, four non-RCT interventions and 23 observational studies. Most studies showed no effect of iodine supplementation on maternal or infant thyroid-stimulating hormone and free-thyroxine. Most RCTs found that supplementation reduced maternal thyroglobulin and in three RCTs, it prevented or diminished the increase in maternal thyroid volume during pregnancy. Three RCTs addressed child neurodevelopment; only one was adequately-powered. Meta-analyses of two RCTs showed no effect on child cognitive [mean difference (MD) (95%CI): -0.18 (-1.22, 0.87)], language [MD (95%CI): 1.28 (-0.28, 2.83)] or motor scores [MD (95%CI): 0.28 (-1.10, 1.66)]. 4 Conclusions: There is insufficient good-quality evidence to support current recommendations for iodine supplementation in pregnancy in areas of mild-to-moderate deficiency. Well designed RCTs with child cognitive outcomes are needed in areas of moderate deficiency (median UIC

Purpose. Previous studies on nutrient intake and status in chronic fatigue syndrome (CFS) were reviewed. Against this background, we investigated whether low mineral and B vitamin status in CFS patients was adequately explained by poor nutritional intake. Subsidiary aims were to explore the demographic, dietary, socio-economic, psychological and general health profiles of CFS patients attending our clinics. Design. A cross-sectional study of 51 CFS patients with biomarker values below the laboratory reference range for minerals and B vitamins. Materials and methods. Dietary and supplemented nutritional intakes were assessed for comparison with laboratory biomarkers in a hospital outpatient clinic. Results. Intakes below the UK reference nutrient intake, particularly of Ca and/or vitamin D, I and Se, were common among these patients. There was little correlation between intakes and biomarkers. Conclusions. Abnormal biomarkers may reflect underlying pathological processes rather than inadequate nutritional intakes and, taken alone, are a poor guide to rational nutritional supplementation. Nevertheless, there appears to be a case for dietary assessment and modest, targeted, vitamin and mineral supplementation in many of these patients. © 2005 Taylor & Francis.

The essential trace mineral, selenium, is of fundamental importance to human health. As a constituent of selenoproteins, selenium has structural and enzymic roles, in the latter context being best-known as an antioxidant and catalyst for the production of active thyroid hormone. Selenium is needed for the proper functioning of the immune system, and appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking selenium to cardiovascular disease risk although other conditions involving oxidative stress and inflammation have shown benefits of a higher selenium status. An elevated selenium intake may be associated with reduced cancer risk. Large clinical trials are now planned to confirm or refute this hypothesis. In the context of these health effects, low or diminishing selenium status in some parts of the world, notably in some European countries, is giving cause for concern.

Purpose As a component of thyroid hormones, adequate iodine intake is essential during pregnancy for fetal neurodevelopment. Across Europe, iodine deficiency is common in pregnancy, but data are lacking on the predictors of iodine status at this life stage. We, therefore, aimed to explore determinants of iodine status during pregnancy in three European populations of differing iodine status. Methods Data were from 6566 pregnant women from three prospective population-based birth cohorts from the United Kingdom (ALSPAC, n = 2852), Spain (INMA, n = 1460), and The Netherlands (Generation R, n = 2254). Urinary iodine-to-creatinine ratio (UI/Creat, µg/g) was measured in spot-urine samples in pregnancy (≤ 18-weeks gestation). Maternal dietary intake, categorised by food groups (g/day), was estimated from food-frequency questionnaires (FFQs). Multivariable regression models used dietary variables (energy-adjusted) and maternal characteristics as predictors of iodine status. Results Median UI/Creat in pregnant women of ALSPAC, INMA, and Generation R was 121, 151, and 210 µg/g, respectively. Maternal age was positively associated with UI/Creat in all cohorts (P ˂ 0.001), while UI/Creat varied by ethnicity only in Generation R (P ˂ 0.05). Of the dietary predictors, intake of milk and dairy products (per 100 g/day) was positively associated with UI/Creat in all cohorts [ALSPAC (B = 3.73, P ˂ 0.0001); INMA (B = 6.92, P = 0.002); Generation R (B = 2.34, P = 0.001)]. Cohort-specific dietary determinants positively associated with UI/Creat included fish and shellfish in ALSPAC and INMA, and eggs and cereal/cereal products in Generation R. Conclusions The cohort-specific dietary determinants probably reflect not only dietary habits but iodine-fortification policies; hence, public-health interventions to improve iodine intake in pregnancy need to be country-specific.

Seafood intake in pregnancy has been positively associated with childhood cognitive outcomes which could potentially relate to the high vitamin-D content of oily fish. However, whether higher maternal vitamin D status [serum 25-hydroxy-vitamin D, 25(OH)D] in pregnancy is associated with a reduced risk of offspring suboptimal neurodevelopmental outcomes is unclear. A total of 7065 mother-child pairs were studied from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort who had data for both serum total 25(OH)D concentration in pregnancy and at least one measure of offspring neurodevelopment (pre-school development at 6–42 months; “Strengths and Difficulties Questionnaire” scores at 7 years; IQ at 8 years; reading ability at 9 years). After adjustment for confounders, children of vitamin-D deficient mothers (< 50.0 nmol/L) were more likely to have scores in the lowest quartile for gross motor development at 30 months (OR 1.20 95% CI 1.03, 1.40), fine motor development at 30 months (OR 1.23 95% CI 1.05, 1.44), and social development at 42 months (OR 1.20 95% CI 1.01, 1.41) than vitamin-D sufficient mothers (≥ 50.0 nmol/L). No associations were found with neurodevelopmental outcomes, including IQ, measured at older ages. However, our results suggest that deficient maternal vitamin D status in pregnancy may have adverse effects on some measures of motor and social development in children under 4 years. Prevention of vitamin D deficiency may be important for preventing suboptimal development in the first 4 years of life.

Low maternal free thyroxine (FT4) has been associated with poor child neurodevelopment in some single-centre studies. Evidence remains scarce for potential adverse effects of high FT4 and whether associations differ in countries with a different iodine status. To assess the association of maternal thyroid function in early pregnancy with child neurodevelopment in countries with a different iodine status. Design, Setting and Participants:Meta-analysis of individual-participant data compromising 9,036 mother-child pairs from three prospective population-based birth cohorts: INMA (Spain), Generation R (The Netherlands) and ALSPAC (United Kingdom). Exclusion criteria were multiple pregnancies, fertility treatments, thyroid interfering medication usage, and known thyroid disease. Main outcomes:Child non-verbal IQ at 5-8 years of age, verbal IQ at 1.5-8 years of age, and autistic traits within the clinical range at 5-8 years of age. Results: FT4 97.5th percentile was associated with a 1.9 (1.0 to 3.4) fold higher risk of autistic traits. No independent associations were found with thyrotropin.Low maternal FT4 was consistently associated with lower IQ across cohorts. Further studies should replicate the findings of autistic traits and investigate the potential modifying role of maternal iodine status. FT4 seems a reliable marker of fetal thyroid state in early pregnancy, regardless of the type of immunoassay

The current study reports on first-trimester reference ranges of plasma mineral Se/Zn/Cu concentration in relation to free thyroxine (FT4), thyrotropin (TSH) and thyroid peroxidase antibodies (TPO-Ab), assessed at 12 weeks’ gestation in 2041 pregnant women, including 544 women not taking supplements containing Se/Zn/Cu. The reference range (2.5th – 97.5th percentiles) in these 544 women was 0.72 – 1.25 μmol/L for Se, 17.15 – 35.98 μmol/L for Cu, and 9.57 – 16.41 μmol/L for Zn. These women had significantly lower mean plasma Se concentration (0.94 μmol/L, SD 0.12) than those (N = 1479) taking Se/Zn/Cu supplements (1.03 μmol/L, SD, 0.14; P < 0.001) while the mean Cu (26.25 μmol/L) and Zn (12.55 μmol/L) concentrations were almost identical in these sub-groups. Women with hypothyroxinemia (FT4 below reference range with normal TSH) had significantly lower plasma Zn concentrations than euthyroid women. After adjusting for co-variates including supplement intake, plasma Se (negatively), Zn and Cu (positively) concentrations were significantly related to logFT4; Se and Cu (but not Zn) were positively and significantly related to logTSH. Women taking additional Se/Zn/Cu supplements were 1.46 (95% CI: 1.09 – 2.04) times less likely to have elevated titres of TPO-Ab at 12 weeks of gestation. We conclude that first-trimester Se reference ranges are influenced by Se-supplement intake while Cu and Zn ranges are not. Plasma mineral Se/Zn/Cu concentration are associated with thyroid FT4 and TSH concentrations. Se/Zn/Cu supplement intake affects TPO-Ab status. Future research should focus on the impact of trace-mineral status during gestation on thyroid function.

Senescent cells (SCs) are associated with the onset and development of multiple chronic diseases. Selective clearance of SCs by senolytic drugs is a potential therapeutic option for a number of age-related diseases. Among senolytic candidates, only dasatinib with quercetin and fisetin meet the rigorous criteria for senolytic drugs, according to a modified version of Koch’s postulates. It is astonishing that two of the three agents, i.e., quercetin and fisetin, are flavonoids, although the mechanism by which they preferentially eliminate SCs is unclear. Herein, we propose a possible selective mechanism; prooxidant activities of quercetin or fisetin are inevitably involved in killing apoptosis-resistant SCs. Among the dietary flavonoids, quercetin is a potent redox-active flavonoid with strong prooxidant activities, and transition metals, such as copper and iron, hugely amplify its prooxidant activities. Fisetin, which has higher senolytic activities than quercetin, has higher prooxidant effects than quercetin in the absence or presence of copper. It appears that the prooxidant activity of flavonoids is an important consideration for screening senolytics. SCs accumulate high levels of copper and iron, and the selective mechanism of quercetin or fisetin is probably associated with copper/iron-promoted oxidative damage in SCs. Copper and iron dramatically enhanced the prooxidant effects of the flavonoid, epigallocatechin-3-gallate, having shown a depletion effect on SCs in rats and high therapeutic efficacy in patients with idiopathic pulmonary fibrosis, largely caused by SCs. Further investigation to evaluate whether epigallocatechin-3-gallate is a senolytic drug, according to Koch’s postulates, is warranted.

Iodine, as a component of the thyroid hormones, is crucial for brain development and is therefore especially important during pregnancy when the brain is developing most rapidly. While randomised controlled trials of pregnant women in regions of severe iodine deficiency have shown that prenatal iodine deficiency causes impaired cognition, less is known of the effects in regions of mild deficiency. This is relevant to the UK as the World Health Organisation now classifies the UK as mildly iodine deficient, based on a national study of 14-15 year old schoolgirls in 2011. We have previously published a study using samples and data from the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC) that found an association between low iodine status in early pregnancy (urinary iodine-to-creatinine ratio

Loss of pulmonary dimethydiselenide via exhalation may help explain a significantly higher death rate from COVID-19 in states with low environmental (atmospheric) Se concentrations. [Display omitted] •US residents only showed a relatively small difference in plasma/serum Se.•Se concentration in alfalfa leaves in US states modelled environmental Se exposure.•States with low alfalfa Se had a higher death rate from COVID-19 than other states.•Atmospheric dimethyldiselenide may reflect Se concentration in alfalfa leaves.•Lung exposure to dimethyldiselenide which activates Nrf2 may explain our results. Environmental selenium (Se) distribution in the US is uneven, yet US residents appear to have a relatively narrow range of serum Se concentrations, according to the NHANES III survey data; this is probably due to the modern food-distribution system. In the US, Se concentration in alfalfa leaves has been used as a proxy for regional Se exposure (low, medium or high, corresponding to ≤ 0.05, 0.06–0.10 and ≥ 0.11 ppm respectively). Se in plants, soil, water, and bacteria can be transformed into volatile dimethyldiselenide, which can be inhaled and excreted via the lung. Hence, pulmonary Se exposure may be different in states with different atmospheric Se levels. We found a significantly higher death rate from COVID-19 in low-Se states than in medium-Se or high-Se states, though the case densities of these states were not significantly different. Because inhaled dimethyldiselenide is a potent inducer of nuclear-factor erythroid 2 p45-related factor 2 (Nrf2), exposure to higher atmospheric dimethyldiselenide may increase Nrf2-dependent antioxidant defences, reducing the activation of NFκB by SARS-CoV-2 in the lung, thereby decreasing cytokine activation and COVID-19 severity. Atmospheric dimethyldiselenide may thereby play a role in COVID-19 mortality, although the extent of its involvement is unclear.

We live in a world with an ever-increasing ageing population. Studying healthy ageing and reducing the socioeconomic impact of age-related diseases is a key research priority for the industrialised and developing countries, along with a better mechanistic understanding of the physiology and pathophysiology of ageing that occurs in a number of age-related musculoskeletal disorders. Arthritis and musculoskeletal disorders constitute a major cause of disability and morbidity globally and result in enormous costs for our health and social-care systems. By gaining a better understanding of healthy musculoskeletal ageing and the risk factors associated with premature ageing and senescence, we can provide better care and develop new and better-targeted therapies for common musculoskeletal disorders. This review is the outcome of a two-day multidisciplinary, international workshop sponsored by the Institute of Advanced Studies entitled “Musculoskeletal Health in the 21st Century” and held at the University of Surrey from 30th June-1st July 2015. The aim of this narrative review is to summarise current knowledge of musculoskeletal health, ageing and disease and highlight strategies for prevention and reducing the impact of common musculoskeletal diseases.

Knowledge of the plasma selenium levels associated with optimised concentration or activity of specific selenoproteins can provide considerable insights from epidemiological data on the possible involvement of those selenoproteins in health, most notably with respect to cancer. For cohort studies, if selenoproteins such as glutathione peroxidase and selenoprotein P are relevant to cancer, one might only expect to see an effect on risk when the concentrations in the cohort range from below, to above, the level needed to optimise the activity or concentration of these enzymes. Similarly, trials would only show a beneficial effect of supplementation if selenium status were raised from below, to above, the optimal concentration for the selenoproteins likely to be implicated in cancer risk, as occurred in the NPC trial but not in SELECT. The most powerful evidence for the involvement of selenoproteins in human health comes from epidemiological studies that have related single nucleotide polymorphisms in selenoproteins to disease risk. The totality of the evidence currently implicates GPx1, GPx4, SEPS1, Sep15, SEPP1 and TXNRD1 in conditions such as cardiovascular disease, pre-eclampsia and cancer. Future studies therefore need to determine not only selenium status, but genotype, both in selenoproteins and related pathways, when investigating the relationship of selenium with disease risk.

The potential of some selenoproteins to protect against oxidative stress led to the expectation that selenium would be protective against type2 diabetes, and indeed in early in vivo and in vitro studies, selenium (as selenate) was shown to have antidiabetic and insulin-mimetic effects. However, more recently, findings from observational cross-sectional studies have raised concern that high selenium exposure may be associated with type2 diabetes or insulin resistance, at least in well-nourished populations, though trial results have been inconsistent. Moreover, the largest trials that investigated the effects of selenium supplementation on diabetes endpoints have had cancer prevention as their primary outcome, casting doubt on the interpretation of posthoc analyses. Factors affecting serum/plasma selenium are not just location and level of disease-associated inflammation but the fact that higher concentrations of plasma selenoprotein P yet lower glutathione peroxidase are found in type2 diabetes compared to normal subjects. From a public health perspective, selenium is marketed as a dietary supplement and is commonly added to multivitamin/mineral preparations that are consumed in many Western countries. Based on current evidence, however, the indiscriminate use of selenium supplements in individuals and populations with adequate-to-high selenium status cannot be justified and may increase risk. In conclusion, although there is a clear link between certain selenoproteins and glucose metabolism or insulin resistance, the relationship between selenium and type2 diabetes is undoubtedly complex. It is possible that the relationship is U-shaped, with possible harm occurring both below and above the physiological range for optimal activity of some or all selenoproteins.

The most accurate results were observed in the study varying physical-activity level, where our model predicted weight-loss to 100% accuracy in both the caloric-restriction and the caloric-restriction-plus exercise groups. A high degree of accuracy was also observed in the study varying degree of caloric restriction, with predicted weight-loss deviating only by 1 and 2 kg from observed weight-loss in the low-calorie-diet and very-low-calorie-diet groups, respectively. 1 Low-fat high-carbohydrate 2 High-fat low-carbohydrate 3 Caloric restriction 4 Energy expended by exercise 5 Low-calorie diet 6 Very low-calorie diet Our model provides further evidence challenging the 3500 kcal rule by illustrating the physiological influence of adaptive thermogenesis, diet-induced thermogenesis and body-composition on weight-loss.

The essential trace element, selenium (Se), is crucial to the brain but it may be potentially neurotoxic, depending on dosage and speciation; Se has been discussed for decades in relation to Alzheimer's disease (AD). Selenoprotein P (SELENOP) is a secreted heparin-binding glycoprotein which serves as the main Se transport protein in mammals. In vivo studies showed that this protein might have additional functions such as a contribution to redox regulation. The current review focuses on recent research on the possible role of SELENOP in AD pathology, based on model and human studies. The review also briefly summarizes results of epidemiological studies on Se supplementation in relation to brain diseases, including PREADViSE, EVA, and AIBL. Although mainly positive effects of Se are assessed in this review, possible detrimental effects of Se supplementation or exposure, including potential neurotoxicity, are also mentioned. In relation to AD, various roles of SELENOP are discussed, i.e. as the means of Se delivery to neurons, as an antioxidant, in cytoskeleton assembly, in interaction with redox-active metals (copper, iron, and mercury) and with misfolded proteins (amyloid-beta and hyperphosphorylated tau-protein).

We have been asked to comment on differences in trace element concentrations between organic and conventional milk found in the recent meta-analysis by Średnicka-Tober and colleagues(1). Such a comment is important because in fact the most significant difference revealed between organic and conventional milk, in terms of contribution to nutrient requirements, is that of iodine. In many countries, and particularly in the UK where iodised salt is rarely used(2), milk is the single biggest contributor to iodine intake(3). By contrast, milk is a relatively inconsequential source of fatty acids, particularly of those desirable long-chain n-3 PUFAs. This calls into question the emphasis placed on the n-3 PUFAs both in the paper and the press release. We will concentrate our comment on the difference in iodine, selenium and iron concentration. We will use the standard meta-analysis data presented by the authors as these are weighted according to the size of the studies (unweighted meta-analyses are generally not considered appropriate) and were the only analyses to find significant differences in mineral concentrations between organic and conventional milk samples. For the same reason, we will use the weighted mean percentage differences derived from the standard meta-analyses.

Iodine is required throughout pregnancy for thyroid hormone production, which is essential for fetal brain development. Studies of iodine status in pregnant women from the United Kingdom (UK) have focused on early gestation (

Including coverage of disease incidence and prevalence, pathology, aetiology and measures of disease assessment and dietary risk factors, Nutrition and ...

Iodine is essential for thyroid hormone production. Milk and dairy products are important sources of iodine in many countries. We aimed to review systematically the variation in milk‑iodine concentration between countries, seasons and farming practice. We searched online food composition tables and published literature for data since 2006. Milk‑iodine concentration was available for 34 countries (from 66 sources) and ranged from 5.5 to 49.9 μg/100 g (median 17.3 μg/100 g). Meta-analyses identified that iodine concentration is significantly higher in: (i) winter than summer milk (mean difference 5.97 μg/100 g; p = 0.001), and (ii) in conventional than in organic milk (mean difference 6.00 μg/100 g; p 

Selenium (Se) is an unusual trace element in having its own codon in mRNA that specifies its insertion into selenoproteins as selenocysteine (Sec), by means of a mechanism requiring a large Sec-insertion complex. This exacting insertion machinery for selenoprotein production has implications for our Se requirements for cancer prevention. If Se may protect against cancer, an adequate intake of Se is desirable. However, the level of intake in Europe and some parts of the world is not adequate for full expression of protective selenoproteins. The evidence for Se as a cancer preventive agent includes that from geographic, animal, prospective and intervention studies. Newly-published prospective studies on oesophageal, gastric-cardia and lung cancer have reinforced previous evidence which is particularly strong for prostate cancer. Interventions with Se have shown benefit in reducing the risk of cancer incidence and mortality in all cancers combined, and specifically in liver, prostate, colorectal and lung cancers. The effect seemed to be strongest in those with the lowest Se status. As the level of Se that appears to be required for optimal effect is higher than that previously understood to be required to maximise the activity of selenoenzymes, the question has been raised as to whether selenoproteins are involved in the anti-cancer process. However, recent evidence showing an association between Se, reduction of DNA damage and oxidative stress together with data showing an effect of selenoprotein genotype on cancer risk implies that selenoproteins are indeed implicated. The likelihood of simultaneous and consecutive effects at different cancer stages still allows an important role for anti-cancer Se metabolites such as methyl selenol formed from γ-glutamyl-selenomethyl-selenocysteine and selenomethylselenocysteine, components identified in certain plants and Se-yeast that have anti-cancer effects. There is some evidence that Se may affect not only cancer risk but also progression and metastasis. Current primary and secondary prevention trials of Se are underway in the USA including the SELECT prostate cancer trial, though a large European trial is still desirable given the likelihood of a stronger effect in populations of lower Se status.

Selenium-enriched yeast (Se-yeast) is a common form of selenium used to supplement dietary intake of this important trace mineral. However, its availability within the EU is under threat owing to concerns expressed by the EC Scientific Committee on Food that Se-yeast supplements are poorly characterised and could potentially cause the build up of selenium in tissues to toxic levels. This review examines the validity of these concerns. Diagrams of the biosynthesis and metabolism of selenium compounds show which species can be expected to occur in Se-yeast preparations. Seyeast manufacture is described together with quality control measures applied by reputable manufacturers. The way in which speciation of Se-yeast is achieved is explained and results on amounts of selenium species in various commercial products are tabulated. In all cases described, selenomethionine is the largest single species, accounting for 54-74% of total selenium. Se-yeast is capable of increasing the activity of the selenoenzymes and its bioavailability has been found to be higher than that of inorganic selenium sources in all but one study. Intervention studies with Seyeast have shown the benefit of this form in cancer prevention, immune response and HIV infection. Of around one dozen supplementation studies, none has shown evidence of toxicity even up to an intake level of 800 μg/d selenium over a period of years. It is concluded that Se-yeast from reputable manufacturers is adequately characterised, of reproducible quality, and that there is no evidence of toxicity even at levels far above the EC Tolerable Upper Intake Level of 300 μg/d.

Breastfeeding mothers often report perceived insufficient milk (PIM) believing their infant is crying too much, which leads to introducing formula and the early abandonment of breastfeeding. We sought to determine if infant crying was associated with reported PIM (yes/no) and number of problems associated with lactation (lactation problem score [LPS] 6‐point Likert scale) before formula introduction. Primiparous breastfeeding mothers were recruited at birth and visited at 1, 2 and 4 weeks. Among those fully breastfeeding at 1 week (N = 230), infant crying variables based on maternal reports were not associated with PIM at 1 week, but LPS was. However, a mother's expectation that her infant would cry more than other infants was associated with increased odds of reporting PIM at 2 and 4 weeks, as were delayed onset of lactation and previous LPS. At 1 week, crying variables (frequency, difficulty in soothing) were associated with LPS along with percent weight change. Delayed onset of lactation, infant care style, number of breastfeeds and previous LPS were longitudinally associated with change in LPS from 1 to 2 weeks and 2 to 4 weeks. Our data suggest that reported infant crying is associated with PIM and LPS in the first 4 weeks of life. Guidance on what to expect in crying behaviour and the impact of infant care style may be beneficial in reducing PIM and LPS in the first month.

Context While the consequences of severe iodine deficiency are beyond doubt, the effects of mild-to-moderate iodine deficiency in pregnancy on child neurodevelopment are less well established. Objective To study the association between maternal iodine status during pregnancy and child IQ and to identify vulnerable time-windows of exposure to suboptimal iodine availability. Design Meta-analysis of individual-participant data from three prospective population-based birth cohorts: Generation R (The Netherlands), INMA (Spain), and ALSPAC (United Kingdom); pregnant women were enrolled between 2002-2006, 2003-2008, and 1990-1992, respectively. Setting General community. Participants 6180 mother-child pairs with measures of urinary iodine and creatinine concentrations in pregnancy and child IQ. Exclusion criteria were multiple pregnancy, fertility treatment, medication affecting the thyroid, and pre-existing thyroid disease. Intervention(s) None. Main Outcome Measure Child non-verbal and verbal IQ assessed at 1.5-8 years of age. Results There was a positive curvilinear association of the urinary iodine-to-creatinine ratio (UI/Creat) with mean verbal IQ only. UI/Creat ˂ 150 µg/g was not associated with lower non-verbal IQ [-0.6 points, 95% CI -1.7 to 0.4, P=0.246] or lower verbal IQ [-0.6, 95% CI -1.3 to 0.1, P=0.082]. Stratified analyses showed that the association of UI/Creat with verbal IQ was only present up to 14 weeks of gestation. Conclusions Fetal brain development is vulnerable to mild-to-moderate iodine deficiency, particularly in the first trimester. Our results show that any potential randomized, controlled trial investigating the effect of iodine supplementation in mild-to-moderate iodine deficient women on child neurodevelopment, should start with supplementation not later than the first trimester.

Evidence that selenium affects the risk of type-2 diabetes is conflicting, with observational studies and a few randomized trials showing both lower and higher risk linked to the level of selenium intake and status. We investigated the effect of selenium supplementation on the risk of type-2 diabetes in a population of relatively low selenium status as part of the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study. Plasma adiponectin concentration, a recognised independent predictor of type-2 diabetes risk and known to be correlated with circulating selenoprotein P, was the biomarker chosen.

Higher selenium status has been shown to improve the clinical outcome of infections caused by a range of evolutionally diverse viruses, including SARS-CoV-2. However, the impact of SARS-CoV-2 on host-cell selenoproteins remains elusive. The present study investigated the influence of SARS-CoV-2 on expression of selenoprotein mRNAs in Vero cells. SARS-CoV-2 triggered an inflammatory response as evidenced by increased IL-6 expression. Of the 25 selenoproteins, SARS-CoV-2 significantly suppressed mRNA expression of ferroptosis-associated GPX4, DNA synthesis-related TXNRD3 and endoplasmic reticulum-resident SELENOF, SELENOK, SELENOM and SELENOS. Computational analysis has predicted an antisense interaction between SARS-CoV-2 and TXNRD3 mRNA, which is translated with high efficiency in the lung. Here, we confirmed the predicted SARS-CoV-2/TXNRD3 antisense interaction in vitro using DNA oligonucleotides, providing a plausible mechanism for the observed mRNA knockdown. Inhibition of TXNRD decreases DNA synthesis which is thereby likely to increase the ribonucleotide pool for RNA synthesis and, accordingly, RNA virus production. The present findings provide evidence for a direct inhibitory effect of SARS-CoV-2 replication on the expression of a specific set of selenoprotein mRNAs, which merits further investigation in the light of established evidence for correlations between dietary selenium status and the outcome of SARS-CoV-2 infection.

Abstract.  Stranges S, Tabák AG, Guallar E, Rayman MP, Akbaraly TN, Laclaustra M, Alfthan G, Mussalo-Rauhamaa H, Viikari JSA, Raitakari OT, Kivimäki M (Health Sciences Research Institute, University of Warwick Medical School, Coventry; University College London, London, UK; Semmelweis University Faculty of Medicine, Budapest, Hungary; Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; National Center for Cardiovascular Research (CNIC), Madrid, Spain; University of Surrey, UK; National Institute of Health and Medical Research (Inserm) U888. F-34000 Montpellier, France; National Institute for Health and Welfare, Helsinki, Finland; Hjelt Institute, University of Helsinki, Helsinki; University of Turku and Turku University Hospital, Turku; University of Turku, Turku; Finnish Institute of Occupational Health and University of Helsinki, Helsinki, Finland). Selenium status and blood lipids: the cardiovascular risk in young finns study. J Intern Med 2011; doi: 10.1111/j.1365-2796.2011.02398.x. Background.  Concern has been recently raised about possible adverse cardio-metabolic effects of high selenium status, such as increased risks of diabetes and hyperlipidaemia. However, most of the evidence comes from selenium-replete populations such as that of the United States. Objectives.  To examine cross-sectional and longitudinal associations of serum selenium with cardiovascular risk factors in Finland where selenium levels were amongst the lowest in the world until the early 1980s before the implementation of a nationwide selenium fertilization programme. Methods.  Serum selenium was measured in 1235 young Finns aged 3-18 years at baseline in 1980 (prefertilization) and in a subgroup (N = 262) at the 6-year follow-up (1986, postfertilization). During the 27-year follow-up, serum lipids, blood pressure, body mass index and smoking were assessed five times (1980, 1983, 1986, 2001 and 2007). Results.  Mean (±SD) serum selenium concentrations were 74.3 ± 14.0 ng mL(-1) in 1980 and 106.6 ± 12.5 ng mL(-1) in 1986 (average increase 32.3 ng mL(-1) ; 95% CI: 30.3 to 34.3, P 

Background Selenium, an essential trace element, is incorporated into selenoproteins with a wide range of health effects. Selenoproteins may reach repletion at a plasma selenium concentration of ~125 μg/L, at which point the concentration of selenoprotein P reaches a plateau; whether sustained concentrations higher than this are beneficial, or indeed detrimental, is unknown. Objective In a population of relatively low selenium status, we aimed to determine the effect on mortality of long-term selenium supplementation at different dose levels. Design The Denmark PRECISE study was a single-centre, randomised, double-blinded, placebocontrolled, multi-arm, parallel clinical trial with four groups. Participants were 491 male and female volunteers aged 60-74 years, recruited at Odense University Hospital, Denmark. The trial was initially designed as a 6-month pilot study, but supplemental funding allowed for extension of the study and mortality assessment. Participants were randomly assigned to treatment with 100, 200, or 300 μg selenium/d as selenium-enriched-yeast or placebo-yeast for 5 years from randomization in 1998–1999 and were followed up for mortality for a further 10 years (through March 31, 2015). Results During 6,871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis, the hazard ratio (95% confidence interval) for all-cause mortality comparing 300 μg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 μg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar. Conclusions A 300 μg/d dose of selenium taken for 5 years in a country with moderately-low selenium status increased all-cause mortality 10 years later. While our study was not initially designed to evaluate mortality and the sample size was limited, our findings indicate that total selenium intake over 300 μg/d and high-dose selenium supplements should be avoided.

Both selenium (Se) deficiency and excess are found in natural locations throughout the world, though Se excess can also be caused by supplementation with Se. Both have been associated with adverse health effects that have often been characterized by a U-shaped relationship. Some health effects, such as increased mortality, are associated with both low and high Se status. Certain people and populations are better able to tolerate low or high Se intake than others; there are a number of possible explanations for this fact. Firstly, it may relate to the presence of polymorphisms (SNPs) in genes that improve the ability to deal with a low or high Se intake. Secondly, high Se status, with apparent absence of toxicity and even beneficial effects, can be found in populations exposed to toxic elements that are known to interact with Se, forming complexes in some cases. Thirdly, beneficial and harmful effects of Se depend on Se dose and form (speciation); for instance, at a high dose, selenomethionine (SeMet) has toxic effects that are mediated by metabolism to selenols/selenolates that can redox-cycle, generate superoxide radicals, and react with thiols/diselenides to produce selenyl sulphides/disulphides. Finally, it is possible that exposure to a high Se intake from birth or from a very young age may alter the composition of the gut microbiota in such a way that excess Se is more readily excreted, thus reducing its toxicity.

We begin by arguing that the often used algorithm for the discovery and use of disease risk factors, stepwise logistic regression, is unstable. We then argue that there are other algorithms available that are much more stable and reliable (e.g. the lasso and gradient boosting). We then propose a protocol for the discovery and use of risk factors using lasso or boosting variable selection. We then illustrate the use of the protocol with a set of prostate cancer data and show that it recovers known risk factors. Finally, we use the protocol to identify new and important SNP based risk factors for prostate cancer and further seek evidence for or against the hypothesis of an anticancer function for Selenium in prostate cancer. We find that the anticancer effect may depend on the SNP-SNP interaction and, in particular, which alleles are present.

Iodine deficiency is present in certain groups of the UK population, notably in pregnant women; this is of concern as iodine is required for fetal brain development. UK milk is rich in iodine and is the principal dietary iodine source. UK sales of milk-alternative drinks are increasing but data are lacking on their iodine content. As consumers may replace iodine-rich milk with milk-alternative drinks, we aimed to measure the iodine concentration of those available in the UK. Using ICP-MS, we determined the iodine concentration of seven types of milk-alternative drink (soya, almond, coconut, oat, rice, hazelnut, and hemp) by analysing 47 products purchased in November/December 2015. For comparison, winter samples of conventional (n=5) and organic (n=5) cows’ milk were included. The median iodine concentration of all of the unfortified milk-alternative drinks (n=44) was low, at 7.3 μg/kg, just 1.7% of our value for winter conventional cows’ milk (median 438 μg/kg). One brand (not the market leader), fortified its soya, oat, and rice drinks with iodine and those drinks had a higher iodine concentration than unfortified drinks, at 280, 287, 266 μg/kg respectively. The iodine concentration of organic milk (median 324 μg/kg) was lower than that of conventional milk. Although many milk-alternative drinks are fortified with calcium, at the time of this study, just three of 47 drinks were fortified with iodine. Individuals who consume milk-alternative drinks that are not fortified with iodine in place of cows’ milk may be at risk of iodine deficiency unless they consume alternative dietary iodine sources.

Metabolism is important for cartilage and synovial joint function. Under adverse microenvironmental conditions, mammalian cells undergo a switch in cell metabolism from a resting regulatory state to a highly metabolically activate state to maintain energy homeostasis. This phenomenon also leads to an increase in metabolic intermediates for the biosynthesis of inflammatory and degradative proteins, which in turn activate key transcription factors and inflammatory signalling pathways involved in catabolic processes, and the persistent perpetuation of drivers of pathogenesis. In the past few years, several studies have demonstrated that metabolism has a key role in inflammatory joint diseases. In particular, metabolism is drastically altered in osteoarthritis (OA) and aberrant immunometabolism may be a key feature of many phenotypes of OA. This Review focuses on aberrant metabolism in the pathogenesis of OA, summarizing the current state of knowledge on the role of impaired metabolism in the cells of the osteoarthritic joint. We also highlight areas for future research, such as the potential to target metabolic pathways and mediators therapeutically.

Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA) and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX) 1 and GPX3 by substrate-specific coupled test procedures, selenoprotein P (SEPP1) concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend = 0.25 to 0.85). SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR) = 3.95, 95% confidence intervals (CI) = 1.42-10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31-32.58), but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p = 0.12-0.69). Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1 concentrations with the risk of EA and aneuploidy, which warrants further investigation. © 2012 Takata et al.

As current treatment options in OA are very limited, OA patients would benefit greatly from some ability to self-manage their condition. Since diet may potentially affect OA, we reviewed the literature on the relationship between nutrition and OA risk or progression, aiming to provide guidance for clinicians. For overweight/obese patients, weight reduction, ideally incorporating exercise, is paramount. The association between metabolic syndrome, type-2 diabetes and OA risk or progression may partly explain the apparent benefit of dietary-lipid modification resulting from increased consumption of long-chain omega-3 fatty-acids from oily fish/fish oil supplements. A strong association between OA and raised serum cholesterol together with clinical effects in statin users suggests a potential benefit of reduction of cholesterol by dietary means. Patients should ensure that they meet the recommended intakes for micronutrients such as vitamin K, which has a role in bone/cartilage mineralization. Evidence for a role of vitamin D supplementation in OA is unconvincing.

Dietary advice and intervention clearly have a place in rheumatology and allow patients to have some control over their own disease. Although there is no evidence for efficacy of ‘fad’ diets, 30–40% of rheumatoid patients can benefit from excluding foods individually identified during the reintroduction phase of an elimination diet. A proportion of patients who follow a vegetarian or Mediterranean-type diet will experience benefit. Patients who are either overweight or obese should participate in weight-loss programmes. Those with osteoarthritis need to concentrate on reducing fat mass while maintaining muscle mass. Arthritic patients, other than those with gout, should increase their intake of oily fish and additionally supplement with fish oil for up to 3 months to see whether they experience benefit. All arthritic patients, particularly those with inflammatory disease, should be advised to ensure a good dietary intake of antioxidants, copper and zinc. Supplementation with selenium and vitamin D may be advisable.

Iodine is a key component of the thyroid hormones which are crucial for brain development. Adequate intake of iodine in pregnancy is important as in utero deficiency may have lifelong consequences for the offspring. Data on the iodine status of UK pregnant women are sparse, and there are no such data for pregnant women in the South East of the UK. A total of 100 pregnant women were recruited to a cross-sectional study carried out at the Royal Surrey County Hospital, Guildford, at their first-trimester visit for an ultrasound scan. The participants provided a spot-urine sample (for the measurement of urinary iodine concentration (UIC) and creatinine concentration) and 24 h iodine excretion was estimated from the urinary iodine:creatinine ratio. Women completed a general questionnaire and a FFQ. The median UIC (85·3 μg/l) indicated that the group was iodine deficient by World Health Organisation criteria. The median values of the iodine:creatinine ratio (122·9 μg/g) and of the estimated 24 h iodine excretion (151·2 μg/d) were also suggestive of iodine deficiency. UIC was significantly higher in women taking an iodine-containing prenatal supplement (n 42) than in those not taking such a supplement (P< 0·001). In the adjusted analyses, milk intake, maternal age and iodine-containing prenatal supplement use were positively associated with the estimated 24 h urinary iodine excretion. Our finding of iodine deficiency in these women gives cause for concern. We suggest that women of childbearing age and pregnant women should be given advice on how to improve their iodine status through dietary means. A national survey of iodine status in UK pregnant women is required. © The Authors 2013.

Iodine is an essential micronutrient incorporated into thyroid hormones. Although iodine deficiency can lead to a broad spectrum of disorders throughout life, it is most critical in the early stages of development, as the foetal brain is extremely dependent on iodine supply. During the last two decades, our understanding of thyroid physiology during gestation has substantially improved. Furthermore, thyroid hormone receptors have been identified and characterised in placental and embryonic tissues, allowing us to elucidate the maternal-foetal transfer of thyroid hormones. Experimental studies have demonstrated that the cyto-architecture of the cerebral cortex can be irreversibly disturbed in iodine deficiency causing abnormal neuron migratory patterns which are associated with cognitive impairment in children. In this context, the role of iodine as key factor in the programming of foetal and infant neurodevelopment, needs to be revisited with a special focus on areas of mild to moderate iodine deficiency. The objective of this review is to summarize the available evidence from both animals and human studies, for the effect of iodine deficiency (particularly, of maternal hypothyroxinemia) on brain development and neurological or behavioural disorders, such as lower intelligence quotient (IQ) or attention deficit hyperactivity disorder (ADHD).

Purpose The trace element iodine is a vital constituent of thyroid hormones. Iodine requirements increase during pregnancy, when even mild deficiency may affect the neurocognitive development of the offspring. Urinary iodine concentration (UIC) is the means of assessing iodine status in population surveys; a median UIC of 100–199 µg/L is deemed sufficient in a non-pregnant population. Milk is the main dietary source of iodine in the UK and Ireland. Methods We surveyed the iodine status of 903 girls aged 14–15 years in seven sites across the island of Ireland. Urine iodine concentration was measured in spot-urine samples collected between March 2014 and October 2015. Food group intake was estimated from iodine-specific food-frequency questionnaire. Milk-iodine concentration was measured at each site in summer and winter. Results The median UIC overall was 111 µg/L. Galway was the only site in the deficient range (median UIC 98 µg/L). All five of the Republic of Ireland sites had UIC ≤ 105 µg/L. In the two sites surveyed twice, UIC was lower in summer vs winter months [117 µg/L (IQR 76–165) vs 130 µg/L (IQR 91–194) (p ˂ 0.01)]. Milk samples collected from Galway and Roscommon had a lower mean iodine concentration than those from Derry/Londonderry (p ˂ 0.05). Milk intake was positively associated with UIC (p ˂ 0.001). Conclusions This is the largest survey of its kind on the island of Ireland, which currently has no iodine-fortification programme. Overall, the results suggest that this young female population sits at the low end of sufficiency, which has implications if, in future, they enter pregnancy with borderline status.

On April 18, 2018 the EUthyroid consortium released the Krakow Declaration on Iodine in response to the increasing concern about the deteriorating commitment of policymakers to address public health strategies against iodine deficiency disorders (IDD) in the European populations. Regulators and policymakers should harmonize obligatory Universal Salt Iodization to ensure free trade of fortified foodstuffs in Europe. Similarly, iodized animal feed requires regulatory approval to ensure free trade within the EU. National governments and public health authorities have to perform harmonized monitoring and evaluation of fortification programs at regular intervals to ensure optimal iodine supply to the population. Scientists, together with public health care workers, patient organizations, industry, and the public should support measures necessary to ensure that IDD prevention programs are sustainable, as appropriate within a rapidly changing environment and further social awareness of the issue. The declaration defines measures and responsibilities to optimize IDD prevention.

Selenium is incorporated into selenoproteins that have a wide range of pleiotropic effects, ranging from antioxidant and anti-inflammatory effects to the production of active thyroid hormone. In the past 10 years, the discovery of disease-associated polymorphisms in selenoprotein genes has drawn attention to the relevance of selenoproteins to health. Low selenium status has been associated with increased risk of mortality, poor immune function, and cognitive decline. Higher selenium status or selenium supplementation has antiviral effects, is essential for successful male and female reproduction, and reduces the risk of autoimmune thyroid disease. Prospective studies have generally shown some benefit of higher selenium status on the risk of prostate, lung, colorectal, and bladder cancers, but findings from trials have been mixed, which probably emphasises the fact that supplementation will confer benefit only if intake of a nutrient is inadequate. Supplementation of people who already have adequate intake with additional selenium might increase their risk of type-2 diabetes. The crucial factor that needs to be emphasised with regard to the health effects of selenium is the inextricable U-shaped link with status; whereas additional selenium intake may benefit people with low status, those with adequate-to-high status might be affected adversely and should not take selenium supplements.

Aims: Long-term selenium supplementation may have adverse effects on glucose metabolism and risk of type-2 diabetes in selenium-replete populations, such as the US. There is limited trial evidence on the effect of selenium supplementation on glucose metabolism in European populations whose selenium status is much lower than that of the US. We investigated the effect of selenium supplementation at different dose levels on changes in HbA1c after 6 months and 2 years in a population of relatively low selenium status. Materials and methods: The Denmark PRECISE study was a single-centre, randomized, double-blinded, placebo-controlled, multi-arm, parallel clinical trial with four groups. In total, 491 volunteers aged 60-74 years were randomly assigned to treatment with 100, 200, or 300 µg selenium/d as selenium-enriched-yeast or placebo-yeast. HbA1c measurements were available for 489 participants at baseline, 435 at 6 months, and 369 after 2 years of selenium supplementation. Analyses were performed by intention to treat. Results: The mean (SD) age, plasma-selenium concentration, and blood HbA1c at baseline were 66.1 (4.1) years, 86.5 (16.3) ng/g, and 36.6 (7.0) mmol/mol, respectively. During the initial 6- month intervention period, mean HbA1c (95% CIs) decreased by 1.5 (-2.8 to -0.2) mmol/mol for 100 µg/d of selenium supplementation and by 0.7 (-2.0 to 0.6) mmol/mol for the 200 and 300 µg/d groups compared with placebo (P = 0.16 for homogeneity of changes across the four groups). After 2 years of selenium supplementation, HbA1c had decreased significantly in all treatment groups, with no difference between active treatment and placebo. Conclusions: Selenium supplementation in an elderly European population of relatively low selenium status did not significantly affect HbA1c levels after 2 years. Our findings corroborate a possible U-shaped response of selenium supplementation on glucose metabolism.

Iodine is required for adequate thyroid hormone production, which is essential for brain development, particularly in the first trimester of pregnancy. Milk is the principal source of iodine in UK diets, and while small studies in Europe have shown organic milk to have a lower iodine concentration than conventional milk, no such study has been conducted in Britain. In view of the increasing popularity of organic milk in the UK, we aimed to compare the iodine concentration of retail organic and conventional milk and to evaluate regional influences in iodine levels. Samples of organic milk (n 92) and conventional milk (n 80), purchased from retail outlets in sixteen areas of the UK (southern England, Wales and Northern Ireland), were analysed for iodine using inductively coupled plasma MS. The region of origin of the milk was determined from information on the label. Organic milk was 42·1 % lower in iodine content than conventional milk (median iodine concentration 144·5 v. 249·5 ng/g; P 

Potentially relevant to the recent appearance of COVID-19 in China is the fact that there is a belt of selenium deficiency running from northeast to southwest in the country and, indeed, China has populations that have both the lowest and the highest selenium status in the world. A set of interesting studies published by the Beck laboratory in the 1990s showed that host selenium deficiency increased the virulence of RNA viruses such as coxsackievirus B3 and influenza A. Passage through a selenium-deficient animal that was unable to produce sufficient antioxidant selenoproteins for its own protection resulted in the virus mutating to a virulent form that caused more severe pathology. Those findings shed light on a human selenium-deficiency disease, a cardiomyopathy known as Keshan disease, named after the area in northeast China where it was endemic. The disease showed a seasonal variation, suggesting a viral cofactor that was later identified as coxsackievirus B3. When the population was supplemented with selenium, the incidence of Keshan disease decreased dramatically.

In the 1990s, selenium was identified as a component of an enzyme that activates thyroid hormone; since this discovery, the relevance of selenium to thyroid health has been widely studied. Selenium, known primarily for the antioxidant properties of selenoenzymes, is obtained mainly from meat, seafood and grains. Intake levels vary across the world owing largely to differences in soil content and factors affecting its bioavailability to plants. Adverse health effects have been observed at both extremes of intake, with a narrow optimum range. Epidemiological studies have linked an increased risk of autoimmune thyroiditis, Graves disease and goitre to low selenium status. Trials of selenium supplementation in patients with chronic autoimmune thyroiditis have generally resulted in reduced thyroid autoantibody titre without apparent improvements in the clinical course of the disease. In Graves disease, selenium supplementation might lead to faster remission of hyperthyroidism and improved quality of life and eye involvement in patients with mild thyroid eye disease. Despite recommendations only extending to patients with Graves ophthalmopathy, selenium supplementation is widely used by clinicians for other thyroid phenotypes. Ongoing and future trials might help identify individuals who can benefit from selenium supplementation, based, for instance, on individual selenium status or genetic profile.

Iodine supply is crucial during pregnancy to ensure the proper thyroid function of mother and baby and support fetal brain development. Little is known about iodine status or its dietary determinants in pregnant women in the Republic of Cyprus. We therefore recruited 128 pregnant women at their first-trimester ultrasound scan to a cross-sectional study. We collected spot-urine samples for the measurement of urinary iodine concentration (UIC, µg/L), and creatinine concentration (Creat, g/L), the latter of which allows us to correct for urine dilution and to compute the iodine-to-creatinine ratio (UI/Creat). Women completed a Food Frequency Questionnaire (FFQ) and a general questionnaire. We used a General Linear model to explore associations between maternal and dietary characteristics with UI/Creat. The median UIC (105 µg/L) indicated iodine deficiency according to the World Health Organisation criterion (threshold for adequacy=150 µg/L) and the UI/Creat was also low at 107 µg/g. Only 32% (n=45) of women reported the use of iodine-containing supplements; users had a higher UI/Creat than non-users (131 µg/g vs. 118 µg/g), though this difference was not significant in the adjusted analysis (P=0.37). Of the dietary components, only egg intake was significantly associated with a higher UI/Creat in adjusted analyses (P=0.018); there was no significant association with milk, dairy products, or fish intake. Our results suggest that pregnant women in Cyprus have inadequate iodine status and are at risk of mild-to-moderate iodine deficiency. Further research on dietary sources in this population is required.

Background Though iodine deficiency in pregnancy is a matter of public-health concern, a functional measure of iodine status is lacking. The thyroid-specific protein, thyroglobulin (Tg), which reflects thyroid size, has shown promise as a functional measure in studies of children and adults, but data in pregnancy are sparse. In a cohort of mildly-to-moderately iodine-deficient pregnant women, we aimed to explore whether serum Tg is a sensitive functional biomarker of iodine status and to examine longitudinal change in Tg with gestational age. Method 230 pregnant women were recruited at an ante-natal clinic at 12 weeks of gestation to the Selenium in PRegnancy INTervention (SPRINT) study, in Oxford, UK. Repeated measures of urinary iodine-to-creatinine ratio, serum TSH and Tg at 12, 20, and 35 weeks of gestation were collected. Women were dichotomised by their iodine-to-creatinine ratio, (

Pre-eclampsia affects 3-5% of pregnant women worldwide and is associated with a range of adverse maternal and fetal outcomes, including maternal and/or fetal death. It particularly affects those with chronic hypertension, pre-gestational diabetes mellitus or a family history of pre-eclampsia. Other than early delivery of the fetus, there is no cure for pre-eclampsia. Since diet or dietary supplements may potentially affect the risk, we have carried out an up-to-date, narrative, literature review to assess the relationship between nutrition and pre-eclampsia. Several nutrients and dietary factors previously believed to be implicated in the risk of pre-eclampsia have now been shown to have no effect on risk; these include vitamins C and E, magnesium, salt, -3 long-chain polyunsaturated fatty acids (fish oils) and zinc. Body-mass index is proportionally correlated with pre-eclampsia risk, therefore women should aim for a healthy pre-pregnancy body-weight and avoid excessive gestational and interpregnancy weight-gain. The association between the risk or progression of the pathophysiology of pre-eclampsia may explain the apparent benefit of dietary modifications resulting from increased consumption of fruits and vegetables (≥400 g/day), plant-based foods and vegetable oils and a limited intake of foods high in fat, sugar and salt. Consuming a high fibre diet (25-30 g/day) may attenuate dyslipidaemia and reduce blood pressure and inflammation. Other key nutrients that may mitigate the risk include increased calcium intake, a daily multi-vitamin/mineral supplement and an adequate vitamin D status. For those with a low selenium intake (such as those living in Europe), fish/seafood intake could be increased to improve selenium intake or selenium could be supplemented in the recommended multi-vitamin/mineral supplement. Milk-based probiotics have also been found to be beneficial in pregnant women at risk. Our recommendations are summarised in a table of guidance for women at particular risk of developing pre-eclampsia.

There is a growing appreciation that it is not just the total intake of dietary selenium (Se) that is important to health but that the species of Se ingested may also be important. This review attempts to catalogue what is known about Se species in food sources and supplements and the health effects in which they are implicated. The biosynthetic pathways involved in Se assimilation by plants and the way in which Se species are metabolized in animals are presented in order to give an insight into the species likely to be present in plant and animal foods. Known data on the species of Se in the food chain and in food supplements are tabulated along with their concentrations and the analytical methodology used. The latter is important since identification that is only based on retention time matching with authentic standards must be considered as tentative: for evidence of structural confirmation, fragmentation of the molecular ion in addition to MS data is required. Bioavailability, as normally defined, is higher for organic Se species. Health effects, both beneficial and toxic, thought to be associated with specific Se species are described. Potent antitumour effects have been attributed to the low-molecular-weight species, Se-methyl-selenocysteine and its γ-glutamyl-derivative, found in a number of edible plants of the Allium and Brassica families. There remain considerable gaps in our knowledge of the forms of Se that naturally occur in foods. Without adequate knowledge of Se speciation, false conclusions may be drawn when assessing Se requirements for optimal health.

Selenium appears to have a beneficial effect on number of adverse pregnancy health conditions. Higher selenium status has been associated with a lower risk of miscarriage and preterm birth, while there is evidence from randomized controlled trials that selenium supplementation may reduce the risk of pre-eclampsia and post-partum thyroid disease. The ability of selenoproteins to reduce oxidative stress, endoplasmic reticulum stress and inflammation, and to protect the endothelium, control eicosanoid production, regulate vascular tone and reduce infection, is likely to be important in these apparently protective effects.

The deficiency of Se, an essential micronutrient, has been implicated in adverse pregnancy outcomes. Our study was designed to determine total serum Se, selenoproteins (extracellular glutathione peroxidase (GPx-3), selenoprotein P (SeP)), selenoalbumin (SeAlb) and selenometabolites in healthy women and their newborns at delivery. This cross-sectional study included eighty-three healthy mother–baby couples. Total Se and Se species concentrations were measured in maternal and umbilical cord sera by an in-series coupling of two-dimensional size-exclusion and affinity HPLC. Additional measurements of serum SeP concentration and of serum GPx-3 enzyme activity were carried out using ELISA. Total Se concentration was significantly higher in maternal serum than in cord serum (68·9 (sd 15·2) and 56·1 (sd 14·6) µg/l, respectively; P

This narrative review addresses the role of the essential trace element, selenium, in type-2 diabetes mellitus (T2DM) and its metabolic co-morbidities, i.e., metabolic syndrome, obesity and non-alcoholic fatty liver disease. We refer to the dietary requirements of selenium and the key physiological roles of selenoproteins. We explore the dysregulated fuel metabolism in T2DM and its co-morbidities, emphasizing the relevance of inflammation and oxidative stress. We describe the epidemiology of observational and experimental studies of selenium in diabetes and related conditions, explaining that the interaction between selenium status and glucose control is not limited to hyperglycemia but extends to hypoglycemia. We propose that the association between high plasma/serum selenium and T2DM/fasting plasma glucose observed in many cross-sectional studies may rely on the upregulation of hepatic selenoprotein-P biosynthesis in conditions of hyperglycemia and insulin resistance. While animal studies have revealed potential molecular mechanisms underlying adverse effects of severe selenium/selenoprotein excess and deficiency in the pathogenesis of insulin resistance and β-cell dysfunction, their translational significance is rather limited. Importantly, dietary selenium supplementation does not appear to be a major causal factor for the development of T2DM in humans though we cannot currently exclude a small contribution of selenium on top of other risk factors, in particular if it is ingested at high (supranutritional) doses. Elevated selenium biomarkers that are often measured in T2DM patients are more likely to be a consequence, rather than a cause, of diabetes.

Background: Thyroid hormone is essential for optimal fetal brain development. Evidence suggests that both low and high maternal thyroid hormone availability may have adverse effects on child neurodevelopmental outcomes, but the effect on behavioral problems remains unclear. We studied the association of maternal thyrotropin (TSH) and free thyroxine (FT4) concentrations during the first 18 weeks of pregnancy with child Attention-Deficit Hyperactivity Disorder (ADHD). Methods: 7669 mother-child pairs with data on maternal thyroid function and child ADHD were selected from three prospective population-based birth cohorts: INMA (N=1073, Spain), Generation R (N=3812, The Netherlands) and ALSPAC (N=2784, United Kingdom). Exclusion criteria were multiple pregnancies, fertility treatments, usage of medication affecting the thyroid, and pre-existing thyroid disease. We used logistic regression models to study the association of maternal thyroid function with the primary outcome, ADHD, assessed via the DSM-IV criteria by parents and/or teachers at a median child age of 4.5 to 7.6 years, and with the secondary outcome, an ADHD symptom score above the 90th percentile. Effect modification by gestational age and sex was tested with interaction terms and stratified analyses. Results: Overall, 233 (3%) children met the criteria for ADHD. When analyzed continuously, neither FT4 nor TSH was associated with a higher risk of ADHD [Odds ratio (OR), 95% Confidence Interval (CI): 1.1 (1.0-1.3), P=0.060 and OR 0.9, 95% CI 0.9-1.1, P=0.385, respectively] or with high symptom scores. When investigating effect modification by gestational age, a higher FT4 was associated with symptoms above the 90th percentile but only in the first trimester [for FT4 per 1SD: OR 1.2 (95% CI 1.0-1.4), P=0.027]. However, these differential effects by gestational age were not consistent. No significant effect modification by sex was observed. Conclusions: We found no clear evidence of an association between maternal thyroid function and child ADHD.

Selenium and iodine are trace elements that are maximally concentrated in the thyroid. Iodine is a substrate for thyroid hormone synthesis, while the selenoproteins protect the thyroid from the oxidative stress incurred. We measured plasma selenium concentration in 241 pregnant women in 1st trimester, previously reported to have iodine deficiency. Mean age was 30.3 years (SD 5.4), BMI 26.2 kg/m2 (SD 4.9) and 53% reported taking supplements. Median urinary-iodine concentration was 73 μg/L (IQR 37-122) (WHO recommendation, ≥150 μg/L). Mean plasma-selenium concentration was 75 μg/L (SD 7.7) which is below the 80-125 μg/L reported to be optimal. Four-day food diaries revealed a selenium intake of 43μg/day (SD 15.9), also below the 55-70 μg/day reported to be optimal. This is the first report of selenium status in pregnancy on the island of Ireland. The possible combined effects of iodine and selenium deficiencies in pregnancy merit further investigation.

Background: Hashimoto's thyroiditis (HT) is considered to be the most common autoimmune disease. It is currently accepted that genetic susceptibility, environmental factors, and immune disorders contribute to its development. With regard to nutritional factors, evidence implicates high iodine intake and deficiencies of selenium and iron with a potential relevance of vitamin D status. To elucidate the role of nutritional factors in the risk, pathogenesis, and treatment of HT, PubMed and the Cochrane Library were searched for publications on iodine, iron, selenium, and vitamin D and risk/treatment of HT. Summary: Chronic exposure to excess iodine intake induces autoimmune thyroiditis, partly because highly iodinated thyroglobulin (Tg) is more immunogenic. Recent introduction of universal salt iodization can have a similar, though transient, effect. Selenoproteins are essential to thyroid action. In particular, the glutathione peroxidases protect the thyroid by removing excessive hydrogen peroxide produced for Tg iodination. Genetic data implicate the anti-inflammatory selenoprotein S in HT risk. There is evidence from observational studies and randomized controlled trials that selenium/selenoproteins can reduce thyroid peroxidase (TPO)-antibody titers, hypothyroidism, and postpartum thyroiditis. Iron deficiency impairs thyroid metabolism. TPO, the enzyme responsible for the production of thyroid hormones, is a heme (iron-containing) enzyme which becomes active at the apical surface of thyrocytes only after binding heme. HT patients are frequently iron deficient, since autoimmune gastritis, which impairs iron absorption, is a common co-morbidity. Treatment of anemic women with impaired thyroid function with iron improves thyroid-hormone concentrations, while thyroxine and iron together are more effective in improving iron status. Lower vitamin D status has been found in HT patients than in controls, and inverse relationships of serum vitamin D with TPO/Tg antibodies have been reported. However, other data and the lack of trial evidence suggest that low vitamin D status is more likely the result of autoimmune disease processes that include vitamin D receptor dysfunction. Conclusions: Clinicians should check patients' iron (particularly in menstruating women) and vitamin D status to correct any deficiency. Adequate selenium intake is vital in areas of iodine deficiency/excess, and in regions of low selenium intake a supplement of 50–100 μg/day of selenium may be appropriate.

Selenium is a trace element essential to human health largely because of its incorporation into selenoproteins that have a wide range of protective functions. Selenium has an ongoing history of reducing the incidence and severity of various viral infections; for example, a German study found selenium status to be significantly higher in serum samples from surviving than non-surviving COVID-19 patients. Furthermore, a significant, positive, linear association was found between the cure rate of Chinese patients with COVID-19 and regional selenium status. Moreover, the cure rate continued to rise beyond the selenium intake required to optimise selenoproteins, suggesting that selenoproteins are probably not the whole story. Nonetheless, the significantly reduced expression of a number of selenoproteins, including those involved in controlling ER stress, along with increased expression of IL-6 in SARS-CoV-2 infected cells in culture suggests a potential link between reduced selenoprotein expression and COVID-19-associated inflammation. In this comprehensive review, we describe the history of selenium in viral infections and then go on to assess the potential benefits of adequate and even supra-nutritional selenium status. We discuss the indispensable function of the selenoproteins in coordinating a successful immune response and follow by reviewing cytokine excess, a key mediator of morbidity and mortality in COVID-19, and its relationship to selenium status. We comment on the fact that the synthetic redox-active selenium compound, ebselen, has been found experimentally to be a strong inhibitor of the main SARS-CoV-2 protease that enables viral maturation within the host. That finding suggests that redox-active selenium species formed at high selenium intake might hypothetically inhibit SARS-CoV-2 proteases. We consider the tactics that SARS-CoV-2 could employ to evade an adequate host response by interfering with the human selenoprotein system. Recognition of the myriad mechanisms by which selenium might potentially benefit COVID-19 patients provides a rationale for randomised, controlled trials of selenium supplementation in SARS-CoV-2 infection.

Iron is an essential element, and typically cornflake-style cereals are fortified with iron to a level up to 14 mg iron per 100 g. Even single cornflakes exhibit magnetic behaviour. We extracted iron microparticles from samples of two own-brand supermarket cornflakes using a strong permanent magnet. Synchrotron iron K-edge x-ray absorption near-edge spectroscopic data were consistent with identification as metallic iron, and x-ray diffraction studies provided unequivocal identification of the extracted iron as body-centred cubic (BCC) -iron. Magnetometry measurements were also consistent with ca. 14 mg/100 g BCC iron. These findings emphasise that attention must be paid to the speciation of trace elements, in relation to their bioavailability. To mimic conditions in the stomach, we suspended the iron extract in dilute HCl (pH 1.0-2.0) at 37oC (body temperature) and found by ICP-MS that over a period of 5 hours, up to 13% of the iron dissolved. This implies that despite its metallic form in the cornflakes, the iron is potentially bioavailable for oxidation and absorption into the body.