Corrigendum: Safe and effective delivery of supplemental iron to healthy adults: a two-phase, randomized, double-blind trial - the safe iron study.

[This corrects the article DOI: 10.3389/fnut.2023.1230061.].

Association of maternal prenatal copper concentration with gestational duration and preterm birth: a multicountry meta-analysis.

BACKGROUND: Copper (Cu), an essential trace mineral regulating multiple actions of inflammation and oxidative stress, has been implicated in risk for preterm birth (PTB). OBJECTIVES: This study aimed to determine the association of maternal Cu concentration during pregnancy with PTB risk and gestational duration in a large multicohort study including diverse populations. METHODS: Maternal plasma or serum samples of 10,449 singleton live births were obtained from 18 geographically diverse study cohorts. Maternal Cu concentrations were determined using inductively coupled plasma mass spectrometry. The associations of maternal Cu with PTB and gestational duration were analyzed using logistic and linear regressions for each cohort. The estimates were then combined using meta-analysis. Associations between maternal Cu and acute-phase reactants (APRs) and infection status were analyzed in 1239 samples from the Malawi cohort. RESULTS: The maternal prenatal Cu concentration in our study samples followed normal distribution with mean of 1.92 µg/mL and standard deviation of 0.43 µg/mL, and Cu concentrations increased with gestational age up to 20 wk. The random-effect meta-analysis across 18 cohorts revealed that 1 µg/mL increase in maternal Cu concentration was associated with higher risk of PTB with odds ratio of 1.30 (95% confidence interval [CI]: 1.08, 1.57) and shorter gestational duration of 1.64 d (95% CI: 0.56, 2.73). In the Malawi cohort, higher maternal Cu concentration, concentrations of multiple APRs, and infections (malaria and HIV) were correlated and associated with greater risk of PTB and shorter gestational duration. CONCLUSIONS: Our study supports robust negative association between maternal Cu and gestational duration and positive association with risk for PTB. Cu concentration was strongly correlated with APRs and infection status suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB. Therefore, maternal Cu could be used as potential marker of integrated inflammatory pathways during pregnancy and risk for PTB.

Safe and effective delivery of supplemental iron to healthy adults: a two-phase, randomized, double-blind trial - the safe iron study.

Introduction: The safety of novel forms of iron in healthy, iron-replete adults as might occur if used in population-based iron supplementation programs was examined. We tested the hypotheses that supplementation with nanoparticulate iron hydroxide adipate tartrate (IHAT), an iron-enriched Aspergillus oryzae product (ASP), or ferrous sulphate heptahydrate (FS) are safe as indicated by erythrocyte susceptibility to malarial infection, bacterial proliferation, and gut inflammation. Responses to FS administered daily or weekly, and with or without other micronutrients were compared. Methods: Two phases of randomized, double-blinded trials were conducted in Boston, MA. Phase I randomized 160 volunteers to six treatments: placebo, IHAT, ASP, FS, and FS plus a micronutrient powder (MNP) administrated daily at 60 mg Fe/day; and FS administered as a single weekly dose of 420 mg Fe. Phase II randomized 86 volunteers to IHAT, ASP, or FS administered at 120 mg Fe/day. Completing these phases were 151 and 77 participants, respectively. The study was powered to detect effects on primary endpoints: susceptibility of participant erythrocytes to infection by Plasmodium falciparum, the proliferation potential of selected pathogenic bacteria in sera, and markers of gut inflammation. Secondary endpoints for which the study was not powered included indicators of iron status and gastrointestinal symptoms. Results: Supplementation with any form of iron did not affect any primary endpoint. In Phase I, the frequency of gastrointestinal symptoms associated with FS was unaffected by dosing with MNP or weekly administration; but participants taking IHAT more frequently reported abdominal pain (27%, p < 0.008) and nausea (4%, p = 0.009) than those taking FS, while those taking ASP more frequently reported nausea (8%, p = 0.009). Surprisingly, only 9% of participants taking IHAT at 120 mg Fe/day (Phase II) reported abdominal pain and no other group reported that symptom. Discussion: With respect to the primary endpoints, few differences were found when comparing these forms of iron, indicating that 28 days of 60 or 120 mg/day of IHAT, ASP, or FS may be safe for healthy, iron-replete adults. With respect to other endpoints, subjects receiving IHAT more frequently reported abdominal pain and nausea, suggesting the need for further study. Clinical Trial Registration: ClinicalTrials.gov, NCT03212677; registered: 11 July 2017.

Selenium status and type 2 diabetes risk.

Optimal selenium (Se) status is necessary for overall health. That status can be affected by food intake pattern, age, sex, and health status. At nutritional levels of intake, Se functions metabolically as an essential constituent of some two dozen selenoproteins, most, if not all, of which have redox functions. Insufficient dietary intake of Se reduces, to varying degrees, the expression of these selenoproteins. Recent clinical and animal studies have indicated that both insufficient and excessive Se intakes may increase risk of type 2 diabetes mellitus (T2D), perhaps by way of selenoprotein actions. In this review, we discuss the current evidence linking Se status and T2D risk, and the roles of 14 selenoproteins and other proteins involved in selenoprotein biosynthesis. Understanding such results can inform the setting of safe and adequate Se intakes.

Dietary Selenium Across Species.

This review traces the discoveries that led to the recognition of selenium (Se) as an essential nutrient and discusses Se-responsive diseases in animals and humans in the context of current understanding of the molecular mechanisms of their pathogeneses. The article includes a comprehensive analysis of dietary sources, nutritional utilization, metabolic functions, and dietary requirements of Se across various species. We also compare the function and regulation of selenogenomes and selenoproteomes among rodents, food animals, and humans. The review addresses the metabolic impacts of high dietary Se intakes in different species and recent revelations of Se metabolites, means of increasing Se status, and the recycling of Se in food systems and ecosystems. Finally, research needs are identified for supporting basic science and practical applications of dietary Se in food, nutrition, and health across species.

Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis.

BACKGROUND: Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations. METHODS: Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis. FINDINGS: In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi. INTERPRETATION: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.

Perspective: Nutritional Status as a Biological Variable (NABV): Integrating Nutrition Science into Basic and Clinical Research and Care.

The field of nutrition has evolved from one focused primarily on discovery of the identities, metabolic functions, and requirements for essential nutrients to one focused on the application of that knowledge to the development and implementation of dietary recommendations to promote health and prevent disease. This evolution has produced a deeper appreciation of not only the roles of nutrients, but also factors affecting their functions in increasingly complex global health contexts. The intersection of nutrition with an increasingly more complex global health context necessitates a view of nutritional status as a biological variable (NABV), the study of which includes an appreciation that nutritional status is: 1) not limited to dietary exposure; 2) intimately and inextricably involved in all aspects of human health promotion, disease prevention, and treatment; and 3) both an input and an outcome of health and disease. This expanded view of nutrition will inform future research by facilitating considerations of the contexts and variability associated with the many interacting factors affecting and affected by nutritional status. It will also demand new tools to study multifactorial relations to the end of increasing precision and the development of evidence-based, safe, and effective standards of health care, dietary interventions, and public health programs.

Selenium Kinetics in Humans Change Following 2 Years of Supplementation With Selenomethionine.

Background: Selenium (Se) is a nutritionally essential trace element and health may be improved by increased Se intake. Previous kinetic studies have shown differences in metabolism of organic vs. inorganic forms of Se [e.g., higher absorption of selenomethionine (SeMet) than selenite (Sel), and more recycling of Se from SeMet than Sel]. However, the effects on Se metabolism after prolonged Se supplementation are not known. Objective: To determine how the metabolism and transport of Se changes in the whole-body in response to Se-supplementation by measuring Se kinetics before and after 2 years of Se supplementation with SeMet. Methods: We compared Se kinetics in humans [n = 31, aged 40 ± 3 y (mean ± SEM)] studied twice after oral tracer administration; initially (PK1), then after supplementation for 2 y with 200 µg/d of Se as selenomethionine (SeMet) (PK2). On each occasion, we administered two stable isotope tracers of Se orally: SeMet, the predominant food form, and selenite (Na276SeO3, or Sel), an inorganic form. Plasma and RBC were sampled for 4 mo; urine and feces were collected for the initial 12 d of each period. Samples were analyzed for tracers and total Se by isotope dilution GC-MS. Data were analyzed using a compartmental model, we published previously, to estimate fractional transfer between pools and pool masses in PK2. Results: We report that fractional absorption of SeMet or Sel do not change with SeMet supplementation and the amount of Se absorbed increased. The amount of Se excreted in urine increases but does not account for all the Se absorbed. As a result, there is a net incorporation of SeMet into various body pools. Nine of the 11 plasma pools doubled in PK2; two did not change. Differences in metabolism were observed for SeMet and Sel; RBC uptake increased 247% for SeMet, urinary excretion increased from two plasma pools for Sel and from two different pools for SeMet, and recycling to liver/tissues increased from one plasma pool for Sel and from two others for SeMet. One plasma pool increased more in males than females in PK2. Conclusions: Of 11 Se pools identified kinetically in human plasma, two did not increase in size after SeMet supplementation. These pools may be regulated and important during low Se intake.

Maternal dietary selenium intake is associated with increased gestational length and decreased risk of preterm delivery.

The first positive genome-wide association study on gestational length and preterm delivery showed the involvement of an Se metabolism gene. In the present study, we examine the association between maternal intake of Se and Se status with gestational length and preterm delivery in 72 025 women with singleton live births from the population-based, prospective Norwegian Mother, Father and Child Cohort Study (MoBa). A self-reported, semi-quantitative FFQ answered in pregnancy week 22 was used to estimate Se intake during the first half of pregnancy. Associations were analysed with adjusted linear and Cox regressions. Se status was assessed in whole blood collected in gestational week 17 (n 2637). Median dietary Se intake was 53 (interquartile range (IQR) 44-62) µg/d, supplements provided additionally 50 (IQR 30-75) µg/d for supplement users (n 23 409). Maternal dietary Se intake was significantly associated with prolonged gestational length (ß per sd = 0·25, 95 % CI, 0·07, 0·43) and decreased risk of preterm delivery (n 3618, hazard ratio per sd = 0·92, 95 % CI, 0·87, 0·98). Neither Se intake from supplements nor maternal blood Se status was associated with gestational length or preterm delivery. Hence, the present study showed that maternal dietary Se intake but not intake of Se-containing supplements, during the first half of pregnancy was significantly associated with decreased risk of preterm delivery. Further investigations, preferably in the form of a large randomised controlled trial, are needed to elucidate the impact of Se on pregnancy duration.

Serum selenium and pancreatic cancer: a prospective study in the Prostate, Lung, Colorectal and Ovarian Cancer Trial cohort.

PURPOSE: Pancreatic cancer(PCa) is one of the most lethal cancers with few known consistent nutrition-related risk factors. Epidemiologic associations between the trace element selenium and PCa are inconsistent. This study examined the association of pre-diagnostic serum selenium with incident PCa. METHODS: We conducted a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Study (PLCO) cohort of men and women 55-70 years old at baseline (1993-2001). In total, 303 PCa cases developed during the 17-year follow-up period (1993-2009). We selected two controls (n = 606) for each case who were alive at the time the case was diagnosed who were matched on age, sex, race, and date of blood draw. We used conditional logistic regression analysis to calculate the odds ratio (OR) and 95% confidence intervals (CI) adjusting for smoking status and diabetes mellitus. RESULTS: Mean serum selenium concentrations were slightly lower in cases (mean, 95% CI: 139.0 ng/ml, 135.6-138.9) compared to controls (142.5 ng/ml, 140.4-142.4, p = 0.08). Overall, serum selenium was not associated with PCa risk (continuous OR: 0.66; 0.32-1.37). There was no significant interaction by sex, smoking, diabetes, or follow-up time (p > 0.05). CONCLUSION: Our results do not support the hypothesis that serum selenium is associated with PCa risk.

Thiamin deficiency in low- and middle-income countries: Disorders, prevalences, previous interventions and current recommendations.

BACKGROUND: Thiamin deficiency is a major public health concern in several low- and middle-income countries (LMICs)-current attention to the problem is lacking. AIM: This review discusses prevalence of thiamin insufficiency and thiamin-deficiency disorders (TDDs) in LMICs, outlines programmatic experience with thiamin interventions, and offers recommendations to improve public-health and research attention to thiamin in LMICs. DISCUSSION: Thiamin insufficiency, i.e. low-blood-thiamin status, is endemic among several Southeast Asian countries: Cambodia (70-100% of infants and 27-100% of reproductive-age women); Laos (13% of hospitalized infants); Thailand (16-25% of children and 30% of elderly adults). Thiamin deficiency accounts for up to 45% of under-5 deaths in Cambodia, 34% of infant deaths in Laos, and 17% of infant deaths in Myanmar. Deficiency also exists in Africa, Asia, and the Americas, but these instances have typically been isolated. Exclusively breastfed infants of thiamin-deficient mothers are at highest risk for TDD and related death. Intervention strategies that have been employed to combat thiamin deficiency include food processing, fortification, supplementation, dietary diversification, and dietary behaviors, all of which have shown varying levels of effectiveness. CONCLUSIONS: We recommend universal thiamin-fortification of context-specific staple-foods in LMICs as a promising solution, as well as thiamin supplementation, particularly for pregnant and lactating women. Food processing regulations, dietary diversification, and modification of dietary behaviors to increase consumption of thiamin-rich foods may provide benefits in some circumstances, especially in countries without universal fortification programs or in populations dependent on food aid.

Safe and effective delivery of supplemental iron to healthy older adults: The double-blind, randomized, placebo-controlled trial protocol of the Safe Iron Study.

The forms of iron currently available to correct iron deficiency have adverse effects, including infectious diarrhea, increased susceptibility to malaria, inflammation and detrimental changes to the gut microbiome. These adverse effects limit their use such that the growing burden of iron deficiency has not abated in recent decades. Here, we summarize the protocol of the "Safe Iron Study", the first clinical study examining the safety and efficacy of novel forms of iron in healthy, iron-replete adults. The Safe Iron Study is a double-blind, randomized, placebo-controlled trial conducted in Boston, MA, USA. This study compares ferrous sulfate heptahydrate (FeSO 4·H 2O) with two novel forms of iron supplements (iron hydroxide adipate tartrate (IHAT) and organic fungal iron metabolite (Aspiron™ Natural Koji Iron)). In Phase I, we will compare each source of iron administrated at a low dose (60 mg Fe/day). We will also determine the effect of FeSO 4 co-administrated with a multiple micronutrient powder and weekly administration of FeSO 4. The forms of iron found to produce no adverse effects, or adverse effects no greater than FeSO 4 in Phase I, Phase II will evaluate a higher, i.e., a therapeutic dose (120 mg Fe/day). The primary outcomes of this study include ex vivo malaria ( Plasmodium falciparum) infectivity of host erythrocytes, ex vivo bacterial proliferation (of selected species) in presence of host plasma and intestinal inflammation assessed by fecal calprotectin. This study will test the hypotheses that the novel forms of iron, administered at equivalent doses to FeSO 4, will produce similar increases in iron status in iron-replete subjects, yet lower increases in ex vivo malaria infectivity, ex vivo bacterial proliferation, gut inflammation. Ultimately, this study seeks to contribute to development of safe and effective forms of supplemental iron to address the global burden of iron deficiency and anemia. Registration: ClinicalTrials.gov identifier: NCT03212677; registered: 11 July 2017.

Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs.

Thiamine is an essential micronutrient that plays a key role in energy metabolism. Many populations worldwide may be at risk of clinical or subclinical thiamine deficiencies, due to famine, reliance on staple crops with low thiamine content, or food preparation practices, such as milling grains and washing milled rice. Clinical manifestations of thiamine deficiency are variable; this, along with the lack of a readily accessible and widely agreed upon biomarker of thiamine status, complicates efforts to diagnose thiamine deficiency and assess its global prevalence. Strategies to identify regions at risk of thiamine deficiency through proxy measures, such as analysis of food balance sheet data and month-specific infant mortality rates, may be valuable for understanding the scope of thiamine deficiency. Urgent public health responses are warranted in high-risk regions, considering the contribution of thiamine deficiency to infant mortality and research suggesting that even subclinical thiamine deficiency in childhood may have lifelong neurodevelopmental consequences. Food fortification and maternal and/or infant thiamine supplementation have proven effective in raising thiamine status and reducing the incidence of infantile beriberi in regions where thiamine deficiency is prevalent, but trial data are limited. Efforts to determine culturally and environmentally appropriate food vehicles for thiamine fortification are ongoing.

Amyloid precursor protein modulates macrophage phenotype and diet-dependent weight gain.

It is well known that mutations in the gene coding for amyloid precursor protein are responsible for autosomal dominant forms of Alzheimer's disease. Proteolytic processing of the protein leads to a number of metabolites including the amyloid beta peptide. Although brain amyloid precursor protein expression and amyloid beta production are associated with the pathophysiology of Alzheimer's disease, it is clear that amyloid precursor protein is expressed in numerous cell types and tissues. Here we demonstrate that amyloid precursor protein is involved in regulating the phenotype of both adipocytes and peripheral macrophages and is required for high fat diet-dependent weight gain in mice. These data suggest that functions of this protein include modulation of the peripheral immune system and lipid metabolism. This biology may have relevance not only to the pathophysiology of Alzheimer's disease but also diet-associated obesity.

Opposing impacts on healthspan and longevity by limiting dietary selenium in telomere dysfunctional mice.

Selenium (Se) is a trace metalloid essential for life, but its nutritional and physiological roles during the aging process remain elusive. While telomere attrition contributes to replicative senescence mainly through persistent DNA damage response, such an aging process is mitigated in mice with inherently long telomeres. Here, weanling third generation telomerase RNA component knockout mice carrying short telomeres were fed a Se-deficient basal diet or the diet supplemented with 0.15 ppm Se as sodium selenate to be nutritionally sufficient throughout their life. Dietary Se deprivation delayed wound healing and accelerated incidence of osteoporosis, gray hair, alopecia, and cataract, but surprisingly promoted longevity. Plasma microRNA profiling revealed a circulating signature of Se deprivation, and subsequent ontological analyses predicted dominant changes in metabolism. Consistent with this observation, dietary Se deprivation accelerated age-dependent declines in glucose tolerance, insulin sensitivity, and glucose-stimulated insulin production in the mice. Moreover, DNA damage and senescence responses were enhanced and Pdx1 and MafA mRNA expression were reduced in pancreas of the Se-deficient mice. Altogether, these results suggest a novel model of aging with conceptual advances, whereby Se at low levels may be considered a hormetic chemical and decouple healthspan and longevity.

Resistant starch analysis of commonly consumed potatoes: Content varies by cooking method and service temperature but not by variety.

Resistant starch (RS) has unique digestive and absorptive properties which may provide health benefits. We conducted a study to determine the contributions of cultivar, cooking method and service temperature on the RS contents of potatoes (Solanum tuberosum L.). We hypothesized that the RS content would vary by variety, cooking method and service temperature. Potatoes of three common commercial varieties (Yukon Gold, Dark Red Norland, and Russet Burbank) were subjected to two methods of cooking (baking or boiling) and three service temperatures: hot (65°C), chilled (4°C) and reheated (4°C for 6d; reheated to 65°C) and analyzed the starch content by modification of a commercially available assay. Results showed that RS content (g/100g) varied by cooking method and service temperature but not variety. Baked potatoes had higher RS contents than boiled; chilled potatoes had more RS than either hot or reheated. These results may assist in dietary choices for reducing chronic disease risk.

Integrating Multiple Analytical Datasets to Compare Metabolite Profiles of Mouse Colonic-Cecal Contents and Feces.

The pattern of metabolites produced by the gut microbiome comprises a phenotype indicative of the means by which that microbiome affects the gut. We characterized that phenotype in mice by conducting metabolomic analyses of the colonic-cecal contents, comparing that to the metabolite patterns of feces in order to determine the suitability of fecal specimens as proxies for assessing the metabolic impact of the gut microbiome. We detected a total of 270 low molecular weight metabolites in colonic-cecal contents and feces by gas chromatograph, time-of-flight mass spectrometry (GC-TOF) and ultra-high performance liquid chromatography, quadrapole time-of-flight mass spectrometry (UPLC-Q-TOF). Of that number, 251 (93%) were present in both types of specimen, representing almost all known biochemical pathways related to the amino acid, carbohydrate, energy, lipid, membrane transport, nucleotide, genetic information processing, and cancer-related metabolism. A total of 115 metabolites differed significantly in relative abundance between both colonic-cecal contents and feces. These data comprise the first characterization of relationships among metabolites present in the colonic-cecal contents and feces in a healthy mouse model, and shows that feces can be a useful proxy for assessing the pattern of metabolites to which the colonic mucosum is exposed.

Plasma Selenium Concentrations Are Sufficient and Associated with Protease Inhibitor Use in Treated HIV-Infected Adults.

BACKGROUND: Selenium is an essential constituent of selenoproteins, which play a substantial role in antioxidant defense and inflammatory cascades. Selenium deficiency is associated with disease states characterized by inflammation, including cardiovascular disease (CVD). Although HIV infection has been associated with low selenium, the role of selenium status in HIV-related CVD is unclear. OBJECTIVES: We sought to assess associations between plasma selenium and markers of inflammation, immune activation, and subclinical vascular disease in HIV-infected adults on contemporary antiretroviral therapy (ART) and to determine if statin therapy modifies selenium status. METHODS: In the Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN trial, HIV-infected adults on stable ART were randomly assigned 1:1 to rosuvastatin or placebo. Plasma selenium concentrations were determined at entry, week 24, and week 48. Spearman correlation and linear regression analyses were used to assess relations between baseline selenium, HIV-related factors and markers of inflammation, immune activation, and subclinical vascular disease. Changes in selenium over 24 and 48 wk were compared between groups. RESULTS: One hundred forty-seven HIV-infected adults were included. All participants were on ART. Median current CD4+ count was 613, and 76% had HIV-1 RNA ≤48 copies/mL (range: <20-600). Median plasma selenium concentration was 122 µg/L (range: 62-200). At baseline, higher selenium was associated with protease inhibitor (PI) use, lower body mass index, and a higher proportion of activated CD8+ T cells (CD8+CD38+human leukocyte antigen-DR+), but not markers of inflammation or subclinical vascular disease. Over 48 wk, selenium concentrations increased in the statin group (P < 0.01 within group), but the change did not differ between groups (+13.1 vs. +5.3 µg/L; P = 0.14 between groups). CONCLUSIONS: Plasma selenium concentrations were within the normal range for the background population and were not associated with subclinical vascular disease in HIV-infected adults on contemporary ART. The association between current PI use and higher selenium may have implications for ART allocation, especially in resource-limited countries. Also, it appears that statin therapy may increase selenium concentrations; however, larger studies are necessary to confirm this finding. This trial was registered at clinicaltrials.gov as NCT01218802.