Publications by authors named "Sherry A Tanumihardjo"

144 Publications

Biological evidence to define a vitamin A deficiency cutoff using total liver vitamin A reserves.

Exp Biol Med (Maywood) 2021 Mar 25:1535370221992731. Epub 2021 Mar 25.

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.

Vitamin A is a fat-soluble vitamin involved in essential functions including growth, immunity, reproduction, and vision. The vitamin A Dietary Reference Intakes (DRIs) for North Americans suggested that a minimally acceptable total liver vitamin A reserve (TLR) is 0.07 µmol/g, which is not explicitly expressed as a vitamin A deficiency cutoff. The Biomarkers of Nutrition for Development panel set the TLR cutoff for vitamin A deficiency at 0.1 µmol/g based on changes in biological response of several physiological parameters at or above this cutoff. The criteria used to formulate the DRIs include clinical ophthalmic signs of vitamin A deficiency, circulating plasma retinol concentrations, excretion of vitamin A metabolites in the bile, and long-term storage of vitamin A as protection against vitamin A deficiency during times of low dietary intake. This review examines the biological responses that occur as TLRs are depleted. In consideration of all of the DRI criteria, the review concludes that induced biliary excretion and long-term vitamin A storage do not occur until TLRs are >0.10 µmol/g. If long-term storage is to continue to be part of the DRI criteria, vitamin A deficiency should be set at a minimum cutoff of 0.10 µmol/g and should be set higher during times of enhanced requirements where TLRs can be rapidly depleted, such as during lactation or in areas with high infection burden. In population-based surveys, cutoffs are important when using biomarkers of micronutrient status to define the prevalence of deficiency and sufficiency to inform public health interventions. Considering the increasing use of quantitative biomarkers of vitamin A status that indirectly assess TLRs, i.e. the modified-relative-dose response and retinol-isotope dilution tests, setting a TLR as a vitamin A deficiency cutoff is important for users of these techniques to estimate vitamin A deficiency prevalence. Future researchers and policymakers may suggest that DRIs should be set with regard to optimal health and not merely to prevent a micronutrient deficiency.
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http://dx.doi.org/10.1177/1535370221992731DOI Listing
March 2021

Vitamin A deficiency has declined in Malawi, but with evidence of elevated vitamin A in children.

Am J Clin Nutr 2021 Mar 5. Epub 2021 Mar 5.

Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.

Background: Reduction of vitamin A deficiency (VAD) in Malawi coincided with introduction of vitamin A-fortified staple foods, alongside continued biannual high-dose vitamin A supplementation (VAS).

Objective: We describe coverage of vitamin A interventions and vitamin A status in the 2015-2016 Malawi Micronutrient Survey.

Methods: Food samples and biospecimens were collected within a representative household survey across 105 clusters. Retinol was measured using ultraviolet excitation fluorescence (sugar) and photometric determination (oil). Preschool children (PSC, aged 6-59 mo, n = 1102), school-age children (SAC, aged 5-14 y, n = 758), nonpregnant women (n = 752), and men (n = 219) were initially assessed for vitamin A status using retinol binding protein (RBP) and modified relative dose response (MRDR). Randomly selected fasted MRDR participants (n = 247) and nonfasted women and children (n = 293) were later assessed for serum retinol, retinyl esters, and carotenoids. Analyses accounted for complex survey design.

Results: We tested sugar and oil samples from 71.8% and 70.5% of the households (n = 2,112), respectively. All of the oil samples and all but one of the sugar samples had detectable vitamin A. National mean retinol sugar and oil contents were 6.1 ± 0.7 mg/kg and 6.6 ± 1.4 mg/kg, respectively. Receipt of VAS in the previous 6 mo was reported by 68.0% of PSC. VAD prevalence (RBP equivalent to <0.7µmol retinol/L) was 3.6% in PSC, and <1% in other groups. One woman and no children had MRDR ≥0.060 indicating VAD. Among fasted PSC and SAC, 18.0% (95% CI: 6.4, 29.6) and 18.8% (7.2, 30.5) had >5% of total serum vitamin A as retinyl esters, and 1.7% (0.0, 4.1) and 4.9% (0.0, 10.2) had >10% of total serum vitamin A as retinyl esters. Serum carotenoids indicated recent intake of vitamin A-rich fruits and vegetables.

Conclusions: Near elimination of VAD in Malawi is a public health success story, but elevated levels of vitamin A among children suggests that vitamin A interventions may need modification.
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http://dx.doi.org/10.1093/ajcn/nqab004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023849PMC
March 2021

Vitamin A-fortified rice increases total body vitamin A stores in lactating Thai women measured by retinol isotope dilution: a double-blind, randomized, controlled trial.

Am J Clin Nutr 2021 Mar 1. Epub 2021 Mar 1.

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.

Background: Lactating women are at increased risk for vitamin A (VA) deficiency due to demands for breast milk content and limited hepatic stores for women in some countries. Previously, consumption of triple-fortified rice, which included VA, iron, and zinc, successfully improved the VA status of Thai children in whom their total body VA stores (TBSs) were doubled in 2 mo.

Objective: This study assessed the efficacy of consuming VA-fortified rice, which delivered 500 µg retinol activity equivalents (RAEs)/d, on TBSs and estimated total liver VA reserves (TLRs) in Thai lactating women using the retinol isotope dilution (RID) test.

Methods: A randomized controlled trial was conducted with 70 lactating women (n = 35/group) who received either VA-fortified rice (500 µg RAEs/d) or unfortified rice for 14 wk on weekdays only. Serum retinol concentrations (SRs), C-reactive protein, and TBSs were assessed before and after the intervention. The paired 13C-RID test was used to measure TBSs. After a baseline blood sample, 2.0 µmol [14,15]-13C2-retinyl acetate was administered orally. A follow-up blood sample was drawn 14 d later. The RID test was repeated after the intervention.

Results: TBSs increased significantly (P < 0.05) in the intervention group from 240 (182, 316) to 331 (251, 447) [geometric means (95% CIs)] µmol retinol, and this change in TBSs was significantly higher (P < 0.05) than that in the control group [+52.9 (-74, 453) compared with -4.3 (-106, 275) µmol retinol]. Estimated TLRs indicated a high prevalence of VA deficiency among these lactating women. Initial and final SRs did not differ by group and did not change over the course of the intervention.

Conclusion: VA-fortified rice improved the VA status of lactating women by increasing TBSs. A targeted approach to disseminate VA interventions among vulnerable groups should be considered in some contexts. This trial was registered at clinicaltrials.gov as NCT03056625.
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http://dx.doi.org/10.1093/ajcn/nqaa418DOI Listing
March 2021

Relation between Timing of High-Dose Vitamin A Supplementation and Modified-Relative-Dose-Response Values in Children 12-23 Months in Uganda.

J Nutr 2021 Apr;151(4):1025-1028

Division of Nutrition, Physical Activity, and Obesity, National Center for Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA, USA.

Background: High-dose vitamin A (VA) supplements (VAS) can temporarily affect VA status. Hence, micronutrient surveys might need to be timed around VAS campaigns to accurately estimate VA deficiency (VAD) prevalence. Little is known about optimal timing of micronutrient surveys when the modified-relative-dose-response (MRDR) is used as a VA indicator.

Objectives: We evaluated the association between days since the end of a VAS campaign and MRDR values in children aged 12-23 mo in Uganda.

Methods: We pooled data from 2 cross-sectional, population-based surveys in eastern Uganda conducted in 2015-2016 (n = 118 children). We estimated the prevalence of VAD (MRDR ≥0.060). Days since the end of a VAS campaign ("days since VAS") was calculated as the interview date minus the end date of the VAS campaign. The MRDR value was assessed using HPLC. We excluded children whose MRDR values were below the limit of detection (<0.007). We used linear regression to evaluate the association between days since VAS and log-transformed MRDR. In adjusted analyses, we controlled for potential confounders. Statistical analyses accounted for the surveys' complex design.

Results: The prevalence of VAD was 5.2% (95% CI: 1.1%, 9.3%). Mean days since VAS was 54.1 d (range 39-68 d). Days since VAS was not associated with log-transformed MRDR in unadjusted analyses ($\hat{\beta } = \ $0.0055; 95% CI: -0.009, 0.020; P = 0.45) or adjusted analyses ($\hat{\beta } = $ -0.0073; 95% CI: -0.024, 0.010; P = 0.39).

Conclusions: MRDR measurement through a nutrition survey began as early as 1.3 mo after the end of a VAS campaign in eastern Uganda. Days since the end of a VAS campaign was not associated with MRDR in Ugandan children aged 12-23 mo. Future studies should consider longitudinal designs and evaluate time since VAS and MRDR in children of different ages and in regions with higher VAD prevalence.
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http://dx.doi.org/10.1093/jn/nxaa424DOI Listing
April 2021

Adequate vitamin A liver stores estimated by the modified relative dose response test are positively associated with breastfeeding but not vitamin A supplementation in Senegalese urban children 9-23 months old: A comparative cross-sectional study.

PLoS One 2021 29;16(1):e0246246. Epub 2021 Jan 29.

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Vitamin A supplementation (VAS) in 6-59-month-old children is recommended but its sustainability is currently questioned. In Senegal, available data suggest that VAS should be maintained, but geographic and age-related specificities need to be addressed to better implement and target VAS programming. The objective of this comparative cross-sectional study, conducted in urban settings of Dakar, was to compare the vitamin A liver stores (VALS) assessed using the modified-relative dose response (MRDR) test between supplemented and non-supplemented 9-23 month-old children and to study their relationship with VAS. The supplemented group (n = 119) received VAS (either 100 000 UI or 200 000 UI) 2 to 6 months before evaluation while the non-supplemented group (n = 110) had not received VAS during the past 6 months. In addition to MRDR, serum retinol concentrations (SR), and biomarkers of subclinical inflammation were measured. Children's health-related data and feeding patterns were collected. Mean MRDR values (VAS: 0.030 ± 0.017, non-VAS: 0.028 ± 0.016, P = 0.389) and inflammation-adjusted SR (VAS: 1.34 ± 0.37, non-VAS: 1.3 ± 0.35, P = 0.515) of children were adequate. Low prevalence of VALS (VAS: 5.2%, non-VAS: 5.4%) and inflammation-adjusted VAD (VAS: 2.6%, non-VAS: 0.9%) were detected despite high presence of infections and inflammation. Children were mostly still being breastfed (VAS: 85.7%, non-VAS: 77.3%) and complementary feeding indicators were similar in both groups. Only breastfeeding was associated with VALS and was found to reduce by 76% at least, the odds of VAD (adjusted OR = 0.24, 95% CI: 0.07-0.8, P = 0.020). Based on MRDR values, VAS was not related to improved VALS and SR as well as VAD reduction among these children with adequate VALS. Reinforcing breastfeeding advocacy and morbidity prevention/control are essential in this setting. Scaling-back VAS in this subpopulation should be examined regarding the risk of hypervitaminosis A after an evaluation of dietary vitamin A intake sufficiency and a more quantitative assessment of VALS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246246PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846024PMC
January 2021

Retinol-binding protein, retinol, and modified-relative-dose response in Ugandan children aged 12-23 months and their non-pregnant caregivers.

Exp Biol Med (Maywood) 2021 Apr 19;246(8):906-915. Epub 2021 Jan 19.

Division of Nutrition, Physical Activity, and Obesity, National Center for Chronic Disease Prevention and Health Promotion, 1242Centers for Disease Control and Prevention, Atlanta, GA 30341, USA.

Retinol-binding protein (RBP), retinol, and modified-relative-dose response (MRDR) are used to assess vitamin A status. We describe vitamin A status in Ugandan children and women using dried blood spot (DBS) RBP, serum RBP, plasma retinol, and MRDR and compare DBS-RBP, serum RBP, and plasma retinol. Blood was collected from 39 children aged 12-23 months and 28 non-pregnant mothers aged 15-49 years as a subsample from a survey in Amuria district, Uganda, in 2016. DBS RBP was assessed using a commercial enzyme immunoassay kit, serum RBP using an in-house sandwich enzyme-linked immunosorbent assay, and plasma retinol/MRDR test using high-performance liquid chromatography. We examined (a) median concentration or value (Q1, Q3); (b) between DBS-RBP, serum RBP, and plasma retinol; and (c) Bland-Altman plots. Median (Q1, Q3) for children and mothers, respectively, were as follows: DBS-RBP 1.15 µmol/L (0.97, 1.42) and 1.73 (1.52, 1.96), serum RBP 0.95 µmol/L (0.78, 1.18) and 1.47 µmol/L (1.30, 1.79), plasma retinol 0.82 µmol/L (0.67, 0.99) and 1.33 µmol/L (1.22, 1.58), and MRDR 0.025 (0.014, 0.042) and 0.014 (0.009, 0.019). DBS RBP-serum RBP was 0.09 for both children and mothers. The mean biases were -0.19 µmol/L (95% limits of agreement [LOA] 0.62, -0.99) for children and -0.01 µmol/L (95% LOA -1.11, -1.31) for mothers. DBS RBP-plasma retinol was 0.11 for children and 0.13 for mothers. Mean biases were 0.33 µmol/L (95% LOA -0.37, 1.03) for children, and 0.29 µmol/L (95% LOA -0.69, 1.27) for mothers. Serum RBP-plasma retinol was 0.75 for children and 0.55 for mothers, with mean biases of 0.13 µmol/L (95% LOA -0.23, 0.49) for children and 0.18 µmol/L (95% LOA -0.61, 0.96) for mothers. Results varied by indicator and matrix. The serum RBP-retinol for children was moderate (0.75), but poor for other comparisons. Understanding the relationships among vitamin A indicators across contexts and population groups is needed.
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http://dx.doi.org/10.1177/1535370220985473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024505PMC
April 2021

Mining maize diversity and improving its nutritional aspects within agro-food systems.

Compr Rev Food Sci Food Saf 2020 07 1;19(4):1809-1834. Epub 2020 May 1.

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, Wisconsin.

Agro-food systems are undergoing rapid innovation in the world and the system's continuum is promoted at different scales with one of the main outcomes to improve nutrition of consumers. Consumer knowledge through educational outreach is important to food and nutrition security and consumer demands guide breeding efforts. Maize is an important part of food systems. It is a staple food and together with rice and wheat, they provide 60% of the world's caloric intake. In addition to being a major contributor to global food and nutrition security, maize forms an important part of the culinary culture in many areas of Africa, the Americas, and Asia. Maize genetics are being exploited to improve human nutrition with the ultimate outcome of improving overall health. By impacting the health of maize consumers, market opportunities will be opened for maize producers with unique genotypes. Although maize is a great source of macronutrients, it is also a source of many micronutrients and phytochemicals purported to confer health benefits. The process of biofortification through traditional plant breeding has increased the protein, provitamin A carotenoid, and zinc contents of maize. The objective of this paper is to review the innovations developed and promoted to improve the nutritional profiles of maize and outcomes of the maize agro-food system.
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http://dx.doi.org/10.1111/1541-4337.12552DOI Listing
July 2020

Global Concerns with B Vitamin Statuses: Biofortification, Fortification, Hidden Hunger, Interactions, and Toxicity.

Compr Rev Food Sci Food Saf 2019 Nov 11;18(6):1968-1984. Epub 2019 Sep 11.

Dept. of Nutritional Sciences, Univ. of Wisconsin-Madison, Madison, WI, 53706, U.S.A.

The prevalence of undernutrition due to insufficient energy intake has been reduced by nearly 50% since 1990. This reduction is largely attributed to improved yields of staple crops, such as wheat, rice, and maize; however, these improvements did little for micronutrient deficiencies that affect an estimated two billion people worldwide. Starchy staple crops are energy dense but are often lacking in one or more B vitamins, making resource-constrained people who consume monotonous diets comprised predominantly of these staples at risk for developing deficiency. B vitamin deficiencies occur due to a poor overall nondiversified diet and rarely occur alone. Many B vitamins are essential cofactors involved in the metabolism of other nutrients, including other B vitamins, whereby the deficiency of one B vitamin affects the metabolism and status measurements of another. Food fortification efforts have nearly eradicated diseases of extreme B vitamin deficiency, such as beriberi from thiamin deficiency and pellagra from niacin deficiency. However, subclinical deficiency, sometimes referred to as hidden hunger, is still common especially in low-income countries. Most dietary B vitamins, due to their water-soluble nature, are not a concern for excessive intakes, but synthetic forms used for fortification and supplements sometimes can have adverse effects when consumed in high amounts. Biofortified crops offer a long-term sustainable method to increase the amount of dietary B vitamins for people who rely on staple crops for most of their caloric intake. Efforts have been made to improve B vitamin content of crops, especially for thiamin, vitamin B , and folate, but none have undergone human feeding trials; therefore, more research is needed to provide sustainable and scalable solutions in many parts of the world.
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http://dx.doi.org/10.1111/1541-4337.12491DOI Listing
November 2019

Breast Milk-Derived Retinol Is a Potential Surrogate for Serum in the 13C-Retinol Isotope Dilution Test in Zambian Lactating Women with Vitamin A Deficient and Adequate Status.

J Nutr 2021 01;151(1):255-263

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.

Background: Vitamin A (VA) deficiency (VAD) affects ∼19 million pregnant women worldwide. The extent of VAD in Zambian women of reproductive age is unknown owing to lack of survey inclusion or the use of static serum retinol concentrations, a low-sensitivity biomarker.

Objectives: This cross-sectional study employed isotopic techniques to determine VA status with serum and milk among women aged 18-49 y (n = 197) either lactating with infants aged 0-24 mo or nonlactating with or without infants.

Methods: Assistants were trained and piloted data collection. Demographic data, anthropometry, and relevant histories were obtained including malaria and anemia. For retinol isotope dilution (RID), baseline fasting blood and casual breast milk samples were collected before administration of 2.0 μmol 13C2-retinyl acetate and 24-h dietary recalls. On day 14, blood (n = 144) and milk (n = 66) were collected. Prevalence of total liver VA reserves (TLR) ≤0.10 μmol/g was defined as VAD with comparison to the DRI assumption of 0.07 μmol/g as minimally acceptable for North Americans.

Results: When a 20% adjustment for dose lost to milk was made in the RID equation for lactation, mean total body VA stores (TBS) for lactating women were 25% lower than for nonlactating women (P < 0.01), which was not the case without adjustment (P = 0.3). Mean ± SD TLR for all women were 0.15 ± 0.11 μmol/g liver. Using retinol purified from breast milk instead of serum for RID analysis yielded similar TBS and TLR, which were highly correlated between methods (P < 0.0001). Serum retinol ≤0.70 μmol/L had 0% sensitivity using either VAD liver cutoff and milk retinol ≤1.0 μmol/L had 42% sensitivity for VAD at 0.10 μmol/g.

Conclusions: Determining accurate VA status among women of reproductive age, especially lactating women, forms a basis for extrapolation to the general population and informing policy development and program implementation.
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http://dx.doi.org/10.1093/jn/nxaa320DOI Listing
January 2021

Metabolism of Neonatal Vitamin A Supplementation: A Systematic Review.

Adv Nutr 2020 Nov 19. Epub 2020 Nov 19.

Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.

A systematic review was conducted to summarize the absorption, transport, storage, and metabolism of oral neonatal vitamin A supplementation (NVAS). This review focused specifically on the neonatal period (first 28 d of life for humans) to inform guidance by WHO on recommendations related to NVAS. A systematic search of international and regional databases was conducted. Inclusion criteria were human or animal studies that gave oral vitamin A as a single or limited number of doses to apparently healthy neonates. Studies evaluating fortification or food-based approaches, dosing with retinoic acid, or studies of neonatal models of disease were excluded. The search retrieved 8847 unique records. After screening by title and abstract, 88 were screened using the full text, and 35 records met inclusion criteria: 13 human and 22 animal studies. Studies indicate that high-dose NVAS is absorbed well by neonates, typically mirroring fat absorption. Doses were primarily stored in the liver and transiently increased in the lung, kidney, spleen, adrenal glands, brain, skin, and adipose tissue, generally with a dose-response. Serum retinol and retinyl esters also transiently increased following NVAS. Although minimal acute adverse effects are noted, there is a lack of data supporting NVAS for improving organ maturation or sustained delivery to target organs. Research gaps include the physiological effects of the short-term increase of vitamin A concentrations in extrahepatic tissues, or whether there are unknown adverse effects over time.
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http://dx.doi.org/10.1093/advances/nmaa137DOI Listing
November 2020

Consensus recommendations for the use of retinoids in ichthyosis and other disorders of cornification in children and adolescents.

Pediatr Dermatol 2021 Jan 10;38(1):164-180. Epub 2020 Nov 10.

Departments of Dermatology and Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Topical and systemic retinoids have long been used in the treatment of ichthyoses and other disorders of cornification. Due to the need for long-term use of retinoids for these disorders, often beginning in childhood, numerous clinical concerns must be considered. Systemic retinoids have known side effects involving bone and eye. Additionally, potential psychiatric and cardiovascular effects need to be considered. Contraceptive concerns, as well as the additive cardiovascular and bone effects of systemic retinoid use with hormonal contraception must also be deliberated for patients of childbearing potential. The Pediatric Dermatology Research Alliance (PeDRA) Use of Retinoids in Ichthyosis Work Group was formed to address these issues and to establish best practices regarding the use of retinoids in ichthyoses based on available evidence and expert opinion.
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http://dx.doi.org/10.1111/pde.14408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984068PMC
January 2021

Systematic Review and Meta-Analysis of the Relative Dose-Response Tests to Assess Vitamin A Status.

Adv Nutr 2020 Oct 31. Epub 2020 Oct 31.

Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.

Vitamin A (VA) is an essential nutrient often lacking in the diets of people in developing countries. Accurate biomarkers of VA status are vital to inform public health policy and monitor interventions. The relative dose-response (RDR) and modified-RDR (MRDR) tests are semi-quantitative screening tests for VA deficiency that have been used in Demographic and Health Surveys and VA intervention studies. A systematic review and meta-analysis of sensitivity and specificity were conducted to summarize the physiological evidence to support the RDR tests as methods to assess VA status and investigate the impact of different pathological and physiological states on the tests. A total of 190 studies were screened for inclusion, with 21 studies comparing the RDR tests with the gold-standard biomarker, liver VA concentration (68% and 80% sensitivity and 85% and 69% specificity for the RDR and MRDR, respectively). Nearly all studies with VA interventions in VA-deficient populations demonstrated a response of the tests to VA intake that would be expected to improve VA status. The impacts of chronic liver disease, protein malnutrition, age, pregnancy and lactation, infection and inflammation, and various other conditions were examined in 51 studies. The RDR and MRDR tests were reported to have been used in 39 observational studies, and the MRDR has been used in at least 6 national micronutrient surveys. The RDR and MRDR are sensitive tests for determining population VA status and assessing VA interventions. Although they are robust to most physiological and pathological states, caution may be warranted when using the tests in neonates, individuals with chronic liver disease, and those with protein or iron malnutrition. Research on further improvements to the tests to increase accessibility, such as sampling breast milk instead of blood or using intramuscular doses in subjects with malabsorption, will allow wider adoption. This review was registered with PROSPERO as CRD42019124180.
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http://dx.doi.org/10.1093/advances/nmaa136DOI Listing
October 2020

Risk factors for anaemia among Ghanaian women and children vary by population group and climate zone.

Matern Child Nutr 2021 04 18;17(2):e13076. Epub 2020 Sep 18.

GroundWork, Fläsch, Switzerland.

Anaemia has serious effects on human health and has multifactorial aetiologies. This study aimed to determine putative risk factors for anaemia in children 6-59 months and 15- to 49-year-old non-pregnant women living in Ghana. Data from a nationally representative cross-sectional survey were analysed for associations between anaemia and various anaemia risk factors. National and stratum-specific multivariable regressions were constructed separately for children and women to calculate the adjusted prevalence ratio (aPR) for anaemia of variables found to be statistically significantly associated with anaemia in bivariate analysis. Nationally, the aPR for anaemia was greater in children with iron deficiency (ID; aPR 2.20; 95% confidence interval [CI]: 1.88, 2.59), malaria parasitaemia (aPR 1.96; 95% CI: 1.65, 2.32), inflammation (aPR 1.26; 95% CI: 1.08, 1.46), vitamin A deficiency (VAD; aPR 1.38; 95% CI: 1.19, 1.60) and stunting (aPR 1.26; 95% CI: 1.09, 1.46). In women, ID (aPR 4.33; 95% CI: 3.42, 5.49), VAD (aPR 1.61; 95% CI: 1.24, 2.09) and inflammation (aPR 1.59; 95% CI: 1.20, 2.11) were associated with anaemia, whereas overweight and obese women had lower prevalence of anaemia (aPR 0.74; 95% CI: 0.56, 0.97). ID was associated with child anaemia in the Northern and Middle belts, but not in the Southern Belt; conversely, inflammation was associated with anaemia in both children and women in the Southern and Middle belts, but not in the Northern Belt. Anaemia control programmes should be region specific and aim at the prevention of ID, malaria and other drivers of inflammation as they are the main predictors of anaemia in Ghanaian children and women.
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http://dx.doi.org/10.1111/mcn.13076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988882PMC
April 2021

High-Dose Neonatal Vitamin A Supplementation to Bangladeshi Infants Increases the Percentage of CCR9-Positive Treg Cells in Infants with Lower Birthweight in Early Infancy, and Decreases Plasma sCD14 Concentration and the Prevalence of Vitamin A Deficiency at Two Years of Age.

J Nutr 2020 11;150(11):3005-3012

USDA Western Human Nutrition Research Center at University of California, Davis, CA, USA.

Background: Vitamin A (VA) stores are low in early infancy and may impair development of the immune system.

Objective: This study determined if neonatal VA supplementation (VAS) affects the following: 1) development of regulatory T (Treg) cells; 2) chemokine receptor 9 (CCR9) expression, which directs mucosal targeting of immune cells; and 3) systemic endotoxin exposure as indicated by changed plasma concentrations of soluble CD14 (sCD14). Secondarily, VA status, growth, and systemic inflammation were investigated.

Methods: In total, 306 Bangladeshi infants were randomly assigned to receive 50,000 IU VA or placebo (PL) within 48 h of birth, and immune function was assessed at 6 wk, 15 wk, and 2 y. Primary outcomes included the following: 1) peripheral blood Treg cells; 2) percentage of Treg, T, and B cells expressing CCR9; and 3) plasma sCD14. Secondary outcomes included the following: 4) VA status measured using the modified relative dose-response (MRDR) test and plasma retinol; 5) infant growth; and 6) plasma C-reactive protein (CRP). Statistical analysis identified group differences and interactions with sex and birthweight.

Results: VAS increased (P = 0.004) the percentage of CCR9+ Treg cells (13.2 ± 1.37%) relative to PL (9.17 ± 1.15%) in children below the median birthweight but had the opposite effect (P = 0.04) in those with higher birthweight (VA, 9.13 ± 0.89; PL, 12.1 ± 1.31%) at 6 and 15 wk (values are combined mean ± SE). VAS decreased (P = 0.003) plasma sCD14 (1.56 ± 0.025 mg/L) relative to PL (1.67 ± 0.032 mg/L) and decreased (P = 0.034) the prevalence of VA deficiency (2.3%) relative to PL (9.2%) at 2 y.

Conclusions: Neonatal VAS enhanced mucosal targeting of Treg cells in low-birthweight infants. The decreased systemic exposure to endotoxin and improved VA status at 2 y may have been due to VA-mediated improvements in gut development resulting in improved barrier function and nutrient absorption. This trial was registered at clinicaltrials.gov as NCT01583972 and NCT02027610.
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http://dx.doi.org/10.1093/jn/nxaa260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675026PMC
November 2020

Findings in 3 clinical trials challenge the accuracy of the Institute of Medicine's estimated average requirements for vitamin A in children and women.

Am J Clin Nutr 2020 Jun 3. Epub 2020 Jun 3.

Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.

Background: Vitamin A (VA) estimated average requirements (EARs) for women and children are extrapolated from rats and adult males. The retinol isotope dilution (RID) test can sensitively characterize VA status and intake requirements.

Objectives: These studies evaluated current EARs for children 4-8 y and women 19-30 y old.

Methods: Zambian children (n = 133, ages 5-7 y), US women (n = 51, ages 19-27 y), and Indonesian women (n = 29, ages 19-30 y) were provided diets or supplements containing 30%-155% of VA EARs for 42-90 d. RID was performed before and after the intervention to quantify changes in total body VA stores (TBSs) and total liver VA reserves (TLRs). Linear regression was performed between VA intake and change in TBSs or TLRs.

Results: Baseline mean ± SD TLRs were hypervitaminotic in Zambian children (1.13 ± 0.41 μmol VA/g liver), optimal in US women (0.46 ± 0.32 μmol/g VA/g liver), and deficient to marginal in Indonesian women (0.10 ± 0.08 μmol VA/g liver). VA intakes, resulting in no change in TBSs or TLRs, were 185 (95% CI: 18, 288) or 257 (95% CI: 124, 411) and 285 or 330 (CIs undefined) μg retinol activity equivalents (RAE)/d in the Zambian and US trials, respectively, but inconclusive in Indonesian women. The regression was not significant in either group of women.

Conclusions: Point estimates of VA intakes to maintain stores were below the current EARs of 275 (children) and 500 (women) μg RAE/d despite the TLRs being higher than the EARs were formulated to maintain (i.e., 0.07 μmol VA/g liver). Interventions based on these EARs may need to be scaled back. Lack of change in VA stores in women taking lower doses may result from physiological adaptation resulting in lower VA utilization. Longer, larger, and controlled studies are needed to accurately define EARs for VA.These trials were registered at Clinicaltrials.gov as NCT04123210 and NCT01814891.
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http://dx.doi.org/10.1093/ajcn/nqaa132DOI Listing
June 2020

Dynamics of vitamin A uptake, storage, and utilization in vocal fold mucosa.

Mol Metab 2020 10 28;40:101025. Epub 2020 May 28.

Division of Otolaryngology, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53792, USA. Electronic address:

Objective: Extrahepatic vitamin A is housed within organ-specific stellate cells that support local tissue function. These cells have been reported in the vocal fold mucosa (VFM) of the larynx; however, it is unknown how vitamin A reaches and is disseminated among VFM target cells, how VFM storage and utilization vary as a function of total body stores, and how these parameters change in the context of pathology. Therefore, in this study, we investigated fundamental VFM vitamin A uptake and metabolism.

Methods: Using cadaveric tissue and serum from human donors representing the full continuum of clinical vitamin A status, we established a concentration range and analyzed the impact of biologic and clinical covariates on VFM vitamin A. We additionally conducted immunodetection of vitamin A-associated markers and pharmacokinetic profiling of orally dosed α-retinyl ester (a chylomicron tracer) in rats.

Results: Serum vitamin A was a significant predictor of human VFM concentrations, suggesting that VFM stores may be rapidly metabolized in situ and replenished from the circulatory pool. On a vitamin A-sufficient background, dosed α-vitamin A was detected in rat VFM in both ester and alcohol forms, showing that, in addition to plasma retinol and local stellate cell stores, VFM can access and process postprandial retinyl esters from circulating chylomicra. Both α forms were rapidly depleted, confirming the high metabolic demand for vitamin A within VFM.

Conclusion: This thorough physiological analysis validates VFM as an extrahepatic vitamin A repository and characterizes its unique uptake, storage, and utilization phenotype.
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http://dx.doi.org/10.1016/j.molmet.2020.101025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322172PMC
October 2020

Overlapping Vitamin A Interventions with Provitamin A Carotenoids and Preformed Vitamin A Cause Excessive Liver Retinol Stores in Male Mongolian Gerbils.

J Nutr 2020 11;150(11):2912-2923

Interdepartmental Graduate Program in Nutritional Sciences, Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.

Background: Vitamin A (VA) deficiency is a public health problem in some countries. Fortification, supplementation, and increased provitamin A consumption through biofortification are efficacious, but monitoring is needed due to risk of excessive VA intake when interventions overlap.

Objectives: Two studies in 28-36-d-old male Mongolian gerbils simulated exposure to multiple VA interventions to determine the effects of provitamin A carotenoid consumption from biofortified maize and carrots and preformed VA fortificant on status.

Methods: Study 1 was a 2 × 2 × 2 factorial design (n = 85) with high-β-carotene maize, orange carrots, and VA fortification at 50% estimated gerbil needs, compared with white maize and white carrot controls. Study 2 was a 2 × 3 factorial design (n = 66) evaluating orange carrot and VA consumption through fortification at 100% and 200% estimated needs. Both studies utilized 2-wk VA depletion, baseline evaluation, 9-wk treatments, and liver VA stores by HPLC. Intestinal scavenger receptor class B member 1 (Scarb1), β-carotene 15,15'-dioxygenase (Bco1), β-carotene 9',10'-oxygenase (Bco2), intestine-specific homeobox (Isx), and cytochrome P450 26A1 isoform α1 (Cyp26a1) expression was analyzed by qRT-PCR in study 2.

Results: In study 1, liver VA concentrations were significantly higher in orange carrot (0.69 ± 0.12 μmol/g) and orange maize groups (0.52 ± 0.21 μmol/g) compared with baseline (0.23 ± 0.069 μmol/g) and controls. Liver VA concentrations from VA fortificant alone (0.11 ± 0.053 μmol/g) did not differ from negative control. In study 2, orange carrot significantly enhanced liver VA concentrations (0.85 ± 0.24 μmol/g) relative to baseline (0.43 ± 0.14 μmol/g), but VA fortificant alone (0.42 ± 0.21 μmol/g) did not. Intestinal Scarb1 and Bco1 were negatively correlated with increasing liver VA concentrations (P < 0.01, r2 = 0.25-0.27). Serum retinol concentrations did not differ.

Conclusions: Biofortified carrots and maize without fortification prevented VA deficiency in gerbils. During adequate provitamin A dietary intake, preformed VA intake resulted in excessive liver stores in gerbils, despite downregulation of carotenoid absorption and cleavage gene expression.
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http://dx.doi.org/10.1093/jn/nxaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023580PMC
November 2020

Metabolomics Reveals Altered Hepatic Bile Acids, Gut Microbiome Metabolites, and Cell Membrane Lipids Associated with Marginal Vitamin A Deficiency in a Mongolian Gerbil Model.

Mol Nutr Food Res 2020 07 22;64(13):e1901319. Epub 2020 Jun 22.

West Coast Metabolomics Center, University of California, Davis, CA, USA.

Scope: This study is designed to provide a broad evaluation of the impacts of vitamin A (VA) deficiency on hepatic metabolism in a gerbil model.

Methods And Results: After 28 days of VA depletion, male Mongolian gerbils (Meriones unguiculatus) are randomly assigned to experimental diets for 28 days. Groups are fed a white-maize-based diet with ≈50 µL cottonseed oil vehicle either alone (VA-, n = 10) or containing 40 µg retinyl acetate (VA+, n = 10) for 28 days. Liver retinol is measured by high-performance liquid chromatography. Primary metabolomics, aminomics, lipidomics, bile acids, oxylipins, ceramides, and endocannabinoids are analyzed in post-mortem liver samples by liquid chromatography-mass spectrometry.

Results: Liver retinol is lower (p < 0.001) in the VA- versus VA+ group, with concentrations indicating marginal VA deficiency. A total of 300 metabolites are identified. Marginal VA deficiency is associated with lower bile acids, trimethylamine N-oxide, and a variety of acylcarnitines, phospholipids and sphingomyelins (p < 0.05). Components of DNA, including deoxyguanosine, cytidine, and N-carbomoyl-beta-alanine (p < 0.05), are differentially altered.

Conclusions: Hepatic metabolomics in a marginally VA-deficient gerbil model revealed alterations in markers of the gut microbiome, fatty acid and nucleotide metabolism, and cellular structure and signaling.
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http://dx.doi.org/10.1002/mnfr.201901319DOI Listing
July 2020

Modified relative dose response values differ between lactating women in the United States and Indonesia.

Exp Biol Med (Maywood) 2020 05 23;245(9):797-804. Epub 2020 Apr 23.

Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.

Impact Statement: Vitamin A (VA) deficiency is a major health issue globally, and lactating women are particularly vulnerable due to increased needs for milk production. Accurate detection of VA deficiency is important; however, most population surveys measure VA status using serum retinol, which is affected by inflammation and lacks sensitivity. The modified relative dose response (MRDR) test qualitatively distinguishes between VA deficiency and sufficiency and could improve population surveys if completed in a randomly selected subsample of individuals in surveys. The original relative dose response test required two blood samples, while MRDR requires only one, a significant improvement in accessibility of the technique by decreasing burden on subjects and investigators. This work demonstrates significant deficiency in Indonesian women compared with US women. In combination with previous research using lactating sows, these human data support milk as a surrogate for blood in the MRDR, which may be less invasive, but requires further validation.
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http://dx.doi.org/10.1177/1535370220921550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273887PMC
May 2020

The "Super-Child" Approach Is Applied To Estimate Retinol Kinetics and Vitamin A Total Body Stores in Mexican Preschoolers.

J Nutr 2020 06;150(6):1644-1651

Department of Nutrition, Research Center for Food and Development, Hermosillo, Sonora, Mexico.

Background: Retinol isotope dilution (RID) and model-based compartmental analysis are recognized techniques for assessing vitamin A (VA) status. Recent studies have shown that RID predictions of VA total body stores (TBS) can be improved by using modeling and that VA kinetics and TBS in children can be effectively studied by applying population modeling ("super-child" approach) to a composite data set.

Objectives: The objectives were to model whole-body retinol kinetics and predict VA TBS in a group of Mexican preschoolers using the super-child approach and to use model predictions of RID coefficients to estimate TBS by RID in individuals.

Methods: Twenty-four healthy Mexican children (aged 3-6 y) received an oral dose (2.96 μmol) of [13C10]retinyl acetate in corn oil. Blood samples were collected from 8 h to 21 d after dosing, with each child sampled at 4 d and at 1 other time. Composite data for plasma labeled retinol compared with time were analyzed using a 6-component model to obtain group retinol kinetic parameters and pool sizes. Model-predicted TBS was compared with mean RID predictions at 4 d; RID estimates at 4 d were compared with those calculated at 7-21 d.

Results: Model-predicted TBS was 1097 μmol, equivalent to ∼2.4 y-worth of VA; using model-derived coefficients, group mean RID-predicted TBS was 1096 μmol (IQR: 836-1492 μmol). TBS at 4 d compared with a later time was similar (P = 0.33). The model predicted that retinol spent 1.5 h in plasma during each transit and recycled to plasma 13 times before utilization.

Conclusions: The super-child modeling approach provides information on whole-body VA kinetics and can be used with RID to estimate TBS at any time between 4 and 21 d postdose. The high TBS predicted for these children suggests positive VA balance, likely due to large-dose VA supplements, and warrants further investigation.
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http://dx.doi.org/10.1093/jn/nxaa048DOI Listing
June 2020

Cyp1b1 directs Srebp-mediated cholesterol and retinoid synthesis in perinatal liver; Association with retinoic acid activity during fetal development.

PLoS One 2020 6;15(2):e0228436. Epub 2020 Feb 6.

Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI.

Background: Cytochrome P450 1b1 (Cyp1b1) deletion and dietary retinol deficiency during pregnancy (GVAD) affect perinatal liver functions regulated by Srebp. Cyp1b1 is not expressed in perinatal liver but appears in the E9.5 embryo, close to sites of retinoic acid (RA) signaling.

Hypothesis: Parallel effects of Cyp1b1 and retinol on postnatal Srebp derive from effects in the developing liver or systemic signaling.

Approach: Cluster postnatal increases in hepatic genes in relation to effects of GVAD or Cyp1b1 deletion. Sort expression changes in relation to genes regulated by Srebp1 and Srebp2.Test these treatments on embryos at E9.5, examining changes at the site of liver initiation. Use in situ hybridization to resolve effects on mRNA distributions of Aldh1a2 and Cyp26a1 (RA homeostasis); Hoxb1 and Pax6 (RA targets). Assess mice lacking Lrat and Rbp4 (DKO mice) that severely limits retinol supply to embryos.

Results: At birth, GVAD and Cyp1b1 deletion stimulate gene markers of hepatic stellate cell (HSC) activation but also suppress Hamp. These treatments then selectively prevent the postnatal onset of genes that synthesize cholesterol (Hmgcr, Sqle) and fatty acids (Fasn, Scd1), but also direct cholesterol transport (Ldlr, Pcsk9, Stard4) and retinoid synthesis (Aldh1a1, Rdh11). Extensive support by Cyp1b1 is implicated, but with distinct GVAD interventions for Srebp1 and Srebp2. At E9.5, Cyp1b1 is expressed in the septum transversum mesenchyme (STM) with β-carotene oxygenase (Bco1) that generates retinaldehyde. STM provides progenitors for the HSC and supports liver expansion. GVAD and Cyp1b1-/- do not affect RA-dependent Hoxb1 and Pax6. In DKO embryos, RA-dependent Cyp26a1 is lost but Hoxb1 is sustained with Cyp1b1 at multiple sites.

Conclusion: Cyp1b1-/- suppresses genes supported by Srebp. GVAD effects distinguish Srebp1 and Srebp2 mediation. Srebp regulation overlaps appreciably in cholesterol and retinoid homeostasis. Bco1/Cyp1b1 partnership in the STM may contribute to this later liver regulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228436PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004353PMC
April 2020

Anemia, micronutrient deficiencies, malaria, hemoglobinopathies and malnutrition in young children and non-pregnant women in Ghana: Findings from a national survey.

PLoS One 2020 30;15(1):e0228258. Epub 2020 Jan 30.

GroundWork, Fläsch, Switzerland.

Nationally representative data on the micronutrient status of Ghanaian women and children are very scarce. We aimed to document the current national prevalence of micronutrient deficiencies, anemia, malaria, inflammation, α-thalassemia, sickle cell disease and trait, and under- and over-nutrition in Ghana. In 2017, a two-stage cross-sectional design was applied to enroll pre-school children (6-59 months) and non-pregnant women (15-49 years) from three strata in Ghana: Northern, Middle and Southern Belt. Household and individual questionnaire data were collected along with blood samples. In total, 2123 households completed the household interviews, 1165 children and 973 women provided blood samples. Nationally, 35.6% (95%CI: 31.7,39.6) of children had anemia, 21.5% (18.4,25.0) had iron deficiency, 12.2% (10.1,14.7) had iron deficiency anemia, and 20.8% (18.1,23.9) had vitamin A deficiency; 20.3%(15.2,26.6) tested positive for malaria, 13.9% (11.1,17.3) for sickle trait plus disease, and 30.7% (27.5,34.2) for α-thalassemia. Anemia and micronutrient deficiencies were more prevalent in rural areas, poor households and in the Northern Belt. Stunting and wasting affected 21.4% (18.0,25.2) and 7.0% (5.1,9.5) of children, respectively. Stunting was more common in rural areas and in poor households. Among non-pregnant women, 21.7% (18.7,25.1) were anemic, 13.7% (11.2,16.6) iron deficient, 8.9% (6.7,11.7) had iron deficiency anemia, and 1.5% (0.8,2.9) were vitamin A deficient, 53.8% (47.6,60.0) were folate deficient, and 6.9% (4.8,9.8) were vitamin B12 deficient. Malaria parasitemia in women [8.4% (5.7,12.2)] was lower than in children, but the prevalence of sickle cell disease or trait and α-thalassemia were similar. Overweight [24.7% (21.0,28.8)] and obesity [14.3% (11.5,17.7)] were more common in wealthier, older, and urban women. Our findings demonstrate that anemia and several micronutrient deficiencies are highly present in Ghana calling for the strengthening of Ghana's food fortification program while overweight and obesity in women are constantly increasing and need to be addressed urgently through governmental policies and programs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228258PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991996PMC
May 2020

The Dawn of a New Era in Vitamin A Assessment.

J Nutr 2020 02;150(2):185-187

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.

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http://dx.doi.org/10.1093/jn/nxz283DOI Listing
February 2020

Perspective: Integration to Implementation (I-to-I) and the Micronutrient Forum-Addressing the Safety and Effectiveness of Vitamin A Supplementation.

Adv Nutr 2020 03;11(2):185-199

Nutrition International, Ottawa, Ontario, Canada.

An ongoing challenge to our ability to address the role of food and nutrition in health promotion and disease prevention is how to design and implement context-specific interventions and guidance that are safe, efficacious, and avoid unintended consequences. The integration to effective implementation (I-to-I) concept is intended to address the complexities of the global health context through engagement of the continuum of stakeholders involved in the generation, translation, and implementation of evidence to public health guidance/programs. The I-to-I approach was developed under the auspices of the Micronutrient Forum and has been previously applied to the question of safety and effectiveness of interventions to prevent and treat nutritional iron deficiency. The present article applies the I-to-I approach to questions regarding the safety and utility of large-dose vitamin A supplementation programs, and presents the authors' perspective on key aspects of the topic, including coverage of the basic and applied biology of vitamin A nutrition and assessment, clinical implications, and an overview of the extant data with regard to both the justification for and utility of available intervention strategies. The article includes some practical considerations based on specific country experiences regarding the challenges of implementing vitamin A-related programs. This is followed by an overview of some challenges associated with engagement of the enabling communities that play a critical role in the implementation of these types of public health interventions. The article concludes with suggestions for potential approaches to move this important agenda forward.
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http://dx.doi.org/10.1093/advances/nmz100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442412PMC
March 2020

Changes in micronutrient and inflammation serum biomarker concentrations after a norovirus human challenge.

Am J Clin Nutr 2019 12;110(6):1456-1464

Hubert Department of Global Health, Emory University, Atlanta, GA, USA.

Background: To accurately assess micronutrient status, it is necessary to characterize the effects of inflammation and the acute-phase response on nutrient biomarkers.

Objective: Within a norovirus human challenge study, we aimed to model the inflammatory response of C-reactive protein (CRP) and α-1-acid glycoprotein (AGP) by infection status, model kinetics of micronutrient biomarkers by inflammation status, and evaluate associations between inflammation and micronutrient biomarkers from 0 to 35 d post-norovirus exposure.

Methods: Fifty-two healthy adults were enrolled into challenge studies in a hospital setting and followed longitudinally; all were exposed to norovirus, half were infected. Post hoc analysis of inflammatory and nutritional biomarkers was performed. Subjects were stratified by inflammation resulting from norovirus exposure. Smoothed regression models analyzed the kinetics of CRP and AGP by infection status, and nutritional biomarkers by inflammation. Linear mixed-effects models were used to analyze the independent relations between CRP, AGP, and biomarkers for iron, vitamin A, vitamin D, vitamin B-12, and folate from 0 to 35 d post-norovirus exposure.

Results: Norovirus-infected subjects had median (IQR) peak concentrations for CRP [16.0 (7.9-29.5) mg/L] and AGP [0.9 (0.8-1.2) g/L] on day 3 and day 4 postexposure, respectively. Nutritional biomarkers that differed (P < 0.05) from baseline within the inflamed group were ferritin (elevated day 3), hepcidin (elevated days 2, 3), serum iron (depressed days 2-4), transferrin saturation (depressed days 2-4), and retinol (depressed days 3, 4, and 7). Nutritional biomarker concentrations did not differ over time within the uninflamed group. In mixed models, CRP was associated with ferritin (positive) and serum iron and retinol (negative, P < 0.05).

Conclusion: Using an experimental infectious challenge model in healthy adults, norovirus infection elicited a time-limited inflammatory response associated with altered serum concentrations of certain iron and vitamin A biomarkers, confirming the need to consider adjustments of these biomarkers to account for inflammation when assessing nutritional status. These trials were registered at clinicaltrials.gov as NCT00313404 and NCT00674336.
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http://dx.doi.org/10.1093/ajcn/nqz201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885472PMC
December 2019

South African preschool children habitually consuming sheep liver and exposed to vitamin A supplementation and fortification have hypervitaminotic A liver stores: a cohort study.

Am J Clin Nutr 2019 07;110(1):91-101

Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI.

Background: In some regions, multiple vitamin A (VA) interventions occur in the same target groups, which may lead to excessive stores. Retinol isotope dilution (RID) is a more sensitive technique than serum retinol to measure VA status.

Objective: We evaluated VA status before and after a high-dose supplement in preschool children living in a region in South Africa with habitual liver consumption and exposed to VA supplementation and fortification.

Methods: After baseline blood samples, subjects (46.7 ± 8.4 mo; n = 94) were administered 1.0 μmol [14,15]-13C2-retinyl acetate to estimate total liver retinol reserves by RID with a follow-up 14-d blood sample. Liver intake was assessed with a frequency questionnaire. In line with current practice, a routine 200,000 IU VA capsule was administered after the RID test. RID was repeated 1 mo later. Serum retinyl esters were evaluated using ultra-performance liquid chromatography.

Results: At baseline, 63.6% of these children had hypervitaminosis A defined as total liver retinol reserves ≥1.0 μmol/g liver, which increased to 71.6% after supplementation (1.13 ± 0.43 to 1.29 ± 0.46 μmol/g; P < 0.001). Total serum VA as retinyl esters was elevated in 4.8% and 6.1% of children before and after supplementation. The odds of having hypervitaminosis A at baseline were higher in children consuming liver ≥1/mo (ratio 3.70 [95% CI: 1.08, 12.6]) and in children receiving 2 (4.28 [1.03, 17.9]) or 3 (6.45 [0.64, 65.41]) supplements in the past 12 mo. Total body stores decreased after the supplement in children in the highest quartile at baseline compared with children with lower stores, who showed an increase (P = 0.007).

Conclusions: In children, such as this cohort in South Africa, with adequate VA intake through diet, and overlapping VA fortification and supplementation, preschool VA capsule distribution should be re-evaluated. This trial was registered at https://clinicaltrials.gov/ct2/show/NCT02915731 as NCT02915731.
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http://dx.doi.org/10.1093/ajcn/nqy382DOI Listing
July 2019

Carrot Leaves Maintain Liver Vitamin A Concentrations in Male Mongolian Gerbils Regardless of the Ratio of α- to β-Carotene When β-Carotene Equivalents Are Equalized.

J Nutr 2019 06;149(6):951-958

Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI.

Background: Carrots are an important horticultural crop that contain provitamin A carotenoids (PACs). Orange carrots have high concentrations of α-carotene, which upon central cleavage yields 1 retinal and 1 α-retinal molecule. The leaves of carrot plants are a source of PACs when consumed.

Objective: Male Mongolian gerbils aged 27-30 d were used to assess the bioefficacy of carrot leaves to maintain vitamin A (VA) status and investigate whether the ratio of α- to β-carotene (α:β-carotene) affected bioefficacy.

Methods: After 3 wk depletion, baseline gerbils were killed (n = 6) and the remaining gerbils (n = 60) were divided into 6 groups to receive 4 VA-deficient, carrot leaf-fortified feeds (1:1.4, 1:2.5, 1:5.0, and 1:80 α:β-carotene ratio) equalized to 4.8 nmol/g β-carotene equivalents (βCEs), or VA-deficient feed with (VA+) or without (VA-) retinyl acetate supplements. Carrot-leaf powder from 4 carrot plants with differing α:β-carotene ratios was used. After 4 wk, gerbils were killed and tissues were collected and analyzed for retinoids by HPLC.

Results: VA+ had higher total liver VA (means ± SD 0.91 ± 0.29 μmol) than all other groups (range: 0.40-0.62) (P ≤ 0.03), and the carrot leaf treatments did not differ from baseline (0.55 ± 0.09 μmol). VA- (0.40 ± 0.23 μmol VA/liver) did not differ from the leaf-fed groups, but 30% became VA deficient (defined as <0.1 μmol VA/g liver). α-Retinol accumulated in livers and lungs and was correlated to total α-carotene consumption (R2 = 0.83 and 0.88, respectively; P < 0.0001). Bioefficacy factors ranged from 4.2 to 6.2 μg βCE to 1 μg retinol.

Conclusions: Carrot leaves maintain VA status and prevent deficiency in gerbils regardless of the α:β-carotene ratio. The bioconversion of PACs from carrot leaves to retinol is similar to what has been reported for other green leafy vegetables, making the consumption of carrot leaves a viable method to improve dietary PAC intake.
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http://dx.doi.org/10.1093/jn/nxz036DOI Listing
June 2019

Retinol isotope dilution accurately predicts liver reserves in piglets but overestimates reserves in lactating sows.

Exp Biol Med (Maywood) 2019 05 19;244(7):579-587. Epub 2019 Mar 19.

Interdepartmental Graduate Program in Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.

Impact Statement: Vitamin A (VA) deficiency and hypervitaminosis A have been reported in groups of people worldwide. Conventional biomarkers of VA deficiency (e.g. serum retinol concentration, dose response tests) are not able to distinguish between sufficiency and hypervitaminosis A. Retinol isotope dilution (RID) predictions of VA status have been validated in humans and animal models from deficiency through toxicity; however, RID during life stages with unique issues related to isotopic tracing, such as infancy and lactation, requires further evaluation. This study investigated RID in piglets and lactating sows as models for human infants and women. In piglets, RID successfully determined VA deficiency (confirmed with liver analysis), and that the tracer mixes quickly. Conversely, in lactating sows, although serum and milk enrichments were similar, traditional RID equations overestimated VA stores, likely due to losses of tracer and higher extrahepatic VA storage than predictions. These data inform researchers about the challenges of using RID during lactation.
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http://dx.doi.org/10.1177/1535370219838785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545696PMC
May 2019

Community mobilization during biofortified orange maize feeding trials in Zambia.

Int J Vitam Nutr Res 2020 Jun 26;90(3-4):257-265. Epub 2019 Feb 26.

University of Wisconsin-Madison, Madison, USA.

In some societies, studies involving blood draws, oral vaccinations, or supplementation are surrounded by myths and disbeliefs. If not clarified, they may affect study implementation and negatively impact the outcome of well-intended studies from inadequate participation. Through participatory action research, this paper suggests how future trials could be enhanced with reference to community mobilization, drawing from the experience of two interventions in Zambian children with nutritionally enhanced, biofortified orange maize conducted by the National Food and Nutrition Commission and Tropical Diseases Research Center (Zambia), and University of Wisconsin-Madison (USA). The preparatory phase included site visits, signing of a Memorandum of Understanding, equipment inventory, hiring staff, and community meetings. Prior results were shared before the second intervention. After Institutional Review Boards' approval of procedures, written informed consent was obtained from caregivers. There was overwhelming community participation attributed to the demystification that the project was run by satanists prior to and during the study. Participation led to excellent compliance with 92.8 and 96.4% of subjects completing the final blood draw in 2010 and 2012, respectively. The results of the trials were successfully shared with the district officials and communities from where the study participants were drawn. The positive response by partners and communities, including information sharing, suggests that community mobilization, with the use of varied methods, is effective for full participation of the target groups in feeding trials and would be the case in similar trials if effectively carried out. Community participation in research studies may result in long-term adoption of biofortified foods.
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http://dx.doi.org/10.1024/0300-9831/a000541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170181PMC
June 2020