Common Micronutrient Deficiency Research Articles

Nutritional Deficiencies in Severe Obesity: a Multiethnic Asian Cohort.

Micronutrient deficiencies are highly prevalent in patients seeking metabolic-bariatric surgery (MBS), although literature remains scant in Asia. In this study, we assess the prevalence of nutritional deficiencies in patients with clinically severe obesity in Singapore and examine factors associated with the deficiencies. This is a prospective, observational study of 577 consecutive patients scheduled to undergo MBS. Nutritional profile including renal panel, calcium, phosphate, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25(OH)D), vitamin B12, folate, ferritin, iron studies, hemoglobin, albumin, and alkaline phosphatase were analyzed. Mean age was 40.6 ± 10.3years, 61.2% female, and mean BMI 42.4 ± 8.4kg/m2. 92.9% had suboptimal vitamin D levels; of which 25.6% had vitamin D insufficiency (25(OH)D < 30mcg/L), 57.5% had vitamin D deficiency (25(OH)D < 20mcg/L), and 9.8% had severe vitamin D deficiency (25(OH)D < 10mcg/L). Younger age, female gender, and higher BMI were independent factors associated with lower 25(OH)D. There was an inverse relationship between iPTH and 25(OH)D, with an inflection point at 25(OH)D of approximately 20mcg/L. Folate deficiency was present in 31% and vitamin B12 deficiency in 9.5% of the cohort. Serum ferritin levels were low in 29.3%. 25(OH)D, ferritin, serum iron, and albumin were also significantly higher in Chinese compared to Malay and Indian patients. Vitamin D deficiency was the most common micronutrient deficiency observed in this multi-ethnic Asian cohort presenting for MBS. Ethnic differences in nutritional status were observed.

Thyroid dysfunction in region of excess iodine intake of eastern Nepal

Iodine deficiency is one of most common micronutrient deficiencies worldwide, the consequences of excess iodine should not be ignored. Both chronic iodine excess and iodine deficiency can result in thyroid dysfunction in populations, especially children and pregnant women if not corrected. This is because children and pregnant women are very vulnerable to iodine deficiency and sensitive to iodine changes

Interventional Strategies for Control of Anemia among Rural Young Women in Coimbatore

Anaemia is the most common micro-nutrient deficiency disorder in the world. The prevalence of anaemia is higher in developing countries than in developed countries. Anaemia affects half a billion women of reproductive age worldwide. India had always been the country with the highest prevalence of anaemia and the home of the largest number of anaemic individuals in the world. A cross sectional community based study was conducted to estimate the prevalence of anaemia among 700 young women in the age group of 19-35 years hailing from different rural areas of Karamadai from Coimbatore district and to assess their iron nutriture. Data on anthropometric measurements, biochemical investigations and dietary details were recorded using a pre-designed, pre-tested proforma. Data were analyzed statistically using mean, standard deviation and ANOVA. Hemoglobin estimation (Cyanmet haemoglobin method) revealed that the prevalence of anaemia among rural women (N = 580) and it was reported that 84.83% of the rural young women were moderately anaemic and 14.83% were mild anaemic. A subsample of 85 moderate anaemic subjects were divided into Group 1 (Nutrition Education + Food supplement intervention), Group 2 (Nutrition Education+Kitchen garden intervention) and Group 3 (Nutrition Education intervention) and subjected to respective intervention for four months. Biochemical analysis revealed significant increase (p≤0.01) in haemoglobin level among the subjects in Group 1, Group 2 and Group 3 after intervention further showing that the majority of rural women improved from moderate to mild level of anaemia and from mild level to normal level of hemoglobin after intervention. Therefore the intervention measures are more effective when they are integrated with other approaches namely better nutritional practices, fortification, dietary modification, infection control, public health measures and income generation programmes. Nutrition education must be made an integral part to all the strategies.

Zinc Deficiency among Lactating Mothers from a Peri-Urban Community of the Ecuadorian Andean Region: An Initial Approach to the Need of Zinc Supplementation.

Zinc is an important mineral for biological and physiological processes. Zinc deficiency (ZD) is one of the most common micronutrient deficiencies worldwide and a crucial determinant of pregnancy outcomes and childhood development. Zinc levels and the zinc supplementation rate among lactating women have not been assessed neither in Ecuador nor in the Andean region. We conducted a pilot study including 64 mothers of infants between eight days to seven months old from a primary care center located in Conocoto, a peri-urban community of Quito, Ecuador. The mothers were interviewed and a fasting blood sample was taken to determine plasma zinc levels. The prevalence of ZD was calculated and compared with the prevalence of ZD among Ecuadorian non-pregnant non-lactating women, and the sample was analysed considering zinc supplementation during pregnancy. The prevalence of ZD among the participants was 81.3% (95% CI: 71.7–90.9), higher than the reported among non-pregnant non-lactating women (G2 = 18.2; p < 0.05). Zinc supplementation rate was 31.2%. No significant differences were found comparing the groups considering zinc supplementation. The insights obtained from this study encourage extending studies to document zinc levels and its interactions among breastfeeding women in areas with a high prevalence of ZD in order to determine the need of zinc supplementation.

Effect of infant feeding practices on iron status in a cohort study of Bolivian infants

BackgroundIron deficiency (ID) is the most common micronutrient deficiency worldwide, with potentially severe consequences on child neurodevelopment. Though exclusive breastfeeding (EBF) is recommended for 6 months, breast milk has low iron content. This study aimed to estimate the effect of the length of EBF on iron status at 6 – 8 months of age among a cohort of Bolivian infants.MethodsMother-infant pairs were recruited from 2 hospitals in El Alto, Bolivia, and followed from one through 6 – 8 months of age. Singleton infants > 34 weeks gestational age, iron-sufficient at baseline, and completing blood draws at 2 and 6 – 8 months of age were eligible for inclusion (N = 270). Ferritin was corrected for the effect of inflammation. ID was defined as inflammation-corrected ferritin < 12 μg/L, and anemia was defined as altitude-corrected hemoglobin < 11 g/dL; IDA was defined as ID plus anemia. The effect of length of EBF (infant received only breast milk with no other liquids or solids, categorized as < 4, 4 – 6, and > 6 months) was assessed for ID, IDA, and anemia (logistic regression) and ferritin (Fer) and hemoglobin (Hb, linear regression).ResultsLow iron status was common among infants at 6 – 8 months: 56% of infants were ID, 76% were anemic, and 46% had IDA. EBF of 4 months and above was significantly associated with ID as compared with EBF < 4 months (4 – 6 months: OR 2.0 [1.1 – 3.4]; > 6 months: 3.3 [1.0 – 12.3]), but not with IDA (4 – 6 months: OR 1.4 [0.8 – 2.4]; > 6 months: 2.2 [0.7 – 7.4]), or anemia (4 – 6 months: OR 1.4 [0.7 – 2.5]; > 6 months: 1.5 [0.7 – 7.2]). Fer and Hb concentrations were significantly lower with increasing months of EBF.ConclusionsResults suggest a relationship between prolonged EBF and ID, but are not sufficient to support changes to current breastfeeding recommendations. More research is needed in diverse populations, including exploration of early interventions to address infant IDA.

Approaches for Reducing the Risk of Early-Life Iron Deficiency-Induced Brain Dysfunction in Children.

Iron deficiency is the most common micronutrient deficiency in the world. Women of reproductive age and young children are particularly vulnerable. Iron deficiency in late prenatal and early postnatal periods can lead to long-term neurobehavioral deficits, despite iron treatment. This may occur because screening and treatment of iron deficiency in children is currently focused on detection of anemia and not neurodevelopment. Anemia is the end-stage state of iron deficiency. The brain becomes iron deficient before the onset of anemia due to prioritization of the available iron to the red blood cells (RBCs) over other organs. Brain iron deficiency, independent of anemia, is responsible for the adverse neurological effects. Early diagnosis and treatment of impending brain dysfunction in the pre-anemic stage is necessary to prevent neurological deficits. The currently available hematological indices are not sensitive biomarkers of brain iron deficiency and dysfunction. Studies in non-human primate models suggest that serum proteomic and metabolomic analyses may be superior for this purpose. Maternal iron supplementation, delayed clamping or milking of the umbilical cord, and early iron supplementation improve the iron status of at-risk infants. Whether these strategies prevent iron deficiency-induced brain dysfunction has yet to be determined. The potential for oxidant stress, altered gastrointestinal microbiome and other adverse effects associated with iron supplementation cautions against indiscriminate iron supplementation of children in malaria-endemic regions and iron-sufficient populations.

Prevalence of iron deficiency and its associated risk factors among primary school children in Kelantan

Iron deficiency anemia (IDA) is the most common micronutrient deficiency that may leads to serious health problems such as poor behavior, cognitive and motor development in children. The main objective of the study was to investigate prevalence of IDA and its associated risk factors of school children. A cross-sectional study was conducted on 249 Malay primary school children (122 males and 127 females), aged 7-9 years old. Venous blood sample was drawn for hemoglobin and serum ferritin analysis. Results revealed that the prevalence of iron deficiency without anemia was 12.6% and 7.7% of the children was found to have iron deficiency anemia. Result showed that birth weight, household size, height, weight and BMI was correlated significantly with iron deficiency based on serum ferritin concentration.

Dietary Iron Repletion following Early-Life Dietary Iron Deficiency Does Not Correct Regional Volumetric or Diffusion Tensor Changes in the Developing Pig Brain.

Iron deficiency is the most common micronutrient deficiency worldwide and children are at an increased risk due to the rapid growth occurring during early life. The developing brain is highly dynamic, requires iron for proper function, and is thus vulnerable to inadequate iron supplies. Iron deficiency early in life results in altered myelination, neurotransmitter synthesis, neuron morphology, and later-life cognitive function. However, it remains unclear if dietary iron repletion after a period of iron deficiency can recover structural deficits in the brain. Twenty-eight male pigs were provided either a control diet (CONT; n = 14; 23.5 mg Fe/L milk replacer) or an iron-deficient diet (ID; n = 14; 1.56 mg Fe/L milk replacer) for phase 1 of the study, from postnatal day (PND) 2 until 32. Twenty pigs (n = 10/diet from phase 1) were used in phase 2 of the study from PND 33 to 61, all pigs were provided a common iron sufficient diet, regardless of their early-life dietary iron status. All pigs remaining in the study were subjected to magnetic resonance imaging (MRI) at PND 32 and again at PND 61 using structural imaging sequences and diffusion tensor imaging (DTI) to assess volumetric and microstructural brain development, respectively. Data were analyzed using a two-way ANOVA to assess the main and interactive effects of early-life iron status and time. An interactive effect was observed for absolute whole brain volumes, in which whole brain volumes of ID pigs were smaller at PND 32 but were not different than CONT pigs at PND 61. Analysis of brain region volumes relative to total brain volume indicated interactive effects (i.e., diet × day) in the cerebellum, olfactory bulb, and putamen-globus pallidus. Main effects of early-life iron status, regardless of imaging time point, were noted for decreased relative volumes of the left hippocampus, right hippocampus, thalamus, and increased relative white matter volume in ID pigs compared with CONT pigs. DTI indicated interactive effects for fractional anisotropy (FA) in the whole brain, left cortex, and right cortex. Main effects of early-life iron status, regardless of imaging time point, were observed for decreased FA values in the caudate, cerebellum, and internal capsule in ID pigs compared with CONT pigs. All comparisons described above were significant at P < 0.05. Results from this study indicate that dietary iron repletion is able to compensate for reduced absolute brain volumes early in life; however, microstructural changes and altered relative brain volumes persist despite iron repletion.

Nutritional rickets among children of Northern Kerala, India

Background: Vitamin D deficiency is a very common micronutrient deficiency in our country and ranks among the 5 most common disease in children worldwide.Methods: To study the presentation and predisposing factors of rickets among children in Northern Kerala.Results: This study was conducted in the department of Pediatrics in a tertiary care hospital in Northern Kerala. Nutritional rickets diagnosis was based on clinical, radiological and biochemical parameters and appearance of provisional zone of calcification after vitamin D therapy. Data was analyzed and presented as percentage and mean. Student t-test was used for statistical analysis of the results.Conclusions: A total of 54 children having a variety of clinical presentations of rickets were seen during the study period. There were 46.3% males and 53.7% females. The mean age of diagnosis was 24 months.70.4% children were exclusively breast fed up to 6 months. None of the breast-fed infants had received vitamin D supplementation according to current guidelines. 66.7% children were not exposed to sunlight. Rickets was commonly found in children with no protein energy malnutrition. Genu varum and wrist widening were the most frequent clinical features observed in 92.6% patients. The radiological and biochemical characteristics of cases were ascertained before and after therapy. The biochemical changes were analyzed by student (t) test. There was a significant decrease in the ALP activity after vitamin D therapy (P= 0.000). Out of these 54 children with rickets 47(87.03%) responded to treatment with vitamin D3 and 7 (12.96%) were resistant to treatment with vitamin D3.

Efficacy of iron supplementation may be misinterpreted using conventional measures of iron status in iron-depleted, nonanemic women undergoing aerobic exercise training

Background: Despite its known detrimental effects, iron deficiency remains the most common micronutrient deficiency in the world. Many interventions that aim to improve iron status involve physically active populations. Intense aerobic exercise training negatively affects iron status; however, the impact of regular moderate aerobic exercise on the effectiveness of iron supplementation remains unclear.Objective: This study aimed to determine whether aerobic training modifies the assessment of the effectiveness of iron supplementation in improving conventional iron status measures.Design: Seventy-two iron-depleted, nonanemic Chinese women [serum ferritin (sFer) <25 μg/L and hemoglobin >110 g/L] were included in an 8-wk, partially blinded, randomized controlled trial with a 2 × 2 factorial design including iron supplements (42 mg elemental Fe/d) or placebo and aerobic training (five 25-min sessions/wk at 75-85% of maximum heart rate) or no training. Linear mixed models were used to evaluate the relation between supplement type, training, and changes in iron status over time, measured by sFer, hemoglobin, soluble transferrin receptor (sTfR), and estimated total body iron.Results: After treatment, both the iron-supplemented trained and untrained groups showed significantly improved sFer, sTfR, and body iron values compared with either of the placebo groups. Similarly, trained participants had significantly higher aerobic fitness measures than untrained participants. Training modified the sFer response to supplementation (training by supplement interaction, P = 0.07), with the iron-supplemented trained group having significantly lower sFer than the iron-supplemented untrained group at week 8 (mean ± SD: 31.8 ± 13.5 and 47.6 ± 15.7 μg/L, respectively; P = 0.042), whereas there was no significant difference between the placebo trained and untrained groups (21.3 ± 12.2 and 20.3 ± 7.0 μg/L, respectively; P = 1.00).Conclusions: Regular aerobic training reduces the apparent effectiveness of iron supplementation in improving sFer and calls into question whether conventional measures of iron status accurately reflect iron metabolism in physically active, nonanemic women. This trial was registered at clinicaltrials.gov as NCT03002090.

Iron Deficiency Affects Seizure Susceptibility in a Time- and Sex-Specific Manner

Iron deficiency (ID) affects more than three billion people worldwide making it the most common micronutrient deficiency. ID is most prevalent during gestation and early life, which is of particular concern since its impact on the developing central nervous system is associated with an increased risk of a wide range of different psychiatric disorders later in life. The cause for this association is not known, but many of these same disorders are also associated with an imbalance between excitation and inhibition (E/I) within the brain. Based on this shared impairment, we asked whether ID could contribute to such an imbalance. Disruptions in the E/I balance can be uncovered by the brain’s response to seizure inducing insults. We therefore tested the seizure threshold under different nutritional models of ID. We found that mice which were postnatally exposed to ID (and were acutely ID) had a decreased seizure threshold and increased susceptibility to certain seizure types. In contrast, mice that were exposed to ID only during gestation had an increased seizure threshold and low seizure incidence. We suggest that exposure to ID during gestation might alter the cellular components that contribute to the establishment of a proper E/I balance later in life. In addition, our data highlight the importance of considering the window of vulnerability since gestational ID and postnatal ID have significantly different consequences on seizure probability.

Iron Nutriture of the Fetus, Neonate, Infant, and Child

Iron is a key nutrient and is essential for the developing fetus, neonate, infant, and child. Iron requirements are high during early stages of life because it is critically important for the production of new red blood cells and muscle cells as well as brain development. Neonates, infants, and children obtain iron from dietary sources including breast milk (lactoferrin) and heme- and non-heme-containing foods. Iron deficiency (ID) is the most common micronutrient deficiency in children and pregnant women worldwide. ID and iron deficiency anemia (IDA) can affect growth and energy levels as well as motor and cognitive performance in the developing child. The fetus is completely dependent on maternal iron crossing through the placenta and, although it is generally well protected against deficiency at birth, ID in mothers can increase the risk of ID and IDA in their children as early as 4 months. This review will discuss the uses of iron, iron requirements, and the sources of iron from conception through childhood. In addition, it will describe the prevalence and clinical manifestations of ID and IDA in children and discuss recommendations for iron supplementation of children and pregnant women.

Impact of milk based micronutrient supplementation in school children in Quito-Ecuador.

The most common micronutrient deficiencies in Ecuadorian schoolchildren are vitamin A (VA), zinc, and iron. The objective of the present study was to test the efficacy of cow's milk as a vehicle for VA, zinc, and iron supplementation. Three hundred twenty-eight children aged 6-10 years were included in a randomized, double blind controlled study; 173 children received 480 mL of whole milk (300 Kcals; G1) daily and 155 children received fortified milk (300 Kcals; G2) daily for 23 weeks. Participants had a nutritional evaluation before and after supplementation. Both treatment groups were comparable for gender, age, weight and height at the beginning of the study. Both types of milk were well accepted by the participating children. Data showed that serum concentrations of VA, zinc, and iron significantly increased within both treatment groups. The increase in serum concentrations of the indicated micronutrients was significantly greater in children with deficiencies than in non-deficient ones. There were not significant differences in serum concentrations of VA, zinc, and iron between groups after supplementation. Data also showed that there was an increase in the percentage of children with normal BMI at the expense of a decrease of the percentage of children with excess weight at the end of the treatment period in G1 whereas in G2 it remained unchanged. Blood lipid profiles were normal before and after milk supplementation in both treatment groups. These data indicated that fortified and non-fortified milk are excellent options to increase serum VA, zinc, and iron concentration in schoolchildren.

Fortification as an effective strategy to bridge iron gaps during complementary feeding

Micronutrient deficiencies (MNDs) during early life are associated with adverse outcomes. Globally, iron deficiency is the most common MND and is particularly common in the first two years of life. Iron is crucial for neurodevelopment, cognition, and immunity. The composition of complementary feeds influences the overall health of an infant. Plant-based complementary foods do not provide enough iron to meet the nutrient needs during 6–23 months of age. Furthermore, the quantities of animal-source foods given to infants are generally inadequate to meet the iron gap. To address this issue, the use of iron-fortified complementary foods should be promoted.

An epidemiological study of anaemia in the women of reproductive age group (15-49 years) residing in field practice area of a medical college, Udaipur (Rajasthan)

Background: Anaemia is one of the most important public health problem that persist worldwide, affecting the infants, young children, adolescents, elderly and child bearing women of developing countries. Among the women of reproductive age group the adolescence period is crucial and dynamic for young females as they begin to develop their capacity for empathy, abstract thinking for physical and mental induration with future time perspective of growth and development. The objectives of the study were to assess the prevalence of anaemia in women of reproductive age group; to study the socio-demographic factors among the study subjectsMethods: A cross- sectional purposive study was conducted on 436 females of reproductive age group, residing in the field practice area of urban health training centre of department of community medicine, Geetanjali medical college and hospital, Udaipur. Study period was from May 2015 to April 2016.Results: The prevalence of anaemia among the age group below 18 years were (71.2%), educated (72.4%), nuclear family (73.3%), married (87.1%), socio-economic status group V (79.9%), menarche (75.15%), and severe anaemia was observed in (3.2%) subjects.Conclusions: Nutritional anaemia is one of the most common micronutrient deficiency observed in the world and is the highest in the adolescent females. The study revealed the statistically significant association of anaemia with various socio-demographic factors.

A5206 - Review of patients requiring iron infusions during a two year period (Jan 2013 Dec 2014) in patients undergoing revision bariatric surgery in an Australian surgical centre

Micronutrient deficiencies are a concern after bariatric surgery. Iron deficiency is a common micronutrient deficiency in this patient group regardless of surgical procedure. Iron deficiency can usually be treated effectively with oral supplements however in some cases an iron infusion is warranted to correct iron levels in patients who do not respond to or are unable to tolerate oral supplements.

Iron deficiency in children aged 6–36 months: National survey on clinical practice of general pediatricians

Iron deficiency (ID) is the most common micronutrient deficiency worldwide, particularly in infancy because of rapid growth and high iron requirements. We conducted a national survey with the aim to assess the clinical practice of general pediatricians (GPs) concerning ID in infants aged 6–36 months. A 15-item questionnaire was distributed to GPs in 16 different regions in Italy between November 2016 and March 2017. The questions evaluated the opinion of GPs on the most frequent causes of ID in children 6–36 months and how they prevented or treated ID (e.g. timing, what type of blood tests, dosage of iron supplementation for prophylaxis and treatment). A total of 2979 questionnaires were filled in. In the opinion of the majority of GPs, the most common cause of ID in children 6–36 months was the early introduction (<12 months) of cow's milk (37.13% of responses). In Italy overall, the majority of GPs do not recommend iron supplementation as prophylaxis (64.78% of responses); this clinical practice is common in breastfed infants only in 3 regions of the South of Italy (Sicily, Puglia, Calabria). For treatment of iron deficiency anemia (IDA), the majority of GPs recommend iron in ferrous form at the dosage of 3 mg/kg/day for at least 3 months. The present study highlights the different clinical practice between North and South regions of Italy concerning ID and the need to clarify whether iron prophylaxis is a useful practice in infants and toddlers aged 6–36 months.

Iron deficiency anaemia in young children (6 to 23 months) in relation to complementary feeding practices in rural Telangana, India

Background: Iron deficiency, is the most common micronutrient deficiency seen in all age groups throughout the world. Young infants are more vulnerable because of growing size and increased demand. Iron deficiency anaemia due to improper complementary feeding practices in young children, will affect growth, cognitive and immune functions of the growing child.Methods: A cross sectional study was conducted from 01-05-2016 to 01-02-2017, at the Department of Paediatrics, S. V. S. Medical College and Hospital, Mahabubnagar, Telangana, India. The study included 130 children attended to our well baby clinics. A questionnaire was filled by mothers after taking consent. Data was Collected data was analysed using statistical package SPSS software version-19. Chi-square test was carried to test the relation. P-Value &lt; 0.05 was considered as significant.Results: Prolonged breast feeding, late weaning, parent’s educational status and socioeconomic status are found to significant (p value &lt;0.05) risk factors in contributing to the development of iron deficiency anaemia.Conclusions: As young infants are more prone for iron deficiency anaemia in the later part of first year, implementation of proper complementary feeding practices as advised by Infant and Young Child Feeding practices are essential.

Co-morbidities and micronutrient deficiencies in children with severe acute malnutrition

Background: To study the co-morbidities and nutritional deficiencies in hospitalized children of severe acute malnutrition (SAM).Methods: One year retrospective chart review of 150 cases of SAM was done in Paediatric unit of a medical college of northern India.Results: The mean age of study group was 17.3 months (6 months to 60 months’ age group). Diarrhoea (34.7%) and respiratory tract infection (31.33%) were the most common co-morbid conditions associated with this study. Tuberculosis was seen in 20% of cases whereas Measles was associated in 6.7% cases. Anaemia and Vitamin A deficiencies were common micronutrient deficiencies. A very high prevalence of intestinal helminthic infestation was present in this study. Ascaris lumbricoides being the most common parasite involved. Polyparasitism was present in 20% of cases.Conclusions: Early identification and management of co-morbidities can improve overall outcome and survival.

The effect of vitamin B12 supplementation in Nepalese infants on growth and development: study protocol for a randomized controlled trial

BackgroundVitamin B12 deficiency is one of the most common micronutrient deficiencies and is associated with poor cognitive development and growth. Vitamin B12 is crucial for normal cell division and differentiation, and it is necessary for the development and myelination of the central nervous system. The aim of the present study is to measure the effect of daily supplementation of vitamin B12 on the neurodevelopment and growth of young children in Nepal.Methods/designWe are conducting an individually randomized, double-blind, placebo-controlled trial with 600 marginally stunted children 6–11 months old (length for age less than −1 z-score). Children are randomized to receive a lipid-based paste containing vitamin B12 or placebo daily for 12 months. The main outcomes are changes in growth (z-scores) and in neurodevelopment measured by the Bayley Scales of Infant and Toddler Development, Third Edition, from baseline until the end of the study.DiscussionIf vitamin B12 supplementation benefits early child development and growth, this will have consequences for dietary recommendations for malnourished children worldwide.Trial registrationsClinicalTrials.gov Identifier: NCT02272842. Registered on 21 October 2014.Universal Trial Number: U1111-1161-5187. Registered on 8 September 2014.