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Background Maternal vitamin D status during pregnancy and lactation is a modifiable factor that may influence offspring musculoskeletal outcomes. However, few randomized trials have tested the effects of prenatal or postpartum vitamin D supplementation on offspring bone and muscle development. Objectives The aim was to examine hypothesized effects of improvements in early-life vitamin D status on childhood musculoskeletal health in Dhaka, Bangladesh. Methods In a previously completed, double-blind, dose-ranging trial, healthy pregnant women (n  = 1300) were recruited at 17–24 weeks' gestation and randomly assigned to a prenatal/postpartum regimen of 0/0, 4200/0, 16,800/0, 28,000/0, or 28,000/28,000 IU cholecalciferol (vitamin D3)/wk until 26 wk postpartum. In this new report, we describe additional follow-up at 4 y of age (n  = 642) for longer-term outcomes. Bone mineral content (BMC) and areal bone mineral density (aBMD) were measured by DXA. Grip strength was tested using a hand-held dynamometer. The primary comparison was children of women assigned to 28,000 IU/wk prenatally compared with placebo. Differences are expressed as means and 95% CIs. Results Total-body-less-head (TBLH) BMC, TBLH aBMD, and grip strength were similar in the combined high-dose prenatal (28,000/0 and 28,000/28,000 IU/wk) compared with placebo groups (mean difference [95% CI] = 0.61 g [–10.90, 12.13], 0.0004 g/cm2 [–0.0089, 0.0097], and 0.02 kg [–0.26, 0.31], respectively). In dose-ranging analyses, TBLH BMC and aBMD, whole-body BMC and aBMD, and grip strength in each of the prenatal vitamin D groups were not significantly different from placebo (P  > 0.05 for all comparisons). Only head aBMD was greater in children of women assigned to the 28,000/28,000-IU regimen compared with placebo (mean difference [95% CI] = 0.024 g/cm2 [0.0009, 0.047], P  = 0.042); the effect was attenuated upon adjustment for child height, weight, and sex (P  = 0.11). Conclusions Maternal prenatal, with or without postpartum, vitamin D supplementation does not improve child BMC, aBMD, or grip strength at 4 y of age. The MDIG trial and present follow-up study were registered prospectively at www.clinicaltrials.gov as NCT01924013 and NCT03537443, respectively. [ABSTRACT FROM AUTHOR]

Censoring due to a limit of detection or limit of quantification happens quite often in many medical studies. Conventional approaches to deal with censoring when analyzing these data include, for example, the substitution method and the complete case (CC) analysis. More recently, maximum likelihood estimation (MLE) has been increasingly used. While the CC analysis and the substitution method usually lead to biased estimates, the MLE approach appears to perform well in many situations. This article proposes an MLE approach to estimate the association between two measurements in the presence of censoring in one or both quantities. The central idea is to use a copula function to join the marginal distributions of the two measurements. In various simulation studies, we show that our approach outperforms existing conventional methods (CC and substitution analyses). In addition, rank-based measures of global association such as Kendall's tau or Spearman's rho can be studied, hence, attention is not only confined to Pearson's product-moment correlation coefficient capturing solely linear association. We have shown in our simulations that our approach is robust to misspecification of the copula function or marginal distributions given a small association. Furthermore, we propose a straightforward MLE method to fit a (multiple) linear regression model in the presence of censoring in a covariate or both the covariate and the response. Given the marginal distribution of the censored covariate, our method outperforms conventional approaches. We also compare and discuss the performance of our method with multiple imputation and missing indicator model approaches. [ABSTRACT FROM AUTHOR]

Background: Very low birthweight (VLBW) preterm infants fed mothers own milk (MOM) need nutritional supplementation, traditionally achieved with cow's milk (CM) derived fortifier CMDF) and preterm formula (PTF) if MOM is insufficient. CM products have been associated with diverse major morbidities. The current recommendation is to preferentially replace PTF with donor milk (DM) to produce a 100% human milk (HM) base diet, usually fortified with CMDF. Objective: To identify whether CMDF, even when fed with a 100% HM base diet, is related to an increased risk of major morbidities. Methods: We identified a randomized trial with an all-HM base diet, comparing CMDF with a fortifier derived from human milk (HMDF), and two additional studies of this design were generated from raw data as subgroup analyses of a randomized controlled trial and a quasi-experimental study. Using these studies, we calculated the impact of CMDF on major morbidities of death, necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), sepsis, bronchopulmonary dysplasia (BPD) and patent ductus arteriosus (PDA). Results: Each study individually provided support for an increase in major morbidities with CMDF. Meta-analyses of pooled data showed that compared to HMDF, the CMDF group had large increases in NEC (RR=3.3; P=0.001), ROP (RR=2.2; P=0.007), PDA (RR=1.6; P=0.009), interruption of feeding (RR=3.4; P=0.001) and a positive mortality/morbidity index based on one or more of death, NEC, sepsis, ROP and BPD (RR=1.4; P=0.006). Conclusions: Despite the increased use of HM in modern neonatal care as a base diet, we found a greater risk of critical morbidities with CMDF compared with HMDF. This burden of morbidity provides evidence that the benefits of an HM base diet, might be, in part, counteracted by multiple adverse outcomes relating to the use of CMDF. [ABSTRACT FROM AUTHOR]

Objectives: To investigate whether prior exposure to non-fluoroquinolone antibiotics increases the risk of fluoroquinolone resistance in Escherichia coli.Methods: This was a secondary analysis of data collected retrospectively in a case-control study linking microbiological test results (isolated bacteria and their susceptibility) of urine samples routinely collected from primary, secondary and tertiary care patients in Belgium with information on prior antibiotic use at the patient level up to 1 year previously.Results: In urine samples from 6125 patients, 7204 E. coli isolates were retrieved [1949 fluoroquinolone-resistant isolates (cases) and 5255 fluoroquinolone-susceptible isolates (controls)]. After adjusting for potential confounders (including fluoroquinolone use) and correcting for multiple testing there were lower odds of fluoroquinolone resistance in E. coli isolates after exposure to cefazolin (OR = 0.65; 95% CI = 0.52-0.81; P = 0.00014) and higher odds after exposure to trimethoprim/sulfamethoxazole (OR = 1.56; 95% CI = 1.23-1.97; P =0.00020) or nitrofurantoin (OR = 1.50; 95% CI = 1.23-1.84; P =0.000083). A sensitivity analysis excluding samples with antibiotic use during the 6 months prior to the sampling date confirmed the higher odds of fluoroquinolone resistance after exposure to trimethoprim/sulfamethoxazole and nitrofurantoin.Conclusions: Assuming no residual confounding or other biases, this study suggests that exposure to non-fluoroquinolone antibiotics, i.e. trimethoprim/sulfamethoxazole and nitrofurantoin, might be causally related to fluoroquinolone resistance in E. coli isolates from urinary samples. Future prospective research is needed to confirm non-fluoroquinolone antibiotics as potential drivers of fluoroquinolone resistance. [ABSTRACT FROM AUTHOR]

Calcium absorption efficiency and bone mineral mass are increased in adolescents who regularly consume inulin-type fructans (ITF). The mechanism of action in increasing absorption is unknown but may be related to increased colonic calcium absorption. We conducted a study in young adults designed to evaluate these mechanisms with a kinetic technique using (42)Ca orally and (46)Ca dosed i.v. Those who responded to 8 wk of supplementation with 8 g of a mixed short and long degree of polymerization ITF by increasing their calcium absorption had kinetic measurements analyzed to evaluate the time course of absorption. The area under the curve of the oral tracer in the blood during the 26 h after dosing was calculated and the time dependence of increased absorption determined. Eight young adults (of 13 studied), with mean calcium intake approximately 900 mg/d, responded to the ITF with an increased calcium absorption of at least 3%. In responders, absorption increased from 22.7 +/- 11.3% to 31.0 +/- 15.3%. Colonic absorption, defined as absorption that occurred >7 h after oral dosing, represented 69.6 +/- 18.6% of the increase, or 49 +/- 28 mg/d. These findings suggest that, in those who respond to ITF, its effects on calcium absorption occur principally in the colon. This benefit to ITF may be especially important when absorption in the small intestine is impaired for anatomic or physiological reasons. [ABSTRACT FROM AUTHOR]

The addition of milk and milk-based products to the diets of individuals subsisting on plant-based diets was reported to have positive effects on nutritional status and functional outcomes such as growth, morbidity, and cognition. We examined the effect of the addition of milk or yogurt on the bioavailability of zinc and iron from a plant-based rural diet. The subjects were 48 Mexican women (30.9 +/- 5.7 y) who habitually consumed a plant-based diet. The women were assigned to 1 of 3 groups: 1) the typical rural Mexican diet, 2) that diet with milk added, or 3) that diet with yogurt for 13 d. Zinc absorption was measured after extrinsically labeling meals with (67)Zn and an i.v. dose of (70)Zn; iron absorption was measured by extrinsically labeling meals with (58)Fe and a reference oral dose of (57)Fe. Including milk and yogurt in the diet increased zinc absorption by 50 and 68%, respectively (P < 0.05). The 3 groups did not differ in the percentage iron absorption. The total amount of zinc absorbed was increased (P < 0.05) by 70% when milk was added to the meal and 78% when yogurt was added. The total amount of iron absorbed did not differ among the groups. The addition of milk and yogurt to a plant-based diet high in phytate increases zinc bioavailability without affecting iron bioavailability. [ABSTRACT FROM AUTHOR]

After 1 y of distributing a milk-based fortified weaning food provided by the Mexican social program PROGRESA, positive effects on physical growth, prevalence of anemia, and several vitamin deficiencies were observed. There was no effect on iron status, which we hypothesized was related to the poor bioavailability of the reduced iron used as a fortificant in PROGRESA. The objective of this study was to compare the iron bioavailability from different iron sources added as fortificants to the weaning food. Children (n = 54) aged 2-4 y were randomly assigned to receive 44 g of the weaning food fortified with ferrous sulfate, ferrous fumarate, or reduced iron + Na(2)EDTA. Iron absorption was measured using an established double-tracer isotopic methodology. Iron absorption from ferrous sulfate (7.9 +/- 9.8%) was greater than from either ferrous fumarate (2.43 +/- 2.3%) or reduced iron + Na(2)EDTA (1.4 +/- 1.3%) (P < 0.01). The absorption of log-(58)Fe sulfate given with the iron source correlated with serum ferritin (s-ferritin) concentration (n = 13, r = 0.63, P = 0.01) and log-(57)Fe absorption (reference dose) (n = 14, r = -0.52, P = 0.02). Absorption from ferrous fumarate and reduced iron + Na2EDTA did not correlate with s-ferritin or absorption of (57)Fe. The recommended daily portion of the fortified complementary food provides an average of 0.256, 0.096, 0.046 mmol (1.44, 0.54, and 0.26 mg) of absorbed iron, if fortified with sulfate, fumarate and reduced iron + Na(2)EDTA, respectively. Ferrous sulfate was more bioavailable than either ferrous fumarate or reduced iron + Na(2)EDTA when added to the milk-based fortified food and more readily met the average daily iron requirements for children 2-3 y of age. [ABSTRACT FROM AUTHOR]

The search for a reliable, convenient indicator of Zn status was the focus of research for several decades. Plasma Zn concentration is still the most widely used clinical measurement, despite the known problems of interpretation. More recently, researchers suggested that isotopically determined kinetic parameters, such as the exchangeable Zn pool (EZP), may more accurately and reliably reflect body Zn status. The objective of this study was to examine the relationship between net body Zn loss and gain during acute changes in dietary Zn intake with biochemical and kinetic indices of Zn status. Five men participated in an 85-d Zn depletion/repletion study. Net body Zn loss and gain were determined from the difference between dietary plus intravenously administered Zn and Zn excretion. Biochemical indicators of Zn status included plasma Zn, plasma alkaline phosphatase activity, and plasma retinol binding protein concentration. Following intravenous administration of (70)Zn or (67)Zn, a compartmental model was used to determine EZP mass, fractional Zn absorption, endogenous zinc excretion (EZE), and plasma Zn flux. The changes in total body zinc correlated best with changes in plasma Zn (r(2) = 0.826, P < 0.001), EZE (r(2) = 0.773, P < 0.001), and plasma Zn flux (r(2) = 0.766, P < 0.001). This study confirms that plasma Zn concentration is a valid indicator of whole-body Zn status in the absence of confounding factors; however, further research is needed to determine how kinetic parameters respond to conditions where plasma Zn concentration is known to be unreliable. [ABSTRACT FROM AUTHOR]

Provision of the bone minerals and vitamin D as fortificants in food or as dietary supplements designed for older infants and toddlers in Latin America is likely to be beneficial and safe. Currently available data are inadequate to establish the precise amounts of these nutrients that would be required for such a supplement. These amounts would vary according to the local base diet. However, reasonable estimates can be made on the basis of current dietary recommendations as well as existing data on bioavailability and customary intake. The strongest case can be made for calcium and vitamin D supplementation. Because excessive dietary calcium can reduce zinc absorption as a result of interactive effects within the intestine, an appropriate ratio of calcium to zinc should be used, even if this means adding zinc as a fortificant or supplement. Magnesium supplementation may be appropriate in some circumstances but it cannot be routinely advocated at present. It is unlikely that phosphorus supplementation is needed for most population groups because of the relatively high usual dietary phosphorus intakes, primarily from phosphate salts added to carbonated beverages and as food preservatives. [ABSTRACT FROM AUTHOR]

Due to their widespread acceptability, multinutrient-fortified foods and beverages may be useful in reducing micronutrient deficiencies, especially in developing countries. We studied the efficacy of a new fortified beverage in improving the nutritional status of children in Botswana. We screened 311 lower income urban school children, ages 6-11 y, in two primary schools near Gaborone. Children were given seven 240-mL servings weekly of either an experimental beverage (EXP) fortified with 12 micronutrients or an isoenergetic placebo drink (CON) for 8 wk. Weight, mid-upper arm circumference, hemoglobin, retinol, ferritin, vitamin B-12, folate and riboflavin status were measured at baseline and at the end of the study. Plasma zinc and serum transferrin receptors also were measured at study end. A total of 145 children in the EXP group and 118 in the CON group completed the trial. Using multivariate analysis, the changes in mid-upper arm circumference, weight for age and total weight were significantly better in the EXP group than in the CON group (P < 0.01). Ferritin, riboflavin and folate status were significantly better in the EXP group than in the CON group at study end (P < 0.01), but serum vitamin B-12 was not. Zinc was significantly higher and transferrin receptors were significantly lower at the conclusion of the study in the EXP group than in the CON group (P < 0.001). Mean plasma retinol concentrations, which were low (<0.7 micro mol/L) in both groups, did not change. We conclude that a micronutrient-fortified beverage may be beneficial as part of a comprehensive nutritional supplementation program in populations at risk for micronutrient deficiencies. [ABSTRACT FROM AUTHOR]

To assess the possibility of ethnic differences in mineral metabolism in prepubertal children, we compared measures of calcium metabolism in 7- and 8-y-old Mexican-American (MA) and non-Hispanic Caucasian (CAU) girls (n = 38) living in southeastern Texas. We found similar fractional calcium absorption, urinary calcium excretion, calcium kinetic values and total-body bone mineral content in the MA and CAU girls. In contrast, parathyroid hormone (PTH) concentrations were greater in MA girls (4.01 +/- 0.47 vs. 1. 96 +/- 0.50 pmol/L, P = 0.005) than in CAU girls. Serum 25-hydroxyvitamin D concentrations were lower in MA girls (68.9 +/- 7.7 vs. 109.4 +/- 8.4 nmol/L, P = 0.001) than in CAU girls, but 1, 25-dihydroxyvitamin D concentrations did not differ between groups. Seasonal variability was seen for 25-hydroxyvitamin D concentrations in girls of both ethnic groups, but values in all of the girls were >30 nmol/L (12 ng/mL). We conclude the following: 1) greater PTH levels in MA girls than CAU girls are present without evidence of vitamin D deficiency; and 2) differences in 25-hydroxyvitamin D and PTH concentrations between MA and CAU girls do not have a large effect on calcium absorption, excretion or bone calcium kinetics. These data do not provide evidence for adjusting dietary recommendations for mineral or vitamin D intake by MA girls. [ABSTRACT FROM AUTHOR]

The major components of calcium metabolism, as evaluated by a dual-tracer stable isotope method, were determined in 100 studies of 68 healthy girls, aged 5-18 y and analyzed from a developmental and regulatory viewpoint. Bone calcium deposition and removal rates were closely correlated with the size of the exchangeable bone calcium compartment. All three quantities, as well as intestinal calcium absorption, peaked at or near menarche. Both bone calcium deposition and removal rates were positively and linearly correlated with calcium absorption. However, in this correlation, because bone calcium deposition increased 70% faster than calcium absorption, most of the increase in the bone calcium compartment and its turnover must have occurred in response to something other than intestinal calcium input; presumably this occurred in response to developmental signals. Nevertheless, the constancy of the serum calcium in the face of a large intestinal calcium input and the modest way in which excretion overcame the calcium load in this population point to the importance of the exchangeable bone calcium compartment, in dynamic equilibrium with the bone mineral, as the site at which most of the load is taken up. In this population of girls, as in older women, this increase in the skeletal calcium balance resulted from a decrease in the bone calcium removal rate that was greater than the corresponding increase in the bone calcium deposition rate. [ABSTRACT FROM AUTHOR]

Calcium absorption and whole-body bone mineral content are greater in young adolescents who receive 8 g/d of Synergy, a mixture of inulin-type fructans (ITF), compared with those who received a maltodextrin control. Not all adolescents responded to this intervention, however. We evaluated 32 responders and 16 nonresponders to the calcium absorptive benefits of ITF. We found no differences in usual dietary calcium intakes. Responders who increased their calcium absorption by at least 3% after 8 wk of Synergy had a greater accretion of calcium to the skeleton over a year based on whole-body dual-energy x-ray absorptiometry data. The absorptive benefit to ITF use in responders is substantial and would be comparable to increasing daily calcium intake by at least 250 mg. Increased intake of ITF may be an important aspect of a multifaceted approach to enhancing peak bone mass. [ABSTRACT FROM AUTHOR]