Intake of B vitamins and the risk of developing islet autoimmunity and type 1 diabetes in the TEDDY study.

PURPOSE: The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years. METHODS: We followed 8500 T1D-susceptible children born in the U.S., Finland, Sweden, and Germany in 2004 -2010 from the Environmental Determinants of Diabetes in the Young (TEDDY) study, which is a prospective observational birth cohort. Dietary intake of seven B vitamins was calculated from foods and dietary supplements based on 24-h recall at 3 months and 3-day food records collected regularly from 6 months to 10 years of age. Cox proportional hazard models were adjusted for energy, HLA-genotype, first-degree relative with T1D, sex, and country. RESULTS: A total of 778 (9.2) children developed at least one autoantibody (any IA), and 335 (3.9%) developed multiple autoantibodies. 280 (3.3%) children had IAA and 319 (3.8%) GADA as the first autoantibody. 344 (44%) children with IA progressed to T1D. We observed that higher intake of niacin was associated with a decreased risk of developing multiple autoantibodies (HR 0.95; 95% CI 0.92, 0.98) per 1 mg/1000 kcal in niacin intake. Higher intake of pyridoxine (HR 0.66; 95% CI 0.46, 0.96) and vitamin B12 (HR 0.87; 95% CI 0.77, 0.97) was associated with a decreased risk of IAA-first autoimmunity. Higher intake of riboflavin (HR 1.38; 95% CI 1.05, 1.80) was associated with an increased risk of GADA-first autoimmunity. There were no associations between any of the B vitamins and the outcomes "any IA" and progression from IA to T1D.  CONCLUSION: In this multinational, prospective birth cohort of children with genetic susceptibility to T1D, we observed some direct and inverse associations between different B vitamins and risk of IA.

Serum 25-hydroxyvitamin D and fatty acids in relation to the risk of microbial infections in children: The TRIGR Divia study.

BACKGROUND & AIMS: Nutrient status may affect the risk of microbial infections and play a role in modulating the immune response against such infections. The aim of this study was to determine whether serum 25-hydroxyvitamin D [25(OH)D] and serum fatty acids in infancy are associated with microbial infections by the age of 18 months. METHODS: Altogether 576 newborn infants from Trial to Reduce IDDM in the Genetically at Risk (TRIGR) born between 2002 and 2007 were included. The concentration of 25(OH)D vitamin and proportions of 26 fatty acids (presented as % of total fatty acids) were analyzed in cord blood serum and in sera taken at 6, 12, and 18 months of age. The cord blood samples and mean of 6-18-month values were used as exposures. Infections were detected by screening IgG antibodies against 10 microbes using enzyme immunoassay and antibodies against 6 coxsackievirus B serotypes by plaque neutralization assay in serum samples taken at 18 months of age. RESULTS: A higher proportion of n-3 polyunsaturated fatty acids (PUFAs) and especially long-chain n-3 PUFAs at birth and at the age of 6-18 months was associated with decreased risk of coxsackievirus B2 infection unadjusted and adjusted for region, case-control status, and maternal type 1 diabetes. Higher proportion of docosapentaenoic acid (DPA, 22:5 n-3) at birth was associated with a decreased risk of respiratory syncytial virus infection. 25(OH)D vitamin concentration was not consistently associated with the risk of infections. When only infected children were included docosahexaenoic acid (DHA, 22:6 n-3) and arachidonic acid (20:4 n-6) proportions were positively associated with IgG antibody levels against influenza A virus. 25(OH)D vitamin concentration showed an inverse association with rotavirus IgG levels among children with rotavirus seropositivity. CONCLUSIONS: In young children with increased susceptibility to type 1 diabetes, long-chain n-3 PUFAs may influence the risk of viral infections and immune response against the infections. However, this association may depend on the type of virus suggesting virus-specific effects.

Serum 25-hydroxyvitamin D concentration in childhood and risk of islet autoimmunity and type 1 diabetes: the TRIGR nested case-control ancillary study.

AIMS/HYPOTHESIS: Our aim was to study the association between serum 25-hydroxyvitamin D (25OHD) concentration and islet autoimmunity and type 1 diabetes in children with an increased genetic risk of type 1 diabetes. METHODS: Serum samples for 25OHD measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children in 15 countries. Case children (n = 244) were defined as having positivity for at least two out of four diabetes-associated autoantibodies measured at any one sample. For each case child, two control children were selected matched for country and date of birth (±1 year) (n = 488). Of the case children, 144 developed type 1 diabetes. Serum 25OHD was measured repeatedly in infancy and childhood and was compared according to age at the first seroconversion (at 6, 12 and 18 months prior to and at seroconversion) and calendar age (0, 6, 12 and 18 months). RESULTS: In children with islet autoimmunity, mean serum 25OHD concentration was lower 18 months prior to the age of first seroconversion of the case children compared with the control children (57.7 vs 64.8 nmol/l, p = 0.007). In children with type 1 diabetes (n = 144), mean serum 25OHD concentration was lower 18 months prior to the age of the first seroconversion (58.0 vs 65.0 nmol/l, p = 0.018) and at the calendar age of 12 months (70.1 vs 75.9 nmol/l, p = 0.031) than in their control counterparts. Analyses were adjusted for month of sample collection, human leucocyte antigen genotype, maternal type 1 diabetes and sex. CONCLUSIONS/INTERPRETATION: The results suggest that early postnatal vitamin D may confer protection against the development of type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00179777.

Early Probiotic Supplementation and the Risk of Celiac Disease in Children at Genetic Risk.

Probiotics are linked to positive regulatory effects on the immune system. The aim of the study was to examine the association between the exposure of probiotics via dietary supplements or via infant formula by the age of 1 year and the development of celiac disease autoimmunity (CDA) and celiac disease among a cohort of 6520 genetically susceptible children. Use of probiotics during the first year of life was reported by 1460 children. Time-to-event analysis was used to examine the associations. Overall exposure of probiotics during the first year of life was not associated with either CDA (n = 1212) (HR 1.15; 95%CI 0.99, 1.35; p = 0.07) or celiac disease (n = 455) (HR 1.11; 95%CI 0.86, 1.43; p = 0.43) when adjusting for known risk factors. Intake of probiotic dietary supplements, however, was associated with a slightly increased risk of CDA (HR 1.18; 95%CI 1.00, 1.40; p = 0.043) compared to children who did not get probiotics. It was concluded that the overall exposure of probiotics during the first year of life was not associated with CDA or celiac disease in children at genetic risk.

Risk factors for chemotherapy-induced nausea in pediatric patients receiving highly emetogenic chemotherapy.

BACKGROUND: Little is known regarding risk factors for chemotherapy-induced nausea (CIN) in pediatric patients. PROCEDURE: A secondary analysis was conducted of a previously published multicenter, prospective, randomized, single-blind, sham-controlled trial assessing the efficacy of acupressure in preventing CIN in pediatric patients receiving highly emetogenic chemotherapy. The primary outcome was nausea severity, self-reported using the Pediatric Nausea Assessment Tool. The relationships between acute and delayed nausea severity and patient- (sex, race, age, and cancer diagnosis) and treatment-related (chemotherapy, antiemetic prophylaxis, CIN, and vomiting control) factors were analyzed by a proportional odds generalized estimating equation approach. The acute phase started with administration of the first and continued for 24 hours after the last chemotherapy dose. The delayed phase started at the end of the acute phase and continued until the next chemotherapy block (maximum seven days). RESULTS: In the acute and delayed phases, 165 and 144 patients provided data for analysis, respectively. Nonwhite race was significantly associated with higher acute phase nausea severity (OR, 1.7; 95% CI, 1.1-2.6). Poor CIN control in the acute phase (OR, 16; 95% CI, 4.0-64.6), diagnosis of a cancer other than a central nervous system (CNS) tumor (OR, 2.5; 95% CI, 1.2-5.3), and cisplatin administration (OR, 3.7; 95% CI, 2.1-6.0) were significantly associated with higher delayed phase nausea severity. CONCLUSION: Acute phase CIN was associated with nonwhite race. Delayed phase CIN was associated with poor acute phase CIN control, diagnosis of non-CNS cancer, and receipt of cisplatin. These findings will inform future antiemetic trial design.

Acupressure bands do not improve chemotherapy-induced nausea control in pediatric patients receiving highly emetogenic chemotherapy: A single-blinded, randomized controlled trial.

BACKGROUND: Chemotherapy-induced nausea and vomiting remain common, distressing side effects of chemotherapy. It has been reported that acupressure prevents chemotherapy-induced nausea in adults, but it has not been well studied in children. METHODS: In this multicenter, prospective, randomized, single-blind, sham-controlled trial, the authors compared acute-phase nausea severity in patients ages 4 to 18 years who were receiving highly emetic chemotherapy using standard antiemetic agents combined with acupressure wrist bands, the most common type of acupressure, versus sham bands. Patients wore acupressure or sham bands continuously on each day of chemotherapy and for up to 7 days afterward. Chemotherapy-induced nausea severity in the delayed phase and chemotherapy-induced vomiting control in the acute and delayed phases also were compared. RESULTS: Of the 187 patients randomized, 165 contributed nausea severity assessments during the acute phase. Acupressure bands did not reduce the severity of chemotherapy-induced nausea in the acute phase (odds ratio [OR], 1.33; 95% confidence limits, 0.89-2.00, in which an OR <1.00 favored acupressure) or in the delayed phase (OR, 1.23; 95% CL, 0.75-2.01). Furthermore, acupressure bands did not improve daily vomiting control during the acute phase (OR, 1.57; 95% CL, 0.95-2.59) or the delayed phase (OR, 0.84; 95% CL, 0.45-1.58). No serious adverse events were reported. CONCLUSIONS: Acupressure bands were safe but did not improve chemotherapy-induced nausea or vomiting in pediatric patients who were receiving highly emetic chemotherapy. Cancer 2018;124:1188-96. © 2017 American Cancer Society.

Maternal use of dietary supplements during pregnancy is not associated with coeliac disease in the offspring: The Environmental Determinants of Diabetes in the Young (TEDDY) study.

Perinatal exposure to nutrients and dietary components may affect the risk for coeliac disease (CD). We investigated the association between maternal use of vitamin D, n-3 fatty acids (FA) and Fe supplements during pregnancy and risk for CD autoimmunity (CDA) and CD in the offspring. Children at increased genetic risk were prospectively followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. CDA was defined as having persistently positive tissue transglutaminase autoantibodies (tTGA). Diagnosis of CD was either biopsy-confirmed or considered likely if having persistently elevated levels of tTGA>100 AU. Of 6627 enrolled children, 1136 developed CDA at a median 3·1 years of age (range 0·9-10) and 409 developed CD at a median 3·9 years of age (range 1·2-11). Use of supplements containing vitamin D, n-3 FA and Fe was recalled by 66, 17 and 94 % of mothers, respectively, at 3-4 months postpartum. The mean cumulative intake over the entire pregnancy was 2014 µg vitamin D (sd 2045 µg), 111 g n-3 FA (sd 303 g) and 8806 mg Fe (sd 7017 mg). After adjusting for country, child's human leucocyte antigen genotype, sex, family history of CD, any breast-feeding duration and household crowding, Cox's proportional hazard ratios did not suggest a statistically significant association between the intake of vitamin D, n-3 FA or Fe, and risk for CDA or CD. Dietary supplementation during pregnancy may help boost nutrient intake, but it is not likely to modify the risk for the disease in the offspring.

Hydrolyzed infant formula and early ß-cell autoimmunity: a randomized clinical trial.

IMPORTANCE: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of ß-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. OBJECTIVE: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. DESIGN, SETTING, AND PARTICIPANTS: A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013. INTERVENTIONS: The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate. MAIN OUTCOMES: AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). RESULTS: The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. CONCLUSIONS AND RELEVANCE: Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.

Use of vitamin D supplements during infancy in an international feeding trial.

OBJECTIVE: To examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial. DESIGN: Longitudinal study. SETTING: Information about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months. SUBJECTS: Infants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia. RESULTS: Daily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80% of the infants), with somewhat lower rates observed in Southern Europe (> 60%). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g., 71% v. 44% at 6 months of age). Less than 2% of infants in the U.S.A. and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements. CONCLUSIONS: Most of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the U.S.A. and Australia very few were given supplementation.

Results of a randomized phase I dose-finding trial of several doses of isoflavones in men with localized prostate cancer: administration prior to radical prostatectomy.

The purpose of this phase I dose-finding randomized controlled trial was to evaluate the safe and effective dose of isoflavones to be used in future clinical trials for prostate cancer prevention. Forty-five eligible men were supplemented with 40, 60, and 80 mg of purified isoflavones or no supplement from biopsy to prostatectomy. Compliance with the study agent, toxicity, and changes in plasma isoflavones, serum steroid hormones, prostate-specific antigen (PSA), and tissue Ki-67 were analyzed from baseline to completion of the study. Forty-four subjects completed the study with a duration of intervention of 30 (+/- 3) days. We observed significant increases in plasma isoflavones with treatment for all doses compared with controls without producing any toxicity. Significant increases in serum total estradiol were observed in the 40 and 60 mg isoflavone-treated arms. However, a significant increase in serum free testosterone was observed in the 60 mg isoflavone-treated arm. Changes in serum sex hormone-binding globulin, PSA, and percentage of tissue Ki-67 were not statistically significant with treatment for this sample size and duration of intervention. Our results identify a safe dose of purified isoflavones for future clinical trials and establish the need for further definitive, well-powered trials to examine the role of isoflavones in prostate carcinogenesis.

A Phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer.

Our purpose was to evaluate the safety and effectiveness of purified isoflavones in producing an increase in plasma isoflavones and a corresponding change in serum sex hormone binding globulin (SHBG) and steroid hormone levels in men diagnosed with early stage prostate cancer. In this Phase II randomized, double-blinded, placebo-controlled trial, 53 prostate cancer patients with a Gleason score of 6 or below were supplemented with 80 mg purified isoflavones or placebo for 12 weeks. Changes in plasma isoflavones, serum steroid hormones, and safety markers were analyzed from baseline to 12 wk. A total of 50 subjects completed the study. Although significant increases in plasma isoflavones (P < 0.001) was observed with no clinical toxicity, the corresponding modulation of serum SHBG, total estradiol, and testosterone in the isoflavone-treated group compared to men receiving placebo was nonsignificant. Increasing plasma isoflavones failed to produce a corresponding modulation of serum steroid hormone levels in men with localized prostate cancer. The study establishes the need to explore other potential mechanisms by which prolonged and consistent purified isoflavone consumption may modulate prostate cancer risk.

Safety of purified isoflavones in men with clinically localized prostate cancer.

Our purpose was to evaluate the safety of 80 mg of purified isoflavones administered to men with early stage prostate cancer. A total of 53 men with clinically localized prostate cancer, Gleason score of 6 or below, were supplemented with 80 mg purified isoflavones or placebo for 12 wk administered in 2 divided doses of 40 mg to provide a continuous dose of isoflavones. Compliance, changes in plasma isoflavones, and clinical toxicity were analyzed at baseline, 4, and 12 wk. A total of 50 subjects completed the 12-wk intervention. A continuous, divided-dose administration of 80 mg/day of purified isoflavones at amounts that exceeded normal American dietary intakes significantly increased (P < 0.001) plasma isoflavones in the isoflavone-treated group compared to placebo and produced no clinical toxicity. With the current evidence on the cancer preventive properties of isoflavones, these results are significant and offer promise for these phytochemicals to be developed as potent agents to prevent cancer progression.

Relative validity of a dietary interview for assessing infant diet and compliance in a dietary intervention trial.

The objective of this study was to assess the relative validity of a dietary interview method for use in an infant population. A dietary interview covering a 1-month period was completed during a study visit at 3 or 6 months of age. It included structured questions and a short food frequency questionnaire (FFQ). The information was compared with data from two 48-h recall interviews conducted during the month previous to the study visit. The agreement between the FFQ and 48-h recalls was analysed as proportion of subjects classified into the same categories of consumption frequency and by the kappa analysis. A total of 100 subjects, at the age of 2-3 months (n = 50) and 5-6 months (n = 50), were included. The kappa values for breastmilk and study formula ranged from 0.82 to 0.95, indicating very good agreement. The agreement for other foods and vitamin D supplementation ranged from fair to very good. We also found a strong correlation for the reported amount of study formula consumed per feeding at 3 months (r(s) = 0.87, n = 24) and 6 months of age (r(s) = 0.73, n = 35) between the questionnaire and 48-h recall data. However, the average amount of study formula per feeding was significantly higher when estimated for a 1-month period, compared with a mean calculated from the two 48-h recalls. As a conclusion, the interview was found to be a useful tool for assessing diet and compliance in a dietary intervention for infants.