Blunted serum 25(OH)D response to vitamin D3 supplementation in children with autism.

Introduction: Data suggest a potential role for vitamin D in autism spectrum disorder (ASD) prevention and treatment. It is likely that the serum response to vitamin D supplementation contributes to its effectiveness. Multiple factors affect serum vitamin D 25(OH)D response to supplementation. Methods: We conducted post-hoc analysis of two double-blind, randomized, placebo-controlled trials (RCT) of vitamin D3 supplementation, one RCT involving children with ASD and another involving children with asthma. Both trials were conducted in the same geographic location (Dublin, Ireland, 53°N), conducted over Winter season and utilized the same vitamin D3 dose (2000 IU/day). Results: We included 18 children with ASD and 17 children with asthma. There was no significant difference in 25(OH)D or age at baseline, however, BMI was significantly lower in ASD (P = 0.03). Compliance with vitamin D supplementation was high in both trials. Despite a significantly longer intervention period (20w vs. 15w; P < 0.0001), ASD children had a significantly lower absolute increase (+26 vs. +45 nmol/l) in 25(OH)D (P = 0.04). Conclusions: Despite similar demographics, children with ASD had a lower increase in 25(OH)D levels with supplementation. Potential mechanisms include altered absorption/metabolism as well as well genetic factors. Clinical and research work relating to vitamin D is ASD should measure 25(OHO)D response to supplementation to assess therapeutic doses.

Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.

BACKGROUND: Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity. OBJECTIVES: To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry. STUDY SELECTION: Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected. STUDY APPRAISAL: Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity. RESULTS: We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality. LIMITATIONS: Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately. CONCLUSIONS: Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013953. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Dietary nitrate improved exercise capacity in COPD but not blood pressure or pulmonary function: a 2 week, double-blind randomised, placebo-controlled crossover trial.

Dietary nitrate may improve exercise tolerance in some healthy and clinical populations. Existing data regarding dietary nitrate in COPD is inconsistent. We conducted a 14d double-blind, randomised, placebo-controlled, crossover trial of daily nitrate-rich beetroot juice (BRJ; 12.9 mmol) versus nitrate-depleted BRJ (PL; 0.5 mmol). At baseline and after each condition, we assessed functional capacity (incremental shuttle walk test; ISWT), ambulatory blood pressure, pulmonary function, quality of life as well as exhaled nitric oxide (eNO), and plasma nitrate/nitrite (NOx). Eight subjects with COPD completed the trial. BRJ supplementation was associated with significantly increased NOx (p < .05) and a 14.6% increase in ISWT distance (+56 m, p = .00004) as well as a trend towards increased eNO compared to PL. There was no other differences. Dietary nitrate appears to have ergogenic effect in subjects with mild-moderate COPD. This effect does not appear to be related to altering blood pressure or pulmonary function.

Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data.

BACKGROUND: A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown. METHODS: For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D3 or vitamin D2 supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953. FINDINGS: Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56-0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11-0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58-1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; pinteraction=0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I2=0·0, p=0·56). INTERPRETATION: Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients. FUNDING: Health Technology Assessment Program, National Institute for Health Research (reference number 13/03/25).

Dietary nitrate as modulator of physical performance and cardiovascular health.

PURPOSE OF REVIEW: Early interventional trials reported improvements in cardiac and exercise outcomes with inorganic nitrate ingestion. The current review aims to provide a brief update of recent evidence regarding ergogenic and cardiovascular effects of dietary nitrate and practical recommendations. RECENT FINDINGS: Recent evidence has been inconsistent and questions remain regarding effective dose, duration, and source of nitrate and cohorts likely to benefit. Dietary nitrate may be most relevant to those with vascular/metabolic impairments, those engaging in short-term, intense exercise, deconditioned individuals, and those with a low dietary nitrate intake. SUMMARY: The evidence for cardiovascular/exercise benefit is plausible but inconsistent. However, dietary nitrate, in contrast to pharmacological nitrate, has a high benefit-risk ratio. Although nitrate supplementation has grown in popularity, it is suggested that increased green vegetables consumption may provide similar/superior benefits to nitrate supplementation in a cheaper, safer, and potentially tastier context.

Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT.

OBJECTIVES: Data suggest a potential role for vitamin D in autism spectrum disorder (ASD). We wanted to assess the effect of vitamin D3 supplementation compared with placebo in children with ASD. DESIGN: This was a double-blind, randomised, placebo-controlled trial. SETTING: A paediatric outpatient centre at high latitude over the winter season in Dublin, Ireland (53°N). PATIENTS: 42 children with ASD. INTERVENTIONS: 2000 IU vitamin D3 supplementation or placebo daily for 20 weeks. MAIN OUTCOME MEASURES: Assessments were completed at baseline and after 20 weeks of supplementation. The primary outcome was the stereotypic behaviour subscale from the Aberrant Behaviour Checklist (ABC). Secondary exploratory outcomes included additional subscales from the ABC, the Social Responsiveness Scale and rating on the Developmental Disabilities-Children's Global Assessment Scale (DD-CGAS) as well as biochemical parameters of total vitamin D status (25-hydroxyvitamin D (25(OH)D)), immunity and systemic inflammation. RESULTS: 38 children completed the trial. Baseline 25(OH)D was 54.2±19.7 nmol/L. Following vitamin D3 supplementation, there was a significant increase in 25(OH)D to 83.8 nmol/L (p=0.0016) but no effect on the primary endpoint. However, there was an improvement in self-care on DD-CGAS (p=0.02). In contrast, there was also a trend toward decreased inappropriate speech in the placebo group (p=0.08). CONCLUSION: Vitamin D supplementation had no effect on the primary outcome with limited and inconsistent effects in children with ASD. Considering the other promising data as well as the relative safety and cheapness of vitamin D supplementation, further trials are warranted. TRIAL REGISTRATION: NCT02508922.

Vitamin D Improves Selected Metabolic Parameters but Not Neuropsychological or Quality of Life Indices in OSA: A Pilot Study.

STUDY OBJECTIVES: Our group and others have reported a high rate of vitamin D deficiency in obstructive sleep apnea (OSA), where vitamin D levels (25(OH) D) correlate negatively with OSA severity and some of its associated metabolic alterations. Data regarding vitamin D supplementation in OSA are lacking. We wanted to evaluate the effect of vitamin D3 supplementation on OSA symptoms and metabolic parameters. METHODS: We conducted a pilot, double-blind, randomized, placebo-controlled trial of daily supplementation with 4,000 IU vitamin D3 (D3) or placebo (PL). We studied 19 Caucasian adults (14 male, mean age 55 y, mean body mass index [BMI] 30.4 kg/m2) with OSA. Fifteen patients were stable on continuous positive airways pressure (CPAP) therapy, whereas four were CPAP naïve. Assessments were completed at baseline and after 15 weeks of supplementation. Outcomes included sleepiness (Epworth Sleepiness Scale), quality of life (Sleep Apnea Quality of Life Inventory), fatigue (fatigue severity scale) and neuropsychological function (trail making test and Connor's Continuous Performance Test II). In addition, we assessed biochemical indices of vitamin D status (25(OH)D, calcium), inflammation (high sensitivity C-reactive protein, and lipoprotein-associated phospholipase A2), lipids (total cholesterol [low-density and high-density lipoprotein]) and glycemic indices (fasting glucose, oral glucose tolerance test). RESULTS: There was no change in BMI, medication, or CPAP usage. Although there was no change in neuropsychological or quality of life indices, we observed a significant increase in 25(OH)D (p = 0.00001) and significant decreases in both low-density lipoprotein (p = 0.04) and lipoprotein-associated phospholipase A2 (p = 0.037) as well as trends toward decreased fasting glucose (p = 0.09) and increased high-density lipoprotein (p = 0.07) in the D3 group compared to PL. CONCLUSIONS: Vitamin D3 supplementation increased vitamin D levels and decreased metabolic markers compared to placebo. Larger trials are required.

Vitamin D3 for uncontrolled childhood asthma: A pilot study.

BACKGROUND: Observational and mechanistic data suggest a role for vitamin D in childhood asthma. However, subsequent interventional trials have been inconsistent. We aimed to assess the effect of 15 weeks of vitamin D3 supplementation compared with placebo (PL) in Irish children with asthma. METHODS: We conducted a double-blind, randomized, PL-controlled trial of vitamin D supplementation (2000 IU/day) in 44 urban, Caucasian children at high latitude. Assessments were completed at baseline and after 15 weeks of supplementation. Outcome measures were lung function, subjective asthma control and biochemical parameters of total vitamin D, allergy, immunity, airway inflammation, and systemic inflammation. Finally, parents/guardians completed a weekly diary during the trial. RESULTS: There was no significant difference in baseline 25(OH)D levels, but there was a significant increase in median 25(OH)D in the vitamin D3 group (57.5-105 nmol/l) compared with the PL group (52.5-57.5 nmol/l) (p < 0.0001). There was no significant difference between groups regarding subjective asthma control. Compared with PL, there was a significant decrease in school days missed due to asthma (1 vs. 5 days, p = 0.04) and alkaline phosphatase (-3.4 vs. +16; p = 0.037) in the vitamin D3 group, but there were no beneficial effects regarding several other secondary end-points. However, there were non-significant, advantageous changes in the PL group compared with the vitamin D3 group in subjective asthma control and lung function, particularly percentage of predicted forced expiratory volume in 1 s (+2.5 vs. -4; p = 0.06). CONCLUSION: Vitamin D3 supplementation led to a significant increase in serum 25(OH)D and decreased school days missed (p = 0.04), but no other advantageous changes in asthma parameters compared with PL. The potential adverse effect of vitamin D deficiency on growth and the potential negative effect of high serum 25(OH)D on pulmonary function warrant further investigation.

Vitamin D as an adjunctive therapy in asthma. Part 2: A review of human studies.

Vitamin D deficiency (VDD) is highly prevalent worldwide, with adverse effects on bone health but also potentially other unfavorable consequences. VDD and asthma-incidence/severity share many common risk factors, including winter season, industrialization, poor diet, obesity, dark skin pigmentation, and high latitude. Multiple anatomical areas relevant to asthma contain both the enzyme responsible for producing activated vitamin D and the vitamin D receptor suggesting that activated vitamin D (1,25-dihydroxyvitamin D) may have important local effects at these sites. Emerging evidence suggests that VDD is associated with increased airway hyperresponsiveness, decreased pulmonary function, worse asthma control, and possibly decreased response to standard anti-asthma therapy. However the effect is inconsistent with preliminary evidence from different studies suggesting vitamin D is both beneficial and detrimental to asthma genesis and severity. Current evidence suggests that supplementation with moderate doses of vitamin D may be appropriate for maintenance of bone health in asthmatics, particularly steroid users. However emerging data from an increasing number of randomized, controlled, intervention studies of vitamin D supplementation in pediatric and adult asthma are becoming available and should help determine the importance, if any of vitamin D for asthma pathogenesis. The purpose of this second of a two-part review is to review the current human literature on vitamin D and asthma, discussing the possible consequences of VDD for asthma and the potential for vitamin D repletion as adjunct therapy.