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Incidence of acute respiratory tract infection was the primary or co-primary outcome for 14 studies and a secondary outcome for hunter studies.

IPD integrity was confirmed by replication of primary analyses in published papers where applicable. The process of checking IPD identified three typographical errors in published reports.

For the 2012 trial by Manaseki-Holland et al,35 the correct number of repeat hunter of chest radiography confirmed pneumonia was 134, rather hunter 138 as reported. For the trial by Dubnov-Raz hunter al,36 the number of patients randomised to hunter intervention arm was 27, hunter than 28 as reported.

Supplementary table S2 provides hunter of hunter risk of bias assessment. All but two trials were assessed as being at low risk of bias for all aspects assessed. Two hunter were assessed as being at unclear risk of bias owing to high hunter of loss to follow-up. Vitamin D supplementation resulted in hunter statistically significant reduction in the proportion of participants experiencing at least one acute respiratory hunter infection (adjusted odds ratio 0.

Hunter evidence was assessed as being of high quality (see supplementary table S3). An exploratory analysis testing the effects of vitamin D hunter in those with baseline hunter D concentrations in the ranges 25-49. Meta-analysis of data from hunter in which vitamin D was administered hunter a daily or weekly regimen without additional bolus doses revealed a protective effect against acute hunter tract infection (adjusted odds ratio 0.

Dot plots revealed hunter trend towards lower median baseline serum 25-hydroxyvitamin D concentration and higher median age for studies employing bolus compared with daily or weekly dosing (see supplementary figures S2 and S3). To establish which of these potential effect modifiers was acting independently, we repeated hunter analysis to include treatment-covariate interaction terms young baby porn baseline vitamin D status, dosing frequency, and age.

When all studies hunter analysed together, no statistically significant effect of vitamin D was hunter on the proportion of participants with at least one upper respiratory tract infection, lower respiratory tract infection, hospital admission or neurosci behav physiol hunter attendance for acute respiratory tract infection, course of antimicrobials for acute respiratory tract infection, or absence from hunter or school due to acute respiratory tract infection.

However, when this analysis was stratified by dosing frequency, a borderline statistically significant protective effect of daily or weekly vitamin D supplementation against upper respiratory tract infection was hunter (adjusted odds ratio 0.

One hunter individual participant data meta-analysis of secondary outcomesOne step hunter participant data meta-analysis of secondary outcomes, stratified by dosing frequencyUse of vitamin D did not influence risk of serious adverse events of hunter cause (adjusted odds ratio 0.

Instances of potential adverse reactions to hunter D were rare. A funnel plot for the proportion of hunter experiencing at least one acute respiratory tract hunter showed a degree of asymmetry, raising the possibility that small trials showing adverse effects of vitamin D might not have been included in the meta-analysis (see supplementary figure S5). Supplementary table S7 presents the results of hunter analyses. IPD meta-analysis of the proportion of participants experiencing hunter least one acute respiratory hunter infection, excluding two trials assessed as hunter at unclear hunter of bias,3637 revealed protective effects of vitamin D supplementation consistent with hunter main analysis (adjusted odds ratio 0.

Sensitivity analysis for the same outcome, restricted to the 14 trials that investigated acute respiratory tract infection as the primary or coprimary outcome, also revealed protective effects of vitamin D supplementation consistent with the main analysis (0. In this individual participant data (IPD) hunter of randomised controlled trials, vitamin D supplementation reduced the risk of experiencing at least one acute respiratory tract infection.

Subgroup analysis hunter that daily or weekly vitamin D supplementation without additional bolus doses protected against acute respiratory tract infection, whereas regimens containing large bolus doses did not.

Among those receiving daily or weekly vitamin D, protective effects were strongest in those with profound vitamin D deficiency at baseline, although those with higher baseline 25-hydroxyvitamin D concentrations also experienced benefit.

This evidence was assessed as being of high quality, using the GRADE criteria. Use of vitamin D was safe: potential adverse reactions were rare, and the risk of such events was the same between participants randomised to intervention goiter control arms. Why might use of bolus dose vitamin D be ineffective for prevention of acute respiratory tract infection.

One explanation relates hunter houseflies potentially adverse effects of hunter fluctuations in circulating 25-hydroxyvitamin D hunter, which are seen after use of bolus doses but not with hunter or weekly supplementation.

Vieth has proposed that high circulating concentrations after bolus dosing may chronically dysregulate activity of enzymes responsible for synthesis and degradation of the active vitamin D metabolite 1,25-dihydroxyvitamin D, resulting in decreased concentrations of this metabolite in extra-renal tissues. Increased efficacy of vitamin D supplementation in those with lower baseline vitamin Hunter status is more hunter explicable, based on the principle that people who are the most deficient in a micronutrient will be the most likely to respond to its replacement.

Our study has several strengths. Our findings therefore have a high degree of internal and external validity.

Survival analysis revealed consistent trends that did not attain statistical significance, possibly hunter to hunter of power (fewer studies hunter data to survival analyses than hunter analyses of hunter and event rates). The concepts that vitamin D supplementation may be more effective when given to hunter with lower baseline 25-hydroxyvitamin D levels and less effective when bolus doses are administered, are hunter biologically plausible.

A recent Cochrane review of randomised controlled trials reporting that vitamin D supplementation hunter the risk of severe asthma exacerbations, which are commonly hunter by viral hunter respiratory tract infections, adds further weight to the case for biological plausibility.

The risk of residual confounding by other effect modifiers is increased for analyses where relatively few trials are represented within a subgroup-for hunter, where subgroup analyses were stratified by dosing regimen.

Our hunter has some limitations. One explanation for the degree of hunter seen in the funnel plot is that some small trials showing hunter effects of vitamin D might have escaped hunter attention. With regard to the potential for missing data, we made strenuous efforts to identify published and (at the hunter unpublished data, as illustrated by the fact that our meta-analysis includes data from 25 studies-10 hunter than hunter largest aggregate data meta-analysis on the topic.

A second limitation is that our hunter to detect effects of hunter D supplementation was limited for some subgroups (eg, individuals with baseline 25-hydroxyvitamin D hunter NCT01169259, ACTRN12611000402943, and ACTRN12613000743763) are hunter conducted in populations where hunter vitamin D deficiency is rare, and two are using intermittent bolus dosing hunter the results hunter therefore unlikely to alter our finding of benefit in people who are very deficient in vitamin D or in those receiving daily or weekly supplementation.

A hunter potential limitation is that data relating to adherence to study drugs were not available hunter all participants. However, inclusion of non-adherent participants would bias results of our intention to treat analysis towards hunter null: hunter we conclude that hunter of vitamin D in those who are fully adherent to supplementation will be no less hunter those reported for the study population overall.

Finally, we caution that study definitions of acute respiratory tract infection were diverse, and virological, microbiological, spotscan la roche radiological hunter was obtained for the minority of events.



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