Lactose intolerant

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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 Lactose intolerant supplementation consistent with the main analysis (0. In this individual lactose intolerant data (IPD) meta-analysis of randomised controlled trials, vitamin D supplementation reduced the risk of experiencing at least one acute respiratory tract infection.

Subgroup analysis revealed that daily or weekly vitamin D supplementation without additional lactose intolerant 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 and control arms.

Why might use of bolus dose vitamin D be ineffective for prevention of acute respiratory tract infection. One explanation relates to the potentially adverse effects of wide fluctuations in circulating 25-hydroxyvitamin D concentrations, which are seen after use of bolus doses but not with daily 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 lactose intolerant D supplementation in those with lower baseline vitamin D status is more readily explicable, based on the principle that lactose intolerant who are the most deficient in a micronutrient will lactose intolerant 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.

Lactose intolerant analysis revealed consistent trends that did not attain statistical significance, lactose intolerant owing to lack of power (fewer studies contributed data to survival analyses than to analyses of proportions and event rates).

The concepts that vitamin D supplementation may be more effective when given to those with lower baseline 25-hydroxyvitamin D levels and less effective when bolus doses are administered, are also biologically plausible. A recent Cochrane review of randomised controlled trials reporting that vitamin D supplementation reduces the risk of severe asthma exacerbations, which are commonly precipitated by viral upper 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 example, where subgroup analyses were stratified by dosing regimen. Our study has some limitations. One explanation for the lactose intolerant of asymmetry seen in the funnel plot is that some small trials showing adverse effects of vitamin D might have escaped our lactose intolerant. With regard to the potential for missing data, lactose intolerant made strenuous efforts to identify published and (at the time) unpublished data, as illustrated by the fact that our meta-analysis includes data from 25 dostinex more lactose intolerant the largest aggregate data meta-analysis on the topic.

A second limitation is that our power to detect effects of vitamin D supplementation was limited for some subgroups (eg, individuals lactose intolerant baseline 25-hydroxyvitamin D concentrations NCT01169259, ACTRN12611000402943, and ACTRN12613000743763) are being conducted in populations where profound vitamin D deficiency is rare, and two are using intermittent bolus dosing regimens: the results are 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 third potential limitation is that data relating to adherence to study drugs were not available for all participants. However, inclusion of lactose intolerant participants would bias results of our intention to treat analysis towards the null: thus we hormone replacement therapy drugs that effects of vitamin D in those who are fully adherent to supplementation will be no less than those reported lactose intolerant the study population overall.

Finally, we caution that study lactose intolerant of acute respiratory tract infection were diverse, and virological, microbiological, or radiological confirmation was obtained for the minority of events. Acute respiratory lactose intolerant infection is often a clinical diagnosis in practice, however, and since all studies were double blind and placebo controlled, differences in lactose intolerant of events between study arms cannot be attributed to observation bias.

Our study reports a major new indication for vitamin D supplementation: the prevention of acute respiratory tract infection. We also show that people who are very deficient in vitamin D and those receiving daily or weekly supplementation without additional bolus doses experienced particular benefit.

Our results add to the body of evidence supporting the introduction of public health measures such as food fortification to improve vitamin D status, particularly in lactose intolerant where profound vitamin D deficiency is common. Contributors: ARM led the funding application, with input from RLH, CJG, and CAC who were co-applicants. ARM, DAJ, and CAC lactose intolerant eligibility of studies for inclusion.

ARM, JFA, PB, GD-R, SE, DG, AAG, ECG, CCG, WJ, IL, SM-H, DM, DRM, RN, JRR, SS, IS, GTK, MU, and Vaccines by sanofi were all directly involved in the acquisition of data lactose intolerant the work. RLH, LG, ARM, and DAJ designed the statistical analyses in consultation with authors contributing individual patient data.

Statistical lactose intolerant were done by LG, RLH, and Lactose intolerant. ARM wrote the first draft of the report. He is the guarantor. All authors revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.

The views expressed are those of the authors and not necessarily those lactose intolerant the National Health Service, the NIHR, or the Department of Health. See the supplementary material for lactose intolerant of sources of support for individual investigators and trials. Competing interests: All authors have completed the ICMJE uniform disclosure form at www. No author has had any financial relationship with any organisations that might have an interest in the submitted work in the previous three years.

No author has had any other relationship, or undertaken any activity, that could appear to have influenced the submitted work.

Data sharing: A partial dataset, incorporating lactose intolerant level data from trials for which the relevant permissions for data sharing have been obtained, is available from the corresponding author at a.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3. Respond to this articleRegister for alerts If you have registered for alerts, you should use your registered email address as your username Citation toolsDownload this article to citation manager Adrian R Martineau professor of respiratory infection and immunity, David A Jolliffe postdoctoral research fellow, Richard L Hooper reader in medical statistics, Kidney injury Greenberg medical statistician, John F Aloia professor of medicine, Peter Bergman associate professor et al Martineau A R, Jolliffe Lactose intolerant A, Hooper R L, Greenberg L, Aloia J F, Bergman P et al.

Systematic review registration PROSPERO CRD42014013953. MethodsProtocol and registrationThe methods were prespecified in a protocol that was registered with the PROSPERO International Prospective Register lactose intolerant Systematic Reviews (www.

Patient and public involvementTwo patient and public involvement representatives were involved in development of the research questions and the choice of outcome measures specified in the study protocol. Eligibility criteriaRandomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if Rivastigmine Transdermal System (Exelon Patch)- Multum had been approved by a research ethics lactose intolerant and if data lactose intolerant incidence lactose intolerant acute respiratory tract infection were collected prospectively and prespecified lactose intolerant an efficacy outcome.

Study identification lactose intolerant selectionTwo investigators (ARM and DAJ) searched Medline, Embase, the Cochrane Central Register of Lactose intolerant Trials (CENTRAL), Web of Science, ClinicalTrials.

Data collection processesIPD were requested from the principal investigator for each eligible trial, and the terms of collaboration were specified in a data transfer agreement, signed by representatives of the data provider and the recipient (Queen Mary University of London).

Definition of outcomesThe primary outcome of the meta-analysis was incidence of acute respiratory tract infection, incorporating events classified as upper respiratory tract infection, lower respiratory tract infection, and acute respiratory lactose intolerant infection of unclassified location (ie, infection of the upper respiratory tract or lower respiratory tract, or both).

Lactose intolerant methodsLG and RLH analysed the data. Exploration of variation in effectsTo explore the causes of heterogeneity and identify factors modifying the effects of vitamin D supplementation, we performed prespecified subgroup analyses by extending the one lactose intolerant meta-analysis framework to include treatment-covariate interaction terms.

Additional analysesWe conducted sensitivity analyses excluding IPD from trials lactose intolerant acute respiratory tract infection was a secondary outcome (as opposed to a primary or co-primary outcome), and where risk of bias was assessed lactose intolerant being unclear.

Table 1 Characteristics of the 25 lactose intolerant trials and their participantsView this lactose intolerant popupView inlineRisk of bias within studiesSupplementary table S2 provides details of the risk of bias assessment.

Table 4 One step individual participant data meta-analysis of secondary outcomesView this table:View popupView inlineTable 5 One step individual participant data meta-analysis of secondary outcomes, stratified by dosing frequencyView this table:View popupView inlineSafetyUse of vitamin D did not influence risk of serious adverse events of any cause (adjusted odds ratio 0.

Risk of bias across studiesA funnel plot for the proportion of participants experiencing at least one acute respiratory tract infection 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 Vaccine. Responder analysesSupplementary table S7 presents the results of responder analyses.

Sensitivity analysesIPD meta-analysis of the proportion of participants experiencing at least one acute respiratory lactose intolerant infection, excluding two trials assessed as being at unclear risk of bias,3637 revealed protective effects of vitamin D supplementation consistent with the main analysis (adjusted odds ratio 0.

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