Effects of vitamin D deficiency on neurobehavioural outcomes in children: a systematic review

Introduction: Vitamin D plays an important role in brain development in experimental studies; however, the effect of vitamin D deficiency on child development remains inadequately characterized. We aimed to estimate the effects of vitamin D deficiency on neurobehavioural outcomes in children up to 18 years of age. Methods: We searched PubMed, EMBASE, PsycINFO, Scopus, Cochrane Library, Web of Science and Open Grey for published studies up to 10th January 2020. We included all studies that assessed the effects of maternal or child vitamin D status or vitamin D supplementation on neurobehavioural outcomes in children. Study findings were synthesized qualitatively as the high level of heterogeneity in study populations and methodologies precluded a quantitative meta-analysis. Results: Our search identified 5,633 studies, of which 31 studies with 31,375 participants from 18 countries were included in the systematic review. Of the studies identified, one was a randomised controlled trial (RCT) of vitamin D supplementation in children, while 30 were observational. The RCT (n=55) reported a beneficial effect of supplementation with lower doses compared to higher doses of vitamin D on motor development. Twelve mother-child studies (n=17,136) and five studies in children (n=1,091) reported an association between low maternal or child 25-hydroxyvitamin D levels and impaired neurobehavioural outcomes in children, while 15 mother-child studies (n=20,778) and eight studies in children (n=7,496) reported no association. Conclusions: Although animal studies point to an effect of vitamin D deficiency on brain development, there are few studies on the effects of vitamin D deficiency on neurobehavioural outcomes in children and their findings are inconsistent. There is a need for well-conducted, adequately powered studies to further determine these effects in children

Prevalence and predictors of vitamin D deficiency in young African children.

BACKGROUND: Children living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children. METHODS: We measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0-8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses. RESULTS: Median age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants. CONCLUSIONS: Approximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and prevalence of inflammation and malaria should be considered in strategies to assess and manage vitamin D deficiency in young children living in Africa

Replication Data for: Prevalence of vitamin D deficiency in Africa - a systematic review and meta-analysis

This dataset presents information obtained from systematic reviews of published vitamin D prevalence studies. The online searches were conducted on PubMed/MEDLINE, Web of Science, Embase, African Journals Online and African Index Medicus. Studies included in the meta-analyis had measured serum 25-hydroxyvitamin concentrations from healthy participants residing in Africa. The dataset comprises of seven (7) .csv files, one (1) R script for replicating figures and tables reported in the paper and codebook describing each individual file and variables. Variables include: year of publication, first author’s name, sample size, method of recruitment, study design, dates or season of blood sample collection, ethnicity, proportion of males, study country, method of vitamin D measurement, mean vitamin D concentrations and prevalence of vitamin D deficiency.</p

Steps in the chemogenomics repositioning workflow and their corresponding results.

<p>The yellow boxes represent <i>P</i>. <i>falciparum</i> sequences, drug targets are shown in blue boxes and drugs in green. Excluded drugs and proteins target have red box outlines.</p

Target-similarity search using <i>Plasmodium falciparum</i> proteome identifies approved drugs with anti-malarial activity and their possible targets

<div><p>Malaria causes about half a million deaths annually, with <i>Plasmodium falciparum</i> being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an <i>in silico</i> chemogenomics approach prior to <i>in vitro</i> verification. All the <i>P</i>. <i>falciparum</i> proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential <i>P</i>. <i>falciparum</i> drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 <i>P</i>. <i>falciparum</i> proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against <i>P</i>. <i>falciparum</i> 3D7 clone. Seven had IC₅₀ values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against <i>P</i>. <i>falciparum</i> and could be adapted for other pathogens.</p></div

Druggability indices of predicted <i>P</i>. <i>falciparum</i> drug targets.

<p>Druggability indices of predicted <i>P</i>. <i>falciparum</i> drug targets.</p

Details of approved drugs predicted to target <i>P</i>. <i>falciparum</i> proteins that have not been tested.

<p>Details of approved drugs predicted to target <i>P</i>. <i>falciparum</i> proteins that have not been tested.</p

Comparison of conserved amino acid residues.

<p>(A) ConSurf server MSA results (color coded according to conservation scores) of the drug target, the human tubulin beta-1 (NCBI accession number NP_110400.1) is overlaid above its BLAST pair-wise alignment with its <i>P</i>. <i>falciparum</i> homolog (NCBI accession number XP_001347369.1). The percent of the shared conserved residues was then determined; (B) 3D molecular structure of the human tubulin beta-1 chain with residues color coded according to their conservations scores, this was part of the ConSurf server results.</p

IC₅₀ values of some previously tested approved drugs that were predicted to have antiplasmodial activity.

<p>IC₅₀ values of some previously tested approved drugs that were predicted to have antiplasmodial activity.</p

<i>In vitro</i> activities of drugs tested against <i>P</i>. <i>falciparum</i> 3D7 strain.

<p><i>In vitro</i> activities of drugs tested against <i>P</i>. <i>falciparum</i> 3D7 strain.</p