Vitamin D in the prevention of exacerbations of asthma in preschoolers (DIVA): Protocol for a multicentre randomised placebo-controlled triple-blind trial

Introduction Preschoolers have the highest rate of emergency visits and hospitalisations for asthma exacerbations of all age groups, with most triggered by upper respiratory tract infections (URTIs) and occurring in the fall or winter. Vitamin D insufficiency is highly prevalent in Canadian preschoolers with recurrent asthma exacerbations, particularly in winter. It is associated with more URTIs and, in patients with asthma, more oral corticosteroid (OCS) use. Although evidence suggests that vitamin D supplements significantly decrease URTIs and asthma exacerbations requiring OCS, there is insufficient data in preschoolers. This study aims to determine the impact of vitamin D 3 supplementation on exacerbations requiring OCS, in preschoolers with recurrent URTI-induced asthma exacerbations. Methods and analysis This is a phase III, randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D 3 supplementation in children aged 1-5 years, with asthma triggered by URTIs and a recent history of frequent URTIs and OCS use. Children (n=865) will be recruited in the fall and early winter and followed for 7 months. They will be randomised to either the (1) intervention: two oral boluses of 100 000 international unit (IU) vitamin D 3 (3.5 months apart) with 400 IU vitamin D 3 daily; or (2) control: identical placebo boluses with daily placebo. The primary outcome is the number of exacerbations requiring OCS per child, documented by medical and pharmacy records. Secondary outcomes include number of laboratory-confirmed viral URTIs, exacerbation duration and severity, parent functional status, healthcare use, treatment deintensification, cost and safety. Ethics and dissemination This study has received ethical approval from all sites. Results will be disseminated via international conferences and manuscripts targeting paediatricians and respirologists, and to families of asthmatic children via our Quebec parents-partners outreach programme. If proven effective, findings may markedly influence the management of URTI-induced asthma in high-morbidity preschoolers and could be directly implemented into practice with an update to clinical guidelines. Trial registration number NCT03365687

Efficacy and safety of open-label etanercept on extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis and psoriatic arthritis: part 1 (week 12) of the CLIPPER study

OBJECTIVE: To investigate the efficacy and safety of etanercept (ETN) in paediatric subjects with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). METHODS: CLIPPER is an ongoing, Phase 3b, open-label, multicentre study; the 12-week (Part 1) data are reported here. Subjects with eoJIA (2-17 years), ERA (12-17 years), or PsA (12-17 years) received ETN 0.8 mg/kg once weekly (maximum 50 mg). Primary endpoint was the percentage of subjects achieving JIA American College of Rheumatology (ACR) 30 criteria at week 12; secondary outcomes included JIA ACR 50/70/90 and inactive disease. RESULTS: 122/127 (96.1%) subjects completed the study (mean age 11.7 years). JIA ACR 30 (95% CI) was achieved by 88.6% (81.6% to 93.6%) of subjects overall; 89.7% (78.8% to 96.1%) with eoJIA, 83.3% (67.2% to 93.6%) with ERA and 93.1% (77.2% to 99.2%) with PsA. For eoJIA, ERA, or PsA categories, the ORs of ETN vs the historical placebo data were 26.2, 15.1 and 40.7, respectively. Overall JIA ACR 50, 70, 90 and inactive disease were achieved by 81.1, 61.5, 29.8 and 12.1%, respectively. Treatment-emergent adverse events (AEs), infections, and serious AEs, were reported in 45 (35.4%), 58 (45.7%), and 4 (3.1%), subjects, respectively. Serious AEs were one case each of abdominal pain, bronchopneumonia, gastroenteritis and pyelocystitis. One subject reported herpes zoster and another varicella. No differences in safety were observed across the JIA categories. CONCLUSIONS: ETN treatment for 12 weeks was effective and well tolerated in paediatric subjects with eoJIA, ERA and PsA, with no unexpected safety findings

Population Genetic Characteristics of the STR Loci D21S11 and FGA in Eight Diverse Human Populations

A highly polymorphic multiplex short tandem repeat (STR) system composed of D21S11, FGA, and the sex-typing system amelogenin (AMG) has been used to investigate allele frequency distributions in two Canadian Caucasian samples (British Columbia and Alberta), three Canadian aboriginal populations (Coastal Salishans from British Columbia, Ojibwa from northern Ontario, and Cree from Saskatchewan), and three ethnic groups from Singapore (Chinese, Malays, and Asian Indians). Using the automated fluorescence detection approach on an ABD 373A DNA Sequencer, we distinguished 20 D21S11 and 22 FGA alleles with a nearly equal representation of two- and four-base variants. An overlap in allele sizes for both STR loci across populations was observed, but frequency differences were noted. Statistical analysis revealed that (1) both D21S11 and FGA loci conform to Hardy-Weinberg equilibrium in all eight surveyed populations based on five different tests and (2) both STR loci are in linkage equilibrium. Results from the 2 X N contingency table exact tests for population differentiation demonstrated that the Canadian samples from two different provinces were not distinguishable from one another at either STR locus and therefore could be combined to form one Caucasian group. Likewise, Chinese and Malays from Singapore did not show significant differences at either STR locus. In contrast, all other examined populations exhibited differences deemed statistically significant. As a complement to our study, we compared D21S11 allele frequency distributions in 21 worldwide populations and FGA allele frequency distributions in 14 populations. Many alleles never previously reported in worldwide populations were identified in Canadian aboriginal and Asian samples from this study. Twenty-four D21S11 and 29 FGA alleles were distinguished in worldwide groups. Interesting similarities in allele frequency distribution patterns across populations suggest that the STR polymorphism at these loci predates the geographic dispersal of ancestral human populations. This study further demonstrates the utility of highly informative STR loci such as D21S11 and FGA in human population evolutionary history and in forensic medicine

The spatial organization of proton and lactate transport in a rat brain tumor.

International audienceTumors create a heterogeneous acidic microenvironment which assists their growth and which must be taken into account in the design of drugs and their delivery. In addition, the acidic extracellular pH (pHe) is itself exploited in several experimental techniques for drug delivery. The way the acidity is created is not clear. We report here the spatial organization of key proton-handling proteins in C6 gliomas in rat brain. The mean profiles across the tumor rim of the Na+/H+ exchanger NHE1, and the lactate-H+ cotransporter MCT1, both showed peaks. NHE1, which is important for extension and migration of cells in vitro, showed a peak 1.55 times higher than in extratumoural tissue at 0.33 mm from the edge. MCT1 had a broader peak, further into the tumor (maximum 1.76 fold at 1.0 mm from the edge). In contrast, MCT4 and the carbonic anhydrase CAIX, which are associated with hypoxia, were not significantly upregulated in the rim. The spatial distribution of MCT4 was highly correlated with that of CAIX, suggesting that their expression is regulated by the same factors. Since protons extruded by NHE1 diffuse away through extracellular clefts, NHE1 requires a continuous source of intracellular protons. From the stoichiometries of metabolic pathways that produce or consume H+, and the greater availability of glucose compared to oxygen in most parts of a tumor, we support the classic view that most of the net proton efflux from C6 gliomas originates in glycolytic formation of lactate and H+ inside the tumor, but add that some lactate is taken up into cells in the rim on MCT1, and some lactate diffuses away, leaving its associated protons available to re-enter cells for extrusion on NHE1. Therapeutic inhibition of NHE1, MCT1 or CAIX is predicted to affect different parts of a tumor