Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy

Background: Allergy immunotherapy targets the immunological cause of allergic rhinoconjunctivitis and allergic asthma and has the potential to alter the natural course of allergic disease.Objective: The primary objective was to investigate the effect of the SQ grass sublingual immunotherapy tablet compared with placebo on the risk of developing asthma.Methods: A total of 812 children (5-12 years), with a clinically relevant history of grass pollen allergic rhinoconjunctivitis and no medical history or signs of asthma, were included in the randomized, double-blind, placebo-controlled trial, comprising 3 years of treatment and 2 years of follow-up.Results: There was no difference in time to onset of asthma, defined by prespecified asthma criteria relying on documented reversible impairment of lung function (primary endpoint). Treatment with the SQ grass sublingual immunotherapy tablet significantly reduced the risk of experiencing asthma symptoms or using asthma medication at the end of trial (odds ratio = 0.66, P Conclusions: Treatment with the SQ grass sublingual immunotherapy tablet reduced the risk of experiencing asthma symptoms and using asthma medication, and had a positive, long-term clinical effect on rhinoconjunctivitis symptoms and medication use but did not show an effect on the time to onset of asthma.</p

Methods for characterising the steel–concrete interface to enhance understanding of reinforcement corrosion: a critical review by RILEM TC 262-SCI

The steel–concrete interface (SCI) is a complex, multi-phase and multi-scale system. It is widely known to influence the performance and long-term durability of concrete structures. However, a fundamental understanding of its properties and effects on corrosion initiation of embedded reinforcing steel remains elusive. This is attributed to its complicated heterogeneity and time-dependent nature, exacerbated by the lack of suitable techniques for systematic and detailed characterisation. This paper, prepared by members of the RILEM Technical Committee 262-SCI, critically reviews available information regarding current methods (laboratory or field-based) for characterising local properties of the SCI that have been identified as governing factors affecting corrosion initiation. These properties include characteristics of the steel such as mill scale and rust layers, and characteristics of the concrete such as interfacial voids, microstructure and moisture content. We evaluated over twenty methods and summarised their advantages, applications and limitations. The findings show a severe lack of well established, non-destructive techniques that are suitable for direct monitoring of the SCI at a representative scale with sufficiently high resolution (spatial, temporal), particularly for moisture related aspects. Several promising novel techniques with significant potential for further development and application were identified and discussed. Finally, we provide several recommendations for future research needs that are required to advance this critically important topic

The impact of comorbidity and stage on ovarian cancer mortality: A nationwide Danish cohort study

<p>Abstract</p> <p>Background</p> <p>The incidence of ovarian cancer increases sharply with age, and many elderly patients have coexisting diseases. If patients with comorbidities are diagnosed with advanced stages, this would explain the poor survival observed among ovarian cancer patients with severe comorbidity. Our aims were to examine the prevalence of comorbidity according to stage of cancer at diagnosis, to estimate the impact of comorbidity on survival, and to examine whether the impact of comorbidity on survival varies by stage.</p> <p>Methods</p> <p>From the Danish Cancer Registry we identified 5,213 patients (> 15 years old) with ovarian cancer diagnosed from 1995 to 2003. We obtained information on comorbidities from the Danish National Hospital Discharge Registry. Vital status was determined through linkage to the Civil Registration System. We estimated the prevalence of comorbidity by stage and computed absolute survival and relative mortality rate ratios (MRRs) by comorbidity level (Charlson Index score 0, 1–2, 3+), using patients with Charlson Index score 0 as the reference group. We then stratified by stage and computed the absolute survival and MRRs according to comorbidity level, using patients with Charlson score 0 and localized tumour/FIGO I as the reference group. We adjusted for age and calendar time.</p> <p>Results</p> <p>Comorbidity was more common among patients with an advanced stage of cancer. One- and five-year survival was higher in patients without comorbidity than in patients with registered comorbidity. After adjustment for age and calendar time, one-year MRRs declined from 1.8 to 1.4 and from 2.7 to 2.0, for patients with Charlson scores 1–2 and 3+, respectively. After adjustment for stage, the MRRs further declined to 1.3 and 1.8, respectively. Five-year MRRs declined similarly after adjustment for age, calendar time, and stage. The impact of severe comorbidity on mortality varied by stage, particularly among patients with tumours with regional spread/FIGO-stages II and III.</p> <p>Conclusion</p> <p>The presence of severe comorbidity was associated with an advanced stage of ovarian cancer. Mortality was higher among patients with comorbidities and the impact of comorbidity varied by stage.</p

Effect of Correlated tRNA Abundances on Translation Errors and Evolution of Codon Usage Bias

Despite the fact that tRNA abundances are thought to play a major role in determining translation error rates, their distribution across the genetic code and the resulting implications have received little attention. In general, studies of codon usage bias (CUB) assume that codons with higher tRNA abundance have lower missense error rates. Using a model of protein translation based on tRNA competition and intra-ribosomal kinetics, we show that this assumption can be violated when tRNA abundances are positively correlated across the genetic code. Examining the distribution of tRNA abundances across 73 bacterial genomes from 20 different genera, we find a consistent positive correlation between tRNA abundances across the genetic code. This work challenges one of the fundamental assumptions made in over 30 years of research on CUB that codons with higher tRNA abundances have lower missense error rates and that missense errors are the primary selective force responsible for CUB

Microarray analysis identifies a set of CXCR3 and CCR2 ligand chemokines as early IFNβ-responsive genes in peripheral blood lymphocytes in vitro: an implication for IFNβ-related adverse effects in multiple sclerosis

BACKGROUND: A substantial proportion of multiple sclerosis (MS) patients discontinue interferon-beta (IFNβ) treatment due to various adverse effects, most of which emerge at the early phase after initiation of the treatment and then diminish with time. At present, the molecular mechanism underlying IFNβ-related adverse effects remains largely unknown. The aim of this study is to identify a comprehensive list of early IFNβ-responsive genes (IRGs) in peripheral blood mononuclear cells (PBMC) that may play a key role in induction of adverse effects. METHODS: Total RNA of PBMC exposed to 50 ng/ml recombinant human IFNβ for 3 to 24 hours in vitro was processed for cDNA microarray analysis, followed by quantitative real-time RT-PCR analysis. RESULTS: Among 1,258 genes on the array, IFNβ elevated the expression of 107 and 87 genes, while it reduced the expression of 22 and 23 genes at 3 and 24 hours, respectively. Upregulated IRGs were categorized into conventional IFN-response markers, components of IFN-signaling pathways, chemokines, cytokines, growth factors, and their receptors, regulators of apoptosis, DNA damage, and cell cycle, heat shock proteins, and costimulatory and adhesion molecules. IFNβ markedly upregulated CXCR3 ligand chemokines (SCYB11, SCYB10 and SCYB9) chiefly active on effector T helper type 1 (Th1) T cells, and CCR2 ligand chemokines (SCYA8 and SCYA2) effective on monocytes, whereas it downregulated CXCR2 ligand chemokines (SCYB2, SCYB1 and IL8) primarily active on neutrophils. CONCLUSION: IFNβ immediately induces a burst of gene expression of proinflammatory chemokines in vitro that have potential relevance to IFNβ-related early adverse effects in MS patients in vivo

Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption

<p>Abstract</p> <p>Background</p> <p>Bone resorption is initiated by osteoclastic acidification of the resorption lacunae. This process is mediated by secretion of protons through the V-ATPase and chloride through the chloride antiporter ClC-7. To shed light on the intracellular signalling controlling extracellular acidification, we screened a protein kinase inhibitor library in human osteoclasts.</p> <p>Methods</p> <p>Human osteoclasts were generated from CD14+ monocytes. The effect of different kinase inhibitors on lysosomal acidification in human osteoclasts was investigated using acridine orange for different incubation times (45 minutes, 4 and 24 hours). The inhibitors were tested in an acid influx assay using microsomes isolated from human osteoclasts. Bone resorption by human osteoclasts on bone slices was measured by calcium release. Cell viability was measured using AlamarBlue.</p> <p>Results</p> <p>Of the 51 compounds investigated only few inhibitors were positive in both acidification and resorption assays. Rottlerin, GF109203X, Hypericin and Ro31-8220 inhibited acid influx in microsomes and bone resorption, while Sphingosine and Palmitoyl-DL-carnitine-Cl showed low levels of inhibition. Rottlerin inhibited lysosomal acidification in human osteoclasts potently.</p> <p>Conclusions</p> <p>In conclusion, a group of inhibitors all indicated to inhibit PKC reduced acidification in human osteoclasts, and thereby bone resorption, indicating that acid secretion by osteoclasts may be specifically regulated by PKC in osteoclasts.</p

Gonadal Transcriptome Alterations in Response to Dietary Energy Intake: Sensing the Reproductive Environment

Reproductive capacity and nutritional input are tightly linked and animals' specific responses to alterations in their physical environment and food availability are crucial to ensuring sustainability of that species. We have assessed how alterations in dietary energy intake (both reductions and excess), as well as in food availability, via intermittent fasting (IF), affect the gonadal transcriptome of both male and female rats. Starting at four months of age, male and female rats were subjected to a 20% or 40% caloric restriction (CR) dietary regime, every other day feeding (IF) or a high fat-high glucose (HFG) diet for six months. The transcriptional activity of the gonadal response to these variations in dietary energy intake was assessed at the individual gene level as well as at the parametric functional level. At the individual gene level, the females showed a higher degree of coherency in gonadal gene alterations to CR than the males. The gonadal transcriptional and hormonal response to IF was also significantly different between the male and female rats. The number of genes significantly regulated by IF in male animals was almost 5 times greater than in the females. These IF males also showed the highest testosterone to estrogen ratio in their plasma. Our data show that at the level of gonadal gene responses, the male rats on the IF regime adapt to their environment in a manner that is expected to increase the probability of eventual fertilization of females that the males predict are likely to be sub-fertile due to their perception of a food deficient environment

Health Literacy and Power.

Comment article

The UK Biobank imaging enhancement of 100,000 participants: rationale, data collection, management and future directions

UK Biobank is a population-based cohort of half a million participants aged 40–69 years recruited between 2006 and 2010. In 2014, UK Biobank started the world’s largest multi-modal imaging study, with the aim of re-inviting 100,000 participants to undergo brain, cardiac and abdominal magnetic resonance imaging, dual-energy X-ray absorptiometry and carotid ultrasound. The combination of large-scale multi-modal imaging with extensive phenotypic and genetic data offers an unprecedented resource for scientists to conduct health-related research. This article provides an in-depth overview of the imaging enhancement, including the data collected, how it is managed and processed, and future direction