Copy number variation and neuropsychiatric problems in females and males in the general population

Neurodevelopmental problems (NPs) are more common in males, whereas anxiety and depression are more common in females. Rare copy number variants (CNVs) have been implicated in neurodevelopmental disorders. The aim of this study was to characterize the relationship between rare CNVs with NPs, anxiety, and depression in a childhood population sample, as well as to examine sex‐specific effects. We analyzed a sample of N = 12,982 children, of whom 5.3% had narrowly defined NPs (clinically diagnosed), 20.9% had broadly defined NPs (based on validated screening measures, but no diagnosis), and 3.0% had clinically diagnosed anxiety or depression. Rare ( 500 kb), type, and putative relevance to NPs. We tested for association of CNV categories with outcomes and examined sex‐specific effects. Medium deletions (OR[CI] = 1.18[1.05–1.33], p = .0053) and large duplications (OR[CI] = 1.45[1.19–1.75], p = .00017) were associated with broadly defined NPs. Large deletions (OR[CI] = 1.85[1.14–3.01], p = .013) were associated with narrowly defined NPs. There were no significant sex differences in CNV burden in individuals with NPs. Although CNVs were not associated with anxiety/depression in the whole sample, in individuals diagnosed with these disorders, females were more likely to have large CNVs (OR[CI] = 3.75[1.45–9.68], p = .0064). Rare CNVs are associated with both narrowly and broadly defined NPs in a general population sample of children. Our results also suggest that large, rare CNVs may show sex‐specific phenotypic effects

Commentary on the EMA Reflection Paper on the use of extrapolation in the development of medicines for paediatrics

Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts. Hopefully, this will help in promoting their diffusion and in opening a forum for discussion with our readers.Pharmacolog

Association between bone mineral density and autoantibodies in patients with rheumatoid arthritis

Objective Autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts.Methods Dual x-ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow-up and in 198 Swedish patients with early RA during 10 years of follow-up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations.Results In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA-positive patients compared to ACPA-negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm(2) (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm(2) (95% CI 0.93-0.97) (P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA-positive group compared to the ACPA-negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08-0.29] versus 0.48 [95% CI 0.33-0.63]) (P < 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti-carbamylated protein antibodies). In the Swedish cohort, ACPA-positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time.Conclusion The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well-managed.Pathophysiology and treatment of rheumatic disease

Software quality management improvement through mentoring: an exploratory study from GSD projects

Proceeding of: OTM 2011 Workshops: Confederated InternationalWorkshops and Posters: EI2N+NSF ICE, ICSP+INBAST, ISDE, ORM, OTMA, SWWS+MONET+SeDeS, and VADER 2011, Hersonissos, Crete, Greece, October 17-21, 2011Software Quality Management (SQM) is a set of processes and procedures designed to assure the quality of software artifacts along with their development process. In an environment in which software development is evolving to a globalization, SQM is seen as one of its challenges. Global Software Development is a way to develop software across nations, continents, cultures and time zones. The aim of this paper is to detect if mentoring, one of the lead personnel development tools, can improve SQM of projects developed under GSD. The results obtained in the study reveal that the influence of mentoring on SQM is just temperate

Scaling ozone responses of forest trees to the ecosystem level in a changing climate

Many uncertainties remain regarding how climate change will alter the structure and function of forest ecosystems. At the Aspen FACE experiment in northern Wisconsin, we are attempting to understand how an aspen/birch/maple forest ecosystem responds to long-term exposure to elevated carbon dioxide (CO 2 ) and ozone (O 3 ), alone and in combination, from establishment onward. We examine how O 3 affects the flow of carbon through the ecosystem from the leaf level through to the roots and into the soil micro-organisms in present and future atmospheric CO 2 conditions. We provide evidence of adverse effects of O 3 , with or without co-occurring elevated CO 2 , that cascade through the entire ecosystem impacting complex trophic interactions and food webs on all three species in the study: trembling aspen ( Populus tremuloides Michx . ), paper birch ( Betula papyrifera Marsh), and sugar maple ( Acer saccharum Marsh). Interestingly, the negative effect of O 3 on the growth of sugar maple did not become evident until 3 years into the study. The negative effect of O 3 effect was most noticeable on paper birch trees growing under elevated CO 2 . Our results demonstrate the importance of long-term studies to detect subtle effects of atmospheric change and of the need for studies of interacting stresses whose responses could not be predicted by studies of single factors. In biologically complex forest ecosystems, effects at one scale can be very different from those at another scale. For scaling purposes, then, linking process with canopy level models is essential if O 3 impacts are to be accurately predicted. Finally, we describe how outputs from our long-term multispecies Aspen FACE experiment are being used to develop simple, coupled models to estimate productivity gain/loss from changing O 3 .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72464/1/j.1365-3040.2005.01362.x.pd

Scientific and regulatory evaluation of mechanistic in silico drug and disease models in drug development: building model credibility

The value of in silico methods in drug development and evaluation has been demonstrated repeatedly and convincingly. While their benefits are now unanimously recognized, international standards for their evaluation, accepted by all stakeholders involved, are still to be established. In this white paper, we propose a risk-informed evaluation framework for mechanistic model credibility evaluation. To properly frame the proposed verification and validation activities, concepts such as context of use, regulatory impact and risk-based analysis are discussed. To ensure common understanding between all stakeholders, an overview is provided of relevant in silico terminology used throughout this paper. To illustrate the feasibility of the proposed approach, we have applied it to three real case examples in the context of drug development, using a credibility matrix currently being tested as a quick-start tool by regulators. Altogether, this white paper provides a practical approach to model evaluation, applicable in both scientific and regulatory evaluation contexts

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P <5 x 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain similar to 7.4% of the population variance in age at menarche, corresponding to similar to 25% of the estimated heritability. We implicate similar to 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Evolution of microstructure and crystallographic texture during dissimilar friction stir welding of duplex stainless steel to low carbon-manganese structural steel

Electron backscattered diffraction (EBSD) was used to analyze the evolution of microstructure and crystallographic texture during friction stir welding of dissimilar type 2205 duplex stainless steel (DSS) to type S275 low carbon-manganese structural steel. The results of microstructural analyses show that the temperature in the center of stirred zone reached temperatures between Ac 1 and Ac 3 during welding, resulting in a minor ferrite-to-austenite phase transformation in the S275 steel, and no changes in the fractions of ferrite and austenite in the DSS. Temperatures in the thermomechanically affected and shoulder-affected zones of both materials, in particular toward the root of the weld, did not exceed the Ac 1 of S275 steel. The shear generated by the friction between the material and the rotating probe occurred in austenitic/ferritic phase field of the S275 and DSS. In the former, the transformed austenite regions of the microstructure were transformed to acicular ferrite, on cooling, while the dual-phase austenitic/ferritic structure of the latter was retained. Studying the development of crystallographic textures with regard to shear flow lines generated by the probe tool showed the dominance of simple shear components across the whole weld in both materials. The ferrite texture in S275 steel was dominated by D 1, D 2, E, E¯ , and F, where the fraction of acicular ferrite formed on cooling showed a negligible deviation from the texture for the ideal shear texture components of bcc metals. The ferrite texture in DSS was dominated by D 1, D 2, I, I¯ , and F, and that of austenite was dominated by the A, A¯ , B, and B¯ of the ideal shear texture components for bcc and fcc metals, respectively. While D 1, D 2, and F components of the ideal shear texture are common between the ferrite in S275 steel and that of dual-phase DSS, the preferential partitioning of strain into the ferrite phase of DSS led to the development of I and I¯ components in DSS, as opposed to E and E¯ in the S275 steel. The formations of fine and ultrafine equiaxed grains were observed in different regions of both materials that are believed to be due to strain-induced continuous dynamic recrystallization (CDRX) in ferrite of both DSS and S275 steel, and discontinuous dynamic recrystallization (DDRX) in austenite phase of DSS