A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies: 10 years' experience; the Juvenile Dermatomyositis National (UK and Ireland) Cohort Biomarker Study and Repository for Idiopathic Inflammatory Myopathies

Objectives: The paediatric idiopathic inflammatory myopathies (IIMs) are a group of rare chronic inflammatory disorders of childhood, affecting muscle, skin and other organs. There is a severe lack of evidence base for current treatment protocols in juvenile myositis. The rarity of these conditions means that multicentre collaboration is vital to facilitate studies of pathogenesis, treatment and disease outcomes. We have established a national registry and repository for childhood IIM, which aims to improve knowledge, facilitate research and clinical trials, and ultimately to improve outcomes for these patients. Methods: A UK-wide network of centres and research group was established to contribute to the study. Standardized patient assessment, data collection forms and sample protocols were agreed. The Biobank includes collection of peripheral blood mononuclear cells, serum, genomic DNA and biopsy material. An independent steering committee was established to oversee the use of data/samples. Centre training was provided for patient assessment, data collection and entry. Results: Ten years after inception, the study has recruited 285 children, of which 258 have JDM or juvenile PM; 86% of the cases have contributed the biological samples. Serial sampling linked directly to the clinical database makes this a highly valuable resource. The study has been a platform for 20 sub-studies and attracted considerable funding support. Assessment of children with myositis in contributing centres has changed through participation in this study. Conclusions: This establishment of a multicentre registry and Biobank has facilitated research and contributed to progress in the management of a complex group of rare muscloskeletal conditions

A categorification of Morelli's theorem

We prove a theorem relating torus-equivariant coherent sheaves on toric varieties to polyhedrally-constructible sheaves on a vector space. At the level of K-theory, the theorem recovers Morelli's description of the K-theory of a smooth projective toric variety. Specifically, let $X$ be a proper toric variety of dimension $n$ and let M_\bR = \mathrm{Lie}(T_\bR^\vee)\cong \bR^n be the Lie algebra of the compact dual (real) torus T_\bR^\vee\cong U(1)^n. Then there is a corresponding conical Lagrangian \Lambda \subset T^*M_\bR and an equivalence of triangulated dg categories \Perf_T(X) \cong \Sh_{cc}(M_\bR;\Lambda), where \Perf_T(X) is the triangulated dg category of perfect complexes of torus-equivariant coherent sheaves on $X$ and \Sh_{cc}(M_\bR;\Lambda) is the triangulated dg category of complex of sheaves on M_\bR with compactly supported, constructible cohomology whose singular support lies in $\Lambda$. This equivalence is monoidal---it intertwines the tensor product of coherent sheaves on $X$ with the convolution product of constructible sheaves on M_\bR.Comment: 20 pages. This is a strengthened version of the first half of arXiv:0811.1228v3, with new results; the second half becomes arXiv:0811.1228v

A Double-Blind, Placebo-Controlled Withdrawal Trial of Dexmethylphenidate Hydrochloride in Children with Attention Deficit Hyperactivity Disorder

Objectives: d,l-threo-methylphenidate HCl (d,l-MPH) is the most common treatment of attention deficit hyperactivity disorder (ADHD). A previous report showed placebo-controlled efficacy for the purified disomer (dexmethylphenidate hydrochloride, d-MPH, Focalin™) with a 2:1 potency compared to dl, and suggested a 6-hour duration of action. This study complements that report by studying the effect of placebo-controlled discontinuation and retesting the duration of action. Methods: A 6-week, open-label titration of d-MPH (2.5–10 mg twice-a-day) was followed by a doubleblind, placebo-controlled, 2-week withdrawal study of responders. Results: In the open titration, 82% of the 89 enrolled patients achieved a Clinical Global Impression— Improvement (CGI-I) rating of much or very much improved. Only 5 patients discontinued for adverse events. Seventy-five patients continued into the placebo-controlled discontinuation. For the randomly assigned d-MPH (n = 35) and placebo (n = 40) groups, mean ages, respectively, were 10.1 ± 2.9 and 9.9 ± 2.7 years, 86% and 78% were male, and 70.6% and 80.0% took the ceiling dose of 10 mg twice-daily, respectively. Each group had 80% combined-type ADHD and 20% inattentive type. By the end of the 2- week, placebo-masked withdrawal, significantly more placebo patients (24 of 39) than d-MPH continuers (6 of 35) relapsed (61.5% versus 17.1%, p = 0.001). Compared to d-MPH continuers, placebo patients deteriorated significantly more in the 2-week period on teacher ratings of the 18 ADHD symptoms rated 0– 3 (p = 0.028), the 3 p.m. and 6 p.m. parent ADHD symptom ratings (p = 0.0026 and p = 0.0381, respectively), and clinic (2–3 p.m.) and home (6 p.m.) Math Tests (p = 0.024 and p < 0.0001, respectively). The 6 p.m. scores replicated the significant effect at 6 hours reported in the previous study. Conclusions: d-MPH is safe, tolerable, and effective, with a 6-hour duration of effect suggested by the significant difference from placebo at 6 hours on a double-blind discontinuation

Potential landscape-scale pollinator networks across Great Britain: structure, stability and influence of agricultural land cover

Understanding spatial variation in the structure and stability of plant-pollinator networks, and their relationship with anthropogenic drivers, is key to maintaining pollination services and mitigating declines. Constructing sufficient networks to examine patterns over large spatial scales remains challenging. Using biological records (citizen science), we constructed potential plant-pollinator networks at 10km resolution across Great Britain, comprising all potential interactions inferred from recorded floral visitation and species co-occurrence. We calculated network metrics (species richness, connectance, pollinator and plant generality) and adapted existing methods to assess robustness to sequences of simulated plant extinctions across multiple networks. We found positive relationships between agricultural land cover and both pollinator generality and robustness to extinctions under several extinction scenarios. Increased robustness was attributable to changes in plant community composition (fewer extinction-prone species) and network structure (increased pollinator generality). Thus, traits enabling persistence in highly agricultural landscapes can confer robustness to potential future perturbations on plant-pollinator networks

Monte Carlo inference for semiparametric Bayesian regression

Data transformations are essential for broad applicability of parametric regression models. However, for Bayesian analysis, joint inference of the transformation and model parameters typically involves restrictive parametric transformations or nonparametric representations that are computationally inefficient and cumbersome for implementation and theoretical analysis, which limits their usability in practice. This paper introduces a simple, general, and efficient strategy for joint posterior inference of an unknown transformation and all regression model parameters. The proposed approach directly targets the posterior distribution of the transformation by linking it with the marginal distributions of the independent and dependent variables, and then deploys a Bayesian nonparametric model via the Bayesian bootstrap. Crucially, this approach delivers (1) joint posterior consistency under general conditions, including multiple model misspecifications, and (2) efficient Monte Carlo (not Markov chain Monte Carlo) inference for the transformation and all parameters for important special cases. These tools apply across a variety of data domains, including real-valued, integer-valued, compactly-supported, and positive data. Simulation studies and an empirical application demonstrate the effectiveness and efficiency of this strategy for semiparametric Bayesian analysis with linear models, quantile regression, and Gaussian processes

De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations

BACKGROUND: Genomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM. METHODS: To understand the contribution of this locus to cardiac malformations, we reviewed the data on 60,000 samples submitted for array comparative genomic hybridization (CGH) studies to Medical Genetics Laboratories at Baylor College of Medicine, and ascertained seven individuals with segmental aneusomy of 17q25. We validated our findings by studying another individual with a de novo submicroscopic deletion of this region from Cytogenetics Laboratory at Cincinnati Children's Hospital. Using bioinformatic analyses including protein-protein interaction network, human tissue expression patterns, haploinsufficiency scores, and other annotation systems, including a training set of 251 genes known to be linked to human cardiac disease, we constructed a pathogenicity score for cardiac phenotype for each of the 57 genes within the terminal 2.0 Mb of 17q25.3. RESULTS: We found relatively high penetrance of cardiovascular defects (~60 %) with five deletions and three duplications, observed in eight unrelated individuals. Distinct cardiac phenotypes were present in four of these subjects with non-recurrent de novo deletions (range 0.08 Mb-1.4 Mb) in the subtelomeric region of 17q25.3. These included coarctation of the aorta (CoA), total anomalous pulmonary venous return (TAPVR), ventricular septal defect (VSD) and atrial septal defect (ASD). Amongst the three individuals with variable size duplications of this region, one had patent ductus arteriosus (PDA) at 8 months of age. CONCLUSION: The distinct cardiac lesions observed in the affected patients and the bioinformatics analyses suggest that multiple genes may be plausible drivers of the cardiac phenotype within this gene-rich critical interval of 17q25.3

Negative Cross Resistance Mediated by Co-treated bed nets: A Potential Means of Restoring Pyrethroid-susceptibility to Malaria Vectors.

Insecticide-treated nets and indoor residual spray programs for malaria control are entirely dependent on pyrethroid insecticides. The ubiquitous exposure of Anopheles mosquitoes to this chemistry has selected for resistance in a number of populations. This threatens the sustainability of our most effective interventions but no operationally practicable way of resolving the problem currently exists. One innovative solution involves the co-application of a powerful chemosterilant (pyriproxyfen or PPF) to bed nets that are usually treated only with pyrethroids. Resistant mosquitoes that are unaffected by the pyrethroid component of a PPF/pyrethroid co-treatment remain vulnerable to PPF. There is a differential impact of PPF on pyrethroid-resistant and susceptible mosquitoes that is modulated by the mosquito's behavioural response at co-treated surfaces. This imposes a specific fitness cost on pyrethroid-resistant phenotypes and can reverse selection. The concept is demonstrated using a mathematical model

Linkage Mapping of Stem Saccharification Digestibility in Rice

Rice is the staple food of almost half of the world population, and in excess 90% of it is grown and consumed in Asia, but the disposal of rice straw poses a problem for farmers, who often burn it in the fields, causing health and environmental problems. However, with increased focus on the development of sustainable biofuel production, rice straw has been recognized as a potential feedstock for non-food derived biofuel production. Currently, the commercial realization of rice as a biofuel feedstock is constrained by the high cost of industrial saccharification processes needed to release sugar for fermentation. This study is focused on the alteration of lignin content, and cell wall chemotypes and structures, and their effects on the saccharification potential of rice lignocellulosic biomass. A recombinant inbred lines (RILs) population derived from a cross between the lowland rice variety IR1552 and the upland rice variety Azucena with 271 molecular markers for quantitative trait SNP (QTS) analyses was used. After association analysis of 271 markers for saccharification potential, 1 locus and 4 pairs of epistatic loci were found to contribute to the enzymatic digestibility phenotype, and an inverse relationship between reducing sugar and lignin content in these recombinant inbred lines was identified. As a result of QTS analyses, several cell-wall associated candidate genes are proposed that may be useful for marker-assisted breeding and may aid breeders to produce potential high saccharification rice varieties