Alterations in white matter microstructure in neurofibromatosis-1.

Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well-characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1-associated brain pathology in conjunction with the typically investigated measures

Exploiting Monotone Convergence Functions in Parallel Programs

Scientific codes which use iterative methods are often difficult to parallelize well. Such codes usually contain \code{while} loops which iterate until they converge upon the solution. Problems arise since the number of iterations cannot be determined at compile time, and tests for termination usually require a global reduction and an associated barrier. We present a method which allows us avoid performing global barriers and exploit pipelined parallelism when processors can detect non-convergence from local information. (Also cross-referenced as UMIACS-TR-96-31.1

Code Generation for Multiple Mappings

There has been a great amount of recent work toward unifying iteration reordering transformations. Many of these approaches represent transformations as affine mappings from the original iteration space to a new iteration space. These approaches show a great deal of promise, but they all rely on the ability to generate code that iterates over the points in these new iteration spaces in the appropriate order. This problem has been fairly well-studied in the case where all statements use the same mapping. We have developed an algorithm for the less well-studied case where each statement uses a potentially different mapping. Unlike many other approaches, our algorithm can also generate code from mappings corresponding to loop blocking. We address the important trade-off between reducing control overhead and duplicating code. (Also cross-referenced as UMIACS-TR-94-87.1

Transitive Closure of Infinite Graphs and its Applications

Integer tuple relations can concisely summarize many types of information gathered from analysis of scientific codes. For example they can be used to precisely describe which iterations of a statement are data dependent of which other iterations. It is generally not possible to represent these tuple relations by enumerating the related pairs of tuples. For example, it is impossible to enumerate the related pairs of tuples in the relation {[i] -> [i+2] | 1 <= i <= n-2}. Even when it is possible to enumerate the related pairs of tuples, such as for the relation {[i,j] -> [i',j'] | 1 <= i,j,i',j' <= 100}, it is often not practical to do so. We instead use a closed form description by specifying a predicate consisting of affine constraints on the related pairs of tuples. As we just saw, these affine constraints can be parameterized, so what we are really describing are infinite families of relations (or graphs). Many of our applications of tuple relations rely heavily on an operation called transitive closure. Computing the transitive closure of these "infinite graphs" is very different from the traditional problem of computing the transitive closure of a graph whose edges can be enumerated. For example, the transitive closure of the first relation above is the relation {[i] -> [i'] | exists beta s.t. i'-i = 2beta and 1 <= i <= i' <= n}. As we will prove, this computation is not computable in the general case. We have developed algorithms that produce exact results in most commonly occurring cases and produce upper or lower bounds (as necessary) in the other cases. This paper will describe our algorithms for computing transitive closure and some of its applications such as determining which inter-processor synchronizations are redundant. (Also cross-referenced as UMIACS-TR-95-48

Effect of slurry composition on the chemical mechanical polishing of thin diamond films

Nanocrystalline diamond (NCD) thin films grown by chemical vapour deposition (CVD) have an intrinsic surface roughness, which hinders the development and per- formance of the films' various applications. Traditional methods of diamond polishing are not effective on NCD thin films. Films either shatter due to the combination of wafer bow and high mechanical pressures or produce uneven surfaces, which has led to the adaptation of the chemical mechanical polishing (CMP) technique for NCD films. This process is poorly understood and in need of optimisation. To compare the effect of slurry composition and pH upon polishing rates, a series of NCD thin films have been polished for three hours using a Logitech Tribo CMP System in conjunction with a polyester/polyurethane polishing cloth and six different slurries. The reduction in surface roughness was measured hourly using an atomic force microscope. The nal surface chemistry was examined using X-ray photoelectron spectroscopy and a scanning electron microscope. It was found that of all the various properties of the slurries, including pH and composition, the particle size was the determining factor for the polishing rate. The smaller particles polishing at a greater rate than the larger ones

A high-resolution integrated map of copy number polymorphisms within and between breeds of the modern domesticated dog

<p>Abstract</p> <p>Background</p> <p>Structural variation contributes to the rich genetic and phenotypic diversity of the modern domestic dog, <it>Canis lupus familiaris</it>, although compared to other organisms, catalogs of canine copy number variants (CNVs) are poorly defined. To this end, we developed a customized high-density tiling array across the canine genome and used it to discover CNVs in nine genetically diverse dogs and a gray wolf.</p> <p>Results</p> <p>In total, we identified 403 CNVs that overlap 401 genes, which are enriched for defense/immunity, oxidoreductase, protease, receptor, signaling molecule and transporter genes. Furthermore, we performed detailed comparisons between CNVs located within versus outside of segmental duplications (SDs) and find that CNVs in SDs are enriched for gene content and complexity. Finally, we compiled all known dog CNV regions and genotyped them with a custom aCGH chip in 61 dogs from 12 diverse breeds. These data allowed us to perform the first population genetics analysis of canine structural variation and identify CNVs that potentially contribute to breed specific traits.</p> <p>Conclusions</p> <p>Our comprehensive analysis of canine CNVs will be an important resource in genetically dissecting canine phenotypic and behavioral variation.</p

Tracking family medicine graduates. Where do they go, what services do they provide and whom do they see?

<p>Abstract</p> <p>Background</p> <p>There are continued concerns over an adequate supply of family physicians (FPs) practicing in Canada. While most resource planning has focused on intake into postgraduate education, less information is available on what postgraduate medical training yields. We therefore undertook a study of Family Medicine (FM) graduates from the University of Toronto (U of T) to determine the type of information for physician resource planning that may come from tracking FM graduates using health administrative data. This study compared three cohorts of FM graduates over a 10 year period of time and it also compared FM graduates to all Ontario practicing FPs in 2005/06. The objectives for tracking the three cohorts of FM graduates were to: 1) describe where FM graduates practice in the province 2) examine the impact of a policy introduced to influence the distribution of new FM graduates in the province 3) describe the services provided by FM graduates and 4) compare workload measures. The objectives for the comparison of FM graduates to all practicing FPs in 2005/06 were to: 1) describe the patient population served by FM graduates, 2) compare workload of FM graduates to all practicing FPs.</p> <p>Methods</p> <p>The study cohort consisted of all U of T FM postgraduate trainees who started and completed their training between 1993 and 2003. This study was a descriptive record linkage study whereby postgraduate information for FM graduates was linked to provincial health administrative data. Comprehensiveness of care indicators and workload measures based on administrative data where determined for the study cohort.</p> <p>Results</p> <p>From 1993 to 2003 there were 857 University of Toronto FM graduates. While the majority of U of T FM graduates practice in Toronto or the surrounding Greater Toronto Area, there are FM graduates from U of T practicing in every region in Ontario, Canada. The proportion of FM graduates undertaking further emergency training had doubled from 3.6% to 7.8%. From 1993 to 2003, a higher proportion of the most recent FM graduates did hospital visits, emergency room care and a lower proportion undertook home visits. Male FM graduates appear to have had higher workloads compared with female FM graduates, though the difference between them was decreasing over time. A 1997 policy initiative to discount fees paid to new FPs practicing in areas deemed over supplied did result in a decrease in the proportion of FM graduates practicing in metropolitan areas.</p> <p>Conclusions</p> <p>We were able to profile the practices of FM graduates using existing and routinely collected population-based health administrative data. Further work tracking FM graduates could be helpful for physician resource forecasting and in examining the impact of policies on family medicine practice.</p

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre