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Recent advances in multi-atlas based algorithms address many of the previous limitations in model-based and probabilistic segmentation methods. However, at the label fusion stage, a majority of algorithms focus primarily on optimizing weight-maps associated with the atlas library based on a theoretical objective function that approximates the segmentation error. In contrast, we propose a novel method—Autocorrecting Walks over Localized Markov Random Fields (AWoL-MRF)—that aims at mimicking the sequential process of manual segmentation, which is the gold-standard for virtually all the segmentation methods. AWoL-MRF begins with a set of candidate labels generated by a multi-atlas segmentation pipeline as an initial label distribution and refines low confidence regions based on a localized Markov random field (L-MRF) model using a novel sequential inference process (walks). We show that AWoL-MRF produces state-of-the-art results with superior accuracy and robustness with a small atlas library compared to existing methods. We validate the proposed approach by performing hippocampal segmentations on three independent datasets: (1) Alzheimer's Disease Neuroimaging Database (ADNI); (2) First Episode Psychosis patient cohort; and (3) A cohort of preterm neonates scanned early in life and at term-equivalent age. We assess the improvement in the performance qualitatively as well as quantitatively by comparing AWoL-MRF with majority vote, STAPLE, and Joint Label Fusion methods. AWoL-MRF reaches a maximum accuracy of 0.881 (dataset 1), 0.897 (dataset 2), and 0.807 (dataset 3) based on Dice similarity coefficient metric, offering significant performance improvements with a smaller atlas library (< 10) over compared methods. We also evaluate the diagnostic utility of AWoL-MRF by analyzing the volume differences per disease category in the ADNI1: Complete Screening dataset. We have made the source code for AWoL-MRF public at: https://github.com/CobraLab/AWoL-MRF.

Osteoarthritis (OA) of the knee affects between 5.4% and 38% of older adults and this prevalence is increasing as the population ages and becomes more obese. As health costs rise, it is important to have accurate and cost-effective methods to assess knee OA and the risk for OA. One risk factor for progression of knee OA is lower extremity (LE) frontal-plane malalignment. The first goal of this thesis was to assess the suitability of knee radiographs and LE photographs for the estimation of frontal-plane LE alignment. In the first study, several versions of the femoral shaft-tibial shaft (FS-TS) angle, assessed from knee radiographs, were compared to the hip-knee-ankle (HKA) angle, assessed from full-length radiographs. We concluded that the FS-TS angle is not a recommended substitute for the HKA angle, because the association between the two measures differs depending on alignment, OA severity and the method of determining the FS-TS angle. In the second study, the hip-knee-ankle angle determined from a pelvis-to-ankle photograph (HKA-P) was assessed for its ability to estimate the HKA angle. The HKA-P angle was reliable and highly correlated to the HKA. It therefore shows promise as an accurate and cost-effective assessment tool for the estimation of LE alignment. Commonly-used grading scales for the severity of knee OA seen on a radiograph emphasize just one feature of OA; therefore the second goal of this thesis was to assess the psychometric properties of the unicompartmental osteoarthritis grade (UCOAG), a composite scale which grades several features of OA in the tibiofemoral (TF) compartment. In the third and fourth studies, the reliability, validity and sensitivity to change of the UCOAG scale was assessed and compared to two commonly-used scales (Kellgren-Lawrence and Osteoarthritis Research Society International joint space narrowing). The UCOAG scale showed moderate to excellent reliability. All three scales demonstrated comparable validity and sensitivity to change. The UCOAG is therefore recommended for the assessment of OA severity and change over time. This research provides evidence for the use of accurate and cost-effective measures to assess LE alignment using photographs, and TF OA severity using radiographs, for clinical assessment and research purposes.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10^−8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

The nuclear pore complex (NPC) is the sole bidirectional gateway for nucleocytoplasmic transport. Despite recent progress in elucidating the NPC symmetric core architecture, the asymmetrically decorated cytoplasmic face, essential for mRNA export and a hotspot for nucleoporin-associated diseases, has remained elusive. Here, we report a composite structure of the entire human cytoplasmic face obtained by combining biochemical reconstitution, crystal structure determination, docking into cryo-electron tomographic reconstructions, and physiological validation, accounting for a third of the NPC’s mass. Whereas an evolutionarily conserved ∼540 kDa hetero-hexameric cytoplasmic filament nucleoporin complex is anchored by species-specific motifs above the central transport channel, attachment of the pentameric NUP358 bundles depends on the double-ring arrangement of the coat nucleoporin complex. Our results and the predictive power of our composite structure provide a rich foundation for elucidating the molecular basis of mRNA export and nucleoporin diseases.

Rising global temperatures over the last decades have increased heat exposure among populations worldwide. An accurate estimate of the resulting impacts on human health demands temporally explicit and spatially resolved monitoring of near-surface air temperature (Ta). Neither ground-based nor satellite-borne observations can achieve this individually, but the combination of the two provides synergistic opportunities. In this study, we propose a two-stage machine learning-based hybrid model to estimate 1 × 1 km2 gridded intra-daily Ta from surface skin temperature (Ts) across the complex terrain of Israel during 2004–2016. We first applied a random forest (RF) regression model to impute missing Ts from the Moderate Resolution Imaging Spectroradiometer (MODIS) Aqua and Terra satellites, integrating Ts from the geostationary Spinning Enhanced Visible and InfraRed Imager (SEVIRI) satellite and synoptic variables from European Centre for Medium-Range Weather Forecasts' (ECMWF) ERA5 reanalysis data sets. The imputed Ts are in turn fed into the Stage 2 RF-based model to estimate Ta at the satellite overpass hours of each day. We evaluated the model's performance applying out-of-sample fivefold cross validation. Both stages of the hybrid model perform very well with out-of-sample fivefold cross validated R2 of 0.99 and 0.96, MAE of 0.42°C and 1.12°C, and RMSE of 0.65°C and 1.58°C (Stage 1: imputation of Ts, and Stage 2: estimation of Ta from Ts, respectively). The newly proposed model provides excellent computationally efficient estimation of near-surface air temperature at high resolution in both space and time, which helps further minimize exposure misclassification in epidemiological studies.

Background. Hepatitis C virus (HCV) coinfection occurs in 20–30% of Canadians living with HIV and is responsible for a heavy burden of morbidity and mortality. Purpose. To update national standards for management of HCV-HIV coinfected adults in the Canadian context with evolving evidence for and accessibility of effective and tolerable DAA therapies. The document addresses patient workup and treatment preparation, antiviral recommendations overall and in specific populations, and drug-drug interactions. Methods. A standing working group with HIV-HCV expertise was convened by The Canadian Institute of Health Research HIV Trials Network to review recently published HCV antiviral data and update Canadian HIV-HCV Coinfection Guidelines. Results. The gap in sustained virologic response between HCV monoinfection and HIV-HCV coinfection has been eliminated with newer HCV antiviral regimens. All coinfected individuals should be assessed for interferon-free, Direct Acting Antiviral HCV therapy. Regimens vary in content, duration, and success based largely on genotype. Reimbursement restrictions forcing the use of pegylated interferon is not acceptable if optimal patient care is to be provided. Discussion. Recommendations may not supersede individual clinical judgement. Treatment advances published since December 2015 are not considered in this document.

Background. Chronic or persistent pain and disability following noncatastrophic “musculoskeletal” (MSK) trauma is a pervasive public health problem. Recent intervention trials have provided little evidence of benefit from several specific treatments for preventing chronic problems. Such findings may appear to argue against formal targeted intervention for MSK traumas. However, these negative findings may reflect a lack of understanding of the causal mechanisms underlying the transition from acute to chronic pain, rendering informed and objective treatment decisions difficult. The Canadian Institutes of Health Research (CIHR) Institute of Musculoskeletal Health and Arthritis (IMHA) has recently identified better understanding of causal mechanisms as one of three priority foci of their most recent strategic plan. Objectives. A 2-day invitation-only active participation workshop was held in March 2015 that included 30 academics, clinicians, and consumers with the purpose of identifying consensus research priorities in the field of trauma-related MSK pain and disability, prediction, and prevention. Methods. Conversations were recorded, explored thematically, and member-checked for accuracy. Results. From the discussions, 13 themes were generated that ranged from a focus on identifying causal mechanisms and models to challenges with funding and patient engagement. Discussion. Novel priorities included the inclusion of consumer groups in research from the early conceptualization and design stages and interdisciplinary longitudinal studies that include evaluation of integrated phenotypes and mechanisms.

Using Southern blot analysis of RT-PCR products, mRNA for three different somatostatin (SS) precursors (PSS-I, -II, and -III), which encode for SS14, goldfish brain (gb)SS28, and [Pro2]SS14, respectively, were detected in goldfish hypothalamus. PSS-I and -II mRNA, but not PSS-III mRNA, were also detected in cultured pituitary cells. We subsequently examined the effects of the mature peptides, SS14, gbSS28, and [Pro2]SS14, on somatotrope signaling and GH secretion. The gbSS28 was more potent than either SS14 or [Pro2]SS14 in reducing basal GH release but was the least effective in reducing basal cellular cAMP. The ability of SS14, [Pro2]SS14, and gbSS28 to attenuate GH responses to GnRH were comparable. However, gbSS28 was less effective than SS14 and [Pro2]SS14 in diminishing dopamine- and pituitary adenylate cyclase-activating polypeptide-stimulated GH release, as well as GH release resulting from the activation of their underlying signaling cascades. In contrast, the actions of a different 28-aminoacid SS, mammalian SS28, were more similar to those of SS14 and [Pro2]SS14. We conclude that, in goldfish, SSs differentially couple to the intracellular cascades regulating GH secretion from pituitary somatotropes. This raises the possibility that such differences may allow for the selective regulation of various aspects of somatotrope function by different SS peptides.