Autism Spectrum Disorder Diagnosis Using Sparse Graph Embedding of Morphological Brain Networks

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder involving a complex cognitive impairment that can be difficult to diagnose early enough. Much work has therefore been done investigating the use of machine-learning techniques on functional and structural connectivity networks for ASD diagnosis. However, networks based on the morphology of the brain have yet to be similarly investigated, despite research findings that morphological features, such as cortical thickness, are affected by ASD. In this paper, we first propose modelling morphological brain connectivity (or graph) using a set of cortical attributes, each encoding a unique aspect of cortical morphology. However, it can be difficult to capture for each subject the complex pattern of relationships between morphological brain graphs, where each may be affected simultaneously or independently by ASD. In order to solve this problem, we therefore also propose the use of high-order networks which can better capture these relationships. Further, since ASD and normal control (NC) high-dimensional connectomic data might lie in different manifolds, we aim to find a low-dimensional representation of the data which captures the intrinsic dimensions of the underlying connectomic manifolds, thereby allowing better learning by linear classifiers. Hence, we propose the use of sparse graph embedding (SGE) method, which allows us to distinguish between data points drawn from different manifolds, even when they are too close to one another. SGE learns a similarity matrix of the connectomic data graph, which then is used to embed the high-dimensional connectomic features into a low-dimensional space that preserves the locality of the original data. Our ASD/NC classification results outperformed several state-of-the-art methods including statistical feature selection, and local linear embedding methods

Characteristics of outdoor falls among older people: A qualitative study

Background Falls are a major threat to older people’s health and wellbeing. Approximately half of falls occur in outdoor environments but little is known about the circumstances in which they occur. We conducted a qualitative study to explore older people’s experiences of outdoor falls to develop understanding of how they may be prevented. Methods We conducted nine focus groups across the UK (England, Wales, and Scotland). Our sample was from urban and rural settings and different environmental landscapes. Participants were aged 65+ and had at least one outdoor fall in the past year. We analysed the data using framework and content analyses. Results Forty-four adults aged 65 – 92 took part and reported their experience of 88 outdoor falls. Outdoor falls occurred in a variety of contexts, though reports suggested the following scenarios may have been more frequent: when crossing a road, in a familiar area, when bystanders were around, and with an unreported or unknown attribution. Most frequently, falls resulted in either minor or moderate injury, feeling embarrassed at the time of the fall, and anxiety about falling again. Ten falls resulted in fracture, but no strong pattern emerged in regard to the contexts of these falls. Anxiety about falling again appeared more prevalent among those that fell in urban settings and who made more visits into their neighbourhood in a typical week. Conclusions This exploratory study has highlighted several aspects of the outdoor environment that may represent risk factors for outdoor falls and associated fear of falling. Health professionals are recommended to consider outdoor environments as well as the home setting when working to prevent falls and increase mobility among older people

T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells

Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62LhighCD44low Sca-1+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells. © 2013 Li et al

Apparently synonymous substitutions in FGFR2affect splicing and result in mild Crouzon syndrome

BACKGROUND: Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2. CASE PRESENTATION: Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis. CONCLUSIONS: These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations

Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12–18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults

Allele-specific miRNA-binding analysis identifies candidate target genes for breast cancer risk

Most breast cancer (BC) risk-associated single-nucleotide polymorphisms (raSNPs) identified in genome-wide association studies (GWAS) are believed to cis-regulate the expression of genes. We hypothesise that cis-regulatory variants contributing to disease risk may be affecting microRNA (miRNA) genes and/or miRNA binding. To test this, we adapted two miRNA-binding prediction algorithms-TargetScan and miRanda-to perform allele-specific queries, and integrated differential allelic expression (DAE) and expression quantitative trait loci (eQTL) data, to query 150 genome-wide significant ( P≤5×10-8 ) raSNPs, plus proxies. We found that no raSNP mapped to a miRNA gene, suggesting that altered miRNA targeting is an unlikely mechanism involved in BC risk. Also, 11.5% (6 out of 52) raSNPs located in 3'-untranslated regions of putative miRNA target genes were predicted to alter miRNA::mRNA (messenger RNA) pair binding stability in five candidate target genes. Of these, we propose RNF115, at locus 1q21.1, as a strong novel target gene associated with BC risk, and reinforce the role of miRNA-mediated cis-regulation at locus 19p13.11. We believe that integrating allele-specific querying in miRNA-binding prediction, and data supporting cis-regulation of expression, improves the identification of candidate target genes in BC risk, as well as in other common cancers and complex diseases.Funding Agency Portuguese Foundation for Science and Technology CRESC ALGARVE 2020 European Union (EU) 303745 Maratona da Saude Award DL 57/2016/CP1361/CT0042 SFRH/BPD/99502/2014 CBMR-UID/BIM/04773/2013 POCI-01-0145-FEDER-022184info:eu-repo/semantics/publishedVersio

Numerical Modeling of Transient Wave Propagation for High Frequency NDT

Electromagnetic nondestructive testing (NDT) methods use frequencies ranging from low (dc) to high (microwave) frequencies [1]. Applications of numerical methods to model two- and three-dimensional low-frequency (dc or eddy current) nondestructive testing phenomena, where displacement currents can be omitted, were extensively examined, [2,3]. These are all interior boundary value problems. Finite element study of ultrasonic wave propagation and scattering in metals, which is again an interior boundary value problem, was recently reported in [4]. However, modeling of wave propagation for high-frequency NDT problems have not yet been attempted. Recently, finite difference methods in time domain have been successfully applied to solve transient electromagnetic wave propagation problems over the atmosphere and the ground [5], and time-dependent eddy current problems [6]. The method used here is a generalization of this work and is designed for numerical modeling of high-frequency electromagnetic wave propagation arising from nondestructive testing applications. The physical situation includes examination of the scattering effects by cracks inside a piece of material (especially dielectrics) or due to surface variations when the material is illuminated by a TM plane wave. This leads to an interface type problem

What Affects Social Attention? Social Presence, Eye Contact and Autistic Traits

Social understanding is facilitated by effectively attending to other people and the subtle social cues they generate. In order to more fully appreciate the nature of social attention and what drives people to attend to social aspects of the world, one must investigate the factors that influence social attention. This is especially important when attempting to create models of disordered social attention, e.g. a model of social attention in autism. Here we analysed participants' viewing behaviour during one-to-one social interactions with an experimenter. Interactions were conducted either live or via video (social presence manipulation). The participant was asked and then required to answer questions. Experimenter eye-contact was either direct or averted. Additionally, the influence of participant self-reported autistic traits was also investigated. We found that regardless of whether the interaction was conducted live or via a video, participants frequently looked at the experimenter's face, and they did this more often when being asked a question than when answering. Critical differences in social attention between the live and video interactions were also observed. Modifications of experimenter eye contact influenced participants' eye movements in the live interaction only; and increased autistic traits were associated with less looking at the experimenter for video interactions only. We conclude that analysing patterns of eye-movements in response to strictly controlled video stimuli and natural real-world stimuli furthers the field's understanding of the factors that influence social attention

Cardiac testing for coronary artery disease in potential kidney transplant recipients.

Patients with chronic kidney disease (CKD) are at increased risk of coronary artery disease (CAD) and adverse cardiac events. Screening for CAD is therefore an important part of preoperative evaluation for kidney transplant candidates. There is significant interest in the role of non-invasive cardiac investigations and their ability to identify patients at high risk of CAD.  We investigated the accuracy of non-invasive cardiac screening tests compared with coronary angiography to detect CAD in patients who are potential kidney transplant recipients. MEDLINE and EMBASE searches (inception to November 2010) were performed to identify studies that assessed the diagnostic accuracy of non-invasive screening tests, using coronary angiography as the reference standard. We also conducted citation tracking via Web of Science and handsearched reference lists of identified primary studies and review articles.   We included in this review all diagnostic cross sectional, cohort and randomised studies of test accuracy that compared the results of any cardiac test with coronary angiography (the reference standard) relating to patients considered as potential candidates for kidney transplantation or kidney-pancreas transplantation at the time diagnostic tests were performed.  We used a hierarchical modelling strategy to produce summary receiver operating characteristic (SROC) curves, and pooled estimates of sensitivity and specificity. Sensitivity analyses to determine test accuracy were performed if only studies that had full verification or applied a threshold of ≥ 70% stenosis on coronary angiography for the diagnosis of significant CAD were included. The following screening investigations included in the meta-analysis were: dobutamine stress echocardiography (DSE) (13 studies), myocardial perfusion scintigraphy (MPS) (nine studies), echocardiography (three studies), exercise stress electrocardiography (two studies), resting electrocardiography (three studies), and one study each of electron beam computed tomography (EBCT), exercise ventriculography, carotid intimal media thickness (CIMT) and digital subtraction fluorography (DSF). Sufficient studies were present to allow hierarchical summary receiver operating characteristic (HSROC) analysis for DSE and MPS. When including all available studies, both DSE and MPS had moderate sensitivity and specificity in detecting coronary artery stenosis in patients who are kidney transplant candidates [DSE (13 studies) - pooled sensitivity 0.79 (95% CI 0.67 to 0.88), pooled specificity 0.89 (95% CI 0.81 to 0.94); MPS (nine studies) - pooled sensitivity 0.74 (95% CI 0.54 to 0.87), pooled specificity 0.70 (95% CI 0.51 to 0.84)]. When limiting to studies which defined coronary artery stenosis using a reference threshold of ≥ 70% stenosis on coronary angiography, there was little change in these pooled estimates of accuracy [DSE (9 studies) - pooled sensitivity 0.76 (95% CI 0.60 to 0.87), specificity 0.88 (95% CI 0.78 to 0.94); MPS (7 studies) - pooled sensitivity 0.67 (95% CI 0.48 to 0.82), pooled specificity 0.77 (95% CI 0.61 to 0.88)]. There was evidence that DSE had improved accuracy over MPS (P = 0.02) when all studies were included in the analysis, but this was not significant when we excluded studies which did not avoid partial verification or use a reference standard threshold of ≥70% stenosis (P = 0.09).   DSE may perform better than MPS but additional studies directly comparing these cardiac screening tests are needed. Absence of significant CAD may not necessarily correlate with cardiac-event free survival following transplantation. Further research should focus on assessing the ability of functional tests to predict postoperative outcome

Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets