Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Research on Youth Exposure to, and Management of, Cyberbullying Incidents in Australia: Synthesis Report

The Australian Government Department of Communications commissioned the UNSW Social Policy Research Centre, the University of South Australia, the University of Western Sydney, the Young and Well Cooperative Research Centre, and the National Children’s and Youth Law Centre to research youth exposure to, and management of, cyberbullying incidents in Australia. The research aims to provide the Australian Government with evidence relating to the desirability of whether to create a new, separate cyberbullying offence and in its consideration of a new civil enforcement regime

Research on Youth Exposure to, and Management of, Cyberbullying Incidents in Australia. Part C: An Evidence-based Assessment of Deterrents to Youth Cyberbullying. Appendix D: Supplementary Data and Analysis

The Australian Government Department of Communications commissioned the Social Policy Research Centre (SPRC) at UNSW Australia, the University of South Australia, the University of Western Sydney, and the Young and Well CRC to research youth exposure to, and management of, cyberbullying incidents in Australia. The research aims to provide the Australian Government with evidence relating to the desirability of whether to create a new, separate cyberbullying offence and in its consideration of a new civil enforcement regime for instances where the victims and cyberbullies are Australian minors at the time of the incidents. This appendix presents supplementary data and analysis that supports the Part C Report: An evidence-based assessment of deterrents to youth cyberbullying

Research on Youth Exposure to, and Management of, Cyberbullying Incidents in Australia. Part C: An Evidence-based Assessment of Deterrents to Youth Cyberbullying. Appendix B: Findings of Research with Adult Stakeholders

The Australian Government, as represented by the Department of Communications, commissioned the Social Policy Research Centre (SPRC) at UNSW Australia, the University of South Australia, the University of Western Sydney, and the Young and Well CRC to research youth exposure to, and management of, cyberbullying incidents in Australia. The research aims to provide the Australian Government with evidence relating to the desirability of whether to create a new, separate cyberbullying offence and in its consideration of a new civil enforcement regime for instances where the victims and cyberbullies are Australian minors at the time of the incidents. The research methods employed were designed to maximise stakeholder reach and engagement, and capitalise on the collective expertise and experiences of a wide range of stakeholders. A number of adult stakeholders were surveyed and engaged (through interviews and workshops) to develop the evidence-base to determine if a new, simplified cyberbullying offence or a new civil enforcement regime were introduced, how such an offence or regime could be implemented, in conjunction with the existing criminal offences, to have the greatest material deterrence effect. This appendix presents the detailed methodology and findings from engaging adult stakeholders in support of the Part C Report: An evidence-based assessment of deterrents to youth cyberbullying. The findings of the youth engagement component of this research are presented separately in Appendix C to the report

Research on Youth Exposure to, and Management of, Cyberbullying Incidents in Australia. Part C: An Evidence-base Assessment of Deterrents to Youth Cyberbullying. Appendix C: Findings of Research with Youth

The Australian Government Department of Communications commissioned the Social Policy Research Centre (SPRC) at the UNSW Australia, the University of South Australia, the University of Western Sydney, and the Young and Well CRC to research youth exposure to, and management of, cyberbullying incidents in Australia. The research aims to provide the Australian Government with evidence relating to the desirability of whether to create a new, separate cyberbullying offence and in its consideration of a new civil enforcement regime for instances where the victims and cyberbullies are Australian minors at the time of the incidents. The methods employed in this research were designed to maximise stakeholder reach and engagement. This appendix presents the detailed methodology and findings of a crowdsourcing survey that examined the awareness and understanding of young people (aged 15-24) in relation to the potential criminality of cyberbullying, appropriate penalties, the range of sentencing options and the deterrent impact of these. The survey also explored perspectives about where young people should be able to find information about cyberbullying. A national youth crowdsourcing campaign (survey) was conducted between 17 February and 7 April 2014 to explore these issues. The findings in this appendix support the Part C Report: An evidence-based assessment of deterrents to youth cyberbullying. The findings of the adult engagement component of this research are presented separately in Appendix B to the same Report

Aqueous Metabolite Trends for the Progression of Nonalcoholic Fatty Liver Disease in Female Bariatric Surgery Patients by Targeted 1H-NMR Metabolomics

Determining biomarkers and better characterizing the biochemical progression of nonalcoholic fatty liver disease (NAFLD) remains a clinical challenge. A targeted 1H-NMR study of serum, combined with clinical variables, detected and localized biomarkers to stages of NAFLD in morbidly obese females. Pre-surgery serum samples from 100 middle-aged, morbidly obese female subjects, grouped on gold-standard liver wedge biopsies (non-NAFLD; steatosis; and fibrosis) were collected, extracted, and analyzed in aqueous (D2O) buffer (1H, 600 MHz). Profiled concentrations were subjected to exploratory statistical analysis. Metabolites varying significantly between the non-NAFLD and steatosis groups included the ketone bodies 3-hydroxybutyrate (↓; p = 0.035) and acetone (↓; p = 0.012), and also alanine (↑; p = 0.004) and a putative pyruvate signal (↑; p = 0.003). In contrast, the steatosis and fibrosis groups were characterized by 2-hydroxyisovalerate (↑; p = 0.023), betaine (↓; p = 0.008), hypoxanthine (↓; p = 0.003), taurine (↓; p = 0.001), 2-hydroxybutyrate (↑; p = 0.045), 3-hydroxyisobutyrate (↑; p = 0.046), and increasing medium chain fatty acids. Exploratory classification models with and without clinical variables exhibited overall success rates ca. 75–85%. In the study conditions, inhibition of fatty acid oxidation and disruption of the hepatic urea cycle are supported as early features of NAFLD that continue in fibrosis. In fibrosis, markers support inflammation, hepatocyte damage, and decreased liver function. Complementarity of NMR concentrations and clinical information in classification models is shown. A broader hypothesis that standard-of-care sera can yield metabolomic information is supported

Research on Youth Exposure to, and Management of, Cyberbullying Incidents in Australia. Part C: An Evidence-based Assessment of Deterrents to Youth Cyberbullying. Appendix A: Literature Review – International Responses to Youth Cyberbullying and Current Australian Legal Context

This literature review was designed to contribute to the evidence-base to determine if a new, simplified cyberbullying offence or a new civil enforcement regime were introduced, how such an offence or regime could be implemented, in conjunction with the existing criminal offences, to have the greatest material deterrence effect. It has drawn upon intersecting domains related to understanding the construct of cyberbullying, as embedded within the literatures of aggression and bullying; and the law as employed in international and Australian settings. This literature review supports the Part C Report: An evidence-based assessment of deterrents to youth cyberbullying

Aqueous Metabolite Trends for the Progression of Nonalcoholic Fatty Liver Disease in Female Bariatric Surgery Patients by Targeted 1H-NMR Metabolomics

Determining biomarkers and better characterizing the biochemical progression of nonalcoholic fatty liver disease (NAFLD) remains a clinical challenge. A targeted 1H-NMR study of serum, combined with clinical variables, detected and localized biomarkers to stages of NAFLD in morbidly obese females. Pre-surgery serum samples from 100 middle-aged, morbidly obese female subjects, grouped on gold-standard liver wedge biopsies (non-NAFLD; steatosis; and fibrosis) were collected, extracted, and analyzed in aqueous (D2O) buffer (1H, 600 MHz). Profiled concentrations were subjected to exploratory statistical analysis. Metabolites varying significantly between the non-NAFLD and steatosis groups included the ketone bodies 3-hydroxybutyrate (↓; p = 0.035) and acetone (↓; p = 0.012), and also alanine (↑; p = 0.004) and a putative pyruvate signal (↑; p = 0.003). In contrast, the steatosis and fibrosis groups were characterized by 2-hydroxyisovalerate (↑; p = 0.023), betaine (↓; p = 0.008), hypoxanthine (↓; p = 0.003), taurine (↓; p = 0.001), 2-hydroxybutyrate (↑; p = 0.045), 3-hydroxyisobutyrate (↑; p = 0.046), and increasing medium chain fatty acids. Exploratory classification models with and without clinical variables exhibited overall success rates ca. 75–85%. In the study conditions, inhibition of fatty acid oxidation and disruption of the hepatic urea cycle are supported as early features of NAFLD that continue in fibrosis. In fibrosis, markers support inflammation, hepatocyte damage, and decreased liver function. Complementarity of NMR concentrations and clinical information in classification models is shown. A broader hypothesis that standard-of-care sera can yield metabolomic information is supported

SARS-CoV-2 spike D614G change enhances replication and transmission

During the evolution of SARS-CoV-2 in humans, a D614G substitution in the spike glycoprotein (S) has emerged; virus containing this substitution has become the predominant circulating variant in the COVID-19 pandemic1. However, whether the increasing prevalence of this variant reflects a fitness advantage that improves replication and/or transmission in humans or is merely due to founder effects remains unknown. Here we use isogenic SARS-CoV-2 variants to demonstrate that the variant that contains S(D614G) has enhanced binding to the human cell-surface receptor angiotensin-converting enzyme 2 (ACE2), increased replication in primary human bronchial and nasal airway epithelial cultures as well as in a human ACE2 knock-in mouse model, and markedly increased replication and transmissibility in hamster and ferret models of SARS-CoV-2 infection. Our data show that the D614G substitution in S results in subtle increases in binding and replication in vitro, and provides a real competitive advantage in vivo-particularly during the transmission bottleneck. Our data therefore provide an explanation for the global predominance of the variant that contains S(D614G) among the SARS-CoV-2 viruses that are currently circulating