An investigation of genetic factors in Ebola virus disease

Introduction The West African Ebola epidemic was the largest Ebola epidemic to date with over 28,000 cases. The large number of cases permitted assessment of different disease phenotypes and outcomes of Ebola virus disease (EVD). Given the variety of disease phenotypes in EVD, a genetic predisposition to disease phenotype and outcome was hypothesised. Methods Samples from 325 deceased patients and 174 surviving patients were provided through the Sierra Leone Ministry of Health-Public Health England Ebola Biobank. Additionally, 1021 household contacts, 1004 community controls and 504 Ebola survivors were recruited in Sierra Leone. Participants provided a saliva sample for DNA extraction and an oral fluid sample for anti-EBOV IgG antibodies. Exome sequencing was undertaken on 250 extreme phenotype cases and genome wide genotyping was undertaken on 2153 Ebola patients, household contacts and community controls. Data analysis of the exome data included within family segregation studies, gene burden testing and pathway analysis. The genotyped data was interrogated through a genome wide association study comparing deceased and surviving cases. Results Of the household contacts, 3.5% were positive for anti-EBOV IgG. Seropositivity correlated with risk exposure level, with the highest risk level demonstrating seropositivity rates of 15.6%. Ebola survivors with more severe acute disease demonstrated lower levels of anti-EBOV IgG antibodies (p=0.01), as did those with more severe post-Ebola syndrome, although this was not significant. Exome sequencing revealed multiple protective mutations within cholesterol metabolism pathways. A key finding was a protective variant in the PCSK9 gene (p=0.002). Preliminary GWAS analysis of deceased versus surviving Ebola patients identified a genome wide significant (p=2.9x10-8) SNP in the Carbonic Anhydrase 5a gene. Conclusions The study established different extreme phenotypes of EVD, including highly exposed antibody negative and asymptomatic antibody positive individuals. Genetic factors affect both susceptibility to and severity of Ebola virus disease; with rare deleterious mutations in genes within cholesterol metabolism pathways, and common polymorphisms determining outcome of exposure to Ebola virus.Open Acces

Virtual reality forensics: forensic analysis of Meta Quest 2

The Meta Quest 2 is one of the most popular Virtual Reality (VR) entertainment headsets to date. The headset, developed by Meta Platforms Inc., immerses the user in a completely simulated environment. Some VR environments can be shared over the Internet to allow users to communicate and interact with one another and share their experiences. Unfortunately, the safety of these VR environments cannot always be guaranteed, generating a risk that users may be exposed to illicit online behaviour in the form of online harassment, grooming, and cyberbullying. Therefore, forensic examiners must be able to conduct sound forensic analysis of VR headsets to investigate these criminal investigations. In this study, we conduct digital forensic acquisition and analysis of the Meta Quest 2 VR headset. Analysis of the forensic image exemplified that there were several digital artefacts relating to user activities, device information and stored digital artefacts that can be extracted in a forensically sound manner. The main contributions of this study include a detailed description of the forensic acquisition process, identification of internal file storage locations, and recovery and analysis of digital artefacts that can be used to aid VR forensic investigations

Model International Mobility Convention

While people are as mobile as they ever were in our globalized world, the movement of people across borders lacks global regulation. This leaves many refugees in protracted displacement and many migrants unprotected in irregular and dire situations. Meanwhile, some states have become concerned that their borders have become irrelevant. International mobility—the movement of individuals across borders for any length of time as visitors, students, tourists, labor migrants, entrepreneurs, long-term residents, asylum seekers, or refugees—has no common definition or legal framework. To address this key gap in international law, and the growing gaps in protection and responsibility that are leaving people vulnerable, the "Model International Mobility Convention" proposes a framework for mobility with the goals of reaffirming the existing rights afforded to mobile people (and the corresponding rights and responsibilities of states) as well as expanding those basic rights where warranted. In 213 articles divided over eight chapters, the Convention establishes both the minimum rights afforded to all people who cross state borders as visitors, and the special rights afforded to tourists, students, migrant workers, investors and residents, forced migrants, refugees, migrant victims of trafficking and migrants caught in countries in crisis. Some of these categories are covered by existing international legal regimes. However, in this Convention these groups are for the first time brought together under a single framework. An essential feature of the Convention is that it is cumulative. This means, for the most part, that the chapters build on and add rights to the set of rights afforded to categories of migrants covered by earlier chapters. The Convention contains not only provisions that afford rights to migrants and, to a lesser extent, States (such as the right to decide who can enter and remain in their territory). It also articulates the responsibilities of migrants vis-à-vis States and the rights and responsibilities of different institutions that do not directly respond to a right held by migrants

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Clinical characteristics of symptomatic hypermobility in children and young people:A scoping review protocol

INTRODUCTION: Joint hypermobility (JH) is a term used to define active or passive joint range of motion that is beyond normal range, accounting for age, sex, and ethnicity. Symptomatic hypermobility is a term that can be used when symptoms are thought to be associated with JH. Children and young people with symptomatic hypermobility complain of musculoskeletal symptoms but also may report symptoms from other domains including gastrointestinal, cardiovascular, psychological, and urogenital. Many of these symptoms are not included in formal diagnostic criteria yet may impact negatively on their quality of life. The pattern of these symptoms may change with age. PURPOSE: To map the literature on clinical characteristics of symptomatic hypermobility in an age and developmental context, to improve our understanding and assist in the clinical assessment of children and young people with symptomatic hypermobility. METHODS: This systematic scoping review will be conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) methodology. Studies that include children and young people from birth to 24 years with a confirmed diagnosis of symptomatic hypermobility, HSD or hEDS using internationally recognised criteria or equivalent diagnoses will be included. Data extraction and analysis will be undertaken using an iterative process. DISCUSSION: Mapping and synthesis of the data will be carried out and gaps and limitations in the literature will be acknowledged. Results will be disseminated in a peer reviewed journal. The search strategy will be made available publicly for transparency