Radiography in Palaeopathology: Where Next?

YesRadiography has frequently been used during palaeopathological research, and plays an important role in the differential diagnosis of many diseases, including Paget¿s disease and carcinomas. Traditionally, radiographs were taken in hospitals with clinical equipment. However industrial radiography techniques have gradually become more commonly used, as their superior image quality and improved potential for diagnoses become recognised. The introduction of radiographic scanners has facilitated the digitisation of these images for dissemination and publication. However this is not all that radiographic digitisation can offer the researcher. Digital image processing (DIP) allows the researcher to focus on an area of interest and to adjust the brightness and contrast of the captured image. This allows the investigation of areas of high radio-opacity and radio-lucency, providing detailed images of the internal structures of bone and pathological lesions undetectable by the naked eye. In addition 3D effects, edge enhancement and sharpening algorithms, available through commonly used image processing software, can be very effective in enhancing the visibility of specific features. This paper will reveal how radiographic digitisation and manipulation can enhance radiographic images of palaeopathological lesions and potentially further our understanding of the bony manifestations of disease

Barriers and facilitators to patient and public engagement and recruitment to digital health interventions: protocol of a systematic review of qualitative studies

Introduction: Patients and the public are beginning to use digital health tools to assist in managing chronic illness, support independent living and self-care, and remain connected to health and care providers. However, engaging with and enrolling in digital health interventions, such as telehealth systems, mobile health applications, patient portals and personal health records, in order to use them varies considerably. Many factors affect people's ability to engage with and sign up to digital health platforms.Objectives: The primary aim is to identify the barriers and facilitators patients and the public experience to engagement and recruitment to digital health interventions. The secondary aim is to identify engagement and enrolment strategies, leading if possible to a taxonomy of such approaches, and a conceptual framework of digital health engagement and recruitment processes.Methods: A systematic review of qualitative studies will be conducted by searching six databases: MEDLINE, CINAHL, PubMed, EMBASE, Scopus and the ACM Digital Library for papers published between 2000 and 2015. Titles and abstracts along with full-text papers will be screened by two independent reviewers against predetermined inclusion and exclusion criteria. A data extraction form will be used to provide details of the included studies. Quality assessment will be conducted using the Consolidated Criteria for Reporting Qualitative Research checklist. Any disagreements will be resolved through discussion with an independent third reviewer. Analysis will be guided by framework synthesis and informed by normalization process theory and burden of treatment theory, to aid conceptualisation of digital health engagement and recruitment processes.Discussion: This systematic review of qualitative studies will explore factors affecting engagement and enrolment in digital health interventions. It will advance our understanding of readiness for digital health by examining the complex factors that affect patients’ and the public's ability to take part

The Gristhorpe coffin and its contents

In July 1834 excavation of a barrow at Gristhorpe, near Scarborough, Yorkshire, recovered an intact, waterlogged, hollowed-out oak coffin containing a perfectly preserved Bronze Age skeleton that had been wrapped in an animal skin and buried with worked flints, a bronze dagger with a whalebone pommel, and a bark vessel apparently containing food residue. Gristhorpe Man became the centrepiece of the Scarborough Philosophical Society’s museum display. In 2004, planned refurbishment of the renamed Rotunda Museum provided the opportunity for a scientific re-examination of the burial and grave goods in order to eluciate the life and death of this extraordinary survival of the British Early Bronze Age. Tree-trunk coffin burials are relatively rare and Gristhorpe Man, with his range of grave goods was likely to have held a special role in society. Analysis of the skeleton included an examination of its skeletal morphology and palaeopathological conditions combined with isotopic analyses of the bones and teeth in order to investigate mobility, diet, and status of the individual whose unusual large stature, dentition, and novel methods of conservation were of particular interest. These analyses, combined with examination of the surviving coffin lid, including the unique ‘face’ carved onto one end of it, the grave goods, and radiocarbon and dendrochronological dating, reveal fascinating insights into the social position, inter-regional contacts and the burial rite associated with this enigmatic mature man who probably saw active combat and who suffered from a benign brain tumour that may have seriously altered his personality in his later years

Interaction between cannabis consumption and childhood abuse in psychotic disorders:preliminary findings on the role of different patterns of cannabis use

Aim: Several studies have suggested that lifetime cannabis consumption and childhood abuse synergistically contribute to the risk for psychotic disorders. This study aimed to extend existing findings regarding an additive interaction between childhood abuse and lifetime cannabis use by investigating the moderating role of type and frequency of cannabis use. Methods: Up to 231 individuals presenting for the first time to mental health services with psychotic disorders and 214 unaffected population controls from South London, United Kingdom, were recruited as part of the Genetics and Psychosis study. Information about history of cannabis use was collected using the Cannabis Experiences Questionnaire. Childhood physical and sexual abuse was assessed using the Childhood Experience of Care and Abuse Questionnaire. Results: Neither lifetime cannabis use nor reported exposure to childhood abuse was associated with psychotic disorder when the other environmental variable was taken into account. Although the combination of the two risk factors raised the odds for psychosis by nearly three times (adjusted OR = 2.94, 95% CI: 1.44–6.02, P = 0.003), no evidence of interaction was found (adjusted OR = 1.46, 95% CI: −0.54 to 3.46, P = 0.152). Furthermore, the association of high-potency cannabis and daily consumption with psychosis was at least partially independent of the effect of childhood abuse. Conclusions: The heavy use of high-potency cannabis increases the risk of psychosis but, in addition, smoking of traditional resin (hash) and less than daily cannabis use may increase the risk for psychosis when combined with exposure to severe childhood abuse.</p

SARS-CoV-2 Mac1 is an essential virulence factor

Several coronavirus (CoV) encoded proteins are being evaluated as targets for antiviral therapies for COVID-19. Included in this set of proteins is the conserved macrodomain, or Mac1, an ADP-ribosylhydrolase and ADP-ribose binding protein. Utilizing point mutant recombinant viruses, Mac1 was shown to be critical for both murine hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV virulence. However, as a potential drug target, it is imperative to understand how a complete Mac1 deletion impacts the replication and pathogenesis of different CoVs. To this end, we created recombinant bacterial artificial chromosomes (BACs) containing complete Mac1 deletions (ΔMac1) in MHV, MERS-CoV, and SARS-CoV-2. While we were unable to recover infectious virus from MHV or MERS-CoV ΔMac1 BACs, SARS-CoV-2 ΔMac1 was readily recovered from BAC transfection, indicating a stark difference in the requirement for Mac1 between different CoVs. Furthermore, SARS-CoV-2 ΔMac1 replicated at or near wild-type levels in multiple cell lines susceptible to infection. However, in a mouse model of severe infection, ΔMac1 was quickly cleared causing minimal pathology without any morbidity. ΔMac1 SARS-CoV-2 induced increased levels of interferon (IFN) and interferon-stimulated gene (ISG) expression in cell culture and mice, indicating that Mac1 blocks IFN responses which may contribute to its attenuation. ΔMac1 infection also led to a stark reduction in inflammatory monocytes and neutrophils. These results demonstrate that Mac1 only minimally impacts SARS-CoV-2 replication, unlike MHV and MERS-CoV, but is required for SARS-CoV-2 pathogenesis and is a unique antiviral drug target.National Institutes of Health (NIH) grant P20GM103648 (RC) National Institutes of Health (NIH) grant 2P01AI060699 (LE) National Institutes of Health (NIH) grant P20GM113117 (ARF) National Institutes of Health (NIH) grant K22AI134993 (ARF) National Institutes of Health (NIH) grant R35GM138029 (ARF) National Science Foundation (NSF) grant 2135167 (RLU) University of Kansas General Research Fund (GRF) and Start-up funds (ARF) NIH Graduate Training at the Biology-Chemistry Interface grant T32GM132061 (CMK) University of Kansas College of Liberal Arts and Sciences Graduate Research Fellowship (CMK) Government of Spain (PID2019-107001RB-I00 AEI/FEDER, UE) LE European Commission (H2020-SC1-2019, ISOLDA Project nº 848166-2) LEN

Antagomir-17-5p Abolishes the Growth of Therapy-Resistant Neuroblastoma through p21 and BIM

We identified a key oncogenic pathway underlying neuroblastoma progression: specifically, MYCN, expressed at elevated level, transactivates the miRNA 17-5p-92 cluster, which inhibits p21 and BIM translation by interaction with their mRNA 3′ UTRs. Overexpression of miRNA 17-5p-92 cluster in MYCN-not-amplified neuroblastoma cells strongly augments their in vitro and in vivo tumorigenesis. In vitro or in vivo treatment with antagomir-17-5p abolishes the growth of MYCN-amplified and therapy-resistant neuroblastoma through p21 and BIM upmodulation, leading to cell cycling blockade and activation of apoptosis, respectively. In primary neuroblastoma, the majority of cases show a rise of miR-17-5p level leading to p21 downmodulation, which is particularly severe in patients with MYCN amplification and poor prognosis. Altogether, our studies demonstrate for the first time that antagomir treatment can abolish tumor growth in vivo, specifically in therapy-resistant neuroblastoma

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children