Showing papers by "Newcastle University published in 2020"

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes.

Abstract: We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells' potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org.

Pan-cancer analysis of whole genomes

Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.

The COVID-19 pandemic and health inequalities.

Abstract: This essay examines the implications of the COVID-19 pandemic for health inequalities. It outlines historical and contemporary evidence of inequalities in pandemics-drawing on international research into the Spanish influenza pandemic of 1918, the H1N1 outbreak of 2009 and the emerging international estimates of socio-economic, ethnic and geographical inequalities in COVID-19 infection and mortality rates. It then examines how these inequalities in COVID-19 are related to existing inequalities in chronic diseases and the social determinants of health, arguing that we are experiencing a syndemic pandemic It then explores the potential consequences for health inequalities of the lockdown measures implemented internationally as a response to the COVID-19 pandemic, focusing on the likely unequal impacts of the economic crisis. The essay concludes by reflecting on the longer-term public health policy responses needed to ensure that the COVID-19 pandemic does not increase health inequalities for future generations.

Digital technologies in the public-health response to COVID-19.

Abstract: Digital technologies are being harnessed to support the public-health response to COVID-19 worldwide, including population surveillance, case identification, contact tracing and evaluation of interventions on the basis of mobility data and communication with the public. These rapid responses leverage billions of mobile phones, large online datasets, connected devices, relatively low-cost computing resources and advances in machine learning and natural language processing. This Review aims to capture the breadth of digital innovations for the public-health response to COVID-19 worldwide and their limitations, and barriers to their implementation, including legal, ethical and privacy barriers, as well as organizational and workforce barriers. The future of public health is likely to become increasingly digital, and we review the need for the alignment of international strategies for the regulation, evaluation and use of digital technologies to strengthen pandemic management, and future preparedness for COVID-19 and other infectious diseases.

COVID-19 and the 5G Conspiracy Theory: Social Network Analysis of Twitter Data.

Abstract: Background: Since the beginning of December 2019, the coronavirus disease (COVID-19) has spread rapidly around the world, which has led to increased discussions across online platforms. These conversations have also included various conspiracies shared by social media users. Amongst them, a popular theory has linked 5G to the spread of COVID-19, leading to misinformation and the burning of 5G towers in the United Kingdom. The understanding of the drivers of fake news and quick policies oriented to isolate and rebate misinformation are keys to combating it. Objective: The aim of this study is to develop an understanding of the drivers of the 5G COVID-19 conspiracy theory and strategies to deal with such misinformation. Methods: This paper performs a social network analysis and content analysis of Twitter data from a 7-day period (Friday, March 27, 2020, to Saturday, April 4, 2020) in which the #5GCoronavirus hashtag was trending on Twitter in the United Kingdom. Influential users were analyzed through social network graph clusters. The size of the nodes were ranked by their betweenness centrality score, and the graph’s vertices were grouped by cluster using the Clauset-Newman-Moore algorithm. The topics and web sources used were also examined. Results: Social network analysis identified that the two largest network structures consisted of an isolates group and a broadcast group. The analysis also revealed that there was a lack of an authority figure who was actively combating such misinformation. Content analysis revealed that, of 233 sample tweets, 34.8% (n=81) contained views that 5G and COVID-19 were linked, 32.2% (n=75) denounced the conspiracy theory, and 33.0% (n=77) were general tweets not expressing any personal views or opinions. Thus, 65.2% (n=152) of tweets derived from nonconspiracy theory supporters, which suggests that, although the topic attracted high volume, only a handful of users genuinely believed the conspiracy. This paper also shows that fake news websites were the most popular web source shared by users; although, YouTube videos were also shared. The study also identified an account whose sole aim was to spread the conspiracy theory on Twitter. Conclusions: The combination of quick and targeted interventions oriented to delegitimize the sources of fake information is key to reducing their impact. Those users voicing their views against the conspiracy theory, link baiting, or sharing humorous tweets inadvertently raised the profile of the topic, suggesting that policymakers should insist in the efforts of isolating opinions that are based on fake news. Many social media platforms provide users with the ability to report inappropriate content, which should be used. This study is the first to analyze the 5G conspiracy theory in the context of COVID-19 on Twitter offering practical guidance to health authorities in how, in the context of a pandemic, rumors may be combated in the future.

The physical oceanography of the transport of floating marine debris

Abstract: Marine plastic debris floating on the ocean surface is a major environmental problem. However, its distribution in the ocean is poorly mapped, and most of the plastic waste estimated to have entered the ocean from land is unaccounted for. Better understanding of how plastic debris is transported from coastal and marine sources is crucial to quantify and close the global inventory of marine plastics, which in turn represents critical information for mitigation or policy strategies. At the same time, plastic is a unique tracer that provides an opportunity to learn more about the physics and dynamics of our ocean across multiple scales, from the Ekman convergence in basin-scale gyres to individual waves in the surfzone. In this review, we comprehensively discuss what is known about the different processes that govern the transport of floating marine plastic debris in both the open ocean and the coastal zones, based on the published literature and referring to insights from neighbouring fields such as oil spill dispersion, marine safety recovery, plankton connectivity, and others. We discuss how measurements of marine plastics (both in situ and in the laboratory), remote sensing, and numerical simulations can elucidate these processes and their interactions across spatio-temporal scales.

Multiple elements of soil biodiversity drive ecosystem functions across biomes.

Abstract: The role of soil biodiversity in regulating multiple ecosystem functions is poorly understood, limiting our ability to predict how soil biodiversity loss might affect human wellbeing and ecosystem sustainability. Here, combining a global observational study with an experimental microcosm study, we provide evidence that soil biodiversity (bacteria, fungi, protists and invertebrates) is significantly and positively associated with multiple ecosystem functions. These functions include nutrient cycling, decomposition, plant production, and reduced potential for pathogenicity and belowground biological warfare. Our findings also reveal the context dependency of such relationships and the importance of the connectedness, biodiversity and nature of the globally distributed dominant phylotypes within the soil network in maintaining multiple functions. Moreover, our results suggest that the positive association between plant diversity and multifunctionality across biomes is indirectly driven by soil biodiversity. Together, our results provide insights into the importance of soil biodiversity for maintaining soil functionality locally and across biomes, as well as providing strong support for the inclusion of soil biodiversity in conservation and management programmes.

An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group.

Abstract: This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), appraises the importance of ischaemia with non-obstructive coronary arteries (INOCA) Angina pectoris affects approximately 112 million people globally Up to 70% of patients undergoing invasive angiography do not have obstructive coronary artery disease, more common in women than in men, and a large proportion have INOCA as a cause of their symptoms INOCA patients present with a wide spectrum of symptoms and signs that are often misdiagnosed as non-cardiac leading to under-diagnosis/investigation and under-treatment INOCA can result from heterogeneous mechanism including coronary vasospasm and microvascular dysfunction and is not a benign condition Compared to asymptomatic individuals, INOCA is associated with increased incidence of cardiovascular events, repeated hospital admissions, as well as impaired quality of life and associated increased health care costs This consensus document provides a definition of INOCA and guidance to the community on the diagnostic approach and management of INOCA based on existing evidence from research and best available clinical practice; noting gaps in knowledge and potential areas for further investigation

A cell atlas of human thymic development defines T cell repertoire formation.

Abstract: The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8αα+ T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.

Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study

Abstract: Parkinson's disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner However, it remains uncertain where the initial α-synuclein aggregates originate We have hypothesized that Parkinson's disease comprises two subtypes A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain We also hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups We included 37 consecutive de novo patients with Parkinson's disease into this case-control PET study Patients with Parkinson's disease were divided into 24 RBD-negative (PDRBD-) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity Colon volume and transit times were assessed with CT scans and radiopaque markers Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA-specific uptake, whereas two-thirds of iRBD patients had normal scans (P < 10-13, ANOVA) When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (P < 10-5, ANOVA) and colon 11C-donepezil standard uptake values (P = 0008, ANOVA) The PDRBD+ group trended towards a reduced mean MRI locus coeruleus: pons ratio compared to PDRBD- (P = 007, t-test) In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (P < 0001, ANOVA) and delayed colonic transit times (P = 001, Kruskal-Wallis) The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal These findings support the existence of brain-first and body-first subtypes of Parkinson's disease

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.

Abstract: COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

Research criteria for the diagnosis of prodromal dementia with Lewy bodies

Abstract: The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.

Strength, Weakness, Opportunity, Threat (SWOT) Analysis of the Adaptations to Anatomical Education in the United Kingdom and Republic of Ireland in Response to the Covid-19 Pandemic.

Abstract: The Covid-19 pandemic has driven the fastest changes to higher education across the globe, necessitated by social distancing measures preventing face-to-face teaching. This has led to an almost immediate switch to distance learning by higher education institutions. Anatomy faces some unique challenges. Intrinsically, anatomy is a three-dimensional subject that requires a sound understanding of the relationships between structures, often achieved by the study of human cadaveric material, models, and virtual resources. This study sought to identify the approaches taken in the United Kingdom and Republic of Ireland to deliver anatomical education through online means. Data were collected from 14 different universities in the United Kingdom and Republic of Ireland and compared adopting a thematic analysis approach. Once themes were generated, they were collectively brought together using a strength, weakness, opportunity, threat (SWOT) analysis. Key themes included the opportunity to develop new online resources and the chance to engage in new academic collaborations. Academics frequently mentioned the challenge that time constrains could place on the quality and effectiveness of these resources; especially as in many cases the aim of these resources was to compensate for a lack of exposure to cadaveric exposure. Comparisons of the actions taken by multiple higher education institutions reveal the ways that academics have tried to balance this demand. Discussions will facilitate decisions being made by higher education institutions regarding adapting the curriculum and assessment methods in anatomy.

The Karl G. Jansky Very Large Array Sky Survey (VLASS). Science Case and Survey Design

Abstract: The Very Large Array Sky Survey (VLASS) is a synoptic, all-sky radio sky survey with a unique combination of high angular resolution (≈2.5\"), sensitivity (a 1σ goal of 70 μJy/beam in the coadded data), full linear Stokes polarimetry, time domain coverage, and wide bandwidth (2-4 GHz). The first observations began in September 2017, and observing for the survey will finish in 2024. VLASS will use approximately 5500 hours of time on the Karl G. Jansky Very Large Array (VLA) to cover the whole sky visible to the VLA (Declination > −40∘), a total of 33,885 deg^2. The data will be taken in three epochs to allow the discovery of variable and transient radio sources. The survey is designed to engage radio astronomy experts, multi-wavelength astronomers, and citizen scientists alike. By utilizing an \"on the fly\" interferometry mode, the observing overheads are much reduced compared to a conventional pointed survey. In this paper, we present the science case and observational strategy for the survey, and also results from early survey observations.

Identifying degradation patterns of lithium ion batteries from impedance spectroscopy using machine learning

Abstract: Forecasting the state of health and remaining useful life of Li-ion batteries is an unsolved challenge that limits technologies such as consumer electronics and electric vehicles. Here, we build an accurate battery forecasting system by combining electrochemical impedance spectroscopy (EIS)—a real-time, non-invasive and information-rich measurement that is hitherto underused in battery diagnosis—with Gaussian process machine learning. Over 20,000 EIS spectra of commercial Li-ion batteries are collected at different states of health, states of charge and temperatures—the largest dataset to our knowledge of its kind. Our Gaussian process model takes the entire spectrum as input, without further feature engineering, and automatically determines which spectral features predict degradation. Our model accurately predicts the remaining useful life, even without complete knowledge of past operating conditions of the battery. Our results demonstrate the value of EIS signals in battery management systems. Forecasting the state of health and remaining useful life of batteries is a challenge that limits technologies such as electric vehicles. Here, the authors build an accurate battery performance forecasting system using machine learning.

Regulation of peptidoglycan synthesis and remodelling.

Abstract: Bacteria surround their cell membrane with a net-like peptidoglycan layer, called sacculus, to protect the cell from bursting and maintain its cell shape. Sacculus growth during elongation and cell division is mediated by dynamic and transient multiprotein complexes, the elongasome and divisome, respectively. In this Review we present our current understanding of how peptidoglycan synthases are regulated by multiple and specific interactions with cell morphogenesis proteins that are linked to a dynamic cytoskeletal protein, either the actin-like MreB or the tubulin-like FtsZ. Several peptidoglycan synthases and hydrolases require activation by outer-membrane-anchored lipoproteins. We also discuss how bacteria achieve robust cell wall growth under different conditions and stresses by maintaining multiple peptidoglycan enzymes and regulators as well as different peptidoglycan growth mechanisms, and we present the emerging role of LD-transpeptidases in peptidoglycan remodelling.

KDIGO Clinical Practice Guideline on the evaluation and management of candidates for kidney transplantation

Abstract: The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, and immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence, and the strengths of recommendations are provided. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.

COVID-19 and pneumothorax: a multicentre retrospective case series

Abstract: Introduction Pneumothorax and pneumomediastinum have both been noted to complicate cases of COVID-19 requiring hospital admission. We report the largest case series yet described of patients with both these pathologies that includes non-ventilated patients. Methods Cases were collected retrospectively from UK hospitals with inclusion criteria limited to a diagnosis of COVID-19 and the presence of either pneumothorax or pneumomediastinum. Patients included in the study presented between March and June 2020. Details obtained from the medical record included demographics, radiology, laboratory investigations, clinical management and survival. Results Seventy-one patients from 16 centres were included in the study, of whom 60 patients had pneumothoraces (six also with pneumomediastinum), whilst 11 patients had pneumomediastinum alone. Two of these patients had two distinct episodes of pneumothorax, occurring bilaterally in sequential fashion, bringing the total number of pneumothoraces included to 62. Clinical scenarios included patients who had presented to hospital with pneumothorax, patients who had developed pneumothorax or pneumomediastinum during their inpatient admission with COVID-19 and patients who developed their complication whilst intubated and ventilated, either with or without concurrent extracorporeal membrane oxygenation. Survival at 28 days was not significantly different following pneumothorax (63.1%±6.5%) or isolated pneumomediastinum (53.0%±18.7%; p=0.854). The incidence of pneumothorax was higher in males. The 28-day survival was not different between the sexes (males 62.5%±7.7% versus females 68.4%±10.7%; p=0.619). Patients above the age of 70 had a significantly lower 28-day survival than younger individuals (≥70 years 41.7%±13.5% survival versus Conclusion These cases suggest that pneumothorax is a complication of COVID-19. Pneumothorax does not seem to be an independent marker of poor prognosis and we encourage active treatment to be continued where clinically possible.

British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic.

Abstract: The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.

Poly(ADP-ribose) polymerase inhibition: past, present and future

Abstract: The process of poly(ADP-ribosyl)ation and the major enzyme that catalyses this reaction, poly(ADP-ribose) polymerase 1 (PARP1), were discovered more than 50 years ago. Since then, advances in our understanding of the roles of PARP1 in cellular processes such as DNA repair, gene transcription and cell death have allowed the investigation of therapeutic PARP inhibition for a variety of diseases — particularly cancers in which defects in DNA repair pathways make tumour cells highly sensitive to the inhibition of PARP activity. Efforts to identify and evaluate potent PARP inhibitors have so far led to the regulatory approval of four PARP inhibitors for the treatment of several types of cancer, and PARP inhibitors have also shown therapeutic potential in treating non-oncological diseases. This Review provides a timeline of PARP biology and medicinal chemistry, summarizes the pathophysiological processes in which PARP plays a role and highlights key opportunities and challenges in the field, such as counteracting PARP inhibitor resistance during cancer therapy and repurposing PARP inhibitors for the treatment of non-oncological diseases. Several poly(ADP-ribose) polymerase (PARP) inhibitors have now been approved as treatments for various types of cancer. In this Review, Curtin and Szabo discuss the history of the development of PARP inhibitors and progress in their use for cancer therapy, as well as the potential for repurposing PARP inhibitors for the treatment of non-oncological diseases such as stroke.