Preliminary interpretative analysis of the QUENCH-18 bundle test using SCDAPSim/mod3.5

A preliminary analysis of the bundle reflood experiment QUENCH-18 is performed with the SCDAPSim/Mod3.5/da code containing the PSI-developed model for oxidation in the presence of air. The simulation follows on from pre-test planning and prediction calculations using the same code and input model. The starting point for the post-test calculations differs from the pre-test only in respect of using the actual boundary conditions. Comparison with measured data enables several aspects of the experiment to be studied. Various treatments of steam and air oxidation kinetics investigate the effect of nitrogen on the oxidation and its continuing influence when air is no longer present. Concerning degradation, different assumptions on failure of the oxide crust indicate how the exposure of relocated metallic melt can enhance the oxidation excursion during reflood. Some modelling and knowledge limitations are identified, particularly regarding oxidation in steam-air mixtures, the roles of nitrogen and zirconium nitride as chemically active species. Several observed features of the facility operation remain unresolved. Simulations suggest that damage to the shroud affected the reflood progression. The bundle may also have been in a highly damaged state, with further impacts on reflooding. Interpretation is therefore provisional, pending more information on the bundle final state. However, the simulation results have significant implications for reactor calculations

Nitriding model for zirconium based fuel cladding in severe accident codes

A model has been developed to describe the nitriding of partially oxidized zirconium based cladding during an air ingress sequence when the reaction has become starved of oxidant (oxygen and/or steam), and the subsequent re-oxidation of nitride following of restoration of coolant. Key aspects of the model are the estimation of oxygen-stabilised alpha zirconium, α-Zr(O), formed during pre-oxidation and its reaction with the nitrogen. Nitriding of metallic Zr is much slower than α-Zr(O), and plays a comparatively minor role. The model is based on data from separate-effects tests comprised pre-oxidation, nitriding in the absence of oxidant, and re-oxidation in the absence of nitrogen, which were used to derive the kinetic parameters for the main reaction processes. Developmental assessment was performed using the test results, demonstrating favourable agreement for the main reaction signatures. Independent assessment against Integral Test data is underway

“A question of trust” and “a leap of faith”-study participants' perspectives on consent, privacy, and trust in smart home research:Qualitative study

BACKGROUND: Ubiquitous, smart technology has the potential to assist humans in numerous ways, including with health and social care. COVID-19 has notably hastened the move to remotely delivering many health services. A variety of stakeholders are involved in the process of developing technology. Where stakeholders are research participants, this poses practical and ethical challenges, particularly if the research is conducted in people’s homes. Researchers must observe prima facie ethical obligations linked to participants’ interests in having their autonomy and privacy respected. OBJECTIVE: This study aims to explore the ethical considerations around consent, privacy, anonymization, and data sharing with participants involved in SPHERE (Sensor Platform for Healthcare in a Residential Environment), a project for developing smart technology for monitoring health behaviors at home. Participants’ unique insights from being part of this unusual experiment offer valuable perspectives on how to properly approach informed consent for similar smart home research in the future. METHODS: Semistructured qualitative interviews were conducted with 7 households (16 individual participants) recruited from SPHERE. Purposive sampling was used to invite participants from a range of household types and ages. Interviews were conducted in participants’ homes or on-site at the University of Bristol. Interviews were digitally recorded, transcribed verbatim, and analyzed using an inductive thematic approach. RESULTS: Four themes were identified—motivation for participating; transparency, understanding, and consent; privacy, anonymity, and data use; and trust in research. Motivations to participate in SPHERE stemmed from an altruistic desire to support research directed toward the public good. Participants were satisfied with the consent process despite reporting some difficulties—recalling and understanding the information received, the timing and amount of information provision, and sometimes finding the information to be abstract. Participants were satisfied that privacy was assured and judged that the goals of the research compensated for threats to privacy. Participants trusted SPHERE. The factors that were relevant to developing and maintaining this trust were the trustworthiness of the research team, the provision of necessary information, participants’ control over their participation, and positive prior experiences of research involvement. CONCLUSIONS: This study offers valuable insights into the perspectives of participants in smart home research on important ethical considerations around consent and privacy. The findings may have practical implications for future research regarding the types of information researchers should convey, the extent to which anonymity can be assured, and the long-term duty of care owed to the participants who place trust in researchers not only on the basis of this information but also because of their institutional affiliation. This study highlights important ethical implications. Although autonomy matters, trust appears to matter the most. Therefore, researchers should be alert to the need to foster and maintain trust, particularly as failing to do so might have deleterious effects on future research

Dying well with reduced agency: a scoping review and thematic synthesis of the decision-making process in dementia, traumatic brain injury and frailty

Background In most Anglophone nations, policy and law increasingly foster an autonomy-based model, raising issues for large numbers of people who fail to fit the paradigm, and indicating problems in translating practical and theoretical understandings of ‘good death’ to policy. Three exemplar populations are frail older people, people with dementia and people with severe traumatic brain injury. We hypothesise that these groups face some over-lapping challenges in securing good end-of-life care linked to their limited agency. To better understand these challenges, we conducted a scoping review and thematic synthesis. Methods To capture a range of literature, we followed established scoping review methods. We then used thematic synthesis to describe the broad themes emerging from this literature. Results Initial searches generated 22,375 references, and screening yielded 49, highly heterogeneous, studies that met inclusion criteria, encompassing 12 countries and a variety of settings. The thematic synthesis identified three themes: the first concerned the processes of end-of-life decision-making, highlighting the ambiguity of the dominant shared decision-making process, wherein decisions are determined by families or doctors, sometimes explicitly marginalising the antecedent decisions of patients. Despite this marginalisation, however, the patient does play a role both as a social presence and as an active agent, by whose actions the decisions of those with authority are influenced. The second theme examined the tension between predominant notions of a good death as ‘natural’ and the drive to medicalise death through the lens of the experiences and actions of those faced with the actuality of death. The final theme considered the concept of antecedent end-of-life decision-making (in all its forms), its influence on policy and decision-making, and some caveats that arise from the studies. Conclusions Together these three themes indicate a number of directions for future research, which are likely to be applicable to other conditions that result in reduced agency. Above all, this review emphasises the need for new concepts and fresh approaches to end of life decision-making that address the needs of the growing population of frail older people, people with dementia and those with severe traumatic brain injury

Deciding Together?:Best Interests and Shared Decision-Making in Paediatric Intensive Care

In the western healthcare, shared decision making has become the orthodox approach to making healthcare choices as a way of promoting patient autonomy. Despite the fact that the autonomy paradigm is poorly suited to paediatric decision making, such an approach is enshrined in English common law. When reaching moral decisions, for instance when it is unclear whether treatment or non-treatment will serve a child’s best interests, shared decision making is particularly questionable because agreement does not ensure moral validity. With reference to current common law and focusing on intensive care practice, this paper investigates what claims shared decision making may have to legitimacy in a paediatric intensive care setting. Drawing on key texts, I suggest these identify advantages to parents and clinicians but not to the child who is the subject of the decision. Without evidence that shared decision making increases the quality of the decision that is being made, it appears that a focus on the shared nature of a decision does not cohere with the principle that the best interests of the child should remain paramount. In the face of significant pressures toward the displacement of the child’s interests in a shared decision, advantages of a shared decision to decisional quality require elucidation. Although a number of arguments of this nature may have potential, should no such advantages be demonstrable we have cause to revise our commitment to either shared decision making or the paramountcy of the child in these circumstances

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Recurrent SARS-CoV-2 mutations in immunodeficient patients

Long-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in immunodeficient patients are an important source of variation for the virus but are understudied. Many case studies have been published which describe one or a small number of long-term infected individuals but no study has combined these sequences into a cohesive dataset. This work aims to rectify this and study the genomics of this patient group through a combination of literature searches as well as identifying new case series directly from the COVID-19 Genomics UK (COG-UK) dataset. The spike gene receptor-binding domain and N-terminal domain (NTD) were identified as mutation hotspots. Numerous mutations associated with variants of concern were observed to emerge recurrently. Additionally a mutation in the envelope gene, T30I was determined to be the second most frequent recurrently occurring mutation arising in persistent infections. A high proportion of recurrent mutations in immunodeficient individuals are associated with ACE2 affinity, immune escape, or viral packaging optimisation.There is an apparent selective pressure for mutations that aid cell–cell transmission within the host or persistence which are often different from mutations that aid inter-host transmission, although the fact that multiple recurrent de novo mutations are considered defining for variants of concern strongly indicates that this potential source of novel variants should not be discounted. © The Author(s) 2022. Published by Oxford University Press