A new sighting study for the fixed concentration procedure to allow for gender differences

The fixed concentration procedure (FCP) has been proposed as an alternative to the median lethal concentration (LC50) test (organisation for economic co-operation and development (OECD) test guideline [TG] 403) for the assessment of acute inhalation toxicity. The FCP tests animals of a single gender (usually females) at a number of fixed concentration levels in a sequential fashion. It begins with a sighting study that precedes the main FCP study and is used to determine the main study starting concentration. In this paper, we propose a modification to the sighting study and suggest that it should be conducted using both male and female animals, rather than just animals of a single gender. Statistical analysis demonstrates that, when females are more sensitive, the new procedure is likely to give the same classification as the original FCP, whereas, if males are more sensitive, the new procedure is much less likely to lead to incorrect classification into a less toxic category. If there is no difference in the LC50 for females and males, the new procedure is slightly more likely to classify into a more stringent class than the original FCP. Overall, these results show that the revised sighting study ensures gender differences in sensitivity do not significantly impact on the performance of the FCP, supporting its use as an alternative test method for assessing acute inhalation toxicity

A statistical evaluation of the effects of gender differences in assessment of acute inhalation toxicity

Acute inhalation toxicity of chemicals has conventionally been assessed by the median lethal concentration (LC50) test (organisation for economic co-operation and development (OECD) TG 403). Two new methods, the recently adopted acute toxic class method (ATC; OECD TG 436) and a proposed fixed concentration procedure (FCP), have recently been considered, but statistical evaluations of these methods did not investigate the influence of differential sensitivity between male and female rats on the outcomes. This paper presents an analysis of data from the assessment of acute inhalation toxicity for 56 substances. Statistically significant differences between the LC50 for males and females were found for 16 substances, with greater than 10-fold differences in the LC50 for two substances. The paper also reports a statistical evaluation of the three test methods in the presence of unanticipated gender differences. With TG 403, a gender difference leads to a slightly greater chance of under-classification. This is also the case for the ATC method, but more pronounced than for TG 403, with misclassification of nearly all substances from Globally Harmonised System (GHS) class 3 into class 4. As the FCP uses females only, if females are more sensitive, the classification is unchanged. If males are more sensitive, the procedure may lead to under-classification. Additional research on modification of the FCP is thus proposed

Taxon interactions control the distributions of cryoconite bacteria colonizing a High Arctic ice cap

Microbial colonization of glacial ice surfaces incurs feedbacks which affect the melting rate of the ice surface. Ecosystems formed as microbe-mineral aggregates termed cryoconite locally reduce ice surface albedo and represent foci of biodiversity and biogeochemical cycling. Consequently, greater understanding the ecological processes in the formation of functional cryoconite ecosystems upon glacier surfaces is sought. Here we present the first bacterial biogeography of an ice cap, evaluating the respective roles of dispersal, environmental and biotic filtration occurring at local scales in the assembly of cryoconite microbiota. 16S rRNA gene amplicon semiconductor sequencing of cryoconite colonizing a Svalbard ice cap coupled with digital elevation modelling of physical parameters reveals the bacterial community is dominated by a ubiquitous core of generalist taxa, with evidence for a moderate pairwise distance-decay relationship. While geographic position and melt season duration are prominent among environmental predictors of community structure, the core population of taxa appears highly influential in structuring the bacterial community. Taxon co-occurrence network analysis reveals a highly modular community structured by positive interactions with bottleneck taxa, predominantly Actinobacteria affiliated to isolates from soil humus. In contrast, the filamentous cyanobacterial taxon (assigned to Leptolyngbya) which dominates the community and bind together granular cryoconite are poorly connected to other taxa. While our study targeted one ice cap, the prominent role of generalist core taxa with close environmental relatives across the global cryosphere indicate discrete roles for cosmopolitan Actinobacteria and Cyanobacteria as respective keystone taxa and ecosystem engineers of cryoconite ecosystems colonizing ice caps. This article is protected by copyright. All rights reserved

Patient safety incidents involving sick children in primary care in England and Wales: a mixed methods analysis

Background: The UK performs poorly relative to other economically developed countries on numerous indicators of care quality for children. The contribution of iatrogenic harm to these outcomes is unclear. As primary care is the first point of healthcare contact for most children, we sought to investigate the safety of care provided to children in this setting. Methods and Findings: We undertook a mixed methods investigation of reports of primary care patient safety incidents involving sick children from England and Wales’ National Reporting and Learning System between 1 January 2005 and 1 December 2013. Two reviewers independently selected relevant incident reports meeting prespecified criteria, and then descriptively analyzed these reports to identify the most frequent and harmful incident types. This was followed by an in-depth thematic analysis of a purposive sample of reports to understand the reasons underpinning incidents. Key candidate areas for strengthening primary care provision and reducing the risks of systems failures were then identified through multidisciplinary discussions. Of 2,191 safety incidents identified from 2,178 reports, 30% (n = 658) were harmful, including 12 deaths and 41 cases of severe harm. The children involved in these incidents had respiratory conditions (n = 387; 18%), injuries (n = 289; 13%), nonspecific signs and symptoms, e.g., fever (n = 281; 13%), and gastrointestinal or genitourinary conditions (n = 268; 12%), among others. Priority areas for improvement included safer systems for medication provision in community pharmacies; triage processes to enable effective and timely assessment, diagnosis, and referral of acutely sick children attending out-of-hours services; and enhanced communication for robust safety netting between professionals and parents. The main limitations of this study result from underreporting of safety incidents and variable data quality. Our findings therefore require further exploration in longitudinal studies utilizing case review methods. Conclusions: This study highlights opportunities to reduce iatrogenic harm and avoidable child deaths. Globally, healthcare systems with primary-care-led models of delivery must now examine their existing practices to determine the prevalence and burden of these priority safety issues, and utilize improvement methods to achieve sustainable improvements in care quality

Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control

Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified

The Voice Characterisation Checklist:Psychometric Properties of a Brief Clinical Assessment of Voices as Social Agents

Aim: There is growing interest in tailoring psychological interventions for distressing voices and a need for reliable tools to assess phenomenological features which might influence treatment response. This study examines the reliability and internal consistency of the Voice Characterisation Checklist (VoCC), a novel 10-item tool which assesses degree of voice characterisation, identified as relevant to a new wave of relational approaches. Methods: The sample comprised participants experiencing distressing voices, recruited at baseline on the AVATAR2 trial between January 2021 and July 2022 (n = 170). Inter-rater reliability (IRR) and internal consistency analyses (Cronbach’s alpha) were conducted. Results: The majority of participants reported some degree of voice personification (94%) with high endorsement of voices as distinct auditory experiences (87%) with basic attributes of gender and age (82%). While most identified a voice intention (75%) and personality (76%), attribution of mental states (35%) to the voice (‘What are they thinking?’) and a known historical relationship (36%) were less common. The internal consistency of the VoCC was acceptable (10 items, α = 0.71). IRR analysis indicated acceptable to excellent reliability at the item-level for 9/10 items and moderate agreement between raters’ global (binary) classification of more vs. less highly characterised voices, κ = 0.549 (95% CI, 0.240–0.859), p < 0.05. Conclusion: The VoCC is a reliable and internally consistent tool for assessing voice characterisation and will be used to test whether voice characterisation moderates treatment outcome to AVATAR therapy. There is potential wider utility within clinical trials of other relational therapies as well as routine clinical practise

The voice characterisation checklist: psychometric properties of a brief clinical assessment of voices as social agents

Aim: There is growing interest in tailoring psychological interventions for distressing voices and a need for reliable tools to assess phenomenological features which might influence treatment response. This study examines the reliability and internal consistency of the Voice Characterisation Checklist (VoCC), a novel 10-item tool which assesses degree of voice characterisation, identified as relevant to a new wave of relational approaches. Methods: The sample comprised participants experiencing distressing voices, recruited at baseline on the AVATAR2 trial between January 2021 and July 2022 (n = 170). Inter-rater reliability (IRR) and internal consistency analyses (Cronbach’s alpha) were conducted. Results: The majority of participants reported some degree of voice personification (94%) with high endorsement of voices as distinct auditory experiences (87%) with basic attributes of gender and age (82%). While most identified a voice intention (75%) and personality (76%), attribution of mental states (35%) to the voice (‘What are they thinking?’) and a known historical relationship (36%) were less common. The internal consistency of the VoCC was acceptable (10 items, α = 0.71). IRR analysis indicated acceptable to excellent reliability at the item-level for 9/10 items and moderate agreement between raters’ global (binary) classification of more vs. less highly characterised voices, κ = 0.549 (95% CI, 0.240–0.859), p < 0.05. Conclusion: The VoCC is a reliable and internally consistent tool for assessing voice characterisation and will be used to test whether voice characterisation moderates treatment outcome to AVATAR therapy. There is potential wider utility within clinical trials of other relational therapies as well as routine clinical practice

PrEdiction of Risk and Communication of outcomE followIng major lower limb amputation – a collaboratiVE study (PERCEIVE): Protocol for the PERCEIVE qualitative study

INTRODUCTION: Deciding whether to proceed with a major lower limb amputation is life-changing and complex, and it is crucial that the right decision is made at the right time. However, medical specialists are known to poorly predict risk when assessing patients for major surgery, and there is little guidance and research regarding decisions about amputation. The process of shared decision-making between doctors and patients during surgical consultations is also little understood. Therefore, the aim of this study is to analyse in depth the communication, consent, risk prediction and decision-making process in relation to major lower limb amputation. METHODS AND ANALYSIS: Consultations between patients and surgeons at which major lower limb amputation is discussed will be audio-recorded for 10–15 patients. Semi-structured follow-up interviews with patients (and relatives/carers) will then be conducted at two time points: as soon as possible/appropriate after a decision has been reached regarding surgery, and approximately 6 months later. Semi-structured interviews will also be conducted with 10–15 healthcare professionals working in the UK National Health Service (NHS) involved in amputation decision-making. This will include surgeons, anaesthetists and specialist physiotherapists at 2–4 NHS Health Boards/Trusts in Wales and England. Discourse analysis will be used to analyse the recorded consultations; interviews will be analysed thematically. Finally, workshops will be held with patients and healthcare professionals to help synthesise and interpret findings. ETHICS AND DISSEMINATION: The study has been approved by Wales REC 7 (20/WA/0351). Study findings will be published in international peer-reviewed journal(s) and presented at national and international scientific meetings. Findings will also be disseminated to a wide NHS and lay audience via presentations at meetings and written summaries for key stakeholder groups

Cisplatin Ototoxicity in Children

Cisplatin is a highly effective chemotherapy medicine used in the treatment of many childhood cancers. Like all medications, cisplatin has many side effects and as always the treatment of cancer in children is a balance between the risks of the medications used and their potential benefits. While many side effects of cisplatin chemotherapy are reversible, one major side effect is permanent and irreversible hearing loss (ototoxicity) in both ears which may worsen with time. The severity of cisplatin-related ototoxicity is associated with age and the cumulative dose received: the younger the child and the higher the total dose, the more severe the hearing loss may be. The spectrum of hearing loss varies from mild to moderate high tone hearing loss, to profound loss across the hearing range and permanent deafness. In addition to hearing loss, some children, especially adolescents, also experience tinnitus and vertigo. Cisplatin ototoxicity is one of most important of the many long-term effects experienced by children who are cured of their cancer. The burden of this toxicity may be compounded by other long-term health issues that emerge with time. This chapter will focus on cisplatin-induced hearing loss, its mechanisms, its health impact on the young person and ways to mitigate or reduce the severity of ototoxicity. This chapter has been written by a multi-disciplinary team including paediatric oncologists, audiologists, a psychologist, a health scientist and a parent of a child growing up with high frequency hearing loss