Temporal Anomalies in Immunological Gene Expression in a Time Series of Wild Mice: Signature of an Epidemic?

Although the ecological importance of coinfection is increasingly recognized, analyses of microbial pathogen dynamics in wildlife usually focus on an ad hoc subset of the species present due to technological limitations on detection. Here we demonstrate the use of expression profiles for immunological genes (pattern recognition receptors, cytokines and transcription factors) as a means to identify, without preconception, the likelihood of important acute microbial infections in wildlife. Using a wood mouse population in the UK as a model we identified significant temporal clusters of individuals with extreme expression of immunological mediators across multiple loci, typical of an acute microbial infection. These clusters were circumstantially associated with demographic perturbation in the summertime wood mouse population. Animals in one cluster also had significantly higher individual macroparasite burdens than contemporaries with “normal” expression patterns. If the extreme transcriptional profiles observed are induced by an infectious agent then this implicates macroparasites as a possible player in mediating individual susceptibility or resilience to infection. The form of survey described here, combined with next generation nucleic acids sequencing methods for the broad detection of microbial infectious agents in individuals with anomalous immunological transcriptional profiles, could be a powerful tool for revealing unrecognized, ecologically important infectious agents circulating in wildlife populations

Improving the Detection, Assessment, Management and Prevention of Delirium in Hospices (the DAMPen-D study): protocol for a co-design and feasibility study of a flexible and scalable implementation strategy to deliver guideline-adherent delirium care

INTRODUCTION: Delirium is a complex condition in which altered mental state and cognition causes severe distress and poor clinical outcomes for patients and families, anxiety and stress for the health professionals and support staff providing care, and higher care costs. Hospice patients are at high risk of developing delirium, but there is significant variation in care delivery. The primary objective of this study is to demonstrate the feasibility of an implementation strategy (designed to help deliver good practice delirium guidelines), participant recruitment and data collection. METHODS AND ANALYSIS: Three work packages in three hospices in the UK with public involvement in codesign, study management and stakeholder groups: (1) experience-based codesign to adapt an existing theoretically-informed implementation strategy (Creating Learning Environments for Compassionate Care (CLECC)) to implement delirium guidelines in hospices; (2) feasibility study to explore ability to collect demographic, diagnostic and delirium management data from clinical records (n=300), explanatory process data (number of staff engaged in CLECC activities and reasons for non-engagement) and cost data (staff and volunteer hours and pay-grades engaged in implementation activities) and (3) realist process evaluation to assess the acceptability and flexibility of the implementation strategy (preimplementation and postimplementation surveys with hospice staff and management, n=30 at each time point; interviews with hospice staff and management, n=15). Descriptive statistics, rapid thematic analysis and a realist logic of analysis will be used be used to analyse quantitative and qualitative data, as appropriate. ETHICS AND DISSEMINATION: Ethical approval obtained: Hull York Medical School Ethics Committee (Ref 21/23), Health Research Authority Research Ethics Committee Wales REC7 (Ref 21/WA/0180) and Health Research Authority Confidentiality Advisory Group (Ref 21/CAG/0071). Written informed consent will be obtained from interview participants. A results paper will be submitted to an open access peer-reviewed journal and a lay summary shared with study site staff and stakeholders. TRIAL REGISTRATION NUMBER: ISRCTN55416525

Improving the Detection, Assessment, Management, and Prevention of Delirium in Hospices (the DAMPen-D study): Feasibility Study of a flexible and scalable implementation strategy to deliver guideline-adherent delirium care

BackgroundDelirium is a complex condition, stressful for all involved. Although highly prevalent in palliative care settings, it remains underdiagnosed and associated with poor outcomes. Guideline-adherent delirium care may improve its detection, assessment, and management. AimTo inform a future definitive study that tests whether an implementation strategy designed to improve guideline-adherent delirium care in palliative care settings improves patient outcomes (reduced proportion of in-patient days with delirium).DesignWith Patient Involvement members, we conducted a feasibility study to assess the acceptability of and engagement with the implementation strategy by hospice staff (intervention), and whether clinical record data collection of process (e.g., guideline-adherent delirium care) and clinical outcomes (evidence of delirium using a validated chart-based instrument;) pre- and 12-weeks post-implementation of the intervention would be possible.Setting/participantsIn-patient admissions in three English hospices.Results Between June 2021-December 2022, clinical record data were extracted from 300 consecutive admissions. Despite data collection during COVID-19, target clinical record data collection (n=300) was achieved. Approximately two-thirds of patients had a delirium episode during in-patient stay at both timepoints. A 6% absolute reduction in proportion of delirium days in those with a delirium episode was observed. Post-implementation improvements in guideline-adherent metrics include: clinical delirium diagnosis 15% to 28%; delirium risk assessment 0% to 16%; screening on admission 7% to 35%.Conclusions Collection of data on delirium outcomes and guideline-adherence from clinical records is feasible. The signal of patient benefit supports formal evaluation in a large-scale study

Improving hospice delirium guideline adoption through an understanding of barriers and facilitators: A mixed-methods co-design study

Objectives This study seeks to understand and address barriers to practitioners’ optimal assessment and management of people with delirium in hospices. Methods Retrospective clinical record review to identify areas of low concordance with guideline-adherent delirium care, followed by a survey of healthcare practitioners to identify barriers and facilitators to optimal care. Qualitative interviews with health care practitioners to explore and develop strategies to address barriers or optimise facilitators and a meeting with senior clinical staff to refine identified strategies. Results Eighty clinical records were reviewed. Elements of poor guideline concordance were identified. Delirium screening on admission was conducted for 61% of admissions. Non-pharmacological management was documented for 59% of those we identified as having delirium from the clinical records. Survey and interview data identified key barriers to delirium assessment as competing priorities, poor knowledge and skills and lack of environmental resources (staff and guidelines, environment). A co-design process resulted in strategies to address barriers and enhance facilitators including champions, educational meetings, audit and feedback, and environmental changes (including careful consideration of the staff skills mix on shift and tools to support non-pharmacological management).  Conclusions Implementation of strategies should result in greater guideline-adherent delirium care. Further work should test this in practice and include both process and clinical outcomes (e.g., reduction in delirium days). We conducted a theoretically underpinned, internationally relevant study in a hospice in England, U

Immunomodulatory parasites and toll-like receptor-mediated tumour necrosis factor alpha responsiveness in wild mammals

BACKGROUND: Immunological analyses of wild populations can increase our understanding of how vertebrate immune systems respond to 'natural' levels of exposure to diverse infections. A major recent advance in immunology has been the recognition of the central role of phylogenetically conserved toll-like receptors in triggering innate immunity and the subsequent recruitment of adaptive response programmes. We studied the cross-sectional associations between individual levels of systemic toll-like receptor-mediated tumour necrosis factor alpha responsiveness and macro- and microparasite infections in a natural wood mouse (Apodemus sylvaticus) population. RESULTS: Amongst a diverse group of macroparasites, only levels of the nematode Heligmosomoides polygyrus and the louse Polyplax serrata were correlated (negatively) with innate immune responsiveness (measured by splenocyte tumour necrosis factor alpha responses to a panel of toll-like receptor agonists). Polyplax serrata infection explained a strikingly high proportion of the total variation in innate responses. Contrastingly, faecal oocyst count in microparasitic Eimeria spp. was positively associated with innate immune responsiveness, most significantly for the endosomal receptors TLR7 and TLR9. CONCLUSION: Analogy with relevant laboratory models suggests the underlying causality for the observed patterns may be parasite-driven immunomodulatory effects on the host. A subset of immunomodulatory parasite species could thus have a key role in structuring other infections in natural vertebrate populations by affecting the 'upstream' innate mediators, like toll-like receptors, that are important in initiating immunity. Furthermore, the magnitude of the present result suggests that populations free from immunosuppressive parasites may exist at 'unnaturally' elevated levels of innate immune activation, perhaps leading to an increased risk of immunopathology

An Immunological Marker of Tolerance to Infection in Wild Rodents

Hosts are likely to respond to parasitic infections by a combination of resistance (expulsion of pathogens) and tolerance (active mitigation of pathology). Of these strategies, the basis of tolerance in animal hosts is relatively poorly understood, with especially little known about how tolerance is manifested in natural populations. We monitored a natural population of field voles using longitudinal and cross-sectional sampling modes and taking measurements on body condition, infection, immune gene expression, and survival. Using analyses stratified by life history stage, we demonstrate a pattern of tolerance to macroparasites in mature compared to immature males. In comparison to immature males, mature males resisted infection less and instead increased investment in body condition in response to accumulating burdens, but at the expense of reduced reproductive effort. We identified expression of the transcription factor Gata3 (a mediator of Th2 immunity) as an immunological biomarker of this tolerance response. Time series data for individual animals suggested that macroparasite infections gave rise to increased expression of Gata3, which gave rise to improved body condition and enhanced survival as hosts aged. These findings provide a clear and unexpected insight into tolerance responses (and their life history sequelae) in a natural vertebrate population. The demonstration that such responses (potentially promoting parasite transmission) can move from resistance to tolerance through the course of an individual’s lifetime emphasises the need to incorporate them into our understanding of the dynamics and risk of infection in the natural environment. Moreover, the identification of Gata3 as a marker of tolerance to macroparasites raises important new questions regarding the role of Th2 immunity and the mechanistic nature of the tolerance response itself. A more manipulative, experimental approach is likely to be valuable in elaborating this further

Orthotic management of instability of the knee related to neuromuscular and central nervous system disorders : qualitative interview study of patient perspectives

OBJECTIVES: Adults with knee instability related to neuromuscular disorders or central nervous conditions often experience mobility problems and rely on orthoses to improve function and mobility. Patient views of device effectiveness and acceptability are underexplored. Our study aimed to elicit device users' perspectives regarding fitting, acceptability, effectiveness and use of orthoses, and identify important treatment outcomes. DESIGN: Qualitative descriptive study using in-depth semistructured interviews. Interview transcriptions were coded and thematically analysed, using 'Framework'. SETTING AND PARTICIPANTS: A purposive sample of 24 adult users of orthotic devices. Nineteen patients were recruited across three National Health Service sites, and five people through charities/patient support groups in England. Half of the participants had been diagnosed with poliomyelitis, and the remainder with multiple sclerosis, Charcot-Marie-Tooth disease, spinal injury or spina bifida, and stroke. The median age of participants was 64.5 years (range 36-80 years). RESULTS: Patients' medical condition impacted significantly on daily life. Participants relied on orthotic devices to enable engagement in daily activities. Patient goals for mobility were linked to individual circumstances. Desired treatment outcomes included reduction in pain, trips and falls, with improved balance and stability. Effectiveness, reliability, comfort and durability were the most valued features of orthoses and associated with reported use. Obtaining suitable footwear alongside orthotic devices was a significant concern. Time pressures during device fitting were viewed negatively. CONCLUSIONS: Orthotic devices for knee instability play a crucial role in promoting, maintaining and enhancing physical and psychological health and well-being, enabling patients to work, engage in family life and enjoy social activities. Future research should consider how best to measure the impact of orthotic devices on patient quality of life and daily functioning outside the clinic setting, as well as device use and any adverse effects. TRIAL REGISTRATION NUMBER: This qualitative study was retrospectively registered as Current Controlled Trials ISRCTN65240228

Economic analysis of the health impacts of housing improvement studies: a systematic review

Background: Economic evaluation of public policies has been advocated but rarely performed. Studies from a systematic review of the health impacts of housing improvement included data on costs and some economic analysis. Examination of these data provides an opportunity to explore the difficulties and the potential for economic evaluation of housing. Methods: Data were extracted from all studies included in the systematic review of housing improvement which had reported costs and economic analysis (n=29/45). The reported data were assessed for their suitability to economic evaluation. Where an economic analysis was reported the analysis was described according to pre-set definitions of various types of economic analysis used in the field of health economics. Results: 25 studies reported cost data on the intervention and/or benefits to the recipients. Of these, 11 studies reported data which was considered amenable to economic evaluation. A further four studies reported conducting an economic evaluation. Three of these studies presented a hybrid ‘balance sheet’ approach and indicated a net economic benefit associated with the intervention. One cost-effectiveness evaluation was identified but the data were unclearly reported; the cost-effectiveness plane suggested that the intervention was more costly and less effective than the status quo. Conclusions: Future studies planning an economic evaluation need to (i) make best use of available data and (ii) ensure that all relevant data are collected. To facilitate this, economic evaluations should be planned alongside the intervention with input from health economists from the outset of the study. When undertaken appropriately, economic evaluation provides the potential to make significant contributions to housing policy

Compensatory mutations reducing the fitness cost of plasmid carriage occur in plant rhizosphere communities

Plasmids drive bacterial evolutionary innovation by transferring ecologically important functions between lineages, but acquiring a plasmid often comes at a fitness cost to the host cell. Compensatory mutations, which ameliorate the cost of plasmid carriage, promote plasmid maintenance in simplified laboratory media across diverse plasmid-host associations. Whether such compensatory evolution can occur in more complex communities inhabiting natural environmental niches where evolutionary paths may be more constrained is, however, unclear. Here, we show a substantial fitness cost of carrying the large conjugative plasmid pQBR103 in Pseudomonas fluorescens SBW25 in the plant rhizosphere. This plasmid fitness cost could be ameliorated by compensatory mutations affecting the chromosomal global regulatory system gacA/gacS, which arose rapidly in plant rhizosphere communities and were exclusive to plasmid carriers. These findings expand our understanding of the importance of compensatory evolution in plasmid dynamics beyond simplified lab media. Compensatory mutations contribute to plasmid survival in bacterial populations living within complex microbial communities in their environmental niche