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The acceptability and feasibility of a guide for sharing the outcome of a memory assessment
Full text linkHow outcomes of assessments for dementia are communicated is a challenging task to navigate for clinicians, patients, and their companions. Miscommunication can result in negative consequences for health-related outcomes including reduced self-esteem and loss of meaningful roles. Interventions to support communication specific to the diagnosis of dementia are required. A prototype intervention has been developed aiming to promote good practice in Memory Assessment Services. This mixed methods project assessed the acceptability and feasibility of a trial to evaluate effectiveness of the intervention. Framework analysis was used following interviews with five clinicians to produce themes relating to the constructs identified in the Theoretical Framework of Acceptability (affective attitude, burden, ethicality, intervention coherence, opportunity costs, perceived effectiveness, self-efficacy). Clinicians reported good acceptability of the intervention and willingness to adopt the intervention into their practice. The recruitment strategy was not feasible for patients and companions and therefore acceptability of the intervention was not assessed from their perspective. Explanations for poor recruitment are explored. An alternative study design to investigate the effectiveness of the intervention is required
The effects of weaning related stress on the emotional health of horses
Full text linkDomestic weaning processes have the potential to cause intense distress in both mares and foals particularly when the mare and foal are separated abruptly and isolated in a confined space. This distress can create patterns of
emotional dysregulation that could have long-term welfare implications. In wild and semi-feral herds, the physical separation of foals from their mothers does not usually occur until they reach sexual maturity at 2-3 years old and go off to form their own herds. Physically separating foals from their mothers at 6 months old in domestic circumstances can cause a range of stress related behaviours such as stereotypies and increased vocalization and defecation during the weaning process. However, progressive separation, where mares and foals spend a brief time away from each other daily, can not only reduced the intense distress experienced by abrupt forms of separation but the health of the mares has shown to improve where progressive weaning separation appears to reduce the likelihood of mastitis. The aim of this thesis was to establish evidence to develop an equine weaning welfare assessment tool.
A narrative literature review was used to capture the background and current understanding of weaning and to establish what was being used for welfare assessment in weaning related research. The first phase literature review identified a lack of use of welfare assessment tools in equine weaning research. The most common assessment tool used in equine behaviour research is an ethogram used largely to assess pain in ridden horses.
A scoping review was conducted to identify and collate the available evidence on the long-term effects and methods of weaning. Systematic searches were conducted in three scientific databases. 366 publications were identified; 22 were retained for inclusion and charting. 18 studies reported behavioural measures, four only reported physiological measures and 12/22 studies used
a combination of both. 15 studies analysed foal behaviour only (15/22), six analysed foals with their dams and one analysed the mare only. Duration of most studies (19/22) was a maximum of 12 months post weaning; three studies continued measurements until the foal age was 3-4 years old.
Finally focus groups were conducted with professionals working in rescue organisations, managing mare/foal populations. This enabled the gathering of first-hand experience and insights from focus group participants. One organisation was into the second year of assessing welfare in relation to a new and progressive form of weaning separation. They had noticed more positive outcomes than the previous forms of abrupt and isolating separation that they had used in the past. Not only was there a reduction of acute and intense distress, but there was also a reduction in mastitis in the mares that had saved the charity money on medications. The organisations consistently reported that they weren’t using official welfare assessment tools however and were relying on caregiver observation of perceived positive or negative emotional states.
This combined approach to gathering data has highlighted that there is a gap for future research to create a welfare assessment tool specifically for weaning that could be used ongoingly throughout the horse’s lifetime. The experience of industry professionals involved in the weaning of mares and foals agrees with the research that abrupt and isolating forms of weaning separation are likely to cause the most intense distress and therefore present a potential welfare issue
Antibiotic resistance in Escherichia coli isolated from United Kingdom dairy cow faeces
Full text linkAntimicrobials are essential tools in modern human and veterinary medicine, but antimicrobial resistance (AMR) is reducing their effectiveness. The global AMR objective of increased stewardship to achieve sustainable antimicrobial use (AMU) has been a priority for many years, with increased attention after 2015. This approach has significantly reduced AMU overall in some key areas. However, the impact of reduced AMU on the risk of AMR needs to be better understood through surveillance of AMU and AMR. This thesis directly contributes to this global objective, making it a crucial part of the ongoing fight against AMR. Specific challenges in the dairy industry have resulted in significant AMU and AMR data gaps. Is the available data sufficient to understand the current risk of resistance, gauge the success of current approaches and inform future decision-making? This work presents a baseline for the antibiotic susceptibility of bovine faecal Escherichia coli (E. coli) from dairy cows on a single farm in the United Kingdom (UK); it also investigates the impact of chemotherapeutic treatment given to cows and the physiological development of cows. Over three years, 38 convenience faecal samples were collected from different bovines across several developmental stages from a single farm. E. coli was selected as the model organism for faecal bacteria as E. coli are well-characterised commensal bacteria and opportunistic pathogens in humans and bovines. A combined approach of direct culture on selective media and antibiotic susceptibility testing of faecal E. coli (the current gold standard) with next-generation short-read sequencing, shotgun metagenomics, and in silico phenotype prediction was used. The total outputs of this combined approach were the isolation of over 800 bovine faecal E. coli with antibiograms to six classes of antibiotics, the identification of three transmissible MDR phenotypes, 160 bovine faecal E. coli whole genomes, and 20 bovine faecal metagenomes. Resistance to several important antibiotics and the associated antibiotic resistance genes have been identified. The genetic diversity of these E. coli and the diversity of the faecal metagenomes from which they were isolated were also investigated. This thesis demonstrates that chemotherapy increases the proportion of antibiotic resistant E. coli in faeces and that this proportion decreases as time after treatment increases. The antibiotic susceptibility phenotypes of the E. coli from all of the adult animals were similar. However, a higher level of antibiotic resistance was identified in the E. coli sourced from dairy calves. The differences in the faecal metagenomes of these developmental groups provide a possible explanation for these differences in E. coli antibiotic susceptibility. Differences in animal physiology and diet affect the faecal metagenome, affecting the microbiome composition. The findings of this thesis contribute evidence for the data gaps around AMR in the UK dairy industry and inform discussions around antimicrobial stewardship, dairy cow faecal microbiomes, and the need for biosecurity measures focusing on calf health as a priority. In conclusion, this thesis represents a significant investigation of antibiotic resistance in E. coli isolated from UK dairy cow faeces
Understanding the role of serum albumin on the regulation of drug uptake transporters in the liver
No full textIntegrative omics approaches for understanding the molecular pathogenesis of dementia with Lewy bodies
No full textThe role of serum inflammatory modulators and the gut microbiome in musculoskeletal trauma
No full textIntroduction
Trauma is one of the leading causes of death in the world, the underlying inflammatory response and biological response to trauma is through to be related to the inflammatory cascade and is regularly monitored clinically in the form of physiological signs and symptoms. Surgery for traumatic injuries is common and there is emerging evidence that the gut microbiome has a part to play in the outcomes associated with traumatic injury. This thesis aims to understand the physiology behind trauma in the context of high-energy rib fracture patients and utilises the inflammatory cytokines, bioactive lipids and endocannabinoids within serum as biomarkers to predict disease and pain.
Methods
Patients were recruited from three cohorts, low-energy frail trauma, high-energy chest trauma and healthy control as comparison groups. Serum and faecal samples were taken for analysis of cytokine, bioactive lipids, endocannabinoid and gut microbiome. Comparison was performed between cohorts with baseline expressions adjusted for age, sex and BMI. For the high-energy cohort comparison was also made with paired testing pre and post-surgery and over time. Gut microbiome diversity analysis was performed utilising alpha and beta diversity metrics.
Results
Patients that have undergone trauma have a higher expression of inflammatory cytokines including IL-6, IL-17a and IL-10, decreased expression of osteoclastic associated modulators including RANKL, CCL3 and CXCL. Immune modulators that change with surgery and time include wound healing mediators CCL4 and IL-22RA, bone metabolism mediators OPG and OSM and inflammatory regulators from the IL-10 superfamily and IFN-γ. Bioactive lipids including16-HETE, 5-HETE, 9-HODE, and 9-oxoODE had lower expression in trauma patients, indicating alterations in inflammation regulation and oxidative stress pathways. Bioactive lipids including 16-HETE, DHA and EPA are predictive of analgesic requirements. Over time, resolvins that are associated with healing are up regulated in surgical patients. Gut diversity indices including richness were less diverse in trauma patients compared with control, with reduced species diversity and less unique species in trauma microbiomes.
Conclusions
Inflammatory mediators are present in abundance in traumatised patients. There is a unique profile for trauma population and changes are seen with surgery and over time. These modulators are associated with clinical parameters relating to pain and are predictive of trauma. The study reveals some of the roles of the inflammasome and it’s associations with the gut microbiome within musculoskeletal trauma
Does measuring quality of delivery for a parent led intervention to treat ADHD in children explain individual variation in outcome?
Full text linkIntroduction: Parent led interventions (PLI) to treat Attention Deficit/Hyperactivity Disorder in children were not found to be effective for ADHD symptoms from non-blinded reports compared with controls. In addition apart from baseline child symptom severity, no factors consistently explained for whom these interventions are effective and why. One reason for individual variation in outcome could be quality of delivery measured in real time. This study developed and applied a bespoke measure of “quality of delivery” to explore this. It was applied to all subjects of the New Forest Parenting Programme arm of the Comparison of Preschool Parenting Interventions (COPPI) trial (n=133).
Structure: Initially this thesis explored the current evidence base behind ADHD associative factors and causality (Chapter One). The role of parenting behaviours and other environmental factors are presented in the context of being protective or further exacerbating baseline ADHD genetic risk. Chapter Two systematically explores the role of attendance measures in explaining individual variation in the effectiveness of parent led interventions to treat ADHD. How the theory form Chapter One is incorporated into the change content and methods behind the intervention applied in the COPPI trial is the focus of Chapter Three with Chapter Four being the methodology behind the current thesis.
Method: The experiential aim of this thesis was whether measuring quality of delivery of a parent led intervention explained individual variation in child behavioural outcomes in this sample. This was a longitudinal, observational study focussing only on trial cases with quantity of delivery (7 sessions or more). The quality measure included 10 targets-for-change with 3 “mentioning” and 4 “exploring” levels. Baseline exploratory-data-analysis identified variables to include in both the quantity (n=133) and quality (n=47) analyses. Outcomes were change scores for ADHD/ODD behaviours for immediate (12-weeks) and extended (6-months) follow-up. Main analysis was full regression including significant baseline variables, quantity and quality of delivery for change scores. Ethics approval was obtained.
Results: (Chapter 5) Exploratory data analysis of the NFPP COPPI arm (n=133) and included thesis individuals (n=47) identified the following baseline factors for inclusion; parent education levels, baseline child ADHD/ODD severity, parental age and weekly disposable and parental ADHD. In the regression for baseline variables vs outcomes only, baseline child symptom and quantity independently predicted outcome (n=133). Once quality was added (n=47), only child baseline severity remained significant. Total quality of delivery did not independently predict any outcome (although for two sub-scales there were some promising findings).
Conclusion: From the ADHD theory-base, empirical findings and surface validity of the New Forest Parenting Programme, one would think a quality of delivery measure applied to delivery videos may have shown significant results. However this study did not add additional understanding around for whom PLI interventions are likely to be effective for child ADHD/ODD and why. It did show some factors associated with attendance and quality of delivery. Also quantity/attendance predicted outcome in this study. This highlights the importance of continuing to measure and present these factors in future trials of this type. Better contemporaneous documentation of quality of delivery should be aimed for in future studies of this type along with focusing on prioritization and delivery optimization of programme components (see discussion; Chapter Six)
Alternative DNA Repair During Meiosis in the Budding Yeast S. cerevisiae
Full text linkIn order for meiosis to occur, DNA double-strand breaks (DSBs) must be induced and subsequently repaired in a homology directed manner; this process is called meiotic recombination. As unrepaired DSBs can have catastrophic consequences for cells, meiotic recombination must be tightly regulated. Despite being studied for decades, new evidence suggests that novel repair pathways and mechanisms are at play during meiosis. By using the budding yeast S. cerevisiae, two alternative DSB repair mechanisms were investigated to readdress our understanding of meiotic DSB processing. The first involves an uncharacterised way of removing the DSB-inducing enzyme Spo11 from DNA. The second seeks to understand which DSB repair pathway is leading to gross chromosomal rearrangements during meiosis.
Meiotic DSBs are initiated by Spo11, which cuts DNA but remains covalently attached. The Spo11 ‘roadblock’ must be removed from the DNA for meiosis to progress. This action is undertaken nucleolytically by the MRX complex, which cleaves the DNA which the Spo11 is bound to (Neale et al., 2005). Whilst this method of Spo11 release via MRX-induced cleavage has long been demonstrated, an alternative mechanism has been overlooked. A recent study showed that when the MRX complex is compromised, recombinant DNA products can be produced (Yun and Kim, 2019), indicating that the Spo11 has somehow been removed independently of the MRX complex. We hypothesised that Spo11 is being removed from DNA by the phosphodiesterase Tdp1, which is upregulated in meiotic prophase (Kugou et al., 2007) and has been shown to remove similar protein adducts from DNA (Nitiss et al., 2006). By investigating this mechanism through fluorescent reporter strains, western blotting, PFGEs and Southern blotting, it was determined that Tdp1 isn’t responsible for the alternative Spo11 removal mechanism.
The second part of this project seeks to define a homology-directed annealing pathway which is utilised to repair meiotic DSBs. This pathway is repairing DNA at non-allelic loci, a process referred to as ectopic recombination, which can generate gross chromosomal rearrangements (Grushcow et al., 1999). Ectopic recombination occurs around 1 % of the
time during meiosis in wildtype S. cerevisiae and is upregulated in strains lacking the checkpoint protein Rad24 (Grushcow et al., 1999, Shinohara and Shinohara, 2013). It was recently shown that whilst short regions of homology are utilised, this pathway is independent of the RecA recombinase homologs Rad51 and Dmc1 (Allison et al., 2023), indicating a pathway which doesn’t utilise strand-invasion. The single strand annealing pathway (SSA) utilises Rad52-Rad59 to anneal ssDNA together with 60-200 bp of homology, with the nuclease complex Rad1-Rad10 required to trim non-homologous trails (Sugawara et al., 2000, Fishman-Lobell et al., 1992). This study shows that the SSA proteins Rad1, Rad10, Rad52, and Rad59 are all present during meiosis in wildtype and rad24Δ backgrounds, and that Rad59 is more abundant in a rad24Δ background when compared to wildtyp
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