An investigation into attitudes towards illegitimate birth as evidenced in the folklore of South West England

This thesis is a comparative, cross-generic, study of attitudes towards illegitimacy as evidenced in folksong and folk narrative genres. It is a regionally based study, focusing specifically on oral materials collected from the counties of Devon, Cornwall and Somerset, in the South West of England since 1970. Hence archival sources, in addition to my own fieldwork, provide the main sources of folklore data for this project. This is the first thesis to draw extensively upon the large body of material known as the Sam Richards Folklore Archive, which includes over 500 hours of taped recordings. The collecting towards this archive was originally inspired by the prolific work of early folksong collectors Sabine Baring-Gould and Cecil Sharp in the South West region. My work on this project is the first broad-based critical analysis of selected materials from the resulting thirty years' collecting. Representations of out-of-wedlock pregnancy in South West folksong are often extremely diverse. Illegitimacy is commonly fused with other types of theme, including seduction and betrayal. By contrast, a fairly narrow depiction of "illegitimate" pregnancy is given in supernatural legends and memorates, local legends and local character anecdotes, where it is consistently seen as having negative repercussions for the woman and sometimes the child, concerned. An extensive overview of folklore scholarship informs my eclectic approach to this study. In the early chapters of this thesis I delineate my source materials in some detail, also setting out the historical context from which my chosen songs and narratives emerged. In my analysis of these materials in Chapters 6, 7, and 8, I have combined the use of detailed textual analysis with a consideration of the creation of meaning in the interaction between text and performance context

University student attitudes to prosocial bystander behaviours

Purpose: Half of British university students experience assault and harassment behaviours; few report them. Bystander intervention training has been recommended as a means of reducing these behaviours, but there is little evidence about their potential effectiveness in UK contexts. This study sought to understand UK students’ attitudes towards reporting and intervening in sexual assault, harassment, and hate crimes. Design: A mixed methods cross sectional survey (N=201; 75.6% women) was conducted in one British university. Open text data were analysed using thematic analysis. Findings: Students considered harassment and assault unacceptable, and were confident to intervene in and likely to report incidents. However, fear of backlash was a barrier to intervening and reporting, and they felt that victims should decide whether to report incidents. Students perceived perpetrators as being ignorant about what constitutes consent, harassment, and assault. They identified a need for university community education about this and how to report incidents and support peers. Research limitations/implications: This cross sectional survey was conducted at one UK University. The data might not reflect other students’ attitudes, and may be subject to response bias. Practical implications: University community bystander training should be acceptable, report and support systems might be utilised by students. This may have potential to reduce prevalence and increase reporting. Originality: This is the first study to investigate UK student attitudes to prosocial bystander behaviours

Gene expression profiling in NOD mice reveals that B cells are highly educated by the pancreatic environment during autoimmune diabetes

Aims/hypothesis: B cells play an important role in driving the development of type 1 diabetes; however, it remains unclear how they contribute to local beta cell destruction during disease progression. Here, we use gene expression profiling of B cell subsets identified in inflamed pancreatic tissue to explore their primary functional role during the progression of autoimmune diabetes. Methods: Transcriptional profiling was performed on FACS-sorted B cell subsets isolated from pancreatic islets and the pancreatic lymph nodes of NOD mice. Results: B cells are highly modified by the inflamed pancreatic tissue and can be distinguished by their transcriptional profile from those in the lymph nodes. We identified both a discrete and a core shared gene expression profile in islet CD19+CD138– and CD19+CD138+ B cell subsets, the latter of which is known to have enriched autoreactivity during diabetes development. On localisation to pancreatic islets, compared with CD138– B cells, CD138+ B cells overexpress genes associated with adhesion molecules and growth factors. Their shared signature consists of gene expression changes related to the differentiation of antibody-secreting cells and gene regulatory networks associated with IFN signalling pathways, proinflammatory cytokines and Toll-like receptor (TLR) activation. Finally, abundant TLR7 expression was detected in islet B cells and was enhanced specifically in CD138+ B cells. Conclusions/interpretation: Our study provides a detailed transcriptional analysis of islet B cells. Specific gene signatures and interaction networks have been identified that point towards a functional role for B cells in driving autoimmune diabetes. Graphical abstract

University student attitudes to prosocial bystander behaviours

Purpose: Half of British university students experience assault and harassment behaviours; few report them. Bystander intervention training has been recommended as a means of reducing these behaviours, but there is little evidence about their potential effectiveness in UK contexts. This study sought to understand UK students’ attitudes towards reporting and intervening in sexual assault, harassment, and hate crimes. Design: A mixed methods cross sectional survey (N=201; 75.6% women) was conducted in one British university. Open text data were analysed using thematic analysis. Findings: Students considered harassment and assault unacceptable, and were confident to intervene in and likely to report incidents. However, fear of backlash was a barrier to intervening and reporting, and they felt that victims should decide whether to report incidents. Students perceived perpetrators as being ignorant about what constitutes consent, harassment, and assault. They identified a need for university community education about this and how to report incidents and support peers. Research limitations/implications: This cross sectional survey was conducted at one UK University. The data might not reflect other students’ attitudes, and may be subject to response bias. Practical implications: University community bystander training should be acceptable, report and support systems might be utilised by students. This may have potential to reduce prevalence and increase reporting. Originality: This is the first study to investigate UK student attitudes to prosocial bystander behaviours

Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

The challenge of developing effective pharmacodynamic biomarkers for preclinical and clinical testing of FGFR signaling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and provides a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signaling inhibition by AZD4547, a potent inhibitor of FGF receptors 1, 2, and 3, a gene expression profiling study was performed in FGFR2-amplified, drug-sensitive tumor cell lines. Consistent with known signaling pathways activated by FGFR, we identified transcript biomarkers downstream of the RAS-MAPK and PI3K/AKT pathways. Using different tumor cell lines in vitro and xenografts in vivo, we confirmed that some of these transcript biomarkers (DUSP6, ETV5, YPEL2) were modulated downstream of oncogenic FGFR1, 2, 3, whereas others showed selective modulation only by FGFR2 signaling (EGR1). These transcripts showed consistent time-dependent modulation, corresponding to the plasma exposure of AZD4547 and inhibition of phosphorylation of the downstream signaling molecules FRS2 or ERK. Combination of FGFR and AKT inhibition in an FGFR2-mutated endometrial cancer xenograft model enhanced modulation of transcript biomarkers from the PI3K/AKT pathway and tumor growth inhibition. These biomarkers were detected on the clinically validated nanoString platform. Taken together, these data identified novel dynamic transcript biomarkers of FGFR inhibition that were validated in a number of in vivo models, and which are more robustly modulated by FGFR inhibition than some conventional downstream signaling protein biomarkers

Keratinocyte growth factor impairs human thymic recovery from lymphopenia

Background: The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates. Methods: Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signaljoint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30. Findings: At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107 /L vs. 7.733x107 /L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocoldefined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groups Conclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.Trial - MRC and Moulton Trust Funding Me (senior Author) - Wellcome Trust Funding

In Vitro Praziquantel Test Capable of Detecting Reduced In Vivo Efficacy in Schistosoma mansoni Human Infections

Although great reductions in human schistosomiasis have been observed after praziquantel (PZQ) mass drug administration (MDA), some individuals remain infected after multiple treatments. Many MDA programs now require monitoring for drug efficacy as a key component. No molecular tools for PZQ resistance currently exist and investigations into the dose of PZQ required to kill 50% of adult worms in vivo (ED50) present ethical, logistical, and temporal restraints. We, therefore, assessed the feasibility and accuracy of a rapid, inexpensive in vitro PZQ test in the laboratory and directly in the field in Uganda under MDA in conjunction with highly detailed infection intensity, clearance, and reinfection data. This test strongly differentiated between subsequently cleared and uncleared infections as well as differences between parasite populations pre- and post-PZQ treatments, advocating its use for on-the-spot monitoring of PZQ efficacy in natural foci. After only a few treatments, uncleared parasites were identified to be phenotypically different from drug-sensitive parasites, emphasizing the urgent need for monitoring of these repeatedly PZQ-treated populations

Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73.

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression

Paediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study of aseptic meningitis

BACKGROUND: The seasonality, clinical and radiographic features and outcome of aseptic meningitis have been described for regional outbreaks but data from a wider geographic area is necessary to delineate the epidemiology of this condition. METHODS: A retrospective chart review was completed of children presenting with aseptic meningitis to eight Canadian pediatric hospitals over a two-year period. RESULTS: There were 233 cases of proven enteroviral (EV) meningitis, 495 cases of clinical aseptic meningitis and 74 cases of possible aseptic meningitis with most cases occurring July to October. Headache, vomiting, meningismus and photophobia were more common in children ≥ 5 years of age, while rash, diarrhea and cough were more common in children < 5 years of age. Pleocytosis was absent in 22.3% of children < 30 days of age with proven EV meningitis. Enterovirus was isolated in cerebrospinal fluid (CSF) from 154 of 389 patients (39.6%) who had viral culture performed, and a nucleic acid amplification test for enterovirus was positive in CSF from 81 of 149 patients (54.3%). Imaging of the head by computerized tomography or magnetic resonance imaging was completed in 96 cases (19.7%) and 24 had abnormal findings that were possibly related to meningitis while none had changes that were definitely related to meningitis. There was minimal morbidity and there were no deaths. CONCLUSION: The clinical presentation of aseptic meningitis varies with the age of the child. Absence of CSF pleocytosis is common in infants < 30 days of age. Enterovirus is the predominant isolate, but no etiologic agent is identified in the majority of cases of aseptic meningitis in Canadian children