Dendritic cell development in haematological malignancies and neoplasia

Phd ThesisDendritic cells (DC) play a major role in the detection of antigens, initiation of immunity and induction and regulation of tolerance. DCs are Bone Marrow (BM) derived and their development may be influenced by haematological malignancy in several ways. Firstly, myelodysplastic, myeloproliferative or leukaemic transformation of bone marrow progenitors may involve DC precursors directly, when they become part of a malignant clone, or indirectly when neoplastic expansion of other lineages compromises the development of DCs. Secondly, neoplasia of the dendritic cell lineage itself may occur in a heterogeneous group of histiocytic disorders including Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECD). The first part of this thesis concerns the effect of haematological malignancies on the generation of DCs; in particular the relationship between DC, monocyte, B and NK lymphoid cell (DCML) deficiency, caused by GATA2 gene mutations, sporadic myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Comprehensive flow cytometric methods for profiling of the DCs and monocytes in the peripheral blood (PB) and peripheral tissues, and the CD34+ progenitors of the BM have been developed. Using these methods, it was possible to see that patients with the three diseases differed on several grounds. DCML deficiencies associated with a younger age of presentation, better preserved haemoglobin, neutrophils and platelets and much more severe defects of DCs, monocytes, and lymphoid cells. In patients with MDS, deficiencies are more moderate and mononuclear cell generation in AML patients is surprisingly preserved. Serum levels of Fms-like tyrosine kinase 3 ligand (FLT3L) also differed, with massively increased levels in DCML deficiency, stable levels in MDS and deficiencies in AML. Finally, strategies of grouping of AML patients have proven to be possible by using progenitor cell or DC related phenotypic markers which may correlate to known cytogenetic abnormalities. The second part of this thesis explores the origin of the cells of LCH and ECD, both neoplasia involving DC-like cells. RT-PCR assays were developed to detect the BRAFV600E mutation, which is present in ~60% of LCH and ECD viii cases. Surprisingly, it was seen that LCH and ECD express BRAFV600E in differing peripheral blood fractions. In LCH, 78-94% of all BRAFV600E alleles were found in HLA-DR+Lineage- cells, localised to the monocytes and CD1c+ myeloid DCs (mDCs). However in ECD, 80-82% of mutated alleles were recovered from the HLA-DR-Lineage- quadrant, localised to CD33+ early myeloid cells, and no mutation was found in the monocytes or mDCs. The final part of the thesis examines whether the circulating cells which carry the BRAFV600E mutation in LCH and ECD can actually develop into LCH-like cells. In order to do this, culture systems were developed with a variety of cytokines and conditions. These experiments showed that CD14+ and CD16+ monocytes and CD1c+ mDCs could all induce the Langerhans Cell (LC) markers CD1a and Langerin in response to GM-CSF, TGFβ and BMP7, however only the CD1c+ mDCs could express Langerin at the high levels seen in LCs, along with EpCam and Birbeck granules. Several techniques have been developed to study DCs in haematological malignancies. Throughout this thesis, these techniques have provided valuable data on the development and homeostasis of human DCs.Tyneside Leukaemia Research Association and the Special Trustees of the Newcastle-upon-Tyne NHS Trust, with additional funding from Bright Red blood cancer charity

The path to transformation, navigating the barriers to forming the transient and the transitional learning groups in interprofessional education

The creation of a new medical school provided new opportunities to develop interprofessional education (IPE) with a pedagogic basis in transformational learning. The programme involved some transient groups – medical students working with different professional groups throughout the year and some learning interventions which proved to be transitional for students in intended and sometimes unintended ways. The path to transformational learning in interprofessional education requires the navigation of different perspectives and beliefs about learning, an element of tenacity and bravery in relation to holding to core pedagogic beliefs and an openness to co-production and evolution of learning elements. Some learning episodes formed a transformative space within a particular time bounded location whilst others led to ongoing relationships and social connections beyond the classroom. Feedback indicated that transformation is not always comfortable or linear for students and the programme identified areas of challenge for both learners and staff as well as opportunities for development and co-creation. This was a large IPE initiative involving staff and students from 9 disciplines across 7 schools and 3 faculties with involvement from service users and stakeholders. The programme incorporated almost 2000 separate student learning episodes. This paper will consider the programme from the perspective of students, creators of the learning elements and participatory staff from different disciplines, exploring the challenges, gains and learning from the initiative. In considering these we suggest that social learning paradigms can help to give insight into their solution. For example, the intended and unintended outcomes could be considered through the perspectives of an integrated social learning paradigm. From the empirical data it is suggested that the paradigms of Activity theory and Complex adaptive systems theory give insight to how intended and unintended transformative learning takes place. These are inter-related as shown in the diagram. Using complex adaptive system theory as part of the activity system theory paradigm, the inter-relationship between the components of the suggested social learning paradigm may be viewed as complex with any one component able to take precedent over the other. It is suggested that the unintended transformative learning and the social connections established outside the classroom arose as a result of the mixed student professionals’ classroom moving through a process of having become a ‘self-organising system’. The students have spontaneously produced a system that could not have been predicted from ‘a knowledge of the previous state’ (i.e. the facilitated teaching session). Analysis of the empirical data through the lens of social learning theories gives insight into the ‘how and why’ transformative learning takes place and might help to plan IPE sessions with greater confidence

Evaluation of a postgraduate examination for primary care: perceptions and performance of general practitioner trainers in the multiple choice paper of the Membership Examination of the Royal College of General Practitioners

This study aimed to investigate the performance of a sample of general practitioner (GP) trainers in the multiple choice paper (MCP) of the Membership Examination of the Royal College of General Practitioners (MRCGP) and to obtain their views of the content of the paper and its relevance to general practice using a written knowledge test and self-administered questionnaire. The participants were volunteer GP trainers in the Northern, Wessex, Kent, Education for Primary Care (2007) 18: 165–72 # 2007 Radcliffe Publishing Limited WHAT IS ALREADY KNOWN IN THIS AREA . Feedback from GP registrar candidates sitting the multiple choice paper (MCP) suggests that the paper has good face and content validity, although pressure of time is a problem. . Candidates find the questions in the paper challenging but most believe they assess common or important problems in general practice. WHAT THIS WORK ADDS . Most trainers in this study believed that the paper assessed knowledge of common or important topics relevant to general practice, that the majority of questions were appropriate, clear and unambiguous and that time pressure was not a problem. . Trainers in this study performed significantly better overall compared to registrars and did so without making prior preparation. SUGGESTIONS FOR FURTHER RESEARCH . Repeating the study with non-trainer GPs could provide further information on the validity of the MCP as an applied knowledge test appropriate for established GPs taking the MRCGP as well as those nearing completion of training Keywords: attitudes, examination, general practice trainers, MRCGP, Surrey and Sussex (KSS) and Northwest deaneries of the UK. The trainers completed a shortened version of an MRCGP MCP paper under examination conditions and provided feedback immediately afterwards. Of 191 trainers invited to participate, 86 (45%) sat the paper and of these, 81 completed the questionnaire. Most trainers believed that the paper assessed knowledge of common or important topics relevant to general practice, that the majority of questions were appropriate, clear and unambiguous and that time pressure was not a problem. Trainers performed significantly better compared to registrars overall, and in questions on medicine related to general practice and practice administration but not research methodology or critical appraisal. They did so without making prior preparation. The findings from this group of trainers lend support to the face validity and content validity of the MRCGP MCP examination as an assessment of applied knowledge of general practice

The Business Models and Economics of Peer-to-Peer lending. ECRI Research Report No 17, May 2016

This paper reviews peer-to-peer (P2P) lending, its development in the UK and other countries, and assesses the business and economic policy issues surrounding this new form of intermediation. P2P platform technology allows direct matching of borrowers’ and lenders’ diversification over a large number of borrowers without the loans having to be held on an intermediary balance sheet. P2P lending has developed rapidly in both the US and the UK, but it still represents a small fraction, less than 1%, of the stock of bank lending. In the UK – but not elsewhere – it is an important source of loans for smaller companies. We argue that P2P lending is fundamentally complementary to, and not competitive with, conventional banking. We therefore expect banks to adapt to the emergence of P2P lending, either by cooperating closely with third-party P2P lending platforms or offering their own proprietary platforms. We also argue that the full development of the sector requires much further work addressing the risks and business and regulatory issues in P2P lending, including risk communication, orderly resolution of platform failure, control of liquidity risks and minimisation of fraud, security and operational risks. This will depend on developing reliable business processes, the promotion to the full extent possible of transparency and standardisation and appropriate regulation that serves the needs of customers

Graded and Filtered Fiber Functors on Tannakian Categories

We study fiber functors on Tannakian categories which are equipped with a grading or a filtration. Our goal is to give a comprehensive set of foundational results about such functors. A main result is that each filtration on a fiber functor can be split by a grading fpqc-locally on the base scheme

The business models and economics of peer-to-peer lending

This paper reviews peer-to-peer (P2P) lending, its development in the UK and other countries, and assesses the business and economic policy issues surrounding this new form of intermediation. P2P platform technology allows direct matching of borrowers’ and lenders’ diversification over a large number of borrowers without the loans having to be held on an intermediary balance sheet. P2P lending has developed rapidly in both the US and the UK, but it still represents a small fraction, less than 1%, of the stock of bank lending. In the UK – but not elsewhere – it is an important source of loans for smaller companies. We argue that P2P lending is fundamentally complementary to, and not competitive with, conventional banking. We therefore expect banks to adapt to the emergence of P2P lending, either by cooperating closely with third-party P2P lending platforms or offering their own proprietary platforms. We also argue that the full development of the sector requires much further work addressing the risks and business and regulatory issues in P2P lending, including risk communication, orderly resolution of platform failure, control of liquidity risks and minimisation of fraud, security and operational risks. This will depend on developing reliable business processes, the promotion to the full extent possible of transparency and standardisation and appropriate regulation that serves the needs of customers

How men and women learn about sex: multi-generational perspectives on insufficient preparedness and prevailing gender norms in Scotland

Attitudes towards sexual health and relationships are learned from a young age, and there is an ongoing need for innovative and comprehensive approaches to sex education that keep pace with rapidly changing contexts of people’s lives. We used thematic analysis of data from two qualitative studies in Scotland to explore learning contexts from a multi-generational perspective, as well as the influence of different socio-cultural factors on provision, access to and experience of sex education. The importance, but inadequacy, of school as a source of learning, was a persistent theme over time. Participants’ strategies to address perceived gaps in knowledge included experience, conversations, vicarious and online learning. Gender and age differences emerged, with younger participants more likely to go online for information, and prevailing gender norms shaping attitudes and behaviours across both study groups. Participants who identified as gay, lesbian or bisexual described feeling particularly unprepared for sex and relationships due to the narrow, heteronormative content received. Although schools continue to be a common source of information, it appears that they fail to equip young people for their post-school sexual life-course. We recommend the mandatory provision of comprehensive, positive, inclusive and skills-based learning to improve people’s chances of forming and building healthy, positive relationships across the lifespan