The role of bacterial interspecies communication in polymicrobial infection of the cystic fibrosis lung

There is an increasing appreciation of the polymicrobial nature of bacterial infections associated with Cystic Fibrosis (CF) and of the important role for interactions in influencing bacterial virulence and response to therapy. Patients with CF are co-infected with Pseudomonas aeruginosa, Burkholderia cenocepacia and Stenotrophomonas maltophilia. These latter bacteria produce signal molecules of the diffusible signal factor (DSF) family, which are cis-2-unsaturated fatty acids. Previous studies showed that DSF from S. maltophilia leads to altered biofilm formation and increased tolerance to antibiotics in P. aeruginosa and that these responses require the P. aeruginosa sensor kinase PA1396. The work in this thesis aims of further elucidate the influence and mechanism of DSF signalling on P. aeruginosa and examine the role that such interspecies signalling play in infection of the CF airway. Next generation sequencing technologies targeting the 16S ribosomal RNA gene were applied to DNA and RNA isolated from sputum taken from cohorts of CF and non-CF subjects to characterise the bacterial community. In parallel, metabolomics analysis of sputum provided insight into the environment of the CF airway. This analysis revealed a number of observations including; that differences in metabolites occur in sputum taken from clinically stable CF patients and those with exacerbation and DNA- and RNA-based methods suggested that a strong relationship existed between the abundance of specific strict anaerobes and fluctuations in the level of metabolites during exacerbation. DSF family signals were also detected in the sputum and a correlation with the presence of DSFproducing organisms was observed. To examine the signal transduction mechanisms used by P. aeruginosa, bioinformatics with site directed mutagenesis were employed to identify signalling partners for PA1396. A pathway suggesting a role for a number of proteins in the regulation of several factors following DSF recognition by PA1396 were observed.

Career choice in medicine

Background: Career Choice in Medicine is an important and problematic topic. Medical education has been framed as professional identity development, yet career choice has not been viewed as a matter of identity. My primary aim was to offer new insights by exploring career choice using Figured Worlds theory, a socio-cultural theory of identity. Graduate retention is a challenge for many countries, including Ireland. My secondary aim was to address a gap in the data on postgraduate trainees in Ireland and to use the Irish case to illustrate points transferable to other contexts. Methodology & Methods: This was a predominantly qualitative Mixed Methods programme of research. My qualitative studies were oriented towards social constructionism. I collated existing data from the Royal College of Physicians of Ireland (RCPI) and HSE-MET to describe trainees and their career paths. I surveyed Basic Specialist Training trainees (n=333) about their career plans. I surveyed new trainees (n=527) about their expectations of training and all RCPI trainees about their experiences of training (n=1246). I conducted semi-structured interviews with 18 medical students and doctors. A subgroup (n=6) provided longitudinal data. Figured Worlds theory and Gee’s discourse tools were used for analysis. Results: I have used the case of medical training and career choice in Ireland to explain how social, political and cultural context, and day to day experiences in the cultural world of medicine, shaped doctors’ career choices. My qualitative findings described a unifying model of career choice, consisting of priming, exposure, positioning and open-endedness, which can guide the design of interventions to shape and support career choice. Conclusion: My original contribution has been to demonstrate the fruitfulness of framing career choice in terms of identity development. This represents a turn in the conversation about career choice, which brings new starting points and moves the dialogue forward.

A medical study on wireless inertial measurement technology as a tool for identifying patients at risk of death or imminent clinical deterioration

This paper provides a system description and preliminary results for an ongoing clinical study currently being carried out at the Mid-Western Regional Hospital, Nenagh, Ireland. The goal of the trial is to determine if wireless inertial measurement technology can be employed to identify elderly patients at risk of death or imminent clinical deterioration. The system measures cumulative movement and provides a score that will help provide a robust early warning to clinical staff of clinical deterioration. In addition the study examines some of the logistical barriers to the adoption of wearable wireless technology in front-line medical care.

Broadening public input into science policy decision making: can the democratic model for science communication influence scientific, innovation and technological trajectories?

This PhD thesis investigates the potential use of science communication models to engage a broader swathe of actors in decision making in relation to scientific and technological innovation in order to address possible democratic deficits in science and technology policy-making. A four-pronged research approach has been employed to examine different representations of the public(s) and different modes of engagement. The first case study investigates whether patient-groups could represent an alternative needs-driven approach to biomedical and health sciences R & D. This is followed by enquiry into the potential for Science Shops to represent a bottom-up approach to promote research and development of local relevance. The barriers and opportunities for the involvement of scientific researchers in science communication are next investigated via a national survey which is comparable to a similar survey conducted in the UK. The final case study investigates to what extent opposition or support regarding nanotechnology (as an emerging technology) is reflected amongst the YouTube user community and the findings are considered in the context of how support or opposition to new or emerging technologies can be addressed using conflict resolution based approaches to manage potential conflict trajectories. The research indicates that the majority of communication exercises of relevance to science policy and planning take the form of a one-way flow of information with little or no facility for public feedback. This thesis proposes that a more bottom-up approach to research and technology would help broaden acceptability and accountability for decisions made relating to new or existing technological trajectories. This approach could be better integrated with and complementary to government, institutional, e.g. university, and research funding agencies activities and help ensure that public needs and issues are better addressed directly by the research community. Such approaches could also facilitate empowerment of societal stakeholders regarding scientific literacy and agenda-setting. One-way information relays could be adapted to facilitate feedback from representative groups e.g. Non-governmental organisations or Civil Society Organisations (such as patient groups) in order to enhance the functioning and socio-economic relevance of knowledge-based societies to the betterment of human livelihoods.

Towards a cognitive neurobiology of brain-gut axis disorders

The past two decades have seen substantial gains in our understanding of the complex processes underlying disturbed brain-gut communication in disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Despite a growing understanding of the neurobiology of brain-gut axis dysfunction, there is a relative paucity of investigations into how the various factors involved in dysregulating the brain-gut axis, including stress, immune activation and pain, could impact on fundamental brain processes such as cognitive performance. To this end, we proposed a cognitive neurobiology of brain-gut axis dysfunction and took a novel approach to examine how disturbed brain-gut interactions may manifest as altered cognitive performance in IBS and IBD, both cross-sectionally and prospectively. We have demonstrated that, disorders of the brain-gut axis are characterised by stable deficits in specific cognitive domains. Specifically, patients with IBS exhibit a consistent hippocampal mediated visuospatial memory impairment. In addition we have found evidence to suggest a similar visuospatial impairment in IBD. However, our most consistent finding within this population was that patients with Crohn’s disease exhibit impaired selective attention/ response inhibition on the classic Stroop interference test. These cognitive deficits may serve to perpetuate and sustain brain-gut axis dysfunction. Furthermore, this research has shed light on some of the underlying neurobiological mechanisms that may be mediating cognitive dysfunction in IBS. Our findings may have significant implications for the individual who suffers from a brain-gut axis disorder and may also inform future treatment strategies. Taken together, these findings can be incorporated into existing neurobiological models of brain-gut axis dysfunction, to develop a more comprehensive model accounting for the cognitive-neurobiology of brain-gut axis disorders. This has furthered our understanding of disease pathophysiology and may ultimately aid in both the diagnosis and treatment of these highly prevalent, but poorly understood disorders.