College of Medicine and Health - Doctoral Theses

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    Real-time surveillance for evidence-based responses to suicide contagion and clustering
    (University College Cork, 2022-04-01) Benson, Ruth; Arensman, Ella; Rigby, Jan; Brunsdon, Chris; Health Research Board
    Background: Although a rare phenomenon, suicide clusters are a cause for great community concern. In recent years, strong emphasis has been placed on the importance of detection and real-time surveillance of suicide clusters. Cluster detection increases understanding on the aetiology of a suicide cluster and provides the basis for targeted intervention to mitigate further contagion through the identification of linked cases and socioecological factors associated with the increased risk of clustering in the affected area or population. Policy makers and public health officials benefit from detection of suicide clusters by means of implementing targeted evidence-based interventions in identified vulnerable populations and high-risk areas in a timely manner. To date, suicide cluster detection has been largely restricted to retrospective investigations, limiting its capacity as a tool for intervention. Aim: The aim of this research was to provide a comprehensive understanding of the real-time surveillance, detection, and responses to suicide contagion and clustering. Methods: The thesis is comprised of five interrelated studies, based on both primary and secondary research. Primary data collection was conducted on coronial records of post-inquest cases of confirmed suicide or open verdicts meeting the criteria for probably suicide, as well as pre-inquest cases of suspected suicide. This research also involved quantitative Census data from the Central Statistics Office (CSO). The retrospective and prospective space-time scan statistics based on a discrete Poisson model was employed via the R software environment using the ‘rsatscan’ and ‘shiny’ packages to conduct the space-time cluster analysis and deliver the mapping and graphic components of the dashboard interface in study 3. Evidence synthesis was conducted by means of narrative review of existing literature in studies 1 and 4, and by comparative review of response to a structured questionnaire in study 2. Study 5 employs a secondary research approach to report on policy and practice implications of real-time suicide surveillance. Results: Study 1 synthesised the existing evidence on quantitative techniques to detect suicide and self-harm clusters detection, revealing that a Poisson-based scan statistical model is most effective in accurately detecting point and echo suicide clusters, while mass clusters are typically detected by a time-series regression model, albeit that limitations exist. Study 2 demonstrated more commonalities than differences in a comparison of the components and practices of real-time suicide surveillance systems internationally. Commonalities included rapid, routine surveillance based on minimal, provisional data to facilitate timely intervention and postvention efforts. Identified differences include timeliness of case submission and system infrastructure. Study 3 tested the validity of the scan statistic as a cluster detection approach inbuilt in a dashboard prototype developed to visually display real-time suicide surveillance data. Study 4 identified consistency in both increased quantity of media reports and portrayal of specific details of suicide cases to be significantly associated with suicide contagion and increased suicide rates or mass clusters. An elevated period of risk of suicide contagion has been found to take place between the first days up to the first three months following the media coverage of suicide. Study 5 demonstrated the importance of real-time suicide surveillance in the context of policy and practice, with a particular reference to public health emergencies and humanitarian crises. Conclusions: The findings of this thesis are of relevance in furthering our knowledge of monitoring, detecting, and responding to suicide clusters. Collectively, the findings from this thesis indicate that we can work more efficiently and collectively to mitigate further suicidal behaviour by utilising real-time, provisional suicide data to guide quicker action. The outcomes of this research have methodological implications in terms of suicide and self-harm cluster detection and real-time suicide surveillance. The implications of this research further extend to suicide prevention and mental health policy, clinical practice, means restriction, crisis planning and response, and media reporting of suicide.
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    Characterisation of the effect of electroporation and electrochemotherapy on cancer cells and immune cells in the tumour microenvironment
    (University College Cork, 2022-10) Bendix, Maura; Brint, Elizabeth K.; Houston, Aileen M.; Amu, Sylvie; Forde, Patrick; Health Research Board; Breakthrough Cancer Research
    Lung cancer is the leading cause of cancer-related death worldwide, with the lung cancer incidence rate expected to rise further. Despite recently developed novel therapy options, 5-year survival rates for lung cancer patients remains below 20% generally and below 5% for late-stage diagnosis, thus additional therapy options are still needed. Electrochemotherapy (ECT), the application of an electric pulse to deliver chemotherapy drugs into cells, could be a new treatment option for lung cancer patients. ECT is a locally very effective treatment, with local tumour reduction of up to 85%, while the systemic effects are more varied. For clinical application ECT treatment modalities have been standardized since 2006, after the ESOPE study, which optimized ECT parameters to 8 pulses at 1000V/cm with 100µs pulse length at 1Hz frequency and either bleomycin or cisplatin as the drug of choice. To evaluate whether ECT could be a potential treatment option for lung cancer patients’ ECT parameters, the needed electric field strength and the needed drug and drug concentration, were optimized for in vitro lung cancer research. In our study, we initially developed a standard operating protocol (SOP) to determine the optimal electric field strength for a given cancer cell line in vitro, while keeping the other ESOPE parameters constant. The developed SOP combined short-, medium-, and long-term assays to fully visualize the impact treatment, at a given field strength, has on the tested cancer cell line. This evaluation showed that human lung cancer cell lines (A549, H460 and SK-MES 1) and the human pancreatic Pan02 cell line have an optimal electric field strength of 800V/cm, the melanoma A375 (human) and B16F10 (murine) cell lines as well as the murine pancreatic Mia-PACA2 cell line have an optimal electric field strength of 700V/cm, while the murine Lewis Lung carcinoma (LLC) cell line has an optimal electric field strength of 1300V/cm. In addition, our study findings demonstrate that cisplatin at 11µM would be the drug of choice when using ECT for lung cancer treatments. In recent years while the importance of the immune system in lung cancer development and treatment results has become increasingly clear, little is known about how ECT treatments impact immune cells. Therefore, the impact of ECT on murine T cells, dendritic cells (DCs) and macrophages was evaluated in vitro. Our data indicates that while T cells are able to tolerate electric field strengths of up to 1400V/cm, DCs and macrophages are significantly negatively impacted by electric field strengths exceeding 800V/cm. Further investigation on the impact of ECT on dendritic cells demonstrated that DCs die via necrosis following ECT treatment, while ECT at electric field strength exceeding 1000V/cm leads to DC maturation and activation of the surviving cells. In addition, DCs remain partially functional following ECT treatment in a stimuli and treatment dependent manner with distinctively different sets of genes upregulated 4-hours post treatment at 800V/cm compared to treatment at 1000V/cm and 1300V/cm. Taken together, our data indicates that it is worthwhile to further investigate ECT as a potential therapy option for lung cancer patients, while more attention needs to be paid to the impact ECT has on immune cells in order to maximize treatment results.
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    Multi-modal assessment of newborns at risk of neonatal hypoxic ischaemic encephalopathy – the MONItOr study
    (University College Cork, 2022) Garvey, Aisling A.; Dempsey, Eugene M.; Murray, Deirdre M.; Boylan, Geraldine B.; National Children’s Research Centre, Crumlin, Ireland
    Background: Hypoxic ischaemic encephalopathy (HIE) is the leading cause of acquired brain injury in term infants. At present, therapeutic hypothermia (TH) is the only approved therapy for infants with moderate-severe HIE. However, it must be commenced before 6 hours of age resulting in a clinical challenge to resuscitate, stabilize, identify and stratify infants in this narrow timeframe. Furthermore, a significant proportion of infants with mild HIE will have neurodevelopmental impairment. Improved, timely identification of infants at risk of brain injury is required. The aim of this study was to improve our knowledge of the early physiology of infants with HIE by describing the evolution of electroencephalography (EEG), near-infrared spectroscopy (NIRS) and non-invasive cardiac output monitoring (NICOM) in infants with all grades of HIE and to determine whether these markers may be helpful in the identification of infants at risk of brain injury. Methods: This prospective observational study was set in a tertiary neonatal unit (November 2017-March 2020). Infants with all grades of HIE had multi-modal monitoring, including EEG, NIRS and NICOM, commenced after delivery and continued for up to 84 hours. All infants had an MRI performed in the first week of life. Healthy term controls were recruited after delivery and had NICOM monitoring at 6 and 24 hours of age. In this thesis, I also included infants recruited previously as part of four historic prospective cohorts that had early EEG monitoring. These infants were combined with infants with mild HIE from the current prospective cohort to examine the difference in EEG features between infants with mild HIE and healthy term controls. Results: Eighty-two infants were recruited in the prospective cohort (30 mild HIE, 25 moderate, 6 severe, 21 controls) and 60 infants were included from the historic cohorts. This study identified significant differences between EEG features of infants with mild HIE and controls in the first 6 hours after birth. Seventy-two percent of infants with mild HIE had some abnormal features on their continuous EEG and quantitative analysis revealed significant differences in spectral shape between the groups. In our cohort, cSO2 increased and FTOE decreased over the first 24 hours in all grades of HIE regardless of TH status. Compared to the moderate group, infants with mild HIE had significantly higher cSO2 at 6 hours (p=0.003), 9 hours (p=0.009) and 12 hours (p=0.032) and lower FTOE at 6 hours (p=0.016) and 9 hours (0.029). Beyond 18 hours, no differences were seen between the groups. NICOM was assessed in infants with HIE and compared with controls. Infants with mild HIE have a significantly higher heart rate at 6 hours of age compared with controls (p=0.034). Infants with moderate HIE undergoing TH have a significantly lower cardiac output compared with mild HIE (p=0.046) and control groups (p=0.040). Heart rate is significantly reduced (p<0.001) but stroke volume is maintained and gradually increases from 6-72 hours despite TH. Finally, we assessed the ability of EEG, NIRS and NICOM to predict short-term outcome (abnormal MRI +/- death in the first week of life). At 6 hours, none of the EEG, NIRS or NICOM measures predicted short-term outcome. At 12 hours of age, both qualitative and quantitative EEG features significantly predicted abnormal short-term outcome. Conclusion: Identification of infants at risk of brain injury immediately after birth is challenging. Objective, early biomarkers are required. This is the first study to combine EEG, NIRS and NICOM in infants with all grades of HIE. Multi-modal monitoring is feasible and this thesis provides novel insights into the underlying physiology and evolution of injury in infants with HIE. Furthermore, it reaffirms the importance of early continuous EEG in HIE.
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    Universal design for learning and anatomy healthcare education
    (University College Cork, 2022-10-06) Dempsey, Audrey M. K.; Nolan, Yvonne M.; Hunt, Eithne; Lone, Mutahira
    Inclusive learning environments and educational experiences for all individuals have been identified as priorities in recent educational policies in the Republic of Ireland (ROI) and Northern Ireland (NI). Driven by these policy mandates, curricula across all disciplines, including anatomy education, are undergoing reform to ensure inclusive learning experiences are afforded to all individuals. Anatomy is a critical component of healthcare curricula. Robust knowledge of anatomy ensures the safe and effective practice of healthcare professionals. Motivation and engagement have been found to play an integral role in successful student learning. However, there are reports of a lack of both motivation and engagement among some healthcare students studying anatomy. Hence there is need to incorporate a specific pedagogical framework in anatomy curricula to enhance motivation and engagement among healthcare students and in turn promote an inclusive learning experience. The aim of this thesis was to determine whether Universal Design for Learning (UDL) would be an appropriate pedagogical framework in the design and delivery of anatomy curricula to enhance healthcare students’ motivation and engagement. Firstly, a scoping review, which is a method of mapping emerging literature, was carried out which established that UDL has not been utilised in anatomy curricula of third level healthcare programmes, specifically medicine, dentistry, occupational therapy or speech and language therapy (Chapter Two). While there are published studies incorporating teaching strategies which align with UDL, and have in turn reported benefits to student learning, none of these studies specifically mention the UDL framework. Motivation levels of first year undergraduate healthcare students in University College Cork (UCC) at the start and end of their anatomy modules were established (Chapter 3) using the Motivated Strategies for Learning Questionnaire (MSLQ), and a change in motivation over the duration of the module was identified. First year healthcare students in UCC and anatomy educators based in the ROI and United Kingdom (UK) were surveyed (Chapter Four and Chapter Five, respectively). The first year healthcare students were informed about UDL as they neared the end of an anatomy module. After informed consent was obtained a paper questionnaire was distributed to potential participants. An online questionnaire was distributed to anatomy educators using the online platform Microsoft Forms and was available for 12 weeks. Both studies highlighted that very few anatomy students or educators were aware of UDL. However, the majority of the participants in both studies acknowledged the potential of the UDL framework to enhance the design and delivery of anatomy curricula. The results of this thesis show that the incorporation of UDL into the design and delivery of third level anatomy curricula could potentially enhance student motivation, engagement and their overall educational experience. More specifically, the results from the scoping review (Chapter Two) indicated that teaching methods which align with UDL enhance anatomy students’ academic performance, motivation and confidence. The results described in Chapter Three highlight the range in motivation levels among anatomy students enrolled in various healthcare programmes both at the start of their respective anatomy modules and at the end. The majority of first year anatomy healthcare students thought that UDL benefits student learning (99%, n=186) and that the implementation of UDL increases student engagement (97%, n=183) (Chapter Four). Finally, the results described in Chapter Five revealed that anatomy educators have a mixed opinion of UDL as some participants were concerned about the time commitment required to implement UDL in anatomy curricula design. Nevertheless, the potential benefit of the utilisation of ULD was acknowledged by the majority of the participants. In summary, students vary in their levels of motivation to study anatomy and the manner in which they prefer to engage with learning material, activities and assessments. The utilisation of the UDL pedagogical framework in anatomy curricula can accommodate learner variability and in turn afford all students the opportunity to reach their individual potential while enhancing and promoting an inclusive third level educational experience.
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    A population-based epidemiologic study of adult neuromuscular disease in the Republic of Ireland
    (University College Cork, 2014) Lefter, Stela; Ryan, Aisling; Hardiman, Orla
    This research project generates for the first time prevalence rates (PR) for all adult neuromuscular diseases (NMD) as well as the incidence rates (IR) for Guillain-Barre syndrome (GBS) in the Republic of Ireland (ROI). Multiple case ascertainment sources were used to achieve as complete as possible case ascertainment to accurately estimate the country-wide prevalence. Acquired demyelinating polyneuropathies represented the biggest cohort (26.0%) followed by muscular dystrophies (22.5%) and myasthenia gravis (19.7%). For GBS, in the 20 year period (1992 to 2012), comparable with other international studies, incidence rates of 0.3-1.3 per 100,000 person-years were attained. Higher PR figures for chronic inflammatory demyelinating polyneuropathy and sporadic inclusion body myositis were found (5.87 per 100,000 and 11.7 per 100,000 in those older than 50 year, respectively) compared with previous studies. The PR for myasthenia gravis in ROI is comparable with countries such as Australia, Italy and Norway but is lower than in Northern Ireland. The PR for Charcot-Marie-Tooth disease and limb girdle muscular dystrophies were similar with United Kingdom PR; however, a definite diagnosis was attained in only one third of Irish patients. Given the fact that paediatric cases were excluded from our study, lower PR figures were obtained for dystophinopathies. Interestingly, the PR for myotonic dystrophy type 1 and facioscapulohumeral muscular dystrophy (FSHD) in the ROI was lower than in United Kingdom but not considerably. A high PR for periodic paralysis (PP) was found in our study, nearly ten times higher for Hyper PP and as twice as high for Hypo PP when compared with figures from England; however, the ROI figures were derived from large families suggesting a founder effect. Of all the inherited NMD, 46% of cases had a definite histopathology and/or genetic diagnosis. The combined PR for inherited and acquired NMD was high, 62.6 per 100,000, when compared with other chronic neurological diseases in ROI. During the course of the study, a definite genetic diagnosis was achieved in families with rare previously unreported NMD in ROI, such as Laing distal myopathy, Andersen Tawil syndrome and FSHD2. This research defines the burden of NMD in the ROI, raises awareness of these conditions, will facilitate earlier intervention where appropriate and will provide a strong argument for service provision for these patients. This research project will serve as a useful originator for future research studies, especially with regard to obtaining genetic confirmation of currently undefined cases.