Medicine - Masters by Research Theses

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    Major trauma in older Irish adults
    (University College Cork, 2023) Junker, Kate; Ó Tuathaigh, Colm; Deasy, Conor
    Introduction: The world’s population is rapidly ageing. In Ireland, the population over sixty five years is expected to increase from 629,800 to 1.6 million by 2051. Such changes in demographics pose a challenge for healthcare and all areas of our service must adapt to meet the needs of this cohort. Major trauma is a leading cause of death and disability worldwide. Recent literature has shown that low falls are the biggest contributor to major trauma. Major trauma in older Irish adults is an area about which little research has been done. The primary aim of this study was to determine the prevalence of major trauma in older Irish adults and describe injuries sustained and their management. This study also explores outcomes for older adults who experience major trauma and makes comparison with younger counterparts. Methods: This is a retrospective secondary analysis of data from the Major Trauma Audit (MTA). The MTA prospectively gathers data on patient care and outcomes following trauma from twenty six participating hospitals in Ireland. This study included all patients who presented to a single centre in Ireland with an injury severity score (ISS) indicative of major trauma over five years. Data was divided into the following age groups; 0-24 years, 25-49 years, 50-64 years, 65-74 years, 75-84 years, and 85 years or older. Data was analysed using SPSS version 28. Descriptive statistics were used to define demographics and injury characteristics and chi-square test was used to make comparisons between groups. Univariate and multivariate logistic regression analysis was used to consider factors associated with specific outcomes. A p-value of <0.05 was considered statistically significant. Results: In the five year period studied, 1,123 cases of major trauma were identified in Cork University Hospital. Of these, 659 were aged less than sixty five years and 464 were aged greater than sixty five years meaning that 41.3% were older adults. The majority of older adults presenting with major trauma were male (56%) but the proportion of females presenting increased with age. Low falls were the most common mechanism of injury (74.1%). 80.6% of older adults were alive thirty days post injury and 47.2% had a good recovery. Conclusion: Major trauma in older Irish adults is becoming an important public health issue. Specialist education and training is required to ensure the needs of this cohort are appropriately met. This study highlights the burden of major trauma in older Irish adults.
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    Defining the patient safety trajectory of breast cancer at a National Cancer Centre
    (University College Cork, 2023) Forrest, Clara; Ó Tuathaigh, Colm; Health Service Executive; University College Cork
    Introduction: One in seven Irish women will develop breast cancer in their lifetime. A well-researched management pathway commences thereafter, involving multiple treatment modalities and specialities. In contrast, there is sparse research examining the patient safety trajectory that mirrors this clinical journey. Learnings from previous events can illuminate this otherwise unknown patient safety trajectory of those with breast cancer. Furthermore, there is little known of patients’ and doctors’ views and experiences of this patient safety trajectory. Aims: This study aimed to characterise patient safety incidents that have occurred during breast cancer care, their contributory and preventative factors, outcome and impact. Using this data, patient safety trajectories were created. In addition, this paper aimed to explore the patient safety views and concerns of patients receiving and doctors providing breast cancer care. Methods: Anonymous, quantitative patient and doctor questionnaires were used. In addition, data related to medical negligence claims involving breast cancer and handled by the State Claims Agency was analysed. Pearson chi-squared test and Fisher’s exact test were utilised for categorical data. The median degrees of harm were used to construct trajectories. Results: 83 patient safety incidents were included (61 medical errors and 22 medical negligence claims). Failure or delay to correctly diagnose was the most commonly implicated adverse event type overall (n=32/83, 38.6%) and was involved in a higher proportion of medical negligence claims than medical errors (p=0.01). Forty percent of events occurred in the outpatient department (n=33/83) and 31% of events took place before a patient’s formal breast cancer diagnosis (n=26/83). Inadequate communication was the most common contributory factor. Events during neoadjuvant chemotherapy and after discharge from follow-up had the highest median degree of harm of 4 (Q1-Q3:3.5-4.5 and Q1-Q3:4.0-4.5). More doctors felt patient safety has worsened in the past five years compared to patients (41.4% vs 13.0%) (p<0.001). Twice as many doctors reported that there were inadequate measures in place to prevent medical error compared to patients (54.3% vs 27.2%) (p<0.001). Conclusion: Patient safety incidents during breast cancer care occur in a variety of settings and during all clinical stages but often occur before diagnosis and involve inadequate communication. Doctors who provide breast cancer care have a more pessimistic outlook on patient safety compared to patients and are more concerned about medical error in breast cancer care. Addressing and acting on the experiences and concerns of those involved in breast cancer care is vital to improve patient safety trajectories for breast cancer patients.
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    An investigation on proteolysis of the ACE2 receptor and its involvement in the cellular uptake and transmission of SARS-CoV-2
    (University College Cork, 2021-12-21) Wakerlin, Samantha Leigh; McCarthy, Justin V.; Lindsay, Andrew; Coleman-Vaughan, Caroline
    The renin-angiotensin system (RAS) is a key physiologic signalling network in blood and tissue homeostasis in humans. Angiotensin-converting enzyme 2 (ACE2) is a key regulator of the protective axis in RAS signalling as it antagonises the mechanisms of Angiotensin II (Ang II), the major vasoactive peptide of the RAS that can be dysregulated and overactive in disease states. The type I transmembrane protein can also function as a viral receptor, as ACE2 has recently been identified as the host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ACE2 undergoes ectodomain shedding by ADAM17 and other host cell proteases, resulting in the release of its catalytic ectodomain into the extracellular space and the C-terminal fragment (CTF) secured in the membrane. Ectodomain shedding is a prerequisite for further cleavage by gamma-secretase in a two-step mechanism known as regulated intramembrane proteolysis, a common fate of many known receptors that function as viral targets. Given the structural similarity of ACE2 to other known substrates of gamma-secretase, the hypothesised role of ACE2 as a substrate for the protease was explored. Here, we show that the ACE2 CTF product of ADAM17/TMPRSS2 shedding is subsequently cleaved by the gamma-secretase protease to produce an intracellular domain (ICD) that is released within the cell. Pharmacological inhibition of gamma-secretase prevents generation of the ACE2 ICD and leads to the accumulation of membrane-anchored ACE2 CTF lacking the catalytic ectodomain. These observations demonstrate that ACE2 is a substrate for gamma-secretase proteolysis, providing a novel pathway for cellular trafficking of ACE2 that may have therapeutic potential in protective RAS signalling or antiviral immunity.
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    Single dose challenges in the diagnosis and management of cow's milk allergy in infants
    (University College Cork, 2021-06-28) d'Art, Yvonne; Hourihane, Jonathan O'B.; Gibson, Louise; Byrne, Aideen; National Children's Research Centre
    Background: Cows milk protein allergy (CMPA) is one of the most common food allergies in infancy. While it usually resolves slowly over time in most cases, it significantly disrupts family life and compromises affected childrens’ nutrition and growth. Parents often display significant anxiety about this condition and we speculated if this anxiety predates or develops in response to the onset of CMPA in their child. Single dose challenges are a new method of assessing dose reactivity in food allergic children. We recruited children referred for evaluation of CMPA to a randomised, controlled trial of single dose exposure to cows milk, using the validated dose of milk that would elicit reactions in 5% of CMPA subjects - the ED05, before implementation of graded exposure to CM (using the 12 step IMAP Milk Tolerance Induction Ladder) at home. Methods: 60 infants were recruited from referrals to 2 tertiary allergy centres and 1 secondary level allergy clinic. Inclusion criteria were age <12 months, a convincing CM allergic reaction <2 months before assessment and positive skin prick test (SPT) to milk +/- raised SpIgE to milk. Children were randomised 2:1 to a single dose of the ED05 for CM - (0.5mg milk protein) given as liquid CM (0.015mls) and observed for 2 hours post ingestion - or to no dose. Results: 60 patients were recruited, 57 (95%) were followed to 6 months, 3 intervention subjects were lost to follow up. By 6 months 27/37 (73%) intervention subjects had reached step 6 or above on the milk ladder compared to 10/20 (50%) control subjects (p=0.048). By 6 months 11/37 (30%) intervention subjects reached step 12 (ie drinking unheated cow’s milk) compared to 2/20 (10%) of the controls (p=0.049). 12 months post randomisation 31/36(86%) of the intervention group and 15/19(79%) of the control group were on step 6 or above.However 23/36(64%) of the intervention group were at step 12 compared to 7/19(37%) of the control group. Maternal state and trait anxiety were significantly associated with their infants’ response/progress on the milk ladder and with changes in skin prick test and spIgE levels at 6 and 12 months. Conclusion Using the 12 step IMAP milk ladder accelerates natural tolerance induction in infants under 12 months with CMPA. A supervised single dose at the ED05 significantly accelerates this further, probably by giving parents the confidence to proceed. Maternal anxiety generally reflects infants’ progress towards tolerance but preexisting high levels of maternal anxiety are associated with poorer progress.
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    Sensitising pancreatic cancer cell lines to electrochemotherapy by modulation of the cell cycle
    (University College Cork, 2021-03) Cooke, Katie Deniese; Forde, Patrick; Collins, Dearbhaile; Breakthrough Cancer Research
    We chose to research pancreatic cancer as pancreatic adenocarcinoma (PAC) is quite the aggressive disease, which even with the vast improvements in cancer treatments over recent years still has limited treatment options. Monotherapy treatment of pancreatic cancer with chemotherapy drugs initially show hopeful results, decreased disease symptoms and can lead to a slight improvement in survival but unfortunately does often ends in recurrence (1–3). Surgery has shown to be successful for respectable tumours followed by chemotherapy. Chemotherapy alone has proven to be associated with chemoresistance and can be quite intense, often patients are not able to continue with strong treatment regimes. FOLFIRINOX is classed as the gold standard for treating PAC, however, patient fitness ultimately determines suitability. Electrochemotherapy (ECT) is a new and emerging cancer therapy which allows for decreased doses of chemotherapy drugs to be used. We have evaluated pancreatic cancer cell lines response to low dose chemotherapy and Electrochemotherapy. The human pancreatic cell lines BxPC-3, PANC-1, and MIAPaCa-2 were used for all experiments in this thesis. Based on previous studies we predicted that PANC-1 cells would be most resistant to drug treatment followed by BxPC-3 and MIAPaCa-2 cells. All cell lines survived treatment with Gemcitabine (GEM) and Nab-paclitaxel (Nab), however, they had decreased survival when treated with 5’Fluorouracil (5’FU). When Electrochemotherapy (ECT) was applied to the cell line using GEM, Nab and 5’FU, cells survived and recovered but again had decreased survival and recovery with 5’FU ECT. Cells were also treated with Oxaliplatin (Ox) ECT, this had more of an impact to cell survival than with GEM/Nab/5’FU ECT. Bleomycin and cisplatin are the conventional drugs used with ECT due to their effectiveness (4,5), but we chose Ox as it is part of the FOLFIRONOX cocktail which is the gold standard for treating patients with PAC. Electrochemotherapy (ECT) has emerged as a promising treatment strategy for patients with pancreatic cancer (PC). ECT is safe for patients and has reduced side effects of systemic chemotherapy as drugs are concentrated to treatment site(6). ECT has shown to be very effective in treating melanoma (7). ECT has recently been used to treat locally advanced PC (8). Development of preclinical and clinical agents that inhibit cell cycle progression have proven effective in the treatment of cancer. Targeting cyclin dependent kinases (CDKs) and cell cycle checkpoint proteins can induce cell cycle arrest and apoptosis in cancer cells. Cell cycle deregulation is regularly seen in pancreatic cancer. Cells grow out of control and can lead to mortality. Controlling the deregulation with cell cycle inhibitors has shown to be beneficial for survival. Our study aimed to investigate CDK4/6 inhibitors and their ability to inhibit cell cycle progression. We specifically chose CDK4/6 inhibitors as they have proven to be quite effective in previous studies of breast cancer(9). Our hypothesis was that using a cell cycle inhibitor as a pre-treatment to ECT would make cells more susceptible to treatment. We used Palbociclib (PAL), a CDK4 inhibitor which causes cell cycle arrest at G1 and prevents cells progressing to S phase. We carried out experiments to investigate CDK4 levels in cells treated with PAL and cell cycle profiles of these cells post treatment. PAL prevents cell from passing to S phase of the cell cycle. We could not finish our planned work due to time, ceased funding and the COVID-19 global pandemic. We theorise that this combination treatment could enhance the efficiency of ECT and could potentially be translated into a clinical study as a new treatment option and improve patient quality of life.