Medicine - Masters by Research Theses

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    The NEST study: NICOM vs ECHO in the screening of transient hypertrophic obstructive cardiomyopathy (HOCUM)
    (University College Cork, 2023) Finn, Bryan Padraig; Ó Tuathaigh, Colm; Dempsey, Eugene M.; University College Cork
    Background: Gestational diabetes mellitus (GDM) is the most common metabolic disorder of pregnancy. An increasing number of infants are exposed to hyperglycaemia antenatally with the national prevalence estimated at 10.1-12.4%. Transient HOCUM (Hypertrophic Obstructive Cardiomyopathy) as well as interatrial/interventricular communications remain the most common cardiac sequelae for such infants. In particular, transient HOCUM has a broad estimated international incidence of 13-44%. The current standard of care for infants born to mothers with GDM (Gestational Diabetes Mellitus) is unchanged from routine care, consisting of a bedside newborn examination. A further echocardiogram is subsequently performed if clinically indicated as a key investigation for the detection of congenital heart disease. There has been a rising interest in NICOM (Non-invasive Cardiac Output Monitoring), a range of novel non-invasive measurements of cardiac output and left ventricular outflow using an array of techniques from electrical bioimpedance to transthoracic bioreactance. The appeal is that these investigations can be carried out at the patient’s bedside without a trained ECHO (Echocardiogram) technician. Aim: Our primary aim was to assess the ability of transthoracic bioreactance (a novel method of cardiac output measurement) in detecting left ventricular outflow tract obstruction in a high-risk group. Echocardiography at present is the most commonly used tool in the detection of such cases, whereby left ventricular outflow tract obstruction is secondary to transient hypertrophic obstructive cardiomyopathy (HOCUM) for infants born to mothers with GDM. We hoped to determine if bioreactance (a NICOM branch technology) could be used as a screening tool when compared with the best available standard of echocardiography. Methods: A single centre prospective observational cohort study was conducted. Our primary objective was to compare bioreactance using the NICOM TM device against the most commonly used method of obtaining LVO measurements: echocardiography in infants born to mothers with GDM. Our goal was to ascertain if NICOM could be used as a screening tool to detect those infants at risk of symptomatic transient HOCUM with LVOTO (left ventricular outflow tract obstruction). For the purposes of secondary objectives, maternal demographic characteristics including BMI (Body Mass Index), maternal age, maternal HbA1C (glycosylated haemoglobin) and method of diabetes control were collected from the electronic healthcare record. Infant demographic and clinical variables collected included infant gestation, anthropomorphic measurements, newborn clinical examination findings and if the infant was admitted to the neonatal unit (indication and treatment received). The data analysis strategy employed was primarily using Pearson’s correlation co-efficient to determine if bioreactance had comparable efficacy to echocardiography in the detection of reduced left ventricular outflow as expected in clinically significant transient HOCUM. Preliminary statistics revealed for Pearson’s correlation- a sample size of 29 patients was required to detect a large correlation (Cohen’s r = 0.5)). This was further assessed using a Bland Altman plot. Otherwise, univariate analysis of the transient HOCUM cohort was carried out using Chi Square tests for categorical variables and independent T-tests for continuous variables. Results: Fifty infants underwent echocardiography while 28/50 of these infants were paired with a NICOM assessment (four echocardiogram data sets lost due to HSE cyberattack). 4/46 patients (8.7%) were noted to have a z-score of >2 for both the interventricular septal wall thickness and left posterior ventricular wall in diastole (LVPWd) consistent with a diagnosis of transient HOCUM with LVOTO. 26 out of 46 infants born to mothers with diabetes had significant thickening (Z-score >2) of either the interventricular septum or the left posterior ventricular wall. Regarding congenital heart defects, VSDs (ventricular septal defects) were found in 8.7% (4/46) of the study population with one patient found to have a >3mm ASD secundum. The incidence of transient HOCUM was not associated with the degree of maternal glycaemic control, maternal BMI or the method of diabetes control (all P > 0.05). Bioreactance LVO measurements poorly correlated with ECHO LVO values (r(25)= 0.2, p=- 0.31) with an ambiguous agreement on Bland Altman analysis. Conclusion: The incidence of transient HOCUM in our cohort (8.7%) was lower than previous studies -13-44%. Transthoracic bioreactance does not appear to be an effective screening tool for transient HOCUM with LVOTO in this high-risk cohort of patients. This is on the basis of a poor Pearson correlation with ECHO derived LVO values and the wide limits of agreement found with the Bland Altman plot. Infants born to mothers with GDM would not benefit from routine echocardiography screening beyond the current standard of care. This is owing to our findings that all cases of clinically relevant congenital heart disease in our cohort would have been detected with the current standard of care- a newborn bedside examination followed by a targeted ECHO as clinically indicated.
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    Induction of transdermal buprenorphine (Butrans®) to extended-release buprenorphine subcutaneous injection (Sublocade®) for opioid use disorder: a case series & a qualitative study on the experiences, barriers, and understanding of opioid agonist treatment among youth with opioid use disorder in Vancouver, British Columbia
    (University College Cork, 2023) Schneiderman, Hannah; Ó Tuathaigh, Colm; Coakley, Niamh; Azar, Pouya; Ignaszewski, Martha; Budd, George; University College Cork
    The opioid crisis is a profound public health crisis, with devastating impacts on individuals, families, and communities in North America. Vancouver is one of the most affected regions in Canada. To combat the rising opioid overdose epidemic, opioid agonist treatment and harm reduction services have become more readily accessible, and patient centered. The most effective approach to decreasing the morbidity and mortality of people with opioid use disorder is opioid agonist treatment. Initiation of opioid agonist treatment, including buprenorphine and methadone, is a complex and crucial step in care for those beginning pharmacological treatment, as well as those transitioning between medications, as poor treatment retention is largely attributed to discomfort during the induction period due to precipitated withdrawal symptoms. A variety of techniques and protocols have been developed to combat treatment barriers, including rapid micro-induction using sublingual buprenorphine-naloxone; this method eliminates the need for an abstinence period prior to administration of the first dose of buprenorphine/naloxone, and lowers the risk of precipitated withdrawal symptoms. We conducted a case series, involving two patients, that demonstrates the efficacy and safety of a novel induction technique using transdermal buprenorphine (Butrans)®, to extended-release buprenorphine subcutaneous injection (Sublocade®) for the treatment of opioid use disorder, done over a 48-hour period. Both patients experienced minimal withdrawal symptoms throughout induction and no adverse effects. This technique, also called the IPPAS method, has similar advantages to that of rapid micro-induction, in addition to reduced nurse workload, steadier blood level concentrations of buprenorphine, and increased accuracy of dose administration. In addition, this technique is more outpatient friendly with less reliance on patients to time their own doses. There is a need for further research among larger patient populations to assess the safety and efficacy of this induction method using transdermal buprenorphine in different settings and patient demographics, including youth with OUD. A population at increased risk of overdose, with lower rates of accessing pharmacological treatment, are youth (15-24 years old). Since 2018, over 1000 people between the age of 0 to 29 have died from illicit drug toxicity in Canada. Despite the effectiveness of opioid agonist treatment for opioid use disorder, only 2.4% of youth who use opioids receive pharmacological treatment compared to 26.3% of adults who use opioids. Another study found that less than 2% of youth who have suffered from a nonfatal opioid-related overdose received the recommended evidence-based pharmacotherapy. Understanding perceptions of OAT among this highly vulnerable young population is essential in combating barriers and harmful perceptions of treatment that lead to reduced treatment access. Few studies have investigated these perceptions among youth. We conducted a qualitative study involving semi-structured interviews among twelve young people with opioid use disorder at Foundry Vancouver-Granville clinic in Vancouver, British Columbia. The findings of this study highlight the complexities involving individual experiences of initiation and retention of opioid agonist treatment, as well as the unique barriers of treatment that young people with opioid use disorder experience. The four major themes identified during thematic analysis include: preparedness to begin opioid agonist treatment, effects of opioid agonist treatment on personal relationships and social life, navigating the pharmacological treatment options, and the role of the healthcare worker. The data from this qualitative research study on the experiences of pharmacological treatment among youth with opioid use disorder can be used to inform future research efforts, clinical practice, and policy change to improve the treatment and social supports available for young people struggling with opioid misuse. Future research is essential to further develop our understanding of young people, and their experiences seeking and retaining opioid agonist treatment for opioid use disorder.
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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.