The effects of centrally acting ACE inhibitors on the rate of cognitive and functional decline in dementia: a KDD approach

Alzheimer’s Disease and other dementias are one of the most challenging illnesses confronting countries with ageing populations. Treatment options for dementia are limited, and the costs are significant. There is a growing need to develop new treatments for dementia, especially for the elderly. There is also growing evidence that centrally acting angiotensin converting enzyme (ACE) inhibitors, which cross the blood-brain barrier, are associated with a reduced rate of cognitive and functional decline in dementia, especially in Alzheimer’s disease (AD). The aim of this research is to investigate the effects of centrally acting ACE inhibitors (CACE-Is) on the rate of cognitive and functional decline in dementia, using a three phased KDD process. KDD, as a scientific way to process and analysis clinical data, is used to find useful insights from a variety of clinical databases. The data used are from three clinic databases: Geriatric Assessment Tool (GAT), the Doxycycline and Rifampin for Alzheimer’s Disease (DARAD), and the Qmci validation databases, which were derived from several different geriatric clinics in Canada. This research involves patients diagnosed with AD, vascular or mixed dementia only. Patients were included if baseline and end-point (at least six months apart) Standardised Mini-Mental State Examination (SMMSE), Quick Mild Cognitive Impairment (Qmci) or Activities Daily Living (ADL) scores were available. Basically, the rates of change are compared between patients taking CACE-Is, and those not currently treated with CACE-Is. The results suggest that there is a statistically significant difference in the rate of decline in cognitive and functional scores between CACE-I and NoCACE-I patients. This research also validates that the Qmci, a new short assessment test, has potential to replace the current popular screening tests for cognition in the clinic and clinical trials.

Early biomarkers to predict grade of encephalopathy following hypoxic ischaemic injury

The standard early markers for identifying and grading HIE severity, are not sufficient to ensure all children who would benefit from treatment are identified in a timely fashion. The aim of this thesis was to explore potential early biomarkers of HIE. Methods: To achieve this a cohort of infants with perinatal depression was prospectively recruited. All infants had cord blood samples drawn and biobanked, and were assessed with standardised neurological examination, and early continuous multi-channel EEG. Cord samples from a control cohort of healthy infants were used for comparison. Biomarkers studied included; multiple inflammatory proteins using multiplex assay; the metabolomics profile using LC/MS; and the miRNA profile using microarray. Results: Eighty five infants with perinatal depression were recruited. Analysis of inflammatory proteins consisted of exploratory analysis of 37 analytes conducted in a sub-population, followed by validation of all significantly altered analytes in the remaining population. IL-6 and IL-6 differed significantly in infants with a moderate/severely abnormal vs. a normal-mildly abnormal EEG in both cohorts (Exploratory: p=0.016, p=0.005: Validation: p=0.024, p=0.039; respectively). Metabolomic analysis demonstrated a perturbation in 29 metabolites. A Cross- validated Partial Least Square Discriminant Analysis model was developed, which accurately predicted HIE with an AUC of 0.92 (95% CI: 0.84-0.97). Analysis of the miRNA profile found 70 miRNA significantly altered between moderate/severely encephalopathic infants and controls. miRNA target prediction databases identified potential targets for the altered miRNA in pathways involved in cellular metabolism, cell cycle and apoptosis, cell signaling, and the inflammatory cascade. Conclusion: This thesis has demonstrated that the recruitment of a large cohortof asphyxiated infants, with cord blood carefully biobanked, and detailed early neurophysiological and clinical assessment recorded, is feasible. Additionally the results described, provide potential alternate and novel blood based biomarkers for the identification and assessment of HIE.

Nvidia, matrox, paper? - Undergraduate game design tools in the humanities and social sciences

Eschewing costly high-tech approaches, this paper looks at the experience of using low-tech approaches to game design assignments as problem based learning and assessment tool over a number of years in undergraduate teaching. General game design concepts are discussed, along with learning outcomes and assessment rubrics in line with Blooms Taxonomy based on evidence from students who had no prior experience of serious game play or design. Approaches to creating game design based assessments are offered.

Athletic groin pain (part 2): a prospective cohort study on the biomechanical evaluation of change of direction identifies three clusters of movement patterns

Background: Athletic groin pain (AGP) is prevalent in sports involving repeated accelerations, decelerations, kicking and change-of-direction movements. Clinical and radiological examinations lack the ability to assess pathomechanics of AGP, but three-dimensional biomechanical movement analysis may be an important innovation. Aim: The primary aim was to describe and analyse movements used by patients with AGP during a maximum effort change-of-direction task. The secondary aim was to determine if specific anatomical diagnoses were related to a distinct movement strategy. Methods: 322 athletes with a current symptom of chronic AGP participated. Structured and standardised clinical assessments and radiological examinations were performed on all participants. Additionally, each participant performed multiple repetitions of a planned maximum effort change-of-direction task during which whole body kinematics were recorded. Kinematic and kinetic data were examined using continuous waveform analysis techniques in combination with a subgroup design that used gap statistic and hierarchical clustering. Results: Three subgroups (clusters) were identified. Kinematic and kinetic measures of the clusters differed strongly in patterns observed in thorax, pelvis, hip, knee and ankle. Cluster 1 (40%) was characterised by increased ankle eversion, external rotation and knee internal rotation and greater knee work. Cluster 2 (15%) was characterised by increased hip flexion, pelvis contralateral drop, thorax tilt and increased hip work. Cluster 3 (45%) was characterised by high ankle dorsiflexion, thorax contralateral drop, ankle work and prolonged ground contact time. No correlation was observed between movement clusters and clinically palpated location of the participant's pain. Conclusions: We identified three distinct movement strategies among athletes with long-standing groin pain during a maximum effort change-of-direction task. These movement strategies were not related to clinical assessment findings but highlighted targets for rehabilitation in response to possible propagative mechanisms. Trial registration number NCT02437942, pre results.

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.

Isolation, characterization, and functional assessment of novel smooth muscle like stem progenitors

Vascular smooth muscle cells (VSMC) are one of the key players in the pathogenesis of cardiovascular diseases. The origin of neointimal VSMC has thus become a prime focus of research. VSMC originate from multiple progenitors cell types. In embryo the well-defined sources of VSMC include; neural crest cells, proepicardial cells and EPC. In adults, though progenitor cells from bone marrow (BM), circulation and tissues giving rise to SMC have been identified, no progress has been made in terms of isolating highly proliferative clonal population of adult stem cells with potential to differentiate into SMC. Smooth muscle like stem progenitor cells (SMSPC) were isolated from cardiopulmonary bypass filters of adult patients undergoing CABG. Rat SMSPC have previously been isolated by our group from the bone marrow of Fischer rats and also from the peripheral blood of monocrotaline induced pulmonary hypertension (MCT-PHTN) animal model. Characterization of novel SMSPC exhibited stem cell characteristics and machinery for differentiation into SMC. The expression of Isl-1 on SMSPC provided unique molecular identity to these circulating stem progenitor cells. The functional potential of SMSPC was determined by monitoring adoptive transfer of GFP+ SMSPC in rodent models of vascular injury; carotid injury and MCT-PHTN. The participation of SMSPC in vascular pathology was confirmed by quantifying the peripheral blood, and engrafted levels of SMSPC using RT-PCR. In terms of translating into clinical practice, SMSPC could be a good tool for detecting the atherosclerotic plaque burden. The current study demonstrates the existence of novel adult stem progenitor cells in circulation, with the potential role in vascular pathology.

Pharmacotherapy optimization in older patients by a structured clinical pharmacist assessment and intervention

Introduction: Older individuals are particularly vulnerable to potentially inappropriate prescribing (PIP), drug related problems (DRPs) and adverse drug reactions (ADRs). A number of different interventions have been proposed to address these issues. However to-date there is a paucity of well-designed trials examining the impact of such interventions. Therefore the aims of this work were to: (i) establish a baseline PIP prevalence both nationally and internationally using the STOPP, Beers and PRISCUS criteria, (ii) identify the most comprehensive method of assessing PIP in older individuals, (iii) develop a structured pharmacist intervention supported by a computer decisions support system (CDSS) and (iv) examine the impact of this intervention on prescribing and incidence of ADRs. Results: This work identified high rates of PIP across all three healthcare settings in Ireland, 84.7% in the long term care, 70.7% in secondary care and 43.3% in primary care being reported. This work identified that for a comprehensive assessment of prescribing to be undertaken, an amalgamation of all three criteria should be deployed simultaneously. High prevalences of DRPs and PIP in older hospitalised individuals were identified. With 82.0% and 76.3% of patients reported to have at least one DRP or PIP instance respectively. The structured pharmacist intervention demonstrated a positive impact on prescribing, with a significant reduction MAI scores being reported. It also resulted in the intervention patients’ having a reduced risk of experiencing an ADR when compared to the control patients (absolute risk reduction of 6.8 (95% CI 1.5% - 12.3%)) and the number needed to treat = 15 (95% CI 8 - 68). However the intervention was found to have no significant effect on length of stay or mortality rate. Conclusion: This work shows that PIP is highly prevalent in older individuals across three healthcare settings in Ireland. This work also demonstrates that a structured pharmacist intervention support by a dedicated CDSS can significantly improve the appropriateness of prescribing and reduce the incidence of ADRs in older acutely ill hospitalised individuals.