Metabolic interventions in heart failure

De kans dat iemand hartfalen ontwikkelt tijdens zijn leven is bijna 1 op 3. De afgelopen jaren is de therapie voor hartfalen verbeterd. De prognose van hartfalen patiënten is vaak slechter dan voor patiënten met kanker. Het hart is één van de grootverbruikers van energie in het lichaam en er wordt gedacht dat verstoringen in de het energie metabolisme hartfalen kunnen veroorzaken. In dit proefschrift onderzochten we verschillende metabole interventies in hartziekten. In deel één onderzochten we klinische aspecten, waaronder de plaats van β-blockers die verschillende metabole bijwerkingen hebben. Behandeling met β-blockers in laag risico patiënten na een bypass operatie was niet geassocieerd met een vermindering van hartziekten. In deel twee onderzochten we de rol van A kinase interacting protein 1 (AKIP1) op veranderingen in het hart bij acute en chronische belasting. Eerder onderzoek in gekweekte hartspiercellen liet zien dat AKIP1 mogelijk geschikt is als aangrijpingspunt voor hartfalen-therapie. Met genetische modificatie zorgden we voor een 40-voudige overexpressie van AKIP1 in hartspiercellen van muizen. In tegenstelling tot onze verwachting had deze toename van AKIP1 geen effect op de hartfunctie wanneer muizen werden blootgesteld aan modellen van verschillende oorzaken voor hartfalen. We zagen wel dat AKIP1 het hart beschermde na een acuut hartinfarct door de afsterving van hartspiercellen tegen te gaan. Deze beschermende werking bleek te berusten op stabilisatie van mitochondriën, de energiefabrieken van het hart. Deze bevindingen suggereren dat AKIP1 verder onderzocht zou moeten worden als potentieel aangrijpingspunt voor therapie bij een hartinfarct

An investigation into the effects of commencing haemodialysis in the critically ill

<b>Introduction:</b> We have aimed to describe haemodynamic changes when haemodialysis is instituted in the critically ill. 3 hypotheses are tested: 1)The initial session is associated with cardiovascular instability, 2)The initial session is associated with more cardiovascular instability compared to subsequent sessions, and 3)Looking at unstable sessions alone, there will be a greater proportion of potentially harmful changes in the initial sessions compared to subsequent ones. <b>Methods:</b> Data was collected for 209 patients, identifying 1605 dialysis sessions. Analysis was performed on hourly records, classifying sessions as stable/unstable by a cutoff of >+/-20% change in baseline physiology (HR/MAP). Data from 3 hours prior, and 4 hours after dialysis was included, and average and minimum values derived. 3 time comparisons were made (pre-HD:during, during HD:post, pre-HD:post). Initial sessions were analysed separately from subsequent sessions to derive 2 groups. If a session was identified as being unstable, then the nature of instability was examined by recording whether changes crossed defined physiological ranges. The changes seen in unstable sessions could be described as to their effects: being harmful/potentially harmful, or beneficial/potentially beneficial. <b>Results:</b> Discarding incomplete data, 181 initial and 1382 subsequent sessions were analysed. A session was deemed to be stable if there was no significant change (>+/-20%) in the time-averaged or minimum MAP/HR across time comparisons. By this definition 85/181 initial sessions were unstable (47%, 95% CI SEM 39.8-54.2). Therefore Hypothesis 1 is accepted. This compares to 44% of subsequent sessions (95% CI 41.1-46.3). Comparing these proportions and their respective CI gives a 95% CI for the standard error of the difference of -4% to 10%. Therefore Hypothesis 2 is rejected. In initial sessions there were 92/1020 harmful changes. This gives a proportion of 9.0% (95% CI SEM 7.4-10.9). In the subsequent sessions there were 712/7248 harmful changes. This gives a proportion of 9.8% (95% CI SEM 9.1-10.5). Comparing the two unpaired proportions gives a difference of -0.08% with a 95% CI of the SE of the difference of -2.5 to +1.2. Hypothesis 3 is rejected. Fisher’s exact test gives a result of p=0.68, reinforcing the lack of significant variance. <b>Conclusions:</b> Our results reject the claims that using haemodialysis is an inherently unstable choice of therapy. Although proportionally more of the initial sessions are classed as unstable, the majority of MAP and HR changes are beneficial in nature

Implementing decision tree-based algorithms in medical diagnostic decision support systems

As a branch of healthcare, medical diagnosis can be defined as finding the disease based on the signs and symptoms of the patient. To this end, the required information is gathered from different sources like physical examination, medical history and general information of the patient. Development of smart classification models for medical diagnosis is of great interest amongst the researchers. This is mainly owing to the fact that the machine learning and data mining algorithms are capable of detecting the hidden trends between features of a database. Hence, classifying the medical datasets using smart techniques paves the way to design more efficient medical diagnostic decision support systems. Several databases have been provided in the literature to investigate different aspects of diseases. As an alternative to the available diagnosis tools/methods, this research involves machine learning algorithms called Classification and Regression Tree (CART), Random Forest (RF) and Extremely Randomized Trees or Extra Trees (ET) for the development of classification models that can be implemented in computer-aided diagnosis systems. As a decision tree (DT), CART is fast to create, and it applies to both the quantitative and qualitative data. For classification problems, RF and ET employ a number of weak learners like CART to develop models for classification tasks. We employed Wisconsin Breast Cancer Database (WBCD), Z-Alizadeh Sani dataset for coronary artery disease (CAD) and the databanks gathered in Ghaem Hospital’s dermatology clinic for the response of patients having common and/or plantar warts to the cryotherapy and/or immunotherapy methods. To classify the breast cancer type based on the WBCD, the RF and ET methods were employed. It was found that the developed RF and ET models forecast the WBCD type with 100% accuracy in all cases. To choose the proper treatment approach for warts as well as the CAD diagnosis, the CART methodology was employed. The findings of the error analysis revealed that the proposed CART models for the applications of interest attain the highest precision and no literature model can rival it. The outcome of this study supports the idea that methods like CART, RF and ET not only improve the diagnosis precision, but also reduce the time and expense needed to reach a diagnosis. However, since these strategies are highly sensitive to the quality and quantity of the introduced data, more extensive databases with a greater number of independent parameters might be required for further practical implications of the developed models

Optimising outcomes for potentially resectable pancreatic cancer through personalised predictive medicine : the application of complexity theory to probabilistic statistical modeling

Survival outcomes for pancreatic cancer remain poor. Surgical resection with adjuvant therapy is the only potentially curative treatment, but for many people surgery is of limited benefit. Neoadjuvant therapy has emerged as an alternative treatment pathway however the evidence base surrounding the treatment of potentially resectable pancreatic cancer is highly heterogeneous and fraught with uncertainty and controversy. This research seeks to engage with conjunctive theorising by avoiding simplification and abstraction to draw on different kinds of data from multiple sources to move research towards a theory that can build a rich picture of pancreatic cancer management pathways as a complex system. The overall aim is to move research towards personalised realistic medicine by using personalised predictive modeling to facilitate better decision making to achieve the optimisation of outcomes. This research is theory driven and empirically focused from a complexity perspective. Combining operational and healthcare research methodology, and drawing on influences from complementary paradigms of critical realism and systems theory, then enhancing their impact by using Cilliers’ complexity theory ‘lean ontology’, an open-world ontology is held and both epistemic reality and judgmental relativity are accepted. The use of imperfect data within statistical simulation models is explored to attempt to expand our capabilities for handling the emergent and uncertainty and to find other ways of relating to complexity within the field of pancreatic cancer research. Markov and discrete-event simulation modelling uncovered new insights and added a further dimension to the current debate by demonstrating that superior treatment pathway selection depended on individual patient and tumour factors. A Bayesian Belief Network was developed that modelled the dynamic nature of this complex system to make personalised prognostic predictions across competing treatments pathways throughout the patient journey to facilitate better shared clinical decision making with an accuracy exceeding existing predictive models.Survival outcomes for pancreatic cancer remain poor. Surgical resection with adjuvant therapy is the only potentially curative treatment, but for many people surgery is of limited benefit. Neoadjuvant therapy has emerged as an alternative treatment pathway however the evidence base surrounding the treatment of potentially resectable pancreatic cancer is highly heterogeneous and fraught with uncertainty and controversy. This research seeks to engage with conjunctive theorising by avoiding simplification and abstraction to draw on different kinds of data from multiple sources to move research towards a theory that can build a rich picture of pancreatic cancer management pathways as a complex system. The overall aim is to move research towards personalised realistic medicine by using personalised predictive modeling to facilitate better decision making to achieve the optimisation of outcomes. This research is theory driven and empirically focused from a complexity perspective. Combining operational and healthcare research methodology, and drawing on influences from complementary paradigms of critical realism and systems theory, then enhancing their impact by using Cilliers’ complexity theory ‘lean ontology’, an open-world ontology is held and both epistemic reality and judgmental relativity are accepted. The use of imperfect data within statistical simulation models is explored to attempt to expand our capabilities for handling the emergent and uncertainty and to find other ways of relating to complexity within the field of pancreatic cancer research. Markov and discrete-event simulation modelling uncovered new insights and added a further dimension to the current debate by demonstrating that superior treatment pathway selection depended on individual patient and tumour factors. A Bayesian Belief Network was developed that modelled the dynamic nature of this complex system to make personalised prognostic predictions across competing treatments pathways throughout the patient journey to facilitate better shared clinical decision making with an accuracy exceeding existing predictive models