Patient-Specific Identification of Atrial Flutter Vulnerability–A Computational Approach to Reveal Latent Reentry Pathways

Atypical atrial flutter (AFlut) is a reentrant arrhythmia which patients frequently develop after ablation for atrial fibrillation (AF). Indeed, substrate modifications during AF ablation can increase the likelihood to develop AFlut and it is clinically not feasible to reliably and sensitively test if a patient is vulnerable to AFlut. Here, we present a novel method based on personalized computational models to identify pathways along which AFlut can be sustained in an individual patient. We build a personalized model of atrial excitation propagation considering the anatomy as well as the spatial distribution of anisotropic conduction velocity and repolarization characteristics based on a combination of a priori knowledge on the population level and information derived from measurements performed in the individual patient. The fast marching scheme is employed to compute activation times for stimuli from all parts of the atria. Potential flutter pathways are then identified by tracing loops from wave front collision sites and constricting them using a geometric snake approach under consideration of the heterogeneous wavelength condition. In this way, all pathways along which AFlut can be sustained are identified. Flutter pathways can be instantiated by using an eikonal-diffusion phase extrapolation approach and a dynamic multifront fast marching simulation. In these dynamic simulations, the initial pattern eventually turns into the one driven by the dominant pathway, which is the only pathway that can be observed clinically. We assessed the sensitivity of the flutter pathway maps with respect to conduction velocity and its anisotropy. Moreover, we demonstrate the application of tailored models considering disease-specific repolarization properties (healthy, AF-remodeled, potassium channel mutations) as well as applicabiltiy on a clinical dataset. Finally, we tested how AFlut vulnerability of these substrates is modulated by exemplary antiarrhythmic drugs (amiodarone, dronedarone). Our novel method allows to assess the vulnerability of an individual patient to develop AFlut based on the personal anatomical, electrophysiological, and pharmacological characteristics. In contrast to clinical electrophysiological studies, our computational approach provides the means to identify all possible AFlut pathways and not just the currently dominant one. This allows to consider all relevant AFlut pathways when tailoring clinical ablation therapy in order to reduce the development and recurrence of AFlut

A Knowledge Graph Framework for Dementia Research Data

Dementia disease research encompasses diverse data modalities, including advanced imaging, deep phenotyping, and multi-omics analysis. However, integrating these disparate data sources has historically posed a significant challenge, obstructing the unification and comprehensive analysis of collected information. In recent years, knowledge graphs have emerged as a powerful tool to address such integration issues by enabling the consolidation of heterogeneous data sources into a structured, interconnected network of knowledge. In this context, we introduce DemKG, an open-source framework designed to facilitate the construction of a knowledge graph integrating dementia research data, comprising three core components: a KG-builder that integrates diverse domain ontologies and data annotations, an extensions ontology providing necessary terms tailored for dementia research, and a versatile transformation module for incorporating study data. In contrast with other current solutions, our framework provides a stable foundation by leveraging established ontologies and community standards and simplifies study data integration while delivering solid ontology design patterns, broadening its usability. Furthermore, the modular approach of its components enhances flexibility and scalability. We showcase how DemKG might aid and improve multi-modal data investigations through a series of proof-of-concept scenarios focused on relevant Alzheimer’s disease biomarkers

Thrombolysis in Acute Myocardial Infarction: An Electrocardiographic Study

The value of thrombolytic therapy in the treatment of acute myocardial infarction is now unchallenged following the publication of large scale clinical trials showing an impressive reduction in mortality. Intravenous administration of a thrombolytic agent in the early hours of myocardial infarction is established practice in all hospitals, from district generals to specialized cardiac centres. The aim is to obtain a patent artery, improve left ventricular function and decrease mortality. The effectiveness of intravenous therapy obviates the need for acute angiography and intracoronary administration, but a definitive statement concerning whether reperfusion has occurred cannot be made. The 12 lead ECG undergoes well recognised dynamic changes in the early phase of myocardial infarction. Successful lysis, either induced or spontaneous, will modify these changes. Whether these modifications can be quantified and used as simple non invasive tests of reperfusion, myocardial salvage and infarct size has caused much speculation. To have such a simple, widely available, reproducible and inexpensive tool would be highly desirable in a clinical setting. This thesis has addressed these questions. The first study demonstrated the rapid fall in ST segment elevation occurring in response to thrombolysis, and introduced a measurement which expresses this fall as a proportion of the admission value. This is termed the Fractional Change and can be applied to either 24 hour tape recordings or to the 12 lead ECG. A Fractional Change Value > 0.5 occurring by 2-3 hours following therapy is highly specific and sensitive for reperfusion. The next study examined whether an electrocardiographic marker of infarct size, the QRS score, was attenuated in patients achieving successful reperfusion compared with a historical cohort of patients with infarctions given no therapy other than simple analgesia. Only patients with anterior infarcts were studied, and although both groups had similar areas of myocardium at jeopardy on admission, the group of patients achieving successful reperfusion had a significant reduction in the QRS score at 48 hours compared to the control group. These initial studies showed that dynamic changes in the ECG can reflect both reperfusion and myocardial salvage, but are limited in that they were performed in relatively small numbers, and the ECG measurements were made and tabulated manually. A method for digitizing 12 lead ECG's with subsequent computer storage of data for comparative analysis has been developed, and incorporates an automatic QRS scoring system. The developmental work involved in setting this system up and its subsequent validation with inter- and intra-observer variation studies is presented in Chapter 5. This system was then used to follow the sequential ECG changes in a prospective angiographically controlled, double blind randomised trial of 128 patients comparing anistreplase with streptokinase. The 90 minute patency rates for both drugs were found to be the same (anistreplase 55%, streptokinase 53%) . Coronary angiography performed at 90 minutes post therapy allowed a detailed correlation between ECG changes on admission and acute coronary anatomy. The findings of this particular study showed that the height of ST segment elevation does not bear any relation to the age of the infarct, that there is a high incidence of reciprocal change early in the course of infarction, and that this is not related to coexisting disease or remote ischaemia, but is likely to be an electrocardiographic mirror phenomenon. Examining the resolution of ST segment elevation and depression showed that it was the rate of fall which discriminates patent from non patent arteries, and that using a Fractional Change Value of 0. 5 to detect reperfusion, calculated at 2 hours post treatment from a single lead showing maximal ST segment elevation, gave the best sensitivity (81%) and specificity (60%), when compared with a number of different parameters. In addition, it appears that the presence of collaterals supplying the infarct area could result in a high Fractional Change Value despite no antegrade perfusion. This study also confirmed that achievement of a patent artery early (i.e. before 90 minutes) significantly attenuated Q wave development, R wave loss and the QRS score in anterior infarction, but did not affect electrocardiographic markers of infarct size when applied to inferior infarcts. In summary, this thesis provides a detailed study of the electrocardiographic changes taking place in acute myocardial infarction, especially as a consequence of treating with thrombolysis, quantitates these changes and shows where they may be used in a clinical setting as non-invasive tests to aid patient management

Improving Satisfaction, Engagement and Clinical Outcomes among Traditionally Underserved Children through Cultural Formulation

Economically disadvantaged and ethnic/racial minority children are more likely to suffer from disruptive behavior problems than their middle-to-upper-income Caucasian counterparts, yet they are less likely to receive quality care and are more likely to drop out of treatment services. Disparities in the reception of and engagement with mental health services suggests that standard mental health practices may not properly consider the unique cultural context of child mental health problems in traditionally underserved families. Initial research focused on adult populations has suggested that incorporating the brief Cultural Formulation Interview (CFI) as part of baseline assessment can promote improved medical communication, leading to stronger rapport with the therapist, and overall patient satisfaction. To date, research on the benefits of augmenting usual mental health assessment with the CFI has mainly been conducted in the context of adult patients, and has yet to examine the potential for the CFI to improve treatment engagement in the context of children’s mental health services. Further, studies on the CFI have only examined its impact on initial engagement and satisfaction with assessment services; research has yet to consider the effects of the CFI on prolonged engagement and/or ultimate clinical response. The current study is the first to assess the effects of the CFI on satisfaction, engagement, and treatment outcomes. Families (N=89) receiving behavior parent training for early child externalizing problems within a large South Florida mental health network serving predominately low-income minority families were randomized at baseline to receive either Assessment as Usual (AAU) or CFI+AAU. Results found that therapists and caregivers were more satisfied with the intake interview when they received the CFI. Specifically, caregivers participating in CFI+AAU reported greater satisfaction with their assessment, and reported higher levels of trust in their therapists, than did caregivers receiving AAU. Additionally, therapists reported greater satisfaction with CFI+AAU than AAU, particularly when working with higher stress families. After controlling for interview length, there was trending significance to suggest CFI+AAU families may have been more likely than AAU families to attend their first post-intake treatment session, and CFI+AAU families were significantly more likely to complete treatment than AAU families. Moreover, those in the CFI+AAU group were associated with significantly better treatment outcomes among families reporting high stigma-related concerns about mental health; in contrast families who received AAU reported significantly better outcomes when families reported low stigma-related concerns at baseline. These promising results underscore how a brief cultural assessment can meaningfully aid in improving engagement in, and clinical response to, mental health services. Further research is needed to determine how and when to best leverage the CFI to improve mental health practices for traditionally underserved populations