Project description:Radiotherapy (RT) is highly effective at directly killing tumor cells and plays an important part in cancer treatments being delivered to around 50% of all cancer patients. The additional immunomodulatory properties of RT have been investigated, and if exploited effectively, have the potential to further improve the efficacy of RT and cancer outcomes. The initial results of combining RT with immunomodulatory agents have generated promising data in pre-clinical studies, which has in turn led to a large number of RT and immunotherapy clinical trials. The overarching aim of these combinations is to enhance anti-tumor immune responses and improve responses rates and patient outcomes. In order to maximize this undoubted opportunity, there remain a number of important questions that need to be addressed, including: (i) the optimal RT dose and fractionation schedule; (ii) the optimal RT target volume; (iii) the optimal immuno-oncology (IO) agent(s) to partner with RT; (iv) the optimal site(s)/route(s) of administration of IO agents; and finally, the optimal RT schedule. In this review, we will summarize progress to date and identify current gaps in knowledge that need to be addressed in order to facilitate effective clinical translation of RT and IO agent combinations.
Project description:Conduction system pacing (CSP) has the potential to achieve physiological-paced activation by pacing the ventricular conduction system. Before CSP is adopted in standard clinical practice, large, randomised, and multi-centre trials are required to investigate CSP safety and efficacy compared to standard biventricular pacing (BVP). Furthermore, there are unanswered questions about pacing thresholds required to achieve optimal pacing delivery while preventing device battery draining, and about which patient groups are more likely to benefit from CSP rather than BVP. In silico studies have been increasingly used to investigate mechanisms underlying changes in cardiac function in response to pathologies and treatment. In the context of CSP, they have been used to improve our understanding of conduction system capture to optimise CSP delivery and battery life, and noninvasively compare different pacing methods on different patient groups. In this review, we discuss the in silico studies published to date investigating different aspects of CSP delivery.
Project description:Cardiac arrhythmia is associated with high morbidity, and its underlying mechanisms are poorly understood. Computational modelling and simulation approaches have the potential to improve standard-of-care therapy for these disorders, offering deeper understanding of complex disease processes and sophisticated translational tools for planning clinical procedures. This review provides a clinician-friendly summary of recent advancements in computational cardiology. Organ-scale models automatically generated from clinical-grade imaging data are used to custom tailor our understanding of arrhythmia drivers, estimate future arrhythmogenic risk and personalise treatment plans. Recent mechanistic insights derived from atrial and ventricular arrhythmia simulations are highlighted, and the potential avenues to patient care (eg, by revealing new antiarrhythmic drug targets) are covered. Computational approaches geared towards improving outcomes in resynchronisation therapy have used simulations to elucidate optimal patient selection and lead location. Technology to personalise catheter ablation procedures are also covered, specifically preliminary outcomes form early-stage or pilot clinical studies. To conclude, future developments in computational cardiology are discussed, including improving the representation of patient-specific fibre orientations and fibrotic remodelling characterisation and how these might improve understanding of arrhythmia mechanisms and provide transformative tools for patient-specific therapy.
Project description:The nervous system has been increasingly recognized as a novel and accessible target in the regulation of inflammation. The use of implantable and invasive devices targeting neural circuits has yielded successful results in clinical settings but does have some risk or adverse effects. Recent advances in technology and understanding of mechanistic pathways have opened new avenues of non-invasive neuromodulation. Through this review we discuss the novel research and outcomes of major modalities of non-invasive neuromodulation in the context of inflammation including transcutaneous electrical, magnetic and ultrasound neuromodulation. In addition to highlighting the scientific observations and breakthroughs, we discuss the underlying mechanisms and pathways for neural regulation of inflammation.
Project description:BackgroundToday's availability of medical imaging and computational resources set the scene for high-fidelity computational modelling of brain biomechanics. The brain and its environment feature a dynamic and complex interplay between the tissue, blood, cerebrospinal fluid (CSF) and interstitial fluid (ISF). Here, we design a computational platform for modelling and simulation of intracranial dynamics, and assess the models' validity in terms of clinically relevant indicators of brain pulsatility. Focusing on the dynamic interaction between tissue motion and ISF/CSF flow, we treat the pulsatile cerebral blood flow as a prescribed input of the model.MethodsWe develop finite element models of cardiac-induced fully coupled pulsatile CSF flow and tissue motion in the human brain environment. The three-dimensional model geometry is derived from magnetic resonance images (MRI) and features a high level of detail including the brain tissue, the ventricular system, and the cranial subarachnoid space (SAS). We model the brain parenchyma at the organ-scale as an elastic medium permeated by an extracellular fluid network and describe flow of CSF in the SAS and ventricles as viscous fluid movement. Representing vascular expansion during the cardiac cycle, a prescribed pulsatile net blood flow distributed over the brain parenchyma acts as the driver of motion. Additionally, we investigate the effect of model variations on a set of clinically relevant quantities of interest.ResultsOur model predicts a complex interplay between the CSF-filled spaces and poroelastic parenchyma in terms of ICP, CSF flow, and parenchymal displacements. Variations in the ICP are dominated by their temporal amplitude, but with small spatial variations in both the CSF-filled spaces and the parenchyma. Induced by ICP differences, we find substantial ventricular and cranial-spinal CSF flow, some flow in the cranial SAS, and small pulsatile ISF velocities in the brain parenchyma. Moreover, the model predicts a funnel-shaped deformation of parenchymal tissue in dorsal direction at the beginning of the cardiac cycle.ConclusionsOur model accurately depicts the complex interplay of ICP, CSF flow and brain tissue movement and is well-aligned with clinical observations. It offers a qualitative and quantitative platform for detailed investigation of coupled intracranial dynamics and interplay, both under physiological and pathophysiological conditions.
Project description:BackgroundRemote coaching might be suited for providing information and support to patients with coronary artery disease (CAD) in the vulnerable phase between hospital discharge and the start of cardiac rehabilitation (CR).ObjectiveThe goal of the research was to explore and summarize information and support needs of patients with CAD and develop an early remote coaching program providing tailored information and support.MethodsWe used the intervention mapping approach to develop a remote coaching program. Three steps were completed in this study: (1) identification of information and support needs in patients with CAD, using an exploratory literature study and semistructured interviews, (2) definition of program objectives, and (3) selection of theory-based methods and practical intervention strategies.ResultsOur exploratory literature study (n=38) and semistructured interviews (n=17) identified that after hospital discharge, patients with CAD report a need for tailored information and support about CAD itself and the specific treatment procedures, medication and side effects, physical activity, and psychological distress. Based on the preceding steps, we defined the following program objectives: (1) patients gain knowledge on how CAD and revascularization affect their bodies and health, (2) patients gain knowledge about medication and side effects and adhere to their treatment plan, (3) patients know which daily physical activities they can and can't do safely after hospital discharge and are physically active, and (4) patients know the psychosocial consequences of CAD and know how to discriminate between harmful and harmless body signals. Based on the preceding steps, a remote coaching program was developed with the theory of health behavior change as a theoretical framework with behavioral counseling and video modeling as practical strategies for the program.ConclusionsThis study shows that after (acute) cardiac hospitalization, patients are in need of information and support about CAD and revascularization, medication and side effects, physical activity, and psychological distress. In this study, we present the design of an early remote coaching program based on the needs of patients with CAD. The development of this program constitutes a step in the process of bridging the gap from hospital discharge to start of CR.
Project description:Cardiac morbidity and mortality increases with the population age. To investigate the underlying pathological mechanisms, and suggest new ways to reduce clinical risks, computational approaches complementing experimental and clinical investigations are becoming more and more important. Here we explore the possible processes leading to the occasional onset and termination of the (usually) non-fatal arrhythmias widely observed in the heart. Using a computational model of a two-dimensional network of cardiac cells, we tested the hypothesis that an ischemia alters the properties of the gap junctions inside the ischemic area. In particular, in agreement with experimental findings, we assumed that an ischemic episode can alter the gap junctions of the affected cells by reducing their average conductance. We extended these changes to include random fluctuations with time, and modifications in the gap junction rectifying conductive properties of cells along the edges of the ischemic area. The results demonstrate how these alterations can qualitatively give an account of all the main types of non-fatal arrhythmia observed experimentally, and suggest how premature beats can be eliminated in three different ways: a) with a relatively small surgical procedure, b) with a pharmacological reduction of the rectifying conductive properties of the gap-junctions, and c) by pharmacologically decreasing the gap junction conductance. In conclusion, our model strongly supports the hypothesis that non-fatal arrhythmias can develop from post-ischemic alteration of the electrical connectivity in a relatively small area of the cardiac cell network, and suggests experimentally testable predictions on their possible treatments.
Project description:During an average individual's lifespan, the human heart pumps nearly 200 million liters of blood delivered by approximately 3 billion heartbeats. Therefore, it is not surprising that native myocardium under this incredible demand is extraordinarily complex, both structurally and functionally. As a result, successful engineering of adult-mimetic functional cardiac tissues is likely to require utilization of highly specialized biomaterials representative of the native extracellular microenvironment. There is currently no single biomaterial that fully recapitulates the architecture or the biochemical and biomechanical properties of adult myocardium. However, significant effort has gone toward designing highly functional materials and tissue constructs that may one day provide a ready source of cardiac tissue grafts to address the overwhelming burden of cardiomyopathic disease. In the near term, biomaterial-based scaffolds are helping to generate in vitro systems for querying the mechanisms underlying human heart homeostasis and disease and discovering new, patient-specific therapeutics. When combined with advances in minimally-invasive cardiac delivery, ongoing efforts will likely lead to scalable cell and biomaterial technologies for use in clinical practice. In this review, we describe recent progress in the field of cardiac tissue engineering with particular emphasis on use of biomaterials for therapeutic tissue design and delivery.
Project description:The origin of the eukaryotic cell remains one of the most contentious puzzles in modern biology. Recent studies have provided support for the emergence of the eukaryotic host cell from within the archaeal domain of life, but the identity and nature of the putative archaeal ancestor remain a subject of debate. Here we describe the discovery of 'Lokiarchaeota', a novel candidate archaeal phylum, which forms a monophyletic group with eukaryotes in phylogenomic analyses, and whose genomes encode an expanded repertoire of eukaryotic signature proteins that are suggestive of sophisticated membrane remodelling capabilities. Our results provide strong support for hypotheses in which the eukaryotic host evolved from a bona fide archaeon, and demonstrate that many components that underpin eukaryote-specific features were already present in that ancestor. This provided the host with a rich genomic 'starter-kit' to support the increase in the cellular and genomic complexity that is characteristic of eukaryotes.
Project description:Materials with optimized band gap are needed in many specialized applications. In this work, we demonstrate that Hellmann-Feynman forces associated with the gap states can be used to find atomic coordinates that yield desired electronic density of states. Using tight-binding models, we show that this approach may be used to arrive at electronically designed models of amorphous silicon and carbon. We provide a simple recipe to include a priori electronic information in the formation of computer models of materials, and prove that this information may have profound structural consequences. The models are validated with plane-wave density functional calculations.