38 research outputs found
Model-based cardiovascular monitoring of acute pulmonary embolism in porcine trials
Introduction:
Diagnosis and treatment of cardiac and circulatory dysfunction can be error-prone and relies heavily on clinical
intuition and experience. Model-based approaches utilising measurements available in the Intensive care unit
(ICU) can provide a clearer physiological picture of a patient’s cardiovascular status to assist medical staff with
diagnosis and therapy decisions. This research tests a subject-specific cardiovascular system (CVS) modelling
technique on measurements from a porcine model of acute pulmonary embolism (APE).
Methods:
Measurements were recorded in 5 pig trials, where autologous blood clots were inserted every two hours into
the jugular vein to simulate pulmonary emboli. Of these measurements only a minimal set of clinically available or
inferable data were used in the identification process (aortic and pulmonary artery pressure, stroke volume, heart
rate, global end diastolic volume, and mitral and tricuspid valve closure times).
The CVS model was fitted to 46 sets of data taken at 30 minute intervals (t=0, 30, 60, …, 270) during the induction
of APE to identify physiological model parameters and their change over time in APE. Model parameters and
outputs were compared to experimentally derived metrics and measurements not used in the identification
method to validate the accuracy of the model and assess its diagnostic capability.
Results:
Modelled mean ventricular volumes and maximum ventricular pressures matched measured values with median
absolute errors of 4.3% and 4.4%, which are less than experimental measurement noise (~10%). An increase in
pulmonary vascular resistance, the main hemodynamic consequence of APE, was identified in all the pigs and
related well to experimental values (R=0.68). Detrimental changes in reflex responses, such as decreased right
ventricular contractility, were noticed in two pigs that died during the trial, diagnosing the loss of autonomous
control. Increases in the ratio of the modelled right to left ventricular end diastolic volumes, signifying the
leftward shift of the intra-ventricular septum seen in APE, compared well to the clinically measured index
(R=0.88).
Conclusions:
Subject-specific CVS models can accurately and continuously diagnose and track acute disease dependent
cardiovascular changes resulting from APE using readily available measurements. Human trials are underway to
clinically validate these animal trial results
Model-based cardiovascular monitoring of large pore hemofiltration during endotoxic shock in pigs
peer reviewe
Minimally invasive, patient specific, beat-by-beat estimation of left ventricular time varying elastance.
peer reviewedBACKGROUND: The aim of this paper was to establish a minimally invasive method for deriving the left ventricular time varying elastance (TVE) curve beat-by-beat, the monitoring of which's inter-beat evolution could add significant new data and insight to improve diagnosis and treatment. The method developed uses the clinically available inputs of aortic pressure, heart rate and baseline end-systolic volume (via echocardiography) to determine the outputs of left ventricular pressure, volume and dead space volume, and thus the TVE curve. This approach avoids directly assuming the shape of the TVE curve, allowing more effective capture of intra- and inter-patient variability. RESULTS: The resulting TVE curve was experimentally validated against the TVE curve as derived from experimentally measured left ventricular pressure and volume in animal models, a data set encompassing 46,318 heartbeats across 5 Pietrain pigs. This simulated TVE curve was able to effectively approximate the measured TVE curve, with an overall median absolute error of 11.4% and overall median signed error of -2.5%. CONCLUSIONS: The use of clinically available inputs means there is potential for real-time implementation of the method at the patient bedside. Thus the method could be used to provide additional, patient specific information on intra- and inter-beat variation in heart function
Incorporating corrosion measurement in hip wear simulators: An added complication or a necessity?
Corrosion is not routinely considered in the assessment of the degradation or the lifetime of total hip replacement bearing surfaces. Biomechanical simulations are becoming ever more complex and are taking into account motion cycles that represent activities beyond a simple walking gait at 1 Hz, marking a departure from the standard ISO BS 14242. However, the degradation is still very often referred to as wear, even though the material loss occurs due to a combination of tribological and corrosion processes and their interactions. This article evaluates how, by incorporating real-time corrosion measurements in total hip replacement simulations, pre-clinical evaluations and research studies can both yield much more information and accelerate the process towards improved implants
A 'synthetic-sickness' screen for senescence re-engagement targets in mutant cancer backgrounds.
Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P. Following rescreen and validation in a second cancer cell line, HCT116 colorectal carcinoma, a panel of 16 of the most robust hits were selected for further validation based on significance and the potential to be targeted by drug-like molecules. Using secondary assays for detection of senescence biomarkers p21, 53BP1 and senescence associated beta-galactosidase (SAβGal) in a panel of HCT116 cell lines carrying cancer-relevant mutations, we show that partial senescence phenotypes can be induced to varying degrees in a context dependent manner, even in the absence of p21 or p53 expression. However, proliferation arrest varied among genetic backgrounds with predominantly toxic effects in p21 null cells, while cells lacking PI3K mutation failed to arrest. Furthermore, we show that the oncogene ECT2 induces partial senescence phenotypes in all mutant backgrounds tested, demonstrating a dependence on activating KRASG13D for growth suppression and a complete senescence response. These results suggest a potential mechanism to target mutant KRAS signalling through ECT2 in cancers that are reliant on activating KRAS mutations and remain refractory to current treatments
Analysis of Aortic Energetics from Pulse Wave Examination in a Porcine Study of Septic Shock
peer reviewe