Pulmonary veins to left atrium cycle length gradient predicts procedural and clinical outcomes of persistent atrial fibrillation ablation.

BACKGROUND Rapid pulmonary vein (PV) activity has been shown to maintain paroxysmal atrial fibrillation (AF). We evaluated in persistent AF the cycle length (CL) gradient between PVs and the left atrium (LA) in an attempt to identify the subset of patients where PVs play an important role. METHODS AND RESULTS Ninety-seven consecutive patients undergoing first ablation for persistent AF were studied. For each PV, the CL of the fastest activation was assessed over 1 minute (PVfast) using Lasso recordings. The PV to LA CL gradient was quantified by the ratio of PVfast to LA appendage (LAA) AF CL. Stepwise ablation terminated AF in 73 patients (75%). In the AF termination group, the PVfast CL was much shorter than the LAA CL resulting in lower PVfast/LAA ratios compared with the nontermination group (71±10% versus 92±7%; P<0.001). Within the termination group, PVfast/LAA ratios were notably lower if AF terminated after PV isolation or limited adjunctive substrate ablation compared with patients who required moderate or extensive ablation (63±6% versus 75±8%; P<0.001). PVfast/LAA ratio <69% predicted AF termination after PV isolation or limited substrate ablation with 74% positive predictive value and 95% negative predictive value. After a mean follow-up of 29±17 months, freedom from arrhythmia recurrence off-antiarrhythmic drugs was achieved in most patients with PVfast/LAA ratios <69% as opposed to the remaining population (80% versus 43%; P<0.001). CONCLUSIONS The PV to LA CL gradient may identify the subset of patients in whom persistent AF is likely to terminate after PV isolation or limited substrate ablation and better long-term outcomes are achieved.

Effect of Pulmonary Hypertension Hemodynamic Presentation on Clinical Outcomes in Patients With Severe Symptomatic Aortic Valve Stenosis Undergoing Transcatheter Aortic Valve Implantation: Insights From the New Proposed Pulmonary Hypertension Classification.

BACKGROUND Pulmonary hypertension (PH) frequently coexists with severe aortic stenosis, and PH severity has been shown to predict outcomes after transcatheter aortic valve implantation (TAVI). The effect of PH hemodynamic presentation on clinical outcomes after TAVI is unknown. METHODS AND RESULTS Of 606 consecutive patients undergoing TAVI, 433 (71.4%) patients with severe aortic stenosis and a preprocedural right heart catheterization were assessed. Patients were dichotomized according to whether PH was present (mean pulmonary artery pressure, ≥25 mm Hg; n=325) or not (n=108). Patients with PH were further dichotomized by left ventricular end-diastolic pressure into postcapillary (left ventricular end-diastolic pressure, >15 mm Hg; n=269) and precapillary groups (left ventricular end-diastolic pressure, ≤15 mm Hg; n=56). Finally, patients with postcapillary PH were divided into isolated (n=220) and combined (n=49) subgroups according to whether the diastolic pressure difference (diastolic pulmonary artery pressure-left ventricular end-diastolic pressure) was normal (<7 mm Hg) or elevated (≥7 mm Hg). Primary end point was mortality at 1 year. PH was present in 325 of 433 (75%) patients and was predominantly postcapillary (n=269/325; 82%). Compared with baseline, systolic pulmonary artery pressure immediately improved after TAVI in patients with postcapillary combined (57.8±14.1 versus 50.4±17.3 mm Hg; P=0.015) but not in those with precapillary (49.0±12.6 versus 51.6±14.3; P=0.36). When compared with no PH, a higher 1-year mortality rate was observed in both precapillary (hazard ratio, 2.30; 95% confidence interval, 1.02-5.22; P=0.046) and combined (hazard ratio, 3.15; 95% confidence interval, 1.43-6.93; P=0.004) but not isolated PH patients (P=0.11). After adjustment, combined PH remained a strong predictor of 1-year mortality after TAVI (hazard ratio, 3.28; P=0.005). CONCLUSIONS Invasive stratification of PH according to hemodynamic presentation predicts acute response to treatment and 1-year mortality after TAVI.

S-nitrosothiol repletion by an inhaled gas regulates pulmonary function

NO synthases are widely distributed in the lung and are extensively involved in the control of airway and vascular homeostasis. It is recognized, however, that the O2-rich environment of the lung may predispose NO toward toxicity. These Janus faces of NO are manifest in recent clinical trials with inhaled NO gas, which has shown therapeutic benefit in some patient populations but increased morbidity in others. In the airways and circulation of humans, most NO bioactivity is packaged in the form of S-nitrosothiols (SNOs), which are relatively resistant to toxic reactions with O2/O\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{2}^{-}}}\end{equation*}\end{document}. This finding has led to the proposition that channeling of NO into SNOs may provide a natural defense against lung toxicity. The means to selectively manipulate the SNO pool, however, has not been previously possible. Here we report on a gas, O-nitrosoethanol (ENO), which does not react with O2 or release NO and which markedly increases the concentration of indigenous species of SNO within airway lining fluid. Inhalation of ENO provided immediate relief from hypoxic pulmonary vasoconstriction without affecting systemic hemodynamics. Further, in a porcine model of lung injury, there was no rebound in cardiopulmonary hemodynamics or fall in oxygenation on stopping the drug (as seen with NO gas), and additionally ENO protected against a decline in cardiac output. Our data suggest that SNOs within the lung serve in matching ventilation to perfusion, and can be manipulated for therapeutic gain. Thus, ENO may be of particular benefit to patients with pulmonary hypertension, hypoxemia, and/or right heart failure, and may offer a new therapeutic approach in disorders such as asthma and cystic fibrosis, where the airways may be depleted of SNOs.

Immunotargeting of antioxidant enzyme to the pulmonary endothelium.

Oxidative injury to the pulmonary endothelium has pathological significance for a spectrum of diseases. Administration of antioxidant enzymes, superoxide dismutase (SOD) and catalase (Cat), has been proposed as a method to protect endothelium. However, neither these enzymes nor their derivatives possess specific affinity to endothelium and do not accumulate in the lung. Previously we have described a monoclonal antibody to angiotensin-converting enzyme (ACE) that accumulates selectively in the lung after systemic injection in rats, hamsters, cats, monkeys, and humans. In the present work we describe a system for selective intrapulmonary delivery of CuZn-SOD and Cat conjugated with biotinylated anti-ACE antibody mAb 9B9 (b-mAb 9B9) by a streptavidin (SA)-biotin bridge. Both enzymes biotinylated with biotin ester at biotin/enzyme ratio 20 retain enzymatic activity and bind SA without loss of activity. We have constructed tri-molecular heteropolymer complexes consisting of b-mAb 9B9, SA, and biotinylated SOD or biotinylated Cat and have studied biodistribution and pulmonary uptake of these complexes in the rat after i.v. injection. Biodistribution of biotinylated enzymes was similar to that of nonmodified enzymes. Binding of SA markedly prolonged lifetime of biotinylated enzymes in the circulation. In contrast to enzymes conjugated with nonspecific IgG, other enzyme derivatives, and nonmodified enzymes, biotinylated enzymes conjugated with b-mAb 9B9 accumulated specifically in the rat lung (9% of injected SOD/g of lung tissue and 7.5% of injected Cat/g of lung tissue). Pulmonary uptake of nonmodified enzymes or derivatives with nonspecific IgG did not exceed 0.5% of injected dose/g. Both SOD and Cat conjugated with b-mAb 9B9 were retained in the rat lung for at least several hours. Trichloracetic acid-precipitable radiolabeled Cat was associated with microsomal and plasma membrane fractions of the lung tissue homogenate. Thus, modification of antioxidant enzymes with biotin and SA-mediated conjugation with b-mAb 9B9 prolongs the circulation of enzymes resulting in selective accumulation in the lung and intracellular delivery of enzymes to the pulmonary endothelium. These results provide the background for an approach to provide protection of pulmonary endothelium against oxidative insults.

Effet préventif de la milrinone inhalée chez les patients avec hypertension pulmonaire subissant une chirurgie cardiaque sous circulation extracorporelle : une approche pharmacométrique

La circulation extracorporelle (CEC) est une technique utilisée en chirurgie cardiaque effectuée des milliers de fois chaque jour à travers le monde. L’instabilité hémodynamique associée au sevrage de la CEC difficile constitue la principale cause de mortalité en chirurgie cardiaque et l’hypertension pulmonaire (HP) a été identifiée comme un des facteurs de risque les plus importants. Récemment, une hypothèse a été émise suggérant que l'administration prophylactique (avant la CEC) de la milrinone par inhalation puisse avoir un effet préventif et faciliter le sevrage de la CEC chez les patients atteints d’HP. Toutefois, cette indication et voie d'administration pour la milrinone n'ont pas encore été approuvées par les organismes réglementaires. Jusqu'à présent, la recherche clinique sur la milrinone inhalée s’est principalement concentrée sur l’efficacité hémodynamique et l'innocuité chez les patients cardiaques, bien qu’aucun biomarqueur n’ait encore été établi. La dose la plus appropriée pour l’administration par nébulisation n'a pas été déterminée, de même que la caractérisation des profils pharmacocinétiques (PK) et pharmacodynamiques (PD) suite à l'inhalation. L'objectif de notre recherche consistait à caractériser la relation exposition-réponse de la milrinone inhalée administrée chez les patients subissant une chirurgie cardiaque sous CEC. Une méthode analytique par chromatographie liquide à haute performance couplée à un détecteur ultraviolet (HPLC-UV) a été optimisée et validée pour le dosage de la milrinone plasmatique suite à l’inhalation et s’est avérée sensible et précise. La limite de quantification (LLOQ) était de 1.25 ng/ml avec des valeurs de précision intra- et inter-dosage moyennes (CV%) <8%. Des patients souffrant d’HP pour lesquels une chirurgie cardiaque sous CEC était prévue ont d’abord été recrutés pour une étude pilote (n=12) et, par la suite, pour une étude à plus grande échelle (n=28) où la milrinone (5 mg) était administrée par inhalation pré-CEC. Dans l'étude pilote, nous avons comparé l'exposition systémique de la milrinone peu après son administration avec un nébuliseur pneumatique ou un nébuliseur à tamis vibrant. L’efficacité des nébuliseurs en termes de dose émise et dose inhalée a également été déterminée in vitro. Dans l'étude à plus grande échelle conduite en utilisant exclusivement le nébuliseur à tamis vibrant, la dose inhalée in vivo a été estimée et le profil pharmacocinétique de la milrinone inhalée a été pleinement caractérisé aux niveaux plasmatique et urinaire. Le ratio de la pression artérielle moyenne sur la pression artérielle pulmonaire moyenne (PAm/PAPm) a été choisi comme biomarqueur PD. La relation exposition-réponse de la milrinone a été caractérisée pendant la période d'inhalation en étudiant la relation entre l'aire sous la courbe de l’effet (ASCE) et l’aire sous la courbe des concentrations plasmatiques (ASC) de chacun des patients. Enfin, le ratio PAm/PAPm a été exploré comme un prédicteur potentiel de sortie de CEC difficile dans un modèle de régression logistique. Les expériences in vitro ont démontré que les doses émises étaient similaires pour les nébuliseurs pneumatique (64%) et à tamis vibrant (68%). Cependant, la dose inhalée était 2-3 fois supérieure (46% vs 17%) avec le nébuliseur à tamis vibrant, et ce, en accord avec les concentrations plasmatiques. Chez les patients, en raison des variations au niveau des facteurs liés au circuit et au ventilateur causant une plus grande dose expirée, la dose inhalée a été estimée inférieure (30%) et cela a été confirmé après récupération de la dose de milrinone dans l'urine 24 h (26%). Les concentrations plasmatiques maximales (Cmax: 41-189 ng/ml) et l'ampleur de la réponse maximale ΔRmax-R0 (0-65%) ont été observées à la fin de l'inhalation (10-30 min). Les données obtenues suite aux analyses PK sont en accord avec les données publiées pour la milrinone intraveineuse. Après la période d'inhalation, les ASCE individuelles étaient directement reliées aux ASC (P=0.045). Enfin, notre biomarqueur PD ainsi que la durée de CEC ont été identifiés comme des prédicteurs significatifs de la sortie de CEC difficile. La comparaison des ASC et ASCE correspondantes a fourni des données préliminaires supportant une preuve de concept pour l'utilisation du ratio PAm/PAPm comme biomarqueur PD prometteur et justifie de futures études PK/PD. Nous avons pu démontrer que la variation du ratio PAm/PAPm en réponse à la milrinone inhalée contribue à la prévention de la sortie de CEC difficile.

Effet préventif de la milrinone inhalée chez les patients avec hypertension pulmonaire subissant une chirurgie cardiaque sous circulation extracorporelle : une approche pharmacométrique

La circulation extracorporelle (CEC) est une technique utilisée en chirurgie cardiaque effectuée des milliers de fois chaque jour à travers le monde. L’instabilité hémodynamique associée au sevrage de la CEC difficile constitue la principale cause de mortalité en chirurgie cardiaque et l’hypertension pulmonaire (HP) a été identifiée comme un des facteurs de risque les plus importants. Récemment, une hypothèse a été émise suggérant que l'administration prophylactique (avant la CEC) de la milrinone par inhalation puisse avoir un effet préventif et faciliter le sevrage de la CEC chez les patients atteints d’HP. Toutefois, cette indication et voie d'administration pour la milrinone n'ont pas encore été approuvées par les organismes réglementaires. Jusqu'à présent, la recherche clinique sur la milrinone inhalée s’est principalement concentrée sur l’efficacité hémodynamique et l'innocuité chez les patients cardiaques, bien qu’aucun biomarqueur n’ait encore été établi. La dose la plus appropriée pour l’administration par nébulisation n'a pas été déterminée, de même que la caractérisation des profils pharmacocinétiques (PK) et pharmacodynamiques (PD) suite à l'inhalation. L'objectif de notre recherche consistait à caractériser la relation exposition-réponse de la milrinone inhalée administrée chez les patients subissant une chirurgie cardiaque sous CEC. Une méthode analytique par chromatographie liquide à haute performance couplée à un détecteur ultraviolet (HPLC-UV) a été optimisée et validée pour le dosage de la milrinone plasmatique suite à l’inhalation et s’est avérée sensible et précise. La limite de quantification (LLOQ) était de 1.25 ng/ml avec des valeurs de précision intra- et inter-dosage moyennes (CV%) <8%. Des patients souffrant d’HP pour lesquels une chirurgie cardiaque sous CEC était prévue ont d’abord été recrutés pour une étude pilote (n=12) et, par la suite, pour une étude à plus grande échelle (n=28) où la milrinone (5 mg) était administrée par inhalation pré-CEC. Dans l'étude pilote, nous avons comparé l'exposition systémique de la milrinone peu après son administration avec un nébuliseur pneumatique ou un nébuliseur à tamis vibrant. L’efficacité des nébuliseurs en termes de dose émise et dose inhalée a également été déterminée in vitro. Dans l'étude à plus grande échelle conduite en utilisant exclusivement le nébuliseur à tamis vibrant, la dose inhalée in vivo a été estimée et le profil pharmacocinétique de la milrinone inhalée a été pleinement caractérisé aux niveaux plasmatique et urinaire. Le ratio de la pression artérielle moyenne sur la pression artérielle pulmonaire moyenne (PAm/PAPm) a été choisi comme biomarqueur PD. La relation exposition-réponse de la milrinone a été caractérisée pendant la période d'inhalation en étudiant la relation entre l'aire sous la courbe de l’effet (ASCE) et l’aire sous la courbe des concentrations plasmatiques (ASC) de chacun des patients. Enfin, le ratio PAm/PAPm a été exploré comme un prédicteur potentiel de sortie de CEC difficile dans un modèle de régression logistique. Les expériences in vitro ont démontré que les doses émises étaient similaires pour les nébuliseurs pneumatique (64%) et à tamis vibrant (68%). Cependant, la dose inhalée était 2-3 fois supérieure (46% vs 17%) avec le nébuliseur à tamis vibrant, et ce, en accord avec les concentrations plasmatiques. Chez les patients, en raison des variations au niveau des facteurs liés au circuit et au ventilateur causant une plus grande dose expirée, la dose inhalée a été estimée inférieure (30%) et cela a été confirmé après récupération de la dose de milrinone dans l'urine 24 h (26%). Les concentrations plasmatiques maximales (Cmax: 41-189 ng/ml) et l'ampleur de la réponse maximale ΔRmax-R0 (0-65%) ont été observées à la fin de l'inhalation (10-30 min). Les données obtenues suite aux analyses PK sont en accord avec les données publiées pour la milrinone intraveineuse. Après la période d'inhalation, les ASCE individuelles étaient directement reliées aux ASC (P=0.045). Enfin, notre biomarqueur PD ainsi que la durée de CEC ont été identifiés comme des prédicteurs significatifs de la sortie de CEC difficile. La comparaison des ASC et ASCE correspondantes a fourni des données préliminaires supportant une preuve de concept pour l'utilisation du ratio PAm/PAPm comme biomarqueur PD prometteur et justifie de futures études PK/PD. Nous avons pu démontrer que la variation du ratio PAm/PAPm en réponse à la milrinone inhalée contribue à la prévention de la sortie de CEC difficile.

Nurse-determined assessment of cardiac output. Comparing a non-invasive cardiac output device and pulmonary artery catheter: a prospective observational study.

Background The accurate measurement of Cardiac output (CO) is vital in guiding the treatment of critically ill patients. Invasive or minimally invasive measurement of CO is not without inherent risks to the patient. Skilled Intensive Care Unit (ICU) nursing staff are in an ideal position to assess changes in CO following therapeutic measures. The USCOM (Ultrasonic Cardiac Output Monitor) device is a non-invasive CO monitor whose clinical utility and ease of use requires testing. Objectives To compare cardiac output measurement using a non-invasive ultrasonic device (USCOM) operated by a non-echocardiograhically trained ICU Registered Nurse (RN), with the conventional pulmonary artery catheter (PAC) using both thermodilution and Fick methods. Design Prospective observational study. Setting and participants Between April 2006 and March 2007, we evaluated 30 spontaneously breathing patients requiring PAC for assessment of heart failure and/or pulmonary hypertension at a tertiary level cardiothoracic hospital. Methods SCOM CO was compared with thermodilution measurements via PAC and CO estimated using a modified Fick equation. This catheter was inserted by a medical officer, and all USCOM measurements by a senior ICU nurse. Mean values, bias and precision, and mean percentage difference between measures were determined to compare methods. The Intra-Class Correlation statistic was also used to assess agreement. The USCOM time to measure was recorded to assess the learning curve for USCOM use performed by an ICU RN and a line of best fit demonstrated to describe the operator learning curve. Results In 24 of 30 (80%) patients studied, CO measures were obtained. In 6 of 30 (20%) patients, an adequate USCOM signal was not achieved. The mean difference (±standard deviation) between USCOM and PAC, USCOM and Fick, and Fick and PAC CO were small, −0.34 ± 0.52 L/min, −0.33 ± 0.90 L/min and −0.25 ± 0.63 L/min respectively across a range of outputs from 2.6 L/min to 7.2 L/min. The percent limits of agreement (LOA) for all measures were −34.6% to 17.8% for USCOM and PAC, −49.8% to 34.1% for USCOM and Fick and −36.4% to 23.7% for PAC and Fick. Signal acquisition time reduced on average by 0.6 min per measure to less than 10 min at the end of the study. Conclusions In 80% of our cohort, USCOM, PAC and Fick measures of CO all showed clinically acceptable agreement and the learning curve for operation of the non-invasive USCOM device by an ICU RN was found to be satisfactorily short. Further work is required in patients receiving positive pressure ventilation.

Passive control of a bi-ventricular assist device : an experimental and numerical investigation

For the last two decades heart disease has been the highest single cause of death for the human population. With an alarming number of patients requiring heart transplant, and donations not able to satisfy the demand, treatment looks to mechanical alternatives. Rotary Ventricular Assist Devices, VADs, are miniature pumps which can be implanted alongside the heart to assist its pumping function. These constant flow devices are smaller, more efficient and promise a longer operational life than more traditional pulsatile VADs. The development of rotary VADs has focused on single pumps assisting the left ventricle only to supply blood for the body. In many patients however, failure of both ventricles demands that an additional pulsatile device be used to support the failing right ventricle. This condition renders them hospital bound while they wait for an unlikely heart donation. Reported attempts to use two rotary pumps to support both ventricles concurrently have warned of inherent haemodynamic instability. Poor balancing of the pumps’ flow rates quickly leads to vascular congestion increasing the risk of oedema and ventricular ‘suckdown’ occluding the inlet to the pump. This thesis introduces a novel Bi-Ventricular Assist Device (BiVAD) configuration where the pump outputs are passively balanced by vascular pressure. The BiVAD consists of two rotary pumps straddling the mechanical passive controller. Fluctuations in vascular pressure induce small deflections within both pumps adjusting their outputs allowing them to maintain arterial pressure. To optimise the passive controller’s interaction with the circulation, the controller’s dynamic response is optimised with a spring, mass, damper arrangement. This two part study presents a comprehensive assessment of the prototype’s ‘viability’ as a support device. Its ‘viability’ was considered based on its sensitivity to pathogenic haemodynamics and the ability of the passive response to maintain healthy circulation. The first part of the study is an experimental investigation where a prototype device was designed and built, and then tested in a pulsatile mock circulation loop. The BiVAD was subjected to a range of haemodynamic imbalances as well as a dynamic analysis to assess the functionality of the mechanical damper. The second part introduces the development of a numerical program to simulate human circulation supported by the passively controlled BiVAD. Both investigations showed that the prototype was able to mimic the native baroreceptor response. Simulating hypertension, poor flow balancing and subsequent ventricular failure during BiVAD support allowed the passive controller’s response to be assessed. Triggered by the resulting pressure imbalance, the controller responded by passively adjusting the VAD outputs in order to maintain healthy arterial pressures. This baroreceptor-like response demonstrated the inherent stability of the auto regulating BiVAD prototype. Simulating pulmonary hypertension in the more observable numerical model, however, revealed a serious issue with the passive response. The subsequent decrease in venous return into the left heart went unnoticed by the passive controller. Meanwhile the coupled nature of the passive response not only decreased RVAD output to reduce pulmonary arterial pressure, but it also increased LVAD output. Consequently, the LVAD increased fluid evacuation from the left ventricle, LV, and so actually accelerated the onset of LV collapse. It was concluded that despite the inherently stable baroreceptor-like response of the passive controller, its lack of sensitivity to venous return made it unviable in its present configuration. The study revealed a number of other important findings. Perhaps the most significant was that the reduced pulse experienced during constant flow support unbalanced the ratio of effective resistances of both vascular circuits. Even during steady rotary support therefore, the resulting ventricle volume imbalance increased the likelihood of suckdown. Additionally, mechanical damping of the passive controller’s response successfully filtered out pressure fluctuations from residual ventricular function. Finally, the importance of recognising inertial contributions to blood flow in the atria and ventricles in a numerical simulation were highlighted. This thesis documents the first attempt to create a fully auto regulated rotary cardiac assist device. Initial results encourage development of an inlet configuration sensitive to low flow such as collapsible inlet cannulae. Combining this with the existing baroreceptor-like response of the passive controller will render a highly stable passively controlled BiVAD configuration. The prototype controller’s passive interaction with the vasculature is a significant step towards a highly stable new generation of artificial heart.

A naturally shaped silicone ventricle evaluated in a mock circulation loop : a preliminary study

Mock circulation loops are used to evaluate the performance of cardiac assist devices prior to animal and clinical testing. A compressible, translucent silicone ventricle chamber that mimics the exact size, shape and motion of a failing heart is desired to assist in flow visualization studies around inflow cannulae during VAD support. The aim of this study was therefore to design and construct a naturally shaped flexible left ventricle and evaluate its performance in a mock circulation loop. The ventricle shape was constructed by the use of CT images taken from a patient experiencing cardiomyopathic heart failure and used to create a 3D image and subsequent mould to produce a silicone ventricle. Different cardiac conditions were successfully simulated to validate the ventricle performance, including rest, left heart failure and VAD support.

Simulation and development of a mock circulation loop with variable compliance

Heart disease is attributed as the highest cause of death in the world. Although this could be alleviated by heart transplantation, there is a chronic shortage of donor hearts and so mechanical solutions are being considered. Currently, many Ventricular Assist Devices (VADs) are being developed worldwide in an effort to increase life expectancy and quality of life for end stage heart failure patients. Current pre-clinical testing methods for VADs involve laboratory testing using Mock Circulation Loops (MCLs), and in vivo testing in animal models. The research and development of highly accurate MCLs is vital to the continuous improvement of VAD performance. The first objective of this study was to develop and validate a mathematical model of a MCL. This model could then be used in the design and construction of a variable compliance chamber to improve the performance of an existing MCL as well as form the basis for a new miniaturised MCL. An extensive review of literature was carried out on MCLs and mathematical modelling of their function. A mathematical model of a MCL was then created in the MATLAB/SIMULINK environment. This model included variable features such as resistance, fluid inertia and volumes (resulting from the pipe lengths and diameters); compliance of Windkessel chambers, atria and ventricles; density of both fluid and compressed air applied to the system; gravitational effects on vertical columns of fluid; and accurately modelled actuators controlling the ventricle contraction. This model was then validated using the physical properties and pressure and flow traces produced from a previously developed MCL. A variable compliance chamber was designed to reproduce parameters determined by the mathematical model. The function of the variability was achieved by controlling the transmural pressure across a diaphragm to alter the compliance of the system. An initial prototype was tested in a previously developed MCL, and a variable level of arterial compliance was successfully produced; however, the complete range of compliance values required for accurate physiological representation was not able to be produced with this initial design. The mathematical model was then used to design a smaller physical mock circulation loop, with the tubing sizes adjusted to produce accurate pressure and flow traces whilst having an appropriate frequency response characteristic. The development of the mathematical model greatly assisted the general design of an in vitro cardiovascular device test rig, while the variable compliance chamber allowed simple and real-time manipulation of MCL compliance to allow accurate transition between a variety of physiological conditions. The newly developed MCL produced an accurate design of a mechanical representation of the human circulatory system for in vitro cardiovascular device testing and education purposes. The continued improvement of VAD test rigs is essential if VAD design is to improve, and hence improve quality of life and life expectancy for heart failure patients.

When and how to treat pulmonary non-tuberculous mycobacterial diseases

Nontuberculous mycobacteria are ubiquitous environmental organisms that have been recognised as a cause of pulmonary infection for over 50 years. Traditionally patients have had underlying risk factors for development of disease; however the proportion of apparently immunocompetent patients involved appears to be rising. Not all patients culture-positive for mycobacteria will have progressive disease, making the diagnosis difficult, though criteria to aid in this process are available. The two main forms of disease are cavitary disease (usually involving the upper lobes) and fibronodular bronchiectasis (predominantly middle and lingular lobes). For patients with disease, combination antibiotic therapy for 12-24 months is generally required for successful treatment, and this may be accompanied by drug intolerances and side effects. Published success rates range from 30-82%. As the progression of disease is variable, for some patients, attention to pulmonary hygiene and underlying diseases without immediate antimycobacterial therapy may be more appropriate. Surgery can be a useful adjunct, though is associated with risks. Randomised controlled trials in well described patients would provide stronger evidence-based data to guide therapy of NTM lung diseases, and thus are much needed.

Modeling circulation of train-set with multiple routing

Planning on utilization of train-set is one of the key tasks of transport organization for passenger dedicated railway in China. It also has strong relationships with timetable scheduling and operation plans at a station. To execute such a task in a railway hub pooling multiple railway lines, the characteristics of multiple routing for train-set is discussed in term of semicircle of train-sets' turnover. In programming the described problem, the minimum dwell time is selected as the objectives with special derive constraints of the train-set's dispatch, the connecting conditions, the principle of uniqueness for train-sets, and the first plus for connection in the same direction based on time tolerance σ. A compact connection algorithm based on time tolerance is then designed. The feasibility of the model and the algorithm is proved by the case study. The result indicates that the circulation model and algorithm about multiple routing can deal with the connections between the train-sets of multiple directions, and reduce the train's pulling in or leaving impact on the station's throat.