Effect of RVAD Cannulation Length on Right Ventricular Thrombosis Risk: An In Silico Investigation.

Left ventricular assist devices (LVADs) have been used off-label as long-term support of the right heart due to the lack of a clinically approved durable right VAD (RVAD). Whilst various techniques to reduce RVAD inflow cannula protrusion have been described, the implication of the protrusion length on right heart blood flow and subsequent risk of thrombosis remains poorly understood. This study investigates the influence of RVAD diaphragmatic cannulation length on right ventricular thrombosis risk using a patient-specific right ventricle in silico model validated with particle image velocimetry. Four cannulation lengths (5, 10, 15 and 25 mm) were evaluated in a one-way fluid-structure interaction simulation with boundary conditions generated from a lumped parameter model, simulating a biventricular supported condition. Simulation results demonstrated that the 25-mm cannulation length exhibited a lower thrombosis risk compared to 5-, 10- and 15-mm cannulation lengths due to improved flow energy distribution (25.2%, 24.4% and 17.8% increased), reduced stagnation volume (72%, 68% and 49% reduction), better washout rate (13.0%, 11.6% and 9.1% faster) and lower blood residence time (6% reduction). In the simulated scenario, our findings suggest that a longer RVAD diaphragmatic cannulation length may be beneficial in lowering thrombosis risk; however, further clinical studies are warranted.

Ventricular Flow Dynamics With an Intra-Ventricular Balloon Pump: An In Vitro Analysis.

Due to the high treatment costs associated with durable ventricular assist devices, an intra-ventricular balloon pump (IVBP) was developed to provide low-cost, short-term support for patients suffering from severe heart failure. It is imperative that intraventricular flow dynamics are evaluated with an IVBP to ensure stagnation points, and potential regions for thrombus formation, are avoided. This study used particle image velocimetry to evaluate flow patterns within the left ventricle of a simulated severe heart failure patient with IVBP support to assess left ventricle pulsatility as an indicator of the likelihood of flow stasis. Two inflation timings were evaluated against the baseline severe heart failure condition: IVBP co-pulsation and IVBP counter-pulsation with respect to ventricular systole. IVBP co-pulsation was found to have a reduced velocity range compared to the severe heart failure condition (0.44 m/s compared to 0.54 m/s). IVBP co-pulsation demonstrated an increase in peak velocities (0.25 m/s directed toward the aortic valve during systole, as opposed to 0.2 m/s in severe heart failure), indicating constructive energy in systole and cardiac output (1.7 L/min increase with respect to severe heart failure baseline - 3.5 L/min) throughout the cardiac cycle. IVBP counter-pulsation, while exhibiting the greatest peak systolic velocity directed to the aortic valve (0.4 m/s) was found to counterasct the natural vortex flow pattern during ventricular filling, as well as inducing a secondary ventricular pulse during diastole and a 23% increase in left ventricle end-diastolic volume (indicative of dilation). Ideal IVBP actuation timing did not result in reduced intraventricular pulsatility, indicating promising blood washout.

In silico Prediction of Thrombosis Risk in a Ventricular Assist Device Supported Right Heart: The Impact of Cannulation Site.

Right ventricular assist device (RVAD) associated thrombosis is a serious complication that may arise due to unfavorable blood flow dynamics (blood stasis) caused by RVAD cannula protrusion within the chambers. This study aims to investigate the thrombosis risk of cannulation via the right atrium (RA) and right ventricle (RV) (diaphragmatic) under full RVAD support using computational fluid dynamics. A HeartWare HVAD inflow cannula was virtually implanted in either the RA or RV of a rigid-walled right heart geometry (including RA, RV, superior, and inferior vena cava) extracted from computed tomography data of a biventricular support patient. Transient simulations, validated with particle image velocimetry, were performed with constant inflow. Thrombosis risk was predicted by analyzing the time-averaged blood velocity, blood stagnation volume, washout rate, and blood residence time (BRT). Results showed that RA cannulation disturbed the physiological swirling flow structure which can be found in an uncannulated RA. This led to a large low-velocity recirculation flow in the RV, increasing the thrombosis risk. Contrarily, RV diaphragmatic cannulation showed better preservation of swirling flow in the RA and flow ejection into the RV. Consequently, RV diaphragmatic cannulation exhibited a better washout rate (99% vs. 57% of old blood was replaced in 12 s), lower blood stagnation volume (0.13 ml vs. 32.85 ml), and BRT (4.2 s vs. 7.1 s) than the RA cannulation in this simulated non-pulsatile case. Our findings suggest that RV diaphragmatic cannulation had a lower thrombosis risk and might be more favorable in a full RVAD-supported setting.

Mechanism of Staple Line Leak After Sleeve Gastrectomy via Isobaric Pressurisation Concentrating Stress Forces at the Proximal Staple Line.

PURPOSE: Staple line leak following sleeve gastrectomy is a significant problem and has been hypothesised to be related to hyperpressurisation in the proximal stomach. There is, however, little objective evidence demonstrating how these forces could be transmitted to the luminal wall. We aimed to define conditions in the proximal stomach and simulate the transmission of stress forces in the post-operative stomach using a finite element analysis (FEA). MATERIALS AND METHODS: The manometry of fourteen patients post sleeve gastrectomy was compared to ten controls. Manometry, boundary conditions, and volumetric CT were integrated to develop six models. These models delineated luminal wall stress in the proximal stomach. Key features were then varied to establish the influence of each factor. RESULTS: The sleeve gastrectomy cohort had a significantly higher peak intragastric isobaric pressures 31.58 ± 2.1 vs. 13.49 ± 1.3 mmHg (p = 0.0002). Regions of stress were clustered at the staple line near the GOJ, and peak stress was observed there in 67% of models. A uniform greater curvature did not fail or concentrate stress under maximal pressurisation. Geometric variation demonstrated that a larger triangulated apex increased stress by 17% (255 kPa versus 218 kPa), with a 37% increase at the GOJ (203kPA versus 148kPA). A wider incisura reduced stress at the GOJ by 9.9% (128 kPa versus 142 kPa). CONCLUSION: High pressure events can occur in the proximal stomach after sleeve gastrectomy. Simulations suggest that these events preferentially concentrate stress forces near the GOJ. This study simulates how high-pressure events could translate stress to the luminal wall and precipitate leak.

Improved Flow Dynamics of Extracorporeal Membrane Oxygenation via Design Modification of Dual-Lumen Cannulas.

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) supports patients with severe respiratory failure not responding to conventional treatments. Single-site jugular venous cannulation with dual-lumen cannulas (DLC) have several advantages over traditional single-lumen cannulas, however, bleeding and thrombosis are common, limiting their clinical utility. This study numerically investigated the effects of DLC side holes on blood flow dynamics since the maximum wall shear stress (WSS) occurs around the side holes. A DLC based on the Avalon Elite 27Fr model was implanted into an idealized 3D model of the vena cava and right atrium (RA). Eight DLCs were developed by changing the number, diameter, and spacing of side holes through an iterative design process. Physiologic flow at the inferior vena cava (IVC) and superior vena cava (SVC) were applied along with a partial ECMO support of 2 L/min. The SST k-ω turbulent model was solved for 6.4 seconds. WSS, washout, stagnation volume, and recirculation were compared. For all DLCs, no stasis region lasted more than one cardiac cycle and a complete washout was obtained in less than 4 seconds. Due to the IVC and SVC backflows, maximum WSS occurred around the DLC side holes at late systole and late diastole. A DLC with 16 and three side holes within the IVC and SVC, respectively, reduced the maximum WSS by up to 67% over the Avalon Elite 27Fr. Improved DLCs provided a more uniform WSS distribution with lower WSS around the side holes, potentially reducing the chance of thrombosis and bleeding.

Improved Drainage Cannula Design to Reduce Thrombosis in Veno-Arterial Extracorporeal Membrane Oxygenation.

Thrombosis is a potentially life-threatening complication in veno-arterial extracorporeal membrane oxygenation (ECMO) circuits, which may originate from the drainage cannula due to unfavorable blood flow dynamics. This study aims to numerically investigate the effect of cannula design parameters on local fluid dynamics, and thus thrombosis potential, within ECMO drainage cannulas. A control cannula based on the geometry of a 17 Fr Medtronic drainage cannula concentrically placed in an idealized, rigid-walled geometry of the right atrium and superior and inferior vena cava was numerically modeled. Simulated flow dynamics in the control cannula were systematically compared with 10 unique cannula designs which incorporated changes to side hole diameter, the spacing between side holes, and side hole angles. Local blood velocities, maximum wall shear stress (WSS), and blood residence time were used to predict the risk of thrombosis. Numerical results were experimentally validated using particle image velocimetry. The control cannula exhibited low blood velocities (59 mm/s) at the cannula tip, which may promote thrombosis. Through a reduction in the side hole diameter (2 mm), the spacing between the side holes (3 mm) and alteration in the side hole angle (30° relative to the flow direction), WSS was reduced by 52%, and cannula tip blood velocity was increased by 560% compared to the control cannula. This study suggests that simple geometrical changes can significantly alter the risk of thrombosis in ECMO drainage cannulas.

Efficacy and Safety Exposure-Response Analysis of Loncastuximab Tesirine in Patients with B cell non-Hodgkin Lymphoma.

We developed an integrated population pharmacokinetic model to investigate loncastuximab tesirine pharmacokinetics (PK) and exposure-response relationships for relapsed/refractory B cell non-Hodgkin lymphoma, including diffuse large B cell lymphoma (DLBCL). The model, based on the recommended dosing schedule (150 µg/kg every 3 weeks [Q3W] for 2 cycles; 75 µg/kg Q3W thereafter) and drug concentrations in phase 1 and 2 studies (DLBCL [n = 284], non-DLBCL [n = 44]), was used to characterize loncastuximab tesirine PK and evaluate exposure covariates. Relationships between exposure (pyrrolobenzodiazepine-conjugated antibody [cAb] cycle 1 average concentration) and (1) efficacy (including overall response rate [ORR; primary endpoint] and overall survival [OS]) and (2) grade ≥ 2 treatment-emergent adverse events were explored. Statistical analyses included univariate and multivariate logistic regression, Kaplan-Meier analysis, and Cox proportional hazard regression. cAb and total Ab were best described by a two-compartment linear model with time-dependent clearance. The cAb steady-state half-life increased to 20.6 days by ~ 15 weeks. cAb exposure was lower for low albumin, mild/moderate hepatic impairment, non-DLBCL subtypes, and Eastern Cooperative Oncology Group scores > 1. Significant positive associations were reported between exposure and ORR (p = 3.21E-6), OS (p = 0.0016), grade ≥ 2 increased gamma-glutamyltransferase, liver function test abnormalities, pain, and skin/nail reactions (p < 0.05). Low albumin, bulky disease, and mild/moderate hepatic impairment had a significant negative effect on OS (p < 0.01). Modeling supports the recommended loncastuximab tesirine dosing schedule. Although reduced exposure and efficacy were predicted for specific covariates (e.g., low albumin, mild/moderate hepatic impairment), dose increases are not recommended. Trial registration: NCT02669017 and NCT03589469.

Understanding the influence of left ventricular assist device inflow cannula alignment and the risk of intraventricular thrombosis.

BACKGROUND: Adverse neurological events associated with left ventricular assist devices (LVADs) have been suspected to be related to thrombosis. This study aimed to understand the risks of thrombosis with variations in the implanted device orientation. A severely dilated pulsatile patient-specific left ventricle, modelled with computational fluid dynamics, was utilised to identify the risk of thrombosis for five cannulation angles. With respect to the inflow cannula axis directed towards the mitral valve, the other angles were 25° and 20° towards the septum and 20° and 30° towards the free wall. RESULTS: Inflow cannula angulation towards the free wall resulted in longer blood residence time within the ventricle, slower ventricular washout and reduced pulsatility indices along the septal wall. Based on the model, the ideal inflow cannula alignment to reduce the risk of thrombosis was angulation towards the mitral valve and up to parallel to the septum, avoiding the premature clearance of incoming blood. CONCLUSIONS: This study indicates the potential effects of inflow cannulation angles and may guide optimised implantation configurations; however, the ideal approach will be influenced by other patient factors and is suspected to change over the course of support.

Population Pharmacokinetics and Exposure-Response Modeling of Golimumab in Adults With Moderately to Severely Active Ulcerative Colitis.

PURPOSE: Golimumab is a fully human monoclonal antibody to tumor necrosis factor-α and is indicated for the treatment of moderately to severely active ulcerative colitis (UC). This study analyzed the population pharmacokinetic (PK) properties of golimumab and exposure-response for efficacy and safety, using data from combined Phase II/III UC studies. METHODS: Data on serum golimumab concentration following IV and subcutaneous (SC) administration were fitted simultaneously using nonlinear mixed-effects modeling for the development of a population PK model. Logistic regression models were used for assessing relationships between serum golimumab concentrations and clinical efficacy outcomes in SC induction and maintenance studies. The percentages of patients developing infections, serious infections, and serious adverse events were assessed by golimumab exposure metric quartiles. FINDINGS: The PK properties of golimumab are well described by a 2-compartment model with first-order absorption and elimination. Typical values of PK parameters in a 70-kg patient were clearance, 0.544 L/d; central and peripheral compartment Vd, 3.43 and 2.27 L, respectively; and intercompartmental clearance, 0.291 L/d. Golimumab t1/2 was 10.5 days; bioavailability following SC administration was 52.2%. Body weight, anti-golimumab antibodies, serum albumin, C-reactive protein, and alkaline phosphatase affected golimumab disposition. A positive exposure-response relationship was established between golimumab concentration and efficacy outcomes. No apparent correlation between golimumab exposure and rate of infections, serious infections, or serious adverse events was observed in patients receiving golimumab 50 or 100 mg SC every 4 weeks through 1 year. IMPLICATIONS: Body weight, serum albumin, and anti-golimumab antibodies explain some of the variability observed in the PK properties of golimumab, and exposure-response findings support the recommended posology of golimumab in UC. ClinicalTrials.gov identifiers: NCT00488774, NCT00487539, and NCT00488631.

Evaluation of an intraventricular balloon pump for short-term support of patients with heart failure.

The high cost of ventricular assist devices results in poor cost-effectiveness when used as a short-term bridging solution, thus a low-cost alternative is desirable. The present study aimed to develop an intraventricular balloon pump (IVBP) for short-term circulatory support, and to evaluate the effect of balloon actuation timing on the degree of cardiac support provided to a simulated in vitro severe heart failure (SHF) patient. A silicone IVBP was designed to avoid contact with internal left ventricular (LV) features (ie, papillary muscles, chordae, aortic, and mitral valves) based on LV computed tomography data of 10 SHF patients with dilated cardiomyopathy. The hemodynamic effects of varying balloon inflation and deflation timing parameters (inflation duty [D] and end-inflation point [σ]) were evaluated in a purpose-built systemic mock circulatory loop. Three IVBP actuation timing categories were defined: co-, transitional, and counterpulsation. Compared to the SHF baseline, co-pulsation increased aortic flow from 3.5 to 5.2 L/min, mean arterial pressure from 72.1 to 94.8 mmHg and ejection fraction from 14.4% to 21.5%, while mean left atrial pressure decreased from 14.6 to 10 mmHg. Transitional and counterpulsation resulted in a double ventricular pulse and extended the duration of increased ventricular pressure, potentially impeding diastolic filling and coronary perfusion. This in vitro study showed the IVBP could restore the hemodynamic balance of a simulated SHF patient with dilated cardiomyopathy to healthy levels.

Numerical simulations of different configured venous anastomosis in microvascular flap transfer.

BACKGROUND: Free flap surgery is a well-established method for covering large defects in the head and neck region. Most cases of flap failure are caused by venous thrombosis. Thus, there is a lot of discussion about the ideal design of venous anastomosis and its impact on the hemodynamics in the vessels. This study concentrates on the simulation of flow patterns of different designs of venous anastomoses. METHODS: First, fluid flow rates were measured using transit-time flow measurement in the veins of 20 patients who received free flaps between 2016 and 2017. Five different designs of porcine anastomoses were scanned using micro-computed tomography, to create three-dimensional models. In the second step, numerical simulations of the blood flow were performed to gain insights into the vessel flow patterns. RESULTS: The simulations revealed recirculation areas in the 60° and 90° end-to-side anastomoses, especially in combination with low fluid flow rates. In addition, there were large areas of recirculation in the 1:3 end-to-end anastomoses. CONCLUSION: The type of venous anastomosis should be decided individually. End-to-side anastomosis can be recommended in cases with high caliber differences or in those with high venous outflow. End-to-end anastomoses should be preferred in conditions with low venous outflow.

The Influence of Rotary Blood Pump Speed Modulation on the Risk of Intraventricular Thrombosis.

Rotary left ventricular assist devices (LVADs) are commonly operated at a constant speed, attenuating blood flow pulsatility. Speed modulation of rotary LVADs has been demonstrated to improve vascular pulsatility and pump washout. The effect of LVAD speed modulation on intraventricular flow dynamics is not well understood, which may have an influence on thromboembolic events. This study aimed to numerically evaluate intraventricular flow characteristics with a speed modulated LVAD. A severely dilated anatomical left ventricle was supported by a HeartWare HVAD in a three-dimensional multiscale computational fluid dynamics model. Three LVAD operating scenarios were evaluated: constant speed and sinusoidal co- and counter-pulsation. In all operating scenarios, the mean pump speed was set to restore the cardiac output to 5.0 L/min. Co- and counter-pulsation was speed modulated with an amplitude of 750 rpm. The risk of thrombosis was evaluated based on blood residence time, ventricular washout, kinetic energy densities, and a pulsatility index map. Blood residence time for co-pulsation was on average 1.8 and 3.7% lower than constant speed and counter-pulsation mode, respectively. After introducing fresh blood to displace preexisting blood for 10 cardiac cycles, co-pulsation had 1.5% less old blood in comparison to counter-pulsation. Apical energy densities were 84 and 27% higher for co-pulsation in comparison to counter-pulsation and constant speed mode, respectively. Co-pulsation had an increased pulsatility index around the left ventricular outflow tract and mid-ventricle. Improved flow dynamics with co-pulsation was caused by increased E-wave velocities which minimized blood stasis. In the studied scenario and from the perspective of intraventricular flow dynamics, co-pulsation of rotary LVADs could minimize the risk of intraventricular thrombosis.

Ventricular flow dynamics with varying LVAD inflow cannula lengths: In-silico evaluation in a multiscale model.

Left ventricular assist devices are associated with thromboembolic events, which are potentially caused by altered intraventricular flow. Due to patient variability, differences in apical wall thickness affects cannula insertion lengths, potentially promoting unfavourable intraventricular flow patterns which are thought to be correlated to the risk of thrombosis. This study aimed to present a 3D multiscale computational fluid dynamic model of the left ventricle (LV) developed using a commercial software, Ansys, and evaluate the risk of thrombosis with varying inflow cannula insertion lengths in a severely dilated LV. Based on a HeartWare HVAD inflow cannula, insertion lengths of 5, 19, 24 and 50 mm represented cases of apical hypertrophy, typical ranges of apical thicknesses and an experimental length, respectively. The risk of thrombosis was evaluated based on blood washout, residence time, instantaneous blood stagnation and a pulsatility index. By introducing fresh blood to displace pre-existing blood in the LV, after 5 cardiac cycles, 46.7%, 45.7%, 45.1% and 41.8% of pre-existing blood remained for insertion lengths of 5, 19, 24 and 50 mm, respectively. Compared to the 50 mm insertion, blood residence time was at least 9%, 7% and 6% higher with the 5, 19 and 24 mm insertion lengths, respectively. No instantaneous stagnation at the apex was observed directly after the E-wave. Pulsatility indices adjacent to the cannula increased with shorter insertion lengths. For the specific scenario studied, a longer insertion length, relative to LV size, may be advantageous to minimise thrombosis by increasing LV washout and reducing blood residence time.

Melt Electrospun Bilayered Scaffolds for Tissue Integration of a Suture-Less Inflow Cannula for Rotary Blood Pumps.

Implantation of left ventricular assist devices typically requires cardiopulmonary bypass support, which is associated with postoperative complications. A novel suture-less inflow cannula, which can be implanted without bypass, uses mild myocardial compression to seal the interface, however, this may lead to necrosis of the myocardium. To circumvent this issue, a bilayered scaffold has been developed to promote tissue growth at the interface between cannula and myocardium. The bilayered scaffold consists of a silicone base layer, which mimics the seal, and a melt electrospun polycaprolactone scaffold to serve as a tissue integration layer. Biocompatibility of the bilayered scaffolds was assessed by analyzing cell viability, morphology, and metabolic activity of human foreskin fibroblasts cultured on the scaffolds for up to 14 days. There was no evidence of cytotoxicity and the cells adhered readily to the bilayered scaffolds, revealing a cell morphology characteristic of fibroblasts, in contrast to the low cell adhesion observed on flat silicone sheets. The rate of cell proliferation on the bilayered scaffolds rose over the 14-day period and was significantly greater than cells seeded on the silicone sheets. This study suggests that melt electrospun bilayered scaffolds have the potential to support tissue integration of a suture-less inflow cannula for cardiovascular applications. Furthermore, the method of fabrication described here and the application of bilayered scaffolds could also have potential uses in a diverse range of biomedical applications.

Population Pharmacokinetics of Desvenlafaxine: Pharmacokinetics in Korean Versus US Populations.

Desvenlafaxine exposure in Korean and US populations was compared using population pharmacokinetic (PK) analysis. Data from a single- and multiple-dose study of desvenlafaxine (50, 100, and 200 mg) in 30 healthy Korean subjects were added to a population PK model previously developed using sparse PK samples from patients with major depressive disorder, including 140 Korean patients, combined with rich PK data from healthy volunteers. The structural PK model was an open 1-compartment linear disposition model with parallel first-order and 0-order inputs. The effects of Korean status on apparent oral clearance (CL/F) and apparent volume of distribution (V/F) were tested against the base model separately. External validation results indicated good agreement between the model predictions and observed desvenlafaxine concentrations for Korean subjects. The geometric mean CL/F and V/F of Korean subjects were 9.1% and 16.7% lower, respectively, than those of US subjects, who had a 20% higher mean body weight. Results for patients with major depressive disorder were similar. There were no meaningful differences for weight-normalized CL/F and V/F values between Korean and US subjects or patients. The minor differences in CL/F and V/F observed between Korean and US populations appear to be solely due to lower body weights in the Korean population.

Development of an In Vitro PIV Setup for Preliminary Investigation of the Effects of Aortic Compliance on Flow Patterns and Hemodynamics.

The aorta with its compliance plays a major role in hemodynamics as it saves a portion of ejected blood during systole which is then released in diastole. The aortic compliance decreases with increasing age, which is related to several cardiovascular imparities and diseases. Changes in flow patterns and pressure curves, due to varying aortic compliance, are difficult to investigate in vivo. As a result, the aim of the present work was to develop an in vitro setup enabling standardized investigations on the effect of compliance changes on flow patterns and pressure curves. Therefore an experimental setup with an anatomically correct silicone phantom of the aortic arch was developed, suitable for optical flow measurements under pulsatile inflow conditions. The setup was developed for precise adjustments of different compliances and optical flow measurements. Particle image velocimetry measurements were carried out downstream of the aortic valve in the center plane perpendicular to the valve with compliance adjusted between 0.62 × 10-3 to 1.82 × 10-3 mmHg-1. Preliminary results of the in vitro investigations showed that decreases in compliance results in significant increases in pressure changes with respect to time (dp/dt) and altered pressure curves in the aortic arch. In terms of flow, an increased aortic stiffness lead to higher mean velocities and decreased vortex development in the aortic sinuses. As in vivo validation and translation remains difficult, the results have to be considered as preliminary in vitro insights into the mechanisms of (age-related) compliance changes.

Numerical prediction of thrombus risk in an anatomically dilated left ventricle: the effect of inflow cannula designs.

BACKGROUND: Implantation of a rotary blood pump (RBP) can cause non-physiological flow fields in the left ventricle (LV) which may trigger thrombosis. Different inflow cannula geometry can affect LV flow fields. The aim of this study was to determine the effect of inflow cannula geometry on intraventricular flow under full LV support in a patient specific model. METHODS: Computed tomography angiography imaging of the LV was performed on a RBP candidate to develop a patient-specific model. Five inflow cannulae were evaluated, which were modelled on those used clinically or under development. The inflow cannulae are described as a crown like tip, thin walled tubular tip, large filleted tip, trumpet like tip and an inferiorly flared cannula. Placement of the inflow cannula was at the LV apex with the central axis intersecting the centre of the mitral valve. Full support was simulated by prescribing 5 l/min across the mitral valve. Thrombus risk was evaluated by identifying regions of stagnation. Rate of LV washout was assessed using a volume of fluid model. Relative haemolysis index and blood residence time was calculated using an Eulerian approach. RESULTS: The inferiorly flared inflow cannula had the lowest thrombus risk due to low stagnation volumes. All cannulae had similar rates of LV washout and blood residence time. The crown like tip and thin walled tubular tip resulted in relatively higher blood damage indices within the LV. CONCLUSION: Changes in intraventricular flow due to variances in cannula geometry resulted in different stagnation volumes. Cannula geometry does not appreciably affect LV washout rates and blood residence time. The patient specific, full support computational fluid dynamic model provided a repeatable platform to investigate the effects of inflow cannula geometry on intraventricular flow.

Improved fabrication of melt electrospun tissue engineering scaffolds using direct writing and advanced electric field control.

Direct writing melt electrospinning is an additive manufacturing technique capable of the layer-by-layer fabrication of highly ordered 3d tissue engineering scaffolds from micron-diameter fibers. The utility of these scaffolds, however, is limited by the maximum achievable height of controlled fiber deposition, beyond which the structure becomes increasingly disordered. A source of this disorder is charge build-up on the deposited polymer producing unwanted coulombic forces. In this study, the authors introduce a novel melt electrospinning platform with dual voltage power supplies to reduce undesirable charge effects and improve fiber deposition control. The authors produced and characterized several 90° cross-hatched fiber scaffolds using a range of needle/collector plate voltages. Fiber thickness was found to be sensitive only to overall potential and invariant to specific tip/collector voltage. The authors also produced ordered scaffolds up to 200 layers thick (fiber spacing 1 mm and diameter 40 µm) and characterized structure in terms of three distinct zones: ordered, semiordered, and disordered. Our in vitro analysis indicates successful cell attachment and distribution throughout the scaffolds, with little evidence of cell death after seven days. This study demonstrates the importance of electrostatic control for reducing destabilizing polymer charge effects and enabling the fabrication of morphologically suitable scaffolds for tissue engineering.

Population-based exposure-efficacy modeling of ustekinumab in patients with moderate to severe plaque psoriasis.

Ustekinumab, a human immunoglobulin G1 kappa (IgG1k) monoclonal antibody that binds with high affinity to human interleukin-12 and interleukin-23, has demonstrated efficacy in patients with psoriasis. The objective of this study was to perform exposure-response modeling to increase the understanding of reduction in disease severity following treatment with ustekinumab in patients with moderate to severe psoriasis who participate in two phase III studies (PHOENIX 1 and PHOENIX 2). Patients were randomly assigned to receive ustekinumab 45 mg or 90 mg (n = 1312; 11,624 Psoriasis Area and Severity Index [PASI] scores) or placebo (n = 665; 3278 PASI scores). Disease severity was assessed using PASI scores. A population mechanism-based exposure-response model of ustekinumab using NONMEM was developed using serum ustekinumab concentrations and PASI scores. The pharmacodynamic response effect was the reduction in PASI score. The placebo effect, although minor, was also integrated into the model. None of the covariate factors evaluated (eg, demographics, baseline disease characteristics, comorbidities) significantly contributed to the between-subject variability in the pharmacodynamic parameters. The developed exposure-response model can serve as a basis to support future alternative dosing regimens for ustekinumab in patients with moderate to severe plaque psoriasis. A robust exposure-response relationship has been confirmed for ustekinumab in psoriasis.

Population pharmacokinetic modeling of ustekinumab, a human monoclonal antibody targeting IL-12/23p40, in patients with moderate to severe plaque psoriasis.

The population pharmacokinetics of ustekinumab are characterized in patients with moderate to severe plaque psoriasis in 2 Phase 3 studies (PHOENIX 1 and PHOENIX 2). Serum concentration data from 1937 patients are analyzed to determine pharmacokinetic characteristics of ustekinumab and to assess factors that may contribute to their variability. The population typical mean (percentage relative standard error) values for apparent clearance, apparent volume of distribution, and absorption rate constant from the final covariate model are 0.465 L.day(-1) (2.0%), 15.7 L (2.0%), and 0.354 day(-1) (16.2%), respectively. The interindividual variabilities for apparent clearance and apparent volume of distribution are 41.0% and 33.2%, respectively. Of the factors evaluated in this analysis, body weight, diabetes, and positive immune response (antibodies to ustekinumab) are important covariates affecting the apparent clearance and/or apparent volume of distribution of ustekinumab. To fully understand the clinical relevance of these results, the covariate findings need to be evaluated concurrently with the efficacy and safety data.