Risks and impacts of thromboembolism in patients with pancreatic cancer.

INTRODUCTION: Patients with pancreatic cancer have a high risk of thromboembolism (TE), which may increase mortality. Most relevant studies have been conducted in Western populations. We investigated risk factors for TE in a predominantly Chinese population of patients with pancreatic cancer, along with effects of TE on overall survival. METHODS: This retrospective cohort study included patients diagnosed with exocrine pancreatic cancer in Prince of Wales Hospital in Hong Kong between 2010 and 2015. Data regarding patient demographics, World Health Organization performance status, stage, treatment, TE-related information, and time of death (if applicable) were retrieved from electronic medical records. Univariate and multivariable logistic regression analyses were performed to identify risk factors for TE. Survival analyses were performed using Kaplan-Meier analysis and Cox proportional hazards regression. RESULTS: In total, 365 patients were included in the study. The overall incidence of TE (14.8%) was lower than in Western populations. In univariate logistic regression analysis, stage IV disease and non-head pancreatic cancer were significantly associated with TE (both P=0.01). Multivariable logistic regression analysis showed that stage IV disease was a significant risk factor (odds ratio=1.08, 95% confidence interval [CI]=1.00-1.17; P=0.046). Median overall survival did not significantly differ between patients with and without TE (4.88 months vs 7.80 months, hazard ratio=1.08, 95% CI=0.80-1.49; P=0.58) and between patients with TE who received anticoagulation treatment or not (5.63 months vs 4.77 months, hazard ratio=0.72, 95% CI=0.40-1.29; P=0.27). CONCLUSION: The incidence of TE was low in our Chinese cohort. Stage IV disease increased the risk of TE. Overall survival was not affected by TE or its treatment.

Report on outcomes of valve-in-valve transcatheter aortic valve implantation and redo surgical aortic valve replacement in the Netherlands.

OBJECTIVE: We sought to investigate real-world outcomes of patients with degenerated biological aortic valve prostheses who had undergone valve-in-valve transcatheter aortic valve implantation (ViV-TAVI) or reoperative surgical aortic valve replacement (redo-SAVR) in the Netherlands. METHODS: Patients who had undergone ViV-TAVI or redo-SAVR for a degenerated biological aortic valve prosthesis in the Netherlands between January 2014 and December 2018 were eligible for this retrospective study. Patients with a prior homograft, active endocarditis or mechanical aortic valve prosthesis were excluded. Patients were matched using the propensity score. The primary endpoint was a composite of 30-day all-cause mortality and in-hospital postoperative stroke. Secondary endpoints were all-cause mortality at different time points, in-hospital postoperative stroke, pacemaker implantation and redo procedures within one year. Baseline characteristics and outcome data were collected from the Netherlands Heart Registration. RESULTS: From 16 cardiac centres, 653 patients were included in the study (374 ViV-TAVI and 279 redo-SAVR). European System for Cardiac Operative Risk Evaluation I (EuroSCORE I) was higher in ViV-TAVI patients (19.4, interquartile range (IQR) 13.3-27.9 vs 13.8, IQR 8.3-21.9, p < 0.01). After propensity score matching, 165 patients were matched with acceptable covariate balance. In the matched cohorts, the primary endpoint was not significantly different for ViV-TAVI and redo-SAVR patients (odds ratio 1.30, 95% confidence interval 0.57-3.02). Procedural, 30-day and 1­year all-cause mortality rates, incidence of in-hospital postoperative stroke, pacemaker implantation and redo procedures within one year were also similar between cohorts. CONCLUSION: Patients with degenerated aortic bioprostheses treated with ViV-TAVI or redo-SAVR have similar mortality and morbidity.

Sutureless aortic valve with supracoronary ascending aortic replacement as an alternative strategy for composite graft replacement in elderly patients.

Aortic valve disease is frequently associated with ascending aorta dilatation and can be treated either by separate replacement of the aortic valve and ascending aorta or by a composite valve graft. The type of surgery is depending on the exact location of the aortic dilatation and the concomitant valvular procedures required. The evidence for elective aortic surgery in elderly high-risk patients remains challenging and therefore alternative strategies could be warranted. We propose an alternative strategy for the treatment of ascending aortic aneurysm and aortic valve pathology with the use of a sutureless, collapsible, stent-mounted aortic valve prosthesis.

Epidemiology of paediatric orthopaedic-related trauma injuries sustained across a lockdown period during the COVID-19 pandemic.

OBJECTIVES: Lockdowns have been implemented by countries to slow down SARS-CoV-2 transmission. Singapore's lockdown was enforced between 7 April 2020 and 1 June 2020. The objective of this study was to compare the epidemiology of paediatric orthopaedic trauma injuries during and immediately after the lockdown, with a non-pandemic period in 2019. METHODS: All paediatric outpatients and inpatients seen in our hospital following an orthopaedic-related traumatic injury from the 8-week lockdown and 8 weeks post-lockdown were evaluated. Cases for matched periods in 2019 were identified retrospectively for baseline comparison. Patient demographics, venue of injury, anatomic location of injury, caregiver supervision and location of procedures performed in the hospital were assessed. RESULTS: 968 and 2810 injuries were observed in 2020 and 2019, respectively. While the proportion of injuries sustained by pre-schoolers and toddlers increased, those sustained by primary and secondary school children decreased in 2020 (p < 0.001). Majority of the injuries during the lockdown were sustained at home compared to schools or public recreational facilities (p < 0.001). Hand (26.2%) and elbow (20.8%) injuries were the most common during the lockdown. The proportion of procedures performed in the Children's Emergency during the lockdown was more than twice that of the same period in 2019 (p < 0.001). CONCLUSION: Our study showed a 2.9-fold decrease in orthopaedic-related injuries seen during the peri-lockdown period compared to a non-pandemic period. Pre-schoolers seem to be most vulnerable to injuries during the lockdown. Hand and elbow injuries were most common.

Surgical treatment of a chronic postmyocardial infarction ventricular septal rupture.

The development of a postmyocardial infarction ventricular septal rupture is an uncommon but frequently fatal complication. Mortality with medical treatment only is extremely high. Septal rupture results in a left-to-right shunt, with right ventricular volume overload, increased pulmonary blood flow, and secondary volume overload of the left atrium and ventricle.  Surgical treatment consists of excluding rather than excising the infarcted septum and ventricular walls. This is accomplished by performance of a left ventriculotomy through the infarcted muscle and securing a glutaraldehyde-fixed bovine pericardium patch to the endocardium of the left ventricle all around the infarcted myocardium.

A multiphysics model of photo-sensitive hydrogels in response to light-thermo-pH-salt coupled stimuli for biomedical applications.

This paper aims to unveil the fundamental response mechanism of photo-sensitive hydrogels subject to light-thermo-pH-salt coupled stimuli, for their potential biomedical uses such as cell scaffolds and extracellular matrices, where biological activity largely depends on internal electrochemical changes. To mimic the microenvironment of biomolecules or cells, we focus on a spirobenzopyran-modified N-isopropylacrylamide hydrogel incorporating acrylic acid as a proton generator and develop a multiphysics model to characterize its behaviour within aqueous solution in response to light intensity, temperature, buffer pH, and salt concentration. The model allows for concurrent chemical reactions, ionic diffusion, electrostatic effects and large mechanical deformation, as well as interaction with the solution domain. Validation was performed by comparison with the published experimental results and showed good agreement. It is demonstrated by the simulation results that the photo-sensitive hydrogel exhibits a varied sensitivity to the external stimuli if incorporated with different molar ratios of acrylic acid. The electrical and pH response characteristics of the hydrogel, especially those in neutral solution, may inspire some potential biomedical applications, such as photo-controlled drug release and cell growth.

Optimization of the cell microenvironment in a dual magnetic-pH-sensitive hydrogel-based scaffold by multiphysics modeling.

A dual magnetic-pH-sensitive hydrogel-based scaffold was studied for optimization of a cell microenvironment by scaffold mechanical deformation and its biochemical response. In particular, the positions of the seeding cells and the concentration of potassium (K+) within the scaffold were optimized by a multieffect-coupling magnetic-pH-stimuli (MECmpH) model based on (i) the threshold of the mechanical force required for a mechanotransduction effect at the cellular level, and (ii) the common biological requirement for cell growth. In this model, the physicochemical mechanisms of a magnetic hydrogel were characterized using magneto-chemo-electro-mechanical coupled effects, including hydrogel magnetization, diffusion of the solvent and ions, ionic polarization, and nonlinear deformation. After validation of the model with experimental data, it was found that a higher pH and current intensity at the electromagnet and a shorter hydrogel-magnet distance contribute to larger scaffold deformation and thus a stronger mechanical force on the cells. Moreover, the cell seeding positions within the magnetic scaffold were optimized for improved cell culture through controlled current intensity in the electromagnet. Furthermore, the physiological concentration of K+ was also optimized by the initial fixed charge density within the scaffold. We concluded that this optimized magnetic scaffold via the MECmpH model may provide an appropriate microenvironment for efficient cell growth.

Modeling of a fast-response magnetic-sensitive hydrogel for dynamic control of microfluidic flow.

A magnetic-sensitive hydrogel-based microfluidic system is designed via a magneto-chemo-hydro-mechanical model for replicating various physiological and pathological conditions in the human body, by which the desired flow patterns can be generated in real time due to the fast-response deformation of the magnetic hydrogel. In the model, the fluid-structure interaction is characterized between the deformable magnetic hydrogel and surrounding fluid flow through the fully coupled arbitrary Lagrangian-Eulerian (ALE) method. Moreover, the physicochemical mechanisms including hydrogel magnetization, fluid diffusion, fluid flow, and hydrogel large deformation are characterized. After validation of the present model with both the finite difference and experimental results in the open literature, the transient behavior of the magnetic hydrogel is investigated, and the results show that the response time for the magnetic hydrogel is improved significantly in a uniform magnetic field compared with that of a hydrogel without the magnetic effect. Furthermore, various patterns of pulsatile flow are generated for mimicking the cell physiological microenvironment experienced by bone marrow stromal cells, and also for the pathological condition at the femoral artery during diastole and systole, respectively. Therefore, the present magnetic-sensitive hydrogel-based microfluidic system via the multiphysics model may provide a relevant humanized manipulation platform to investigate cell behavior and function through microfluidic chips.

Optimization of Deformable Magnetic-Sensitive Hydrogel-Based Targeting System in Suspension Fluid for Site-Specific Drug Delivery.

For optimization of the targeting performance of the magnetic hydrogel subject to the magneto-chemo-hydro-mechanical coupled stimuli, a multiphysics model for a suspension fluid flow in a blood vessel is developed, in which a deformable magnetic-sensitive hydrogel-based drug targeting system moves with fluid. In this model, the fluid-structure interaction of the movable and deformable magnetic hydrogel with surrounding fluid flow is characterized through the fully coupled arbitrary Lagrangian-Eulerian algorithm. Moreover, the four physicochemical responsive mechanisms are considered, including hydrogel magnetization, solvent diffusion, fluid flow, and nonlinear large deformation. After the present model is examined by the experimental data in open literature, the transient behaviors of the motion and deformation of the magnetic hydrogel are investigated in suspension flow. It is found that the higher flow velocity and/or the larger hydrogel size accelerate the movement of the hydrogel, while the smaller hydrogel size contributes to the larger swelling ratio. Furthermore, the performance of the magnetic targeting system is optimized for delivering the drug-loaded hydrogel to the desired site by tuning the maximum magnetic field strength, the maximum inlet flow velocity, and the magnet position. Therefore, it is confirmed that the present optimizable magnetic hydrogel-based drug targeting system via the multiphysics model may provide a promising efficient platform for site-specific drug delivery.

Modeling the Impact of pH- and Oxygen-Coupled Stimuli on Osmotic Pressure and Electrical Potential Responses of Hemoglobin-Loaded Polyampholyte Hydrogel.

A unique character of (bio) responsive materials is their capability to convert specific environmental biochemical cues into an electromechanical response. Thereby, this paper describes the impact of pH- and oxygen-coupled stimuli on osmotic pressure and electrical potential responses of hemoglobin-loaded polyampholyte hydrogel. Herein, a multiphysics model is developed for elucidating the multiphysical interaction between immobile functional components bounded onto polymeric network chains of the hydrogel and hydrogen ion-oxygen-enriched environmental solution. Two constitutive relationships are incorporated into the model to capture: (1) ionization of fixed charge group as a function of its ionization strength coupled with hydrogen ion concentration and (2) bioactivity of hemoglobin as a function of both its ionization and saturation states. The multiphysics model is verified by comparing with experimental observations in open-literature, capturing the oxygen-induced hemoglobin saturation and the pH-actuated deformation of polyampholyte hydrogel. The numerical finding demonstrates that the pH-activated osmotic pressure response of the present hemoglobin-loaded polymeric system is independent of ambient oxygen O2, whereas its electrical potential response is insensitive of ambient oxygen O2 level at pH neutral conditions. Furthermore, the pH-induced swelling deformation of initially balanced polyampholyte hydrogel changes from a "V-" to a "bowl"-shaped like pattern with increase in fixed acidic and basic group ionization strength, whereas the initially unbalanced polyampholyte hydrogel achieves a collapse state at environmental pH coinciding with acid-base dissociation constant of dominant immobile charge group, if the initial dominant immobile charge group density is twice that of its counter one.

Development of a Multiphysics Model to Characterize the Responsive Behavior of Magnetic-Sensitive Hydrogels with Finite Deformation.

A novel multiphysics model is developed in this paper for simulation of the responsive behavior of the magnetic-sensitive hydrogel, with the effects of magneto-chemo-mechanical coupled fields, which is termed the multi-effect-coupling magnetic-stimulus (MECm) model. In this work, the magnetic susceptibility for magnetization of the general magnetic hydrogel is defined as a function of finite deformation, instead of a constant for an ideal magnetic hydrogel. The present constitutive equations, formulated by the second law of thermodynamics, account for the effects of the chemical potential, the externally applied magnetic field, and the finite deformation. In particular, a novel free energy density is proposed with consideration of the magnetic effect associated with finite deformation, instead of volume fraction. After examination with published experimental data, it is confirmed that the MECm model can well capture the responsive behavior of the magnetic hydrogel, including the deformation and its instability and hysteresis under a uniform or nonuniform magnetic field. The parameter studies are then carried out for influences of the magnetic and geometric properties, including the magnetic intensity, shear modulus, and volume fraction of the magnetic particles, on the behavior of the magnetic hydrogel, for a deeper insight into the fundamental mechanism of the magnetic hydrogels.

Development of a multiphysics model to characterize the responsive behavior of urea-sensitive hydrogel as biosensor.

A remarkable feature of biomaterials is their ability to deform in response to certain external bio-stimuli. Here, a novel biochemo-electro-mechanical model is developed for the numerical characterization of the urea-sensitive hydrogel in response to the external stimulus of urea. The urea sensitivity of the hydrogel is usually characterized by the states of ionization and denaturation of the immobilized urease, as such the model includes the effect of the fixed charge groups and temperature coupled with pH on the activity of the urease. Therefore, a novel rate of reaction equation is proposed to characterize the hydrolysis of urea that accounts for both the ionization and denaturation states of the urease subject to the environmental conditions. After examination with the published experimental data, it is thus confirmed that the model can characterize well the responsive behavior of the urea-sensitive hydrogel subject to the urea stimulus, including the distribution patterns of the electrical potential and pH of the hydrogel. The results point to an innovative means for generating electrical power via the enzyme-induced pH and electrical potential gradients, when the hydrogel comes in contact with the urea-rich solution, such as human urine.

Tibial tubercle to trochlear groove distance and index in children with one-time versus recurrent patellar dislocation: a magnetic resonance imaging study.

PURPOSE: To compare the tibial tubercle to trochlear groove (TT-TG) distance and index using magnetic resonance imaging (MRI) between children with onetime and recurrent patellar dislocation. METHODS: Records of first-time acute patellar dislocations from 2007 to 2012 were reviewed. 20 males and 23 females aged 10 to 17 years at presentation were included for measurements of the bony and cartilaginous-tendon TT-TG distance and index. Recurrent patellar dislocation was defined as having more than one episode of dislocation within 2 years of the index injury. RESULTS: The recurrent dislocation rate was 30.2% (13 out of 43). Patients with recurrent patellar dislocation had a higher mean bony TT-TG distance (17.4 vs. 14.2 mm, p=0.026), cartilaginous-tendon TT-TG distance (18.8 vs. 15.3 mm, p=0.029), and TT-TG index (0.41 vs. 0.33, p=0.008), compared with one-timers. Males had a larger patellofemoral joint than females (49.0 vs. 44.8 mm, p=0.01). The risk of recurrent patellar dislocation was higher in patients with a bony TT-TG distance >14 mm (relative risk [RR]=6.4), a cartilaginoustendon TT-TG distance >13.5 mm (RR=8.8), and a TTTG index >0.26 (RR=6.7). CONCLUSION: Children with recurrent patellar dislocation have higher TT-TG distance and index when compared with one-timers.

Two-dimensional numerical modeling for separation of deformable cells using dielectrophoresis.

In this paper, we numerically explore the possibility of separating two groups of deformable cells, by a very small dielectrophoretic (DEP) microchip with the characteristic length of several cell diameters. A 2D two-fluid model is developed to describe the separation process, where three types of forces are considered, the aggregation force for cell-cell interaction, the deformation force for cell deformation, and the DEP force for cell dielectrophoresis. As a model validation, we calculate the levitation height of a cell subject to DEP force, and compare it with the experimental data. After that, we simulate the separation of two groups of cells with different dielectric properties at high and low frequencies, respectively. The simulation results show that the deformable cells can be separated successfully by a very small DEP microchip, according to not only their different permittivities at the high frequency, but also their different conductivities at the low frequency. In addition, both two groups of cells have a shape deformation from an original shape to a lopsided slipper shape during the separation process. It is found that the cell motion is mainly determined by the DEP force arising from the electric field, causing the cells to deviate from the centerline of microchannel. However, the cell deformation is mainly determined by the deformation force arising from the fluid flow, causing the deviated cells to undergo an asymmetric motion with the deformation of slipper shape.

Computational analysis of dynamic interaction of two red blood cells in a capillary.

The dynamic interaction of two red blood cells (RBCs) in a capillary is investigated computationally by the two-fluid model, including their deformable motion and interaction. For characterization of the deformation, the RBC membrane is treated as a curved two-dimensional shell with finite thickness by the shell model, and allowed to undergo the stretching strain and bending deformation. Moreover, a Morse potential is adopted to model the intercellular interaction for the aggregation behavior, which is characterized as the weak attraction at far distance and strong repulsion at near distance. For validation of the present technique, the dynamic interaction of two RBCs in static blood plasma is simulated firstly, where the RBCs aggregate slowly until a balanced configuration is achieved between the deformation and aggregation forces. The balanced configuration is in good agreement with the results reported previously. Three important effects on the dynamic behavior of RBCs are then analyzed, and they are the initial RBC shape, RBC deformability, and the intercellular interaction strength. It is found that the RBC is less deformed into a well-known parachute shape when the initial RBC shape is larger. Similarly, if the elastic shear modulus and bending stiffness of RBC membrane increase, the RBC resistance to deformation becomes higher, such that the RBC is less deformed. The simulation results also demonstrate that the RBC deformability strongly depends on the intercellular interaction strength. The RBCs deform more easily as the intercellular interaction strength increases.

Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells.

Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase pump, leading to autophagy induction through the activation of the Ca(2+)/calmodulin-dependent kinase kinase-AMP-activated protein kinase-mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells.

Numerical modeling of motion trajectory and deformation behavior of a cell in a nonuniform electric field.

The motion trajectory and deformation behavior of a neutral red blood cell (RBC) in a microchannel subjected to an externally applied nonuniform electric field are numerically investigated, where both the membrane mechanical force and the dielectrophoresis (DEP) force are considered. The simulation results demonstrate that the DEP force is significantly influenced by several factors, namely, the RBC size, electrode potential, electric frequency, RBC permittivity, and conductivity, which finally results in the different behaviors of the cell motion and deformation in the nonuniform electric field.

Numerical design of microfluidic-microelectric hybrid chip for the separation of biological cells.

A miniature microfluidic-microelectric hybrid chip is numerically designed for separation of biological cells, where the characteristic length of the chip is close to the cell radius. A mathematical model is developed to characterize the motion and deformation of a biological cell in the hydrodynamic and nonuniform electric coupled fields, in which the mechanical and dielectric behaviors of the cell are taken into consideration. Subsequently, the model is validated by comparing with the experimental results published previously. By taking a red blood cell (RBC) as the sample of biological cell, the chip structure is numerically designed from the viewpoints of the electrode width, fluid flow velocity, and electric potential, respectively. Using the designed microfluidic-microelectric hybrid chip, the effects of the shape and initial position of the RBC on the separation ability are then analyzed. After that, the separation of the RBCs with the different permittivities or conductivities using the designed chip is simulated, and the deformation behaviors of the RBCs are discussed as well. At the high frequency, the permittivities of the RBCs play a dominant role in the separation of the RBCs, which causes the RBCs moving toward or away from the electrode array. However, the conductivity of the RBC plays a significant role at the low frequency. With suitable suspending fluid therefore, the separation of cells with different permittivities or conductivities can be achieved using the microfluidic-microelectric hybrid chip designed by the present work.

Modeling and simulation of microfluid effects on deformation behavior of a red blood cell in a capillary.

A modified SIMPER algorithm is developed for analysis of microfluid effects on the motion and deformation of a red blood cell (RBC) in a capillary. With consideration of very small Reynolds number in microfluidics, this algorithm not only speeds up the convergence of the momentum equations by combining the advantages of the SIMPLEC and SIMPLER algorithms together, but also satisfies the continuity equation with higher accuracy by integrating a fine adjustment technique. In order to validate the modified SIMPLER algorithm, the behavior of RBC in a capillary is simulated at different velocities. When the mean RBC velocity is 0.1mm/s, the RBC exhibits a characteristic parachute shape in the steady state, which agrees well with the numerical results previously reported. Apart from that, a quantitative validation with the experimental data is performed by examining the relationship between the mean velocity and deformation index of the RBC, showing an excellent agreement. The effects of crucial parameters are investigated systematically on the motion and deformation of the RBC, including the RBC radius, elastic modulus and bending stiffness of RBC membrane, initial velocity of suspending fluid, as well as the density and viscosity ratios of the suspending fluid to RBC. The simulation results demonstrate that all of the parameters have influences on the RBC behavior by changing the interaction between the RBC and suspending fluid.