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.

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.

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.

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.

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.

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.

Ethyl acetate fraction of the root of Rubia cordifolia L. inhibits keratinocyte proliferation in vitro and promotes keratinocyte differentiation in vivo: potential application for psoriasis treatment.

Psoriasis is a skin disease associated with hyperproliferation and aberrant differentiation of keratinocytes. Our previous studies have identified the root of Rubia cordifolia L. as a potent antiproliferative and apoptogenic agent in cultured HaCaT cells (IC(50) 1.4 microg/ml). In the present study, ethanolic extract of Radix Rubiae was fractioned sequentially with hexane, ethyl acetate (EA), n-butanol and water. EA fraction was found to possess most potent antiproliferative action on HaCaT cells (IC(50) 0.9 microg/ml). Mechanistic study revealed that EA fraction induced apoptosis on HaCaT cells, as it was capable of inducing apoptotic morphological changes. Annexin V-PI staining assay also demonstrated that EA fraction significantly augmented HaCaT apoptosis. In addition, EA fraction decreased mitochondrial membrane potential in a concentration- and time-dependent manner. The standardized EA fraction was formulated into topical gel and its keratinocyte-modulating action was tested on mouse tail model. EA fraction dose-dependently increased the number and thickness of granular layer and epidermal thickness on mouse tail skin, indicative of the keratinocyte differentiation-inducing activity. Taking the in vitro and in vivo findings together, the present preclinical study confirms that EA fraction is a promising antipsoriatic agent warranting further development for psoriasis treatment.

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.

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.

The inhibitory effect of Gleditsia sinensis on cyclooxygenase-2 expression in human esophageal squamous cell carcinoma.

The anti-cancer effects of the anomalous fruit extract of Gleditsia sinensis (GSE) attributed to its apoptotic activity, telomerase inhibition and anti-angiogenesis in a panel of solid and non-solid tumor cell lines including esophageal squamous cell carcinoma (ESCC) have been intensively investigated by us in previous studies. Cyclooxygenase-2 (COX-2) has been well described as another promising target of cancer therapy for ESCC, and novel therapeutic agents are still being sought which target COX-2 expression. However, the anti-cancer effect of GSE through the suppression of COX-2 expression has not been previously investigated. In the present study, the anti-cancer effects of GSE on eight ESCC cell lines (KYSE 30, KYSE 150, KYSE 450, KYSE 510, KYSE 520, HKESC-3, HKESC-4 and SLMT-1) of Chinese and Japanese origins were first studied by MTS cytotoxicity assays. The effects of GSE on COX-2 expression levels and on the housekeeping form COX-1 were also investigated by multiplex RT-PCR analysis. Moreover, the anti-proliferative effect of GSE on KYSE 510 was also studied by anchorage-independent clonogenicity assay in soft agar. The results showed that GSE induced a dose- and time-dependent cytotoxicity on all of the eight ESCC cell lines and caused positive anti-proliferative action on KYSE 510 in the anchorage-independent clonogenicity assay, suggesting that GSE suppressed the in vitro growth of the ESCC cell lines. More importantly, the MRNA expression levels of COX-2, but not COX-1, in all of the ESCC cell lines were suppressed by GSE in a dose-dependent fashion. The overall results of the present study show that the anti-cancer effect of GSE on the ESCC cell lines is associated with the suppression of COX-2 expression, but not COX-1. Our findings also open a new chapter for the future advancement of GSE as a novel anti-cancer agent or as an adjuvant of traditional cancer treatments.

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.

Identification of a novel tumor transforming gene GAEC1 at 7q22 which encodes a nuclear protein and is frequently amplified and overexpressed in esophageal squamous cell carcinoma.

By comparative DNA fingerprinting, we identified a 357-bp DNA fragment frequently amplified in esophageal squamous cell carcinomas (ESCC). This fragment overlaps with an expressed sequence tag mapped to 7q22. Further 5' and 3'-rapid amplification of cDNA ends revealed that it is part of a novel, single-exon gene with full-length mRNA of 2052 bp and encodes a nuclear protein of 109 amino acids ( approximately 15 kDa). This gene, designated as gene amplified in esophageal cancer 1 (GAEC1), was located within a 1-2 Mb amplicon at 7q22.1 identified by high-resolution 1 Mb array-comparative genomic hybridization in 6/10 ESCC cell lines. GAEC1 was ubiquitously expressed in normal tissues including esophageal and gastrointestinal organs; with amplification and overexpression in 6/10 (60%) ESCC cell lines and 34/99 (34%) primary tumors. Overexpression of GAEC1 in 3T3 mouse fibroblasts caused foci formation and colony formation in soft agar, comparable to H-ras and injection of GAEC1-transfected 3T3 cells into athymic nude mice formed undifferentiated sarcoma in vivo, indicating that GAEC1 is a transforming oncogene. Although no significant correlation was observed between GAEC1 amplification and clinicopathological parameters and prognosis, our study demonstrated that overexpressed GAEC1 has tumorigenic potential and suggest that overexpressed GAEC1 may play an important role in ESCC pathogenesis.

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.

Transient simulation of kinetics of electric-sensitive hydrogels.

Kinetics of the hydrogels responsive to electric stimulus due to an externally applied electric field is modeled for the first time through transient simulation. The mathematical model employed is called the multi-effect-coupling electric-stimulus (MECe) model, which is developed with consideration of multi-phases and multi-physics. Transient simulation by the MECe model is examined with available experimental data and good agreement is achieved. The kinetics of ionic concentration of diffusive species is simulated. The simulation also predicts the influences of several important parameters on the hydrogel deformation, including the externally applied electric voltage, initially fixed charge density and surrounding bath solution concentration.

Modeling and simulation of deformation of hydrogels responding to electric stimulus.

A model for simulation of pH-sensitive hydrogels is refined in this paper to extend its application to electric-sensitive hydrogels, termed the refined multi-effect-coupling electric-stimulus (rMECe) model. By reformulation of the fixed-charge density and consideration of finite deformation, the rMECe model is able to predict the responsive deformations of the hydrogels when they are immersed in a bath solution subject to externally applied electric field. The rMECe model consists of nonlinear partial differential governing equations with chemo-electro-mechanical coupling effects and the fixed-charge density with electric-field effect. By comparison between simulation and experiment extracted from literature, the model is verified to be accurate and stable. The rMECe model performs quantitatively for deformation analysis of the electric-sensitive hydrogels. The influences of several physical parameters, including the externally applied electric voltage, initial fixed-charge density, hydrogel strip thickness, ionic strength and valence of surrounding solution, are discussed in detail on the displacement and average curvature of the hydrogels.

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.