A low dimensional surrogate model for a fast estimation of strain in the thrombus during a thrombectomy procedure.

BACKGROUND: Intra-arterial thrombectomy is the main treatment for acute ischemic stroke due to large vessel occlusions and can consist in mechanically removing the thrombus with a stent-retriever. A cause of failure of the procedure is the fragmentation of the thrombus and formation of micro-emboli, difficult to remove. This work proposes a methodology for the creation of a low-dimensional surrogate model of the mechanical thrombectomy procedure, trained on realizations from high-fidelity simulations, able to estimate the evolution of the maximum first principal strain in the thrombus. METHOD: A parametric finite-element model was created, composed of a tapered vessel, a thrombus, a stent-retriever and a catheter. A design of experiments was conducted to sample 100 combinations of the model parameters and the corresponding thrombectomy simulations were run and post-processed to extract the maximum first principal strain in the thrombus during the procedure. Then, a surrogate model was built with a combination of principal component analysis and Kriging. RESULTS: The surrogate model was chosen after a sensitivity analysis on the number of principal components and was tested with 10 additional cases. The model provided predictions of the strain curves with correlation above 0.9 and a maximum error of 28%, with an error below 20% in 60% of the test cases. CONCLUSIONS: The surrogate model provides nearly instantaneous estimates and constitutes a valuable tool for evaluating the risk of thrombus rupture during pre-operative planning for the treatment of acute ischemic stroke.

A multiparametric advection-diffusion reduced-order model for molecular transport in scaffolds for osteoinduction.

Scaffolds are microporous biocompatible structures that serve as material support for cells to proliferate, differentiate and form functional tissue. In particular, in the field of bone regeneration, insertion of scaffolds in a proper physiological environment is known to favour bone formation by releasing calcium ions, among others, triggering differentiation of mesenchymal cells into osteoblasts. Computational simulation of molecular distributions through scaffolds is a potential tool to study the scaffolds' performance or optimal designs, to analyse their impact on cell differentiation, and also to move towards reduction in animal experimentation. Unfortunately, the required numerical models are often highly complex and computationally too costly to develop parametric studies. In this context, we propose a computational parametric reduced-order model to obtain the distribution of calcium ions in the interstitial fluid flowing through scaffolds, depending on several physical parameters. We use the well-known Proper Orthogonal Decomposition (POD) with two different variations: local POD and POD with quadratic approximations. Computations are performed using two realistic geometries based on a foamed and a 3D-printed scaffolds. The location of regions with high concentration of calcium in the numerical simulations is in fair agreement with regions of bone formation shown in experimental observations reported in the literature. Besides, reduced-order solutions accurately approximate the reference finite element solutions, with a significant decrease in the number of degrees of freedom, thus avoiding computationally expensive simulations, especially when performing a parametric analysis. The proposed reduced-order model is a competitive tool to assist the design of scaffolds in osteoinduction research.

A Data-Driven Learning Method for Constitutive Modeling: Application to Vascular Hyperelastic Soft Tissues.

We address the problem of machine learning of constitutive laws when large experimental deviations are present. This is particularly important in soft living tissue modeling, for instance, where large patient-dependent data is found. We focus on two aspects that complicate the problem, namely, the presence of an important dispersion in the experimental results and the need for a rigorous compliance to thermodynamic settings. To address these difficulties, we propose to use, respectively, Topological Data Analysis techniques and a regression over the so-called General Equation for the Nonequilibrium Reversible-Irreversible Coupling (GENERIC) formalism (M. Grmela and H. Ch. Oettinger, Dynamics and thermodynamics of complex fluids. I. Development of a general formalism. Phys. Rev. E 56, 6620, 1997). This allows us, on one hand, to unveil the true "shape" of the data and, on the other, to guarantee the fulfillment of basic principles such as the conservation of energy and the production of entropy as a consequence of viscous dissipation. Examples are provided over pseudo-experimental and experimental data that demonstrate the feasibility of the proposed approach.

On the Modeling of Patient-Specific Transcatheter Aortic Valve Replacement: A Fluid-Structure Interaction Approach.

PURPOSE: Transcatheter aortic valve replacement (TAVR) is a minimally invasive treatment for high-risk patients with aortic diseases. Despite its increasing use, many influential factors are still to be understood and require continuous investigation. The best numerical approach capable of reproducing both the valves mechanics and the hemodynamics is the fluid-structure interaction (FSI) modeling. The aim of this work is the development of a patient-specific FSI methodology able to model the implantation phase as well as the valve working conditions during cardiac cycles. METHODS: The patient-specific domain, which included the aortic root, native valve and calcifications, was reconstructed from CT images, while the CAD model of the device, metallic frame and pericardium, was drawn from literature data. Ventricular and aortic pressure waveforms, derived from the patient's data, were used as boundary conditions. The proposed method was applied to two real clinical cases, which presented different outcomes in terms of paravalvular leakage (PVL), the main complication after TAVR. RESULTS: The results confirmed the clinical prognosis of mild and moderate PVL with coherent values of regurgitant volume and effective regurgitant orifice area. Moreover, the final release configuration of the device and the velocity field were compared with postoperative CT scans and Doppler traces showing a good qualitative and quantitative matching. CONCLUSION: In conclusion, the development of realistic and accurate FSI patient-specific models can be used as a support for clinical decisions before the implantation.

The Effect of Cell Morphology on the Permeability of the Nuclear Envelope to Diffusive Factors.

A recent advance in understanding stem cell differentiation is that the cell is able to translate its morphology, i.e., roundish or spread, into a fate decision. We hypothesize that strain states in the nuclear envelope (NE) cause changes in the structure of the nuclear pore complexes. This induces significant changes in the NE's permeability to the traffic of the transcription factors involved in stem cell differentiation which are imported into the nucleus by passive diffusion. To demonstrate this, we set up a numerical model of the transport of diffusive molecules through the nuclear pore complex (NPC), on the basis of the NPC deformation. We then compared the prediction of the model for two different cell configurations with roundish and spread nuclear topologies with those measured on cells cultured in both configurations. To measure the geometrical features of the NPC, using electron tomography we reconstructed three-dimensional portions of the envelope of cells cultured in both configurations. We found non-significant differences in both the shape and size of the transmembrane ring of single pores with envelope deformation. In the numerical model, we thus assumed that the changes in pore complex permeability, caused by the envelope strains, are due to variations in the opening configuration of the nuclear basket, which in turn modifies the porosity of the pore complex mainly on its nuclear side. To validate the model, we cultured cells on a substrate shaped as a spatial micro-grid, called the "nichoid," which is nanoengineered by two-photon laser polymerization, and induces a roundish nuclear configuration in cells adhering to the nichoid grid, and a spread configuration in cells adhering to the flat substrate surrounding the grid. We then measured the diffusion through the nuclear envelope of an inert green-fluorescent protein, by fluorescence recovery after photobleaching (FRAP). Finally, we compared the diffusion times predicted by the numerical model for roundish vs. spread cells, with the measured times. Our data show that cell stretching modulates the characteristic time needed for the nuclear import of a small inert molecule, GFP, and the model predicts a faster import of diffusive molecules in the spread compared to roundish cells.

Development of an UPLC-MS/MS micromethod for quantitation of cinitapride in plasma and its application in a pharmacokinetic interaction trial.

AIM: Cinitapride (CIN) is a benzamide-derived molecule used for the treatment of gastroesophageal reflux and dyspepsia. Its pharmacokinetics are controversial due to the use of supratherapeutic doses and the lack of sensitive methodology. Therefore, a sensitive and accurate micromethod was developed for its quantitation in human plasma. RESULTS: CIN was extracted from 300 µl of heparinized plasma by liquid-liquid extraction using cisapride as internal standard, and analyzed with an ultra performance liquid chromatograph employing positive multiple-reaction monitoring-MS. CONCLUSION: The method proved to be rapid, accurate and stable within a range between 50 and 2000 pg/ml and was successfully validated and applied in a pharmacokinetic interaction trial, where it was demonstrated that oral co-administration of simethicone does not modify the bioavailability of CIN.

Development of a UPLC-MS/MS method for the quantification of sildenafil by DBS, and its use on pediatric pulmonary hypertension.

BACKGROUND: Sildenafil is used for the treatment of pediatric pulmonary hypertension. A dried blood spot (DBS)-based LC-MS method for sildenafil quantitation was developed and applied to a group of patients. RESULTS: DBS showed high portability and stability of samples, and the method was selective and linear for quantitation of sildenafil (5-3,000 ng/ml) and N-desmethyl-sildenafil (3-1,500 ng/ml). After a single oral dose of sildenafil (1 mg/kg), method evidenced poor metabolism in these patients. CONCLUSION: The method was successfully applied in peripheral blood and can be used for both pharmacokinetics and therapeutic drug monitoring. DBS proved to have advantages during sample translation and preservation of analytes. Data suggest that hazardous blood sildenafil levels may be reached in this population.

Comparison of fasting bioavailability among 100-mg commercial, 100-mg generic, and 50-mg chewable generic sildenafil tablets in healthy male Mexican volunteers: a single-dose, 3-period, crossover study.

BACKGROUND: Sildenafil citrate (SIL) was the first oral drug registered in Mexico for the treatment of erectile dysfunction. However, succinct pharmacokinetic data are available in the Mexican population. OBJECTIVE: The goals of the present work were: (1) to design a specific method to quantify SIL plasma levels by using UPLC-MS/MS; (2) to compare oral SIL bioavailability in Mexican men with pharmacokinetic data in other populations; (3) to fulfill local regulatory requests; and (4) to describe the relative tolerability of a new 50-mg chewable tablet. METHODS: This was a randomized, single-dose, 3-period, 6-sequence crossover study in healthy male volunteers. In each period, subjects received single oral doses of 100 mg of sildenafil (1 commercial [reference(⁎)], 1 generic [test 1(†)], or 2 chewable generic tablets [test 2(‡)]), with a 4-day washout period between each dose. Serial blood samples were collected for up to 24 hours. SIL was measured in heparinized plasma by using a validated UPLC-MS/MS method. Pharmacokinetic parameters included C(max), T(max), AUC(0-24), and AUC(0-∞). Bioequivalence was established if 90% CIs for mean test:reference ratios of log-transformed C(max) and AUC fell within the range of 0.80 to 1.25. Tolerability was assessed on the basis of a clinical interview with the subject and monitoring of vital signs. RESULTS: Demographic data showed a homogeneous population. Validation of analytical method proved to be linear within the range of 1 to 1000 ng/mL, with selectivity, accuracy, and precision. 90% CIs for test 1:reference ratios were 86.52 to 113.56, 94.75 to 108.84, and 94.97 to 108.82 for the logarithm parameters C(max), AUC(0-24), and AUC(0-∞), respectively. The 90% CIs for the test 2:reference ratios were 82.14 to 107.24, 98.26 to 112.56, and 99.19 to 113.34 for C(max), AUC(0-24), and AUC(0-∞). Regarding relative tolerability, slight cephalea was the most common adverse effect. CONCLUSIONS: The developed analytical method was validated in compliance with local requirements and was useful for sildenafil measurement. This single-dose study under fasting conditions suggests that both test products met the Mexican regulatory criteria for assuming bioequivalence in these healthy, male Mexican volunteers. The clinical data suggest that the chewable tablets were well tolerated by volunteers.

Development of a method by UPLC-MS/MS for the quantification of tizoxanide in human plasma and its pharmacokinetic application.

BACKGROUND: Nitazoxanide (NTZ) is used for the treatment of gastrointestinal tract colonization by anaerobic bacteria, viruses and other pathogens that represent a major cause of morbidity in Latin America. The aim of the present work was to develop and validate a UPLC-MS/MS method for the selective quantification of tizoxanide (TZN, the major metabolite of NTZ) in human plasma using niclosamide as internal standard; and examine its pharmacokinetic application in healthy volunteers. Nine male subjects received a single oral dose of a NTZ 500-mg tablet under fasting conditions. RESULTS: The method was linear between 0.1 and 10 µg/ml and capable of separating signals from free-TZN and those delivered by in-source collision-induced dissociation of TZN-glucuronide, quantifying it with accuracy and precision. Mean maximum plasma concentration was 6.79 µg/ml and was reached at 2.4 h post-dose. CONCLUSION: The method was validated, fulfilling regulatory guidelines. Results suggest low pharmacokinetic variability in the assayed population.

Finite-element simulation of flexor digitorum longus or flexor digitorum brevis tendon transfer for the treatment of claw toe deformity.

Claw toe deformity sometimes leads to dorsiflexion of the metatarsophalangeal joint (MPJ) and plantar flexion of the proximal (PIPJ) and distal interphalangeal (DIPJ) joints. Flexor digitorum longus tendon transfer (FDL) is currently the gold standard for the correction of this problem. Transfer of the flexor digitorum brevis (FDB) has been recently proposed as an alternative method to treat such deformity. The aim of this work is to compare the biomechanical outcome of these two methods by means of finite-element simulation. The results show that the reduction in the dorsal displacement of the proximal phalanx (PP) for the second and third toes were very similar (about 4.3 mm for each intervention), both achieving a significant reduction in MPJ dorsiflexion when compared to no intervention (displacements are reduced by approximately 51%). In the fourth and fifth toes, only a small correction in the deformity was achieved with both the techniques (10% and 7%, respectively). FDB and FDL tendon transfer reduced the stress level when compared with the non-operated pathologic foot (the reduction of stresses for the second and third PP ranged between 20% and 40%). FDB transfer resulted in a more uniform distribution of stress along the entire toe, although differences were small in all cases. These results confirm that both the tendon-transfer techniques are effective in the treatment of claw toe deformity. Therefore, the choice of technique is at the discretion of the surgeon.

Crecimiento y nutrición en la infancia y riesgo para enfermedad cardiovascular en la adultez / Growth and nutrition in children and cardiovascular disease risk in adulthood

Las Enfermedades Cardiovasculares (ECV) son la principal causa de mortalidad a nivel mundial y nacional. La persistente prevalencia global de la mortalidad por ECV y su incremento exponencial en poblaciones con crecientes índices de pobreza, han conducido al diseño e implementación de estrategias de prevención, con base en la historia natural de la aterosclerosis, la cual está presente desde la vida fetal. La presencia de factores de riesgo para ECV en la infancia con persistencia hasta la adultez soporta la hipótesis de programación fetal cardiometabólica para explicar el impacto de la nutrición sobre el desarrollo de ECV, desde el inicio de la vida. Con el objeto de establecer los lineamientos nutricionales para niños venezolanos de 0 a 9 años de edad, en el Segundo Consenso Venezolano Pediátrico de Nutrición: nutrición temprana y salud a corto y largo plazo, se evaluó la evidencia epidemiológica publicada a nivel nacional y global sobre factores metabólicos y conductuales para riesgo de ECV relacionados con la nutrición presentes en niños. Se presentan las conclusiones y recomendaciones del grupo de trabajo: crecimiento y nutrición en la infancia y riesgo para enfermedad cardiovascular en la adultez. El análisis de la evidencia revisada permite afirmar que la alimentación del niño de 0 a 9 años tiene impacto en la presencia de factores de riesgo para ECV en el adulto. Se sugieren estrategias para la nutrición del niño con el fin de garantizar un crecimiento y desarrollo adecuado con un estado de salud cardiovascular óptima.

Cardiovascular diseases (CVD) remains the leading cause of death globally and nationally. The global persistent mortality prevalence of CVD and its exponential increase in countries with poverty index increasing have led to design of prevention strategies, based on the natural history of atherosclerosis, which is present from the fetal life. The presence of CVD risk factors in childhood with persistence into adulthood supports cardiometabolic fetal programming hypothesis to explain the impact of dietary habits on the development of CVD, from the beginning of life. In order to establish nutritional guidelines for Venezuelan children of 0-9 years old, in the Second Venezuelan Pediatric Nutrition Consensus: early nutrition and health in the short and long term, the national and global epidemiological evidence published for metabolic and behavioral risk factors for CVD related to nutrition present in children was evaluated. Growth and nutrition in childhood and risk for cardiovascular disease in adulthood working group: findings and recommendations of the working group are presented. The evidence analysis suggest that the nutrition of children from 0 to 9 years has an impact on the presence of risk factors for CVD in adults. Strategies for child nutrition are suggested in order to ensure proper growth and development with a state of optimal cardiovascular health.

Development of an ultra-performance liquid chromatography technique coupled with mass spectrometry for the measurement of tacrolimus in micro-samples of whole blood, and its application on a pharmacokiinetic trial.

OBJECTIVE: The aim was to develop a rapid, specific, sensitive and accurate chromatographic technique coupled with mass spectrometry for the measurement of tacrolimus (CAS 104987-11-3) in microsamples of whole blood, and its application on a pharmacokinetic pilot trial. METHODS: A fast gradient was designed in an ultra-performance liquid chromatography, and coupled with a mass spectrometer for the quantification of tacrolimus in 100 microl samples of EDTA whole blood. Multiple reaction monitoring was used for the measurement of tacrolimus (m/z(+1) 821.49-->4768.35 Th) and sirolimus as internal standard (m/z(+1) 931.69-->864.39 Th). The method was validated according to Mexican regulatory guidelines. Twenty-four young healthy male volunteers with similar hematocrit values participated in the pharmacokinetic trial; an oral single dose of one 5 mg tacrolimus capsule was administered and kinetic profiles were described since 0 h until 24 h post-dose. RESULTS: Method showed to be accurate, precise and linear over the range from 1 to 80 ng/ml, having an absolute recovery of 94%. Molecule was stable for two months at -70 degrees C, and heparin interfered with its quantification. Total run-time is around 1.5 min. Mean maximum blood concentration was 32.63 +/- 1.74 ng/ml, and was reached at 1 h post-dose; elimination half-life was 14.18 +/- 5.71 h. CONCLUSIONS: Method developed is not time-consuming, inexpensive, and sensitive enough for its application during pharmacokinetic trials, and can be suitable for therapeutic drug monitoring in transplanted patients. Pharmacokinetic data obtained in Mexican population are quite similar to previously reported in international literature.