Analysis of HCV quasispecies dynamic under selective pressure of combined therapy

Background: The quasispecies composition of Hepatitis C virus (HCV) could have important implications with regard to viral persistence and response to interferon-based therapy. The complete NS5A was analyzed to evaluate whether the composition of NS5A quasispecies of HCV 1a/1b is related to responsiveness to combined interferon pegylated (PEG-IFN) and ribavirin therapy.Methods: Viral RNA was isolated from serum samples collected before, during and after treatment from virological sustained responder (SVR), non-responder (NR) and the end-of-treatment responder patients (ETR). NS5A region was amplified, cloned and sequenced. Six hundred and ninety full-length NS5A sequences were analyzed.Results: This study provides evidence that lower nucleotide diversity of the NS5A region pre-therapy is associated with viral clearance. Analysis of samples of NRs and the ETRs time points showed that genetic diversity of populations tend to decrease over time. Post-therapy population of ETRs presented higher genetic distance from baseline probably due to the bottleneck phenomenon observed for those patients in the end of treatment. The viral effective population of those patients also showed a strong decrease after therapy. Otherwise, NRs demonstrated a continuous variation or stability of effective populations and genetic diversity over time that did not seem to be related to therapy. Phylogenetic relationships concerning complete NS5A sequences obtained from patients did not demonstrate clustering associated with specific response patterns. However, distinctive clustering of pre/post-therapy sequences was observed. In addition, the evolution of quasispecies over time was subjected to purifying or relaxed purifying selection. Codons 157 (P03), 182 and 440 (P42), 62 and 404 (P44) were found to be under positive selective pressure but it failed to be related to the therapy.Conclusion: These results confirm the hypothesis that a relationship exists between NS5A heterogeneity and response to therapy in patients infected with chronic hepatitis C. © 2013 Jardim et al.; licensee BioMed Central Ltd.

Comparison of cyclic fatigue and torsional resistance in reciprocating single-file systems and continuous rotary instrumentation systems

As compared with continuous rotary systems, reciprocating motion is believed to increase the fatigue resistance of NiTi instruments. We compared the cyclic fatigue and torsional resistance of reciprocating single-file systems and continuous rotary instrumentation systems in simulated root canals. Eighty instruments from the ProTaper Universal, WaveOne, MTwo, and Reciproc systems (n = 20) were submitted to dynamic bending testing in stainless-steel simulated curved canals. Axial displacement of the simulated canals was performed with half of the instruments (n = 10), with back-and-forth movements in a range of 1.5 mm. Time until fracture was recorded, and the number of cycles until instrument fracture was calculated. Cyclic fatigue resistance was greater for reciprocating systems than for rotary systems (P < 0.05). Instruments from the Reciproc and WaveOne systems significantly differed only when axial displacement occurred (P < 0.05). Instruments of the ProTaper Universal and MTwo systems did not significantly differ (P > 0.05). Cyclic fatigue and torsional resistance were greater for reciprocating systems than for continuous rotary systems, irrespective of axial displacement.

Measure functional differential equations and functional dynamic equations on time scales

We study measure functional differential equations and clarify their relation to generalized ordinary differential equations. We show that functional dynamic equations on time scales represent a special case of measure functional differential equations. For both types of equations, we obtain results on the existence and uniqueness of solutions, continuous dependence, and periodic averaging.

Resistance to Flexural Fatigue of Reciproc R25 Files under Continuous Rotation and Reciprocating Movement

Introduction: The aim of the present work was to evaluate the resistance to flexural fatigue of Reciproc R25 nickel-titanium files, 25 mm, used in continuous rotation motion or reciprocation motion, in dynamic assays device. Methods: Thirty-six Reciproc R25 files were divided into 2 groups (n = 18) according to kinematics applied, continuous rotary (group CR) and reciprocation motion (group RM). The files were submitted to dynamic assays device moved by an electric engine with 300 rpm of speed that permitted the reproduction of pecking motion. The files run on a ring's groove of temperate steel, simulating instrumentation of a curved root canal with 400 and 5 mm of curvature radius. The fracture of file was detected by sensor of device, and the time was marked. The data were analyzed statistically by Student's t test, with level of significance of 95%. Results: The instruments moved by reciprocating movement reached significantly higher numbers of cycles before fracture (mean, 1787.78 cycles) when compared with instruments moved by continuous rotary (mean, 816.39 cycles). Conclusions: The results showed that the reciprocation motion improves flexural fatigue resistance in nickel-titanium instrument Reciproc R25 when compared with continuous rotation movement. (J Endod 2012;38:684-687)

OPTIMIZATION AND CONTROL OF A CONTINUOUS POLYMERIZATION REACTOR

This work studies the optimization and control of a styrene polymerization reactor. The proposed strategy deals with the case where, because of market conditions and equipment deterioration, the optimal operating point of the continuous reactor is modified significantly along the operation time and the control system has to search for this optimum point, besides keeping the reactor system stable at any possible point. The approach considered here consists of three layers: the Real Time Optimization (RTO), the Model Predictive Control (MPC) and a Target Calculation (TC) that coordinates the communication between the two other layers and guarantees the stability of the whole structure. The proposed algorithm is simulated with the phenomenological model of a styrene polymerization reactor, which has been widely used as a benchmark for process control. The complete optimization structure for the styrene process including disturbances rejection is developed. The simulation results show the robustness of the proposed strategy and the capability to deal with disturbances while the economic objective is optimized.

Stochastic models and dynamic measures for the characterization of bistable circuits

During the last few years, a great deal of interest has risen concerning the applications of stochastic methods to several biochemical and biological phenomena. Phenomena like gene expression, cellular memory, bet-hedging strategy in bacterial growth and many others, cannot be described by continuous stochastic models due to their intrinsic discreteness and randomness. In this thesis I have used the Chemical Master Equation (CME) technique to modelize some feedback cycles and analyzing their properties, including experimental data. In the first part of this work, the effect of stochastic stability is discussed on a toy model of the genetic switch that triggers the cellular division, which malfunctioning is known to be one of the hallmarks of cancer. The second system I have worked on is the so-called futile cycle, a closed cycle of two enzymatic reactions that adds and removes a chemical compound, called phosphate group, to a specific substrate. I have thus investigated how adding noise to the enzyme (that is usually in the order of few hundred molecules) modifies the probability of observing a specific number of phosphorylated substrate molecules, and confirmed theoretical predictions with numerical simulations. In the third part the results of the study of a chain of multiple phosphorylation-dephosphorylation cycles will be presented. We will discuss an approximation method for the exact solution in the bidimensional case and the relationship that this method has with the thermodynamic properties of the system, which is an open system far from equilibrium.In the last section the agreement between the theoretical prediction of the total protein quantity in a mouse cells population and the observed quantity will be shown, measured via fluorescence microscopy.

Dynamic wetting of complex liquids

A simple dependency between contact angle θ and velocity or surface tension has been predicted for the wetting and dewetting behavior of simple liquids. According to the hydrodynamic theory, this dependency was described by Cox and Voinov as θ ∼ Ca^(1/3) (Ca: Capillary number). For more complex liquids like surfactant solutions, this prediction is not directly given.rnHere I present a rotating drum setup for studying wetting/dewetting processes of surfactant solutions on the basis of velocity-dependent contact angle measurements. With this new setup I showed that surfactant solutions do not follow the predicted Cox-Voinov relation, but showed a stronger contact angle dependency on surface tension. All surfactants independent of their charge showed this difference from the prediction so that electrostatic interactions as a reason could be excluded. Instead, I propose the formation of a surface tension gradient close to the three-phase contact line as the main reason for the strong contact angle decrease with increasing surfactant concentration. Surface tension gradients are not only formed locally close to the three-phase contact line, but also globally along the air-liquid interface due to the continuous creation/destruction of the interface by the drum moving out of/into the liquid. By systematically hindering the equilibration routes of the global gradient along the interface and/or through the bulk, I was able to show that the setup geometry is also important for the wetting/dewetting of surfactant solutions. Further, surface properties like roughness or chemical homogeneity of the wetted/dewetted substrate influence the wetting/dewetting behavior of the liquid, i. e. the three-phase contact line is differently pinned on rough/smooth or homogeneous/inhomogeneous surfaces. Altogether I showed that the wetting/dewetting of surfactant solutions did not depend on the surfactant type (anionic, cationic, or non-ionic) but on the surfactant concentration and strength, the setup geometry, and the surface properties.rnSurfactants do not only influence the wetting/dewetting behavior of liquids, but also the impact behavior of drops on free-standing films or solutions. In a further part of this work, I dealt with the stability of the air cushion between drop and film/solution. To allow coalescence between drop and substrate, the air cushion has to vanish. In the presence of surfactants, the vanishing of the air is slowed down due to a change in the boundary condition from slip to no-slip, i. e. coalescence is suppressed or slowed down in the presence of surfactant.

Postreperfusion cardiac arrest and resuscitation during orthotopic liver transplantation: dynamic visualization and analysis of physiologic recordings

We recently reported on the Multi Wave Animator (MWA), a novel open-source tool with capability of recreating continuous physiologic signals from archived numerical data and presenting them as they appeared on the patient monitor. In this report, we demonstrate for the first time the power of this technology in a real clinical case, an intraoperative cardiopulmonary arrest following reperfusion of a liver transplant graft. Using the MWA, we animated hemodynamic and ventilator data acquired before, during, and after cardiac arrest and resuscitation. This report is accompanied by an online video that shows the most critical phases of the cardiac arrest and resuscitation and provides a basis for analysis and discussion. This video is extracted from a 33-min, uninterrupted video of cardiac arrest and resuscitation, which is available online. The unique strength of MWA, its capability to accurately present discrete and continuous data in a format familiar to clinicians, allowed us this rare glimpse into events leading to an intraoperative cardiac arrest. Because of the ability to recreate and replay clinical events, this tool should be of great interest to medical educators, researchers, and clinicians involved in quality assurance and patient safety.

Dynamic merge of discrete goods flow – Impact on throughput and efficiency

Continuous conveyors with a dynamic merge were developed with adaptable control equipment to differentiate these merges from competing Stop-and-Go merges. With a dynamic merge, the partial flows are manipulated by influencing speeds so that transport units need not stop for the merge. This leads to a more uniform flow of materials, which is qualitatively observable and verifiable in long-term measurements. And although this type of merge is visually mesmerizing, does it lead to advantages from the view of material flow technology? Our study with real data indicates that a dynamic merge shows a 24% increase in performance, but only for symmetric or nearly symmetric flows. This performance advantage decreases as the flows become less symmetric, approaching the throughput of traditional Stop-and-Go merges. And with a cost premium for a continuous merge of approximately 10% due to the additional technical components (belt conveyor, adjustable drive engines, software, etc.), this restricts their economical use.

Comparison of gadoteric acid and gadobutrol for detection as well as morphologic and dynamic characterization of lesions on breast dynamic contrast-enhanced magnetic resonance imaging

OBJECTIVE In contrast to conventional breast imaging techniques, one major diagnostic benefit of breast magnetic resonance imaging (MRI) is the simultaneous acquisition of morphologic and dynamic enhancement characteristics, which are based on angiogenesis and therefore provide insights into tumor pathophysiology. The aim of this investigation was to intraindividually compare 2 macrocyclic MRI contrast agents, with low risk for nephrogenic systemic fibrosis, in the morphologic and dynamic characterization of histologically verified mass breast lesions, analyzed by blinded human evaluation and a fully automatic computer-assisted diagnosis (CAD) technique. MATERIALS AND METHODS Institutional review board approval and patient informed consent were obtained. In this prospective, single-center study, 45 women with 51 histopathologically verified (41 malignant, 10 benign) mass lesions underwent 2 identical examinations at 1.5 T (mean time interval, 2.1 days) with 0.1-mmol kg doses of gadoteric acid and gadobutrol. All magnetic resonance images were visually evaluated by 2 experienced, blinded breast radiologists in consensus and by an automatic CAD system, whereas the morphologic and dynamic characterization as well as the final human classification of lesions were performed based on the categories of the Breast imaging reporting and data system MRI atlas. Lesions were also classified by defining their probability of malignancy (morpho-dynamic index; 0%-100%) by the CAD system. Imaging results were correlated with histopathology as gold standard. RESULTS The CAD system coded 49 of 51 lesions with gadoteric acid and gadobutrol (detection rate, 96.1%); initial signal increase was significantly higher for gadobutrol than for gadoteric acid for all and the malignant coded lesions (P < 0.05). Gadoteric acid resulted in more postinitial washout curves and fewer continuous increases of all and the malignant lesions compared with gadobutrol (CAD hot spot regions, P < 0.05). Morphologically, the margins of the malignancies were different between the 2 agents, whereas gadobutrol demonstrated more spiculated and fewer smooth margins (P < 0.05). Lesion classifications by the human observers and by the morpho-dynamic index compared with the histopathologic results did not significantly differ between gadoteric acid and gadobutrol. CONCLUSIONS Macrocyclic contrast media can be reliably used for breast dynamic contrast-enhanced MRI. However, gadoteric acid and gadobutrol differed in some dynamic and morphologic characterization of histologically verified breast lesions in an intraindividual, comparison. Besides the standardization of technical parameters and imaging evaluation of breast MRI, the standardization of the applied contrast medium seems to be important to receive best comparable MRI interpretation.

Dynamic intraligamentary stabilization: novel technique for preserving the ruptured ACL

PURPOSE Replacement of the torn anterior cruciate ligament (ACL) with a transplant is today`s gold standard. A new technique for preserving and healing the torn ACL is presented. HYPOTHESIS a dynamic intraligamentary stabilization (DIS) that provides continuous postinjury stability of the knee and ACL in combination with biological improvement of the healing environment [leucocyte- and platelet-rich fibrin (L-PRF) and microfracturing] should enable biomechanically stable ACL self-healing. METHODS Ten sportive patients were treated by DIS employing an internal stabilizer to keep the unstable knee in a posterior translation, combined with microfracturing and platelet-rich fibrin induction at the rupture site to promote self-healing. Postoperative clinical [Tegner, Lysholm, International Knee Documentation Committee (IKDC), visual analogue scale patient satisfaction score] and radiological evaluation, as well as assessment of knee laxity was performed at 6 weeks, 3, 6, 12, and 24 months. RESULTS One patient had a re-rupture 5 months postoperative and was hence excluded from further follow-ups. The other nine patients presented the following outcomes at 24 months: median Lysholm score of 100; IKDC score of 98 (97-100); median Tegner score of 6 (range 9-5); anterior translation difference of 1.4 mm (-1 to 3 mm); median satisfaction score of 9.8 (9-10). MRI showed scarring and continuity of the ligament in all patients. CONCLUSIONS DIS combined with microfracturing and L-PRF resulted in stable clinical and radiological healing of the torn ACL in all but one patient of this first series. They attained normal knee scores, reported excellent satisfaction and could return to their previous levels of sporting activity. LEVEL OF EVIDENCE Case series with no comparison group, Level IV.

The Effects of Credit Risk on Dynamic Portfolio Management: A New Computational Approach

The study investigates the role of credit risk in a continuous time stochastic asset allocation model, since the traditional dynamic framework does not provide credit risk flexibility. The general model of the study extends the traditional dynamic efficiency framework by explicitly deriving the optimal value function for the infinite horizon stochastic control problem via a weighted volatility measure of market and credit risk. The model's optimal strategy was then compared to that obtained from a benchmark Markowitz-type dynamic optimization framework to determine which specification adequately reflects the optimal terminal investment returns and strategy under credit and market risks. The paper shows that an investor's optimal terminal return is lower than typically indicated under the traditional mean-variance framework during periods of elevated credit risk. Hence I conclude that, while the traditional dynamic mean-variance approach may indicate the ideal, in the presence of credit-risk it does not accurately reflect the observed optimal returns, terminal wealth and portfolio selection strategies.