Pre-specified Interval Research Articles

Natural History of Perihematomal Edema After Intracerebral Hemorrhage Measured by Serial Magnetic Resonance Imaging

knowledge on the natural history and clinical impact of perihematomal edema (PHE) associated with intracerebral hemorrhage is limited. We aimed to define the time course, predictors, and clinical significance of PHE measured by serial magnetic resonance imaging. patients with primary supratentorial intracerebral hemorrhage ≥ 5 cm(3) underwent serial MRIs at prespecified intervals during the first month. Hematoma (H(v)) and PHE (E(v)) volumes were measured on fluid-attenuated inversion recovery images. Relative PHE was defined as E(v)/H(v). Neurologic assessments were performed at admission and with each MRI. Barthel Index, modified Rankin scale, and extended Glasgow Outcome scale scores were assigned at 3 months. twenty-seven patients with 88 MRIs were prospectively included. Median H(v) and E(v) on the first MRI were 39 and 46 cm(3), respectively. Median peak absolute E(v) was 88 cm(3). Larger hematomas produced a larger absolute E(v) (r(2)=0.6) and a smaller relative PHE (r(2)=0.7). Edema volume growth was fastest in the first 2 days but continued until 12 ± 3 days. In multivariate analysis, a higher admission hematocrit was associated with a greater delay in peak PHE (P=0.06). Higher admission partial thromboplastin time was associated with higher peak rPHE (P=0.02). Edema volume growth was correlated with a decline in neurologic status at 48 hours (81 vs 43 cm(3), P=0.03) but not with 3-month functional outcome. PHE volume measured by MRI increases most rapidly in the first 2 days after symptom onset and peaks toward the end of the second week. The timing and magnitude of PHE volume are associated with hematologic factors. Its clinical significance deserves further study.

Iterative Learning Control of Strict-feedback Nonlinear Time-varying Systems

摘要: 针对一类含未知时变参数的严格反馈非线性系统, 提出一种实现有限作业区间轨迹跟踪控制的迭代学习算法. 基于Lyapunov-like方法设计控制器, 回避了常规迭代学习控制中受控系统非线性特性需满足全局Lipschitz连续条件的要求. 以反推设计(Backstepping)方法设计控制器, 为使得虚拟控制项可导, 引入一级数收敛序列; 将时变参数展开为有限项多项式形式, 在控制器设计中采取双曲正切函数处理余项对于系统跟踪性能的影响. 理论分析表明, 闭环系统所有信号有界, 并能够实现系统输出完全收敛于理想轨迹. 关键词: 迭代学习控制 / 时变系统 / Lyapunov-like / 反推设计

The Ross operation — a feasible and safe option in the setting of a bicuspid aortic valve?

The Ross operation in the setting of a bicuspid aortic valve (BAV) remains controversial. Using data from the German Ross Registry, we sought to investigate the effect of the presence of a BAV on autograft function and diameters over time after the Ross operation compared with the presence of a tricuspid aortic valve (TAV). A total of 1277 patients (mean age 42.2 + or - 15.3 years) with intra-operatively documented aortic valve morphology during the Ross operation were analysed in the present study (sub-coronary technique, n=648, root replacement technique, n=629 patients). A BAV was present in 70.9% of patients. Clinical and echocardiographic follow-up was performed preoperatively and at pre-specified intervals (mean follow-up 5.7 + or - 3.8 years, 6806 patient-years). Hierarchical multilevel modelling techniques were used for the statistical analysis of serial measurements and comparisons among groups. Initial neo-aortic regurgitation was lower in the BAV group (0.52 vs 0.62 aortic insufficiency (AI) grades, p=0.008), whereas the annual increase of it did not differ among groups. In both surgical techniques, no significant development of neo-aortic regurgitation (<0.02 AI grades per year) could be detected. Initial aortic annulus and sinus dimensions did not differ in the presence of a BAV. However, BAV patients developed a higher degree of annulus and sinus dilatation over time (0.20mm per year vs 0.06 mm per year, p=0.003; 0.24 vs 0.11 mm per year, p=0.013). This effect persisted when allowing for the two different surgical techniques. Baseline sinotubular junction (STJ) diameters did not differ among groups and annual increase thereof was similar (29.15 mm vs 28.9 mm, p=0.69; 0.44 mm vs 0.35 mm, p=0.15). For the observed time period, postoperative neo-aortic regurgitation after the Ross procedure did not differ between patients with a BAV or a TAV. Root dimensions, although clinically not relevant, increased in both valve entities supporting surgical reinforcement strategies. We cannot consider a BAV as a contraindication for the Ross operation.

Gradient-based shape optimisation of conformal array antennas

We present and test a gradient-based shape optimisation method for the minimisation of the active reflection coefficient for conformal array antennas. The goal function is an average of the active reflection coefficient with respect to all antenna elements, a prespecified frequency interval, and a set of excitation modes. The sensitivity of the goal function with respect to changes of the antenna&apos;s shape is based on the continuum form of Maxwell&apos;s equations, which provides good flexibility for the choice of field solver. The sensitivity is formulated in terms of the field solution of the original antenna problem and a similar adjoint field problem, which gives the sensitivity for an arbitrary number of design parameters given the solution of Maxwell&apos;s equations. We test the optimisation method in two dimensions for array antennas that conform to a circular cylinder, where both uniform arrays and arrays that occupy a part of the cylinder&apos;s circumference are considered. For some cases, we find that it is feasible to reduce the active reflection coefficient for arrays that partially cover the circumference of the cylinder by means of end elements that differ from the bulk elements of the array. In general, substantial reductions in the active reflection coefficient can be achieved by relatively small shape changes of the antenna elements. For the test cases considered in this article, the optimisation method typically converges to an optimised design within 5–15 iterations.

Supporting Fault-Tolerance for Time-Critical Events in Distributed Environments

In this paper, we consider the problem of supporting fault tolerance foradaptiveandtime-criticalapplications in heterogeneous and unreliable grid computing environments. Our goal for this class of applications is to optimize a user-specifiedbenefit functionwhile meeting the time deadline. Our first contribution in this paper is a multi-objective optimization algorithm for scheduling the application onto the most efficient and reliable resources. In this way, the processing can achieve the maximum benefit while also maximizing thesuccess-rate, which is the probability of finishing execution without failures. However, for the cases where failures do occur, we have developed ahybrid failure recoveryscheme to ensure that the application can complete within the pre-specified time interval. Our experimental results show that our scheduling algorithm can achieve better benefit when compared to several heuristics-based greedy scheduling algorithms, while still having a negligible overhead. Benefit is further improved when we apply the hybrid failure recovery scheme, and the success-rate becomes 100%.

Pharmacokinetic interaction study between eslicarbazepine acetate and lamotrigine in healthy subjects

Anti-epileptic drugs are often used in combination. Both eslicarbazepine (main metabolite of eslicarbazepine acetate, ESL) and lamotrigine undergo conjugation with glucuronic acid, and both eslicarbazepine and its glucuronide and lamotrigine glucuronide undergo extensive renal elimination; therefore, there is a potential for interaction. This study investigated the interaction between ESL and lamotrigine in healthy subjects. Open-label study in two parallel groups of 16 healthy volunteers each. After an 8-day treatment with ESL or lamotrigine, ESL (1200 mg once-daily) and lamotrigine (150 mg once-daily) were co-administered for 19 days. Geometric mean ratios (GMR) and 90% confidence intervals (90% CI) for maximum plasma concentration (C(max)) and area under the plasma concentration-time curve in the dosing interval (AUC(0-24)) were calculated for eslicarbazepine (ESL active metabolite) and lamotrigine. The C(max) and AUC(0-24) GMR (90% CI) were, respectively, 95% (87-102%) and 96% (91-102%) for eslicarbazepine, and 88% (82-94%) and 86% (81-92%) for lamotrigine. The 90% CI of the C(max) and AUC(0-24) GMR fell within the prespecified acceptance interval (80-125%) both for eslicarbazepine and lamotrigine. There was no significant pharmacokinetic interaction between ESL and lamotrigine in healthy subjects. Therefore, no dosage adjustment appears to be usually required in either lamotrigine or ESL when the drugs are co-administered.

Intermittent preventive treatment of malaria in infancy

Intermittent preventive treatment (IPT) of malaria refers to the administration of doses of an antimalarial at prespecified intervals to prevent malaria—essentially a form of chemoprophylaxis. The focus has been on falciparum malaria in Africa. The most widely used and evaluated drug has been sulfadoxine–pyrimethamine, an antimalarial that for a period succeeded chloroquine as first-line treatment for falciparum malaria but then rapidly succumbed to resistance in many areas.1–5 IPT with sulfadoxine–pyrimethamine was first studied in pregnancy, for which it is now recommended in areas of sustained high transmission.

Effect of eslicarbazepine acetate on the pharmacokinetics of metformin in healthy subjects

Eslicarbazepine acetate (ESL) is a new voltage-gated sodium channel blocker currently in development for the treatment of neuropathic pain, including that of diabetic origin. The primary objective was to investigate the effect of ESL on the pharmacokinetics of metformin, a commonly used oral antidiabetic drug. Randomized, open-label, two-way crossover study in 20 healthy subjects. The volunteers received an 850 mg single-dose of metformin hydrochloride on two occasions - once as such and once after pre-treatment with an oral once-daily dose of ESL 1200 mg for 6 days - separated by a washout period of at least 2 weeks. The bioequivalence approach was used for assessing the effect of ESL on the pharmacokinetics of metformin. Test/Reference geometric mean ratios (GMR) and 90% confidence intervals (90% CI) were calculated for AUC0- yen, AUC0-12 and Cmax of metformin. Test/Reference metformin GMR (90% CI) was 0.95 (0.86; 1.05) for AUC0- yen, 0.95 (0.88; 1.06) for AUC0-12, and 0.88 (0.77; 1.00) for Cmax. Formal bioequivalence could not be demonstrated for metformin Cmax. However, the extent of exposure to metformin, as reflected by AUC0-12 and AUC0- yen, allows the claim of bioequivalence since the 90% CI of the GMR fall within the pre-specified bioequivalence acceptance interval (0.80; 1.25). Once-daily administration of ESL 1,200 mg had no relevant effect on the systemic exposure to metformin pharmacokinetics in healthy subjects.

Population Pharmacokinetics of Fluconazole in Young Infants

Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 . (weight/1)(0.75) . (BGA/26)(1.739) . (PNA/2)(0.237) . serum creatinine (SCRT)(-4.896) (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 . (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

Proactive Retransmission and Buffer Management for Layered Video Transmission over Wireless Channel

Hybrid FEC/ARQ, which is a mixture of forward error correction (FEC) and automatic repeat request (ARQ), is a well-known technique aiming for packet-loss recovery to guarantee quality of service (QoS) for real-time communications. In this paper, focusing on layered video transmission over wireless network environment, we propose a proactive retransmission scheme for hybrid FEC/ARQ. In the proposed scheme, a receiver host periodically sends probe packets to a sender host in order to check wireless channel state. If the sender host does not receive any probe packet during a pre-specified interval, it regards the wireless channel as being in burst loss state, and it proactively retransmits packets expected to be lost during the burst loss period. The buffer management associated with layered video coding is also taken into consideration. The performance of the proposed scheme is investigated by simulation. Numerical examples show that the proposed scheme transmits packets of the base layer more successfully than the conventional FEC/ARQ.

Reentry Flight Clearance Using Interval Analysis

The objective of the present paper is to evaluate the application of a promising new mathematical technique called interval analysis for reentry flight clearance. Whereas a Monte Carlo approach clears the vehicle only for a finite number of sets of uncertainty parameters, the new approach clears the vehicle within prespecified uncertainty parameter intervals. The new approach is applied to the reentry trajectory of the Delft Aerospace Reentry Test Demonstrator, a hypothetical ballistic reentry vehicle equipped with an attitude-stabilizing flight control system. As the clearance requirement, the stability of the system is chosen, which is evaluated using two different mathematical criteria: worst-case linear eigenvalue analysis and nonlinear Lyapunov analysis. The new approach, based on interval analysis, is applied in an evaluation of both criteria. Subsequently, Monte Carlo analysis was performed to verify the validity of these results. I. Introduction R EENTRY flight is inseparable from the present and future spaceflight missions. During the reentry flight, a vehicle has to follow a predefined trajectory toward a designated landing area. Trajectory tracking, flight stability, and landing precision are important aspects in the reentry flight. The predefined trajectory has to be tracked with a sufficient margin of error. The stability margin has to be fulfilled against the variation and uncertainty in flight parameters such as aerothermodynamic parameters, mass, and inertia.Theaccuracyoflandingisimportantaswelltoensurethatthe vehicle and its contents reach the target ground intact. All of these aspects need to be analyzed and evaluated in a systematic way to ensure the stability and performance of the reentry vehicle. To certify a reentry vehicle as safe to fly, the reentry flight model has to be evaluated before actual flight. This is known as the reentry flight model clearance, or reentry flight clearance for short. One exampleofthe flightmodelclearanceistheevaluationofthestability and performance of the reentry vehicle model in its flight envelope. AsillustratedinFig.1,thereentry flightenvelopeisdefinedalongthe nominal flight trajectory. The flight safety is checked by evaluating the regions in the flight envelope using predefined stability or performance criteria. The region in which the criteria are fulfilled is then “cleared,” which means that, under the defined flight condition, the vehicle can fly safely in this region. The right-hand side of Fig. 1 shows a blown-up view of the envelope with flyable and nonflyable regionsasaresultoftheclearance.The flyableareasareshownbythe shaded rectangles in the flight envelope. Thechallengeforthereentry flightclearanceliesinthefactthatthe mathematical models of reentry vehicles and the environments are generally nonlinear. Moreover, the models may contain uncertainty due to the unknowns and variations in the dynamics or parameters. Therefore, to produce a reliable clearance result, mathematical analysis methods that account for the nonlinearity and uncertainty in the models are needed. To answer this question, this paper contributesasystematic approachtoperform reentry flightclearance using interval analysis. This method can meet the aforementioned challenge,for itcanbeapplied tolinearaswellasnonlinearsystems, and can account for the uncertainty in the system model. To give the reader an overview of the method, the algorithm is described in Sec. V. The strong point of the method is illustrated using an example of clearance for a nonlinear system. In the sequence, we perform clearance on a reentry vehicle model with a flight control system, with stability robustness in the presence of uncertainty as the clearance criteria (see Sec. VI). The mathematical modelofthesystemisnonlinearwithuncertainparameters.Toshow that the method canbe applied tolinear as well as nonlinear systems, both linearized and nonlinear models of the system are evaluated. The clearance is performed inside the vehicle’s reentry flight envelope. For the linearized system, the eigenvalue criteria is applied, whereas for the nonlinear system, the Lyapunov function isevaluated.TheresultsarevalidatedusingMonteCarloanalysis.As literature survey,Secs.IIandIIIprovidethereader withanoverview of the current clearance practice and of the available methods, which leads to the choice of the clearance method in this paper.

Double threshold autoregressive conditionally heteroscedastic model building by genetic algorithms

Asymmetric behaviour in both mean and variance is often observed in real time series. The approach we adopt is based on double threshold autoregressive conditionally heteroscedastic (DTARCH) model with normal innovations. This model allows threshold nonlinearity in mean and volatility to be modelled as a result of the impact of lagged changes in assets and squared shocks, respectively. A methodology for building DTARCH models is proposed based on genetic algorithms (GAs). The most important structural parameters, that is regimes and thresholds, are searched for by GAs, while the remaining structural parameters, that is the delay parameters and models orders, vary in some pre-specified intervals and are determined using exhaustive search and an Asymptotic Information Criterion (AIC) like criterion. For each structural parameters trial set, a DTARCH model is fitted that maximizes the (penalized) likelihood (AIC criterion). For this purpose the iteratively weighted least squares algorithm is used. Then the best model according to the AIC criterion is chosen. Extension to the double threshold generalized ARCH (DTGARCH) model is also considered. The proposed methodology is checked using both simulated and market index data. Our findings show that our GAs-based procedure yields results that comparable to that reported in the literature and concerned with real time series. As far as artificial time series are considered, the proposed procedure seems to be able to fit the data quite well. In particular, a comparison is performed between the present procedure and the method proposed by Tsay [Tsay, R.S., 1989, Testing and modeling threshold autoregressive processes. Journal of the American Statistical Association, Theory and Methods, 84, 231–240.] for estimating the delay parameter. The former almost always yields better results than the latter. However, adopting Tsay's procedure as a preliminary stage for finding the appropriate delay parameter may save computational time specially if the delay parameter may vary in a large interval.

Planning Horizon Procedures for Machine Replacement Models

This paper develops efficient forward algorithms and planning horizon results for several machine replacement models under an improving technological environment over time. The models are that of cost minimization, profit maximization, and cost minimization with probabilistic breakdowns. The conditions of the improving technological environment are stated in terms of operating costs, incremental profits, and expected operating costs, respectively, for these models. The state of technology can be assumed to improve every period or every so many periods. The conditions are fairly general and are likely to be satisfied by most improving technologies. What is shown, specifically, is that there exists a forecast horizon T such that the optimal replacement decision for the first machine (new or existing) based on the forecast of machine technology until period T remains optimal for any longer (than T) horizon, and for that matter, the infinite horizon problem. In particular, it is possible to decide whether it is optimal to replace an existing machine at the beginning of a period or keep it at least one more period with much less information than the entire future forecast of technology. It should be noted that the forecasts become less precise farther into the future and that requiring an infinite horizon forecast for decision-making would be unrealistic. Because the planning horizon results obtained in this paper free the solution from an arbitrary horizon and ascertain the optimality of the first period decision or the first few periods decisions based on the forecast of technology only up to some finite period T, these results represent a major advance in the machine replacement literature. These planning horizon results also enable us to develop a computationally highly efficient forward algorithm for the models under consideration. The algorithm is illustrated with a numerical example. Another important corollary of the planning horizon results is that the optimal number of machine replacements cannot decrease as the length of the horizon (planning period) increases. Planning horizon procedures are shown to be easily extendable to the existing machine case as well as the case when machine lives are constrained within a prespecified finite interval. The paper concludes with various suggestions for future research efforts.

Extremum-Seeking-Based Receding-Horizon Optimal Control of Plasma Current Profile in the DIII-D Tokamak

A key goal in the control of a magnetic fusion reactor is to maintain current profiles that are compatible with a high fraction of self-generated non-inductive current as well as with magnetohydrodynamic (MHD) stability at high plasma pressure. This enables high fusion gain and noninductive sustainment of plasma current for steady-state operation. The approach taken toward establishing such plasma current profiles at the DIII-D tokamak is to create the desired profile during the plasma current ramp-up and early flattop phases. The evolution in time of the current profile is related to the evolution of the poloidal flux, which is modeled in normalized cylindrical coordinates using a nonlinear partial differential equation (PDE) usually referred to as the magnetic diffusion equation. We propose, and test in simulations, an extremum-seeking-based, receding-horizon, diffusivity-interior-boundary control scheme designed to match as close as possible a desired current profile within a prespecified time interval.

Fixed-Dose Combination Tablet of Repaglinide and Metformin is Bioequivalent to Concomitantly Administered Individual Tablets of Repaglinide and Metformin

Repaglinide and metformin enhance insulin secretion and decrease hepatic gluconeogenesis, respectively, and are commonly coadministered as separate formulations to treat patients with type 2 diabetes mellitus. A single combination therapy tablet offers increased patient convenience and the subsequent potential for increased therapy compliance. The aim of this randomized, single-blind, three-period crossover study was to determine the bioequivalence of a fixed-dose combination (FDC) tablet of repaglinide/metformin 2 mg/500 mg versus repaglinide 2 mg and metformin 500 mg coadministered as separate formulations. Secondary objectives included a comparison of the dose proportionality of an FDC tablet of repaglinide/metformin 1 mg/500 mg and an FDC tablet of repaglinide/metformin 2 mg/500 mg, as well as the safety and tolerability of repaglinide and metformin in combination tablet therapy. Healthy subjects (n = 93, age 18-45 years) were randomized to one of six possible treatment sequences (Williams design) of an FDC tablet of repaglinide/metformin 2 mg/500 mg, repaglinide 2 mg and metformin 500 mg coadministered as separate tablets and an FDC of repaglinide/metformin 1 mg/500 mg. Fifty-five subjects completed the study. Four primary pharmacokinetic endpoints (area under the plasma concentration-time curve [AUC] from time 0 hours to infinity; AUC from time 0 to 24 hours; AUC from time 0 hours to time t [the last time of measurable concentration after dosing]; and the maximum plasma concentration) were used to assess bioequivalence and dose proportionality. The safety and tolerability of repaglinide and metformin in combination tablet therapy were also evaluated. Both repaglinide and metformin in the combination tablet were determined to be bioequivalent to the individual tablets of repaglinide 2 mg and metformin 500 mg, as the limits of the 90% confidence interval of the mean treatment ratio for all pharmacokinetic parameters were contained within the pre-specified interval required for bioequivalence (0.8, 1.25). Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was determined to be dose proportional to an FDC of repaglinide/metformin 1 mg/500 mg for all analysed endpoints. No withdrawals as a result of adverse events occurred during this study. In addition, no clinically relevant abnormalities were found during physical examinations, in vital signs, ECG parameters or clinical laboratory parameters. An FDC tablet of repaglinide/metformin 2 mg/500 mg was bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg. Additionally, an FDC tablet of repaglinide/metformin 2 mg/500 mg was dose proportional to an FDC tablet of repaglinide/metformin 1 mg/500 mg. Finally, no unexpected safety concerns were noted with repaglinide/metformin combination tablet therapy. Our results suggest that FDC tablets of repaglinide and metformin would provide safety and efficacy comparable to that of repaglinide and metformin administered as separate formulations.

An effective and fast heuristic for the Dial-a-Ride problem

Dial-a-Ride is an emerging transport system, in which a fleet of vehicles, without fixed routes and schedules, carries people from the desired pickup point to the desired delivery point, during a pre-specified time interval. It can be modeled as an $$\mathcal{NP}$$ -hard routing and scheduling problem, with a suitable mixed integer programming formulation. Exact approaches to this problem are too limited to tackle real-life instances (hundred of trips), therefore heuristics are needed. The heuristic method proposed in this paper builds an auxiliary graph and then solves an assignment problem on this graph. The auxiliary graph is obtained by replacing pairs of nodes with a single one and associating an ad hoc cost function to the new set of arcs. Two different simple methods are employed to transform the infeasible solution given by the assignment problem into a feasible one. The proposed algorithms have been tested on instances created using the Milan network and shown to be fast and effective.

Phase II trial of DNA methyltransferase 1 inhibition with the antisense oligonucleotide MG98 in patients with metastatic renal carcinoma: A National Cancer Institute of Canada Clinical Trials Group investigational new drug study

DNA methyltransferases (DNMTs) methylate DNA, promoting local chromatin condensation and consequent repression of gene expression. The purpose of this two-stage phase II trial was to assess the antitumor activity of MG98, a second generation antisense oligodeoxynucleotide inhibitor of human DNMT 1, in patients with metastatic renal carcinoma (MRC). Untreated adult patients with measurable MRC were treated with MG98 at a dose of 360 mg/m2 via 2-h iv infusion twice weekly for three consecutive weeks out of four. The primary endpoint was objective response or absence of progression for at least eight weeks. Pharmacokinetics and DNMT1 mRNA levels in peripheral blood mononuclear cells (PBMCs) were also analyzed at pre-specified intervals. Seventeen eligible patients received a median of two cycles of treatment (range, 1-7), and no objective responses were seen. Nine patients had progressive disease, six had stable disease, and the study was stopped after the first stage. The most common symptomatic toxicities were rigors, fatigue, fever, and nausea. Hematological toxicity was mild. Seven patients treated with prior nephrectomy had grade 3 or 4 elevations in hepatic transaminases. Significantly higher Cmax and AUC(0-->inf) values were observed in these patients. No conclusive pattern of decreased DNMT1 activity in PBMCs was detected post MG98 treatment. The lack of objective responses observed may be explained by a lack of target effect or the choice of tumor type. Transaminitis was observed in patients with prior nephrectomy and appeared to be associated with altered drug exposure in these patients.

Robust interval-based regulation for anaerobic digestion processes

A robust regulation law is applied to the stabilization of a class of biochemical reactors exhibiting partially known highly nonlinear dynamic behavior. An uncertain environment with the presence of unknown inputs is considered. Based on some structural and operational conditions, this regulation law is shown to exponentially stabilize the aforementioned bioreactors around a desired set-point. This approach is experimentally applied and validated on a pilot-scale (1 m3) anaerobic digestion process for the treatment of raw industrial wine distillery wastewater where the objective is the regulation of the chemical oxygen demand (COD) by using the dilution rate as the manipulated variable. Despite large disturbances on the input COD and state and parametric uncertainties, this regulation law gave excellent performances leading the output COD towards its set-point and keeping it inside a pre-specified interval.

Coding Approaches to Fault Tolerance in Linear Dynamic Systems

This paper discusses fault tolerance in discrete-time dynamic systems, such as finite-state controllers or computer simulations, with focus on the use of coding techniques to efficiently provide fault tolerance to linear finite-state machines (LFSMs). Unlike traditional fault tolerance schemes, which rely heavily-particularly for dynamic systems operating over extended time horizons-on the assumption that the error-correcting mechanism is fault free, we are interested in the case when all components of the implementation are fault prone. The paper starts with a paradigmatic fault tolerance scheme that systematically adds redundancy into a discrete-time dynamic system in a way that achieves tolerance to transient faults in both the state transition and the error-correcting mechanisms. By combining this methodology with low-complexity error-correcting coding, we then obtain an efficient way of providing fault tolerance to k identical unreliable LFSMs that operate in parallel on distinct input sequences. The overall construction requires only a constant amount of redundant hardware per machine (but sufficiently large k) to achieve an arbitrarily small probability of overall failure for any prespecified (finite) time interval, leading in this way to a lower bound on the computational capacity of unreliable LFSMs.

On the Design of an Observer-Based Controller for Linear Systems with Unknown Delay

In this paper, we present two alternative observer-based H∞, control design methods for linear dynamic systems with unknown delay, the later is assumed to evolve in a pre-specified interval. Based on the Lyapunov-Krasovskii functional and some algebraic manipulations, we design observer-based control laws that guarantee the asymptotic stability of the closed-loop control system and the estimation errors. The obtained results are given in terms of linear matrix inequalities. The theoretical claims and the methods reliability are clearly illustrated via two simple examples.