A tutorial on pseudospectral methods for computational optimal control

[English] This paper is a tutorial introduction to pseudospectral optimal control. With pseudospectral methods, a function is approximated as a linear combination of smooth basis functions, which are often chosen to be Legendre or Chebyshev polynomials. Collocation of the differential-algebraic equations is performed at orthogonal collocation points, which are selected to yield interpolation of high accuracy. Pseudospectral methods directly discretize the original optimal control problem to recast it into a nonlinear programming format. A numerical optimizer is then employed to find approximate local optimal solutions. The paper also briefly describes the functionality and implementation of PSOPT, an open source software package written in C++ that employs pseudospectral discretization methods to solve multi-phase optimal control problems. The software implements the Legendre and Chebyshev pseudospectral methods, and it has useful features such as automatic differentiation, sparsity detection, and automatic scaling. The use of pseudospectral methods is illustrated in two problems taken from the literature on computational optimal control. [Portuguese] Este artigo e um tutorial introdutorio sobre controle otimo pseudo-espectral. Em metodos pseudo-espectrais, uma funcao e aproximada como uma combinacao linear de funcoes de base suaves, tipicamente escolhidas como polinomios de Legendre ou Chebyshev. A colocacao de equacoes algebrico-diferenciais e realizada em pontos de colocacao ortogonal, que sao selecionados de modo a minimizar o erro de interpolacao. Metodos pseudoespectrais discretizam o problema de controle otimo original de modo a converte-lo em um problema de programa cao nao-linear. Um otimizador numerico e entao empregado para obter solucoes localmente otimas. Este artigo tambem descreve sucintamente a funcionalidade e a implementacao de um pacote computacional de codigo aberto escrito em C++ chamado PSOPT. Tal pacote emprega metodos de discretizacao pseudo-spectrais para resolver problemas de controle otimo com multiplas fase. O PSOPT permite a utilizacao de metodos de Legendre ou Chebyshev, e possui caractersticas uteis tais como diferenciacao automatica, deteccao de esparsidade e escalonamento automatico. O uso de metodos pseudo-espectrais e ilustrado em dois problemas retirados da literatura de controle otimo computacional.

Evaluating and optimizing oral formulations of live bacterial vaccines using a gastro-small intestine model

Gastrointestinal (GI) models that mimic physiological conditions in vitro are important tools for developing and optimizing biopharmaceutical formulations. Oral administration of live attenuated bacterial vaccines (LBV) can safely and effectively promote mucosal immunity but new formulations are required that provide controlled release of optimal numbers of viable bacterial cells, which must survive gastrointestinal transit overcoming various antimicrobial barriers. Here, we use a gastro-small intestine gut model of human GI conditions to study the survival and release kinetics of two oral LBV formulations: the licensed typhoid fever vaccine Vivotif comprising enteric coated capsules; and an experimental formulation of the model vaccine Salmonella Typhimurium SL3261 dried directly onto cast enteric polymer films and laminated to form a polymer film laminate (PFL). Neither formulation released significant numbers of viable cells when tested in the complete gastro-small intestine model. The poor performance in delivering viable cells could be attributed to a combination of acid and bile toxicity plus incomplete release of cells for Vivotif capsules, and to bile toxicity alone for PFL. To achieve effective protection from intestinal bile in addition to effective acid resistance, bile adsorbent resins were incorporated into the PFL to produce a new formulation, termed BR-PFL. Efficient and complete release of 4.4x107 live cells per dose was achieved from BR-PFL at distal intestinal pH, with release kinetics controlled by the composition of the enteric polymer film, and no loss in viability observed in any stage of the GI model. Use of this in vitro GI model thereby allowed rational design of an oral LBV formulation to maximize viable cell release.

Is a lower dose of vitamin D supplementation enough to increase 25(OH)D status in a sunny country?

Calcium and vitamin D are essential nutrients for bone metabolism Vitamin D can either be obtained from dietary sources or cutaneous synthesis. The study was conducted in subtropic weather; therefore, some might believe that the levels of solar radiation would be sufficient in this area. To evaluate calcium and vitamin D supplementation in postmenopausal women with osteoporosis living in a sunny country. A 3-month controlled clinical trial with 64 postmenopausal women with osteoporosis, mean age 62 +/- A 8 years. They were randomly assigned to either the supplement group, who received 1,200 mg of calcium carbonate and 400 IU (10 mu g) of vitamin D(3,) or the control group. Dietary intake assessment was performed, bone mineral density and body composition were measured, and biochemical markers of bone metabolism were analyzed. Considering all participants at baseline, serum vitamin D was under 75 nmol/l in 91.4% of the participants. The concentration of serum 25(OH)D increased significantly (p = 0.023) after 3 months of supplementation from 46.67 +/- A 13.97 to 59.47 +/- A 17.50 nmol/l. However, the dose given was limited in effect, and 86.2% of the supplement group did not reach optimal levels of 25(OH)D. Parathyroid hormone was elevated in 22.4% of the study group. After the intervention period, mean parathyroid hormone tended to decrease in the supplement group (p = 0.063). The dose given (400 IU/day) was not enough to achieve 25(OH)D concentration, considered optimal for bone health.

Optimal subdivision of land in agrarian reform projects: an analysis using genetic algorithms

J.A. Ferreira Neto, E.C. Santos Junior, U. Fra Paleo, D. Miranda Barros, and M.C.O. Moreira. 2011. Optimal subdivision of land in agrarian reform projects: an analysis using genetic algorithms. Cien. Inv. Agr. 38(2): 169-178. The objective of this manuscript is to develop a new procedure to achieve optimal land subdivision using genetic algorithms (GA). The genetic algorithm was tested in the rural settlement of Veredas, located in Minas Gerais, Brazil. This implementation was based on the land aptitude and its productivity index. The sequence of tests in the study was carried out in two areas with eight different agricultural aptitude classes, including one area of 391.88 ha subdivided into 12 lots and another of 404.1763 ha subdivided into 14 lots. The effectiveness of the method was measured using the shunting line standard value of a parceled area lot`s productivity index. To evaluate each parameter, a sequence of 15 calculations was performed to record the best individual fitness average (MMI) found for each parameter variation. The best parameter combination found in testing and used to generate the new parceling with the GA was the following: 320 as the generation number, a population of 40 individuals, 0.8 mutation tax, and a 0.3 renewal tax. The solution generated rather homogeneous lots in terms of productive capacity.

Conversion coefficients from air kerma to personal dose equivalent in mammography

In this work, the scattered X-ray beams produced by a mammography unit with a Mo/Mo, Mo/Rh and W/Rh anode/filter combinations were applied in the evaluation of the Hp(10, 0) and mean conversion coefficients from air kerma to the personal dose equivalent ((C) over barH(p(10,0 degrees))). The higher values of H(p)(10,0 degrees) are related to the Mo/Rh combination whereas the lower ones are for the W/Rh target/filter. (C) over barH(p(10,0 degrees)) values are in the range 0.19-0.54 Sv/Gy, where the higher values comprise the W/Rh combination. (C) 2009 Elsevier Ltd. All rights reserved.

A novel MAP-MRF approach for multispectral image contextual classification using combination of suboptimal iterative algorithms

In this paper we present a novel approach for multispectral image contextual classification by combining iterative combinatorial optimization algorithms. The pixel-wise decision rule is defined using a Bayesian approach to combine two MRF models: a Gaussian Markov Random Field (GMRF) for the observations (likelihood) and a Potts model for the a priori knowledge, to regularize the solution in the presence of noisy data. Hence, the classification problem is stated according to a Maximum a Posteriori (MAP) framework. In order to approximate the MAP solution we apply several combinatorial optimization methods using multiple simultaneous initializations, making the solution less sensitive to the initial conditions and reducing both computational cost and time in comparison to Simulated Annealing, often unfeasible in many real image processing applications. Markov Random Field model parameters are estimated by Maximum Pseudo-Likelihood (MPL) approach, avoiding manual adjustments in the choice of the regularization parameters. Asymptotic evaluations assess the accuracy of the proposed parameter estimation procedure. To test and evaluate the proposed classification method, we adopt metrics for quantitative performance assessment (Cohen`s Kappa coefficient), allowing a robust and accurate statistical analysis. The obtained results clearly show that combining sub-optimal contextual algorithms significantly improves the classification performance, indicating the effectiveness of the proposed methodology. (C) 2010 Elsevier B.V. All rights reserved.

Insights into exazaphosphorine resistance and possible approaches to its circumvention

The oxazaphosphorines cyclophosphamide, ifosfamide and trofosfamide remain a clinically useful class of anticancer drugs with substantial antitumour activity against a variety of solid tumors and hematological malignancies. A major limitation to their use is tumour resistance, which is due to multiple mechanisms that include increased DNA repair, increased cellular thiol levels, glutathione S-transferase and aldehyde dehydrogenase activities, and altered cell-death response to DNA damage. These mechanisms have been recently re-examined with the aid of sensitive analytical techniques, high-throughput proteomic and genomic approaches, and powerful pharmacogenetic tools. Oxazaphosphorine resistance, together with dose-limiting toxicity (mainly neutropenia and neurotoxicity), significantly hinders chemotherapy in patients, and hence, there is compelling need to find ways to overcome it. Four major approaches are currently being explored in preclinical models, some also in patients: combination with agents that modulate cellular response and disposition of oxazaphosphorines; antisense oligonucleotides directed against specific target genes; introduction of an activating gene (CYP3A4) into tumor tissue; and modification of dosing regimens. Of these approaches, antisense oligonucleotides and gene therapy are perhaps more speculative, requiring detailed safety and efficacy studies in preclinical models and in patients. A fifth approach is the design of novel oxazaphosphorines that have favourable pharmacokinetic and pharmacodynamic properties and are less vulnerable to resistance. Oxazaphosphorines not requiring hepatic CYP-mediated activation (for example, NSC 613060 and mafosfamide) or having additional targets (for example, glufosfamide that also targets glucose transport) have been synthesized and are being evaluated for safety and efficacy. Characterization of the molecular targets associated with oxazaphosphorine resistance may lead to a deeper understanding of the factors critical to the optimal use of these agents in chemotherapy and may allow the development of strategies to overcome resistance.

Olanzapine / fluoxetine combination for treatment resistant depression : efficacy and clinical utility

Antidepressant monotherapy is a first-line treatment for depression; however, not all sufferers will adequately respond to treatment. When treating a patient with treatment-resistant depression, the clinician needs to consider all factors which may contribute to an inadequate response to an antidepressant. These include accuracy of diagnosis and medication adherence, as well as the patient’s personality, lifestyle, life events and social circumstances. If it is determined that treatment resistance is due to failure of efficacy of antidepressant monotherapy, then an augmentation strategy using an atypical antipsychotic may be considered. Treatment using olanzapine/fluoxetine combination (OFC) is one of many options. Four randomized, acute-phase trials have suggested OFC is useful for reducing Montgomery–Åsberg Depression Rating Scale scores after inadequate response to antidepressant monotherapy. OFC has been useful at doses of olanzapine/fluoxetine 6/25, 6/50, 12/25 and 12/50 mg/day, with 1/5 mg/day suggested to be an ineffective dose. Treatment with OFC has been associated with some side effects, including weight gain and the metabolic syndrome, somnolence, dry mouth, increased appetite and headache. Treatment decisions therefore need to be made to balance the risks and benefits.

A survey of combination antidepressant use in Australia

Objective: The aim of this study was to survey doctors working in psychiatry in Australia about the practice of using two antidepressants simultaneously.

Method: A postal survey was sent to all doctors in psychiatry in Australia enquiring about their prescribing history and their attitudes to combination antidepressants and related issues.

Results: Seventy-nine percent of respondents had used combination antidepressants. The most frequently reported combination was a selective serotonin reuptake inhibitor combined with a tricyclic antidepressant. Combinations of mirtazepine with venlafaxine and other antidepressants were the next most frequently used. Seventeen percent of respondents reported having seen a complication from combination antidepressants, 75% believed that Australian GPs should be given information on the use of combination antidepressants, 89% wished for more information on this topic, and 88% believed patients had a right to be informed of this option in their treatment. Use of combination antidepressants was more frequent than exceeding the recommended maximum dose of an individual antidepressant.

Conclusion: Combination antidepressants are used far more frequently in Australia than suspected previously. Research into safe and evidence-based practice is strongly indicated.

Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.

Patients and methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m2 dose every three weeks

Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6–99 weeks) and 1-year survival was 71%.

Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

Epidemiologic merit of obese-years, the combination of degree and duration of obesity

This study aims to test the effect of combining the degree and the duration of obesity into a single variable-obese-years-and to examine whether obese-years is a better predictor of the risk of diabetes than simply body mass index (BMI) or duration of obesity. Of the original cohort of the Framingham Heart Study, 5,036 participants were followed up every 2 years for up to 48 years (from 1948). The variable, obese-years, was defined by multiplying for each participant the number of BMI units above 30 kg/m(2) by the number of years lived at that BMI. Associations with diabetes were analyzed by using time-dependent Cox proportional hazards regression models adjusted for potential confounders. The incidence of type-2 diabetes increased as the number of obese-years increased, with adjusted hazard ratios of 1.07 (95% confidence interval: 1.06, 1.09) per additional 10 obese-years. The dose-response relation between diabetes incidence and obese-years varied by sex and smoking status. The Akaike Information Criterion was lowest in the model containing obese-years compared with models containing either the degree or duration of obesity alone. A construct of obese-years is strongly associated with risk of diabetes and could be a better indicator of the health risks associated with increasing body weight than BMI or duration of obesity alone.

Capecitabine and oral cyclophosphamide : a novel oral treatment combination for advanced cancer

Background: This dose escalation study assessed feasibility of a totally oral chemotherapy regimen using cyclophosphamide and capecitabine. The rationale for this combination was based on the observation that preclinical models of cyclophosphamide up-regulated tumor thymidine phosphorylase and increased the activation of capecitabine. Methods: Eligible patients with advanced cancer were treated with oral cyclophosphamide and capecitabine on a 28-day cycle. If no dose limiting toxicities (DLT) were encountered during the first two treatment cycles, the next patient group was assigned to the next highest dose level until the maximum tolerable dose (MTD) was determined. Results: Twenty-seven patients entered treatment. The majority of non-DLT were grades 1 and 2. DLT experienced in the first 8-week observation period were grade 3 diarrhea (one patient, level III) and grade 3 emesis (two patients, level V). MTD was observed at level 5, 1331 mg/m2/day capecitabine days 1–28 with 125 mg/m2/day cyclophosphamide days 1–14 of the 28-day cycle. The recommended phase II dose is therefore 1331 mg/m2/day capecitabine with 100 mg/m2/day cyclophosphamide. The best response evaluation showed four partial responses (breast, colon, ovary and pancreas). Conclusion: Cyclophosphamide and capecitabine can be combined at their full oral single agent dose with promising tolerability and activity.

Do leatherback turtles Dermochelys coriacea forage during the breeding season? A combination of data-logging devices provide new insights

Animals which undertake migrations from foraging grounds to suitable breeding areas must adopt strategies in these new conditions in order to minimise the rate at which body condition deteriorates (which will occur due to oogenesis or provisioning for young). For some animals this involves continuing foraging, whereas for others the optimal strategy is to fast during the breeding season. The leatherback turtle undertakes long-distance migrations from temperate zones to tropical breeding areas, and in some of these areas it has been shown to exhibit diving behaviour indicative of foraging. We used conventional time–depth recorders and a single novel mouth-opening sensor to investigate the foraging behaviour of leatherback turtles in the southern Caribbean. Diving behaviour suggested attempted foraging on vertically migrating prey with significantly more diving to a more consistent depth occurring during the night. No obvious prey manipulation was detected by the mouth sensor, but rhythmic mouth opening did occur during specific phases of dives, suggesting that the turtle was relying on gustatory cues to sense its immediate environment. Patterns of diving in conjunction with these mouth-opening activities imply that leatherbacks are attempting to forage during the breeding season and that gustatory cues are important to leatherbacks.

Sizing solar home systems for optimal development impact

The paper compares the development impact of three different sized solar home systems (SHS) (10, 40 and 80 Wp) installed in rural East Timor. It describes research aimed to determine whether the higher cost of the larger systems was justified by additional household benefits. To assess the development impact of these different sizes of SHS the research used a combination of participatory and quantitative tools. Participatory exercises were conducted with seventy-seven small groups of SHS users in twenty-four rural communities and supplemented with a household survey of 195 SHS users.

The combined results of these evaluation processes enabled the three sizes of SHS to be compared for two types of benefits—those associated with carrying out important household tasks and attributes of SHS which were advantageous compared to the use of non-electric lighting sources. The research findings showed that the small, 10 Wp SHS provided much of the development impact of the larger systems. It suggests three significant implications for the design of SHS programs in contexts such as East Timor: provide more small systems rather than fewer large ones; provide lighting in the kitchen wherever possible; and carefully match SHS operating costs to the incomes of rural users.

Estimation and extrapolation of optimal treatment and testing strategies

We review recent developments in the estimation of an optimal treatment strategy or regime from longitudinal data collected in an observational study. We also propose novel methods for using the data obtained from an observational database in one health-care system to determine the optimal treatment regime for biologically similar subjects in a second health-care system when, for cultural, logistical, or financial reasons, the two health-care systems differ (and will continue to differ) in the frequency of, and reasons for, both laboratory tests and physician visits. Finally, we propose a novel method for estimating the optimal timing of expensive and/or painful diagnostic or prognostic tests. Diagnostic or prognostic tests are only useful in so far as they help a physician to determine the optimal dosing strategy, by providing information on both the current health state and the prognosis of a patient because, in contrast to drug therapies, these tests have no direct causal effect on disease progression. Our new method explicitly incorporates this no direct effect restriction.