Comparison of two population pharmacokinetic programs, NONMEM and P-PHARM, for tacrolimus

Objectives: To compare the population modelling programs NONMEM and P-PHARM during investigation of the pharmacokinetics of tacrolimus in paediatric liver-transplant recipients. Methods: Population pharmacokinetic analysis was performed using NONMEM and P-PHARM on retrospective data from 35 paediatric liver-transplant patients receiving tacrolimus therapy. The same data were presented to both programs. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F). Covariates screened for influence on these parameters were weight, age, gender, post-operative day, days of tacrolimus therapy, transplant type, biliary reconstructive procedure, liver function tests, creatinine clearance, haematocrit, corticosteroid dose, and potential interacting drugs. Results: A satisfactory model was developed in both programs with a single categorical covariate - transplant type - providing stable parameter estimates and small, normally distributed (weighted) residuals. In NONMEM, the continuous covariates - age and liver function tests - improved modelling further. Mean parameter estimates were CL/F (whole liver) = 16.3 1/h, CL/F (cut-down liver) = 8.5 1/h and V/F = 565 1 in NONMEM, and CL/F = 8.3 1/h and V/F = 155 1 in P-PHARM. Individual Bayesian parameter estimates were CL/F (whole liver) = 17.9 +/- 8.8 1/h, CL/F (cutdown liver) = 11.6 +/- 18.8 1/h and V/F = 712 792 1 in NONMEM, and CL/F (whole liver) = 12.8 +/- 3.5 1/h, CL/F (cut-down liver) = 8.2 +/- 3.4 1/h and V/F = 221 1641 in P-PHARM. Marked interindividual kinetic variability (38-108%) and residual random error (approximately 3 ng/ml) were observed. P-PHARM was more user friendly and readily provided informative graphical presentation of results. NONMEM allowed a wider choice of errors for statistical modelling and coped better with complex covariate data sets. Conclusion: Results from parametric modelling programs can vary due to different algorithms employed to estimate parameters, alternative methods of covariate analysis and variations and limitations in the software itself.

Checklist of health promotion environments at worksites (CHEW): Development and measurement characteristics

Purpose. Health promotion policy frameworks, recent theorizing, and research all emphasize understanding and mobilizing environmental influences to change particular health-related behaviors in specific settings. The workplace is a key environmental setting. The Checklist of Health Promotion Environments at Worksites (CHEW) was designed as a direct observation instrument to assess characteristics of worksite environments that are known to influence health-related behaviors. Methods. The CHEW is a 112-item checklist of workplace environment features hypothesized to be associated, both positively and negatively, with physical activity, healthy eating, alcohol consumption, and smoking. The three environmental domains assessed are (1) physical characteristics of the worksite, (2) features of the information environment, and (3) characteristics of the immediate neighborhood around the workplace. The conceptual rationale and development studies for the CHEW are described, and data from observational studies of 20 worksites are reported. Results. The data on CHEW-derived environmental attributes showed generally good reliability and identified meaningful sets of variables that plausibly may influence health-related behaviors. With the exception of one information environment attribute, intraclass correlation coefficients ranged from 0.80 to 1.00. Descriptive statistics on selected physical and information environment characteristics indicated that vending machines, showers, bulletin boards, and signs prohibiting smoking were common across worksites. Bicycle racks, visible stairways, and signs related to alcohol consumption, nutrition, and health. promotion were relatively uncommon. Conclusions. These findings illustrate the types of data on environmental attributes that can be derived, their relevance for program planning, and how they can characterize variability across worksites. The CHEW is a promising observational measure that has the potential to assess environmental influences on health behaviors and to evaluate workplace health promotion programs.

A simulation tool for demand response programs implementation

The design and development of simulation models and tools for Demand Response (DR) programs are becoming more and more important for adequately taking the maximum advantages of DR programs use. Moreover, a more active consumers’ participation in DR programs can help improving the system reliability and decrease or defer the required investments. DemSi, a DR simulator, designed and implemented by the authors of this paper, allows studying DR actions and schemes in distribution networks. It undertakes the technical validation of the solution using realistic network simulation based on PSCAD. DemSi considers the players involved in DR actions, and the results can be analyzed from each specific player point of view.

Development and validation of the Portuguese version of the WHOQOL-OLD module

OBJECTIVE: The increasing proportion of older adults in the general population and the specific characteristics of this age group show the need for the development of specific instruments to measure quality of life in older adults. The study aimed at describing the development and validation of the Portuguese version of the World Health Organization Quality of Life for Older Persons (WHOQOL-OLD) module. METHODS: The WHOQOL-OLD instrument was administered in a sample of 424 older adults in the city of Porto Alegre, Southern Brazil, in 2005. The questionnaire comprises 24 items divided into six facets: sensory abilities; autonomy; past, present and future activities; social participation; death and dying; and intimacy. Besides the WHOQOL-OLD module, the WHOQOL-BREF, BDI and BHS instruments were also applied. The instrument's internal consistency was assessed using Cronbach's alpha coefficient. RESULTS: The instrument showed adequate internal consistency (Cronbach's coefficients ranging from 0.71 to 0.88), discriminant validity (p<0.01), concurrent validity (correlation coefficients ranging from -0.61 to -0.50) and test-retest reliability (correlation coefficients ranging from 0.58 to 0.82). Findings concerning criterion validity need further studies. CONCLUSIONS: The WHOQOL-Old module is a useful alternative with good psychometric performance in the investigation of quality of life in older adults.

A debugging engine for parallel and distributed programs

Dissertação apresentada para a obtenção do Grau de Doutor em Informática pela Universidade Nova de Lisboa, Faculdade de Ciências e Tecnologia.

Type-based protocol conformance and aliasing control in concurrent java programs

Dissertação para obtenção do Grau de Mestre em Engenharia Informática

Development of a fuzzy qualitative risk assessment model applied to construction industry

Dissertação para obtenção do Grau de Doutor em Engenharia Industrial

Malaria in the State of Amazonas: a typical Brazilian tropical disease influenced by waves of economic development

In Brazil, more than 99% of malaria cases are reported in the Amazon, and the State of Amazonas accounts for 40% of this total. However, the accumulated experience and challenges in controlling malaria in this region in recent decades have not been reported. Throughout the first economic cycle during the rubber boom (1879 to 1912), malaria was recorded in the entire state, with the highest incidence in the villages near the Madeira River in the Southern part of the State of Amazonas. In the 1970s, during the second economic development cycle, the economy turned to the industrial sector and demanded a large labor force, resulting in a large migratory influx to the capital Manaus. Over time, a gradual increase in malaria transmission was observed in peri-urban areas. In the 1990s, the stimulation of agroforestry, particularly fish farming, led to the formation of permanent Anopheline breeding sites and increased malaria in settlements. The estimation of environmental impacts and the planning of measures to mitigate them, as seen in the construction of the Coari-Manaus gas pipeline, proved effective. Considering the changes occurred since the Amsterdam Conference in 1992, disease control has been based on early diagnosis and treatment, but the development of parasites that are resistant to major antimalarial drugs in Brazilian Amazon has posed a new challenge. Despite the decreased lethality and the gradual decrease in the number of malaria cases, disease elimination, which should be associated with government programs for economic development in the region, continues to be a challenge.

Contribution to drug discovery and development for tauopathies using yeast as a model

This work aimed to contribute to drug discovery and development (DDD) for tauopathies, while expanding our knowledge on this group of neurodegenerative disorders, including Alzheimer’s disease (AD). Using yeast, a recognized model for neurodegeneration studies, useful models were produced for the study of tau interaction with beta-amyloid (Aβ), both AD hallmark proteins. The characterization of these models suggests that these proteins co-localize and that Aβ1-42, which is toxic to yeast, is involved in tau40 phosphorylation (Ser396/404) via the GSK-3β yeast orthologue, whereas tau seems to facilitate Aβ1-42 oligomerization. The mapping of tau’s interactome in yeast, achieved with a tau toxicity enhancer screen using the yeast deletion collection, provided a novel framework, composed of 31 genes, to identify new mechanisms associated with tau pathology, as well as to identify new drug targets or biomarkers. This genomic screen also allowed to select the yeast strain mir1Δ-tau40 for development of a new GPSD2TM drug discovery screening system. A library of unique 138 marine bacteria extracts, obtained from the Mid-Atlantic Ridge hydrothermal vents, was screened with mir1Δ-tau40. Three extracts were identified as suppressors of tau toxicity and constitute good starting points for DDD programs. mir1Δ strain was sensitive to tau toxicity, relating tau pathology with mitochondrial function. SLC25A3, the human homologue of MIR1, codes for the mitochondrial phosphate carrier protein (PiC). Resorting to iRNA, SLC25A3 expression was silenced in human neuroglioma cells, as a first step towards the engineering of a neural model for replicating the results obtained in yeast. This model is essential to understand the mechanisms of tau toxicity at the mitochondrial level and to validate PiC as a relevant drug target. The set of DDD tools here presented will foster the development of innovative and efficacious therapies, urgently needed to cope with tau-related disorders of high human and social-economic impact.

Measuring university-to-work success: development of a new scale

Purpose – The purpose of this paper is to develop a subjective multidimensional measure of early career success during university-to-work transition. Design/methodology/approach – The construct of university-to-work success (UWS) was defined in terms of intrinsic and extrinsic career outcomes, and a three-stage study was conducted to create a new scale. Findings – A preliminary set of items was developed and tested by judges. Results showed the items had good content validity. Factor analyses indicated a four-factor structure and a second-order model with subscales to assess: career insertion and satisfaction, confidence in career future, income and financial independence, and adaptation to work. Third, the authors sought to confirm the hypothesized model examining the comparative fit of the scale and two alternative models. Results showed that fits for both the first- and second-order models were acceptable. Research limitations/implications – The proposed model has sound psychometric qualities, although the validated version of the scale was not able to incorporate all constructs envisaged by the initial theoretical model. Results indicated some direction for further refinement. Practical implications – The scale could be used as a tool for self-assessment or as an outcome measure to assess the efficacy of university-to-work programs in applied settings. Originality/value – This study provides a useful single measure to assess early career success during the university-to-work transition, and might facilitate testing of causal models which could help identify factors relevant for successful transition.

From software extensions to product lines of dataflow programs

Abstract Dataflow programs are widely used. Each program is a directed graph where nodes are computations and edges indicate the flow of data. In prior work, we reverse-engineered legacy dataflow programs by deriving their optimized implementations from a simple specification graph using graph transformations called refinements and optimizations. In MDE-speak, our derivations were PIM-to-PSM mappings. In this paper, we show how extensions complement refinements, optimizations, and PIM-to-PSM derivations to make the process of reverse engineering complex legacy dataflow programs tractable. We explain how optional functionality in transformations can be encoded, thereby enabling us to encode product lines of transformations as well as product lines of dataflow programs. We describe the implementation of extensions in the ReFlO tool and present two non-trivial case studies as evidence of our work’s generality

Development of specific ITS markers for plant DNA identification within herbivorous insects

DNA based techniques have proved to be very useful methods to study trophic relationships 17 between pests and their natural enemies. However, most predators are best defined as omnivores, 18 and the identification of plant-specific DNA should also allow the identification of the plant 19 species the predators have been feeding on. In this study, a PCR approach based on the 20 development of specific primers was developed as a self-marking technique to detect plant DNA 21 within the gut of one heteropteran omnivorous predator (Macrolophus pygmaeus) and two 22 lepidopteran pest species (Helicoverpa armigera and Tuta absoluta). Specific tomato primers 23 were designed from the ITS 1-2 region, which allowed the amplification of a tomato DNA 24 fragment of 332 bp within the three insect species tested in all cases (100% of detection at t = 0) 25 and did not detect DNA of other plants nor of the starved insects. Plant DNA half-lives at 25ºC 26 ranged from 5.8h, to 27.7h and 28.7h within M. pygmaeus, H. armigera and T. absoluta, 27 respectively. Tomato DNA detection within field collected M. pygmaeus suggests dietary mixing 28 in this omnivorous predator and showed a higher detection of tomato DNA in females and 29 nymphs than males. This study provides a useful tool to detect and to identify plant food sources 30 of arthropods and to evaluate crop colonization from surrounding vegetation in conservation 31 biological control programs.

Development and growth of the early juveniles of the spider crab Maja squinado (Brachyura: Majoidea) in an individual culture system

The spider crab Maja squinado is an endangered Mediterranean species; therefore, culturing it successfully is essential for developing restocking programs. The survival, growth and development of post-larval stages (juvenile crabs, C1-C8) were studied using larvae obtained from adult individuals collected in the Catalan Sea. The juvenile crab stages were cultured individually from a megalopal stage using a semi-open recirculation system to obtain the precise growth data of each juvenile crab stage until C8. Development up to C8 at 20ºC lasted 154±10 days. Survival from C1 to C8 was 5.8 %. Moult increment values in cephothoracic length were similar in all the crab stages (21-35 %). Intermoult duration (9±1 in C1-C2 to 51±8 days in C7-C8) increased sharply from juvenile stage 5. Males and females can be distinguished from C4 based on sexual dimorphism in the pleopods and the presence of gonopores. The allometric growth of the pleon is sex-dependent from C4, with females showing positive allometry and males isometric growth. The juvenile growth rate was lower compared with that of the previously studied Atlantic species Maja brachydactyla.

Laboratory evaluation of the effects of triflumuron on the development of Rhodnius prolixus nymph

Studies were carried out to evaluate the efficacy of the growth regulator, triflumuron (TFM) (Starycide® sc 480 Bayer), for disrupting the development of Rhodnius prolixus fifth-instar nymph by oral, topical or continuous treatment. All treatments were able to induce high levels of mortality, delay development and molt inhibition. Oral treatment induced molt inhibition in all insects that survived at doses of 0.25, 0.50 and 5.0 mg/mL of a blood meal. The highest levels of both mortality in 24 h and molt inhibition were always observed after topical treatment. The lowest doses needed to obtain considerable biological effects were always observed after continuous treatment. In this way, the highest levels of mortality within 30 days were detected after continuous treatment, which also induced an extended inter-molting period, a lower number of over-aged nymphs and the highest level of molting in nymphs that survived. Moreover, the effects of TFM on insects were often displayed in a dose response manner. These results indicate that TFM acts as a potent growth inhibitor of R. prolixus nymphs and has the potential to be used in integrated vector control programs against hematophagous triatomine species.

Conceiving Comparative Policy Analysis : Implementing Air Quality Improvement Programs

The comparative analysis of air quality control policies provides an interesting field for studies of comparative policy analysis including program formulation and implementation processes. In European countries, the problem is comparable, whereas implementation structures, programs and policy impacts vary to a considerable extent. Analysis testing possibilities and constraints of air control policies under varying conditions are likely to contribute to a further development of a theory of policy analysis. This paper presents the analytical framework applied in a continuing empirical study explaining program formulation and implementation processes with respect to the different actors involved. Concrete emitter behavior can be explained by interaction processes at the very local level, by program elements of national legislation, and by structural constraints under which such programs are produced.