Simulation-based systematic review of imatinib population pharmacokinetics and PK-PD relationships in chronic myeloid leukemia (CML) patients

Objectives: Several population pharmacokinetic (PPK) and pharmacokinetic-pharmacodynamic (PK-PD) analyses have been performed with the anticancer drug imatinib. Inspired by the approach of meta-analysis, we aimed to compare and combine results from published studies in a useful way - in particular for improving the clinical interpretation of imatinib concentration measurements in the scope of therapeutic drug monitoring (TDM). Methods: Original PPK analyses and PK-PD studies (PK surrogate: trough concentration Cmin; PD outcomes: optimal early response and specific adverse events) were searched systematically on MEDLINE. From each identified PPK model, a predicted concentration distribution under standard dosage was derived through 1000 simulations (NONMEM), after standardizing model parameters to common covariates. A "reference range" was calculated from pooled simulated concentrations in a semi-quantitative approach (without specific weighting) over the whole dosing interval. Meta-regression summarized relationships between Cmin and optimal/suboptimal early treatment response. Results: 9 PPK models and 6 relevant PK-PD reports in CML patients were identified. Model-based predicted median Cmin ranged from 555 to 1388 ng/ml (grand median: 870 ng/ml and inter-quartile range: 520-1390 ng/ml). The probability to achieve optimal early response was predicted to increase from 60 to 85% from 520 to 1390 ng/ml across PK-PD studies (odds ratio for doubling Cmin: 2.7). Reporting of specific adverse events was too heterogeneous to perform a regression analysis. The general frequency of anemia, rash and fluid retention increased however consistently with Cmin, but less than response probability. Conclusions: Predicted drug exposure may differ substantially between various PPK analyses. In this review, heterogeneity was mainly attributed to 2 "outlying" models. The established reference range seems to cover the range where both good efficacy and acceptable tolerance are expected for most patients. TDM guided dose adjustment appears therefore justified for imatinib in CML patients. Its usefulness remains now to be prospectively validated in a randomized trial.

Systematic review of population pharmacokinetic analyses of imatinib and relationships with treatment outcomes

Several population pharmacokinetic (PPK) analyses of the anticancer drug imatinib have been performed to investigate different patient populations and covariate effects. The present analysis offers a systematic qualitative and quantitative summary and comparison of those. Its primary objective was to provide useful information for evaluating the expectedness of imatinib plasma concentration measurements in the frame of therapeutic drug monitoring. The secondary objective was to review clinically important concentration-effect relationships to provide help in evaluating the potential suitability of plasma concentration values. Nine PPK models describing total imatinib plasma concentration were identified. Parameter estimates were standardized to common covariate values whenever possible. Predicted median exposure (Cmin) was derived by simulations and ranged between models from 555 to 1388 ng/mL (grand median: 870 ng/mL and interquartile "reference" range: 520-1390 ng/mL). Covariates of potential clinical importance (up to 30% change in pharmacokinetic predicted by at least 1 model) included body weight, albumin, α1 acid glycoprotein, and white blood cell count. Various other covariates were included but were statistically not significant or seemed clinically less important or physiologically controversial. Concentration-response relationships had more importance below the average reference range and concentration-toxicity relationships above. Therapeutic drug monitoring-guided dosage adjustment seems justified for imatinib, but a formal predictive therapeutic range remains difficult to propose in the absence of prospective target concentration intervention trials. To evaluate the expectedness of a drug concentration measurement in practice, this review allows comparison of the measurement either to the average reference range or to a specific range accounting for individual patient characteristics. For future research, external PPK model validation or meta-model development should be considered.

Systematic and biogeographic relationships of the Japanese white-toothed shrew (Crocidura dsinezumi)

To assess the zoogeographic and phylogenetic relationships of C. dsinezumi, its systematic position has been investigated through electrophoretic comparisons. These comparisons comprise typical Indomalayan and Palaearctic species, including C. russula, the supposed sister taxon of the Japanese white-toothed shrew. The range of measured genetic distances that separate dsinezumi from the other shrews (Nei's D = 0.232-0.406) is typical for interspecific comparisons among Crocidura taxa. Our results reinforce morphologic considerations that suggest C. dsinezumi be treated as a valid species. Phylogenetic relationships deduced from a cladistic treatment of allozyme data refute the possibility that the western Palaearctic C. russula is the sister taxon of C. dsinezumi. Zoogeographic interpretation of the genetic results indicates that the Southeast Asian representatives constitute a clade distinct from one that includes the Palaearctic species. However, C. dsinezumi is difficult to assign to either clade due to many intermediate or plesiomorphic electrophoretic characters. Unlike the major karyologic and biochemical separation that divides Afrotropical and Palaearctic species, the subdivision between Palaearctic and Indomalayan Crocidura is not correlated with any trend in karyotypic evolution. It also is shown that the Eurasiatic species of Crocidura possessing 2n = 40 chromosomes (including C. dsinezumi) do not represent a particular clade, but probably share a plesiomorphic character. Further analysis of other Indian or Asiatic species is needed to test whether the Palaearctic versus Indomalayan separation is due to real zoogeographic barriers or whether it is the result of limited samples.

A systematic review of diapoma (teleostei: characiformes: characidae: stevardiinae: diapomini) with descriptions of two new species from southern Brazil

Diapoma is reviewed and four species are recognized: (1) Diapoma thauma, new species, from streams of the rio Jacuí basin, state of Rio Grande do Sul; (2) D. pyrrhopteryx, new species collected from the rio Canoas and streams flowing into this basin in the states of Rio Grande do Sul and Santa Catarina, Brazil; (3) Diapoma terofali, from streams flowing into rio Uruguay in Uruguay and Rio Grande do Sul, Brazil and streams flowing into rio de la Plata, Argentina; and (4) Diapoma speculiferum, from lowland coastal streams in Rio Grande do Sul, Brazil and Uruguay. Diapoma pyrrhopteryx possess the posteroventral opercular elongation typical of D. speculiferum, type species of the genus, but which is absent in D. thauma and D. terofali. Nonetheless, all the diapomin species have the caudal pouch organ about equally developed in both sexes and the dorsal portion of the pouch opening bordered by a series of 3 to 8 elongated scales, the two derived features that characterize the group. The two previously described species, D. speculiferum and D. terofali, are redescribed. Previous hypotheses of relationships among the diapomin genera Planaltina, Diapoma and Acrobrycon are discussed on the basis of preliminary morphological information. It is proposed that the Diapomini is a monophyletic group. An identification key, information on sexual dimorphism, gonad anatomy, reproductive mode and distribution of the species of Diapoma are provided.

Molecular phylogeny of the freshwater prawn genus Macrobrachium (Decapoda, Palaemonidae), with emphasis on the relationships among selected American species

The genus Macrobrachium Bate, 1868 is one of the best examples of widespread crustacean genera distributed globally throughout tropical and subtropical waters. Previous investigators have noted the systematic complexity of the group, and have suggested rearrangements within the family Palaemonidae. Our phylogenetic analysis of new mitochondrial DNA sequences of 58 species of Macrobrachium distributed mainly in America support the hypothesis of monophyly of this genus, if Cryphiops Dana, 1852 is accepted as a generic synonym. We concluded that the independent evolution of different types of life cycle (abbreviated larval development-ALD and extended larval development-ELD) must have occurred more than once in the history of the group. Similarly, we also concluded that the current type species of the genus, Macrobrachium americanum Bate, 1868, should not be considered valid, as previously proposed. The synonymy of two members of the `olfersi` species complex (M. birai Lobao, Melo&Fernandes, 1986 and M. holthuisi Genofre&Lobao, 1978) with M. olfersi (Wiegmann, 1836) was confirmed. Similar results were found in comparing M. petronioi Melo, Lobao&Fernandes, 1986 and M. potiuna (Muller, 1880), in which the genetic divergence placed M. petronioi within the level of intraspecific variation of M. potiuna. The taxonomic status of the genus Cryphiops, as well as theories on the origin of Macrobrachium, is also called into question.

The identity of Paratrizygia conformis Tonnoir (Diptera, Mycetophilidae), with comments on its systematic position

Paratrizygia conformis, the type-species of the genus Paratrizygia, from Tasmania, is redescribed from the holotype. The wing venation and male terminalia are illustrated in detail. The question of the monophyly of the genus-which has four additional species in Chile and southern Argentina, and four species in the Atlantic Forest, in Brazil-is addressed. Comments are made on the relationships of the genus in the Azana-group of Sciophilinae. The hypothesis of monophyly of Paratrizygia is retained, as indicated by the presence of modified, elongated spines on a distal fold of tergite 9.

An investigation into commitment in non-Western industrial marketing relationships

This paper reports an investigation into the antecedents of commitment in non-Western industrial marketing relationships. The authors draw the antecedents from extant literature and posit that commitment is related to trust (integrity and reliability), communication quality, conflict, and similarity (social, ethnic, and economic). It is further argued that trust mediates the effects of communication, conflict, and similarity on commitment. As an extension, the authors examine the moderating effects of normative contracts (an implicit understanding of roles and responsibilities) on the construct interrelationships. The hypotheses are tested using data collected from approximately 150 industrial marketing relationships sampled from overseas Chinese firms. The results generally support the authors' framework; however, the mediating hypotheses are not supported. There is evidence of systematic differences in the effects of the studied antecedents on commitment and trust. Furthermore, a multigroup analysis provides evidence of significant moderating effects due to contracting mode. The study provides new insights into the theory and practice of industrial marketing. (C) 2003 Elsevier Science Inc. All rights reserved.

Quality of life of the caregivers of people with aphasia. A systematic review.

Purpose: Systematic review to identify the factors associated to the quality of life (QOL) of the caregivers of people with aphasia (PWA). Methods: Studies were searched using Medline, Pubmed, Cochrane Library, CINAHL, PsycINFO and Web of Science databases. Peer-reviewed papers that studied the QOL of PWA’s caregivers or the consequences of aphasia in caregivers’ life were included. Findings were extracted from the studies that met the inclusion criteria. Results: No data is available reporting particularly the QOL of PWA caregivers’ or their QOL predictors. Nevertheless, it was possible to extract aspects related to QOL from the studies that report the consequences of aphasia, and life changes in PWA’s caregivers. Nine (9) studies including PWA’s caregivers were found, but only 5 reported data separately on them. Methodological heterogeneity impedes cross-study comparisons, although some considerations can be made. PWA’s caregivers reported life changes such as: loss of freedom; social isolation; new responsibilities; anxiety; emotional loneliness; need for support and respite. Conclusions: Changes in social relationships, in emotional status, increased burden and need for support and respite were experienced by PWA’s caregivers. Stroke QOL studies need to include PWA caregivers’ and report separately on them. Further research is needed in this area in order to determine their QOL predictors and identify what interventions and referrals better suit their needs.

Exposure to psychosocial risk factors in the context of work: a systematic review

ABSTRACT OBJECTIVE To analyze the scientific literature about the effects of exposure to psychosocial risk factors in work contexts. METHODS A systematic review was performed using the terms “psychosocial factors” AND “COPSOQ” in the databases PubMed, Medline, and Scopus. The period analyzed was from January 1, 2004 to June 30, 2012. We have included articles that used the Copenhagen Psychosocial Questionnaire (COPSOQ) as a measuring instrument of the psychosocial factors and the presentation of quantitative or qualitative results. German articles, psychometric studies or studies that did not analyze individual or work factors were excluded. RESULTS We included 22 articles in the analysis. Individual factors, such as gender, age, and socioeconomic status, were analyzed along with work-related factors such as labor demands, work organization and content, social relationships and leadership, work-individual interface, workplace values, justice and respect, personality, health and well-being, and offensive behaviors. We analyzed the sample type and the applied experimental designs. Some population groups, such as young people and migrants, are more vulnerable. The deteriorated working psychosocial environment is associated with physical health indicators and weak mental health. This environment is also a risk factor for the development of moderate to severe clinical conditions, predicting absenteeism or intention of leaving the job. CONCLUSIONS The literature shows the contribution of exposure to psychosocial risk factors in work environments and their impact on mental health and well-being of workers. It allows the design of practical interventions in the work context to be based on scientific evidences. Investigations in specific populations, such as industry, and studies with more robust designs are lacking.

Systematic identification of genomic markers of drug sensitivity in cancer cells.

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.

Systematic studies on Anopheles galvaoi Causey, Deane & Deane from the subgenus Nysssorhynchus blanchard (Diptera: Culicidae)

Anopheles galvaoi, a member of the subgenus Nyssorhynchus, is redescribed based on morphological characters of the adults male and female, fourth-instar larva and pupa. Female, male genitalia, larval and pupal stages are illustrated. Data about medical importance, bionomics, and distribution are given based on literature records. Adult female of An. galvaoi can be easily misidentified as An. benarrochi Gabaldón and An. aquasalis Curry. A few characters are indicated for identifying female and immatures of An. galvaoi. Phylogenetic relationships among An. galvaoi and six other species of the Oswaldoi Subgroup are estimated using COII mtDNA and ITS2 rDNA gene sequences. Lectotype of An. galvaoi, an adult female from Rio Branco, State of Acre, is invalidated.

Adult consequences of late adolescent alcohol consumption: a systematic review of cohort studies.

Alcohol is responsible for a significant portion of the global burden of disease. There is widespread concern reported in the media and other sources about drinking trends among young people, particularly heavy episodic or “binge” drinking. Prominent among policy responses, in the UK and elsewhere, have been attempts to manage antisocial behaviour related to intoxication in public spaces. Much less attention has been given to the longer term effects of excessive drinking in adolescence on later adult health and well-being. Some studies suggest that individuals “mature out” of late adolescent drinking behaviour, whilst others identify enduring effects on drinking and broader health and social outcomes in adulthood. If adolescent drinking does not cause later difficulties in adulthood then intervention approaches aimed at addressing the acute consequences of alcohol, such as unintentional injuries and anti-social behaviour, may be the most appropriate solution. If causal relationships do exist, however, this approach will not address the cumulative harms produced by alcohol, unless such intervention successfully modifies the long-term relationship with alcohol, which seems unlikely. To address this issue a systematic review of cohort studies was conducted, as this approach provides the strongest observational study design to evaluate evidence for causal inference.This resource was contributed by The National Documentation Centre on Drug Use.

New grass phylogeny resolves deep evolutionary relationships and discovers C4 origins.

• Grasses rank among the world's most ecologically and economically important plants. Repeated evolution of the C(4) syndrome has made photosynthesis highly efficient in many grasses, inspiring intensive efforts to engineer the pathway into C(3) crops. However, comparative biology has been of limited use to this endeavor because of uncertainty in the number and phylogenetic placement of C(4) origins. • We built the most comprehensive and robust molecular phylogeny for grasses to date, expanding sampling efforts of a previous working group from 62 to 531 taxa, emphasizing the C(4)-rich PACMAD (Panicoideae, Arundinoideae, Chloridoideae, Micrairoideae, Aristidoideae and Danthonioideae) clade. Our final matrix comprises c. 5700 bp and is > 93% complete. • For the first time, we present strong support for relationships among all the major grass lineages. Several new C(4) lineages are identified, and previously inferred origins confirmed. C(3)/C(4) evolutionary transitions have been highly asymmetrical, with 22-24 inferred origins of the C(4) pathway and only one potential reversal. • Our backbone tree clarifies major outstanding systematic questions and highlights C(3) and C(4) sister taxa for comparative studies. Two lineages have emerged as hotbeds of C(4) evolution. Future work in these lineages will be instrumental in understanding the evolution of this complex trait.

In search of good relationships to music : understanding aspiration and challenge in developing music school teacher practices

This study focuses on teacher practices in publicly funded music schools in Finland. As views on the aims of music education change and broaden, music schools across Europe share the challenge of developing their activities in response. In public and scholarly debate, there have been calls for increased diversity of contents and concepts of teaching. In Finland, the official national curriculum for state-funded music schools builds on the ideal that teaching and learning should create conditions which promote ‘a good relationship to music’. The meaning of this concept has been deliberately left open in order to leave room for dialogue, flexibility, and teacher autonomy. Since what is meant by ‘good’ is not defined in advance, the notion of ‘improving’ practices is also open to discussion. The purpose of the study is to examine these issues from teachers’ point of view by asking what music school teachers aim to accomplish as they develop their practices. Methodologically, the study introduces a suggestion for building empirical research on Alperson’s ‘robust’ praxial approach to music education, a philosophical theory which is strongly committed to practitioner perspectives and musical diversity. A systematic method for analysing music education practices, interpretive practice analysis, is elaborated with support from interpretive research methods originally used in policy analysis. In addition, the research design shows how reflecting conversations (a collaborative approach well-known in Nordic social work) can be fruitfully applied in interpretive research and combined with teacher inquiry. Data have been generated in a collaborative project involving five experienced music school teachers and the researcher. The empirical material includes transcripts from group conversations, data from teacher inquiry conducted within the project, and transcripts from follow-up interviews. The teachers’ aspirations can be understood as strivings to reinforce the connection between musical practices and various forms of human flourishing such that music and flourishing can sustain each other. Examples from their practices show how the word ‘good’ receives its meaning in context. Central among the teachers’ concerns is their hope that students develop a free and sustainable interest in music, often described as inspiration. I propose that ‘good relationships to music’ and ‘inspiration’ can be understood as philosophical mediators which support the transition from an indeterminate ‘interest in music’ towards specific ways in which music can become a (co-)constitutive part of living well in each person’s particular circumstances. Different musical practices emphasise different aspects of what is considered important in music and in human life. Music school teachers consciously balance between a variety of such values. They also make efforts to resist pressure which might threaten the goods they think are most important. Such goods include joy, participation, perseverance, solid musical skills related to specific practices, and a strong sense of vitality. The insights from this study suggest that when teachers are able to create inspiration, they seem to do so by performing complex work which combines musical and educational aims and makes general positive contributions to their students’ lives. Ensuring that teaching and learning in music schools remain as constructive and meaningful as possible for both students and teachers is a demanding task. The study indicates that collaborative, reflective and interdisciplinary work may be helpful as support for development processes on both individual and collective levels of music school teacher practices.

Elusive relationships within order fabales: phylogenetic analyses using matK and rbcL sequence data

The order Fabales, including Leguminosae, Polygalaceae, Quillajaceae and Surianaceae, represents a novel hypothesis emerging from angiosperm molecular phylogenies. Despite good support for the order, molecular studies to date have suggested contradictory, poorly supported interfamilial relationships. Our reappraisal of relationships within Fabales addresses past taxon sampling deficiencies, and employs parsimony and Bayesian approaches using sequences from the plastid regions rbcL (166 spp.) and matK (78 spp.). Five alternative hypotheses for interfamilial relationships within Fabales were recovered. The Shimodaira-Hasegawa test found the likelihood of a resolved topology significantly higher than the one calculated for a polytomy, but did not favour any of the alternative hypotheses of relationship within Fabales. In the light of the morphological evidence available and the comparative behavior of rbcL and matK, the topology recovering Polygalaceae as sister to the rest of the order Fabales with Leguminosae more closely related to Quillajaceae + Surianaceae, is considered the most likely hypothesis of interfamilial relationships of the order. Dating of selected crown clades in the Fabales phylogeny using penalized likelihood suggests rapid radiation of the Leguminosae, Polygalaceae, and (Quillajaceae + Surianaceae) crown clades.