Quantitative justification for target concentration intervention - parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides

Aims [1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration. Methods Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (>=20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance. Results A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h(-1) 70 kg(-1); intercompartmental clearance (CLic), 1 l h(-1) 70 kg(-1); volume of central compartment (V-1), 19.5 l 70 kg(-1); volume of peripheral compartment (V-2) 11.2 l 70 kg(-1). Conclusions Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80-125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.

CEDIA (R) sirolimus assay compared with HPLC-MS/MS and HPLC-UV in transplant recipient specimens

The role of the therapeutic drug monitoring laboratory in support of immunosuppressant drug therapy is well established, and the introduction of sirolimus (SRL) is a new direction in this field. The lack of an immunoassay for several years has restricted the availability of SRL assay services. The recent availability of a CEDIA (R) SRL assay has the potential to improve this situation. The present communication has compared the CEDIA (R) SRL method with 2 established chromatographic methods, HPLC-UV and HPLC-MS/MS. The CEDIA (R) method, run on a Hitachi 917 analyzer, showed acceptable validation criteria with within-assay precision of 9.1% and 3.3%, and bias of 17.1% and 5.8%, at SRL concentrations of 5.0 mu g/L and 20 mu g/L, respectively. The corresponding between-run precision values were 11.5% and 3.3% and bias of 7.1% and 2.9% at 5.0 mu g/L and 20 mu g/L, respectively, The lower limit of quantification was found to be 3.0 mu g/L. A series of 96 EDTA whole-blood samples predominantly from renal transplant recipients were assayed by the 3 methods for comparison. It was found that the CEDIA (R) method showed a Deming regression line of CEDIA = 1.20 X HPLC-MS/MS - 0.07 (r = 0.934, SEE = 1.47), with a mean bias of 20.4%. Serial blood samples from 8 patients included in this evaluation showed that the CEDIA (R) method reflected the clinical fluctuations in the chromatographic methods, albeit with the variable bias noted. The CEDIA (R) method on the H917 analyzer is therefore a useful adjunct to SRL dosage individualization in renal transplant recipients.

Comparison of the reintroduced MEIA (R) assay with HPLC-MS/MS for the determination of whole-blood sirolimus from transplant recipients

Therapeutic monitoring with dosage individualization of sirolimus drug therapy is standard clinical practice for organ transplant recipients. For several years sirolimus monitoring has been restricted as a result of lack of an immunoassay. The recent reintroduction of the microparticle enzyme immunoassay (MEIA (R)) for sirolimus on the IMx (R) analyser has the potential to address this situation. This Study, using patient samples, has compared the MEIA (R) sirolimus method with an established HPLC-tandem mass spectrometry method (HPLC-MS/MS). An established HPLC-UV assay was used for independent cross-validation. For quality control materials (5, 11, 22 mu g/L), the MEIA (R) showed acceptable validation criteria based on intra-and inter-run precision (CV) and accuracy (bias) of < 8% and < 13%, respectively. The lower limit of quantitation was found to be approximately 3 mu g/L. The performance of the immunoassay was compared with HPLC-MS/MS using EDTA whole-blood samples obtained from various types of organ transplant recipients (n = 116). The resultant Deming regression line was: MEIA = 1.3 x HPLC-MS/MS+ 1.3 (r = 0.967, s(y/x) = 1) with a mean bias of 49.2% +/- 23.1 % (range, -2.4% to 128%; P < 0.001). The reason for the large and variable bias was not explored in this study, but the sirolimus-metabolite cross-reactivity with the MEIA (R) antibody could be a substantive contributing factor. Whereas the MEIA (R) sirolimus method may be an adjunct to sirolimus dosage individualization in transplant recipients, users must consider the implications of the substantial and variable bias when interpreting results. In selected patients where difficult clinical issues arise, reference to a specific chromatographic method may be required.

Prediction of functional capacity in chronic heart failure patients using myocardial tissue Doppler

Background. Exercise therapy improves functional capacity in CHF, but selection and individualization of training would be helped by a simple non-invasive marker of peak VO2. Peak VO2 in these pts is difficult to predict without direct measurement, and LV ejection fraction is a poor predictor. Myocardial tissue velocities are less load-dependent, and may be predictive of the exercise response in CHF pts. We sought to use tissue velocity as a predictor of peak VO2 in CHF pts. Methods. Resting 2D-echocardiography and tissue Doppler imaging were performed in 182 CHF pts (159 male, age 62±10 years) before and after metabolic exercise testing. The majority of these patients (129, 71%) had an ischemic cardiomyopathy, with resting EF of 35±13% and a peak VO2 of 13.5±4.7 ml/kg/min. Results. Neither resting EF (r=0.15) nor peak EF (r=0.18, both p=NS) were correlated with peak VO2. However, peak VO2 correlated with peak systolic velocity in septal (Vss, r=0.31) and lateral walls (Vsl, r=0.26, both p=0.01). In a general linear model (r2 = 0.25), peak VO2 was calculated from the following equation: 9.6 + 0.68*Vss - 0.09*age + 0.06*maximum HR. This model proved to be a superior predictor of peak VO2 (r=0.51, p=0.01) than the standard prediction equations of Wasserman (r= -0.12, p=0.01). Conclusions. Resting tissue Doppler, age and maximum heart rate may be used to predict functional capacity in CHF patients. This may be of use in selecting and following the response to therapy, including for exercise training.

Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • 6-Mercaptopurine (6-MP) and azathioprine (AZA) are both inactive prodrugs that require intracellular activation into the active 6-thioguanine nucleotides (6-TGNs). • This metabolic process undergoes three different competitive pathways that are catalysed by three different enzymes; xanthine oxidase (XO), thiopurine methyltransferase (TPMT) and inosine triphosphatase (ITPA), all of which exhibit genetic polymorphisms. • Although the impact of genetic variation in the TPMT gene on treatment outcome and toxicity has been demonstrated, the role of other polymorphisms remains less well known. WHAT THIS STUDY ADDS • New information on the allelic variation of these three enzymes (XO, TPMT and ITPA) and their influence on 6-MP/AZA metabolism and toxicity. • Confirmation of the association of TPMT polymorphism with haematological toxicity. • Identified potential genetic characteristics that may contribute to higher risk of adverse events (such as ITPA IVS2+21A→C mutation). AIMS - To examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD). METHODS - Clinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6-MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase, inosine triphosphatase (C94→A and IVS2+21A→C) and thiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined. RESULTS - Thiopurine methyltransferase variant alleles were associated with a preferential metabolism away from 6-methylmercaptopurine nucleotides (P = 0.008 in ALL patients, P = 0.038 in IBD patients) favouring 6-thioguanine nucleotides (6-TGNs) (P = 0.021 in ALL patients). Interestingly, carriers of inosine triphosphatase IVS2+21A→C variants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients, P = 0.047 in IBD patients). The study confirmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association between inosine triphosphatase IVS2+21A→C variants with thrombocytopenia (P = 0.012). CONCLUSIONS - Pharmacogenetic polymorphisms in the 6-MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization.

Psychophysiological responses to visceral and somatic pain in functional chest pain identify clinically relevant pain clusters

Background: Despite chronic pain being a feature of functional chest pain (FCP) its experience is variable. The factors responsible for this variability remain unresolved. We aimed to address these knowledge gaps, hypothesizing that the psychophysiological profiles of FCP patients will be distinct from healthy subjects. Methods: 20 Rome III defined FCP patients (nine males, mean age 38.7 years, range 28-59 years) and 20 healthy age-, sex-, and ethnicity-matched controls (nine males, mean 38.2 years, range 24-49) had anxiety, depression, and personality traits measured. Subjects had sympathetic and parasympathetic nervous system parameters measured at baseline and continuously thereafter. Subjects received standardized somatic (nail bed pressure) and visceral (esophageal balloon distension) stimuli to pain tolerance. Venous blood was sampled for cortisol at baseline, post somatic pain and post visceral pain. Key Results: Patients had higher neuroticism, state and trait anxiety, and depression scores but lower extroversion scores vs controls (all p < 0.005). Patients tolerated less somatic (p < 0.0001) and visceral stimulus (p = 0.009) and had a higher cortisol at baseline, and following pain (all p < 0.001). At baseline, patients had a higher sympathetic tone (p = 0.04), whereas in response to pain they increased their parasympathetic tone (p ≤ 0.008). The amalgamating the data, we identified two psychophysiologically distinct 'pain clusters'. Patients were overrepresented in the cluster characterized by high neuroticism, trait anxiety, baseline cortisol, pain hypersensitivity, and parasympathetic response to pain (all p < 0.03). Conclusions & Inferences: In future, such delineations in FCP populations may facilitate individualization of treatment based on psychophysiological profiling. © 2013 John Wiley & Sons Ltd.

Encouraging majority support for immigrant access to health services:multiple categorization and social identity complexity as antecedents of health equality

Health disparities between groups remain even after accounting for established causes such as structural and economic factors. The present research tested, for the first time, whether multiple social categorization processes can explain enhanced support for immigrant health (measured by respondents’ behavioral intention to support immigrants’ vaccination against A H1N1 disease by cutting regional public funds). Moreover, the mediating role of individualization and the moderating role of social identity complexity were tested. Findings showed that multiple versus single categorization of immigrants lead to support their right to health and confirmed the moderated mediation hypothesis. The potential in developing this sort of social cognitive intervention to address health disparities is discussed.

Geoquímica de elementos maiores e traços de granitoides neoproterozoicos da província Borborema e sua correlação com propriedades físicas de rochas

This paper discusses the correlation of thermal conductivity, density and magnetic susceptibility with composition of major and trace elements of Neoproterozoic igneous bodies from Borborema Province, Northeastern Brazil. These properties were used as potential markers among the studied magmatic suites. For the correlation between petrophysical and geochemical properties it was considered a set of 195 chemical analyzes of granitoid rocks, separated by the degree of acidity in basic, intermediate and acidic. Major (SiO2, Al2O3, Fe2O3, MgO, CaO, Na2O, K2O and TiO2) and some trace elements (Rb, Sr, Ba, Zr, Th and U) that are usually linked to the formation of the most common minerals of igneous rocks were used. The results show that SiO2 has the best positive correlation with the thermal conductivity, while Al2O3, CaO, Fe2O3, MgO and TiO2 exhibit negative correlation for the same property. The correlation with density is opposite to that one for these oxides with the thermal conductivity. The magnetic susceptibility did not correlate with the elements studied. The results for thermal conductivity and density indicate a tendency of SiO2 and oxides with higher affinity with mafic minerals (Al2O3, CaO, Fe2O3, TiO2 and MgO) in controlling these petrophysical parameters. The set of samples was divided into five different magmatic suites based on their lithogeochemical aspects into: i) peralkaline / alkaline; ii) alkaline; iii) calc-alkaline; iv) high potassium calcium alkaline; and v) shoshonitic. Data analysis showed that the thermal conductivity and density presented good results in the individualization of these suites, notably between peralkaline / alkaline, alkaline suites, calc-alkaline and shoshonitic. However, the high-K calc-alkaline suite overlapped with the other. In contrast, the magnetic susceptibility did not show effective results for separating the five chemical suites.

El concepto de ciudadanía en la obra de Dominique Schnapper: entre el tipo ideal sociológico y el ideal de sociedad democrática

Este artículo analiza la evolución del concepto de ciudadanía en la obra de Dominique Schnapper como uno de los ejemplos más destacados en la sociología contemporánea de una aproximación completa a la cuestión. A través de un recorrido exhaustivo por su obra, el objetivo es profundizar en la comprensión de la tensión entre la dinámica democrática y la idea de ciudadanía en cuanto que tipo ideal del vínculo social y como principio regulador de las sociedades democráticas. La autora propone en sus primeros trabajos una noción de ciudadanía vinculada al proceso político de construcción de la nación que no distingue entre la definición de un tipo ideal sociológico y la construcción de un ideal de sociedad. Esta confusión se corrige al introducir posteriormente en el análisis la incidencia de la democracia sobre las experiencias individuales de la ciudadanía, aportando una perspectiva de análisis de gran utilidad tanto para la comprensión de la dinámica contemporánea de las sociedades democráticas como para la necesaria defensa de la ciudadanía como vínculo social fundamental y como principio fundador de la legitimidad política.

Onderwijs moet op de schop

Weergave van een interview met Ton Mooij over de aard en inrichting van optimaal universitair onderwijs, ook voor cognitief hoogbegaafde studenten.

(Des)igualdades de Género nas Organizações de Trabalho: o caso de uma autarquia local

Em Portugal, cerca de duas centenas de organizações estão empenhadas a criar e implementar Planos para a igualdade de homens e mulheres. Entre elas estão empresas públicas e privadas, autarquias, associações empresariais, organizações do setor terciário, associações de desenvolvimento, universidades, ministérios e outros departamentos governativos. A pesquisa que aqui se expõe inscreveu-se num projeto mais amplo de diagnóstico em realização na Câmara Municipal da Lousã, que se encontra a promover um Plano Municipal para a Igualdade. Nesse âmbito mostrou-se necessário fazer um diagnóstico interno à organização com uma perspetiva de género, quer em termos de desigualdades de género na composição e situação dos seus efetivos quer de forma a conhecer as representações das pessoas que trabalham na autarquia, em torno do fenómeno da (des)igualdade de mulheres e homens. Para a sua realização foi feita análise estatística a dados fornecidos pela organização, e aplicou-se um inquérito por questionário ao pessoal ao serviço da autarquia. Concluiu-se que estamos na presença do fenómeno da desigualdade em função do sexo na estrutura da organização traduzida pela segregação ocupacional e segregação vertical, sendo os homens que apresentam os maiores níveis de antiguidade, que justificarão, de certa forma, as disparidades salariais existentes. Confirmamos uma dualidade entre o ideal de mulher como mãe e dona-de-casa e o de mulher como pessoa independente, especialmente quando são evocadas as consequências da sua atividade profissional sobre os/as filhos/as e a vida familiar. O papel de cuidar surge assim como o obstáculo a conceções menos tradicionalistas e individualizadoras da identidade feminina que nos remete para uma mudança na atribuição do lugar social de homens e mulheres dentro e fora da família. Sobressai a valorização e enfatização da maternidade e do cuidado das crianças na identidade feminina; ao passo que aos homens se atribui uma maior valorização da atividade profissional. Esta constatação comprova a ambivalência e dicotomia de valores e atitudes entre uma fuga à convencional polarização entre papéis “masculinos” e “femininos” rígida e estereotipadamente definidos. / In Portugal, about two hundred organizations are committed to create and implement plans for men and women’s equality. These include public and private companies, local authorities, business associations, third sector organizations, development associations, universities, ministries and other governmental departments. The research exposed here is part of a broader diagnostic project taking placa in the City Hall, of Lousã which is promoting a Municipal Plan for Equality. In this context it was necessary to make an internal diagnosis to the organization from a perspective of gender, either in terms of gender inequalities in the composition and status of their workers or in order to know the workers representations around the phenomenon of women and men’s equality. To make it passible the organization provided statistical data which was analysed and subsequentaly a questionnaire was applied to the municipality staff. We concluded that there is the phenomenon of gender inequality in the structure of the organization namely occupational/professional segregation and vertical segregation, - men having the highest levels of seniority, which may justify in some way the existing wage gap. The study confirms a duality between the ideal of woman as a mother and housewife and the woman as an independent person, especially when the consequences suggested are related to their professional activity on their children and life family. The role of caring emerges as the obstacle to less traditionalist conceptions of female identity and individualization, which leads us to talk about a change of the social position of men and women within and outside the family. It points out the valuation and emphasizing of motherhood and care in female identity, whereas men are given a greater appreciation of the professional activity. This conclusion confirms the ambivalence and dichotomy of values and attitudes between escape from the conventional polarization between rigid and stereotypically defined roles of "male" and "female".

Muscular anatomy of the pectoral and forelimb of caiman crocodilus crocodilus (linnaeus, 1758) (crocodylia: alligatoridae)

v. 17, n. 2, p. 285-295, abr./jun. 2016.

Schulwege in den beiden deutschen Staaten. Kinder- und Jugendkulturen zwischen Elternhaus und Schule

Der Schulweg ist ein Intermedium zwischen dem Zuhause und der Schule. Hier findet die Transformation vom Kind bzw. Jugendlichen zum Schüler oder Schülerin statt. Auf diesem Weg bilden sich einzigartige Kinder- und Jugendkulturen. Gerade diese „space-time“ fand in der erziehungswissenschaftlichen Forschung bisher kaum Beachtung. Denn Untersuchungen zum Schulweg befassen sich oftmals mit dem Weg als physikalische Größe oder Fragen aus psychologischer Perspektive nach Problemen wie Angstzuständen. Hintergrund ist dabei immer, den Schulweg für die Kinder angenehmer und schöner zu gestalten. Nicht beachtet wird, dass er von den Erwachsenen in der Regel nicht kontrolliert wird. Die vorliegende Studie blickt aus historischer Perspektive auf Schulwege in den beiden deutschen Staaten der 1970er Jahren. Es wird herausgearbeitet, wie sich Kinder- und Jugendkulturen in der Bundesrepublik und in der DDR auf Schulwegen konstituiert haben. (DIPF/Orig.)

Das bildungstheoretische Potenzial inklusiver Pädagogik. Meilensteine der Konstruktion von Bildung und Behinderung am Beispiel von Kindern mit Lernschwierigkeiten

Inklusion erfordert Veränderungen, Umbau und Umdenken auf vielen Ebenen. Ob Teilhabe gelingt, entscheidet sich letztlich im pädagogischen Alltag. So muss in einem inklusiven Bildungssystem auch geklärt werden, was Bildung ausmacht, wenn sie alle Kinder adressiert. Was bedeutet hier Bildung und in welchem Zusammenhang stehen die Konstrukte von Bildung und Behinderung? Wurden doch traditionell die Grenzen des ersten systemwirksam mit der Zuschreibung des zweiten markiert. Das vorliegende Buch thematisiert in historischer Perspektive die sich verändernden Vorstellungen über Bildung, Behinderung(en) und Gerechtigkeit im Bildungssystem sowie die damit verbundenen kontroversen Debatten sowie die häufig uneinheitlichen, teils gegenläufigen Entwicklungen der sogenannten Sonder- und der sogenannten Regelpädagogik. Die Analyse arbeitet die Beiträge integrations- und inklusionspädagogischer Theorien (Reiser, Feuser, Prengel, Wocken, Reich) zu einem gemeinsamen Bildungsverständnis für alle Kinder heraus. Diese Potenziale integrations- und inklusionspädagogischer Theoriebildung werden eingeordnet in bildungstheoretische Dimensionen sowie in die aktuellen Debatten um Inklusion und Bildung als Menschenrecht. (DIPF/Orig.)

Infertilidade na síndrome do ovário poliquístico : evidências sobre o tratamento

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014