CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients

BACKGROUND After heart transplantation (HTx), the interindividual pharmacokinetic variability of immunosuppressive drugs represents a major therapeutic challenge due to the narrow therapeutic window between over-immunosuppression causing toxicity and under-immunosuppression leading to graft rejection. Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants, data in the context of HTx are scarce. We thus assessed the role of genetic variation in CYP3A4, CYP3A5, POR, NR1I2, and ABCB1 acting jointly in immunosuppressive drug pathways in tacrolimus (TAC) and ciclosporin (CSA) dose requirement in HTx recipients. METHODS Associations between 7 functional genetic variants and blood dose-adjusted trough (C0) concentrations of TAC and CSA at 1, 3, 6, and 12 months after HTx were evaluated in cohorts of 52 and 45 patients, respectively. RESULTS Compared with CYP3A5 nonexpressors (*3/*3 genotype), CYP3A5 expressors (*1/*3 or *1/*1 genotype) required around 2.2- to 2.6-fold higher daily TAC doses to reach the targeted C0 concentration at all studied time points (P ≤ 0.003). Additionally, the POR*28 variant carriers showed higher dose-adjusted TAC-C0 concentrations at all time points resulting in significant differences at 3 (P = 0.025) and 6 months (P = 0.047) after HTx. No significant associations were observed between the genetic variants and the CSA dose requirement. CONCLUSIONS The CYP3A5*3 variant has a major influence on the required TAC dose in HTx recipients, whereas the POR*28 may additionally contribute to the observed variability. These results support the importance of genetic markers in TAC dose optimization after HTx.

Von Staatsbürgern und Bürgern eigenen Sinnes

Infolge der Unabhängigkeitsbewegung Lateinamerikas im frühen 19. Jahrhundert entstanden im Andenraum dei drei Republiken Ecuador, Peru und Bolivien. Der Beitrag untersucht einerseits die Umsetzung des von Vertretern der kreolisch-mestizischen Mehrheitsgesellschaft aus Europa übertragenen Modells des Nationalstaats, andererseits die von der indigenen Bevölkerung entwickelten Vorstellungen und Strategien politischer Partizipation, die verschiedenen Formen der Ablehnung, Übernahme und Umdeutung der nationalstaatlichen Ordnung aufweisen.

In vitro performance of a pen-type laser fluorescence device and bitewing radiographs for approximal caries detection in permanent and primary teeth.

AIM To evaluate the performance of a pen‑type laser fluorescence device (DIAGNOdent 2190; LFpen, KaVo, Germany) and bitewing radiographs (BW) for approximal caries detection in permanent and primary teeth. MATERIALS AND METHODS A total of 246 anterior approximal surfaces (102 permanent and 144 primary) were selected. Contact points were simulated using sound teeth. Two examiners assessed all approximal surfaces using LFpen and BW. The teeth were histologically assessed for the reference standard. Optimal cut‑off limits were calculated for LFpen for primary and permanent teeth. Sensitivity, specificity, accuracy and area under the receiver operating characteristic curve (Az) were calculated for D1 (enamel and dentin lesions) and D3 (dentin lesions) thresholds. The reproducibility was assessed by intraclass correlation coefficient (ICC) and Cohen's weighted kappa values. RESULTS For permanent teeth, the LFpen cut‑off were 0- 27 (sound), 28- 33 (enamel caries) and >33 (dentin caries). For primary teeth, the LFpen cut‑off were 0- 7 (sound), 8- 32 (enamelcaries) and >32 (dentin caries). The LFpen presented higher sensitivity values than BW for primary teeth (0.58 vs. 0.32 at D1 and 0.80 vs. 0.47 at D3) and permanent teeth (0.80 vs. 0.57 at D1 and 0.94 vs. 0.51 at D3). Specificity did not show a significant difference between the methods. Rank correlations with histology were 0.59 and 0.83 (LFpen) and 0.36 and 0.70 (BW) for primary and permanent teeth, respectively, considering all lesions. ICC values for LFpen were 0.71 (inter) and 0.86 (intra) for permanent teeth and 0.94 (inter) and 0.90/0.99 for primary teeth. Kappa values for BW were 0.69 (inter) and 0.68/0.90 (intra) for permanent teeth and 0.64 (inter) and 0.89/0.89 for primary teeth. CONCLUSION LFpen presented better reproducibility for primary and permanent teeth and higher accuracy in detecting caries lesions at D1 threshold than BW for permanent teeth. LFpen should be used as an adjunct method for approximal caries detection.

Shaping gender inequalities: critical moments and critical places

Purpose – There is much scientific interest in the connection between the emergence of gender-based inequalities and key biographical transition points of couples in long-term relationships. Little empirical research is available comparing the evolution of a couple’s respective professional careers over space and time. The purpose of this paper is to contribute to filling this gap by addressing the following questions: what are the critical biographical moments when gender (in)equalities within a relationship begin to arise and consolidate? Which biographical decisions precede and follow such critical moments? How does decision making at critical moments impact the opportunities of both relationship partners in gaining equal access to paid employment? Design/methodology/approach – These questions are addressed from the perspectives of intersectionality and economic citizenship. Biographical interviewing is used to collect the personal and professional narratives of Swiss-, bi-national and migrant couples. The case study of a Swiss-Norwegian couple illustrates typical processes by which many skilled migrant women end up absently or precariously employed. Findings – Analysis reveals that the Scandinavian woman’s migration to Switzerland is a primary and critical moment for emerging inequality, which is then reinforced by relocation (to a small town characterized by conservative gender values) and the subsequent births of their children. It is concluded that factors of traditional gender roles, ethnicity and age intersect to create a hierarchical situation which affords the male Swiss partner more weight in terms of decision making and career advancement. Practical implications – The paper’s findings are highly relevant to the formulation of policies regarding gender inequalities and the implementation of preventive programmes within this context. Originality/value – Little empirical research is available comparing the evolution of a couple’s respective professional careers over space and time. The originality of this paper is to fill this research gap; to include migration as a critical moment for gender inequalities; to use an intersectional and geographical perspective that have been given scant attention in the literature; to use the original concept of economic citizenship; and to examine the case of a bi-national couple, which has so far not been examined by the literature on couple relationships.