Settlement and drainage analysis of the Franeker bridge embankments, the Netherlands

In this paper a case-based consolidation analysis of one cross-section of bridge embankments in Franeker, the Netherlands is presented. Consolidation coefficients (cv), final primary settlements and the duration of these settlements are re-calculated from the monitored time-settlement data using the simple approach outlined in this paper and are compared to the pre-design values deduced based on laboratory and field site investigation. Use of the case-based data is made to overcome uncertainties in preliminary design input parameters. In this case the uncertainties mainly concern changes in settlement parameters after partial drainage of the soft clayey and peat foundation soil layers, and the soil volume affected by drainage. Although reasonable design predictions by conventional consolidation analysis could be made of the settlements at the end of the construction period, final settlement and duration were overestimated. The paper also presents monitored drainage data and demonstrates that the calculations of drainage quantities improve if separate volumes proportional to the various embankment stages are used

CYP3A4*22 Genotype-Guided Dosing of Kinase Inhibitors in Cancer Patients

INTRODUCTION: A genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The primary aim of this study was to investigate if the systemic exposure is non-inferior after a dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to patients without this SNP (i.e., wildtype patients) receiving the standard dose. METHODS: In this multicenter, prospective, non-inferiority study, patients were screened for the presence of CYP3A4*22. Patients with the CYP3A4*22 SNP received a 20-33% dose reduction. At steady state, a pharmacokinetic (PK) analysis was performed and compared to the PK results from wildtype patients treated with the registered dose using a two-stage individual patient data meta-analysis approach. RESULTS: In total, 207 patients were included in the final analysis. The CYP3A4*22 SNP was found in 16% of the patients in the final analysis (n = 34). Most of the included patients received imatinib (37%) or pazopanib (22%) treatment. The overall geometric mean ratio (GMR) comparing the exposure of the CYP3A4*22 carriers to the exposure of the wildtype CYP3A4 patients was 0.89 (90% confidence interval: 0.77-1.03). CONCLUSION: Non-inferiority could not be proven for dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to the registered dose in wildtype patients. Therefore, an up-front dose reduction based upon the CYP3A4*22 SNP for all KIs does not seem an eligible new way of personalized therapy. TRIAL REGISTRATION: International Clinical Trials Registry Platform Search Portal; number NL7514; registered 11/02/2019