Saturable elimination of piperacillin in critically ill patients: implications for continuous infusion.

The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (Vp) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (Km) and the maximum elimination rate for Michaelis-Menten elimination (Vmax) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for Km and Vmax were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for Km lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients.

Measuring antibiotics in exhaled air in critically ill, non-ventilated patients: A feasibility and proof of concept study.

PURPOSE: Measurement of antibiotic concentrations is increasingly used to optimize antibiotic therapy. Plasma samples are typically used for this, but other matrices such as exhaled air could be an alternative. MATERIALS AND METHODS: We studied 11 spontaneously breathing intensive care unit patients receiving either piperacillin/tazobactam or meropenem. Patients exhaled in the ExaBreath® device, from which the antibiotic was extracted. The presence of antibiotics was also determined in the condensate found in the device and in the plasma. RESULTS: Piperacillin or meropenem could be detected in the filter in 9 patients and in the condensate in 10. Seven patients completed the procedure as prescribed. In these patients the median quantity of piperacillin in the filter was 3083 pg/filter (range 988-203,895 pg/filter), and 45 pg (range 6-126 pg) in the condensate; meropenem quantity was 21,168 pg/filter, but the quantity in the condensate was below the lower limit of quantification. There was no correlation between the concentrations in the plasma and quantities detected in the filter or condensate. CONCLUSIONS: Piperacillin and meropenem can be detected and quantified in exhaled air of non-ventilated intensive care unit patients; these quantities did not correlate with plasma concentrations of these drugs.

Integration of microarray and textual data improves the prognosis prediction of breast, lung and ovarian cancer patients.

Microarray data are notoriously noisy such that models predicting clinically relevant outcomes often contain many false positive genes. Integration of other data sources can alleviate this problem and enhance gene selection and model building. Probabilistic models provide a natural solution to integrate information by using the prior over model space. We investigated if the use of text information from PUBMED abstracts in the structure prior of a Bayesian network could improve the prediction of the prognosis in cancer. Our results show that prediction of the outcome with the text prior was significantly better compared to not using a prior, both on a well known microarray data set and on three independent microarray data sets.

The t(4;8) is mediated by homologous recombination between olfactory receptor gene clusters, but other 4p16 translocations occur at random.

The t(4;8)(p16;p23) is the second most common constitutional chromosomal translocation and is caused by an ectopic meiotic recombination between the olfactory receptor gene clusters (ORGC), located on chromosome 4p and 8p. Given that ORGCs are scattered across the genome and make-up about 0.1% of the human genome we reasoned that translocations between 4p16 and other chromosomes might be mediated by ectopic recombination between different ORGC. In 13 patients, we mapped the breakpoints of either a balanced or unbalanced translocation between chromosome 4p16 and different chromosomes. For all four t(4;8) cases, the breakpoints fall within the 4p and 8pter ORGC, confirming that non-allelic homologous recombination (NAHR) between the ORGC is the main mechanism of the t(4;8) formation. For the nine other translocations, the breakpoints on chromosome 4 mapped to different loci, one of them within the ORGC and in two flanking the ORGC. In these three cases, the translocation breakpoint at the reciprocal chromosome did not contain ORGC sequences. We conclude that only the t(4;8) is mediated by NAHR between ORGC.

Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports.

BACKGROUND: Chromosomal abnormalities are a major cause of mental retardation and multiple congenital anomalies (MCA/MR). Screening for these chromosomal imbalances has mainly been done by standard karyotyping. Previous array CGH studies on selected patients with chromosomal phenotypes and normal karyotypes suggested an incidence of 10-15% of previously unnoticed de novo chromosomal imbalances. OBJECTIVE: To report array CGH screening of a series of 140 patients (the largest published so far) with idiopathic MCA/MR but normal karyotype. RESULTS: Submicroscopic chromosomal imbalances were detected in 28 of the 140 patients (20%) and included 18 deletions, seven duplications, and three unbalanced translocations. Seventeen of 24 imbalances were confirmed de novo and 19 were assumed to be causal. Excluding subtelomeric imbalances, our study identified 11 clinically relevant interstitial submicroscopic imbalances (8%). Taking this and previously reported studies into consideration, array CGH screening with a resolution of at least 1 Mb has been undertaken on 432 patients with MCA/MR. Most imbalances are non-recurrent and spread across the genome. In at least 8.8% of these patients (38 of 432) de novo intrachromosomal alterations have been identified. CONCLUSIONS: Array CGH should be considered an essential aspect of the genetic analysis of patients with MCA/MR. In addition, in the present study three patients were mosaic for a structural chromosome rearrangement. One of these patients had monosomy 7 in as few as 8% of the cells, showing that array CGH allows detection of low grade mosaicisims.