Therapeutic drug monitoring of imatinib: Bayesian and alternative methods to predict trough levels

Background: The imatinib trough plasma concentration (C(min)) correlates with clinical response in cancer patients. Therapeutic drug monitoring (TDM) of plasma C(min) is therefore suggested. In practice, however, blood sampling for TDM is often not performed at trough. The corresponding measurement is thus only remotely informative about C(min) exposure. Objectives: The objectives of this study were to improve the interpretation of randomly measured concentrations by using a Bayesian approach for the prediction of C(min), incorporating correlation between pharmacokinetic parameters, and to compare the predictive performance of this method with alternative approaches, by comparing predictions with actual measured trough levels, and with predictions obtained by a reference method, respectively. Methods: A Bayesian maximum a posteriori (MAP) estimation method accounting for correlation (MAP-ρ) between pharmacokinetic parameters was developed on the basis of a population pharmacokinetic model, which was validated on external data. Thirty-one paired random and trough levels, observed in gastrointestinal stromal tumour patients, were then used for the evaluation of the Bayesian MAP-ρ method: individual C(min) predictions, derived from single random observations, were compared with actual measured trough levels for assessment of predictive performance (accuracy and precision). The method was also compared with alternative approaches: classical Bayesian MAP estimation assuming uncorrelated pharmacokinetic parameters, linear extrapolation along the typical elimination constant of imatinib, and non-linear mixed-effects modelling (NONMEM) first-order conditional estimation (FOCE) with interaction. Predictions of all methods were finally compared with 'best-possible' predictions obtained by a reference method (NONMEM FOCE, using both random and trough observations for individual C(min) prediction). Results: The developed Bayesian MAP-ρ method accounting for correlation between pharmacokinetic parameters allowed non-biased prediction of imatinib C(min) with a precision of ±30.7%. This predictive performance was similar for the alternative methods that were applied. The range of relative prediction errors was, however, smallest for the Bayesian MAP-ρ method and largest for the linear extrapolation method. When compared with the reference method, predictive performance was comparable for all methods. The time interval between random and trough sampling did not influence the precision of Bayesian MAP-ρ predictions. Conclusion: Clinical interpretation of randomly measured imatinib plasma concentrations can be assisted by Bayesian TDM. Classical Bayesian MAP estimation can be applied even without consideration of the correlation between pharmacokinetic parameters. Individual C(min) predictions are expected to vary less through Bayesian TDM than linear extrapolation. Bayesian TDM could be developed in the future for other targeted anticancer drugs and for the prediction of other pharmacokinetic parameters that have been correlated with clinical outcomes.

A Note on improving Contact Times in Panel Surveys

With increasing costs for conducting surveys, many survey agencies resort to implementing call strategies. Obtaining contact in panel surveys as early as possible, without annoying people by contacting them at undesired times and ultimately causing them to refuse, requires using efficient call time strategies. In this research, the author uses call data from the Swiss Household Panel (SHP), a centralized Computer Assisted Telephone Interview (CATI) survey with a randomized (experimental) call-household assignment. Using random effects models, the author analyzes the efficiency gains of obtaining initial contact by assigning optimal times to first calls, and times and spacing to second and later calls depending on household sociodemography and prior call patterns. The author concludes with some recommendations for making early and successful contact during fieldwork.

Fat embolism syndrome after combined aesthetic surgery.

Fat embolism syndrome is a rare complication that develops after extended soft tissue disruption by liposuction, in particular if combined with time consuming, multiple procedures. Early signs are non-specific and often not considered, so that diagnosis and correct management may be delayed. We report a case in which liposuction combined with other aesthetic surgical procedures caused a fat embolism syndrome in a 46-year-old woman, which was followed by multiple organ failure and the development of sepsis with perimammary abscesses. Extended liposuction of the abdomen and thighs, bilateral augmentation mammaplasty, and stripping of both greater saphenous veins were combined.

Quantitative Assessment of T1 Relaxation and Diffusion as a Prognostic Tool for Brain Development: A Longitudinal Preliminary Study on Preterm Babies

BACKGROUND: Despite major advances in care of premature infants, survivors exhibit mild cognitive deficits in around 40%. Beside severe intraventricular haemorrhages (IVH) and cystic periventricular leucomalacia (PVL), more subtle patterns such as grade I and II IVH, punctuate WM lesions and diffuse PVL might be linked to the cognitive deficits. Grey matter disease is also recognized to contribute to long-term cognitive impairment.¦OBJECTIVE: We intend to use novel MR techniques to study more precisely the different injury patterns. In particular MP2RAGE (magnetization prepared dual rapid echo gradient) produces high-resolution quantitative T1 relaxation maps. This contrast is known to reflect tissue anomalies such as white matter injury in general and dysmyelination in particular. We also used diffusion tensor imaging, a quantitative technique known to reflect white matter maturation and disease.¦DESIGN/METHODS: All preterm infants born under 30 weeks of GA were included. Serial 3T MR-imaging using a neonatal head-coil at DOL 3, 10 and at term equivalent age (TEA), using DTI and MP2RAGE sequences was performed. MP2RAGE generates a T1 map and allows calculating the relaxation time T1. Multiple measurements were performed for each exam in 12 defined white and grey matter ROIs.¦RESULTS: 16 patients were recruited: mean GA 27 2/7 w (191,2d SD±10,8), mean BW 999g (SD±265). 39 MRIs were realized (12 early: mean 4,83d±1,75, 13 late: mean 18,77d±8,05 and 14 at TEA: 88,91d±8,96). Measures of relaxation time T1 show a gradual and significant decrease over time (for ROI PLIC mean±SD in ms: 2100.53±102,75, 2116,5±41,55 and 1726,42±51,31 and for ROI central WM: 2302,25±79,02, 2315,02±115,02 and 1992,7±96,37 for early, late and TEA MR respectively). These trends are also observed in grey matter area, especially in thalamus. Measurements of ADC values show similar monotonous decrease over time.¦CONCLUSIONS: From these preliminary results, we conclude that quantitative MR imaging in very preterm infants is feasible. On the successive MP2RAGE and DTI sequences, we observe a gradual decrease over time in the described ROIs, representing the progressive maturation of the WM micro-structure and interestingly the same evolution is observed in the grey matter. We speculate that our study will provide normative values for T1map and ADC and might be a predictive factor for favourable or less favourable outcome.

Fallers in postacute rehabilitation have worse functional recovery and increased health services use.

OBJECTIVES: To determine characteristics associated with single and multiple fallers during postacute rehabilitation and to investigate the relationship among falls, rehabilitation outcomes, and health services use. DESIGN: Retrospective cohort study. SETTING: Geriatric postacute rehabilitation hospital. PARTICIPANTS: Patients (n = 4026) consecutively admitted over a 5-year period (2003-2007). MEASUREMENTS: All falls during hospitalization were prospectively recorded. Collected patients' characteristics included health, functional, cognitive, and affective status data. Length of stay and discharge destination were retrieved from the administrative database. RESULTS: During rehabilitation stay, 11.4% (458/4026) of patients fell once and an additional 6.3% (253/4026) fell several times. Compared with nonfallers, fallers were older and more frequently men. They were globally frailer, with lower Barthel score and more comorbidities, cognitive impairment, and depressive symptoms. In multivariate analyses, compared with 1-time fallers, multiple fallers were more likely to have lower Barthel score (adjOR: 2.45, 95% CI: 1.48-4.07; P = .001), cognitive impairment (adjOR: 1.43, 95% CI: 1.04-1.96; P = .026), and to have been admitted from a medicine ward (adjOR: 1.55, 95% CI: 1.03-2.32; P = .035). Odds of poor functional recovery and institutionalization at discharge, as well as length of stay, increased incrementally from nonfallers to 1-time and to multiple fallers. CONCLUSION: In these patients admitted to postacute rehabilitation, the proportion of fallers and multiple fallers was high. Multiple fallers were particularly at risk of poor functional recovery and increased health services use. Specific fall prevention programs targeting high-risk patients with cognitive impairment and low functional status should be developed in further studies.

Intraocular implants for extended drug delivery: therapeutic applications.

An overview of ocular implants with therapeutic application potentials is provided. Various types of implants can be used as slow release devices delivering locally the needed drug for an extended period of time. Thus, multiple periocular or intraocular injections of the drug can be circumvented and secondary complications minimized. The various compositions of polymers fulfilling specific delivery goals are described. Several of these implants are undergoing clinical trials while a few are already commercialized. Despite the paramount progress in design, safety and efficacy, the place of these implants in our clinical therapeutic arsenal remains limited. Miniaturization of the implants allowing for their direct injection without the need for a complicated surgery is a necessary development avenue. Particulate systems which can be engineered to target specifically certain cells or tissues are another promising alternative. For ocular diseases affecting the choroid and outer retina, transscleral or intrasscleral implants are gaining momentum.

Complex patterns of global spread in invasive insects: eco-evolutionary and management consequences

The advent of simple and affordable tools for molecular identification of novel insect invaders and assessment of population diversity has changed the face of invasion biology in recent years. The widespread application of these tools has brought with it an emerging understanding that patterns in biogeography, introduction history and subsequent movement and spread of many invasive alien insects are far more complex than previously thought. We reviewed the literature and found that for a number of invasive insects, there is strong and growing evidence that multiple introductions, complex global movement, and population admixture in the invaded range are commonplace. Additionally, historical paradigms related to species and strain identities and origins of common invaders are in many cases being challenged. This has major consequences for our understanding of basic biology and ecology of invasive insects and impacts quarantine, management and biocontrol programs. In addition, we found that founder effects rarely limit fitness in invasive insects and may benefit populations (by purging harmful alleles or increasing additive genetic variance). Also, while phenotypic plasticity appears important post-establishment, genetic diversity in invasive insects is often higher than expected and increases over time via multiple introductions. Further, connectivity among disjunct regions of global invasive ranges is generally far higher than expected and is often asymmetric, with some populations contributing disproportionately to global spread. We argue that the role of connectivity in driving the ecology and evolution of introduced species with multiple invasive ranges has been historically underestimated and that such species are often best understood in a global context.

Time for change: a roadmap to guide the implementation of the World Anti-Doping Code 2015

A medical and scientific multidisciplinary consensus meeting was held from 29 to 30 November 2013 on Anti-Doping in Sport at the Home of FIFA in Zurich, Switzerland, to create a roadmap for the implementation of the 2015 World Anti-Doping Code. The consensus statement and accompanying papers set out the priorities for the antidoping community in research, science and medicine. The participants achieved consensus on a strategy for the implementation of the 2015 World Anti-Doping Code. Key components of this strategy include: (1) sport-specific risk assessment, (2) prevalence measurement, (3) sport-specific test distribution plans, (4) storage and reanalysis, (5) analytical challenges, (6) forensic intelligence, (7) psychological approach to optimise the most deterrent effect, (8) the Athlete Biological Passport (ABP) and confounding factors, (9) data management system (Anti-Doping Administration & Management System (ADAMS), (10) education, (11) research needs and necessary advances, (12) inadvertent doping and (13) management and ethics: biological data. True implementation of the 2015 World Anti-Doping Code will depend largely on the ability to align thinking around these core concepts and strategies. FIFA, jointly with all other engaged International Federations of sports (Ifs), the International Olympic Committee (IOC) and World Anti-Doping Agency (WADA), are ideally placed to lead transformational change with the unwavering support of the wider antidoping community. The outcome of the consensus meeting was the creation of the ad hoc Working Group charged with the responsibility of moving this agenda forward.

Phylogenetic Code in the Cloud - Can it Meet the Expectations?

Cloud computing has recently become very popular, and several bioinformatics applications exist already in that domain. The aim of this article is to analyse a current cloud system with respect to usability, benchmark its performance and compare its user friendliness with a conventional cluster job submission system. Given the current hype on the theme, user expectations are rather high, but current results show that neither the price/performance ratio nor the usage model is very satisfactory for large-scale embarrassingly parallel applications. However, for small to medium scale applications that require CPU time at certain peak times the cloud is a suitable alternative.