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.

24-hour ambulatory electrocardiographic monitoring is unhelpful in the investigation of older persons with recurrent falls

Although frequently used in the assessment of patients with falls, it is unclear whether 24-hour ambulatory electrocardiography contributes to their assessment in older persons. The aim of this study is to identify electrocardiographic abnormalities in patients with recurrent falls and case controls, and determine whether 24-hour ambulatory electrocardiography identifies causal arrhythmias for falls. 24-hour ambulatory electrocardiography recordings were compared for the type and prevalence of arrhythmias and symptom correlation in consecutive older subjects with recurrent falls attending the accident and emergency department and in case controls (no previous falls or syncope).

Life Expectancy and All Age All Cause Mortality Monitoring (Overall and Health Inequalities) - Update to include data for 2007

The latest annual update on life expectancy data and all age all cause mortality rates, with data updated to 2005-07, which are used to monitor progress against Department of Health targets for overall life expectancy in England, and for the gap in life expectancy between the areas with the worst health and deprivation indicators (the Spearhead group) and the England average, was released on 13th November 2008 according to the arrangements approved by the UK Statistics Authority.

Mortality target monitoring (life expectancy and all-age all-cause mortality, overall and inequalities)

The latest annual update on life expectancy data and all age all cause mortality rates, with data updated to 2006-08, which are used to monitor progress against Department of Health targets for overall life expectancy in England, and for the gap in life expectancy between the areas with the worst health and deprivation indicators (the Spearhead group) and the England average, was released on 5th November 2009 according to the arrangements approved by the UK Statistics Authority. �� The key points from the latest release are: �� - The overall life expectancy and all age all cause mortality (AAACM) trends for both males and females are broadly on course to deliver the target of 78.6 years for men and 82.5 years for women by 2010 (2009-11). �� - In 2006-08, life expectancy at birth in England continued to increase for both males and females, and reached its highest level on record at 77.7 years for males and 81.9 years for females. �� - Three-year average AAACM rates for England have fallen in each period since 1995-97. �� - In 2006-08, average life expectancy at birth in the Spearhead Group was 75.8 years for males and 80.4 years for females, having increased in each period since 1995-97. �� - However, England average life expectancy at birth has increased more quickly over this period, and, in 2006-08, the relative gap ��� i.e. percentage difference - in life expectancy at birth between England and the Spearhead Group was wider than at the baseline for the target (1995-97) for both males and females. �� - For males the relative gap was 7% wider than at the baseline (compared with 4% wider in 2005-07), for females 14% wider (compared with 11% wider in 2005-07).�� �� Therefore, the target to narrow the life expectancy gap between the Spearhead Group and the England average, by at least 10% by 2010, remains challenging.��Three-year average AAACM rates for the Spearhead Group have fallen in each period since 1995-97 for both males and females. Download Mortality target monitoring (life expectancy and all-age all-cause mortality, overall and inequalities): update to include data for 2008 (PDF, 683K)Download pre-release access list (PDF, 10k)��

Imaging and quantifying salt-tracer transport in a riparian groundwater system by means of 3D ERT monitoring

Determining groundwater flow paths of infiltrated river water is necessary for studying biochemical processes in the riparian zone, but their characterization is complicated by strong temporal and spatial heterogeneity. We investigated to what extent repeat 3D surface electrical resistance tomography (ERT) can be used to monitor transport of a salt-tracer plume under close to natural gradient conditions. The aim is to estimate groundwater flow velocities and pathways at a site located within a riparian groundwater system adjacent to the perialpine Thur River in northeastern Switzerland. Our ERT time-lapse images provide constraints on the plume's shape, flow direction, and velocity. These images allow the movement of the plume to be followed for 35 m. Although the hydraulic gradient is only 1.43 parts per thousand, the ERT time-lapse images demonstrate that the plume's center of mass and its front propagate with velocities of 2x10(-4) m/s and 5x10(-4) m/s, respectively. These velocities are compatible with groundwater resistivity monitoring data in two observation wells 5 m from the injection well. Five additional sensors in the 5-30 m distance range did not detect the plume. Comparison of the ERT time-lapse images with a groundwater transport model and time-lapse inversions of synthetic ERT data indicate that the movement of the plume can be described for the first 6 h after injection by a uniform transport model. Subsurface heterogeneity causes a change of the plume's direction and velocity at later times. Our results demonstrate the effectiveness of using time-lapse 3D surface ERT to monitor flow pathways in a challenging perialpine environment over larger scales than is practically possible with crosshole 3D ERT.

Monitoring of resistance to the pyrethroid cypermethrin in Brazilian Aedes aegypti (Diptera: Culicidae) populations collected between 2001 and 2003

Resistance to cypermethrin of different Aedes aegypti Brazilian populations, collected at two successive periods (2001 and 2002/2003), was monitored using the insecticide-coated bottles bioassay. Slight modifications were included in the method to discriminate between mortality and the knock down effect. Although this pyrethroid was recently started to be used in the country to control the dengue vector, a decrease in susceptibility was noted between both periods analyzed, particularly in the city of Rio de Janeiro. The results indicate that resistance is due at least in part to a target site alteration.

Monitoring trends in health in the East Midlands

A report published in 2002, Monitoring the State of the East Midlands. Sustainable Development Objectives and Targets for the East Midlands. Health Indicators, proposed a set of seven high-level health indicators for monitoring health status and health inequalities in the Region. The report also proposed a number of health improvement and health inequality reduction targets drawn from key national and regional strategy documents including Saving Lives: Our Healthier Nation and The East Midlands Integrated Regional Strategy. These relate to: - Life expectancy at birth. - Teenage pregnancy rate. - Mortality rate from circulatory disease in people aged under 75. - Mortality rate from cancer in people aged under 75. - Mortality rate from accidents in people of all ages. - Suicide rate in people of all ages. - Prevalence of cigarette smoking in people aged 16 and over. Progress towards these targets will indicate that the twin aims of the regional public health strategy Investment for Health - to improve health and to reduce health inequalities - are being achieved. This report updates these indicators with the latest available data. At the time of writing, data were available for years up to and including 2003 for most indicators. Please note that the latest data are provisional at this stage.

Health inequality target monitoring: update to include data for 2006

These reports summarise progress against Department of Health inequality targets for 2010 in the following areas: Infant mortality; life expectancy at birth for males and for females; cancer (premature mortality rate) and all circulatory diseases (premature mortality rate). Key facts Infant mortality The inequality gap in the infant mortality rate has reduced for the second consecutive period, though not yet by a sufficient amount to meet the target, based on the trend since the current socio economic classifications were introduced in 2001. Life expectancy at birth (males and females) The inequality gaps in male and female life expectancy at birth have both increased since the baseline. If current trends continue, the target would not be met. Cancer mortality The inequality gap in cancer mortality has declined since the baseline (despite a slight increase in the latest period), and the minimum requirement for the 2010 target has already been met. All circulatory diseases mortality The inequality gap in circulatory disease mortality has declined, and is on track to meet the target.

Mortality target monitoring: infant mortality, inequalities. Update to include data for 2008

The 2008 annual update on infant mortality rates to monitor progress against the Department of Health infant mortality inequality PSA target.

Health monitoring for black and minority ethnic groups

This paper explores some aspects of health monitoring in relation to black and ethnic minority populations in London. It considers where research in London and elsewhere has shown evidence of inequalities between ethnic groups, and draws out the issues for recording, analysis and sharing of ethnic-specific data.

Assessing, measuring and monitoring local health inequalities

This briefing has been put together by Eastern Region PHO outlining how to measure and monitor health inequalities in a local area, such as a primary care trust (PCT) or a local authority. It has been designed to help support action to tackle health inequalities in new NHS organisations and for Local Area Agreements (LAAs). Click on the link to view the document.

A one-year monitoring of nicotine use in sport: frontier between potential performance enhancement and addiction issues

Tobacco consumption is a global epidemic responsible for a vast burden of disease. With pharmacological properties sought-after by consumers and responsible for addiction issues, nicotine is the main reason of this phenomenon. Accordingly, smokeless tobacco products are of growing popularity in sport owing to potential performance enhancing properties and absence of adverse effects on the respiratory system. Nevertheless, nicotine does not appear on the 2011 World Anti-Doping Agency (WADA) Prohibited List or Monitoring Program by lack of a comprehensive large-scale prevalence survey. Thus, this work describes a one-year monitoring study on urine specimens from professional athletes of different disciplines covering 2010 and 2011. A method for the detection and quantification of nicotine, its major metabolites (cotinine, trans-3-hydroxycotinine, nicotine-N′-oxide and cotinine-N-oxide) and minor tobacco alkaloids (anabasine, anatabine and nornicotine) was developed, relying on ultra-high pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC-TQ-MS/MS). A simple and fast dilute-and-shoot sample treatment was performed, followed by hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) operated in positive electrospray ionization (ESI) mode with multiple reaction monitoring (MRM) data acquisition. After method validation, assessing the prevalence of nicotine consumption in sport involved analysis of 2185 urine samples, accounting for 43 different sports. Concentrations distribution of major nicotine metabolites, minor nicotine metabolites and tobacco alkaloids ranged from 10 (LLOQ) to 32,223, 6670 and 538 ng/mL, respectively. Compounds of interest were detected in trace levels in 23.0% of urine specimens, with concentration levels corresponding to an exposure within the last three days for 18.3% of samples. Likewise, hypothesizing conservative concentration limits for active nicotine consumption prior and/or during sport practice (50 ng/mL for nicotine, cotinine and trans-3-hydroxycotinine and 25 ng/mL for nicotine-N′-oxide, cotinine-N-oxide, anabasine, anatabine and nornicotine) revealed a prevalence of 15.3% amongst athletes. While this number may appear lower than the worldwide smoking prevalence of around 25%, focusing the study on selected sports highlighted more alarming findings. Indeed, active nicotine consumption in ice hockey, skiing, biathlon, bobsleigh, skating, football, basketball, volleyball, rugby, American football, wrestling and gymnastics was found to range between 19.0 and 55.6%. Therefore, considering the adverse effects of smoking on the respiratory tract and numerous health threats detrimental to sport practice at top level, likelihood of smokeless tobacco consumption for performance enhancement is greatly supported.

Individual monitoring of medical staff working in interventional radiology in Switzerland using double dosimetry

Physicians who frequently perform fluoroscopic examinations are exposed to high intensity radiation fields. The exposure monitoring is performed with a regular personal dosimeter under the apron in order to estimate the effective dose. However, large parts of the body are not protected by the apron (e.g. arms, head). Therefore, it is recommended to wear a supplemental dosimeter over the apron to obtain a better representative estimate of the effective dose. The over-apron dosimeter can also be used to estimate the eye lens dose. The goal of this study was to investigate the relevance of double dosimetry in interventional radiology. First the calibration procedure of the dosimeters placed over the apron was tested. Then, results of double dosimetry during the last five years were analyzed. We found that the personal dose equivalent measured over a lead apron was underestimated by ∼20% to ∼40% for X-ray beam qualities used in radiology. Measurements made over five-year period confirm that the use of a single under-apron dosimeter is inadequate for personnel monitoring. Relatively high skin dose (>10 mSv/month) would have remained undetected without a second dosimeter placed on the apron.

Electronic monitoring of compliance to lipid-lowering therapy in clinical practice

Nonadherence to treatment is a common problem in the clinical management of hypercholesterolemic patients. This study was carried out with the aim of monitoring the daily compliance to a 6-month course of lipid-lowering therapy, using a microelectronic device, the Medication Event Monitoring System (MEMS), versus pill count. Forty men with primary hypercholesterolemia were prescribed fluvastatin 1 x 40 mg daily, provided in a MEMS package to record the date and time of each opening of the pillbox. Thirty-nine of 40 patients (98%) completed the study. Total cholesterol and LDL cholesterol levels decreased significantly (18% and 25%, p < 0.001) during the 6-month therapy period. A high mean rate of compliance was achieved by MEMS using the following three indexes--compliance to total prescribed dose (88.8% +/- 13.5%), compliance to prescribed days (82.4% +/- 19.5%), and compliance to prescribed time of day (81.86% +/- 19.5%)--and by pill count (93.4% +/- 9.5%). In addition, the MEMS provided some patterns of nonadherence to medication, undetectable by pill count alone, such as a drug holiday in 38% of cases, a drug omission for more than 7 consecutive days in 9% of cases, and, conversely, use of more than the one prescribed daily dose in 47% of cases. A significant correlation between the rate of compliance and the decrease in LDL cholesterol was observed only when the compliance was assessed by MEMS. The results indicate that MEMS is a useful tool for monitoring compliance in clinical practice and may possibly increase adherence to long-term lipid-lowering therapy.