Pragmatic approach for interpreting antiretroviral drug concentrations based on a systematic review of population pharmacokinetic studies

Objectives: The study objective was to derive reference pharmacokinetic curves of antiretroviral drugs (ART) based on available population pharmacokinetic (Pop-PK) studies that can be used to optimize therapeutic drug monitoring guided dosage adjustment.¦Methods: A systematic search of Pop-PK studies of 8 ART in adults was performed in PubMed. To simulate reference PK curves, a summary of the PK parameters was obtained for each drug based on meta-analysis approach. Most models used one-compartment model, thus chosen as reference model. Models using bi-exponential disposition were simplified to one-compartment, since the first distribution phase was rapid and not determinant for the description of the terminal elimination phase, mostly relevant for this project. Different absorption were standardized for first-order absorption processes.¦Apparent clearance (CL), apparent volume of distribution of the terminal phase (Vz) and absorption rate constant (ka) and inter-individual variability were pooled into summary mean value, weighted by number of plasma levels; intra-individual variability was weighted by number of individuals in each study.¦Simulations based on summary PK parameters served to construct concentration PK percentiles (NONMEM®).¦Concordance between individual and summary parameters was assessed graphically using Forest-plots. To test robustness, difference in simulated curves based on published and summary parameters was calculated using efavirenz as probe drug.¦Results: CL was readily accessible from all studies. For studies with one-compartment, Vz was central volume of distribution; for two-compartment, Vz was CL/λz. ka was directly used or derived based on the mean absorption time (MAT) for more complicated absorption models, assuming MAT=1/ka.¦The value of CL for each drug was in excellent agreement throughout all Pop-PK models, suggesting that minimal concentration derived from summary models was adequately characterized. The comparison of the concentration vs. time profile for efavirenz between published and summary PK parameters revealed not more than 20% difference. Although our approach appears adequate for estimation of elimination phase, the simplification of absorption phase might lead to small bias shortly after drug intake.¦Conclusions: Simulated reference percentile curves based on such an approach represent a useful tool for interpretating drug concentrations. This Pop-PK meta-analysis approach should be further validated and could be extended to elaborate more sophisticated computerized tool for the Bayesian TDM of ART.

Use of active personal dosemeters in interventional radiology and cardiology: Tests in hospitals - ORAMED project

Although active personal dosemeters (APDs) are not used quite often in hospital environments, the possibility to assess the dose and/or dose rate in real time is particularly interesting in interventional radiology and cardiology (IR/IC) since operators can receive relatively high doses while standing close to the primary radiation field.A study concerning the optimization of the use of APDs in IR/IC was performed in the framework of the ORAMED project, a Collaborative Project (2008-2011) supported by the European Commission within its 7th Framework Program. This paper reports on tests performed with APDs on phantoms using an X-ray facility in a hospital environment and APDs worn by interventionalists during routine practice in different European hospitals.The behaviour of the APDs is more satisfactory in hospitals than in laboratories with respect to the influence of the tube peak high voltage and pulse width, because the APDs are tested in scattered fields with dose equivalent rates generally lower than 1 Sv.h(-1).

The TRANSMED Atlas: geological-geophysical fabric of the Mediterranean region - Final report of the project

Geological research on the Mediterranean region is presently characterized by the transition from disciplinary to multidisciplinary research, as well as from national to international investigations. In order to synthesize and integrate the vast disciplinary and national datasets which are available, it is necessary to implement maximum interaction among geoscientists of different backgrounds. The creation of project-oriented task forces in universities and other research institutions, as well as the development of large international cooperation programs, is instrumental in pursuing such a multidisciplinary and supranational approach. The TRANSMED Atlas, an official publication of the 32nd International Geological Congress (Florence 2004), is the result of an international scientific cooperation program which brought together for over two years sixty-three structural geologists, geophysicists, marine geologists, petrologists, sedimentologists, stratigraphers, paleogeographers, and petroleum geologists coming from eighteen countries, and working for the petroleum industry, academia, and other institutions, both public and private. The TRANSMED Atlas provides an updated, synthetic, and coherent portrayal of the overall geological-geophysical structure of the Mediterranean domain and the surrounding areas. The initial stimulus for the Atlas came from the realization of the extremely heterogeneous nature of the existing geological-geophysical data about such domain. These data have been gathered by universities, oil companies, geological surveys and other institutions in several countries, often using different procedures and standards. In addition, much of these data are written in languages and published in outlets that are not readily accessible to the general international reader. By synthesizing and integrating a wealth of preexisting and new data derived from surficial geology, seismic sections at various scales, and mantle tomographies, the TRANSMED Atlas provides for the first time a coherent geological overview of the Mediterranean region and represents an ideal springboard for future studies.

Four years with FALCON - an ESTRO educational project: achievements and perspectives.

Variability in anatomical contouring is one of the important uncertainties in radiotherapy. FALCON (Fellowship in Anatomic deLineation and CONtouring) is an educational ESTRO (European SocieTy for Radiation and Oncology) project devoted to improve interactive teaching, the homogeneity in contouring and to compare individual contours with endorsed guidelines or expert opinions. This report summarizes the experience from the first 4 years using FALCON for educational activities within ESTRO School and presents the perspectives for the future.

Measurements of eye lens doses in interventional radiology and cardiology: Final results of the ORAMED project

Within the ORAMED project (Optimization of Radiation Protection of Medical Staff) a coordinated measurement program for occupationally exposed medical staff was performed in different hospitals in Europe (www.oramed-fp7.eu). The main objective was to obtain a set of standardized data on extremity and eye lens doses for staff involved in interventional radiology and cardiology and to optimize radiation protection. Special attention was given to the measurement of the doses to the eye lenses. In this paper an overview will be given of the measured eye lens doses and the main influence factors for these doses. The measured eye lens doses are extrapolated to annual doses. The extrapolations showed that monitoringof the eye lens should be performed on routine basis.

Prevalence and Clinical Outcomes for Patients With ALK-Positive Resected Stage I to III Adenocarcinoma: Results From the European Thoracic Oncology Platform Lungscape Project.

PURPOSE: The prevalence of anaplastic lymphoma kinase (ALK) gene fusion (ALK positivity) in early-stage non-small-cell lung cancer (NSCLC) varies by population examined and detection method used. The Lungscape ALK project was designed to address the prevalence and prognostic impact of ALK positivity in resected lung adenocarcinoma in a primarily European population. METHODS: Analysis of ALK status was performed by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) in tissue sections of 1,281 patients with adenocarcinoma in the European Thoracic Oncology Platform Lungscape iBiobank. Positive patients were matched with negative patients in a 1:2 ratio, both for IHC and for FISH testing. Testing was performed in 16 participating centers, using the same protocol after passing external quality assessment. RESULTS: Positive ALK IHC staining was present in 80 patients (prevalence of 6.2%; 95% CI, 4.9% to 7.6%). Of these, 28 patients were ALK FISH positive, corresponding to a lower bound for the prevalence of FISH positivity of 2.2%. FISH specificity was 100%, and FISH sensitivity was 35.0% (95% CI, 24.7% to 46.5%), with a sensitivity value of 81.3% (95% CI, 63.6% to 92.8%) for IHC 2+/3+ patients. The hazard of death for FISH-positive patients was lower than for IHC-negative patients (P = .022). Multivariable models, adjusted for patient, tumor, and treatment characteristics, and matched cohort analysis confirmed that ALK FISH positivity is a predictor for better overall survival (OS). CONCLUSION: In this large cohort of surgically resected lung adenocarcinomas, the prevalence of ALK positivity was 6.2% using IHC and at least 2.2% using FISH. A screening strategy based on IHC or H-score could be envisaged. ALK positivity (by either IHC or FISH) was related to better OS.

Main objectives and new aspects of combination treatment of hypertension

AIM: To review the various pharmacological approaches currently proposed for the treatment of hypertension. RESULTS: With the evolution of pharmacological treatment of hypertension, various classes of agent (diuretics, beta-blockers, angiotensin converting enzyme inhibitors, calcium antagonists and alpha 1-blockers) have become available for the initiation of antihypertensive therapy. As monotherapy, each type of agent will normalize blood pressure in about half of all hypertensive patients. Replacing one drug with another that acts through a different mechanism improves the probability of controlling blood pressure. Another way to increase the number of responders is to increase the dose; however, this often results in more side effects. A preferable way of improving efficacy is to combine low doses of drugs that have different impacts on the cardiovascular system, thus opposing the compensatory responses that tend to limit the blood pressure drop. CONCLUSION: Low-dose drug combinations are generally well tolerated and the treatment of hypertension can be simplified by using fixed-dose combinations. These combinations have the potential to become a valuable alternative in the initiation of antihypertensive therapy.

Relation between atherogenic dyslipidemia and the Adult Treatment Program-III definition of metabolic syndrome (Genetic Epidemiology of Metabolic Syndrome Project).

Genetic Epidemiology of Metabolic Syndrome is a multinational, family-based study to explore the genetic basis of the metabolic syndrome. Atherogenic dyslipidemia (defined as low plasma high-density lipoprotein cholesterol with elevated triglycerides (<25th and >75th percentile for age, gender, and country, respectively) identified affected subjects for the metabolic syndrome. This report examines the frequency at which atherogenic dyslipidemia predicts the metabolic syndrome of the National Cholesterol Education Program Adult Treatment Panel III (ATP-III). One thousand four hundred thirty-six (854 men/582 women) affected patients by our criteria were compared with 1,672 (737 men/935 women) unaffected persons. Affected patients had more hypertension, obesity, and hyperglycemia, and they met a higher number of ATP-III criteria (3.2 +/- 1.1 SD vs 1.3 +/- 1.1 SD, p <0.001). Overall, 76% of affected persons also qualified for the ATP-III definition (Cohen's kappa 0.61, 95% confidence interval 0.59 to 0.64), similar to a separate group of 464 sporadic, unrelated cases (75%). Concordance increased from 41% to 82% and 88% for ages < or =35, 36 to 55, and > or =55 years, respectively. Affected status was also independently associated with waist circumference (p <0.001) and fasting glucose (p <0.001) but not systolic blood pressure (p = 0.43). Thus, the lipid-based criteria used to define affection status in this study substantially parallels the ATP-III definition of metabolic syndrome in subjects aged >35 years. In subjects aged <35 years, atherogenic dyslipidemia frequently occurs in the absence of other metabolic syndrome risk factors.

Sequencing and characterizing the genome of Estrella lausannensis as an undergraduate project: training students and biological insights.

With the widespread availability of high-throughput sequencing technologies, sequencing projects have become pervasive in the molecular life sciences. The huge bulk of data generated daily must be analyzed further by biologists with skills in bioinformatics and by "embedded bioinformaticians," i.e., bioinformaticians integrated in wet lab research groups. Thus, students interested in molecular life sciences must be trained in the main steps of genomics: sequencing, assembly, annotation and analysis. To reach that goal, a practical course has been set up for master students at the University of Lausanne: the "Sequence a genome" class. At the beginning of the academic year, a few bacterial species whose genome is unknown are provided to the students, who sequence and assemble the genome(s) and perform manual annotation. Here, we report the progress of the first class from September 2010 to June 2011 and the results obtained by seven master students who specifically assembled and annotated the genome of Estrella lausannensis, an obligate intracellular bacterium related to Chlamydia. The draft genome of Estrella is composed of 29 scaffolds encompassing 2,819,825 bp that encode for 2233 putative proteins. Estrella also possesses a 9136 bp plasmid that encodes for 14 genes, among which we found an integrase and a toxin/antitoxin module. Like all other members of the Chlamydiales order, Estrella possesses a highly conserved type III secretion system, considered as a key virulence factor. The annotation of the Estrella genome also allowed the characterization of the metabolic abilities of this strictly intracellular bacterium. Altogether, the students provided the scientific community with the Estrella genome sequence and a preliminary understanding of the biology of this recently-discovered bacterial genus, while learning to use cutting-edge technologies for sequencing and to perform bioinformatics analyses.