Quality assurance in road traffic analyses in Switzerland.

Swiss laboratories performing toxicological road traffic analyses have been authorized for many years by the Swiss Federal Roads Office (FEDRO). In 2003 FEDRO signed a contract with the Swiss Society of Legal Medicine (SSLM) to organize the complete quality management concerning road traffic analyses. For this purpose a multidisciplinary working group was established under the name of "road traffic commission (RTC)". RTC has to organize external quality control, to interpret the results of these controls, to perform audits in the laboratories and to report all results to FEDRO. Furthermore the working group can be mandated for special tasks by FEDRO. As an independent organization the Swiss Center for Quality Control (CSCQ) in Geneva manages the external quality controls in the laboratory over the past years. All tested drugs and psychoactive substances are listed in a federal instruction. The so-called 'zero tolerance substances' (THC, morphine, cocaine, amphetamine, methamphetamine, MDMA and MDEA) and their metabolites have to be tested once a year, all other substances (benzodiazepines, zolpidem, phenobarbital, etc.) periodically. Results over the last years show that all laboratories are generally within the confidence interval of +/-30% of the mean value. In cases of non-conformities measures have to be taken immediately and reported to the working group. External audits are performed triennially but accredited laboratories can combine this audit with the approval of the Swiss Accreditation Service (SAS). During the audits a special checklist filled in by the laboratory director is assessed. Non-conformities have to be corrected. During the process of establishing a new legislation, RTC had an opportunity of advising FEDRO. In collaboration with FEDRO, RTC and hence SSLM can work actively on improving of quality assurance in road traffic toxicological analyses, and has an opportunity to bring its professional requests to the federal authorities.

Harmonization of immune biomarker assays for clinical studies.

Assays that measure a patient's immune response play an increasingly important role in the development of immunotherapies. The inherent complexity of these assays and independent protocol development between laboratories result in high data variability and poor reproducibility. Quality control through harmonization--based on integration of laboratory-specific protocols with standard operating procedures and assay performance benchmarks--is one way to overcome these limitations. Harmonization guidelines can be widely implemented to address assay performance variables. This process enables objective interpretation and comparison of data across clinical trial sites and also facilitates the identification of relevant immune biomarkers, guiding the development of new therapies.

Fracture imaging within a granitic rock aquifer using multiple-offset single-hole and cross-hole GPR reflection data

The sparsely spaced highly permeable fractures of the granitic rock aquifer at Stang-er-Brune (Brittany, France) form a well-connected fracture network of high permeability but unknown geometry. Previous work based on optical and acoustic logging together with single-hole and cross-hole flowmeter data acquired in 3 neighbouring boreholes (70-100 m deep) has identified the most important permeable fractures crossing the boreholes and their hydraulic connections. To constrain possible flow paths by estimating the geometries of known and previously unknown fractures, we have acquired, processed and interpreted multifold, single- and cross-hole GPR data using 100 and 250 MHz antennas. The GPR data processing scheme consisting of timezero corrections, scaling, bandpass filtering and F-X deconvolution, eigenvector filtering, muting, pre-stack Kirchhoff depth migration and stacking was used to differentiate fluid-filled fracture reflections from source generated noise. The final stacked and pre-stack depth-migrated GPR sections provide high-resolution images of individual fractures (dipping 30-90°) in the surroundings (2-20 m for the 100 MHz antennas; 2-12 m for the 250 MHz antennas) of each borehole in a 2D plane projection that are of superior quality to those obtained from single-offset sections. Most fractures previously identified from hydraulic testing can be correlated to reflections in the single-hole data. Several previously unknown major near vertical fractures have also been identified away from the boreholes.

FGF21 signalling pathway and metabolic traits - genetic association analysis.

Fibroblast growth factor 21 (FGF21) is a novel master regulator of metabolic profile. The biological actions of FGF21 are elicited upon its klotho beta (KLB)-facilitated binding to FGF receptor 1 (FGFR1), FGFR2 and FGFR3. We hypothesised that common polymorphisms in the FGF21 signalling pathway may be associated with metabolic risk. At the screening stage, we examined associations between 63 common single-nucleotide polymorphisms (SNPs) in five genes of this pathway (FGF21, KLB, FGFR1, FGFR2, FGFR3) and four metabolic phenotypes (LDL cholesterol - LDL-C, HDL-cholesterol - HDL-C, triglycerides and body mass index) in 629 individuals from Silesian Hypertension Study (SHS). Replication analyses were performed in 5478 unrelated individuals of the Swiss CoLaus cohort (imputed genotypes) and in 3030 directly genotyped individuals of the German Myocardial Infarction Family Study (GerMIFS). Of 54 SNPs that met quality control criteria after genotyping in SHS, 4 (rs4733946 and rs7012413 in FGFR1; rs2071616 in FGFR2 and rs7670903 in KLB) showed suggestive association with LDL-C (P=0.0006, P=0.0013, P=0.0055, P=0.011, respectively) and 1 (rs2608819 in KLB) was associated with body mass index (P=0.011); all with false discovery rate q<0.5. Of these, only one FGFR2 polymorphism (rs2071616) showed replicated association with LDL-C in both CoLaus (P=0.009) and men from GerMIFS (P=0.017). The direction of allelic effect of rs2071616 upon LDL-C was consistent in all examined populations. These data show that common genetic variations in FGFR2 may be associated with LDL-C in subjects of white European ancestry.

HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer.

The transmembrane protein HER2 is over-expressed in approximately 15% of invasive breast cancers as a result of HER2 gene amplification. HER2 proteolytic cleavage (HER2 shedding) generates soluble truncated HER2 molecules that include only the extracellular domain and the concentration of which can be measured in the serum fraction of blood. HER2 shedding also generates a constitutively active truncated intracellular receptor of 95kDa (p95(HER2)). Another soluble truncated HER2 protein (Herstatin), which can also be found in serum, is the product of an alternatively spliced HER2 transcript. Recent preclinical findings may provide crucial insights into the biological and clinical relevance of increased sHER2 concentrations for the outcome of HER2-positive breast cancer and sensitivity to trastuzumab and lapatinib treatment. We present here the most recent findings about the role and biology of sHER2 based on data obtained using a standardized test, which has been cleared by FDA in 2000, for measuring sHER2. This test includes quality control assessments and has been already widely used to evaluate the clinical utility of sHER2 as a biomarker in breast cancer. We will describe in detail data concerning the assessment of sHER2 as a surrogate maker to optimize the evaluation of the HER2 status of a primary tumor and as a prognosis and predictive marker of response to therapies, both in early and metastatic breast cancer.

Epidemiology of pulmonary hypertension: new data from the Swiss registry.

since 1999 data from pulmonary hypertension (PH) patients from all PH centres in Switzerland were prospectively collected. We analyse the epidemiological aspects of these data. PH was defined as a mean pulmonary artery pressure of >25 mm Hg at rest or >30 mm Hg during exercise. Patients with pulmonary arterial hypertension (PAH), PH associated with lung diseases, PH due to chronic thrombotic and/or embolic disease (CTEPH), or PH due to miscellaneous disorders were registered. Data from adult patients included between January 1999 and December 2004 were analysed. 250 patients were registered (age 58 +/- 16 years, 104 (41%) males). 152 patients (61%) had PAH, 73 (29%) had CTEPH and 18 (7%) had PH associated with lung disease. Patients <50 years (32%) were more likely to have PAH than patients >50 years (76% vs. 53%, p <0.005). Twenty-four patients (10%) were lost to followup, 58 patients (26%) died and 150 (66%) survived without transplantation or thrombendarterectomy. Survivors differed from patients who died in the baseline six-minute walking distance (400 m [300-459] vs. 273 m [174-415]), the functional impairment (NYHA class III/IV 86% vs. 98%), mixed venous saturation (63% [57-68] vs. 56% [50-61]) and right atrial pressure (7 mm Hg [4-11] vs. 11 mm Hg [4-18]). PH is a disease affecting adults of all ages. The management of these patients in specialised centres guarantees a high quality of care. Analysis of the registry data could be an instrument for quality control and might help identify weak points in assessment and treatment of these patients.

Criteria for EASO-collaborating centres for obesity management.

Obesity is recognised as a global epidemic and the most prevalent metabolic disease world-wide. Specialised obesity services, however, are not widely available in Europe, and obesity care can vary enormously across European regions. The European Association for the Study of Obesity (EASO, www.easo.org) has developed these criteria to form a pan-European network of accredited EASO-Collaborating Centres for Obesity Management (EASO-COMs) in accordance with accepted European and academic guidelines. This network will include university, public and private clinics and will ensure that the obese and overweight patient is managed by a holistic team of specialists and receives comprehensive state-ofthe-art clinical care. Furthermore, the participating centres, under the umbrella of EASO, will work closely for quality control, data collection, and analysis as well as for education and research for the advancement of obesity care and obesity science.

Introducing systematic dispatcher-assisted cardiopulmonary resuscitation (telephone-CPR) in a non-Advanced Medical Priority Dispatch System (AMPDS): implementation process and costs.

OBJECTIVE: In order to improve the quality of our Emergency Medical Services (EMS), to raise bystander cardiopulmonary resuscitation rates and thereby meet what is becoming a universal standard in terms of quality of emergency services, we decided to implement systematic dispatcher-assisted or telephone-CPR (T-CPR) in our medical dispatch center, a non-Advanced Medical Priority Dispatch System. The aim of this article is to describe the implementation process, costs and results following the introduction of this new "quality" procedure. METHODS: This was a prospective study. Over an 8-week period, our EMS dispatchers were given new procedures to provide T-CPR. We then collected data on all non-traumatic cardiac arrests within our state (Vaud, Switzerland) for the following 12months. For each event, the dispatchers had to record in writing the reason they either ruled out cardiac arrest (CA) or did not propose T-CPR in the event they did suspect CA. All emergency call recordings were reviewed by the medical director of the EMS. The analysis of the recordings and the dispatchers' written explanations were then compared. RESULTS: During the 12-month study period, a total of 497 patients (both adults and children) were identified as having a non-traumatic cardiac arrest. Out of this total, 203 cases were excluded and 294 cases were eligible for T-CPR. Out of these eligible cases, dispatchers proposed T-CPR on 202 occasions (or 69% of eligible cases). They also erroneously proposed T-CPR on 17 occasions when a CA was wrongly identified (false positive). This represents 7.8% of all T-CPR. No costs were incurred to implement our study protocol and procedures. CONCLUSIONS: This study demonstrates it is possible, using a brief campaign of sensitization but without any specific training, to implement systematic dispatcher-assisted cardiopulmonary resuscitation in a non-Advanced Medical Priority Dispatch System such as our EMS that had no prior experience with systematic T-CPR. The results in terms of T-CPR delivery rate and false positive are similar to those found in previous studies. We found our results satisfying the given short time frame of this study. Our results demonstrate that it is possible to improve the quality of emergency services at moderate or even no additional costs and this should be of interest to all EMS that do not presently benefit from using T-CPR procedures. EMS that currently do not offer T-CPR should consider implementing this technique as soon as possible, and we expect our experience may provide answers to those planning to incorporate T-CPR in their daily practice.

A user's guide to the encyclopedia of DNA elements (ENCODE).

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome.

Genome-wide association study of major recurrent depression in the U.K. population.

OBJECTIVE: Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders. METHOD: Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry. RESULTS: Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1. CONCLUSIONS: This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.

Comparison of the polynomial model against explicit measurements of noise components for different mammography systems.

Given the adverse impact of image noise on the perception of important clinical details in digital mammography, routine quality control measurements should include an evaluation of noise. The European Guidelines, for example, employ a second-order polynomial fit of pixel variance as a function of detector air kerma (DAK) to decompose noise into quantum, electronic and fixed pattern (FP) components and assess the DAK range where quantum noise dominates. This work examines the robustness of the polynomial method against an explicit noise decomposition method. The two methods were applied to variance and noise power spectrum (NPS) data from six digital mammography units. Twenty homogeneously exposed images were acquired with PMMA blocks for target DAKs ranging from 6.25 to 1600 µGy. Both methods were explored for the effects of data weighting and squared fit coefficients during the curve fitting, the influence of the additional filter material (2 mm Al versus 40 mm PMMA) and noise de-trending. Finally, spatial stationarity of noise was assessed.Data weighting improved noise model fitting over large DAK ranges, especially at low detector exposures. The polynomial and explicit decompositions generally agreed for quantum and electronic noise but FP noise fraction was consistently underestimated by the polynomial method. Noise decomposition as a function of position in the image showed limited noise stationarity, especially for FP noise; thus the position of the region of interest (ROI) used for noise decomposition may influence fractional noise composition. The ROI area and position used in the Guidelines offer an acceptable estimation of noise components. While there are limitations to the polynomial model, when used with care and with appropriate data weighting, the method offers a simple and robust means of examining the detector noise components as a function of detector exposure.

Multicentre validation study of nucleic acids extraction from FFPE tissues.

In most pathology laboratories worldwide, formalin-fixed paraffin embedded (FFPE) samples are the only tissue specimens available for routine diagnostics. Although commercial kits for diagnostic molecular pathology testing are becoming available, most of the current diagnostic tests are laboratory-based assays. Thus, there is a need for standardized procedures in molecular pathology, starting from the extraction of nucleic acids. To evaluate the current methods for extracting nucleic acids from FFPE tissues, 13 European laboratories, participating to the European FP6 program IMPACTS (www.impactsnetwork.eu), isolated nucleic acids from four diagnostic FFPE tissues using their routine methods, followed by quality assessment. The DNA-extraction protocols ranged from homemade protocols to commercial kits. Except for one homemade protocol, the majority gave comparable results in terms of the quality of the extracted DNA measured by the ability to amplify differently sized control gene fragments by PCR. For array-applications or tests that require an accurately determined DNA-input, we recommend using silica based adsorption columns for DNA recovery. For RNA extractions, the best results were obtained using chromatography column based commercial kits, which resulted in the highest quantity and best assayable RNA. Quality testing using RT-PCR gave successful amplification of 200 bp-250 bp PCR products from most tested tissues. Modifications of the proteinase-K digestion time led to better results, even when commercial kits were applied. The results of the study emphasize the need for quality control of the nucleic acid extracts with standardised methods to prevent false negative results and to allow data comparison among different diagnostic laboratories.

New considerations on the management of osteoporosis in Central and Eastern Europe (CEE): summary of the "3rd Summit on Osteoporosis-CEE", November 2009, Budapest, Hungary.

INTRODUCTION: In November 2009, the "3rd Summit on Osteoporosis-Central and Eastern Europe (CEE)" was held in Budapest, Hungary. The conference aimed to tackle issues regarding osteoporosis management in CEE identified during the second CEE summit in 2008 and to agree on approaches that allow most efficient and cost-effective diagnosis and therapy of osteoporosis in CEE countries in the future. DISCUSSION: The following topics were covered: past year experience from FRAX® implementation into local diagnostic algorithms; causes of secondary osteoporosis as a FRAX® risk factor; bone turnover markers to estimate bone loss, fracture risk, or monitor therapies; role of quantitative ultrasound in osteoporosis management; compliance and economical aspects of osteoporosis; and osteoporosis and genetics. Consensus and recommendations developed on these topics are summarised in the present progress report. CONCLUSION: Lectures on up-to-date data of topical interest, the distinct regional provenances of the participants, a special focus on practical aspects, intense mutual exchange of individual experiences, strong interest in cross-border cooperations, as well as the readiness to learn from each other considerably contributed to the establishment of these recommendations. The "4th Summit on Osteoporosis-CEE" held in Prague, Czech Republic, in December 2010 will reveal whether these recommendations prove of value when implemented in the clinical routine or whether further improvements are still required.

Contrôle de qualité en urologie [Quality assessment in urology].

Quality control (QuaCo) in urology is mandatory to standardize or even increase the level of care. While QuaCo is undertaken at every step in the clinical pathway, it should focus on the patient's comorbidities and on the urologist and its complication rate. Resulting from political and economical pressures, comparing QuaCo and outcomes between urologists and institutions is nowadays often performed. However, careful interpretation of these comparisons is mandatory to avoid potential discriminations. Indeed, the reader has to make sure that patients groups and surgical techniques are comparable, definitions of complications are similar, classification of complications is standardized, and finally that the methodology in collecting data is irreproachable.