Subject-based steroid profiling and the determination of novel biomarkers for DHT and DHEA misuse in sports.

Doping with natural steroids can be detected by evaluating the urinary concentrations and ratios of several endogenous steroids. Since these biomarkers of steroid doping are known to present large inter-individual variations, monitoring of individual steroid profiles over time allows switching from population-based towards subject-based reference ranges for improved detection. In an Athlete Biological Passport (ABP), biomarkers data are collated throughout the athlete's sporting career and individual thresholds defined adaptively. For now, this approach has been validated on a limited number of markers of steroid doping, such as the testosterone (T) over epitestosterone (E) ratio to detect T misuse in athletes. Additional markers are required for other endogenous steroids like dihydrotestosterone (DHT) and dehydroepiandrosterone (DHEA). By combining comprehensive steroid profiles composed of 24 steroid concentrations with Bayesian inference techniques for longitudinal profiling, a selection was made for the detection of DHT and DHEA misuse. The biomarkers found were rated according to relative response, parameter stability, discriminative power, and maximal detection time. This analysis revealed DHT/E, DHT/5β-androstane-3α,17β-diol and 5α-androstane-3α,17β-diol/5β-androstane-3α,17β-diol as best biomarkers for DHT administration and DHEA/E, 16α-hydroxydehydroepiandrosterone/E, 7β-hydroxydehydroepiandrosterone/E and 5β-androstane-3α,17β-diol/5α-androstane-3α,17β-diol for DHEA. The selected biomarkers were found suitable for individual referencing. A drastic overall increase in sensitivity was obtained.The use of multiple markers as formalized in an Athlete Steroidal Passport (ASP) can provide firm evidence of doping with endogenous steroids. Copyright © 2010 John Wiley & Sons, Ltd.

Growth, yield, water and effluent quality in ponds with different management during tambaqui juvenile production

The objective of this work was to evaluate the effect of pond management on fish feed, growth, yield, survival, and water and effluent quality, during tambaqui (Colossoma macropomum) juvenile production. Fish were distributed in nine 600 m² earthen ponds, at a density of 8 fish per m²; the rearing period was 60 days. Three different pond management were applied: limed and fertilized (LimFer), limed (Lim), and natural (Nat). Fish were fed with a commercial ration containing 34% crude protein three times daily. There were no significant differences in fish growth or yield. Three main items found in tambaqui stomach were insect, zooplankton and ration, without a significant difference among treatments in proportion. Alkalinity, hardness, and CO2 were greater in LimFer and Lim ponds. Chlorophyll a, transparency, ammonia, nitrite, temperature, and dissolved oxygen of pond water were not significantly different among treatments. Biochemical oxygen demand, total phosphorus, orthophosphate, ammonia, and nitrite were significantly greater in effluents from LimFer ponds. Pond fertilization should be avoided, because growth and yield were similar among the three pond management systems tested; besides, it produces a more impacting effluent.

Population pharmacokinetics in chronic myeloid leukaemia patients: observations under field-conditions

Introduction: Therapeutic drug monitoring (TDM) of imatinib has been increasingly proposed for chronic myeloid leukaemia (CML) patients, as several studies have found a correlation between trough concentrations (Cmin) >=1000ng/ml and improved response. The pharmacological monitoring project of EUTOS (European Treatment and Outcome Study) was launched to increase the availability of imatinib TDM, standardize labs, and validate proposed Cmin thresholds. Using the collected data, the objective of this analysis was to characterize imatinib Population pharmacokinetics (Pop-PK) in a large cohort of European patients, to quantify its variability and the influence of demographic factors and comedications, and to derive individual exposure variables suitable for further concentration-effect analyses.¦Methods: 4095 PK samples from 2478 adult patients were analyzed between 2006 and 2010 by LC-MS-MS and considered for Pop-PK analysis by NONMEM®. Model building used data from 973 patients with >=2 samples available (2590 samples). A sensitivity analysis was performed using all data. Available comedications (27%) were classified into inducers or inhibitors of P-glycoprotein, CYP3A4/5 and organic-cation-transporter-1 (hOCT-1).¦Results: A one-compartment model with linear elimination, zero-order absorption fitted the data best. Estimated Pop-PK parameters (interindividual variability, IIV %CV) for a 40-year old male patient were: clearance CL = 17.3 L/h (37.7%), volume V = 429L (51.1%), duration of absorption D1 = 3.2h. Outliers, reflecting potential compliance and time recording errors, were taken into account by estimating an IIV on the residual error (35.4%). Intra-individual residuals were 29.1% (proportional) plus ± 84.6 ng/mL (additive). Female patients had a 15.2% lower CL (14.6 L/h). A piece-wise linear effect of age estimated a CL of 18.7 L/h at 20 years, 17.3 L/h at 40 and 13.8 L/h at 60 years. These covariates explained 2% (CL) and 4.5% (V) of IIV variability. No effect of comedication was found. The sensitivity analysis expectedly estimated increased IIV, but similar fixed effect parameters.¦Conclusion: Imatinib PK was well described in a large cohort of CML patients under field conditions and results were concordant with previous studies. Patient characteristics explain only little IIV, confirming limited utility of prior dosage adjustment. As intra-variability is smaller than inter-patient variability, dose adjustment guided by TDM could however be beneficial in order to bring Cmin into a given therapeutic target.

A systematic review of glomerular hyperfiltration assessment and definition in the medical literature.

BACKGROUND AND OBJECTIVES: Evaluation of glomerular hyperfiltration (GH) is difficult; the variable reported definitions impede comparisons between studies. A clear and universal definition of GH would help in comparing results of trials aimed at reducing GH. This study assessed how GH is measured and defined in the literature. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Three databases (Embase, MEDLINE, CINAHL) were systematically searched using the terms "hyperfiltration" or "glomerular hyperfiltration". All studies reporting a GH threshold or studying the effect of a high GFR in a continuous manner against another outcome of interest were included. RESULTS: The literature search was performed from November 2012 to February 2013 and updated in August 2014. From 2013 retrieved studies, 405 studies were included. Threshold use to define GH was reported in 55.6% of studies. Of these, 88.4% used a single threshold and 11.6% used numerous thresholds adapted to participant sex or age. In 29.8% of the studies, the choice of a GH threshold was not based on a control group or literature references. After 2004, the use of GH threshold use increased (P<0.001), but the use of a control group to precisely define that GH threshold decreased significantly (P<0.001); the threshold did not differ among pediatric, adult, or mixed-age studies. The GH threshold ranged from 90.7 to 175 ml/min per 1.73 m(2) (median, 135 ml/min per 1.73 m(2)). CONCLUSION: Thirty percent of studies did not justify the choice of threshold values. The decrease of GFR in the elderly was rarely considered in defining GH. From a methodologic point of view, an age- and sex-matched control group should be used to define a GH threshold.

Ink dating using thermal desorption and gas chromatography / mass spectrometry: comparison of results obtained in two laboratories

Recent ink dating methods focused mainly on changes in solvent amounts occurring over time. A promising method was developed at the Landeskriminalamt of Munich using thermal desorption (TD) followed by gas chromatography / mass spectrometry (GC/MS) analysis. Sequential extractions of the phenoxyethanol present in ballpoint pen ink entries were carried out at two different temperatures. This method is applied in forensic practice and is currently implemented in several laboratories participating to the InCID group (International Collaboration on Ink Dating). However, harmonization of the method between the laboratories proved to be a particularly sensitive and time consuming task. The main aim of this work was therefore to implement the TD-GC/MS method at the Bundeskriminalamt (Wiesbaden, Germany) in order to evaluate if results were comparable to those obtained in Munich. At first validation criteria such as limits of reliable measurements, linearity and repeatability were determined. Samples were prepared in three different laboratories using the same inks and analyzed using two TDS-GC/MS instruments (one in Munich and one in Wiesbaden). The inter- and intra-laboratory variability of the ageing parameter was determined and ageing curves were compared. While inks stored in similar conditions yielded comparable ageing curves, it was observed that significantly different storage conditions had an influence on the resulting ageing curves. Finally, interpretation models, such as thresholds and trend tests, were evaluated and discussed in view of the obtained results. Trend tests were considered more suitable than threshold models. As both approaches showed limitations, an alternative model, based on the slopes of the ageing curves, was also proposed.

Cross-country differences in disclosure quality: a study of fair value disclosures by european real estate companies

Companies are under IAS 40 required to report fair values of investment properties on the balance sheet or to disclose them in the notes. The standard requires also that companies have to disclose the methods and significant assumptions applied in determining fair values of investment properties. However, IAS 40 does not include any illustrative examples or other guidance on how to apply the disclosure requirements. We use a sample with publicly traded companies from the real estate sector in the EU. We find that a majority of the companies use income based methods for the measurement of fair values but there are considerable cross-country variations in the level of disclosures about the assumptions used in determining fair values. More specifically, we find that Scandinavian and German origin companies disclose more than French and English origin companies. We also test whether disclosure quality is associated with enforcement quality measured with the “Rule of Law” index according to Kaufmann et al. (2010), and associated with a secrecy- versus transparency-measure based on Gray (1988). We find a positive association between disclosure and earnings quality and a negative association with secrecy.

Auditory stimulation does not induce implicit memory during anaesthesia

Background and aim of the study: Formation of implicit memory during general anaesthesia is still debated. Perceptual learning is the ability to learn to perceive. In this study, an auditory perceptual learning paradigm, using frequency discrimination, was performed to investigate the implicit memory. It was hypothesized that auditory stimulation would successfully induce perceptual learning. Thus, initial thresholds of the frequency discrimination postoperative task should be lower for the stimulated group (group S) compared to the control group (group C). Material and method: Eighty-seven patients ASA I-III undergoing visceral and orthopaedic surgery during general anaesthesia lasting more than 60 minutes were recruited. The anaesthesia procedure was standardized (BISR monitoring included). Group S received auditory stimulation (2000 pure tones applied for 45 minutes) during the surgery. Twenty-four hours after the operation, both groups performed ten blocks of the frequency discrimination task. Mean of the thresholds for the first three blocks (T1) were compared between groups. Results: Mean age and BIS value of group S and group C are respectively 40 } 11 vs 42 } 11 years (p = 0,49) and 42 } 6 vs 41 } 8 (p = 0.87). T1 is respectively 31 } 33 vs 28 } 34 (p = 0.72) in group S and C. Conclusion: In our study, no implicit memory during general anaesthesia was demonstrated. This may be explained by a modulation of the auditory evoked potentials caused by the anaesthesia, or by an insufficient longer time of repetitive stimulation to induce perceptual learning.

Taxometric analysis of DSM-IV and DSM-5 alcohol use disorders.

BACKGROUND: With preparations currently being made for the Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5), one prominent issue to resolve is whether alcohol use disorders are better represented as discrete categorical entities or as a dimensional construct. The purpose of this study was to investigate the latent structure of DSM-4th edition (DSM-IV) and proposed DSM-5 alcohol use disorders. METHODS: The study used the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) to conduct taxometric analyses of DSM-IV and DSM-5 alcohol use disorders defined by different thresholds to determine the taxonic or dimensional structure underlying the disorders. RESULTS: DSM-IV and DSM-5 alcohol abuse and dependence criteria with 3+ thresholds demonstrated a dimensional structure. Corresponding thresholds with 4+ criteria were clearly taxonic, as were thresholds defined by cut-offs of 5+ and 6+ criteria. CONCLUSIONS: DSM-IV and DSM-5 alcohol use disorders demonstrated a hybrid taxonic-dimensional structure. That is, DSM-IV and DSM-5 alcohol use disorders may be taxonically distinct compared to no disorder if defined by a threshold of 4 or more criteria. However, there may be dimensional variation remaining among non-problematic to subclinical cases. A careful and systematic program of structural research using taxometric and psychometric procedures is warranted.

Alcohol use and frailty in community-dwelling older persons aged 65 to 70 years.

Background: Alcohol use has beneficial as well as adverse consequences on health, but few studies examined its role in the development of age-related frailty. Objectives: To describe the cross-sectional and longitudinal association between alcohol intake and frailty in older persons. Design: The Lausanne cohort 65+ population-based study, launched in 2004. Setting: Community. Participants: One thousand five hundred sixty-four persons aged 65-70 years. Measurements: Annual data collection included demographics, health and functional status, extended by a physical examination every 3 years. Alcohol use (AUDIT-C), and Fried's frailty criteria were measured at baseline and 3-year follow-up. Participants were categorized into robust (0 frailty criterion) and vulnerable (1+ criteria). Results: Few participants (13.0%) reported no alcohol consumption over the past year, 57.8% were light-to-moderate drinkers, while 29.3% drank above recommended thresholds (18.7% "at risk" and 10.5% "heavy" drinkers). At baseline, vulnerability was most frequent in non-drinkers (43.0%), least frequent in light-to-moderate drinkers (26.2%), and amounted to 31.9% in "heavy" drinkers showing a reverse J-curve pattern. In multivariate analysis, compared to light-to-moderate drinkers, non-drinkers had twice higher odds of prevalent (adjOR: 2.24; 95%CI:1.39-3.59; p=.001), as well as 3-year incident vulnerability (adjOR: 2.00; 95%CI:1.02-3.91; p=.043). No significant association was observed among "at risk" and "heavy" drinkers. Conclusion: Non-drinkers had two-times higher odds of prevalent and 3-year incident vulnerability, even after adjusting for their baseline poorer health status. Although residual confounding is still possible, these results likely reflect a healthy survival effect among drinkers while those who experienced health- or alcohol-related problems stopped drinking earlier.

Practical Data Collection: Establishing Methods and Procedures for Measuring Water Clarity and Turbidity of Storm Water Run-Off from Active Major Highway Construction Sites, 2014

In anticipation of regulation involving numeric turbidity limit at highway construction sites, research was done into the most appropriate, affordable methods for surface water monitoring. Measuring sediment concentration in streams may be conducted a number of ways. As part of a project funded by the Iowa Department of Transportation, several testing methods were explored to determine the most affordable, appropriate methods for data collection both in the field and in the lab. The primary purpose of the research was to determine the exchangeability of the acrylic transparency tube for water clarity analysis as compared to the turbidimeter.

Surgical safety and hospital volume across a wide range of interventions

OBJECTIVES:: For certain major operations, inpatient mortality risk is lower in high-volume hospitals than those in low-volume hospitals. Extending the analysis to a broader range of interventions and outcomes is necessary before adopting policies based on minimum volume thresholds. METHODS:: Using the United States 2004 Nationwide Inpatient Sample, we assessed the effect of intervention-specific and overall hospital volume on surgical complications, potentially avoidable reoperations, and deaths across 1.4 million interventions in 353 hospitals. Outcome variations across hospitals were analyzed through a 3-level hierarchical logistic regression model (patients, surgical interventions, and hospitals), which took into account interventions on multiple organs, 144 intervention categories, and structural hospital characteristics. Discriminative performance and calibration were good. RESULTS:: Hospitals with more experience in a given intervention had similar reoperation rates but lower mortality and complication rates: odds ratio per volume deciles 0.93 and 0.97. However, the benefit was limited to heart surgery and a small number of other operations. Risks were higher for hospitals that performed more interventions overall: odds ratio per 1000 for each event was approximately 1.02. Even after adjustment for specific volume, mortality varied substantially across both high- and low-volume hospitals. CONCLUSION:: Although the link between specific volume and certain inpatient outcomes suggests that specialization might help improve surgical safety, the variable magnitude of this link and the heterogeneity of hospital effect do not support the systematic use of volume-based referrals. It may be more efficient to monitor risk-adjusted postoperative outcomes and to investigate facilities with worse than expected outcomes.

Profiling of steroid metabolites after transdermal and oral administration of testosterone by ultra-high pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

The screening of testosterone (T) misuse for doping control is based on the urinary steroid profile, including T, its precursors and metabolites. Modifications of individual levels and ratio between those metabolites are indicators of T misuse. In the context of screening analysis, the most discriminant criterion known to date is based on the T glucuronide (TG) to epitestosterone glucuronide (EG) ratio (TG/EG). Following the World Anti-Doping Agency (WADA) recommendations, there is suspicion of T misuse when the ratio reaches 4 or beyond. While this marker remains very sensitive and specific, it suffers from large inter-individual variability, with important influence of enzyme polymorphisms. Moreover, use of low dose or topical administration forms makes the screening of endogenous steroids difficult while the detection window no longer suits the doping habit. As reference limits are estimated on the basis of population studies, which encompass inter-individual and inter-ethnic variability, new strategies including individual threshold monitoring and alternative biomarkers were proposed to detect T misuse. The purpose of this study was to evaluate the potential of ultra-high pressure liquid chromatography (UHPLC) coupled with a new generation high resolution quadrupole time-of-flight mass spectrometer (QTOF-MS) to investigate the steroid metabolism after transdermal and oral T administration. An approach was developed to quantify 12 targeted urinary steroids as direct glucuro- and sulfo-conjugated metabolites, allowing the conservation of the phase II metabolism information, reflecting genetic and environmental influences. The UHPLC-QTOF-MS(E) platform was applied to clinical study samples from 19 healthy male volunteers, having different genotypes for the UGT2B17 enzyme responsible for the glucuroconjugation of T. Based on reference population ranges, none of the traditional markers of T misuse could detect doping after topical administration of T, while the detection window was short after oral TU ingestion. The detection ability of the 12 targeted steroids was thus evaluated by using individual thresholds following both transdermal and oral administration. Other relevant biomarkers and minor metabolites were studied for complementary information to the steroid profile, including sulfoconjugated analytes and hydroxy forms of glucuroconjugated metabolites. While sulfoconjugated steroids may provide helpful screening information for individuals with homozygotous UGT2B17 deletion, hydroxy-glucuroconjugated analytes could enhance the detection window of oral T undecanoate (TU) doping.

Médecine d'urgence [Emergency medicine: updates 2012].

We review some of the most influential papers from 2012 in the different aspects of emergency medicine, such as prehospital medicine, resuscitation, early diagnosis and timely ED discharge and treatment. In particular, intramuscular benzodiazepines have been shown to be efficient in prehospital status epilepticus, epinephrines usefulness in cardiopulmonary resuscitation has been challenged, colloids have been shown to be deleterious in the treatment of severe sepsis and septic shock, the time window for thrombolysis in acute stroke will probably be extended, acute pyelonephritis treatment duration can be decreased, new D-dimers thresholds for older patients may prevent further diagnosis tests, and hs-Troponin may allow earlier discharge of low coronary risk patients.

Evaluating spine micro-architectural texture (via TBS) discriminates major osteoporotic fractures from controls both as well as and independent of site matched BMD: the Eastern European TBS study.

The aim of the study was to assess the clinical performance of the model combining areal bone mineral density (aBMD) at spine and microarchitecural texture (TBS) for the detection of the osteoporotic fracture. The Eastern European Study is a multicenter study (Serbia, Bulgaria, Romania and Ukraine) evaluating the role of TBS in routine clinical practice as a complement to aBMD. All scans were acquired on Hologic Discovery and GE Prodigy densitometers in a routine clinical manner. The additional clinical values of aBMD and TBS were analyzed using a two steps classification tree approach (aBMD followed by TBS tertiles) for all type of osteoporotic fracture (All-OP Fx). Sensitivity, specificity and accuracy of fracture detection as well as the Net Reclassification Index (NRI) were calculated. This study involves 1031 women subjects aged 45 and older recruited in east European countries. Clinical centers were cross-calibrated in terms of BMD and TBS. As expected, areal BMD (aBMD) at spine and TBS were only moderately correlated (r (2) = 0.19). Prevalence rate for All-OP Fx was 26 %. Subjects with fracture have significant lower TBS and aBMD than subjects without fracture (p < 0.01). TBS remains associated with the fracture even after adjustment for age and aBMD with an OR of 1.27 [1.07-1.51]. When using aBMD T-score of -2.5 and the lowest TBS tertile thresholds, both BMD and TBS were similar in terms of sensitivity (35 vs. 39 %), specificity (78 vs. 80 %) and accuracy (64 vs. 66 %). aBMD and TBS combination, induced a significant improvement in sensitivity (+28 %) and accuracy (+17 %) compared to aBMD alone whereas a moderate improvement was observed in terms of specificity (+9 %). The overall combination gain was 36 % as expressed using the NRI. aBMD and TBS combination decrease significantly the number of subjects needed to diagnose from 7 for aBMD alone to 2. In a multi-centre Eastern European cohort, we have shown that the use of TBS in addition to the aBMD permit to reclassified correctly more than one-third of the overall subjects. Furthermore, the number of subjects needed to diagnose fell to 2 subjects. Economical studies have to be performed to evaluate the gain induced by the use of TBS for the healthcare system.

How to redesign a virtual library website: a case study

This abstract presents how we redesigned, with user-centred design methods, the way we organize and present the content on the UOC Virtual Library website. The content is now offered in a way that is more intuitive, usable and easy to understand, based on criteria of customization, transparency and proximity.The techniques used to achieve these objectives included benchmarking, interviews and focus groups during the user requirement capture phase and user tests to assess the process and results.