Functional calibration procedure for 3D knee joint angle description using inertial sensors.

Measurement of three-dimensional (3D) knee joint angle outside a laboratory is of benefit in clinical examination and therapeutic treatment comparison. Although several motion capture devices exist, there is a need for an ambulatory system that could be used in routine practice. Up-to-date, inertial measurement units (IMUs) have proven to be suitable for unconstrained measurement of knee joint differential orientation. Nevertheless, this differential orientation should be converted into three reliable and clinically interpretable angles. Thus, the aim of this study was to propose a new calibration procedure adapted for the joint coordinate system (JCS), which required only IMUs data. The repeatability of the calibration procedure, as well as the errors in the measurement of 3D knee angle during gait in comparison to a reference system were assessed on eight healthy subjects. The new procedure relying on active and passive movements reported a high repeatability of the mean values (offset<1 degrees) and angular patterns (SD<0.3 degrees and CMC>0.9). In comparison to the reference system, this functional procedure showed high precision (SD<2 degrees and CC>0.75) and moderate accuracy (between 4.0 degrees and 8.1 degrees) for the three knee angle. The combination of the inertial-based system with the functional calibration procedure proposed here resulted in a promising tool for the measurement of 3D knee joint angle. Moreover, this method could be adapted to measure other complex joint, such as ankle or elbow.

Diagnostic Accuracy of (18)F-FDG-PET and PET/CT in the Differential Diagnosis between Malignant and Benign Pleural Lesions: A Systematic Review and Meta-Analysis.

RATIONALE AND OBJECTIVES: To systematically review and meta-analyze published data about the diagnostic accuracy of fluorine-18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) and PET/computed tomography (CT) in the differential diagnosis between malignant and benign pleural lesions. METHODS AND MATERIALS: A comprehensive literature search of studies published through June 2013 regarding the diagnostic performance of (18)F-FDG-PET and PET/CT in the differential diagnosis of pleural lesions was carried out. All retrieved studies were reviewed and qualitatively analyzed. Pooled sensitivity, specificity, positive and negative likelihood ratio (LR+ and LR-) and diagnostic odds ratio (DOR) of (18)F-FDG-PET or PET/CT in the differential diagnosis of pleural lesions on a per-patient-based analysis were calculated. The area under the summary receiver operating characteristic curve (AUC) was calculated to measure the accuracy of these methods. Subanalyses considering device used (PET or PET/CT) were performed. RESULTS: Sixteen studies including 745 patients were included in the systematic review. The meta-analysis of 11 selected studies provided the following results: sensitivity 95% (95% confidence interval [95%CI]: 92-97%), specificity 82% (95%CI: 76-88%), LR+ 5.3 (95%CI: 2.4-11.8), LR- 0.09 (95%CI: 0.05-0.14), DOR 74 (95%CI: 34-161). The AUC was 0.95. No significant improvement of the diagnostic accuracy considering PET/CT studies only was found. CONCLUSIONS: (18)F-FDG-PET and PET/CT demonstrated to be accurate diagnostic imaging methods in the differential diagnosis between malignant and benign pleural lesions; nevertheless, possible sources of false-negative and false-positive results should be kept in mind.

β-Glucan Antigenemia Anticipates Diagnosis of Blood Culture-Negative Intraabdominal Candidiasis.

Rationale: Life-threatening intraabdominal candidiasis (IAC) occurs in 30 to 40% of high-risk surgical intensive care unit (ICU) patients. Although early IAC diagnosis is crucial, blood cultures are negative, and the role of Candida score/colonization indexes is not established. Objectives: The aim of this prospective Fungal Infection Network of Switzerland (FUNGINOS) cohort study was to assess accuracy of 1,3-β-d-glucan (BG) antigenemia for diagnosis of IAC. Methods: Four hundred thirty-four consecutive adults with abdominal surgery or acute pancreatitis and ICU stay 72 hours or longer were screened: 89 (20.5%) at high risk for IAC were studied (68 recurrent gastrointestinal tract perforation, 21 acute necrotizing pancreatitis). Diagnostic accuracy of serum BG (Fungitell), Candida score, and colonization indexes was compared. Measurements and Main Results: Fifty-eight of 89 (65%) patients were colonized by Candida; 29 of 89 (33%) presented IAC (27 of 29 with negative blood cultures). Nine hundred twenty-one sera were analyzed (9/patient): median BG was 253 pg/ml (46-9,557) in IAC versus 99 pg/ml (8-440) in colonization (P < 0.01). Sensitivity and specificity of two consecutive BG measurements greater than or equal to 80 pg/ml were 65 and 78%, respectively. In recurrent gastrointestinal tract perforation it was 75 and 77% versus 90 and 38% (Candida score ≥ 3), 79 and 34% (colonization index ≥ 0.5), and 54 and 63% (corrected colonization index ≥ 0.4), respectively. BG positivity anticipated IAC diagnosis (5 d) and antifungal therapy (6 d). Severe sepsis/septic shock and death occurred in 10 of 11 (91%) and 4 of 11 (36%) patients with BG 400 pg/ml or more versus 5 of 18 (28%, P = 0.002) and 1 of 18 (6%, P = 0.05) with BG measurement less than 400 pg/ml. β-Glucan decreased in IAC responding to therapy and increased in nonresponse. Conclusions: BG antigenemia is superior to Candida score and colonization indexes and anticipates diagnosis of blood culture-negative IAC. This proof-of-concept observation in strictly selected high-risk surgical ICU patients deserves investigation of BG-driven preemptive therapy.

Carotid-Subclavian Artery Index : Validation of an Echocardiographic Index to Detect Coarctation : P67

Introduction: Due to patency of the arterial duct and the parallel circulation during the fetal life, coarctation remains a difficult diagnosis prenatally and even shortly after birth. Fisrtly, our study aimed to assess accuracy of a new cardiographie index based on morphologie measurements of the distal aortic arch, the Carotid-Subclavian Artery Index (CSA Index), the ratio of the distal transverse aortic arch diameter to the distance between the left carotid artery and the left subclavian artery, in detecting coarctation in newborns, infants and children, independently of other cardiac lesions. Secondly, to assess the additive value of another morphologie index in predicting coarctation, the 1/0 ratio, the ratio of isthmus to descending aorta diameter. Methods: It is a retrospective cohort study in a tertiary care children's hospital. Offline echocardiographic measurements of great vessels and aortic arch dimensions were done in 69 patients with coarctation. We calculate their CSA index, and their 1/0 ratio. Values of CSA Index and 1/0 ratio from coarctation group were compared with those from a normal local control population. Results: 69 echocardiograms from patients with coarctation were analysed. Compared with controls, patients with coarctation had a significantly lower CSA index (0.88 ±0.49 vs 2.65 ±0.82, p <0.0001) and 1/0 ratio. The same significant difference was observed, independently of age and other associated defects, even complex ones. CSA Index confirmed its good sensitivity and specificity (99% and 96% respectively). This was not improved by adding the I/D ratio. Conclusions: An abnormal CSA index is highly suggestive of coarctation independently of age, of the presence of a patent ductus arteriosus or of other cardiac defects. The addition of another anatomie index, the I/D ratio, was not helpful in our study.

Effect of conditioned media, nutritive elements, and mitotic synchronization on the accuracy of the cytogenetic analysis in acute nonlymphocytic leukemia patients presenting with inv(16)/t(16;16) or t(15;17).

To improve the yield of the cytogenetic analysis in patients with acute nonlymphocytic leukemia (ANLL), six culture conditions for bone marrow or peripheral blood cells were tested in parallel. Two conditioned media (CM), phytohemagglutinin leukocyte PHA-LCM and 5637 CM, nutritive elements (NE), and methotrexate (MTX) cell synchronization were investigated in 14 patients presenting with either inv(16)/ t(16;16) (group 1, n = 9 patients) or t(15;17) (group 2, n = 5). The criteria used to identify the most favorable culture conditions were the mitotic index (MI), the morphological index (MorI), and the percentage of abnormal metaphases. In the presence of PHA-LCM and 5637 CM, the MI were significantly increased in group 2, whereas in the MTX conditions, MI remained very low in both groups. The values of the MorI did not reveal any significant changes in chromosome resolution between the conditions in either group. The addition of NE did not have a positive effect in quantity or quality of metaphases. Because of the variability of the response of leukemic cells to different stimulations in vitro, several culture conditions in parallel are required to ensure a satisfactory yield of the chromosome analysis in ANLL.

Sensitivity and specificity of NT-proBNP to detect heart failure at post mortem examination.

NT-proBNP, a marker of cardiac failure, has been shown to be stable in post mortem samples. The aim of this study was to assess the accuracy of NT-proBNP to detect heart failure in the forensic setting. One hundred sixty-eight consecutive autopsies were included in the study. NT-proBNP blood concentrations were measured using a chemiluminescent immunoassay kit. Cardiac failure was assessed by three independent forensic experts using macro- and microscopic findings complemented by information about the circumstances of body discovery and the known medical story. Area under the receiving operator curve was of 65.4% (CI 95%, from 57.1 to 73.7). Using a standard cut-off value of >220 pg/mL for NT-proBNP blood concentration, heart failure was detected with a sensitivity of 50.7% and a specificity of 72.6%. NT-proBNP vitreous humor values were well correlated to the ones measured in blood (r (2) = 0.658). Our results showed that NT-proBNP can corroborate the pathological findings in cases of natural death related to heart failure, thus, keeping its diagnostic properties passing from the ante mortem to the post mortem setting. Therefore, biologically inactive polypeptides like NT-proBNP seem to be stable enough to be used in forensic medicine as markers of cardiac failure, taking into account the sensitivity and specificity of the test.

Validity of an arterial pressure waveform analysis device: does the puncture site play a role in the agreement with intermittent pulmonary artery catheter thermodilution measurements?

OBJECTIVE: The measurement of cardiac output is a key element in the assessment of cardiac function. Recently, a pulse contour analysis-based device without need for calibration became available (FloTrac/Vigileo, Edwards Lifescience, Irvine, CA). This study was conducted to determine if there is an impact of the arterial catheter site and to investigate the accuracy of this system when compared with the pulmonary artery catheter using the bolus thermodilution technique (PAC). DESIGN: Prospective study. SETTING: The operating room of 1 university hospital. PARTICIPANTS: Twenty patients undergoing cardiac surgery. INTERVENTIONS: CO was determined in parallel by the use of the Flotrac/Vigileo systems in the radial and femoral position (CO_rad and CO_fem) and by PAC as the reference method. Data triplets were recorded at defined time points. The primary endpoint was the comparison of CO_rad and CO_fem, and the secondary endpoint was the comparison with the PAC. MEASUREMENTS AND MAIN RESULTS: Seventy-eight simultaneous data recordings were obtained. The Bland-Altman analysis for CO_fem and CO_rad showed a bias of 0.46 L/min, precision was 0.85 L/min, and the percentage error was 34%. The Bland-Altman analysis for CO_rad and PAC showed a bias of -0.35 L/min, the precision was 1.88 L/min, and the percentage error was 76%. The Bland-Altman analysis for CO_fem and PAC showed a bias of 0.11 L/min, the precision was 1.8 L/min, and the percentage error was 69%. CONCLUSION: The FloTrac/Vigileo system was shown to not produce exactly the same CO data when used in radial and femoral arteries, even though the percentage error was close to the clinically acceptable range. Thus, the impact of the introduction site of the arterial catheter is not negligible. The agreement with thermodilution was low.

An adaptive multiscale method for density-driven instabilities

Accurate modeling of flow instabilities requires computational tools able to deal with several interacting scales, from the scale at which fingers are triggered up to the scale at which their effects need to be described. The Multiscale Finite Volume (MsFV) method offers a framework to couple fine-and coarse-scale features by solving a set of localized problems which are used both to define a coarse-scale problem and to reconstruct the fine-scale details of the flow. The MsFV method can be seen as an upscaling-downscaling technique, which is computationally more efficient than standard discretization schemes and more accurate than traditional upscaling techniques. We show that, although the method has proven accurate in modeling density-driven flow under stable conditions, the accuracy of the MsFV method deteriorates in case of unstable flow and an iterative scheme is required to control the localization error. To avoid large computational overhead due to the iterative scheme, we suggest several adaptive strategies both for flow and transport. In particular, the concentration gradient is used to identify a front region where instabilities are triggered and an accurate (iteratively improved) solution is required. Outside the front region the problem is upscaled and both flow and transport are solved only at the coarse scale. This adaptive strategy leads to very accurate solutions at roughly the same computational cost as the non-iterative MsFV method. In many circumstances, however, an accurate description of flow instabilities requires a refinement of the computational grid rather than a coarsening. For these problems, we propose a modified iterative MsFV, which can be used as downscaling method (DMsFV). Compared to other grid refinement techniques the DMsFV clearly separates the computational domain into refined and non-refined regions, which can be treated separately and matched later. This gives great flexibility to employ different physical descriptions in different regions, where different equations could be solved, offering an excellent framework to construct hybrid methods.

Accuracy of prehospital triage of trauma patients by emergency physicians: a retrospective study in western Switzerland.

OBJECTIVE: Accurate identification of major trauma patients in the prehospital setting positively affects survival and resource utilization. Triage algorithms using predictive criteria of injury severity have been identified in paramedic-based prehospital systems. Our rescue system is based on prehospital paramedics and emergency physicians. The aim of this study was to evaluate the accuracy of the prehospital triage performed by physicians and to identify the predictive factors leading to errors of triage.METHODS: Retrospective study of trauma patients triaged by physicians. Prehospital triage was analyzed using criteria defining major trauma victims (MTVs, Injury Severity Score >15, admission to ICU, need for immediate surgery and death within 48 h). Adequate triage was defined as MTVs oriented to the trauma centre or non-MTV (NMTV) oriented to regional hospitals.RESULTS: One thousand six hundred and eighti-five patients (blunt trauma 96%) were included (558 MTV and 1127 NMTV). Triage was adequate in 1455 patients (86.4%). Overtriage occurred in 171 cases (10.1%) and undertriage in 59 cases (3.5%). Sensitivity and specificity was 90 and 85%, respectively, whereas positive predictive value and negative predictive value were 75 and 94%, respectively. Using logistic regression analysis, significant (P<0.05) predictors of undertriage were head or thorax injuries (odds ratio >2.5). Predictors of overtriage were paediatric age group, pedestrian or 2 wheel-vehicle road traffic accidents (odds ratio >2.0).CONCLUSION: Physicians using clinical judgement provide effective prehospital triage of trauma patients. Only a few factors predicting errors in triage process were identified in this study.

Niche, distribution and global change : modeling insights into biogeography and conservation biology Olivier Broennimann

RESUME Les évidences montrant que les changements globaux affectent la biodiversité s'accumulent. Les facteurs les plus influant dans ce processus sont les changements et destructions d'habitat, l'expansion des espèces envahissantes et l'impact des changements climatiques. Une évaluation pertinente de la réponse des espèces face à ces changements est essentielle pour proposer des mesures permettant de réduire le déclin actuel de la biodiversité. La modélisation de la répartition d'espèces basée sur la niche (NBM) est l'un des rares outils permettant cette évaluation. Néanmoins, leur application dans le contexte des changements globaux repose sur des hypothèses restrictives et demande une interprétation critique. Ce travail présente une série d'études de cas investiguant les possibilités et limitations de cette approche pour prédire l'impact des changements globaux. Deux études traitant des menaces sur les espèces rares et en danger d'extinction sont présentées. Les caractéristiques éco-géographiques de 118 plantes avec un haut degré de priorité de conservation sont revues. La prévalence des types de rareté sont analysées en relation avec leur risque d'extinction UICN. La revue souligne l'importance de la conservation à l'échelle régionale. Une évaluation de la rareté à échelle globale peut être trompeuse pour certaine espèces car elle ne tient pas en compte des différents degrés de rareté que présente une espèce à différentes échelles spatiales. La deuxième étude test une approche pour améliorer l'échantillonnage d'espèces rares en incluant des phases itératives de modélisation et d'échantillonnage sur le terrain. L'application de l'approche en biologie de la conservation (illustrée ici par le cas du chardon bleu, Eryngium alpinum), permettrait de réduire le temps et les coûts d'échantillonnage. Deux études sur l'impact des changements climatiques sur la faune et la flore africaine sont présentées. La première étude évalue la sensibilité de 227 mammifères africains face aux climatiques d'ici 2050. Elle montre qu'un nombre important d'espèces pourrait être bientôt en danger d'extinction et que les parcs nationaux africains (principalement ceux situé en milieux xériques) pourraient ne pas remplir leur mandat de protection de la biodiversité dans le futur. La seconde étude modélise l'aire de répartition en 2050 de 975 espèces de plantes endémiques du sud de l'Afrique. L'étude propose l'inclusion de méthodes améliorant la prédiction des risques liés aux changements climatiques. Elle propose également une méthode pour estimer a priori la sensibilité d'une espèce aux changements climatiques à partir de ses propriétés écologiques et des caractéristiques de son aire de répartition. Trois études illustrent l'utilisation des modèles dans l'étude des invasions biologiques. Une première étude relate l'expansion de la laitue sáuvage (Lactuca serriola) vers le nord de l'Europe en lien avec les changements du climat depuis 250 ans. La deuxième étude analyse le potentiel d'invasion de la centaurée tachetée (Centaures maculosa), une mauvaise herbe importée en Amérique du nord vers 1890. L'étude apporte la preuve qu'une espèce envahissante peut occuper une niche climatique différente après introduction sur un autre continent. Les modèles basés sur l'aire native prédisent de manière incorrecte l'entier de l'aire envahie mais permettent de prévoir les aires d'introductions potentielles. Une méthode alternative, incluant la calibration du modèle à partir des deux aires où l'espèce est présente, est proposée pour améliorer les prédictions de l'invasion en Amérique du nord. Je présente finalement une revue de la littérature sur la dynamique de la niche écologique dans le temps et l'espace. Elle synthétise les récents développements théoriques concernant le conservatisme de la niche et propose des solutions pour améliorer la pertinence des prédictions d'impact des changements climatiques et des invasions biologiques. SUMMARY Evidences are accumulating that biodiversity is facing the effects of global change. The most influential drivers of change in ecosystems are land-use change, alien species invasions and climate change impacts. Accurate projections of species' responses to these changes are needed to propose mitigation measures to slow down the on-going erosion of biodiversity. Niche-based models (NBM) currently represent one of the only tools for such projections. However, their application in the context of global changes relies on restrictive assumptions, calling for cautious interpretations. In this thesis I aim to assess the effectiveness and shortcomings of niche-based models for the study of global change impacts on biodiversity through the investigation of specific, unsolved limitations and suggestion of new approaches. Two studies investigating threats to rare and endangered plants are presented. I review the ecogeographic characteristic of 118 endangered plants with high conservation priority in Switzerland. The prevalence of rarity types among plant species is analyzed in relation to IUCN extinction risks. The review underlines the importance of regional vs. global conservation and shows that a global assessment of rarity might be misleading for some species because it can fail to account for different degrees of rarity at a variety of spatial scales. The second study tests a modeling framework including iterative steps of modeling and field surveys to improve the sampling of rare species. The approach is illustrated with a rare alpine plant, Eryngium alpinum and shows promise for complementing conservation practices and reducing sampling costs. Two studies illustrate the impacts of climate change on African taxa. The first one assesses the sensitivity of 277 mammals at African scale to climate change by 2050 in terms of species richness and turnover. It shows that a substantial number of species could be critically endangered in the future. National parks situated in xeric ecosystems are not expected to meet their mandate of protecting current species diversity in the future. The second study model the distribution in 2050 of 975 endemic plant species in southern Africa. The study proposes the inclusion of new methodological insights improving the accuracy and ecological realism of predictions of global changes studies. It also investigates the possibility to estimate a priori the sensitivity of a species to climate change from the geographical distribution and ecological proprieties of the species. Three studies illustrate the application of NBM in the study of biological invasions. The first one investigates the Northwards expansion of Lactuca serriola L. in Europe during the last 250 years in relation with climate changes. In the last two decades, the species could not track climate change due to non climatic influences. A second study analyses the potential invasion extent of spotted knapweed, a European weed first introduced into North America in the 1890s. The study provides one of the first empirical evidence that an invasive species can occupy climatically distinct niche spaces following its introduction into a new area. Models fail to predict the current full extent of the invasion, but correctly predict areas of introduction. An alternative approach, involving the calibration of models with pooled data from both ranges, is proposed to improve predictions of the extent of invasion on models based solely on the native range. I finally present a review on the dynamic nature of ecological niches in space and time. It synthesizes the recent theoretical developments to the niche conservatism issues and proposes solutions to improve confidence in NBM predictions of the impacts of climate change and species invasions on species distributions.

Test result-based sampling: an efficient design for estimating the accuracy of patient safety indicators.

OBJECTIVE: Accuracy studies of Patient Safety Indicators (PSIs) are critical but limited by the large samples required due to low occurrence of most events. We tested a sampling design based on test results (verification-biased sampling [VBS]) that minimizes the number of subjects to be verified. METHODS: We considered 3 real PSIs, whose rates were calculated using 3 years of discharge data from a university hospital and a hypothetical screen of very rare events. Sample size estimates, based on the expected sensitivity and precision, were compared across 4 study designs: random and VBS, with and without constraints on the size of the population to be screened. RESULTS: Over sensitivities ranging from 0.3 to 0.7 and PSI prevalence levels ranging from 0.02 to 0.2, the optimal VBS strategy makes it possible to reduce sample size by up to 60% in comparison with simple random sampling. For PSI prevalence levels below 1%, the minimal sample size required was still over 5000. CONCLUSIONS: Verification-biased sampling permits substantial savings in the required sample size for PSI validation studies. However, sample sizes still need to be very large for many of the rarer PSIs.

Sensitive determination of D-lactic acid and L-lactic acid in urine by high-performance liquid chromatography-tandem mass spectrometry.

D-lactic acid in urine originates mainly from bacterial production in the intestinal tract. Increased D-lactate excretion as observed in patients affected by short bowel syndrome or necrotizing enterocolitis reflects D-lactic overproduction. Therefore, there is a need for a reliable and sensitive method able to detect D-lactic acid even at subclinical elevation levels. A new and highly sensitive method for the simultaneous determination of L- and D-lactic acid by a two-step procedure has been developed. This method is based on the concentration of lactic acid enantiomers from urine by supported liquid extraction followed by high-performance liquid chromatography-tandem mass spectrometry. The separation was achieved by the use of an Astec Chirobiotic? R chiral column under isocratic conditions. The calibration curves were linear over the ranges of 2-400 and 0.5-100 µmol/L respectively for L- and D-lactic acid. The limit of detection of D-lactic acid was 0.125 µmol/L and its limit of quantification was 0.5 µmol/L. The overall accuracy and precision were well within 10% of the nominal values. The developed method is suitable for production of reference values in children and could be applied for accurate routine analysis.

Factor structure of early smoking experiences and associations with smoking behavior: valence or sensitivity model?

The Early Smoking Experience (ESE) questionnaire is the most widely used questionnaire to assess initial subjective experiences of cigarette smoking. However, its factor structure is not clearly defined and can be perceived from two main standpoints: valence, or positive and negative experiences, and sensitivity to nicotine. This article explores the ESE's factor structure and determines which standpoint was more relevant. It compares two groups of young Swiss men (German- and French-speaking). We examined baseline data on 3,368 tobacco users from a representative sample in the ongoing Cohort Study on Substance Use Risk Factors (C-SURF). ESE, continued tobacco use, weekly smoking and nicotine dependence were assessed. Exploratory structural equation modeling (ESEM) and structural equation modeling (SEM) were performed. ESEM clearly distinguished positive experiences from negative experiences, but negative experiences were divided in experiences related to dizziness and experiences related to irritations. SEM underlined the reinforcing effects of positive experiences, but also of experiences related to dizziness on nicotine dependence and weekly smoking. The best ESE structure for predictive accuracy of experiences on smoking behavior was a compromise between the valence and sensitivity standpoints, which showed clinical relevance.

Neutral and selection-driven decay of sexual traits in asexual stick insects.

Environmental shifts and lifestyle changes may result in formerly adaptive traits becoming non-functional or maladaptive. The subsequent decay of such traits highlights the importance of natural selection for adaptations, yet its causes have rarely been investigated. To study the fate of formerly adaptive traits after lifestyle changes, we evaluated sexual traits in five independently derived asexual lineages, including traits that are specific to males and therefore not exposed to selection. At least four of the asexual lineages retained the capacity to produce males that display normal courtship behaviours and are able to fertilize eggs of females from related sexual species. The maintenance of male traits may stem from pleiotropy, or from these traits only regressing via drift, which may require millions of years to generate phenotypic effects. By contrast, we found parallel decay of sexual traits in females. Asexual females produced altered airborne and contact signals, had modified sperm storage organs, and lost the ability to fertilize their eggs, impeding reversals to sexual reproduction. Female sexual traits were decayed even in recently derived asexuals, suggesting that trait changes following the evolution of asexuality, when they occur, proceed rapidly and are driven by selective processes rather than drift.

Determination of the Enantiomers of Mianserin and its Metabolites in Plasma by Capillary Electrophoresis After Liquid-Liquid Extraction and On-Column Sample Preconcentration

Capillary electrophoresis has drawn considerable attention in the past few years, particularly in the field of chiral separations because of its high separation efficiency. However, its routine use in therapeutic drug monitoring is hampered by its low sensitivity due to a short optical path. We have developed a capillary zone electrophoresis (CZE) method using 2mM of hydroxypropyl-β-cyclodextrin as a chiral selector, which allows base-to-base separation of the enantiomers of mianserin (MIA), desmethylmianserin (DMIA), and 8-hydroxymianserin (OHMIA). Through the use of an on-column sample concentration step after liquid-liquid extraction from plasma and through the presence of an internal standard, the quantitation limits were found to be 5 ng/mL for each enantiomer of MIA and DMIA and 15 ng/mL for each enantiomer of OHMIA. To our knowledge, this is the first published CE method that allows its use for therapeutic monitoring of antidepressants due to its sensitivity down to the low nanogram range. The variability of the assays, as assessed by the coefficients of variation (CV) measured at two concentrations for each substance, ranged from 2 to 14% for the intraday (eight replicates) and from 5 to 14% for the interday (eight replicates) experiments. The deviations from the theoretical concentrations, which represent the accuracy of the method, were all within 12.5%. A linear response was obtained for all compounds within the range of concentrations used for the calibration curves (10-150 ng/mL for each enantiomer of MIA and DMIA and 20-300 ng/mL for each enantiomer of OHMIA). Good correlations were calculated between [(R) + (S)]-MIA and DMIA concentrations measured in plasma samples of 20 patients by a nonchiral gas chromatography method and CZE, and between the (R)- and (S)-concentrations of MIA and DMIA measured in plasma samples of 37 patients by a previously described chiral high-performance liquid chromatography method and CZE. Finally, no interference was noted from more than 20 other psychotropic drugs. Thus, this method, which is both sensitive and selective, can be routinely used for therapeutic monitoring of the enantiomers of MIA and its metabolites. It could be very useful due to the demonstrated interindividual variability of the stereoselective metabolism of MIA.