Limited sampling strategies for estimation of cyclosporine exposure in pediatric hematopoietic stem cell transplant recipients : methodological improvement and introduction of sampling time deviation analysis.

Le suivi thérapeutique est recommandé pour l’ajustement de la dose des agents immunosuppresseurs. La pertinence de l’utilisation de la surface sous la courbe (SSC) comme biomarqueur dans l’exercice du suivi thérapeutique de la cyclosporine (CsA) dans la transplantation des cellules souches hématopoïétiques est soutenue par un nombre croissant d’études. Cependant, pour des raisons intrinsèques à la méthode de calcul de la SSC, son utilisation en milieu clinique n’est pas pratique. Les stratégies d’échantillonnage limitées, basées sur des approches de régression (R-LSS) ou des approches Bayésiennes (B-LSS), représentent des alternatives pratiques pour une estimation satisfaisante de la SSC. Cependant, pour une application efficace de ces méthodologies, leur conception doit accommoder la réalité clinique, notamment en requérant un nombre minimal de concentrations échelonnées sur une courte durée d’échantillonnage. De plus, une attention particulière devrait être accordée à assurer leur développement et validation adéquates. Il est aussi important de mentionner que l’irrégularité dans le temps de la collecte des échantillons sanguins peut avoir un impact non-négligeable sur la performance prédictive des R-LSS. Or, à ce jour, cet impact n’a fait l’objet d’aucune étude. Cette thèse de doctorat se penche sur ces problématiques afin de permettre une estimation précise et pratique de la SSC. Ces études ont été effectuées dans le cadre de l’utilisation de la CsA chez des patients pédiatriques ayant subi une greffe de cellules souches hématopoïétiques. D’abord, des approches de régression multiple ainsi que d’analyse pharmacocinétique de population (Pop-PK) ont été utilisées de façon constructive afin de développer et de valider adéquatement des LSS. Ensuite, plusieurs modèles Pop-PK ont été évalués, tout en gardant à l’esprit leur utilisation prévue dans le contexte de l’estimation de la SSC. Aussi, la performance des B-LSS ciblant différentes versions de SSC a également été étudiée. Enfin, l’impact des écarts entre les temps d’échantillonnage sanguins réels et les temps nominaux planifiés, sur la performance de prédiction des R-LSS a été quantifié en utilisant une approche de simulation qui considère des scénarios diversifiés et réalistes représentant des erreurs potentielles dans la cédule des échantillons sanguins. Ainsi, cette étude a d’abord conduit au développement de R-LSS et B-LSS ayant une performance clinique satisfaisante, et qui sont pratiques puisqu’elles impliquent 4 points d’échantillonnage ou moins obtenus dans les 4 heures post-dose. Une fois l’analyse Pop-PK effectuée, un modèle structural à deux compartiments avec un temps de délai a été retenu. Cependant, le modèle final - notamment avec covariables - n’a pas amélioré la performance des B-LSS comparativement aux modèles structuraux (sans covariables). En outre, nous avons démontré que les B-LSS exhibent une meilleure performance pour la SSC dérivée des concentrations simulées qui excluent les erreurs résiduelles, que nous avons nommée « underlying AUC », comparée à la SSC observée qui est directement calculée à partir des concentrations mesurées. Enfin, nos résultats ont prouvé que l’irrégularité des temps de la collecte des échantillons sanguins a un impact important sur la performance prédictive des R-LSS; cet impact est en fonction du nombre des échantillons requis, mais encore davantage en fonction de la durée du processus d’échantillonnage impliqué. Nous avons aussi mis en évidence que les erreurs d’échantillonnage commises aux moments où la concentration change rapidement sont celles qui affectent le plus le pouvoir prédictif des R-LSS. Plus intéressant, nous avons mis en exergue que même si différentes R-LSS peuvent avoir des performances similaires lorsque basées sur des temps nominaux, leurs tolérances aux erreurs des temps d’échantillonnage peuvent largement différer. En fait, une considération adéquate de l'impact de ces erreurs peut conduire à une sélection et une utilisation plus fiables des R-LSS. Par une investigation approfondie de différents aspects sous-jacents aux stratégies d’échantillonnages limités, cette thèse a pu fournir des améliorations méthodologiques notables, et proposer de nouvelles voies pour assurer leur utilisation de façon fiable et informée, tout en favorisant leur adéquation à la pratique clinique.

Quantifying nitrous oxide emissions from sugarcane cropping systems : Optimum sampling time and frequency

Nitrous oxide (N2O) emissions from soil are often measured using the manual static chamber method. Manual gas sampling is labour intensive, so a minimal sampling frequency that maintains the accuracy of measurements would be desirable. However, the high temporal (diurnal, daily and seasonal) variabilities of N2O emissions can compromise the accuracy of measurements if not addressed adequately when formulating a sampling schedule. Assessments of sampling strategies to date have focussed on relatively low emission systems with high episodicity, where a small number of the highest emission peaks can be critically important in the measurement of whole season cumulative emissions. Using year-long, automated sub-daily N2O measurements from three fertilised sugarcane fields, we undertook an evaluation of the optimum gas sampling strategies in high emission systems with relatively long emission episodes. The results indicated that sampling in the morning between 09:00–12:00, when soil temperature was generally close to the daily average, best approximated the daily mean N2O emission within 4–7% of the ‘actual’ daily emissions measured by automated sampling. Weekly sampling with biweekly sampling for one week after >20 mm of rainfall was the recommended sampling regime. It resulted in no extreme (>20%) deviations from the ‘actuals’, had a high probability of estimating the annual cumulative emissions within 10% precision, with practicable sampling numbers in comparison to other sampling regimes. This provides robust and useful guidance for manual gas sampling in sugarcane cropping systems, although further adjustments by the operators in terms of expected measurement accuracy and resource availability are encouraged. By implementing these sampling strategies together, labour inputs and errors in measured cumulative N2O emissions can be minimised. Further research is needed to quantify the spatial variability of N2O emissions within sugarcane cropping and to develop techniques for effectively addressing both spatial and temporal variabilities simultaneously.

Suboptimal filtering and nonlinear time scale transformation for the analysis of multiexponential decays

Multiexponential decays may contain time-constants differing in several orders of magnitudes. In such cases, uniform sampling results in very long records featuring a high degree of oversampling at the final part of the transient. Here, we analyze a nonlinear time scale transformation to reduce the total number of samples with minimum signal distortion, achieving an important reduction of the computational cost of subsequent analyses. We propose a time-varying filter whose length is optimized for minimum mean square error

Quality characteristics of Moroccan sweet paprika (Capsicum annuum L.) at different sampling times

"La Niora" is a red pepper variety cultivated in Tadla Region (Morocco) which is used for manufacturing paprika after sun drying. The paprika quality (nutritional, chemical and microbiological) was evaluated immediately after milling, from September to December. Sampling time mainly affected paprika color and the total capsaicinoid and vitamin C contents. The commercial quality was acceptable and no aflatoxins were found, but the microbial load sometimes exceeded permitted levels.

Sliding mode for detection and accommodation of computation time delay fault

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Linear matrix inequality-based robust model predictive control for time-delayed systems

This work addresses the solution to the problem of robust model predictive control (MPC) of systems with model uncertainty. The case of zone control of multi-variable stable systems with multiple time delays is considered. The usual approach of dealing with this kind of problem is through the inclusion of non-linear cost constraint in the control problem. The control action is then obtained at each sampling time as the solution to a non-linear programming (NLP) problem that for high-order systems can be computationally expensive. Here, the robust MPC problem is formulated as a linear matrix inequality problem that can be solved in real time with a fraction of the computer effort. The proposed approach is compared with the conventional robust MPC and tested through the simulation of a reactor system of the process industry.

(Table 1) Surface water chemistry of northern Victoria Land lakes

Concentrations of major ions, silicate and nutrients (total N and P) were measured in samples of surface water from 28 lakes in ice-free areas of northern Victoria Land (East Antarctica). Sixteen lakes were sampled during austral summers 2001/02, 2003/04, 2004/05 and 2005/06 to assess temporal variation in water chemistry. Although samples showed a wide range in ion concentrations, their composition mainly reflected that of seawater. In general, as the distance from the sea increased, the input of elements from the marine environment (through aerosols and seabirds) decreased and there was an increase in nitrate and sulfate concentrations. Antarctic lakes lack outflows and during the austral summer the melting and/or ablation of ice cover, water evaporation and leaching processes in dry soils determine a progressive increase in water ion concentrations. During the five-year monitoring survey, no statistically significant variation in the water chemistry were detected, except for a slight (hardly significant) increase in TN concentrations. However, Canonical Correspondence Analysis (CCA) indicated that other factors besides distance from the sea, the presence of nesting seabirds, the sampling time and percentage of ice cover affect the composition of water in Antarctic cold desert environments.

Chemistry of hot waters sampled from basaltic basement at DSDP Hole 83-504B

Seawater that has been altered by reaction with basaltic basement has been sampled from Deep Sea Drilling Project Hole 504B, located on 5.9-m.y.-old crust on the southern flank of the Costa Rica Rift. Fourteen water samples have been collected on Legs 69, 70, and 83, both before and after renewed drilling on the latter two legs, at temperatures from 69 to 133°C and pressures from 390 to 425 bars. The water sampled prior to renewed drilling on Leg 83 had occupied the hole for nearly 2 yr. since it was last flushed with surface seawater at the end of Leg 70. Despite some contamination by seawater during sampling, the composition of two of these waters has been determined by using nitrate as a tag for the contaminant. Both the 80 and 115°C waters have seawater chlorinity, but have lost considerable Mg, Na, K, sulfate, and 02, and have gained Ca, alkalinity, Si, NH3 and H2S. The loss of sulfate is due to anhydrite precipitation, as indicated by the d34S value of the remaining dissolved sulfate. The 87Sr/86Sr ratio has been lowered to 0.7086 for the 80°C water and 0.7078 for the 115°C water, whereas the Sr concentration is nearly unchanged. The changes in major element composition relative to seawater are also larger for the 115°C water, indicating that the basement formation water at this site probably varies in composition with depth. Based on their direction relative to seawater, the compositional changes for the 80 and 115°C waters do not complement the changes inferred for the altered rocks from Hole 504B, suggesting that the bulk composition of the altered rocks, like their mineralogy, is largely unrelated to the present thermal and alteration regime in the hole. The exact nature of the reacted seawaters cannot be determined yet, however. During its 2 yr. residence in the hole, the surface seawater remaining at the end of Leg 70 would have reacted with the wall rocks and exchanged with their interstitial formation waters by diffusion and possibly convection. How far these processes have proceeded is not yet certain, although calculations suggest that diffusion alone could have largely exchanged the surface seawater for interstitial water. The d18O of the samples is indistinguishable from seawater, however, and the d14C of the 80°C sample is similar to that of ocean bottom water. Although the interpretation of these species is ambiguous, that of tritium should not be. Tritium analyses, which are in progress, should clarify the nature of the reacted seawaters obtained from the hole.

Growth, survival, gene expression, microbiota and tryptic activity during feeding of Scophthalmus maximus first feeding larvae with beta-glucan (MacroGard)

Reflecting the natural biology of mass spawning fish aquaculture production of fish larvae is often hampered by high and unpredictable mortality rates. The present study aimed to enhance larval performance and immunity via the oral administration of an immunomodulator, beta-glucan (MacroGard®) in turbot (Scophthalmus maximus). Rotifers (Brachionus plicatilis) were incubated with or without yeast beta-1,3/1,6-glucan in form of MacroGard® at a concentration of 0.5 g/L. Rotifers were fed to first feeding turbot larvae once a day. From day 13 dph onwards all tanks were additionally fed untreated Artemia sp. nauplii (1 nauplius ml/L). Daily mortality was monitored and larvae were sampled at 11 and 24 dph for expression of 30 genes, trypsin activity and size measurements. Along with the feeding of beta-glucan daily mortality was significantly reduced by ca. 15% and an alteration of the larval microbiota was observed. At 11 dph gene expression of trypsin and chymotrypsin was elevated in the MacroGard® fed fish, which resulted in heightened tryptic enzyme activity. No effect on genes encoding antioxidative proteins was observed, whilst the immune response was clearly modulated by beta-glucan. At 11 dph complement component c3 was elevated whilst cytokines, antimicrobial peptides, toll like receptor 3 and heat shock protein 70 were not affected. At the later time point (24 dph) an anti-inflammatory effect in form of a down-regulation of hsp 70, tnf-alpha and il-1beta was observed. We conclude that the administration of beta-glucan induced an immunomodulatory response and could be used as an effective measure to increase survival in rearing of turbot.

Sampling times for monitoring tacrolimus in stable adult liver transplant recipients

The aim of this study was to determine the most informative sampling time(s) providing a precise prediction of tacrolimus area under the concentration-time curve (AUC). Fifty-four concentration-time profiles of tacrolimus from 31 adult liver transplant recipients were analyzed. Each profile contained 5 tacrolimus whole-blood concentrations (predose and 1, 2, 4, and 6 or 8 hours postdose), measured using liquid chromatography-tandem mass spectrometry. The concentration at 6 hours was interpolated for each profile, and 54 values of AUC(0-6) were calculated using the trapezoidal rule. The best sampling times were then determined using limited sampling strategies and sensitivity analysis. Linear mixed-effects modeling was performed to estimate regression coefficients of equations incorporating each concentration-time point (C0, C1, C2, C4, interpolated C5, and interpolated C6) as a predictor of AUC(0-6). Predictive performance was evaluated by assessment of the mean error (ME) and root mean square error (RMSE). Limited sampling strategy (LSS) equations with C2, C4, and C5 provided similar results for prediction of AUC(0-6) (R-2 = 0.869, 0.844, and 0.832, respectively). These 3 time points were superior to C0 in the prediction of AUC. The ME was similar for all time points; the RMSE was smallest for C2, C4, and C5. The highest sensitivity index was determined to be 4.9 hours postdose at steady state, suggesting that this time point provides the most information about the AUC(0-12). The results from limited sampling strategies and sensitivity analysis supported the use of a single blood sample at 5 hours postdose as a predictor of both AUC(0-6) and AUC(0-12). A jackknife procedure was used to evaluate the predictive performance of the model, and this demonstrated that collecting a sample at 5 hours after dosing could be considered as the optimal sampling time for predicting AUC(0-6).

High resolution optical time-domain reflectometry based on correlation utilizing an all-fiber chaotic source

We propose a high-resolution optical time domain reflectometry (OTDR) based on an all-fiber supercontinuum source. The source simply consists of a laser with moderate power and a section of fiber which has a zero dispersion wavelength near the laser's central wavelength. Spectrum and time domain properties of the source are investigated, showing that the source has great capability in nonlinear optics, such as correlation OTDR. We analyze one of the key factors limiting the operational range of such an OTDR, i.e., sampling time. Finally, we experimentally demonstrate a correlation OTDR with 25km sensing range and 5.3cm spatial resolution, as a verification of theoretical analysis.

Improved dynamic headspace sampling and detection using capillary microextraction of volatiles coupled to gas chromatography mass spectrometry

Sampling and preconcentration techniques play a critical role in headspace analysis in analytical chemistry. My dissertation presents a novel sampling design, capillary microextraction of volatiles (CMV), that improves the preconcentration of volatiles and semivolatiles in a headspace with high throughput, near quantitative analysis, high recovery and unambiguous identification of compounds when coupled to mass spectrometry. The CMV devices use sol-gel polydimethylsiloxane (PDMS) coated microglass fibers as the sampling/preconcentration sorbent when these fibers are stacked into open-ended capillary tubes. The design allows for dynamic headspace sampling by connecting the device to a hand-held vacuum pump. The inexpensive device can be fitted into a thermal desorption probe for thermal desorption of the extracted volatile compounds into a gas chromatography-mass spectrometer (GC-MS). The performance of the CMV devices was compared with two other existing preconcentration techniques, solid phase microextraction (SPME) and planar solid phase microextraction (PSPME). Compared to SPME fibers, the CMV devices have an improved surface area and phase volume of 5000 times and 80 times, respectively. One (1) minute dynamic CMV air sampling resulted in similar performance as a 30 min static extraction using a SPME fiber. The PSPME devices have been fashioned to easily interface with ion mobility spectrometers (IMS) for explosives or drugs detection. The CMV devices are shown to offer dynamic sampling and can now be coupled to COTS GC-MS instruments. Several compound classes representing explosives have been analyzed with minimum breakthrough even after a 60 min. sampling time. The extracted volatile compounds were retained in the CMV devices when preserved in aluminum foils after sampling. Finally, the CMV sampling device were used for several different headspace profiling applications which involved sampling a shipping facility, six illicit drugs, seven military explosives and eighteen different bacteria strains. Successful detection of the target analytes at ng levels of the target signature volatile compounds in these applications suggests that the CMV devices can provide high throughput qualitative and quantitative analysis with high recovery and unambiguous identification of analytes.

Evaluation of non-contact sampling and detection of explosives using receiver operating characteristic curves

The growing need for fast sampling of explosives in high throughput areas has increased the demand for improved technology for the trace detection of illicit compounds. Detection of the volatiles associated with the presence of the illicit compounds offer a different approach for sensitive trace detection of these compounds without increasing the false positive alarm rate. This study evaluated the performance of non-contact sampling and detection systems using statistical analysis through the construction of Receiver Operating Characteristic (ROC) curves in real-world scenarios for the detection of volatiles in the headspace of smokeless powder, used as the model system for generalizing explosives detection. A novel sorbent coated disk coined planar solid phase microextraction (PSPME) was previously used for rapid, non-contact sampling of the headspace containers. The limits of detection for the PSPME coupled to IMS detection was determined to be 0.5-24 ng for vapor sampling of volatile chemical compounds associated with illicit compounds and demonstrated an extraction efficiency of three times greater than other commercially available substrates, retaining >50% of the analyte after 30 minutes sampling of an analyte spike in comparison to a non-detect for the unmodified filters. Both static and dynamic PSPME sampling was used coupled with two ion mobility spectrometer (IMS) detection systems in which 10-500 mg quantities of smokeless powders were detected within 5-10 minutes of static sampling and 1 minute of dynamic sampling time in 1-45 L closed systems, resulting in faster sampling and analysis times in comparison to conventional solid phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) analysis. Similar real-world scenarios were sampled in low and high clutter environments with zero false positive rates. Excellent PSPME-IMS detection of the volatile analytes were visualized from the ROC curves, resulting with areas under the curves (AUC) of 0.85-1.0 and 0.81-1.0 for portable and bench-top IMS systems, respectively. Construction of ROC curves were also developed for SPME-GC-MS resulting with AUC of 0.95-1.0, comparable with PSPME-IMS detection. The PSPME-IMS technique provides less false positive results for non-contact vapor sampling, cutting the cost and providing an effective sampling and detection needed in high-throughput scenarios, resulting in similar performance in comparison to well-established techniques with the added advantage of fast detection in the field.

Assessment of the cortisol awakening response: Real-time analysis and curvilinear effects of sample timing inaccuracy

The cortisol awakening response (CAR) is typically measured in the domestic setting. Moderate sample timing inaccuracy has been shown to result in erroneous CAR estimates and such inaccuracy has been shown partially to explain inconsistency in the CAR literature. The need for more reliable measurement of the CAR has recently been highlighted in expert consensus guidelines where it was pointed out that less than 6% of published studies provided electronic-monitoring of saliva sampling time in the post-awakening period. Analyses of a merged data-set of published studies from our laboratory are presented. To qualify for selection, both time of awakening and collection of the first sample must have been verified by electronic-monitoring and sampling commenced within 15 min of awakening. Participants (n = 128) were young (median age of 20 years) and healthy. Cortisol values were determined in the 45 min post-awakening period on 215 sampling days. On 127 days, delay between verified awakening and collection of the first sample was less than 3 min (‘no delay’ group); on 45 days there was a delay of 4–6 min (‘short delay’ group); on 43 days the delay was 7–15 min (‘moderate delay’ group). Cortisol values for verified sampling times accurately mapped on to the typical post-awakening cortisol growth curve, regardless of whether sampling deviated from desired protocol timings. This provides support for incorporating rather than excluding delayed data (up to 15 min) in CAR analyses. For this population the fitted cortisol growth curve equation predicted a mean cortisol awakening level of 6 nmols/l (±1 for 95% CI) and a mean CAR rise of 6 nmols/l (±2 for 95% CI). We also modelled the relationship between real delay and CAR magnitude, when the CAR is calculated erroneously by incorrectly assuming adherence to protocol time. Findings supported a curvilinear hypothesis in relation to effects of sample delay on the CAR. Short delays of 4–6 min between awakening and commencement of saliva sampling resulted an overestimated CAR. Moderate delays of 7–15 min were associated with an underestimated CAR. Findings emphasize the need to employ electronic-monitoring of sampling accuracy when measuring the CAR in the domestic setting.