Development of sampling methods for Raman analysis of solid dosage forms of therapeutic and illicit drugs

The results of a study aimed at determining the most important experimental parameters for automated, quantitative analysis of solid dosage form pharmaceuticals (seized and model 'ecstasy' tablets) are reported. Data obtained with a macro-Raman spectrometer were complemented by micro-Raman measurements, which gave information on particle size and provided excellent data for developing statistical models of the sampling errors associated with collecting data as a series of grid points on the tablets' surface. Spectra recorded at single points on the surface of seized MDMA-caffeine-lactose tablets with a Raman microscope (lambda(ex) = 785 nm, 3 mum diameter spot) were typically dominated by one or other of the three components, consistent with Raman mapping data which showed the drug and caffeine microcrystals were ca 40 mum in diameter. Spectra collected with a microscope from eight points on a 200 mum grid were combined and in the resultant spectra the average value of the Raman band intensity ratio used to quantify the MDMA: caffeine ratio, mu(r), was 1.19 with an unacceptably high standard deviation, sigma(r), of 1.20. In contrast, with a conventional macro-Raman system (150 mum spot diameter), combined eight grid point data gave mu(r) = 1.47 with sigma(r) = 0.16. A simple statistical model which could be used to predict sigma(r) under the various conditions used was developed. The model showed that the decrease in sigma(r) on moving to a 150 mum spot was too large to be due entirely to the increased spot diameter but was consistent with the increased sampling volume that arose from a combination of the larger spot size and depth of focus in the macroscopic system. With the macro-Raman system, combining 64 grid points (0.5 mm spacing and 1-2 s accumulation per point) to give a single averaged spectrum for a tablet was found to be a practical balance between minimizing sampling errors and keeping overhead times at an acceptable level. The effectiveness of this sampling strategy was also tested by quantitative analysis of a set of model ecstasy tablets prepared from MDEA-sorbitol (0-30% by mass MDEA). A simple univariate calibration model of averaged 64 point data had R-2 = 0.998 and an r.m.s. standard error of prediction of 1.1% whereas data obtained by sampling just four points on the same tablet showed deviations from the calibration of up to 5%.

Evaluation of sampling methods for learning from imbalanced data

The problem of learning from imbalanced data is of critical importance in a large number of application domains and can be a bottleneck in the performance of various conventional learning methods that assume the data distribution to be balanced. The class imbalance problem corresponds to dealing with the situation where one class massively outnumbers the other. The imbalance between majority and minority would lead machine learning to be biased and produce unreliable outcomes if the imbalanced data is used directly. There has been increasing interest in this research area and a number of algorithms have been developed. However, independent evaluation of the algorithms is limited. This paper aims at evaluating the performance of five representative data sampling methods namely SMOTE, ADASYN, BorderlineSMOTE, SMOTETomek and RUSBoost that deal with class imbalance problems. A comparative study is conducted and the performance of each method is critically analysed in terms of assessment metrics. © 2013 Springer-Verlag.

Assessing abundance and diversity patterns of soil microarthropod assemblages in northern Victoria Land (Antarctica)

This study aimed to: (1) assess differences between two quantitative sampling methods of soil microarthropods (visual census vs. stone washing) in ice-free areas located along a latitudinal gradient (from 72 degrees 37'S to 74 degrees 42'S) in northern Victoria Land (Antarctica); (2) furnish preliminary results on the abundance and diversity of mites and springtails in the studied areas. Visual census yielded reliable density estimates for adult collembolans and larger prostigmatic mites but did not detect small species. The study updates the distribution of several mites, including the southernmost record of an Oribatida species at global scale. Species composition was correlated with latitude but the uneven abundance distribution and local high beta-diversity probably reflect habitat fragmentation and population isolation. Under this circumstance nested sampling design should be usefully employed. Priorities and suitable methods for studying terrestrial microarthropod communities in continental Antarctica are discussed.

The positive impact of cytological specimens for EGFR mutation testing in non-small cell lung cancer:a single South East Asian laboratory's analysis of 670 cases

To compare the rejection rates of non-small cell lung cancer (NSCLC) samples obtained by differing sampling methods for testing by Sanger sequencing for epidermal growth factor receptor (EGFR) mutations. To assess the association between unsatisfactory outcomes and the quantity of DNA extracted from cytological versus histological samples.

Paediatricians' opinions of microneedle-mediated monitoring: a key stage in the translation of microneedle technology from laboratory into clinical practice

Microneedle (MN) arrays could offer an alternative method to traditional drug delivery and blood sampling methods. However, acceptance among key end-users is critical for new technologies to succeed. MNs have been advocated for use in children and so, paediatricians are key potential end-users. However, the opinions of paediatricians on MN use have been previously unexplored. The aim of this study was to investigate the views of UK paediatricians on the use of MN technology within neonatal and paediatric care. An online survey was developed and distributed among UK paediatricians to gain their opinions of MN technology and its use in the neonatal and paediatric care settings, particularly for MN-mediated monitoring. A total of 145 responses were obtained, with a completion response rate of 13.7 %. Respondents believed an alternative monitoring technique to blood sampling in children was required. Furthermore, 83 % of paediatricians believed there was a particular need in premature neonates. Overall, this potential end-user group approved of the MN technology and a MN-mediated monitoring approach. Minimal pain and the perceived ease of use were important elements in gaining favour. Concerns included the need for confirmation of correct application and the potential for skin irritation. The findings of this study provide an initial indication of MN acceptability among a key potential end-user group. Furthermore, the concerns identified present a challenge to those working within the MN field to provide solutions to further improve this technology. The work strengthens the rationale behind MN technology and facilitates the translation of MN technology from lab bench into the clinical setting.

Adherence to antiepileptic medicines in children: A multiple-methods assessment involving dried blood spot sampling

Purpose: To evaluate adherence to prescribed antiepileptic drugs (AEDs) in children with epilepsy using a combination of adherence-assessment methods.
Methods: A total of 100 children with epilepsy (=17 years old) were recruited. Medication adherence was determined via parental and child self-reporting (=9 years old), medication refill data from general practitioner (GP) prescribing records, and via AED concentrations in dried blood spot (DBS) samples obtained from children at the clinic and via self- or parental-led sampling in children's own homes. The latter were assessed using population pharmacokinetic modeling. Patients were deemed nonadherent if any of these measures were indicative of nonadherence with the prescribed treatment. In addition, beliefs about medicines, parental confidence in seizure management, and the presence of depressed mood in parents were evaluated to examine their association with nonadherence in the participating children.
Key Findings: The overall rate of nonadherence in children with epilepsy was 33%. Logistic regression analysis indicated that children with generalized epilepsy (vs. focal epilepsy) were more likely (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.37-15.81) to be classified as nonadherent as were children whose parents have depressed mood (OR 3.6, 95% CI 1.16-11.41).
Significance: This is the first study to apply the novel methodology of determining adherence via AED concentrations in clinic and home DBS samples. The present findings show that the latter, with further development, could be a useful approach to adherence assessment when combined with other measures including parent and child self-reporting. Seizure type and parental depressed mood were strongly predictive of nonadherence. © 2013 International League Against Epilepsy.
Key Words: Adherence, Epilepsy, Dried blood spots, MARS, Depressed mood.

Comparison of granulometric methods and sampling strategies used in marine habitat classification and Ecological Status assessment

Sediment particle size analysis (PSA) is routinely used to support benthic macrofaunal community distribution data in habitat mapping and Ecological Status (ES) assessment. No optimal PSA Method to explain variability in multivariate macrofaunal distribution has been identified nor have the effects of changing sampling strategy been examined. Here, we use benthic macrofaunal and PSA grabs from two embayments in the south of Ireland. Four frequently used PSA Methods and two common sampling strategies are applied. A combination of laser particle sizing and wet/dry sieving without peroxide pre-treatment to remove organics was identified as the optimal Method for explaining macrofaunal distributions. ES classifications and EUNIS sediment classification were robust to changes in PSA Method. Fauna and PSA samples returned from the same grab sample significantly decreased macrofaunal variance explained by PSA and caused ES to be classified as lower. Employing the optimal PSA Method and sampling strategy will improve benthic monitoring. © 2012 Elsevier Ltd.

Systematic random sampling of the comet assay

The comet assay is a technique used to quantify DNA damage and repair at a cellular level. In the assay, cells are embedded in agarose and the cellular content is stripped away leaving only the DNA trapped in an agarose cavity which can then be electrophoresed. The damaged DNA can enter the agarose and migrate while the undamaged DNA cannot and is retained. DNA damage is measured as the proportion of the migratory ‘tail’ DNA compared to the total DNA in the cell. The fundamental basis of these arbitrary values is obtained in the comet acquisition phase using fluorescence microscopy with a stoichiometric stain in tandem with image analysis software. Current methods deployed in such an acquisition are expected to be both objectively and randomly obtained. In this paper we examine the ‘randomness’ of the acquisition phase and suggest an alternative method that offers both objective and unbiased comet selection. In order to achieve this, we have adopted a survey sampling approach widely used in stereology, which offers a method of systematic random sampling (SRS). This is desirable as it offers an impartial and reproducible method of comet analysis that can be used both manually or automated. By making use of an unbiased sampling frame and using microscope verniers, we are able to increase the precision of estimates of DNA damage. Results obtained from a multiple-user pooled variation experiment showed that the SRS technique attained a lower variability than that of the traditional approach. The analysis of a single user with repetition experiment showed greater individual variances while not being detrimental to overall averages. This would suggest that the SRS method offers a better reflection of DNA damage for a given slide and also offers better user reproducibility.

Methods and code for 'classical' age-modelling of radiocarbon sequences.

Age–depth models form the backbone of most palaeoenvironmental studies. However, procedures for constructing chronologies vary between studies, they are usually not explained sufficiently, and some are inadequate for handling calibrated radiocarbon dates. An alternative method based on importance sampling through calibrated dates is proposed. Dedicated R code is presented which works with calibrated radiocarbon as well as other dates, and provides a simple, systematic, transparent, documented and customizable alternative. The code automatically produces age–depth models, enabling exploration of the impacts of different assumptions (e.g., model type, hiatuses, age offsets, outliers, and extrapolation).

Metronidazole Population Pharmacokinetics in Preterm Neonates Using Dried Blood-Spot Sampling

OBJECTIVES: To characterize the population pharmacokinetics of metronidazole in preterm neonates.
PATIENTS AND METHODS: Data were collected prospectively from 32 preterm neonates who received intravenous metronidazole for the treatment of or prophylaxis against necrotizing enterocolitis. Dried
blood spots (n 203) on ?lter paper were analyzed by highperformance liquid chromatography, and the data were subjected to pharmacokinetic analysis performed by using nonlinear mixed-effect modeling.
RESULTS: A 1-compartment model best described the data. Signi?cant covariates were weight (WT) and postmenstrual age (PMA). The ?nal population models for metronidazole clearance (CL) and volume of distribution (V) were: CL 0.0247 (WT/1.00)0.75 (1 0.107 [PMA 30]) and V 0.726 WT, where CL is in liters per hour, WT is in kilograms, PMA is in weeks, and V is in liters. This model predicts that the half-life of metronidazole decreases rapidly from 40 hours at 25 weeks’ PMA to 19 hours at 32 weeks’ PMA, after which it starts to plateau. This decrease in half-life is the result of a 5-fold increase in CL compared with only a 2.5-fold increase in V during the same period.
CONCLUSIONS: Currently, there are no speci?c dose recommendations for metronidazole in preterm neonates. However, a dosing scheme for preterm neonates that takes into consideration both the weight and PMA has been suggested and should avoid administration of doses that are excessive or more frequent than necessary.

Preservation methods alter stable isotope values in gelatinous zooplankton: implications for interpreting trophic ecology

Jellyfish are increasingly topical within studies of marine food webs. Stable isotope analysis represents a valuable technique to unravel the complex trophic role of these long-overlooked species. In other taxa, sample preservation has been shown to alter the isotopic values of species under consideration, potentially leading to misinterpretation of trophic ecology. To identify potential preservation effects in jellyfish, we collected Aurelia aurita from Strangford Lough (54(o)22'44.73aEuro(3)N, 5(o)32'53.44aEuro(3)W) during May 2009 and processed them using three different methods prior to isotopic analysis (unpreserved, frozen and preserved in ethanol). A distinct preservation effect was found on delta N-15 values: furthermore, preservation also influenced the positive allometric relationship between individual size and delta N-15 values. Conversely, delta C-13 values remained consistent between the three preservation methods, conflicting with previous findings for other invertebrate, fish and mammalian species. These findings have implications for incorporation of jellyfish into marine food webs and remote sampling regimes where preservation of samples is unavoidable.

Limitations of instantaneous water quality sampling in surface-water catchments: Comparison with near-continuous phosphorus time-series data.

The validity of load estimates from intermittent, instantaneous grab sampling is dependent on adequate spatial coverage by monitoring networks and a sampling frequency that re?ects the variability in the system under study. Catchments with a ?ashy hydrology due to surface runoff pose a particular challenge as intense short duration rainfall events may account for a signi?cant portion of the total diffuse transfer of pollution from soil to water in any hydrological year. This can also be exacerbated by the presence of strong background pollution signals from point sources during low flows. In this paper, a range of sampling methodologies and load estimation techniques are applied to phosphorus data from such a surface water dominated river system, instrumented at three sub-catchments (ranging from 3 to 5 km2 in area) with near-continuous monitoring stations. Systematic and Monte Carlo approaches were applied to simulate grab sampling using multiple strategies and to calculate an estimated load, Le based on established load estimation methods. Comparison with the actual load, Lt, revealed signi?cant average underestimation, of up to 60%, and high variability for all feasible sampling approaches. Further analysis of the time series provides an insight into these observations; revealing peak frequencies and power-law scaling in the distributions of P concentration, discharge and load associated with surface runoff and background transfers. Results indicate that only near-continuous monitoring that re?ects the rapid temporal changes in these river systems is adequate for comparative monitoring and evaluation purposes. While the implications of this analysis may be more tenable to small scale ?ashy systems, this represents an appropriate scale in terms of evaluating catchment mitigation strategies such as agri-environmental policies for managing diffuse P transfers in complex landscapes.

Assessing modern ground survey methods and airborne laser scanning for digital terrain modelling:A case study from the Lake District, England

This paper compares the applicability of three ground survey methods for modelling terrain: one man electronic tachymetry (TPS), real time kinematic GPS (GPS), and terrestrial laser scanning (TLS). Vertical accuracy of digital terrain models (DTMs) derived from GPS, TLS and airborne laser scanning (ALS) data is assessed. Point elevations acquired by the four methods represent two sections of a mountainous area in Cumbria, England. They were chosen so that the presence of non-terrain features is constrained to the smallest amount. The vertical accuracy of the DTMs was addressed by subtracting each DTM from TPS point elevations. The error was assessed using exploratory measures including statistics, histograms, and normal probability plots. The results showed that the internal measurement accuracy of TPS, GPS, and TLS was below a centimetre. TPS and GPS can be considered equally applicable alternatives for sampling the terrain in areas accessible on foot. The highest DTM vertical accuracy was achieved with GPS data, both on sloped terrain (RMSE 0.16. m) and flat terrain (RMSE 0.02. m). TLS surveying was the most efficient overall but veracity of terrain representation was subject to dense vegetation cover. Therefore, the DTM accuracy was the lowest for the sloped area with dense bracken (RMSE 0.52. m) although it was the second highest on the flat unobscured terrain (RMSE 0.07. m). ALS data represented the sloped terrain more realistically (RMSE 0.23. m) than the TLS. However, due to a systematic bias identified on the flat terrain the DTM accuracy was the lowest (RMSE 0.29. m) which was above the level stated by the data provider. Error distribution models were more closely approximated by normal distribution defined using median and normalized median absolute deviation which supports the use of the robust measures in DEM error modelling and its propagation. © 2012 Elsevier Ltd.

An intelligent configuration-sampling based local motion planner for robotic manipulators

Manipulator motion planning is a task which relies heavily on the construction of a configuration space prior to path planning. However when fast real-time motion is needed, the full construction of the manipulator's high-dimensional configu-ration space can be too slow and expensive. Alternative planning methods, which avoid this full construction of the manipulator's configuration space are needed to solve this problem. Here, one such existing local planning method for manipulators based on configuration-sampling and subgoal-selection has been extended. Using a modified Artificial Potential Fields (APF) function, goal-configuration sampling and a novel subgoal selection method, it provides faster, more optimal paths than the previously proposed work. Simulation results show a decrease in both runtime and path lengths, along with a decrease in unexpected local minimum and crashing issues.

Potassium canrenoate treatment in paediatric patients: a population pharmacokinetic study using novel dried blood spot sampling

Objective: To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate (K-canrenoate) in paediatric patients.

Methods: Data were collected prospectively from 37 paediatric patients (median weight 2.9?kg, age range 2 days–0.85 years) who received intravenous K-canrenoate for management of retained fluids, for example in heart failure and chronic lung disease. Dried blood spot (DBS) samples (n?=?213) from these were analysed for canrenone content and the data subjected to pharmacokinetic analysis using nonlinear mixed-effects modelling. Another group of patients (n?=?16) who had 71 matching plasma and DBS samples was analysed separately to compare canrenone pharmacokinetic parameters obtained using the two different matrices.

Results: A one-compartment model best described the DBS data. Significant covariates were weight, postmenstrual age (PMA) and gestational age. The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) in DBS were CL/F (l/h)?=?12.86?×? (WT/70.0)0.75?×?e [0.066?×? (PMA?-?40]) and V/F (l)?=?603.30?×? (WT/70)?×?(GA/40)1.89 where weight is in kilograms. The corresponding values of CL/F and V/F in a patient with a median weight of 2.9?kg are 1.11?l/h and 20.48?l, respectively. Estimated half-life of canrenone based on DBS concentrations was similar to that based on matched plasma concentrations (19.99 and 19.37?h, respectively, in 70?kg patient).

Conclusion: The range of estimated CL/F in DBS for the study population was 0.12–9.62?l/h; hence, bodyweight-based dosage adjustment of K-canrenoate appears necessary. However, a dosing scheme that takes into consideration both weight and age (PMA/gestational age) of paediatric patients seems more appropriate.