COGNITIVE AND LINGUISTIC FACTORS OF READING ARABIC: THE ROLE OF MORPHOLOGICAL AWARENESS IN READING

Scientific reading research has produced substantial evidence linking specific reading components to a range of constructs including phonological awareness (PA), morphological awareness, orthographic processing (OP), rapid automatized naming, working memory and vocabulary. There is a paucity of research on Arabic, although 420 million people around the world (Gordon, 2005) speak Arabic. As a Semitic language, Arabic differs in many ways from Indo-European languages. Over the past three decades, literacy research has begun to elucidate the importance of morphological awareness (MA) in reading. Morphology is a salient aspect of Arabic word structure. This study was designed to (a) examine the dimensions underlying MA in Arabic; (b) determine how well MA predicts reading; (c) investigate the role of the standard predictors in different reading outcomes; and (d) investigate the construct of reading in Arabic. This study was undertaken in two phases. In Phase I, 10 MA measures and two reading measures were developed, and tested in a sample of 102 Grade 3 Arabic-speaking children. Factor analysis of the 10 MA tasks yielded one predominant factor supporting the construct validity of MA in Arabic. Hierarchical regression analyses, controlling for age and gender, indicated that the MA factor solution accounted for 41– 43% of the variance in reading. In Phase II, the widely studied predictor measures were developed for PA and OP in addition to one additional measure of MA (root awareness), and three reading measures In Phase II, all measures were administered to another sample of 201 Grade 3 Arabic-speaking children. The construct of reading in Arabic was examined using factor analysis. The joint and unique effects of all standard predictors were examined using different sets of hierarchical regression analyses. Results of Phase II showed that: (a) all five reading measures loaded on one factor; (b) MA consistently accounted for unique variance in reading, particularly in comprehension, above and beyond the standard predictors; and (c) the standard predictors had differential contributions. These findings underscore the contribution of MA to all components of Arabic reading. The need for more emphasis on including morphology in Arabic reading instruction and assessment is discussed.

Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers.

Tumor genomic instability and selective treatment pressures result in clonal disease evolution; molecular stratification for molecularly targeted drug administration requires repeated access to tumor DNA. We hypothesized that circulating plasma DNA (cpDNA) in advanced cancer patients is largely derived from tumor, has prognostic utility, and can be utilized for multiplex tumor mutation sequencing when repeat biopsy is not feasible. We utilized the Sequenom MassArray System and OncoCarta panel for somatic mutation profiling. Matched samples, acquired from the same patient but at different time points were evaluated; these comprised formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (primary and/or metastatic) and cpDNA. The feasibility, sensitivity, and specificity of this high-throughput, multiplex mutation detection approach was tested utilizing specimens acquired from 105 patients with solid tumors referred for participation in Phase I trials of molecularly targeted drugs. The median cpDNA concentration was 17 ng/ml (range: 0.5-1600); this was 3-fold higher than in healthy volunteers. Moreover, higher cpDNA concentrations associated with worse overall survival; there was an overall survival (OS) hazard ratio of 2.4 (95% CI 1.4, 4.2) for each 10-fold increase in cpDNA concentration and in multivariate analyses, cpDNA concentration, albumin, and performance status remained independent predictors of OS. These data suggest that plasma DNA in these cancer patients is largely derived from tumor. We also observed high detection concordance for critical 'hot-spot' mutations (KRAS, BRAF, PIK3CA) in matched cpDNA and archival tumor tissue, and important differences between archival tumor and cpDNA. This multiplex sequencing assay can be utilized to detect somatic mutations from plasma in advanced cancer patients, when safe repeat tumor biopsy is not feasible and genomic analysis of archival tumor is deemed insufficient. Overall, circulating nucleic acid biomarker studies have clinically important multi-purpose utility in advanced cancer patients and further studies to pursue their incorporation into the standard of care are warranted.

Free fatty acid receptor 1 (GPR40) agonists containing spirocyclic periphery inspired by LY2881835

The free fatty acid receptor 1 (FFA1), a G protein-coupled receptor (GPCR) naturally activated by long-chain fatty acids is a novel target for the treatment of metabolic diseases. The basic amine spirocyclic periphery of Eli Lilly's drug candidate LY2881835 for treatment of type 2 diabetes mellitus (which reached phase I clinical trials) inspired a series of novel FFA1 agonists. These were designed to incorporate the 3-[4-(benzyloxy)phenyl]propanoic acid pharmacophore core decorated with a range of spirocyclic motifs. The latter were prepared via the Prins cyclization and subsequent modification of the 4-hydroxytetrahydropyran moiety in the Prins product. Here, we synthesize 19 compounds and test for FFA1 activity. Within this pilot set, a nanomolar potency (EC50=55nM) was reached. Four lead compounds (EC50 range 55-410nM) were characterized for aqueous solubility, metabolic stability, plasma protein binding and Caco-2 permeability. While some instability in the presence of mouse liver microsomes was noted, mouse pharmacokinetic profile of the compound having the best overall ADME properties was evaluated to reveal acceptable bioavailability (F=10.3%) and plasma levels achieved on oral administration.

Public Perceptions of the Midwest's Pavements - Executive Summary: Iowa

This report summarizes Iowa results of a five year, Pooled Fund study involving the Wisconsin, Iowa, and Minnesota Departments of Transportation (DOTs) designed to 1) assess the public's perceptions of the DOTs' pavement improvement strategies and 2) develop customer-based thresholds of satisfaction with pavements on rural two lane highways in each state as related to the DOTs' physical indices, such as pavement ride and condition. The primary objective was to seek systematic customer input to improve the DOTs' pavement improvement policies by 1) determining how drivers perceive the DOTs' pavements in terms of comfort and convenience but also in terms of other tradeoffs the DOTs had not previously considered, 2) determining relationships between perceptions and measured pavement condition thresholds (including a general level of tolerance of winter ride conditions in two of the states), and 3) identifying important attributes and issues that may not have been considered in the past. Secondary objectives were 1) to provide a tool for systematic customer input in the future and 2) to provide information which can help structure public information programs. A University of Wisconsin-Extension survey lab conducted the surveys under the direction of a multi-disciplinary team from Marquette University. Approximately 4500 drivers in the 3 states participated in the 3 phases of the project. Researchers conducted 6 focus groups in each state, approximately 400 statewide telephone interviews in each state and 700-800 targeted telephone interviews in each state. Approximately 400 winter ride interviews were conducted in Wisconsin and Minnesota. A summary of the method for each survey is included. In Phase I, focus groups were conducted with drivers to get an initial indication of what the driving public believes in regards to pavements and to frame issues for inclusion in the more representative statewide surveys of drivers conducted in Phase II. Phase II interviews gathered information about improvement policy tradeoff issues and about preliminary thresholds of improvement in terms of physical pavement indices. In Phase III, a two step recruitment and post-drive interview procedure yielded thresholds of ride and condition index summarized for each state. Results show that, in general, the driving public wants longer lasting pavements and are willing to pay for them. They want to minimize construction delay, improve entire sections of highway at one time but they dislike detours, and prefer construction under traffic even if it stretches out construction time. Satisfaction with pavements does not correlate directly to a high degree with physical pavement indices, but was found instead to be a complex, multi-faceted phenomenon. A psychological model was applied to explain satisfaction to a respectable degree for the social sciences. Results also indicate a high degree of trust in the 3 DOTs which is enhanced when the public is asked for input on specific highway segments. Conclusions and recommendations include a 3-step methodology for other state studies.

Concrete deterioration due to sulfide-bearing aggregates

Dans la région de Trois-Rivières (Québec, Canada), plus de 1 000 bâtiments résidentiels et commerciaux montrent de graves problèmes de détérioration du béton. Les problèmes de détérioration sont liés à l’oxydation des sulfures de fer incorporés dans le granulat utilisé pour la confection du béton. Ce projet de doctorat vise à mieux comprendre les mécanismes responsables de la détérioration de béton incorporant des granulats contenant des sulfures de fer, et ce afin de développer une méthodologie pour évaluer efficacement la réactivité potentielle de ce type de granulats. Un examen pétrographique détaillé de carottes de béton extraites de fondations résidentielles montrant différents degré d’endommagement a été réalisé. Le granulat problématique contenant des sulfures de fer a été identifié comme un gabbro à hypersthène incorporant différentes proportions (selon les différentes localisations dans les deux carrières d’origine) de pyrrhotite, pyrite, chalcopyrite et pentlandite. Les produits de réaction secondaires observés dans les échantillons dégradés comprennent des formes minérales de "rouille", gypse, ettringite et thaumasite. Ces observations ont permis de déterminer qu’en présence d’eau et d’oxygène, la pyrrhotite s’oxyde pour former des oxyhydroxides de fer et de l’acide sulfurique qui provoquent une attaque aux sulfates dans le béton. Tout d’abord, la fiabilité de l’approche chimique proposée dans la norme européenne NF EN 12 620, qui consiste à mesurer la teneur en soufre total (ST,% en masse) dans le granulat pour détecter la présence (ou non) de sulfures de fer, a été évaluée de façon critique. Environ 50% (21/43) des granulats testés, représentant une variété de types de roches/lithologies, a montré une ST > 0,10%, montrant qu’une proportion importante de types de roches ne contient pas une quantité notable de sulfure, qui, pour la plupart d’entre eux, sont susceptibles d’être inoffensifs dans le béton. Ces types de roches/granulats nécessiteraient toutefois d’autres tests pour identifier la présence potentielle de pyrrhotite compte tenu de la limite de ST de 0,10 % proposée dans les normes européennes. Basé sur une revue exhaustive de la littérature et de nombreuses analyses de laboratoire, un test accéléré d’expansion sur barres de mortier divisé en deux phases a ensuite été développé pour reproduire, en laboratoire, les mécanismes de détérioration observés à Trois-Rivières. Le test consiste en un conditionnement de 90 jours à 80°C/80% RH, avec 2 cycles de mouillage de trois heures chacun, par semaine, dans une solution d’hypochlorite de sodium (eau de javel) à 6% (Phase I), suivi d’une période pouvant atteindre 90 jours de conditionnement à 4°C/100 % HR (Phase II). Les granulats ayant un potentiel d’oxydation ont présenté une expansion de 0,10 % au cours de la Phase I, tandis que la formation potentielle de thaumasite est détectée par le regain rapide de l’expansion suivi par la destruction des échantillons durant la Phase II. Un test de consommation d’oxygène a également été modifié à partir d’un test de Drainage Minier Acide, afin d’évaluer quantitativement le potentiel d’oxydation des sulfures de fer incorporés dans les granulats à béton. Cette technique mesure le taux de consommation d’oxygène dans la partie supérieure d’un cylindre fermé contenant une couche de matériau compacté afin de déterminer son potentiel d’oxydation. Des paramètres optimisés pour évaluer le potentiel d’oxydation des granulats comprennent une taille de particule inférieure à 150 μm, saturation à 40 %, un rapport de 10 cm d’épaisseur de granulat par 10 cm de dégagement et trois heures d’essai à 22ᵒC. Les résultats obtenus montrent que le test est capable de discriminer les granulats contenant des sulfures de fer des granulats de contrôle (sans sulfures de fer) avec un seuil limite fixé à 5% d’oxygène consommé. Finalement, un protocole d’évaluation capable d’estimer les effets néfastes potentiels des granulats à béton incorporant des sulfures de fer a été proposé. Le protocole est divisé en 3 grandes phases: (1) mesure de la teneur en soufre total, (2) évaluation de la consommation d’oxygène, et (3) un test accéléré d’expansion sur barres de mortier. Des limites provisoires sont proposées pour chaque phase du protocole, qui doivent être encore validées par la mise à l’essai d’un plus large éventail de granulats.

Self-reported fatigue and associated factors six years after stroke

Several studies have found that fatigue is one of the most commonly reported symptoms after stroke and the most difficult to cope with. The present study aimed to investigate the presence and severity of self-reported fatigue six years after stroke onset and associated factors. The cohort "Life After Stroke Phase I" (n = 349 persons) was invited at six years to report fatigue (Fatigue Severity Scale 7-item version), perceived impact of stroke and global recovery after stroke (Stroke Impact Scale), anxiety and depression (Hospital Anxiety and Depression Scale), life satisfaction (Life Satisfaction Checklist) and participation in everyday social activities (Frenchay Activities Index). At six years 37% of the 102 participants in this cross-sectional study reported fatigue. The results showed that in nearly all SIS domains the odds for post-stroke fatigue were higher in persons with a higher perceived impact. Furthermore, the odds for post-stroke fatigue were higher in those who had experienced a moderate/severe stroke and had signs of depression and anxiety. Fatigue is still present in one-third of persons as long as six years after stroke onset and is perceived to hinder many aspects of functioning in everyday life. There is an urgent need to develop and evaluate interventions to reduce fatigue.

Functional Magnetic Resonance Imaging Neurofeedback and Motor training for Parkinson’s Disease: Randomised Trial

Objective: Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) uses feedback of the patient’s own brain activity to self-regulate brain networks which in turn could lead to a change in behaviour and clinical symptoms. The objective was to determine the effect of neurofeedback and motor training and motor training (MOT) alone on motor and non-motor functions in Parkinson’s disease (PD) in a 10-week small Phase I randomised controlled trial. Methods: 30 patients with PD (Hoehn & Yahr I-III) and no significant comorbidity took part in the trial with random allocation to two groups. Group 1 (NF: 15 patients) received rt-fMRI-NF with motor training. Group 2 (MOT: 15 patients) received motor training alone. The primary outcome measure was the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale-Motor scale (MDS-UPDRS-MS), administered pre- and post-intervention ‘off-medication’. The secondary outcome measures were the ‘on-medication’ MDS-UPDRS, the Parkinson’s disease Questionnaire-39, and quantitative motor assessments after 4 and 10 weeks. Results: Patients in the NF group were able to upregulate activity in the supplementary motor area by using motor imagery. They improved by an average of 4.5 points on the MDS-UPDRS-MS in the ‘off-medication’ state (95% confidence interval: -2.5 to -6.6), whereas the MOT group improved only by 1.9 points (95% confidence interval +3.2 to -6.8). However, the improvement did not differ significantly between the groups. No adverse events were reported in either group. Interpretation: This Phase I study suggests that NF combined with motor training is safe and improves motor symptoms immediately after treatment, but larger trials are needed to explore its superiority over active control conditions. Clinical Trial website : Unique Identifier: NCT01867827 URL: https://clinicaltrials.gov/ct2/show/NCT01867827?term=NCT01867827&rank=1

Curricular training report: 7 months as a study coordinator at Blueclinical LTD

The present report describes in detail the activities undertaken under the coordination of clinical and observational studies during the curricular internship at Blueclinical Ltd., inserted in the Master of Pharmaceutical Biomedicine. Blueclinical Ltd.company operates in three different areas: R&D consultancy, management and coordination of trial centers, and a phase I unit. The curricular internship had the duration of seven months during which I was able to perform different tasks relating to coordination of clinical trials in Centro Hospitalar do Baixo Vouga, E.P.E., (CHBV) in Aveiro, Portugal. This academic internship allowed me to develop theoretical and practical skills in the field of clinical trials and observational studies. I also had the opportunity to further the knowledge I gained throughout my academic journey. During this internship, I had the opportunity to interact with different health professionals and develop my knowledge in the field of several therapeutic indications. I also could interact with distinct monitors and sponsors. This experience allowed me to improve time management, communication and problems resolution skills.

Curricular trainig report as study coordinator in Blueclinical Ltd.

The present report describes in detail the activities and knowledge aquired during my internship as study coordinator in Blueclinical – Investigação e Desenvolvimento em Saúde, Ltd., in order to obtain the master degree in Pharmaceutical Biomedicine. According to the type of services provided, Blueclinical is formed by three business units: Blueclinical Clinical Research Partnership, Blueclinical Phase I and Blueclinical Research and Development. The fact of belonging to such a company gave me the opportunity to be in touch with different areas of pharmaceutical development and to contact with different research teams, which for me was an added advantage to the integration and consolidation of knowledge, as well as in the development and improvement of soft and hard skills. The main activity developed was the coordination of clinical studies, in Unidade Local de Saúde de Matosinhos, E.P.E., which was one of the institutions that established a partnership with Blueclinical, Ltd. During my internship I was able to contact with various stages of development and coordination of clinical trials, which will be reported in this report.

Curricular internship report in medical writing at Blueclinical, Portugal

The contents of this report are a summary of the activities carried out during the 8-month internship as an Associate Medical Writer at Blueclinical Ltd, Matosinhos, Portugal. Mainly my activities were related to medical writing, particularly writing the clinical research protocols, clinical study reports, writing manuscript and preparing poster presentations. In addition to these activities, I also participated in performance of a clinical trial from beginning to end. During the period of its realization, I was able to familiarize myself with all the steps of the Phase I clinical trial.

Propuesta metodológica para la renovación de los sistemas y procesos de administración de los mercados eléctricos: el caso colombiano

El mercado eléctrico ha evolucionado en Colombia desde 1995, fortaleciéndose institucionalmente, dinamizando su desarrollo, y enfrentando grandes desafíos. Los sistemas de administración, que soportan el funcionamiento del mercado, han evolucionado a la par, aunque algunos se encuentran aislados entre sí o han sido desarrollados en plataformas diferentes, lo que dificulta la sostenibilidad y el mantenimiento, y reducen la facilidad de incorporar cambios. Al referenciarse con otros mercados en el mundo, se observa gran dinámica en la incorporación de tecnologías en información y comunicaciones, avances regulatorios o requerimientos de clientes. Se requiere una renovación tecnológica que conserve el conocimiento adquirido, y permita incorporar fácilmente las tendencias del mercado. Este artículo presenta los resultados de la propuesta metodológica para la renovación tecnológica enmarcada en el proyecto Colciencias CNBT 833559938649 de investigación tecnológica, Sistema para la administración del mercado de energía eléctrica en Colombia, Fase I.

Investigating a Hybrid Metaheuristic For Job Shop Rescheduling

Previous research has shown that artificial immune systems can be used to produce robust schedules in a manufacturing environment. The main goal is to develop building blocks (antibodies) of partial schedules that can be used to construct backup solutions (antigens) when disturbances occur during production. The building blocks are created based upon underpinning ideas from artificial immune systems and evolved using a genetic algorithm (Phase I). Each partial schedule (antibody) is assigned a fitness value and the best partial schedules are selected to be converted into complete schedules (antigens). We further investigate whether simulated annealing and the great deluge algorithm can improve the results when hybridised with our artificial immune system (Phase II). We use ten fixed solutions as our target and measure how well we cover these specific scenarios.

A altura de dossel e a adubação nitrogenada da pastagem podem afetar a nutrição nitrogenada do milho, num sistema de integração lavoura pecuária?

We conducted a field experiment near Abelardo Luz, Santa Catarina, from October 2012 to April 2014, to evaluate the effect interaction of nitrogen fertilization and height of canopy over the N nutrition of corn subsequently grown to pasture. The data belonging to this thesis are related to the first two production cycles obtained in sorghum pasture (2012/2013), oat (2013) and corn crop (2013/2014). In the evaluation of forage sorghum and oat it was used the same experimental design, consisting of randomized complete block in a factorial arrangement (2 x 2) with three replications. The first factor was considered canopy height (Low and High) and the second factor was the fertilization of cover crop pasture (0 and 200 kg N.ha-1). In phase I and II, the combination of factors evaluators were prepared in the same experimental unit. For corn crop the design was a randomized complete block in a factorial design (2X2X4X6) with three replications. Factors considered in corn were: canopy height of pasture (Low and High), nitrogen application times (NG - nitrogen in the grains and NP - nitrogen in pasture), nitrogen fertilization in corn (0, 100, 200 and 300 kg N.ha-1) and time (46, 53, 60, 67, 76 and 103 days after sowing the maize). In phases I and II, in general the use of N in the pasture increased the productive potential of the pasture and animal management and canopy height has changed the dynamics of structural components and botanical pasture. In cold conditions for long periods and not acclimatized plants the adoption of high nitrogen fertilization and height high grazing pasture leave vulnerable to damage caused by the freezing of plants. The anticipation of nitrogen fertilization on pasture positively affects the corn crop by increasing the accumulated dry matter and N content in the plant. Nitrogen nutritional content of corn with the anticipation of fertilization in pasture is suitable for obtaining high crop production in integrated crop-livestock system. When used nitrogen only coverage in corn sufficiency level in the nitrogen nutrition is achieved with the use of 100 kg N.ha-1. With the use of 200 kg N ha -1 NG and NP no difference in nitrogen content and nitrogen nutrition index.

In vitro studies of drug transformations: application to forensic toxicology

The forensic toxicologist faces challenges in the detection of drugs and poisons in biological samples due to transformations which occur both during life and after death. For example, changes can result from drug metabolism during life or from the use of formalin solution for post mortem embalming purposes. The former requires the identification of drug metabolites and the latter the identification of chemical reaction products in order to know which substances had been administered. The work described in this thesis was aimed at providing ways of tackling these challenges and was divided into two parts. Part 1 investigated the use of in vitro drug metabolism by human liver microsomes (HLM) to obtain information on drug metabolites and Part 2 investigated the chemical reactions of drugs and a carbamate pesticide with formalin solution and formalin-blood. The initial aim of part I was to develop an in vitro metabolism method using HLM, based on a literature review of previous studies of this type. MDMA was chosen as a model compound to develop the HLM method because its metabolism was known and standards of its metabolites were commercially available. In addition, a sensitive and selective method was developed for the identification and quantitation of hydrophilic phase I drug metabolites using LC/MS/MS with a conventional reverse-phase (C18) column. In order to obtain suitable retention factors for polar drug metabolites on this column, acetyl derivatives were evaluated for converting the metabolites to more lipophilic compounds and an optimal separation system was developed. Acetate derivatives were found to be stable in the HPLC mobile phase and to provide good chromatographic separation of the target analytes. In vitro metabolism of MDMA and, subsequently, of other drugs involved incubation of 4 µg drug substance in pH 7.4 buffer with an NADPH generating system (NGS) at 37oC for 90 min with addition of more NGS after 30 min. The reaction was stopped at 90 min by the addition of acetonitrile before extraction of the metabolites. Acetate derivatives of MDMA metabolites were identified by LC/MS/MS using multiple reaction monitoring (MRM). Three phase I metabolites (both major and minor metabolites) of MDMA were detected in HLM samples. 3,4-dihydroxy-methamphetamine and 4-hydroxy-3-methoxymethamphetamine were found to be major metabolites of MDMA whereas 3,4-methylenedioxyamphetamine was found to be a minor metabolite. Subsequently, ten MDMA positive urines were analysed to compare the metabolite patterns with those produced by HLM. An LC/MS method for MDMA and its metabolites in urine samples was developed and validated. The method demonstrated good linearity, accuracy and precision and insignificant matrix effects, with limits of quantitation of 0.025 µg/ml. Moreover, derivatives of MDMA and its metabolites were quantified in all 10 positive human urine samples. The urine metabolite pattern was found to be similar to that from HLM. The second aim of Part 1 was to use the HLM system to study the metabolism of some new psychoactive substances, whose misuse worldwide has necessitated the development of analytical methods for these drugs in biological specimens. Methylone and butylone were selected as representative cathinones and para-methoxyamphetamine (PMA) was chosen as a representative ring-substituted amphetamine, because of the involvement of these drugs in recent drug-related deaths, because of a relative lack of information on their metabolism, and because reference standards of their metabolites were not commercially available. An LC/MS/MS method for the analysis of methylone, butylone, PMA and their metabolites was developed. Three phase I metabolites of methylone and butylone were detected in HLM samples. Ketone reduction to β-OH metabolites and demethylenation to dihydroxy-metabolites were found to be major phase I metabolic pathways of butylone and methylone whereas N-demethylation to nor-methylone and nor-butylone were found to be minor pathways. Also, demethylation to para-hydroxyamphetamine was found to be a major phase I metabolic pathway of PMA whereas β-hydroxylation to β-OH-PMA was found to be a minor pathway. Formaldehyde is used for embalming, to reduce decomposition and preserve cadavers, especially in tropical countries such as Thailand. Drugs present in the body can be exposed to formaldehyde resulting in decreasing concentrations of the original compounds and production of new substances. The aim of part II of the study was to evaluate the in vitro reactions of formaldehyde with selected drug groups including amphetamines (amphetamine, methamphetamine and MDMA), benzodiazepines (alprazolam and diazepam), opiates (morphine, hydromorphone, codeine and hydrocodone) and with a carbamate insecticide (carbosulfan). The study would identify degradation products to serve as markers for the parent compounds when these were no longer detectable. Drugs standards were spiked in 10% formalin solution and 10% formalin blood. Water and whole blood without formalin were used for controls. Samples were analysed by LC/MS/MS at different times from the start, over periods of up to 30 days. Amphetamine, methamphetamine and MDMA were found to rapidly convert to methamphetamine, DMA and MDDMA respectively, in both formalin solution and formalin blood, confirming the Eschweiler-Clarke reaction between amine-containing compounds and formaldehyde. Alprazolam was found to be unstable whereas diazepam was found to be stable in both formalin solution and water. Both were found to hydrolyse in formalin solution and to give open-ring alprazolam and open-ring diazepam. Other alprazolam conversion products attached to paraformaldehyde were detected in both formalin solution and formalin blood. Morphine and codeine were found to be more stable than hydromorphone and hydrocodone in formalin solution. Conversion products of hydromorphone and hydrocodone attached to paraformaldehyde were tentatively identified in formalin solution. Moreover, hydrocodone and hydromorphone rapidly decreased within 24 h in formalin blood and could not be detected after 7 days. Carbosulfan was found to be unstable in formalin solution and was rapidly hydrolysed within 24 h, whereas in water it was stable up to 48 h. Carbofuran was the major degradation product, plus smaller amounts of other products, 3-ketocarbofuran and 3-hydrocarbofuran. By contrast, carbosulfan slowly hydrolysed in formalin-blood and was still detected after 15 days. It was concluded that HLM provide a useful tool for human drug metabolism studies when ethical considerations preclude their controlled administration to humans. The use of chemical derivatisation for hydrophilic compounds such as polar drug metabolites for analysis by LC/MS/MS with a conventional C18 column is effective and inexpensive, and suitable for routine use in the identification and quantitation of drugs and their metabolites. The detection of parent drugs and their metabolites or conversion and decomposition products is potentially very useful for the interpretation of cases in forensic toxicology, especially when the original compounds cannot be observed.

Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration

Erratum in: Low-frequency and common genetic variation in ischemic stroke: The METASTROKE collaboration. [Neurology. 2016]