Contributions to an improved phenytoin monitoring and dosing in hospitalized patients

Phenytoin (PHT) is one of the mostly used and well established anticonvulsants for the treatment of epilepsy and a standard in the antiepileptic prophylaxis in adults with severe traumatic brain injuries before and after neurosurgical intervention. Its therapeutic use is challenging as PHT has a narrow therapeutic range and shows non-linear kinetics. It is extensively metabolized by a variety of CYP enzymes. PHT shows 85-95% binding to plasma proteins mostly albumin. This renders PHT also an important drug interaction candidate. Therefore, therapeutic drug monitoring is often required. A rational timing for good interpretation of the lab data translated in optimal individual dosing are necessary. Therapeutic guidance especially in teaching hospitals are needed and have to be implemented. Bayesian Forecasting (BF) versus conventional dosing (CD): a retrospective, long-term, single centre analysis In the hospital, medication management for effective antiepileptic therapy with PHT often needs rapid IV loading and subsequent dose adjustment according to TDM. To investigate PHT performance in reaching therapeutic target serum concentration, a BF regimen was compared to CD, according to the official summary of product characteristics. In a Swiss acute care teaching hospital (Kantonsspital Aarau), a retrospective, single centre, and long-term analysis was assessed by using all PHT serum tests from the central lab from 1997 to 2007. The BF regimen consisted of a guided, body weight-adapted rapid IV PHT loading over five days with pre-defined TDM time points. The CD was applied without written guidance. Assuming non-normally distributed data, non-parametric statistical methods were used. A total of 6’120 PHT serum levels (2’819 BF and 3’301 CD) from 2’589 patients (869 BF and 1’720 CD) were evaluated and compared. 63.6% of the PHT serum levels from the BF group were within the therapeutic range versus only 34.0% in the CD group (p<0.0001). The mean BF serum level was 52.0 ± 22.1 µmol/L (within target range), whereas the mean serum level of the CD was 39.8 ± 28.2 µmol/L (sub-target range). In the BF group, men had small but significantly lower PHT serum levels compared to women (p<0.0001). The CD group showed no significant gender difference (p=0.187). A comparative sub-analysis of age-related groups (children, adolescents, adults, seniors, and elderly) showed significant lower target levels (p<0.0001) for each group in the CD group, compared to BF. Comparing the two groups, BF showed significantly better performance in reaching therapeutic PHT serum levels. Free PHT assessment However, total serum drug levels of difficult-to-dose drugs like PHT are sometimes insufficient. The knowledge of the free fraction is necessary for correct dosing. In a subgroup analysis of the above BF vs. CD study we evaluated the suitability of the Sheiner-Tozer algorithm to calculate the free PHT fraction in hypoalbuminemic patients. Free PHT serum concentrations were calculated from total PHT concentration in hypoalbuminemic patients and compared with the measured free PHT. The patients were separated into two groups (a low albumin group; 35 ≤ albumin ≥ 25 g/L and a very low albumin group; albumin < 25 g/L). These two groups were compared and statistically analysed for the calculated and the measured free PHT concentration. The calculated (1.2 mg/L, SD=0.7) and the measured (1.1 mg/L, SD=0.5) free PHT concentration correlated. The mean difference in the low and the very low albumin group was 0.10 mg/L (SD=1.4, n=11) and 0.13 mg/L (SD=0.24, n=12), respectively. Although the variability of the data could be a bias, no statistically significant difference between the groups was found: t-test (p=0.78), the Passing-Bablok regression, the Spearman’s rank correlation coefficient of r=0.907 and p=0.00, and the Bland-Altman plot including the regression analysis between the calculated and the measured value (M=0.11, SD=0.28). We concluded that in absence of a free PHT serum concentration measurement also in hypoalbuminemic patients, the Sheiner-Tozer algorithm represents a useful tool to assist TDM to calculate or control free PHT by using total PHT and the albumin concentration. GC-MS Analysis of biological PHT samples To correlate PHT blood serum levels, with “brain PHT levels” (the site of action of PHT), extracellular fluid from microdialysates in neurosurgical patients could be analyzed for PHT by an appropriate quantifying analytical method. In this investigation we describe the development and validation of a sensitive gas chromatography–mass spectrometry (GC–MS) method to identify and quantitate PHT in brain microdialysate, saliva and blood from human samples. For sample clean-up a SPE was performed with a nonpolar C8-SCX column. The eluate was evaporated with nitrogen (50°C) and derivatized with trimethylsulfonium hydroxide before GC-MS analysis. 5-(p-methylphenyl)-5-phenylhydantoin was used as internal standard. The MS was run in scan mode and the identification was made with three ion fragment masses. All peaks were identified with MassLib. Spiked PHT samples showed recovery after SPE of ≥ 94%. The calibration curve (PHT 50 to 1’200 ng/ml, n=6 at six concentration levels) showed good linearity and correlation (r2 > 0.998). The limit of detection was 15 ng/mL, the limit of quantification was 50 ng/mL. Dried extracted samples were stable within a 15% deviation range for ≥ 4 weeks at room temperature. The method met International Organization for Standardization standards and was able to detect and quantify PHT in different biological matrices and patient samples. The GC-MS method with SPE is specific, sensitive, robust and well reproducible and therefore, an appropriate candidate for pharmacokinetic assessment of PHT concentrations in different biological samples of treated patients

Discourse comprehension and simulation of positive emotions

Recent research has suggested that emotional sentences are understood by constructing an emotion simulation of the events being described. The present study aims to investigate whether emotion simulation is also involved in online and offline comprehension of larger language segments such as discourse. Participants read a target text describing positive events while their facial postures were manipulated to be either congruent (matching condition) or incongruent (mismatching condition) with emotional valence of the text. In addition, a control condition was included in which participants read the text naturally (without a manipulation of facial posture). The influence of emotion simulation on discourse understanding was assessed by online (self-paced reading times) and offline (verbatim and inference questions) measures of comprehension. The major result was that participants read faster the target text describing positive emotional events while their bodily systems were prepared for processing of positive emotions (matching condition) rather than unprepared (control condition) or prevented from positive emotional processing (mismatching condition). Simulation of positive emotions did not have a significant impact on offline explicit and implicit discourse comprehension. This pattern of results suggests that emotion simulation has an impact on online comprehension, but may not have any effect on offline discourse processing

Der Resultativ in den slavischen Sprachen

Resultative constructions are defined according to the St. Petersburg school of typology. In Slavic, there are three main types of resultatives, the subject resultative, the object resultative and the possessive resultative. Subject resultatives are more developed in West Slavic than in East Slavic, possessive resultatives can be found in all Slavic languages, but while in West Slavic and South Slavic they are constructed with an auxiliary meaning ‘have’, in East Slavic they are mostly built with ‘be’ and an adessive bearer of the resultative state. In three Slavic varieties they developed into a dynamic perfect: North West Russian dialects, Kashubian, and Macedonian. In all three cases language contact might have played a decisive role. Object resultatives are the most common in all Slavic languages. While in most Slavic languages they are formally identical with the dynamic passive, in Polish, Standard Czech and Sorbian dialects there are formal devices to distinguish them

Hydrophilic and amphiphilic water pollutants: using advanced analytical methods for classic and emerging contaminants

Organic pollutants are a highly relevant topic in environmental science and technology. This article briefly reviews historic developments, and then focuses on the current state of the art and future perspectives on the qualitative and quantitative trace determination of polar organic contaminants, which are of particular concern in municipal and industrial wastewater effluents, ambient surface waters, run-off waters, atmospheric waters, groundwaters and drinking waters. The pivotal role of advanced analytical methods is emphasized and an overview of some contaminant classes is presented. Some examples of polar water pollutants, which are discussed in a bit more detail here, are chosen from projects tackled by the research group led by the author of this articl

The Rhine red, the fish dead—the 1986 Schweizerhalle disaster, a retrospect and long-term impact assessment

Background: The November 1, 1986 fire at a Sandoz Ltd. storehouse at Schweizerhalle, an industrial area near Basel, Switzerland, resulted in chemical contamination of the environment. The storehouse, which was completely destroyed by the fire, contained pesticides, solvents, dyes, and various raw and intermediate materials. The majority of the approximately 1,250t of stored chemicals was destroyed in the fire, but large quantities were introduced into the atmosphere, into the Rhine River through runoff of the fire-fighting water, and into the soil and groundwater at the site. The chemicals discharged into the Rhine caused massive kills of benthic organisms and fish, particularly eels and salmonids. Public and private reaction to the fire and subsequent chemical spill was very strong. This happened only a few months after the Chernobyl accident and it destroyed the myth of immunity of Switzerland regarding such catastrophes. Aim: This article reviews the damaging events of November 1986 and aims at striking stock two decades later. Results and discussion: In the aftermath of this once-per-century accident, the aim was to obtain new knowledge for the environmental sciences and to achieve progress for water pollution control issues. The following themes are discussed: mitigation measures by the chemical industry and by the governmental authorities, activities of environmental protection organizations, chemical and biological monitoring, alert organization, ecological damages, ecotoxicological effects assessment, recovery and alteration of the river biology, return of the salmon, drinking water supplies, research programs, education of environmental scientists, and visions for the future. Conclusions: The catastrophic pollution of the Rhine in November 1986 has triggered by the openly visible damages of the river biology that subsequently significant progress was made towards the prevention of such environmental catastrophes. The crucial risk reduction measures in the chemical industry, legal regulations and controls as well as chemical and biological monitoring of the river water quality were substantially improved. Politics and chemical industry have learned their lectures and have proceeded accordingly. Recommendations: A drastic acute contamination, as it has happened at Schweizerhalle in 1986, is clearly recognizable by the toxic effects, which it is causing. This can lead to mitigation activities, which are positive considering a long-term perspective. However, the less obvious effects of chronic water pollution should receive more attention as well as the ongoing alteration of the biocenosis. A high water quality must be demanded for using water from the Rhine to produce drinking water. In that context, micropollutants should also be considered and particular attention should be payed to emerging contaminants. Perspectives: The big chemical storehouse fire of 1986 had an important impact on the transboundary cooperation and has improved the willingness for international cooperation. The fire catastrophe of Schweizerhalle has triggered many activities in particular for the Rhine River. Overall, the effects are positive on the basis of a long-term perspective. The applied whole basin approach gives an example on a global basis for other river systems, which still are more heavily pollute

Trace Determinations of Individual Organic Pollutants – 25 Years of Research at the Swiss Federal Institute for Environmental Science and Technology (EAWAG)

An overview is given on analytical developments and applications for the determination of organic trace pollutants which have been performed at EAWAG since 1972. Gas and liquid chromatographic methods are of crucial importance. The presented examples include environmental hydrocarbons, semivolatile compounds and detergent-derived chemicals

Southern Sudan Health Care

Statement of Concept: The concept of my creative project was use pictures, film, and music, and to create short yet visually inspiring promotional videos for the John Dau Sudan Foundation (JDSF), a non-profit organization started by former Lost Boy of Sudan, John Bul Dau. These videos were made to serve a variety of purposes for JDSF including: helping John Dau in acquiring speaking engagements, assisting JDSF in raising money for the clinic, raising awareness on the inadequate healthcare and struggles for Southern Sudan, and serving as web content for JDSF’s website. Context of Work: I have been working with John Bul Dau via my Policy Studies major since sophomore year. It was then, as the Visuals TA for an introductory policy studies class (PAF 101), that I was responsible for putting together a presentation for the class to educate them on John’s life story and create a PowerPoint presentation John could use as he spoke. I found that there wasn’t much available that was short enough to show audiences that may be unfamiliar with his life story and the problems he tackles. So I decided team up with JDSF to create videos that could be used for similar purposes. In doing this, I was asked to travel with John to film a speaking engagement in New York City and provide JDSF with copies to be sent out. Medium/Processes: To create my project I used a combination of pictures, video, and music to create a short video and a recording of a speaking engagement. This included filming my subject with V1U cameras from Newhouse and editing using both Avid and Final Cut. The V1U cameras I used recorded video and interviews onto mini-DV tapes, which I ingested into computers in the non-linear Avid editing suites. I then edited and exported this video from Avid to a Quicktime file that could be burned onto a DVD using Final Cut Pro and iDVD. In my project, I used Quicktime files of video taken and brought back from Sudan by John Dau and jpeg files given to the JDSF by a professional photographer. I edited these together with music to make the multimedia video using Final Cut Express. Conclusion: For my creative project, I used pictures, film, and music to create a short emotion-evoking video would be useful to former Lost Boy of Sudan John Bul Dau and the John Dau Sudan Foundation in raising money and awareness in their efforts to transform healthcare in Sudan. I also traveled with John Dau to New York City to film an honorable speaking engagement as a featured storyteller at a club called The Moth and provided JDSF with DVD copies. I used both Avid and Final Cut Express to edit the videos and a variety of sources for background research and specific information

Eating Disorders as a Lens Social Change in China

From the Washington University Senior Honors Thesis Abstracts (WUSHTA), 2017. Published by the Office of Undergraduate Research. Joy Zalis Kiefer, Director of Undergraduate Research and Associate Dean in the College of Arts & Sciences; Lindsey Paunovich, Editor; Helen Human, Programs Manager and Assistant Dean in the College of Arts and Sciences Mentor: Zhao M