In vivo testing of a novel adjustable glaucoma drainage device.

PURPOSE: We report on the in vivo testing of a novel noninvasively adjustable glaucoma drainage device (AGDD), which features an adjustable outflow resistance, and assess the safety and efficiency of this implant. METHODS: Under general anesthesia, the AGDD was implanted on seven white New Zealand rabbits for a duration of 4 months under a scleral flap in a way analogous to the Ex-PRESS device and set in an operationally closed position. The IOP was measured on a regular basis on the operated and control eyes using a rebound tonometer. Once a month the AGDD was adjusted noninvasively from its fully closed to its fully open position and the resulting pressure drop was measured. The contralateral eye was not operated and served as control. After euthanization, the eyes were collected for histology evaluation. RESULTS: The mean preoperative IOP was 11.1 ± 2.4 mm Hg. The IOP was significantly lower for the operated eye (6.8 ± 2 mm Hg) compared to the nonoperated eye (13.1 ± 1.6 mm Hg) during the first 8 days after surgery. When opening the AGDD from its fully closed to fully open position, the IOP dropped significantly from 11.2 ± 2.9 to 4.8 ± 0.9 mm Hg (P < 0.05). CONCLUSIONS: Implanting the AGDD is a safe and uncomplicated surgical procedure. The fluidic resistance was noninvasively adjustable during the postoperative period with the AGDD between its fully closed and fully open positions.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

A new alternative method for testing skin irritation using a human skin model: a pilot study.

Studies assessing skin irritation to chemicals have traditionally used laboratory animals; however, such methods are questionable regarding their relevance for humans. New in vitro methods have been validated, such as the reconstructed human epidermis (RHE) model (Episkin®, Epiderm®). The comparison (accuracy) with in vivo results such as the 4-h human patch test (HPT) is 76% at best (Epiderm®). There is a need to develop an in vitro method that better simulates the anatomo-pathological changes encountered in vivo. To develop an in vitro method to determine skin irritation using human viable skin through histopathology, and compare the results of 4 tested substances to the main in vitro methods and in vivo animal method (Draize test). Human skin removed during surgery was dermatomed and mounted on an in vitro flow-through diffusion cell system. Ten chemicals with known non-irritant (heptylbutyrate, hexylsalicylate, butylmethacrylate, isoproturon, bentazon, DEHP and methylisothiazolinone (MI)) and irritant properties (folpet, 1-bromohexane and methylchloroisothiazolinone (MCI/MI)), a negative control (sodiumchloride) and a positive control (sodiumlaurylsulphate) were applied. The skin was exposed at least for 4h. Histopathology was performed to investigate irritation signs (spongiosis, necrosis, vacuolization). We obtained 100% accuracy with the HPT model; 75% with the RHE models and 50% with the Draize test for 4 tested substances. The coefficients of variation (CV) between our three test batches were <0.1, showing good reproducibility. Furthermore, we reported objectively histopathological irritation signs (irritation scale): strong (folpet), significant (1-bromohexane), slight (MCI/MI at 750/250ppm) and none (isoproturon, bentazon, DEHP and MI). This new in vitro test method presented effective results for the tested chemicals. It should be further validated using a greater number of substances; and tested in different laboratories in order to suitably evaluate reproducibility.

Testing the effects of genetic crossing distance on embryo survival within a metapopulation of brown trout (Salmo trutta)

Predicting progeny performance from parental genetic divergence can potentially enhance the efficiency of supportive breeding programmes and facilitate risk assessment. Yet, experimental testing of the effects of breeding distance on offspring performance remains rare, especially in wild populations of vertebrates. Recent studies have demonstrated that embryos of salmonid fish are sensitive indicators of additive genetic variance for viability traits. We therefore used gametes of wild brown trout (Salmo trutta) from five genetically distinct populations of a river catchment in Switzerland, and used a full factorial design to produce over 2,000 embryos in 100 different crosses with varying genetic distances (FST range 0.005-0.035). Customized egg capsules allowed recording the survival of individual embryos until hatching under natural field conditions. Our breeding design enabled us to evaluate the role of the environment, of genetic and nongenetic parental contributions, and of interactions between these factors, on embryo viability. We found that embryo survival was strongly affected by maternal environmental (i.e. non-genetic) effects and by the microenvironment, i.e. by the location within the gravel. However, embryo survival was not predicted by population divergence, parental allelic dissimilarity, or heterozygosity, neither in the field nor under laboratory conditions. Our findings suggest that the genetic effects of inter-population hybridization within a genetically differentiated meta-population can be minor in comparison to environmental effects.

The Development of an Internal Testing Process for a Bluetooth Product

BlueGiga Technologies on uusi Bluetooth -teknologiaa soveltava pk-yritys. Yrityksen tuotekehitysprosessia täydentämään tarvittiin testausprosessi. Testausprosessin luominen oli haastavaa, koska Bluetooth -teknologia on uutta ja yritys on vielä nuori. Lisäksi se integroi kovo- ja ohjelmistokomponentteja tuotteissaan. Testaus aloitettiin evaluoimalla standardinmukaista tapaa dokumentoida testit. Tämän jälkeen tutkittiin BlueGigan ohjelmistokehitysprosessin suhdetta olemassa oleviin ohjelmistokehitysprosesseihin. Samanaikaisesti perehdyttiin Bluetooth -kvalifikaation testaukselle asettamiin vaatimuksiin. Tämän seurauksena TTCN:ää kokeiltiin helppolukuisen testitapauksen määrittelyssä. Käyttötapauksiin perustuvan testauksen sopivuutta Wireless Remote Access Platform:in (WRAP) testaamiseen arvioitiin kokeilemalla sitä Man-to-Machine -käyttötapauksen testaamisessa. Yllämainittujen tehtävien aikana kerätyn tiedon ja hankittujen kokemusten pohjalta laadittiin testausprosessi, joka kattaa yksikkö-, integraatio- ja järjestelmätason testauksen. Painopiste on järjestelmätason testauksessa. Prosessi määrittelee myös vastuuhenkilön tai -henkilöt eri testaustasoille.

Interface Implementation for GPRS/PCU Software Testing with Emulators

Jatkuvasti lisääntyvä matkapuhelinten käyttäjien määrä, internetin kehittyminen yleiseksi tiedon ja viihteen lähteeksi on luonut tarpeen palvelulle liikkuvan työaseman liittämiseksi tietokoneverkkoihin. GPRS on uusi teknologia, joka tarjoaa olemassa olevia matka- puhelinverkkoja (esim. NMT ja GSM) nopeamman, tehokkaamman ja taloudellisemman liitynnän pakettidataverkkoihin, kuten internettiin ja intranetteihin. Tämän työn tavoitteena oli toteuttaa GPRS:n paketinohjausyksikön (Packet Control Unit, PCU) testauksessa tarvittavat viestintäajurit työasemaympristöön. Aidot matkapuhelinverkot ovat liian kalliita, eikä niistä saa tarvittavasti lokitulostuksia, jotta niitä voisi käyttää GPRS:n testauksessa ohjelmiston kehityksen alkuvaihessa. Tämän takia PCU-ohjelmiston testaus suoritetaan joustavammassa ja helpommin hallittavassa ympäristössä, joka ei aseta kovia reaaliaikavaatimuksia. Uusi toimintaympäristö ja yhteysmedia vaativat PCU:n ja muiden GPRS-verkon yksiköiden välisistä yhteyksistä huolehtivien ohjelman osien, viestintäajurien uuden toteutuksen. Tämän työn tuloksena syntyivät tarvittavien viestintäajurien työasemaversiot. Työssä tarkastellaan eri tiedonsiirtotapoja ja -protokollia testattavan ohjelmiston vaateiden, toteutetun ajurin ja testauksen kannalta. Työssä esitellään kunkin ajurin toteuttama rajapinta ja toteutuksen aste, eli mitkä toiminnot on toteutettu ja mitä on jätetty pois. Ajureiden rakenne ja toiminta selvitetään siltä osin, kuin se on oleellista ohjelman toiminnan kannalta.

Statistical hypothesis testing and common misinterpretations: should we abandon p-value in forensic science applications?

Many people regard the concept of hypothesis testing as fundamental to inferential statistics. Various schools of thought, in particular frequentist and Bayesian, have promoted radically different solutions for taking a decision about the plausibility of competing hypotheses. Comprehensive philosophical comparisons about their advantages and drawbacks are widely available and continue to span over large debates in the literature. More recently, controversial discussion was initiated by an editorial decision of a scientific journal [1] to refuse any paper submitted for publication containing null hypothesis testing procedures. Since the large majority of papers published in forensic journals propose the evaluation of statistical evidence based on the so called p-values, it is of interest to expose the discussion of this journal's decision within the forensic science community. This paper aims to provide forensic science researchers with a primer on the main concepts and their implications for making informed methodological choices.

Development of techniques for testing the effect of the E1 region on adenovirus integration /

Adenoviral vectors are currently the most widely used gene therapeutic vectors, but their inability to integrate into host chromosomal DNA shortened their transgene expression and limited their use in clinical trials. In this project, we initially planned to develop a technique to test the effect of the early region 1 (E1) on adenovirus integration by comparing the integration efficiencies between an E1-deleted adenoviral vector (SubE1) and an Elcontaining vector (SubE3). However, we did not harvest any SubE3 virus, even if we repeated the transfection and successfully rescued the SubE1 virus (2/4 transfections generated viruses) and positive control virus (6/6). The failure of rescuing SubE3 could be caused by the instability of the genomic plasmid pFG173, as it had frequent intemal deletions when we were purifying It. Therefore, we developed techniques to test the effect of E1 on homologous recombination (HR) since literature suggested that adenovirus integration is initiated by HR. We attempted to silence the E1 in 293 cells by transfecting E1A/B-specific small interfering RNA (siRNA). However, no silenced phenotype was observed, even if we varied the concentrations of E1A/B siRNA (from 30 nM to 270 nM) and checked the silencing effects at different time points (48, 72, 96 h). One possible explanation would be that the E1A/B siRNA sequences are not potent enough to Induce the silenced phenotype. For evaluating HR efficiencies, an HR assay system based on bacterial transfonmatJon was designed. We constmcted two plasmids ( designated as pUC19-dl1 and pUC19-dl2) containing different defective lacZa cassettes (forming white colonies after transformation) that can generate a functional lacZa cassette (forming blue colonies) through HR after transfecting into 293 cells. The HR efficiencies would be expressed as the percentages of the blue colonies among all the colonies. Unfortunately, after transfonnation of plasmid isolated from 293 cells, no colony was found, even at a transformation efficiency of 1.8x10^ colonies/pg pUC19, suggesting the sensitivity of this system was low. To enhance the sensitivity, PCR was used. We designed a set of primers that can only amplify the recombinant plasmid fomied through HR. Therefore, the HR efficiencies among different treatments can be evaluated by the amplification results, and this system could be used to test the effect of E1 region on adenovirus integration. In addition, to our knowledge there was no previous studies using PCR/ Realtime PCR to evaluate HR efficiency, so this system also provides a PCR-based method to carry out the HR assays.

Attachment and alcohol : testing a motivational model of problem drinking /

The purpose of this study was to replicate and extend a motivational model of problem drinking (Cooper, Frone, Russel, & Mudar, 1995; Read, Wood, Kahler, Maddock & Tibor, 2003), testing the notion that attachment is a common antecedent for both the affective and social paths to problem drinking. The model was tested with data from three samples, first-year university students (N=679), students about to graduate from university (N=206), and first-time clients at an addiction treatment facility (N=21 1). Participants completed a battery of questionnaires assessing alcohol use, alcohol-related consequences, drinking motives, peer models of alcohol use, positive and negative affect, attachment anxiety and attachment avoidance. Results underscored the importance of the affective path to problem drinking, while putting the social path to problem drinking into question. While drinking to cope was most prominent among the clinical sample, coping motives served as a risk factor for problem drinking for both individuals identified as problem drinkers and university students. Moreover, drinking for enhancement purposes appeared to be the strongest overall predictor of alcohol use. Results of the present study also supported the notion that attachment anxiety and avoidance are antecedents for the affective path to problem drinking, such that those with higher levels of attachment anxiety and avoidance were more vulnerable to experiencing adverse consequences related to their drinking, explained in terms of diminished affect regulation. Evidence that nonsecure attachment is a potent predictor of problem drinking was also demonstrated by the finding that attachment anxiety was directly related to alcohol-related consequences over and above its indirect relationship through affect regulation. However, results failed to show that attachment anxiety or attachment avoidance increased the risk of problem drinking via social influence.

The Effect of Trainer Muscularity and Expertise on Self-Presentational Concerns, Body Image, and Performance in College Men during One-Repetition Maximum Testing

This study attempted to manipulate self-presentational efficacy to examine the effect on social anxiety, social physique anxiety, drive for muscularity, and maximal strength performance during a one-repetition maximum (1-RM) chest press and leg press test. Ninety-nine college men with a minimum of six months of previous weight training experience were randomly assigned to complete a 1-RM protocol with either a muscular male trainer described as an expert or a lean male trainer described as a novice. Participants completed measures of self-presentation and body image prior to meeting their respective trainer, and following the completion of the 1-RM tests. Although the self-presentational efficacy manipulation was not successful, the trainers were perceived significantly differently on musculature and expertise. The group with the muscular, expert trainer reported higher social anxiety and attained higher 1-RM scores for the chest and leg press. Thus, trainer characteristics can affect strength performance and self-presentational concerns in this population.

Optimal and Robust Designs of Step-stress Accelerated Life Testing Experiments for Proportional Hazards Models

Accelerated life testing (ALT) is widely used to obtain reliability information about a product within a limited time frame. The Cox s proportional hazards (PH) model is often utilized for reliability prediction. My master thesis research focuses on designing accelerated life testing experiments for reliability estimation. We consider multiple step-stress ALT plans with censoring. The optimal stress levels and times of changing the stress levels are investigated. We discuss the optimal designs under three optimality criteria. They are D-, A- and Q-optimal designs. We note that the classical designs are optimal only if the model assumed is correct. Due to the nature of prediction made from ALT experimental data, attained under the stress levels higher than the normal condition, extrapolation is encountered. In such case, the assumed model cannot be tested. Therefore, for possible imprecision in the assumed PH model, the method of construction for robust designs is also explored.

Stress testing a complement of value-a-risk.

Rapport de stage (maîtrise en finance mathématique et computationnelle)