Opioid maintenance therapy in Switzerland: an overview of the Swiss IMPROVE study.

BACKGROUND/AIMS: Switzerland's drug policy model has always been unique and progressive, but there is a need to reassess this system in a rapidly changing world. The IMPROVE study was conducted to gain understanding of the attitudes and beliefs towards opioid maintenance therapy (OMT) in Switzerland with regards to quality and access to treatment. To obtain a "real-world" view on OMT, the study approached its goals from two different angles: from the perspectives of the OMT patients and of the physicians who treat patients with maintenance therapy. The IMPROVE study collected a large body of data on OMT in Switzerland. This paper presents a small subset of the dataset, focusing on the research design and methodology, the profile of the participants and the responses to several key questions addressed by the questionnaires. METHODS: IMPROVE was an observational, questionnaire-based cross-sectional study on OMT conducted in Switzerland. Respondents consisted of OMT patients and treating physicians from various regions of the country. Data were collected using questionnaires in German and French. Physicians were interviewed by phone with a computer-based questionnaire. Patients self-completed a paper-based questionnaire at the physicians' offices or OMT treatment centres. RESULTS: A total of 200 physicians and 207 patients participated in the study. Liquid methadone and methadone tablets or capsules were the medications most commonly prescribed by physicians (60% and 20% of patient load, respectively) whereas buprenorphine use was less frequent. Patients (88%) and physicians (83%) were generally satisfied with the OMT currently offered. The current political framework and lack of training or information were cited as determining factors that deter physicians from engaging in OMT. About 31% of OMT physicians interviewed were ≥60 years old, indicating an ageing population. Diversion and misuse were considered a significant problem in Switzerland by 45% of the physicians. CONCLUSION: The subset of IMPROVE data presented gives a present-day, real-life overview of the OMT landscape in Switzerland. It represents a valuable resource for policy makers, key opinion leaders and drug addiction researchers and will be a useful basis for improving the current Swiss OMT model.

Phase I/IIa study of cilengitide and temozolomide with concomitant radiotherapy followed by cilengitide and temozolomide maintenance therapy in patients with newly diagnosed glioblastoma.

Purpose: Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. Patients and Methods: Patients (age >= 18 to >= 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. Results: Fifty-two patients ( median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% ( 95% CI, 21% to 46%). Median PFS was 8 months ( 95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival ( OS) rates were 68% ( 95% CI, 53% to 79%) and 35% ( 95% CI, 22% to 48%). Median OS was 16.1 months ( 95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. Conclusion: Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation. J Clin Oncol 28:2712-2718. (C) 2010 by American Society of Clinical Oncology

Synthesis of Best Practice for Increasing Protection and Visibility of Highway Maintenance Vehicles, CTRE Final Report Iowa DOT Project TR-475, August 2002

The purpose of this research project is to study current practices in enhancing visibility and protection of highway maintenance vehicles involved in moving operations such as snow removal and shoulder operations, crack sealing, and pothole patching. The results will enable the maintenance staff to adequately assess the applicability and impact of each strategy to their use and budget. The report’s literature review chapter examines the use of maintenance vehicle warning lights, retroreflective tapes, shadow vehicles and truck-mounted attenuators, and advanced vehicle control systems, as well as other practices to improve visibility for both snowplow operators and vehicles. The chapter concludes that the Manual on Uniform Traffic Control Devices does not specify what color or kind of warning lights to use. Thus, a wide variety of lights are being used on maintenance vehicles. The study of the relevant literatures also suggests that there are no clear guidelines for moving work zones at this time. Two types of surveys were conducted to determine current practices to improve visibility and safety in moving work zones across the country and in the state of Iowa. In the first survey of state departments of transportation, most indicated using amber warning lights on their maintenance vehicles. Almost all the responding states indicated using some form of reflective material on their vehicles to make them more visible. Most participating states indicated that the color of their vehicles is orange. Most states indicated using more warning lights on snow removal vehicles than their other maintenance vehicles. All responding state agencies indicated using shadow vehicles and/or truck-mounted attenuators during their moving operations. In the second survey of Iowa counties, most indicated using very similar traffic control and warning devices during their granular road maintenance and snow removal operations. Mounting warning signs and rotating or strobe lights on the rear of maintenance vehicles is common for Iowa counties. The most common warning devices used during the counties’ snow removal operations are reflective tapes, warning flags, strobe lights, and auxiliary headlamps.

X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

Background: Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects. Results: Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%). Conclusion:This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.

Molecular role of Cx37 in advanced atherosclerosis: a micro-array study.

Recently, we showed that connexin37 (Cx37) protects against early atherosclerotic lesion development by regulating monocyte adhesion. The expression of this gap junction protein is altered in mouse and human atherosclerotic lesions; it is increased in macrophages newly recruited to the lesions and disappears from the endothelium of advanced plaques. To obtain more insight into the molecular role of Cx37 in advanced atherosclerosis, we used micro-array analysis for gene expression profiling in aortas of ApoE(-/-) and Cx37(-/-)ApoE(-/-) mice before and after 18 weeks of cholesterol-rich diet. Out of >15,000 genes, 106 genes were significantly differentially expressed in young mice before diet (P-value of <0.05, fold change of >0.7 or <-0.7, and intensity value >2.2 times background). Ingenuity pathway analysis (IPA) revealed differences in genes involved in cell-to-cell signaling and interaction, cellular compromise and nutritional disease. In addition, we identified 100 genes that were significantly perturbed after the cholesterol-rich diet. Similar to the analysis on 10-week-old mice, IPA revealed differences in genes involved in cell-to-cell signaling and interaction as well as to immuno-inflammatory disease. Furthermore, we found important changes in genes involved in vascular calcification and matrix degradation, some of which were confirmed at protein level by (immuno-)histochemistry. In conclusion, we suggest that Cx37 deficiency alters the global differential gene expression profiles in young mice towards a pro-inflammatory phenotype, which are then further influenced in advanced atherosclerosis. The results provide new insights into the significance of Cx37 in plaque calcification.

Web-based Implementation of Winter Maintenance Decision Support System Using GIS and Remote Sensing, May 2005

Winter maintenance, particularly snow removal and the stress of snow removal materials on public structures, is an enormous budgetary burden on municipalities and nongovernmental maintenance organizations in cold climates. Lately, geospatial technologies such as remote sensing, geographic information systems (GIS), and decision support tools are roviding a valuable tool for planning snow removal operations. A few researchers recently used geospatial technologies to develop winter maintenance tools. However, most of these winter maintenance tools, while having the potential to address some of these information needs, are not typically placed in the hands of planners and other interested stakeholders. Most tools are not constructed with a nontechnical user in mind and lack an easyto-use, easily understood interface. A major goal of this project was to implement a web-based Winter Maintenance Decision Support System (WMDSS) that enhances the capacity of stakeholders (city/county planners, resource managers, transportation personnel, citizens, and policy makers) to evaluate different procedures for managing snow removal assets optimally. This was accomplished by integrating geospatial analytical techniques (GIS and remote sensing), the existing snow removal asset management system, and webbased spatial decision support systems. The web-based system was implemented using the ESRI ArcIMS ActiveX Connector and related web technologies, such as Active Server Pages, JavaScript, HTML, and XML. The expert knowledge on snow removal procedures is gathered and integrated into the system in the form of encoded business rules using Visual Rule Studio. The system developed not only manages the resources but also provides expert advice to assist complex decision making, such as routing, optimal resource allocation, and monitoring live weather information. This system was developed in collaboration with Black Hawk County, IA, the city of Columbia, MO, and the Iowa Department of transportation. This product was also demonstrated for these agencies to improve the usability and applicability of the system.

A systolic array for linear MIMO detection based on an all-swap lattice reduction algorithm

A systolic array to implement lattice-reduction-aided lineardetection is proposed for a MIMO receiver. The lattice reductionalgorithm and the ensuing linear detections are operated in the same array, which can be hardware-efficient. All-swap lattice reduction algorithm (ASLR) is considered for the systolic design.ASLR is a variant of the LLL algorithm, which processes all lattice basis vectors within one iteration. Lattice-reduction-aided linear detection based on ASLR and LLL algorithms have very similarbit-error-rate performance, while ASLR is more time efficient inthe systolic array, especially for systems with a large number ofantennas.

Heterozygote advantage and the maintenance of polymorphism for multilocus traits.

Explaining how polymorphism is maintained in the face of selection remains a puzzle since selection tends to erode genetic variation. Provided an infinitely large unsubdivided population and no frequency-dependance of selective values, heterozygote advantage is the text book explanation for the maintenance of polymorphism when selection acts at a diallelic locus. Here, we investigate whether this remains true when selection acts at multiple diallelic loci. We use five different definitions of heterozygote advantage that largely cover this concept for multiple loci. Using extensive numerical simulations, we found no clear associations between the presence of any of the five definitions of heterozygote advantage and the maintenance of polymorphism at all loci. The strength of the association decreases as the number of loci increases or as recombination decreases. We conclude that heterozygote advantage cannot be a general mechanism for the maintenance of genetic polymorphism at multiple loci. These findings suggest that a correlation between the number of heterozygote loci and fitness is not warranted on theoretical ground.

Phenotypes influencing low physical activity in maintenance dialysis.

OBJECTIVE: The "Pas à Pas" initiative aimed at evaluating the weekly physical activity (PA) and its determinants in a large cohort of dialysis patients. SETTING: Physical inactivity is a risk factor for mortality in maintenance dialysis patients and is still poorly documented in this population. DESIGN: A prospective national epidemiological study was performed. SUBJECTS: A total of 1,163 patients on maintenance dialysis (hemodialysis and peritoneal dialysis) were included. INTERVENTION AND MAIN OUTCOME MEASURE: PA was recorded during seven consecutive days using a pedometer to measure daily step numbers. RESULTS: Median age was 63 years (Q1 51-Q3 75). Sixty-three percent were sedentary (<5000 steps/day) with a median of 3,688 steps/day (1,866-6,271)]. PA level was similar between hemodialysis patients and those on peritoneal dialysis (3,693 steps [1,896-6,307] vs. 3,320 [1,478-5,926], P = .33). In hemodialysis patients, PA was lower on dialysis days compared with nondialysis days (2,912 [1,439-5,232] vs. 4,054 [2,136-7,108], respectively, P < .01). PA gradually decreased with age, 57% being sedentary between 50 and 65 years and 83% of patients after 80 years. Beyond this age effect, we identified, for the first time, specific phenotypes of patients with lower PA, such as inflammation, cardiovascular disease, protein energy wasting, obesity, and diabetes. By contrast, previous kidney transplantation and a higher muscle mass were associated with higher PA. CONCLUSIONS: Dialysis patients present a very low level of PA with high sedentary. Acting on patient's modifiable phenotypes may help to increase PA to improve morbidity, mortality, and quality of life.

Altered expression of the transcription factor Mef2c during retinal degeneration in Rpe65-/- mice.

Purpose. To investigate the role of the myocyte enhancer factor 2 (Mef2) transcription factor family in retinal diseases, Mef2c expression was assessed during retinal degeneration in the Rpe65(-/-) mouse model of Leber's congenital amaurosis (LCA). Mef2c-dependent expression of photoreceptor-specific genes was further addressed. Methods. Expression of Mef2 members was analyzed by oligonucleotide microarray, quantitative PCR (qPCR) and in situ hybridization. Mef2c-dependent transcriptional activity was assayed by luciferase assay in HEK293T cells. Results. Mef2c was the only Mef2 member markedly downregulated during retinal degeneration in Rpe65(-/-) mice. Mef2c mRNA level was decreased by more than 2 fold at 2 and 4 months and by 3.5 fold at 6 months in retinas of Rpe65(-/-) mice. Downregulation of Mef2c at the protein level was confirmed in Rpe65(-/-) retinas. The decrease in Mef2c mRNA levels in the developing Rpe65(-/-) retinas, from post-natal day (P)13 onward, was concomitant with the decreased expression of the rod-specific transcription factors Nrl and Nr2e3. Nrl was further shown to drive Mef2c transcriptional activity, supporting a physiological role for Mef2c in the retina. In addition, Mef2c appeared to act as a transcriptional repressor of its own expression, as well as those of the retina-specific retinal G-protein coupled receptor (Rgr), rhodopsin and M-opsin genes. Conclusions. These findings highlight the early altered regulation of the rod-specific transcriptional network in Rpe65-related disease. They further indicate that Mef2c may act as a novel transcription factor involved in the development and the maintenance of photoreceptor cells.

Local Roads Maintenance Workers’ Manual, June 2006

This manual describes best roadway maintenance practices for Iowa's local roads and streets, from the center line to shoulders, ditches, and drainage, with chapters on public relations, bridge maintenance, and snow and ice control. Each chapter contains safety tips, information(as appropriate) on managing quality control, and a list of references for further information.

Evolutionary games on complex networks : the emergence and maintenance of cooperation

Abstract The object of game theory lies in the analysis of situations where different social actors have conflicting requirements and where their individual decisions will all influence the global outcome. In this framework, several games have been invented to capture the essence of various dilemmas encountered in many common important socio-economic situations. Even though these games often succeed in helping us understand human or animal behavior in interactive settings, some experiments have shown that people tend to cooperate with each other in situations for which classical game theory strongly recommends them to do the exact opposite. Several mechanisms have been invoked to try to explain the emergence of this unexpected cooperative attitude. Among them, repeated interaction, reputation, and belonging to a recognizable group have often been mentioned. However, the work of Nowak and May (1992) showed that the simple fact of arranging the players according to a spatial structure and only allowing them to interact with their immediate neighbors is sufficient to sustain a certain amount of cooperation even when the game is played anonymously and without repetition. Nowak and May's study and much of the following work was based on regular structures such as two-dimensional grids. Axelrod et al. (2002) showed that by randomizing the choice of neighbors, i.e. by actually giving up a strictly local geographical structure, cooperation can still emerge, provided that the interaction patterns remain stable in time. This is a first step towards a social network structure. However, following pioneering work by sociologists in the sixties such as that of Milgram (1967), in the last few years it has become apparent that many social and biological interaction networks, and even some technological networks, have particular, and partly unexpected, properties that set them apart from regular or random graphs. Among other things, they usually display broad degree distributions, and show small-world topological structure. Roughly speaking, a small-world graph is a network where any individual is relatively close, in terms of social ties, to any other individual, a property also found in random graphs but not in regular lattices. However, in contrast with random graphs, small-world networks also have a certain amount of local structure, as measured, for instance, by a quantity called the clustering coefficient. In the same vein, many real conflicting situations in economy and sociology are not well described neither by a fixed geographical position of the individuals in a regular lattice, nor by a random graph. Furthermore, it is a known fact that network structure can highly influence dynamical phenomena such as the way diseases spread across a population and ideas or information get transmitted. Therefore, in the last decade, research attention has naturally shifted from random and regular graphs towards better models of social interaction structures. The primary goal of this work is to discover whether or not the underlying graph structure of real social networks could give explanations as to why one finds higher levels of cooperation in populations of human beings or animals than what is prescribed by classical game theory. To meet this objective, I start by thoroughly studying a real scientific coauthorship network and showing how it differs from biological or technological networks using divers statistical measurements. Furthermore, I extract and describe its community structure taking into account the intensity of a collaboration. Finally, I investigate the temporal evolution of the network, from its inception to its state at the time of the study in 2006, suggesting also an effective view of it as opposed to a historical one. Thereafter, I combine evolutionary game theory with several network models along with the studied coauthorship network in order to highlight which specific network properties foster cooperation and shed some light on the various mechanisms responsible for the maintenance of this same cooperation. I point out the fact that, to resist defection, cooperators take advantage, whenever possible, of the degree-heterogeneity of social networks and their underlying community structure. Finally, I show that cooperation level and stability depend not only on the game played, but also on the evolutionary dynamic rules used and the individual payoff calculations. Synopsis Le but de la théorie des jeux réside dans l'analyse de situations dans lesquelles différents acteurs sociaux, avec des objectifs souvent conflictuels, doivent individuellement prendre des décisions qui influenceront toutes le résultat global. Dans ce cadre, plusieurs jeux ont été inventés afin de saisir l'essence de divers dilemmes rencontrés dans d'importantes situations socio-économiques. Bien que ces jeux nous permettent souvent de comprendre le comportement d'êtres humains ou d'animaux en interactions, des expériences ont montré que les individus ont parfois tendance à coopérer dans des situations pour lesquelles la théorie classique des jeux prescrit de faire le contraire. Plusieurs mécanismes ont été invoqués pour tenter d'expliquer l'émergence de ce comportement coopératif inattendu. Parmi ceux-ci, la répétition des interactions, la réputation ou encore l'appartenance à des groupes reconnaissables ont souvent été mentionnés. Toutefois, les travaux de Nowak et May (1992) ont montré que le simple fait de disposer les joueurs selon une structure spatiale en leur permettant d'interagir uniquement avec leurs voisins directs est suffisant pour maintenir un certain niveau de coopération même si le jeu est joué de manière anonyme et sans répétitions. L'étude de Nowak et May, ainsi qu'un nombre substantiel de travaux qui ont suivi, étaient basés sur des structures régulières telles que des grilles à deux dimensions. Axelrod et al. (2002) ont montré qu'en randomisant le choix des voisins, i.e. en abandonnant une localisation géographique stricte, la coopération peut malgré tout émerger, pour autant que les schémas d'interactions restent stables au cours du temps. Ceci est un premier pas en direction d'une structure de réseau social. Toutefois, suite aux travaux précurseurs de sociologues des années soixante, tels que ceux de Milgram (1967), il est devenu clair ces dernières années qu'une grande partie des réseaux d'interactions sociaux et biologiques, et même quelques réseaux technologiques, possèdent des propriétés particulières, et partiellement inattendues, qui les distinguent de graphes réguliers ou aléatoires. Entre autres, ils affichent en général une distribution du degré relativement large ainsi qu'une structure de "petit-monde". Grossièrement parlant, un graphe "petit-monde" est un réseau où tout individu se trouve relativement près de tout autre individu en termes de distance sociale, une propriété également présente dans les graphes aléatoires mais absente des grilles régulières. Par contre, les réseaux "petit-monde" ont, contrairement aux graphes aléatoires, une certaine structure de localité, mesurée par exemple par une quantité appelée le "coefficient de clustering". Dans le même esprit, plusieurs situations réelles de conflit en économie et sociologie ne sont pas bien décrites ni par des positions géographiquement fixes des individus en grilles régulières, ni par des graphes aléatoires. De plus, il est bien connu que la structure même d'un réseau peut passablement influencer des phénomènes dynamiques tels que la manière qu'a une maladie de se répandre à travers une population, ou encore la façon dont des idées ou une information s'y propagent. Ainsi, durant cette dernière décennie, l'attention de la recherche s'est tout naturellement déplacée des graphes aléatoires et réguliers vers de meilleurs modèles de structure d'interactions sociales. L'objectif principal de ce travail est de découvrir si la structure sous-jacente de graphe de vrais réseaux sociaux peut fournir des explications quant aux raisons pour lesquelles on trouve, chez certains groupes d'êtres humains ou d'animaux, des niveaux de coopération supérieurs à ce qui est prescrit par la théorie classique des jeux. Dans l'optique d'atteindre ce but, je commence par étudier un véritable réseau de collaborations scientifiques et, en utilisant diverses mesures statistiques, je mets en évidence la manière dont il diffère de réseaux biologiques ou technologiques. De plus, j'extrais et je décris sa structure de communautés en tenant compte de l'intensité d'une collaboration. Finalement, j'examine l'évolution temporelle du réseau depuis son origine jusqu'à son état en 2006, date à laquelle l'étude a été effectuée, en suggérant également une vue effective du réseau par opposition à une vue historique. Par la suite, je combine la théorie évolutionnaire des jeux avec des réseaux comprenant plusieurs modèles et le réseau de collaboration susmentionné, afin de déterminer les propriétés structurelles utiles à la promotion de la coopération et les mécanismes responsables du maintien de celle-ci. Je mets en évidence le fait que, pour ne pas succomber à la défection, les coopérateurs exploitent dans la mesure du possible l'hétérogénéité des réseaux sociaux en termes de degré ainsi que la structure de communautés sous-jacente de ces mêmes réseaux. Finalement, je montre que le niveau de coopération et sa stabilité dépendent non seulement du jeu joué, mais aussi des règles de la dynamique évolutionnaire utilisées et du calcul du bénéfice d'un individu.

Study of Iowa's Current Road Use Tax Funds (RUTF) and Future Road Maintenance and Construction Needs, 2006

The 81st General Assembly of the Iowa Legislature, in Section 85 of House File 868, required the Iowa Department of Transportation (DOT) to conduct a study of current Road Use Tax Fund (RUTF)revenues, and projected roadway construction and maintenance needs.

Study of Iowa’s Current Road Use Tax Funds (RUTF) and Future Road Maintenance and Construction Needs, 2006

The 81st General Assembly of the Iowa legislature, in Section 85 of House File 868, required the Iowa Department of Transportation (Iowa DOT) to conduct a study of current Road Use Tax Fund (RUTF) revenues, and projected roadway construction and maintenance needs. With input from Iowa’s cities, counties and other interested groups, the Iowa DOT completed this report for submittal to the legislature.