Strategies and tools for preventing neurotoxicity: to test, to predict and how to do it

A change in paradigm is needed in the prevention of toxic effects on the nervous system, moving from its present reliance solely on data from animal testing to a prediction model mostly based on in vitro toxicity testing and in silico modeling. According to the report published by the National Research Council (NRC) of the US National Academies of Science, high-throughput in vitro tests will provide evidence for alterations in"toxicity pathways" as the best possible method of large scale toxicity prediction. The challenges to implement this proposal are enormous, and provide much room for debate. While many efforts address the technical aspects of implementing the vision, many questions around it need also to be addressed. Is the overall strategy the only one to be pursued? How can we move from current to future paradigms? Will we ever be able to reliably model for chronic and developmental neurotoxicity in vitro? This paper summarizes four presentations from a symposium held at the International Neurotoxicology Conference held in Xi"an, China, in June 2011. A. Li reviewed the current guidelines for neurotoxicity and developmental neurotoxicity testing, and discussed the major challenges existing to realize the NCR vision for toxicity testing. J. Llorens reviewed the biology of mammalian toxic avoidance in view of present knowledge on the physiology and molecular biology of the chemical senses, taste and smell. This background information supports the hypothesis that relating in vivo toxicity to chemical epitope descriptors that mimic the chemical encoding performed by the olfactory system may provide a way to the long term future of complete in silico toxicity prediction. S. Ceccatelli reviewed the implementation of rodent and human neural stem cells (NSCs) as models for in vitro toxicity testing that measures parameters such as cell proliferation, differentiation and migration. These appear to be sensitive endpoints that can identify substances with developmental neurotoxic potential. C. Sun ol reviewed the use of primary neuronal cultures in testing for neurotoxicity of environmental pollutants, including the study of the effects of persistent exposures and/or in differentiating cells, which allow recording of effects that can be extrapolated to human developmental neurotoxicity.

Converter-flux-based current control of voltage source PWM rectifiers - analysis and implementation

Pulsewidth-modulated (PWM) rectifier technology is increasingly used in industrial applications like variable-speed motor drives, since it offers several desired features such as sinusoidal input currents, controllable power factor, bidirectional power flow and high quality DC output voltage. To achieve these features,however, an effective control system with fast and accurate current and DC voltage responses is required. From various control strategies proposed to meet these control objectives, in most cases the commonly known principle of the synchronous-frame current vector control along with some space-vector PWM scheme have been applied. Recently, however, new control approaches analogous to the well-established direct torque control (DTC) method for electrical machines have also emerged to implement a high-performance PWM rectifier. In this thesis the concepts of classical synchronous-frame current control and DTC-based PWM rectifier control are combined and a new converter-flux-based current control (CFCC) scheme is introduced. To achieve sufficient dynamic performance and to ensure a stable operation, the proposed control system is thoroughly analysed and simple rules for the controller design are suggested. Special attention is paid to the estimationof the converter flux, which is the key element of converter-flux-based control. Discrete-time implementation is also discussed. Line-voltage-sensorless reactive reactive power control methods for the L- and LCL-type line filters are presented. For the L-filter an open-loop control law for the d-axis current referenceis proposed. In the case of the LCL-filter the combined open-loop control and feedback control is proposed. The influence of the erroneous filter parameter estimates on the accuracy of the developed control schemes is also discussed. A newzero vector selection rule for suppressing the zero-sequence current in parallel-connected PWM rectifiers is proposed. With this method a truly standalone and independent control of the converter units is allowed and traditional transformer isolation and synchronised-control-based solutions are avoided. The implementation requires only one additional current sensor. The proposed schemes are evaluated by the simulations and laboratory experiments. A satisfactory performance and good agreement between the theory and practice are demonstrated.

Preventive and therapeutic strategies in critically ill patients with highly resistant bacteria.

The antibiotic pipeline continues to diminish and the majority of the public remains unaware of this critical situation. The cause of the decline of antibiotic development is multifactorial and currently most ICUs are confronted with the challenge of multidrug-resistant organisms. Antimicrobial multidrug resistance is expanding all over the world, with extreme and pandrug resistance being increasingly encountered, especially in healthcare-associated infections in large highly specialized hospitals. Antibiotic stewardship for critically ill patients translated into the implementation of specific guidelines, largely promoted by the Surviving Sepsis Campaign, targeted at education to optimize choice, dosage, and duration of antibiotics in order to improve outcomes and reduce the development of resistance. Inappropriate antimicrobial therapy, meaning the selection of an antibiotic to which the causative pathogen is resistant, is a consistent predictor of poor outcomes in septic patients. Therefore, pharmacokinetically/pharmacodynamically optimized dosing regimens should be given to all patients empirically and, once the pathogen and susceptibility are known, local stewardship practices may be employed on the basis of clinical response to redefine an appropriate regimen for the patient. This review will focus on the most severely ill patients, for whom substantial progress in organ support along with diagnostic and therapeutic strategies markedly increased the risk of nosocomial infections.

Innovative implementation by non-state actors in environment-related areas : towards a positive implementation gap ?

This contribution (presented in the first International Conference on Public Policy (ICPP) in Grenoble in June 2013) explores the phenomena of innovation in action ("innovative implementation"). To do so, we operationalize "innovative implementation" as a strategy by which (coalitions of) non-state actors seek to develop ad hoc solutions to address a given environmental issue, going beyond what is provided for in formal policy designs. Following an inductive research strategy, we elaborate a conceptual framework whose main advantage is to bring the actors and their coalition (in all their diversity) back in the analysis. More concretely, we state that perceiving implementation as broader 'social interaction processes' (De Boer & Bressers 2011) within which actors play strategic 'games' (Bardach 1977, Scharpf 1997) opens interesting lines of research to better account for their innovative and strategic behaviours. In a second step, we apply this framework to three strategies of innovative implementation in different contexts, and identify on this basis empirical regularities in the individual pathways related to the emergence and success (or failure) of these strategies.

Safer-drinking strategies used by chronically homeless individuals with alcohol dependence.

Chronically homeless individuals with alcohol dependence experience severe alcohol-related consequences. It is therefore important to identify factors that might be associated with reduced alcohol-related harm, such as the use of safer-drinking strategies. Whereas effectiveness of safer-drinking strategies has been well-documented among young adults, no studies have explored this topic among more severely affected populations, such as chronically homeless individuals with alcohol dependence. The aims of this study were thus to qualitatively and quantitatively document safer-drinking strategies used in this population. Participants (N=31) were currently or formerly chronically homeless individuals with alcohol dependence participating in a pilot study of extended-release naltrexone and harm-reduction counseling. At weeks 0 and 8, research staff provided a list of safer-drinking strategies for participants to endorse. Implementation of endorsed safer-drinking strategies was recorded at the next appointment. At both time points, strategies to buffer the effects of alcohol on the body (e.g., eating prior to and during drinking) were most highly endorsed, followed by changing the manner in which one drinks (e.g., spacing drinks), and reducing alcohol consumption. Quantitative analyses indicated that all participants endorsed safer-drinking strategies, and nearly all strategies were implemented (80-90% at weeks 0 and 8, respectively). These preliminary findings indicate that chronically homeless people with alcohol dependence use strategies to reduce harm associated with their drinking. Larger randomized controlled trials are needed to test whether interventions that teach safer-drinking strategies may reduce overall alcohol-related harm in this population.

Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies.

PURPOSE: We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. METHODS: We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. RESULTS: A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. CONCLUSION: This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.

Strategy Formulation and Implementation Case of High Tech Instruments

The strategy process is a method for strategy formulation and implementation. The strategy process is commonly used especially within bigger companies. It is important to link the strategy formulation and implementation. The objective of this thesis has been to find out improvement areas for the case company’s strategy process. The theoretical framework based on literature emphasizes on strategy process as a method for strategy formulation and implementation. The theoretical framework, several mainly ad hoc interviews and author’s observation were used as tools to analyze the case company’s strategy process. The hierarchy in between the various corporate levels provides the foundation to formulate and implement the strategies. These strategies include the corporate and strategic business area level strategies. The recommendations to improve the case company’s strategy process were formulated at corporate and strategic business area levels. These recommendations were formulated based on research and experience gained throughout the work. The role of strategic projects to implement the strategies more efficiently and organizational control over distribution were found as potential improvement areas. The resource allocation prioritizing towards the most important strategic projects was also an important improvement area.

Analytical Strategies for Doping Control Purposes: Needs, Challenges, and Perspectives.

The fight against doping in sports has been governed since 1999 by the World Anti-Doping Agency (WADA), an independent institution behind the implementation of the World Anti-Doping Code (Code). The intent of the Code is to protect clean athletes through the harmonization of anti-doping programs at the international level with special attention to detection, deterrence and prevention of doping.1 A new version of the Code came into force on January 1st 2015, introducing, among other improvements, longer periods of sanctioning for athletes (up to four years) and measures to strengthen the role of anti-doping investigations and intelligence. To ensure optimal harmonization, five International Standards covering different technical aspects of the Code are also currently in force: the List of Prohibited Substances and Methods (List), Testing and Investigations, Laboratories, Therapeutic Use Exemptions (TUE) and Protection of Privacy and Personal Information. Adherence to these standards is mandatory for all anti-doping stakeholders to be compliant with the Code. Among these documents, the eighth version of International Standard for Laboratories (ISL), which also came into effect on January 1st 2015, includes regulations for WADA and ISO/IEC 17025 accreditations and their application for urine and blood sample analysis by anti-doping laboratories.2 Specific requirements are also described in several Technical Documents or Guidelines in which various topics are highlighted such as the identification criteria for gas chromatography (GC) and liquid chromatography (LC) coupled to mass spectrometry (MS) techniques (IDCR), measurements and reporting of endogenous androgenic anabolic agents (EAAS) and analytical requirements for the Athlete Biological Passport (ABP).

Eligibility to treatment and economic effect of the implementation of the new U.S. or European Society of Hypertension/European Society of Cardiology hypertension guidelines.

OBJECTIVE: To evaluate the population and economic impact of implementing the new Joint National Committee (JNC) or European Society of Hypertension (ESH)/European Society of Cardiology (ESC) hypertension guidelines in the Swiss population. METHODS: Cross-sectional, population-based sample (6708 participants) collected between 2003 and 2006 in the city of Lausanne, Switzerland. Blood pressure categories were defined according to both the JNC (JNC-7 and JNC-8) and the ESH/ESC (2007 and 2013) guidelines. RESULTS: The proportion of participants aged 35-60 years eligible for drug treatment was 25.6% [95% confidence interval (CI) 24.4-26.9%] and 24.8% (95% CI 23.6-26.0%) for the JNC-7 and the JNC-8 guidelines, respectively; for participants aged 60-75 years, the values were 62.3% (95% CI 60.1-64.5%) and 46.8% (95% CI 44.5-49.0%), respectively. Shifting from the JNC-7 to the JNC-8 guidelines would lead to an annual saving of 163.6 million Swiss francs (187.7 million US dollars or 134.5 million European euro). The proportion of participants aged 35-75 years without chronic kidney disease, diabetes mellitus or reported history of cardiovascular disease and eligible for treatment was 30.2% (95% CI 29.0-31.4%) for the ESH/ESC 2007 and 2013 guidelines. For participants with chronic kidney disease, diabetes mellitus or reported history of cardiovascular disease, the values were 73.6% (95% CI 70.8-76.3%) and 55.6% (95% CI 52.5-58.8%), respectively. Shifting from the ESH/ESC 2007 to the ESH/ESC 2013 guidelines would lead to an annual saving of 86.9 million Swiss francs (99.5 million US dollars or 71.4 million European euro). CONCLUSION: In Switzerland, shifting from the JNC-7 to the JNC-8 guidelines or from the ESH/ESC 2007 to the ESH/ESC 2013 guidelines would decrease the prevalence of patients eligible for treatment and increase the percentage of treated patients within blood pressure goals. Both strategies lead to potential savings in antihypertensive drug treatment.

Present and future methodology for the implementation of decision support systems for traffic management

Real-time predictions are an indispensable requirement for traffic management in order to be able to evaluate the effects of different available strategies or policies. The combination of predicting the state of the network and the evaluation of different traffic management strategies in the short term future allows system managers to anticipate the effects of traffic control strategies ahead of time in order to mitigate the effect of congestion. This paper presents the current framework of decision support systems for traffic management based on short and medium-term predictions and includes some reflections on their likely evolution, based on current scientific research and the evolution of the availability of new types of data and their associated methodologies.

Regional innovation strategies and sustainability in selected EU countries

This study focuses on regional innovation strategy (RIS) and sustainability aspects in selected regions of European Union (EU) countries. It is known that RIS helps a region to innovate locally and to compete globally and it is considered as one of the main policy tools of the EU for innovation support at a regional level. This study is conducted to explore the existence and adoption of RIS in different regions of selected EU countries, and to highlight and compare regional RIS characteristics. The study is also aimed at identifying the factors that characterise the formulation and implementation of RIS as well as the problems associated thereof. In this study, six regions of EU countries are considered: Päijät-Häme Region (Finland); London Region (United Kingdom); Mid-West Region (Ireland); Veneto Region (Italy); Eastern Region (Poland); and West Region (Romania). Data and information are collected by sending questionnaires to the respective regional authorities of these selected regions. Based on the gathered information and analysis, RIS or equivalent strategy document serves as a blueprint for forwarding innovative programmes towards regional sustainability. The objectives of RIS in these regions are found to be dependent on the priority sectors and state of the region’s development. The current environmental sustainability aspects are focused on eco-design, eco-products, and eco-innovation, although each region also has its own specific aspects supported by RIS. Likewise, regional policies typically follow the RIS yet translated in various sectoral focus or priority areas. The main enhancing factors supporting RIS among selected regions have some similarities and variations; among others, some regions are strongly supported by EU while others have support from own regional agencies, organisations and professional networks. RIS implementation is not without challenges and despite the differences in challenges, almost all of reviewed regions consider financial resource as a common problem. Generally, it is learned from this study that RIS and regional sustainability are reinforcing each other mutually. In this study, the strong focus is given towards environmental sustainability in the regions although regional sustainability also includes economic and social aspects. A well-focused and prioritised RIS is beneficial for regional sustainable development.

De-escalation of commitment management strategy in IT project management methodology: case of ERP implementation project by IT consulting company

According to several surveys and observations, the percentage of successfully conducted IT projects without over-budgeting and delays in time schedule are extremely low. Many projects also are evaluated as failures in terms of delivered functionality. Nuldén (1996) compares IT projects with bad movies; after watching for 2 hours, one still tries to finish it even though one understands that it is a complete waste of time. The argument for that is 'I've already invested too much time to terminate it now'. The same happens with IT projects: sometimes the company continues wasting money on these projects for a long time, even though there are no expected benefits from these projects. Eventually these projects are terminated anyway, but until this moment, the company spends a lot. The situation described above is a consequence of “escalation of commitment” - project continuation even after a manager receives negative feedback of the project’s success probability. According to Keil and Mähring (2010), even though escalation can occur in any type of project, it is more common among complex technological projects, such as IT projects. Escalation of commitment very often results in runaway projects. In order to avoid it, managers use de-escalation strategies, which allow the resources to be used in more effective. These strategies lead to project termination or turning around, which stops the flow of wasted investments. Numbers of researches explore escalation of commitment phenomena based on experiments and business cases. Moreover, during the last decade several frameworks were proposed for de-escalation strategy. However, there is no evidence of successful implementation of the de-escalation of commitment strategy in the literature. In addition, despite that fact that IT project management methodologies are widely used in the companies, none of them cover the topic of escalation of commitment risks. At the same time, there are no researches proposing the way to implement de-escalation of commitment strategy into the existing project management methodology The research is focused on a single case of large ERP implementation project by the consulting company. Hence, the main deliverables of the study include suggestions of improvement in de-escalation methods and techniques in the project and in the company. Moreover, the way to implement these methods into existing project management methodology and into the company general policies is found.

Energy-efficient control strategies for variable speed driven parallel pumping systems based on pump operation point monitoring with frequency converters

The pumping processes requiring wide range of flow are often equipped with parallelconnected centrifugal pumps. In parallel pumping systems, the use of variable speed control allows that the required output for the process can be delivered with a varying number of operated pump units and selected rotational speed references. However, the optimization of the parallel-connected rotational speed controlled pump units often requires adaptive modelling of both parallel pump characteristics and the surrounding system in varying operation conditions. The available information required for the system modelling in typical parallel pumping applications such as waste water treatment and various cooling and water delivery pumping tasks can be limited, and the lack of real-time operation point monitoring often sets limits for accurate energy efficiency optimization. Hence, alternatives for easily implementable control strategies which can be adopted with minimum system data are necessary. This doctoral thesis concentrates on the methods that allow the energy efficient use of variable speed controlled parallel pumps in system scenarios in which the parallel pump units consist of a centrifugal pump, an electric motor, and a frequency converter. Firstly, the suitable operation conditions for variable speed controlled parallel pumps are studied. Secondly, methods for determining the output of each parallel pump unit using characteristic curve-based operation point estimation with frequency converter are discussed. Thirdly, the implementation of the control strategy based on real-time pump operation point estimation and sub-optimization of each parallel pump unit is studied. The findings of the thesis support the idea that the energy efficiency of the pumping can be increased without the installation of new, more efficient components in the systems by simply adopting suitable control strategies. An easily implementable and adaptive control strategy for variable speed controlled parallel pumping systems can be created by utilizing the pump operation point estimation available in modern frequency converters. Hence, additional real-time flow metering, start-up measurements, and detailed system model are unnecessary, and the pumping task can be fulfilled by determining a speed reference for each parallel-pump unit which suggests the energy efficient operation of the pumping system.

Creating an open-books implementation framework for a maintenance-related value-based life-cycle model

This study is a qualitative action research by its nature with elements of personal design in the form of a tangible model implementation framework construction. Utilized empirical data has been gathered via two questionnaires in relation to the arranged four workshop events with twelve individual participants. Five of them represented maintenance customers, three maintenance service providers and four equipment providers respectively. Further, there are two main research objectives in proportion to the two complementary focusing areas of this thesis. Firstly, the value-based life-cycle model, which first version has already been developed prior to this thesis, requires updating in order to increase its real-life applicability as an inter-firm decision-making tool in industrial maintenance. This first research objective is fulfilled by improving appearance, intelligibility and usability of the above-mentioned model. In addition, certain new features are also added. The workshop participants from the collaborating companies were reasonably pleased with made changes, although further attention will be required in future on the model’s intelligibility in particular as main results, charts and values were all reckoned as slightly hard to understand. Moreover, upgraded model’s appearance and added new features satisfied them the most. Secondly and more importantly, the premises of the model’s possible inter-firm implementation process need to be considered. This second research objective is delivered in two consecutive steps. At first, a bipartite open-books supported implementation framework is created and its different characteristics discussed in theory. Afterwards, the prerequisites and the pitfalls of increasing inter-organizational information transparency are studied in empirical context. One of the main findings was that the organizations are not yet prepared for network-wide information disclosure as dyadic collaboration was favored instead. However, they would be willing to share information bilaterally at least. Another major result was that the present state of companies’ cost accounting systems will definitely need implementation-wise enhancing in future since accurate and sufficiently detailed maintenance data is not available. Further, it will also be crucial to create supporting and mutually agreed network infrastructure. There are hardly any collaborative models, methods or tools currently in usage. Lastly, the essential questions about mutual trust and predominant purchasing strategies are cooperation-wise important. If inter-organizational activities are expanded, a more relational approach should be favored in this regard. Mutual trust was also recognized as a significant cooperation factor, but it is hard to measure in reality.

The Formation Of Internationalization Strategies Within The Construction Industry:Vision and Strategy

Internationalization represents a complex topic that has been researched for quite some time. However, since it continues to be extremely current a topic, its significance has not diminished, but maybe even increased in importance. Companies today face extreme pressure to enter new markets in the hope of growing, becoming more profitable, increasing market share, attracting new customers and meeting the requirements of its share- and stakeholders. In the increasingly global business environment of today, companies are facing both challenges and possible advantages of internationalization. Few companies are not operating internationally and it is becoming the question of ‘Why not?’ rather than ‘Why?’ to internationalize business operations. Internationalization and the importance of strategy are discussed in this research from the viewpoint of three case companies that were interviewed about internationalization strategies. This research project is a qualitative study that answers the research question of How is a business strategy constructed for entering a new market? The sub-questions are • How are goals set and what indicators are used to monitor the achievement of these goals? • What are the key characteristics of a strategy implementation process? The research method chosen for this study is a multiple-case study. Three case companies were chosen for the interviews in order to gain in-depth data of internationalization strategies within the construction industry.