Revisiting antimicrobial therapy in critically ill patients through pharmacometri

Contains fulltext : 251476.pdf (Publisher’s version ) (Open Access)Radboud University, 29 augustus 2022Promotor : Burger, D.M. Co-promotores : Bruggemann, R.J.M., Heine, R. ter, Schouten, J.A

Integration of a polyomavirus recombinant containing highly repetitive sequence : analysis of the junctions and genome rearrangements

Studies on the integration of exogenous DNA into the genomes of mammalian cells have established that three different recombination mechanisms are involved; sites-pecific, illegitimate and homologous recombination. Since no essential functions have been found to be necessarily associated with the exogenous molecule it is beleived that this process faithfully reflects the natural recombination mechanisms of the cell. The DNA tumour virus paradigm has led to the development of a linear "replacement" model for integration by illegitimate recombination - model which predicts an excision of host DNA similar to the length of DNA inserted. RmI is a naturally occurring thermosensitive Py recombinant that contains an insertion (INS) of mouse cellular DNA. RmI should have the potential to integrate by any or all three of site-specific, illegitimate, or homologous recombination mechanisms. Firstly, RmI contains viral Py sequences known to integrate by illegitimate recombination. Secondly, RmI contains B2 and MT repetitive sequences both of which have 100,000 homologous copies dispersed throughout the rat genome any one of which could serve as a target for homologous integration. Finally the junctions between Ins and the Py sequences of RmI display features that suggest that RmI may be capable of site-specific recombination. My previous work on the integration of RmI into the genomes of rat cells showed that at the temperature non-permissive for replication, integration was non random with respect to the sequences of RmI. One region of RmI was underrepresented, whereas two regions, including the region of Ins containing the repetitive elements B2 and MT, were significantly overrepresented. Furthermore, the lengths of the integrated genomes tended importantly toward the unit length of RmI contrary to what was observed at the permissive temperature. In an effort to further define the integration mechanism and in particular to determine the nature of the viral-cellular junctions at the molecular level as well as to characterize the host site before and after integration, the cellular DNAs flanking 6 junctions from 3 transformed cell lines were cloned (4 in this study, 2 were previously cloned) and the sequences across 4 of these junctions were determined (one previously determined, 3 were determined here). The cloned DNAs were used to map the rearrangements of the cellular DNA caused by the integration of RmI. Furthermore, the fate of the rearranged intervening host sequences in one of the clones was determined. The results show that the overrepresentation of the repetitive sequences was due to their acting as hotspots for illegitimate recombination. Even though the host genome contained over 105 potential targets for homologous recombination we found no evidence for homologous integration, and conclude that it is not an efficient procedure in the case of RmI. Furthermore, contrary to previous reports which suggested that exogenous DNA integrated preferentially into repetitive sequences of the host, we found that the DNA flanking all but one junction was unique sequence DNA. Even though RmI was transfected in the presence of carrier DNA, the results presented here show that it integrated directly into the rat cellular DNA. This shows that transgenomes are not necessary intermediates for the integration of (circular) DNA even when transfected in the presence of carrier. The minimum lengths of the rearrangements caused to the host DNA by RmI's integration into two of the clones was determined to be 12 kbp for an insertion of 7 kbp and 55 kbp for an insertion of 6 kbp. It was further established that the intervening host DNA in the latter clone had been deleted. We show (for the first time by hybridization) that in the case of the third clone the DNAs flanking the insertion on either side were linked before integration. The rearrangement caused by RmI's integration is complex but can be partially explained by an inversion event of approximately 20 kbp for an insertion of 7 kbp. The length and nature of the rearrangements are incompatible with a linear insertion-replacement model, and are more easily explained by an integration mechanism in which the incoming exogenous DNA recombines with a looped structure of chromosomal DNA. Such a model, which takes into account recent findings on chromatin structure, is presented

The Nursing Shortage: a Fresh Perspective

The current nursing shortage in the United States has the potential to become a major public health crisis (US Department, 2004). In recent years, a trend has developed that demonstrates a lack of interest on the part of young adults aged fifteen to eighteen years old towards nursing careers (Hoke, 2006). This research examines the attitudes and perceptions of young people, aged fifteen to eighteen years old; towards the field of nursing. The Methodology used to answer the research question was a survey tool developed by the author. The survey was created using the survey development site, Zoomerang©. Following IRB approval, the survey was piloted and then made available to the target population via the social networking site, Facebook©. Descriptive statistics were run on the 223 total responses received. The results of the survey suggest that students in the target population have a positive view towards nursing and may see it as a very lucrative career option; however, it does not seem as if they are being provided with the necessary information they might need to make the decision to become a nurse. The methodology for this study was very effective and provides a great opportunity for future research to be done. The hope is that this study will open doors for additional research to be done in the future, and that it will also spark an interest and possibly change the way that administrators and others think about and act upon recruiting young people towards the profession. Providing students with the necessary information and resources to make career decisions will impact the lives of future generations for many years to come

Proactive improvement of logistics service providers as driver of customer loyalty

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Purpose: The purpose of this paper is to provide a differentiated view of relationship-specific proactive improvement of logistics service providers (LSPs) that distinguishes between the cost and performance and the effect that these two dimensions of innovation have on three distinct customer loyalty dimensions (retention, extension, and referrals). Design/methodology/approach: A confirmatory empirical study was conducted based on social exchange theory and customer value theory. The survey responses from 298 firms were analysed using structural equation modelling and multi-group analysis to test for direct effects and moderation. Findings: Both dimensions of relationship-specific proactive improvement by LSPs (cost and performance) are strong drivers of all three customer loyalty dimensions and, thus, are important to customer relationship management and relevant areas to be considered within innovation management. The effect on customer loyalty is moderated by the dynamism of the customer’s market. Proactive cost improvements are more important under high dynamism, while proactive performance improvements, contrary to initial assumptions, are more important when dynamism is low. Research limitations/implications: Future studies should analyse other cultural settings, differentiate between functional and relationship value provided, consider other services, investigate how LSPs can facilitate proactive improvement and improve innovation management, and explore how customers can foster proactive improvement. Practical implications: The currently low level of proactive improvement should be increased if LSPs want to enhance customer loyalty. In doing so, LSPs ought to consider the dynamism of their customers’ markets. Originality/value: The paper is the first to provide a differentiated view on the role of relationship-specific proactive innovation that distinguishes between cost and performance improvements and illustrates their effects on three distinct customer loyalty dimensions

Horizontal cooperations between logistics service providers : motives, structure, performance

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Purpose – This paper aims to provide a comprehensive overview of the motives, structure and performance attributes of horizontal cooperations between logistics service providers (LSPs). Based on an analytical classification model, distinctive types of logistics cooperation that characterize the logistics landscape are identified. Design/methodology/approach – Empirical data were collected on horizontal LSP cooperations from managers of German LSPs. Different uni- and multi-variate statistical methods including ANOVA and cluster analysis were applied to the dataset of 226 cooperations for a total of 6,081 involved parties. Findings – Horizontal cooperations with other LSPs are an organizational form used by 57 percent of LSPs. Cooperation decisions are substantially driven by external market objectives. Six distinctive types of cooperation are identified. They reveal the dominance of multi-lateral and international networks that are mainly based on contractual agreements. There is a clear preference for partners with similar market competencies and for strong functional integration. Despite its inherent complexity, performance of these cooperations is high – its less than 19 percent failure rate makes these cooperations substantially more stable than cooperations within manufacturing industries. Research limitations/implications – This study is limited to an exploratory, descriptive approach in providing a sound understanding of the cooperation landscape. Practical implications – The findings contribute transparency to horizontal LSP cooperations and a common understanding of their idiosyncrasies. The conclusions help logistics managers to position themselves better within the cooperation landscape. Further, the analyses offer managers a conceptual classification of horizontal LSP cooperations and some guidance on how to structure their individual LSP cooperations more successfully. Originality/value – This paper is the first empirical study that defines the types of cooperation that comprise the logistics cooperation landscape. The analysis integrates a holistic perspective of their contractual, organizational, functional, geographical, service and resource scope and matches them with underlying motives and performance attributes

The influence of relational competencies on supply chain resilience : a relational view

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Purpose – The purpose of this research is to explore the resilience domain, which is important in the field of supply chain management; it investigates the effects relational competencies have for resilience and the effect resilience, in turn, has on a supply chain’s customer value. Design/methodology/approach – The research is empirical in nature and employs a confirmatory approach that builds on the relational view as a primary theoretical foundation. It utilizes survey data collected from manufacturing firms from three countries, which is analyzed using structural equation modeling. Findings – It is found that communicative and cooperative relationships have a positive effect on resilience, while integration does not have a significant effect. It is also found that improved resilience, obtained by investing in agility and robustness, enhances a supply chain’s customer value. Practical implications – Some findings contrast the expectations derived from theory. Particularly, practitioners can learn that integration has a limited role in enhancing resilience. Originality/value – The study distinguishes between a proactive and reactive dimension of resilience: robustness and agility. The relational view serves as the theoretical basis to explain the effects between three types of relational competencies (communication, cooperation, and integration) and the above-mentioned two dimensions of resilience. Keywords Relational competencies, Supply chain management, Risk management, Supply chain resilience, Supply chain agility, Supply chain robustnes