Characterization of Renal Anionic Drug Transport Capacity in Kidney Transplant Recipients with Persistent BK Viremia: Pharmacokinetic and Pharmacodynamic Studies of Cidofovir

Kidney transplantation is the treatment of choice for end-stage renal disease (ESRD), and drug therapy plays a significant role in the management of transplant recipients. A variety of commonly used drugs are actively secreted by transporters in the kidney, yet the functional expression and activity of these proteins in transplant patients has not been investigated. The first objective of this research was to characterize anionic tubular secretion capacity in kidney transplant recipients by evaluating the pharmacokinetics of cidofovir, a prototypical organic anion transporter substrate frequently used to treat BK virus infections in this patient population. A sensitive and specific analytical technique was developed to measure cidofovir concentrations in human plasma. Pharmacokinetic analysis of cidofovir in adult kidney transplant recipients suggested reduced OAT1-mediated secretion in these patients. The mechanistic basis of this observation was evaluated in a syngeneic rat model of kidney transplantation, which established that the transplant process itself leads to a sustained reduction in the expression of anionic transport proteins localized to the basolateral membrane of the renal proximal tubule. Additionally, apical anionic transporters were differentially regulated in this model. The next objective was to evaluate the pharmacodynamics of cidofovir in kidney transplant patients. This study demonstrated that cidofovir transiently reduced the degree of BK viremia and viruria in vivo, though the effect was not sustained, and viral loads returned to baseline by the next sampling period. A retrospective analysis employed serum creatinine-based estimates of cidofovir clearance in a large cohort of kidney transplant recipients to approximate aggregate cidofovir exposure, and correlated drug exposure with virologic response. Higher systemic exposure was significantly associated with a larger reduction in the degree of BK viremia. However, only 11% of the variance in the decline in the BK viral load could be explained by variation in cumulative cidofovir exposure, indicating that other factors, likely immune-mediated, play a major role in viral clearance. Collectively, this work broadens our understanding of drug disposition in kidney transplant recipients and provides fundamental knowledge that may improve the treatment of BK virus infections

Impacts of unconventional oil and gas development on atmospheric aerosol particles

2017 Summer.Includes bibliographical references.Rising demands for global energy production and shifts in the economics of fossil fuel production have recently driven rapid increases in unconventional oil and gas drilling operations in the United States. Limited field measurements of atmospheric aerosol particles have been conducted to understand the impacts of unconventional oil and gas extraction on air quality. These impacts can include emissions of greenhouse gases, the release of volatile organic compounds that can be hazardous and precursors to tropospheric ozone formation, and increases in atmospheric aerosol particles. Aerosol particles can also contribute to climate change, degrade visibility and negatively impact human health and the environment. Aerosol formation can result from a variety of activities associated with oil and gas drilling operations, including emission of particles and/or particle precursors such as nitrogen oxides from on-site power generation, evaporation or leaking of fracking fluids or the produced fuel, flaring, the generation of road dust, and increases in traffic and other anthropogenic emissions associated with growing populations near drilling locations. The work presented here details how activities associated with unconventional oil and gas extraction impact aerosol particle characteristics, sources, and formation in remote regions. An air quality field study was conducted in the Bakken formation region during a period of rapid growth in oil production by unconventional techniques over two winters in 2013 and 2014. The location and time of year were chosen because long term IMPROVE network monitoring records show an increasing trend in particulate nitrate concentrations and haze in the Bakken region during the winter, strongly contrasting with sharp decreases observed across most of the U.S. The comprehensive suite of instrumentation deployed for the Bakken Air Quality Study (BAQS) included measurements of aerosol concentrations, composition, and scattering, gaseous precursors important for aerosol formation, volatile organic compounds, and meteorology. Regional measurements of inorganic aerosol composition were collected, with average concentrations of total inorganic PM2.5 between 4.78 – 6.77 µg m-3 and 1.99 – 2.52 µg m-3 for all sampling sites during the 2013 and 2014 study periods, respectively. The maximum inorganic PM2.5 concentration observed was 21.3 µg m-3 for a 48 hour filter sample collected at Fort Union National Historical Site, a site located within a dense area of oil wells. Organic aerosol measurements obtained during the second study at the north unit of Theodore Roosevelt National Park (THRO-N) featured an average concentration of 1.1 ± 0.7 µg m-3. While oil production increased from 2013 to 2014, the lower PM2.5 in 2014 can be explained by the meteorological differences. During the first study, increased snow cover, atmospheric stability, solar illumination, and differences in the dominant wind direction contributed to higher PM2.5. The enhanced concentrations of inorganic PM2.5 measured in the Bakken region were tied to regional oil and gas development. Elevated concentrations of PM2.5 were observed during periods of air mass stagnation and recirculation and were associated with VOC emissions aged less than a day, both indicating a predominant influence from local emissions. High PM2.5 concentrations occurred when low i-/n-pentane VOC ratios were observed, indicating strong contributions from oil and gas operations. The hourly measurements of gas and aerosol species in an extremely cold environment also provided a unique data set to investigate how well thermodynamic aerosol models represent the partitioning of ammonium nitrate. In general, during the coldest temperatures, the models overpredicted the formation of particulate nitrate. The formation of additional PM2.5 in this region is more sensitive to availability of N(-III) species during the coldest periods but increasingly sensitive to available N(V) when temperatures are relatively warmer and ammonia availability increases. These measurements and modeling results show that continued growth of oil and gas drilling operations in remote areas such as the Bakken region could lead to increased PM2.5 and impact haze formation in nearby federally protected lands

Occupational exposure to diacetyl and 2,3-pentanedione

This criteria document is derived from the NIOSH evaluation of critical health effects studies of occupational exposure to diacetyl and 2,3-pentanedione. It provides recommendations for controlling workplace exposures including recommended exposure limits derived by using current quantitative risk assessment methodology on human and animal health effects data. Using cross-sectional pulmonary function data from diacetyl-exposed employees, NIOSH conducted assessments to determine the exposure-response relationship and to identify risk of pulmonary function decrease at various levels of diacetyl exposure. NIOSH found that a relationship exists between diacetyl exposures and lower pulmonary function. Utilizing this analysis, NIOSH recommends keeping exposure to diacetyl below a concentration of 5 parts per billion as a time-weighted average during a 40-hour work week. To further protect against effects of short-term exposures, NIOSH recommends a short-term exposure limit for diacetyl of 25 parts per billion for a 15-minute time period. In many operations, 2,3-pentanedione is being used to substitute for diacetyl. Published toxicological studies indicate that 2,3-pentanedione exposure can cause damage similar to that caused by diacetyl in laboratory studies. Therefore, NIOSH recommends keeping occupational exposure to 2,3-pentanedione below a level comparable to the level recommended for diacetyl. However, the recommended sampling and analytical method can only reliably quantify it to 9.3 parts per billion in an 8-hour sample. NIOSH also recommends a short-term exposure limit for 2,3-pentanedione of 31 parts per billion during a 15-minute period. Engineering and work practices are available to control diacetyl and 2,3-pentanedione exposures below the recommended exposure limits. A hierarchy of controls including elimination, substitution, engineering controls, administrative controls, and the use of personal protective equipment should be followed to control workplace exposures. NIOSH urges employers to disseminate this information to employees and customers. NIOSH also requests that professional and trade associations and labor organizations inform their members about the hazards of occupational exposure to these flavoring compounds. NIOSH appreciates the time and effort of the expert peer, stakeholder, and public reviewers whose comments and input strengthened this document.Suggested citation: NIOSH [2016]. Criteria for a recommended standard: occupational exposure to diacetyl and 2,3-pentanedione. By McKernan LT, Niemeier RT, Kreiss K, Hubbs A, Park R, Dankovic D, Dunn KH, Parker J, Fedan K, Streicher R, Fedan J, Garcia A, Whittaker C, Gilbert S, Nourian F, Galloway E, Smith R, Lentz TJ, Hirst D, Topmiller J, Curwin B. Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2016-111.NIOSH No 200488541. Introduction -- 2. Assessing Occupational Exposure in Employees -- 3. Effects of Exposure in Employees -- 4. Toxicology of Diacetyl and 2,3-Pentanedione -- 5. Quantitative Risk Assessment Based on Employee Data -- 6. Quantitative Risk Assessment Based on Animal Data -- 7. Basis of the Recommended Standards for Diacetyl and 2,3-Pentanedione -- 8. Hazard Prevention and Control of Exposures to Diacetyl and 2,3-Pentanedione -- 9. Medical Monitoring and Surveillance of Exposed Employees -- 10. Exposure Monitoring in Occupational Safety and Health Programs -- 11. Research Needs -- Appendix A. OSHA PV2118 (Diacetyl) -- Appendix B. OSHA 1012 (Acetoin and Diacetyl) -- Appendix C. Acetoin Diacetyl 1013 -- Appendix D. 2, 3-Pentanedione -- Appendix E. Volatile Organic Compounds (Screening) 2549 [NIOSH Manual of Analytical Methods (NMAM), Fourth Edition, 5/15/96] -- Appendix F. Correcting Diacetyl Concentrations from Air Samples Collected with NIOSH Method 2557 [J Occup Environ Hyg. 2011 Feb;8(2):59-70. doi: 10.1080/15459624.2011.540168.] -- Appendix G. JEM Tables for Four Plants -- Appendix H. Development of a Job Exposure Matrix for Company G -- Appendix I. Typical Protocol for Collecting Air Samples for Diacetyl and 2, 3-Pentanedione

Fractal Dimension as a Predictor of Organizational Change Success

As many as two thirds of organizational change (OC) initiatives fail to achieve their outcome objectives. Researchers have demonstrated that successful change requires alignment among all levels of an organization. However, contemporary OC models do not quantify the degree of hierarchical alignment during the change process. The purpose of this quantitative, correlational study was to examine whether the fractal dimension of hierarchical alignment (predictor variable) was associated with OC success (criterion variable) as described by the self-organizing fractal theory (SOFT). The research question addressed the association between the fractal dimension related to the alignment of OC beliefs and behavioral intentions across an organizational hierarchy and subsequent OC success. The instrument included creolization and change resistance themes to collect primary survey data through the self-selection of 125 North American aerospace workers who had participated in a formal change process. Pearson’s product-moment, Spearman rank, and Kendall’s tau correlation coefficients revealed a strong positive association between fractal dimension and OC success. Subsequent regression analysis reinforced the positive correlation and explained at least 56% of the observed variation in OC success. The results contributed to scholarly OC research by providing proof-of-concept demonstration that SOFT is applicable to OC research. This study also contributed to social change by creating measures that may lead to improved change management, resulting in less resource waste, lower employee stress, and improved change outcomes

Applications and Experiences of Quality Control

The rich palette of topics set out in this book provides a sufficiently broad overview of the developments in the field of quality control. By providing detailed information on various aspects of quality control, this book can serve as a basis for starting interdisciplinary cooperation, which has increasingly become an integral part of scientific and applied research

Constraints on movement variability during a discrete multi-articular action

The aim of this programme of work was to examine how the manipulation of organismic and task constraints affected movement variability during a basketball shooting task. The specific constraints that were manipulated included task expertise, state anxiety and dioptric blur (organismic constraints), and, shooting distance and attentional focus instruction (task constraints). The aim of Study 1 was to investigate the effect of shooting distance and task expertise on movement variability. Task expertise was characterised by decreased coordination variability and heightened compensatory variability between wrist, elbow and shoulder joints. However, no significant difference was found in joint angle variability at release as a function of task expertise. There was no significant change in movement variability with shooting distance, a finding that was consistent across all expertise groups. In Study 2, the aims were to examine the effect of induced dioptric blur on shooting performance and movement variability during basketball free-throw shooting, and, to ascertain whether task expertise plays a mediating role in the capacity to stabilise performance against impaired visual information. Significant improvements in shooting performance were noted with the introduction of moderate visual blur (+1.00 and +2.00 D). This performance change was evident in both expert and novice performers. Only with the onset of substantial dioptric blur (+3.00 D), equivalent to the legal blindness limit, was there a significant decrease in coordination variability. Despite the change in coordination variability at +3.00 D, there was no significant difference in shooting performance when compared to the baseline condition. The aims of Study 3 were to examine the effect of elevated anxiety on shooting performance and movement variability and, again, to determine whether task expertise plays a mediating role in stabilising performance and movement kinematics against perturbation from emotional fluctuations. Commensurate with the results of Study 2, both expert and novice performers were able to stabilise performance and movement kinematics, this time with elevated anxiety. Stabilisation was achieved through the allocation of additional attentional resources to the task. Study 4, had two aims. The first was to examine the interactive effects of practice and focus of attention on both performance and learning of an accuracy-based, discrete multi-articular action. The second was to identify potential focus-dependent changes on joint kinematics, intra-limb coordination and coordination variability. Support was found for the role of an external focus of attention on shooting performance during both acquisition and retention. However, there was evidence to suggest that internal focus instruction could play a pivotal role in shaping emerging patterns of intra-limb coordination and channelling the learners‟ search towards a smaller range of kinematic solutions within the perceptual-motor workspace. Collectively, this programme of work consistently highlighted the fundamental role that constraints play in governing shooting performance, movement variability and, more broadly, perceptual-motor organisation. For instance, task expertise was characterised by decreased coordination variability and heightened compensatory control. However, in light of the data pertaining to joint angle variability at release, general assumptions about expertise-variability relations cannot be made and should be viewed with caution. In addition, there is strong evidence to suggest that adaptation to constraints is, perhaps, a universal human response, and consequently not mediated by task expertise. Further research is needed to fully elucidate this proposition

Software Development Outsourcing Decision Support Tool with Neural Network Learning

The Air Force (AF) needs an evolving software tool for guiding decision makers through the complexities of software outsourcing. Previous research identified specific outsourcing strategies and linked them to goals and consequences through a variety of relationship rules. These strategies and relationship rules were inserted into a decision support tool. Since that time, more historical data and outsourcing literature has been collected thus necessitating an update to such a tool. As the number of software outsourcing projects are completed, the AF must capture the outsourcing decision experiences which guided the projects and their outcomes. In order to efficiently incorporate this new experience, the decision tool must be redesigned to allow the additional knowledge to be added in such a way that the decision rule base is automatically updated. With this new feature, the tool would increase its precision of predicting software outsourcing success as the software outsourcing knowledge evolves. Capturing software outsourcing as knowledge instead of raw information will help guide decision makers down paths proven to succeed staying clear of risks that historically plagued software outsourcing projects of the past. Software outsourcing decision makers desire not only a characterization of past experiences and predictions of future outcomes, but also reasons to help them make informed decisions

Fuzzy Sets in Business Management, Finance, and Economics

This book collects fifteen papers published in s Special Issue of Mathematics titled “Fuzzy Sets in Business Management, Finance, and Economics”, which was published in 2021. These paper cover a wide range of different tools from Fuzzy Set Theory and applications in many areas of Business Management and other connected fields. Specifically, this book contains applications of such instruments as, among others, Fuzzy Set Qualitative Comparative Analysis, Neuro-Fuzzy Methods, the Forgotten Effects Algorithm, Expertons Theory, Fuzzy Markov Chains, Fuzzy Arithmetic, Decision Making with OWA Operators and Pythagorean Aggregation Operators, Fuzzy Pattern Recognition, and Intuitionistic Fuzzy Sets. The papers in this book tackle a wide variety of problems in areas such as strategic management, sustainable decisions by firms and public organisms, tourism management, accounting and auditing, macroeconomic modelling, the evaluation of public organizations and universities, and actuarial modelling. We hope that this book will be useful not only for business managers, public decision-makers, and researchers in the specific fields of business management, finance, and economics but also in the broader areas of soft mathematics in social sciences. Practitioners will find methods and ideas that could be fruitful in current management issues. Scholars will find novel developments that may inspire further applications in the social sciences