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Dose-finding studies in drug development for rare genetic diseases

The small patient populations inherent to rare genetic diseases present many challenges to the traditional drug development paradigm. One major challenge is generating sufficient data in early phase studies to inform dose selection for later phase studies and dose optimization for clinical use of the drug. However, optimizing the benefit-risk profile of drugs through appropriate dose selection during drug development is critical for all drugs, including those being developed to treat rare diseases. Recognizing the challenges of conducting dose finding studies in rare disease populations and the importance of dose selection and optimization for successful drug development, we assessed the dose-finding studies and analyses conducted for drugs recently approved for rare genetic diseases. Of the 40 marketing applications for new molecular entity (NME) drugs and biologics approved by the United States Food and Drug Administration for rare genetic diseases from 2015 to 2020, 21 (53%) of the development programs conducted at least one dedicated dose-finding study. In addition, the majority of drug development programs conducted clinical studies in healthy subjects and included population pharmacokinetic and exposure–response analyses; some programs also conducted clinical studies in patient populations other than the disease for which the drug was initially approved. The majority of primary endpoints utilized in dedicated dose-finding studies were biomarkers, and the primary endpoint of the safety and efficacy study matched the primary endpoint used in the dose finding study in 9 of 13 (69%) drug development programs where primary study endpoints were assessed. Our study showed that NME drug development programs for rare genetic diseases utilize multiple data sources for dosing information, including studies in healthy subjects, population pharmacokinetic analyses, and exposure–response analyses. In addition, our results indicate that biomarkers play a key role in dose-finding studies for rare genetic disease drug development programs. Our findings highlight the need to develop study designs and methods to allow adequate dose-finding efforts within rare disease drug development programs that help overcome the challenges presented by low patient prevalence and other factors. Furthermore, the frequent reliance on biomarkers as endpoints for dose-finding studies underscores the importance of biomarker development in rare diseases.

60 APPLIED LIFE SCIENCES↗

Association of Maternal Social Relationships With Cognitive Development in Early Childhood

This study examines how different types of social network structures are associated with early cognitive development in children. Objectives To assess how social relationships and structures are associated with early cognitive development and to elucidate whether variations in the mother’s social networks alter a child’s early cognitive development patterns. Design, Setting, and Participants This cohort study used data from 1082 mother-child pairs in the University of Tennessee Health Science Center–Conditions Affecting Neurocognitive Development and Learning and Early Childhood project to examine the association between networks of different levels of complexity (triad, family, and neighborhood) and child cognitive performance after adjustment for the mother’s IQ, birth weight, and age, and the father’s educational level. The final model was adjusted for the household poverty level. Data were collected from December 2006 through January 2014 and analyzed from October through November 2018. Exposures The child-mother relationship, child-mother-father triad, family setting, child’s dwelling network, mother’s social support network, and neighborhood networks. Main Outcomes and Measures Measure of cognitive development of the child using Bayley Scales of Infant Development (BSID) at 2 years of age. Results Of 1082 participants, 544 (50.3%) were males and 703 (65.1%) were African American; the mean (SD) age was 2.08 (0.12) years. Large family size had a negative association with early cognitive development, with a mean 2.21-point decrease in BSID coefficient score (95% CI, 0.40 to 4.02; P = .01). Mother’s social support network size was positively associated early cognitive development, with a mean 0.40-point increase in BSID coefficient score (95% CI, 0.001 to 0.80; P = .05). Knowing many neighbors was not statistically significantly associated with early cognitive development, with a mean 1.39-point increase in BSID coefficient score (95% CI, -0.04 to 2.83; P = .06). Conclusions and Relevance The findings suggest that maternal social relationships are associated with cognitive development in children and that social relationships beyond the mother-child-father triad are significantly associated with children’s cognitive development. This study investigates the environmental influences on child health outcomes and, specifically, how early cognitive development is associated with social networks for the primary caregiver.

60 APPLIED LIFE SCIENCES↗

Historical Pattern Analysis of Global Geothermal Power Capacity Development: Preprint

Between 1913 and 1958, Italy was the only country with an operational geothermal power plant until New Zealand installed its first plant in 1958. At present, 24 countries are involved in the geothermal power market, and they have a combined installed capacity of 16,127 GW. This study analyzes the historical patterns of geothermal power capacity in the world and in individual countries to investigate the ideal global geothermal development pattern by examining the annual cumulative capacity (ACC) and the annual capacity addition (ACA) graphs of the historical development of geothermal power capacity in 24 countries. First, the global patterns are analyzed using these graphs in five periods (1945-1957, 1958-1976, 1977-1991, 1992-2002, and 2003-2020) that are marked by a series of characteristics of ACA peaks separated by two major troughs. Then, five characteristic patterns are developed in five periods globally. These patterns correspond to the early-stage linear, the first acceleration, the first steady-state linear, the second acceleration, and the second steady-state linear developments. A positive relationship exists between global patterns and the 5-year shifted oil-price curve: two major factors influenced global development: 1) increasing oil prices and increasing awareness of global climate change, and 2) global development of geothermal power. Last, we investigate these patterns in each country. The top ten countries, which comprise 93.3% of the world's total installed capacity are separated into five groups based on the availability and characteristics of patterns globally developed in five periods. Group-1 (the United States) has an installed capacity of 3,794 MW, Group-2 (Mexico and Philippines) 963-1935 MW, Group-3 (New Zealand, Italy, Iceland, and Japan) 601-1,037 MW, and Group-4 (Indonesia, Kenya, and Turkiye) 944-2,356 MW. The remaining 14 countries (6.7%), which are called Group 5, are still in an immature stage and have installed capacities of 7-262 MW and are not involved in pattern analysis. Overall, geothermal power in the world is in its third stage of development, which had its peak development after 1977. A fourth development peak may be expected to occur after this through business-as-usual cases. The biggest barrier to the development of the global geothermal power market is the risk associated with exploration and drilling. If risk mitigation systems and funds are employed, the growth of geothermal power production projects could accelerate.

GEOTHERMAL ENERGY↗

Historical Pattern Analysis of Global Geothermal Power Capacity Development

Between 1913 and 1958, Italy was the only country with an operational geothermal power plant until New Zealand installed its first plant in 1958. At present, 24 countries are involved in the geothermal power market, and they have a combined installed capacity of 16,127 GW. This study analyzes the historical patterns of geothermal power capacity in the world and in individual countries to investigate the ideal global geothermal development pattern by examining the annual cumulative capacity (ACC) and the annual capacity addition (ACA) graphs of the historical development of geothermal power capacity in 24 countries. First, the global patterns are analyzed using these graphs in five periods (1945-1957, 1958-1976, 1977-1991, 1992-2002, and 2003-2020) that are marked by a series of characteristics of ACA peaks separated by two major troughs. Then, five characteristic patterns are developed in five periods globally. These patterns correspond to the early-stage linear, the first acceleration, the first steady-state linear, the second acceleration, and the second steady-state linear developments. A positive relationship exists between global patterns and the 5-year shifted oil-price curve: two major factors influenced global development: 1) increasing oil prices and increasing awareness of global climate change, and 2) global development of geothermal power. Last, we investigate these patterns in each country. The top ten countries, which comprise 93.3% of the world's total installed capacity are separated into five groups based on the availability and characteristics of patterns globally developed in five periods. Group-1 (the United States) has an installed capacity of 3,794 MW, Group-2 (Mexico and Philippines) 963-1935 MW, Group-3 (New Zealand, Italy, Iceland, and Japan) 601-1,037 MW, and Group-4 (Indonesia, Kenya, and Turkiye) 944-2,356 MW. The remaining 14 countries (6.7%), which are called Group 5, are still in an immature stage and have installed capacities of 7-262 MW and are not involved in pattern analysis. Overall, geothermal power in the world is in its third stage of development, which had its peak development after 1977. A fourth development peak may be expected to occur after this through business-as-usual cases. The biggest barrier to the development of the global geothermal power market is the risk associated with exploration and drilling. If risk mitigation systems and funds are employed, the growth of geothermal power production projects could accelerate.

GEOTHERMAL ENERGY↗

Under-capacitated and over-powered? Rural austerity and asymmetrical negotiating relationships in US wind energy development

Though rural local governments are central actors in renewable energy development, local governments in the United States (US) remain systematically under-funded. This paper considers what the manifestations of austerity in local governments broadly and rural localities specifically mean for renewable energy development and for energy transitions. Drawing on a survey of 262 elected county officials with experience with wind energy in eight US states, this paper asks how local officials understand the impacts of wind development, how local governments are involved in wind energy negotiations, how the resources and expertise needed to navigate negotiations are distributed among counties, and analyze the relationship between local capacity, access to resources, and involvement in negotiations. We find that local officials express simultaneously affective and material concerns with the impacts of wind development and see negotiations with the developer as central to realizing local benefits. However, the expertise and staffing needed to negotiate with developers is less accessible to poorer or sparsely populated counties, and counties with lower overall revenues have narrower scopes of negotiation, and counties incre. Our results suggest that uneven rural capacity heightens an already asymmetrical relationship between localities and developers. In analyzing how infrastructure developments are shaped by relationships between localities and developers that are conditioned by austerity and (under)capacity, this paper contributes to and bridges scholarly discussions on rural austerity, rescaling, and renewable energy transitions. These results challenge conventional wisdoms around centralizing energy siting processes, contextualize popular and academic debates about opposition to renewable energy development, and highlight the need for rural reinvestment to realize meaningfully participatory energy developments.

Elmallah, Salma↗

Corrigendum to ‘Under-capacitated and over-powered? Rural austerity and asymmetrical negotiating relationships in US wind energy development’ [J. Rural Stud., 119 (2025) 1–14]

The authors regret that there is an incomplete sentence in the abstract of the article, and request that the portion “, and counties incre” be deleted from the abstract (found at the end of the sentence beginning with “However …”). The portion to be deleted is underlined and bolded below. The authors would like to apologise for any inconvenience caused. Current abstract: Though rural local governments are central actors in renewable energy development, local governments in the United States (US) remain systematically under-funded. This paper considers what the manifestations of austerity in local governments broadly and rural localities specifically mean for renewable energy development and for energy transitions. Drawing on a survey of 262 elected county officials with experience with wind energy in eight US states, this paper asks how local officials understand the impacts of wind development, how local governments are involved in wind energy negotiations, how the resources and expertise needed to navigate negotiations are distributed among counties, and analyze the relationship between local capacity, access to resources, and involvement in negotiations. We find that local officials express simultaneously affective and material concerns with the impacts of wind development and see negotiations with the developer as central to realizing local benefits. However, the expertise and staffing needed to negotiate with developers is less accessible to poorer or sparsely populated counties, and counties with lower overall revenues have narrower scopes of negotiation, and counties incre. Our results suggest that uneven rural capacity heightens an already asymmetrical relationship between localities and developers. In analyzing how infrastructure developments are shaped by relationships between localities and developers that are conditioned by austerity and (under)capacity, this paper contributes to and bridges scholarly discussions on rural austerity, rescaling, and renewable energy transitions. These results challenge conventional wisdoms around centralizing energy siting processes, contextualize popular and academic debates about opposition to renewable energy development, and highlight the need for rural reinvestment to realize meaningfully participatory energy developments.

Elmallah, Salma↗

FINAL REPORT - Development of High Pressure Hydrogen Storage Tank for Storage and Gaseous Truck Delivery

The “Development of High Pressure Hydrogen Storage Tanks for Storage and Gaseous Truck Delivery” project [DE-FG36-08GO18062] was initiated on 01 July 2008. Hexagon Lincoln (then Lincoln Composites) received grant funding from the U.S. Department of Energy to support the design and development of an improved bulk hauling and storage solution for hydrogen in terms of cost, safety, weight and volumetric efficiency. The development of this capability required parallel development and qualification of large all-composites pressure vessels, a custom ISO container to transport and store said tanks, and performance of trade studies to identify optimal operating pressure for the system. Qualification of the 250 bar TITAN® module was completed in 2009 with supervision from the American Bureau of Shipping [ABS], and the equipment has been used internationally for bulk transportation of fuel gases since 2010. Phase 1 of the project was successfully completed in 2012 with the issuance of USDOT SP 14951, the special permit authorizing the manufacture, marking, sale and use of TITAN® Mobile Pipeline® equipment in the United States. The introduction of tube trailers with light weight composite tankage has meant that 2 to 3 times as much gaseous fuel can be transported with each trip. This increased hauling efficiency offers dramatically reduced operating costs and has enabled a profitable business model for over-the-road compressed natural gas delivery. The economic drivers of this business opportunity vary from country to country and region to region, but in many places gas distribution companies have realized profitable operations. Additional testing was performed in 2015 to characterize hydrogen-specific operating protocols for use of TITAN® systems in CHG service at 250 bar. This program demonstrated that existing compression and decompression methodologies can efficiently and safely fill and unload lightweight bulk hauling systems. Hexagon Lincoln and U.S. DOE agreed to continue into Phase 2 of the project without pursuing the development of higher pressure capabilities as originally planned. At 250 bar, development of equipment for hydrogen transport is supported by strong activity in the adjacent natural gas transportation sector. Trade studies performed since 2011 indicate optimization of hauling efficiency and system cost for hydrogen transport at about 350 bar (5076 psi). However, due to reduced efficiency of compression of natural gas above 250 bar, 350 bar operation is not an attractive option for natural gas transportation. The CHG market is not developed at this time, and it is difficult to forecast the arrival of significant revenues. On the investment side, the cost to fully qualify a large tank module at 350 bar is estimated at $3MM to $5MM. There is insufficient CHG market definition to support a stand-alone business case for this investment without near term revenue in the adjacent CNG transportation market. Therefore development of a 350 bar TITAN® system was deferred and not pursued under this project. Hexagon Lincoln continues to support the development of tankage and equipment for operation at 350 bar and above; with 700 bar vehicle tanks and 950 bar tanks for ground storage applications. Phase 2 activities were focused on reducing system cost, increasing system capacity, increasing system safety and characterization of polymer material performance specific to hydrogen pressure vessel usage. With the successful launch of TITAN® modules and trailers in natural gas transportation, over 600 units have been produced through the end of 2016, resulting in improved purchasing power for raw materials and manufactured components. This has allowed Hexagon Lincoln to approach the current project goals for system cost. At $590/kg of compressed hydrogen delivered, the system cost of the baseline TITAN® module is below the project’s 2015 target of $730/kg H2 delivered, and very close to the project’s 2020 target of $575/kg H2 delivered. [Based on product pricing in 1Q2017.] Emphasis was placed on configuration of larger capacity systems within the vehicle weights and dimensions allowed on federal and state highways in the United States and other countries. These activities resulted in the design and development of integrated tube trailer systems that have increased delivery capacities by 45%. The hydrogen delivery capacity of our largest system is 845 kg, exceeding the project’s 2015 target of 700 kg H2 delivered. Emerging technologies offering improvement of the safety systems used on the equipment were investigated, with particular focus on improving the reliability and cost of the emergency venting system for fire protection. Finally, investment in our materials laboratory improved detection and characterization of hydrogen-induced damage in polymer materials, supporting the development of operational protocols to avoid damage to pressure vessel liners and valve components.

08 HYDROGEN↗

Lab-Scale Development of a Solid Sorbent for CO 2 Capture Process for Coal-Fired Power Plants

It is increasingly clear that CO 2 capture and sequestration (CCS) must play a critical role in curbing worldwide CO 2 emissions to the atmosphere. Development of these technologies to cost-effectively remove CO 2 from coal-fired power plants is very important to mitigating the impact these power plants have within the world’s power generation portfolio. Currently, conventional CO 2 capture technologies, such as aqueous-monoethanolamine based solvent systems, are prohibitively expensive and if implemented could result in a 75 to 100% increase in the cost of electricity for consumers worldwide. Solid sorbent CO 2 capture processes – such as RTI’s 3rd Generation Solid Sorbent CO 2 Capture Process – are promising alternatives to conventional, liquid solvents. Supported amine sorbents – of the nature RTI has developed – are particularly attractive due to their potential for high CO 2 loadings, excellent stability over multiple cycles, reduced corrosivity/volatility and a potential to reduce the regeneration energy needed to carry out CO 2 capture. The remaining challenges for these sorbent processes have provided the framework for the project team’s research and development and target for advancing the technology beyond lab-scale testing. Previous work in this area has failed to adequately address various technology challenges such as sorbent stability and regenerability, sorbent scale-up, improved physical strength and attrition-resistance, proper heat management and temperature control, proper solids handling, as well as the proper coupling of process engineering advancements that are tailored for a promising sorbent technology. Under a cooperative agreement with the US Department of Energy, and part of NETL’s CO 2 Capture Program, RTI has led an effort to address and mitigate the challenges associated with solid sorbent CO 2 capture. The overall objective of this project was to mitigate the technical and economic risks associated with the performance and scale-up of solid sorbent-based CO 2 capture processes, enabling subsequent larger pilot demonstrations and ultimately commercial deployment. An integrated development approach has been a key focus of this project in which sorbent development, process development, and economic analyses have informed each of the other development processes. Development efforts have focused on developing novel hybrid solids-based CO 2 capture sorbents and improving their performance stability, refining process engineering and design, and evaluating the viability of the technology through detailed economic analyses. Sorbent advancements have led to a next generation, commercially-viable CO 2 capture sorbent exhibiting performance stability in various gas environments and a physically strong fluidizable form. The team has reduced sorbent production costs and optimized the production and scale-up of novel metal-organic framework (MOF) hybrid solids-based CO 2 capture sorbents, fluidizable sorbents. Refinement of the process engineering and design at the lab-scale research unit has demonstrated promising CO 2 capture performance in simulated coal-fired flue gas conditions. Long-term testing has informed the project team on the process conditions needed to operate a solids-based system for optimal performance. Data collected from all phases of testing has been used to develop a detailed techno-economic assessment of RTI’s technology. These detailed analyses show that RTI’s technology has significant economic advantages over current amine scrubbing and potential to achieve the DOE’s Carbon Capture Program’s goal of >90% CO 2 capture rate at a cost of almost $40/tonne CO 2 captured by 2025. Through this integrated technology development approach, the project team has advanced RTI’s 3rd generation CO 2 capture technology to TRL-3, according to the DOE/FE definitions for Technology Readiness Levels. At a broader level, this project has advanced the whole of the solid sorbent CO 2 capture field, with advancements in process engineering and design, technical risk mitigation, sorbent scale-up optimization, and an understanding of the commercial viability and applicability of solid sorbent CO 2 capture technologies for the U.S. existing fleet of coal-fired power plants.

20 FOSSIL-FUELED POWER PLANTS↗

Laser Powder Bed Fusion Additive Manufacture Nb1Zr Development

Next generation fission and fusion nuclear reactors require materials that can withstand operating temperatures greater than 500 °C, neutron irradiation doses of up to 200 displacements per atom (dpa), and potentially corrosive coolants such as the alkali liquid metals sodium, lithium, and NaK (Na33K eutectic alloy). Refractory alloys, such as Nb1Zr (Nb-1wt%Zr) and Molybdenum alloy TZM (Mo-0.5wt%Ti-0.08wt%Zr) have been traditionally considered viable candidates for advanced fission and fusion reactor concepts. However, it is relatively difficult to generate complex geometries of interest from these alloys using traditional manufacturing methods. In addition, there needs to be a concentrated effort to address refractory metal challenges at elevated temperature operation. In order to generate complex geometries of interest, modern manufacturing techniques are considered to increase the technological readiness level (TRL), cost-effectiveness, and schedule savings. This work focused on the continued development of laser powder bed fusion (L-PBF) additive manufacturing (AM) to improve both design flexibility, evaluate microstructure and properties, and ultimately accelerate the TRL and qualification of these processes and alloys for components to potentially be put into service. Niobium alloy Nb1Zr was identified through a down-selection process outlined in previous reports as a candidate to develop in L-PBF AM. Historically, Nb1Zr had been explored for high temperature fast spectrum fission reactors for both terrestrial and space applications. Molybdenum alloy TZM has also been considered for these reactor concepts due to exceptional high-temperature strength, creep resistance, and stability under irradiation. L-PBF AM of TZM has previously been investigated at LANL under the Microreactor program, NASA, ORNL, and in academia. However, due to the crack prone nature of TZM, L-PBF AM of TZM resulted in significant microcracking and additional development is required to pursue viable maturation. Other AM methods have been found to be more successful in printing TZM, and those alternatives approaches are discussed in this effort. The efforts detailed in this report focused on continued development of Nb1Zr through L-PBF and development of TZM via L-PBF and electron powder bed fusion (E-PBF). The objective of this work was to further the development of these AM techniques for the chosen refractory alloys, elucidating and addressing associated challenges through characterization of several demonstration builds. At LANL, Nb1Zr builds were completed using an EOS M290 and M400 machines, and a refractory alloy-dedicated L-PBF system, the Xact Metal XM200G, was installed. The XM200G primary purpose was to do the Nb1Zr parameter development process; however, due to difficulties associated with the machine installation and qualification process, it was decided to pivot development to the larger M400 and M290 machines. Although the supply of Nb1Zr powder was limited, it was sufficient to generate sub-scale metallographic specimens for the purpose of parameter development. This was first accomplished on the EOS M400 then the M290 due to machine schedule availability. Further development of TZM has been initiated at the University of Texas El Paso (UTEP) under contract with LANL to use both a heated build envelope L-PBF machine and E-PBF machine that have been found in the literature to mitigate microcracking. UTEP was provided with TZM powder and build plates to support parallel TZM parameter development across both machines. As part of the contract, UTEP will also be conducting microstructural characterization once optimized process parameters have been identified. The optimized process parameters for each machine will be used to generate a series of metallographic, mechanical, and surface finish specimens for subsequent characterization and testing. In the next section, we provide a detailed discussion of the methodology used for investigating the feasibility of leveraging these alloys for use in advanced reactor applications.

36 MATERIALS SCIENCE↗

Development of the Licensing Procedure and Regulatory Framework for the Spent Fuel Storage facility in Korea - 16423

The Public Engagement Commission on SNF management (PECOS) published the recommendation report on the spent fuel management of Korea in June, 2015. Based on this report, the future national policy for spent fuel management of Korea has been established, taking into consideration the national/international trends on policy and technology development. Regardless of the recommendation report of PECOS, Spent fuel storage casks are necessary in Korea. Therefore, various types of spent fuel storage casks are now being developed by Korea vendors. For example, Concrete storage casks and dual purpose metal casks are now under development by the KORAD (Korea Radioactive waste agency) for future use in the interim storage facility. Unfortunately, there is no independent licensing procedure for spent fuel storage casks in Nuclear Safety Act (NSA) because is the casks are considered an integral part of the interim storage facility safety equipment. Furthermore, the definition of radioactive waste in the NSA was changed recently. Now, spent fuel is separated from the definition of 'radioactive waste'. Spent fuel can only become radioactive waste by the decision through the meeting of the relative ministers of Korea government. For that reason, the licensing procedure for interim spent fuel storage facilities was separated from the current 'disposal facility, etc.' in accordance with the article 63 of NSA. The aim of this study is to develop the licensing procedure for the storage cask, and also to develop a revised draft of interim storage facility procedure within the NSA. Once this independent licensing procedure on the spent fuel storage cask is introduced to the NSA, it is expected that developers or operators can develop and commercialize the storage cask in Korea. In this study, an independent licensing procedure for the spent fuel storage facility was developed including the storage cask licensing procedure for the NSA. The procedure was composed of the permit for construction and operation of interim storage facility, criteria for permit, inspection criteria, periodic safety review, and decommissioning criteria, etc. The detailed contents of these requirements were also developed to introduce the regulatory framework for the interim storage facility. Particularly, periodic safety review and decommissioning criteria were developed in accordance with the recommendation of IRRS (International Regulatory Review Service) of IAEA. The developed licensing procedure for spent fuel storage facility will be introduced in NSA in response to the revised definition of NSA and the recommendation report of PECOS. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Distribution Development for the RDX Regional Model at Los Alamos National Laboratory - 20385

Representing uncertainty in model inputs often means finding a balance between uncertainty and physical reality. Developing wide distributions may seem conservative in principle, but this approach may lead to unrealistic model results. Characterizing the current state of knowledge of stochastic inputs presents many challenges, especially if the data available are limited or have limited relevance to the site. Relationships among these inputs may also be important to represent but are typically complex or difficult to define. Often special adjustments must be made to account for reduced credibility in particular data. If parameters are strongly related to one another, a correlation structure may be developed for input to the model. Other techniques such as regression models may be used to incorporate relationships between the information available and the desired parameters. The process of developing distributions must consider details of the model in terms of what the distribution is meant to represent. This paper uses the example of a probabilistic fate and transport model for hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in the regional aquifer at Los Alamos National Laboratory (LANL). For many parameters, a single draw is applied to all space and time over which the model is run, for a single iteration. This simplification is often made for many reasons, and can often be beneficial, but also adds additional complexity in the distribution development process. Defining the distributional goals as they relate to the modeling process is an important step, which should take place prior to evaluation of the data. Usually, the distributions developed are meant to characterize the average value of the parameter over the spatial and temporal domain of the model. Distribution development requires consideration of many sources of information on the parameter where available, ideally from multiple references. Examples of different sources include data from different references but also from different conditions, measurement methods, or experimental types. Depending on these conditions and the reliability or relevance of particular references, different sources of data may each contribute valuable information but have varying relevance to the site. In these cases, weighting data unequally is a useful way to incorporate this information. As an example, aqueous dispersivity data are available for a variety of rock types. Only a few values are available for the desired rock type, and this is not enough to develop a distribution. Therefore, dispersivity values from other rock types are included in distribution development but are down-weighted such that the best data have the most influence on the distribution developed. In another case, K{sub d} distributions in the model are meant to represent a known composition of multiple soil types. Data from these materials are weighted accordingly to develop a distribution for the weighted average K{sub d} across soil types. Other cases include varying reliability of different sources, and weighting data according to the confidence in these sources. In some cases, input parameters are correlated with one another. An example is advective porosity, which is positively correlated with total porosity and must be less than total porosity. Paired data with both parameters must exist to discern the relationship between the two parameters and if it is necessary to build a correlation structure into the model. In general, correlated parameters may be represented in the model by a multivariate distribution, or perhaps more desirably, capturing the correlation within the developed distributions which may be treated as independent from one another. In the example of porosity, this can be done by transforming advective porosity into a proportion of total porosity which may be drawn independently from the distribution of total porosity. This paper explores how complex data and correlations can be incorporated to meet the distributional goals of the model, using the RDX regional model as a detailed example. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Confronting barriers and recognizing opportunities: Developing effective community-based environmental monitoring programs to meet the needs of Aboriginal communities

Aboriginal communities can be negatively affected by resource development, but often they do not have a full opportunity to participate in project review and the resulting monitoring and mitigation activities. Cumulative impacts of resource development are also typically neglected in monitoring protocols that focus on a limited number of environmental values, rather than adopting a long-term, holistic view of development over time and space. Community-based environmental monitoring (CBEM) is emerging as a way to meaningfully include local Aboriginal citizens in the decision-making process as well as the assessment of the long-term impacts of the development of natural resources. We explored opportunities and barriers for developing CBEM programs that meet the needs of small and rural Aboriginal communities that are faced with the rapid and wide-spread development of natural resources. We conducted interviews with a local Aboriginal community, and natural resource management practitioners who could provide perspectives on the application of CBEM to resource management in north-central British Columbia, Canada. Results demonstrate that CBEM offers a locally adapted and culturally appropriate approach to facilitate the participation of Aboriginal communities in natural resource decision making and management. The interpretation of the specific role and purpose of CBEM differed among participants, depending on their objectives for and concerns about natural resource development. However, all parties were consistent in viewing CBEM as an effective method for engaging in dialogue, cooperation, and tracking environmental change. The development or improvement of CBEM programs should consider the efficacy of monitoring protocols, social cohesion and relationships, ability to inform decision-making, and effectiveness of CBEM for the members of the community. - Highlights: • We explored how to develop effective CBEM with a focus on Aboriginal communities. • We identified opportunities and barriers for developing CBEM programs. • CBEM can facilitate Aboriginal community participation in natural resource management.

54 ENVIRONMENTAL SCIENCES↗

A Poisson equation method for prescribing fully developed non-Newtonian inlet conditions for computational fluid dynamics simulations in models of arbitrary cross-section

Prescribing inlet boundary conditions for computational fluid dynamics (CFD) simulations of internal flow in complex geometries such as anatomical vascular models is challenging. In the absence of patient-specific inlet velocity data, a common approach for long blood vessels is to assume that the inlet flow is fully developed. In vessels of irregular cross section, however, prescribing fully developed conditions is complicated due to the lack of a general closed-form analytical solution. In this study, we develop a simple Poisson equation method for prescribing fully developed inlet conditions for the flow of either Newtonian or non-Newtonian fluids in CFD models of arbitrary cross-section. We first derive the generalized Poisson equation for fully developed flow of a non-Newtonian fluid and we then develop and verify a methodology for numerically computing the solution on any planar boundary domain. In addition, we develop a simple extension of the method for prescribing a non-orthogonal inlet velocity that represents fully developed flow from an upstream tube that is connected to the CFD inlet at a non-orthogonal angle. This may be used to investigate a common source of uncertainty in CFD simulations of internal flow that is due to a lack of information concerning the exact streamwise flow direction at the inlets. Comparison to several Newtonian and non-Newtonian benchmark verification solutions shows the method to be extremely accurate. As a practical demonstration case, we use the method to prescribe fully developed conditions on multiple non-circular inlets for the non-Newtonian flow of blood in a patient-specific model of the inferior vena cava (IVC). Finally, we further demonstrate the utility of the method by performing a sensitivity study using the patient-specific IVC model, wherein we investigate the influence of inlet velocity flow direction on the non-Newtonian IVC hemodynamics. Given its simplicity and computational efficiency, the method is shown to be far superior to alternative approaches for prescribing fully developed inlet conditions in such complicated geometries. In conclusion, to facilitate the adoption of our Poisson equation method, we have distributed our OpenFOAM source code and the associated test cases from this study as open-source software.

97 MATHEMATICS AND COMPUTING↗

Time-resolved Proteome Profiling of Normal Lung Development

The biochemical networks mediating normal lung development remain unclear with important implications for ameliorating morbidity and mortality in premature infants. Here we perform integrative proteomics and metabolomics analyses of murine lungs from embryonic to early adult ages to characterize the molecular networks mediating normal lung development. Multi-omics analysis identified 8,932 proteins and 158 polar metabolites providing a deep and comprehensive view of the lung proteome and metabolome during normal development. Analysis of the proteomics data revealed ten discrete expression modules driving lung development and the underlying regulatory and signaling network modulating these expression modules. Of interest our data suggest the action of protein ubiquitination in regulating lung development extends beyond the pseudoglandular stage previously described. Combined analysis of the proteomics and metabolomics supported the notion of increased cell proliferation earlier in lung development. Additionally, comparison of the proteomics data with a recent transcriptome analysis revealed biological processes under post-transcriptional control during lung development. Our study provides a unique resource for understanding normal lung development, and potentially avenues for developing strategies to address disrupted development.

computational network analysis, lung development, ↗

Live imaging reveals a conserved role of fatty acid β-oxidation in early lymphatic development in zebrafish

Highlights: • Fatty acid β-oxidation (FAO) co-determines lymphatic development in the zebrafish. • Silencing of Cpt1a, key enzyme of FAO, disrupts initiation of lymphangiogenesis. • The importance of FAO for lymphatic development is conserved across species. During embryonic development, lymphatic endothelial cells (LECs) differentiate from venous endothelial cells (VECs), a process that is tightly regulated by several genetic signals. While the aquatic zebrafish model is regularly used for studying lymphangiogenesis and offers the unique advantage of time-lapse video-imaging of lymphatic development, some aspects of lymphatic development in this model differ from those in the mouse. It therefore remained to be determined whether fatty acid β-oxidation (FAO), which we showed to regulate lymphatic formation in the mouse, also co-determines lymphatic development in this aquatic model. Here, we took advantage of the power of the zebrafish embryo model to visualize the earliest steps of lymphatic development through time-lapse video-imaging. By targeting zebrafish isoforms of carnitine palmitoyltransferase 1a (cpt1a), a rate controlling enzyme of FAO, with multiple morpholinos, we demonstrate that reducing CPT1A levels and FAO flux during zebrafish development impairs lymphangiogenic secondary sprouting, the initiation of lymphatic development in the zebrafish trunk, and the formation of the first lymphatic structures. These findings not only show evolutionary conservation of the importance of FAO for lymphatic development, but also suggest a role for FAO in co-regulating the process of VEC-to-LEC differentiation in zebrafish in vivo.

60 APPLIED LIFE SCIENCES↗

How R Developers explain their Package Choice: A Survey

Background: Contemporary software development relies heavily on reusing already implemented functionality, usually in the form of packages. Aims: We aim to shed light on developers' preferences when selecting packages in R language. Method: To do that, we create and administer a survey to over 1000 developers who have added one of two common dataframe enhancement libraries in R to their projects: data.table or tidyr. We design a questionnaire using the Social Contagion Theory (SCT) following prior work on technology adoption and ensure that key dimensions affecting developer choice are considered. Results: Of the 1085 developers we contacted, 803 completed the survey asking them to prioritize various factors known to affect developer perceptions of package quality and to provide their background. Most developers self-identified as data scientists with two to five years of work experience. We found significant differences between the preferences of developers who chose data.table and tidyr. Surprisingly, package reputation based on easy-to-see measures, such as the number of stars on GitHub, was not an important factor for either group. Conclusions: Our findings demonstrate the inherently social nature of package adoption. They can help design future studies on how different populations of developers make decisions on which software packages to use in their projects. Finally, package developers and maintainers can benefit by better understanding the prime concerns of the users of their packages.

Malviya Thakur, Addi↗

Equipment Loan for Concentrated PV Cavity Converter (PVCC) Research: (CRADA CRD-08-285 Final Report)

Interest in High Concentration Photovoltaics (HCPV) for terrestrial applications has significantly grown in recent years. A major driver behind this growth trend is the availability of high efficiency multi-junction (MJ) cells that promise reliable operation under high concentrations (500 to 1000 suns). The primary impact of HCPV on the solar electricity cost is the dramatic reduction in cell cost. For terrestrial HCPV systems, operating at concentrations >/=500 suns, the expensive MJ cells are marginally affordable. Most recently, triple-junction test cells have achieved a conversion efficiency of over 40% under concentrated sunlight. Photovoltaic Cavity Converter (PVCC) is a multi-bandgap, high concentration PV device developed by United Innovations, Inc., under subcontract to NREL. The lateral- (2- dimensional) structure of PVCC, as opposed to vertical multi-junction (MJ) structure, helps to circumvent most of the developmental challenges MJ technology has yet to overcome. This CRADA will allow the continued development of this technology by United Innovations. cost. For terrestrial HCPV systems, operating at concentrations >/=500 suns, the expensive MJ cells are marginally affordable. Most recently, triple-junction test cells have achieved a conversion efficiency of over 40% under concentrated sunlight. Photovoltaic Cavity Converter (PVCC) is a multi-bandgap, high concentration PV device developed by United Innovations, Inc., under subcontract to NREL. The lateral- (2- dimensional) structure of PVCC, as opposed to vertical multi-junction (MJ) structure, helps to circumvent most of the developmental challenges MJ technology has yet to overcome. This CRADA will allow the continued development of this technology by United Innovations. cost. For terrestrial HCPV systems, operating at concentrations >/=500 suns, the expensive MJ cells are marginally affordable. Most recently, triple-junction test cells have achieved a conversion efficiency of over 40% under concentrated sunlight. Photovoltaic Cavity Converter (PVCC) is a multi-bandgap, high concentration PV device developed by United Innovations, Inc., under subcontract to NREL. The lateral- (2- dimensional) structure of PVCC, as opposed to vertical multi-junction (MJ) structure, helps to circumvent most of the developmental challenges MJ technology has yet to overcome. This CRADA will allow the continued development of this technology by United Innovations. cost. For terrestrial HCPV systems, operating at concentrations >/=500 suns, the expensive MJ cells are marginally affordable. Most recently, triple-junction test cells have achieved a conversion efficiency of over 40% under concentrated sunlight. Photovoltaic Cavity Converter (PVCC) is a multi-bandgap, high concentration PV device developed by United Innovations, Inc., under subcontract to NREL. The lateral- (2- dimensional) structure of PVCC, as opposed to vertical multi-junction (MJ) structure, helps to circumvent most of the developmental challenges MJ technology has yet to overcome. This CRADA will allow the continued development of this technology by United Innovations.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗

Principle Findings from Development of a Recirculated Exhaust Gas Intake Sensor (REGIS) Enabling Cost-Effective Fuel Efficiency Improvement

Kick-off of the Bosch scope of work for the REGIS project started in October 2012. The primary work-packages included in the Bosch scope of work were the following: overall project management, development of the EGR sensor (design of sensor element, design of protection tube, and design of mounting orientation), development of EGR system control strategy, build-up of prototype sensors, evaluation of system performance with the new sensor and the new control strategy, long-term durability testing, and development of a 2nd generation sensor concept for continued technology development after the REGIS project. The University of Clemson was a partner with Bosch in the REGIS project. The Clemson scope of work for the REGIS project started in June 2013. The primary work-packages included in the Clemson scope of work were the following: development of EGR system control strategy, and evaluation of system performance with the new sensor and new control strategy. This project was split into phase I, phase II and phase III. Phase I work was completed by the end of June 2014 and included the following primary work packages: development of sensor technical requirements, assembly of engine testbench at Clemson, design concept for sensor housing, connector, and mounting orientation, build-up of EGR flow test benches at Bosch, and build-up of first sensor prototypes. Phase II work was completed by the end of June 2015 and included the following primary work pack ages: development of an optimizing function and demonstration of robustness of sensor, system control strategy implementation and initial validation, completion of engine in the loop testing of developed control algorithm, completion of sensor testing including characteristic line, synthetic gas test stand, and pressure dependency characterization, demonstration of benefits of control w/o sensing via simulation, development of 2nd generation sensor concept. Notable technical achievements from phase II were the following: publication of two new technical papers by Clemson detailing the control strategies used for the EGR system control. The two papers was published in the 2016 SAE World Congress in April 2016. The titles of each paper are, “Physics-Based Exhaust Pressure and Temperature Estimation for Low Pressure EGR Control in Turbocharged Gasoline Engines,” by K. Siokos, and “A Control Algorithm for Low Pressure – EGR Systems using a Smith Predictor with Intake Oxygen Sensor Feedback”, by R. Koli. All phase III work packages have been completed. The primary work packages in phase III were the following: completion of long-term sensor durability testing, final demonstration of benefits of EGR control w/o sensing, final decision of the second generation sensor development path.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗