A Phenological Model for a Southern Population of Mountain Pine Beetle

The mountain pine beetle (MPB, Dendroctonus ponderosae Hopkins) attacks living Pinus trees across a widespread area of western North America, causing significant ecological and economic damage. The ability to make accurate predictions of how MPB populations across this range will respond to temperatures, which affect MPB progress through life stages, is essential. Northern and southern populations of MPB are genetically different in response to temperature, requiring geographic-specific model parameters. There is not currently a predictive model for the southern MPB life cycle, despite concerns that those populations may be more susceptible to increased numbers of generations per year, which would have devastating impacts on pine forests. In this thesis I develop a novel oviposition model for populations of southern MPB, which I incorporate into a cohort model that allows estimation of previously unknown development rates for the southern MPB teneral adult stage, resulting in a complete southern MPB life cycle model. In Chapter 2 I develop a predictive oviposition model for a southern population of mountain pine beetle using the oviposition (egg-laying) rate curve developed by McManis et al. (2019), incorporating variation in both oviposition rate and fecundity. I also introduce a method for determining the time delay before oviposition, t0. The model can return the probability of oviposition for a season of MPB attacks using phloem (inner-bark) temperature and adult MPB attack data collected from the field. I also develop an asymptotic approximation of MPB oviposition that is less complex as well as less computationally taxing. The detailed oviposition model and its asymptotic approximation are compared with other previously used modeling methods. The predictive capacity of each model is evaluated against laboratory data collected on southern MPB oviposition. McManis et al. (2018) parameterized development from eggs through pupation for a southern MPB population, but were unable to procure developmental data for the difficult-to-observe teneral adult stage. In Chapter 3 I determine developmental rates for the teneral adult stage using a phenology model and the field data for a southern population of MPB.I first present the incorporated models as well as teneral adult rate curves tested while developing the model. Then I explain the method by which the teneral adult rate curves were parameterized and how the Brière curve was determined to be most suitable. The resulting model is validated using an additional tree from the field data. The complete model is then used to examine the potential for bivoltinism in a southern population of MPB by increasing the mean temperature and testing for the successful emergence of a second generation. My model estimates that that southern MPB are unlikely to become bivoltine in warmer temperatures due to upper developmental thresholds of teneral adults

Authentication of reprocessing plant safeguards data through correlation analysis

This report investigates the feasibility and benefits of two new approaches to the analysis of safeguards data from reprocessing plants. Both approaches involve some level of plant modeling. All models involve some form of mass balance, either applied in the usual way that leads to material balances for individual process vessels at discrete times or applied by accounting for pipe flow rates that leads to material balances for individual process vessels at continuous times. In the first case, material balances are computed after each tank-to-tank transfer. In the second case, material balances can be computed at any desired time. The two approaches can be described as follows. The first approach considers the application of a new multivariate sequential test. The test statistic is a scalar, but the monitored residual is a vector. The second approach considers the application of recent nonlinear time series methods for the purpose of empirically building a model for the expected magnitude of a material balance or other scalar variable. Although the report restricts attention to monitoring scalar time series, the methodology can be extended to vector time series

Twenty Years of Capacity Building across the Cancer Prevention and Control Research Network

PURPOSE: to improve population health, community members need capacity (i.e., knowledge, skills, and tools) to select and implement evidence-based interventions (EBIs) to fit the needs of their local settings. Since 2002, the Centers for Disease Control and Prevention has funded the national Cancer Prevention and Control Research Network (CPCRN) to accelerate the implementation of cancer prevention and control EBIs in communities. The CPCRN has developed multiple strategies to build community members\u27 capacity to implement EBIs. This paper describes the history of CPCRN\u27s experience developing and lessons learned through the use of five capacity-building strategies: (1) mini-grant programs, (2) training, (3) online tools, (4) evidence academies, and (5) evaluation support for partners\u27 capacity-building initiatives. METHODS: We conducted a narrative review of peer-reviewed publications and grey literature reports on CPCRN capacity-building activities. Guided by the Interactive Systems Framework, we developed histories, case studies, and lessons learned for each strategy. Lessons were organized into themes. RESULTS: Three themes emerged: the importance of (1) community-engagement prior to and during implementation of capacity-building strategies, (2) establishing and sustaining partnerships, and (3) co-learning at the levels of centers, networks, and beyond. CONCLUSION: CPCRN activities have increased the ability of community organizations to compete for external funds to support implementation, increased the use of evidence in real-world settings, and promoted the broad-scale implementation of cancer control interventions across more than eight states. Lessons from this narrative review highlight the value of long-term thematic networks and provide useful guidance to other research networks and future capacity-building efforts

Combined cognitive and vocational interventions after mild to moderate traumatic brain injury: study protocol for a randomized controlled trial

Background A considerable proportion of patients with mild to moderate traumatic brain injury (TBI) experience long-lasting somatic, cognitive, and emotional symptoms that may hamper their capacity to return to work (RTW). Although several studies have described medical, psychological, and work-related factors that predict RTW after TBI, well-controlled intervention studies regarding RTW are scarce. Furthermore, there has traditionally been weak collaboration among health-related rehabilitation services, the labor and welfare sector, and workplaces. Methods/design This study protocol describes an innovative randomized controlled trial in which we will explore the effect of combining manualized cognitive rehabilitation (Compensatory Cognitive Training [CCT]) and supported employment (SE) on RTW and related outcomes for patients with mild to moderate TBI in real-life competitive work settings. The study will be carried out in the southeastern region of Norway and thereby be performed within the Norwegian welfare system. Patients aged 18–60 years with mild to moderate TBI who are employed in a minimum 50% position at the time of injury and sick-listed 50% or more for postconcussive symptoms 2 months postinjury will be included in the study. A comprehensive assessment of neurocognitive function, self-reported symptoms, emotional distress, coping style, and quality of life will be performed at baseline, immediately after CCT (3 months after inclusion), following the end of SE (6 months after inclusion), and 12 months following study inclusion. The primary outcome measures are the proportion of participants who have returned to work at 12-month follow-up and length of time until RTW, in addition to work stability as well as work productivity over the first year following the intervention. Secondary outcomes include changes in self-reported symptoms, emotional and cognitive function, and quality of life. Additionally, a qualitative RTW process evaluation focused on organizational challenges at the workplace will be performed. Discussion The proposed study will combine cognitive and vocational rehabilitation and explore the efficacy of increased cross-sectoral collaboration between specialized health care services and the labor and welfare system. If the intervention proves effective, the project will describe the cost-effectiveness and utility of the program and thereby provide important information for policy makers. In addition, knowledge about the RTW process for persons with TBI and their workplaces will be provided. Trial registration ClinicalTrials.gov, NCT03092713. Registered on 10 March 2017

Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity

Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development

Applying Theory to Explain the Influence of Factors External to an Organization on the Implementation of an Evidence-Based Intervention

Despite its widely acknowledged influence on implementation, limited research has been done on how the external environment (i.e., outer setting) determines when organizations adopt and implement new interventions. Determinant frameworks identify several outer setting-level factors such as funding streams, inter-organizational relationships, and peer pressure. However, these frameworks do not explain how or why outer-setting factors influence implementation. To advance research in this area, we argue for the importance of deriving theory-based propositions from organization theory to explain how outer setting factors influence organizations. Drawing on the work of the Organization Theory in Implementation Science (OTIS) project, we identified 20 propositions from five classic organization theories—Complexity Theory, Contingency Theory, Institutional Theory, Resource Dependence Theory, and Transaction Cost Economics. We then applied those propositions to hypothesize relationships among outer setting factors, implementation strategies, and implementation outcomes in five case studies of evidenced-based tobacco control interventions. The five case studies address the implementation of smoke-free policies, community health worker-led tobacco education and cessation programs, 5 A's (Ask, Advise, Assess, Assist, and Arrange), point-of-sale tobacco marketing policy interventions, and quitlines. The case studies illustrate how propositions may be used to guide the selection and testing of implementation strategies. Organization theories provide a menu of propositions that offer guidance for selecting and optimizing high-leverage implementation strategies that target factors at the level of outer setting. Furthermore, these propositions suggest testable hypotheses regarding the mechanisms underlying the influence of outer-setting factors on how and why organizations adopt and implement interventions

Toward a More Comprehensive Understanding of organizational influences On Implementation: the organization theory For Implementation Science Framework

INTRODUCTION: Implementation is influenced by factors beyond individual clinical settings. Nevertheless, implementation research often focuses on factors related to individual providers and practices, potentially due to limitations of available frameworks. Extant frameworks do not adequately capture the myriad organizational influences on implementation. Organization theories capture diverse organizational influences but remain underused in implementation science. to advance their use among implementation scientists, we distilled 70 constructs from nine organization theories identified in our previous work into theoretical domains in the Organization Theory for Implementation Science (OTIS) framework. METHODS: The process of distilling organization theory constructs into domains involved concept mapping and iterative consensus-building. First, we recruited organization and implementation scientists to participate in an online concept mapping exercise in which they sorted organization theory constructs into domains representing similar theoretical concepts. Multidimensional scaling and hierarchical cluster analyses were used to produce visual representations (clusters) of the relationships among constructs in concept maps. Second, to interpret concept maps, we engaged members of the Cancer Prevention and Control Research Network (CPCRN) OTIS workgroup in consensus-building discussions. RESULTS: Twenty-four experts participated in concept mapping. Based on resulting construct groupings\u27 coherence, OTIS workgroup members selected the 10-cluster solution (from options of 7-13 clusters) and then reorganized clusters in consensus-building discussions to increase coherence. This process yielded six final OTIS domains: organizational characteristics (e.g., size; age); governance and operations (e.g., organizational and social subsystems); tasks and processes (e.g., technology cycles; excess capacity); knowledge and learning (e.g., tacit knowledge; sense making); characteristics of a population of organizations (e.g., isomorphism; selection pressure); and interorganizational relationships (e.g., dominance; interdependence). DISCUSSION: Organizational influences on implementation are poorly understood, in part due to the limitations of extant frameworks. to improve understanding of organizational influences on implementation, we distilled 70 constructs from nine organization theories into six domains. Applications of the OTIS framework will enhance understanding of organizational influences on implementation, promote theory-driven strategies for organizational change, improve understanding of mechanisms underlying relationships between OTIS constructs and implementation, and allow for framework refinement. Next steps include testing the OTIS framework in implementation research and adapting it for use among policymakers and practitioners

Highly conserved interaction profiles between clinically relevant mutants of the cytomegalovirus CDK-like kinase pUL97 and human cyclins: functional significance of cyclin H

The complex host interaction network of human cytomegalovirus (HCMV) involves the regulatory protein kinase pUL97, which represents a viral cyclin-dependent kinase (CDK) ortholog. pUL97 interacts with the three human cyclin types T1, H, and B1, whereby the binding region of cyclin T1 and the pUL97 oligomerization region were both assigned to amino acids 231-280. We further addressed the question of whether HCMVs harboring mutations in ORF-UL97, i.e., short deletions or resistance-conferring point mutations, are affected in the interaction with human cyclins and viral replication. To this end, clinically relevant UL97 drug-resistance-conferring mutants were analyzed by whole-genome sequencing and used for genetic marker transfer experiments. The recombinant HCMVs indicated conservation of pUL97-cyclin interaction, since all viral UL97 point mutants continued to interact with the analyzed cyclin types and exerted wild-type-like replication fitness. In comparison, recombinant HCMVs UL97 Δ231-280 and also the smaller deletion Δ236-275, but not Δ241-270, lost interaction with cyclins T1 and H, showed impaired replication efficiency, and also exhibited reduced kinase activity. Moreover, a cellular knock-out of cyclins B1 or T1 did not alter HCMV replication phenotypes or pUL97 kinase activity, possibly indicating alternative, compensatory pUL97-cyclin interactions. In contrast, however, cyclin H knock-out, similar to virus deletion mutants in the pUL97-cyclin H binding region, exhibited strong defective phenotypes of HCMV replication, as supported by reduced pUL97 kinase activity in a cyclin H-dependent coexpression setting. Thus, cyclin H proved to be a very relevant determinant of pUL97 kinase activity and viral replication efficiency. As a conclusion, the results provide evidence for the functional importance of pUL97-cyclin interaction. High selective pressure on the formation of pUL97-cyclin complexes was identified by the use of clinically relevant mutants