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OBJECTIVES/GOALS: Our overall objective is to develop a directly observable and reproducible method of enhanced blood flow through tumor vessels (i.e. dynamic control) at the time of systemic treatment delivery. Our central hypothesis is that the dynamic control of tumor vessels will improve (1) systemic drug delivery and (2) effector cell trafficking to target tumor. METHODS/STUDY POPULATION: B16 melanoma cells were inoculated into C57BL/6 (B6) mice (male and female) in both regional (hind leg) and systemic (flank) models. Dynamic control consisted of an IV saline bolus (500 ul) and phenylephrine (10 ug). Tumor vessel response was observed in real-time through window chambers using intravital microscopy (IVM). Dynamic control was combined with melphalan (20 mg/ml) either regionally (isolated limb perfusion) or systemically. Outcomes included tumor growth, survival, IHC, and toxicity. Dynamic control will be combined with adoptive transfer of effector T cells. B6 mice will be inoculated with B16/OVA (flank with window chamber) and treated with fluorescently labeled (calcein), OVA-specific CD8+ T cells from OT-1 transgenic mice. IVM, IHC, and flow cytometry will be used to measure T cell trafficking. RESULTS/ANTICIPATED RESULTS: Dynamic control (1) restored blood flow in non-functional tumor vessels and (2) increased and then transiently reversed blood flow in functional vessels. Vessel diameters did not change, suggesting that shunting of systemic blood to the tumor vasculature accounted for the observed changes. Dynamic control augmented tumor responses in our regional therapy model of melanoma. Increases in DNA adduct formation (melphalan mechanism of action) detected by IHC, decreased tumor growth, and increased survival were observed with dynamic control. There was no increased limb toxicity. Similarly, dynamic control augmented responses in our systemic therapy model (decreased tumor growth and improved survival). We anticipate that dynamic control will improve trafficking of effector T cells in the next set of experiments. DISCUSSION/SIGNIFICANCE OF IMPACT: Heterogeneous responses to systemic therapies represent a major gap in current cancer treatment. An essential requirement for any effective therapy is its ability to reach tumor via the tumor-associated vasculature. We have therefore developed an approach to enhance drug delivery (dynamic control), which we also plan to test in clinical trials.
In recent years, scholarship on international organisations (IO) has devoted increasing attention to the relations in which IOs are embedded. In this article, we argue that the rationalist-institutionalist core of this scholarship has been marked by agentic, repressive understandings of power and we propose an alternative approach to power as productive in and of relations among IOs. To study productive power in IO relations, we develop a theoretical framework centred on the concept of ‘metagovernance norms’ as perceptions about the proper ‘governance of governance’ that are shared among IOs in a governance field. Drawing on discourse theory, we contend that metagovernance norms unfold productive power effects, as dominant notions of how to govern well and effectively (i) fix meanings, excluding alternative understandings and (ii) are inscribed into practices and institutions, hence reshaping inter-organisational relations over time. To illustrate our framework, we trace metagovernance norms in discourses among health IOs since the 1990s. We find a historical transformation from beliefs in the virtues of partnerships, pluralisation, and innovation, towards discursive articulations that emphasise harmonisation, order, and alignment. Moreover, we expose the productive power of metagovernance norms by showing how they were enacted through practices and institutions in the global health field.
Several well-known observer scales, including the Hamilton Depression Scale (HAM-D), Montgomery-Åsberg Scale (MADRS), Major Depression Rating Scale (MDS), Melancholia Scale (MES), and Inventory for Depressive Symptomatology (IDS) used for measuring severity of depressive states have been compared by their responsiveness in an open trial including patients treated with a combination of citalopram and mianserin. The patients fulfilled the Diagnostic and Statistical Manual (DSM)-IV criteria for major depressive episode, and all scored 18 or more on the HAM-D before treatment. Onset of antidepressant action was defined as an improvement of rating scale scores of 25% or more of pre-treatment scores. A response to treatment was defined as a reduction of 50% or more on the pre-treatment scores. The results showed that the number of treatment days until improvement was 11 to 13 with no difference between the scales. The days until response were between 18 and 21 with no difference between the scales. In conclusion, the depression scales were found to be equal in their ability to detect changes in depressive symptoms during treatment. The mean of days to response was 19 for the combination of citalopram and mianserin. This is similar to the response for the combination of fluoxetine and pinolol.
The authors demonstrate that multicomponent metallic alloy nanofoams can be synthesized by the polymeric templating method. The present approach enabled alloy compositions not accessible via commonly used dealloying or co-deposition methods. The authors report the synthesis of a Cu50Ni50 alloy nanofoam using electrospinning polymeric templating, which exhibits distinct polycrystallinity, process-driven segregation, and enhanced mechanical strength over pure Cu nanofoams. Transmission electron microscopy revealed microscopic grain formation and their variable compositions. The processing method is applicable to the synthesis of a wide range of multicomponent metal porous materials, creating new research opportunities for noble alloy foams not available through wet electrochemical routes.
Compliance with college emergency notifications can minimize injury; however, time is often wasted in alert verification. Building on prior research, this study assesses using health-behavior theory to predict rapid compliance to emergency notifications across a range of scenarios and within a diverse college population.
Cross-sectional, student data were collected in 2017-2018 (n = 1529). The Theory of Planned Behavior and Protection Motivation Theory were used to explain intention to comply with emergency notifications in scenarios: robbery, shooter, fire, chemical spill, protest, health emergency, and air quality. Regression models assessed associations between constructs and intention to rapidly comply with each notification.
The most consistent predictors of rapid compliance were attitudes and subjective norms (adjusted odds ratio [AOR]: 1.057-1.118; 95% CI: 1.009-1.168). Scenarios prone to rapid developments such as robbery, shooter, and fire were associated with increased perceived threat and response efficacy (AOR: 1.024-1.082; 95% CI: 1.003-1.132) Slower developing situations such as air quality and health hazards were associated with increased perceived control (AOR: 1.027-1.073; 95% CI: 1.031-1.117).
This study identified attitude and subjective norms as consistent predictors of rapid compliance and improves understanding of additional constructs across scenarios. Campuses may benefit from leveraging concepts from health-behavior theory to provide targeted intervention focusing on factors associated with rapid compliance.
In ‘Calculating Correct Compilers’ (Bahr & Hutton, 2015), we developed a new approach to calculating compilers directly from specifications of their correctness. Our approach only required elementary reasoning techniques and has been used to calculate compilers for a wide range of language features and their combination. However, the methodology was focused on stack-based target machines, whereas real compilers often target register-based machines. In this article, we show how our approach can naturally be adapted to calculate compilers for register machines.
Measuring the elastic and plastic properties with nanoindentation is predicated on the indentation not fracturing the material. In this study, an unloading curve analysis is used to identify indentation-induced fracture in brittle molecular organic crystals to define conditions, where properties measurements are accurate, and for calculating the toughness. Single crystals of cyclotetramethylene tetranitramine (HMX) and idoxuridine were indented from 1 to 300 mN with indenter probes of varying acuity to identify fracture initiation loads. Idoxuridine displayed no fracture up to and at 100 mN, with fracture occurrence then seen at an increasing rate until every indentation made induced fracture at 300 mN. HMX displayed no fracture up to and at 4 mN, with fracture then occurring at an increasing rate until every sample fractured at 8 mN. The toughness of HMX and idoxuridine is ≈0.28 ≈ 0.4–0.5 MPa/m1/2, respectively.
Concurrently assessing localized residual stresses and mechanical properties in cases where there are gradients in stresses and properties (such as those resulting in metallic alloys from shot peening processes) is challenging. Most indentation-based stress measurements assume uniform properties, which is not necessarily the case in this common industrial process. By using the energy envelope describing the total work of indentation by a load–displacement curve from instrumented indentation, localized residual stresses after shot peening were evaluated experimentally. A framework is developed to describe the appropriate indentation depth at which to assess properties that effectively define the volumetric resolution of the method. The residual stresses predicted via the nanoindentation experiment and energy analysis were validated with X-ray measurement of residual stresses on a shot-peened 52100 steel. The energy method can be applied directly from the indentation load–displacement curve without considering the contact area.
Term graph rewriting provides a formalism for implementing term rewriting in an efficient manner by emulating duplication via sharing. Infinitary term rewriting has been introduced to study infinite term reduction sequences. Such infinite reductions can be used to model non-strict evaluation. In this paper, we unify term graph rewriting and infinitary term rewriting thereby addressing both components of lazy evaluation: non-strictness and sharing. In contrast to previous attempts to formalise infinitary term graph rewriting, our approach is based on a simple and natural generalisation of the modes of convergence of infinitary term rewriting. We show that this new approach is better suited for infinitary term graph rewriting as it is simpler and more general. The latter is demonstrated by the fact that our notions of convergence give rise to two independent canonical and exhaustive constructions of infinite term graphs from finite term graphs via metric and ideal completion. In addition, we show that our notions of convergence on term graphs are sound w.r.t. the ones employed in infinitary term rewriting in the sense that convergence is preserved by unravelling term graphs to terms. Moreover, the resulting infinitary term graph calculi provide a unified framework for both infinitary term rewriting and term graph rewriting, which makes it possible to study the correspondences between these two worlds more closely.
A synthesis method to form conformal core-shell foams of metals and alloys on a carbon nanotube (CNT) scaffold by electroplating from a single bath electrolyte is demonstrated in this work. A triple cyclic pulse electrodeposition technique was used to deposit Ni and Cu layers on the CNT scaffold, and electron microscopy was then used to identify conditions amenable to conformal and island growth morphologies. Nanoindentation of the resulting metallic foam structure, using a flat punch/compression geometry, demonstrates that adding conformal metallic shells to the CNT turf to create a metal coated low density foam increases both the hardness and elastic modulus; however, once island growth initiates there is no significant subsequent increase in mechanical properties with increases in deposited metals.
IN SEINEM GESPRÄch mit Johann Peter Eckermann vom 18. Januar 1827 erklärte Goethe im Hinblick auf die Novelle, dass er “mit der Prosa jetzt am besten gefahren” sei. Aus der Vorgeschichte der Novelle ist bekannt, dass er 1797 im Anschluss an Hermann und Dorothea ein episches Gedicht in Hexametern unter dem Titel “Die Jagd” geplant hatte. Doch Schiller war gegen die Behandlung des Themas in Hexametern und riet zu achtzeiligen Stanzen. Dreißig Jahre später nahm Goethe das Thema der “Wunderbaren Jagd” wieder auf, wie er in seinem Tagebuch vom 4. Oktober 1826 notierte. Wilhelm von Humboldt teilte er wenige Wochen später mit, dass er den damals aufgegebenen Plan “prosaisch auszuführen” gedenke, “da es denn für eine Novelle gelten mag” (Brief vom 22. Oktober 1826). Dabei ergibt sich die Frage, warum Goethe das Thema der Novelle nicht vollständig in Prosa abgehandelt hat. Im Schlussteil der Novelle, vom Auftritt der Schaustellerfamilie an, geht die Textgestaltung von der Prosa teilweise ins Lyrische über und gipfelt in den Liedstrophen des Knaben der Schaustellerfamilie. Goethe unternimmt hier eine Neuvermessung von Prosa und Lyrik, die im Widerspruch zu seinen anfänglichen Werk-Aussagen steht. Er ging zu lyrischen Einlagen über, weil er die Prosa zur Vermittlung seiner Ideen nicht geeignet fand. Der Wechsel von Prosa und Lyrik steht also, so lautet mein Argument, in Zusammenhang mit der von Jane K. Brown herausgestellten dialektischen “Progression der Gattungshierarchie vom Realen zum Idealen.” Im Gegensatz zur neoklassizistischen Unterscheidung der Gattungen in der bildenden Kunst habe Goethe in der Novelle ein eigenes Konzept für die Literatur entwickelt, das das Reale dialektisch mit dem Idealen verbindet. Dabei wird das Reale der Prosa zugeschrieben und das Ideale der Lyrik, wobei das eine nicht ohne das andere fungieren kann.
Meine These besteht in der Annahme, dass Goethe mit der Novelle ein Modell eines gewaltlosen Kreislaufs beziehungsweise Austauschs von Gesellschaft und Natur zu vermitteln suchte, für das es seinerzeit keine Terminologie gab. Diese Lücke wurde erst um die Mitte des 19. Jahrhunderts mit dem Begriff der Ökologie geschlossen. Goethe hielt die Lyrik für die Vermittlung dieses Modells geeigneter als die Prosa, wie er im Gespräch mit Eckermann vom 18. Januar 1827 darlegte: “ein ideeller, ja lyrischer Schluß war nötig und mußte folgen; denn nach der pathetischen Rede des Mannes, die schon poetische Prosa ist, mußte eine Steigerung kommen, ich mußte zur lyrischen Poesie, ja zum Liede selbst übergehen.”
Because of considerably increased farmland prices, not only in Germany, the question arises whether farmland is still affordable for farmers. Hence, there is a call for price caps. If farmland prices are to be capped by political intervention, identifying the main farmland price determinants especially for the highest prices is essential. Using quantile regression for German standard farmland values, we find heterogeneous relationships across the estimated quantiles for several covariates. Nonagricultural factors are often more pronounced at the upper tail of the conditional distribution. We recommend focusing primarily on factors in the upper quantiles to prevent further farmland price increases.
People living in low- and middle-income countries (LMIC) are at increased risk for exposure to major natural disasters, which places them at increased risk for mental health problems. Evidence is less clear, however, regarding the effects of less severe but more frequent natural disasters, which are likely to increase due to global climate change.
To examine the mental health and life functioning, and their predictors, of people living in central coastal Vietnam – an area characterised by high risk for natural disasters and poverty.
One thousand individuals were randomly selected from five provinces in central coastal Vietnam. Individuals were assessed cross-sectionally for exposure to major storms and other traumatic events (Post-traumatic Diagnostic Scale, or PDS), financial stress (Chronic Financial Stress Scale), depression (PHQ-9), anxiety (GAD-7), post-traumatic stress disorder (PTSD) (PDS), somatic syndrome (SCL-90-R), alcohol dependence (ICD-10), self-perceived general physical health (SF-36), and functional impairment (PDS life functioning section); caseness was determined using the various measures' algorithms.
22.7% of the sample (n=227) met caseness criteria in one or more mental health domains, and 22.1% (n=221) reported moderate to severe functional impairment. Lifetime exposure to typhoons and other major storms was 99% (n=978), with 77% (n=742) reporting traumatic major storm exposure. Moderate to high levels of financial stress were reported by 30% (n=297). Frequency of exposure to major storms was not associated with increased risk for mental health problems but traumatic exposure to a major storm was. Overall, the strongest predictor of mental health problems was financial stress. Number of traumatic typhoons and other major storms in turn were significant predictors (r2=0.03) of financial stress. The primary predictor of alcohol dependence was male gender, highlighting the importance of gender roles in development of alcohol abuse in countries like Vietnam.
Individuals living in central coastal Vietnam have elevated rates of PTSD, somatic syndrome, and functional impairment but not depression or anxiety. Financial stress was the strongest predictor of mental health problems. Results suggest the importance of conducting broad assessments when providing mental health support for disaster-impacted communities. Study results suggest that one indirect consequence of predicted global climate change may be increased prevalence of mental health problems in communities such as that assessed in the present study, due to increased risk for traumatic storm-related exposure and through indirect effects on financial stress, but not through a general increased risk for major storms. Such results also indicate that when supporting LMIC communities that have experienced natural disasters, it will be important to consider the broader community context including poverty, in addition to the direct effects of the disaster.
The exotic characteristics of nanoscopic metallic materials bestows diverse functionalities that are increasingly being utilized for a broad range of applications. Polymer substrates present robust architectures for nanoparticle anchoring as well as modulating attendant size-induced aggregation. However, in principle, interfacial adhesion of a polymer-metal material system is weak, making the susceptibility to delamination a challenge. We have deposited copper particles on model polymer thin film and fibrous architectures to study adhesion behavior on these distinct geometries. The average sizes of copper nanoparticles deposited on electrospun fibers for metallization times of 3 and 5 minutes were 13 and 10 nm, whereas the metal island sizes under same metallization times on thin films was 79nm and 81nm. Scratch tests using a nanoindentation system were unable to generate macroscopic film delamination, but did exhibit apparent removal of individual particles, with adhesion forces of 14.9μN, 36μN, and 28.8μN obtained for films metallized for 1, 3, and 5 minutes respectively. Macroscopic tensile testing of fiber mats showed the metallization maintains conformity with the polymer ligament, albeit, with intermittent fracture of the conformal metal coating, signifying substantial adhesion exists between the metallic layer and the PAN fiber.
A synthesis method to form foams consisting of a shell of metals conformally coated on carbon nanotube (CNT) arrays by electroplating from a single bath electrolyte is demonstrated in this work. A triple cyclic pulse electrodeposition technique was used to deposit Ni and Cu layers on the CNT arrays, and electron microscopy was then used to identify conditions amenable to semi-conformal and island growth morphologies. Nanoindentation of the resulting metallic-CNT composite foam structure, using a flat punch/compression geometry, demonstrates that adding metallic shells to the CNT turf to create a metallic low density foam increases both the hardness and elastic modulus; however, once island growth initiates there is no significant subsequent increase in mechanical properties with increases in deposited metals.
A polycrystalline Cu foam with sub-micron ligament sizes was formed by creating a non-woven fabric via electrospinning with a homogeneous mixture of polyvinyl alcohol(PVA)-and copper acetate(Cu(Ac)2). Thermogravimetric measurement of the electrospun fabric of the precursor solution is reported. Oxidizing the precursor fabric at 773K formed an oxide nano-foam; subsequent heating at 573K with a reducing gas transformed the CuO nano-foam to Cu with a similar ligament and meso-scale pore size morphology. A cross-section prepared by focused ion beam lift-out shows the polycrystalline structure with multi-scale porosity. The mechanical property of the Cu nano-foam is measured by nano-indentation. The load-depth curves and deduced mechanical properties suggest that additional intra-ligament pores lead to unique structure-property relations in this non-conventional form of metal.