Building capacity for dissemination and implementation research: One university’s experience

Abstract Background While dissemination and implementation (D&I) science has grown rapidly, there is an ongoing need to understand how to build and sustain capacity in individuals and institutions conducting research. There are three inter-related domains for capacity building: people, settings, and activities. Since 2008, Washington University in St. Louis has dedicated significant attention and resources toward building D&I research capacity. This paper describes our process, challenges, and lessons with the goal of informing others who may have similar aims at their own institution. Activities An informal collaborative, the Washington University Network for Dissemination and Implementation Research (WUNDIR), began with a small group and now has 49 regular members. Attendees represent a wide variety of settings and content areas and meet every 6 weeks for half-day sessions. A logic model organizes WUNDIR inputs, activities, and outcomes. A mixed-methods evaluation showed that the network has led to new professional connections and enhanced skills (e.g., grant and publication development). As one of four, ongoing, formal programs, the Dissemination and Implementation Research Core (DIRC) was our first major component of D&I infrastructure. DIRC’s mission is to accelerate the public health impact of clinical and health services research by increasing the engagement of investigators in later stages of translational research. The aims of DIRC are to advance D&I science and to develop and equip researchers with tools for D&I research. As a second formal component, the Washington University Institute for Public Health has provided significant support for D&I research through pilot projects and a small grants program. In a third set of formal programs, two R25 training grants (one in mental health and one in cancer) support post-doctoral scholars for intensive training and mentoring in D&I science. Finally, our team coordinates closely with D&I functions within research centers across the university. We share a series of challenges and potential solutions. Conclusion Our experience in developing D&I research at Washington University in St. Louis shows how significant capacity can be built in a relatively short period of time. Many of our ideas and ingredients for success can be replicated, tailored, and improved upon by others

Translation inhibition by rocaglates activates a species-specific cell death program in the emerging fungal pathogen Candida auris

Fungal infections are a major contributor to infectious disease-related deaths worldwide. Recently, global emergence of the fungal pathogen Candida auris has caused considerable concern because most C. auris isolates are resistant to fluconazole, the most commonly administered antifungal, and some isolates are resistant to drugs from all three major antifungal classes. To identify novel agents with bioactivity against C. auris, we screened 2,454 compounds from a diversity-oriented synthesis collection. Of the five hits identified, most shared a common rocaglate core structure and displayed fungicidal activity against C. auris These rocaglate hits inhibited translation in C. auris but not in its pathogenic relative Candida albicans Species specificity was contingent on variation at a single amino acid residue in Tif1, a fungal member of the eukaryotic initiation factor 4A (eIF4A) family of translation initiation factors known to be targeted by rocaglates. Rocaglate-mediated inhibition of translation in C. auris activated a cell death program characterized by loss of mitochondrial membrane potential, increased caspase-like activity, and disrupted vacuolar homeostasis. In a rocaglate-sensitized C. albicans mutant engineered to express translation initiation factor 1 (Tif1) with the variant amino acid that we had identified in C. auris, translation was inhibited but no programmed cell death phenotypes were observed. This surprising finding suggests divergence between these related fungal pathogens in their pathways of cellular responses to translation inhibition. From a therapeutic perspective, the chemical biology that we have uncovered reveals species-specific vulnerability in C. auris and identifies a promising target for development of new, mechanistically distinct antifungals in the battle against this emerging pathogen. IMPORTANCE Emergence of the fungal pathogen Candida auris has ignited intrigue and alarm within the medical community and the public at large. This pathogen is unusually resistant to antifungals, threatening to overwhelm current management options. By screening a library of structurally diverse molecules, we found that C. auris is surprisingly sensitive to translation inhibition by a class of compounds known as rocaglates (also known as flavaglines). Despite the high level of conservation across fungi in their protein synthesis machinery, these compounds inhibited translation initiation and activated a cell death program in C. auris but not in its relative Candida albicans Our findings highlight a surprising divergence across the cell death programs operating in Candida species and underscore the need to understand the specific biology of a pathogen in attempting to develop more-effective treatments against it.Published versio

Measuring The Equations Of State In A Relaxed Magnetohydrodynamic Plasma

We report measurements of the equations of state of a fully relaxed magnetohydrodynamic (MHD) laboratory plasma. Parcels of magnetized plasma, called Taylor states, are formed in a coaxial magnetized plasma gun, and are allowed to relax and drift into a closed flux conserving volume. Density, ion temperature, and magnetic field are measured as a function of time as the Taylor states compress and heat. The theoretically predicted MHD and double adiabatic equations of state are compared to experimental measurements. We find that the MHD equation of state is inconsistent with our data

Magnetothermodynamics: Measurements Of The Thermodynamic Properties In A Relaxed Magnetohydrodynamic Plasma

We have explored the thermodynamics of compressed magnetized plasmas in laboratory experiments and we call these studies ‘magnetothermodynamics’. The experiments are carried out in the Swarthmore Spheromak eXperiment device. In this device, a magnetized plasma source is located at one end and at the other end, a closed conducting can is installed. We generate parcels of magnetized plasma and observe their compression against the end wall of the conducting cylinder. The plasma parameters such as plasma density, temperature and magnetic field are measured during compression using HeNe laser interferometry, ion Doppler spectroscopy and a linear dot{B} probe array, respectively. To identify the instances of ion heating during compression, a PV diagram is constructed using measured density, temperature and a proxy for the volume of the magnetized plasma. Different equations of state are analysed to evaluate the adiabatic nature of the compressed plasma. A three-dimensional resistive magnetohydrodynamic code (NIMROD) is employed to simulate the twisted Taylor states and shows stagnation against the end wall of the closed conducting can. The simulation results are consistent to what we observe in our experiments

Synergetic Exploitation of the Sentinel-2 Missions for Validating the Sentinel-3 Ocean and Land Color Instrument Terrestrial Chlorophyll Index Over a Vineyard Dominated Mediterranean Environment

[EN] Continuity to the Medium Resolution Imaging Spectrometer (MERIS) Terrestrial Chlorophyll Index (MTCI) will be provided by the Ocean and Land Color Instrument (OLCI) on-board the Sentinel-3 missions. To ensure its utility in a wide range of scientific and operational applications, validation efforts are required. In the past, direct validation has been constrained by the need for costly airborne hyperspectral data acquisitions, due to the lack of freely available high spatial resolution imagery incorporating appropriate spectral bands. The Multispectral Instrument (MSI) on-board the Sentinel-2 missions now offers a promising alternative. We explored the synergetic use of MSI data for validation of the OLCI Terrestrial Chlorophyll Index (OTCI) over the Valencia Anchor Station, a large agricultural site in the Valencian Community, Spain. Using empirical and machine learning techniques applied to MSI data, in situ measurements were upscaled to the moderate spatial resolution of the OTCI. An RMSECV of 0.09 g.m(-2) (NRMSECV = 20.93%) was achieved, highlighting the valuable information MSI data can provide when used in synergy with OLCI data for land product validation. Good agreement between the OTCI and upscaled in situ measurements was observed (r = 0.77, p < 0.01), providing increased confidence to users of the product over vineyard dominated Mediterranean environments.This work was supported in part by the European Space Agency and European Commission through the Sentinel-3 Mission Performance Centre.Brown, LA.; Dash, J.; Lidón, A.; Lopez-Baeza, E.; Dransfeld, S. (2019). Synergetic Exploitation of the Sentinel-2 Missions for Validating the Sentinel-3 Ocean and Land Color Instrument Terrestrial Chlorophyll Index Over a Vineyard Dominated Mediterranean Environment. IEEE Journal of Selected Topics in Applied Earth Observations and Remote Sensing. 12(7):2244-2251. https://doi.org/10.1109/JSTARS.2019.28999982244225112

Economic rationalisation of health behaviours: the dangers of attempting policy discussions in a vacuum

When analysing the health behaviours of any group of people, understanding the constraints and possibilities for individual agency as shaped by the broader societal context is critical. In recent decades, our understanding of the ways in which physical and social environments influence health and health behaviours has expanded greatly. The authors of a recent analysis of Australian Aboriginal health data using an economic ‘rational choice model,’ published in this journal, claim to make a useful contribution to policy discussions relating to Aboriginal health, but neglect context. By doing so, they neglect the very factors that determine the success or failure of policy change. Notwithstanding the technical sophistication of the analyses, by ignoring most relevant determinants of health, the conclusions misrepresent the lives of Aboriginal and Torres Strait Islander people and therefore risk perpetuating harm, rather than improving health.Rachel Reilly, Kevin Rowley Joanne Luke Joyce Doyle Rebecca Ritte Rebekah O, Shea Alex Brow

Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNFα

Activated macrophages secrete an array of proinflammatory cytokines, including tumor necrosis factor-α (TNFα) and interleukin 6 (IL-6), that are temporally secreted for sequential roles in inflammation. We have previously characterized aspects of the intracellular trafficking of membrane-bound TNFα and its delivery to the cell surface at the site of phagocytic cups for secretion (Murray, R.Z., J.G. Kay, D.G. Sangermani, and J.L. Stow. 2005. Science. 310:1492–1495). The trafficking pathway and surface delivery of IL-6, a soluble cytokine, were studied here using approaches such as live cell imaging of fluorescently tagged IL-6 and immunoelectron microscopy. Newly synthesized IL-6 accumulates in the Golgi complex and exits in tubulovesicular carriers either as the sole labeled cargo or together with TNFα, utilizing specific soluble NSF attachment protein receptor (SNARE) proteins to fuse with the recycling endosome. Within recycling endosomes, we demonstrate the compartmentalization of cargo proteins, wherein IL-6 is dynamically segregated from TNFα and from surface recycling transferrin. Thereafter, these cytokines are independently secreted, with TNFα delivered to phagocytic cups but not IL-6. Therefore, the recycling endosome has a central role in orchestrating the differential secretion of cytokines during inflammation

In Vitro Fertilization and Risk for Hypertensive Disorders of Pregnancy: Associations With Treatment Parameters

With an increasing proportion of pregnancies being conceived using assisted-reproductive technology, important changes to in vitro fertilization (IVF) such as the use of cryopreserved oocytes or embryos have been made. It is now established that adverse maternal and infant perinatal outcomes are associated with both assisted reproductive technologies and subfertility

Global response of clear-air turbulence to climate change

Clear-air turbulence (CAT) is one of the largest causes of weather-related aviation incidents. Here we use climate model simulations to study the impact that climate change could have on global CAT by the period 2050–2080. We extend previous work by analyzing eight geographic regions, two flight levels, five turbulence strength categories, and four seasons. We find large relative increases in CAT, especially in the midlatitudes in both hemispheres, with some regions experiencing several hundred per cent more turbulence. The busiest international airspace experiences the largest increases, with the volume of severe CAT approximately doubling over North America, the North Pacific, and Europe. Over the North Atlantic, severe CAT in future becomes as common as moderate CAT historically. These results highlight the increasing need to improve operational CAT forecasts and to use them effectively in flight planning, to limit discomfort and injuries among passengers and crew