Quality and Publication of Emergency Medicine Trials Registered in ClinicalTrials.gov

Introduction: Promoting emergency medicine (EM) clinical trials research remains a priority. To characterize the status of clinical EM research, this study assessed trial quality, funding source, and publication of EM clinical trials and compared EM and non-EM trials on these key metrics. We also examined the volume of EM trials and their subspecialty areas.Methods: We abstracted data from ClinicalTrials.gov (February 2000 - September 2013) and used individual study National Clinical Trial numbers to identify published trials (January 2007 - September 2016). We used descriptive statistics and chi-square tests to examine study characteristics by EM and non-EM status, and Kaplan-Meier curves and log-rank tests to compare time to publication of completed EM and non-EM studies.Results: We found 638 interventional EM trials and 59,512 non-EM interventional trials conducted in the United States between February 2000 and September 2013, registered on ClinicalTrials.gov. EM studies were significantly less likely than non-EM studies to be National Institutes of Health-funded or to evaluate a drug or biologic. However, EM studies had significantly larger sample sizes, and were significantly more likely to use randomization and blinding. Overall, 34.3% of EM and 26.0% of non-EM studies were published in peer-reviewed journals. By subspecialty, more EM trials concerned medical/surgical and psychiatric/neurological conditions than trauma.Conclusion: Although EM studies were less likely to have received federal or industry funding, and the EM portfolio consisted of only 638 trials over the 14-year study period, the quality of EM trials surpassed that of non-EM trials, based on indices such as randomization and blinding. This novel finding bodes well for the future of clinical EM research, as does the higher proportion of published EM than non-EM trials. Our study also revealed that trauma studies were under-represented among EM studies. Periodic assessment of EM trials with the metrics used here could provide an informative and valuable longitudinal view of progress in clinical EM research

Medium development strategies and scale down models for a high density high productivity cell line

Medium Development at Regeneron continues to enhance fed batch culture productivity. These efforts have been enabled through the development of high throughput scale down models in shake flasks and the ambr® 250. Design of Experiment (DOE) approaches have been applied to optimize the operating conditions in the small scale models leading to performance for growth and titer that match benchtop bioreactor with no off-set. The development of these representative scale down models and our approach to medium development will be described. A medium development case study will be presented from a recent Regeneron fed batch process with a cell line achieving high cell densities and depleting the culture of key amino acids. The traditional medium development approach of supplementing the culture with the depleted nutrients was unsuccessful: high amino acid consumption rates required large amounts of amino acids resulting in significantly increased culture osmolality and reduced productivity. Leveraging high throughput culture systems and multifactor DOEs, multiple medium composition factors in combination were rapidly evaluated. Mathematical models relating medium input factors to process outputs are generated that allow for process optimization. Using this approach, a new feeding strategy was developed that limits increases in osmolality and yields titers approaching 10g/L in both the scale down systems and a process that has been implemented for clinical scale manufacturing of a monoclonal antibody

Development of scale down models for perfusion bioreactor medium optimization

Due to the complex nature of balancing \u3e50 individual media components, the development and optimization of bioreactor medium for high performing perfusion bioreactors is a resource intensive, multivariate problem that greatly benefits from the availability of predictive high through-put scale-down models that simulate the bioreactor system. For that purpose, both a 10 mL long-term block model and 50 mL shaker tube model were developed and optimized to settings that balance oxygen transfer, culture health, and productivity. The long-term block model was limited by the volume needed for culture sampling; as a result, the shaker tube model was developed with a 7.5x increase in working volume. This shaker tube model was then applied to adequately characterize cell nutrient consumption profiles and subsequently inform medium development through multivariate design of experiments (DOE). Within two rounds of studies in the scale-down models, Regeneron’s first-generation perfusion medium formulation achieved approximately 100% increase in productivity compared to the initial medium. The improved nutrient strategy optimized in shaker tubes translated to several cell lines in the benchtop and pilot scale bioreactor perfusion system, indicating the predictive capabilities of the small-scale model. These results highlight the benefits of using small-scale models to shorten development time for perfusion process implementation

The Role of Fraternity/Sorority Affiliation in Supporting College Student Mental Health and Wellness

Mental health is a growing concern in the United States, even more exacerbated by the recent COVID-19 pandemic. Mental health among youth and young adult populations has also received attention in recent years. However, prior research suggests a higher sense of social support among active members of the fraternity/sorority community is associated with lower depression levels. The extent to which fraternity/sorority involvement helps address mental health among members is theorized but not demonstrated in the research. Using large-scale data, this study examined mental health experiences and behaviors of the fraternity/ sorority community and compared results with unaffiliated students. Findings suggest students in the fraternity/sorority community report higher levels of positive mental health

Making sense of multivariate community responses in global change experiments

Ecological communities are being impacted by global change worldwide. Experiments are a powerful tool to understand how global change will impact communities by comparing control and treatment replicates. Communities consist of multiple species, and their associated abundances make multivariate methods an effective approach to study community compositional differences between control and treated replicates. Dissimilarity metrics are a commonly employed multivariate measure of compositional differences; however, while highly informative, dissimilarity metrics do not elucidate the specific ways in which communities differ. Integrating two multivariate methods, dissimilarity metrics and rank abundance curves (RACs), have the potential to detect complex differences based on dissimilarity metrics and detail the how these differences came about through differences in richness, evenness, species ranks, or species identity. Here we use a database of 106 global change experiments located in herbaceous ecosystems and explore how patterns of ordinations based on dissimilarity metrics relate to RAC-based differences. We find that combining dissimilarity metrics alongside RAC-based measures clarifies how global change treatments are altering communities. We find that when there is no difference in community composition (no distance between centroids of control and treated replicates), there are rarely differences in species ranks or species identities and more often differences in richness or evenness alone. In contrast, when there are differences between centroids of control and treated replicates, this is most often associated with differences in ranks either alone or co-occurring with differences in richness, evenness, or species identities. We suggest that integrating these two multivariate measures of community composition results in a deeper understanding of how global change impacts communities

A framework for quantifying the magnitude and variability of community responses to global change drivers

A major challenge in global change ecology is to predict the trajectory and magnitude of community change in response to global change drivers (GCDs). Here, we present a new framework that not only increases the predictive power of individual studies, but also allows for synthesis across GCD studies and ecosystems. First, we suggest that by quantifying community dissimilarity of replicates both among and within treatments, we can infer both the magnitude and predictability of community change, respectively. Second, we demonstrate the utility of integrating rank abundance curves with measures of community dissimilarity to understand the species-level dynamics driving community changes and propose a series of testable hypotheses linking changes in rank abundance curves with shifts in community dissimilarity. Finally, we review six case studies that demonstrate how our new conceptual framework can be applied. Overall, we present a new framework for holistically predicting community responses to GCDs that has broad applicability in this era of unprecedented global change and novel environmental conditions

Current and Emerging Uses of Statins in Clinical Therapeutics: A Review

Statins, a class of cholesterol-lowering medications that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, are commonly administered to treat atherosclerotic cardiovascular disease. Statin use may expand considerably given its potential for treating an array of cholesterol-independent diseases. However, the lack of conclusive evidence supporting these emerging therapeutic uses of statins brings to the fore a number of unanswered questions including uncertainties regarding patient-to-patient variability in response to statins, the most appropriate statin to be used for the desired effect, and the efficacy of statins in treating cholesterol-independent diseases. In this review, the adverse effects, costs, and drug–drug and drug–food interactions associated with statin use are presented. Furthermore, we discuss the pleiotropic effects associated with statins with regard to the onset and progression of autoimmune and inflammatory diseases, cancer, neurodegenerative disorders, strokes, bacterial infections, and human immunodeficiency virus. Understanding these issues will improve the prognosis of patients who are administered statins and potentially expand our ability to treat a wide variety of diseases

A Small Molecule Inhibitor of Redox-Regulated Protein Translocation into Mitochondria

SummaryThe mitochondrial disulfide relay system of Mia40 and Erv1/ALR facilitates import of the small translocase of the inner membrane (Tim) proteins and cysteine-rich proteins. A chemical screen identified small molecules that inhibit Erv1 oxidase activity, thereby facilitating dissection of the disulfide relay system in yeast and vertebrate mitochondria. One molecule, mitochondrial protein import blockers from the Carla Koehler laboratory (MitoBloCK-6), attenuated the import of Erv1 substrates into yeast mitochondria and inhibited oxidation of Tim13 and Cmc1 in in vitro reconstitution assays. In addition, MitoBloCK-6 revealed an unexpected role for Erv1 in the carrier import pathway, namely transferring substrates from the translocase of the outer membrane complex onto the small Tim complexes. Cardiac development was impaired in MitoBloCK-6-exposed zebrafish embryos. Finally, MitoBloCK-6 induced apoptosis via cytochrome c release in human embryonic stem cells (hESCs) but not in differentiated cells, suggesting an important role for ALR in hESC homeostasis

It's about time: A synthesis of changing phenology in the Gulf of Maine ecosystem

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Staudinger, M. D., Mills, K. E., Stamieszkin, K., Record, N. R., Hudak, C. A., Allyn, A., Diamond, A., Friedland, K. D., Golet, W., Henderson, M. E., Hernandez, C. M., Huntington, T. G., Ji, R., Johnson, C. L., Johnson, D. S., Jordaan, A., Kocik, J., Li, Y., Liebman, M., Nichols, O. C., Pendleton, D., Richards, R. A., Robben, T., Thomas, A. C., Walsh, H. J., & Yakola, K. It's about time: A synthesis of changing phenology in the Gulf of Maine ecosystem. Fisheries Oceanography, 28(5), (2019): 532-566, doi: 10.1111/fog.12429.The timing of recurring biological and seasonal environmental events is changing on a global scale relative to temperature and other climate drivers. This study considers the Gulf of Maine ecosystem, a region of high social and ecological importance in the Northwest Atlantic Ocean and synthesizes current knowledge of (a) key seasonal processes, patterns, and events; (b) direct evidence for shifts in timing; (c) implications of phenological responses for linked ecological‐human systems; and (d) potential phenology‐focused adaptation strategies and actions. Twenty studies demonstrated shifts in timing of regional marine organisms and seasonal environmental events. The most common response was earlier timing, observed in spring onset, spring and winter hydrology, zooplankton abundance, occurrence of several larval fishes, and diadromous fish migrations. Later timing was documented for fall onset, reproduction and fledging in Atlantic puffins, spring and fall phytoplankton blooms, and occurrence of additional larval fishes. Changes in event duration generally increased and were detected in zooplankton peak abundance, early life history periods of macro‐invertebrates, and lobster fishery landings. Reduced duration was observed in winter–spring ice‐affected stream flows. Two studies projected phenological changes, both finding diapause duration would decrease in zooplankton under future climate scenarios. Phenological responses were species‐specific and varied depending on the environmental driver, spatial, and temporal scales evaluated. Overall, a wide range of baseline phenology and relevant modeling studies exist, yet surprisingly few document long‐term shifts. Results reveal a need for increased emphasis on phenological shifts in the Gulf of Maine and identify opportunities for future research and consideration of phenological changes in adaptation efforts.This work was supported by the Department of the Interior Northeast Climate Adaptation Science Center (G14AC00441) for MDS, AJ, and KY; the National Science Foundation's Coastal SEES Program (OCE‐1325484) for KEM, ACT, MEH, and AA; the National Aeronautics and Space Administration (NNX16 AG59G) for ACT, KEM, NRR, and KSS; the USGS Climate Research and Development Program for TGH; National Science & Engineering Research Council of Canada, University of New Brunswick, Environment Canada, Sir James Dunn Wildlife Research Centre, and New Brunswick Wildlife Trust Fund for AD. We also thank the Regional Association for Research on the Gulf of Maine for support, and the Gulf of Maine Research Institute for hosting and providing in kind resources for a two day in‐person workshop in August 2016. We greatly appreciate contributions from K. Alexander, G. Calandrino, C. Feurt, I. Mlsna, N. Rebuck, J. Seavey, and J. Sun for helping shape the initial scope of the manuscript. We thank J. Weltzin and two anonymous reviewers for their constructive comments. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the views of the Northeast Climate Adaptation Science Center, U.S. Geological Survey, National Oceanographic and Atmospheric Administration, Fisheries and Oceans Canada or the US Environmental Protection Agency. This manuscript is submitted for publication with the understanding that the United States Government is authorized to reproduce and distribute reprints for Governmental purposes. None of the authors have conflicts of interest to declare in association with the contents of this manuscript

STAGES: the Space Telescope A901/2 Galaxy Evolution Survey

We present an overview of the Space Telescope A901/2 Galaxy Evolution Survey (STAGES). STAGES is a multiwavelength project designed to probe physical drivers of galaxy evolution across a wide range of environments and luminosity. A complex multi-cluster system at z~0.165 has been the subject of an 80-orbit F606W HST/ACS mosaic covering the full 0.5x0.5 (~5x5 Mpc^2) span of the supercluster. Extensive multiwavelength observations with XMM-Newton, GALEX, Spitzer, 2dF, GMRT, and the 17-band COMBO-17 photometric redshift survey complement the HST imaging. Our survey goals include simultaneously linking galaxy morphology with other observables such as age, star-formation rate, nuclear activity, and stellar mass. In addition, with the multiwavelength dataset and new high resolution mass maps from gravitational lensing, we are able to disentangle the large-scale structure of the system. By examining all aspects of environment we will be able to evaluate the relative importance of the dark matter halos, the local galaxy density, and the hot X-ray gas in driving galaxy transformation. This paper describes the HST imaging, data reduction, and creation of a master catalogue. We perform Sersic fitting on the HST images and conduct associated simulations to quantify completeness. In addition, we present the COMBO-17 photometric redshift catalogue and estimates of stellar masses and star-formation rates for this field. We define galaxy and cluster sample selection criteria which will be the basis for forthcoming science analyses, and present a compilation of notable objects in the field. Finally, we describe the further multiwavelength observations and announce public access to the data and catalogues.Comment: 29 pages, 22 figures; accepted to MNRAS. Full data release available at http://www.nottingham.ac.uk/astronomy/stage