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OBJECTIVES/GOALS: A functional precision medicine platform to identify therapeutic targets for a glioblastoma patient with Li Fraumeni syndrome was performed. Comparative transcriptomics identified druggable targets and patient derived organoids and a 3D-PREDICT drug screening assay was used to validate the pipeline and identify further therapeutic targets. METHODS/STUDY POPULATION: A comparative transcriptomics pipeline was used to identify druggable genes that are uniquely overexpressed in our patient of interest relative to a cancer compendium of 12,747 tumor RNA sequencing datasets including 200 GBMs. Mini-ring patient derived organoid-based drug viability assays were performed to validate the comparative transcriptomics data. Additionally, a spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. RESULTS/ANTICIPATED RESULTS: Using comparative transcriptomics STAT1 and STAT2 were found to be significantly overexpressed in our patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitor, as a potential therapy. Druggable pathways predicted using comparative transcriptomics corresponded with ruxolitinib sensitivity in a panel of patient derived organoids screened with this compound. Cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. Additionally, 3D-PREDICT screening identified the mTOR inhibitor everolimus as a potential candidate. These two targeted therapies were selected for our patient and resulted in radiographic disease stability. DISCUSSION/SIGNIFICANCE: This research illustrates the use of comparative transcriptomics to identify druggable pathways irrespective of actionable DNA mutations present. Our results are promising and serve to highlight the importance of functional precision medicine in tailoring treatment regimes to specific patients.
The present study reports the validity of multiple assessment methods for tracking changes in body composition over time and quantifies the influence of unstandardised pre-assessment procedures. Resistance-trained males underwent 6 weeks of structured resistance training alongside a hyperenergetic diet, with four total body composition evaluations. Pre-intervention, body composition was estimated in standardised (i.e. overnight fasted and rested) and unstandardised (i.e. no control over pre-assessment activities) conditions within a single day. The same assessments were repeated post-intervention, and body composition changes were estimated from all possible combinations of pre-intervention and post-intervention data. Assessment methods included dual-energy X-ray absorptiometry (DXA), air displacement plethysmography, three-dimensional optical imaging, single- and multi-frequency bioelectrical impedance analysis, bioimpedance spectroscopy and multi-component models. Data were analysed using equivalence testing, Bland–Altman analysis, Friedman tests and validity metrics. Most methods demonstrated meaningful errors when unstandardised conditions were present pre- and/or post-intervention, resulting in blunted or exaggerated changes relative to true body composition changes. However, some methods – particularly DXA and select digital anthropometry techniques – were more robust to a lack of standardisation. In standardised conditions, methods exhibiting the highest overall agreement with the four-component model were other multi-component models, select bioimpedance technologies, DXA and select digital anthropometry techniques. Although specific methods varied, the present study broadly demonstrates the importance of controlling and documenting standardisation procedures prior to body composition assessments across distinct assessment technologies, particularly for longitudinal investigations. Additionally, there are meaningful differences in the ability of common methods to track longitudinal body composition changes.
Prolonged survival of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on environmental surfaces and personal protective equipment may lead to these surfaces transmitting this pathogen to others. We sought to determine the effectiveness of a pulsed-xenon ultraviolet (PX-UV) disinfection system in reducing the load of SARS-CoV-2 on hard surfaces and N95 respirators.
Chamber slides and N95 respirator material were directly inoculated with SARS-CoV-2 and were exposed to different durations of PX-UV.
For hard surfaces, disinfection for 1, 2, and 5 minutes resulted in 3.53 log10, >4.54 log10, and >4.12 log10 reductions in viral load, respectively. For N95 respirators, disinfection for 5 minutes resulted in >4.79 log10 reduction in viral load. PX-UV significantly reduced SARS-CoV-2 on hard surfaces and N95 respirators.
With the potential to rapidly disinfectant environmental surfaces and N95 respirators, PX-UV devices are a promising technology to reduce environmental and personal protective equipment bioburden and to enhance both healthcare worker and patient safety by reducing the risk of exposure to SARS-CoV-2.
Hispanics/Latinos in the United States are less aware of their cholesterol levels and have a higher burden of associated adverse cardiovascular and cerebrovascular outcomes than non-Latino whites. Investigations of the associations between cholesterol levels and cognition in this population have often occurred within the context of metabolic syndrome and are limited to select lipids despite the fact that triglycerides (TGs) may be more relevant to the health of Hispanics/Latinos.
Baseline data from the Hispanic Community Health Study/Study of Latinos, collected from 2008 to 2011, was used to investigate the associations of lipid levels (i.e., TG, total cholesterol, TC; low-density and high-density lipoprotein cholesterol, LDL-C and HDL-C) with cognition (i.e., learning, memory, verbal fluency, and digit symbol substitution, DSS), adjusting for relevant confounders.
In 7413 participants ages 45 to 74 years from Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American backgrounds, separate, fully adjusted linear regression models revealed that TG levels were inversely associated with DSS performance; however, this relationship was no longer significant once additional cardiovascular disease risk factors were added to the model (p = .06). TC and LDL-C levels (separately) were positively associated with learning and verbal fluency regardless of adjustments (p-values < .05). Separate analyses investigating the effect modification by background and sex revealed a particularly robust association between TC levels and DSS performance for Puerto Ricans and Central Americans (albeit in opposite directions) and an inverse relationship between TG levels and DSS performance for women (p-values < .02).
It is important to consider individual lipid levels and demographic characteristics when investigating associations between cholesterol levels and cognition in Hispanics/Latinos.
Drawing on a landscape analysis of existing data-sharing initiatives, in-depth interviews with expert stakeholders, and public deliberations with community advisory panels across the U.S., we describe features of the evolving medical information commons (MIC). We identify participant-centricity and trustworthiness as the most important features of an MIC and discuss the implications for those seeking to create a sustainable, useful, and widely available collection of linked resources for research and other purposes.
As the IAU heads towards its second century, many changes have simultaneously transformed Astronomy and the human condition world-wide. Amid the amazing recent discoveries of exoplanets, primeval galaxies, and gravitational radiation, the human condition on Earth has become blazingly interconnected, yet beset with ever-increasing problems of over-population, pollution, and never-ending wars. Fossil-fueled global climate change has begun to yield perilous consequences. And the displacement of people from war-torn nations has reached levels not seen since World War II.
The San Francisco Fire Department’s (SFFD; San Francisco, California USA) Homeless Outreach and Medical Emergency (HOME) Team is the United States’ first Emergency Medical Services (EMS)-based outreach effort using a specially trained paramedic to redirect frequent users of EMS to other types of services. The effectiveness of this program at reducing repeat use of emergency services during the first seven months of the team’s existence was examined.
A retrospective analysis of EMS use frequency and demographic characteristics of frequent users was conducted. Clients that used emergency services at least four times per month from March 2004 through May 2005 were contacted for intervention. Patterns for each frequent user before and after intervention were analyzed. Changes in EMS use during the 15-month study interval was the primary outcome measurement.
A total of 59 clients were included. The target population had a median age of 55.1 years and was 68% male. Additionally, 38.0% of the target population was homeless, 43.4% had no primary care, 88.9% had a substance abuse disorder at time of contact, and 83.0% had a history of psychiatric disorder. The HOME Team undertook 320 distinct contacts with 65 frequent users during the study period. The average EMS use prior to HOME Team contact was 18.72 responses per month (SD=19.40), and after the first contact with the HOME Team, use dropped to 8.61 (SD=10.84), P<.001.
Frequent users of EMS suffer from disproportionate comorbidities, particularly substance abuse and psychiatric disorders. This population responds well to the intervention of a specially trained paramedic as measured by EMS usage.
TangherliniN, VillarJ, BrownJ, RodriguezRM, YehC, FriedmanBT, WadaP. The HOME Team: Evaluating the Effect of an EMS-based Outreach Team to Decrease the Frequency of 911 Use Among High Utilizers of EMS. Prehosp Disaster Med. 2016;31(6):603–607.
Objectives: The Forced Choice Recognition (FCR) trial of the California Verbal Learning Test, 2nd edition, was designed as an embedded performance validity test (PVT). To our knowledge, this is the first systematic review of classification accuracy against reference PVTs. Methods: Results from peer-reviewed studies with FCR data published since 2002 encompassing a variety of clinical, research, and forensic samples were summarized, including 37 studies with FCR failure rates (N=7575) and 17 with concordance rates with established PVTs (N=4432). Results: All healthy controls scored >14 on FCR. On average, 16.9% of the entire sample scored ≤14, while 25.9% failed reference PVTs. Presence or absence of external incentives to appear impaired (as identified by researchers) resulted in different failure rates (13.6% vs. 3.5%), as did failing or passing reference PVTs (49.0% vs. 6.4%). FCR ≤14 produced an overall classification accuracy of 72%, demonstrating higher specificity (.93) than sensitivity (.50) to invalid performance. Failure rates increased with the severity of cognitive impairment. Conclusions: In the absence of serious neurocognitive disorder, FCR ≤14 is highly specific, but only moderately sensitive to invalid responding. Passing FCR does not rule out a non-credible presentation, but failing FCR rules it in with high accuracy. The heterogeneity in sample characteristics and reference PVTs, as well as the quality of the criterion measure across studies, is a major limitation of this review and the basic methodology of PVT research in general. (JINS, 2016, 22, 851–858)
Salamanca lies on the right bank of the river Tormes, a tributary of the Douro, on the northern sub-plateau of the Iberian peninsula (fig. 1). Although hardly mentioned in Roman historical sources, it is a reference point for work on Roman territory because the surveyor Frontinus (De Agrorum Qualitate [ed. Thulin 1971] 1–2) used Salmantica (in Lusitania) and Palantia (in Citerior) to exemplify ager per extremitatem mensura comprehensus, the system of land organization characteristic of stipendiary cities. Frontinus was writing in Flavian times, but the creation of ager mensura comprehensus in Lusitania occurred in the Augustan period, as is confirmed by remarkable epigraphic documentation. In N Lusitania, a total of 11 boundary-stones (termini Augustales) are known, nine from the reign of Augustus (and two of these provide explicit reference to Salmantica) and two from that of Claudius. The dates provided by Augustus’ tribunicia potestas allow us to date the surveying operations delimiting the urban territories to between A.D. 4–5 (the inscriptions from Peroviseu and Ul) and A.D. 5–6 (the inscriptions from Sao Salvador, Ledesma, Ciudad Rodrigo, and the new one from Jarandilla de la Vera). The Augustan ager mensura comprehensus may have conditioned the model of the subsequent rural settlement by creating a framework for territorial occupation being organized around the villa from the Flavian period on. The villa would dominate the rural countryside, until it disappeared around the first decades of the 5th c. as part of a process that can be associated with the breaking down of imperial authority and the arrival of the Germanic peoples in the year 409. Almost nothing is known about Salamanca’s territory during the Islamic occupation until the first official repopulation took place under the king of Leon, Ramiro II, in 939–49. The lack of attested settlements in the Douro valley between the 8th and 10th c. is a key question for the organization of the border area between the Islamic state of Al-Andalus and the kingdom of Leon, but scholars generally reject the thesis formulated in 1966 by C. Sánchez Albornoz, which tended to present the lands of the Douro valley as practically depopulated.
Arid zones of northern Venezuela are represented by isolated areas, important from an ornithological and ecological perspective due to the occurrence of restricted-range species of birds. We analysed the prevalence and molecular diversity of haemosporidian parasites of wild birds in this region by screening 527 individuals (11 families and 20 species) for parasite mitochondrial DNA. The overall prevalence of parasites was 41%, representing 17 mitochondrial lineages: 7 of Plasmodium and 10 of Haemoproteus. Two parasite lineages occurred in both the eastern and western regions infecting a single host species, Mimus gilvus. These lineages are also present throughout northern and central Venezuela in a variety of arid and mesic habitats. Some lineages found in this study in northern Venezuela have also been observed in different localities in the Americas, including the West Indies. In spite of the widespread distributions of some of the parasite lineages found in northern Venezuela, several, including some that are relatively common (e.g. Ven05 and Ven06), have not been reported from elsewhere. Additional studies are needed to characterize the host and geographical distribution of avian malaria parasite lineages, which will provide a better understanding of the influence of landscape, vector abundance and diversity, and host identity on haemosporidian parasite diversity and prevalence.
X-ray powder diffraction data for ErH2−xDx formed by hydrogen (i.e., protium)–deuterium loading of Er metal are reported. Lattice parameters for the varying hydrogen–deuterium compositions followed Vergard’s law behavior. The cubic lattice parameter at room temperature for ErH2−xDx obeys a linear relationship according to the formula a=5.1287−1.1120×10−4⋅x, where a is the lattice parameter of the fluorite-type structure and x is the mole percent of deuterium. Microstrain measurements suggest a possible ordering of hydrogen and deuterium in the composition ErH1D1.
Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene–nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient–genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries.