Project description:CONTEXT:Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. OBJECTIVE:To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress. DESIGN AND PARTICIPANTS:Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N?=?83], sepsis [N?=?100], and combat stress [N?=?105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration). MAIN OUTCOME MEASURE:We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. RESULTS:Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. CONCLUSIONS:Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.
Project description:Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans. Keywords: Gene expression profiling of human blood leukocytes in response to in vivo endotoxin administration. Overall design: Healthy male and female subjects were intravenously administered either endotoxin or only vehicle (control). Arterial blood samples were collected before infusion (0 hours) and at post infusion times of 2, 4, 6, 9, and 24 hours. Blood leukocytes were isolated and analyzed using Affymetrix GeneChip arrays.
Project description:The U.S. National Institutes of Health (NIH) annually invests approximately $22 billion in biomedical research through its extramural grant programs. Since fiscal year (FY) 2010, all persons involved in research during the previous project year have been required to be listed on the annual grant progress report. These new data have enabled the production of the first-ever census of the NIH-funded extramural research workforce. Data were extracted from All Personnel Reports submitted for NIH grants funded in FY 2009, including position title, months of effort, academic degrees obtained, and personal identifiers. Data were de-duplicated to determine a unique person count. Person-years of effort (PYE) on NIH grants were computed. In FY 2009, NIH funded 50,885 grant projects, which created 313,049 full- and part-time positions spanning all job functions involved in biomedical research. These positions were staffed by 247,457 people at 2,604 institutions. These persons devoted 121,465 PYE to NIH grant-supported research. Research project grants each supported 6 full- or part-time positions, on average. Over 20% of positions were occupied by postdoctoral researchers and graduate and undergraduate students. These baseline data were used to project workforce estimates for FYs 2010-2014 and will serve as a foundation for future research.
Project description:The glucocorticoid hormone cortisol has been shown to impair episodic memory performance. The present study examined the effect of two doses of hydrocortisone (synthetic cortisol) administration on autobiographical memory retrieval. Healthy volunteers (n = 66) were studied on two separate visits, during which they received placebo and either moderate-dose (0.15 mg/kg IV; n = 33) or high-dose (0.45 mg/kg IV; n = 33) hydrocortisone infusion. From 75 to 150 min post-infusion subjects performed an Autobiographical Memory Test and the California Verbal Learning Test (CVLT). The high-dose hydrocortisone administration reduced the percent of specific memories recalled (p = .04), increased the percent of categorical (nonspecific) memories recalled (p < .001), and slowed response times for categorical memories (p < .001), compared with placebo performance. Under moderate-dose hydrocortisone the autobiographical memory performance did not change significantly with respect to percent of specific or categorical memories recalled or reaction times. Performance on the CVLT was not affected by hydrocortisone. These findings suggest that cortisol affects accessibility of autobiographical memories in a dose-dependent manner. Specifically, administration of hydrocortisone at doses analogous to those achieved under severe psychosocial stress impaired the specificity and speed of retrieval of autobiographical memories.
Project description:Transcriptomic analysis of Streptococcus pneumoniae TIGR4 wildtype and it's isogenic ccpA mutant, grown in chemically defined media supplemented with physiological levels of carbohydrates to mimic the human nasopharynx and bloodstream. The goal is to examine how anatomical site-specific carbohydrate availability impacts S. pneumoniae physiology and virulence. Overall design: 6 mRNA profiles of Streptococcus pneumoniae wildtype and ccpA mutant samples that were grown in chemically defined media supplemented with physiological levels of carbohydrates to mimic the human nasopharynx and bloodstream. BioProject: PRJNA781242 Funding Source: This work was supported by NIH National Institute of Allergy and Infectious Diseases (NIAID) grants AI148368, AI114800, AI156898, and AI146149 to C.J.O. and AI146149 to H.T. H.I. is supported by NIH grant T32 HL129948. The High-Field NMR facility at the University of Alabama at Birmingham was established through NIH grant S10RR026478 and is currently supported through the comprehensive cancer center (NCI grant P30 CA013148).
Project description:Objective:Several publication databases now index the associated funding agency and grant number metadata with their publication records. Librarians who are familiar with the particulars of these databases can assist investigators and administrators with data gathering for publication summaries and metrics required for renewals of and progress reports for National Institutes of Health (NIH) grants. Methods:Publication lists were pulled from three main indexers of publication-associated funding information (NIH RePORTER, PubMed, and Web of Science), using iterative search strategies. All discovered variations for the cited grant number of interest were recorded and tested. Publication lists were compared for overall coverage. Results:A total of 986 publications citing the single grant number of interest were returned from the given time frame: 920 were found in PubMed, 860 in NIH RePORTER, and 787 in Web of Science. Web of Science offered the highest percentage of publications that were not found in the other 2 sources (n=63). Analysis of publication funding acknowledgments uncovered 21 variations of the specific NIH award of interest that were used to report funding support. Conclusions:This study shows that while PubMed returns the most robust list of publications, variations in the format of reported funding support and indexing practices meant no one resource was sufficient to capture all publications that cited a given NIH project grant number. Librarians looking to help build grant-specific publication lists will need to use multiple resources and be aware of the most frequently reported grant variations to identify a comprehensive list of supported publications.
Project description:PURPOSE:Implementation science offers methods to evaluate the translation of genomic medicine research into practice. The extent to which the National Institutes of Health (NIH) human genomics grant portfolio includes implementation science is unknown. This brief report's objective is to describe recently funded implementation science studies in genomic medicine in the NIH grant portfolio, and identify remaining gaps. METHODS:We identified investigator-initiated NIH research grants on implementation science in genomic medicine (funding initiated 2012-2016). A codebook was adapted from the literature, three authors coded grants, and descriptive statistics were calculated for each code. RESULTS:Forty-two grants fit the inclusion criteria (~1.75% of investigator-initiated genomics grants). The majority of included grants proposed qualitative and/or quantitative methods with cross-sectional study designs, and described clinical settings and primarily white, non-Hispanic study populations. Most grants were in oncology and examined genetic testing for risk assessment. Finally, grants lacked the use of implementation science frameworks, and most examined uptake of genomic medicine and/or assessed patient-centeredness. CONCLUSION:We identified large gaps in implementation science studies in genomic medicine in the funded NIH portfolio over the past 5 years. To move the genomics field forward, investigator-initiated research grants should employ rigorous implementation science methods within diverse settings and populations.
Project description:BACKGROUND:Pegloticase is a recombinant porcine-like uricase enzyme that is FDA-approved for the treatment of chronic refractory gout in adults. Some patients receiving pegloticase develop anti-drug antibodies, which leads to both loss of pegloticase efficacy and an increased risk for infusion reactions. In the pivotal trials, all patients received pre-infusion medications before each pegloticase dose, including intravenous (IV) hydrocortisone. In clinical practice, many clinicians use methylprednisolone for pre-infusion therapy with pegloticase; however, the efficacy of methylprednisolone compared with hydrocortisone as a pre-infusion medication for pegloticase has not been established. OBJECTIVE:The aim of this study was to compare the efficacy of methylprednisolone versus hydrocortisone as a pre-infusion medication for pegloticase. METHODS:Data were retrospectively collected from 92 qualifying patients treated with pegloticase and administered pre-infusion prophylaxis with either intravenous hydrocortisone or methylprednisolone. Patient demographics, steroid type and dose, duration of pegloticase therapy, overall number of infusions, and number of infusion reactions were assessed. RESULTS:Patients treated with methylprednisolone as a pre-infusion medication received on average 8.5 pegloticase infusions versus 4.9 infusions for patients who were treated with hydrocortisone (p?<?0.001). In addition, a significantly lower proportion of patients receiving methylprednisolone had their course of therapy terminated early due to infusion reactions (8.2%) versus patients receiving hydrocortisone (41.9%, p?<?0.01). CONCLUSION:In this retrospective chart-review project, patients were able to have a longer duration of pegloticase therapy, received a significantly greater number of infusions, and experienced fewer infusion reactions when methylprednisolone was used as the corticosteroid for pre-infusion prophylaxis compared with hydrocortisone.
Project description:In animal models, corticosterone elevations are associated with hippocampal changes that can be prevented with phenytoin. In humans, Cushing's syndrome and long-term prescription corticosteroid use are associated with a reduction in the hippocampal volume. However, little is known about the effects of short-term corticosteroid administration on the hippocampus. The current report examines changes in the hippocampal volume during a brief hydrocortisone exposure and whether volumetric changes can be blocked by phenytoin. A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in healthy adults (n=17). Participants received hydrocortisone (160 mg/day)/placebo, phenytoin/placebo, both medications together, or placebo/placebo, with 21-day washouts between the conditions. Structural MRI scans and cortisol levels were obtained following each medication condition. No significant difference in the total brain volume was observed with hydrocortisone. However, hydrocortisone was associated with a significant 1.69% reduction in the total hippocampal volume compared with placebo. Phenytoin blocked the volume reduction associated with hydrocortisone. Reduction in hippocampal volume correlated with the change in cortisol levels (r=-0.58, P=0.03). To our knowledge, this is the first report of structural hippocampal changes with brief corticosteroid exposure. The correlation between the change in hippocampal volume and cortisol level suggests that the volume changes are related to cortisol elevation. Although the findings from this pilot study need replication, they suggest that the reductions in hippocampal volume occur even during brief exposure to corticosteroids, and that hippocampal changes can, as in animal models, be blocked by phenytoin. The results may have implications both for understanding the response of the hippocampus to stress as well as for patients receiving prescription corticosteroids.
Project description:Survival of junior scientists in academic biomedical research is difficult in today's highly competitive funding climate. National Institute of Health (NIH) data on first-time R01 grantees indicate the rate at which early investigators drop out from a NIH-supported research career is most rapid 4 to 5 years from the first R01 award. The factors associated with a high risk of dropping out, and whether these factors impact all junior investigators equally, are unclear. We identified a cohort of 1,496 investigators who received their first R01-equivalent (R01-e) awards from the National Institute of Allergy and Infectious Diseases between 2003 and 2010, and studied all their subsequent NIH grant applications through 2016. Ultimately, 57% of the cohort were successful in obtaining new R01-e funding, despite highly competitive conditions. Among those investigators who failed to compete successfully for new funding (43%), the average time to dropping out was 5 years. Investigators who successfully obtained new grants showed remarkable within-person consistency across multiple grant submission behaviors, including submitting more applications per year, more renewal applications, and more applications to multiple NIH Institutes. Funded investigators appeared to have two advantages over their unfunded peers at the outset: they had better scores on their first R01-e grants and they demonstrated an early ability to write applications that would be scored, not triaged. The cohort rapidly segregated into two very different groups on the basis of PI consistency in the quality and frequency of applications submitted after their first R01-e award. Lastly, we identified a number of specific demographic factors, intitutional characteristics, and grant submission behaviors that were associated with successful outcomes, and assessed their predictive value and relative importance for the likelihood of obtaining additional NIH funding.