University of Tennessee Health Science Center
UTHSC Digital Commons (University of Tennessee Health Science Center)Not a member yet
1172 research outputs found
Sort by
Increasing eBook usage: The importance of investing time and money into access points
Get PDFOBJECTIVE In January 2020, the Library migrated to a new Library Management System (LMS), Ex Libris Alma and Primo, that combines the functionality of a discovery service and the features of a traditional catalog. The Library’s eBooks, which were previously only accessible via a discovery service, are now discoverable along with other library resources via one access point. The objective of this study is to measure eBook usage over the 2017-2020 period as one means of determining the effect of user access points on eBook usage.
METHODS Counter Book Report 2 (R4) eBook usage statistics from January to August for the years 2017 to 2020 were obtained from the Library’s four major packages that contain eBooks – LWW Health Sciences Library, ClinicalKey, AccessMedicine, and Case Files Collection. 2017 was the first year when all four major packages had been acquired by the Library. One sample t-tests were performed to examine whether or not there was a statistically significant increase in eBook usage.
RESULTS The percent increase in eBook usage from January to August 2017 and January to August 2018 was 9.98%. The percent increase from January to August 2018 and January to August 2019 was 12%. Using a one sample t-test between percentages, at the .05 critical alpha level, the difference is not significant. t(1129)=1.45, p=.147. The percent increase from January to August 2019 and January to August 2020 was 37.09%. Using a one sample t-test between percentages, at the .05 critical alpha level, the difference is significant. t(1129)=12.893, p\u3c.001.
CONCLUSIONS After the migration to the new LMS there was an overall significant increase in eBook usage. Investing time, such as merging eBooks into one access point, and money, i.e. the purchase of a robust LMS, may lead to increased eBook usage
Dissecting Drivers of Basal Immunity and Acute Responses to Viral Infection
Get PDFHeterogeneity in the human immune system can lead to limited vaccine efficacy, poor response to therapeutics, increased susceptibility to immune mediated diseases, and differential outcome to infection. Studies to date have suggested a role for biological, environmental, and genetic factors in immune variation; however, they are often focused on a specific subset of the population (e.g. ancestral group, age range) which can exclude phenotypes unique to a diverse population and bias results. To address this gap, we have utilized samples from healthy or influenza virus infected subjects from 8 distinct populations in 5 countries to conduct an integrative analysis of the unique and interactive effects of age (biological), herpesvirus serostatus (environmental), and genetics on variation in basal immunity and acute responses.
At baseline, we have found differences between diverse populations in plasma cytokine levels, circulating leukocyte phenotypes, CD8 T cell receptor repertoires, and gene expression. Variation was observed for growth factors, chemokines, immunomodulators, and proinflammatory cytokines. Additionally, compared to Nicaraguans, Memphians exhibit higher activated myeloid and lymphoid subsets, and have CD8 T cell receptor repertoires which are significantly more clonal and less diverse. Moreover, analysis of peripheral blood mononuclear cell gene expression, after stimulation with pathogen recognition receptor ligands representative of bacterial or viral infection, shows differential responses dependent on condition and cohort. With respect to genetics, an analysis of 94 single nucleotide polymorphisms (SNPs) illustrates significant differences in minor allele frequencies in immune related genes with potential effects on transcription, as 38 were expression quantitative trait loci (eQTL) in 26 genes (25 cytokines and 1 transcription factor). Importantly, variation in the expression of immune transcription factors and effector molecules coupled with variation in the differentiation of leukocyte subsets may lead to differences in acute immune responses.
Results from subjects with naturally acquired influenza infection show herpesviruses are largely beneficial and improve illness outcome. Herpes simplex virus is associated with decreased duration of influenza virus shedding, and cytomegalovirus is associated with increased functional antibody titers and decreased symptom severity scores. Utilizing a regression model to account for age, sex, herpesviruses, and genetics, we found herpesviruses have unique and interactive effects on cytokine levels that are specific to anatomical location. Additionally, of the 25 cytokines with an eQTL, 11 had significant genetic influence during flu infection. Interestingly, all 11 of these cytokines were identified as correlates of severity in an analysis of 4 independent populations. Furthermore, associations between cytokine levels and influenza severity were consistent in cohorts of similar ancestral and environmental backgrounds or age range, and several unique correlates were identified for each population.
Lastly, utilizing mouse models of influenza and murine cytomegalovirus (MCMV) co-infection, we have found co-infection augments innate immunity and enhances functional CD8 T cell responses against influenza epitopes, but impairs MCMV-specific responses. These data suggest prior infection with herpesviruses are beneficial to acute infection, but the reciprocal effects of heterologous infections on herpesvirus immunity are detrimental and may lead to eventual loss of herpesvirus control. Together, these results provide novel insight into the scope of immune variation across diverse populations, the unique and interactive effects of factors which drive immune heterogeneity, the subsequent consequences on differential outcome during infection, and how prior infectious exposures can affect acute immune responses
Development and Characterization of Selective CB2R Inverse Agonists as a Novel Anti-Inflammatory Therapy for Neuroinflammation – Mechanisms of Action in Murine and Human Microglia Models Provide Valuable Insights into Their Therapeutic Potential
Get PDFIntroduction: Recently, research has revealed the presence of cannabinoid receptor 2 (CB2R) in the central nervous system (CNS); since then, the receptor has emerged as a promising therapeutic target for treating multiple neurodegenerative diseases (NDD) such as Alzheimer’s (AD), Parkinson’s (PD), Human Immunodeficiency Virus (HIV) and Multiple Sclerosis (MS). The restricted and upregulated expression of CB2R in activated microglia and lack of psychotropic activity make this receptor an attractive target for discovering novel therapy to treat neuroinflammatory diseases for which there is currently no curative treatment. Methodology: A library of compounds were synthesized and evaluated in ACTOne and TANGO-bla functional assays for CB1 and CB2 activity in combination with affinity measurements for the CB1/2 receptors. Moreover, the compounds that demonstrated no activity at functional assays with high binding affinities to CB2R were further assessed in antagonist (competition) studies against the non-selective cannabinoid agonist CP 55,940. Compound 45 demonstrated CB2R inverse agonism at G-protein signaling with high potency, efficacy, and affinity in the binding and functional assays and was selected for further evaluation in murine and human microglia inflammatory models. On cell polarization assays were done to measure microglia M1 and M2 surface markers expression. Scratch assay and ROS measurements were performed to assess the effects of drug treatment on microglia migration and ROS production. Extensive signaling pathway studies were conducted to identify the downstream signaling mechanism for compound 45 and cytoskeleton staining was performed to evaluate the microglia morphological changes upon 45 treatment. A molecular docking study was utilized to explore ligand protein molecular interaction between 45 and CB2R. Additionally, the similarities and differences in the activity of compound 45, relative to standard CB2R agonist and inverse agonist, were examined in the aforementioned assays. Results: Compound 45 demonstrated the highest affinity and selectivity towards CB2R that translated to higher potency in CB2R ACTOne functional assay, whereas no functional activity was detected at CB1R. Moreover, testing compound 45 in the TANGO-bla assay revealed neutral antagonism at β-arrestins signaling, confirming the G-protein functional selectivity of this class of compounds. Treatment with compound 45 triggered a shift in murine and human microglia polarization from a pro-inflammatory (M1) to an anti-inflammatory (M2) phenotype after 24 hours of treatment. The M1 markers were significantly decreased and M2 markers significantly increased relative to LPS stimulus. These results were further confirmed using microscopic examination wherein compound 45 induced a remarkable transformation of microglia into ramified morphology with a small cell body and several elongated cell projections, indicating microglia adopted an anti-inflammatory M2 phenotype. Moreover, compound 45 significantly reduced cell migration, suppressed the M1 associated ROS production which causes neurotoxicity and cell damage. Additionally, the application of compound 45 significantly increased JNK, c-JUN, CREB, and p38 phosphorylation levels and decreased ERK1/2 and NF-κB representing a unique anti-inflammatory mechanism of CB2R inverse agonists in activated microglia. The molecular docking study of compound 45 revealed that the thiophene C ring constrained the toggle switch residue Trp 258 via multiple π-π stacking interactions that stabilized CB2R in the inactive state and led to 45 inverse agonism activity at CB2R. These results were distinctly different when compared to standard CB2R agonists and inverse agonists, suggesting further research is needed to explore more precisely the utility of CB2R based therapeutics in human CNS disorders. Conclusion: The results of these studies provided valuable information that aids in the development of new analogs of the biaryl-aryl scaffold for treating neuroinflammation in human neurodegenerative diseases
Health Information Management Careers: The Importance of Skillset and Location on Salary
Get PDFHealth information management is an engaging and dynamic occupational field that employs thousands of individuals throughout the United States across the spectrum of health care providing organizations. The ability to navigate these opportunities is influenced heavily by the location of available positions and the skillsets desired by employers. Through study of workforce development data and research in health information management one is able to determine the location and skillset of positions that will help distinguish oneself in a competitive marketplace that values not only education and experience, but the ability to lead in a field that is rapidly changing and growing as the health care industry responds to a consumer that is empowered in their own health and demands more of the industry as a whole
MUC13 Modulated Nanomechanical and Biophysical Responses in Pancreatic Cancer Cells
Get PDFPancreatic adenocarcinoma is one of the deadliest forms of cancer. Even with recent advances in diagnostic tools, chemotherapeutic regimens, and biomarkers for earlier detection, it still has dismal survival rates. Part of the reason for this is the inherent difficulty in detecting and treating this disease. Recent findings suggest that the altered expression of mucins, including MUC13, may be useful molecular signatures for early disease diagnosis, chemotherapy response and predicting patient survival. MUC13, a recently identified transmembrane glycoprotein, is normally associated with forming a protective barrier on epithelial tissues. However, its overexpression/aberrant subcellular localization has been associated with cancer, disease aggressiveness, poorer patient prognosis and drug resistance via alterations of multiple oncogenic signaling pathways. The main objective of this study is to investigate if MUC13 expression influences nanomechanical and biophysical characteristics of pancreatic cancer cells that might contribute to aggressive nature of this disease. To achieve this goal, we performed innovative nanoindentation analyses using atomic force microscopy in conjunction with standard biochemical assays. To combat this malignant disease, multiple approaches have been considered over the years. Recently, a unique biophysical method of cancer detection has been explored in other cancers, whereby an atomic force microscope (AFM) is used to measure the differences in rigidity and adhesion between normal and cancerous cells. AFMs work by using a thin metallic cantilever with a sharp probe which is brought into contact with a sample. Due to the interactions between the probe and the sample, various data can be extracted. AFMs have been used for decades to acquire high resolution, three-dimensional images of a sample, however it is also possible to acquire other types of data. For cancer research, biophysical data can help to differentiate between cancerous cells and their healthy counterparts. Current evidence suggests that normal cells have a greater rigidity than their cancerous counterparts in most malignancies, however literature dealing with pancreatic cancer is limited. In this report, a comprehensive overview of various pancreatic cell lines (both cancerous and non-cancerous) was physically investigated. We noted that there was a significant trend in the reduction of biophysical characteristics associated with differentiation status - namely, poorly differentiated pancreatic cancer cells (MIA PaCa-2, AsPC-1 and Panc-1) have significantly lower rigidity values as compared to moderately differentiated (BxPC-3), well differentiated (HPAF-II) and normal pancreatic epithelia (HPNE). A positive correlation was seen between the adhesion data and aggregation assays - notably, less aggregation was seen in cancer cells as compared to HPNE cells, an
Genetic Variation and Sex Mediate Differential Responses to ∆-9-tetrahydrocannabinol among Inbred Mice
Get PDFThe plant Cannabis sativa has been used by people for both recreational and medicinal use for thousands of years, but scientific investigation of the plant and its components didn’t begin until the early nineteen hundreds when Cannabis components known as phytocannabinoids were characterized and later isolated. In the 1970’s, ∆9-tetrahydrocannabinol (THC) was isolated and recognized as the major constituent responsible for the psychoactive and intoxicating effects associated with consumption of cannabis. This opened the door for intensive research in the field that lead to the discovery of the endogenous cannabinoid system and its associated receptors, effectors of signaling, and biosynthetic enzymes.
The primary cannabinoid receptor, cannabinoid receptor 1, is a G-protein coupled receptor (GPCR) that primarily associates with Gi/o proteins, giving it the properties of having mainly inhibitory actions by decreasing release of neurotransmitters and hormones. Upon receptor activation, the Gi/o protein disassociates with and inhibits adenylyl cyclase, decreasing cAMP production, a major second messenger of the cell. After stimulation by cannabinoids, cannabinoid receptors undergo a desensitization process where they are internalized by β-arrestins. This internalization subjects the receptors to intracellular trafficking during which the majority are degraded. This causes a decrease in surface levels of cannabinoid receptors and makes the cells less sensitive to agonists.
Cannabis is among the most widely used psychoactive drugs in the world. In the United States, use and legalization of cannabis continues to grow. The spreading use and legalization of cannabis has the social consequence of a diminished sense of risk to the individual. This can be harmful in and of itself, but cannabis THC concentrations in the U.S. have tripled over the last 20 years, giving rise to a more potent drug, potentially increasing risk of adverse effects associated with use. Effects of acute, short term use include faulty judgment and perception, memory impairment, motor skill dysfunction, alteration of mood, and low levels of attention and alertness. Effects associated with more chronic, long term use include risk of dependence, an increased risk of developing psychotic disorders such as schizophrenia, and long-term cognitive impairment.
For cannabis, and other drugs of abuse, initial response and/or tolerance to drug effects can predict later dependence and problematic use. In the work presented here, we identify sex and genetic (strain) differences in initial response and rapid tolerance to THC, the main psychoactive ingredient in cannabis, between highly genetically divergent inbred mouse strains—C57BL/6J (B6) and DBA/2J (D2). To identify variation in THC response we use the cannabinoid-induced tetrad test which quantifies the strength of agonist mediated cannabinoid receptor signaling by measuring the level of motor activity, nociception, and hypothermia elicited by receptor activation. We then extend our study of THC response variation to the BXD genetic reference population derived from B6 and D2 strains. Increasing the number of strains tested by tenfold (N=20) we detect significant strain and sex variation in THC response and use online tools to perform QTL mapping and correlation searches to begin to uncover potential genetic drivers of variation in response to THC
Vitamin D Levels Affect Survival in a BCR-ABL Acute Lymphoblastic Leukemia Mouse Model but Do Not Cause Vitamin-Drug Interactions
Get PDFIt is a well-established phenomenon that dietary components containing CYP3A inducers or inhibitors if co-administered with drugs that are CYP3A4 substrates lead to marked drug-drug interactions. Because vitamin D is known to regulate intestinal CYP3A expression and gut CYP3A expression plays an important role in pre-systemic metabolism of CYP3A drugs, we determined the impact of vitamin D (VD3) status on systemic exposure and efficacy of chemotherapeutic agents that are CYP3A substrates. We employed VD3 sufficient and deficient mice to perform pharmacokinetics (PK) and anti-leukemic efficacy studies.
First, using hCYP3A4 transgenic mouse model we evaluated the intestinal, hepatic and renal expression of hCYP3A4, mouse CYPs and transporters in VD3 sufficient vs. deficient mice. We observed that female VD3 deficient mice had significantly lower duodenal mouse Cyp3a11 and hCYP3A4 expression than VD3 sufficient mice. Since intestinal CYP3A plays a significant role in first pass metabolism of drugs that are administered orally, chemotherapeutic agents such as dexamethasone (DEX) and dasatinib which are given orally to the patients were chosen to study the effect of VD3 status on systemic exposure of these CYP3A4 substrates.
In C57BL/6 mice, we performed dexamethasone PK study, where we observed male VD3 deficient mice had higher plasma DEX levels compared to sufficient mice on day 3.5. No significant differences were observed in females.
Another CYP3A4 substrate, dasatinib PK was also performed where AUC’s were not significantly different between groups. However, during early absorption at t = 0.25 hr, VD3 deficient male mice had significantly higher dasatinib plasma levels compared to VD3 sufficient mice. In conclusion, VD3 levels (sufficient vs. deficient) significantly altered intestinal Cyp3a expression in female hCYP3A4 mice, and in male’s, plasma exposure was different for orally administered DEX at 3.5 days, dasatinib at 0.25 hr. Ultimately, there was no significant effect of VD3 status on DEX or dasatinib PK indicating no potential vitamin drug interactions. However, DEX being a potential CYP3A inducer, we also observed significant induction of multiple mouse Cyp3a’s in intestine of VD3 deficient but not VD3 sufficient mice. This differential induction of Cyp3a’s due to vitamin D status could lead to drug interactions with other co-administered CYP3A substrates.
Given the high prevalence of VD3 deficiency in acute lymphoblastic leukemia (ALL) patients, we evaluated the effect of vitamin D deficiency on survival outcome from pre-B cell Arf -/- BCR-ABL acute lymphoblastic leukemia in a murine model. Vitamin D sufficient mice died earlier (p
To investigate the mechanism by which vitamin D affected the survival and disease growth in VD3 sufficient mice, we performed in vitro studies and demonstrated 1, 25-dihydroxy vitamin D (1, 25-(OH)2VD3) increased the number of BCR-ABL ALL cells only when co-cultured with bone marrow stroma. 1, 25-(OH)2VD3 induced CXCL12 production in vivo and in vitro in bone marrow stromal cells and CXCL12 increased stromal migration and the number of BCR-ABL blasts. Vitamin D together with ALL reprogrammed the marrow environment by increasing production of Type I and V collagens, potentially trapping ALL blasts and CXCL12 expression to support tumor progression and leukemia cell homing.
In conclusion, although vitamin D deficiency did not cause significant interactions with anti-leukemic CYP3A4 substrates, there was a significant effect on disease progression and survival of mice from BCR-ABL ALL
Using preliminary data and prospective power analyses for mid-stream revision of projected group and subgroup sizes in pragmatic patient-centered outcomes research
Get PDFPragmatic clinical trials are commonly used in patient-centered outcomes research to assess heterogeneity of treatment effects. Patient-Centered Outcomes Research Institute (PCORI) methodology standards for assessing heterogeneity of treatment effects are extremely rigorous, but their implementation in real-world settings can be difficult. Predicting recruitment effectiveness and subgroup characteristics is often challenging and may require mid-stream revision of projected group and subgroup sizes. Yet, little real-world data are available to demonstrate methodologically valid approaches to address situations where such revisions are necessary. These data were used for mid-stream revision of group and subgroup sizes in the Management of Diabetes in Everyday Life (MODEL) clinical trial. The planned number of randomized participants retained over the one-year study period was reduced from 800 to 581 due to recruitment difficulties among potential participants residing in rural areas. Prospective power analyses are based on the revised target of 581 participants retained and the proportions of 167 participants with various key baseline characteristics, who had been randomized in MODEL by January 2018, as reported to the Patient Center Outcomes Research Institute (PCORI) and the MODEL Data Safety and Monitoring Committee. Power calculations are based on two-sided t-tests with type-I error rates of 0.05 and the assumption that effect sizes will range from small (standardized difference = 0.36) to medium (= 0.50). The primary outcome variables are how many days in the previous week participants 1) ate healthy meals, 2) participated in at least 30 minutes of physical activity, and 3) took medications as prescribed. The POWER procedure of SAS 9.4 was used for all analyses. These data, along with the approach, can assist statisticians as they plan future pragmatic clinical trials evaluating heterogeneity of treatment effects. These data can help inform investigators, conducting patient-centered outcomes research, as they define subgroups for either confirmatory analyses for testing heterogeneity of treatment effects or for exploratory analyses where estimation of confidence bounds may be useful for generating future hypotheses. (This work was supported through a Patient-Centered Outcomes Research Institute (PCORI) Project Program Award (SC15-1503-28336), www.ClinicalTrials.gov and Identifier: NCT02957513 [1].
US Guided Management of Undifferentiated Dyspneic Patient in the ED
Get PDFIntro: Undifferentiated dyspnea can be a complicated presentation muddled by patient comorbidities and similar symptomology shared among etiologies. Some studies have shown increased mortality and length of stay in the hospital when incorrectly initially diagnosed in the ED. US has been shown more effective at differentiating these causes and improves diagnostic accuracy. This study will implement US exam upon initial exam of patient and chart time to diagnosis/treatment, length of stay in ED, length of stay in hospital admissions versus discharge rates, and 30 day mortality. ADHF and COPD/asthma patient differentiation will be the focus.
Methods: Prospective cohort study of more than 18 years that present with the primary complaint of dyspnea with more than one complicating comorbid condition. Initial exam by physician will be accompanied by cardiothoracic US previously verified.
Results: Study powered by previous year average of time to diagnosis of institution. Patient characteristics, distribution by diagnostic category, and characteristics found on US in correlation with diagnosis will be included for multivariate analysis.
Conclusions: We expect to see a significant difference in our time to diagnosis/treatment and mortality rate