Introducing First Year Medical Students to Personalized Medicine Concepts in a Small Group Activity

Presented as a Poster Presentation at 2020 IUSM Education Day.An individuals’ genetic profile is becomingly an increasingly important parameter in healthcare decisions. This small group activity was developed to introduce first year medical students in the Molecules to Cells and Tissues course to the concept and significance of Pharmacogenomics and personalized medicine. Additionally, this activity provided students with an opportunity to work with a large dataset and use the information to impact clinical decision making. This activity has two cases, takes student groups approximately 2 hours to complete, and requires internet access. Case materials are available through the learning management system Canvas, and include open-ended questions to guide students through the cases. In these cases students explore the functional significance of different alleles of a panel of cytochrome P450 genes. The group activity has the students examine a large data set of cytochrome P450 genes and cognate alleles to determine their prevalence in the local population and calculate the individuals’ gene scores. The students are then asked to explain the impact of the genotype (or gene score) on the resulting patient phenotype (i.e. the functional significance of the genotype). The first case involves a breast cancer survivor support group in which patients taking Taxol discuss lack of adequate pain relief from opioids and the potential impact of concomitant use of natural compounds/supplements on drug metabolism. The second case involves a patient presenting with recurrent stroke-like symptoms despite being on the anticoagulant medication clopidogrel. The patient is initially suspected to be non-compliant, but is later determined to be a poor metabolizer of the anticoagulant clopidogrelto its active form thus decreasing its efficacy. The expertise of the IUSM Medical Genetics research faculty was leveraged to provide a large data set of cytochrome P450 genes and cognate alleles. The selection of cytochrome P450 was based upon delivering content focused on the biochemistry of the enzyme system and provided an opportunity to highlight the drug interaction database available through IUSM Clinical Pharmacology (The FlockhartTable™ ; https://drug-interactions.medicine.iu.edu/). The addition of natural compounds was to draw students’ attention to the Natural Medicines database, which is the recommended source for evidence-based data on complementary and alternative medicine. Natural Medicines is available through the Ruth Lilly Medical Library and can be searched by substance or condition. It provides both a summary of the literature available on substances as well as the level of evidence or quality of studies done on the substance

The Master Well Owner Network: Volunteers Educating Pennsylvania Well Owners

The Master Well Owner Network (MWON) was created to expand the capacity of Penn State Extension by training volunteers who would provide education to rural residents about private water system management. Eight workshops were conducted throughout Pennsylvania, and 243 volunteers representing 55 of 67 counties in Pennsylvania successfully completed the training. MWON volunteer reports have been very positive, with education provided directly to over 7,000 Pennsylvania residents and another 29,000 educated through the mass media. MWON\u27s successes in Pennsylvania may serve as a model for other states that wish to increase outreach to the private water system education audience

Vegetation and Acidification

In this chapter, the impact of watershed acidification treatments on WS3 at the Fernow Experimental Forest (FEF) and at WS9 on vegetation is presented and summarized in a comprehensive way for the first time. WS7 is used as a vegetative reference basin for WS3, while untreated plots within WS9 are used as a vegetative reference for WS9. Bioindicators of acidification impacts that will be considered include several measures of tree and stand growth rates, foliar chemistry, bolewood chemistry, and herbaceous species composition and diversity. These studies enhance our understanding of the inter-relationships of changes in soil conditions caused by the acidification treatment and the condition of forest vegetation

What is the microbiome of the human home?

There is currently little known about the range and diversity of microorganisms in the indoor home, particularly in the context of modern airtight homes. People spend a great deal of time in their homes, especially those at the extremes of age, and it is possible that the indoor microbiome could impact upon human health in ways not yet understood. This project aimed to systematically screen sites in 100 houses in the Lanarkshire community in order to determine the amount and type of cultivable aerobic bacteria and fungi in the home. It was hoped to be able to characterise the microbiome of the ‘normal’ home. Chosen sites were: indoor bathroom handle; telephone; kettle handle; bedside table; top of bedroom door; TV remote; toilet handle; and bedroom window sill (Table 1). These sites were screened using double-sided dipslides coated with nutrient and staphylococcal selective agars (Figure 1). Bacteria and fungi were quantified for each site and staphylococci and Gram- negative bacilli identified if possible. Each of the eight sampled sites revealed its own distinct microbiological character, both in the type and amount of cultivable microbes. Human pathogens, particularly S.aureus, were more likely to be associated with commonly touched sites such as TV remote, kettle handle and telephone. Whole houses also demonstrated unique microbiological characteristics, with morphologically similar and identifiable microbes observed at multiple sites within the same home. Each home thus displayed it own unique microbiome but with identifiable similarities between other homes according to site

Disruption of Transforming Growth Factor β Signaling by a Novel Ligand-dependent Mechanism

Transforming growth factor (TGF)-β is the prototype in a family of secreted proteins that act in autocrine and paracrine pathways to regulate cell development and function. Normal cells typically coexpress TGF-β receptors and one or more isoforms of TGF-β, thus the synthesis and secretion of TGF-β as an inactive latent complex is considered an essential step in regula-ting the activity of this pathway. To determine whether intracellular activation of TGF-β results in TGF-β ligand–receptor interactions within the cell, we studied pristane-induced plasma cell tumors (PCTs). We now demonstrate that active TGF-β1 in the PCT binds to intracellular TGF-β type II receptor (TβRII). Disruption of the expression of TGF-β1 by antisense TGF-β1 mRNA restores localization of TβRII at the PCT cell surface, indicating a ligand-induced impediment in receptor trafficking. We also show that retroviral expression of a truncated, dominant-negative TβRII (dnTβRII) effectively competes for intracellular binding of active ligand in the PCT and restores cell surface expression of the endogenous TβRII. Analysis of TGF-β receptor–activated Smad2 suggests the intracellular ligand–receptor complex is not capable of signaling. These data are the first to demonstrate the formation of an intracellular TGF-β–receptor complex, and define a novel mechanism for modulating the TGF-β signaling pathway

Development of a non-human primate BCG infection model for the evaluation of candidate tuberculosis vaccines.

The lack of validated immunological correlates of protection makes tuberculosis vaccine development difficult and expensive. Using intradermal bacille Calmette-Guréin (BCG) as a surrogate for aerosol Mycobacterium tuberculosis (M.tb) in a controlled human infection model could facilitate vaccine development, but such a model requires preclinical validation. Non-human primates (NHPs) may provide the best model in which to do this. Cynomolgus and rhesus macaques were infected with BCG by intradermal injection. BCG was quantified from a skin biopsy of the infection site and from draining axillary lymph nodes, by culture on solid agar and quantitative polymerase chain reaction. BCG was detected up to 28 days post-infection, with higher amounts of BCG detected in lymph nodes after high dose compared to standard dose infection. Quantifying BCG from lymph nodes of cynomolgus macaques 14 days post-high dose infection showed a significant reduction in the amount of BCG detected in the BCG-vaccinated compared to BCG-naïve animals. Demonstrating a detectable vaccine effect in the lymph nodes of cynomolgus macaques, which is similar in magnitude to that seen in an aerosol M.tb infection model, provides support for proof-of-concept of an intradermal BCG infection model and evidence to support the further evaluation of a human BCG infection model

The influence of haemoglobin and iron on in vitro mycobacterial growth inhibition assays.

The current vaccine against tuberculosis, live attenuated Mycobacterium bovis BCG, has variable efficacy, but development of an effective alternative is severely hampered by the lack of an immune correlate of protection. There has been a recent resurgence of interest in functional in vitro mycobacterial growth inhibition assays (MGIAs), which provide a measure of a range of different immune mechanisms and their interactions. We identified a positive correlation between mean corpuscular haemoglobin and in vitro growth of BCG in whole blood from healthy UK human volunteers. Mycobacterial growth in peripheral blood mononuclear cells (PBMC) from both humans and macaques was increased following the experimental addition of haemoglobin (Hb) or ferric iron, and reduced following addition of the iron chelator deferoxamine (DFO). Expression of Hb genes correlated positively with mycobacterial growth in whole blood from UK/Asian adults and, to a lesser extent, in PBMC from South African infants. Taken together our data indicate an association between Hb/iron levels and BCG growth in vitro, which may in part explain differences in findings between whole blood and PBMC MGIAs and should be considered when using such assays

We’re All Infected: Legal Personhood, Bare Life and The Walking Dead

This article argues that greater theoretical attention should be paid to the figure of the zombie in the fields of law, cultural studies and philosophy. Using The Walking Dead as a point of critical departure concepts of legal personhood are interrogated in relation to permanent vegetative states, bare life and the notion of the third person. Ultimately, the paper recommends a rejection of personhood; instead favouring a legal and philosophical engagement with humanity and embodiment. Personhood, it is suggested, creates a barrier in law allowing individuals in certain contexts (and in certain embodied states) to be rendered non-persons and thus outside the scope of legal rights. An approach that rejects personhood in favour of embodiment would allow individuals to enjoy their rights without being subject to such discrimination. It is also suggested that the concept of the human, itself complicated by the figure of the zombie, allows for legal engagement with a greater number of putative rights claimants including admixed embryos, cyborgs and the zombie

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy