Running the River Stupid: Swiftwater Rescue Training Proves Relevant to Leading Middle Schoolers, a Teacher Discovers

The author takes readers on her training course in canoe rescue techniques, and then shows how often she uses water rescue to motivate her work with adolescents

A Realistic Path Towards a More Affordable Healthcare System for the United States

This study was performed in order to try to discover ways in which the American healthcare system can improve and become more affordable for its citizens. The main focus was to see how implementing a universal healthcare system could benefit the United States. I analyzed aspects of many different universal healthcare system structures and chose aspects that I think should or should not be included in a revised version of the US healthcare system. There was a strong focus on the aspects of Japan and Costa Rica’s healthcare systems. I also pointed out weaknesses in the US healthcare system that definitely need to be addressed. Within the study, I concluded that the United States charges its citizens far too much for their healthcare services, and performs worse than many comparable countries of similar economic prowess. I concluded that aspects of a universal healthcare system could prove to be beneficial in reducing these high costs and providing helpful coverage to millions of Americans who are uninsured

Extracellular matrix components indicate remodelling activity in different fibrosis stages of human non-alcoholic fatty liver disease

AIMS: The composition of several important extracellular matrix components (ECM) has not yet been elucidated in human non-alcoholic fatty liver disease (NAFLD). We aim to investigate the proportion of hepatic stellate cells (HSCs) and activity of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in human NAFLD liver tissue with respect to severity of inflammation and fibrosis. METHODS AND RESULTS: Histopathological features were quantified by NAFLD activity score and grading assignment. The collagen proportionate area (CPA) was measured. Slides were stained with alpha-smooth muscle actin (alpha-SMA), as a marker of activated HSCs, and alpha-SMA was quantified digitally. Zymography was performed to measure the proteolytic activity of MMP-2 and MMP-9. TIMP-1 and TIMP-2 protein concentration was measured with enzyme-linked immunosorbent assay (ELISA). alpha-SMA was higher in severe fibrosis (6.3%, interquartile range 2.9-13.1) than mild and no fibrosis (median 1.1 and 0.9%, P < 0.001) and correlated strongly with CPA (Rs = 0.870, P < 0.001). ProMMP-2 activity in severe (4.1%, IQR 2.6-16.2) and mild fibrosis (2.7%, IQR 1.9-3.9) was higher than in no fibrosis (1.5%, (IQR 0.95-2.1); P = 0.001 and P = 0.046) and showed a moderate positive correlation with CPA (Rs = 0.495, P = 0.001). TIMP-1 and TIMP-2 were significantly higher in severe fibrosis than mild or no fibrosis. Both showed moderate correlation with CPA (TIMP-1: Rs = 0.471, P = 0.002 and TIMP-2: Rs = 0.325, P = 0.036). MMP-9 correlated as the only ECM component to inflammation severity. CONCLUSIONS: Advanced human NAFLD-fibrosis has a distinct ECM composition with increased HSCs and increased TIMP inhibition, but there is also ongoing remodelling activity of MMP-2

Speaking up: using OSTEs to understand how medical students address professionalism lapses

Background: Objective-structured teaching encounters (OSTEs) are used across many disciplines to assess teaching ability. The OSTE detailed in this paper assesses 191 fourth-year medical students’ (M4) ability to identify and address lapses in professionalism based on Association of American Medical Colleges’ professionalism competencies. The research questions addressed are: How frequently do M4s address professionalism lapses observed during an OSTE? What factors influence whether M4s provide feedback when they observe professionalism lapses in an OSTE? Methods: Standardized patients (SPs) and standardized learners (SLs) were recruited and trained to participate in a standardized encounter with specific cognitive, social, and behavioral errors, including professionalism lapses. M4s viewed this encounter and then offered feedback to the SL, while remotely observed by faculty. Post-encounter, the SL and faculty completed identical checklists to assess both teaching readiness and ability to address professionalism concerns. Results: An analysis of frequencies showed that six of the Association of American Medical Colleges’ nine professional competencies were addressed in the checklist and/or discussed in the focus group. Analysis of transcribed debriefing sessions confirmed that M4s did not consistently address professionalism lapses by their peers. Conclusions: In focus groups, M4s indicated that, while they noticed professionalism issues, they were uncomfortable discussing them with the SLs. Findings of the current study suggest how medical educators might support learners’ ability to address lapses in professionalism as well as topics for future research

Short-Stay Nursing Home Rehabilitation Patients: Transitional Care Problems Pose Research Challenges

We conducted a NIH-funded clinical intervention pilot study to improve depression care for short-stay nursing home Medicare-reimbursed rehabilitation patients. Despite a solid theoretical and clinical grounding and the support of a large nursing home company, we encountered several roadblocks to implementation, including 1) involving patients and families, 2) communication between providers, 3) involving community primary care physicians (PCP), 4) staff time constraints, and 5) conducting research with short-stay patients. While frustrating from a research standpoint, these roadblocks closely reflect problems identified by the American Geriatrics Society (AGS) as impeding the delivery of high quality transitional care in geriatrics. We describe these research roadblocks as we encountered them in the clinical setting and place each within the larger context of challenges associated with care transitions, especially for older persons with complex health needs receiving nursing home rehabilitation. Finally, we offer recommendations for researchers conducting much needed research within geriatric transitional care settings, including starting early in the care transition chain and assisting patients and families to provide continuity across care settings

An epithelial-immune circuit amplifies inflammasome and IL-6 responses to SARS-CoV-2

Elevated levels of cytokines IL-1β and IL-6 are associated with severe COVID-19. Investigating the underlying mechanisms, we find that while primary human airway epithelia (HAE) have functional inflammasomes and support SARS-CoV-2 replication, they are not the source of IL-1β released upon infection. In leukocytes, the SARS-CoV-2 E protein upregulates inflammasome gene transcription via TLR2 to prime, but not activate, inflammasomes. SARS-CoV-2-infected HAE supply a second signal, which includes genomic and mitochondrial DNA, to stimulate leukocyte IL-1β release. Nuclease treatment, STING, and caspase-1 inhibition but not NLRP3 inhibition blocked leukocyte IL-1β release. After release, IL-1β stimulates IL-6 secretion from HAE. Therefore, infection alone does not increase IL-1β secretion by either cell type. Rather, bi-directional interactions between the SARS-CoV-2-infected epithelium and immune bystanders stimulates both IL-1β and IL-6, creating a pro-inflammatory cytokine circuit. Consistent with these observations, patient autopsy lungs show elevated myeloid inflammasome gene signatures in severe COVID-19., IL-1β and IL-6 are increased in severe COVID-19. Examining the underlying mechanisms, Barnett et al. show that SARS-CoV-2 E protein primes, and DNA from infected epithelial cells activates, inflammasome-dependent IL-1β secretion from leukocytes, which in turn stimulates IL-6 release from epithelial cells

A Multitrait Locus Regulates Sarbecovirus Pathogenesis

Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genomewide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. IMPORTANCE Host genetic variation is an important determinant that predicts disease outcomes following infection. In the setting of highly pathogenic coronavirus infections genetic determinants underlying host susceptibility and mortality remain unclear. To elucidate the role of host genetic variation on sarbecovirus pathogenesis and disease outcomes, we utilized the Collaborative Cross (CC) mouse genetic reference population as a model to identify susceptibility alleles to SARS-CoV and SARS-CoV-2 infections. Our findings reveal that a multitrait loci found in chromosome 9 is an important regulator of sarbecovirus pathogenesis in mice. Within this locus, we identified and validated CCR9 and CXCR6 as important regulators of host disease outcomes. Specifically, both CCR9 and CXCR6 are protective against severe SARS-CoV, SARS-CoV-2, and SARS-related HKU3 virus disease in mice. This chromosome 9 multitrait locus may be important to help identify genes that regulate coronavirus disease outcomes in humans

Improving Anthracycline Therapy Through Carbonyl Reductase Inhibition

Human Carbonyl Reductase (HCBR) is an enzyme responsible for converting a chemotherapeutic class of drugs known as anthracyclines into cardiotoxic metabolites while simultaneously reducing their chemotherapeutic efficacy. My research goal is to identify inhibitors of HCBR that may be of pharmacologic value by maintaining the chemotherapeutic properties of these drugs while reducing their cardiotoxicity; outcomes that may lead to dosage reductions during chemotherapy. The methodology involves evaluating chemical compounds for HCBR inhibition potential using a standard assay containing Menadione, NADPH, and HCBR in a phosphate buffer. All test experiments use UV spectrophotometry to determine reaction activity compared against controls. One HCBR inhibitor was identified which initially appeared promising particularly because of its appealing molecular structure that suggested it may be well received in humans. Subsequent IC-50 studies to determine effective inhibitory concentrations revealed questionable pharmacologic value. My research will continue to test other chemical compounds for possible HCBR inhibition. My research endeavors have provided a wonderful outlet for my curiosity and have helped solidify my understanding of bench research and its contribution in the learning process of disease and biological systems. (NIH Grant # P20 RR016454