Indian warfare, household competency, and the settlement of the western Virginia frontier, 1749 to 1794

The thesis of this dissertation is that Indian-related violence and warfare had a profound influence on the duration and nature of the frontier experience of those men and women who settled in the western Virginia backcountry between 1749 and 1794. Recurrent attacks by Shawnees, Delawares, Mingos, and Indians from the Great Lakes region caused such widespread death, destruction, and depopulation that it effectively prolonged the period of austere and difficult living conditions for over forty years. This conclusion contradicts the assertions of some recent scholars who have argued that crude living conditions lasted for only a year or two on the Appalachian frontier, and that economic conditions improved rapidly. While this may have been the case in some sub-regions of Appalachia that experienced minimal upheaval from Indian attacks, this was not the case in trans-Allegheny West Virginia. The negative influence of Indian-associated violence manifested itself not only in how long it took Euro-Americans to gain hegemony over the region, but also in the household economies of the individual families. By using competency as a model for understanding household economics, it is demonstrated that although many settlers embraced the commercial economy when possible, the rigors of life on the oftentimes-violent frontier frequently left them no option but to shift their focus of their household production away from commercial production in favor of subsistence activities

Association of Hospital Racial Composition and Payer Mix With Mortality in Acute Coronary Syndrome.

Background Patient characteristics insufficiently explain disparities in cardiovascular outcomes among hospitalized patients, suggesting a role for community or hospital-level factors. Here, we evaluate the association of hospital racial composition and payer mix with all-cause inpatient mortality for patients hospitalized with acute coronary syndrome (ACS). Methods and Results Using the National Inpatient Sample, we identified adult hospitalizations from 2014 with a primary diagnosis of ACS (n=550 005). We divided National Inpatient Sample hospitals into quartiles based on percent of minority (black, Hispanic, Asian or Pacific Islander, Native American race/ethnicity) and low-income payer (Medicaid or uninsured) discharges in 2014. We utilized logistic regression to determine whether hospital minority or low-income payer makeup associated with all-cause inpatient mortality among those admitted for ACS . In adjusted models, ACS patients admitted to hospitals with >12.4% to 25.4% (Quartile 2), >25.4% to 44.3% (Q3), and >44.3% (Q4) minority discharges experienced a 14% (OR 1.14, 95% CI 1.06-1.23), 13% (OR 1.13, 95% CI 1.04-1.23), and 15% (OR 1.15, 95% CI 1.04-1.26) increased odds of all-cause inpatient mortality compared with hospitals with ≤12.4% (Q1) minority discharges. ACS patients admitted to hospitals with >18.7% to 25.7% (Q2) and >34.0% (Q4) low-income payer discharges experienced a 9% (OR 1.09, 1.01-1.17) and 9% (OR 1.09, 1.00-1.19) increased odds of all-cause inpatient mortality when compared with hospitals with ≤18.7% (Q1) low-income payer discharges. Conclusions Hospital minority and low-income payer makeup positively associate with odds of all-cause inpatient mortality among patients admitted for acute coronary syndrome

Commercialism, subsistence, and competency on the Western Virginia frontier, 1765--1800

Since the early nineteenth century, Americans have frequently associated the pioneers of the Appalachian Mountains with subsistence farming, economic independence, and a certain degree of hostility toward capitalism. This thesis disproves the myth of pioneer self-sufficiency by demonstrating how the men and women who settled in western Virginia during the final third of the eighteenth century used a variety of tactics in their struggle to achieve a competency. Although subsistence activities, such as hunting and farming, undoubtedly held an important place in the backcountry domestic economy, the settlers also interacted with the commercial market as both producers and consumers of a wide range of commodities. In the final analysis, this thesis adds to the growing body of scholarship which challenges the concept of Appalachian exceptionalism

Differential Disease Susceptibilities in Experimentally Reptarenavirus-Infected Boa Constrictors and Ball Pythons.

Inclusion body disease (IBD) is an infectious disease originally described in captive snakes. It has traditionally been diagnosed by the presence of large eosinophilic cytoplasmic inclusions and is associated with neurological, gastrointestinal, and lymphoproliferative disorders. Previously, we identified and established a culture system for a novel lineage of arenaviruses isolated from boa constrictors diagnosed with IBD. Although ample circumstantial evidence suggested that these viruses, now known as reptarenaviruses, cause IBD, there has been no formal demonstration of disease causality since their discovery. We therefore conducted a long-term challenge experiment to test the hypothesis that reptarenaviruses cause IBD. We infected boa constrictors and ball pythons by cardiac injection of purified virus. We monitored the progression of viral growth in tissues, blood, and environmental samples. Infection produced dramatically different disease outcomes in snakes of the two species. Ball pythons infected with Golden Gate virus (GoGV) and with another reptarenavirus displayed severe neurological signs within 2 months, and viral replication was detected only in central nervous system tissues. In contrast, GoGV-infected boa constrictors remained free of clinical signs for 2 years, despite high viral loads and the accumulation of large intracellular inclusions in multiple tissues, including the brain. Inflammation was associated with infection in ball pythons but not in boa constrictors. Thus, reptarenavirus infection produces inclusions and inclusion body disease, although inclusions per se are neither necessarily associated with nor required for disease. Although the natural distribution of reptarenaviruses has yet to be described, the different outcomes of infection may reflect differences in geographical origin.IMPORTANCE New DNA sequencing technologies have made it easier than ever to identify the sequences of microorganisms in diseased tissues, i.e., to identify organisms that appear to cause disease, but to be certain that a candidate pathogen actually causes disease, it is necessary to provide additional evidence of causality. We have done this to demonstrate that reptarenaviruses cause inclusion body disease (IBD), a serious transmissible disease of snakes. We infected boa constrictors and ball pythons with purified reptarenavirus. Ball pythons fell ill within 2 months of infection and displayed signs of neurological disease typical of IBD. In contrast, boa constrictors remained healthy over 2 years, despite high levels of virus throughout their bodies. This difference matches previous reports that pythons are more susceptible to IBD than boas and could reflect the possibility that boas are natural hosts of these viruses in the wild

Mechanical circulatory support in acute myocardial infarction and cardiogenic shock: Challenges and importance of randomized control trials

BACKGROUND: Acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) is associated with significant morbidity and mortality. METHODS: We provide an overview of previously conducted studies on the use of mechanical circulatory support (MCS) devices in the treatment of AMI-CS and difficulties which may be encountered in conducting such trials in the United States. RESULTS: Well powered randomized control trials are difficult to conduct in a critically ill patient population due to physician preferences, perceived lack of equipoise and challenges obtaining informed consent. CONCLUSIONS: With growth in utilization of MCS devices in patients with AMI-CS, efforts to perform well-powered, randomized control trials must be undertaken

The Gap to Fill: Rationale for Rapid Initiation and Optimal Titration of Comprehensive Disease-modifying Medical Therapy for Heart Failure with Reduced Ejection Fraction

There are gaps in the use of therapies that save lives and improve quality of life for patients with heart failure with reduced ejection fraction, both in the US and abroad. The evidence is clear that initiation and titration of guideline-directed medical therapy (GDMT) and comprehensive disease-modifying medical therapy (CDMMT) to maximally tolerated doses improves patient-focused outcomes, yet observational data suggest this does not happen. The purpose of this review is to describe the gap in the use of optimal treatment worldwide and discuss the benefits of newer heart failure therapies including angiotensin receptor-neprilysin inhibitors and sodium-glucose cotransporter 2 inhibitors. It will also cover the efficacy and safety of such treatments and provide potential pathways for the initiation and rapid titration of GDMT/CDMMT

Insulin Stimulates Adipogenesis through the Akt-TSC2-mTORC1 Pathway

BACKGROUND:The signaling pathways imposing hormonal control over adipocyte differentiation are poorly understood. While insulin and Akt signaling have been found previously to be essential for adipogenesis, the relative importance of their many downstream branches have not been defined. One direct substrate that is inhibited by Akt-mediated phosphorylation is the tuberous sclerosis complex 2 (TSC2) protein, which associates with TSC1 and acts as a critical negative regulator of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). Loss of function of the TSC1-TSC2 complex results in constitutive mTORC1 signaling and, through mTORC1-dependent feedback mechanisms and loss of mTORC2 activity, leads to a concomitant block of Akt signaling to its other downstream targets. METHODOLOGY/PRINCIPAL FINDINGS:We find that, despite severe insulin resistance and the absence of Akt signaling, TSC2-deficient mouse embryo fibroblasts and 3T3-L1 pre-adipocytes display enhanced adipocyte differentiation that is dependent on the elevated mTORC1 activity in these cells. Activation of mTORC1 causes a robust increase in the mRNA and protein expression of peroxisome proliferator-activated receptor gamma (PPARgamma), which is the master transcriptional regulator of adipocyte differentiation. In examining the requirements for different Akt-mediated phosphorylation sites on TSC2, we find that only TSC2 mutants lacking all five previously identified Akt sites fully block insulin-stimulated mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis. Finally, renal angiomyolipomas from patients with tuberous sclerosis complex contain both adipose and smooth muscle-like components with activated mTORC1 signaling and elevated PPARgamma expression. CONCLUSIONS/SIGNIFICANCE:This study demonstrates that activation of mTORC1 signaling is a critical step in adipocyte differentiation and identifies TSC2 as a primary target of Akt driving this process. Therefore, the TSC1-TSC2 complex regulates the differentiation of mesenchymal cell lineages, at least in part, through its control of mTORC1 activity and PPARgamma expression

Small Molecules Targeting Human UDP-GlcNAc 2-Epimerase

Uridine diphosphate N-acetylglucosamine 2-epimerase (GNE) is a key enzyme in the sialic acid biosynthesis pathway. Sialic acids are primarily terminal carbohydrates on glycans and play fundamental roles in health and disease. In search of effective GNE inhibitors not based on a carbohydrate scaffold, we performed a high-throughput screening campaign of 68,640 drug-like small molecules against recombinant GNE using a UDP detection assay. We validated nine of the primary actives with an orthogonal real-time NMR assay and verified their IC50 values in the low micromolar to nanomolar range manually. Stability and solubility studies revealed three compounds for further evaluation. Thermal shift assays, analytical size exclusion, and interferometric scattering microscopy demonstrated that the GNE inhibitors acted on the oligomeric state of the protein. Finally, hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed which sections of GNE were shifted upon the addition of the inhibitors. In summary, we have identified three small molecules as GNE inhibitors with high potency in vitro, which serve as promising candidates to modulate sialic acid biosynthesis in more complex systems