MEDICA@MUSC (Medical University of South Carolina)
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The Relationship between Post-Stroke Depression and Post-Stroke Dysphagia
Get PDFBackground: Post-stroke dysphagia and post-stroke depression (PSD) can have devastating effects on stroke survivors and substantial financial impacts on the healthcare system; however, there is a dearth of research examining this patient population. Thus, we studied the incidence, risk, and cost of PSD in patients with post-stroke dysphagia. Methods: We conducted a retrospective, cross-sectional study of individuals with a primary diagnosis of acute ischemic stroke and secondary diagnoses of dysphagia and/or depression using administrative claims data from the 2017 Medicare 5% Limited Data Set. Additionally, we developed a novel dysphagia severity index for use with administrative data and applied it to our data sets. Results: Persons with post-stroke dysphagia were as, or slightly more, likely to have PSD compared to the general stroke population. Those with dysphagia (irrespective of severity) had greater odds and hazard of diagnosis of PSD in the 90 days after discharge, and those with dysphagia and PSD incurred higher healthcare costs. Conclusion: Our results supported an association between post-stroke dysphagia and PSD and that the presence of PSD in patients with post-stroke dysphagia increased post-discharge cost. Thus, future research is warranted to further explore the effects of PSD on post-stroke dysphagia
Risk of Readmissions for Medical and Surgical Patients Who “Self-Discharge” Leaving Hospitals Against Medical Advice
Get PDFResearch indicates that as hospital costs increase and Emergency Room wait times grow, more patients leave facilities against medical advice at the detriment to their medical condition and higher risk for mortality (Reese, 2019). Discharges against medical advice (DAMA), in which a patient chooses to leave the hospital without physician approval, is a growing problem for patients and providers (Taqueti, 2007; Carrese, 2006). Patients who DAMA only represent 1-2% of hospital admissions; however, this small group is quite significant due to their high readmission and mortality rates (Lee et al., 2016). It is therefore important to understand characteristics of these patients and challenges associated with their readmittance to improve patient outcomes and minimize economic burden on the U.S. healthcare system (Lee et al., 2016; Reese, 2019). This retrospective analytic study reviewed the risk of readmissions of DAMA patients by analyzing hospital billing data of patients across Florida, Georgia, Kentucky, and Mississippi. Descriptive statistics, demographic characteristics, and diagnosis related data yielded insight on the risk of readmissions and the impact DAMA has upon patients’ health status upon being readmitted
Interactions Between Stress, Ethanol, and THC Exposure and Effects on Prefrontal Reliant Signaling and Behavior
Get PDFPost-traumatic stress disorder (PTSD) and substance use disorder (SUD) are two highly prevalent and highly debilitating psychological conditions that often occur comorbidly. In accordance with the self-medication hypothesis, drugs like alcohol and cannabis are used following exposure to a traumatic event to acutely reduce anxiety, but, in the long term, these substances cause impairments in learning and memory processes in the prefrontal cortex and reduce the effectiveness of therapeutic treatments for these disorders. As such, the overarching hypothesis of this dissertation is that exposure to stress, alcohol, and cannabis lead to alterations in learning and memory due to modifications in prefrontal cortex signaling, and it is further hypothesized that these impairments can be reversed by normalizing glutamatergic function in this region. These experiments were divided into three main branches of study using behavioral pharmacology as well as optogenetics and fiber photometry to investigate the deleterious effects of stress, cannabis, and alcohol exposure on cognitive functioning and glutamate signaling in the prefrontal cortex. In the first set of studies, restraint stress was followed by set-shifting and alcohol self-administration behavioral tasks to examine stress-induced changes in cognitive flexibility and drug seeking behavior respectively. These experiments established stress induced increases in ethanol seeking and relapse like behavior as well as impairments in cognitive flexibility. The second set of studies established the detrimental effects of alcohol exposure on fear learning during extinction training. Further, this effect was shown to be dependent on glutamatergic activity in the prefrontal cortex using microinjection and optogenetic studies. In the third set of studies, THC vapor and chronic ethanol administration led to deficits in prefrontal cortex reliant behaviors including cognitive flexibility, ethanol seeking, and responses to fear stimuli, and fiber photometry was used to measure effects of these drugs on prefrontal cortex glutamate signaling. Additionally, the pharmaceutical compounds CDPPB and N-acetylcysteine (NAC) were used to pharmacologically reverse the behavioral and signaling impairments that occur as a result of alcohol and cannabis exposure respectively. Taken together, the data presented within this dissertation highlight the effects of alcohol and cannabis on prefrontal cortex-reliant signaling and behavior and use clinically available therapeutics to treat these deficits in a model of PTSD/SUD comorbidity
Elucidating the Contribution of the BAF A12T Mutation to Cellular Mechanisms of Premature Aging
Get PDFThe nuclear envelope is a dynamic structure and organizing hub for cell structure and function. The underlying nuclear lamina is composed of a thick network of intermediate filaments, Lamin A/C and B, and inner nuclear membrane-associated proteins such as Lap2, Emerin and Man1. BAF, a central organizing protein, is a small, dimeric, essential protein that binds to dsDNA, proteins of the inner nuclear membrane and Lamin A. Cells with perturbations of the nuclear lamina display dysmorphic nuclei which have the potential to lead to altered gene expression, increased DNA damage events, and premature cellular senescence. In this study, we address a single amino acid substitution from Alanine 12 to Threonine (A12T) in BAF that gives rise to a nuclear morphology defect. At the clinical level, patients who inherit a homozygous BAF A12T mutation have a rare premature aging syndrome called Nestor Guillermo Progeria Syndrome (NGPS) with symptoms such as osteolysis, adipolysis and craniofacial defects that present at approximately two years of age and progress rapidly, ultimately shortening patient lifespan significantly. Tissues of mesenchymal origin appear to be most severely impacted in this disease, leading to the hypothesis that mesenchymal stem cells are preferentially affected. To address the cellular and organismal pathology of NGPS, we used CRISPR/Cas9 technology to establish BAFA12T/BAFA12T human induced pluripotent stem cells (hiPSCs). A12T BAF iPSCs appeared normal, however when differentiated to induced mesenchymal stem cells (iMSCs), A12T BAF cells exhibited a marked increase in cellular senescence and an elevated cellular stress response. The mechanism of A12T BAF’s contribution of this cell-type specific pathology was not well understood. Our data indicate that A12T BAF ‘s binding to Lamin A is greatly diminished, thereby weakening the Lamin A network of the nuclear lamina and the structural integrity of the nuclear envelope. Mechanosensitive iMSCs are unable to withstand this weakened network and the nuclei appear to rupture, thereby causing cellular stress and ultimately, senescence. Our results indicate that the A12T BAF mutation is necessary but not sufficient to cause premature cellular aging. All cell types expressing BAFA12T/BAFA12T have dysmorphic nuclei, however cells derived from BAFA12T/BAFA12T mice are viable and primary dermal fibroblasts are not senescent, nor do they demonstrate elevated levels of DNA damage. Furthermore, A12T BAF mice do not have shortened lifespans nor do they have defects in mesenchymal derived tissue. These data highlight the nuances of this mutation’s effect both at the cellular and organismal level and elucidates a new role for BAF at the nuclear envelope as a key player in cell mechanosensitivity and the network of the nucleoskeleton and cytoskeleton
Lung Pre-Existing Immunity Predisposes to Poor Posttransplant Outcomes
No full textLung transplant (LTx) patients have the lowest long-term survival rates compared to other solid organ transplants. The complications after LTx such as primary graft dysfunction (PGD) and ultimately chronic lung allograft dysfunction (CLAD) are the main reasons for poor survival. A large number of risk factors such as underlying pulmonary disease diagnosis, age, donor and recipient cigarette smoking history, and the severity of ischemia reperfusion injury (IRI) have all been associated with increased risk of post-LTx complications and poor outcome. Historically, humoral and cellular alloimmune responses have long been the focus of immune-related graft injury. However, in recent years, the contribution of humoral and cellular autoimmune responses to graft injury and transplant outcome has come to light. Lung-specific autoantibodies that recognize non-HLA antigens and autoreactive lymphocytes have been hypothesized to contribute to graft injury and have been correlated with PGD, CLAD, and survival. Mounting evidence suggests that autoimmunity can develop during pulmonary disease progression before LTx and may influence alloreactive and autoreactive immune responses following LTx. The goal of these proposed studies is to demonstrate that pre-existing autoimmunity predisposes to exacerbated graft injury and leads to worse outcomes. We first examined the relationship between autoantibodies and PGD development. We accomplished this goal by characterizing the circulating antibody landscape in a cohort of COPDLTx patients that did or did not develop PGD. We measured total immunoglobulin levels and circulating elastin and collagen autoantibody levels pre- and post-LTx. No significant differences were seen in total, elastin, or collagen IgM, IgG, IgG1, IgG2, IgG3, and IgG4 antibodies between PGD+ and PGD- recipients. Antibody function can be greatly altered by glycosylation changes to the antibody Fc region and recent studies have reported altered IgG glycosylation profiles in COPD patients. We therefore utilized a novel mass spectrometry-based multiplexed N-glycoprotein imaging approach and measured changes in IgG-specific antibody N-glycan structures. COPD-LTx recipients who developed PGD had significantly increased IgG1 N-glycan signatures as compared PGD- recipients. We show that immunoglobulin and autoreactive antibody levels are not significantly different in COPD LTx recipients that develop PGD. However, using a novel IgG glycomic analysis we were able to demonstrate multiple significant increases in IgG1 specific N-glycan signatures that were predictive of PGD development. Taken together, these data represent a potential novel method for identifying COPD patients at risk for PGD development and may provide clues to mechanisms by which antibody N-glycan signatures could contribute to antibody-mediated PGD pathogenesis. In the second aspect of our studies, we examined how recipient CS exposure impacts autoreactive-mediated graft damage. CS exposure has previously been implicated in exacerbating IRI and LTx outcome. Using a chronic CS-exposure mouse model of emphysema and a syngeneic orthotopic left LTx model, we were able to assess the contribution of pre-existing autoimmunity specifically on autoreactive-mediated graft injury. We were able to demonstrate that recipient pre-LTx CS exposure promotes an exacerbated pro-inflammatory immune response thereby inducing severe autoreactive-mediated graft injury, autoantibody production, and IL-17 production. These data suggest that recipient CS-exposure predisposes LTx patients to a more sever autoreactive immune response. Previous work from our lab and others proposed that complement activation is a key component in IRI and autoantibody-mediated graft injury. Therefore, we utilized a novel, bifunctional injury-site natural antibody targeted complement inhibitor, C2scFv-Crry, to assess the contribution of complement in CS-mediated graft damage and the efficacy of acute complement inhibition on reducing autoreactive-mediated graft damage. We found that acute complement inhibition significantly reduced CS-associated inflammation, graft injury, and autoantibody production. These results suggest that complement plays a central role in promoting autoreactive-mediated graft injury and demonstrate the efficacy of a novel complement inhibitor to reduce CS-associated autoreactive-mediated graft damage. Altogether, the data presented here show the deleterious effects of pre-existing autoimmunity in LTx graft injury and suggest that acute complement inhibition may be a promising therapeutic intervention strategy to reduce autoreactive-mediated graft damage
Porphyromonas gingivalis Targets Ectonucleotidase-CD73 and IL-6/STAT3 Pathway for Intracellular Survival in Human Epithelial Cells
No full textPorphyromonas gingivalis (P.g) is an important opportunistic pathogen and etiological agent in chronic periodontitis. As a major colonizer of oral mucosa, P.g uses multiple mechanisms to survive in human gingival epithelial cells (GECs), key initial defense cells of the oral cavity. Cell surface nucleotide-metabolizing enzyme, ectonucleotidase-CD73, has emerged as a central component of the homeostatic-machinery that counterbalances the danger-molecule, ATP-driven proinflammatory response in immune cells. While the importance of CD73 in microbial host fitness and symbiosis is gradually being unraveled, there remains a significant gap in knowledge of CD73 and its role in epithelial cells. Upon invasion of GECs, P.g significantly elevates host CD73 activity/expression concurrent with treatment of AMP. Enhanced induction of active CD73 increases P.g intracellular growth. Inhibition of CD73 markedly increases ROS generation upon eATP treatment in GECs, indicating active CD73 can function as a negative regulator of ROS. Interestingly, CD73 and P.g cross-modulation significantly abrogates pro-inflammatory IL-6 in GECs and exogenous IL-6 treatment to infected GECs suppresses the intracellular bacteria via amplified ROS production. However, CD73 overexpression significantly restores the reduced bacterial levels in GECs. Furthermore, temporal studies revealed CD73 suppresses pro-inflammatory STAT3 activation while P.g significantly decreases IL-6-induced STAT3 activation/phosphorylation in GECs. Functional studies via cellular transfection of GECs with recombinant P.g tyrosine-phosphatases showed significantly increased STAT3-dephosphorylation. When infected by isogenic P.g mutants lacking tyrosine-phosphatases, time-dependent STAT3-dephosphorylation by wildtype P.g is significantly reversed. Confocal microscopy further indicated P.g specifically utilizes the enzymes to deactivate phosphorylated STAT3 localized around the perinuclear space of GECs. Interestingly, isogenic P.g tyrosine-phosphatase mutants induce significantly elevated IL-6 production by GECs compared to wildtype P.g, resulting in compromised long-term intracellular survival. Together, these findings illuminate 1) the local extracellular-purine-metabolism, in which CD73 serves as a core molecular switch, can alter intracellular microbial colonization resistance; 2) host-adaptive pathogens such as P.g can target host ectonucleotidases, as well as pro-inflammatory cytokine IL-6 production via STAT3 activation; and 3) utilize bacterial tyrosine-phosphatases to disarm specific innate defenses for successful intracellular persistence in mucosal epithelia. Thus, we depict novel and specific cell-microbe adaptation mechanisms that can drive oral microbial-dysbiosis and may be targeted therapeutically in mucosa
Selective Targeting of CD38 Cyclase and Hydrolase Activity for Immune Cell Modulation
Get PDFWith the advent of checkpoint inhibitors (CIs), immunotherapies have revolutionized the field of oncology and the ways in which malignancies are treated. Many of the CIs on the market today function by preventing the ligation of immunosuppressive receptors on a subset of lymphocytes known as T cells. As such, T cells that infiltrate the tumor microenvironment (TME) are able to elicit cytotoxic effects, resulting in a rapid reduction in tumor burden. Patients responding to CI therapies experience increased survival rates, however, the number of non-responding patients, or patients who develop resistance, is unacceptably high. One mechanism contributing to the lack of CI response is associated with the metabolic collapse experienced by tumor infiltrating lymphocytes (TIL), rendering immune cells with an exhausted phenotype. As tumor cells rely on a Warburg metabolism, the TME is devoid of nutrients and presents a barren and oftentimes hypoxic environment for TIL. Deprived of the essential factors for cellular processes, TIL are unable to elicit cytotoxic mechanisms regardless of CI treatment. Recent literature has suggested that the ectoenzyme CD38 plays a critical role in regulating not only the harsh metabolic milieu of the TME but of T cell effector function as well. Most notably CD38 regulates cellular energetics by metabolizing the cofactor NAD+, thus removing an essential electron carrier and substrate required for numerous cellular processes. Interestingly, CD38 metabolizes NAD+ via one of two separate reactions, cyclase or hydrolase, thus producing two products. Our central hypothesis is that small molecule inhibitors of CD38 will promote phenotypic reprogramming of T cells, allowing for heightened effector function. Our group has identified CD38 activity-selective small molecule inhibitors that can be used to explore the significance of these two CD38- dependent biochemical reactions on T cell effector function and metabolism. These inhibitors were identified via screening of a curated small molecule library against recombinant CD38. Further investigation of enzyme kinetics revealed both cyclase and hydrolase hit compounds inhibit CD38 through uncompetitive mechanisms. Focusing on reaction specificity, our hit compounds are being optimized to explore uncompetitive inhibition of the CD38:NAD complex. Optimized activity-selective inhibitors will allow more detailed mechanistic studies of the role of CD38 and NAD+ in immunometabolism while increasing IFNg and T cell effector function. Lead compounds may also result in the development of first-in-class immunotherapeutic agents
An Exploratory Multiple Case Study Examining the Strategic Use of Health Policy Referenda by Interest Groups in California Elections
No full textThe citizen referendum is the epitome of democracy, encouraging public participation in policymaking. The transformation of California\u27s initiative landscape over the last century primarily reflects a system dominated by interest groups and political professionals. This qualitative exploratory multiple case study examined interest groups\u27 strategic use of referenda after legislative failure. The analysis aims to surface potential overuse of California\u27s initiative system and uncover a probable cause for referenda reform. The research followed Robert Yin\u27s qualitative case study framework using pattern matching, explanation building, time-series analysis, logic models, and cross-case synthesis techniques. The study also seeks to advance our understanding of the strategic use of referenda to accomplish alternative goals. The results present two examples of an interest group, Services Employees International Union-United Healthcare Workers (SEIU-UHW), introducing referenda after legislative failure, and findings suggest opportunities for potential reform
A Multidimensional Model: Assessing Space Needs in Healthcare Facilities in Response to COVID-19
Get PDFThe assessment of space needs in healthcare facilities has become a growing issue as a result of COVID-19 and its impact on the US healthcare system. Healthcare leaders and facility decision makers have a unique opportunity to evaluate space needs by rightsizing and adapting to reflect current and future pandemic-related events. This paper aims to support the decision-making process by presenting an integrative developmental model of a conceptual framework conceived through a synthesis of the existing literature. Three major dimensions have been identified in the Findings which serve as a foundational guide to addressing space needs: processes, people and the built environment. Processes: highlights operational-enablement activities and the need to redefine tasks across the spectrum of on-site to remote; the potential to reengineer directional flow of people through facilities and how people arrive and wait; infection and prevention controls (IPC) through proximity parameters and cleaning protocols. People: considers patient mix through evaluating degree of patient segmentation and desired utilization levels for healthcare services; worker engagement and how spaces will encourage productivity, collaboration and flexibility; visitor management through enhanced communication efforts and outlining accessibility and tracking needs. Built environment explores elements of space planning including agile design, spatial configuration and touchless functionality; the impact of technology through again, touchless functions, level of infrastructure and changing privacy and security implications; facility components through the intensified role of mechanical systems, signage to support major processes and reworking of furniture, fixtures and equipment (FF&E)
Individual and Community Socioeconomic Predictors of High Risk and Low Birthweight in Maternity Deserts in Mississippi
Get PDFObjective: Performing a retrospective analysis of all live births to Mississippi residents for 2018, using the HCUP SID database; this study examines the relationship between individual and community-level socioeconomic characteristics to high risk and low birth weight outcomes among maternity health care deserts in Mississippi. Methods: Statistical differences between the subjects and the reference group were examined using Chi-square (χ2) tests and Fisher’s exact test. Logistic regression was used to assess mothers\u27 risk in OB desert county for any adverse event after controlling for race and gender. Results: On average, babies in OB desert county had a likelihood of neonatal death 29.26% vs. 22.14% (P=0.0457). Black, female gender, and delivered by Cesarean Section (P=.0001) with a greater likelihood of an adverse event. Conclusion: There are many consequences associated with limited access to care. Besides low birth weight, prematurity, and maternal morbidity, there are increased risks for Cesarean Section. Findings indicate a need for collaborative efforts to improve access to care and improved advocacy for vaginal birth