MEDICA@MUSC (Medical University of South Carolina)
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Southeastern Rural Provider Participation and Performance Trends in Merit-Based Incentive Payment System (MIPS) 2018 Performance Year Results
Get PDFThe purpose of this study is to identify trends in participation, clinician performance, program scores, and payment adjustments received for rural and urban providers during the MIPS 2018 Performance Year. Five contiguous states in the southeastern US were selected for this study due to their significant rural population: Alabama, Georgia, South Carolina, North Carolina, and Tennessee. Descriptive statistics were used to summarize participation and performance data for rural and urban providers in the Southeastern US, as reported in the 2018 QPP Experience Report Public Use File and made publically available by CMS. The study findings extend prior evidence that has shown that value-based payment programs disproportionately penalize rural healthcare providers when compared to their urban counterparts (Johnston, 2020; Khuller, 2020; Navathe, 2019). It will be vital for CMS to identify and appropriately address barriers to participation and performance faced by rural healthcare providers to ensure the success of the MIPS program
Assessment of Sex Differences in Basic Renal Mitochondrial Bioenergetics
Get PDFKidney diseases are closely linked with mitochondrial dysfunction, oxidative stress, and inflammation. Furthermore, it is established that sex plays an important role in the onset, development and severity of renal diseases. Recently, it has been revealed that sex hormones are implicated in mitochondrial bioenergetics. Despite information accumulated regarding the role of mitochondria in renal disease states, little is known about the bioenergetics of renal mitochondria in normal physiology, and no studies looked at sex differences pre-disease onset. We hypothesized that there are sex-related differences in renal mitochondrial bioenergetics in young, healthy rats. To test this hypothesis, we utilized renal tissue and live mitochondria isolated from healthy Sprague-Dawley rats 10-11 weeks of age. Assessment of oxygen consumption rates from male and female renal mitochondria revealed that female mitochondria have lower respiration vs male mitochondria in a pyruvate/malate containing buffer which stimulates ETC Complex I. Sex differences were de-accentuated in a succinate-based buffer which stimulates ETC Complex II. Next, female mitochondria displayed similar membrane potential in the cortex, but higher membrane potential in the medulla vs males. Analysis of renal cortical electron micrographs revealed lower density and number of female mitochondria in renal proximal tubules, as compared to males; however, female mitochondria were larger in size. Furthermore, female renal mitochondria displayed higher ROS levels and lower antioxidant capacity, while the activity of superoxide dismutase (SOD) was significantly higher in female renal cortex vs in male cortex. The link between mitochondrial ROS production and calcium handling prompted the quantification of mitochondrial calcium uptake and mitochondrial permeability transition pore (mPTP) opening. We observed that although male and female renal mitochondria have similar amounts of calcium uptake, the mPTP opens earlier in female mitochondria. Taken together, these data suggest that female renal mitochondria are potentially more sensitive to oxidative stress, which allows for faster mPTP opening and elimination of dysfunctional mitochondria. Observed sex-related discrepancies in renal mitochondrial function prior to the onset of disease could be contributing to renoprotection generally observed in females pre-menopaus
The Role of Complement in Traumatic Brain Injury
Get PDFActivation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). However, the complement system is complex and comprises more than 50 components, many of which remain to be investigated in the normal and injured brain. In order to start delineating the various roles of complement components, we here used high-throughput NanoString and mass cytometric analyses to comprehensively characterize the complement transcriptome and the immune cellular expression of complement receptors in the brain after TBI, and in relation to other neuroinflammatory pathways. We also assessed the effect of complement inhibition with CR2-Crry on the neuroinflammatory transcriptome and immune cellular profile of TBI brains. The analyses were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury (and 1- and 2 years post injury for complement transcriptome). The transcriptomic analysis showed dysregulation of 40+ complement genes within 4 weeks after TBI that was partially sustained through 2 years post injury. The mass cytometric analysis showed increased abundance of 13 immune cell types, most of which had increased expression of C5aR1 acutely after TBI and of CD11c at day 28 after TBI. This analysis also showed chronic emergence of a distinct CXCR1+CD11c+ microglial subpopulation. Moreover, complement inhibition was neuroprotective and was associated with significant reversal of neuroinflammatory transcriptomic changes, including markers of neurotoxic astrogliosis and neuronal and synaptic loss, and with decreased immune cell infiltration after TBI. Reasoning that C5aR1 promoted immune cell infiltration, we also showed that targeted C5aR1 inhibition significantly decreased immune cell numbers but failed to alter behavioral outcomes. Overall, our findings demonstrate that complement gene dysregulation occurs extensively after severe open-head TBI and persists chronically, hence expanding the set of potential complement therapeutic targets (e.g., CD11c) and extending their window of treatment. Moreover, the resistance of some immune and synaptic genes to CR2-Crry treatment suggests adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. Future therapeutic studies will focus on developing therapeutic tools for specific targeting of the dysregulated complement effectors and receptors and for assessing the benefits of non-complement adjuvant therapy
Molecular and Developmental Etiologies Underlying Mitral Valve Prolapse: Novel Mechanisms of PDGFRα and DCHS1
No full textCardiac valve diseases are serious heart conditions and present a significant burden on human health by affecting 2.5% of the population. Mitral Valve Prolapse (MVP) is one of the most common forms of valve disease and progression of it results in complications such as blood regurgitation, arrhythmia, and sudden cardiac death. Nonsurgical treatments for MVP do not exist and therapeutic development has been hindered by incomplete understanding of disease etiology. Recent studies from our lab and others have emphasized the inheritance and developmental basis of MVP through the identification of several causal genes. Familial and GWAS studies in humans potentiated the discovery of candidates including primary cilia gene, DZIP1 and cytoskeleton associated genes such as Dachsous Cadherin Related-1, DCHS1. With genetically accurate mouse models, we have illustrated their function in valve disease and have begun to define mechanisms that explain disease inception during critical developmental timepoints. Studies performed through this dissertation were aimed to advance our understanding of molecular mechanisms that are associated with primary cilia and mediated by DCHS1. First, the expression and function of platelet-derived growth factor (PDGF) signaling through cilia specific receptor, PDGFRα, was investigated. Immunofluorescence staining revealed a unique expression profile of PDGFRα in the valve endothelium and motivated the conditional ablation Pdgfra in a subset of endothelial cells in mice. Our data suggest that PDGFRα contributes to valvulogenesis by stabilizing endothelial-mesenchymal transition, independently of primary cilia. Additional studies investigated DCHS1-based mechanisms and through proteomic and biochemical approaches, identified novel protein interactors including cytoplasmic proteins, Lix-1 Like (LIX1L) and Septin-9 (SEPT9). Perturbation of the DCHS1-LIX1L-SEPT9 protein complex in vivo and in vitro characterized the interaction with and regulation of the actin cytoskeleton during valvulogenesis. Together, these findings elucidate mechano-biochemical cues of MVP disease inception and thus, highlight the complex and critical homeostasis of developing valve tissues
Waring Library Society Newsletter, Fall 2021
Get PDFThe Fall edition includes an end of the year message from WLS President Dr. James H. Tolley and an update on the work of the Bicentennial Steering Committee from the Waring’s Curator Dr. Brian Fors. Also, in this issue, Ms. Tabitha Samuel discusses the recent acquisition of the photography of MUSC MICU Nurse Alan Hawes to the MUSC COVID-19 Archive and Ms. Brooke Fox announces plans for the Waring’s 2022 HIV/AIDS Symposium, marking the 40th anniversary of the diagnosis of the first AIDS patient in South Carolina. Finally, Ms. Anna Schuldt announces the remaining events for the 2022 Waring Library Society Lecture Series and the Student History Club, and provides insight into her work with photographing the inventory of the College of Pharmacy’s Alumni Museum.https://medica-musc.researchcommons.org/wls-newsletters/1004/thumbnail.jp
Personalized Stroke Rehabilitation
Get PDFStroke continues to be a leading cause of disability. Many individuals who suffer a stroke will receive specialized rehabilitation designed to maximize recovery and restore independence with daily activities. Yet, recovery is still highly variable with heterogeneity in treatment response that is still poorly understood. In recent years, the growing burden of stroke has pushed for moving away from a “one size fits all” approach with the concept of precision or personalized rehabilitation to generate evidence for clinicians to provide the right care, to the right patient, at the right time. The collection of research in this dissertation addresses key areas of personalized rehabilitation related to standardized outcome measurement, identification of biomarkers, and individualized response to treatment parameters in three parts. Part I illustrates how principals of item response theory can be used to inform a personalized measurement approach through clinical applications of Rasch analysis. Part II demonstrates how muscle coordination is linked with biomechanical variables of walking performance that can be used as potential biomarkers of recovery. Lastly, Part III shows how interindividual differences in treatment response could inform individualized prescription for transcranial direct stimulation for recovery of walking post-stroke as an example of how to approach personalized rehabilitation
Obesity and the Hippocampus: How Diet-Induced Insulin Resistance Contributes to Memory Impairment
Get PDFOver 93 million Americans are obese, a condition which also increases the risk for developing neurocognitive disorders such as Alzheimer’s disease. Insulin is critically important for maintaining homeostasis in the central nervous system, but in order to play this role it has to be transported in from the periphery. Interestingly, peripheral hyperinsulinemia is linked to reduced central nervous system insulin. The overarching hypothesis of this dissertation is that chronic hyperinsulinemia reduces hippocampal insulin transport, thereby dysregulating insulin receptor signaling proteins and leading to memory impairment. In order to test this hypothesis, we assessed the high-fat diet mouse model in two hippocampal-dependent memory tasks. Hippocampi isolated from high-fat diet fed mice were probed for insulin levels and signs of insulin resistance. Hippocampal microvessels were also isolated and probed for dysfunction of the insulin receptor. These latter studies were followed up through in vitro mechanistic analysis of the insulin receptor during experimental hyperinsulinemia. Our findings indicate that high-fat diet feeding leads to hippocampal-dependent memory impairment and dysfunctional changes in the hippocampal insulin signaling cascade. Our hyperinsulinemic brain endothelial cell studies suggest that impaired insulin receptor functioning at this barrier underlies impaired receptor internalization, a key step in the transcytosis mechanism. Interestingly, inhibition of a major negative modulator of the insulin receptor signaling system in brain endothelial cells improved receptor functioning, indicating this as a potential therapeutic target going forward. In conclusion, the consequences of peripheral hyperinsulinemia may be an important mechanism connecting obesity with memory impairment and Alzheimer’s disease, and reversing impairment of the brain microvascular insulin receptor may be a potentially novel therapeutic approach
Age-Related Translational and Post-translational Regulation of the Pro-Osteogenic Chemokine CXCL12 in the Bone Marrow Microenvironment
No full textOsteoporosis is a disease that leads to high morbidity and mortality. It represents a reduced bone formation to bone resorption ratio. With most current treatments for osteoporosis targeting bone resorption, there is a need for new interventions that can increase osteogenesis. CXCL12 is a pro-osteogenic chemokine that can recruit bone marrow mesenchymal stem cells (BMSCs) to injury sites and increase their proliferation and osteogenic differentiation. This work aims to study mechanisms for translational and post-translational regulation of CXCL12 via the aryl hydrocarbon receptor (AhR), miRNAs, and the enzyme dipeptidyl peptidase 4 (DPP4). We utilized a wild type and mutated 3’-UTR luciferase assay to demonstrate direct regulation of CXCL12 by miR-29b-1-5p. We also showed that this inhibition of CXCL12 translation is downstream of AhR activation by kynurenine (KYN), a tryptophan metabolite that accumulates in bone marrow with aging. Using ELISA, we showed that total CXCL12 levels declined in the murine bone marrow. We also showed that cell culture media from aged BMSCs contained higher levels of KYN compared to BMSCs isolated from younger mice. Treating BMSCs with KYN lead to inhibition of osteogenic differentiation and decreased CXCL12 levels in cell culture media, while adding a miR-29b-1-5p inhibitor blocked KYN’s effect on CXCL12 levels. Post-translationally, CXCL12 is cleaved by DPP4 within minutes of its release. Using proteomics and phospho-proteomics approaches, we demonstrated that DPP4-cleaved CXCL12 is a functional antagonist to “intact” CXCL12. We showed that cleaved CXCL12 inhibits osteogenesis and osteoclastogenesis, and induces senescence in BMSCs. We also utilized BRET assays to show that cleaved CXCL12 can still signal via the ACKR3 β-arrestin pathway, but cannot activate G-protein signaling downstream of CXCR4 activation. Interestingly, using immunoprecipitation mass spectrometry, we found that while cleaved CXCL12 makes up almost 54% of total CXCL12 in human plasma, it made up almost 78% of total CXCL12 in bone marrow interstitial fluid. In conclusion, we demonstrated how CXCL12 is important for BMSCs osteogenic differentiation and explored two mechanisms that inhibit pro-osteogenic functions of CXCL12 with age; KYN-driven epigenetic inhibition and a DPP4 generated CXCL12 metabolite with cryptic CXCR4 and ACKR3 receptor based signaling. These two pathways could provide two potential clinical targets for prevention and/or treatment of osteoporosis
Outcomes and Factors Influencing Relapse and Recidivism in a Rural Substance Abuse Treatment Program Collaborative
Get PDFIntensive Outpatient programs for mental health and substance abuse have been shown to be an effective option for individuals with substance use disorders. Despite this, there are few options for individuals seeking this form of treatment in rural communities. It is often believed that high quality programs that address the core systemic social issues that underlie substance use disorders are too expensive for small rural healthcare organizations to utilize. This model shows one treatment program that is able to address multiple social safety net issues and produce positive outcomes in a rural setting by leveraging community partnerships, as well as discussing future policy implications
Job-Related Factors Affecting Retention of Millennial RT During COVID-19
Get PDFBackground: The new generation of respiratory therapists (RTs) entering healthcare today pose a new challenge for leadership. Leaders are faced with the challenge of balancing the needs of the Generation-Y (millennial) workforce, along with the challenges of caring for an aging patient population (Piper, 2008). The safety and quality of services for the next generation of patients depends upon finding reasonable and viable solutions to retain the next generation workforce. Early experience during the coronavirus disease (COVID-19) pandemic and predictive modeling indicate that the need for RTs will exceed the current supply (Hester, Cartwright & Hawkins, 2020). Objective: To identify job-related factors affecting retention of millennial RTs during COVID- 19 crisis. Methods: An exploratory pilot survey utilizing structured questions to identify respondent personal characteristics which have been linked to satisfaction and turnover in the literature. Open-ended narrative responses to elicit responses on poorly understood factors that are specific to Respiratory Therapy millennial job turnover are utilized. Univariate statistics are utilized to describe differences between categories of responses. Narrative responses were analyzed using qualitative assessments to identify themes. The study is classified as a Quality Improvement (QPI) study by the Medical University of South Carolina Investigative Review Board. Results: A total of 56 surveys were mailed out utilizing REDCap data management survey platform. Of the 56 administered, 23 surveys were returned of which 3 surveys excluded that did not identify as a millennial RT. Conclusions: It was shown that during the COVID-19 Pandemic, social media was the fastest and most convenient way to alert applicants about a job. RT workload increased during the COVID-19 Pandemic due to the increase in Respiratory Illnesses associated with the virus. Modifiable job-related factors such as an increase in pay, time off, and an organization’s overall capacity to respond to the pandemic are major factors for overall job satisfaction and a RTs intent to remain with their organization. These responses may form a relevant foundation for the development and validation of a national RT job satisfaction survey for use during the COVID- 19 pandemic