MEDICA@MUSC (Medical University of South Carolina)
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New Insights into Mechanisms of Collagen Dysfunction: Fibrosis in Mitral Valve Prolapse and Hypermobile Ehlers-Danlos Syndrome
No full textCollagen is the most abundant protein in the human body and is essential for the structure and function of tissues and organs, including the joints, skin and heart. Collagen assembly and homeostasis can be disrupted in various pathological conditions, including cardiovascular diseases and connective tissue diseases. Mitral valve prolapse (MVP) is a common cardiac valve disease affecting 2.5% of the population. Treatment for MVP is limited to surgical intervention. Reports have indicated that myocardial fibrosis is common in MVP, and many cases of surgical repair go on to have ventricular dysfunction. Analyses of biopsies from patients revealed regionalized LV fibrosis, that was also observed in our MVP mouse model (Dzip1S14R/+). Using this model, we tracked the progression of fibrosis and investigated the roles of inflammation, mechanical strain and mechanosensing primary cilia in the development of fibrosis in MVP. The localization of fibrosis in MVP suggests a response in the papillary and inferobasal myocardium to increased tension from the prolapsing valve and raises an important clinical question about the timeline of surgical intervention in MVP. Contrary to fibrosis, the Ehlers-Danlos Syndromes (EDS) are a group of heritable connective tissue disorders that result in tissue laxity due to changes in collagen genes, or key genes for collagen assembly and function. The hypermobile subtype of EDS (hEDS) is the most common type affecting 1 in 500 individuals. hEDS causes joint hypermobility, musculoskeletal manifestations, and is marked by the presence of several comorbid conditions. The genetic basis of hEDS has remained unknown or lacked a significant understanding of the underlying molecular mechanisms. These studies outline the identification of a novel gene for hEDS, generation of a genetically accurate mouse model, and insights into disease mechanisms and the impact on collagen fibrillogenesis. We have also developed a clinical registry of more than 1,000 individuals with hEDS for additional genetic studies and clinical data collection. hEDS lacks a straightforward diagnostic test and has no direct treatment options, which highlights the need for a better understanding of the genetics and biology of hEDS and comorbidities that will guide development of molecular diagnostic tools and therapies
Costs, Treatment Approaches, and Access to Care for Stroke Survivors
Get PDFBarriers to rehabilitation for stroke survivors exist despite evidence supporting improvements in independence and quality of life. Telerehabilitation is emerging as a viable option to improve costs and access. While there is growing evidence for telerehabilitation efficacy, the associated costs are unknown. Additionally, to inspire changes in reimbursement and policy, more evidence of access disparities is needed. The overall objective of this project is to provide depth to the costs, treatment approaches, and access to care for stroke survivors. We completed three separate projects to address our objective. Our time-driven, activity-based costing analysis compared marginal costs in the care delivery process for telerehabilitation versus outpatient rehabilitation. Though there are many benefits to telerehabilitation, improvements in care delivery efficiency are necessary to improve widespread adoption. Next, we examined the first-year costs for stroke survivors and associated acute interventions. Costs increase with stroke severity Finally, we explored stroke survivor access to rehabilitation and stratified by stroke severity and rural/nonrural and socially disadvantaged communities. Stroke survivors have inconsistent access to community-based rehabilitation. Socially disadvantaged and rural communities receive less and different approaches to rehabilitation. These findings support a future study exploring the cost-effectiveness of implementing a telerehabilitation program versus traditional outpatient care
A Serotonin-Mediated Aversive Mechanism Influences Individually Variable Resilience toAcquire and Relapse to Cocaine-Seeking
Get PDFAlthough cocaine and other psychostimulants are highly rewarding, they also produce aversive effects that influence drug-seeking, and that are stronger in some individuals than others for poorly understood reasons. We now find in rats that cocaine depolarizes neurons of the rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons, and a driver of punishment learning. This activation is mediated by post-synaptic serotonin 2C receptors, and is particularly strong in subsets of animals having heightened aversive responses to cocaine, among whom it slows the initial acquisition of cocaine self-administration and reduced cue-induced relapse for cocaine after extinction. These resilience phenotypes are lost upon delivery into RMTg, but not adjacent sites, of 5-HT2CR antagonist or shRNA-mediated knockdown of this receptor. Hence, 5-HT2CRs in RMTg may contribute to innate, and individually variable, protection against cocaine-seeking
A Randomized Study Evaluating Modules Promoting Occupational Therapy Student Communication with Diverse and Underserved Communities
Get PDFA Paraventricular Thalamo-accumbal Circuit Necessary for Behavioral Inhibition is Dysfunctional During Opioid Use and Dependence
Get PDFSuppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behaviors and opioid use disorder (OUD). Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. Here, we investigate the posterior paraventricular thalamus (pPVT) as a behavioral mediator due to its strong connectivity with brain structures important for reward processing, such as the nucleus accumbens (NAc). We and others have found pPVT-NAc neuronal activity is inhibited during reward seeking, but activated when such behaviors would be inappropriate, such as during stress or satiety. However, it is unclear whether pPVT-NAc activity is necessary and sufficient for the suppression reward seeking, and whether opioid use modifies this circuit’s role in motivated behaviors. To investigate this, we first developed a head-restrained operant self-administration paradigm to use in combination with in vivo two-photon calcium imaging. Using this strategy, we identified pPVT-NAc neuronal ensembles that are inhibited upon sucrose self-administration and seeking, but are tonically active when this behavior is suppressed. Subsequent electrophysiological, optogenetic, and chemogenetic experiments revealed that pPVT-NAc neurons innervate accumbal parvalbumin interneurons (PV-INs) through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking. However, acute opioid injections rapidly dysregulated pPVT-NAc ensemble dynamics, weakened pPVT-NAc innervation of downstream neurons, and unleashed reward seeking in a manner that dependent on pPVT µ-opioid receptors. To further investigate this opioid-induced pPVT-NAc plasticity, we next paired chronic heroin self-administration with two-photon calcium imaging, and found that activity in pPVT-NAc neurons is profoundly reduced during heroin use and seeking. Ensuing electrophysiological experiments demonstrated long-lasting adaptations at pPVT-NAc to PV-IN synapses, an effect that functionally disinhibits heroin seeking. Finally, selective restoration of activity at pPVT-NAc to PV-IN synapses abolished cue-, drug-, and stress-triggered relapse. Together, these findings reveal a thalamo-accumbal to PV-IN circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids, though restoration of this circuit following chronic heroin encourages behavioral inhibition and prevents relapse in OUD
A North Carolina Zip Code Specific Analysis of Community and Environmental Social Determinants of Health Variables and Health Outcomes: Mortality and Ambulatory Care Sensitive Conditions
Get PDFThe COVID-19 pandemic elevated public awareness of the impact of health inequities and the role that social determinants of health (SDOH) play in population health outcomes. Despite the utility, healthcare providers remain ill-informed on the community level SDOH data needed to improve health outcomes due to this information not being integrated into the Electronic Health Record (EHR) (Cantor and Thorpe, 2018; Park, 2018). Therefore, the association between community and environmental SDOH variables at the zip code level, using North Carolina hospital admissions data for infant mortality, adult mortality, and ambulatory care sensitive conditions (ACSC) were evaluated through logistic regression to determine the impact of the social vulnerability index (SVI) on health outcomes. Whereby, high SVI (OR=1.13, 95% CI: 1.05-1.23) was associated with 13 percent increased risk of infant mortality, 15 percent increased odds of adult mortality (OR=1.15, 95% CI: 1.06-1.25), and 19 percent increased odds of ACSC diagnosis (OR=1.19, 95% CI: 1.14-1.23), among those admitted to the hospital, when controlling for age, sex, and insurance status
Let’s Get R.E.A.L.: Developing a Shared Definition of Structural Racism is the First Step Towards Health Equity
Get PDFRecent events bought to the forefront the need to address structural racism in the US, specifically within the institution of healthcare. Organizations such as the American Public Health Association (APHA, 2021), American Medical Association (AMA) (O’Reilly, 2020), Center for Disease Control and Prevention (CDC) (Walensky, 2021) recognize racism as a fundamental driver of persistent health disparities in minority populations. Additionally, healthcare accreditation organizations such as National Council on Quality Assurance (NCQA, 2022) launched initiatives that strategically work to achieve health equity. More so, organizations across healthcare are creating roles such as Chief Health Equity Officer or Chief Diversity Officer to spearhead the internal work of addressing racism within healthcare. However, this work is slow-moving and disjointed. There is limited research on structural racism in healthcare, and there is not currently a widely accepted definition of the concept. It is often used interchangeably with closely related concepts of systemic institutional racism. Measurements of structural racism are in their infancy. This project posits that before we can research and measure the impact of structural racism in healthcare, we must have a shared understanding of the concept. This qualitative research project interviewed nine experts in the field of healthcare to develop a shared definition of structural racism, understand how it impacts healthcare, and gather recommendations for future work. Structural racism is a complex phenomenon that seeped into every US institution. Achieving health equity requires decision-makers with adequate resources to increase access to care and educate our healthcare workforce
Characteristics and Function of PVT Synaptic Inputs to NAc Cell Populations Following Opioid Use
Get PDFThe posterior paraventricular thalamus (pPVT) plays a crucial role in reward-seeking behaviors due to its connectivity with brain structures which are important for reward processing, such as the nucleus accumbens shell (NAcSh). Previous studies have shown that PVT neurons form functional synapses with dopamine 1 receptor- (D1) and dopamine 2 receptor-expressing (D2) medium spiny neurons, as well as parvalbumin (PV) interneurons within NAc; however, how pPVT connections to downstream NAc (pPVT-NAc) neurons contribute to reward-seeking is unclear. While we have recently shown that pPVT-NAc can act to inhibit reward-seeking when it is inappropriate, it is unknown how pPVT downstream targets contribute to this behavioral inhibition. Additionally, I have shown that chronic heroin use causes pPVT-NAc to become dysfunctional by no longer suppressing reward-seeking, yet it remains unknown how chronic heroin use changes pPVT innervation of NAc neurons. This project uses patch-clamp electrophysiology in combination with optogenetics to characterize the innervation of pPVT onto downstream NAc neurons. I hypothesized that pPVT innervation of PV interneurons within the NAc is critical for suppression of reward-seeking behavior and that this synaptic input is inhibited by opioid use. Using D2- and PV-cre transgenic mice, I expressed channelrhodopsin in pPVT projection neurons to the NAc, and patched onto fluorescently tagged D2-, D2+, or PV+ neurons. In naïve animals, I evaluated the innervation of pPVT on each cell type and determined whether calcium-permeable AMPA receptors (CP-AMPARs) were present, to identify the mechanism of excitatory input provided by the pPVT. I found that pPVT forms functional synapses with D1s and D2s and that this innervation does not utilize CP-AMPARs under normal circumstances. The posterior PVT also innervates PVs, and induces CP-AMPAR activation, seen through AMPAR rectification index and CP-AMPAR antagonist (IEM-1460) sensitivity. Next, I measured plasticity in pPVT synaptic inputs to each cell type 24 hrs following the last day of either saline or heroin self-administration, or heroin extinction. I found that the pPVT-NAc pathway undergoes synaptic plasticity following opioid use through a reduction of CP-AMPARs, reducing synaptic input between pPVT and NAc. Results show that pPVT neuronal innervation of PVs within the NAc may play a role in the suppression of reward-seeking behaviors in relation to heroin use and heroin extinction and leads to feedforward inhibition of D1 and D2 neurons. Together, these data reveal that pPVT differentially innervates these cell types, and the synaptic input between pPVT and PVs is inhibited by opioid use. Furthermore, these data aid in the identification of precise circuits that are required for the suppression of reward-seeking and reveal how they are modified in opioid use disorder
Interprofessional Staff Perspectives on the Adoption of OR Black Box Technology and Critical Event Simulations to Improve Patient Safety: A Multi-Methods Survey
No full textMedical errors still plague healthcare. Operating Room Black Boxes (ORBB) and ORBB-simulations (ORBBSIM) can improve patient safety, yet a paucity of implementation literature exists. Overcoming implementation barriers is critical. This study’s aim was to obtain rich insights about the adoption of ORBB and ORBBSIM. Interprofessional OR staff were invited to complete two surveys assessing staff’s perceptions using TeamSTEPPS’s validated Teamwork Perceptions Questionnaire (T- TPQ) and open-ended questions. Descriptive statistics were calculated for quantitative variables, and inductive phenomenological content analysis was used for qualitative. Survey 1 captured 71 responses from 334 invited (RR 21%) while survey 2 captured 47 responses from 157 (RR 29.9%). UTSW’s T-TPQ score was 65.2, with Communication (70.4) the highest construct and Leadership (58.0) the lowest. Quality Improvement (QI), Patient Safety, and Objective Case Review were the most common perceived ORBB benefits. Trends suggest a reciprocal benefit of dual ORBB and ORBBSIM adoption. Trends also suggest, dual implementation can promote Psychological Safety, culture, trust, and technology comfort. The need for an implementation plan built on change management principles and a constructive culture were key findings. This blueprint provides a paradigm to help organizations adopt ORBB and ORBBSIM. Outcomes can establish an empirical paradigm for future studies
Benefits to Opening a Comprehensive Outpatient Medical Nutrition Therapy Center
Get PDFMedical Nutrition Therapy (MNT) can reduce costs related to medication, physician utilization, and hospital admissions in addition to improving patient clinical outcomes (Morris et al., 2017). MNT can be a cost-effective way to manage co-morbidities and prevent or delay the progression of chronic disease(s) (Morris et al., 2017). While registered dietitians have always played a vital role in the health of their patients, reimbursement for medical nutrition therapy services is limited. During a patient’s hospital admission, dietitians prescribe nutrition interventions and implement a plan of care. After a patient is discharged, they often are not followed by a dietitian. Current healthcare systems lack the ability for patients to continue the reinforcement education needed to sustain nutritional improvements. The development of a comprehensive outpatient MNT center can provide patients with access to a dietitian post-discharge. Literature review consensus is favorable towards post-discharge nutrition interventions being effective at reducing unplanned readmissions, decreasing mortality rates and improving patient quality of life. Increasing patient access to MNT can not only yield profits from services rendered but, downstream the healthcare system can see positive impacts through the reduction of unplanned readmissions, costs of hospital services rendered, length of stay and Physician utilization (Briggs Early & Stanley, 2018; Toulson Davisson Correia et al., 2021)