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Utilization of Model-Based Approaches to Maximize Efficacy of Antibiotics for the Treatment of Mycobacterium abscessus Pulmonary Infection
No full textPrevalence and incidence of Mycobacterium abscessus (Mab) pulmonary infections have increased and been recognized as a major cause of mortality, particularly in certain patient populations, such as cystic fibrosis (CF) patients. Due to the intrinsic multidrug resistance mechanisms and biofilm (BF) formation properties of Mab, effective treatment remains challenging, as these factors significantly diminish the antibacterial activity of drugs. Current treatment guidelines recommend prolonged therapy, generally more than 12 months with a multidrug combination of at least four agents. However, no optimal combination, regimen, or treatment duration has been universally established for Mab pulmonary infections (Mab-PI). Therefore, the selective and strategic use of the most potent agents available against Mab is essential. Although simple and standardized antibacterial susceptibility testing methods are broadly applicable and clinically interpretable, the methods inherently fail to account for drug-specific properties, or the pathophysiological conditions present in actual infections. These limitations raise the risk of inaccurate clinical translation when in vitro results are interpreted without such context. Therefore, there is an urgent need to develop evaluation methodologies that integrate both drug characteristics and pathogen-specific properties to enable successful clinical treatment. Tigecycline (TGC), one of the preferred drugs listed in treatment guidelines for Mab-PI, has demonstrated excellent therapeutic efficacy, including in CF patients. However, its clinical utility is limited by its narrow therapeutic window and chemical instability in aqueous environments. Consequently, identifying clinical strategies to optimize both efficacy and safety, or to determine suitable combination partners for multidrug regimens, remains highly constrained. To address these limitations, we utilized TGC as a model compound and proposed a model-based methodological framework that can overcome the limitations of conventional antibacterial evaluation methods, enabling a quantitative assessment of an intrinsic antibacterial activity of drugs against Mab by incorporating key factors that influence experimental outcomes. Furthermore, a Hollow-Fiber Infection Model (HFIM) was employed to experimentally evaluate drug efficacy under more biologically relevant conditions that account for BF formation and the resulting time-dependent reduction in drug susceptibility. Model-based interpretation of HFIM-based dynamic time-kill curve experiments provided a strong rationale for drug inhalation strategies aimed at maximizing local drug concentrations at the site of infection. The clear therapeutic limitations of current treatments for Mab-PI underscore the importance of developing new agents or novel combination regimens. Since Mab is an opportunistic pathogen, the host immune status plays a critical role in infection, progression and treatment outcomes. Accordingly, drug efficacy evaluation requires immune-deficient models, but the development of a suitable model for this purpose has been challenging. In this regard, a physiologically based infection kinetic model was devised to quantitatively evaluate the contribution of individual immune cell types to bacterial clearance following Mab exposure in immune-deficient mouse models. This approach identified NSG mice, combined with intratracheal inoculation, as an ideal in vivo animal model for assessing antibacterial efficacy of drugs against Mab-PI. Lastly, a human physiologically based pharmacokinetic (PBPK) model for inhaled TGC was developed to predict exposure in the systemic circulation and major organs associated with toxicity. Based on clinically and preclinically established adverse event thresholds, 125 mg Q3D was identified as optimized dosing strategy capable of maximizing bacterial killing efficacy while minimizing toxicity. The model-based approaches introduced here offer novel insights into the use of TGC and are expected to inform treatment strategies for Mab-PI, with potential for broad application to other potent antibiotics, including those recommended in treatment guidelines, and the identification of optimal combination regimens
The Impact of Intersectional Stigma on Shared Decision- Making and Antiretroviral Therapy Adherence for Young Latinos in the Deep South: Perspectives from HIV Clinicians
No full textIntroduction. HIV treatment and prevention have seen significant advancements over the past four decades, with antiretroviral therapy (ART) enabling people living with HIV to achieve viral suppression and live long, healthy lives. However, disparities persist among Hispanic/Latino populations in the southern United States. In the Deep South region of the U.S., young Latino men face potential intersecting stigmas related to HIV status, sexual orientation, ethnicity, and immigration status. Stigma is an established barrier to healthcare access and optimal health outcomes. This study explored how HIV clinicians in the Deep South perceive the impact of intersectional stigma on shared decision-making (SDM) and antiretroviral therapy adherence for young Latino men living with HIV. Methods. This qualitative study employed semi-structured, virtual interviews with 11 HIV clinicians practicing in the Deep South. Data were analyzed using the Framework Method. Results. Clinicians identified cultural norms, religious beliefs, language barriers, and immigration-related fears as major contributors to intersectional stigma, which often led to non-disclosure of HIV status and reluctance to engage in care. They emphasized that building trust is essential but challenging, as patients’ guardedness is shaped by anticipated stigma. To foster stronger relationships, clinicians reported using neutral language and patient-centered approaches; however, shared decision-making was inconsistently practiced. Structural barriers, including bureaucratic processes and transportation challenges, further constrained consistent access to medication. Resources such as bilingual staff, on-site pharmacies, medication samples, and support from case managers or social workers were considered vital for improving ART adherence. Although clinicians demonstrated empathy and awareness of their patients’ intersectional challenges, they acknowledged gaps in consistently translating this understanding into practice. Conclusions. HIV clinicians in the Deep South recognize the influence of intersectional stigma on young Latino men living with HIV. While many clinicians employ patient- centered strategies to mitigate the impact of stigma on SDM and ART adherence, systemic barriers persist. Addressing these challenges requires both clinic-level interventions and broader policy-level reforms to reduce stigma. This study underscores the need for tailored interventions that bridge clinicians and systems to actionable practices to improve health outcomes for this population
Evaluating the Efficacy of the Implementation of a Food Insecurity Screening Tool in Identifying Risk Amongst NICU Families
Full text linkPurpose/Background
Infants admitted to the Neonatal Intensive Care Unit (NICU) are critically ill and at risk of increased infections, developmental delays, and higher readmission rates after discharging due to complex health needs when compared to healthy term newborns. Nutrition has been widely recognized as an important predictor of readmission and developmental delay. However, current practice often does not provide any screening for food insecurity (FI) in NICU families, which assumes security and displays a gap in care surrounding discharge planning. This quality improvement project implements the use of an FI screening tool for NICU families to help practitioners identify FI as a modifiable risk factor for hospital readmission and adverse outcomes.
Methods
The use of an FI screening tool was implemented over a 2-month period from October 1, 2024 to November 30, 2024 in the NICU at a large level III community hospital in Nashville, TN. All parents and legal caregivers (age 18 or older) of NICU infants were requested to complete a three-question food insecurity screening tool and return it anonymously to a designated submission box at the unit’s check-in desk. In addition, a second box of local food resources was placed in the same location to facilitate ease of access for families desiring resource provision. Bedside nurses were asked to inform parents and legal caregivers of the purpose of the food insecurity tool and the availability of resources.
Results
A total of 32 NICU families returned the anonymous FI screening tool, which included basic demographic data collection. 25% of NICU families identified as food insecure.
Implications for Nursing Practice
This quality improvement project demonstrates a significant proportion of NICU infants may be discharged to food insecure homes. Current practice often neglects to conduct screening and food resource provision. However, routine FI screening practices for NICU families would help identify infants at risk for nutrition-related adverse health outcomes
Social Determinants of Health Screening – Evaluating Its Influence on Glycated Hemoglobin Levels in the Pediatric Population: A Scoping Review
Full text linkPurpose/Background
Social determinants of health (SDOH) have a significant impact on health outcomes. Pediatric patients with type one diabetes mellitus (T1DM) with adverse SDOH have inferior glycemic control, higher healthcare utilization, and increased risks of complications. SDOH screenings are not standard practice in pediatric T1DM care despite literature demonstrating that screening can improve outcomes. This scoping review aims to summarize existing evidence surrounding SDOH screenings and their impact on pediatric T1DM outcomes.
Methods
A scoping literature review was conducted from August 2022 to November 2024 via CINAHL, Cochrane, EBSCO, Elsevier, and PubMed. Inclusion criteria included peer-reviewed articles, English language, publication within fifteen years, and free, full-text availability. The Ohio State University rapid critical appraisal tool was used to assess validity and reliability. Twelve articles were selected based on their relevance and quality. An outcomes table was utilized to identify common effects and recommendations among these articles.
Results
This review determined that SDOH influence pediatric T1DM outcomes and that SDOH screenings can improve outcomes, including glycated hemoglobin levels. The literature recommends various screening tools and implementation strategies, but no standard tool or strategy has been established. We were unable to conduct a study evaluating real-time T1DM patient biomarkers or outcomes following SDOH screening without student access to our local facility’s electronic charting system. However, our literature review was able to outline SDOH screening’s positive influence on outcomes in this population.
Implications for Nursing Practice
Our review demonstrates that the literature supports universal implementation of SDOH screenings. Their incorporation can improve glycemic control, healthcare utilization, and caregiver support. This scoping review highlights a need for further research to establish a standard SDOH screening tool and evaluate its effect on pediatric T1DM outcomes
Sugammadex for Reversal of Neuromuscular Blocking Agents versus Neostigmine - Safety Comparison
Full text linkPurpose/Background
Sugammadex and neostigmine are two common drugs used to reverse neuromuscular blockade in anesthesia, but they differ in mechanism of action, side effects, and cost.
Sugammadex provides rapid reversal, has fewer side effects, and has a lower risk of bradycardia than neostigmine. This scoping review examines the frequency of bradycardia in adult surgical patients receiving sugammadex versus neostigmine.
Methods
A scoping review was completed of peer-reviewed articles comparing the incidence of bradycardia in adult surgical patients after the administration of sugammadex and neostigmine for neuromuscular blockade reversal. Findings indicate that sugammadex resulted in fewer adverse events, including bradycardia, than neostigmine. Articles were critically appraised for quality and relevance, and results were synthesized to evaluate clinical outcomes and complications.
Results
The scoping review included ten articles assessing the safety profiles of sugammadex and neostigmine for neuromuscular blockade reversal, focusing on the incidence of bradycardia. High-quality evidence from randomized controlled trials and meta-analyses consistently demonstrated that sugammadex was associated with a lower incidence of bradycardia and adverse effects than neostigmine. Sugammadex showed particularly favorable outcomes in patients at high cardiovascular risk, such as those undergoing cardiac surgery. While some Level IV studies reported mixed results, including occasional increases in bradycardia with sugammadex, the majority of evidence highlighted its superior safety and efficacy. These findings support the administration of sugammadex as a safer alternative to neostigmine, though patient-specific considerations remain essential.
Implications for Nursing Practice
The findings of this scoping review suggest that using sugammadex for neuromuscular blockade reversal reduces the incidence of bradycardia compared to neostigmine, enhancing patient safety. Effective implementation of sugammadex in clinical practice requires standardized protocols and ongoing evaluation to ensure optimal patient outcomes. Further studies are necessary to explore long-term safety, cost-effectiveness, and broader clinical applications of sugammadex
Protein Kinase D1 in Myeloid Cells Promotes Disease Progression and Severity in S. rectivirgula Induced Hypersensitivity Pneumonitis
No full textIntroduction: Hypersensitivity pneumonitis (HP) is an inflammation driven interstitial lung disease characterized by inflammation of the interstitium, bronchioles, and alveoli of the lung that leads to granuloma formation. Myeloid lineage immune cells play a critical role in the early and late stages of the disease, and this activity is mediated through toll-like receptors (TLRs) expressed by these cells. Protein kinase D1 (PKD1) has previously been identified as a critical signaling molecule in the TLR signaling pathways of all TLR family members except for TLR3. Our previous research found that activation of protein kinase D1 (PKD1) in the lungs following exposures to Saccharopolyspora rectivirgula, a common antigen trigger for HP, contributes to acute pulmonary inflammation, IL-17A expression in the lungs, and development of HP. The purpose of our research is to elucidate the impact of PKD1 activation in myeloid cells on the onset, progression, and severity of S. rectivirgula induced HP. The method Methods: WT mice and mice in which PKD1 is knocked out in myeloid cells (the PKD1mKO group) were exposed intranasally to S. rectivirgula over short (2 hr, 6 hr, 24 hr) or extended periods of time (3-15 weeks). Disease onset and severity was analyzed by measuring mRNA expression and protein levels of inflammatory cytokines and chemokines in the lung using quantitative real-time PCR and enzyme-linked immunosorbent assays respectively. Flow cytometry was used to assess populations of different immune cells as well as surface marker expression. Masson’s Trichrome staining and hematoxylin and eosin staining was performed on tissue sections from the lung to assess alveolitis, granuloma formation, and fibrosis. Results: Compared to PKD1-sufficient WT controls, PKD1mKO animals displayed a more suppressed immune response, with lower levels of cytokines such as IL-6, IL-17A, TNFα, and IFNγ. Chemokine levels of CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10 were also lowered. Neutrophilic alveolitis was decreased, as was granuloma formation and fibrosis over longer exposure periods. Minor alterations in B cell populations and levels of immunoglobulin subtypes were altered, with PKD1mKO lungs containing more immature B cells and less plasma cells than the WT counterparts, and immunoglobulin M being more expressed in the PKD1mKO group. In the PKD1mKO group, MHC-II expression was reduced on myeloid cells, which corresponded T cell activation marker CD69 also being reduced in this group. Finally, CXCR3+CCR6+ nonconventional Th1 cells in the lungs were significantly reduced in PKD1mKO mice after repeated S. rectivirgula exposures. Discussion: Our results demonstrate that PKD1 in myeloid-lineage cells plays an essential role in the onset and progression of HP caused by repeated exposure to S. rectivirgula. The mechanisms by which this occurs include: contributing to Th1/Th17 polarizing proinflammatory responses, alveolitis, the accumulation of pathogenic nonconventional Th1 cells in the lungs, impacting B cell maturation and immunoglobulin class switching, and granuloma formation and fibrosis in the airways
The Impact of Social Determinants of Health on Cardiometabolic Outcomes and Medication Adherence Among Vulnerable Populations in West Tennessee
No full textBackground: Social determinants of health (SDoH) are non-medical risk factors that play a major role in shaping outcomes and can contribute to health disparities. It is critical to understand the effects of multiple domains of SDoH and their associations with cardiometabolic disease outcomes, especially among vulnerable populations. Objectives: This dissertation includes three research studies with the following aims: (1) to investigate the association of multiple domains of individual-level SDoH risk factors with uncontrolled HbA1c, blood pressure, and lipid levels in West Tennessee, (2) to identify and map census tract Hot Spots and Cold Spots of uncontrolled diabetes, hypertension, and hyperlipidemia in Shelby County, TN, and characterize these Hot and Cold spots based on neighborhood-level SDoH risk factors at the census tract level, and (3) to examine the mediating effect of nonadherence to hypoglycemic medications on the association between SDoH and uncontrolled diabetes among Medicaid patients in West Tennessee. Methods: The first study was retrospective and cross-sectional. We conducted unadjusted logistic regression analysis to examine the association between each SDoH domain and uncontrolled HbA1c, blood pressure, and lipid levels. Next, multivariable logistic regression models were used to examine the association between the cumulative PRAPARE tool score, categorized into risk tiers, and uncontrolled HbA1c, blood pressure, and lipid levels. The second study used a combination of spatial epidemiology and statistical analysis to identify and characterize census tract-level Hot and Cold spots of uncontrolled cardiometabolic conditions. Patient residence addresses were geocoded to census tracts using Esri ArcGIS Pro. Hot Spot analysis was conducted using the Getis-Ord Gi* statistic to identify significant census-level clusters for uncontrolled cardiometabolic conditions. Logistic regression models were then fit to examine the association between census-level SDoH risk factors and the likelihood of a census tract being categorized as a Hot Spot. The third study followed a retrospective cohort design and used causal mediation analysis to examine whether nonadherence to hypoglycemic medications mediates the association between SDoH and uncontrolled HbA1c. Results:The first study included three exclusive subsamples of 3,534 patients with diabetes and complete A1c measurements, 10,418 patients with hypertension and recorded blood pressure measurements, and 2,205 patients with hyperlipidemia and lipid level assessments. Across the three cardiometabolic conditions, SDoH risk factors, including Black race, other race, Hispanic ethnicity, lack of housing, lack of insurance, lack of access to basic needs, stress, and transportation issues, were strongly associated with uncontrolled HbA1c, blood pressure, and lipid levels in univariate models. Our adjusted models showed a dose-response relationship between cumulative SDoH risk categories and uncontrolled diabetes. Patients in the moderate-risk (AOR = 1.13, 95% CI = 0.94–1.36), high-risk (AOR = 1.37,95% CI = 1.12–1.69), and very high-risk SDoH categories (AOR = 1.53, 95% CI =1.13–2.06) were more likely to have uncontrolled diabetes (HbA1c\u3e8%) compared to those in the lowest-risk category. In the second study, we identified 40 significant Hot Spot clusters of uncontrolled diabetes, 67 significant Hot Spot clusters of uncontrolled hypertension, and 22 significant Hot Spot clusters of uncontrolled lipid levels. Results from the multivariable logistic regression analysis showed that census tracts with higher proportions of African American and uninsured residents were more likely to be Hot Spots for uncontrolled diabetes and hypertension. Finally, in the third study, our results revealed that medication nonadherence was a significant mediator of the association between SDoH risk factors and uncontrolled HbA1c. Medication nonadherence mediated approximately 27% of the association between SDoH risk factors and poor glycemic control. Conclusions: The study findings show that patient-reported SDoH risk factors were strongly associated with uncontrolled cardiometabolic outcomes, especially with uncontrolled diabetes. In addition, our study identified distinct geographic clustering of uncontrolled cardiometabolic conditions across Shelby County, with Hot Spots associated with adverse SDoH. Furthermore, adverse health behaviors, such as medication nonadherence, significantly mediated the association between SDoH risk factors and uncontrolled diabetes, suggesting that medication nonadherence is one of the mechanisms by which SDoH affects uncontrolled diabetes
Social Determinants of Health Screening in the Pediatric Population: Evaluating the Effectiveness of Staff Education
Full text linkSocial Determinants of Health (SDOH) are conditions that influence health outcomes. SDOHs are screened and addressed in many clinics and hospitals to reduce patients\u27 social needs. Research indicates how unaddressed SDOH can negatively impact chronic illness, along with the daily life of pediatric patients. SDOH\u27s role in pediatric patients includes food security, housing stability, access to healthcare, caregiver education, and parental mental health. Previous research has addressed these factors; however, the lack of staff education prevents effective compliance and follow-up on SDOH screening. Challenges remain in implementing and integrating SDOH into routine well-child visits. This scoping review will evaluate and assess the effectiveness of staff education on SDOH and its effect on the compliance of SDOH screenings for subsequent well-child visits
The Impact of Hyperglycemia on Post-Reperfusion Outcomes in Patients with Hyperacute Ischemic Stroke
Full text linkStroke is a major contributor to disability in the United States, with ischemic stroke accounting for approximately 87% of all cases. The use of approved reperfusion therapies, including intravenous thrombolysis with tissue plasminogen activator (tPA) and mechanical thrombectomy, has significantly improved functional outcomes for ischemic stroke patients. However, hyperglycemia at the time of hospital arrival is associated with worse outcomes, including increased infarct growth, higher rates of disability, and elevated mortality. Despite this, current stroke guidelines neither exclude hyperglycemic patients from receiving reperfusion therapy nor recommend glucose management during the hyperacute phase of care. While recent studies suggest that mild to moderate hyperglycemia can be safely treated with intravenous insulin, there is insufficient evidence to support that glucose management improves stroke outcomes. The impact of hyperglycemia treatment immediately before or after reperfusion therapy remains largely unexplored, presenting a critical gap in acute stroke care.
This dissertation examines the role of hyperglycemia in reperfusion-eligible stroke patients through three interconnected studies aimed at improving glucose management strategies. First a scoping review of existing clinical trials investigating glucose control in stroke patients, providing a comprehensive analysis of interventions aimed at managing hyperglycemia during the acute and hyperacute phases of stroke care. This review synthesizes evidence on the effectiveness, safety, and feasibility of various glucose-lowering strategies, including intravenous insulin administration and other pharmacological and non-pharmacological approaches. Furthermore, it highlights gaps in knowledge regarding the optimal timing of intervention, the impact of glucose variability, and the clinical thresholds at which treatment should be initiated to maximize patient outcomes.
Summary of findings from the scoping review was used to develop a qualitative study. Interviews with emergency department nurses’ and stroke coordinators were conducted to explore perceptions of barriers to timely glucose management in acute stroke patients. The results were published in Stroke Clinician journal in November 2024.
A retrospective study assessing the relationship between admission hyperglycemia, hemoglobin A1c levels, home diabetic medication use, and post-reperfusion outcomes, including functional recovery and complications such as symptomatic intracerebral hemorrhage. Patients were grouped into ≥180 mg/dL and \u3c 180 mg/dL admission glucose for comparison between groups. Additionally, patients were grouped into diabetic groups to compare against dichotomous good outcome (mRS 0-2) and bad outcome (mRs 3-6). Those in the hyperglycemia group demonstrated significantly worse discharge NIHSS(p=0.034) and 3-month mRS (p=0.035) scores compared to the lowest glucose value patients. There were no significant differences in brain hemorrhage rates. Untreated diabetes patients had higher proportion of bad outcomes compared to non-diabetes patients (p=0.006) and to controlled diabetes patients (p=0.019). The median time from any reperfusion intervention to first hyperglycemic time was 14 hours and 5 minutes (IQR 4:32-32:36) for all patients, however in the lower glucose value group median was 18:36 (IQR 4:49-41:31) versus 7:49 (IQR 2:19-22:16; Z= -2.414, p=0.016) in the hyperglycemic group.
The findings from these studies aim to bridge the existing gap in hyperglycemia management in ischemic stroke care. By identifying barriers to treatment, assessing current clinical practices, and evaluating patient outcomes, this dissertation contributes to the ongoing effort to optimize glucose control strategies in the hyperacute phase of stroke management. Addressing hyperglycemia as a modifiable factor in reperfusion therapy has the potential to improve functional recovery and reduce morbidity in ischemic stroke patients
