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Investigating FIT Kit Completion for CRC Screening in Younger Adults in Rural Areas
Get PDFRural regions have higher incidence rates of colorectal cancer (CRC) than urban regions, while screening is lower in rural residents than in urban residents. Rural residents experience barriers to CRC screening due to a lack of access to healthcare, perceived lack of privacy, and other cultural factors. The fecal immunochemical tests (FITs) may provide an inexpensive and convenient alternative for those lacking access to a colonoscopy or sigmoidoscopy. In a clinical trial, we investigated factors that influenced the return of a FIT kit for CRC screening among 1,230 rural residents in a midwestern U.S. state. Participants were selected from two cancer screening databases maintained by the state health department. Participants returning and not returning the FIT kit were compared for differences by age category (45–54, 55–64, 65–74), gender (female vs. male), race (non-white vs. white), and ethnicity (Hispanic vs. not Hispanic) using chi-square tests and logistic regression. Cox proportional hazard models and Kaplan–Meier curves were used to assess differences in FIT kit return time by age and gender. The youngest age group was significantly less likely to return the FIT kit and were slower at returning it when they did. In models adjusted for age category, females were significantly more likely to return the FIT kit than males and returned the FIT kit sooner than males. The results suggest that efforts are needed to reach those 45 to 55, especially males, who are not likely to see the need for CRC screening
Development of Long-Acting Antiviral and Antimicrobial Prodrug Nanoformulations
No full textOver the past decade, the global burden of infectious diseases has increased substantively, underscoring the need for more effective treatment strategies. However, the discovery and development of new drugs with desirable safety, pharmacokinetics, and efficacy is a time consuming and costly process with great uncertainty around success rate. As an alternative to new drug development, prodrugs and novel drug delivery systems have increasingly been explored. Both serve to overcome the drug development challenges. Such drug formulations that permit extended dosing intervals of potent native drugs serve multiple purposes by promoting patient adherence to in improving treatment outcomes. This is especially noteworthy in treating chronic infectious diseases that include, but are not limited to, the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and tuberculosis (TB). Each demonstrates immediate needs and strong preferences for long acting (LA) treatments. At the time of writing this dissertation, no US Food and Drug Administration (FDA) approved LA injectable regimen for HBV and TB infections were available. Therefore, this work describes our efforts towards development of LA prodrug formulations for treatment and prevention of HIV, HBV, and TB infections. To this end, a library of tenofovir (TFV) ProTides and diester (phosphonate) prodrugs were synthesized and shown to exhibit efficacy against both HIV and HBV infections. Notably, using two mouse models of HBV infection, we demonstrate that transformation of daily TFV into LA ProTide and phosphonate prodrug formulations could potentially overcome the limitations of existing regimens to significantly improve treatment of chronic HBV infection. Specifically, a single intramuscular injection of the LA TFV ProTide and phosphonate prodrug formulations into infected mice achieved sustained suppression of HBV replication with no notable adverse events. By contrast, a parenterally administered tenofovir alafenamide (TAF) control exhibited minimal effects. The viral load remained unchanged from baseline or increased in non-treated control animals. We also describe transformation of lamivudine (3TC), a highly water-soluble nucleoside reverse transcriptase inhibitor used in combination with other drugs to treat HIV and HBV infections, into a hydrophobic lipidated phenylalanine carboxylate ester prodrug named 3TC-F-C18. The new formulation demonstrated improved intracellular drug delivery in vitro and pharmacokinetics (PK) profiles in BALB/cJ mice. We also demonstrate how the LA prodrug approach could potentially be applied to TB therapies. Specifically, isoniazid (INH), a highly water-soluble anti-TB drug used for treatment and prevention of TB infection was chemically modified into two hydrophobic and lipophilic prodrugs named INHP and INHP1. Both INH prodrugs were then nanoformulated into aqueous surfactant stabilized nanosuspensions that improved drug uptake and retention by human monocyte derived macrophages with no observed cytotoxic effects. Collectively, this dissertation demonstrates how compound specific prodrug strategies could potentially be used to transform frequently administered HIV, HBV, and TB therapies into LA formulations with improved PK and efficacy profiles
Healthy Aging Modulates the Neural Oscillatory Activity Underlying Basic Visual Processing and Verbal Working Memory
Get PDFWorldwide economic and medical improvements have led to profound demographic shifts towards an older overall population. Unfortunately, with older age comes a variety of neurological changes which act to decrease individual quality of life and independence. Since the advent of functional neuroimaging, investigation of age-related changes in neural activity has been of particular interest. However, changes in population-level neural dynamics with age remain poorly characterized. Herein, we utilized magnetoencephalography (MEG), comprehensive neuropsychological assessments, and advanced analytical techniques to investigate spectrally-specific changes in neural oscillatory activity in a healthy aging population. First, we examined age-related deficiencies in visual processing using a well-established visual entrainment paradigm (Chapter 1). Next, we used a more complex visual grating paradigm to allow us to characterize age-related changes in visual gamma oscillations, as well as how these changes relate to individual processing speed (Chapter 2). Finally, we extended our investigation into higher-order cognition by utilizing a Sternberg working memory paradigm (Chapter 3). Overall, these results provide novel insights into the oscillatory underpinnings of age-related changes in cognition and serve as a foundation for future research into oscillatory deficits in patients affected by neuropsychological disorders which are prevalent in older individuals (e.g., Alzheimer’s disease, Parkinson’s disease, Dementia with Lewy Bodies)
The Impact of a Living with Diabetes Experience on Students\u27 Attitudes and Perceptions
No full textIntroduction: Patients with diabetes experience significant changes in their life as they live with the disease. These changes can impact their psychosocial wellbeing as well as their day-to-day activities. Pharmacists are involved in many aspects of diabetes care and having increased understanding and empathy for patients can impact how they deliver care. A Living with Diabetes experience was designed for third year pharmacy students in an elective course to help future pharmacists gain a better understanding of the impact diabetes has on a patient’s life. This project’s objective is to assess the impact of this experience on pharmacy students’ attitudes towards patients with diabetes and increase their empathy in caring for them. Methods: The Living with Diabetes Experience requires students to wear a continuous glucose monitor (CGM) for at least 3 days. This monitor is connected to an app on their phone that can send alerts from their CGM. The CGMs are donated through a partnership with Dexcom. Students must also keep a detailed food diary, including counting all carbohydrates and calculating insulin doses based on predetermined insulin to carbohydrate ratios. Students receive unexpected hypoglycemic events that they must address in real-time to demonstrate the unanticipated burden or stress these events can cause. Students fill out a pre-experience survey with questions related to their attitudes on what it is like to have diabetes, including the challenges they may face. The same survey is given post-experience. Students also write a one-page post experience reflection paper. Survey and reflection data will be analyzed, and themes identified from the qualitative data to determine impact of the learning activity. IRB application will be submitted this month. Results/ Conclusion: The learning activity is scheduled to occur in February 2024 and results/ conclusions will be available after the activity
Implementation of a Doula-Supported Postpartum Wellness Toolkit in a Black Community-Based Maternal Wellness Program
Get PDFObjective: The objective of this project was to expand the areas of focus within a maternal wellness program at a Black community center and to evaluate the satisfaction levels of the doulas who utilized the material during postpartum home visits. The toolkit covers a range of postpartum topics in the areas of nutrition, exercise, sexual health, mindfulness, and social support as well as a postpartum mental health screening tool.
Design: This quality improvement project included three distinct phases: The pre-implementation phase, the implementation phase, and the post-implementation phase.
Setting: The project location was a Black community center in Lincoln, Nebraska.
Methods: The project involved pre-implementation, implementation, and post-implementation phases. The DNP team worked with the program doulas and maternal wellness program director to create a postpartum wellness toolkit. The doulas received guidance for utilizing the toolkit, delivered the toolkit to participants, and participated in pre- and post-intervention surveys.
Findings: The toolkit received positive feedback from the doulas who participated in the project. They found it to be relevant, culturally sensitive, and effective. Although the response rate was low, the doulas who completed the survey responded favorably regarding the toolkit’s ability to improve program participants\u27 mental and physical wellbeing. This aligns with previous research demonstrating the benefits of utilizing a community-based postpartum wellness program and care from culturally congruent doulas.
Conclusion: Implementation of the postpartum wellness toolkit increased the general satisfaction of the doula participants. The majority of the survey respondents indicated that it was a useful resource that included holistic and culturally relevant content and allowed effective and efficient use.
Recommendation: Based on the results of this project, the postpartum wellness toolkit should continue to be used with specific modifications as needed by the maternal wellness program. Survey participants responded favorably to the toolkit’s potential to enhance program participant wellness. By continuing to use the toolkit for an extended period, the doulas will become more familiar with how various topics can be applied to individual scenarios. Further education is advised to ensure that all current and future staff are well-informed about the toolkit’s content and purpose
Lung-Delivered IL-10 Therapy Elicits Beneficial Effects via Immune Modulation in Organic Dust Exposure-Induced Lung Inflammation
Get PDFEfficacious therapeutic options capable of resolving inflammatory lung disease associated with environmental and occupational exposures are lacking. This study sought to determine the preclinical therapeutic potential of lung-delivered recombinant interleukin (IL)-10 therapy following acute organic dust exposure in mice. Here, C57BL/6J mice were intratracheally instilled with swine confinement organic dust extract (ODE) (12.5%, 25%, 50% concentrations) with IL-10 (1 μg) treatment or vehicle control intratracheally-administered three times: 5 hr post-exposure and then daily for 2 days. The results showed that IL-10 treatment reduced ODE (25%)-induced weight loss by 66% and 46% at Day 1 and Day 2 post-exposure, respectively. IL-10 treatment reduced ODE (25%, 50%)-induced lung levels of TNFα (-76%, -83% [reduction], respectively), neutrophil chemoattractant CXCL1 (-51%, -60%), and lavage fluid IL-6 (-84%, -89%). IL-10 treatment reduced ODE (25%, 50%)-induced lung neutrophils (-49%, -70%) and recruited CD11cintCD11b+ monocyte-macrophages (-49%, -70%). IL-10 therapy reduced ODE-associated expression of antigen presentation (MHC Class II, CD80, CD86) and inflammatory (Ly6C) markers and increased anti-inflammatory CD206 expression on CD11cintCD11b+ cells. ODE (12.5%, 25%)-induced lung pathology was also reduced with IL-10 therapy. In conclusion, the studies here showed that short-term, lung-delivered IL-10 treatment induced a beneficial response in reducing inflammatory consequences (that were also associated with striking reduction in recruited monocyte-macrophages) following acute complex organic dust exposure
Therapeutic Effects of BET Protein Inhibition in B-cell Malignancies and Beyond
Get PDFChronic lymphocytic leukemia (CLL) develops through a combination of intrinsic genetic defects, constitutively active survival/proliferation signaling pathways, and complex microenvironment interactions. Redundant tumor microenvironment (TME) immuno-suppressive mechanisms and epigenetic maintenance of terminal T-cell dysfunction also greatly hinder anti-tumor T-cell responses in CLL. Small-molecule agents targeting the B-cell receptor (BCR) pathway and anti-apoptotic proteins alone or in combination with chemo-immunotherapy have revolutionized the management of CLL, yet there is still a significant need for novel therapeutic strategies to yield durable tumor elimination. Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that bind to acetyl-lysine residues on histones to regulate gene transcription. BET proteins, such as BRD4, have pleiotropic functions in normal biology and disease states. In CLL, BRD4 regulates key pathways contributing to pathogenesis (e.g., expression of MYC and BCR pathway components) and TME interactions, including T-cell function and differentiation. This work firstly evaluated the pre-clinical efficacy of novel small molecule inhibitors capable of concomitantly inhibiting BRD4 and BCR pathway components BTK and PI3K (SRX3305 and SRX3333) in CLL. These compounds specifically inhibit their molecular targets and are cytotoxic to CLL cells at low micro-molar doses, even in the presence of supportive TME stimuli and BTK inhibitor resistance. Furthermore, I found that a novel BET inhibitor (OPN-51107) alleviates immuno-suppressive networks in the CLL TME and repairs inherent T-cell defects. In pre-clinical models of CLL, OPN-51107 treatment reduced expression of immune inhibitory receptors, enhanced T-cell proliferation and effector function, shifted the T-cell transcription factor landscape, and altered CLL T-cell exhaustion-associated chromatin organization to promote a progenitor T-cell phenotype. At the beginning of the COVID-19 pandemic, I additionally evaluated the usage of BET inhibitors to combat SARS-CoV-2 infection. Apabetalone (RVX-208), a BET inhibitor approved for clinical use in cardiovascular disorders, was found to reduce expression of cell surface receptors involved in SARS-CoV-2 entry and inhibit SARS-CoV-2 infection akin to anti-viral agents. Collectively, these studies demonstrate the enormous potential of BET protein inhibition to be used as a component of treatment regimens for hematological malignancies, such as CLL, as well as non-oncology applications
Assessment of In-Vitro and In-Vivo Pre-Clinical Pharmacokinetics of EPZ015666; A Novel Small molecule for medulloblastoma treatment
No full textGroup 3 medulloblastoma (MB) has the worst prognosis of the MB subgroups associated with elevated MYC expression and a 5-year survival rate of
Quantitation of EPZ was performed on a Shimadzu LC-MS/MS system utilizing electrospray ionization operated in positive mode. The validated assay was linear from 0.2 to 500 ng/mL. Metabolic stability studies demonstrated slow intrinsic clearance of EPZ in mouse and human liver microsomes, suggesting no CYP-mediated metabolism. Additionally, EPZ exhibited low binding affinity to plasma and brain proteins and high apparent permeability across artificial membranes, indicating efficient membrane penetration. Drug transporter studies identified EPZ as a substrate of OATP1B1.
In an in-vivo pharmacokinetic study, healthy male BALB/c mice received a single oral EPZ dose of 100 mg/kg. The maximum plasma concentration (Cmax) was 10154.31 ± 2450.74, and clearance was 12.41 ± 4.17. Furthermore, EPZ achieved brain concentrations of 874.23 ± 412.71 ng/g. These findings collectively suggest EPZ’s potential suitability for oral administration and ability to cross the BBB
Facilitators and Barriers to Implementing Effective Interprofessional Education: A Mixed Methods Study of Academic Health Institutions with Centralized Interprofessional Education Administrative Structures
No full textInterprofessional education (IPE) is pivotal in preparing future healthcare professionals for collaborative practice, yet its effective implementation remains challenging. The purpose of this mixed methods study of multiple academic health institution cases was to explore and understand how early and late IPE adopters perceive effective IPE implementation in academic health institutions. Combining frameworks for complex innovation implementation and curriculum development with surveys and interviews reveals the facilitators and barriers of effective IPE implementation. Consistent with the framework for complex innovation implementation, leadership and administrative support, resource allocation, logistical planning, and program evaluation emerged as key facilitators of effective IPE implementation. Barriers included coordination difficulties, resource scarcity, lack of leadership and institutional support, and evaluation challenges. These findings suggest that successful IPE implementation requires a comprehensive and multifaceted approach guided by a theoretical framework that considers structural supports, organizing processes, and measuring outcomes. This study informs efforts to effectively implement IPE in healthcare education and interprofessional collaborative practice for the purpose of improving the quality and safety of healthcare