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Search Strategies for Review of the Preference Assessment Literature for People with Intellectual and Developmental Disabilities
Get PDFDesign and Investigation of Small Molecule Drugs for Potential Treatment of CNS Disorders, Flaviviral Infections, and Cancers
Get PDFChapter 1 discusses the development of antagonists against the dopamine 4 receptor (D4R) that is expressed in the motor, associative, and limbic subdivisions of the basal ganglia network and is involved in Parkinson’s disease (PD). Levodopa is the firstline drug for the management of PD symptoms but its long-term use often leads to development of levodopa-induced dyskinesia (LID). D4R antagonists have been shown to decrease the abnormal involuntary movement scores in mouse models of LID. Chapter 1 outlines the development and optimization of selective D4R antagonists for potential treatment of LID. During the investigation of our D4R antagonists we discovered that they displayed activity against sigma 1 receptor (σ1R) - a multifunctional receptor, involved in a variety of neurological conditions. We report the results of the investigation of D4R antagonists for their role as σ1R modulators.
Chapter 2 outlines our efforts to develop inhibitors against some or all of flaviviruses. Flaviviruses are positive-stranded RNA viruses that include the disease agents: Dengue, Zika, West Nile, Yellow fever, and Japanese encephalitis. In collaboration with our partners we developed a hypothesis that inhibiting the key flaviviral enzyme RNA-dependent RNA polymerase would lead to the decrease of more than one type of flavivirus. We developed and optimized a library of flaviviral inhibitors and had them tested for activity and toxicity. We identified potent flaviviral inhibitors and developed a lead scaffold that displayed activity against more than one type of flavivirus, thus providing support for our hypothesis.
Chapter 3 discusses the investigation of inhibitors of claudin-1 protein for potential treatment of colorectal cancer (CRC). CRC is the third most commonly diagnosed cancer worldwide and one of the most lethal cancer types. Studies implicate claudin-1 in the development of metastasis and drug-resistance in CRC. We designed a diverse library of claudin-1 inhibitors and performed a structure-activity relationship study resulting in the identification of a potent lead scaffold and targets for future optimization.
Chapter 4 describes the development of inhibitors and degraders against the microtubule-associate serine/threonine kinase like (MASTL), a key regulator of mitosis, overexpressed in a number of cancers, including CRC. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional protein degraders that potentially possess significant advantages over the small molecule inhibitors. We designed the first-of-a-kind library of MASTL PROTACs and investigated them for activity against MASTL side-by-side with MASTL inhibitors. We outline the synthetic procedures, results of our investigation, and discuss future directions for the development of these promising therapeutic tools
Specifically Targeting MUC16 for Fluorescence-Guided Surgery of Pancreatic Ductal Adenocarcinoma
No full textPancreatic cancer is a lethal disease with a low 5-year survival rate and a high rate of resection recurrence. However, surgery remains the only treatment with curative potential for pancreatic cancer. Many factors such as high desmoplasia, a lack of intraoperative imaging, and micrometastatic disease contribute to the high rate of incomplete resections in pancreatic cancer. Fluorescence-guided surgery (FGS) is a potential intraoperative tool for application in surgical resection. FGS works through passive or active targeting of a free dye or dye-containing moiety (e.g. antibody, peptide, and nanoparticles) to specifically fluoresce the tumor compared to the surrounding normal, fibrotic, and background tissues. Mucin 16 (MUC16), a transmembrane mucin, is upregulated in 60-80% of pancreatic ductal adenocarcinoma patients, the most prevalent type of pancreatic cancer. In previous research, our group has indicated that MUC16 may be a good target for FGS through active targeting via an antibody-dye conjugate.
While FGS has shown promise in pancreatic cancer resection, its use is limited by the number of patients eligible for surgical resection and the limited number of targeting moieties available. In the past two decades, neoadjuvant therapy or treatment given prior to surgery has emerged as a method to downstage the tumor and increase the number of pancreatic cancer patients eligible for surgical resection. Currently, neoadjuvant therapy most commonly consists of chemotherapeutic treatment. As chemotherapeutic treatment has been shown to impact protein expression in tissues, it is important to investigate the effect of chemotherapy treatment on biomarker expression to determine the ability to target the biomarker for FGS after treatment. Likewise, applicable targeting moieties for FGS in pancreatic cancer are often limited by the presence of high liver fluorescence. High liver background fluorescence can reduce the ability to visualize the tumor signal as well as limit the visualization of any liver micrometastatic disease. Recently, a zwitterionic dye, ZW800-1, has shown promise for application in FGS via increased tumor targeting with diminished liver background fluorescence. In this research, we investigated the expression of MUC16 after neoadjuvant chemotherapy treatment and the ability of huAR9.6-ZW800-1 to target MUC16 for FGS and diminish liver background fluorescence
Bioactive Metabolites of OMEGA-6 and OMEGA-3 Fatty Acids are Associated with Inflammatory Cytokine Concentrations in Maternal and Infant Plasma at the Time of Delivery
No full textBackground & aims Inflammation is necessary for a healthy pregnancy. However, unregulated or excessive inflammation during pregnancy is associated with severe maternal and infant morbidities, such as pre-eclampsia, abnormal infant neurodevelopment, or preterm birth. Inflammation is regulated in part by the bioactive metabolites of omega-6 (n-6) and omega-3 (n-3) fatty acids (FAs). N-6 FAs have been shown to promote pro-inflammatory cytokine environments in adults, while n-3 FAs have been shown to contribute to the resolution of inflammation; however, how these metabolites affect maternal and infant inflammation is still uncertain. The objective of this study was to predict the influence of n-6 and n-3 FA metabolites on inflammatory biomarkers in maternal and umbilical cord plasma at the time of delivery. Methods Inflammatory biomarkers (IL-1β, IL-2, IL-6, IL-8, IL-10, and TNFα) for maternal and umbilical cord plasma samples in 39 maternal-infant dyads were analyzed via multi-analyte bead array. Metabolites of n-6 FAs (arachidonic acid and linoleic acid) and n-3 FAs (eicosapentaenoic acid and docosahexaenoic acid) were assayed via liquid chromatography-mass spectrometry. Linear regression models assessed relationships between maternal and infant inflammatory markers and metabolite plasma concentrations. Results Increased plasma concentrations of maternal n-6 metabolites were predictive of elevated pro-inflammatory cytokine concentrations in mothers; similarly, higher plasma concentrations of umbilical cord n-6 FA metabolites were predictive of elevated pro-inflammatory cytokine concentrations in infants. Higher plasma concentrations of maternal n-6 FA metabolites were also predictive of elevated pro-inflammatory cytokines in infants, suggesting that maternal n-6 FA status has an intergenerational impact on the inflammatory status of the infant. In contrast, maternal and cord plasma concentrations of n-3 FA metabolites had a mixed effect on inflammatory status in mothers and infants, which may be due to the inadequate maternal dietary intake of n-3 FAs in our study population. Conclusions Our results reveal that maternal FA status may have an intergenerational impact on the inflammatory status of the infant. Additional research is needed to identify how dietary interventions that modify maternal FA intake prior to or during pregnancy may impact maternal and infant inflammatory status and associated long-term health outcomes
Optimizing Learning Experiences: The Integration of Individualized Learning Agreements for Emergency Medicine Residents
No full textIntroduction: A common tool used to facilitate self-regulated learning in medical education is the individual learning plan (ILP), a learner-driven and iterative instrument designed to tailor training opportunities to individual learner needs. Although commonly utilized in medical education, few specialties, historically Pediatrics and more recently Family Medicine, require incorporation of ILPs in resident programming. There is no requirement for Emergency Medicine residencies to utilize ILP’s. In July 2023, the UNMC Emergency Medicine residency program started a pilot project aimed at incorporating an ILP, entitled Individualized Learning Agreements (ILA), for all 36 residents. Design: At the beginning of the 2023 academic year, a Microsoft Form was emailed to all 36 residents exploring questions about worries and goals for next 2 months, detailed study plan for the year, and level of accountability preference from the program. Initial submissions were reviewed, and suggestions were sent back to each resident. Check-ins occurred via Microsoft Form every two months, although residents could opt-in to more frequent check-ins. Questions on each check-in included progress on study plan, achievement of goals, opportunity to list new worries and goals, and confirmation of accountability need. Each check-in also allowed for specific questions related to current trends in the residency. Impact: The initial form was completed by 35/36 (97.2%) residents. Data from the most recent (6-month) check-in showed that while ILA’s were mostly followed ‘Some of the time’ (69.7%), 93.9% still felt they were learning and 87.9% felt the ILA was beneficial to their education. Conclusion and Future Direction: Preliminary data would suggest that the ILA is a useful educational tool for Emergency Medicine Residents. Further analysis is needed to assess objective metrics and to explore barriers to more expansive implementation. Future direction will include the incorporation of a coaching model and discussion on resident career and academic interests
Effect of Increased Midlevel Provider Led Education in the PICU
No full textStepping into the educator role can be intimidating but continuing to further knowledge of bedside staff is vital in the intensive care setting. The presence of APPs and the introduction of fellows in the pediatric ICU provides an additional teaching resource. One barrier to midlevel providers acting as educators is lack of comfort in that role. Our research aims to explore the utilization of topic summary sheets to encourage these midlevel providers to engage in teaching activities with the bedside RNs. These one-page summary sheets will be utilized to provide a teaching guide. We will assess the RN perception of quality and quantity of teaching in the ICU and topic knowledge. Data will be collected using surveys and pre- and post-tests to assess knowledge levels. Results of this study will be utilized to further optimize teaching in the pediatric ICU
Learner Influence on Pediatric Patient Experience: Exploring Family Members’ Perspectives
No full textBackground: The patient experience in pediatric settings is influenced by complex interactions between the patient, parent/guardian, learners, and providers. This study aimed to understand the influence of healthcare learners on care satisfaction in pediatric settings using patient experience feedback from family members. Methods: NRC Health “Feedback Management” data from a regional Children’s hospital was collected from August 1st, 2020 to August 31st, 2023 using key identifiers related to learners (e.g. “Student,” “Resident,” “Trainee,” “Learner,” “Fellow”). Each viable survey underwent reflexive thematic analysis by two independent reviewers. Additionally, two investigators independently assigned values to each comment regarding both the learner and overall interactions using a three-point scale (3=positive, 2=neutral, 1=negative). Inter-rater reliability was 0.983 for learner-specific comments and 0.970 for overall experience comments. Strongly positive and strongly negative remarks of the learner interaction were isolated and evaluated. Results: The dataset consisted of 302 eligible narrative comments from patients/parents that included one or more keywords. The average rating was 2.273/3 for learner interactions and 2.199/3 for overall interactions. The reflexive thematic analysis generated 24 primary themes and 21 subthemes that were grouped under five overarching categories of learner-specific patient care experience: Communication, Learner Effects, Rapport, Care Delivery, and Competency. Feedback involving positive interactions focused on recognition of the learner, positive rapport building, and effective information explanation. Feedback involving negative learner interactions emphasized task repetition, lack of communication, poor bedside manner, and increased visit time. Conclusions: Learners fill an important role on the pediatric medical team through experiential learning. This study shows that the presence and involvement of learners can influence pediatric care satisfaction, both positively and negatively. The resulting themes from family member narratives emphasize relevant clinical learning environmental factors that impact perceptions of the pediatric care experience
Genetic Drivers and Tumor Milieu Analysis in Mantle Cell Lymphoma
No full textMantle Cell Lymphoma (MCL) is a B-cell lymphoma characterized by t(11;14) leading to CyclinD1 (CCND1) overexpression with highly variable clinical response. Although the tumor intrinsic mechanisms have been fairly studied, the role of the tumor microenvironment (TME) in survival and therapeutic responses is marginally examined. Herein, we integrated high-throughput genomics and characterized TME using a highly multiplexed, spatially resolved, single-cell digital pathology approach termed imaging mass cytometry (IMC) to delineate the tumor-immune landscape. We identified eight MCL genomic subtypes with distinct signatures and prognoses. Subsets C2, C5, and C6 had poorer outcomes with a 5-year overall survival (OS) of 33-50% and a median OS of 3.2-4.5 years. In contrast, subtypes C1, C3, C4, C7, and C8 showed better survival, with a 5-year OS of 62-88% and a median OS of 8.2-11.8 years. Subtypes with complex genomic alterations, like deletions and mutations involving TP53 and regions on chromosomes 13, 17, and 11, correlated with shorter survival. Conversely, subtypes with gains in MYC, mutation/deletion of ATM, mutations in SP140, and deletions on chromosome 6 associated with longer survival, broadly categorizing the subtypes into two groups based on survival outcomes. Extrinsic factors such as TME reveal nine major cellular compartments, with neoplastic cells constituting 58% and various immune cell types forming the tumor milieu. Notably, TP53-altered genetic subtypes were characterized by an increase in T-regulatory, CD8+ T-cells, and endothelial cells, alongside heightened exhaustion markers on immune and neoplastic cells. Poor prognostic indicators included elevated PDL-2 or low HLADR on CD8+ T cells and high CD45RA on SOX11+/- malignant cells. Spatial analysis identified distinct cellular neighborhoods correlated with TP53 alterations. Thus, to further explore the underlying pathobiology of this most lethal TP53 subtype in MCL, we generated modified cell lines to study the functional significance of p53 deficiency in MCL. We v performed RNA-seq on these p53-modified cells to determine their transcriptomic features. Notably, we found that BCR signaling was remarkably repressed upon WT p53 expression, suggesting that p53 deficiency may contribute to resistance against BTK inhibitor treatment. Using the CUT&RUN assay to determine the TP53 targets, besides canonical targets, we observed changes in an expansive list of genes and pathways upon p53 modification, including the BCR signaling. Interestingly, PTPN6, targeted by TP53 and a negative regulator of BCR, modulated BCR pathway activity which may potentially alter ibrutinib responsiveness. Thus, this study suggests a more granular risk stratification recovering previously known subtypes and identifying novel subgroups. TME analysis of the TP53 altered subgroup demonstrates that, far from being histopathologically monotonous, MCL has a complex tumor-immune architecture, and that changes in tumor topology can be correlated with clinically relevant features. This analysis identified candidate biomarkers and therapeutic targets such as TIM-3, PD-L2, HLA-DR that are relevant for combination treatment strategies in immuno-oncology and cellular therapies. Loss of PTPN6 could act as an alternative biomarker in patients with p53 functional loss likely to respond to ibrutinib treatment indicating pharmacological inhibition of PTPN6 might be a novel approach to enhance the efficacy of BCR-targeted therapies
Effects of an Educational Evidence-Based Website to Improve Breast Health Knowledge and Self-Efficacy of Breast Self-Examination: Interim Analysis
Get PDFPurpose and Aims
Breast disease, whether benign or malignant, encompasses a wide array of diagnoses. Breast self- examination (BSE) is a simple screening assessment that improves early recognition and diagnosis. With changes in the 2021 ACOG practice guidelines from mandatory to optional provider-performed clinical breast examinations (CBE), it is imperative for patients to possess basic breast health knowledge and accurate BSE techniques. Current standard patient education is provided via brochures or pamphlets. An educational multimedia website was created using ACOG guidelines to impart knowledge and demonstrate proper BSE techniques. Aims were to evaluate changes in participant’s (1) breast health knowledge (2) self-efficacy in performing BSE.
Theoretical Framework
The educational intervention was developed using the Health Belief Model (HBM) which assesses individuals’ behavior and actions regarding health conditions. Model concepts include 1.) health susceptibility, 2.) seriousness, 3.) benefits/barriers to a behavior, 4.) cues to action, and 5.) self-efficacy. This research assessed behavior towards breast health knowledge and self- efficacy of BSE.
Methods
A single group, pre/post efficacy design was used. Breast health knowledge was assessed with the Breast Health Assessment (BHA) and consisted of three subscales; (1) breast cancer signs and symptoms (2) breast cancer risk, and (3) BSE knowledge. The Champions Health Belief Model Scale (CHBM) assessed BSE self-efficacy and consisted of five subscales; (1) susceptibility, (2) seriousness, (3) BSE benefits, (4) BSE barriers, (5) BSE efficacy, (6) health motivation, (7) mammography benefits, and (8) mammography barriers. The validated instruments were collected at pre-intervention (Time 1) and 1-month post-intervention (Time 2). Paired t-tests determined change in all outcome measures. Participants were provided the website link at Time 1 and had access throughout the study. To reduce attrition, text and email reminders were sent at Time 2.
Interim Analysis
A convenience sample of 62 participants were enrolled. The BHA and CHBM at Time 2 were completed by 18 and 24 participants, respectively. Statistically significant increases were found in the BHA subscale of “breast cancer signs and symptoms (p=.024, d=.58), and on the CHBM subscale of “mammography barriers” (p= .023, d=.51). A positive trend was demonstrated in the BHA subscale of “BSE knowledge” as was the CHBM subscale of “BSE efficacy.” Mean age was 44 years (SD = 12.7). Most of the sample were Caucasian and college educated. Thirty-six percent were on hormone contraception or replacement therapy. Eighteen percent had a personal history of breast disease and 46% had a family history of breast cancer.
Conclusion
Participants gained the greatest knowledge with the BHA subscale of breast cancer signs and symptoms and the CHBM subscale of mammography benefits. These findings may translate to increased awareness of early detection and diagnosis. Interim analysis demonstrates attrition to be higher than expected. Considerations to improve retention include provision of one-on-one education of content and use of website at Time 1. Weekly “booster videos” may promote retention. Limitations include time between pre- and post-intervention (1 month). This is an interim analysis; final data has not yet been measured
Bridging the Information Divide: Leveraging the Learning Health System to Understand Rural-Urban Health Disparities in the COVID-19 Era
No full textThe examination of healthcare disparities, which the COVID-19 pandemic exacerbated, revealed a pronounced divide between rural and urban settings. This divide particularly underscored the challenges of integrating rural healthcare into the Learning Health System (LHS) and utilizing real-world data (RWD) in response to a public health emergency. Our investigation expanded the growing body of literature on the rural mortality penalty, encompassing the period following the COVID-19 pandemic. By employing an LHS-enabled centralized platform of RWD, we assessed the impact of rurality on adverse COVID-19 outcomes (Aim 1), focusing on inpatient adverse events and the effectiveness of treatments and vaccinations across demographics. Our efforts also included exploring associations with adverse post-COVID-19 events, post-vaccination breakthrough infections, variations in treatment effectiveness, and temporal trends in adverse events following the vaccine rollout. We investigated the informatics challenges and methodological approaches necessary for studying rural populations using RWD (Aim 2). This task involved strategies for managing data harmonized from various sources, optimizing data quality and usability, and navigating the complexities of integrating and analyzing diverse datasets from different contributing centers across the US. We assessed the current state of rural healthcare\u27s integration within the LHS (Aim 3), identifying steps toward advancing a rural-inclusive model. This assessment thoroughly evaluated achievements and gaps in data standardization, system adaptation, and rural engagement, aiming to develop targeted recommendations for enhancing rural health integration. Despite the barriers, using the LHS enabled the demonstration of higher hospitalization and mortality rates, alongside increased rates of breakthrough infections post-vaccination, in rural compared to urban areas. Better incorporation of rural communities into the LHS will offer clearer insights into these growing disparities, equipping providers, public health officials, and policymakers with enhanced tools and resources to address ongoing and future public health crises