MEDICA@MUSC (Medical University of South Carolina)
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Defining a Dynamic Architecture of Protein Tyrosine Phosphatases
No full textProtein tyrosine phosphatases (PTPs), a critical class of signaling enzymes, are principally responsible for balancing the actions of kinases through the dephosphorylation of tyrosine residues on substrate proteins. As such, this family is involved in myriad pathways and individual members are able to perform both oncogenic and tumor-suppressing roles. However, while clinical success has been achieved in targeting kinases, PTPs have remained therapeutically challenging. Orthosteric inhibition is limited in PTPs due to their highly conserved fold, leading to off-target effects, and their highly charged active site, requiring highly polar molecules with poor bioavailability. These challenges posit the allosteric inhibition of PTPs as an attractive therapeutic avenue. In kinases, a key milestone to the development of allosteric inhibitors was the identification of active and inactive conformations in the structure of these proteins, such as the alignment of the regulatory spine residues and various conformations of the DFG motif. However, no analogous definition exists for PTPs. We seek to define such conformations through molecular dynamics simulations, biochemical characterization, and large-scale analysis of publicly available crystal structures. Through investigating the dynamics of three diverse PTPs (PTP1B from Homo sapiens, YopH from Yersinia pestis, and TbPTP1 from Trypanosoma brucei) we have identified residues that drive the basal dynamics required for catalysis. Additionally, we have characterized a unique residues in PTP1B, centered around F225, that includes residues involved in allosteric regulation. Through examining the interface of the dual PTP domains in the receptor PTP LAR, we have determined the mechanism for substrate specificity induced by the otherwise inactive D2 domain. Finally, by employing a modified algorithm originally used to identify the kinase regulatory spine in conjunction with modern machine learning techniques, we have analyzed available crystal structures of diverse PTP domains. This has led to the identification of a conformational change in F225 (PTP1B numbering) that is required for PTPs to adopt their active conformation. In total, we have defined a conserved dynamic architecture in PTPs that enables their regulation in a complex signaling environment
Analysis of the Immune Response After Readministration of a Novel AAV6 Gene Therapy Containing TLR9 Inhibitory Sequences
Get PDFTherapeutic options for the treatment of Surfactant Protein-B (SP-B) deficiency, an autosomal recessive disorder that leads to fatal respiratory distress, are extremely limited with the exception of double lung transplantation. One method for treating this monogenic lung disease is with adeno-associated virus (AAV) gene therapy treatment that delivers the hSFTPB transgene into the lungs. The transient nature of AAV transgene expression led to a need for sustained gene expression, which could possibly be achieved through redosing. The main obstacle with redosing is the innate immune response and subsequent inflammatory response pathways that are activated after recognition of unmethylated CpG motifs in the AAV genome by toll-like receptor 9 (TLR9). Through readministration of an engineered AAV6.2FF vector with TLR9 inhibitory (TLR9i) sequences incorporated into the genome, prolonged survival in a mouse model of SP-B deficiency was demonstrated compared to a single dose of gene therapy. However, the specific gene or gene pathways impacted following TLR9 suppression have not been well characterized. I hypothesize that the incorporation of TLR9i sequences into the modified AAV6 vector genome will permit readministration through suppression of multiple immune response genes involved in the interferon pathways. This will be explored through two main aims: the production and purification of AAV vectors for assessment studies, and through exploration of gene expression analysis data to further characterize the immune response after repeat doses of the gene therapy treatment with and without TLR9 inhibition.
To assess the immune response following TLR9 inhibition, RNA was isolated from lung tissue in mice treated with single or repeat doses of AAV with (AAV-hSPBTLR9i) and without (AAV-hSPB) the TLR9i sequences, and analyzed by nCounter (Nanostring) gene expression analysis.
The gene expression analysis assessed over 700 different host response genes, with AAV-hSPB redosing treatment showing greater than 100 significant gene expression changes compared to less than 10 genes in mice redosed with AAV-hSPBTLR9i. Several genes were further examined including Serpina1a, Zbp1, Cxcl10, Stat1, and Mx1 due to their roles in regulating or responding to the immune response. Examination with qPCR, showed a significant increase in expression in genes involved in interferon response pathways including Mx1 and Stat1 following AAV-hSPB redosing but not AAV-hSPBTLR9i redosing. Another gene we examined was Tbx21 (T-bet), a marker for T helper cells (Th1) by immune cell profiling, which showed the highest levels after a repeat dose of AAV-hSPB but was reduced with AAV-hSPBTLR9i.
In conclusion, the AAV-hSPBTLR9i permits AAV redosing by suppressing multiple immune response genes including some involved in the interferon response pathway, as well as Th1 cells. For neonates with SP-B deficiency, the incorporation of the TLR9i sequences, and subsequent suppression of immune response genes, could allow for readministration of a gene therapy treatment to improve survival
The Role of School-Based Occupational Therapists and Social Determinants of Health in Social Emotional Learning Programming
Get PDFSocial Emotional Learning (SEL) is comprised of fundamental life skills for educational success typically including self-awareness, social-awareness, self-management, relationship and responsible decisioning making. Despite growing support for the incorporation of SEL into the K-12th grade classroom, researchers continue to neglect to analyze who should be responsible for implementing programming and how to design programs that are specific to student needs. A doctoral capstone project was conducted to explore the role of school-based Occupational Therapists (OTs) and Social Determinants of Health (SDOH) in SEL program creation and implementation for a Title 1 school in North Charleston, South Carolina. Preliminary qualitative surveys revealed that an average of 34.4% of participating school families at the partner school, believed their children’s ability to attend school was hindered by transportation, housing and food insecurity. In addition, 100% of participating school staff reported that a free, at-home summer SEL enrichment program would be beneficial to their students. As a result, the Summer SEL Enrichment Program was created. This unique program is comprised of 5 core and 3 bonus activities incorporating SEL core competencies, state education standards and OT developmental milestones as appropriate for ages/grade level ranges (K-2nd grade and 3rd-5th grade). In addition, SDOH-related barriers were considered to allow access for all K-5th grade students to participate, and sponsored prizes were provided by community partners. Finally, this collaborative project demonstrated that school-based OT practitioners have unique qualifications to oversee the creation and implementation of such programs; however, practitioners are frequently hindered by outdated practice models, high caseload numbers, limited staffing and perceived scope of practice. Advocating for the expansion of the scope of practice for school-based OTs and a change in current practice standards to promote educational success would allow for the further creation and operation of more student and region specific SEL programming
The Use of Spirituality to Enhance the Well-Being in Individuals Who Are Homeless
No full textBackground: Homelessness significantly impacts emotional, physical, and social well-being, often stripping individuals of their sense of purpose and damaging their relationships. This quality improvement project explored the use of spiritual interventions to address these multidimensional challenges among homeless populations. Methodology: A faith-based tool- kit was created and implemented to integrate lessons, resources, and hands-on activities centered on emotional, physical, sense of purpose, and fostering positive relationships. Women aged 25 to 60 at the Light House Shelter participated in a 1-2 hour group session that included a lesson, educational handouts, and a hands-on activity. Each group session at the Lighthouse was scheduled bi-weekly due to consistent work schedules. Sessions at the men\u27s shelter, the Archer House, included providing educational handouts to men aged 28 to 65. The sessions at the men’s shelter were impromptu and 1:1 due to their extremely, busy work schedules and lack of interest in participating in a group setting. These interventions were designed to foster emotional stability, physical health, a renewed sense of purpose, and stronger interpersonal relationships based on their needs. Results: The findings indicate substantial improvements in the overall well-being of homeless women who participated in the spiritual intervention programs. Notably, participants reported enhanced emotional resilience, improved physical health, a clearer sense of purpose, and more meaningful relationships. Among homeless men, the educational components of the intervention proved highly effective, resulting in increased awareness of different spiritual interventions. The toolkit empowered staff members, equipping them with the knowledge and confidence to facilitate faith-based activities independently. Furthermore, community partners at the men\u27s shelters we be able integrated spiritual practices beyond typical Bible study lessons into their ministries, enhancing their outreach and support efforts. Conclusion: The incorporation of spiritual interventions significantly boosts the emotional, physical, and relational well-being of homeless individuals. This approach not only benefits the participants but also strengthens the capacity of staff and community partners to deliver faith-based support, ultimately fostering a more holistic and sustainable model of care for homeless populations
Discovery and Development of Epigenetic Inhibitors Targeting KDM4B to Alleviate Chronic Inflammatory Response in Periodontal Disease
No full textThis study describes the synthesis and biological evaluation of small molecule KDM4B inhibitors for use in modulating immune responses in periodontal disease (PD). Periodontal disease begins with the accumulation of bacterial plaque in the oral cavity, triggering an inflammatory response that damages host tissues. Despite standard treatments such as scaling and root planing (SRP) to remove biofilm, the host immune response can remain hyperactive, leading to ongoing tissue destruction and bacterial-driven inflammatory bone loss.
Research suggests that the microenvironment of periodontal disease induces epigenetic alterations, particularly through increased activity of lysine-specific demethylase 4B (KDM4B). Previous studies using a murine macrophage model demonstrated that periodontal inflammation could be induced by exposing macrophages to lipopolysaccharide (LPS) from Aggregatibacter actinomycetemcomitans (A.a.), a pathogen associated with aggressive periodontitis. This form of periodontitis is notably resistant to SRP and persists even in the absence of plaque, presenting significant clinical challenges. Further, a non-selective KDM inhibitor reversed the pro-inflammatory response of macrophages to A.a. LPS in vitro, highlighting KDMs as a promising therapeutic target.
In the current study, we focused on improving the selective of KDM inhibitors leading to a first-in-class KDM4B inhibitor. The synthesis and evaluation of derivatives led to the discovery of a compound 39, which exhibited an IC50 of 170 nM against recombinant KDM4B and demonstrated immunosuppressive activity in the Aa LPS challenge model. Additionally, 39 reduced osteoclast formation in vitro. These findings suggest that compound 39 should continue to be developed as a potential therapeutic agent for modulating the immune response in periodontal disease
A Retrospective Analysis of Primary Breast Cancer Surgical Procedures (Mastectomy versus Breast Conserving Surgery) Performed on Women living in Rural and Urban Counties in South Carolina
Get PDFWomen dealing with a diagnosis of breast cancer may be challenged when attempting to seek and obtain medical care while living in a rural community. It is not known whether geography impacts the decision-making process for women considering elective breast cancer surgery (mastectomy versus breast conserving surgery (BCS)) in South Carolina. We performed a retrospective analysis of breast cancer surgical options offered to women to examine if a difference exists in both rural and urban settings. Although there was a higher proportion of women in South Carolina who elected to undergo a mastectomy instead of BCS (4,416 [79.5%] vs. 1,139 [20.5%]) no difference was noted in the type of surgery performed based on the woman’s geographical location
The Impact of Socialization on Mental Health in Older Adults: An Occupational Therapy Guided Approach
No full textBackground: Roughly 28 % of older adults in the United States experience social isolation, a condition linked to higher rates of depression, cognitive decline, chronic disease, and premature mortality. Although research shows that regular social engagement improves health and longevity, many older adults lack programs that are both accessible and engaging.
Purpose: This capstone project explored whether a brief, community-based program—the Ageless Adventures Club—could lessen loneliness and foster inclusion among adults aged 60 + in Bluffton, South Carolina.
Methods: A mixed-methods needs assessment (n = 46) identified transportation, mobility, and cost as primary barriers to participation. Guided by the Model of Social Interaction, a bi‑weekly, eight-week series combined expert-led discussions (e.g., occupational therapy access, mental‑health awareness, heart health) with interactive activities such as social gaming, balance games, and modified Zumba. Attendance averaged 17 participants per session. The Revised UCLA Loneliness Scale and open-ended questions were administered before and after the program. Descriptive statistics captured changes in loneliness, feeling left out, and isolation, while qualitative comments provided context.
Results: Feelings of being left out declined from 94 % to 90 %, suggesting a modest gain in inclusion. Conversely, reported loneliness rose slightly (59 % to 62 %), and isolation remained at 76 %. Uneven participation and anonymous surveys limited the ability to match individual pre-‑ and post-scores, complicating impact estimates.
Discussion: The program confirmed the promise and limits of short-term group interventions. Consistent attendance and modest inclusion gains were encouraging, yet loneliness and isolation proved resilient. Findings reinforce the need for multifaceted strategies that address transportation, offer smaller interest-based groups, and provide flexible scheduling.
Conclusions & Next Steps: The Ageless Adventures Club offers a scalable template for community partners and occupational therapists seeking to combat social isolation. Future iterations will integrate follow-up surveys, an implementation guide, remote‑support options, wider publicity, and a suggestion box, with relaunch planned for June/July 2025
Soft Skills Training for Young Autistic Adults to Promote Community Participation: Empowering Neurodivergent Growth and Community Engagement (ENGAGE)
Get PDFObjective: Young autistic adults often struggle with soft skills essential for community engagement. Identifying services for soft skills training is challenging, limiting their community involvement. This quality improvement project aims to address the need for soft skills training to enhance social interaction for young autistic adults.
Methods: A needs assessment was conducted with stakeholders from the Adult Day Program at Avondale House in Houston, TX, to gather information on current resources, training, and clients\u27 ability to apply skills in the community. Six autistic adult clients were recommended to participate in the 12-week soft skills training program called ENGAGE. The RTI-E assessment was used in a non-standardized format to establish baseline communication skills, which informed the creation of ENGAGE. The program was implemented with at least one staff member and 5-6 adult clients.
Results: The needs assessment revealed that conversation with peers (64%), conversation with staff (73%), asking for help (73%), responding to feedback (73%), understanding verbal cues (73%), and confirming understanding of instructions (91%) were important. Qualitative data indicated difficulties in developing and applying soft skills in public settings, interacting with others, and teamwork. ENGAGE was implemented and measured through targeted rubrics. The minimum score was 1 (needs improvement), with a maximal score within each criterion of 4 (excellent). Post-ENGAGE implementation, classroom assessments showed improvements in communication (1.67 to 2.33), teamwork (1.5 to 2.33), adaptability (1.83 to 2.25), emotional regulation (1.67 to 2.42), problem-solving (1.5 to 1.92), and initiative (1.83 to 2.25). Community outings also showed improvements in communication (1.67 to 2.5), teamwork (1.71 to 2.5), adaptability (1.81 to 2.5), emotional regulation (2.05 to 2.67), problem-solving (1.48 to 2.17), and initiative (1.58 to 2.17). Staff satisfaction surveys indicated high satisfaction and confidence with ENGAGE, with most responses scored as 4 (agree). Management at Avondale House rated their satisfaction with the program as 5 (strongly agree). A thematic analysis identified overarching themes of engagement and motivation, social interaction and teamwork, challenges and barriers, skill development, and emotional responses.
Conclusion: The needs assessment indicated that young autistic adults benefit from soft skills training that supports the translation of skills from familiar settings to the community. The ENGAGE program, incorporating weekly classroom sessions and tasks encouraging client interaction, resulted in positive feedback from clients and staff. Over 12 weeks, there was a positive trend in all the criteria assessed, leading to overall satisfaction from management and staff for soft skills acquisition in their clients
Comparative Analysis of Inpatient and Outpatient Total Hip Arthroplasty: Cost, Rehabilitation, and Complexity
No full textBackground: Osteoarthritis in the hip joint leads to worn or damaged cartilage, resulting in bones scraping against each other. This scraping creates rough surfaces, causing significant pain and limiting mobility in daily activities. THA becomes necessary when other less invasive options fail to alleviate symptoms such as pain, stiffness, swelling, and reduced range of motion. Due to high out-of-pocket costs and the rapid spread of COVID-19, CMS took a substantial stride in healthcare policy by introducing the CMS-1736-FC ruling in December 2020. This ruling, effective from January 2021, facilitated the reclassification of eleven procedures, including Total Hip Arthroplasties (THAs), from inpatient-only to outpatient status.
Methods: The study will be a propensity-matched retrospective quantitative cohort study with three objectives: compare total costs and readmission rates between OP and IP THA, explore rehabilitation impact and costs post-IP vs. OP THA, and address potential medical complexity differences using Charlson Comorbidity Score and The Elixhauser Comorbidity Index. The inclusion criteria for this study were set for adults 18 years old and older who had an elective THA. In contrast, the exclusion criteria were set for patients who underwent an emergent THA, had metastatic cancer to the hip joint, or underwent a revision of THA.
Results: The adjusted model for THA total costs concludes that surgery undertaken in the IP setting cost, on average, 7,823-8,457; p \u3c 0.0001) more than one undertaken in the OP setting. The adjusted mean values of IP vs. OP THA Rehab Costs (90 Days Post-THA) indicate OP rehabilitation, on average, costs 247-254; p \u3c 0.0001). The adjusted mean Rehabilitation Days (90 Days Post-THA) indicate an additional 2.7 days of rehabilitation post-IP THA vs. OP (95% CI 2.3-3.1 days; p \u3c 0.0001). Adjusted All-Cause Readmission (90 Days Post-THA) Outpatient vs. Inpatient variable had a Hazard Ratio of 2.211, which indicates patients undergoing IP THA were 2.2 times more prone to experience readmission within 90 days post-THA than those who underwent OP THA. The unadjusted model concludes that IP readmission rates (90 days post-THA) were 2.6 times higher than OP (p \u3c 0.0001). All models were adjusted for Age, Region, and Charlson Comorbidity Score.
Conclusion: THA procedures conducted in an OP setting demonstrated lower costs than those performed in a traditional IP setting. However, upon closer examination of rehabilitation costs 90 days post-THA, it became apparent that OP rehabilitation costs exceeded those associated with IP care. This finding may be attributed to the prevalence of episode-based payment systems, commonly known as bundled payments, exemplified by CMS\u27s Comprehensive Care for Joint Replacement (CJR) model for Medicare beneficiaries. Payers frequently provide bundled payments for inpatient THA, encompassing post-THA IP rehabilitation services reimbursement. Subsequently, the data revealed that OP THA results in a statistically significant decrease in rehabilitation duration compared to the traditional IP method. Lastly, OP THA demonstrated lower observed readmission rates than traditional IP THA
Exploring the Perceptions and Experiences of Remote Work Among Administrative Healthcare Personnel at an Academic Medical Center in the Southeastern United States: A Qualitative Investigation
Get PDFThis qualitative study investigates the attitudes and experiences of administrative healthcare employees toward remote work at an Academic Medical Center (AMC) in the Southeastern United States. Amid the COVID-19 pandemic, healthcare organizations rapidly shifted toward remote work to ensure safety, prompting questions regarding the sustainability of this model. Through semi-structured interviews, participants expressed a preference for remote work, citing increased productivity and job satisfaction. Flexibility emerged as a key benefit, allowing employees to effectively integrate professional and personal responsibilities. However, maintaining boundaries between work and personal life posed challenges, necessitating clear policies and support structures. This project contributes to existing literature by exploring remote work within a large-scale academic medical center, offering insights into its impact on productivity, job satisfaction, and work-life integration. Findings indicate a favorable attitude toward remote work among administrative healthcare employees, suggesting its potential as a working model for administrative personnel in the healthcare space