MEDICA@MUSC (Medical University of South Carolina)
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Personalization and Optimization of Noninvasive Brain Stimulation for Transdiagnostic Applications
No full textNoninvasive brain stimulation, including transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES), can effectively treat numerous psychiatric and neurological diagnoses, including depression, tobacco use disorder, obsessive compulsive disorder, and migraine headaches. However, despite FDA-approval for multiple TMS treatments, many patients still fail to respond to treatment. In addition, while tES is a promising technology, there are no FDA-approved treatments to date. In TMS and tES, developing more personalized and optimized dosing to ensure that each patient receives sufficient target engagement of the intended brain region could lead to higher and more consistent response rates across patients and diagnoses.
This dissertation is comprised of 10 studies exploring the utility of electric field (E-field) modeling to personalize and optimize stimulation approaches transdiagnostically using TMS and tES. E-field modeling accurately estimates the stimulation intensity at the cortical target using current flow models with experimentally derived tissue conductivity values. The present work includes the development of prospective E-field based dosing approaches, technical refinement of modeling methodology, and the use of E-field modeling to strategically derive novel tES electrode positioning that maximizes on-target stimulation intensity while minimizing off-target effects.
Regarding TMS, we found that the standard clinically applied 120% motor threshold intensity over the prefrontal cortex is insufficient to produce the same E-fields elicited over the motor cortex and with high inter-individual variability. In tES, one-size-fits-all 2mA stimulation produced a wide range of individual cortical stimulation intensities, and reverse-calculation E-field dosing can reduce the variability over 100x. The cortical intensity at the brain target is behaviorally meaningful, with older adult participants having significantly larger working memory improvements when they experienced higher E-fields from 2mA. Utilizing E-field modeling to derive novel tES electrode placement strategies in 3000 models, we found that smaller electrodes placed equidistant and surrounding the cortical target produces over double the on-target E-field as traditional approaches with a fraction of the off-target effects. Finally, our research has begun to address the technical hurdles necessary to implement prospective personalized E-field dosing. Using T1 and T2-weighted scans maximizes model accuracy, and outcome measure selection critically impacts modeling results, such that the average volume overlap between common outcome measure methods is only 6%.
In sum, E-field modeling is a useful approach to personalize and optimize TMS and tES. With the reverse-calculation dosing approach, data suggestive of a positive dose-response curve, and standardization of MR scan type and outcome measure selection between studies, future experiments can begin to test the therapeutic utility of individualizing E-field dosing prospectively
The Association of Foreign PHI on AME & Death
Get PDFBackground: Recent data shows at least 1.5 million people are affected by adverse medication events (AME) every year. The purpose of this study is to see if increased use of FPHI is associated with lower instances of AME’s and lower mortality rates for hospitals.
Methods: Using a retrospective analysis and logistic regression, this study examines the relationship between IT use and quality. Specific metrics include AMEs and mortality rates in hospitals in the United States. Demographic data are used to control for confounders, CPT, DRG, and AHRQ questions are used as classifying variables for High IT utilization.
Results: Unadjusted rates of AME’s were higher among high-IT hospitals than non-high-It hospitals (27.8% vs. 15.8%; p
Conclusions: There is a clear association between the increased use of FPHI and lower adverse medication events (AME) rates. Studies have shown that of all the AME’s yearly 50% are preventable and the finding presented here show that high use of FPHI could potentially lower the odds of an AME by 36%. Given these findings, hospitals may want to consider incentivizing the utilization of FPHI in their Eds
Cancer-Specific Perturbations to Arginine Metabolism Blunt Replication and Performance of Oncolytic Myxoma Virus
Get PDFOncolytic virotherapy (OV) is a class of immunotherapy for treatment of malignancy. Using viruses that exhibit natural coincidental tropisms for cancer, or others that have been engineered to the same effect, intentional infection of lesions leads to two therapeutically beneficial effects: (1) direct destruction of the infected tumor through virally-mediated cell lysis, and (2) recruitment of an otherwise blunted or absent anti-cancer immune response to affect both local and disseminated disease. A surfeit of cancer-specific changes are accumulated during progression from first genetic insult to clinical detection, presenting a dramatically altered underlying biology of cell and tissue. The viruses employed within OV have been characterized over decades, however, all largely within the context of normal and otherwise-healthy host cells bearing infections. As such, these disparities between cancerous tissues and their normal counterparts may pose barriers to viral infection not encountered or compensated for.
Dysregulations within cellular metabolism are a hallmark of cancer, and the replication of all viruses – oncolytic or not – is contingent on access to host metabolites. Despite this, no research has been conducted evaluating how metabolic changes within tumors may lead to resistance to OV infection. One such dysregulated metabolic pathway is synthesis and consumption of L-arginine (Arg), a semi-essential amino acid whose bioavailability is required for the in vitro replication of several oncolytic viruses. Cancer types such as hepatocellular carcinoma, sarcoma, and melanoma often clinically present as functionally auxotrophic for this amino acid due to epigenetic silencing of argininosuccinate synthetase 1 (ASS1), an enzyme responsible for the conversion of citrulline and aspartate into the Arg precursor argininosuccinate (AS). Additionally, the recruitment of Arginase-1 (ARG1) positive myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) further insult Arg availability within the TME.
Here, we show that the in vitro replication of oncolytic myxoma virus (MYXV) is dependent on the presence of bioavailable Arg, with insight towards several stages within the viral life cycle. We demonstrate that the presence of MDSCs negatively reduces viral burden within infected tumors in a B16F10 model of murine melanoma, with their depletion capable of reducing initial required MYXV dose to elicit a therapeutic response, and these effects possibly attributable to an expression of ARG1 as evidenced within cocultures ex vivo. Secondly, we determine the role of ASS1 in mediating tumoral capacity for viral replication in vitro and in vivo using CRISPR/Cas9 generated ASS1KO cell lines. Here, we find tumors formed from functionally ASS1KO B16F10 melanoma cells display multi-log reductions in MYXV replication during oncolytic virotherapy (OV) as well as significantly poorer therapeutic responses. Lastly, we demonstrate that reconstitution of Arg biosynthesis through ASS1-armed MYXV constructs at least partially rescues these effects. Collectively, these studies demonstrate an Arg-dependent replication of MYXV that may be affected by cancer-specific changes within Arg metabolism and consumption. This work is the first to characterize a metabolic barrier to achieving optimal viral replication within tumors, and indicates that consideration towards tumoral metabolism may improve replication and therapeutic efficacy of OV agents
Healthcare Employees’ Perceptions on the Effects of Internal Audits
Get PDFWith limited research on the perceptions of internal audits, this study was
able to add more literature to the subject. The study’s aim was to survey
employee perceptions of the effects of internal audits. This study will provide organizations with results pertaining to how employees perceive the usefulness of internal audits. The study team conducted a single-site study and invited the healthcare organization\u27s employee population to participate in the study. The survey captured 40 responses from 361 invitees (11%). The survey explored the perceptions on six categories of internal audits: Efficiency, Ethical Behavior, Effectiveness, Auidotr-Auditee Relationship Exchange, Learning from Audit, and Top Management Support. Each category\u27s effect on internal audits was weighed by the “Strongly Agree” selection. 1.) 84 (29.9%) Top management, 2.) 55 (19.6%) Learning from Audit, 3.) 48 (17.1%) Auditor-Auditee Relationship Exchange, 4.) 42 (14.9%) Efficiency, 5.) 38 (13.5%) Ethical Behavior, and 6.) 14 (4.9%) Effectiveness. Furthermore, each category received its top response count for the selection of “Agree”. Therefore it was quite evident that each category is perceived to be an effect of internal audits. The survey results of this study can guide organizations on key areas of internal audits
Student Engagement Interest Group: Preparing Students for the Library and Health Information Workforce
Get PDFBACKGROUND
The purpose of the Network of the National Library of Medicine’s (NNLM) Student Engagement Interest Group (SEIG) is to advance the mission of NNLM by sharing participating regional offices and center\u27s (ROCs) student engagement-related activities and prioritizing those appropriate for national coordination. Additionally, the SEIG prioritizes students, high school age and older, from traditionally marginalized communities and those underrepresented in biomedical research when conducting student engagement activities.
Since the creation of the SEIG, the group has explored how NNLM can support students in acquiring experience in a professional setting, gaining access to mentors who can guide them in preparation to enter the library and information workforce and develop knowledge and skills to become better versed in health information resources.
DESCRIPTION
The SEIG consists of 10 members that meet once a month to identify and develop NNLM-wide strategies and metrics to advance student engagement, implement and evaluate strategies in increasing student engagement across the country, including those from underrepresented populations in biomedical research, and guide the development of programs that enhance skills of students in NLM resources and interest within the health professions, including health sciences librarianship.
Some examples the SEIG has discussed for promoting student engagement are sharing project ideas that would benefit the intern or practicum student’s overall experience and support their areas of interest, methods to engage with LIS and iSchool programs to recruit potential students for practicums and internships, and providing opportunities to acquire knowledge and tools for students that may not be able to obtain in their program.
CONCLUSIONS
The SEIG made great progress in supporting LIS/iSchool students in acquiring knowledge and experiences to better prepare them for the library and information field. This progress led to hosting practicums and internships across several ROCs. For instance, the group collaborated with Region 1 to create a plan on how NNLM can support the University of Kentucky students participating in the Alternative Spring Break.
The committee also produced a draft of the student engagement handbook that NNLM ROCs can use as a guide to effectively recruit, host, and provide quality mentorship experiences for students choosing to spend their practicum or internship time with the NNLM program. The handbook is anticipated to be finalized and implemented in the coming year