MEDICA@MUSC (Medical University of South Carolina)
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Influence of Canonical and Non-Canonical IFNLR1 Isoform Expression on Interferon Lambda Signaling
Get PDFInterferon lambdas (IFNLs) are innate immune cytokines that induce antiviral cellular responses by signaling through a heterodimer composed of IL10RB and the interferon lambda receptor 1 (IFNLR1). Multiple IFNLR1 transcriptional variants are expressed in vivo and are predicted to encode distinct protein isoforms whose function is not fully established. IFNLR1 isoform 1 has the highest relative transcriptional expression and encodes the full-length functional form that supports canonical IFNL signaling. IFNLR1 isoforms 2 and 3 have lower relative expression and are predicted to encode signaling defective proteins. To gain insight into IFNLR1 function and regulation, we explored how altering relative expression of IFNLR1 isoforms influenced the cellular response to IFNLs. To achieve this, we generated and functionally characterized stable HEK293T clones expressing doxycycline-inducible FLAG-tagged IFNLR1 isoforms. Minimal FLAG-IFNLR1 isoform 1 overexpression markedly increased IFNL3-dependent expression of antiviral and pro-inflammatory genes, a phenotype that could not be further augmented by expressing higher levels of FLAG-IFNLR1 isoform 1. Expression of low levels of FLAG-IFNLR1 isoform 2 led to partial induction of antiviral genes, but not pro-inflammatory genes, after IFNL3 treatment, a phenotype that was largely abrogated at higher FLAG-IFNLR1 isoform 2 expression levels. Expression of FLAG-IFNLR1 isoform 3 partially augmented antiviral gene expression after IFNL3 treatment. In addition, FLAG-IFNLR1 isoform 1 significantly reduced cellular sensitivity to the type-I IFN IFNA2 when overexpressed. These results identify a unique influence of canonical and non-canonical IFNLR1 isoforms on mediating the cellular response to interferons and provide insight into possible pathway regulation in vivo
Association Between Arkansas Cannabis Program Implentation and Drug Overdoses
Get PDFOverdose rates have been on the rise in the United States. In 2018 Arkansas launched its medical cannabis program. The effects of cannabis are still not widely known due to limited research and legislation. Utilizing state issued reports, we examined if a state medical cannabis program had any impact on overdose rates between 2018 and 2020. Data was examined from the Arkansas Prescription Drug Monitoring Program and the Arkansas Medical Marijuana program to determine if a pattern could be recognized on the impact of state medical cannabis programs. Data was examined at a county level to determine if any change had occurred between 2018 and 2020. While largely inconclusive there is some evidence to suggest the state cannabis program could have a positive impact, but further and more detailed research is needed
Orphan Drug Reimbursement Trends
No full textBackground: Orphan drugs are developed to treat rare diseases that affect a small number of individuals. Due to the limited patient demand, orphan drugs are expensive to develop and bring to market. After the passage of the Orphan Drug Act in 1983, over 600 drugs have been approved. However, the coverage and reimbursement for these drugs by commercial health insurance and Medicare are not well understood. Methods: The orphan drugs approved by the FDA between 2015 - 2016 were identified via FDA Search Orphan Drug. A collection of paid claims data was examined on a retrospective basis using the 2016-2020 MarketScan® (Truven Analytics) Medicare and Private Insurance databases to determine the existence and differences in the reimbursement among commercial health insurers and Medicare for first-in-class orphan drugs launched between 2015 - 2016. Two cohorts of patients were identified and matched for their clinical conditions: commercial health insurance and Medicare. Descriptive statistics were reported using mean and standard deviation for continuous measures and frequencies and percentages for categorical variables to investigate relationships between the outcome variables, controlling for age, sex, insurance plan, and the approved rare disease indication. Results: All seven orphan drugs were covered by commercial health insurance and Medicare, when applicable. However, the orphan drug coverage, out-of-pocket costs, and cost of treatment varied across commercial health insurance and Medicare programs. Further, for all orphan drugs analyzed, commercial health insurance pays higher payments to providers and commercially-insured patients pay significantly higher maximum out-of-pocket costs than Medicare beneficiaries. Conclusion: This study highlights the complex landscape of coverage and reimbursement trends for orphan drugs by commercial health insurance and Medicare. These insights provide valuable information for stakeholders in the healthcare industry to guide future research and development efforts. In addition, the study emphasizes the crucial need for continued surveillance and evaluation of the orphan drug sector to ensure patients\u27 access to affordable and effective treatments
Telehealth Impact on National Emergency Department Utilization Among Children with Type 1 Diabetes Mellitus
Get PDFBackground: The COVID-19 pandemic brought challenges to patient care as healthcare entities and systems were forced to move care virtually in many instances. Some organizations were poised for this challenge while others struggled, however, most were concerned with how well patients were being managed as telehealth became a primary method in care delivery. This study aims to evaluate the impact of telehealth services on ED utilization rates for children ages 0-12 years with a new diagnosis of Type 1 diabetes mellitus.
Methods: Using linear regression analyses and individual and state fixed effects models, over 67000 emergency department (ED) and telehealth claims were reviewed as well as over 3000 total daily visits. The findings were displayed in line graphs for comparison and descriptive tables.
Conclusion: Data analysis showed that telehealth care may be an effective tool in reducing emergency department utilization for children within the defined cohort. Although ED and telehealth were rare events, through both models, telehealth was not shown to increase the probability of an ED claim/visit
A PNPLA3-Deficient iPSC-Derived Hepatocyte Screen Identifies Drugs to Potentially Reduce Steatosis in Nonalcoholic Fatty Liver Disease
No full textBackground and Aims: The incidence of Nonalcoholic Fatty Liver Disease (NAFLD) is dramatically increasing in adults and children, while effective pharmacological treatments remain unavailable. NAFLD can progress from lipid accumulation in the liver to more severe inflammation, cirrhosis, and cancer. It is the most common cause of chronic liver disease and is projected to be the leading cause of end-stage liver disease in the next decade. Many etiologies contribute to NAFLD. A single nucleotide polymorphism (SNP) in the Patatin-like Phospholipase Domain Containing Protein (PNPLA3 I148M) has the most significant genetic association with the disease and all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the scarcity of a cellular platform that recapitulates PNPLA3 I148Mmediated onset of lipid accumulation in human hepatocytes. We used hepatocytes generated from PNPLA3 I148M induced Pluripotent Stem Cells (iPSCs) to model the effect of the polymorphism on lipid content and lipid droplet accumulation, providing a platform to identify small molecules with potential therapeutic value using an established high-throughput screening platform.
Approach and Results: We generated isogenic PNPLA3 I148M/M and PNPLA3 ∆1/∆2 iPSCs using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9. Using established protocols, we differentiated the resulting cells into hepatocytes and measured the efficiency of differentiation. Using BODIPY 493/503 staining, we determined lipid accumulation in our iPSC- x derived hepatocytes. We then performed a small molecule screen to identify compounds that reduce lipid accumulation in the PNPLA3 variant cells. Both the PNPLA3 I148M/M and PNPLA3 ∆1/∆2 iPSC-induced hepatocytes revealed a significant increase in lipid content compared to control iPSC-induced hepatocytes. Our small molecule screen identified lead compounds that target specific pathways, including Src/PI3K/Akt signaling, that limit lipid accumulation in PNPLA3- deficient iPSC-hepatocytes. We showed that drugs that are currently in clinical trials and that target the same pathways are promising treatments for PNPLA3-derived NAFLD.
Conclusions: We conclude that human iPSC-derived hepatocytes with the PNPLA3 I148M variant or PNPLA3 loss-of-function alleles, can be used to effectively model the onset of NAFLD. We demonstrate that the model also provides a platform to identify molecular pathways with potential therapeutic value and that off-label use of therapeutics that target Src/PI3K/Akt signaling pathways can limit lipid accumulation in PNPLA3 mutant cells
The Effectiveness of Using a Community-Based Yoga Program to Increase Feelings of Inclusion in Adults with Intellectual Disabilities
Get PDFLet’s Make a Deal: Gamification of Literature Searching
Get PDFBackground: In the Doctor of Pharmacy program at our institution, first-year pharmacy students (P1s) are introduced to literature searching during the Introduction to Drug Information course. The liaison librarian embedded into this course found that students were struggling with feeling confident in their literature searching skills despite participating in active-learning activities. An area of opportunity was identified through the course evaluation feedback that students wanted more fun and engaging ways to practice literature searching. This paper will discuss one librarian’s experience with gamification, and provide two examples of gamified literature searching instruction sessions.Description: Introduction to Drug Information is set up in a completely flipped classroom style, where students watch pre-class videos, and complete pre-class assignments before coming to an in-person 50-minute lecture. During these in-person lectures, active learning techniques are used to reinforce the skills taught in the pre-class videos. Literature searching is taught over a two-week period and is broken up into basic searching techniques and advanced searching techniques. Previously, the active learning strategy utilized was a handout that students needed to complete before being reviewed as a group. After reviewing the literature and conference abstracts for currently used techniques, two more interactive strategies were selected. A crossword puzzle was created for the basic literature searching instruction, and a virtual escape room was created for the advanced literature searching instruction. Students were given the option to work individually or in small groups. Initial feedback from the students has been positive, and formalized feedback will be collected at the conclusion of the course.Conclusion: Overall the gamification of literature searching in this course was a success in getting students more engaged with the content. Student feedback after each session was positive, and a comparison of end-of-year evaluations showed that students enjoyed gamification, even going as far as to ask for more games and more group work. Students scored higher on their literature searching assignment after implementing these activities and the librarian received fewer emails asking for clarification or requesting to meet. Future steps include a research project to evaluate ways to incentivize student engagement with flipped content throughout the course
