University of Tennessee Health Science Center
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Tune Up Your Teaching Toolbox
Get PDFOccupational therapy (OT) educators strive to prepare entry-level practitioners who have the expertise to meet the diverse health care needs of society. A variety of instructional methods are used in the University of Tennessee Health Science Center (UTHSC) MOT program, including traditional lecture-based instruction (LBI), problem-based learning (PBL), team-based learning (TBL), and game-based learning (GBL). Research suggests that active learning strategies develop the critical thinking and problem-solving skills that are necessary for effective clinical reasoning and decision-making abilities. PBL, TBL, GBL are being successfully implemented in the UTHSC MOT Program to enhance the learning process and improve student engagement
Maintaining the Master Patient Index: The impact of patient registration processes on data integrity
Get PDFThe master patient index is one of the most important components within a healthcare system. It ensures that an individual patient is given a unique identifier that is used across the various separate clinical, financial and administrative systems and ensures that all information about that patient is organized and complete. Ensuring the MPI is accurate is critical since errors can have significant costs- both financially and in terms of patient outcomes. Patient registrars are the first line of defense when it comes to correctly identifying incoming patients and is where many errors in the MPI occur. Errors can be simple misspellings in a patient name, unknowingly assigning a patient a second medical record number, or the worst type, registering a patient under a different patient’s MRN leading to intertwined medical histories being viewed by providers. This study looked specifically at a major health system in Richmond, Virginia to determine the existing workflows on how patients were identified in the MPI and how errors were corrected once known. A literature review was performed to determine if any evidence based practices exist for maintaining MPI data integrity and how the focus health system compares. In addition, two other comparable health organizations were surveyed to determine how they compare with the target and with national standards. It was found that the health system of focus did not have a MPI quality program in place at all which explains why it struggles with errors. A plan for a MPI program using criteria in the Improvement Focused Model was created and implemented. This plan focused on better collection of data on errors, more standardized procedures for registrars, and constructive feedback to registrars when errors do occur. Although after a relatively short period of implementation, there was little difference seen in the number of new errors being generated, it did find that there were a relatively few areas that were creating the majority of errors. Focus on these areas will undoubtedly help reduce future errors. Other factors that impact the lack of a decrease of errors is the complexity of how new registrations are created- some are generated by interfaces and have no human intervention at all. The takeaway from this study is that there are many more players with a critical role in data integrity than previously expected and that a quality MPI integrity program needs to be an ongoing program that focuses on continuous education, monitoring, and feedback to those players involved
Adverse Effects of Asparaginase in Pediatric Patients with Acute Lymphoblastic Leukemia
Get PDFAcute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. Asparaginase is a critical treatment component for ALL. However, its use is complicated by adverse effects, such as hypersensitivity, osteonecrosis and pancreatitis.
Hypersensitivity to asparaginase typically requires discontinuation of current formulation and substitution with other formulations, but the differential diagnosis can be challenging, and the diagnostic utility of antibody tests is unclear. We comprehensively analyzed anti-Elspar (native E.coli asparaginase) IgG antibodies in 410 pediatric patients treated on an asparaginaseintensive front-line clinical trial. Of 169 patients (41.2%) who exhibited clinical allergy, 147 (87.0%) were positive for anti-Elspar antibody. Of 241 patients without clinical allergy, 89 (36.9%) had detectable antibody. Among those positive for antibody, the antibody titers were higher in those who developed allergy than in those who did not (P \u3c 1.0 × 10-15). Antibody measures at week 7 of continuation therapy had a sensitivity of 87%-88% and a specificity of 68%-69% for predicting or confirming clinical reactions. Antibodies were inversely associated with serum asparaginase activity (P = 7.0 × 10-6 ). Interestingly, high antibodies were associated with a lower risk of osteonecrosis (odds ratio = 0.83; 95% confidence interval, 0.78-0.89; P = 0.007), which is a dose-limiting adverse effect of glucocorticoids but has also been linked to asparaginase treatment. We conclude that antibodies were related to clinical allergy and to low systemic exposure to asparaginase, leading to lower risk of other adverse effects of therapy. Measures of serum antibodies to asparaginase can be useful in patients with ALL.
Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. After 6 weeks of treatment, mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone (44% vs. 10%, P = 0.006). Primary epiphyseal arteriopathy, an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007). As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001). This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027) and asparaginase (P = 0.036). We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.
Acute pancreatitis is a serious complication of asparaginase with no definitive treatment. Risk factors for asparaginase-induced pancreatitis, especially the genetic predisposition, have not been clearly identified. We studied 5398 pediatric patients with ALL and showed that older age, higher exposure to asparaginase, higher Native American ancestry or African ancestry were independent clinical risk factors for pancreatitis. To determine genetic risk factors, we performed a genome-wide association study. A rare nonsense variant rs199695765 in CPA2, a pancreatic enzyme, was highly associated with pancreatitis (odds ratio = 588, 95% confidence interval 66.8- 5166, P = 9.0 ×10-9 ). A gene-level analysis showed an excess of additional CPA2 variants in those who did versus did not develop pancreatitis (P = 0.018). Furthermore, common variants in genes critical to purine metabolism and cytoskeleton function were also associated with development of pancreatitis. Our findings are consistent with a mixed genetic architecture underlying serious adverse drug effects, wherein a combination of rare but highly penetrant and common but weakly penetrant genetic risk factors contribute to genetic risk. For the patients carrying the highly penetrant variants, consideration should be given to treatment with a nonasparaginase containing ALL chemotherapy regimens.
Overall, we studied the major adverse effects of asparaginase in patients treated for ALL. These findings will provide important guidance for precision medicine
Overcoming Acquired Resistance to BRAF Inhibitors by Novel Synergistic Drug Combination and Discovery of Novel Smac Mimetics as Selective Survivin Inhibitors
Get PDFThe first part (Chapter 1 and 2) of this dissertation presents a novel combination study of melanoma therapy. Acquired clinical resistance to vemurafenib, a selective BRAFV600E inhibitor, arises frequently after short term chemotherapy. Since the inhibitions of targets in the RAFMEK-ERK pathway result in G0/G1 cell cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell cycle arrest and progress to subsequent G2/M phase. We hypothesized that a combined therapy using vemurafenib with a G2/M phase blocking agent will trap resistant cells and overcome vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of our novel tubulin inhibitor ABI-274 and vemurafenib on parental human A375 and MDA-MB-435 melanoma cell lines to be 0.32 and 0.1, respectively, suggesting strong synergy for the combination. We then developed an A375RF21 subline with significant acquired resistance to vemurafenib and confirmed the strong synergistic effect. Next we studied the potential mechanisms of overcoming vemurafenib resistance. Flow cytometry confirmed that the combination of ABI-274 and vemurafenib synergistically arrested cells in G1/G2/M phase, and significantly increased apoptosis in both parental A375 and the vemurafenib-resistant A375RF21 cells. Western blot analysis revealed that the combination treatment effectively reduced the level of phosphorylated and total AKT, activated the apoptosis cascade, and increased cleaved caspase-3 and cleaved PARP, but had no significant influence on the level of ERK phosphorylation. Finally, in vivo co-administration of vemurafenib with ABI-274 showed strong synergistic efficacy in the vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current BRAF inhibition therapy.
The second part (Chapter 3 to 5) of this dissertation focuses on the discovery of a series of small molecule survivin inhibitors. Inhibitors of apoptosis (IAP) proteins are widely considered as promising cancer drug targets, especially for drug-resistant tumors. Mimicking the IAP-binding motif of second mitochondria-derived activator of caspases (Smac) is a rational strategy to design potential IAP inhibitors. In this report, we used the bioactive conformation of AVPI tetrapeptide in the N-terminus of Smac as a template and performed a shape-based virtual screening against a drug-like compound library to identify novel IAP inhibitors. Top hits were subsequently docked to available IAP crystal structures as a secondary screening followed by validation using in vitro biological assays. Four novel hit compounds were identified that potently inhibited cell growth in two human melanoma (A375 and M14) and two human prostate (PC-3 and DU145) cancer cell lines. The best compound, UC-112, has IC50 values ranging from 0.7 to 3.4 µM. UC-112 also potently inhibits the growth of P-glycoprotein (Pgp) overexpressed multidrug-resistant cancer cells, strongly activates capase-3/7 and caspase-9 activities, and selectively down-regulates survivin level at a concentration as low as 1 µM. Co-incubation of UC-112 with a known proteasome inhibitor (MG132) rescued survivin inhibition, consistent with the anticipated mechanism of action for UC-112. As a single agent, UC-112 strongly inhibits tumor growth and reduces both XIAP and survivin levels in an A375 human melanoma xenograft model in vivo. Three analogs generated from UC-112 structural modification along with template compound UC-112 were submitted to NCI-60 cancer cell line screening. The results indicated that structural modification of UC-112 to give our best compound MX106 has improved activity by four fold (2.2 µM for UC-112 vs. 0.5 µM for MX106, average GI50 values over all cancer cell lines in the NCI-60 panel).Western blot analyses demonstrated the new compounds maintained high selectivity for survivin inhibition over other members in the inhibitiors of apoptosis protein family. When tested in an A375 human melanoma xenograft model, the most active compound MX106 effectively suppressed tumor growth and strongly induced cancer cell apoptosis in tumor tissues. Taken together, this novel scaffold is promising for the development of selective survivin inhibitors as potential anticancer agents
Medicaid Discontinuity among Adults with Cardiovascular Disease or High Risk Conditions: Associations with Medication Adherence and Health Care Utilization
Get PDFBACKGROUND: Medicaid coverage among adults is often characterized by discontinuity – loss of Medicaid coverage, and churning, or entering and exiting Medicaid – over short durations. Little is known about the impact of having discontinuous Medicaid coverage on access to care, preventive care, pharmacotherapy, primary care, and hospitalizations, among non-elderly adults with cardiovascular disease (CVD) or high-risk conditions.
OBJECTIVES: This dissertation employed a three empirical research papers approach to pursue the following aims: (1) characterize the adult subpopulations with CVD or conditions placing them at high risk for CVD who lack continuous Medicaid coverage, and examine the characteristics associated with Medicaid discontinuity, (2) examine associations between Medicaid discontinuity, medication adherence and medication utilization, and (3) examine the associations between Medicaid discontinuity, access to care, preventive care, primary care visits, and hospitalizations.
METHODS: This was a retrospective comparative analysis of the 2002–2011 Medical Expenditure Panel Survey employing a repeated cross-sectional study design. Study sample included adults aged 18–64 years diagnosed with ≥1 CVD (defined as acute myocardial infarction, coronary artery disease, congestive heart failure, peripheral and visceral atherosclerosis, or stroke) or high-risk conditions for CVD (defined as hypertension, lipid disorders, diabetes, or chronic kidney disease) who reported having Medicaid coverage any time during survey year. Individuals having continuous, full-year Medicaid coverage (Continuous Medicaid) were compared to those with(Discontinuous–Uninsured), and separately to those with(Discontinuous–Insured). Associations between Medicaid discontinuity, access to care, and preventive care were estimated using multivariate logistic regression. Medication adherence, measured as medication possession ratio (MPR) with adequate adherence being considered at MPR\u3e0.8, was estimated using multivariate logistic regression. Medication utilization, measured as the number of all-cause, and disease-specific prescription drug fills, was estimated using multivariate negative binomial regression. Four health care services utilization outcomes – inpatient, emergency room (ER), hospital outpatient, and office-based physician visits – measured as both, number of all-cause and number of disease-specific visits, were estimated using either zero-inflated negative binomial regression or negative binomial regression depending on the distribution of the outcome of interest.
RESULTS: Overall, 31.8% of adults with CVD or high-risk conditions for CVD hadcoverage, majority of whom (23.5%) belonged to the Discontinuous– Uninsured group. Of those who had Medicaid at the beginning of the year, only 21.9% of the Discontinuous–Uninsured, and 8% of the Discontinuous–Insured still had Medicaid by the year end. Male gender, minority race/ethnicity, receiving disability benefits or participating in a federal assistance program, Medicaid managed care enrollment, and diagnosis of respiratory illnesses were the characteristics associated with lower odds of Medicaid discontinuity, whereas being married, residing in the South, having higher income, or education, being employed, and having fair to poor perceived health status were associated with higher odds of Medicaid discontinuity. Overall adherence to commonly prescribed therapeutic medication classes, measured as average MPR, was not significantly different between the Continuous Medicaid and the two discontinuous coverage groups, whereas examination of class-specific adherence yielded mixed results. Discontinuous Medicaid coverage was associated with significantly lower allcause and disease-specific prescription drug utilization among both the discontinuous Medicaid groups. Medicaid discontinuity was associated with poor access to care, and higher diseasespecific inpatient and ER hospitalizations among both the discontinuous Medicaid coverage groups. Additionally, among the Discontinuous–Uninsured, Medicaid discontinuity was associated with lower odds of routine medical checkup, lower all-cause primary care office visits, and higher disease-specific hospital outpatient visits.
CONCLUSION: Among non-elderly adults with CVD or high-risk conditions, for CVD having discontinuous Medicaid coverage was found to be associated with poor access to care and preventive care, poor adherence to certain medication classes and lower utilization of prescription medications, higher hospitalizations for CVD or associated conditions, and lower primary care office visits. Disruptions in and loss of Medicaid coverage among adults with CVD or high-risk conditions may lead to negative health outcomes due to the disruptions in continuity of care and inability to appropriately manage these disease conditions. This research provides strong support for implementation of policies to stabilize Medicaid coverage and reduce Medicaid discontinuity among individuals with CVD or high-risk conditions for CVD, such as the 12 month continuous Medicaid eligibility provisions currently in place for low-income children. Such policies will greatly improve some of the adverse access to care, preventive care, pharmacotherapy, and medical care outcomes observed in this study. Vulnerable populations with chronic, debilitating conditions may benefit from such policies to a greater extent compared to the overall low-income adult population. Simultaneously, reenrollment and outreach strategies may need to be more efficiently implemented to ensure individuals who are eligible for Medicaid, continue to remain enrolled in Medicaid. Such enabling strategies employed by Medicaid managed care organizations may be adopted by State Medicaid agencies to ensure greater continuity in Medicaid coverage for low-income vulnerable populations with chronic and debilitating diseases
The Impact of CIWA-Ar Tool on Healthcare Professionals
Get PDFAlcohol is one of the most abused substances worldwide. The regular consumption of alcohol can lead to dependency which depresses the central nervous system. Consequently, when a heavy drinker is no longer consuming alcohol, the central nervous system is no longer suppressed and may go into a hyperexcitable state known as alcohol withdrawal syndrome (AWS). Symptoms can vary from mild to life threatening. Patients who experience alcohol withdrawal symptoms often have a more complicated hospitalization, an extended length of stay, and increased utilization of intensive care and medical services. The Clinical Institute Withdrawal Assessment of Alcohol Scale-revised (CIWA-Ar) is a tool that can be used to objectively assess patients for the development of AWS. By using the CIWA-Ar to assess patients, nurses can quantify the potential for the development of AWS and therefore initiate treatment for patients who require therapy.
The purpose of this research is to evaluate the impact that CIWA-Ar has on care provided by healthcare professionals
Functional Activity and Switching of Novel Cannabinergic Ligands
Get PDFPursuant to the discovery of the cannabinoid receptors, research in this field has grown exponentially over the last 2 decades. With their utility in various disease states such as heart disease, cancer, stroke, neurodegenerative and inflammation, cannabinoids stand poised to become a great therapeutic agent. This research seeks to better understand the functional mechanism of cannabinoids, in the hopes of ascertaining which molecular attributes confer desirable selectivity and functional activity.
Looking first at classical benzchromene core analogues, we have shown that presence of an aromatic substitution at C-1\u27 imparts a CB1 agonist, CB2 antagonist. This is a unique mechanism and one of the first examples of an agent with dual affinity and opposing activity.
In the triaryl series of compounds, more insight is gained for the functional pharmacophore of cannabinoids. With this series of compounds we are able to learn that minor changes are able to confer profound differences, such as C-1\u27-gem-dimethyl derivatives are agonists while C-1\u27 ketones are inverse agonists.
Within these triaryl series, newly synthesized derivatives help to round out the functional pharmacology for these compounds - allowing a more direct comparison to the previously synthesized classical core compounds. In total, a more thorough understanding of the function, which follows form of several cannabinergic compounds, is gained through this exercise and research
Design, Development, Characterization and Testing of CD22 Targeted Long Circulating Liposomal Drug Delivery Systems for B Cell Malignancies
Get PDFHematological malignances of the B cells affect almost 130,000 people in the United States every year of which approximately 44,000 lose their lives. Therapies for B cell malignancies such as doxorubicin, have limitations due to dose related adverse effects such as neutropenia and cardiomyopathy. AD 198 is a novel PKC-delta activating agent that has cytotoxic superiority over doxorubicin by being able to circumvent resistance mechanisms developed by the cancer cells towards doxorubicin and being cadioprotective from the damage caused to cardiomyocytes by doxorubicin. Targeted delivery of AD 198 is crucial to moderate the non-specific interactions of the chemotherapeutic agent with healthy cells. The objective of this work was to design, develop and evaluate AD 198 loaded liposomal formulations for targeted delivery to CD22 overexpressing B cell cancers. Liposomes were prepared by the classical Bangham method followed by size reduction by extrusion. Anti-CD22 Fab’ were generated and conjugated to the long circulating AD 198 liposomes by thioether bonds. Physicochemical parameters of the CD22 targeted liposomal formulation such as size, zeta-potential, drug encapsulation, drug release and drug targeting were optimized to maximize efficacy and stability of the nanoparticles. In vitro studies established that uptake of the targeted liposomes was via an endocytotic pathway independent of the conventional proteins involved in clathrin and caveolae dependent endocytosis. Uptake was preferentially higher in CD22 overexpressing malignant B cells (Daudi) compared to cells devoid of CD22 (Jurkat). Intracellular localization of the targeted liposomes was observed to be in endolysosomes which suggests that drug release was via lysosomal enzymatic breakdown of the liposomal structure which would release encapsulated AD 198. Cytotoxicity was also observed to be higher in Daudi cells compared to Jurkat cells whereas free solution AD 198 had comparable cytotoxicity in both cell types. The mechanism of cell death was deduced to be apoptosis by the activation of apoptotic proteins such as caspase-3, and by the inhibition of oncoproteins such as c-myc. Stability of the dispersed liposomal formulation was inadequate for long term storage. To address this concern, lyophilized formulations were developed and optimized to maximize long term storage as displayed by short term stability studies. It was determined that targeted drug delivery with liposomal AD 198 was more potent and specific compared to other untargeted formulations
Challenges in the Pharmacokinetics of Therapeutic Proteins
Get PDFDue to the complex structure and complicated disposition pattern of therapeutic macromolecules, their pharmacokinetic interpretation has many challenges. Two of these challenges were investigated in this dissertation: 1) the error of classical bioavailability assessment observed during subcutaneous (SC) administration of therapeutic macromolecules that undergo target-mediated drug disposition (TMDD) and 2) the ontogeny of the neonatal Fc receptor (FcRn) expression along with its effect on the pharmacokinetics of monoclonal antibodies (mAbs) during development.
TMDD often well describes the pharmacokinetics of therapeutic proteins that have high specificity and affinity of binding to their target receptors. The target receptors can be saturated by therapeutic proteins under therapeutic concentration due to their limited expression and availability in the body. Consequently, clearance through this pathway will reach its maximum and nonlinear pharmacokinetics will be observed upon further increasing dose if TMDD is a major elimination process. This, in turn, will impact the bioavailability estimation. Bioavailability estimations based on the classic AUC approach can be erroneous in this situation, mainly due to the incorrect assumption of dose-independent constant clearance that cannot be applied to therapeutic proteins that undergo TMDD. To shed light on this issue, a simulation study was performed with two model drugs: filgrastim and denosumab. Their published structural pharmacokinetic models and model parameters were employed in the simulations of plasma concentration-time profiles at different IV and SC doses. The bioavailability was calculated as the ratio of dose-normalized AUC after SC administration to that after IV administration.
The overestimation was extreme when high SC and low IV doses of both protein drugs were used for the estimations, whereas excessive underestimation was observed with the combination of low SC and high IV doses. These biases in the bioavailability estimation resulted from the transition from low plasma concentration (at low doses) to high plasma concentration (at high doses), which shifted the major elimination pathway from TMDD to the unspecific linear clearance pathway. The changes in clearance resulted in parallel changes in dosenormalized AUCs and were very dynamic in the dose range of 0.1 – 5 µg/kg for filgrastim and below 60 mg for denosumab; thus caution is necessary when bioavailability of these two therapeutic proteins is estimated in these dose ranges using conventional method. To minimize the error of conventional bioavailability estimation of protein drugs that undergo TMDD, the bioavailability should be estimated at similar IV and SC doses or the assessment should be performed in dose ranges that yield constant dose-normalized AUCs (0.01 – 0.1 µg/kg or 5 – 10000 µg/kg for filgrastim, and 60 – 210 mg for denosumab). Moreover, an alternative estimation method could be applied, which determines the ratio of IV and SC doses that generate equally shaped concentration-time profile by applying a variable rate IV infusion, thereby resulting in equal AUCs as suggested by others.
FcRn has been evidenced as a salvage pathway from lysosomal clearance for mAbs and Fc conjugated proteins; thus it can prolong the existence of these protein drugs in systemic circulation. The ontogeny of FcRn expression and its effect on the pharmacokinetics of mAbs should be of special concern if therapeutic mAbs are used in both pediatrics and adults. The down-regulation of FcRn during the development may shortened the half-life of therapeutic mAbs observed in adults. To address this problem, FcRn expression was quantified in various organs of C57BL/6J mice from postnatal days 2 through 70, the pharmacokinetics of AMG589 were studied in different age groups of C57BL/6J mice, and the correlation between the FcRn expression levels and the pharmacokinetics of AMG589 at various developmental stages of mice were explored using a nonlinear-mixed effects modeling-based population pharmacokinetic approach.
FcRn showed ontogenetic changes in liver, lungs, and kidneys. Two-fold increases in FcRn expression were observed in liver and lungs of 10-day-old mice, whereas FcRn expression in the kidneys was doubled in 10- and 42-day-old mice. However, the ontogeny of FcRn expression could not be correlated to the prolonged persistence of AMG589 observed in 42 day old mice. A population pharmacokinetic approach revealed that after accounting for the effect of body weight by allometric scaling, age and FcRn expression in skin influenced the pharmacokinetics of AMG589 in different age groups of mice. Decreasing volume of distribution of AMG589 was observed during development. Interestingly, clearance of AMG589 was negatively correlated with the expression of FcRn in the skin, even though FcRn expression in skin did not show any ontogeny. These results suggest that body weight, age, and FcRn expression in skin could affect the pharmacokinetics of fully-human mAbs. However, regardless of the species difference in physiology, body weight should be considered during dosage regimen design, especially for pediatric patients who show a highly dynamic change in body size at early age.
In summary, the findings in this dissertation have pointed out the weakness of the classical bioavailability estimation for protein drugs that undergo TMDD and have determined the factors that should be considered for dose adjustments of therapeutic mAbs in different-aged populations
The Role of Occupational Therapy in the Prevention of Infant Torticollis & Plagiocephaly
Get PDFAOTA includes health promotion as an Intervention approach in the Occupational Therapy Practice Framework: Domain and Process. As health care professionals, occupational therapy practitioners are responsible for promoting public health and wellness. Occupational therapists need to educate parents and caregivers about the importance of varying infant positions, providing tummy time, and limiting infant time spent in baby gear