Now showing items 1-20 of 38058

    • Identifying Barriers to Adherence Amongst Patients Speaking Different Languages

      Forbes, Stephanie; Orsini, Roxanna; Trinh, Henry; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: To compare the factors associated with patient non-adherence to medications in relationship to preferred language. Subjects: United States residents enrolled in Medicare Part D and MTM eligible January 2018 through December 2018. Methods: The sample population was divided into preferred language of either English or non-English. Targeted medication review (TMR) from January 2018 to December 2018 was provided by SinfoníaRx. Reasons given for non-adherence between English and non-English were grouped into one of the five following categories: adverse drug reaction, cost, forgetfulness, misunderstood instructions/self-adjusted, and refill issues. English and non-English groups were compared by counting the number of patients citing each reason and calculating percentages. The composite of the five reported patient barriers (adverse drug reaction, cost, forgetfulness, misunderstood instructions/self-adjusted, and refill issues) was compared between the two language groups using a Chi square test with an alpha priori level of 0.05. Main Results: A total of 201 patients were included in this study (100 English and 101 non-English). The majority of patients resided between 60-69 years of age for English patients and was evenly distributed for age ranges between 60-69 and 70-79 for non-English patients. The composite of all five reported patient barriers compared between English and non-English is statistically significant (p=0.0043). Conclusions: Factors associated with patient non-adherence to medications appear to be dependent on preferred language.
    • Analysis of Medical Tourism at the Andrade Port of Entry

      Warholak, Terri; Miller, Andrea; Woods, Nicole; Smith, Rebecca; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: To identify which medications and/or medical services are being sought most frequently, the reason for these specific instances of medical tourism, perceived efficacy or satisfaction of these medications and services, and the likelihood of people continuing to receive their healthcare in Mexico. Methods: Utilizing a cross-sectional survey design, 427 participants were recruited to participate in an anonymous electronic 12 question survey at or near the US-Mexico border at the Andrade port of entry. Main Results: Most participants had a high-school diploma or four-year university degree, and the most common income bracket reported was between $25,000-$50,000 annually. Respondents reported traveling from four different countries, and of those from the US, 29 different home states were reported. The average age of participants was 64.5, with a range between 19 and 93. Dental was the most common medical service, and antibiotics were the most common class of medications reported on the survey. The majority of participants stated comparable or better efficacy of Mexican products, and expressed intent to continue to participate in medical tourism. Conclusions: Based on the survey, patients feel as though these medications are just as good as what they would get in the states and will continue to buy them until research proves otherwise. Further research should be done to determine if these medications purchased in Mexico are indeed what they claim to be.
    • Impact of Depression on Health-Related Quality of Life Among Older Adults with Myocardial Infarction in the United States

      Bhattacharjee, Sandipan; Vadiei, Nina; Howard, Brooke; Lundgren, Terra; Morse, Shawn; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: We assessed the effect of depression on health-related quality of life (HRQoL) among myocardial infarction (MI) survivors in the United States (US). Methods: Using the 2015 Behavioral Risk Factor Surveillance System (BRFSS) data, our study sample consisted of survey participants who were MI survivors aged 50 years and older who also reported having depression post-MI. Our dependent variable (HRQoL) comprised of number of days physical and mental health was poor during the past 30 days; activity limitations; received recommended sleep; how often emotional support received; life satisfaction and perceived general health. We conducted multivariable binomial and multinomial logistic regression analyses examining the association of presence/absence of depression on HRQoL after adjusting for demographic, socioeconomic and other health variables (a-priori α=0.05). Main Results: Our study sample consisted of 20,483 adults with MI; 5,343 (26.19%) reported having depression. Survivors with depression were more likely to report fair/poor general health, limitations in activity, dissatisfaction with life, and a greater number of poor mental and physical health days compared to those without depression. For example: MI survivors with depression reported 2.7 times more (Adjusted Odds Ratio: 2.65: 95% Confidence Interval 2.06-3.45; p<0.0001) fair/poor perceived general health than MI survivors without depression. There was no difference in level of emotional support or sleep quality. Conclusions: In this nationally representative sample of adults in the US, MI survivors with depression had poorer HRQoL compared to MI survivors without depression. These findings underline the need for developing appropriate supportive care for MI survivors with depression.
    • Assessment of Pharmacists’ and Pharmacy Students’ Confidence and Knowledge of Common Asthma Inhaler Devices

      Phan, Hanna; Spencer, Jenene; Hall-Lipsy, Elizabeth; Luu, Michael; Nguyen, Vy Thuy; Lee, Yvonne; Chandler, Krystal; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: To compare pharmacists’ and pharmacy students’ confidence and knowledge level with educating/counseling adolescents/adults, caregivers, and children on appropriate technique and use of common inhaler devices. To identify possible factors that may influence pharmacists’ and pharmacy students’ knowledge and confidence level with educating/counseling patients/caregivers on appropriate technique and use of common inhaler devices. Methods: A survey study using a questionnaire tool consisting of confidence level and knowledge-based questions was distributed to first through fourth year pharmacy students as well as pharmacists registered through the Arizona Pharmacy Association. Main Results: Pharmacists were more confident and knowledgeable with their ability to educate on appropriate inhaler device technique compared to pharmacy students. Both the pharmacist group and pharmacy student group reported health fairs and coursework highest as contributing factors to their knowledge. In general, pharmacists and students were more comfortable with their knowledge of inhaler devices that are more commonly prescribed. Conclusion: Confidence and knowledge level with their ability to educate on appropriate inhaler device technique in all devices and demographics of patients were higher in the pharmacist group than the pharmacy student group.
    • Meta-Analysis of Safety Effectiveness Profile and Overall Response Rate of Metastatic Renal Cell Carcinoma Treatments

      Abraham, Ivo; Kojs, Pawel; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: The aim of this project was to determine the overall efficacy of metastatic renal cell carcinoma pharmacotherapeutic agents as well as determine which chemotherapeutic treatment had the lowest side effect profile. Methods: Overall, a MESH database search was done in PubMed that pulled relative clinical trials that examined chemotherapeutic medications for metastatic renal cell carcinoma. From there the papers were analyzed based on particular demographics such as: Drug Treatment, Drug Comparator, Overall Survival, Progression Free Survival, and Overall Response Rate. This was done through a fixed effects analysis comparing the odds ratios for the different mediations. A network diagram was also developed to show the relationship of the studies. Data was then further analyzed for overall side effect profiles which looked at the total number of adverse events in a study. Main Results: The main result is that Nivolumab + Ipilimumab has the lowest Odds Ratio OR = 0.08 ( 0.03 – 0.21, 95% CI) when compared to Lenvatinib. This is in terms of overall response. With regards to the side effect profiles of the medications, Nivolumab vs Everolimus produced the lowest side effect profile with roughly 27%. Conclusions Nivolumab appears to be the medication that has the greatest overall response rate and least adverse side effect profile. This also depends if the medication is combined with Ipilimumab for greater overall treatment response.
    • Assessing Arizona Pharmacists’ Knowledge of and Confidence with Photosensitizing Drugs

      Spencer, Jenene; Kilgore, Megan; Throckmorton, Hannah; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: To assess Arizona pharmacists’ knowledge of and confidence with identifying and counseling about photosensitizing drugs to determine the need for further education in this subject area. Methods: A voluntary anonymous questionnaire was administered in person at the 2018 Arizona Pharmacy Association Annual Convention. Sixty of the 136 Arizona licensed pharmacists in attendance completed the questionnaire consisting of opinion, knowledge, and demographic sections. A passing grade for the knowledge section was defined as eighty percent accuracy. A score of eighty percent was chosen as the minimum passing rate based on conventionally used rules of competence. T-tests and chi-square tests were used to analyze any differences between the pass and fail groups. Main Results: There was no difference between pass and fail groups with regard to age, gender, years practicing, years spent in Arizona, and practice setting (p greater than 0.05) or with regard to their confidence with counseling about photosensitizing drugs (p greater than 0.05). Pharmacists reported feeling “mostly confident” about identifying photosensitizing drugs (n equals 33), with a range of “not at all” (n equals 2) to “very” (n equals 11) confident. Only 19 (32 percent) of the 60 pharmacists who completed the survey passed the knowledge section with a score of eighty percent or greater. Conclusions: Twice as many pharmacists did not achieve a passing score for the knowledge assessment despite most pharmacists reporting they feel “mostly confident” counseling about photosensitizing drugs. These results demonstrate a need for more education either in college curriculums or continuing education regarding photosensitizing drugs and reactions.
    • Comparing Evidence-Based Learning Methods in a Self-Care Therapeutics Classroom

      Cooley, Janet; Giblin, Lauren; Gonzales, Caitlin; Lychwick, Megan; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Objectives: The objectives of this study were to examine how teaching using case study or role play affects the retention rate of the material being taught in the form of test scores, as well as to assess which teaching styles students prefer. Methods: This study was a dependent groups design. One group was the case study activity and the other group was the role play activity. All students received both interventions. 106 subjects participated in the study and were second year pharmacy students at the University of Arizona College of Pharmacy who were enrolled in the Self Care Therapeutics course on either the Tucson or Phoenix campus. Data was collected from the final exam on the number of correct answers for topics taught using the two teaching methods. A survey was also administered during class time to record student satisfaction with the activity. The data was analyzed using a paired t-test and an alpha level of 0.05. Results: Case study questions were answered correctly on the final exam 83.7% of the time while role play questions were answered correctly 89% of the time. This produced a p-value of 0.057 with no statistically significant difference between the two groups. Case study activities scored higher in survey responses regarding student satisfaction with a statistically significant p-value of 0.027. Conclusions: In conclusion, case study and role play learning strategies did not produce statistically significant difference in test scores. Students responded significantly more positively to case study activities than role play activities.
    • Up to Date or Out of Date: Pharmacist Knowledge of Plan B Contraceptive Regulations in the United States of America

      Leal, Sandra; Daconta, Jesse; Padilla, Craig; Rosa, Lauren; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims:​ To assess pharmacists’ knowledge of emergency contraceptive (EC) regulations in a community pharmacy setting around the United States (U.S.) according to the FDA and their state. Methods: ​Authors collected every community pharmacy phone number from 15 different states by contacting each state board of pharmacy. Over 1% of pharmacies were called and the data collected included whether or not the pharmacist knew the EC laws, the gender of the pharmacist, and the ages each pharmacist responded with. Main Results: ​Out of the 308 pharmacists who completed the interview, 158 were males and 150 were females. 62.0% (98/158) of men and 59.3% (89/150) of women did not know the EC regulations. The average ages each incorrect pharmacist gave were: 18 (96/187; 51.3%), 17 (51/187; 27.3%), 16 (20/187; 10.7%), 15 (14/187; 7.5%), 14 (3/187; 1.6%), 13 (1/187; 0.53%), and 11 (1/187; 0.53%). There was no significant difference between men and women in regards to the correct answer (38.0% males vs. 40.7% women; ​X ​ 2 ​ (2, N = 308) = 0.2338, p > 0.05). Overall, 39.3% (121/308) of pharmacists knew EC regulations and 60.7% (187/308) did not. Conclusions: ​The majority of pharmacists around the U.S. are out of date when dealing with EC regulations.
    • Research-related Curriculum and its Applications in US College of Pharmacy Programs

      Slack, Marion; Cushing, Justin; Merchant, Stephen; Schapker, Allie; May, Rebecca; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: To quantify the number of PharmD programs that require completion of a research project. To describe the types of research being undertaken within PharmD programs. To compare current responses with those obtained in the last survey (2007). Methods: Collaborative effort including students and faculty at three pharmacy programs (AZ, FL and MI). Cross-sectional analysis utilizing the survey (with modifications) developed in 2007. Peer review of questions (face-validity); format included dichotomous response, multiple-choice, and open response. Qualtrics® survey distributed via email to Academic Affairs (or comparative) Dean at AACP affiliate institutions. Descriptive analyses; duplicate responses combined when possible. Project was deemed exempt by IRB. Main Results: Seventy-four programs responded (54% response rate). A total of 22 (30%) programs have a required student research project compared to 25% in 2007. Project requirements were similar among the programs requiring a project: proposal (95%), IRB application (90%), collect and analyze data (77%), prepare a written report (86%), and present findings (82%). The most common methods of collecting data were surveys (91%) and chart reviews (86%). Research related coursework was similar between programs except for research methods courses, which were 36% among programs requiring a research project, and 14% among those not requiring a project. Conclusions: The number of programs requiring student research appears to have increased since 2007. Based on the survey data, students could expect to have similar research experiences in any of the colleges requiring a research project. Most colleges provide coursework related to research.
    • Preformulation studies on trametinib and panobinostat for a prospective topical combination product for the treatment of melanoma

      Myrdal, Paul; Younis, Usir; Slack, Marion; Horn, Jonah; Patel, Sid; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: Specific Aim #1: Evaluate the stability of both pharmacologic agents in the varying conditions (pH and temperature). Our working hypothesis #1 is that both agents will degrade readily at an elevated temperature (65°C) and pH (>7). Specific Aim #2: Determine the solubility profiles of both pharmacologic agents in varying conditions (pH and solvent). Our working hypothesis #2 is that solubility of panobinostat and trametinib will be greatest at a pH <7, as well as in a polyethylene glycol (PEG) solvent. Methods: Data for quantity, solubility, and stability will be recorded for trametinib and panobinostat. 1. Standards: Stock solutions of both compounds will be repeatedly diluted into 5 concentrations in varying solvents until a quantifiable, distinct peak is present on the HPLC around 6-8 minutes. 2. Solubility: In order to test the solubility of both compounds, 1-2 mg of each drug will be put into varying solvents and buffers. If the drug is visibly in solution, 1-2 mg more of drug will be added at a time until a limit of solubility is determined. a. Trametinib: The solubility as a function of pH will be conducted at four pH values between 3.0 and 9.0, as well as with various solvents (ACN, EtOH, PEG400, and PG). Each sample will be saturated with raw drug and allowed to agitate for at least 30 min. Samples will then be visually inspected to ensure that solid drug is still in excess, then will be filtered through an RC filter. The filtrate will be diluted appropriately with distilled water and analyzed using the HPLC assay. b. Panobinostat: The solubility as a function of pH will be conducted at ten pH values between 4.0 and 10.0, as well as with various solvents (10% ACN, 10% DMSO, 10% PEG, and 100% PEG). Each sample will be saturated with raw drug and allowed to agitate for at least 30 min. Samples will then be visually inspected to ensure that solid drug is still in excess, then will be filtered through an RC filter. The filtrate will be diluted appropriately with distilled water and analyzed using the HPLC assay. 3. Stability: The stability of both agents will be tested in various conditions including temperature, pH, and solvents. Stability results will be obtained until peaks varied from that of the original determined during respective standards. a. Trametinib: The influence of pH will be studied with a citrate buffer (pH 2.0), and a borate buffer (pH 9.0). The pH will be adjusted with distilled water. b. Panobinostat: The influence of pH on the stability will be studied with a citrate buffer (pH 4.0 and 5.1), a phosphate buffer (pH 6.0, 7.0, 7.4, and 8.0), and a borate buffer (pH 9 and 10). The pH will be adjusted with NaOH or concentrated HCl. The influence of solvents will be studied with 10% ACN, 10% DMSO, 10% PEG, and 100% PEG. Main Results: 1. Panobinostat: a. Solubility – Increased solubility around pH < 6.5, and > 8.5. Intrinsic solubility seems to be around 7.4 to 7.8. Solubility in 100% PEG appears to be roughly 2750 ug/mL, while in 10% showed moderate solubility (~140 ug/mL). b. Stability – 1st order degradation is noted, with higher rates with an increase in pH for the most part. The most distinguished degradation is seen at pH 7 for this experiment. Higher temperatures (65 C) yielded faster degradation. With respect to both experimented temperatures (48 C and 65 C), pH 4 and 5.1 appeared to be most stable (see attached graphs). Stability in PEG complex was poor. c. Dermabase: Drug crystals present in both phases: Not in solution. 2. Trametinib: a. Solubility – @63 C: Not soluble in MeOH, low solubility in EtOH and PG, pH 3 solubility > 2 mg/mL, ~1.93 mg/mL in PEG, 0.73 mg/mL in ACN. Limit of quantification > 40 nanograms. b. Stability – Relatively stable in light, degrades fast a pH 9, slow at pH 2. New peak present at pH 2, degradation around 11%. c. Dermabase: Drug crystals present in both phases: Not in solution. Conclusion: 1. The two medications in combination were incompatible in solution in Dermabase. 2. Additional research will need to be completed in efforts to get these two medications to go into a solution. 3. However, time, money, and the unfortunate death of the preceptor terminated further research for this project.
    • Comparing Cytochrome P450 Variant Alleles Tested and Reported in Clinical Pharmacogenomic Testing Panels

      Leal, Sandra; Hoogervorst, Meghan; Patel, Sidhi; Pina, Joel; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: To evaluate and describe the variability in cytochrome P450 genetic polymorphisms tested by laboratories offering pharmacogenomic (PGx) genotyping panels using website information and sample reports for various genetic panels. Methods: This was a descriptive study evaluating pharmacogenomic testing company websites for cytochrome P450 genetic polymorphisms. An information extraction form was developed to assess which genetic polymorphisms for CYPs 2C9, 2C19, 2D6, 3A4, and 3A5 were tested and reported for each PGx company website offering genotyping panels. Each student investigator completed an electronic copy of the extraction form for each PGx website to confirm consistency of findings. Main Results: Of the ten PGx allele panels that were reviewed, consistency varied greatly as CYP2C19 had the highest consistency frequency amongst the panels reviewed with 4 out of 11 alleles having concordance (36.4%), followed by CYP2D6 (23.7%), CYP3A5 (16.7%), CYP2C9 (12.5%) and CYP3A4 (0%). Conclusions: As the laboratories that offer PGx testing rapidly increases with the field of PGx, the consistency of reporting amongst companies is different. From the ten panels that were reviewed it can be concluded that each company is dissimilar in the alleles tested and reported. PGx testing is becoming widely used to safely personalize medication therapy for various medical disease states. Currently, the variation in testing panels make it difficult for clinicians to incorporate the results into clinical practice with confidence.
    • Economic Evaluation of FOLFIRINOX vs nab-paclitaxel plus gemcitabine in advanced pancreatic cancer

      McBride, Ali; Abraham, Ivo; Hanson, Thomas; Komerdelj, Ivan; Fletcher, Stephanie; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: Determine if FOLFIRINOX or nab-paclitaxel plus gemcitabine (NAB+G) has no difference in the cost per life year gained as a first line treatment for metastatic pancreatic cancer. Methods: This study used a retrospective chart review. Charts were accessed via the UACC electronic health records EPIQ and Cerner. Data collected consist of demographic information, number of co-morbidities, biological markers, treatment type, treatment duration, treatment dosing, supportive care measures, hospitalizations, and patient survival. Primary outcomes were assessed based on cost per life year gained. Average monthly cost of treatment is based off of known literature values. Main Results: Patients in the FOLFIRINOX group showed higher rates of provider visits. The average number of visits was 14.3 vs 7.6 in FOLFIRINOX and NAB+G respectively (p=0.014). The cost per life year gained was $86,493 for the FOLFIRINOX group and $146,652 for the NAB+G group. Conclusions: This study determined that patients treated with FOLFIRINOX experience significantly more provider visits during the course of their treatment when compared to nab-paclitaxel plus gemcitabine. While the average total cost of treatment was similar, the cost per life year gained was greater in the nab-paclitaxel plus gemcitabine group.
    • Patterns and Predictors of Depression Treatment among Older Adults with Dementia and Depression in Ambulatory Care Settings in the United States

      Bhattacharjee, Sandipan; Sun, Chongwoo; Gobin, Philippe; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: Dementia, or neurocognitive disorder (NCD), is the deterioration of performance in mental function, and is a disease state only expected to become more prevalent in the coming decades. Depression is twice as likely to develop in this population and is also shown to increase the rate of decline in those with NCD. This study was designed to determine patterns and predictors of depression treatment in elderly dementia patients in the ambulatory care setting in the United States using the Anderson Behavioral Model (ABM) Methods: We conducted retrospective cross-sectional study design by using multiple years (2005–2015) of data from the National Ambulatory Medical Care Survey (NAMCS), an ongoing yearly survey administered by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC). The NAMCS uses a multistage probability design to obtain systematic random weekly samples of patients from physicians across the nation using a Patient Record Form capable of recording up to three diagnoses codes and eight prescription medications for each visit. A weighted frequency for national prevalence values was generated from our data analysis. A multivariate regression analysis was completed to determine which predisposing, enabling, and need factors were significant determinants to the nature of antidepressant treatment. Main Results: A total of 655 (un-weighted) ambulatory visits by older adults with dementia and depression were recorded by National Ambulatory Medical Care Survey, or a national estimate of 14.46 million elderly patients visits with both NCD and depression. Predisposing factors such as race, age, sex, geographic region, and metro/non-metro; enabling factors such as insurance and physician specialty; and need factors such as new prescription drug, new patient, or reason for visit, or chronic disease states, were recorded. Multivariate analysis revealed gender, physician specialty, metro/non-metro, geographical region, and number of medications were significant determinants in how an elder NCD patient in the ambulatory setting receives treatment for depression. Conclusions: 62.89% of patients were treated for depression, with 61.45% of all patients receiving an antidepressant and 4.94% of patients receiving psychotherapy. Psychotherapy was utilized infrequently in this population, and SSRIs were the most common form of pharmacotherapy. This suggests this patient population is vulnerable to untreated depression and reveals a need for long-term studies investigating health outcomes in these patients.
    • Pharmacists’ Attitudes Toward Including Diagnosis or Clinical Indication on Prescriptions

      Warholak, Terri; Murata, Joseph; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: To assess Arizona pharmacists’: support for the inclusion of diagnosis or clinical indication on prescription orders; current access to diagnosis or clinical indication on prescriptions orders; perceived barriers to and/or concerns about requiring diagnosis or clinical indication on prescription orders in Arizona. Methods: This was a descriptive study with data obtained from questionnaires. The questionnaire consisted of 3 recall questions from the participant’s experiences, 11 questions regarding the participant’s opinion about the topic, and 5 descriptive and demographic questions about the participant. Main Results: Participants were licensed pharmacists in the state of Arizona who attended a presentation on enhanced pharmacist clinical decision-making information at the Arizona Pharmacy Association Southwest Clinical Pharmacy Seminar. 96.3% of participants supported requiring diagnosis or clinical indication on prescription orders. They reported a mean of 25.2% of current prescription orders including a diagnosis or clinical indication. Major challenges identified in requiring diagnosis or clinical indication included potential software transmission problems, prescriber having no definitive diagnosis or clinical indication for a medication, additional prescriber time, and concerns that inclusion may result in insurers rejecting claims for off-label use. Conclusions: Most respondents supported requiring diagnosis or clinical indication on prescription orders and reported about one-fourth of prescription orders they currently receive including a diagnosis or clinical indication. Multiple perceived barriers and concerns were identified by the participants.
    • Systematic review meta analysis of adherence measures for common chronic medications used in the treatment of cystic fibrosis

      Phan, Hanna; Slack, Marion; Martin, Jennifer; Park, Haeun; Park, Sohyun; Tam, Katie; College of Pharmacy, The University of Arizona (The University of Arizona., 2019)
      Specific Aims: The aim of this systematic review and meta analysis is to determine the best method to measure medication adherence in cystic fibrosis patients by assessing the rates of adherence to cystic fibrosis medications using different measuring methods. Methods: Using multiple bibliographic databases (including Embase, Pubmed, Cochrane, PsychINFO, WHO, Web of Science, Scopus, and IPS) and reviewing grey literature and association websites, a systematic literature search of articles related to medication adherence in cystic fibrosis patients was conducted in February 2018. The limits applied to all articles were the English language and publication dates between 1989 to the present day. The literature screening was conducted by 3 pharmacy students, professors at the University of Arizona College of Pharmacy, and members of the Cystic Fibrosis Foundation (CFF). The studies were assessed for quality using a abstract and data extraction screening tool. Main Results: The bibliographic database searches generated 1,955 articles, and the grey literature and association websites generated 15 articles. 1,549 of the 1,955 articles and 0 of the 15 articles met the inclusion criteria and underwent data extraction screening. Then, after the abstract screening, 42 articles were identified for eligible to proceed to data extraction. Medication adherence was measured using paper/hard copy reminder tool, pager application, mobile application, electronic device, medication container with tracking, education sessions, and medication organizer. Conclusions: In the preliminary results, seven studies were included in the meta-analysis measuring five different methods of adherence: written diary, electronic monitoring, self-report, Medication Possession Ratio (MPR) and Proportion of Days Covered (PDC). Overall, adherence measured by written diary was significantly different than all other adherence measures except MPR. Further data analysis will be conducted when the data extraction and review is completed by Cystic Fibrosis clinicians and experts.
    • Development of New Organic Photoredox Catalysis Driven by Visible Light

      Wang, Wei; Zhang, Yueteng; Wondrak, Georg T.; Hulme, Christopher; Njardarson, Jon T. (The University of Arizona., 2020)
      Development of efficient and sustainable synthetic technologies for molecular construction is the central goal in modern organic synthesis. In recent decades, organocatalysis has become one of the viable tools in organic synthesis with notable features including easy manipulation, low cost, and/or less susceptible to air and moisture. Organophotoredox catalysis has merged as a front runner in organocatalysis. My Ph.D. study focuses on the development of novel visible-light mediated organic photoredox catalysis strategies for the construction of structurally diverse molecular architectures in distinct ways. In the first efforts, a metal- and oxidant-free organophotocatalytic method for preparing structurally diverse thioesters from readily accessible, abundant aldehydes, has been realized. Excited by blue light, the simple and cost-effective 9,10-phenanthrenequinone (PQ) promotes hydrogen atom transfer (HAT) to selectively generate acyl radicals from corresponding aldehydes without inducing crossover reactivity of thioesters. In situ formed acyl radicals then react with thiosulfonate S-esters to efficiently produce thioesters. The mild and efficient method exhibits excellent substrate scope and outstanding functional group tolerance. Significantly, it is proved to be useful in a late-stage functionalization of complex molecules. Direct H/D exchange at formyl groups represents the most straightforward approach to C-1 deuterated aldehydes. Along this line, a new photoredox catalytic, visible-light mediated neutral radical approach has been developed via a unique double-HAT process. Selective control of highly reactive acyl radical enables driving the formation of deuterated products when an excess of D2O is employed. The power of H/D exchange process has been demonstrated for both aromatic aldehydes and aliphatic substrates, and more important late-stage deuterium incorporation into complex structures with uniformly high deuteration level (>90%). The direct dearomatization of indoles represents the most straightforward access to indolines. However, the exiting dearomative methods largely restrict to electron-rich indoles or go through an ionic process using strong nucleophiles. Toward this end, an unprecedented organophotocatalytic process by harnessing nucleophilic radicals to react with electron-deficient indoles was developed. The preparative power of this radical-engaged strategy has been demonstrated by direct addition of in situ formed nucleophilic radicals from readily accessible feedstock carboxylic acids, into structurally diverse electrophilic indoles including (thio)ester, amide, ketone, nitrile and thus delivering a series of trans-2,3-disubstituted indolines with uniformly high stereoselectivity (> 20:1 dr). Moreover, this approach has also been successfully applied to other aromatic heterocycles such as pyrroles, benzofurans and benzothiophenes.
    • After Compatibilism: Essays on Freedom and Responsibility

      McKenna, Michael S.; Wallace, Robert Hamilton; Sartorio, Carolina; Timmons, Mark; Horgan, Terence; Nelkin, Dana K. (The University of Arizona., 2020)
      This dissertation is a series of standalone essays. Together, they form a critique of contemporary compatibilist approaches to the problem of free will and determinism, and they offer an alternative methodology for approaching questions about freedom and responsibility. Compatibilist approaches to the free will problem exist on a spectrum from the more normative to the more metaphysical. Views at the metaphysical end of the spectrum typically understand free will in terms of abilities. In Chapter 1, I argue that these views face a powerful dilemma: they either fail to explain these abilities or fail to show that these abilities are compatible with the thesis of physical determinism. Perhaps a commitment to abilities could be given up, but I argue that takes us too far afield from the intuitive way we understand ourselves as free agents. Compatibilist approaches at the normative end of the spectrum have been largely influenced by P.F. Strawson’s responsibility naturalism. Views of this sort begin by carefully attending to the features of our responsibility practices in order to glean the nature of the sort of freedom that grounds apt responsibility ascriptions. In Chapter 2, I defend a version of this view from a decisive objection: Strawsonian compatibilism seems to make evildoers exempt from moral responsibility. Nevertheless, in Chapter 3, I argue that Strawson's program cannot properly insulate itself from metaphysical concerns about abilities. The methodology may actually support a powerful form of incompatibilism about free will and determinism. This casts the entire contemporary project that draws on his work in a suspect light. Drawing lessons from these two failures, in Chapter 4, I offer a practice-based argument for realism about freedom and responsibility—the view that we really are free and responsible— that is neutral with respect to questions about the compatibility of freedom and determinism. The argument does not depend on any particular metaphysical theory of abilities or particular view of our moral practices. I argue in Chapter 5 that, given this realist framework, we have reason to think that whatever ends up being true about the abilities that characterize free and responsible agents, they will be compatible with determinism after all.
    • Immune-Related Adverse Events (irAEs) of Immune Checkpoint Inhibitors (ICIs) in Advanced Melanoma Patients

      Abraham, Ivo; Almutairi, Abdulaali R.; Erstad, Brian; Slack, Marion; Mcbride, Ali (The University of Arizona., 2020)
      Abstract (1): Background: The use of ipilimumab, nivolumab, and pembrolizumab as monotherapies or in combination has transformed the management of advanced melanoma even though these drugs are associated with a new profile of immune-related adverse events (irAEs). The incidence of irAEs from clinical trials of these agents is an important factor for clinicians when treating patients with advanced melanoma. In the current study, we aimed to profile the incidence of potential irAEs of these agents when used as monotherapy and as combination therapy. Methods: We searched the Medline, Embase, and Cochrane databases; clinicaltrials.gov; and websites of regulatory agencies in the USA, Europe, Australia, and Japan for phase 1-3 trials of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma. Random effect meta-analysis was utilized to profile the incidence of potential irAEs. Results: A total of 58 reports of 35 trials including 6331 patients with advanced melanoma and reporting irAE data were included in the meta-analyses. We found higher incidences of potential irAEs in combination therapies versus monotherapies for most of the types of irAEs. Among the monotherapies, ipilimumab users had the most frequent incidence of potential irAEs related to the gastrointestinal system (diarrhea, 29%; and colitis, 8%) and skin (rash, 31%; pruritus, 27%; and dermatitis, 10%), with hypophysitis in 4% of the patients. The most frequent potential irAEs among nivolumab users were maculopapular rash (13%), erythema (4%), hepatitis (3%), and infusion-related reactions (3%), while they were arthralgia (12%), hypothyroidism (8%), and hyperglycemia (6%) among pembrolizumab users. Conclusion: Especially the combination therapies tend to elevate the incidence of potential irAEs. Clinicians should be vigilant about irAEs following combination therapy as well as gastrointestinal and skin irAEs following ipilimumab therapy, in addition to being aware of potential irAEs leading to hyperglycemia, thyroid, hepatic, and musculoskeletal disorders following nivolumab and pembrolizumab therapy. Abstract (2): Importance Anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) antibody (ipilimumab) and anti-programmed cell death 1(anti-PD1) antibodies (nivolumab and pembrolizumab), have been shown to have a beneficial effect in treating melanoma but their risk of immune-related hypothyroidism (ir-hypothyroidism) in elderly patients from a real-world setting is limited. Objective To estimate the risk of ir-hypothyroidism in elderly with advanced melanoma treated with anti-CTLA4 or anti-PD1 in real-world setting. Design, Setting, and Participants SEER-Medicare data was used to identify elderly patients (≥65 years) diagnosed with advanced melanoma between 2011 and 2015 who were de novo users of anti-CTLA4 or anti-PD1. We estimated the risk of ir-hypothyroidism between users of anti-PD1 and anti-CTLA4. We used a propensity weighting approach by using the inverse probability of treatment weighting (IPTW) method to adjust for potential confounders. We utilized proportional hazards models to estimate the risk of ir-hypothyroidism and performed several sensitivity analyses to estimate the risk over ranges of follow-up periods as well as including patients with different stages of melanoma. Exposure Anti-CTLA4 or anti-PD1. Main Outcomes and Measures The risk of ir-hypothyroidism between the initiation of the treatment and up to 90 days from the last dose was measured as a hazard ratio (HR) and its 95% confidence interval (95%CI). Results Our sample had 210 elderly patients with advanced melanoma (164 anti-CTLA4, and 46 anti-PD1 (11 nivolumab, 35 pembrolizumab)). There was no statistical difference in the risk of ir-hypothyroidism between anti-PD1 and anti-CTLA4 (HR 2.15, 95%CI 0.83-5.53). Comparing the individual medications to each other showed a lower risk among users of ipilimumab versus nivolumab (HR 0.15, 95%CI 0.06-0.40) and pembrolizumab versus nivolumab (HR 0.13, 95%CI 0.03-0.55). Sensitivity analyses using a cohort of all-stages melanoma did not show a difference in the risk of ir-hypothyroidism between anti-CTLA4 and anti-PD1 and between individual medications. Conclusions and Relevance In our retrospective study of claims data of elderly patients diagnosed with melanoma, there was no statistical difference in the risk of ir-hypothyroidism between users of anti-CTLA4 or anti-PD1. However, advanced melanoma patients treated with ipilimumab or pembrolizumab may have a lower risk of ir-hypothyroidism compared to nivolumab users. Abstract (3): Purpose Melanoma treatment was advanced significantly by the approval of anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) agents (ipilimumab) and anti-programmed cell death 1 (anti-PD1) agents (nivolumab and pembrolizumab). However, these agents have been associated with gastrointestinal immune-related adverse events (irAEs) including colitis, which could lead to treatment discontinuation. We aimed to estimate the incidence and the risk of colitis in elderly patients with advanced melanoma treated with anti-CTLA4 and anti-PD1 in the real-world setting. Patients and Methods Elderly patients (age ≥ 65 years) diagnosed with advanced melanoma between 2011 and 2015 and treated with anti-CTLA4 or anti-PD1 agents were identified from the SEER-Medicare data. We estimated the risk of colitis from starting the treatment up to 90 days from the last dose of therapy. We used the log-rank test and logistic regression with adjustment for potential confounders using the inverse probability of treatment weighting (IPTW) method. Also, we conducted several sensitivity analyses using different follow-up periods and including all-stages of melanoma. Results A total of 274 elderly patients with advanced melanoma were included in our cohort. The risk of colitis was similar between the anti-PD1 users of and anti-CTLA4 groups based on log-rank test (p=0.17) and logistic regression model (OR 2.86, 95%CI 0.36-25). The 12-month cumulative incidence of colitis was 9.27% in the anti-CTLA4 vs. 4.64% in the anti-PD1 group. Sensitivity analyses for patients with all-stage melanoma showed a significantly lower risk of colitis in anti-PD1 compared to anti-CTLA4 treated patients based on a log-rank test (p=0.017) and logistic regression model (OR of 0.21, 95%CI 0.09-0.53). Conclusion Elderly with advanced melanoma who were treated with anti-CTLA-4 or anti-PD1 had a statistically similar risk of developing colitis. However, there was a statistical difference in the risk of colitis between anti-CTLA4 or anti-PD1 users among all-stages melanoma patients.
    • Characterization and Exploitation of Divergent Substrate Binding Within HspA5 for the Development of Selective Inhibitors

      Chapman, Eli; Ambrose, Andrew; Khanna, May; Wang, Jun; Zhang, Donna (The University of Arizona., 2020)
      Hsp70s are among the most highly conserved proteins in all of biology. These molecular machines function through cofactor interaction and ATP binding and hydrolysis. Through iterative binding and release of exposed hydrophobic residues on client proteins, Hsp70s are able to prevent intermolecular aggregation and promote folding progression toward the native sate. The human proteome contains 8 canonical Hsp70 proteins that vary in tissue specificity, inducibility, and organellular localization. Because Hsp70s are relatively promiscuous with regard to client selection, Hsp70s play a significant role in folding a large proportion of the proteome. Hsp70s are implicated in numerous neurodegenerative diseases and cancer because of their ability to regulate protein homeostasis within cells. In recent years, many groups have attempted to develop selective inhibitors of Hsp70 isoforms to better understand the role of individual isoforms in biology. Through rational design, forced localization, and serendipity, inhibitors have been discovered, however discovery of a molecule that interacts with a single isoform remains elusive. Herein lies a report validating the substrate binding domain of Hsp70 as a targetable site for the development of selective inhibitors. Using a fluorescence polarization (FP) peptide binding assay, a pilot screen revealed hexachlorophene as a selective inhibitor of HspA5. While this molecule is not a lead, it serves as a proof a concept that small molecules can be selective towards Hsp70 isoforms through interaction with the substrate binding domain. From here, an expansion of the assay and scale up of the screen revealed 4.8 as a potent (IC50 = 162 nM) and selective HspA5 inhibitor (20-fold for HspA5 vs HspA9 and at least 300-fold for all other Hsp70s). Through the development of the assay used to discover these compounds it was discovered that Hsp70 isoforms appear to interact differently with substrate peptides. From here, the peptide binding pattern of each canonical human Hsp70 isoform was characterized which led to the development of an algorithm for predicting client interactions with specific Hsp70s. These results highlight the functional variance that exists between Hsp70s in their interaction with peptide substrates, and the possibility for exploiting these differences in inhibitor development.
    • Novel Methods For Next-Generation Sequencing Data With Applications in Microbiome Studies

      An, Lingling; Carter, Kyle Matthew; Watkins, Joseph; Zhang, Helen H.; Slack, Donald (The University of Arizona., 2020)
      Humans maintain a symbiotic relationship with the billions of microbes that exist within and upon the body. The collection of microbes within the body can be considered as a second genome, providing a plethora of unique information about their host. High-throughput next generation sequencing technologies have allowed researchers to build microbial profiles based on microbial RNA sequences for individuals/patients, providing a rich avenue of data to be utilized in statistical models in various field including medicine and forensics. In this dissertation, I present three novel projects which utilize next-generation sequencing based microbiome profiles. In the first project, I proposed a new approach based on microbiome dissimilarity measurements, with applications in forensic trace evidence analysis. This approach utilizes bootstrap Aitchison distances between communities to identify groups of microbial samples and improve current source tracking applications for evidence analysis by removing samples that are highly dissimilar to the evidence. The last two projects focus on detection of mediation effects when the microbes are treated as mediators in clinical mediation models. The second project aims to identify mediation of immune response genes on human gut inflammation non-parametrically by applying information theory concepts from machine learning. The third project expands the scope of mediation modeling by considering time series data in conjunction with mediation. Comprehensive simulation experiments show a drastic improvement in the detection of mediation effects compared to current standard methods for models which utilize microbiome as a mediator.