• 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.
• Voltage-Controlled Effects in Magnetic Tunnel Junctions

  Wang, Weigang; Xu, Meng; LeRoy, Brian; Zhang, Shufeng; Schaibley, John R.; Kong, Tai (The University of Arizona., 2020)

  Spintronics, different from traditional electronics, explores additional routes to manipulate electrons through its spin degree of freedom. During its development, magnetic tunnel junctions (MTJs) have been playing a significant role. This is partially due to their fantastic properties such as symmetry-conserving tunneling, which leads to very large magnetoresistance (TMR) and sensitive detection of spin configuration. The relatively simple core structure of the ferromagnet/tunneling barrier/ferromagnet makes it possible to incorporate MTJs into the well-developed fabrication process and a large variety of material systems. Moreover, in recent years, the voltage-controlled effects discovered at FM/Oxide interfaces enables researchers to explore magneto-electric properties of MTJ and more functionalities have been proposed and verified especially in magnetic switching. In this work, we focus our attention on the voltage-controlled effects based on the conventional CoFeB/MgO magnetic tunnel junctions. After a brief introduction to the fundamentals of spin-dependent transport and perpendicular magnetic anisotropy (PMA) in the CoFeB/MgO MTJs. We divert our efforts to various voltage-controlled mechanism discovered in recent years. Chapter 2 briefly touches on the basic experimental technique used in this work. In Chapter 3, we will introduce a revised MTJ nanopillar fabrication procedure which dramatically lowers the requirement for fabricating high-quality MTJ and increases the yield significantly. Chapter 4 will involve interfacial engineering at CoFeB/MgO interface in MTJs. By dusting a thin layer of heavy metal (Ir), in addition to controlling the annealing condition, the VCMA coefficient can be significantly enhanced and the voltage induced switching energy can be greatly reduced, which demonstrated the promises to incorporate MTJs into next-generation memory applications. In Chapter 5, a novel voltage-controlled exchange bias (VCEB) effect is reported and its implication on magnetic switching and further enhancement of TMR is discussed. The last chapter will briefly cover the potential improvement of finished work and topics for future research.
• Tribal Strategic and Sustainable Climate Change Adaptation: A Case Study of the Confederated Salish and Kootenai Tribes

  Gimblett, Howard R.; Rae, Lynn; Trosper, Ronald L.; Colombi, Benedict J. (The University of Arizona., 2020)

  Native nations are at the forefront of the climate change crisis and one of the most vulnerable populations to the impacts, but they also possess the most knowledge and experience with adaptation. A growing number of Native nations and tribal institutions are preparing for climate change and developing strategies, formal plans, and initiatives to increase the resiliency of their communities. Moreover, many American Indian tribes are considered models for climate change adaptation because they are tackling complex climate change problems across multiple scales with fewer resources to increase the resiliency of their communities. Previously published research shows that Native nations that exercise sovereignty and self-governance while maintaining cultural continuity are having greater success at managing their land and natural resources (Jorgenson 2007). There is, however, limited understanding of tribal climate change adaptation and additional information is needed to understand how tribes are exercising self-governance and approaching climate change issues to advance adaptation planning and implementation. The purpose of this research is to identify and consider some of the challenges of tribal climate change adaptation and the strategic approaches that tribes are using to manage and protect their land, natural resources and communities. This research involves a limited review of the tribal natural resource planning and climate change adaptation literature, and a case study with the Confederated Salish and Kootenai Tribes (CSKT) of the Flathead Reservation to assess the strategies and resources utilized by their communities to support adaptation planning. A total of 11 semi-structured interviews were conducted with CSKT leaders and department representatives to consider tribal perspectives and experiences in the adaptation planning and implementation process. Additionally, a small group discussion was conducted with CSKT Elders to understand how climate change is affecting the Tribes’ communities and cultures. This research and the case study findings demonstrate the transformative potential for tribal community development and climate change adaptation when aspects of tribal sovereignty, self-governance, and strategic and sustainable natural resource management are embedded into tribal planning and decision-making processes. While there are varying challenges and complexities associated with tribal climate change adaptation that must be considered, the findings offer examples and insights that may help other tribes further develop existing strengths, protect cultural and spiritual values, and increase community resilience. This research also considers future research needs and next steps to support tribal climate change adaptation.
• Social Structure, Body Size, and Sensory Ecology in Hymenoptera Brain Evolution

  Gronenberg, Wulfila; Keating Godfrey, Rebekah; Nighorn, Alan; Papaj, Daniel; Cai, Haijiang (The University of Arizona., 2020)

  Sociality, like the evolution of multicellularity, is considered a major transition in the evolution of biological complexity. While there is strong foundational knowledge about traits that preceed the evolution of cooperative behaviors and complex forms of social structure, relatively little is known about the role of sociality or social life in individual trait evolution, particularly as it relates to the brain. Hymenoptera (sawflies, wasps, bees, and ants) range from solitary to advanced social species, providing ample comparisons for studying sociality and neural trait evolution. However, hypotheses about sociality and brain evolution have developed separate from studies of trait evolution in insects, and the first chapter of this work suggests unification of trait evolution methods with brain evolution theory. We suggest that recent advances in counting cells and synapses, and quantifying neuron phenotypes and circuit identity be used in trait-based studies of brain evolution in social insects. In the fourth chapter we test a method for quantifying total brain cell number and show this may serve as a meaningful trait for comparisons across Hymenopteran clades. While sociality is generally cited as a major evolutionary transition, superorganisms specifically represent a unique level of biological organization because there exists developmental division of reproductive labor; In superorganisms the colony, not the individual, serves as the reproductive unit upon which natural selection acts. This means the expression of traits at the individual level are selected upon at the collective level of the colony. This form of social organization evolved independently in bees, wasps, and the ancestor to all ants. Thus, all ants are superorganisms and ants show the greatest diversity in colony structure, making them a natural experiment to test how social structure drives individual trait evolution. In the second and third chapter of this work we provide evidence that colony size, a measure of social complexity, is associated with behavioral and neural trait evolution in ants. Specifically, we show that colony size scales inversely with measures of exploratory drive and relative investment in the antennal lobes, a sensory region of the brain responsibly for processing olfactory information. Furthermore, we find that closely related Sonoran Desert species that vary in colony size show differences in sensory systems related to social cue processing, particularly those involved in assessing nestmate identity. We find the large-colony species, Dorymyrmex bicolor has a greater density and number of sensilla basiconica and more glomeruli in the T6 cluster of the antennal lobe, sensory structures and regions responsible in part for processing nestmate cuticular hydrocarbons, than the small-colony Dorymyrmex insanus. Our data suggest habitat structure is also an important drivers in brain evolution in ants, as we find that species living in deserts show less investment in visual processing regions than those living in swamp environments of temperate forests.
• Exploring Long-term Earthquake Deformation in Southern California using Field-based Geologic and Space-based Geodetic Methods

  Bennett, Richard A.; Guns, Katherine; Beck, Susan; Davis, George; Harig, Christopher; Richardson, Randall (The University of Arizona., 2020)

  The San Andreas plate boundary zone in southern California is characterized by a broad network of interlacing faults, working within different provinces of activity to accommodate modern Pacific – North America plate boundary motion. These tectonic provinces vary in their fault morphology from transpressional east-west trending faults of the Transverse Ranges, to transtensional northwest trending faults of the southern Mojave in the Eastern California Shear Zone (ECSZ), to the main dextral Southern San Andreas Fault (SSAF) running through the center of it all. Characterizing how strain accumulation translates to earthquake deformation along different areas of a plate boundary fault system is a critical goal for better understanding how faults can work together to accommodate plate boundary motion and for assessing the seismic hazards along individual faults in the system. Achieving this goal, however, requires integrating different perspectives and evidence from all aspects of the active tectonics field, from field-based measurements of paleoseismic offsets and chronologies through tectonic geomorphology and paleoseismic trenching, to modern space-based observations of crustal velocities and strain rates using Global Positioning System (GPS) and Interferometric Synthetic Aperture Radar (InSAR) measurements, to measurements of crustal seismicity and seismic waveform analysis of recent events, to synthesis modeling studies based on crustal dynamics. In this dissertation, I have endeavored to complete an interdisciplinary analysis of fault motion and crustal deformation in southern California, in order to better characterize the current slip rates of faults in and around San Gorgonio Pass and in particular, to deepen our understanding of the possible mechanisms of slip and strain transfer that must exist between the SSAF system and the southern ECSZ system. In this effort, I have sought to quantify the effect of ongoing viscoelastic postseismic displacements on the modern deformation field in southern California. I have found that postseismic displacements caused by twelve large magnitude earthquakes are measureable with high precision GPS measurements and thus are affecting crustal velocity estimates. Some of these earthquakes occurred over a century ago, revealing a possibility that postseismic deformation and its effect on the deformation field can last longer than we currently assume. Accounting for these postseismic displacements using the method developed in this work leads to a more accurate time-invariant GPS velocity field. We apply our newly created postseismic-reduced velocity field to elastic fault block models of faults in and around San Gorgonio Pass, and find that removing postseismic motions from the deformation field reduces misfit statistics by up to 50%, depending on fault geometry, when compared with our observed (unreduced) GPS velocity field. In addition, removing postseismic displacements also decreases estimated fault slip rates on nearly all faults in our model. Only one of our fifteen model block geometries is able to resolve a persistent slip rate discrepancy along the Mojave and San Bernardino sections of the SSAF system, and it can only do so with the removal of all activity on ECSZ faults. This intriguing result may be further evidence for a possible balancing connection between the SSAF system and the ECSZ system. Lastly, in order to determine whether block rotation may still be a mechanism of slip transfer between the SSAF and ECSZ, and to fill a gap in our knowledge of Eastern Transverse Ranges (ETR) fault slip rates, I conduct the first tectonic-geomorphologic slip rate study along the Blue Cut Fault. Geomorphic mapping and 10Be surface exposure dating indicate an overall time-averaged slip rate of 1.66 ± 0.44 mm/yr (± 2σ uncertainties), however an analysis of individual surface slip rates indicates that rates of slip may have slowed since ~102 – 68 ka. A slowing Blue Cut Fault suggests a slowing rate of possible block rotation, and implies that other mechanisms of slip transfer must be at work in order to enable elastic strain transfer from the SSAF to the recently active ECSZ.
• Analysis on Nonlinear Emission from Gold Nanoparticles and Advanced Phase Retrieval Techniques for Adaptive Optics Microscopes

  Milster, Thomas D.; Eguchi, Akira; Kieu, Khanh Q.; Takashima, Yuzuru (The University of Arizona., 2020)

  Multiphoton (MP) imaging with short-wave infrared (SWIR) excitation is one of the powerful techniques to achieve deep tissue imaging. Image quality of the MP microscope is improved with adaptive optics (AO) by compensating extrinsic aberration caused by transmission through a sample. However, the AO-MP microscope has issues, such as the requirement of a proper guide star and improvement of the detection and correction techniques of the extrinsic aberration. In this dissertation, three studies are provided to overcome these issues. The first study focuses on characterization of nonlinear emission from aggregated 50 nm gold nanoparticles (GNPs) excited by a femtosecond laser at 1560 nm, which are potentially attractive guide stars for the sensor-less AO microscopy with SWIR excitation. The study clarifies nonlinear emission characteristics of GNP aggregates, including emission spectra, power dependence, polarization properties, and relationships between brightness and morphology. A critical point in the discussion is SWIR fs excitation, because the previously proposed mechanism does not explain observed nonlinear emission properties with this source. Previously unknown results that are characteristics of nonlinear emission from GNPs are explained by plasmon enhanced polarized hot electrons. The second study presents application of phase retrieval for measurement and correction of extrinsic aberrations with random phase diversity and Gerchberg's reconstruction algorithm. Optimum design parameters of the random phase patterns to improve accuracy and convergence are investigated with Fried's parameter applied to Kolmogorov turbulence. A liquid crystal on silicon (LCoS) spatial light modulator (SLM) is used to experimentally generate random diversity as a demonstration of correcting extrinsic aberration. The results provide the first optimization study using an LCoS and the Gerchberg algorithm in a sensor-less AO application. The third study presents a new single-shot phase retrieval technique called complex diversity. Multiple irradiance data are obtained by a computer-generated hologram (CGH) designed to generate multiple diffraction orders with different diversity values. Complex-number pupil filters containing both amplitude and phase values associated with the individual diffraction orders are determined by numerical propagation from the CGH, and they are used for reconstruction of the extrinsic aberration. The complex diversity technique estimates extrinsic Kolmogorov aberration better than conventional single-shot techniques for a distant point object.

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