The Fifth Annual Duke CTSA Career Development Symposium

Featuring presentations from:

Duke CTSA KL2 and TL1 Scholars Duke Multidisciplinary K12 Urologic

Research (KURe) Scholars University of North Carolina CTSA KL2 Scholars

Wake Forest University CTSA KL2 Scholars

April 30, 2019 Searle Center Lecture Hall

8:30am – 3:00pm

The CTSA initiative is led by the National Center for Advancing Translational Sciences (NCATS) at the

National Institutes of Health.

Schedule of Presentations

8:30 – 9:00 Breakfast for Scholars

9:00 – 10:00 Being Mentored and Being a Mentor: Our Stories Career Development Panel Discussion

L. Ebony Boulware, MD, MPH Professor, Department of Medicine, General Internal Medicine Chief, Division of General Internal Medicine Director, Duke Clinical and Translational Science Institute Vice Dean for Translational Sciences Professor, Department of Family Medicine and Community Health

Kathleen Cooney, MD Professor, Department of Medicine, Medical Oncology Chair, Department of Medicine

Allan Kirk, MD, PhD David C. Sabiston, Jr. Professor of Surgery, Abdominal Transplant Chair of Surgery Professor, Department of Pediatrics Professor, Department of Immunology

Scott Kollins, PhD Professor, Department of Psychiatry and Behavioral Sciences Professor, Department of Psychology and Neuroscience

Stephen Kritchevsky, PhD Co-Director, J. Paul Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine Associate Dean of Faculty Development, Translational Science Institute Professor, Department of Gerontology and Geriatrics Medicine

Oluwadamilola "Lola" Fayanju, MD, MA, MPHS Assistant Professor, Department of Surgery, Surgical Oncology Duke CTSA KL2 Scholar

Kathryn Dickerson, PhD Assistant Professor, Department of Psychiatry and Behavioral Sciences, Translational Neuroscience Duke CTSA KL2 Scholar

Rasheed Gbadegesin, MBBS, MD, FASN (Moderator) Professor, Department of Pediatrics Professor, Department of Medicine Co-Director, Duke CTSA-KL2 program Associate Director, Duke Pediatric Research Scholars (DPRS)

10:00 – 10:15 Break

10:15 – 11:45 Moderated Poster Presentations Duke KL2 Scholars Lavanya Vasudevan, PhD, MPH, CPH Assistant Professor, Department of Family Medicine and Community Health Assistant Research Professor, Duke Global Health Institute “Parental hesitancy and uptake of childhood vaccines”

Carlene Moore, PhD Assistant Professor, Department of Neurology “Molecular and cellular signaling mechanisms of TRPV4 in the skin: A therapeutic target for pain, inflammation and itch”

Noreen Bukhari-Parlakturk, MD, PhD Assistant Professor, Department of Neurology “A Comparative Analysis of Writing Impairment in Focal Hand Dystonia”

Oluwadamilola "Lola" Fayanju, MD, MPHS Assistant Professor, Department of Surgery “A Case-control Study Examining Disparities in Surgical Oncology Trial Participation among Breast Cancer Patients”

Andrada Neacsiu, PhD Assistant Professor, Department of Psychiatry and Behavioral Sciences “Establishing the Therapeutic Target for CBT-Enhanced Neuromodulation for Transdiagnostic Emotion Dysregulation”

Duke TL1 Postdoctoral Scholars Andrew Murray, PhD Postdoctoral Scholar, Department of Medicine, Division of Hematological Malignancies and Cellular Therapy “Hormone regulation of breast cancer cell interactions with the bone marrow vasculature”

Erin Hisey, PhD Postdoctoral Scholar, Department of Cell Biology “Neural Circuit Basis of Developmental Brain Disorders”

Joseph Saelens, PhD Postdoctoral Scholar, Department of Medicine, Division of Infectious Diseases “Sickle-trait disrupts the transcriptional network underlying the pathogenic program of P. falciparum”

Duke KURe Scholar Maryellen S. Kelly, DNP, CPNP Clinical Associate, School of Nursing “Diabetic Uropathy as a Predictor of Medical Visits for Lower Urinary Tract Symptoms: a Population-Based Analysis”

UNC CTSA KL2 Scholar Gauri Rao, PharmD, MS Assistant Professor, UNC Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics

“Evaluation of Pharmacodynamic (PD) Activity and Emergence of Resistance of Novel Combination Regimens: Polymyxin B (PMB), Meropenem (MEM) and ZTI-01 (Fosfomycin for Injection, FOF) against Klebsiella Pneumoniae Carbapenemase-Producing Klebsiella pneumoniae (KPC-KP)”

Wake Forest CTSA KL2 Scholar Chandylen Nightingale, PhD, MPH Assistant Professor, Department of Social Sciences and Health Policy “Interest in Supportive Care Programs among Head and Neck Cancer Caregivers”

11:45 – 12:15 BREAK - Box Lunches Provided

Podium Presentations 12:15 – 12:30 Alan Zambeli-Ljepović, BS – Duke TL1 Predoctoral Scholar Third-Year Medical Student

“Extent of Surgery for Low Risk Thyroid Cancer in Elderly: Equipoise in Survival, but Not in Short-Term Outcomes”

12:30 – 12:45 Maya Talbott, BS – Duke TL1 Predoctoral Scholar Third-Year Medical Student

“Benefit-Risk Tradeoffs for Surgical Options in Low-Risk Thyroid Cancer: Designing a Discrete-Choice Experiment”

12:45 – 1:00 Samantha Schilling, MD, MSHP – UNC KL2 Scholar Assistant Professor, Department of Pediatrics

“Child Adult Relationship Enhancement in Primary Care (PriCARE): A randomized trial of a skill-based parent training with parent mentor adaptation”

1:00 – 1:15 Kenneth T. Kishida, PhD – Wake Forest KL2 Scholar Assistant Professor, Department of Physiology and Pharmacology "Real-time monitoring of dopamine and serotonin during conscious choice and moment-to-moment changes in subjective experience in humans."

1:15 – 1:30 Eric Gonzalez, PhD – Duke KURe Scholar Postdoctoral Research Fellow, Department of Biomedical Engineering

“Chronic Monitoring of Voiding Function in a Novel Model of Detrusor Underactivity”

1:30 – 1:45 Michael Cary, PhD, RN – Duke KL2 Scholar Assistant Professor, Department of Medicine, Division of Hematologic Malignancies & Cell Therapy “Multiple Chronic Conditions associated with Hospital Readmission among Hip Fracture Patients”

1:45 – 2:00 Kathryn Dickerson, PhD – Duke KL2 Scholar Assistant Professor, Department of Psychiatry and Behavioral Sciences, Translational Neuroscience “Using Neurofeedback to Drive Cognitive Change”

2:00 – 2:15 Rasheeda Hall, MD, MBA, MHS – Duke KL2 Scholar Assistant Professor, Department of Medicine, Division of Nephrology “Understanding Functional Disability in Older Dialysis Patients”

2:15 – 3:00 Reception – Celebration of graduating KL2 and TL1 scholars We invite all of you to stay for a brief reception to celebrate the CTSA scholars who are completing their respective programs this year. We congratulate each one of them and wish them luck in their future endeavors!

Noreen Bukhari-Parlakturk, MD, PhD Assistant Professor of Neurology

“A Comparative Analysis of Writing Impairment in Focal Hand Dystonia”

Background: Focal hand dystonia is a common task-specific dystonia presenting with intermittent muscle contractions and/or abnormal postures of the hand. Writer’s cramp (WC) dystonia is a subtype occurring during the task of handwriting. There are currently examiner-based rating scales, patient-reported disability scales and software measures of writing kinematics and writing accuracy. The correlations between these three data categories and with disease severity remains unclear and presents a challenge for selecting outcome measures for interventional studies. In this study, we evaluated symptoms and signs of dystonia across these data categories to identify measures that can distinguish between healthy volunteers (HV) and WC subjects. Methods: 12 right-handed WC subjects and age-matched HV were recruited. Subjects performed a dystonia-inducing intervention of 20minute paragraph writing with their dystonic right hand on a digital tablet with pressure sensitive stylus under video recording. To evaluate the effect of intervention, subjects performed sentence-copying at pre and post-intervention timepoints. Data was analyzed using Two-way repeated measures ANOVA and linear regression. Results: Software writing kinematics show significant baseline differences between HV and WC subjects across all disease severity. Prolonged writing, however, selectively affects automated writing accuracy of WC subjects. Conclusions: WC subjects have baseline handwriting deficits that do not significantly affect their writing accuracy. During prolonged writing, however, WC subjects are unable to compensate for their handwriting deficits resulting in decline in writing accuracy. Implications: Writing kinematics and writing accuracy are objective writing measurements that can be used to test therapeutic interventions for focal hand dystonia.

Michael P. Cary, Jr., PhD, RN Assistant Professor of Nursing

“Multiple Chronic Conditions associated with Hospital Readmission

among Hip Fracture Patients” Background: Hip fracture patients frequently present with multiple chronic conditions (MCCs). MCCs increase risk for developing complications and mortality but less is known about the effects of MCCs on risk for hospital readmission. Emerging research suggests specific combinations of MCCs may have synergistic effects, a greater risk than would be expected based on the impact of each condition individually (additive effects). Methods: Using 2015 data from the Medicare Provider and Analysis Review File and mortality as a competing risk, our objective was to determine the effects of MCCs on hospital readmission among hospitalized Medicare beneficiaries with hip fracture. We defined MCCs as dyads (2 chronic conditions). Results: Of 101,486 hip fracture patients included in the analysis, 73% were female, 92% were non-Hispanic white, and the mean age was 84 years of age; 30-day hospital readmission rate was 12%. In the adjusted model, most dyads had additive effects. However, one dyad had a more-than additive (synergistic) association with 30-day readmission: Chronic Kidney Disease & Diabetes (HR 1.32, 95% CI 1.23–1.41). We also found several dyads associated with a less-than additive (antagonistic) association with 30-day readmission: Chronic Kidney Disease & Lung Disease (HR 1.39, 95% CI 1.30–1.49), Chronic Kidney Disease & Heart Disease (HR 1.35, 95% CI 1.28–1.43), and Chronic Kidney Disease & Depression (HR 1.20, 95% CI 1.13–1.28). Conclusions: MCCs adversely affects 30-day hospital readmission in hip fracture patients, with specific dyads having a synergistic rather than antagonistic impact on readmission risk. These results identify patients at highest risk for targeting interventions. Implications: Clinicians should consider aggressive management of diabetes in hip fracture patients with chronic kidney disease. Strategies might include monitoring hemoglobin A1C levels, reducing potential complications, and variable responses to insulin therapy as kidney dysfunction progresses.

Kathryn Dickerson, PhD Assistant Professor of Psychiatry and Behavioral Sciences

“Using Neurofeedback to Drive Cognitive Change” Background: Neurofeedback is an increasingly popular tool used to investigate both basic science and clinical questions. Our group has used fMRI neurofeedback in a variety of contexts including examining volitional regulation of the dopamine system in healthy adults. In this study, we aimed to provide individuals with a history of depression an index of biological change based on therapeutic experiences. By showing them real-time neurofeedback while they used therapeutic strategies to cope with negative mood we aimed to demonstrate the link between therapeutic strategies and brain-based biological change. Methods: We recruited 14 individuals with cognitive behavioral therapy (CBT) experience to participate in a six-week study, including one real-time fMRI neurofeedback session. During the neurofeedback session, we asked individuals to remember negative autobiographical memories and use CBT strategies to regulate negative mood. After each memory and strategy period (30s), we showed individuals dynamic feedback from the anterior cingulate cortex (ACC; 5s), an area implicated in mood and depression. Results: We found the expected pattern of results in the ACC, hippocampus, insula, and amygdala: increased activation following recall of negative memories and decreased activation following strategy use. Furthermore, the change in ACC activation from the memory period to the strategy period (memory – strategy ACC activity) predicted individual’s perceived strategy efficacy and frequency of use one month following the scan session. Conclusions: These results suggest that even a single neurofeedback session can have a lasting impact on therapeutic outcomes. Implications: Our findings suggest that neurofeedback can be used to modulate cognition and behavior.

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Oluwadamilola “Lola” Fayanju, MD, MA, MPHS Assistant Professor of Surgery

“A Case-control Study Examining Disparities in Surgical Oncology Trial Participation among Breast Cancer Patients”

Background: Clinical trial participation among racial/ethnic minorities remains low despite national efforts. We sought to determine how participation in surgical trials for breast cancer has changed over time and what characteristics are associated with likelihood of participation. Methods: Patients enrolled in NCI-sponsored breast surgical oncology trials from 2000-2012 (n=17,125) were compared to trial-eligible women with breast cancer in the National Cancer Data Base diagnosed in 2000-2012 (n=792,719). Race-specific trial participation was plotted over time by income and reported as a proportion of the combined cohorts. Factors associated with likelihood of trial participation were estimated using logistic regression; we report odds ratios (ORs) with 95% confidence intervals (CIs). p<0.05 was considered significant for all analyses. Results: Likelihood of participation declined across all groups due to a decrease in the scale and number of trials. In 2000-2003, Asian/Pacific-Islander (API, 7.17%), Hispanic (3.48%), and white (7.13%) patients from the highest income group had higher participation than their lower-income counterparts (API 3.95%, Hispanic 2.67%, white 5.96%), but by 2008-2012, only high-income white patients participated more than lower-income whites (0.32% vs 0.25%, all p<0.01). Black (OR 0.78, 95% CI 0.73-0.83) and Hispanic (OR 0.81, 95% CI 0.74-0.89) patients were less likely to participate than whites, but there were significant interactions between income and race/ethnicity, with high-income black patients being ~50% less likely to participate than lower-income black patients (all p<0.001). Conclusions: Multifaceted interventions will be needed to address persistent disparities in surgical trial participation, which reflect complex interactions between race/ethnicity and other patient characteristics.

Eric Gonzalez, PhD Postdoctoral Research Fellow of Biomedical Engineering

“Chronic Monitoring of Voiding Function in a Novel Model of Detrusor

Underactivity” Background: Detrusor underactivity (DU) is an understudied health concern with inadequate clinical management. The limited availability of animal models impedes the development of new therapeutic approaches. The objective of the current studies was to monitor chronic voiding behavior in an obesity animal model of DU and determine the contributions attributed to myogenic or neurogenic pathology. Methods: Obese prone (OP) rats were fed a 45-60% fat diet to induce DU. Chronic voiding behavior was assessed twice per week for up to 30 weeks in metabolic cages. After testing, bladder strips and mid-urethral rings were mounted in tissue baths and viability was assessed with KCl. Both bladder strips and urethral rings underwent concentration response curves to carbachol. Bladder strips also underwent electric field stimulation (EFS) with or without atropine or alpha,beta-methylene ATP, whereas urethral rings underwent both EFS and caffeine to determine neural and calcium function respectively. Results: Urinary frequency increased and voided volume decreased over 11 weeks of monitoring voiding behavior in OP rats with indwelling bladder catheters (p≤0.001). Bladder contraction force to KCl, carbachol, and EFS was decreased in OP rats compared to naive controls suggesting impairment of cholinergic-mediated contractions (p≤0.01). In addition, external urethral sphincter dysfunction was demonstrated in the mid-urethral ring of OP rats which exhibited decreased peak and sustained contractile force to EFS and caffeine respectively. Conclusions/Implications: Impaired cholinergic signaling may be contributing to incomplete bladder emptying in OP rats. Targeting these deficits with concurrent pharmacotherapy and neuromodulation may be one approach to recover voiding function.

Rasheeda Hall, MD, MBA, MHS Assistant Professor of Medicine, Division of Nephrology

“Understanding Functional Disability in Older Dialysis Patients” Background: Over 60% of older adults starting dialysis experience functional disability within six months. This functional disability contributes to significant morbidity and mortality, and could potentially be mitigated through geriatric assessment (GA). The objective of this project was to define characteristics and measures for a GA intervention tailored for older dialysis patients. Methods: 1) a retrospective study to identify change in Short Form-12 physical component score (SF-12 PCS) and associated clinical factors; 2) a prospective study to evaluate utility of specific physical performance measures (e.g., short physical performance battery (SPPB)); 3) a qualitative study to gain stakeholder perspectives on functional disability. Results: In the retrospective cohort (n=1,371; mean age: 79.9±4.5), average change in SF-12 PCS was small (-0.9±9.6), but 40% (n=539) experienced a clinically relevant SF-12 PCS decline. No clinical factors were associated with SF-12 PCS change. In the prospective study (n=35), mean SPPB at baseline, 3 months, and 6 months was 6.37±2.95 (n=35), 6.61±2.63 (n=28), and 6.67±2.99 (n=24), respectively. A clinically meaningful SPPB change over 6 months was found in 66% (n=16). In our qualitative study, we engaged 42 patients and providers who expressed factors that influence functional ability include mobility, medications, care coordination, and social support. Conclusions: The SPPB is an effective outcome measure and tool for identifying vulnerable patients for a GA intervention tailored to meets the needs of older dialysis patients. Implications: A GA intervention should be conducted to identify its potential efficacy in mitigating functional disability in a vulnerable subset of older dialysis patients.

Erin Hisey, PhD Postdoctoral Scholar of Cell Biology

“Neural Circuit Basis of Developmental Brain Disorders”

Multiple mutations associated with human brain disorders such as schizophrenia (SZ), intellectual disability (ID), and autism involve genes which encode regulators of the synaptic cytoskeleton. Cognitive deficits, such as working memory impairments, are co-morbid across SZ, ID, and ASD, and currently little is known regarding the neural circuit perturbations that lead to cognitive disruptions. Conditional deletion of an actin cytoskeletal regulator (ArpC3) in mice leads to a dramatic alteration of spine synapse morphology and number as well as cognitive impairments. Though preliminary evidence suggests that rescue of ArpC3 expression in frontal cortex (FC) can restore both episodic and working memory, the specific neural circuit in the FC that underlies these forms of memory is unknown. We chose to examine the functional role of FC cells projecting to the lateral entorhinal cortex (LEC), a brain region known to be involved in complex forms of object recognition and associative learning, in learning and memory. Using a combination of intersectional genetic silencing, circuit-specific conditional knockdown and in vivo imaging in behaving mice, we found that FC-LEC cells play a role in working memory, possibly encoding decision-making points in time, as well as a previously unappreciated role in anxiety-like behavior.

Maryellen S. Kelly, DNP, CPNP Clinical Associate, School of Nursing

“Diabetic Uropathy as a Predictor of Medical Visits for Lower Urinary Tract

Symptoms: a Population-Based Analysis”

Introduction: Diabetes mellitus (DM) adversely impacts multiple organ systems. Diabetic bladder dysfunction (DBD), or diabetic uropathy, is increasingly recognized as both a short- and long-term complication of diabetes in adults in the form of Lower Urinary Tract Symptoms (LUTS). However, there is little population-based data to characterize the overall impact of DBD on patients. We hypothesized that a diagnosis of DM would be associated with increased odds of LUTS complaints. Methods: We performed a cross-sectional time-series analysis of outpatient encounters for patients aged >18 years recorded in the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey (NAMCS/NHAMCS) dataset over a 7-year period (2009-2015). Patients were excluded if they had diagnosis codes indicating bladder cancer, congenital obstructive uropathy, or neurogenic bladder. Survey weighting and clustering were used to generate national annual estimates of the prevalence of diagnosed LUTS during outpatient visits in the population meeting study inclusion/exclusion criteria. As per NAMCS/NHAMCS guidelines, weighted descriptive statistics were calculated. Weighted logistic regression models were used to estimate the probability of a LUTS diagnosis adjusting for year, age, gender, race/ethnicity, insurance status, and DM. Results: We identified 6.2 billion weighted (397,465 unweighted) outpatient visits between 2009-2015. Of these encounters, 60% were made by males, 72% by non-Hispanic whites, 32% by >64-year-olds, and 39% by the privately insured. DM was noted in 15% of encounters; LUTS were noted in 3%. There was a trend towards increasing diagnosis of LUTS over time (OR 1.04, p=0.005), ranging from 2% in 2009 to 3% in 2015. 3% of patients with diabetes had a diagnosis of LUTS compared to 2% among those without diabetes. In multivariable analysis, DM was not significantly associated with LUTS (p=0.47). Older age (OR 1.34, p<0.01), female gender (OR 1.42, p<0.01), Hispanic ethnicity (OR 1.20, p=0.004), public insurance status (OR 1.20, p=0.0002), and study year (OR 1.04, p=0.05) were positively associated with diagnosis of LUTS. Conclusions: DM was not significantly associated with LUTS presentation in adults between 2009-2015 in this database. Older age at the time of encounter, female gender, Hispanic ethnicity, and public insurance status were associated with increased odds of LUTS diagnoses.

Kenneth T. Kishida, PhD Assistant Professor of Physiology and Pharmacology

"Real-time monitoring of dopamine and serotonin during conscious choice and

moment to-moment changes in subjective experience in humans." The ascending neuromodulatory systems that release dopamine, serotonin, or norepinephrine throughout the brain are critical for healthy brain function and are thought to underlie a wide range of psychiatric and neurological disorders. Until recently, it was not possible to monitor the release of these neurotransmitters in the human brain with the temporal resolution necessary to link real-time fluctuations in dopamine, serotonin, or norepinephrine with ongoing choice behavior nor moment-to-moment changes in conscious subjective feelings. We have developed a novel approach, which we call ‘elastic net electrochemistry’, that permits simultaneous and co-localized detection of the release of these neuromodulators with sub-second temporal resolution. This approach requires electrodes implanted in the brain, thus we have been using this approach in humans undergoing deep brain stimulation electrode implantation surgery and now in patients undergoing stereo-EEG monitoring. We have paired these first-of-their kind measurements with tasks designed to investigate the computational underpinnings of human choice behavior and associated moment-to-moment changes in subjective experience. We believe such work is likely to lead to novel insights into how these neuromodulatory systems contribute to the changes in behavior and subjective feeling associated with psychiatric and neurological dysfunction.

Carlene Moore, PhD Assistant Professor of Neurology

“Molecular and cellular signaling mechanisms of TRPV4 in the skin: A

therapeutic target for pain, inflammation and itch”

Background: The prevalence of pain and the responses to both acute and chronic pain differs by ethnicity. In particular, compared to Caucasian Americans (CA), other ethnic groups including African Americans (AA) are more susceptible to acute nociceptive pain and to the development of long-term chronic pain. To understand this health disparity, we addressed whether there is a difference between AA and CA in the expression and function of TRPV4 in pain relevant tractable models. We focused on TRPV4 signaling, because we previously demonstrated that skin keratinocyte TRPV4 was a molecular master-regulator of the skin’s UVB response, the resulting tissue damage and pain. To study pain in human model systems, keratinocytes are readily available.

Methods: Primary cultured human keratinocytes derived from subjects of different ethnicity, AA and CA were isolated from operatively-removed foreskin, obtained from Duke Children's Hospital in accordance to institutionally approved IRB protocol. Ca2+ imaging of keratinocytes in response to chemical activators was used to determine differences in TRPV4-dependent signaling, in addition cell viability assays. RT-qPCR, Western blotting, Immunocytochemistry were employed to probe gene expression of pro-algesic mediators and their TRPV4-dependency by use of TRPV4-selective inhibitors

Results: AA and CA skin keratinocytes express similar basal levels of TRPV4. Inhibition of TRPV4 enhanced cell viability in both CA and AA keratinocytes. Following a mildly inflammatory UVB exposure, TRPV4 channels in AA keratinocytes showed a more robust net change in calcium influx conduction in response to selective chemical activation of TRPV4, suggesting channel sensitization.

Conclusions: TRPV4 in AA keratinocytes is more readily sensitized than in CA by UVB, likely as a result of pro-inflammatory mediators released under inflammatory conditions. This represents an important novel finding of ethnic differences of “forefront signaling” in the integument where keratinocytes participate in pain/itch sensory transduction.

Implications: This is the first report a sensory transduction molecule - a TRP channel, with divergent biological response to an ambient stimulus – UVB - based on ethnicity. Knowing that TRPV4 channels in keratinocytes are preferentially sensitized in AA vs. CA, we will now develop the mechanistic insights that underlie the observed differences. These might pave the way for a personalized medicine approach that can be readily implemented to the integument.

Andrew Murray, PhD Postdoctoral Scholar of Medicine, Division of Hematological Malignancies and

Cellular Therapy

“Hormone regulation of breast cancer cell interactions with the bone marrow vasculature”

Background: The primary cause of death among patients with hormone receptor positive (HR+) breast cancer (BCa) is metastatic relapse, most commonly occurring first in the bone. E-selectin (e-sel), which is constitutively expressed by a specialized subset of bone marrow (BM) microvessels, mediates tumor cell entry into the bone. Therefore, we sought to examine the effects of estrogen and hormonal therapies on HR+ BCa expression of e-sel ligands. Methods: HR+ BCa cells were stimulated with estradiol+/-4-OHT (tamoxifen active metabolite) and analyzed by flow cytometry, western blotting, and intravital imaging to determine changes in e-sel ligand expression and functional E-sel/e-sel ligand interactions. Results: Flow analysis revealed that estradiol and 4-OHT negatively regulate e-sel ligand expression on BCa cells with increased effects in E2+4-OHT combination treatment. Western blot analysis of functional e-sel ligands pulled down by e-sel immunoprecipitation revealed that E2 + 4-OHT decreased expression of functional e-sel ligands. To determine whether decreased e-sel ligand binding altered BCa interaction with the BM vasculature, cells were treated with E2 + 4-OHT or vehicle and subsequently engrafted into mice. Two hours post engraftment, real-time intravital video capture revealed that BCa cells treated with E2 + 4-OHT showed decreased rolling interactions and adherence to the BM vasculature. Conclusions: Estradiol and 4-OHT treatment decrease HR+ BCa binding to e-sel and the adhesive interactions of circulating tumor cells with vasculature at the bone metastatic site.

Implications: This data suggests a novel method by which tamoxifen down regulates factors that mediate tumor cell entry into the BM.

Andrada Neacsiu, PhD Assistant Professor of Psychiatry and Behavioral Sciences

“Establishing the Therapeutic Target for CBT-Enhanced Neuromodulation for Transdiagnostic Emotion Dysregulation”

Background: Despite rapid advancements in understanding the brain bases of psychopathology, there have been few attempts to translate neuroscientific findings into novel interventions for psychiatric patients. In particular, difficulties calming down when upset (or emotional dysregulation) is a problem that cuts across psychopathology and for which novel treatments are needed. Emerging evidence highlights that successful interventions reduce emotional dysregulation by impacting the impaired fronto-amygdala circuits responsible for difficulties modulating emotional arousal. Nevertheless, such interventions are long, cumbersome, and have limited effectiveness. Therefore, the aim of this study is to examine a one-time neuroscience-driven intervention for emotional dysregulation.

Methods: Adults who meet criteria for any DSM-V disorder and who report difficulties with emotion regulation are randomly assigned to undergo a novel one-time intervention including cognitive restructuring and neurostimulation. Functional imaging results are used to target the neurostimulation. Short term and long term assessments include a multi-method battery of measures.

Results: Preliminary results show that administering the novel intervention is feasible and acceptable.

Conclusions: When completed, the proposed investigation has the potential to provide crucial information about the optimal neural target for neurostimulation in those who have difficulties managing emotions as well as about our success in engaging this target with neurostimulation and cognitive restructuring. Given NIMH’s current emphasis on experimental therapeutics, understanding the neural signature of emotional dysregulation is critical for future intervention development and application.

Implications: Our findings have the potential to radically enhance current mental health treatments.

Chandylen Nightingale, PhD, MPH Assistant Professor of Social Sciences and Health Policy

“Interest in Supportive Care Programs among Head and Neck Cancer Caregivers”

Background/ Purpose: To inform development of targeted supportive care programs, we evaluated interest among head and neck cancer (HNC) caregivers. Methods: Informal caregivers of patients with HNC scheduled for major surgery completed surveys to assess health behaviors and interest in supportive care programs (by program type, timing, and delivery mode). Caregivers also completed measures of caregiver burden (the Burden Interview-Screening Version), mental and physical health (VR-12), depression (CES-D), and anxiety (PROMIS). Descriptive statistics summarized caregivers’ interest levels. Chi-square tests and t-tests compared caregivers who were very interested versus somewhat or not interested in supportive care programs. Results: Caregivers (n=32; mean age=60 years (SD= 11.3)) were predominately white (84.4%), female (84.4%), and partnered with the patient (75.0%). Most caregivers were very/somewhat interested in programs focused on diet/exercise (71.0%), cancer education (65.6%), stress reduction (62.5%), and finances, caregiving, and well-being (56.3%). Caregivers were most likely to endorse interest in programs offered during the patient’s medical treatment (62.5% extremely/very likely to participate). Caregivers very interested in any type of supportive care program reported poorer mental health (p=.02) and higher anxiety (p=.01) compared to those less interested.

Conclusions: HNC caregivers are interested in a variety of supportive care programs, especially those reporting worse mental health. Supportive care programs offered during the patient’s medical treatment may be most attractive. These findings helped support the development of a web-based intervention, Caregiver Oncology Needs Evaluation Tool (CONNECT), to identify HNC caregivers’ supportive care needs and connect them with tailored resources at the hospital, community, and national level.

Gauri Rao, PharmD, MS Assistant Professor of Pharmacy

“Evaluation of Pharmacodynamic (PD) Activity and Emergence of Resistance of

Novel Combination Regimens: Polymyxin B (PMB), Meropenem (MEM) and ZTI-01 (Fosfomycin for Injection, FOF) against Klebsiella Pneumoniae Carbapenemase-

Producing Klebsiella pneumoniae (KPC-KP)” Introduction: Carbapenem-resistant Klebsiella pneumoniae are resistant to multiple antibiotic classes and often necessitate the use of combination therapy to ensure adequate killing and prevent the emergence of resistance. Combined with the limited number of treatment options, the need for optimized combination therapy is urgent. We aimed to evaluate the PD of PMB, MEM, FOF as two or three drug combinations (combo) against KPC-KP in a dynamic hollow-fiber infection model (HFIM) to assess the rate and extent of emergence of resistance to assist with the design & optimization of these combination regimens. Methods: Two clinical isolates, BAA2146 (MICPMB 0.5 mg/liter; MICMEM 64 mg/liter; MICFOF 16 mg/liter) and BRKP76 (MICPMB, 0.5 mg/liter; MICMEM 64 mg/liter; MICFOF, 32 mg/liter) at an initial inoculum of 107 CFU/ml, were evaluated over 168 h in a HFIM simulating clinically relevant PMB (2.5-mg/kg front loading dose as a 1 h-infusion (inf) followed by 1.5-mg/kg dose q12h as a 1-h inf; PMB FL with Maint 1.5), MEM (2 g as a 3-h inf q8h) and FOF (6 g q8h as a 0.5-h inf) as mono- and combo regimens. Three-drug regimens simulating similar exposure for MEM and FOF combined with 1) PMB as a 2.5-mg/kg FL dose 1 h-inf followed by a 0.5-mg/kg dose q12h as a 1-h inf (PMB FL with Maint 0.5), or 2) as a traditional 0.5-mg/kg (PMB Trad 0.5), or 3)1.5-mg/kg PMB dose q12h as a 1-h inf (PMB Trad 1.5) or 4) as a 2.5-mg/kg (PMB FL 2.5) or 5) 5-mg/kg front loading dose (PMB FL 5) 1 h-inf for the first 24 h followed by no maintenance. Emergence of resistance was evaluated by performing population analysis profiles (PAPs) and determining MICs. Results: PMB, MEM or FOF monotherapy was ineffective and selected for resistance by 24 h. The area under the drug exposure curve (AUC_PK) for PMB in regimens evaluated were determined. PMB FL 2.5 & 5, PMB FL with Maint 0.5, PMB Trad 0.5 & 1.5 reduced PMB exposure by 84%, 68%, 56%, 67% and 2%, respectively compared to PMB FL with Maint 1.5. Efficacy of PD activity was evaluated by calculating the area under the colony forming units curve over 168 h (AUCFU0-168). PMB Trad 0.5 & 1.5 had greater killing effect for BAA2146 with 6.4 and 6.5-log reduction compared to 5.2 and 5.6 log-reduction for KP76. The PMB FL with Maint 0.5 resulted in similar AUCFU0-168 of 6.4-log for BAA2146 and 6.1-log for KP76. PMB FL 2.5 & 5 resulted in bacterial eradication by 32 and 48h, respectively for KP76. For BAA2146, the same initial PD effect for both PMB FL 2.5 & 5.0 during 0-24 h was followed by a steady regrowth pattern by 72 h with PMB FL 2.5 having a greater AUCFU0-

168 log reduction of 2.3 compared to 1.4 by PMB FL 5. Conclusion: Further evaluation of these novel dosing strategies with reduced PMB footprint is warranted to optimize therapy. Currently, RNA-seq analysis for the regimens that did not result in sustained PD activity is being performed to get insights into the emergence of resistance under drug pressure for further optimization.

Joseph Saelens, PhD Postdoctoral Scholar of Medicine, Division of Infectious Diseases

“Sickle-trait disrupts the transcriptional network underlying the pathogenic program

of P. falciparum” Background: Sickle-trait hemoglobin (HbAS) confers near-complete protection from severe, life-threatening falciparum malaria in African children. Despite this clear protection, the molecular mechanisms by which HbAS confers these protective phenotypes remain incompletely understood.

Methods: We performed time-series comparative transcriptomic analyses of the asexual stage of Plasmodium falciparum in normal (HbAA) and HbAS erythrocytes. Late schizonts of P. falciparum reference strain 3D7 were isolated using Percoll gradients and inoculated into parallel cultures in HbAA and HbAS erythrocytes. Newly-invaded ring forms were purified from each culture, and over 48 hours parasites from each independent culture were sampled for microscopy and RNA isolation every 3 hours. RNA from each timepoint was sequenced on the Illumina NovaSeq6000 platform, generating ~120 million 151 base pair paired-end reads for each of 16 timepoints over the asexual cycle. We quantified transcripts using STAR and modeled differential expression of parasite transcripts between HbAA and HbAS erythrocytes with DESeq2. We identified periodic gene expression using persistent homology, Lomb-Scargle, JTK-CYCLE, and de Lichtenberg algorithms, and measured the impact of HbAS on P. falciparum’s periodic gene expression using the Characterizing Loss of Cell Cycle Synchrony (CLOCCS) software.

Results/Conclusions: These analyses reveal sickle-trait broadly disrupts the highly-structured gene expression of P. falciparum, suggesting that sickle-trait confers its protective effect by neutralizing the transcriptional programs that underlie the pathogenic mechanisms P. falciparum deploys in blood stage infections.

Implications: Understanding the aberrant transcriptional program in sickle-trait erythrocytes will help to identify new targets for the next generation of rationally designed therapeutic and preventive malaria measures.

Samantha Schilling, MD, MSHP Assistant Professor of Pediatrics

“Child Adult Relationship Enhancement in Primary Care (PriCARE): A randomized

trial of a skill-based parent training with parent mentor adaptation” Background: PriCARE is a 6-session group training designed to teach positive parenting skills. Parent engagement in such programs is a common implementation barrier. Our primary objective was to measure PriCARE’s impact on child behavior and parenting practices. Our secondary objective was to examine the impact of involving a parent mentor in PriCARE on program attendance and stigma. Methods: Parents of 2-to-6-year-old children were randomized to PriCARE (n=50), PriCARE with mentor (n=50) or control (n=50). Child behavior and parenting practices were measured at baseline and 10 weeks using the Eyberg Child Behavior Inventory (ECBI) and the Parenting Scale (PS). Stigma was measured at 10 weeks. Linear regression models compared mean ECBI and PS change scores from 0 to 10 weeks in PriCARE and control groups and mean attendance and stigma scores between the 2 PriCARE groups. Results: Decreases in mean ECBI intensity and problem scores between 0 and 10 weeks were greater in the PriCARE groups, reflecting larger improvements in behavior [intensity: -7 (-2, -13) vs 4 (-2,11), p=.014; problem: -2 (-1, -4) vs 1 (-1,2), p=.007]. Scores on all PS sub-scales reflected greater improvements in parenting behaviors in PriCARE groups compared to control (all p<0.04). Of those randomized to PriCARE, 66% attended 3 or more sessions. There was no difference in attendance (mean 3.36 vs 3.80), ECBI, or PS change scores between PriCARE and PriCARE mentor groups (all p>.15). Parents randomized to the mentor reported lower stigma associated with attending a parenting group (3.75 vs 5.04, p=.02). Conclusions: PriCARE shows promise in improving behavior in preschool-aged children and increasing positive parenting practices. Adapting PriCARE with a parent mentor may decrease stigma, but does not impact evaluation or implementation outcomes.

Maya Talbott, BS Third-Year Medical Student

“Quantifying Benefit-Risk Tradeoffs for Surgical Options in Low-Risk

Thyroid Cancer” Background: Since 1975, the incidence of thyroid cancer has tripled. Surgery is the mainstay of treatment, and tradeoffs between the two surgical options (lobectomy and total thyroidectomy) are preference sensitive, yet patients’ perspectives have not been well studied. We designed a discrete-choice experiment (DCE) to quantify tradeoffs relevant to surgical options for low-risk thyroid cancer. Methods: Participants completed 6 choice tasks in which they were asked to choose between experimentally-designed surgical options with varying levels of risk of nerve damage, hypocalcemia, need for a second surgery, need for daily thyroid medication, and cancer recurrence. Random-parameters logit models and resulting preference weight estimates were used to infer patients’ preferences for surgical profiles representing lobectomy and total thyroidectomy. Results: From 2017-18, 150 adult patients requiring surgery for a low-risk thyroid cancer or thyroid nodule were enrolled. Median age was 58 years; 80% were female. Results suggested that patients on average favored total thyroidectomy largely due to an assumed 40% risk of requiring a second surgery after lobectomy. If the risk of needing a second surgery can be reduced to 31% or less, the average patient would favor lobectomy over total thyroidectomy. Conclusions: Patients facing decisions about surgery for thyroid cancer will encounter varying levels of surgery-related risks due to tumor characteristics and experience of their surgeon. Preference assessments are essential to promoting shared decision-making for low-risk thyroid cancer. Implications: By characterizing patient preference, DCEs have the potential to improve patient satisfaction and outcomes, and shape regulation and health care policy.

Lavanya Vasudevan, PhD, MPH, CPH Assistant Professor in Family Medicine and Community Health

and Global Health

“Parental hesitancy and uptake of childhood vaccines”

Background: Recent vaccine-preventable outbreaks have renewed the spotlight on parental vaccine hesitancy - a behavior where parents decline or delay vaccines for their children. Due to parental hesitancy, many children remain under-immunized and at risk for deadly infections, despite the availability of effective vaccines. To counter this challenge, the national HealthyPeople 2020 initiative has set a goal to ‘achieve and maintain effective vaccination coverage levels for universally recommended vaccines among young children’. Yet, in many states including North Carolina, the overall coverage for childhood vaccines is 70%, which is well below the levels needed to achieve effective herd immunity. This research study seeks to identify key concerns contributing to parent vaccine hesitancy at Duke. Methods: We will identify key parental concerns using a cross-sectional survey (n=300) with hesitant and non-hesitant parents from three pediatric primary care practices at Duke. Survey questions include socio-demographics, vaccination knowledge and beliefs, and access to information sources via social media. Surveys will be conducted over the telephone or online using the QualtricsXM survey platform. Data on vaccine uptake will be extracted from the North Carolina Immunization Registry. Primary outcome is a parental vaccine hesitancy score. In addition, we will describe key vaccine concerns among parents. Secondary outcomes are the coverage and timeliness of vaccine uptake among children, and association of timely vaccine uptake with the parental hesitancy score. Results: Study activities began in March 2019. The study team sent out 157 recruitment letters and made 87 follow up calls to 72 prospective participants. Of the 30 parents reached, 7 (23%) consented to participate and 6 interviews are completed to-date. Discussion: Study challenges include long timeframe required to secure regulatory approvals and exclusion of records with maternal, fetal, newborn, or child death. Challenges in data collection include inability to reach parents and low recruitment rates. Current efforts are focused on reaching more parents until recruitment and survey targets are met. Implications: Identification of key parental concerns will enable development of tailored interventions to reduce parental hesitancy and promote vaccine uptake consistent with HealthyPeople 2020 goals for immunizations.

Alan Zambeli-Ljepović, BS Third-Year Medical Student

“Extent of Surgery for Low Risk Thyroid Cancer in Elderly: Equipoise in

Survival, but Not in Short-Term Outcomes” Background: Total thyroidectomy is more common than lobectomy for low risk papillary thyroid cancer (PTC), despite equipoise in survival. Since postoperative morbidity increases with age, we aimed to investigate how extent of thyroidectomy affects short-term outcomes among older patients. Methods: Using the SEER-Medicare database, we identified patients ≥66 years treated for PTC ≤2 cm between 1996-2011. We used multivariable logistic regression to evaluate the effect of extent of surgery on complications, emergency department (ED) visits, and unplanned readmissions. Results: Among 3341 selected patients, 77.3% were female, mean age was 72.9 years, and tumors averaged 0.8 cm. 67.6% underwent total thyroidectomy; 32.4% underwent lobectomy. Total thyroidectomy was associated with complications [odds ratio (OR)=1.99] and readmissions (OR=1.59); both P<0.01. Complications were higher in females (OR=1.34), blacks (vs. whites, OR=1.65), and those with ≥2 comorbidities (vs. 0, OR=1.43); all P<0.01. Black patients and those with ≥2 comorbidities had more ED visits (OR=1.50 and 1.92, respectively) and readmissions (OR=2.19 and 2.29); all P<0.01. Conclusions: Total thyroidectomy for older adults with low risk PTC may lead to potentially avoidable complications and readmissions, particularly in black and female patients. In many cases, lobectomy may be a safer and less costly alternative.

Duke CTSA KL2 Program

Program Co-Directors: Laura Svetkey, MD, MHHS Rasheed Gbadegesin, MBBS, MD, FASN Kimberly Johnson, MD

The Duke CTSA Research Career Development Award Program (Duke CTSA KL2) trains a diverse group of scholars in state-of-the-art clinical and translational research methods. The KL2 provides skilled and personalized mentoring, a coordinated and tailored scientific and career development curriculum, and the opportunity to conduct clinical or translational research. Scholars are expected to complete the KL2 program equipped and inspired to become independent investigators. The program contributes to fostering and preparing the next generation of clinical and translational investigators, with an emphasis on enrollment of underrepresented minority scholars as well as training for all scholars in health disparities and minority health research. KL2 Scholars are awarded at least 75% protected effort for 3 years, $20,000/year for research expenses, and $2,500/year for travel to professional meetings. The CTSA KL2 has supported 18 scholars, nine of whom are currently supported by the KL2. Rasheeda Hall graduated in February 2018, Michael Cary will graduate from the KL2 this June, and Katie Dickerson will graduate from the KL2 in November. We are excited to welcome Amanda Eudy, PhD, Kevin Southerland, MD, and Sarahn Wheeler, MD to the KL2 program this summer.

Duke CTSA TL1 Scholarship

Program Co-Directors: David Edelman, MD, MHS Sallie Permar, MD, PhD Kevin Thomas, MD

The Duke CTSA TL1 Scholarship program offers clinical and translational research experience and training for pre-doctoral students in medicine. The scholarship’s provision of research training enhances programs designed to expose students to clinical and translational research earlier in their careers. CTSA TL1 Scholars graduate from Duke University with a Master’s degree. The Duke CTSA Scholarship is a two-year scholarship, adding one additional year to medical school for TL1 scholars. The scholarship provides a stipend for each full year of study, as well as additional funds for CRTP tuition, research expenses, and travel to scientific meetings. Since its initiation in 2013, 24 scholars have entered the program. Priscila Cunha, Maya Talbott, and Alan Zambeli-Ljepović will graduate from the program this year.

DUKE CTSA TL1 POSTDOCTORAL PROGRAM AND PHYSICIAN RESEARCH FELLOWSHIPS

Program Co-Directors: David Edelman, MD, MHS

Sallie Permar, MD, PhD Kevin Thomas, MD

Duke CTSA TL1 POSTDOCTORAL Training Program

The Duke CTSA TL1 postdoctoral program provides 2 years of funded time to support the research training of outstanding junior scientists with a PhD and no more than 2 prior years on a federal postdoctoral training grant. We have particular interest in applicants who are interested in broadening their previous training to include a new category of research methodology (e.g., bench science trainees looking to gain training in translational or clinical research, or vice versa) and applicants looking to obtain training in data science methodology. Scholars receive tailored professional development support, an NIH-scale postdoctoral stipend, and federally designated training-related expenses.

Duke CTSA TL1 PHYSICIAN Research Fellowship

The Duke CTSA TL1 physician fellowship provides 2 years of funded time to support the research training of physician-scientists. We have particular interest in physician trainees with an MD or MD/PHD who are interested in broadening their previous training to include a new category of research methodology (e.g., bench science trainees looking to gain training in translational or clinical research, or vice versa) and applicants looking to obtain training in data science methodology. Scholars receive tailored professional development support, an NIH-scale postdoctoral stipend, and federally designated training-related expenses. Erin Hisey, PhD, Andrew Murray, PhD, and Joseph Saelens, PhD, are the first recipients of the CTSA TL1 Postdoctoral Award. We are excited to welcome Ashley Nelson, PhD, and Jordan Ezekian, MD, to the program this summer.