Advancing workforce diversity by leveraging the Clinical and Translational Science Awards (CTSA) program.

Clinical trials continue to disproportionately underrepresent people of color. Increasing representation of diverse backgrounds among clinical research personnel has the potential to yield greater representation in clinical trials and more efficacious medical interventions by addressing medical mistrust. In 2019, North Carolina Central University (NCCU), a Historically Black College and University with a more than 80% underrepresented student population, established the Clinical Research Sciences Program with support from the Clinical and Translational Science Awards (CTSA) program at neighboring Duke University. This program was designed to increase exposure of students from diverse educational, racial, and ethnic backgrounds to the field of clinical research, with a special focus on health equity education. In the first year, the program graduated 11 students from the two-semester certificate program, eight of whom now hold positions as clinical research professionals. This article describes how leveraging the CTSA program helped NCCU build a framework for producing a highly trained, competent, and diverse workforce in clinical research responsive to the call for increased diversity in clinical trial participation.

A novel cross-institutional college internship program to train future diverse leaders in clinical research with data-driven approaches to assess impact.

The field of Clinical Research, like many other scientific disciplines, has struggled to recruit and retain talented researchers from diverse communities. While there is a strong history of documenting the problem, having a diverse and inclusive workforce is hindered by the lack of data-driven approaches, cross-institutional partnerships, access to mentors, and positive immersive experiences for people from underrepresented groups. Here, we describe a novel initiative for North Carolina Central University Clinical Research Sciences Program (NCCU-CRSP) student interns to partner with Duke University to have immersive clinical and pre-clinical research training in a 15-week internship as the culminating experience towards their degree for a Bachelor of Science in Clinical Research. The goals of the internship are: 1) to give hands-on training to enhance the impact of classroom-based learning, 2) broaden their understanding of the wide swath of positions available to them, 3) promote their sense of self-efficacy, confidence, science identity, research identity, and connections to the pre-clinical and clinical community, and 4) prepare them to be workforce ready upon graduating. The students dedicate 75% of their time to clinical research with Duke University at Pickett Road and 25% to pre-clinical research in the Collective for Psychiatric Neuroengineering in the Duke Psychiatry Department of the School of Medicine. They will also receive eight 1-h professional development training sessions from the Duke-NCCU Clinical and Translational Science Initiative's Workforce Development Team and five 1-h sessions based on the Entering Research Curriculum developed by the Center for the Improvement of Mentored Experiences in Research (CIMER). Finally, they will be brought in as a cohort and coached on peer mentoring and mutual support frameworks to enhance their sense of community. These student-interns will perform pre- and post-internship self-assessment surveys to quantify their self-efficacy, feelings of belonging, access to research opportunities and mentors, and to give details of their future education and career goals. We will evaluate the impact of the internship using validated tools and apply these findings for future optimization of program design and tactical advice for other programs with shared missions. Furthermore, we will email them on an annual basis with follow-up surveys to assess the longitudinal impact of this internship program, their educational experiences at NCCU, what job titles they hold, how prepared they feel for their roles, and what they hope their future career trajectory will be. Collectively, these approaches will apply theoretical frameworks developed by social and cognitive psychology, vocational theory, and educational research to clinical research training with the goals of recruiting and training talented and diverse leaders within clinical research. We hope that by evaluating our successes, failures, strengths, and liabilities through empirically derived evidence we will also inspire future studies that use data-driven approaches to elevate our approaches as we work together to train and recruit talented researchers from diverse communities into our scientific enterprise and to launch them with more in-depth experiential learning that will empower them to succeed.

COVID-19 vaccine hesitancy in underserved communities of North Carolina.

BACKGROUND: In the United States, underserved communities including Blacks and Latinx are disproportionately affected by COVID-19. This study sought to estimate the prevalence of COVID-19 vaccine hesitancy, describe attitudes related to vaccination, and identify correlates among historically marginalized populations across 9 counties in North Carolina. METHODS: We conducted a cross-sectional survey distributed at free COVID-19 testing events in underserved rural and urban communities from August 27 -December 15, 2020. Vaccine hesitancy was defined as the response of "no" or "don't know/not sure" to whether the participant would get the COVID-19 vaccine as soon as it became available. RESULTS: The sample comprised 948 participants including 27.7% Whites, 59.6% Blacks, 12.7% Latinx, and 63% female. 32% earned <$20K annually, 60% owned a computer and ~80% had internet access at home. The prevalence of vaccine hesitancy was 68.9% including 62.7%, 74%, and 59.5% among Whites, Blacks, and Latinx, respectively. Between September and December, the largest decline in vaccine hesitancy occurred among Whites (27.5 percentage points), followed by Latinx (17.6) and only 12.0 points among Blacks. 51.2% of respondents reported vaccine safety concerns, 23.7% wanted others to get vaccinated first, and 63.1% would trust health care providers about the COVID-19 vaccine. Factors associated with hesitancy in multivariable logistic regression included being female (OR = 1.90 95%CI [1.36, 2.64]), being Black (OR = 1.68 1.16, 2.45]), calendar month (OR = 0.76 [0.63, 0.92]), safety concerns (OR = 4.28 [3.06, 5.97]), and government distrust (OR = 3.57 [2.26, 5.63]). CONCLUSIONS: This study engaged the community to directly reach underserved minority populations at highest risk of COVID-19 that permitted assessment of vaccine hesitancy (which was much higher than national estimates), driven in part by distrust, and safety concerns.

COVID-19 Vaccine Hesitancy in Underserved Communities of North Carolina.

BACKGROUND: In the United States, underserved communities including Blacks and Latinx are disproportionately affected by COVID-19, and widespread vaccination is critical for curbing this pandemic. This study sought to estimate the prevalence of COVID-19 vaccine hesitancy, describe attitudes related to vaccination, and identify correlates among racial minority and marginalized populations across 9 counties in North Carolina. METHODS: We conducted a cross-sectional survey with a self-administered questionnaire distributed at free COVID-19 testing events in underserved rural and urban communities from August 27 - December 15, 2020. Vaccine hesitancy was defined as the response of "no" or "don't know/not sure" to whether the participant would get the COVID-19 vaccine as soon as it became available. RESULTS: The sample comprised 948 participants including 27.7% Whites, 59.6% Blacks, 12.7% Latinx, and 63% female. Thirty-two percent earned <$20K annually, 60% owned a computer and ∼80% had internet access at home. The prevalence of vaccine hesitancy was 68.9% including 62.7%, 74%, and 59.5% among Whites, Blacks, and Latinx, respectively. Between September and December, the largest decline in vaccine hesitancy occurred among Whites (27.5 percentage points), followed by Latinx (17.6) and the smallest decline was among Black respondents (12.0). 51.2% of the respondents reported vaccine safety concerns, 23.7% wanted others to get of the respondents reported they would trust health care providers with information about the COVID-19 vaccine. Factors associated with hesitancy in multivariable logistic regression included being female (OR=1.90 95%CI[1.36, 2.64]), being Black (OR=1.68 [1.106 2.45]), calendar month (OR=0.76 [0.63, 0.92]), safety concerns (OR=4.28 [3.06, 5.97]), and government distrust (OR=3.57 [2.26, 5.63]). CONCLUSIONS: This study reached underserved minority populations in a number of different locations to investigate COVID-19 vaccine hesitancy. We built on existing relationships and further engaged the community, stake holders and health department to provide free COVID-19 testing. This direct approach permitted assessment of vaccine hesitancy (which was much higher than national estimates), distrust, and safety concerns. HIGHLIGHTS: This study surveyed 948 adults at COVID-19 testing sites in 9 counties of North Carolina between August 27 and December 15, 2020 where vaccine hesitancy was widespread including 74% in Blacks, 62.7% in Whites and 59.5% in Latinx.Vaccine hesitancy declined over time but remained high for Blacks.On-site surveys conducted in underserved areas that were paper-based and self-administered permitted reaching adults with no internet (17%), no cell phone (20%), no computer (40%) and yearly incomes less than 20K (31%).Widespread vaccine hesitancy in predominately minority communities of NC must be addressed to successfully implement mass COVID-19 vaccination programs.

Development and Validation of the BREAST-Q Breast-Conserving Therapy Module.

BACKGROUND: In breast cancer surgery, patient-reported outcome measures are needed to measure outcomes best reported by patients (e.g., psychosocial well-being). This study aimed to develop and validate a new BREAST-Q module to address the unique concerns of patients undergoing breast-conserving therapy (BCT). METHODS: Phase 1 involved qualitative and cognitive interviews with women who had BCT and clinical expert input to establish content for the BCT module. A field-test (phase 2) was performed, and Rasch measurement theory (RMT) analysis was used for item reduction and examination of reliability and validity. Validation of the item-reduced scales in a clinical sample (phase 3) was conducted for further assessment of their psychometric properties. RESULTS: Qualitative interviews with 24 women resulted in the addition of 15 new items across multiple existing BREAST-Q scales and the development of two new scales (Adverse Effects of Radiation and Satisfaction With Information-Radiation Therapy). Feedback from 15 patients and 5 clinical experts were used to refine the instructions, response options, and item wording. An RMT analysis of data from 3497 women resulted in item reduction. The final set of scales showed evidence of ordered response option thresholds, good item fit, and good reliability, except for the Adverse Effects of the Radiation Scale. Validity and reliability were further supported by the phase 3 data from 3125 women. CONCLUSIONS: The BREAST-Q BCT module can be used in research and clinical care to evaluate quality metrics and to compare surgical outcomes across all breast cancer surgery patients.

Isolation and identification of three new chromones from the leaves of Pimenta dioica with cytotoxic, oestrogenic and anti-oestrogenic effects.

CONTEXT: Pimenta dioica (L.) Merr. (Myrtaceae) is used in Costa Rican traditional medicine for women's health. Our previous work showed that P. dioica extracts were oestrogenic. OBJECTIVES: This work identifies phytochemicals from P. dioica that are responsible for the plant's oestrogen-like activities. MATERIALS AND METHODS: P. dioica leaves were collected in Costa Rica in 2005. Fractions resulting from chromatographic separation of a methanol extract were tested at 50 µg/mL in a competitive oestrogen receptor-binding assay. Active compounds were isolated by HPLC and identified by NMR and MS. Pure compounds were tested at 1 µM in the oestrogen-responsive SEAP reporter gene assay. The effects on cell viability, cytotoxicity and apoptosis were investigated in breast cancer (MCF-7 and SK-BR3) and gastric cancer (AGS and NCI-N87) cell lines using the ApoTox-Glo and Caspase-Glo assays and qPCR. RESULTS: Quercitrin and three new chromones, including a 2-phenoxychromone, 6,8-di-C-methylcapillarisin (1) were isolated and identified. Compound 1 caused a 6.2-fold increase in SEAP expression at 1 µM (p < 0.05). This activity was blocked by the ER antagonist ICI 182,780. Compound 2 caused a 6.0-fold increase in SEAP, inhibited the growth of MCF-7, AGS and NCI-N87 cells (IC50 54.27, 38.13 and 51.22 µg/mL, respectively), and induced apoptosis via caspase 8 and increased the Bax/Bcl-2 mRNA ratio in MCF-7 cells. Compound 3 was anti-oestrogenic in MCF-7 cells. DISCUSSION AND CONCLUSIONS: Compounds from P. dioica have oestrogenic, anti-oestrogenic and cytotoxic effects that may explain the ethnomedical use of this plant.

Case Studies from the Clinic: Initiating and Implementing Patient-Reported Outcome Measures.

INTRODUCTION: Self-reporting by patients though the use of electronic patient-reported outcome (PRO) measures has been shown to use increase patient satisfaction with care, and improve patient-provider communication, symptom management, and health quality. Additionally, PROs are increasingly used in research to expand understanding regarding the relative risks, benefits, and burdens of interventions. While experience embedding patient-reported outcomes (PROs) into registries and clinical workflow is growing, there is little in the literature to guide those interested in incorporating PROs into routine clinical care and for use in research. CASE DESCRIPTIONS: The NIH Health Care Systems Research Collaboratory PRO Core interviewed investigators from seven programs to get their first-hand experiences on the incorporation of PROs for both care and research, and the investigators have contributed to this manuscript as authors. FINDINGS: We use these case studies to present practical approaches to initiating and implementing PROS, including instrument selection, tips for integrating PRO collection systems into clinical workflow, considerations for user experience and data collection, and the methods to assess and monitor quality. CONCLUSION: Because the decision to initiate and implement PRO collection impacts many different stakeholders, the solution requires collaboration among the involved parties, careful planning, and integration into clinical workflow.

Using Patient Reported Outcomes in Oncology Clinical Practice.

BACKGROUND AND AIMS: Patient reported outcomes (PROs) are increasingly being implemented into the care of patients with cancer. The use of a standard set of PROs (e.g., pain) in cancer is becoming established and there is interest in what additional PROs might provide valuable information. The goal of this observational study was to examine how the PROs of self-efficacy for pain and other symptoms assessed at the point of service were associated with pain, symptom severity and distress, and physical and psychosocial functioning in a sample of breast and gastrointestinal patients. We also sought to examine differences in these relationships by cancer type (breast and gastrointestinal) as well as understand differences in self-assessment mode (paper/pencil or electronic tablet). METHODS: 178 patients with breast (n=65) and gastrointestinal cancer (n = 113) completed the Chronic Pain Self Efficacy Scale, M.D. Anderson Symptom Inventory, and Functional Assessment of Cancer Therapy-General questionnaires. Measures were completed with paper and pencil and electronically using a tablet computer while patients waited for their clinical appointment. Responses from the initial completed questionnaires on both the paper and electronic instruments were analyzed. RESULTS: Patients' self-efficacy scores for pain and other symptoms correlated positively with pain, symptom severity and distress, and physical and psychosocial functioning; patients with lower levels of self-efficacy reported poorer outcomes and functioning overall. The results were independent of cancer type and mode of assessment. No statistically significant differences were found in the PROs when collected by electronic technology versus paper-pencil mode; patients were very satisfied with using the tablet computer to complete the PRO measures. CONCLUSIONS AND IMPLICATIONS: Our results suggest that self-efficacy for pain and symptom management may be a beneficial addition to clinic-based PRO assessment batteries for patients with cancer and other chronic diseases. Existing short, validated symptom self-efficacy scales could easily be integrated into clinical practice to help healthcare providers identify patients that might benefit from intervention. Study results also support existing research that suggests electronic approaches are a practical way to collect PRO data, including self-efficacy data, in the clinic. Overall, our data suggest that patients who have particularly low levels of self-efficacy for pain and symptom management may be at risk for higher levels of pain and disability. Thus, if self-efficacy for pain and symptom management were routinely collected at the time of clinical service, psychosocial interventions to improve self-efficacy for pain and symptom management, and in turn overall quality of life, could be implemented in a timely fashion.

Patient-Reported Outcomes After Choice for Contralateral Prophylactic Mastectomy.

PURPOSE: The rate of contralateral prophylactic mastectomies (CPMs) continues to rise, although there is little evidence to support improvement in quality of life (QOL) with CPM. We sought to ascertain whether patient-reported outcomes and, more specifically, QOL differed according to receipt of CPM. METHODS: Volunteers recruited from the Army of Women with a history of breast cancer surgery took an electronically administered survey, which included the BREAST-Q, a well-validated breast surgery outcomes patient-reporting tool, and demographic and treatment-related questions. Descriptive statistics, hypothesis testing, and regression analysis were used to evaluate the association of CPM with four BREAST-Q QOL domains. RESULTS: A total of 7,619 women completed questionnaires; of those eligible, 3,977 had a mastectomy and 1,598 reported receipt of CPM. Women undergoing CPM were younger than those who did not choose CPM. On unadjusted analysis, mean breast satisfaction was higher in the CPM group (60.4 v 57.9, P < .001) and mean physical well-being was lower in the CPM group (74.6 v 76.6, P < .001). On multivariable analysis, the CPM group continued to report higher breast satisfaction (P = .046) and psychosocial well-being (P = .017), but no difference was reported in the no-CPM group in the other QOL domains. CONCLUSION: Choice for CPM was associated with an improvement in breast satisfaction and psychosocial well-being. However, the magnitude of the effect may be too small to be clinically meaningful. Such patient-reported outcomes data are important to consider when counseling women contemplating CPM as part of their breast cancer treatment.

A national snapshot of satisfaction with breast cancer procedures.

PURPOSE: Women with early-stage breast cancer face the complex decision to undergo one of three equally effective oncologic surgical strategies: breast-conservation surgery with radiation (BCS), mastectomy, or mastectomy with breast reconstruction. With comparable oncologic outcomes and survival rates, evaluations of satisfaction with these procedures are needed to facilitate the decision-making process and to optimize long-term health. METHODS: Women recruited from the Army of Women with a history of breast cancer surgery took electronically administered surgery-specific surveys, including the BREAST-Q© and a background survey evaluating patient-, disease-, and procedure-specific factors. Descriptive statistics and regression analysis were used to evaluate the effect of procedure type on breast satisfaction scores. RESULTS: Overall, 7,619 women completed the questionnaires. Linear regression revealed that women who underwent abdominal flap, or buttock or thigh flap reconstruction reported the highest breast satisfaction score, scoring an average of 5.6 points and 14.4 points higher than BCS, respectively (p < 0.0001 and p = 0.027, respectively). No difference in satisfaction was observed in women who underwent latissimus dorsi flap reconstruction compared with those who underwent BCS. Women who underwent implant reconstruction reported scores 8.6 points lower than BCS (p < 0.0001). Those with mastectomies without reconstruction or complex surgical histories scored, on average, 10 points lower than BCS (p < 0.0001). CONCLUSION: Women who underwent autologous tissue reconstruction reported the highest breast satisfaction, while women undergoing mastectomy without reconstruction reported the lowest satisfaction. These findings emphasize the value of patient-reported outcome measures as an important guide to decision making in breast surgery and underscore the importance of multidisciplinary participation early in the surgical decision-making process.

Assessing the value of patient-generated data to comparative effectiveness research.

The goal of comparative effectiveness research is to assess medical therapies and allow patients, health care providers, payers, and policy makers to make evidence-based decisions about the most appropriate therapies in routine clinical practice. To conduct this type of research and to inform health care delivery, data about the impact of interventions on patient outcomes are needed. Methods of generating evidence for comparative effectiveness research provide opportunities to engage patients and understand their experiences with illness and its treatment. In this article we assess the need for, uses of, and strengths and weaknesses of patient-generated data. We also review in brief federal and medical society efforts to create new streams of patient-generated data for clinical and research use. We observe that the key to high-quality patient-generated data is to have immediate and actionable data so that patients experience the importance of the data for their own care as well as research purposes. We conclude that leveraging the emerging wealth of "big data" being generated by patient-facing technologies such as systems to collect patient-reported outcomes data and patient-worn sensors is critical to developing the evidence base that informs decisions made by patients, providers, and policy makers in pursuit of high-value medical care.

Estrogenic and progestagenic effects of extracts of Justicia pectoralis Jacq., an herbal medicine from Costa Rica used for the treatment of menopause and PMS.

OBJECTIVES: To investigate the biological activities of Justicia pectoralis Jacq. (Acanthaceae), an herbal medicine used in Costa Rica (CR) for the management of menopausal symptoms and dysmenorrhea. STUDY DESIGN: The aerial parts of J. pectoralis were collected, dried and extracted in methanol. To establish possible mechanisms of action of JP for the treatment of menopausal symptoms, the estrogenic and progesterone agonists, and antiinflammatory activities were investigated. MAIN OUTCOME MEASURES: The methanol extract (JP-M) was tested in ER and PR binding assays, a COX-2 enzyme inhibition assay, the ERbeta-CALUX assay in U2-OS cells, as well as reporter and endogenous gene assays in MCF-7 K1 cells. RESULTS: The JP-M extract inhibited COX-2 catalytic activity (IC(50) 4.8 microg/mL); bound to both ERalpha and ERbeta (IC(50) 50 microg/mL and 23.1 microg/mL, respectively); induced estrogen-dependent transcription in the ERbeta-CALUX; and bound to the progesterone receptor (IC(50) 22.8 microg/mL). The extract also modulated the expression of endogenous estrogen responsive genes pS2, PR, and PTGES in MCF-7 cells at a concentration of 20 microg/mL. Activation of a 2 ERE-construct in transiently transfected MCF-7 cells by the extract was inhibited by the estrogen receptor antagonist ICI 182,780, indicating that the effects were mediated through the estrogen receptor. Finally, the extract weakly enhanced the proliferation of MCF-7 cells, however this was not statistically significant as compared with DMSO controls. CONCLUSIONS: Extracts of J. pectoralis have estrogenic, progestagenic and anti-inflammatory effects, and thus have a plausible mechanism of action, explaining its traditional use for menopause and PMS.

Estrogenic effects of herbal medicines from Costa Rica used for the management of menopausal symptoms.

OBJECTIVE: Outcomes from the Women's Health Initiative have demonstrated adverse effects associated with hormone therapy and have prioritized the need to develop new alternative treatments for the management of menopause and osteoporosis. To this end, we have been investigating natural herbal medicines used by Costa Rican women to manage menopausal symptoms. METHODS: Seventeen plant species were collected and extracted in Costa Rica. To establish possible mechanisms of action and to determine their potential future use for menopause or osteoporosis, we investigated the estrogenic activities of the herbal extracts in an estrogen-reporter gene estrogen receptor (ER) beta-Chemically Activated Luciferase Expression assay in U2-OS cells and in reporter and endogenous gene assays in MCF-7 cells. RESULTS: Six of the plant extracts bound to the ERs. Four of the six extracts stimulated reporter gene expression in the ER-beta-Chemically Activated Luciferase Expression assay. All six extracts modulated expression of endogenous genes in MCF-7 cells, with four extracts acting as estrogen agonists and two extracts, Pimenta dioica and Smilax domingensis, acting as partial agonist/antagonists by enhancing estradiol-stimulated pS2 mRNA expression but reducing estradiol-stimulated PR and PTGES mRNA expression. Both P. dioica and S. domingensis induced a 2ERE-luciferase reporter gene in transient transfected MCF-7 cells, which was inhibited by the ER antagonist ICI 182,780. CONCLUSIONS: This work presents a plausible mechanism of action for many of the herbal medicines used by Costa Rican women to treat menopausal symptoms. However, it further suggests that studies of safety and efficacy are needed before these herbs should be used as alternative therapies to hormone therapy.

Effects of cranberry extracts and ursolic acid derivatives on P-fimbriated Escherichia coli, COX-2 activity, pro-inflammatory cytokine release and the NF-kappabeta transcriptional response in vitro.

Cranberry, the fresh or dried ripe fruit of Vaccinium macrocarpon Ait. (Ericaceae), is currently used as adjunct therapy for the prevention and symptomatic treatment of urinary tract infections. Data from clinical trials suggest that extracts of cranberry or cranberry juice reduce the bacterial load of E. coli and also suppress the inflammatory symptoms induced by E. coli infections. A methanol extract prepared from 10 kg of dehydrated cranberries did not directly inhibit the growth of E coli strains ATCC 700336 or ATCC 25922 in concentrations up to 256 mug/mL in vitro. However, the methanol extract (CR-ME) inhibited the activity of cyclooxygenase-2, with an IC(50) of 12.8 mug/mL. Moreover, CR-ME also inhibited the NF-kappabeta transcriptional activation in human T lymphocytes with an IC(50) of 19.4 mug/mL, and significantly (p < 0.01) inhibited the release of interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor-alpha from E. coli lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells in vitro, at a concentration of 50 mug/mL. The extract had no effect on inducible nitric oxide synthase activity in the murine macrophage cell line RAW 264.7. The compounds responsible for this activity were identified using a novel LC-MS based assay as ursolic acid and ursolic acid derivatives. Taken together, these data suggest CR-ME and its constituent chemical compounds target specific pathways involved in E. coli-induced inflammation.

Black cohosh (Actaea racemosa) for the mitigation of menopausal symptoms: recent developments in clinical safety and efficacy.

The purpose of this article is to assess recent data supporting the safety and efficacy of black cohosh products for the mitigation of menopause-related symptoms. Searches of the published literature in Napralert, Cochrane Library and PubMed databases were performed from 2003 to 2006. Information from drug regulatory agencies from five different countries was obtained to evaluate safety. While there are a few contradictory studies, the majority of the clinical trials indicate that extracts of black cohosh (Actaea racemosa L.) improve menopause-related symptoms. However, to date, at least 50 cases of possible hepatotoxicity have been reported. Although previous safety reviews suggest that black cohosh is well tolerated, the increasing numbers of these case reports indicates that further preclinical toxicological evaluations of black cohosh are urgently needed. At this time, it appears prudent to advise menopausal women with underlying liver disease, autoimmune diseases or those taking medications that may impact liver function not to use products containing black cohosh.