Publications by authors named "Naomi C Brownstein"

27 Publications

  • Page 1 of 1

COVID-19 vaccine behaviors and intentions among a national sample of United States adults ages 18-45.

Prev Med 2022 Apr 7;160:107038. Epub 2022 Apr 7.

Department of Oncologic Sciences, University of South Florida, United States of America; Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, FL, United States of America; Center for Immunization and Infection Research in Cancer, Moffitt Cancer Center, Tampa, FL, United States of America; Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, United States of America.

Background: Vaccination for SARS-CoV-2, the virus that causes COVID-19 illness, is an important public health tool to reduce hospitalizations and deaths.

Purpose: This report focuses on intentions and behaviors related to COVID-19 vaccination among United States (U.S.) adults ages 18-45.

Methods: From February 25-March 24, 2021, we conducted an online survey assessing COVID-19 vaccine intentions and behaviors, health beliefs, vaccine attitudes, and sociodemographic characteristics. Participants were adults aged 18-45, living throughout the U.S. with oversampling in Florida, panelists of a research panel company directly or via verified partners, and able to read, write, and understand English. Associations between COVID-19 vaccination uptake, intentions, and other study variables were examined through multivariable logistic and proportional odds regression analyses.

Results: Among participants in the final analytic sample (n = 2722), 18% reported having received at least one dose of a COVID-19 vaccine. Approximately 31% of unvaccinated participants reported strong intentions to receive a COVID-19 vaccine in the next year, whereas 35% reported strong intentions to receive a COVID-19 vaccine if it were strongly recommended by a healthcare provider. All COVID-19 vaccination outcomes were associated with male gender, sexual minority status, higher levels of education, and previous influenza vaccination. All vaccination intention outcomes were associated with vaccine attitudes and geographic region. Vaccination status and intentions were differentially associated with multiple additional sociodemographic, attitudinal, and/or healthcare experience variables.

Conclusions: Several demographic variables, vaccine attitudes, and healthcare experiences were found to contribute to COVID-19 vaccine receipt and intentions. Targeted efforts are necessary to increase uptake of the vaccine in the U.S.
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http://dx.doi.org/10.1016/j.ypmed.2022.107038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8988441PMC
April 2022

Longitudinal patient-reported outcomes and survival among early-stage non-small cell lung cancer patients receiving stereotactic body radiotherapy.

Radiother Oncol 2022 02 23;167:116-121. Epub 2021 Dec 23.

Department of Radiation Oncology, Moffitt Cancer Center, USA; Department of Thoracic Oncology, Moffitt Cancer Center, USA. Electronic address:

Background And Purpose: The study objective was to determine whether longitudinal changes in patient-reported outcomes (PROs) were associated with survival among early-stage, non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiation therapy (SBRT).

Materials And Methods: Data were obtained from January 2015 through March 2020. We ran a joint probability model to assess the relationship between time-to-death, and longitudinal PRO measurements. PROs were measured through the Edmonton Symptom Assessment Scale (ESAS). We controlled for other covariates likely to affect symptom burden and survival including stage, tumor diameter, comorbidities, gender, race/ethnicity, relationship status, age, and smoking status.

Results: The sample included 510 early-stage NSCLC patients undergoing SBRT. The median age was 73.8 (range: 46.3-94.6). The survival component of the joint model demonstrates that longitudinal changes in ESAS scores are significantly associated with worse survival (HR: 1.04; 95% CI: 1.02-1.05). This finding suggests a one-unit increase in ESAS score increased probability of death by 4%. Other factors significantly associated with worse survival included older age (HR: 1.04; 95% CI: 1.03-1.05), larger tumor diameter (HR: 1.21; 95% CI: 1.01-1.46), male gender (HR: 1.87; 95% CI: 1.36-2.57), and current smoking status (HR: 2.39; 95% CI: 1.25-4.56).

Conclusion: PROs are increasingly being collected as a part of routine care delivery to improve symptom management. Healthcare systems can integrate these data with other real-world data to predict patient outcomes, such as survival. Capturing longitudinal PROs-in addition to PROs at diagnosis-may add prognostic value for estimating survival among early-stage NSCLC patients undergoing SBRT.
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http://dx.doi.org/10.1016/j.radonc.2021.12.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934278PMC
February 2022

The impact of socioeconomic status on survival in stage III colon cancer patients: A retrospective cohort study using the SEER census-tract dataset.

Cancer Med 2021 08 30;10(16):5643-5652. Epub 2021 Jun 30.

Department of Hematology and Medical Oncology, Moffitt Cancer Center, University of South Florida, Tampa, FL, USA.

Background: The impact of socioeconomic status (SES) has been described for screening and accessing treatment for colon cancer. However, little is known about the "downstream" effect in patients who receive guideline-concordant treatment. This study assessed the impact of SES on cancer-specific survival (CSS) and overall survival (OS) for stage III colon cancer patients.

Methods: The SEER Census Tract-Level SES Dataset from 2004 to 2015 was used to identify stage III colon adenocarcinoma patients who received curative-intent surgery and adjuvant chemotherapy. The predictor variable was census tract SES. SES was analyzed as quintiles. The outcome variables were OR and CSS. Statistical analysis included chi square tests for association, Kaplan-Meier, Cox, Fine and Gray regression for survival analysis.

Results: In total, 27,222 patients met inclusion criteria. Lower SES was associated with younger age, Black or Hispanic race/ethnicity, Medicaid/uninsured, higher T stage, and lower grade tumors. CSS at the 25th percentile was 54 months for the lowest SES quintile and 80 for the highest. Median OS was 113 months for the lowest SES quintile and not reached for highest. The 5-year CSS rate was 72.4% for the lowest SES quintile compared to 78.9% in the highest (p < 0.001). The 5-year OS rate was 66.5% for the lowest SES quintile and 74.6% in the highest (p < 0.001).

Conclusion: This is the first study to evaluate CSS and OS in an incidence-based cohort of stage III colon cancer patients using a granular, standardized measure of SES. Despite receipt of guideline-based treatment, SES was associated with disparities in CSS and OS.
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http://dx.doi.org/10.1002/cam4.4099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366079PMC
August 2021

Patient-reported symptom burden in routine oncology care: Examining racial and ethnic disparities.

Cancer Rep (Hoboken) 2022 03 24;5(3):e1478. Epub 2021 Jun 24.

Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida, USA.

Background: Racial and ethnic disparities are well-documented in cancer outcomes such as disease progression and survival, but less is known regarding potential disparities in symptom burden.

Aims: The goal of this retrospective study was to examine differences in symptom burden by race and ethnicity in a large sample of cancer patients. We hypothesized that racial and ethnic minority patients would report greater symptom burden than non-Hispanic and White patients.

Methods And Results: A total of 5798 cancer patients completed the Edmonton Symptom Assessment Scale-revised (ESAS-r-CSS) at least once as part of clinical care. Two indicators of symptom burden were evaluated: (1) total ESAS-r-CSS score (i.e., overall symptom burden) and (2) number of severe symptoms (i.e., severe symptomatology). For patients completing the ESAS-r-CSS on multiple occasions, the highest score for each indicator was used. Zero-inflated negative binomial regression analyses were conducted, adjusting for other sociodemographic and clinical characteristics. Symptomology varied across race. Patients who self-identified as Black reported higher symptom burden (p = .016) and were more likely to report severe symptoms (p < .001) than self-identified White patients. Patients with "other" race were also more likely to report severe symptoms than White patients (p = .032), but reported similar total symptom burden (p = .315). Asian and Hispanic patients did not differ from White or non-Hispanic patients on symptom burden (ps > .05).

Conclusion: This study describes racial disparities in patient-reported symptom burden during routine oncology care, primarily observed in Black patients. Clinic-based electronic symptom monitoring may be useful to detect high symptom burden, particularly in patients who self-identify their race as Black or other. Future research is needed to reduce symptom burden in racially diverse cancer populations.
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http://dx.doi.org/10.1002/cnr2.1478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955049PMC
March 2022

Predictive values, uncertainty, and interpretation of serology tests for the novel coronavirus.

Sci Rep 2021 03 9;11(1):5491. Epub 2021 Mar 9.

Moffitt Cancer Center, Department of Biostatistics and Bioinformatics, Tampa, FL, USA.

Antibodies testing in the coronavirus era is frequently promoted, but the underlying statistics behind their validation has come under more scrutiny in recent weeks. We provide calculations, interpretations, and plots of positive and negative predictive values under a variety of scenarios. Prevalence, sensitivity, and specificity are estimated within ranges of values from researchers and antibodies manufacturers. Illustrative examples are highlighted, and interactive plots are provided in the Supplementary Information. Implications are discussed for society overall and across diverse locations with different levels of disease burden. Specifically, the proportion of positive serology tests that are false can differ drastically from up to 3%-88% for people from different places with different proportions of infected people in the populations while the false negative rate is typically under 10%.
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http://dx.doi.org/10.1038/s41598-021-84173-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943825PMC
March 2021

Predictive values, uncertainty, and interpretation of serology tests for the novel coronavirus.

medRxiv 2020 Dec 15. Epub 2020 Dec 15.

Antibodies testing in the coronavirus era is frequently promoted, but the underlying statistics behind their validation has come under more scrutiny in recent weeks. We provide calculations, interpretations, and plots of positive and negative predictive values under a variety of scenarios. Prevalence, sensitivity, and specificity are estimated within ranges of values from researchers and antibodies manufacturers. Illustrative examples are highlighted, and interactive plots are provided in the Supplementary Material. Implications are discussed for society overall and across diverse locations with different levels of disease burden. Specifically, the proportion of positive serology tests that are false can differ drastically from up to 3% to 88% for people from different places with different proportions of infected people in the populations while the false negative rate is typically under 10%.
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http://dx.doi.org/10.1101/2020.06.04.20122358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302289PMC
December 2020

Innovations in research and clinical care using patient-generated health data.

CA Cancer J Clin 2020 05 20;70(3):182-199. Epub 2020 Apr 20.

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida.

Patient-generated health data (PGHD), or health-related data gathered from patients to help address a health concern, are used increasingly in oncology to make regulatory decisions and evaluate quality of care. PGHD include self-reported health and treatment histories, patient-reported outcomes (PROs), and biometric sensor data. Advances in wireless technology, smartphones, and the Internet of Things have facilitated new ways to collect PGHD during clinic visits and in daily life. The goal of the current review was to provide an overview of the current clinical, regulatory, technological, and analytic landscape as it relates to PGHD in oncology research and care. The review begins with a rationale for PGHD as described by the US Food and Drug Administration, the Institute of Medicine, and other regulatory and scientific organizations. The evidence base for clinic-based and remote symptom monitoring using PGHD is described, with an emphasis on PROs. An overview is presented of current approaches to digital phenotyping or device-based, real-time assessment of biometric, behavioral, self-report, and performance data. Analytic opportunities regarding PGHD are envisioned in the context of big data and artificial intelligence in medicine. Finally, challenges and solutions for the integration of PGHD into clinical care are presented. The challenges include electronic medical record integration of PROs and biometric data, analysis of large and complex biometric data sets, and potential clinic workflow redesign. In addition, there is currently more limited evidence for the use of biometric data relative to PROs. Despite these challenges, the potential benefits of PGHD make them increasingly likely to be integrated into oncology research and clinical care.
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http://dx.doi.org/10.3322/caac.21608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488179PMC
May 2020

Bayesian analysis of survival data with missing censoring indicators.

Biometrics 2021 03 4;77(1):305-315. Epub 2020 May 4.

Department of Statistics, Florida State University, Tallahassee, Florida.

In some large clinical studies, it may be impractical to perform the physical examination to every subject at his/her last monitoring time in order to diagnose the occurrence of the event of interest. This gives rise to survival data with missing censoring indicators where the probability of missing may depend on time of last monitoring and some covariates. We present a fully Bayesian semi-parametric method for such survival data to estimate regression parameters of the proportional hazards model of Cox. Theoretical investigation and simulation studies show that our method performs better than competing methods. We apply the proposed method to analyze the survival data with missing censoring indicators from the Orofacial Pain: Prospective Evaluation and Risk Assessment study.
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http://dx.doi.org/10.1111/biom.13280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733523PMC
March 2021

Crafting effective messages to enhance safe infant sleep.

J Am Assoc Nurse Pract 2020 Feb 4;33(6):441-450. Epub 2020 Feb 4.

Department of Family and Child Sciences, Florida State University, Tallahassee, Florida.

Background: Health care professionals are continually challenged by the need to provide health information in a way that successfully changes health practices. Research has documented this as a concern in relation to safe infant sleep health campaigns. Often, caregivers' knowledge of recommended practices is not associated with a change in infant sleep choices.

Purpose: Health campaigns, including most safe infant sleep efforts, often share specific risk factors and steps for avoiding risk, that is, in a verbatim format. Research has shown that caregivers' behavior may be more likely to change when presented with messages based on their general understanding of risk, that is, gist-based format. This research examines caregivers' responses as related to verbatim- and gist-based safe sleep information.

Methods: Five hundred forty-one caregivers of infants were shown 12 images depicting infants in safe or unsafe sleep spaces. Images varied across three commercially available spaces, infant race, and presence/absence of one policy-based risk factor.

Results: Differences in caregivers' discernment of safe and unsafe sleep images paralleled reported differences in knowledge of safe sleep recommendations. Discernment of safe/unsafe images was greater for White than Black caregivers, as well as for females in comparison with male caregivers. Gist-based considerations, such as familiarity with the sleeper depicted or infant race, were also associated with caregivers' discernment of safe/unsafe images.

Implications For Practice: Attending to both gist- and verbatim-based knowledge regarding safe infant sleep campaign information may help to effectively facilitate caregivers' ability to always create safe sleep spaces for their infants.
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http://dx.doi.org/10.1097/JXX.0000000000000365DOI Listing
February 2020

Descriptive statistics and visualization of data from the datasets package with implications for clusterability.

Data Brief 2019 Aug 24;25:104004. Epub 2019 May 24.

Department of Computer Engineering, Santa Clara University, 500 El Camino Real, Santa Clara, CA, 95053, USA.

The manuscript describes and visualizes datasets from the package in the statistical software, focusing on descriptive statistics and visualizations that provide insights into the clusterability of these datasets. These publicly available datasets are contained in the software system, and can be downloaded at https://www.r-project.org/, with documentation provided at https://stat.ethz.ch/R-manual/R-devel/library/datasets/html/00Index.html. Further information on clusterability is found in the companion to this article, ? (https://doi.org/10.1016/j.patcog.2018.10.026). Brief descriptions and graphs of the variables contained in each dataset are provided in the form of means, extrema, quartiles, standard deviation and standard error. Two-dimensional plots for each pair of variables are provided. Original references to the data sets are included when available. Further, each dataset is reduced to a single dimension by each of two different methods: pairwise distances and principal component analysis. For the latter, only the first component is used. Histograms of the reduced data are included for every dataset using both methods.
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http://dx.doi.org/10.1016/j.dib.2019.104004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612012PMC
August 2019

Baby Box Distributions: Public Health Benefit or Concern?

Public Health Rep 2019 Jul/Aug;134(4):328-331. Epub 2019 May 8.

5 Department of Family and Child Sciences, Florida State University, Tallahassee, FL, USA.

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http://dx.doi.org/10.1177/0033354919847731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598133PMC
November 2019

The Role of Expert Judgment in Statistical Inference and Evidence-Based Decision-Making.

Am Stat 2019 20;73(1):56-68. Epub 2019 Mar 20.

Department of Biostatistics and Bioinformatics, Duke University, Durham, NC.

This article resulted from our participation in the session on the "role of expert opinion and judgment in statistical inference" at the October 2017 ASA Symposium on Statistical Inference. We present a strong, unified statement on roles of expert judgment in statistics with processes for obtaining input, whether from a Bayesian or frequentist perspective. Topics include the role of subjectivity in the cycle of scientific inference and decisions, followed by a clinical trial and a greenhouse gas emissions case study that illustrate the role of judgments and the importance of basing them on objective information and a comprehensive uncertainty assessment. We close with a call for increased proactivity and involvement of statisticians in study conceptualization, design, conduct, analysis, and communication.
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http://dx.doi.org/10.1080/00031305.2018.1529623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474725PMC
March 2019

Tests of trend between disease outcomes and ordinal covariates discretized from underlying continuous variables: simulation studies and applications to NHANES 2007-2008.

BMC Med Res Methodol 2019 01 5;19(1). Epub 2019 Jan 5.

Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Background: Many epidemiological studies test trends when investigating the association between a risk factor and a disease outcome. Continuous exposures are commonly discretized when the outcome is nonlinearly related to exposure as well as to facilitate interpretation and reduce measurement error. Guidance is needed regarding statistically valid trend tests for epidemiological data of this nature.

Methods: The association between a discretized variable and a disease is modeled through logistic regression or survival analysis. Linear regression is then conducted by regressing the odds ratio or relative risk on the midpoint of the exposure interval. The trend test is based on the slope of the regression line. In order to investigate the performance of this approach, we conducted simulation studies, considering ten different approaches for the linear regression based on the inclusion or exclusion of an intercept in the model and the form of the weights. The proposed methods are applied to the National Health and Nutrition Examination Survey (NHANES) 2007-2008 for illustration.

Results: The simulation studies show that eight of these methods are valid, and the relative efficiency depends on the underlying relationship between the covariate and the outcome.

Conclusions: The significance of the study is its potential to help practitioners select an appropriate method to test for trend in their future studies that utilize ordinal covariates.
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http://dx.doi.org/10.1186/s12874-018-0630-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321711PMC
January 2019

Maternal residential exposure to specific agricultural pesticide active ingredients and birth defects in a 2003-2005 North Carolina birth cohort.

Birth Defects Res 2019 04 28;111(6):312-323. Epub 2018 Dec 28.

Office of Research and Development, U.S. Environmental Research Triangle Park, Research Triangle Park, North Carolina.

Background: Previously we observed elevated odds ratios (ORs) for total pesticide exposure and 10 birth defects: three congenital heart defects and structural defects affecting the gastrointestinal, genitourinary and musculoskeletal systems. This analysis examines association of those defects with exposure to seven commonly applied pesticide active ingredients.

Methods: Cases were live-born singleton infants from the North Carolina Birth Defects Monitoring Program linked to birth records for 2003-2005; noncases served as controls (total n = 304,906). Pesticide active ingredient exposure was assigned using a previously constructed metric based on crops within 500 m of residence, dates of pregnancy, and likely chemical application dates for each pesticide-crop combination. ORs (95% CI) were estimated with logistic regression for categories of exposure compared to unexposed. Models were adjusted for maternal race/ethnicity, age at delivery, education, marital status, and smoking status.

Results: Associations varied by birth defect and pesticide combinations. For example, hypospadias was positively associated with exposures to 2,4-D (OR : 1.39 [1.18, 1.64]), mepiquat (OR : 1.10 [0.90, 1.34]), paraquat (OR : 1.14 [0.93, 1.39]), and pendimethalin (OR : 1.21 [1.01, 1.44]), but not S-metolachlor (OR : 1.00 [0.81, 1.22]). Whereas atrial septal defects were positively associated with higher levels of exposure to glyphosate, cyhalothrin, S-metolachlor, mepiquat, and pendimethalin (ORs ranged from 1.22 to 1.35 for 50th to <90th exposures, and 1.72 to 2.09 for >90th exposures); associations with paraquat were null or inconsistent (OR 50th to <90th: 1.05 (0.87, 1.27).

Conclusion: Our results suggest differing patterns of association for birth defects with residential exposure to seven pesticide active ingredients in North Carolina.
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http://dx.doi.org/10.1002/bdr2.1448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445756PMC
April 2019

Comprehensive Community-Based Intervention and Asthma Outcomes in African American Adolescents.

Pediatrics 2018 10 5;142(4). Epub 2018 Sep 5.

School of Nursing, Columbia University, New York, New York.

: media-1vid110.1542/5804911922001PEDS-VA_2017-3737 BACKGROUND: African American adolescents appear to be the most at risk for asthma morbidity and mortality even compared with other minority groups, yet there are few successful interventions for this population that are used to target poorly controlled asthma.

Methods: African American adolescents (age 12-16 years) with moderate-to-severe persistent asthma and ≥1 inpatient hospitalization or ≥2 emergency department visits in 12 months were randomly assigned to Multisystemic Therapy-Health Care or an attention control group ( = 167). Multisystemic Therapy-Health Care is a 6-month home- and community-based treatment that has been shown to improve illness management and health outcomes in high-risk adolescents by addressing the unique barriers for each individual family with cognitive behavioral interventions. The attention control condition was weekly family supportive counseling, which was also provided for 6 months in the home. The primary outcome was lung function (forced expiratory volume in 1 second [FEV]) measured over 12 months of follow-up.

Results: Linear mixed-effects models revealed that compared with adolescents in the comparison group, adolescents in the treatment group had significantly greater improvements in FEV secondary outcomes of adherence to controller medication, and the frequency of asthma symptoms. Adolescents in the treatment group had greater reductions in hospitalizations, but there were no differences in reductions in emergency department visits.

Conclusions: A comprehensive family- and community-based treatment significantly improved FEV, medication adherence, asthma symptom frequency, and inpatient hospitalizations in African American adolescents with poorly controlled asthma. Further evaluation in effectiveness and implementation trials is warranted.
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http://dx.doi.org/10.1542/peds.2017-3737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317763PMC
October 2018

Improving Underrepresented Minority in Medicine Representation in Medical School.

South Med J 2018 04;111(4):203-208

From the Brody School of Medicine, East Carolina University, Greenville, North Carolina, the Florida State University College of Medicine, Tallahassee, and the Department of Family and Preventive Medicine, University of Utah School of Medicine, Salt Lake City.

Objectives: Despite the efforts of various leading organizations in medical education, representation of black students in US medical schools has declined since the mid-1990s. The Florida State University College of Medicine (FSUCOM) has undertaken efforts to increase black and other underrepresented minority in medicine (URMM) representation in medical school through the Bridge to Clinical Medicine Program. This program is described and analyzed by the authors.

Methods: Demographic information, Medical College Admission Test scores, undergraduate grade point average, US Medical Licensing Examination (USMLE) scores (Steps 1 and 2), residency match information, and current practice location from 2006 to 2015 were collected from the FSUCOM. Data were analyzed using SAS and linear regression analyses were performed, comparing Bridge students with the College of Medicine and national averages.

Results: Sixty percent of Bridge students were black, 21% were other URMM, and the remainder were non-URMM. Black Bridge students scored 7.4 points lower on their Medical College Admission Test, and other-URMM Bridge students scored 6.0 points lower ( < 0.0001) than their non-URMM non-Bridge classmates. Black Bridge students also started with a grade point average that was 0.28 points lower than their non-URMM non-Bridge counterparts, but there was no statistical difference for other-URMM Bridge students. Black students, regardless of Bridge participation, were less likely to pass USMLE Step 1 when compared with non-URMM classmates ( < 0.0001). For USMLE Step 2, however, there were no significant differences in passing rates for Bridge students compared with non-Bridge students.

Conclusions: The FSUCOM Bridge program has not only increased its URMM enrollment but it also has effectively doubled the number of black students in its medical college. Other universities could produce similar results using the program outlined in this article.
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http://dx.doi.org/10.14423/SMJ.0000000000000792DOI Listing
April 2018

Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle.

Psychopharmacology (Berl) 2017 Feb 11;234(3):393-401. Epub 2016 Nov 11.

Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Tallahassee, FL, USA.

Rationale: Repeated intermittent exposure to ketamine has rapid and long-lasting antidepressant effects, but the abuse potential has only been assessed at high doses. Furthermore, while females are more susceptible to depression and more sensitive to ketamine's antidepressant-like effects, the abuse potential for ketamine in females is unknown.

Objectives: The objectives of this study are to determine the reinforcing properties of low-dose intermittent ketamine in adult rats of both sexes and determine whether cycling gonadal hormones influence females' response to ketamine. In male rats, we also aimed to determine whether reinstatement to intermittent ketamine is comparable to intermittent cocaine.

Methods: Male rats intravenously self-administered cocaine (0.75 mg/kg/infusion) or ketamine (0.1 mg/kg/infusion) once every fourth day, while intact cycling female rats self-administered ketamine only during preidentified stages of their 4-day estrus cycle, when gonadal hormones are either high (proestrus) or low (diestrus). After acquiring self-administration, rats underwent daily extinction training followed by cue-primed and drug-primed reinstatement to assess drug-seeking behavior.

Results: Diestrus-trained females fail to maintain ketamine self-administration and did not display reinstatement to ketamine-paired cues. Males and proestrus-trained females reinstated to ketamine-paired cues. Ketamine-primed reinstatement was dependent on simultaneous cue presentation. Male rats reinstated to cocaine priming independent of cue presentation.

Conclusion: These findings indicate that females's responsivity to this dose of ketamine depends on stage of cycle, as only proestrus-trained females and males respond to ketamine's reinforcing effects under this treatment paradigm.
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http://dx.doi.org/10.1007/s00213-016-4470-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384643PMC
February 2017

Ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry and tandem mass spectrometry for peptide de novo amino acid sequencing for a seven-protein mixture by paired single-residue transposed Lys-N and Lys-C digestion.

Rapid Commun Mass Spectrom 2017 Jan;31(2):207-217

Ion Cyclotron Resonance Program, National High Magnetic Field Laboratory, Florida State University, 1800 East Paul Dirac Drive, Tallahassee, FL, 32310, USA.

Rationale: Bottom-up tandem mass spectrometry (MS/MS) is regularly used in proteomics to identify proteins from a sequence database. De novo sequencing is also available for sequencing peptides with relatively short sequence lengths. We recently showed that paired Lys-C and Lys-N proteases produce peptides of identical mass and similar retention time, but different tandem mass spectra. Such parallel experiments provide complementary information, and allow for up to 100% MS/MS sequence coverage.

Methods: Here, we report digestion by paired Lys-C and Lys-N proteases of a seven-protein mixture: human hemoglobin alpha, bovine carbonic anhydrase 2, horse skeletal muscle myoglobin, hen egg white lysozyme, bovine pancreatic ribonuclease, bovine rhodanese, and bovine serum albumin, followed by reversed-phase nanoflow liquid chromatography, collision-induced dissociation, and 14.5 T Fourier transform ion cyclotron resonance mass spectrometry.

Results: Matched pairs of product peptide ions of equal precursor mass and similar retention times from each digestion are compared, leveraging single-residue transposed information with independent interferences to confidently identify fragment ion types, residues, and peptides. Selected pairs of product ion mass spectra for de novo sequenced protein segments from each member of the mixture are presented.

Conclusions: Pairs of the transposed product ions as well as complementary information from the parallel experiments allow for both high MS/MS coverage for long peptide sequences and high confidence in the amino acid identification. Moreover, the parallel experiments in the de novo sequencing reduce false-positive matches of product ions from the single-residue transposed peptides from the same segment, and thereby further improve the confidence in protein identification. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/rcm.7783DOI Listing
January 2017

Nanoparticle analysis sheds budding insights into genetic drivers of extracellular vesicle biogenesis.

J Extracell Vesicles 2016 13;5:31295. Epub 2016 Jul 13.

Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA;

Background: Extracellular vesicles (EVs) are important mediators of cell-to-cell communication in healthy and pathological environments. Because EVs are present in a variety of biological fluids and contain molecular signatures of their cell or tissue of origin, they have great diagnostic and prognostic value. The ability of EVs to deliver biologically active proteins, RNAs and lipids to cells has generated interest in developing novel therapeutics. Despite their potential medical use, many of the mechanisms underlying EV biogenesis and secretion remain unknown.

Methods: Here, we characterized vesicle secretion across the NCI-60 panel of human cancer cells by nanoparticle tracking analysis. Using CellMiner, the quantity of EVs secreted by each cell line was compared to reference transcriptomics data to identify gene products associated with vesicle secretion.

Results: Gene products positively associated with the quantity of exosomal-sized vesicles included vesicular trafficking classes of proteins with Rab GTPase function and sphingolipid metabolism. Positive correlates of larger microvesicle-sized vesicle secretion included gene products involved in cytoskeletal dynamics and exocytosis, as well as Rab GTPase activation. One of the identified targets, CD63, was further evaluated for its role in vesicle secretion. Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 knockout of the CD63 gene in HEK293 cells resulted in a decrease in small vesicle secretion, suggesting the importance of CD63 in exosome biogenesis.

Conclusion: These observations reveal new insights into genes involved in exosome and microvesicle formation, and may provide a means to distinguish EV sub-populations. This study offers a foundation for further exploration of targets involved in EV biogenesis and secretion.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947197PMC
http://dx.doi.org/10.3402/jev.v5.31295DOI Listing
July 2016

Maternal residential exposure to agricultural pesticides and birth defects in a 2003 to 2005 North Carolina birth cohort.

Birth Defects Res A Clin Mol Teratol 2016 Apr 11;106(4):240-9. Epub 2016 Mar 11.

National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina.

Background: Birth defects are responsible for a large proportion of disability and infant mortality. Exposure to a variety of pesticides have been linked to increased risk of birth defects.

Methods: We conducted a case-control study to estimate the associations between a residence-based metric of agricultural pesticide exposure and birth defects. We linked singleton live birth records for 2003 to 2005 from the North Carolina (NC) State Center for Health Statistics to data from the NC Birth Defects Monitoring Program. Included women had residence at delivery inside NC and infants with gestational ages from 20 to 44 weeks (n = 304,906). Pesticide exposure was assigned using a previously constructed metric, estimating total chemical exposure (pounds of active ingredient) based on crops within 500 meters of maternal residence, specific dates of pregnancy, and chemical application dates based on the planting/harvesting dates of each crop. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for four categories of exposure (<10(th) , 10-50(th) , 50-90(th) , and >90(th) percentiles) compared with unexposed. Models were adjusted for maternal race, age at delivery, education, marital status, and smoking status.

Results: We observed elevated ORs for congenital heart defects and certain structural defects affecting the gastrointestinal, genitourinary and musculoskeletal systems (e.g., OR [95% confidence interval] [highest exposure vs. unexposed] for tracheal esophageal fistula/esophageal atresia = 1.98 [0.69, 5.66], and OR for atrial septal defects: 1.70 [1.34, 2.14]).

Conclusion: Our results provide some evidence of associations between residential exposure to agricultural pesticides and several birth defects phenotypes. Birth Defects Research (Part A) 106:240-249, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdra.23479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833532PMC
April 2016

Status of Tenure Among Black and Latino Faculty in Academic Medicine.

J Racial Ethn Health Disparities 2017 04 1;4(2):134-139. Epub 2016 Mar 1.

Florida State University College of Medicine, Tallahassee, FL, USA.

Tenure has been used for years to recruit, promote, and retain faculty in higher education and has been associated with job security and academic freedom. Absence of tenure and not being in tenure-earning tracks is grouped with the challenges faced by underrepresented minorities in academic medicine. Those challenges include being found at the assistant professor rank more often, having more clinical responsibilities, and not being in leadership positions as often as compared to non-minority faculty. The role of tenure and tenure tracks is unclear as it relates to the presence of minority faculty. This article presents a look at the status of tenure among black and Latino faculty in academic medicine at US medical schools.
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http://dx.doi.org/10.1007/s40615-016-0210-7DOI Listing
April 2017

Effect of zinc supplementation on neuronal precursor proliferation in the rat hippocampus after traumatic brain injury.

Exp Neurol 2016 May 20;279:96-103. Epub 2016 Feb 20.

Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, United States; Program in Neuroscience, Florida State University College of Medicine, Tallahassee, FL, United States. Electronic address:

There is great deal of debate about the possible role of adult-born hippocampal cells in the prevention of depression and related mood disorders. We first showed that zinc supplementation prevents the development of the depression-like behavior anhedonia associated with an animal model of traumatic brain injury (TBI). This work then examined the effect of zinc supplementation on the proliferation of new cells in the hippocampus that have the potential to participate in neurogenesis. Rats were fed a zinc adequate (ZA, 30ppm) or zinc supplemented (ZS, 180ppm) diet for 4wk followed by TBI using controlled cortical impact. Stereological counts of EdU-positive cells showed that TBI doubled the density of proliferating cells 24h post-injury (p<0.05), and supplemental zinc significantly increased this by an additional 2-fold (p<0.0001). While the survival of these proliferating cells decreased at the same rate in ZA and in ZS rats after injury, the total density of newly born cells was approximately 60% higher in supplemented rats 1wk after TBI. Furthermore, chronic zinc supplementation resulted in significant increases in the density of new doublecortin-positive neurons one week post-TBI that were maintained for 4wk after injury (p<0.01). While the effect of zinc supplementation on neuronal precursor cells in the hippocampus was robust, use of targeted irradiation to eliminate these cells after zinc supplementation and TBI revealed that these cells are not the sole mechanism through which zinc acts to prevent depression associated with brain injury, and suggest that other zinc dependent mechanisms are needed for the anti-depressant effect of zinc in this model of TBI.
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http://dx.doi.org/10.1016/j.expneurol.2016.02.017DOI Listing
May 2016

Parameter estimation in Cox models with missing failure indicators and the OPPERA study.

Stat Med 2015 Dec 4;34(30):3984-96. Epub 2015 Aug 4.

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, U.S.A.

In a prospective cohort study, examining all participants for incidence of the condition of interest may be prohibitively expensive. For example, the "gold standard" for diagnosing temporomandibular disorder (TMD) is a physical examination by a trained clinician. In large studies, examining all participants in this manner is infeasible. Instead, it is common to use questionnaires to screen for incidence of TMD and perform the "gold standard" examination only on participants who screen positively. Unfortunately, some participants may leave the study before receiving the "gold standard" examination. Within the framework of survival analysis, this results in missing failure indicators. Motivated by the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study, a large cohort study of TMD, we propose a method for parameter estimation in survival models with missing failure indicators. We estimate the probability of being an incident case for those lacking a "gold standard" examination using logistic regression. These estimated probabilities are used to generate multiple imputations of case status for each missing examination that are combined with observed data in appropriate regression models. The variance introduced by the procedure is estimated using multiple imputation. The method can be used to estimate both regression coefficients in Cox proportional hazard models as well as incidence rates using Poisson regression. We simulate data with missing failure indicators and show that our method performs as well as or better than competing methods. Finally, we apply the proposed method to data from the OPPERA study.
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http://dx.doi.org/10.1002/sim.6604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715503PMC
December 2015

Paired single residue-transposed Lys-N and Lys-C digestions for label-free identification of N-terminal and C-terminal MS/MS peptide product ions: ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry and tandem mass spectrometry for peptide de novo sequencing.

Rapid Commun Mass Spectrom 2015 Apr;29(7):659-66

National High Magnetic Field Laboratory, Florida State University, 1800 East Paul Dirac Drive, Tallahassee, FL, 32310, USA.

Rationale: Paired Lys-N and Lys-C proteases produce peptides of identical mass and similar retention time, but different tandem mass spectra. Data from these parallel experiments provide constraints that are applied before data analysis. With this approach, we can find matched spectra before analysis, distinguish ion type, and determine residue level confidence.

Methods: Aliquots are digested separately by Lys-N and Lys-C peptidases, and analyzed by reversed-phase nano-flow liquid chromatography, collision-induced dissociation, and 14.5 T Fourier transform ion cyclotron resonance mass spectrometry. Matched pairs of fragmentation spectra with equal precursor mass and similar retention times from each digestion are compared, leveraging single-residue transposed information with independent interferences to confidently identify fragment ion type, residues, and peptides. The paired spectra are solved together as a single de novo sequencing problem.

Results: Two pairs of spectra of a de novo sequenced 18-mer are presented. In one example, the 18-mer has coverage of all residues except the N- and C- terminal lysines and their adjacent residues. The confidence level is high due to six pairs of transposed ions. In the other example, the coverage is incomplete. Nonetheless, nine pairs of transposed ions facilitate identification of two trimer sequence tags with high confidence, one with medium confidence, and additional sequence information with residue-by-residue confidence, thus demonstrating the value of residue-by-residue confidence.

Conclusions: Sequence identity and variability, such as post-translational modifications (PTMs), are essential to understanding biological function and disease. The present method facilitates discovery of new peptides with multiple levels of confidence, promises potential characterization of PTMs, and validates peptides from databases. Independent validation may be of interest for a number of applications.
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http://dx.doi.org/10.1002/rcm.7137DOI Listing
April 2015

Study protocol, sample characteristics, and loss to follow-up: the OPPERA prospective cohort study.

J Pain 2013 Dec;14(12 Suppl):T2-19

Regional Center for Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Endodontics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Unlabelled: When studying incidence of pain conditions such as temporomandibular disorder (TMD), repeated monitoring is needed in prospective cohort studies. However, monitoring methods usually have limitations and, over a period of years, some loss to follow-up is inevitable. The OPPERA prospective cohort study of first-onset TMD screened for symptoms using quarterly questionnaires and examined symptomatic participants to definitively ascertain TMD incidence. During the median 2.8-year observation period, 16% of the 3,263 enrollees completed no follow-up questionnaires, others provided incomplete follow-up, and examinations were not conducted for one third of symptomatic episodes. Although screening methods and examinations were found to have excellent reliability and validity, they were not perfect. Loss to follow-up varied according to some putative TMD risk factors, although multiple imputation to correct the problem suggested that bias was minimal. A second method of multiple imputation that evaluated bias associated with omitted and dubious examinations revealed a slight underestimate of incidence and some small biases in hazard ratios used to quantify effects of risk factors. Although "bottom line" statistical conclusions were not affected, multiply-imputed estimates should be considered when evaluating the large number of risk factors under investigation in the OPPERA study.

Perspective: These findings support the validity of the OPPERA prospective cohort study for the purpose of investigating the etiology of first-onset TMD, providing the foundation for other papers investigating risk factors hypothesized in the OPPERA project.
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http://dx.doi.org/10.1016/j.jpain.2013.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3855654PMC
December 2013

An evaluation of metrics for assessing maternal exposure to agricultural pesticides.

J Expo Sci Environ Epidemiol 2014 Sep-Oct;24(5):497-503. Epub 2013 Oct 23.

Birth Defects Monitoring Program, State Center for Health Statistics, North Carolina Division of Public Health, Raleigh, North Carolina, USA.

We evaluate the use of three different exposure metrics to estimate maternal agricultural pesticide exposure during pregnancy. Using a geographic information system-based method of pesticide exposure estimation, we combine data on crop density and specific pesticide application amounts/dates to create the three exposure metrics. For illustration purposes, we create each metric for a North Carolina cohort of pregnant women, 2003-2005, and analyze the risk of congenital anomaly development with a focus on metric comparisons. Based on the results, and the need to balance data collection efforts/computational efficiency with accuracy, the metric which estimates total chemical exposure using application dates based on crop-specific earliest planting and latest harvesting information is preferred. Benefits and drawbacks of each metric are discussed and recommendations for extending the analysis to other states are provided.
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http://dx.doi.org/10.1038/jes.2013.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997755PMC
May 2015
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