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Scholarly Activity

Duke OB/GYN Residency allows for involvement in clinical and basic research. Each year, residents are recognized during Hammond Research Day, an annual event where current residents and fellows present their research projects. 

2017 Hammond Research Day Resident Awards

(abstracts listed below)

2017 Research Day Award Winners

Fellow First Prize                               
Lauren Cobb, MD                

Resident First Prize                           
Laura Newcomb, MD            

Resident Second Prize (tie)              
Charlotte Gamble, MD, MPH        
Alejandro Landa, MD            

 

2017 Hammond Research Day Abstracts

 

Title: A pilot genome-scale DNA methylation study in women with interstitial cystitis/bladder pain syndrome

Fellow: Megan S. Bradley MD

Faculty Mentor: Nazema Y. Siddiqui MD MHSc

Objective: To perform a pilot genome scale DNA methylation assessment study using voided urine samples from female patients with interstitial cystitis/bladder pain syndrome (IC/BPS) as compared to age− and race−matched controls. 

Methods: A total of 30 IC/BPS patients and 24 age− and race−matched controls were enrolled. IC/BPS patients had an Interstitial Cystitis Symptom Index score of >8; controls had no bladder symptoms. DNA was extracted from pelleted urine sediment and genomic DNA underwent quantitative DNA methylation data using the Illumina Infinium MethylationEPIC BeadChip.  Two−sided paired t−tests were used to compare average methylation at each CpG site, with the Bonferroni correction to adjust for multiple comparisons.

Results: Our cohort consisted of 16 participants (8 IC/BPS and 8 controls) after exclusion of screen failures, subjects with positive urine cultures, absence of study data or poor DNA yield. The median age was 43.5 years (IQR 33.8, 65.0), median BMI of 27.1 (IQR 22.7, 31.4), and the majority were Caucasian (16/18, 88.9%). After pre−processing and exclusion of unreliable probes, 688,417 CpG sites were analyzed. In head to head comparisons, no sites were significantly differently methylated between IC/BPS and controls. However, in an exploratory pathway analysis, the MAPK pathway was overrepresented by member genes with differentially methylated CpG sites.

Conclusion: DNA methylation profiling is feasible from voided urine specimens. Our results suggest that altered methylation could be occurring in genes within or downstream of the MAPK pathway, though this hypothesis requires further validation with larger samples sizes using quantitative DNA methylation techniques.

 

Title: Factors affecting utilization and effectiveness of 17-hydroxyprogesterone caproate for the prevention of recurrent preterm birth

Resident: Annalies E. DeNoble MD MSc

Faculty Mentor: Geeta K. Swamy MD

Objective: To determine what factors impact 17-hydroxyprogesterone caproate (17OHP) use to prevent recurrent preterm birth (PTB). Second, to assess predictors of recurrent PTB in women receiving 17OHP.

Methods: This retrospective cohort study included women with a singleton pregnancy who delivered within one academic health system from January 2014 through December 2015. Eligible women had a history of ≥1 spontaneous, singleton PTBs. Primary outcomes were counseling about, receipt of, and adherence to 17OHP therapy. The secondary outcome was recurrent PTB in 17OHP users. Demographic and clinical predictors were determined using stepwise logistic regression.

Results: Of 410 eligible subjects, 69.3% (N=284) were counseled about and 36% (N=148) received 17OHP; 72% (N=83/115 in-office users) were adherent. Hispanic ethnicity (aOR 0.33; 95% CI 0.16-0.70), each week delay in prenatal care (aOR 0.92; 95% CI 0.89-0.95), and each prior term birth (aOR 0.68; 95% CI 0.56-0.82) predicted lower odds of 17OHP counseling. Each week delay in prenatal care (aOR 0.87; 95% CI 0.83-0.91) and each additional week gestation of the earliest prior PTB (aOR 0.93; 95% CI 0.89-0.98) also decreased the odds of receiving 17OHP. Maternal age (aOR 1.20; 95% CI 1.07-1.34) and the number of prior term births (aOR 0.60; 95% CI 0.36-0.99) predicted adherence to 17OHP therapy. Among 17OHP users, each prior spontaneous PTB significantly increased the odds of recurrent PTB (aOR 1.87; 95% CI 1.12-3.12).

Conclusion: Utilization of evidence-based 17OHP therapy remains suboptimal: cultural and access to care barriers for eligible women may impede efforts to decrease recurrent PTB rates.

 

Title: Missed opportunities: quantifying significant family histories in breast and ovarian cancer patients with BRCA1/2

Resident:  Charlotte R. Gamble MD

Faculty Mentor:  Laura J. Havrilesky MD MHSc

Objective: The purpose of this study was to quantify, among women with high-risk breast or ovarian cancer who were subsequently found to be BRCA1/2 mutation carriers, the proportion who have family histories (FH) that would have been sufficient to qualify them for genetic evaluation prior to their first cancer diagnosis.

Methods: This retrospective cohort study included patients with hormone receptor positive breast cancer (HRBC) <45yo, triple negative breast cancer (TNBC) <60yo, or ovarian cancer (OC) at any age. All patients were treated at a single institution from 2010-2016. Descriptive statistics were calculated to assess differences among cancer type, mutation type, race, and insurance status.  Intervals between diagnosis, treatment, and genetic appointment were compared. Positive FH was defined based on NCCN guidelines during years of diagnosis.

Results: Of 103 subjects meeting inclusion criteria, a significant FH was present in 82.3% with TNBC (28/34), 83.7% with HRBC (36/43), and 81.5% with OC (22/27). FH was present in 84% of BRCA1 patients (n=33), 78% of BRCA2 patients (n=46), 79.4% of White patients (n=78) and 90% of Black or African American patients (n=21).   

Conclusion: Although limited by sample size, this study suggests that a family history sufficient to warrant testing prior to cancer diagnosis is overwhelmingly present in this highest risk cancer group, and underscores the importance of assiduous familial risk assessment for women in the primary care setting.   

 

Title: Obesity is associated with altered angiogenic gene expression in endometrioid endometrial cancer

Fellow:  Lauren P. Cobb MD

Mentor:  Angeles A. Secord MD MHSc

Objective: Obesity has been associated with worse outcomes in endometrioid endometrial cancer (EEC) and increased tumor aggressiveness in a genetically engineered mouse model. We sought to evaluate the association between obesity and angiogenic genes to determine if metformin mitigates these effects.

Methods: We evaluated the association between 168 angiogenic candidate genes and body mass index (BMI) in the TCGA endometrial cancer database (n=290) and a unique EEC LKB1fl/flp53fl/fl mouse model (n=20). Mice received 60% calories from fat in a high-fat diet (HFD), mimicking diet-induced obesity, versus 10% calories from fat in a low-fat diet (LFD). After confirming tumor growth, HFD (n=5) and LFD mice (n=5) were treated with metformin (200 mg/kg/day) or control. Tumors were analyzed using RNASeq for differential expression of angiogenic genes.

Results: Twenty-one candidate angiogenic genes (p<0.05) were differentially associated with BMI in the TCGA database. Evaluation of these genes in the mouse model revealed association between increased Edil3 expression in HFD versus LFD mice (2.2 fold change (FC); p=0.03). HFD mice receiving Metformin demonstrated an interaction effect reducing Edil3 expression (9.6 FC; P=0.009). Exploratory analysis in the mice revealed differential expression of 20 angiogenic genes including increased expression of the following potent pro-angiogenic genes (LEP (4 FC); VEGFA (2.8 FC)).

Conclusion: Obesity may alter the tumor microenvironment and promote tumor progression via differential modulation of angiogenic pathways in EEC. Specifically Edil3 may play an important role in this microenvironment serve as a novel target. Metformin was associated with significant reduction of pro-angiogenic genes.

 

Title: Randomized controlled trial to assess the impact of intraurethral lidocaine on urodynamic voiding parameters

Resident: Cassandra K. Kisby MD

Faculty Mentor: Cindy L. Amundsen MD

Objective: Determine whether intraurethral anesthesia 1) decreases voiding efficiency (VE; voided volume/(voided volume + residual volume)) and 2) impacts other urodynamic parameters in healthy female volunteers during urodynamics (UDS).

Methods: Randomized double-blind placebo-controlled study of women 18-60 years. Exclusion criteria were: neurologic or bladder pain conditions, recurrent or active urinary tract infections, morbid obesity, >2 responses of “sometimes” or more on the Lower Urinary Tract Symptoms Questionnaire, pregnancy, and pelvic organ prolapse. Subjects completed a Visual Analog Scale (VAS) to assess pain. They performed baseline uroflow to confirm a normal voiding pattern, followed by physiologic filling to ≥250mL. Subjects were randomized to receive 5mL of intraurethral aqueous gel (KY) or 2% lidocaine gel (Urojet), and then underwent standard UDS.

Results: 23 randomized subjects (12 placebo, 11 lidocaine) were included. VAS scores were similar at baseline and during UDS between groups. Baseline uroflow VE was similar between the placebo and lidocaine groups. After study drug administration, VE was not different between groups (89.5±4.9 vs. 87.3±8.3, p=0.44). There were no differences in sensation during cystometry, maximum urethral closure pressure, or micturition parameters (maximum detrusor pressure (Pdet) and Pdet at maximum flow). The placebo group had a lower percentage of intermittent flow pattern (0% vs. 36%, p=0.02) and a lower rate of increased electromyographic (EMG) activity during micturition (25% vs. 73%, p=0.02).

Conclusion: Intraurethral administration of lidocaine did not decrease voiding efficiency compared to placebo. The lidocaine group had a greater percentage of intermittent flow patterns and increased EMG activity during micturition.

 

Title: A randomized controlled trial of patient pain perception with tenaculum placement during in-office procedures

Resident: Tashima E. Lambert MD

Faculty Mentor: Beverly A. Gray MD

Objective: The single-tooth tenaculum is used in most gynecologic procedures involving cervical and uterine instrumentation.  The objective of this study is to compare pain with tenaculum use based on the method of placement:  Slow method versus cough method.

Methods: A randomized controlled trial of 66 women presenting for intrauterine devices, powered to detect 16 mm difference in pain, included women age 18 years or older.  Patients were randomized to tenaculum placement via slow method versus cough method.  The primary outcome was pain at time of tenaculum placement measured on a 100-mm Visual Analog Scale.  Secondary outcomes included overall pain with device insertion and provider satisfaction with tenaculum grasp.  Pain scores were analyzed with Wilcoxon rank sum test.  Provider satisfaction was analyzed with Fisher’s exact test.

Results: Sixty-six women were enrolled, 33 randomized to each arm.  Average pain score with slow placement was 44 (SD 24.4) with median of 44 (IQR = 21,63).  Average pain score with cough placement was 35.5 (SD 23.9) with median of 32 (IQR = 19,54).  There was no significant difference in pain scores between methods of tenaculum placement (p=0.16).  There was no significant difference in overall pain scores (p=0.12).  Provider satisfaction was not associated with one method over the other (p=1).  Anxiety was significantly associated with pain at the time of tenaculum placement (p=0.01).

Conclusion: Providers should utilize the method of tenaculum placement of their choice since neither method significantly improves pain or provider satisfaction.  Pain with tenaculum use is significantly associated with anxiety.

 

Title: MMP activation in human fetal membranes by TNF-α and Ureaplasma parvum

Fellow: James M. Edwards MD

Faculty Mentor: Amy P. Murtha MD

Objective: Infection-induced inflammation causes matrix metalloproteinase (MMP) enzyme activation in the fetal membranes leading to membrane damage and preterm birth.  We hypothesize that Ureaplasma parvum (UP), an organism commonly associated with preterm birth, causes MMP activation via ERK-mediated TNF-α signaling.

Methods:  Full thickness human fetal membranes were mounted in a tension-free dual-chamber tissue explant system and the choriodecidua was treated with UP or TNF-α After 24 hours of treatment, conditioned media from the maternal and fetal compartments were collected and fetal membranes were harvested. MMP activity levels were assessed in media from each compartment using gel zymography.  Next, fetal membrane ERK and IkB-a signaling was assessed via Western blotting.  An ANOVA model was fitted on the log transformation and inference was made on treatment effect for each biologic marker. We conducted pairwise comparison with adjustment for multiple testing if overall treatment effect was detected.

Results:  Six replicates were performed for each treatment. Overall treatment effect was detected for amnion MMP-2 activity (p<0.001) and amnion MMP-9 activity (p=0.009). Phosphorylated ERK and IkB-a were increased with treatment, but not statistically significant (p=0.37 and p=0.55).  Pairwise comparison revealed significant increases in MMP-2 and -9 activity level for TNF-α compared to control (p=0.002 and p=0.017) and UP compared to control (p<0.001 and p=0.011).

Conclusion:  TNF-α and UP treatment of the choriodecidua increased MMP activity in the fetal compartment.  MMP activation in the fetal compartment by UP induced TNF-α signaling may lead to membrane damage and preterm birth.

 

Title: Transvaginal cerclage and risk factors associated with failed cerclage and preterm delivery

Resident:   Alejandro J. Landa MD

Faculty Mentor: Andra H. James MD MPH

Objective: To evaluate risk factors associated with preterm delivery in patients with a transvaginal cerclage.

Methods:  This study is a retrospective chart review of all women with a transvaginal cerclage (both history indicated and rescue cerclage) placed between January 2010 and July 2016 at Duke University Medical Center. The presence of various risk factors was compared among women who delivered preterm (<37 weeks) and those who did not. Univariate and Multivariate analysis were stratified by type of cerclage.

Results: 296 women were identified for a total of 337 transvaginal cerclages; 55 transvaginal cerclage events were excluded, for a final count of 282 singleton pregnancies. In the cohort with history indicated cerclage, preterm birth < 37 weeks was associated with an increase in BMI (p= 0.012), black race (p= 0.0128), presence of funneling (p =0.05) and shorter cervical length after cerclage (p =0.002). In the rescue cerclage group, preterm delivery at <37 weeks was associated with more use of tocolytics after cerclage (p=0.04), and shorter cervical length after cerclage placement (p =0.0001) as well as at 24-25 weeks (p =0.0006). After multivariable logistic regression, preterm delivery at <37 weeks was still associated with shorter cervical length after cerclage placement in the history indicated cerclage (OR= 0.95 (0.91, 0.99) and in the rescue cerclage group (OR= 0.93 (0.87, 1)).

Conclusion: Shorter cervical length measurements after a cerclage placement (either history indicated or rescue) are associated with preterm delivery at <37 weeks.

 

Title: Correlation of virtual reality and dry lab robotic technical skills

Resident: Laura K. Newcomb MD

Faculty Member: Nazema Y. Siddiqui MD MHSc

Objective: To determine whether a set of virtual reality (VR) surgical simulation drills have correlative validity when compared to the validated Robotic Objective Structured Assessment of Technical Skills (R-OSATS) dry lab drills. 

Methods: We performed a prospective methods comparison study.. We evaluated 20 residents, six fellows, and four faculty totaling 30 participants from the departments of OB/GYN, Urology, and General Surgery. Participants completed five VR drills on the daVinci Skills Simulator and five dry lab drills. that tested similar metrics. Participants were randomized to the order of completion. VR drills were scored automatically by the simulator. Dry lab drills were recorded, reviewed by three blinded experts, and scored using the R-OSATS assessment tool. Spearman correlation coefficients were calculated comparing simulator scores and R-OSATS scores for the same surgeon.

Results: We e evaluated 20 residents, six fellows, and four faculty totaling 30 participants from the departments of OB/GYN, Urology, and General Surgery. The correlation for overall summary scores between VR and dry lab drills was strong (r=0.87, p<0.01). Each of the five  VR drills was also found to have a statistically significant correlation to its corresponding dry lab drill with correlation coefficients ranging from  (r=0.49 to 0.73 (all p-values <0.01). , p<0.01). The performance on VR drills also confirmed construct validity.  with fFaculty and fellows had consistently consistently higher overall scores than performing significantly better than residents (median VR scores: 437 for faculty, 408 for fellows, 311 for residents; p<0.01).    

Conclusion: We selected a core set of VR drills that reliably correlate with validated dry lab R-OSATS drills.  Because dry lab drills require significant time and effort from the evaluators, this set of VR drills could serve as an ancillary method of determining trainee competency.

 

Title: Male obesity and estrogen levels influence DNA methylation reprogramming in sperm

Fellow: Sanaz Keyhan MD

Faculty Mentor: Susan Murphy PhD

Objective: To determine if steroid hormone levels are associated with altered DNA methylation and to examine the relationship between male overweight/obese status and DNA methylation profiles throughout the sperm genome.

Methods:  This was a retrospective cross-sectional study of semen and blood from 45 normal weight (BMI < 25 kg/m2) and 18 overweight/obese (BMI ≥ 25 kg/m2) Caucasian men. Infinium HumanMethylation450 BeadChip arrays were used to identify CpG loci showing differential methylation in sperm using linear regression models with validation by bisulfite pyrosequencing or sequencing of cloned alleles. Estradiol and testosterone levels from all individuals were analyzed using linear regression models to identify associations between hormone levels, BMI, and sperm DNA methylation.

Results:  We identified 3,061 CpG sites significantly associated with BMI (P <0.05). Of these, 2,281 sites had gene annotations (Illumina). The differentially methylated CpG sites were significantly enriched for genes involved in embryonic development, neuronal development, and cell adhesion. Moreover, many of the significant differentially methylated CpG sites show significant interactions between BMI and both testosterone and estradiol. Analysis of individual sperm DNA sequences revealed that the methylation differences affect a subset of sperm rather than being randomly distributed across all sperm.

Conclusion:  We found significant differences in sperm DNA methylation comparing overweight/obese to normal weight men at multiple CpG sites. Many of the associated genes have key regulatory roles in developmental, metabolic, and inflammatory processes. These DNA methylation alterations may be heritable, and depending on their impact on gene expression, could have the potential to impede normal development. 

 

Title: Utilization of long-acting reversible contraceptive (LARC) methods postpartum among women who received group prenatal care: a retrospective cohort study

Resident: Nichelle A. Satterfield MD

Faculty Mentor: Beverly A. Gray MD

Objective: The study purpose was to evaluate uptake of LARC methods postpartum among women who received group prenatal care versus traditional prenatal care. Secondary measures included obstetric and delivery outcomes, triage visits, and pregnancy rates within one year of delivery. We hypothesized LARC uptake would be higher for patients enrolled in Centering.

Methods: A retrospective cohort design was used to evaluate those who delivered a singleton live birth over one year. The two cohorts were women enrolled in CenteringPregnancy® group prenatal care and those who participated in traditional care at the same facility. Data was collected from prenatal, labor and delivery, and postpartum records.

Results: Of the 5,579 women who delivered during this time interval 753 women met inclusion criteria for the study; 146 in Centering care and 607 in traditional care. There were no significant differences in LARC desired at discharge between the two groups. A higher percentage of group prenatal care patients presented for postpartum care (84.2 vs 74.6, P=0.019), but there were no significant differences in LARC utilization or pregnancy rates at one year. Centering patients attended significantly more prenatal visits however also had more triage visits. Other obstetric and infant measures were similar between the two groups.

Conclusion: Although there were no significant differences between Centering and traditional prenatal care patients in regard to LARC desired at discharge and LARC uptake postpartum, there was a trend towards a higher number of Centering patients electing LARC at time of discharge, reflecting the increased education on this topic.

 

Title:  Reduction of cesarean delivery surgical site infections using an evidence-based care bundle

Fellow: Margaret S. Villers MD MSCR

Mentor: Geeta K. Swamy MD

Objective: Cesarean delivery (CD) surgical site infections (SSI) are associated with significant patient morbidity and increased health care utilization. In 2013, our institutional CD SSI rate was 10%, which is above the national average. We implemented an evidence-based bundle of initiatives to reduce cesarean delivery SSIs.

Methods: Beginning in January 2016, we implemented a bundle aimed at the reduction of CD SSIs. The bundle, utilized for all CDs, consisted of: preoperative skin preparation with 2% chlorhexidine cloths, preoperative vaginal cleansing with chlorhexidine gluconate, and use of fenestrated surgical drapes. Negative pressure wound therapy (NPWT) was utilized in women with a BMI ≥ 40 or with high risk of post-operative infection. We compared the SSI rate from January-December 2016 to the rate from January-December 2014. Bivariable analysis performed using c2 and Mann-Whitney U tests. Logistic regression models were fitted to adjust for significant covariates.

Results: The pre- and post-bundle cohorts include 1061 and 1010 women who underwent CD, respectively. Compliance with all components of the bundle improved from 72% to 93%. The SSI rate decreased from 7.3% to 3.1% after implementation of the bundle. The overall wound complication rate (infection, seroma, and hematoma) decreased from 9% to 5.3% after bundle implementation. After controlling for covariates, the odds (95% CI) of SSI and wound complication were 0.38 (0.24 – 0.60) and 0.54 (0.37 – 0.78), respectively.

Conclusion: Development and implementation of an evidence-based care bundle optimized for our patient population resulted in a significant reduction of CD SSIs.

 

Title: Prognostic implications of lymphovascular space invasion on nodal recurrence in patients with stage I endometrioid endometrial adenocarcinoma after complete surgical staging

Resident: Ashley E. Veade MD

Faculty Mentor: Laura J. Havrilesky MD MHSc

Objective:  To investigate the predictive value of lymphovascular space invasion (LVSI) for nodal recurrence in patients with Stage I endometrioid endometrial cancer (EC) following full surgical staging.

Methods:  From 1/1998 to 2/2015, 630 patients undergoing full surgical staging for stage IA or IB endometrioid EC were identified using the Duke EC database. Subjects with lymph node metastasis were excluded. A retrospective analysis was performed using logistic regression to identify predictors of nodal recurrence. Cox proportional hazard modeling was used to predict progression free survival (PFS). Hazard ratios (HR) and 95% confidence intervals (CI) for PFS and overall survival (OS) were estimated using the Kaplan-Meier method. Survival curves were compared using the log rank test.

Results:  275 subjects met inclusion criteria.  LVSI was present in 48 subjects (17.5%). Nodal recurrences were identified in 9 LVSI+ subjects (18.8%) compared to 2 LVSI- subjects (0.88%).  In bivariate analysis, LVSI (p < 0.001) and grade (p=0.046) were significant predictors of nodal recurrence after adjusting for adjuvant radiation. In multivariate analysis adjusting for competing covariates, LVSI was the only significant predictor of nodal recurrence (p=0.002). LVSI (HR=2.1 CI: 1.05-4.3, p=0.037) and grade 3 (HR=2.5 CI: 1.3-4.9, p=0.01) were significant univariate predictors of PFS.  In Kaplan Meier analysis, LVSI + was associated with shorter PFS (p=0.033) and OS (p=0.046).

Conclusion:  The presence of LVSI in patients with fully staged, stage I endometrioid EC is a significant independent predictor of nodal recurrence. Given these findings, adjuvant therapy to nodal basins could be considered in these patients.