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Item Integration of In Vitro Binding Mechanism Into the Semiphysiologically Based Pharmacokinetic Interaction Model Between Ketoconazole and Midazolam(Wiley, 2013-09-11) Quinney, Sara K.; Knopp, Shawn; Chang, Chien; Hall, Stephen D.; Li, Lang; Obstetrics and Gynecology, School of MedicineIn vitro screening for drug-drug interactions is an integral component of drug development, with larger emphasis now placed on the use of in vitro parameters to predict clinical inhibition. However, large variability exists in Ki reported for ketoconazole with midazolam, a model inhibitor-substrate pair for CYP3A. We reviewed the literature and extracted Ki for ketoconazole as measured by the inhibition of hydroxymidazolam formation in human liver microsomes. The superset of data collected was analyzed for the impact of microsomal binding, using Langmuir and phase equilibrium binding models, and fitted to various inhibition models: competitive, noncompetitive, and mixed. A mixed inhibition model with binding corrected by an independent binding model was best able to fit the data (Kic = 19.2 nmol/l and Kin = 39.8 nmol/l) and to predict clinical effect of ketoconazole on midazolam area under the concentration-time curve. The variability of reported Ki may partially be explained by microsomal binding and choice of inhibition model.Item Dietary Inflammatory Index Is Differentially Associated With Cardiometabolic Health After Pregnancy on the Basis of Adverse Pregnancy Outcome Exposure(American Heart Association, 2024) Jancsura, McKenzie K.; Wirth, Michael D.; Helsabeck, Nathan P.; Mercer, Brian M.; Haas, David M.; Greenland, Philip; McNeil, Rebecca; Levine, Lisa D.; Silver, Robert M.; Yee, Lynn M.; Saade, George R.; Khan, Sadiya S.; Chung, Judith H.; Grobman, William A.; Obstetrics and Gynecology, School of MedicineBackground: Inflammatory diets may influence risk of cardiovascular disease. Subsequent cardiovascular disease is also influenced by adverse pregnancy outcomes (APOs) such as preterm birth, small-for-gestational-age birth, gestational diabetes, and hypertensive disorders of pregnancy. However, the associations between inflammatory diet, APOs, and cardiometabolic health remain unclear. Methods and results: We used data from the nuMoM2b (Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-Be) HHS (Heart Health Study) to assess the relationship between dietary quality and cardiometabolic health. We calculated Energy-Adjusted Dietary Inflammatory Index scores representing the inflammatory burden in a person's diet. We used linear regression to determine the association between Energy-Adjusted Dietary Inflammatory Index score and cardiometabolic outcomes. We performed stratified analyses for outcomes with a significant interaction between Energy-Adjusted Dietary Inflammatory Index and APO. Data were available from 3249 participants at a median of 3.1 years after delivery. Higher Energy-Adjusted Dietary Inflammatory Index scores were associated with higher body mass index (B=0.29 kg/m2 [95% CI, 0.16-0.42]), waist circumference (0.66 cm [95% CI, 0.39-0.93]), diastolic blood pressure (0.26 mm Hg [95% CI, 0.09-0.44]), mean arterial pressure (0.23 mm Hg [95% CI, 0.06-0.40]), triglycerides (2.11 mg/dL [95% CI, 1.05-3.18]), creatinine (2.78 mg/dL [95% CI, 1.13-4.44]), insulin (exp[B]=1.04 [95% CI, 1.03-1.05]) and C-reactive protein (exp[B]=1.07 [95% CI, 1.04-1.10]), and lower high-density lipoprotein cholesterol (-0.41 mg/dL [95% CI, -0.66 to -0.37]) (all P<0.01). Significant interactions with APO (P<0.05) were identified for body mass index and waist circumference, with stratified analysis revealing stronger associations for individuals with APOs. Conclusions: A more proinflammatory diet was associated with worse cardiometabolic health measures, and these relationships differed by a person's APO history. Further investigation should establish how dietary modifications after pregnancy may potentially mitigate cardiovascular disease risk.Item "I'm supposed to be a helper": Spiritual distress of abortion providers after the Dobbs decision(Elsevier, 2025-02-22) Bode, Leah M.; Kumar, Komal A.; McQuillan, Josie C.; Scott, Nicole P.; Bernard, Caitlin; Obstetrics and Gynecology, School of MedicineBackground: The Dobbs v. Jackson Women's Health Organization decision has undoubtably affected the practice of abortion providers nationally. We hypothesized that Dobbs has also impacted the ways in which providers experience meaning and purpose through their work, which are elements of spirituality. Objective: We sought to describe the spectrum of spirituality of abortion providers and understand whether and how the Dobbs decision caused spiritual distress. Study design: For this qualitative study, we conducted video interviews with 26 abortion providers from 17 states between November 2022 and February 2023. States were classified according to the Guttmacher Institute classifications from most restrictive to very protective as of December 2022. Interviews included questions such as, "Can you describe your own sense of spirituality or spiritual identity?" and "How does your spiritual belief inform your response to the Dobbs decision?" Results: Participants' states of practice were well-distributed across the abortion restrictive-protective spectrum. The majority of participants were spiritual, while less than half identified as part of an organized religion. Many participants felt a spiritual call or obligation to provide abortion care and 46% described abortion as a spiritual act for provider and/or patient. Most participants experienced spiritual distress (74%), including those practicing in states across the restrictive-protective spectrum. Of note, 92% of participants described their spirituality as helpful in coping with the effects of the fall of Roe v. Wade. Sources of strength included advocacy, agency, legislative work, and community; over half specifically cited the abortion provider community. Conclusions: The Dobbs decision-and subsequent state-level abortion restrictions-impacts abortion providers by causing spiritual distress. While many abortion-restrictive laws are influenced by religious or spiritual beliefs, it is important to recognize that abortion providers are also spiritual individuals.Item Perceived benefits and barriers to the use of long-acting injectable antiretroviral treatment among adolescents and young people living with HIV in Western Kenya: qualitative findings from the KuwaFree! LiveFree! Study(Frontiers Media, 2025-03-07) Hassan, Shukri A.; Munyoro, Dennis; Maju, Mehar; Biegon, Whitney; Bakari, Salim; Kaguiri, Eunice; Jumah, Anjellah; Omollo, Mark; Obare, Valerie; Bernard, Caitlin; Apondi, Edith; Were, Edwin; Patel, Rena C.; Obstetrics and Gynecology, School of MedicineIntroduction: Adolescents and young people living with HIV (AYPLHIV) face significant hurdles in adhering to daily oral antiretroviral therapy (ART). Long-acting (LA) ART, such as injectable cabotegravir and rilpivirine, may help overcome these hurdles. However, little is known about the perceived benefits and barriers to LA ART usage by AYPLHIV in resource-limited settings. Methods: We conducted focus group discussions (FGDs) with four target groups of adolescents/youth, providers, policymakers, and other advocates in western Kenya from November 2021 to April 2022. The FGDs elicited participants' thoughts on LA ART implementation in Kenya, particularly the benefits and barriers of LA ART use amongst AYPLHIV. Our analysis combined both inductive and deductive approaches, beginning with open coding of the data, then organizing them in predetermined socio-ecological model (SEM) domains. Results and discussion: We conducted a total of seven FGDs with 58 participants across four stakeholder groups: AYPLHIV (2 FGDs, n = 14), healthcare providers (2 FGDs, n = 19), health/youth advocates (2 FGDs, n = 16), and policymakers (1 FGD, n = 9). We identified several benefits, largely centered around the individual and interpersonal level, as well as barriers, largely centered around the health systems levels. Participants viewed LA ART as a welcome alternative to oral ART due to benefits like improved adherence, reduced pill burden, increased convenience, enhanced privacy, decreased stigma, lower risk of accidental disclosure, and convergence in using LA contraception. At the interpersonal level, LA ART was valued for furthering relationships, especially for AYPLHIV (e.g., dating). At the health systems level, LA ART expanded first-line treatment options. Conversely, barriers to health systems integration included conflicts with service models, increased clinic burden, supply chain issues, and waste disposal. Individual-level barriers included fears of injections, side effects, concerns about a new drug, and reduced effectiveness if mixing LA ART with oral ART. Conclusions: The perceived benefits of LA ART for AYPLHIV, centering on individual and interpersonal levels of positive impacts, appear in tension with the anticipated barriers for health systems readiness in Kenya. While the prospect of offering LA ART is overwhelming positive, country programs will have to invest in health systems readiness before rolling out LA ART.Item Maternal Preconception Omega-6, Omega-3, and Omega-6:Omega-3 Intake and Uterine Artery Indices in Mid-Gestation(Thieme, 2025) Finch, Amara; Joss-Moore, Lisa; Allshouse, Amanda A.; Blue, Nathan; Haas, David M.; Grobman, William; Parry, Samuel; Saade, George; Silver, Robert M.; Obstetrics and Gynecology, School of MedicineObjective: Maternal preconception diet influences pregnancy health and fetal outcomes. We examined the relationship between preconception fatty acid (FA) intake and uterine artery indices in mid-gestation in a large, heterogeneous cohort of nulliparous individuals. Study design: This is a secondary analysis of the nuMom2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be) study. Dietary ω-6 and ω-3 FA intake was assessed with food frequency questionnaires and uterine artery indices were obtained via Doppler studies in the second trimester. For our primary outcome of pulsatility index (PI) > 1.6, we compared proportions by each dichotomous FA exposure and tested differences with chi-square test. Results: For PI > 1.6, odds ratio for the unfavorable FA quartile compared with remaining quartiles for the exposures were 0.96 to 1.25, p = 0.157 (ω-6 FA); 0.97 to 1.26, p = 0.124 (ω-3 FA); 0.87 to 1.14, p = 1.00 (ω-6:ω-3 FA ratio). Conclusion: No significant associations between self-reported maternal preconception ω-6 and ω-3 FA intake and uterine artery Doppler indices measured during the second trimester were observed.Item Facilitating Global Collaborations for Pregnancy and Pediatric Biomarker Research Through a Biobank Database: The COPPER Project(Elsevier, 2024) Faysal, Hani; Quinney, Sara K.; Haas, David M.; Obstetrics and Gynecology, School of MedicineItem Durotaxis and extracellular matrix degradation promote the clustering of cancer cells(Elsevier, 2025-01-24) Potomkin, Mykhailo; Kim, Oleg; Klymenko, Yuliya; Alber, Mark; Aranson, Igor S.; Obstetrics and Gynecology, School of MedicineEarly stages of metastasis depend on the collective behavior of cancer cells and their interaction with the extracellular matrix (ECM). Cancer cell clusters are known to exhibit higher metastatic potential than single cells. To explore clustering dynamics, we developed a calibrated computational model describing how motile cancer cells biochemically and biomechanically interact with the ECM during the initial invasion phase, including ECM degradation and mechanical remodeling. The model reveals that cluster formation time, size, and shape are influenced by ECM degradation rates and cellular compliance to external stresses (durotaxis). The results align with experimental observations, demonstrating distinct cell trajectories and cluster morphologies shaped by biomechanical parameters. The simulations provide valuable insights into cancer invasion dynamics and may suggest potential therapeutic strategies targeting early-stage invasive cells.Item Short-term tocolytics for preterm delivery – current perspectives(Dove Press, 2014-03-27) Haas, David M.; Benjamin, Tara; Sawyer, Renata; Quinney, Sara K.; Obstetrics and Gynecology, School of MedicineAdministration of short-term tocolytic agents can prolong pregnancy for women in preterm labor. Prolonging pregnancy has many benefits because it allows for other proven interventions, such as antenatal corticosteroid administration, to be accomplished. This review provides an overview of currently utilized tocolytic agents and the evidence demonstrating their efficacy for prolonging pregnancy by at least 48 hours. General pharmacological principles for the clinician regarding drugs in pregnancy are also briefly discussed. In general, while the choice of the best first-line short-term tocolytic drug is not clear, it is evident that use of these agents has a clear place in current obstetric therapeutics.Item Adjuvant therapy for endometrial cancer(Asian Society of Gynecologic Oncology, 2014) DeLeon, Maria C.; Ammakkanavar, Natraj R.; Matei, Daniela; Obstetrics and Gynecology, School of MedicineEndometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer.Item Maternal vitamin D status, fetal growth patterns, and adverse pregnancy outcomes in a multisite prospective pregnancy cohort(Elsevier, 2025) Beck, Celeste; Blue, Nathan R.; Silver, Robert M.; Na, Muzi; Grobman, William A.; Steller, Jonathan; Parry, Samuel; Scifres, Christina; Gernand, Alison D.; Obstetrics and Gynecology, School of MedicineBackground: Few studies have examined maternal vitamin D status and fetal growth patterns across gestation. Furthermore, time points in pregnancy at which maternal vitamin D status is most critical for optimal fetal growth and pregnancy outcomes are uncertain. Objectives: Our objective was to examine whether first and second trimester maternal vitamin D status are associated with fetal growth patterns and pregnancy outcomes. Methods: We conducted a secondary analysis using data and samples from a multisite prospective cohort study of nulliparous pregnant females in the United States. We measured serum 25-hydroxyvitamin D (25(OH)D) for 351 participants at 6-13 and 16-21 weeks of gestation. Fetal growth was measured by ultrasound at 16-21 and 22-29 weeks of gestation, and neonatal anthropometric measures at birth. We constructed fetal growth curves using length, weight, and head circumference z-scores, and calculated risk of preterm birth (<37 wk) and small for gestational age (SGA). We examined outcomes across 25(OH)D concentrations assessed continuously, using Institute of Medicine (IOM) cutoffs (<50 compared with ≥50 nmol/L), and using exploratory cutoffs (<40, 40-59.9, 60-79.9, ≥80 nmol/L). Results: Vitamin D insufficiency (25(OH)D <50 nmol/L) was prevalent in 20% of participants in the first trimester. Each 10 nmol/L increase in first trimester 25(OH)D was associated with a 0.05 [95% confidence interval (CI): 0.01, 0.10] increase in length-for-age z-score but was not associated with weight or head circumference. There were no differences in risk of preterm birth or SGA using IOM cutoffs; participants with first trimester 25(OH)D <40 compared with ≥80 nmol/L had 4.35 (95% CI: 1.14, 16.55) times risk of preterm birth. Second trimester 25(OH)D was not associated with fetal growth patterns or with pregnancy outcomes. Conclusions: First trimester 25(OH)D is positively associated with linear growth. Low first trimester 25(OH)D (<40 nmol/L) is associated with a higher risk of preterm birth. Second trimester 25(OH)D is not associated with fetal growth or pregnancy outcomes assessed.