The International Society for the Study of Vulvovaginal Disease (ISSVD) Vulvar Awareness Day Campaign: Knowledge of Vulvovaginal Diseases Among Italian Obstetrics and Gynecology Residents.

Bevilacqua F, Selk A, Stockdale C, Vieira-Baptista P, Adedipe T, Bohl T, Marozio L, Borella F, Gallio N, Pollano B, Robba E, Barbierato I, Benedetto C, Preti M.

J Low Genit Tract Dis. 2023 Nov 8. doi: 10.1097/LGT.0000000000000777. Epub ahead of print. PMID: 37906606.

Objectives: The objective of this study is to investigate vulvovaginal disease (VVD) awareness in Italian obstetrics and gynecology (Ob/Gyn) residents.

Materials and methods: A 25-question survey on VVD basic knowledge (17 questions) and willingness to improve it (8 questions) was distributed through Ob/Gyn resident online group chats, from different Italian Universities in January 2023. A total number of 250 residents were invited to participate; 124 responses were obtained (response rate: 50%). Data were collected and analyzed using descriptive statistics through REDCap.

• Overall, 87 of the 124 respondents (70%) fully completed the questionnaire and represented the study group. Residents were distributed among years of residency: 15% first year, 31% second year, 23% third year, 11% fourth year, and 20% fifth year. Most (60%) never attended a VVD clinic during residency, with an increasing percentage of attendance in later residency years (15% at first year vs 65% at fifth).Participants reported low knowledge of vulvar precancerous lesions and vulvoscopy but better knowledge of vaginitis, vulvar self-examination, and lichen sclerosus. Of the respondents, 50% were not satisfied with the education provided during residency, and more than 60% lacked confidence in managing VVD.All participants expressed a strong desire to improve their knowledge and skills, with 100% agreeing that every gynecologist should know the "basics" and 98% wanting to improve their knowledge through webinars (45%), lessons (34%), newsletters, and videos (19%).

Conclusion: Our findings indicate a significant need to improve VVD knowledge among Italian Ob/Gyn residents. Further efforts are necessary to provide information about VVD and comprehensive training programs in Italian Universities.

Believing women: a qualitative exploration of provider disbelief and pain dismissal among women with interstitial cystitis/bladder pain syndrome from the MAPP research network.

Brown VL, James A, Hunleth J, Bradley CS, Farrar JT, Gupta P, Lai HH, Lowder JL, Moldwin R, Rodriguez LV, Yang CC, Sutcliffe S.

Int Urogynecol J. 2023 Nov 22. doi: 10.1007/s00192-023-05677-0. Epub ahead of print. PMID: 37991567.

Introduction and hypothesis: Although allusions to the importance of a good physician-patient relationship are present throughout the interstitial cystitis/bladder pain syndrome (IC/BPS) literature, qualitative analysis of patients' perspectives on the clinical encounter is lacking, particularly among women who are most commonly affected by IC/BPS. Therefore, we adopted a patient-centered experiential approach to understanding female patients' perception of clinical encounters.

• We re-analyzed previously collected data from a qualitative study on patient flare experiences including eight focus groups of female IC/BPS patients (n = 57, mean = 7/group). Qualitative analysis applied grounded theory to index all physician-patient interactions, then thematically coded these interactions to elucidate common experiences of clinical encounters.

Results: Women with IC/BPS shared common experiences of provider disbelief and pain dismissal. Discussions with participants demonstrated the extent to which these negative encounters shape patients' health care-seeking behavior, outlook, and psychosocial well-being. Appearing in more than one guise, provider disbelief and dismissal occurred as tacit insinuations, explicit statements, silence, oversimplification, and an unwillingness to listen and discuss alternative treatment. As a result, women adopted several strategies including: rotating specialists; "testing" physicians; self-advocacy; self-management; avoiding the stigma of chronic pain; crying; and opting for alternative medicine over biomedicine.

• The prevalence of provider disbelief and pain dismissal among women with IC/BPS indicates a need to improve physician-patient communication, informed by the struggles, anxieties, and gendered inequities that female patients with chronic pain experience in their diagnostic journey. Results suggest that further investigation into the power dynamics of clinical encounters might be required.

In situ profiling reveals metabolic alterations in the tumor microenvironment of ovarian cancer after chemotherapy.

Corvigno S, Badal S, Spradlin ML, Keating M, Pereira I, Stur E, Bayraktar E, Foster KI, Bateman NW, Barakat W, Darcy KM, Conrads TP, Maxwell GL, Lorenzi PL, Lutgendorf SK, Wen Y, Zhao L, Thaker PH, Goodheart MJ, Liu J, Fleming N, Lee S, Eberlin LS, Sood AK.

NPJ Precis Oncol. 2023 Nov 3;7(1):115. doi: 10.1038/s41698-023-00454-0. PMID: 37923835

In this study, we investigated the metabolic alterations associated with clinical response to chemotherapy in patients with ovarian cancer. Pre- and post-neoadjuvant chemotherapy (NACT) tissues from patients with high-grade serous ovarian cancer (HGSC) who had poor response (PR) or excellent response (ER) to NACT were examined. Desorption electrospray ionization mass spectrometry (DESI-MS) was performed on sections of HGSC tissues collected according to a rigorous laparoscopic triage algorithm. Quantitative MS-based proteomics and phosphoproteomics were performed on a subgroup of pre-NACT samples. Highly abundant metabolites in the pre-NACT PR tumors were related to pyrimidine metabolism in the epithelial regions and oxygen-dependent proline hydroxylation of hypoxia-inducible factor alpha in the stromal regions. Metabolites more abundant in the epithelial regions of post-NACT PR tumors were involved in the metabolism of nucleotides, and metabolites more abundant in the stromal regions of post-NACT PR tumors were related to aspartate and asparagine metabolism, phenylalanine and tyrosine metabolism, nucleotide biosynthesis, and the urea cycle. A predictive model built on ions with differential abundances allowed the classification of patients' tumor responses as ER or PR with 75% accuracy (10-fold cross-validation ridge regression model). These findings offer new insights related to differential responses to chemotherapy and could lead to novel actionable targets.

Resection of an endocardial uterine sarcoma metastasis to the tricuspid valve apparatus with valve repair.

Arshava AE, Isaacson AL, Goodheart MJ, Bashir MA.

JTCVS Tech. 2023 Jul 10;21:109-112. doi: 10.1016/j.xjtc.2023.06.015. PMID: 37854803; PMCID: PMC10580036.

Delivery outcomes in the subsequent pregnancy following the conservative management of placenta accreta spectrum disorder: A systematic review and meta-analysis.

Javinani A, Qaderi S, Hessami K, Shainker SA, Shamshirsaz AA, Fox KA, Mustafa HJ, Subramaniam A, Khandelwal M, Sandlin AT, Duzyj CM, Lyell DJ, Zuckerwise LC, Newton JM, Kingdom JC, Harrison RK, Shrivastava VK, Greiner AL, Lotfin R, Genc MR, Atasi LK, Abdel-Razeq SS, Bennett KA, Carusi DA, Einerson BD, Gilner JB, Carver AR, Silver RM, Shamshirsaz AA.

Am J Obstet Gynecol. 2023 Oct 31:S0002-9378(23)00802-5. doi: 10.1016/j.ajog.2023.10.047. Epub ahead of print. PMID: 37918506.

• Cesarean hysterectomy is generally presumed to decrease maternal morbidity and mortality secondary to placenta accreta spectrum disorder (PAS). Recently, uterine-sparing techniques have been introduced in conservative management of PAS to preserve fertility and potentially reduce surgical complications. However, despite often expressing the intention for future conception, few data are available regarding the subsequent pregnancy outcome after conservative management of PAS. Thus, we aimed to perform a systematic review and meta-analysis to assess the subsequent pregnancy outcomes following conservative management of PAS.

Data sources: PubMed, Scopus, and Web of Science databases were searched from inception to September 2022.

Study eligibility criteria: We included all studies, with the exception of case studies, that reported the first subsequent pregnancy outcomes in individuals with a previous history of PAS who underwent any type of conservative management.

Study appraisal and synthesis method: The R programming language with the "meta" package was used. The random effects model and inverse variance method were used to pool the proportion of pregnancy outcomes.

Results: We identified five studies involving 1,458 subjects that were eligible for quantitative synthesis. The type of conservative management included placenta left in situ (n=1), resection surgery (n=1), and not reported in three studies. The PAS recurrence rate in the subsequent pregnancy was 11.8% (95% CI: 1.1-60.3, I2 = 86.4%), and 1.9% (95% CI: 0.0-34.1, I2 = 82.4%) underwent Cesarean hysterectomy. Postpartum hemorrhage occurred in 10.3% (95% CI: 0.3-81.4, I2 = 96.7%). A composite adverse maternal outcome was reported in 22.7% of subjects (95% CI: 0.0-99.4, I2 = 56.3%).

Conclusion: Favorable pregnancy outcome is possible following successful conservation of the uterus in a PAS pregnancy. Approximately one out of four subsequent pregnancies following conservative management of PAS experienced significant adverse maternal outcomes. Given such high incidence of adverse outcomes and morbidity, patient and provider preparation is vital when managing this population.

Study Design and Protocol of the Multisite Pregnancy 24/7 Cohort Study.

Whitaker KM, Jones MA, Smith K, Catov J, Feghali M, Kline CE, Santillan M, Santillan D, Zimmerman B, Gibbs BB.

Am J Epidemiol. 2023 Nov 3:kwad208. doi: 10.1093/aje/kwad208. Epub ahead of print. PMID: 37939072.

• Inequities in COVID-19 vaccine accessibility and reliable COVID-related information disproportionately affected marginalized racial and ethnic communities in the U.S. The Get Out the Vaccine (GOTVax) program, an innovative statewide government-funded COVID-19 vaccine canvassing program in California, aimed to reduce structural barriers to COVID-19 vaccination in high-risk communities with low vaccination rates. GOTVax consisted of a community-academic-government partnership with 34 local trusted community-based organizations' (CBOs) to conduct COVID-19 vaccine outreach, education, and vaccine registration. The purpose of this qualitative evaluation study was to explore the barriers and facilitators of using local CBOs to deploy a geographically, racially, and ethnically diverse state-wide COVID-19 vaccine outreach program.
• Semi-structured online interviews were conducted with participating GOTVax CBO leaders from November 2021 to January 2022. Transcripts were analyzed using reflexive thematic analysis.

Results: Thirty-one of 34 CBOs participated (91% response rate). Identified themes encompassed both facilitators and barriers to program participation. Key facilitators included leveraging trust through recognized entities; promoting empathetic, tailored outreach; and flexibility of milestone-based CBO funding contracts for rapid program implementation. Barriers included navigating community sociopolitical, geographic, and cultural factors; managing canvassers' safety; desiring metrics for self-evaluation of outreach success; mitigating canvassing technology challenges; and concerns of program infrastructure initially limiting outreach. CBOs problem-solved barriers with academic and government partners.

Conclusions: Between May and December 2021, the GOTVax program reached over 2 million California residents and registered over 60,000 residents for COVID-19 vaccination. Public health campaigns may improve benefits from leveraging the expertise of community-trusted CBOs and universities by providing flexible infrastructure and funding, allowing CBOs to seamlessly tailor outreach most applicable to local minoritized communities.

Neonatal immune cells have heightened responses following in-utero exposure to chorioamnionitis or COVID-19.

Gilley A, Boly TJ, Paden A, Bermick J.

Pediatr Res. 2023 Nov 10. doi: 10.1038/s41390-023-02888-5. Epub ahead of print. PMID: 37949998.

• Chorioamnionitis alters neonatal immune responses. Gestational COVID-19 infection is associated with adverse pregnancy outcomes, but its impact on neonatal immunity is unclear. We hypothesized that gestational COVID-19 exposure would result in exaggerated neonatal immune responses, similar to chorioamnionitis-exposed neonates.
• Term umbilical cord blood mononuclear cells (CBMCs) were isolated from neonates exposed to chorioamnionitis, gestational COVID-19 or unexposed controls. CBMCs were cultured and stimulated with heat-killed Escherichia coli, Streptococcus agalactiae or Staphylococcus epidermidis. A multiplexed protein assay was used to measure cytokine levels in cell culture supernatants and flow cytometry was used to evaluate cellular-level cytokine expression.
• Both chorioamnionitis-exposed and COVID-19 exposed CBMCs demonstrated upregulation of IL-1β and IL-6 compared to unexposed CBMCs, while only COVID-19 exposure resulted in IL-8 upregulation. There were no differences between chorioamnionitis-exposed and COVID-19 exposed CBMCs when these groups were directly compared. Flow cytometry demonstrated immune cell subset specific differences in cytokine expression between the exposure groups.
• : The fetal/neonatal response to maternal inflammation differed based on immune cell subset and etiology of inflammation, but the global neonatal cytokine responses were similar between exposure groups. This suggests that targeting perinatal inflammation rather than the specific etiology may be a possible therapeutic approach.

Impact: Neonatal immune cells have similar pathogen-associated global cytokine responses, but different cell-level immune responses, following in-utero exposure to chorioamnionitis or COVID-19. This is the first study to directly compare immune responses between neonates exposed to chorioamnionitis and COVID-19. This suggests that the fetal/neonatal cellular response to perinatal inflammation differs based on the etiology and severity of maternal inflammation, but still results in a similar overall inflammatory profile regardless of the cause of perinatal inflammation.

Decision regret among couples experiencing infertility: a mixed methods longitudinal cohort study.

Cusatis R, Johnson C, Schoyer KD, Tsaih SW, Balza J, Sandlow J, Flynn KE.

Reprod Health. 2023 Nov 9;20(1):165. doi: 10.1186/s12978-023-01699-5. PMID: 37940984; PMCID: PMC10633954.

• : Decisions for how to resolve infertility are complex and may lead to regret. We examined whether couples and individuals who sought a consultation from a reproductive specialist for infertility later expressed decisional regret about their family-building choices and whether regret was associated with parental role, family-building paths, or outcomes.

Methods: This longitudinal mixed methods study included women and their partners who completed a questionnaire prior to their initial consultation with a reproductive specialist and 6 years later. The six-year questionnaire included the Ottawa Decision Regret Scale referencing "the decisions you made about how to add a child to your family." A score of 25+ indicates moderate-to-severe regret. Additional items invited reflections on family-building decisions, treatments, and costs. A systematic content analysis assessed qualitative themes.

• Forty-five couples and 34 individuals participated in the six-year questionnaire (76% retention rate), Half (n = 61) of participants expressed no regret, which was similar by role (median 0 for women and supporting partners, F = .08; p = .77). One in 5 women and 1 in 7 partners expressed moderate-to-severe regret. Women who did not pursue any treatment had significantly higher regret (median 15; F = 5.6, p < 0.01) compared to those who pursued IVF (median 0) or other treatments (median 0). Women who did not add a child to their family had significantly higher regret (median 35; F = 10.1, p < 0.001) than those who added a child through treatment (median 0), through fostering/adoption (median 0), or naturally (median 5). Among partners, regret scores were not associated with family-building paths or outcomes. More than one-quarter of participants wished they had spent less money trying to add a child to their family. Qualitative themes included gratitude for parenthood despite the burdensome process of family-building as well as dissatisfaction or regret about the process. Results should be confirmed in other settings to increase generalizability.
• This longitudinal study provides new insight into the burden of infertility. For women seeking parenthood, any of the multiple paths to parenthood may prevent future decision regret. Greater psychosocial, financial, and decision support is needed to help patients and their partners navigate family-building with minimal regret.

Caprini Model Integration into an Electronic Medical Record to Improve Perioperative Venous Thromboembolism Prophylaxis.

Akella S, Russo D, Bradley CS, Kowalski JT.

Obstet Gynecol. 2023 Oct 5. doi: 10.1097/AOG.0000000000005390. Epub ahead of print. PMID: 37797334.

This quality-improvement retrospective cohort study of patients undergoing major elective nononcologic gynecologic surgery compares the proportion of patients receiving appropriate perioperative venous thromboembolism (VTE) chemoprophylaxis before and after a novel integration of the Caprini risk-assessment model (RAM) into the electronic medical record (EMR). A sample size of 83 patients in each group (166 total) was calculated to provide 80% power and show a 20% increase in appropriate administration of VTE prophylaxis, with an alpha of 0.05. Heparin was appropriately used in 24 patients (28.9%) in the pre-Caprini-RAM group and 39 patients (47.0%) in the post-Caprini-RAM group (P=.016). There were no differences in bleeding events, transfusions, or other secondary outcomes. Integrating the Caprini-RAM into an EMR for patients undergoing nononcologic gynecologic surgery significantly improved appropriate use of VTE chemoprophylaxis.

Reply By Authors.

Mawla I, Schrepf A, Kutch JJ, Helmuth ME, Smith AR, Ichesco E, Yang CC, Andreev VP, Kreder KJ, Bradley CS, Magnotta VA, Kirkali Z, Harris RE, Lai HH, Harte SE.

J Urol. 2023 Oct 5:101097JU000000000000369902. doi: 10.1097/JU.0000000000003699.02. Epub ahead of print. PMID: 37796787.

Naturalistic Bladder Filling Reveals Subtypes in Overactive Bladder Syndrome That Differentially Engages Urinary Urgency-Related Brain Circuits: Results From the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN)

Mawla I, Schrepf A, Kutch JJ, Helmuth ME, Smith AR, Ichesco E, Yang CC, Andreev VP, Kreder KJ, Bradley CS, Magnotta VA, Kirkali Z, Harris RE, Lai HH, Harte SE.

J Urol. 2023 Oct 5:101097JU0000000000003699. doi: 10.1097/JU.0000000000003699. Epub ahead of print. PMID: 37796776.

Purpose: Overactive bladder (OAB) may be attributed to dysfunction in supraspinal brain circuits. Overactive bladder participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) study reported sensations of urinary urgency during a bladder-filling paradigm while undergoing brain functional MRI to map supraspinal dysfunction.

Materials and methods: OAB participants and controls (CONs) completed 2 resting-state functional MRI scans following consumption of 350 mL water. Scans were conducted at fuller and emptier bladder states, interleaved with voiding. Urgency ratings (0-10) were assessed. Patterns of urgency during bladder filling were investigated using latent class trajectory models. Clusters of participants encompassing each pattern (ie, subtype) were derived from aggregated groups of OAB and CON independent of diagnosis.

Results: Two distinct patterns of urgency trajectories were revealed: first subtype with OAB and CON who were unresponsive to bladder filling (OAB-1 and CON-1) and second highly responsive subtype predominantly containing OAB (OAB-2). OAB-2 participants scored significantly higher on urinary symptoms but not pain or psychosocial measures. Neuroimaging analyses showed change in urgency due to both bladder filling and voided volume related to multiple loci of brain network connectivity in OAB-2, and in some cases, different than OAB-1 and/or CON-1. Sensorimotor to dorsomedial/dorsolateral prefrontal connectivity mediated the relationship between stimulus (voided volume) and percept (urgency) in OAB-2.

Conclusions: Our results reveal different OAB subtypes with latent class trajectory models of urgency ratings during natural bladder filling. Functional MRI revealed differences in pathophysiology between subtypes, namely sensorimotor-prefrontal connectivity is a key locus in OAB patients with higher urinary symptoms.

Impact of Sling at Time of Prolapse Surgery on Overactive Bladder.

Kowalski JT, Maetzold E, Kenne KA, Bradley CS.

Urogynecology (Phila). 2023 Sep 20. doi: 10.1097/SPV.0000000000001411. Epub ahead of print. PMID: 37737833.

Importance: Prolapse surgery and sling surgery both lead to improvement in overactive bladder. However, less is known regarding how slings performed concurrently with less is know about how overactive bladder symptoms change in patients having prolapse surgery with a sling compared to prolapse surgery without a sling.

• The primary aim was to compare change in postoperative overactive bladder symptoms in patients with preoperative overactive bladder who underwent sling placement versus no sling with prolapse surgery.

Study design: This was a secondary analysis of a cohort study evaluating overactive bladder in patients undergoing prolapse surgery. Sling procedures were performed concomitantly for treatment or prevention of stress incontinence. Baseline and 3-month follow-up urinary symptoms were assessed with the Overactive Bladder Questionnaire Short Form (OAB-q SF) and Urinary Distress Inventory-6 (UDI-6).

• Of patients with overactive bladder, 26 (40.0%) underwent midurethral sling (MUS) placement and 39 (60.0%) no sling. Preoperative OAB-q SF bother (score [SD], 46.8 [20.2] vs 40.2 [22.1]; P = 0.23) was similar between groups, but UDI-6 scores (59.2 [28.8] vs 43.8 [29.1]; P = 0.04) were higher in the sling group. At 3 months, the change (improvement) in OABq-SF bother (-16.9 [24.1] vs -22.4 [23.0]; P = 0.36), OABq-SF health-related quality of life (22.8 [28.6] vs 22.9 [23.9]; P = 0.99), and UDI-6 (-38.8 [32.9] vs -34.0 [27.8]; P = 0.53) were similar in the MUS and no MUS groups.

Conclusion: Patients with prolapse and overactive bladder undergoing prolapse surgery with a sling had similar improvements in OAB-q SF bother scores compared with those who did not have a sling.

Twelve Month Outcomes of Pelvic Organ Prolapse Surgery in Patients With Uterovaginal or Posthysterectomy Vaginal Prolapse Enrolled in the Multicenter Pelvic Floor Disorders Registry.

Ferrando CA, Bradley CS, Meyn LA, Brown HW, Moalli PA, Heisler CA, Murarka SM, Foster RT Sr, Chung DE, Whitcomb EL, Gutman RE, Andy UU, Shippey SH, Anger J, Yurteri-Kaplan LA.

Urogynecology (Phila). 2023 Oct 1;29(10):787-799. doi: 10.1097/SPV.0000000000001410. PMID: 37733440.

Objective: The aim of the study was to compare 12-month subjective and objective outcomes between 3 approaches to apical pelvic organ prolapse (POP) surgery in patients presenting with uterovaginal or posthysterectomy vaginal prolapse enrolled in the Pelvic Floor Disorders Registry for Research.

Study design: This was an analysis of a multicenter, prospective registry that collected both patient- and physician-reported data for up to 3 years after conservative (pessary) and surgical treatment for POP. Twelve-month subjective and anatomic outcomes for patients who underwent surgical treatment were extracted from the registry for analysis. Pelvic organ prolapse recurrence was defined as a composite outcome and compared between the 3 apical surgery groups (native tissue repair, sacrocolpopexy, colpocleisis) as well as the 2 reconstructive surgery groups (native tissue repair and sacrocolpopexy).

• A total of 1,153 women were enrolled in the registry and 777 (67%) opted for surgical treatment, of whom 641 underwent apical repair and were included in this analysis (404 native tissue repair, 187 sacrocolpopexy, and 50 colpocleisis). The overall incidence of recurrence was as follows: subjective 6.5%, anatomic 4.7%, retreatment 7.2%, and composite 13.6%. The incidence of recurrence was not different between the 3 surgical groups. When baseline patient characteristics were controlled for, composite POP recurrence between the native tissue and sacrocolpopexy groups remained statistically nonsignificant. Concurrent perineorrhaphy with any type of apical POP surgery was associated with a lower risk of recurrence (adjusted odds ratio, 0.43; 95% confidence interval, 0.25-0.74; P = 0.002) and prior hysterectomy was associated with a higher risk (adjusted odds ratio, 1.77, 95% confidence interval, 1.04-3.03; P = 0.036).

Conclusion: Pelvic Floor Disorders Registry for Research participants undergoing native tissue apical POP repair, sacrocolpopexy, and colpocleisis surgery had similar rates of POP recurrence 12 months after surgery.

Anti-angiogenic mechanisms and serotonergic dysfunction in the Rgs2 knockout model for the study of psycho-obstetric risk.

Gumusoglu SB, Kiel MD, Gugel A, Schickling BM, Weaver KR, Lauffer MC, Sullivan HR, Coulter KJ, Blaine BM, Kamal M, Zhang Y, Devor EJ, Santillan DA, Gantz SC, Santillan MK.

Neuropsychopharmacology. 2023 Oct 17. doi: 10.1038/s41386-023-01749-3. Epub ahead of print. PMID: 37848733.

Psychiatric and obstetric diseases are growing threats to public health and share high rates of co-morbidity. G protein-coupled receptor signaling (e.g., vasopressin, serotonin) may be a convergent psycho-obstetric risk mechanism. Regulator of G Protein Signaling 2 (RGS2) mutations increase risk for both the gestational disease preeclampsia and for depression. We previously found preeclampsia-like, anti-angiogenic obstetric phenotypes with reduced placental Rgs2 expression in mice. Here, we extend this to test whether conserved cerebrovascular and serotonergic mechanisms are also associated with risk for neurobiological phenotypes in the Rgs2 KO mouse. Rgs2 KO exhibited anxiety-, depression-, and hedonic-like behaviors. Cortical vascular density and vessel length decreased in Rgs2 KO; cortical and white matter thickness and cell densities were unchanged. In Rgs2 KO, serotonergic gene expression was sex-specifically changed (e.g., cortical Htr2a, Maoa increased in females but all serotonin targets unchanged or decreased in males); redox-related expression increased in paraventricular nucleus and aorta; and angiogenic gene expression was changed in male but not female cortex. Whole-cell recordings from dorsal raphe serotonin neurons revealed altered 5-HT1A receptor-dependent inhibitory postsynaptic currents (5-HT1A-IPSCs) in female but not male KO neurons. Additionally, serotonin transporter blockade by the SSRI sertraline increased the amplitude and time-to-peak of 5-HT1A-IPSCs in KO neurons to a greater extent than in WT neurons in females only. These results demonstrate behavioral, cerebrovascular, and sertraline hypersensitivity phenotypes in Rgs2 KOs, some of which are sex-specific. Disruptions may be driven by vascular and cell stress mechanisms linking the shared pathogenesis of psychiatric and obstetric disease to reveal future targets.

International urogynecological consultation chapter 4.1: definition of outcomes for pelvic organ prolapse surgery.

Kowalski JT, Barber MD, Klerkx WM, Grzybowska ME, Toozs-Hobson P, Rogers RG, Milani AL.

Int Urogynecol J. 2023 Oct 11. doi: 10.1007/s00192-023-05660-9. Epub ahead of print. PMID: 37819369.

Introduction and hypothesis: This manuscript of Chapter 4 of the International Urogynecological Consultation (IUC) on Pelvic Organ Prolapse (POP) reviews the literature and makes recommendations on the definition of success in the surgical treatment of pelvic organ prolapse.

Methods: An international group containing seven urogynecologists performed an exhaustive search of the literature using two PubMed searches and using PICO methodology. The first search was from 01/01/2012-06/12/2022. A second search from inception to 7/24/2022 was done to access older references. Publications were eliminated if not relevant to the clinical definition of surgical success for the treatment of POP. All abstracts were reviewed for inclusion and any disagreements were adjudicated by majority consensus of the writing group. The resulting list of articles were used to inform a comprehensive review and creation of the definition of success in the surgical treatment of POP.

Outcomes: The original search yielded 12,161 references of which 45 were used by the writing group. Ultimately, 68 references are included in the manuscript. For research purposes, surgical success should be primarily defined by the absence of bothersome patient bulge symptoms or retreatment for POP and a time frame of at least 12 months follow-up should be used. Secondary outcomes, including anatomic measures of POP and related pelvic floor symptoms, should not contribute to a definition of success or failure. For clinical practice, surgical success should primarily be defined as the absence of bothersome patient bulge symptoms. Surgeons may consider using PASS (patient acceptable symptom state) or patient goal attainment assessments, and patients should be followed for a minimum of at least one encounter at 6-12 weeks post-operatively. For surgeries involving mesh longer-term follow-up is recommended.

Trichomoniasis {book chapter}

Munzy CA, Stockdale CK, Kissinger PJ.

In: De Seat F, Vieira Baptista P, editors. Infections in gynecology, Gynecology Module Volume 12, The Continuous Textbook of Women’s Medicine Series. GLOWM: The Alliance for Global Women’s Medicine; 2023 August. ISSN 1756-2228; doi:103843/GLOWM.419923.

Global Expression Analysis of Endometrial Cancer Cells in Response to Progesterone Identifies New Therapeutic Targets.

Thiel KW, Newtson AM, Devor EJ, Zhang Y, Malmrose PK, Bi J, Losh HA, Davies S, Smith LE, Padilla J, Leiva SM, Grueter CE, Breheny P, Hagan CR, Pufall MA, Gertz J, Guo Y, Leslie KK.

J Steroid Biochem Mol Biol. 2023 Sep 14:106399. doi: 10.1016/j.jsbmb.2023.106399. Epub ahead of print. PMID: 37716459.

Abstract

Progesterone prevents development of endometrial cancers through its receptor (PR) although the molecular mechanisms have yet to be fully characterized. In this study, we performed a global analysis of gene regulation by progesterone using human endometrial cancer cells that expressed PR endogenously or exogenously. We found progesterone strongly inhibits multiple components of the platelet derived growth factor receptor (PDGFR), Janus kinase (JAK), signal transducer and activator of transcription (STAT) pathway through PR. The PDGFR/JAK/STAT pathway signals to control numerous downstream targets including AP-1 transcription factors Fos and Jun. Treatment with inhibitors of the PDGFR/JAK/STAT pathway significantly blocked proliferation in multiple novel patient-derived organoid models of endometrial cancer, and activation of this pathway was found to be a poor prognostic signal for the survival of patients with endometrial cancer from The Cancer Genome Atlas. Our study identifies this pathway as central to the growth-limiting effects of progesterone in endometrial cancer and suggests that inhibitors of PDGFR/JAK/STAT should be considered for future therapeutic interventions.

Well-being and stress vulnerability in ovarian cancer survivors during the COVID-19 pandemic.

Telles R, Zia S, Greteman B, Thaker P, Penedo F, Charlton M, Goodheart M, Armer J, Noble A, Sood A, Lutgendorf S.

J Psychosoc Oncol. 2023 Aug 17:1-16. doi: 10.1080/07347332.2023.2244474. Epub ahead of print. PMID: 37587850.

• This study was designed to examine (1) whether ovarian cancer (OC) survivors would have greater well-being vs. elevated distress compared to community members during a universal health stressor (COVID-19) and (2) how resources and risk factors at diagnosis predicted vulnerability to a subsequent health-related stressor.

Methods: One hundred seventeen OC survivors were recruited from two academic medical centers and compared to a community-based sample on COVID-related distress and disruption. Latent class analysis identified differentially impacted groups of survivors.

Results: Survivors reported lower distress than community members. Predictors of higher distress included shorter-term survivorship, greater disruption, and poorer emotional well--being (EWB) at diagnosis. Survivors were divided into high- and low-COVID-19-impact subgroups; high-impact individuals endorsed higher perceived stress and lower EWB at diagnosis.

Conclusion: Survivors reported lower COVID-related distress than community participants. While depression at diagnosis did not predict later distress, EWB was a strong predictor of response to a novel health-related stressor.

Inflammatory Biomarker Profiles in Very Preterm Infants within the Context of Preeclampsia, Chorioamnionitis, and Clinically Diagnosed Postnatal Infection.

Ewald JT, Steinbrekera B, Bermick JR, Santillan DA, Colaizy TT, Santillan MK, Roghair RD.

Pediatr Rep. 2023 Aug 10;15(3):483-493. doi: 10.3390/pediatric15030044. PMID: 37606448; PMCID: PMC10443264.

Preterm delivery can be precipitated by preeclampsia or infection, and preterm infants are at heightened risk of postnatal infection. Little is known about the ontogeny of inflammatory biomarkers in extremely preterm infants. We hypothesized that suspected prenatal infection (clinical chorioamnionitis or spontaneous preterm labor) and clinically diagnosed postnatal infection would be associated with unique biomarker signatures, and those patterns would be influenced by the degree of prematurity. Venous blood was collected daily for the first week and weekly for up to 14 additional weeks from 142 neonates born at 22-32 weeks gestation. A custom array was utilized to measure monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6). C-reactive protein (CRP) levels were obtained from the electronic medical record. Independent of gestational age, MCP-1 was significantly increased (p < 0.001) in association with maternal preeclampsia, but MCP-1 was decreased (p < 0.01), and CRP was increased (p < 0.01) in the presence of chorioamnionitis with funisitis. IL-6 and CRP were both increased in infants diagnosed with postnatal infection, with peak levels observed on days 2 and 3, respectively. In conclusion, suspected prenatal and postnatal infections and non-infectious complications of pregnancy are associated with unique biomarker profiles, independent of gestational age, including over a 2-fold increase in MCP-1 among newborns of mothers with preeclampsia. Further, in those clinically diagnosed with a postnatal infection in the absence of antenatal infection concerns, IL-6 increases before CRP, emphasizing a potential role for expanded biomarker screening if antibiotics are initially avoided in infants delivered for maternal indications.

Efferocytosis of viable versus heat-inactivated MSC induces human monocytes to distinct immunosuppressive phenotypes.

Schrodt MV, Behan-Bush RM, Liszewski JN, Humpal-Pash ME, Boland LK, Scroggins SM, Santillan DA, Ankrum JA.

Stem Cell Res Ther. 2023 Aug 17;14(1):206. doi: 10.1186/s13287-023-03443-z. PMID: 37592321; PMCID: PMC10433682.

• Immunomodulation by mesenchymal stromal cells (MSCs) can occur through trophic factor mechanisms, however, intravenously infused MSCs are rapidly cleared from the body yet a potent immunotherapeutic response is still observed. Recent work suggests that monocytes contribute to the clearance of MSCs via efferocytosis, the body's natural mechanism for clearing dead and dying cells in a non-inflammatory manner. This begs the questions of how variations in MSC quality affect monocyte phenotype and if viable MSCs are even needed to elicit an immunosuppressive response.
• Herein, we sought to dissect MSC's trophic mechanism from their efferocytic mechanisms and determine if the viability of MSCs prior to efferocytosis influences the resultant phenotype of monocytes. We cultured viable or heat-inactivated human umbilical cord MSCs with human peripheral blood mononuclear cells for 24 h and observed changes in monocyte surface marker expression and secretion profile. To isolate the effect of efferocytosis from MSC trophic factors, we used cell separation techniques to remove non-efferocytosed MSCs before challenging monocytes to suppress T-cells or respond to inflammatory stimuli. For all experiments, viable and heat-inactivated efferocytic-licensing of monocytes were compared to non-efferocytic-licensing control.
• We found that monocytes efferocytose viable and heat-inactivated MSCs equally, but only viable MSC-licensed monocytes suppress activated T-cells and suppression occurred even after depletion of residual MSCs. This provides direct evidence that monocytes that efferocytose viable MSCs are immunosuppressive. Further characterization of monocytes after efferocytosis showed that uptake of viable-but not heat inactivated-MSC resulted in monocytes secreting IL-10 and producing kynurenine. When monocytes were challenged with LPS, IL-2, and IFN-γ to simulate sepsis, monocytes that had efferocytosed viable MSC had higher levels of IDO while monocytes that efferocytosed heat inactivated-MSCs produced the lowest levels of TNF-α.
• : Collectively, these studies show that the quality of MSCs efferocytosed by monocytes polarize monocytes toward distinctive immunosuppressive phenotypes and highlights the need to tailor MSC therapies for specific indications.

First Trimester Prediction of Preterm Birth in Patient Plasma with Machine-Learning-Guided Raman Spectroscopy and Metabolomics.

Synan L, Ghazvini S, Uthaman S, Cutshaw G, Lee CY, Waite J, Wen X, Sarkar S, Lin E, Santillan M, Santillan D, Bardhan R

ACS Appl Mater Interfaces. 2023 Aug 7. doi: 10.1021/acsami.3c04260. Epub ahead of print. PMID: 37549133.

Preterm birth (PTB) is the leading cause of infant deaths globally. Current clinical measures often fail to identify women who may deliver preterm. Therefore, accurate screening tools are imperative for early prediction of PTB. Here, we show that Raman spectroscopy is a promising tool for studying biological interfaces, and we examine differences in the maternal metabolome of the first trimester plasma of PTB patients and those that delivered at term (healthy). We identified fifteen statistically significant metabolites that are predictive of the onset of PTB. Mass spectrometry metabolomics validates the Raman findings identifying key metabolic pathways that are enriched in PTB. We also show that patient clinical information alone and protein quantification of standard inflammatory cytokines both fail to identify PTB patients. We show for the first time that synergistic integration of Raman and clinical data guided with machine learning results in an unprecedented 85.1% accuracy of risk stratification of PTB in the first trimester that is currently not possible clinically. Correlations between metabolites and clinical features highlight the body mass index and maternal age as contributors of metabolic rewiring. Our findings show that Raman spectral screening may complement current prenatal care for early prediction of PTB, and our approach can be translated to other patient-specific biological interfaces.

Breastfeeding Benefits both the Parent and the Baby.

Goodrich A.

Iowa Corridor Breastfeeding Coalition, 15 August 2023. BLOG

In preparing for the birth of your baby, you will hear about different ways that the baby can be fed. While formula is a suitable alternative for families who are not able or do not desire to breastfeed (or chest feed), it is important to acknowledge that breastfeeding benefits both the baby and the nursing person in ways that formula is not able to.

Predicting the onset of preeclampsia by longitudinal monitoring of metabolic changes throughout pregnancy with Raman spectroscopy.

Ghazvini S, Uthaman S, Synan L, Lin EC, Sarkar S Santillan MK, Santillan DA, Bardhan R.

Bioeng Transl Med. 2023;e10595. doi:10.1002/btm2.10595.

Preeclampsia is a life-threatening pregnancy disorder. Current clinical assays cannot predict the onset of preeclampsia until the late 2nd trimester, which often leads to poor maternal and neonatal outcomes. Here we show that Raman spectroscopy combined with machine learning in pregnant patient plasma enables rapid, highly sensitive maternal metabolome screening that predicts preeclampsia as early as the 1st trimester with >82% accuracy. We identified 12, 15 and 17 statistically significant metabolites in the 1st, 2nd and 3rd trimesters, respectively. Metabolic pathway analysis shows multiple pathways corresponding to amino acids, fatty acids, retinol, and sugars are enriched in the preeclamptic cohort relative to a healthy pregnancy. Leveraging Pearson's correlation analysis, we show for the first time with Raman Spectroscopy that metabolites are associated with several clinical factors, including patients' body mass index, gestational age at delivery, history of preeclampsia, and severity of preeclampsia. We also show that protein quantification alone of proinflammatory cytokines and clinically relevant angiogenic markers are inadequate in identifying at-risk patients. Our findings demonstrate that Raman spectroscopy is a powerful tool that may complement current clinical assays in early diagnosis and in the prognosis of the severity of preeclampsia to ultimately enable comprehensive prenatal care for all patients.

Microbial Communities in Gynecological Cancers and Their Association with Tumor Somatic Variation.

Gonzalez-Bosquet J, McDonald ME, Bender DP, Smith BJ, Leslie KK, Goodheart MJ, Devor EJ.

Cancers (Basel). 2023 Jun 23;15(13):3316. doi: 10.3390/cancers15133316. PMID: 37444425; PMCID: PMC10340580.

There are strong correlations between the microbiome and human disease, including cancer. However, very little is known about potential mechanisms associated with malignant transformation in microbiome-associated gynecological cancer, except for HPV-induced cervical cancer. Our hypothesis is that differences in bacterial communities in upper genital tract epithelium may lead to selection of specific genomic variation at the cellular level of these tissues that may predispose to their malignant transformation. We first assessed differences in the taxonomic composition of microbial communities and genomic variation between gynecologic cancers and normal samples. Then, we performed a correlation analysis to assess whether differences in microbial communities selected for specific single nucleotide variation (SNV) between normal and gynecological cancers. We validated these results in independent datasets. This is a retrospective nested case-control study that used clinical and genomic information to perform all analyses. Our present study confirms a changing landscape in microbial communities as we progress into the upper genital tract, with more diversity in lower levels of the tract. Some of the different genomic variations between cancer and controls strongly correlated with the changing microbial communities. Pathway analyses including these correlated genes may help understand the basis for how changing bacterial landscapes may lead to these cancers. However, one of the most important implications of our findings is the possibility of cancer prevention in women at risk by detecting altered bacterial communities in the upper genital tract epithelium.

Relationships Between Urinary and Nonurinary Symptoms in Treatment-Seeking Women in LURN.

Smith AR, Mansfield SA, , Kenton KS, Helmuth ME, Cameron AP, Kirkali Z, Bretschneider CE, Andreev V, Sarma A, Lane G, Collins SA, Cella D, Lai HH, Harte SE, Griffith JW; LURN Study Group.

Urogynecology (Phila). 2023 Jun 27. doi: 10.1097/SPV.0000000000001388. Epub ahead of print. PMID: 37428882.

• Physical health and psychological health represent modifiable factors in the causal pathway of lower urinary tract symptoms (LUTS).

Objectives: Understand the relationship between physical and psychological factors and LUTS over time.

Study design: Adult women enrolled in the Symptoms of Lower Urinary Tract Dysfunction Research Network observational cohort study completed the LUTS Tool and Pelvic Floor Distress Inventory, including urinary (Urinary Distress Inventory), prolapse (Pelvic Organ Prolapse Distress Inventory), and colorectal anal (Colorectal-Anal Distress Inventory) subscales at baseline, 3 months, and 12 months. Physical functioning, depression, and sleep disturbance were measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires; relationships were assessed using multivariable linear mixed models.

• Of 545 women enrolled, 472 had follow-up. Median age was 57 years; 61% and 78% reported stress urinary incontinence and overactive bladder, respectively; and 81% reported obstructive symptoms. The PROMIS depression scores were positively associated with all urinary outcomes (range, 2.5- to 4.8-unit increase per 10-unit increase in depression score; P < 0.01 for all). Higher sleep disturbance scores were associated with higher urgency, obstruction, LUTS Total Severity, Urinary Distress Inventory, and Pelvic Floor Distress Inventory (1.9- to 3.4-point increase per 10-unit increase, all P < 0.02). Better physical functioning was associated with less severe urinary symptoms except stress urinary incontinence (2.3- to 5.2-point decrease per 10-unit increase, all P < 0.01). All symptoms decreased over time; however, no association was detected between baseline PROMIS scores and trajectories of LUTS over time.
• Nonurologic factors demonstrated small to medium cross-sectional associations with urinary symptom domains, but no significant association was detected with changes in LUTS. Further work is needed to determine whether interventions targeting nonurologic factors reduce LUTS in women.

Incidence and risk factors for postpartum mood and anxiety disorders among women veterans.

Pratt AA, Sadler AG, Thomas EBK, , Ryan GL, Mengeling MA.

Gen Hosp Psychiatry. 2023 Jun 25;84:112-124. doi: 10.1016/j.genhosppsych.2023.06.013. Epub ahead of print. PMID: 37433239.

Background: Our aim was to determine rates of postpartum mood and anxiety disorders (PMADs) among U.S. women Veterans and the overlap among PMADs. We further sought to identify PMAD risk factors, including those unique to military service.

• A national sample of women Veterans completed a computer-assisted telephone interview (N = 1414). Eligible participants were aged 20-45 and had separated from service within the last 10 years. Self-report measures included demographics, general health, reproductive health, military exposures, sexual assault, childhood trauma, and posttraumatic stress disorder (PTSD). The PMADs of interest were postpartum depression (PPD), postpartum anxiety (PPA) and postpartum PTSD (PPPTSD). This analysis included 1039 women Veterans who had ever been pregnant and who answered questions about PPMDs related to their most recent pregnancy.
• A third (340/1039, 32.7%) of participants were diagnosed with at least one PMAD and one-fifth (215/1039, 20.7%) with two or more. Risk factors common for developing a PMAD included: a mental health diagnosis prior to pregnancy, a self-report of ever having had a traumatic birth experience, and most recent pregnancy occurring during military service. Additional risk factors were found for PPD and PPPTSD.
• Women Veterans may be at an increased risk for developing PMADs due to high rates of lifetime sexual assault, mental health disorders, and military-specific factors including giving birth during military service and military combat deployment exposures.

Rectovaginal Fistula From Untreated Ulcerative Colitis in Pregnancy: A Case Report and Review of the Literature

Altshuler PC, Bradford E, van Swaay A, Gaffney R.

Cureus. 2023 Jun 19;15(6):e40662. doi: 10.7759/cureus.40662. PMID: 37485139; PMCID: PMC10356568.

Inflammatory bowel disease can have reproductive consequences depending on disease severity at the time of conception and antepartum management. A 37-year-old G1 with ulcerative pancolitis initially did not disclose her medical history to the obstetrics providers. She developed worsening hematochezia and microcytic anemia and declined antepartum treatment of ulcerative colitis. She then developed a rectovaginal fistula, underwent cesarean delivery but declined intraoperative management of the fistula, and started treatment after significant postpartum weight loss. She was ultimately lost to follow-up care. For patients with ulcerative colitis, a multidisciplinary team approach should be utilized to identify barriers to care, prevent disease progression, and optimize pregnancy outcomes. Delivery methods should be individualized to the patient, and further studies are necessary to establish guidelines.

Cotyledonoid dissecting leiomyoma in pregnancy: a case report

Samuel Choice, Mildrede Bonglack, , Audai Alrwashdeh,

Proc Obstet Gynecol. 2023;12(1): Article 6 [10 p.].

Cotyledonoid dissecting leiomyoma (CDL) is a rare variant of uterine leiomyoma characterized by intramural dissection within the uterine corpus and a distinctive gross appearance resembling the cotyledons of the placenta. Despite their alarming, sarcomatous appearance both macroscopically and radiographically, these tumors are typically associated with bland histologic findings. Approximately 70 cases of CDL have been described in the literature. This case represents the second described case of CDL in pregnancy, the first in which a pregnancy was carried to term. A 28-year-old primigravid was incidentally found to have a massive, exophytic growth of the uterus on ultrasound with concomitant 14-week intrauterine pregnancy. The pregnancy was monitored with serial growth ultrasounds. She was delivered at 37 weeks via Cesarean section. After being lost to follow-up, the patient presented 2.5 years later with worsening abdominal fullness and persistent uterine mass.

Changing the Name of the Subspecialty (Back) to Urogynecology and Reconstructive Pelvic Surgery.

Barber MD, , Wendel GD Jr.

Obstet Gynecol. 2023 Jul 1;142(1):4-5. doi: 10.1097/AOG.0000000000005251.

Changing the Name of the Subspecialty (Back) to Urogynecology and Reconstructive Pelvic Surgery.

Barber MD, , Wendel GD Jr.

Urogynecology (Phila). 2023 Jul 1;29(7):593-594. doi: 10.1097/SPV.0000000000001382. Epub 2023 Jun 22.

Neurobiology and long-term impact of bladder-filling pain in humans: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) research network study.

Schrepf AD, Mawla I, Naliboff BD, Gallop B, Moldwin RM, Tu F, Gupta P, Harte S, Krieger JN, Yang C, Rodriguez L, Williams D, Magnotta V, Ichesco E, Harris RE, Clemens Q, Mullins C, Kutch JJ.

Pain. 2023 Jun 6. doi: 10.1097/j.pain.0000000000002944. Epub ahead of print.

Pain with bladder filling remains an unexplained clinical presentation with limited treatment options. Here, we aim to establish the clinical significance of bladder filling pain using a standardized test and the associated neural signature. We studied individuals diagnosed with urologic chronic pelvic pain syndrome (UCPPS) recruited as part of the multidisciplinary approach to the study of chronic pelvic pain (MAPP) study. Patients with urologic chronic pelvic pain syndrome (N = 429) and pain-free controls (N = 72) underwent a test in which they consumed 350 mL of water and then reported pain across an hour-long period at baseline and 6 months. We used latent class trajectory models of these pain ratings to define UCPPS subtypes at both baseline and 6 months. Magnetic resonance imaging of the brain postconsumption was used to examine neurobiologic differences between the subtypes. Healthcare utilization and symptom flare-ups were assessed over the following 18 months. Two distinct UCPPS subtypes were identified, one showing substantial pain related to bladder filling and another with little to no pain throughout the test. These distinct subtypes were seen at both baseline and 6 month timepoints. The UCPPS subtype with bladder-filling pain (BFP+) had altered morphology and increased functional activity in brain areas involved in sensory and pain processing. Bladder-filling pain positive status predicted increased symptom flare-ups and healthcare utilization over the subsequent 18 months when controlling for symptom severity and a self-reported history of bladder-filling pain. These results both highlight the importance of assessing bladder filling pain in heterogeneous populations and demonstrate that persistent bladder-filling pain profoundly affects the brain.

Particles and Prejudice: Nanomedicine Approaches to Reducing Health Disparities in Endometrial Cancer.

Rowlands CE, Folberg AM, Beickman ZK, Leslie KK, Givens BE.

Small. 2023 Jun 13:e2300096. doi: 10.1002/smll.202300096. Epub ahead of print.

Endometrial cancer is the most common gynecological malignancy worldwide and unfortunately has a much higher mortality rate in Black women compared with White women. Many potential factors contribute to these mortality rates, including the underlying effects of systemic and interpersonal racism. Furthermore, other trends in medicine have potential links to these rates including participation in clinical trials, hormone therapy, and pre-existing health conditions. Addressing the high incidence and disparate mortality rates in endometrial cancer requires novel methods, such as nanoparticle-based therapeutics. These therapeutics have been growing in increasing prevalence in pre-clinical development and have far-reaching implications in cancer therapy. The rigor of pre-clinical studies is enhanced by the likeness of the model to the human body. In systems for 3D cell culture, for example, the extracellular matrix mimics the tumor more closely. The increasing emphasis on precision medicine can be applied to cancer using nanoparticle-based methods and applied to pre-clinical models by using patient-derived model data. This review highlights the intersections of nanomedicine, precision medicine, and racial disparities within endometrial cancer and provides insights into reducing health disparities using recent scientific advances on the nanoscale.

Prognostic stratification of endometrial cancers with high microsatellite instability or no specific molecular profile.

Gonzalez-Bosquet J, Weroha SJ, Bakkum-Gamez JN, Weaver AL, McGree ME, Dowdy SC, Famuyide AO, Kipp BR, Halling KC, Yadav S, Couch FJ, Podratz KC.

Front Oncol. 2023 May 23;13:1105504. doi: 10.3389/fonc.2023.1105504.

• To identify high-risk disease in clinicopathologic low-risk endometrial cancer (EC) with high microsatellite instability (MSI-H) or no specific molecular profile (NSMP) and therapeutic insensitivity in clinicopathologic high-risk MSI-H/NSMP EC.

Methods: We searched The Cancer Genome Atlas for DNA sequencing, RNA expression, and surveillance data regarding MSI-H/NSMP EC. We used a molecular classification system of E2F1 and CCNA2 expression and sequence variations in POLE, PPP2R1A, or FBXW7 (ECPPF) to prognostically stratify MSI-H/NSMP ECs. Clinical outcomes were annotated after integrating ECPPF and sequence variations in homologous recombination (HR) genes.

Results: Data were available for 239 patients with EC, which included 58 MSI-H and 89 NSMP cases. ECPPF effectively stratified MSI-H/NSMP EC into distinct molecular groups with prognostic implications: molecular low risk (MLR), with low CCNA2 and E2F1 expression, and molecular high risk (MHR), with high CCNA2 and E2F1 expression and/or PPP2R1A and/or FBXW7 variants. The 3-year disease-free survival (DFS) rate was 43.8% in the MHR group with clinicopathologic low-risk indicators and 93.9% in the MLR group (P<.001). In the MHR group, wild-type HR genes were present in 28% of cases but in 81% of documented recurrences. The 3-year DFS rate in patients with MSI-H/NSMP EC with clinicopathologic high-risk indicators was significantly higher in the MLR (94.1%) and MHR/HR variant gene (88.9%) groups than in the MHR/HR wild-type gene group (50.3%, P<.001).

• ECPPF may resolve prognostic challenges for MSI-H/NSMP EC by identifying occult high-risk disease in EC with clinicopathologic low-risk indicators and therapeutic insensitivity in EC with clinicopathologic high-risk indicators.

Methylation Signature Implicated in Immuno-Suppressive Activities in Tubo-Ovarian High-Grade Serous Carcinoma.

Wang C, Block MS, Cunningham JM, Sherman ME, McCauley BM, Armasu SM, Vierkant RA, Traficante N; Australian Ovarian Cancer Study Group; Talhouk A, Ramus SJ, Pejovic N, Köbel M, Jorgensen BD, Garsed DW, Fereday S, Doherty JA, Ariyaratne D, Anglesio MS, Widschwendter M, Pejovic T, Bowtell DD, Winham SJ, Goode EL.

Cancer Epidemiol Biomarkers Prev. 2023 Apr 3;32(4):542-549. doi: 10.1158/1055-9965.EPI-22-0941. PMID: 36790339; PMCID: PMC10073286.

Background: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features.

• We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1.
• : Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.10-2.46; P = 0.015; N = 325 published set HR, 2.87; 95% CI, 2.17-3.81; P = 2.2 × 10-13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599; HR, 2.22; 95% CI, 1.66-2.95; P = 4.1 × 10-8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10-7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10-4) in covariate-adjusted analysis.
• Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment.

Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.

Health Disparities in Ovarian Cancer: Report From the Ovarian Cancer Evidence Review Conference.

Mei S, Chelmow D, Gecsi K, Barkley J, Barrows E, Brooks R, , Jeudy M, O'Hara JS, Burke W.

Obstet Gynecol. 2023 Jul 1;142(1):196-210. doi: 10.1097/AOG.0000000000005210. Epub 2023 Jun 7. PMID: 37348095; PMCID: PMC10278570.

Health disparity, defined by the Centers for Disease Control and Prevention (CDC) as "preventable differences in the burden of disease, injury, violence, or opportunities to achieve optimal health that are experienced by socially disadvantaged populations," is seen across multiple diseases. We conducted an evidence review of health disparities and inequities and their mitigation strategies related to ovarian cancer as part of a CDC-sponsored project to develop educational materials for clinicians on the prevention and early diagnosis of gynecologic cancers. Our review found profound disparities in outcomes such as survival, treatment, and stage at diagnosis by factors such as race and ethnicity, insurance, socioeconomic status, and geographic location. We found little direct evidence on mitigation strategies. Studies support equivalent response to equivalent treatment between groups, suggesting that adherence to National Comprehensive Cancer Network guidelines can at least partially mitigate some of the differences.

Executive Summary of the Ovarian Cancer Evidence Review Conference.

Burke W, Barkley J, Barrows E, Brooks R, Gecsi K, , Jeudy M, Mei S, O'Hara JS, Chelmow D.

Obstet Gynecol. 2023 Jul 1;142(1):179-195. doi: 10.1097/AOG.0000000000005211. Epub 2023 Jun 7. PMID: 37348094; PMCID: PMC10278568.

The Centers for Disease Control and Prevention awarded funding to the American College of Obstetricians and Gynecologists to develop educational materials for clinicians on gynecologic cancers. The American College of Obstetricians and Gynecologists convened a panel of experts in evidence review from the Society for Academic Specialists in General Obstetrics and Gynecology and content experts from the Society of Gynecologic Oncology to review relevant literature, best practices, and existing practice guidelines as a first step toward developing evidence-based educational materials for women's health care clinicians about ovarian cancer. Panel members conducted structured literature reviews, which were then reviewed by other panel members and discussed at a virtual meeting of stakeholder professional and patient advocacy organizations in February 2022. This article is the executive summary of the relevant literature and existing recommendations to guide clinicians in the prevention, early diagnosis, and special considerations of ovarian cancer. Substantive knowledge gaps are noted and summarized to provide guidance for future research.

Man vs. nature: Who will choose the fittest sperm?

Singh P, Mancuso AC, Van Voorhis BJ.

Fertil Steril. 2023 Jun 10:S0015-0282(23)00598-8. doi: 10.1016/j.fertnstert.2023.06.010. Epub ahead of print. PMID: 37302781.

Postmortem diagnosis of very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in a neonate with sudden cardiac death.

Singh P, Amaro D, Obi O, Kiran F, Hediger E, Toler TL, Dickson PI, Grange DK.

JIMD Rep. 2023 Apr 30;64(4):261-264. doi: 10.1002/jmd2.12365. PMID: 37404675; PMCID: PMC10315371.

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive long chain fatty acid β-oxidation disorder with a variable clinical spectrum, ranging from an acute neonatal presentation with cardiac and hepatic failure to childhood or adult onset of symptoms with hepatomegaly or rhabdomyolysis provoked by illness or exertion. Neonatal cardiac arrest or sudden unexpected death can be the presenting phenotype in some patients, emphasizing the importance of early clinical suspicion and intervention. We report a patient who had a cardiac arrest and died at one day of age. Following her death, the newborn screen reported biochemical evidence of VLCAD deficiency, which was confirmed with pathologic findings at autopsy and by molecular genetic testing.

Defining infertility: a qualitative interview study of patients and physicians.

Summers KM, Scherer A, Chasco EE, Ryan GL.

J Reprod Infant Psychol. 2023 Jun 8:1-15. doi: 10.1080/02646838.2023.2221277. Epub ahead of print. PMID: 37288784.

• To investigate if infertility patients and physicians apply a traditional biomedical model of disease in their conceptualisation of infertility, examine any contradictions and conflicts in conceptualisations, and examine areas of concordance and discordance between physicians and patients.

Methods: Semi-structured interviews were conducted with 20 infertility patients and 18 infertility physicians between September 2010 and April 2012. Interviews were analysed qualitatively to determine physician and patient conceptualisations of infertility, reactions to the definition of infertility as a disease, and potential benefits and concerns related to application of a disease label to the condition.

• Most physicians (n = 14/18) and a minority of patients (n = 6/20) were supportive of defining infertility as a disease. Many of the patients who agreed with classifying infertility as a disease expressed that they had not personally defined it as such previously. Physicians (n = 14) and patients (n = 13) described potential benefits of a disease label, including increases in research funding, insurance coverage, and social acceptability. Some patients (n = 10) described potential stigma as a negative consequence. When describing appraisals of infertility, both physicians (n = 7) and patients (n = 8) invoked religious/spiritual concepts. The potential for religious/spiritual appraisal to contribute to stigmatising or de-stigmatising infertility was discussed.

Conclusion: Our findings contradict the assumption that infertility physicians and patients are fully supportive of defining infertility as a disease. While potential benefits of the disease label were recognised by both groups, caution against potential for stigmatisation and unsolicited invocation of religion/spirituality suggest a more holistic model may be appropriate.    

Pregnancy Complicated by Non-Compaction Cardiomyopathy in the Mother and Fetus: A Case Report of Both Maternal Management and Prenatal Diagnosis.

O'Connor E, Saylor L, O'Nan S, Schnettler W.

Obstet Gynecol Cases Rev. 2023;10(2):238. doi.org/10.23937/2377-9004/1410238

Left ventricular noncompaction cardiomyopathy (LVNC) is a rare form of familial cardiomyopathy attributed to failure of ventricular compaction during embryogenesis. Scant data exists regarding the management approach to pregnant patients with this condition. Additionally, few cases are reported in which both the mother and fetus are simultaneously affected by this condition during the antepartum period. This case is unique in that the patient carried a known genetic and echocardiographic diagnosis of LVNC, prior children born with confirmed LVNC by genetic and echocardiographic findings, and the current pregnancy affected by a perinatal diagnosis of LVNC via sonographicfindings.

Association of ABO Blood Group, Age, Body Mass Index and Symptomatic COVID-19 Infection with Signal Levels of Antibodies to COVID-19.

Maxwell T, Wendt L, Castaneda C, Marsden K, Merrill AE, Swartz S, Steffen H, Johnson AL, Ten Eyck P, Rysavy MB, Jackson JB.

Gynecol Reprod Health. 2022; 6(1): 1-5. doi:10.33425/2639-9342.1174.

Objective: To determine if ABO blood group, age, body mass index (BMI), or symptomatic COVID-19 infection are associated with COVID-19 antibody response in unvaccinated COVID-19 antibody positive pregnant women at time of delivery.

• At the time of delivery, 2,499 consecutive pregnant women were tested for ABO blood group and antibodies to both the spike protein and nucleocapsid protein of the COVID-19 virus. The DiaSorin assay was used for antibody to spike protein analysis and the Roche assay for antibody to nucleocapsid protein. Gamma regression models with a log link were used to compare antibody signals, with blood group, age, and BMI as the predictors.
• 260 (10.4%) of 2,499 women who had not been vaccinated for COVID-19, were positive for both spike and nucleocapsid protein antibodies to COVID-19. The mean signal for COVID-19 nucleocapsid antibody was significantly lower for blood group AB (p=0.028) compared with blood group O. A relationship between blood group and presence of symptomatic COVID-19 was detected (p = 0.028), with asymptomatic individuals having blood group B at a higher rate than the symptomatic individuals do. No other significant pairwise differences between blood groups were detected. There was no significant difference in signal level of antibodies to COVID-19 spike protein between any of the blood groups. Mean signals for antibodies to spike and nucleocapsid proteins were significantly higher in older women (p=0.001 for spike protein antibody and p=0.002 for nucleocapsid antibody). Significantly higher signal levels of antibody to spike and nucleocapsid proteins were found in women with class 2/3 obesity (p=0.022 and p=0.003, respectively).

Conclusions: Pregnant women of AB blood group had lower antibody signal to nucleocapsid protein compared to the O blood group, and women of older age and greater BMI had higher antibody signal to COVID-19 spike and nucleocapsid proteins. There was a significant association between women with blood group B and asymptomatic infections.

Evaluation of Maternal Near Miss Events At Tibebe Ghion Specialized Hospital In Bahir Dar, Ethiopia.

De Haan JL, Rysavy MB, Misgan E, Manorot A, Wole B, Addis N, Wu C, Worku A.

Ethiopian Journal of Reproductive Health. 2023 Jan;15 (1):1-9.

• Maternal mortality and morbidity are significant challenges in Ethiopia. The maternal mortality ratio remains high with recent estimates of 412 maternal deaths per 100,000 live births as of 2016 in the nation. Maternal Near Miss events (MNM) are severe morbidities in which a woman narrowly escapes death. In order to develop ways to improve maternal mortality and morbidity, this study sought to estimate: 1) the prevalence of maternal mortality and MNM; and 2) the associated risk factors for these events, at a tertiary referral hospital in Bahir Dar, Ethiopia.

METHODS: This was a cross-sectional study of 658 consecutive delivering pregnant patients and their neonates at Tibebe Ghion Specialized Hospital (TGSH) in Bahir Dar, Ethiopia, from February 26-June 10, 2020. Demographic and outcome data were collected as part of a quality improvement initiative using the REDCap mobile app. Univariate and multivariate logistic regression were used to investigate the relationship between the key demographic and clinical variables with MNM. The creation of the database was approved by the TGSH clinical care committee in February 2020 and the University of Iowa Institutional Review Board approved the de-identified data analyses.

RESULTS: There were no maternal deaths and 70 MNM during the study period. The median patient age was 26 years (IQR 23-30); 49% of women were nulliparous, and 56% delivered vaginally. Patients had higher odds of experiencing MNM if living in a rural area (OR=3.71, p<0.01) or with a hypertensive disorder of pregnancy (OR=2.27, p=0.03). The postpartum hemorrhage rate was 1.7%.

• The MNM and mortality rates at TGSH were less than elsewhere in the region. Living in a rural area and having hypertensive disorders of pregnancy were major predictors of MNM events. Future quality improvement projects should be developed to increase antenatal care attendance, help rural women receive antenatal care, and improve treatment for hypertensive disorders in pregnancy.

Radiation Exposure during sacral neuromodulation lead placement: multi-institutional descriptive study

Burns R, Ferari C, , Kovacevic N, Orzel J, Padmanabhan P, Peterson C, Powell C, Nakatsuka H, Vollstedt A, Walter B.

The Journal of Urology. 2023 Apr;209(Supplement 4):e514. doi: 10.1097/JU.0000000000003275.03.

The effect of older age on treatment outcomes in women with advanced ovarian cancer receiving chemotherapy: An NRG-Oncology/Gynecologic Oncology Group (GOG-0182-ICON5) ancillary study.

Sia TY, Tew WP, Purdy C, Chi DS, Menzin AW, Lovecchio JL, Bookman MA, Cohn DE, Teoh DG, Friedlander M,, Mutch DG, Gershenson DM, Tewari KS, Wenham RM, Wahner Hendrickson AE, Lee RB, Gray HJ, Secord AA, Van Le L, Lichtman SM

Gynecol Oncol. 2023 May 4;173:130-137. doi: 10.1016/j.ygyno.2023.03.018. Epub ahead of print. PMID: 37148580.

• To assess the effect of age on overall survival (OS) in women with ovarian cancer receiving chemotherapy. Secondary objectives were to describe the effect of age on treatment compliance, toxicities, progression free survival (PFS), time from surgery to chemotherapy, and rates of optimal cytoreduction.
• Women enrolled in GOG 0182-ICON5 with stage III or IV epithelial ovarian cancer (EOC) who underwent surgery and chemotherapy between 2001 and 2004 were included. Patients were divided into ages <70 and ≥ 70 years. Baseline characteristics, treatment compliance, toxicities, and clinical outcomes were compared.
• We included a total of 3686 patients, with 620 patients (16.8%) ≥ 70 years. OS was 37.2 months in older compared to 45.0 months in younger patients (HR 1.21, 95% CI, 1.09-1.34, p < 0.001). Older patients had an increased risk of cancer-specific-death (HR 1.16, 95% CI, 1.04-1.29) as well as non-cancer related deaths (HR 2.78, 95% CI, 2.00-3.87). Median PFS was 15.1 months in older compared to 16.0 months in younger patients (HR 1.10, 95% CI, 1.00-1.20, p = 0.056). In the carboplatin/paclitaxel arm, older patients were just as likely to complete therapy and more likely to develop grade ≥ 2 peripheral neuropathy (35.7 vs 19.7%, p < 0.001). Risk of other toxicities remained equal between groups.

Conclusions: In women with advanced EOC receiving chemotherapy, age ≥ 70 was associated with shorter OS and cancer specific survival. Older patients receiving carboplatin and paclitaxel reported higher rates of grade ≥ 2 neuropathy but were not more likely to suffer from other chemotherapy related toxicities. Clintrials.gov: NCT00011986.

Mediators of the association between childhood trauma and pain sensitivity in adulthood: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network analysis.

Pierce J, Harte SE, Afari N, Griffith JW, Kim J,, Naliboff BD, Rodriguez LV, Taple BJ, Williams D, Harris RE, Schrepf A; MAPP Research Network.

Pain. 2023 May 5. doi: 10.1097/j.pain.0000000000002895. Epub ahead of print. PMID: 37144687.

Urologic chronic pelvic pain syndrome (UCPPS) is a complex, debilitating condition in which patients often report nonpelvic pain in addition to localized pelvic pain. Understanding differential predictors of pelvic pain only vs widespread pain may provide novel pathways for intervention. This study leveraged baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network's Symptom Pattern Study to investigate the impact of childhood sexual and nonsexual violent trauma on pelvic and nonpelvic pain sensitivity among adult patients with UCPPS, as well as potential mediators of this association. Study participants who met inclusion criteria for UCPPS completed questionnaires assessing childhood and recent trauma, affective distress, cognitive dysfunction, and generalized sensory sensitivity. Experimental pain sensitivity was also evaluated using standardized pressure pain applied to the pubic region and the arm. Bivariate analyses showed that childhood violent trauma was associated with more nonviolent childhood trauma, more recent trauma, poorer adult functioning, and greater pain sensitivity at the pubic region, but not pain sensitivity at the arm. Path analysis suggested that childhood violent trauma was indirectly associated with pain sensitivity at both sites and that this indirect association was primarily mediated by generalized sensory sensitivity. More experiences of recent trauma also contributed to these indirect effects. The findings suggest that, among participants with UCPPS, childhood violent trauma may be associated with heightened pain sensitivity to the extent that trauma history is associated with a subsequent increase in generalized sensory sensitivity.

FGFR2 mutations promote endometrial cancer progression through dual engagement of EGFR and Notch signalling pathways.

Dixit G, Skurski J, Dickerson EB, Nothnick WB, Issuree PD, Leslie KK, Maretzky T

Clin Transl Med. 2023 May;13(5):e1223. doi: 10.1002/ctm2.1223. PMID: 37165578; PMCID: PMC10172618.

Background: Mutations in the receptor tyrosine kinase gene fibroblast growth factor receptor 2 (FGFR2) occur at a high frequency in endometrial cancer (EC) and have been linked to advanced and recurrent disease. However, little is known about how these mutations drive carcinogenesis.

Methods: Differential transcriptomic analysis and two-step quantitative real-time PCR (qRT-PCR) assays were applied to identify genes differentially expressed in two cohorts of EC patients carrying mutations in the FGFR2 gene as well as in EC cells harbouring mutations in the FGFR2. Candidate genes and target signalling pathways were investigated by qRT-PCR assays, immunohistochemistry and bioinformatics analysis. The functional roles of differently regulated genes were analysed using in vitro and in vivo experiments, including 3D-orthotypic co-culture systems, cell proliferation and migration protocols, as well as colony and focus formation assays together with murine xenograft tumour models. The molecular mechanisms were examined using CRISPR/Cas9-based loss-of-function and pharmacological approaches as well as luciferase reporter techniques, cell-based ectodomain shedding assays and bioinformatics analysis.

Results: We show that common FGFR2 mutations significantly enhance the sensitivity to FGF7-mediated activation of a disintegrin and metalloprotease (ADAM)17 and subsequent transactivation of the epidermal growth factor receptor (EGFR). We further show that FGFR2 mutants trigger the activation of ADAM10-mediated Notch signalling in an ADAM17-dependent manner, highlighting for the first time an intimate cooperation between EGFR and Notch pathways in EC. Differential transcriptomic analysis in EC cells in a cohort of patients carrying mutations in the FGFR2 gene identified a strong association between FGFR2 mutations and increased expression of members of the Notch pathway and ErbB receptor family. Notably, FGFR2 mutants are not constitutively active but require FGF7 stimulation to reprogram Notch and EGFR pathway components, resulting in ADAM17-dependent oncogenic growth.

Conclusions: These findings highlight a pivotal role of ADAM17 in the pathogenesis of EC and provide a compelling rationale for targeting ADAM17 protease activity in FGFR2-driven cancers.

Carboplatin dosing in the treatment of ovarian cancer: An NRG oncology group study.

Praiss AM, Miller A, Smith J, Lichtman SM, Bookman M, Aghajanian C, Sabbatini P, Backes F, Cohn DE, Argenta P, Friedlander M, Mutch DG, Gershenson DM, Tewari KS, Wenham RM, Wahner Hendrickson AE, Lee RB, Gray H, Secord AA, Van Le L, O'Cearbhaill RE

Gynecol Oncol. 2023 May 23;174:213-223. doi: 10.1016/j.ygyno.2023.05.013. Epub ahead of print. PMID: 37229879.

Objective: To determine the effects of using National Comprehensive Cancer Network (NCCN) guidelines to estimate renal function on carboplatin dosing and explore adverse effects associated with a more accurate estimation of lower creatinine clearance (CrCl).

Methods: Retrospective data were obtained for 3830 of 4312 patients treated on GOG182 (NCT00011986)-a phase III trial of platinum-based chemotherapy for advanced-stage ovarian cancer. Carboplatin dose per patient on GOG182 was determined using the Jelliffe formula. We recalculated CrCl to determine dosing using Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (with/without NCCN recommended modifications) formulas. Associations between baseline CrCl and toxicity were described using the area under the receiver operating characteristic curve (AUC). Sensitivity and positive predictive values described the model's ability to discriminate between subjects with/without the adverse event.

• AUC statistics (range, 0.52-0.64) showed log(CrClJelliffe) was not a good predictor of grade ≥3 adverse events (anemia, thrombocytopenia, febrile neutropenia, auditory, renal, metabolic, neurologic). Of 3830 patients, 628 (16%) had CrCl <60 mL/min. Positive predictive values for adverse events ranged from 1.8%-15%. Using the Cockcroft-Gault, Cockcroft-Gault with NCCN modifications, and MDRD (instead of Jelliffe) formulas to estimate renal function resulted in a >10% decrease in carboplatin dosing in 16%, 32%, and 5.2% of patients, respectively, and a >10% increase in carboplatin dosing in 41%, 9.6% and 12% of patients, respectively.
• The formula used to estimate CrCl affects carboplatin dosing. Estimated CrCl <60 mL/min (by Jelliffe) did not accurately predict adverse events. Efforts continue to better predict renal function. Endorsing National Cancer Institute initiatives to broaden study eligibility, our data do not support a minimum threshold CrCl <60 mL/min as an exclusion criterion from clinical trials.

Maternal and Fetal Mitochondrial Gene Dysregulation in Hypertensive Disorders of Pregnancy.

Ricci CA, Reid DM, Sun J, Phillips NR, Goulopoulou S.

Physiol Genomics. 2023 May 15. doi: 10.1152/physiolgenomics.00005.2023. Epub ahead of print.

Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive. Here, we investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH; further, we measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) were conducted in publicly available high throughput sequencing transcriptomic datasets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia. Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, while 9 were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, while fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load. Our findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy.

Systematic Review of Interventions to Reduce Suicide Risk in Transgender and Gender Diverse Youth.

Christensen JA, Oh J, , Imhof RL, Croarkin PE, Bostwick JM, McKean AJS.

Child Psychiatry Hum Dev. 2023 May 10. doi: 10.1007/s10578-023-01541-w. Epub ahead of print. PMID: 37162659.

Transgender youth experience high rates of suicidal ideation and suicide attempts. This systematic review sought to examine interventions for suicide prevention in transgender children and adolescents. Literature related to suicide in the transgender population was systematically collected in accordance with PRISMA criteria. Searches identified studies with at least one suicide prevention method for participants ages 24 years or younger with gender identity and sex clearly defined. Primary outcomes include suicide-related thoughts and behaviors. A total of 1558 citations were identified with 17 articles meeting inclusion criteria. Interventions with potential effectiveness included a gender-affirming crisis hotline, medical care via interdisciplinary gender clinics, online media-based outreach, safety and connectedness in schools, and family system-based interventions. In the included studies, the overall quality of evidence was low and the risk of bias high. Further high-quality studies are needed.

International Society for the Study of Vulvovaginal Disease recommendations for the diagnosis and treatment of vaginitis.

Vieira-Baptista P, , Sobel J (eds). Lisbon: Admedic, 2023. doi: 10.59153/adm.rdtv.001. (booklet)

Early and recent exposure to adversity, TLR-4 stimulated inflammation, and diurnal cortisol in women with interstitial cystitis/bladder pain syndrome: A MAPP research network study.

Lutgendorf SK, Zia S, Luo Y, O'Donnell M, van Bokhoven A, Bradley CS, Gallup R, Pierce J, Taple BJ, Naliboff BD, Quentin Clemens J, Kreder KJ, Schrepf A.

Brain Behav Immun. 2023 Mar 29;111:116-123. doi: 10.1016/j.bbi.2023.03.024. Epub ahead of print. PMID: 37001828. 

Both early (ELA) and recent life adversity (RLA) have been linked with chronic pain conditions and persistent alterations of neuroendocrine and inflammatory responses. Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic urologic disorder characterized by bladder and/or pelvic pain, and excessive urinary frequency and/or urgency. IC/BPS has been associated with high levels of ELA as well as a distinct inflammatory signature. However, associations between ELA and RLA with inflammatory mechanisms in IC/BPS that might underlie the link between adversity and symptoms have not been examined. Here we investigated ELA and RLA in women with IC/BPS as potential risk factors for inflammatory processes and hypothalamic-pituitaryadrenal (HPA) abnormalities using data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Women with IC/BPS and healthy controls (n = 154 and 32, respectively) completed surveys, collected salivary cortisol at awakening and bedtime for 3 days, and gave a blood sample which was analyzed for 7 LPS-stimulated cytokines and chemokines (IL-6, TNFα, IL-1β, MIP1α, MCP1, IL-8, and IL-10). Two cytokine/chemokine composites were identified using principal components analysis. Patients with greater exposure to RLA or cumulative ELA and RLA of at least moderate severity showed elevated levels of a composite of all cytokines, adjusting for age, body mass index, and study site. Furthermore, there was a trending relationship between ELA and the pro-inflammatory composite score. Nocturnal cortisol and cortisol slope were not associated with ELA, RLA, or inflammation. The present findings support the importance of adverse events in IC/BPS via a biological mechanism and suggest that ELA and RLA should be assessed as risk factors for inflammation as part of a clinical workup for IC/BPS.

Closure of Labor & Delivery units in rural counties is associated with reduced adequacy of prenatal care, even when prenatal care remains available.

Radke SM, Smeins L, Ryckman KK, Gruca TS.

J Rural Health. 2023 Mar 30. doi: 10.1111/jrh.12758. Epub ahead of print. PMID: 36999217. 

Purpose: Closure of rural Labor & Delivery (L&D) units can impact timely access to hospital-based obstetrical care. Iowa has lost over a quarter of its L&D units in the previous decade. Assessing the effect of these closures on prenatal care in those rural communities is important to understanding the full effect of unit closures on maternal health care.

Methods: Using birth certificate data in Iowa from 2017 to 2019, the initiation of prenatal care and adequacy of prenatal visits were assessed for 47 rural counties in Iowa. Of these, 7 experienced a closure of the only L&D unit between 1/1/2018 and 1/1/2019. The impact of these closures is modeled for all birthing parents and compared for Medicaid versus non-Medicaid recipients.

Findings: All 7 counties that experienced the loss of their only L&D unit continued to have prenatal care services available. Experiencing a closure of an L&D unit was associated with a lower likelihood of overall adequate prenatal care but not significantly associated with a lower rate of first-trimester prenatal care utilization. Among Medicaid recipients of the communities where an L&D unit closed, there was an association of closure with both a lower likelihood of adequate prenatal care and entry to prenatal care after the first trimester.

Conclusions: Utilization of prenatal care is lower in rural communities following L&D unit closure, especially among Medicaid recipients. This suggests that the overall maternal health systems were disrupted by the closure of the L&D unit, impacting the utilization of services that remained available to the community.

Healthcare decision makers' perspectives on the creation of new genetic counselor positions in North America: Exploring the case for psychiatric genetic counseling.

Chanouha N, Cragun DL, Pan VY, Austin JC, Hoell C.

J Genet Couns. 2023 Apr;32(2):514-525. doi: 10.1002/jgc4.1663. Epub 2022 Dec 7. PMID: 36479728.

Mental illnesses are common and highly heritable. Patients and their families want and benefit from receiving psychiatric genetic counseling (pGC). Though the pGC workforce is among the smallest of genetic counseling (GC) specialties, genetic counselors (GCs) want to practice in this area. A major barrier to the expansion of the pGC workforce is limited availability of advertised positions, but it remains unclear why this is the case. We used a qualitative approach to explore drivers for and barriers to the creation of GC positions (including pGC) at large centralized genetic centers in the United States and Canada that offer multiple specialty GC services. Individuals with responsibilities for making decisions about creating new clinical GC positions were interviewed using a semi-structured guide, and an interpretive description approach was used for inductive data analysis. From interviews with 12 participants, we developed a theoretical model describing how the process of creating new GC positions required institutional prioritization of funding, which was primarily allocated according to physician referral patterns, which in turn were largely driven by availability of genetic testing and clinical practice guidelines. Generating revenue for the institution, improving physician efficiency, and reinforcing institutional mission were all regarded as valued outcomes that bolstered prioritization of funding for new GC positions. Evidence of patient benefit arising from new GC positions (e.g., pGC) seemed to play a lesser role. These findings highlight the tension between how institutions value GC (generating revenue, reacting to genetic testing), and how the GC profession sees its value (providing patient benefit, focus on counseling).

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer.

Eskander RN, Sill MW, Beffa L, Moore RG, Hope JM, Musa FB, Mannel R, Shahin MS, Cantuaria GH, Girda E, Mathews C, Kavecansky J, Leath Iii CA, Gien LT, Hinchcliff EM, Lele SB, Landrum LM, Backes F, O'Cearbhaill RE, Al Baghdadi T, Hill EK, Thaker PH, John VS, Welch S, Fader AN, Powell MA, Aghajanian C.

N Engl J Med. 2023 Mar 27. doi: 10.1056/NEJMoa2302312. Epub ahead of print. PMID: 36972022.

Background: Standard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear.

Methods: In this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort.

Results: In the 12-month analysis, Kaplan-Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy.

Conclusions: In patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.).

Creating affiliations, learning, and mindfulness for in vitro fertilization patients (CALM IVF): a clinical trial

Whynott RM, Summers KM, Mejia RB, Segre LS, Ryan G, Pawlak SA.

F S Rep. 2023 Jan 7;4(1):61-71. doi: 10.1016/j.xfre.2023.01.002. PMID: 36959953; PMCID: PMC10028477.

Objective: Determine if group psychoeducational support can improve in vitro fertilization (IVF) patients' quality of life (QoL).

Design: Randomized controlled trial (NCT04048772).

Setting: University-affiliated IVF clinic.

Patients: Women (n = 76) and male partners undergoing initial autologous IVF cycle from August 2019, to December 2020.

Interventions: Couples were assigned to groups based on projected oocyte retrieval date. Groups were randomly assigned to the control or intervention arm. Clinic closures because of the COVID-19 pandemic delayed treatment for a portion of participants. Groups were conducted in person before and virtually during the pandemic.

Main outcome measures: The primary outcome was a change in fertility quality of life (FertiQoL) from baseline to 3 days after retrieval. Secondary outcomes were changes in depression (Patient Health Questionnaire 9), anxiety (Generalized Anxiety Disorder 7), resilience (Connor-Davidson Resilience scale), IVF knowledge scores, and the likelihood of return to treatment.

Results: Knowledge scores among women in Creating Affiliations, Learning, and Mindfulness (CALM) for IVF groups significantly increased compared with control (mean difference 13.19 [3.53 - 22.84]) before the pandemic. During the pandemic, women in CALM IVF had significant improvement in the social FertiQoL score compared with controls (10.42 [1.79 - 19.04]). Compared with controls, male CALM IVF participants had significantly greater improvement in total FertiQoL (mean difference 6.68 [0.39 - 12.98]), treatment FertiQoL (8.26 [0.69 - 15.82]), and resilience (Connor-Davidson 1.13 [0.54 - 1.72]). Immediate return to care did not significantly differ between arms.

Conclusions: For women undergoing IVF, group psychoeducational programs can improve IVF knowledge and social QoL during a pandemic. Participation in a group psychoeducational program can improve QoL and resilience in IVF dyad male partners.

Clinical trial registration number: Trial registration NCT04048772.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) consensus statement on the management of vaginal intraepithelial neoplasia.

Kesic V, Carcopino X, Preti M, Vieira-Baptista P, Bevilacqua F, Bornstein J, Chargari C, Cruickshank M, Erzeneoglu E, Gallio N, Gultekin M, Heller D, Joura E, Kyrgiou M, Madić T, Planchamp F, Regauer S, Reich O, Esat Temiz B, Woelber L, Zodzika J, Stockdale C.

Int J Gynecol Cancer. 2023 Mar 23:ijgc-2022-004213. doi: 10.1136/ijgc-2022-004213. Epub ahead of print. PMID: 36958755.

The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD), and the European Federation for Colposcopy (EFC) developed consensus statements on pre-invasive vulvar lesions in order to improve the quality of care for patients with vaginal intraepithelial neoplasia (VaIN). The management of VaIN varies according to the grade of the lesion: VaIN 1 (low grade vaginal squamous intraepithelial lesions (SIL)) can be subjected to follow-up, while VaIN 2-3 (high-grade vaginal SIL) should be treated. Treatment needs individualization according to the patient's characteristics, disease extension and previous therapeutic procedures. Surgical excision is the mainstay of treatment and should be performed if invasion cannot be excluded. Total vaginectomy is used only in highly selected cases of extensive and persistent disease. Carbon dioxide (CO2) laser may be used as both an ablation method and an excisional one. Reported cure rates after laser excision and laser ablation are similar. Topical agents are useful for persistent, multifocal lesions or for patients who cannot undergo surgical treatment. Imiquimod was associated with the lowest recurrence rate, highest human papillomavirus (HPV) clearance, and can be considered the best topical approach. Trichloroacetic acid and 5-fluorouracil are historical options and should be discouraged. For VaIN after hysterectomy for cervical intraepithelial neoplasia (CIN) 3, laser vaporization and topical agents are not the best options, since they cannot reach epithelium buried in the vaginal scar. In these cases surgical options are preferable. Brachytherapy has a high overall success rate but due to late side effects should be reserved for poor surgical candidates, having multifocal disease, and with failed prior treatments. VaIN tends to recur and ensuring patient adherence to close follow-up visits is of the utmost importance. The first evaluation should be performed at 6 months with cytology and an HPV test during 2 years and annually thereafter. The implementation of vaccination against HPV infection is expected to contribute to the prevention of VaIN and thus cancer of the vagina. The effects of treatment can have an impact on quality of life and result in psychological and psychosexual issues which should be addressed. Patients with VaIN need clear and up-to-date information on a range of treatment options including risks and benefits, as well as the need for follow-up and the risk of recurrence.

The Low Prevalence and High Cost of Routine Antiphospholipid Antibody Testing in Patients with Recurrent Pregnancy Loss.

Cafun RG, Merrill A, Bhagavathi SM, Summers KM, Bettendorf BA, Van Voorhis BJ.

Fertil Steril. 2023 Mar 25:S0015-0282(23)00235-2. doi: 10.1016/j.fertnstert.2023.03.026. Epub ahead of print. PMID: 36972747.

A pilot evaluation of social needs among gynecologic oncology patients in inpatient versus outpatient settings.

Greenwood A, Nora A, Hartman C, Summers K, Syrop C, Haugsdal M.

Proc Obstet Gynecol. 2023;12(1): Article 4 [14 p.]. DOI: https://doi.org/10.17077/2154-4751.31886

The WHO defines social determinants of health (SDoH) as the conditions in which we are born, grow, work, and live as well as other large systems that positively or negatively affect our health. Many healthcare systems currently lack the resources and strategies required to accurately assess and address SDoH. Action must be taken because studies have found that chronic diseases, including cancer, are affected by SDoH. The aim of this study is to identify the incidence of social needs in an inpatient gynecologic oncology population and its relation to patient demographics and clinical diagnostic data to guide and inform future intervention. Patients agreeing to participate in the study completed a needs assessment survey during their inpatient stay at the hospital between November 2020 to March 2021. The survey contained seven questions, six of which were questions screening for social needs including food and housing security, transportation means, financial stability, health literacy, and social support. Responses were considered positive if any degree of need was reported. Demographic and cancer diagnosis data were then collected and included zip code, race, cancer stage and age at diagnosis, treatment history, and number of hospital admissions and length of stay over the past 12 months. The most substantial reported needs across all gynecologic malignancies were social support (65%), health literacy (37%), and financial need (22%). Less need was reported in the categories of food (11%), housing (7%), and transportation (4%). SDoH have been studied in the outpatient gynecologic population and the needs seen in this study are similar to the needs of that population. However, there are likely different challenges and frequencies of unmet need in the different types of gynecologic cancers that may affect the stage at which their cancer is diagnosed as well as the number of hospital admissions related to their cancer care.

Prevalence of maternal complications and neonatal outcomes at a Midwest academic health center.

Swartz SR, Kenne KA, Steffen HA, Bujimalla PV, Wendt LH, Jackson JB, Rysavy MB.

Proc Obstet Gynecol. 2023;12(1): Article 5 [12 p.]. DOI: https://doi.org/10.17077/2154-4751.31887

Introduction: The University of Iowa Hospitals and Clinics (UIHC) serves as the main referral center for Iowa and has seen increased delivery volumes following many hospital closures across the state. Maternal characteristics are also shifting as pre-pregnancy obesity of reproductive-age women is increasing nationally and in Iowa; average maternal age at first delivery has also increased over time. The aim of the current study was to characterize the outcomes of the delivering population at UIHC over a one-year period to better understand the population we serve, as well as compare our population to state and national delivering populations.

Methods: This study is a secondary analysis of a pre-existing prospectively gathered database related to COVID-19 in pregnancy. The current study included all pregnant patients who delivered or underwent procedures for a spontaneous or induced second-trimester abortion on the labor and delivery unit at UIHC between May 1, 2020, and April 30, 2021. Demographic and clinical data including maternal characteristics, delivery information, maternal complications, and neonatal outcomes were obtained from the electronic medical record and double entered in a Research Electronic Data Capture (REDCap) database. Continuous and categorical variables were summarized using medians and ranges.

Results: The median maternal age among the 2497 delivering patients was 30 (IQR 26, 33). The median pre-delivery body mass index (BMI) was 32 (IQR 28, 37), which included 439 patients (17.6%) with BMI >40 at time of delivery. 1769 (70.8%) patients listed White as their self-defined race and 2275 (91.0%) listed English as their preferred language. 23% had hypertensive disease of pregnancy. The patients delivered a total of 2603 neonates, with 907 (34.8%) born by cesarean section. 18.7% of deliveries were preterm and 16.6% of neonates had low birth weight.

Discussion: The delivering population at UIHC has a high rate of obesity and preeclampsia, both of which place patients at higher risk for other obstetric complications. The cesarean section rate was significantly higher than the national rate of 31.8% (p=0.0017). Understanding common complications in our changing population will better equip providers to care for these patients; providing these data also creates a resource for other researchers.

Clinically Important Differences for Pain and Urinary Symptoms in Urologic Chronic Pelvic Pain Syndrome: A MAPP Network Study.

Stephens-Shields AJ, Lai HH, Landis JR, Kreder K, Rodriguez LV, Naliboff BD, Afari N, Sutcliffe S, Moldwin R, Griffith JW, Clemens JQ,  Bradley CS, Quallich S, Gupta P, Harte SE, Farrar JT.

J Urol. 2023 Feb 27:101097JU0000000000003394. doi: 10.1097/JU.0000000000003394. Epub ahead of print. PMID: 36848118. 

Objectives: Symptom heterogeneity in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome, collectively termed urologic chronic pelvic pain syndrome (UCPPS), has resulted in difficulty in defining appropriate clinical trial endpoints. We determine clinically important differences (CIDs) for 2 primary symptom measures, Pelvic Pain Severity (PPS) and Urinary Symptom Severity (USS), and evaluate subgroup differences.

Methods: The Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study enrolled individuals with UCPPS. We defined CIDs by associating changes in PPS and USS over 3 to 6 months with marked improvement on a global response assessment using regression and receiver operating characteristic curves. We evaluated CIDs for absolute and percent change and examined differences in CIDs by sex-diagnosis, presence of Hunner lesions, pain type, pain widespreadness, and baseline symptom severity.

Results: An absolute change of -4 was clinically important in PPS among all patients, but CID estimates differed by pain type, presence of Hunner lesions, and baseline severity. PPS CID estimates for percent change were more consistent across subgroups and ranged from 30 to 57 percent. The absolute change USS CID was -3 for female participants and -2 for male participants with CP/CPPS only. Patients with greater baseline severity required larger decreases in symptoms to feel improved. Estimated CIDs had lower accuracy among participants with low baseline symptoms.

Conclusion: A reduction of 30-50% in PSS is a clinically meaningful endpoint for future therapeutic trials in UCPPS. USS CIDs are more appropriately defined separately for male and female participants.

Urinary Biomarkers and Overactive Bladder Symptoms Before and After Prolapse Surgery.

Maetzold EC, Santillan DA, Kenne KA, Bradley CS, Ten Eyck P, Wendt L, Funk M, Kowalski JT.

Urogynecology (Hagerstown). 2023 Feb 1;29(2):266-272. doi: 10.1097/SPV.0000000000001316. PMID: 36735443. 

Importance: Women with pelvic organ prolapse (POP) have increased prevalence of overactive bladder (OAB) and the evaluation of urinary biomarkers associated with OAB in the setting of POP is limited.

Objective: The objective is to determine whether associations exist between urinary biomarkers measured before POP surgery with postoperative OAB symptoms.

Study design: In this prospective cohort study, women with anterior and/or apical POP beyond the hymen undergoing POP surgery were assessed using the OAB Questionnaire Short Form (OAB-q SF) and the Urogenital Distress Inventory 6 (UDI-6) preoperatively and 3 months postoperatively. A first morning voided urine specimen was collected preoperatively and 3 months postoperatively. Urinary biomarkers for inflammation, neuroinflammation, and tissue remodeling were measured. Univariate generalized linear models measured the relationship between biomarkers and symptoms. Between- and within-cohort assessments were made using 2-sample paired and unpaired t tests, respectively.

Results: Seventy-seven participants with OAB (n = 67, 87.0%) and without OAB (n = 10, 13.0%) were enrolled. Seventy-four participants (96%) completed 3-month follow up. The OAB-q SF and UDI-6 scores significantly improved between preoperative and postoperative measures. Preoperative urinary biomarkers did not demonstrate significant correlations with postoperative OAB-q SF or UDI-6 scores. No significant differences were measured in preoperative biomarkers between patients with and without OAB or when comparing preoperative and postoperative biomarkers in patients with OAB.

Conclusions: Urinary biomarkers for tissue remodeling, inflammation, and neuroinflammation were not significantly correlated with OAB symptoms in a population of patients with OAB and POP.

Pelvic Pain and Pelvic Floor Muscle Dysfunction in Women Seeking Treatment for Prolapse.

Gore A, Kenne KA, Kowalski JT, Bradley CS. 

Urogynecology (Hagerstown). 2023 Feb 1;29(2):225-233.  doi: 10.1097/SPV.0000000000001323. PMID: 36735438.

Importance: Pelvic floor muscle dysfunction (PFMD) can cause pelvic pain, but its associations with pelvic organ prolapse (POP) and POP treatment outcomes are poorly understood.

Objectives: The objectives of this study were to determine (1) if pelvic pain is associated with PFMD in women seeking POP treatment and (2) if baseline PFMD in women seeking management of POP is associated with improvement in pelvic pain at 12 months.

Study design: This was an ambispective cohort study of women enrolled at one site of the Pelvic Floor Disorders Registry. Pelvic floor muscle dysfunction was identified if tenderness was reported on a standardized pelvic floor muscle examination at baseline. Outcomes included a pelvic pain questionnaire (score 0-70, assessed pain in the past 24 hours in 7 pelvic locations) and the Global Health-10 overall average pain rating (0-10).

Results: One hundred forty-four women planning surgery (118) or pessary (26) were included. Twenty (13.9%) had baseline PFMD. Women with PFMD versus no PFMD had greater baseline Pelvic Pain scores (median [IQR], 9.7 [4-23] vs 2.5 [0-7], P < 0.001) and overall average pain (4 [3-6] vs 1 [0-3], P < 0.001). In 107 women with 12-month treatment outcomes, those with PFMD at baseline had greater improvement in pelvic pain compared with those without PFMD (change score -6.5 [-15.2 to 0] vs 0 [-3 to 0] respectively, P = 0.03). Overall pain improved after treatment in the no PFMD group but not in the PFMD group.

Conclusions: Patients with baseline PFMD vs none undergoing treatment for prolapse had higher baseline pelvic pain and greater improvement in pelvic pain at 12 months.

Bypassing of nearest labor & delivery unit is contingent on rurality, wealth, and race.

Carrel M, Keino BC, Novak NL, Ryckman KK, Radke S.

Birth. 2023 Mar;50(1):5-10. doi: 10.1111/birt.12712. Epub 2023 Feb 8.  PMID: 36752116.

Patient decisions to bypass the closest labor & delivery (L&D) facility in favor of other birthing locations can have consequences for the provision of health care in rural and micropolitan areas as patient volumes decline and payer mixes change. Among 220 589 uncomplicated births in Iowa, we document characteristics of birth parents who bypass their closest birthing facility, show how this bypassing behavior results in changed travel times to delivery facilities across the rural/urban divide, and indicate the parts of the state where bypassing behavior is most prevalent. From 2013 to 2019, 55.2% of deliveries occurred in facilities that were further from birthing parents' residences than the closest L&D facility. Bypassing is associated with White, non-Hispanic race/ethnicity, and private insurance status. Although bypassing is least common among micropolitan birth parents, this group has the greatest travel burden to birthing facilities and exhibits increasing rates of bypassing over time. Perinatal quality improvement programs can target locations and populations where low-risk birthing parents can be encouraged to deliver close to home if medically appropriate, particularly in small towns and rural areas. This can potentially alleviate the risk of obstetric deserts by ensuring L&D units maintain patient volumes necessary to continue operations.

Virome Analysis and Association of Positive Coxsackievirus B Serology during Pregnancy with Congenital Heart Disease

Garand M, Huang SSY, Goessling LS, Wan F, Santillan DA, Santillan MK, Brar A, Wylie TN, Wylie KM, Eghtesady P

Microorganisms. 2023 Jan 19;11(2):262. doi: 10.3390/microorganisms11020262. PMID: 36838226; PMCID: PMC9963073. 

Background: We have previously shown coxsackievirus B (CVB) to be a potent inducer of congenital heart disease (CHD) in mice. The clinical relevance of these findings in humans and the roles of other viruses in the pathogenesis of CHD remain unknown.

Methods: We obtained plasma samples, collected at all trimesters, from 89 subjects (104 pregnancies), 73 healthy controls (88 pregnancies), and 16 with CHD-affected birth (16 pregnancies), from the Perinatal Family Tissue Bank (PFTB). We performed CVB IgG/IgM serological assays on plasma. We also used ViroCap sequencing and PCR to test for viral nucleic acid in plasma, circulating leukocytes from the buffy coat, and in the media of a co-culture system.

Results: CVB IgG/IgM results indicated that prior exposure was 7.8 times more common in the CHD group (95% CI, 1.14-54.24, adj. p-value = 0.036). However, the CVB viral genome was not detected in plasma, buffy coat, or co-culture supernatant by molecular assays, although other viruses were detected.

Conclusion: Detection of viral nucleic acid in plasma was infrequent and specifically no CVB genome was detected. However, serology demonstrated that prior CVB exposure is higher in CHD-affected pregnancies. Further studies are warranted to understand the magnitude of the contribution of the maternal blood virome to the pathogenesis of CHD.

Associations Between Urological Chronic Pelvic Pain Syndrome Symptom Flares, Illness Impact, and Health Care Seeking Activity: Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study.

Sutcliffe S, Newcomb C, Bradley CS, Clemens JQ, Erickson B, Gupta P, Lai HH, Naliboff B, Strachan E, Stephens-Shields A.

J Urol. 2023 Jan 11:101097JU0000000000003155. doi: 10.1097/JU.0000000000003155. Epub ahead of print. PMID: 36630590. 

Purpose: Most studies on interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome use typical or average levels of pelvic pain or urological symptom intensity as their outcome, as both are associated with reduced quality of life. Symptom exacerbations or "flares" have also been found to be associated with reduced quality of life, but no studies, to our knowledge, have investigated whether these associations are independent of typical pelvic pain levels and thus might be useful additional outcome measures (or stated differently, whether reducing flare frequency even without reducing mean pain intensity may be important to patients).

Materials and methods: We used screening visit and weekly run-in period data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Symptom Patterns Study to investigate associations between flare frequency and multiple measures of illness impact and health care seeking activity, independent of typical nonflare and overall pelvic pain levels.

Results: Among the 613 eligible participants, greater flare frequency was associated with worse condition-specific illness impact (standardized β coefficients=0.11-0.68, P trends < .0001) and health care seeking activity (odds ratios=1.52-3.94, P trends .0039 to < .0001) in analyses adjusted for typical nonflare and overall pelvic pain levels. Experiencing ≥1/d was also independently associated with worse general illness impact (standardized β coefficients=0.11-0.25).

Conclusions: Our findings suggest that flare frequency and possibly other flare characteristics may be worth considering as additional outcome measures in urological chronic pelvic pain syndrome research to support the development of new preventive and therapeutic flare strategies.

Circulating microparticle proteins predict pregnancies complicated by placenta accreta spectrum.

Yu HY, Gumusoglu SB, Cantonwine DE, Carusi DA, Gurnani P, Schickling B, Doss RC, Santillan MK, Rosenblatt KP, McElrath TF.

Sci Rep. 2023 Jan 5;12(1):21922. doi: 10.1038/s41598-022-24869-0.  PMID: 36604494; PMCID: PMC9814521. 

Placenta accreta spectrum (PAS) is characterized by abnormal attachment of the placenta to the uterus, and attempts at placental delivery can lead to catastrophic maternal hemorrhage and death. Multidisciplinary delivery planning can significantly improve outcomes; however, current diagnostics are lacking as approximately half of pregnancies with PAS are undiagnosed prior to delivery. This is a nested case-control study of 35 cases and 70 controls with the primary objective of identifying circulating microparticle (CMP) protein panels that identify pregnancies complicated by PAS. Size exclusion chromatography and liquid chromatography with tandem mass spectrometry were used for CMP protein isolation and identification, respectively. A two-step iterative workflow was used to establish putative panels. Using plasma sampled at a median of 26 weeks' gestation, five CMP proteins distinguished PAS from controls with a mean area under the curve (AUC) of 0.83. For a separate sample taken at a median of 35 weeks' gestation, the mean AUC was 0.78. In the second trimester, canonical pathway analyses demonstrate over-representation of processes related to iron homeostasis and erythropoietin signaling. In the third trimester, these analyses revealed abnormal immune function. CMP proteins classify PAS well prior to delivery and have potential to significantly reduce maternal morbidity and mortality.

Public opinions regarding infertility treatment insurance coverage among marginalized patient populations.

Iwamoto A, Summers KM, Mancuso AC.

J Assist Reprod Genet. 2023 Jan 5. doi: 10.1007/s10815-022-02687-7. Epub ahead of print. PMID: 36602655. 

Purpose: To assess public support for insurance coverage of infertility treatment among marginalized patient groups.

Methods: A cross-sectional, web survey-based study using a national sample of 1226 US adults. Participants responded to questions measuring their beliefs and attitudes towards support for infertility treatment insurance coverage among specific patient populations. We then evaluated the opinions of only the participants who supported infertility treatment insurance coverage for patients meeting the standard definition of infertility. Associations between demographic data of participants and support for infertility treatment insurance coverage among these marginalized groups were queried.

Results: Of the total responses, 61.9% of the respondents generally supported insurance coverage for infertility. Of the total responses, 54.5% did not support any insurance coverage for lesbian, gay, or transgender patients. Of those who generally supported the insurance coverage for infertility, 53.0% supported coverage for gay patients requiring infertility services, 54.6% supported coverage for lesbian patients, and 42.5% supported coverage for transgender patients. Of the total responses, 47.6% did not support insurance for green card holders, undocumented immigrants, or refugees. Of those who supported the insurance coverage for infertility in general, 63.6% supported insurance coverage for patients with green cards, 29.8% for refugees, and 20.7% for undocumented patients. For disability and genetic conditions, 39.5% did not support coverage for any groups. Of those who support the insurance coverage for infertility in general, there was most support for patients with physical disabilities (60.2%) followed by genetic disease (47.9%), then mental disabilities (31.4%).

Conclusion: Even among those who support insurance coverage for infertility in general, approximately less than half of them supported these same treatments for marginalized groups, including the diverse sexuality and gender (DSG), immigrant, and disabled populations. Increased education and awareness of infertility is needed among the general population to garner acceptance of infertility as a disease and support insurance coverage of infertility treatment for all persons.

Invasive or More Direct Measurements Can Provide an Objective Early-Stopping Ceiling for Training Deep Neural Networks on Non-invasive or Less-Direct Biomedical Data.

Bartlett CW, Bossenbroek J, Ueyama Y, McCallinhart P, Peters OA, Santillan DA, Santillan MK, Trask AJ, Ray WC.

SN Comput Sci. 2023;4(2):161. doi: 10.1007/s42979-022-01553-8. Epub 2023 Jan 12.  PMID: 36647373; PMCID: PMC9836982.

Early stopping is an extremely common tool to minimize overfitting, which would otherwise be a cause of poor generalization of the model to novel data. However, early stopping is a heuristic that, while effective, primarily relies on ad hoc parameters and metrics. Optimizing when to stop remains a challenge. In this paper, we suggest that for some biomedical applications, a natural dichotomy of invasive/non-invasive measurements, or more generally proximal vs distal measurements of a biological system can be exploited to provide objective advice on early stopping. We discuss the conditions where invasive measurements of a biological process should provide better predictions than non-invasive measurements, or at best offer parity. Hence, if data from an invasive measurement are available locally, or from the literature, that information can be leveraged to know with high certainty whether a model of non-invasive data is overfitted. We present paired invasive/non-invasive cardiac and coronary artery measurements from two mouse strains, one of which spontaneously develops type 2 diabetes, posed as a classification problem. Examination of the various stopping rules shows that generalization is reduced with more training epochs and commonly applied stopping rules give widely different generalization error estimates. The use of an empirically derived training ceiling is demonstrated to be helpful as added information to leverage early stopping in order to reduce overfitting.

Integration of Genomic and Clinical Retrospective Data to Predict Endometrioid Endometrial Cancer Recurrence.

Gonzalez-Bosquet J, Gabrilovich S, McDonald ME, Smith BJ, Leslie KK, Bender DD, Goodheart MJ, Devor E.

Int J Mol Sci. 2022 Dec 16;23(24):16014. doi: 10.3390/ijms232416014. PMID: 36555654; PMCID: PMC9785370.

Endometrial cancer (EC) incidence and mortality continues to rise. Molecular profiling of EC promises improvement of risk assessment and treatment selection. However, we still lack robust and accurate models to predict those at risk of failing treatment. The objective of this pilot study is to create models with clinical and genomic data that will discriminate patients with EC at risk of disease recurrence. We performed a pilot, retrospective, case-control study evaluating patients with EC, endometrioid type: 7 with recurrence of disease (cases), and 55 without (controls). RNA was extracted from frozen specimens and sequenced (RNAseq). Genomic features from RNAseq included transcriptome expression, genomic, and structural variation. Feature selection for variable reduction was performed with univariate ANOVA with cross-validation. Selected variables, informative for EC recurrence, were introduced in multivariate lasso regression models. Validation of models was performed in machine-learning platforms (ML) and independent datasets (TCGA). The best performing prediction models (out of &gt;170) contained the same lncRNA features (AUC of 0.9, and 95% CI: 0.75, 1.0). Models were validated with excellent performance in ML platforms and good performance in an independent dataset. Prediction models of EC recurrence containing lncRNA features have better performance than models with clinical data alone.

Using Genomic Variation to Distinguish Ovarian High-Grade Serous Carcinoma from Benign Fallopian Tubes.

Gonzalez-Bosquet J, Cardillo ND, Reyes HD, Smith BJ, Leslie KK, Bender DP, Goodheart MJ, Devor EJ.

Int J Mol Sci. 2022 Nov 26;23(23):14814. doi: 10.3390/ijms232314814. PMID: 36499142; PMCID: PMC973893

The preoperative diagnosis of pelvic masses has been elusive to date. Methods for characterization such as CA-125 have had limited specificity. We hypothesize that genomic variation can be used to create prediction models which accurately distinguish high grade serous ovarian cancer (HGSC) from benign tissue.

Methods: In this retrospective, pilot study, we extracted DNA and RNA from HGSC specimens and from benign fallopian tubes. Then, we performed whole exome sequencing and RNA sequencing, and identified single nucleotide variants (SNV), copy number variants (CNV) and structural variants (SV). We used these variants to create prediction models to distinguish cancer from benign tissue. The models were then validated in independent datasets and with a machine learning platform.

Results: The prediction model with SNV had an AUC of 1.00 (95% CI 1.00-1.00). The models with CNV and SV had AUC of 0.87 and 0.73, respectively. Validated models also had excellent performances.

Conclusions: Genomic variation of HGSC can be used to create prediction models which accurately discriminate cancer from benign tissue. Further refining of these models (early-stage samples, other tumor types) has the potential to lead to detection of ovarian cancer in blood with cell free DNA, even in early stage.

Enhancing progestin therapy via HDAC inhibitors in endometrial cancer.

Li Y, Zhou W, Li L, Li JW, Li T, Huang C, Lazaro-Camp VJ, Kavlashvili T, Zhang Y, Reyes H, Li Y, Dai D, Zhu W, Meng X, Leslie KK, Yang S.

Am J Cancer Res. 2022 Nov 15;12(11):5029-5048.  PMID: 36504895; PMCID: PMC9729913.

Uterine endometrial cancer (EC) incidence and deaths are on the rise. Hormone therapy, a traditional treatment regimen for this disease, uses progesterone and its synthetic analogue, progestin, to induce cell differentiation, apoptosis, and inhibition of invasion. This therapy is highly effective for progesterone receptor (PR) positive tumors in the short term. However, responsiveness decreases over time due to loss of PR expression; acquired resistance leads to treatment failure and poor prognosis. Primary resistance occurs in advanced, PR-negative tumors. Regardless, progestin therapy can be effective if the PR downregulation mechanism is reversed and if functional PR expression is restored. Using histone deacetylase inhibitors (HDACi), we inhibited cell proliferation in three EC cell lines and restored functional PR expression at the mRNA and protein levels. Two HDACi were tested using an endometrial xenograft tumor model: entinostat, an oral drug, and romidepsin, an IV drug. In vitro and in vivo studies support that entinostat decreased EC tumor growth, induced differentiation, and increased expression of the PR-targeted gene, PAEP. These findings supported the approval of a new NIH NCTN clinical trial, NRG-GY011, which concluded that dual treatment of MPA and entinostat, decreased expression of the proliferation marker, Ki67, but did not increase PR expression relative to single treatment with MPA in this short-term study. Therefore, a more potent HDACi, romidepsin, was investigated. Romidepsin treatment inhibited tumor growth and enhanced progestin treatment efficacy. More importantly, PR, PAEP, and KIAA1324 expressions were upregulated. Using a chromatin immunoprecipitation assay, we verified that HDACi can reverse PR downregulation mechanisms in mice models. Other potential drug efficacy markers, such as CD52, DLK1, GALNT9, and GNG2, were identified by transcriptome analysis and verified by q-PCR. Many of the upregulated drug efficacy markers predict favorable patient outcomes, while downregulated genes predict worse survival. Here, our current data suggests that romidepsin is a more potent HDACi that has the potential to achieve more robust upregulation of PR expression and may be a more promising candidate for future clinical trials.

ECPPF (E2F1, CCNA2, POLE, PPP2R1A, FBXW7) stratification: Profiling high-risk subtypes of histomorphologically low-risk and treatment-insensitive endometrioid endometrial cancer.

Gonzalez-Bosquet J, Weroha SJ, Bakkum-Gamez JN, Weaver AL, McGree ME, Dowdy SC, Famuyide AO, Kipp BR, Halling KC, Yadav S, Couch FJ, Podratz KC.

PLoS One. 2022 Dec 1;17(12):e0278408. doi: 10.1371/journal.pone.0278408. PMID: 36454788; PMCID: PMC9714733. 

In endometrial cancer, occult high-risk subtypes (rooted in histomorphologically low-risk disease) with insensitivity to adjuvant therapies impede improvements in therapeutic efficacy. Therefore, we aimed to assess the ability of molecular high-risk (MHR) and low-risk (MLR) ECPPF (E2F1, CCNA2, POLE, PPP2R1A, FBXW7) stratification to profile recurrence in early, low-risk endometrioid endometrial cancer (EEC) and insensitivity to platinum-based chemotherapy or radiotherapy (or both) in high-risk EEC. Using The Cancer Genome Atlas endometrial cancer database, we identified 192 EEC cases with available DNA sequencing and RNA expression data. Molecular parameters were integrated with clinicopathologic risk factors and adverse surveillance events. MHR was defined as high (-H) CCNA2 or E2F1 log2 expression (≥2.75), PPP2R1A mutations (-mu), or FBXW7mu; MLR was defined as low (-L) CCNA2 and E2F1 log2 expression (<2.75). We assessed 164 cases, plus another 28 with POLEmu for favorable-outcomes comparisons. MHR and MLR had significantly different progression-free survival (PFS) rates (P < .001), independent of traditional risk factors (eg, TP53mu), except for stage IV disease. PFS of CCNA2-L/E2F1-L paralleled that of POLEmu. ECPPF status stratified responses to adjuvant therapy in stage III-IV EEC (P < .01) and profiled stage I, grade 1-2 cases with risk of recurrence (P < .001). MHR was associated with CTNNB1mu-linked treatment failures (P < .001). Expression of homologous recombination repair (HR) and cell cycle genes was significantly elevated in CCNA2-H/E2F1-H compared with CCNA2-L/E2F1-L (P<1.0E-10), suggesting that HR deficiencies may underlie the favorable PFS in MLR. HRmu were detected in 20.7%. No treatment failures were observed in high-grade or advanced EEC with HRmu (P = .02). Favorable PFS in clinically high-risk EEC was associated with HRmu and MLR ECPPF (P < .001). In summary, MLR ECPPF and HRmu were associated with therapeutic efficacy in EEC. MHR ECPPF was associated with low-risk, early-stage recurrences and insensitivity to adjuvant therapies.

Postnatal Leptin Levels Correlate with Breast Milk Leptin Content in Infants Born before 32 Weeks Gestation.

Chatmethakul T, Schmelzel ML, Johnson KJ, Walker JR, Santillan DA, Colaizy TT, Roghair RD.

Nutrients. 2022 Dec 8;14(24):5224. doi: 10.3390/nu14245224.  PMID: 36558383; PMCID: PMC9782260. 

Perinatal leptin deficiency and reduced intake of mother's milk may contribute to the development of childhood obesity. Preterm infants have reduced leptin production, and they are at heightened risk of neonatal leptin deficiency. Because fresh human milk contains significantly more leptin than donor milk, we used a cross-over design to determine if blood leptin levels in maternal milk-fed preterm infants fall during conversion to donor human milk. Infants born between 22 0/7 and 31 6/7 weeks gestation on exclusive maternal milk feedings were enrolled into a 21-day cross-over trial. On days 1-7 and 15-21, infants were fed maternal milk, and on days 8-14, infants were fed donor milk. On day 1, study infants had a mean postmenstrual age of 33 weeks. Plasma leptin correlated with milk leptin, and leptin levels in maternal milk far exceed the leptin levels of donor milk. Plasma leptin did not increase during donor milk administration, but it did following resumption of maternal milk (p &lt; 0.05). In this crossover trial, preterm infant blood leptin levels correlated with milk leptin content. This suggests that preterm infants can enterally absorb leptin from human milk, and leptin-rich breast milk may be a targeted therapy for the prevention of obesity.