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Age is named as a risk factor for pelvic organ prolapse (POP), despite not being the primary outcome for many observational studies. Postmenopausal status is another associated factor but has many confounders. We aimed to systematically review the role of age and/or postmenopausal status in POP development. Systematic review addressing age and hormones, more specifically by postmenopausal status, from inception to March 2020 in four databases (PubMed, Embase, WOS, Cochrane Library). Quality of evidence was classified by the ROBINS-I classification for non-randomized studies. Experimental studies, animal studies, studies linking age with recurrent POP and case series were excluded. Effect estimates were collected from adjusted odds ratio plus 95% confidence intervals. Significance level was 5%. A discussion exploring mechanistic factors was also included. Nineteen studies (11 cross sectional, 6 cohort and 2 case control) were included for quantitative analysis. Only two studies presented a low overall risk of bias for age; most of the domains were of moderate risk. Every additional year was responsible for a 10% increase in the risk to develop POP (OR = 1.102 [1.021–1.190]; i2 = 80%, random analysis, p = 0.012). This trend was confirmed when age was dichotomized into a cutoff of 35 (p = 0.035) and 50 (p

OBJECTIVE Using the American Urogynecologic Society multicenter Pelvic Floor Disorder Registry for Research, we (1) compared generic quality of life (QOL) in women planning pelvic organ prolapse (POP) treatment (surgery vs pessary), (2) correlated generic and condition-specific QOL scores, and (3) identified associations between generic QOL and other factors. METHODS This cross-sectional analysis assessed generic physical and mental QOL using the Patient-Reported Outcomes Measurement Information System Global Health Scale at baseline. Global Physical and Mental T-scores center on a representative US population sample (mean [SD], 50 [10]; higher scores, better health). Condition-specific QOL was assessed with Pelvic Floor Distress Inventory, Pelvic Floor Impact Questionnaire, and POP/Urinary Incontinence Sexual Function Questionnaire. Linear regression models identified associations between clinical factors and Global Physical/Mental scores. RESULTS Five hundred sixty-eight women (419 surgery, 149 pessary) were included. Surgery patients were younger, heavier, and more often sexually active (all P's ≤ 0.01). Global Physical scores were lower in the surgery versus pessary group, but not likely clinically meaningful (mean [SD], 48.8 [8.1] vs 50.4 [8.5]; P = 0.035); Global Mental scores were similar (51.4 [8.4] vs 51.9 [9.5], P = 0.56). Global Health scores correlated with Pelvic Floor Distress Inventory, Pelvic Floor Impact Questionnaire, and POP/Urinary Incontinence Sexual Function Questionnaire scores (all P's < 0.0001). In multivariable models, menopause was associated with better physical QOL, and constipation, coronary artery disease, pelvic pain, and increased body mass index with worse physical QOL. Age was associated with better mental QOL, and constipation, fecal incontinence, pelvic pain, and coronary artery disease with worse mental QOL. CONCLUSIONS Women choosing POP surgery versus pessary had similar physical and mental generic QOL.

OBJECTIVES: The primary objective of this study is to compare patient versus physician rankings of adverse event (AE) and adverse symptom (AS) severity after pelvic reconstructive surgery. Secondary objectives include to estimate the association between patient rankings of AEs/ASs with decision-making and quality-of-life outcomes and to determine whether patient perspective about AE/AS changes over time. METHODS: This is a supplementary study, Patient-Perspectives in Adverse Event Reporting (PPAR), to the index trial, ASPIRe (Apical Suspension Repair for Vault Prolapse In a Three-Arm Randomized Trial Design). During the trial, AEs/ASs will be assessed by physicians longitudinally every 6 months, which includes a determination of the AE/AS grade severity. For PPAR, additional patient perspective will be measured for 19 predetermined AEs/ASs at the time of identification and again at 12 and 36 months post-operatively. Decision-making and quality-of-life questionnaires will be collected at these time points. The primary outcome, the overall interrater agreement between patient and physician rankings for AE/AS severity, will be determined using a repeated-measures concordance correlation coefficient. RESULTS: To date, the index trial has completed enrollment, and follow-up is ongoing. CONCLUSIONS: The PPAR methods for incorporating patient perspective in the measurement of AEs/ASs to determine their agreement with physician ranking, long-term relevance, and impact on treatment decision making and quality of life are described. This will contribute to improved measurements of AEs/ASs in future research with the goal of improving patient counseling and informing expectations and treatment decision making.

Objective To test the hypothesis that preoperative pelvic floor muscle injections and pudendal nerve blocks with bupivacaine and dexamethasone would decrease postoperative pain after vaginal native tissue prolapse repairs, compared with saline and bupivacaine. Methods We conducted a three-arm, double-blind, randomized trial of bilateral transobturator levator ani muscle injections and transvaginal pudendal nerve blocks before vaginal reconstructive and obliterative prolapse procedures (uterosacral ligament suspension, sacrospinous ligament fixation, levator myorrhaphy, or colpocleisis). Women were randomized to one of three study medication groups: 0.9% saline, 0.25% bupivacaine, or combination 0.25% bupivacaine with 4 mg dexamethasone. Our primary outcome was a numeric rating scale pain score on postoperative day 1. Using an analysis of variance evaluated at the two-sided 0.05 significance level, an assumed variance of the means of 0.67, and SD of 1.75, we calculated 21 women per arm to detect a 2-point change on the numeric rating scale (90% power), which we increased to 25 per arm to account for 20% attrition and the use of nonparametric statistical methods. Results From June 2017 through April 2019, 281 women were screened and 75 (26.7%) were randomized with no differences in baseline demographics among study arms. There was no significant difference in median pain scores on postoperative day 1 among study groups (median [interquartile range] pain score 4.0 [2.0-7.0] for placebo vs 4.0 [2.0-5.5] for bupivacaine vs 4.0 [1.5-5.0] for bupivacaine with dexamethasone, P=.92). Conclusion Preoperative pelvic floor muscle injections and pudendal nerve blocks with bupivacaine and dexamethasone did not improve postoperative pain after vaginal native tissue prolapse procedures. Clinical trial registration ClinicalTrials.gov, NCT03040011.

Polypropylene mesh is frequently used in urogynecology procedures; however, pain and mesh exposure into the vagina occur in ~10% of cases. Mesh-induced pain, which occurs with or without exposure, persists after removal in 50% of cases. Chronic pain history predicts poor response to mesh removal but only a fraction have this diagnosis. We hypothesize that mesh induced pain is correlated with fibrosis and failure to improve with a heightened inflammatory and fibrotic host response. Women undergoing mesh removal were offered participation in a mesh biorepository. Standardized questionnaires including visual analog scale (VAS) pelvic pain scores were completed at enrollment and 6 months after removal. Responders were considered those with ≥13 mm VAS improvement. 30 mesh-tissue explants were randomly selected for analysis. Samples were labeled for CD8, CD4 (Th) and FoxP3 (Tregs). Peri-fiber collagen deposition (fibrosis) was measured using a customized semi-quantitative assay. Concentrations of TGF-b1, bFGF, MCP-1, PDGF-BB, and IGFBP-1 in tissue were determined by immunoassay and compared to vaginal control biopsies with pathway analysis. VAS pain scores were correlated with degree of histologic fibrosis. Responders had more Tregs (7.8 vs 0.3 per mm2, p = 0.036) and patients were 1.6 times as likely to be a responder for every additional Treg/mm2 (p = 0.05). Pro-fibrotic TGF-β1 was doubled in nonresponders (p = 0.032). On pathway analysis, decreased bFGF and increased PDGF-BB provide a possible mechanism for upregulation of TGF-β1. In conclusion, fibrosis is a plausible mechanism of pain complications and the adaptive immune response likely contributes to mitigation/prevention of complications and recovery in affected patients. Statement of Significance Polypropylene mesh improves anatomical outcomes in urogynecologic procedures, but is associated with complications, including pain and exposure through the vaginal epithelium. Mesh-induced pain is difficult to treat, and it is unclear why only half of women experience pain improvement after mesh removal. In this study, patient pain correlated with the presence of fibrosis and women with more T regulatory cells and lower TGF-β1 were more likely to have pain improvement following mesh removal. These findings implicate fibrosis as a mechanism of pain complications and suggest that the adaptive immune response may be responsible for prevention of complication and recovery. This improved understanding of how mesh can lead to pain moves us closer to the ultimate goal of preventing mesh complications.

INTRODUCTION AND HYPOTHESIS: The protocol and analysis methods for the Defining Mechanisms of Anterior Vaginal Wall Descent (DEMAND) study are presented. DEMAND was designed to identify mechanisms and contributors of prolapse recurrence after two transvaginal apical suspension procedures for uterovaginal prolapse. METHODS: DEMAND is a supplementary cohort study of a clinical trial in which women with uterovaginal prolapse randomized to (1) vaginal hysterectomy with uterosacral ligament suspension or (2) vaginal mesh hysteropexy underwent pelvic magnetic resonance imaging (MRI) at 30-42 months post-surgery. Standardized protocols have been developed to systematize MRI examinations across multiple sites and to improve reliability of MRI measurements. Anatomical failure, based on MRI, is defined as prolapse beyond the hymen. Anatomic measures from co-registered rest, maximal strain, and post-strain rest (recovery) sequences are obtained from the “true midsagittal” plane defined by a 3D pelvic coordinate system. The primary outcome is the mechanism of failure (apical descent versus anterior vaginal wall elongation). Secondary outcomes include displacement of the vaginal apex and perineal body, and elongation of the anterior wall, posterior wall, perimeter, and introitus of the vagina between (1) rest and strain and (2) rest and recovery. RESULTS: Recruitment and MRI trials of 94 participants were completed by May 2018. CONCLUSIONS: Methods papers which detail studies designed to evaluate anatomic outcomes of prolapse surgeries are few. We describe a systematic, standardized approach to define and quantitatively assess mechanisms of anatomic failure following prolapse repair. This study will provide a better understanding of how apical prolapse repairs fail anatomically.

Objective To compare temporal trends of urogynecologic mesh medical device reports with sentinel U.S. Food and Drug Administration (FDA) notices and to examine all linked reports of patient death. Methods The Reed Tech Navigator is an online tool used to extract and analyze data in the Manufacturer and User Facility Device Experience database. We used FDA product codes to search for reports of synthetic mesh for stress urinary incontinence (SUI) and pelvic organ prolapse (POP). Reports with "death" listed as a patient event were queried further. Results There were 43,970 medical device reports involving urogynecologic mesh reported to the FDA between August 2000 and January 2019, with most occurring after the 2011 FDA communication (n=43,018, 97.8%). Of these medical device reports, 64.6% (n=28,422) were for SUI products, 27.0% (n=11,876) were for transvaginal POP products, and 8.4% (n=3,672) were for transabdominal POP products. Peak reporting occurred in 2013, which corresponded with the first major plaintiff verdicts and class action vaginal mesh settlement. There were 645 (1.5%) medical device reports of death, with 49.3% (n=318) having no cause of death identified. Only four (0.6%) could be directly attributed to the initial surgery. Conclusion Since 2011, urogynecologic mesh has been the focus of thousands of medical device reports annually, although the data submitted are often incomplete. Few reported deaths are directly attributable to mesh products, and the majority lack sufficient information to draw causal conclusions. A high-quality registry is necessary to improve our understanding of the patient effect from urogynecologic mesh products.

Background A description of energy-based genitourinary non-surgical devices (energy-based devices) safety data is outlined given their rapid adoption. Objectives The authors sought to describe adverse events for energy-based devices in the Manufacturer and User Facility Device Experience database and to compare with similar devices and other subspecialty applications. We hypothesized that products with genitourinary applications had similar adverse events to dermatologic or general surgery applications. Methods The authors used Reed Tech Navigator to compile adverse events reports for all registered energy-based devices. Individual adverse events reports associated with (1) non-ablative, (2) fractionated, (3) unfractionated, (4) radiofrequency, and (5) hybrid laser technologies were categorized. Adverse event characteristics were compared among genitourinary applications (n = 39) and other subspecialty applications within the same devices (n = 79). Results Eighteen manufacturers were identified, which collectively manufacture 43 products with genitourinary applications. Thirty-nine genitourinary adverse events were reported and isolated to 6 manufacturers with 11 products, of which 82% (n = 32) were injuries, 15% (n = 6) were device malfunction, and 3% (n = 1) were related to improper maintenance. Local treatment reactions were the most commonly reported injury (62%, n = 21). Adverse events varied by device type, with CO2 lasers having more burns and radiofrequency devices having higher rates of sensation loss. Comparing similar technology types, genitourinary energy-based devices had the fewest adverse events reports per device in the Manufacturer and User Facility Device Experience database. Conclusions Adverse events were reported for one-quarter of the products currently available, and most were local treatment reactions. The reporting of adverse events is equal to that of other subspecialties, suggesting similar risk profiles. Improved reporting is needed to fully evaluate the safety of individual energy-based devices. Level of Evidence: 4

OBJECTIVE: To present the design of the Apical Suspension Repair for Vault Prolapse in a Three-Arm Randomized Trial (ASPIRe) which compares the efficacy and safety of three apical repairs: native tissue transvaginal repair, transvaginal mesh, and sacral colpopexy. METHODS: Patient selection criteria, primary and secondary outcome measures including patient-reported outcome questionnaires, masking, surgeon certification, procedure standardization, adverse events collection and adjudication, and cost analysis will be described for this multi-centered randomized trial. Given the unique risks/ benefits of each technique, a non-inferiority design will be used to compare apical transvaginal mesh to mesh sacral colpopexy. A superiority design will be used to compare the two mesh repairs to native tissue transvaginal apical repair. Survival analysis will be used to assess a composite primary outcome for success composed of a subjective measure (no prolapse symptoms), objective measure (no prolapse beyond the hymen) and no prolapse retreatment, with a minimum follow up of 36 months. Secondary outcome measures collected every 6 months include assessment of validated general and condition-specific quality of life measures, global impression of improvement, satisfaction and regret, body image, and sexual function. RESULTS: Randomization and surgical treatment of 360 participants is complete and the study is in the follow-up phase. CONCLUSIONS: This report will provide valuable insight on the design of a novel 3-arm surgical trial utilizing mesh versus native tissue to repair vaginal vault prolapse. This trial will provide level 1 evidence on the risks and benefits of mesh augmented versus native tissue apical repairs.

Polypropylene mesh is widely used in urogynecologic surgery, but complications rates (pain and exposure) approach 10%. Emerging evidence implicates the adaptive immune system in regulating the foreign body response to mesh, particularly regulatory T cells (Tregs), which modify macrophage differentiation and down-regulate CD8+ effector T cells. We hypothesize that Tregs protect against a profibrotic response, a likely mechanism of pain complications. Here, thin sections of mesh-tissue complexes removed for the primary complaint of pain (N = 14) or exposure (N = 15) were labeled for CD8, CD4 (Th), and FoxP3 (Tregs) via immunofluorescence. The same sections were analyzed for localized collagen deposition via a customized semi-quantitative assessment (0.25 mm2 grid) after trichrome staining. TGF-β1 concentrations were determined by enzyme-linked immunosorbent assay. Fewer Treg and CD4+ cells were found in fibrotic areas versus non-fibrotic areas (503 and 550/cm2 fewer, respectively, both P Statement of Significance The use of polypropylene mesh has been associated with improved outcomes in urogynecologic surgery, but is associated with significant complications, including pain and exposure through the vaginal epithelium. The host immune response features a prolonged inflammatory reaction containing innate immune cells and T lymphocytes clustered in capsules around the mesh fibers. This study uncovers the inverse relationship between T regulatory cells and the extent of fibrosis around the mesh, suggesting an anti-fibrotic effect. In addition, concentrations of T regulatory and T effector cells and levels of fibrosis connect these two most common complications into one mechanistic pathway. These new insights into the immune response to implanted mesh are an important step in understanding the causes of these surgical complications.

INTRODUCTION AND HYPOTHESIS: We compared the impact of a mesh manufactured from the soft elastomer, polydimethylsiloxane (PDMS) to that of a widely used lightweight polypropylene (PP) mesh. To achieve a similar overall device stiffness between meshes, the PDMS mesh was made with more material and therefore, was heavier and less porous. We hypothesized that the soft polymer PDMS mesh, despite having more material, would have a similar impact on the vagina as the PP mesh. METHODS: PDMS and PP meshes were implanted onto the vagina of 20 rabbits via colpopexy. Ten rabbits served as Sham. At 12 weeks, mesh-vagina complexes were explanted and assessed for contractile function, histomorphology, total collagen, and glycosaminoglycan content. Outcome measures were compared using one-way ANOVA and Kruskal-Wallis testing with appropriate post-hoc testing. RESULTS: Relative to Sham, vaginal contractility was reduced following the implantation of PP (p=0.035) but not the softer PDMS (p=0.495). PP had an overall greater negative impact on total collagen and glycosaminoglycan content, decreasing by 53% (p

Objective The shape of the sacrum-coccyx was defined and compared in nulliparous, pregnant, and parous women to provide insight into anatomical adaptations that afford vaginal delivery. Design A retrospective study comparing midsagittal anatomical measurements based on MRI of the sacrum and coccyx from 63 subjects. Setting Magee-Womens Research Institute and Northshore University HealthSystem. Population 23 nulliparous, 14 pregnant, and 26 parous women who had an MRI taken that included the necessary bony anatomy. Methods Twelve measurements were taken on scans between the ages of 20 and 49 that had a pelvic MRI scan with or without contrast were analyzed. Subjects were categorized based on parity and gravidity. Main Outcome Measures Length, angles, and curvature indices describing midsagittal sacrum and coccyx shape Results Overall pregnant women had a significantly straighter and more posteriorly oriented coccyx when compared to nulliparous women. This was reflected by a change in 3 measures at the univariate level. The coccygeal curvature index was higher in pregnant (89.2  10.0) women relative to nulliparous (78.7  6.6, p=0.003) and parous (80.0  5.5, p=0.004) women. The sacrococcygeal curvature index and sacrococcygeal angle also increased in the pregnant as compared to the nulliparous group (73.3  5.8 versus 79.2  3.7, p=0.016; 92.8  10.9 versus 109.3  9.4, p=0.002, respectively) with no difference between pregnant and parous groups for these measurements. Conclusions Pregnancy-induced posterior motion of the coccyx, which allowed for the combined sacrum-coccyx shape to straighten, effectively widens the obstetric outlet for vaginal delivery.

Objectives Postpartum urinary incontinence estimates range from 13% to 47%. Clinical factors associated with incontinence 1 year after first delivery are varied. We assessed the prevalence of and factors associated with urinary incontinence in primiparous women at 12 months postpartum. Methods Ancillary analysis of 99 nulliparous women from a prospective cohort study that assessed participants during the first and third trimesters and 12 months postpartum. Our primary outcome was urinary incontinence 12 months postpartum. Women were asked "How often do you experience urine leakage?" and considered to have urinary incontinence if a response other than "never" was reported. We collected vaginal swabs for assessment of matrix metalloproteinase-9 activity, a measure of tissue remodeling. Bivariable and logistic regression analyses were used to compare women with and without postpartum urinary incontinence. Results Of 99 primiparous women, 55% (n = 54) reported urinary incontinence at 12 months postpartum. Logistic regression demonstrated that urinary incontinence during pregnancy (odds ratio, 34.3; 95% confidence interval, 7.9-149.2) and a decrease in matrix metalloproteinase 9 activity between the first and third trimesters (odds ratio, 19.34; 95% confidence interval, 3.47-107.84) were associated with postpartum urinary incontinence. The sensitivity and specificity of urinary incontinence during pregnancy for predicting postpartum urinary incontinence were 87% and 67%, respectively. The positive and negative predictive values were 76% and 81%, respectively. Conclusions Urinary incontinence affected 55% of primiparous women at 12 months postpartum. Urinary incontinence during pregnancy was strongly associated with postpartum incontinence. Importantly, vaginal tissue protease activity during pregnancy represents a possible mechanism for and biomarker of postpartum urinary incontinence.

Author(s): Ferrante, Kimberly L; Gantz, Marie G; Sridhar, Amaanti; Smith, Ariana; Rahn, David D; Ellington, David R; Weidner, Alison C; Wohlrab, Kyle; Mazloomdoost, Donna; Moalli, Pamela; Lukacz, Emily S; NICHD Pelvic Floor Disorders Network | Abstract: ObjectivesThere is a paucity of data on postoperative exercise and how it relates to surgical failure, specifically after midurethral sling (MUS) surgery. We aimed to assess if women with higher self-reported activity levels as measured by strenuous exercise are more likely to experience stress urinary incontinence (SUI) symptoms after MUS than women with lower self-reported activity.MethodsThis is a secondary analysis of Operations and Pelvic Muscle Training in the Management of Apical Support Loss: the OPTIMAL Trial, a randomized trial comparing sacrospinous ligament suspension versus uterosacral ligament suspension, both with concomitant retropubic MUS. Participants completed a validated assessment of activity preoperatively and postoperatively. Women in the upper quartile for strenuous exercise (≥90 minutes per week) were compared with the remaining participants. Symptomatic SUI was defined as retreatment or reoperation for SUI and/or any positive response to Pelvic Floor Disorders Inventory stress incontinence questions 20 to 22.ResultsA total of 351 participants in the OPTIMAL study received MUS along with their prolapse repair and had postoperative exercise and Pelvic Floor Disorders Inventory data. At 2 years, 87 (29%) of 305 exercised strenuously for at least 90 minutes per week, and 63 (23%) of 277 experienced SUI. Women who were less active at 2 years were significantly more likely to experience SUI than women who were more active (26.6% vs 12.8%, P = 0.0138).ConclusionsIn this study, symptomatic SUI occurred more frequently in women with lower self-reported exercise levels 2 years after MUS surgery.

Objectives The 2016 American Urogynecologic Society Prolapse Consensus Conference brought together thought leaders in the field of pelvic organ prolapse (POP). The goal was to identify critical areas of need for future research. This article summarizes the findings. Methods Prior to the conference, 5 major focus areas were identified. Focus areas were explored over the 2-day conference. Clinicians, clinical and basic science researchers, and representatives from government agencies, industry, patient advocacy groups, and the public convened to identify the major gaps in knowledge in each of these focus areas. Results The 5 major topics were as follows: (1) mechanistic research on pelvic supportive structures and how these are altered with pregnancy, delivery, and aging; (2) novel prostheses or implants that address pathophysiology and provide mechanical support; (3) large-scale community-based research; (4) clinical trials to optimize outcomes after POP surgery; and (5) evidence-based quality measures for POP outcomes. Key recommendations were made for each topic. Conclusions Critical gaps in our knowledge were identified. These limit scientific discovery across all 5 topic areas. Further scientific progress would be advanced by (1) developing a standardized group of POP outcomes and quality measures for large trials and community-based research, (2) creating specimen biorepositories that are integrated with robust clinical data, and (3) developing collaborative teams with expertise from a variety of disciplines, convened to tackle our most challenging and complex scientific questions.

OBJECTIVE To evaluate characteristics associated with treatment failure 1 year after midurethral sling in women with mixed urinary incontinence. METHODS Four-hundred three women who participated in a randomized trial that compared midurethral sling and behavioral and pelvic floor muscle therapy (combined group) compared with midurethral sling alone for mixed incontinence with 1-year follow-up data were eligible for this planned secondary analysis. Overall treatment failure was defined as meeting criteria for subjective or objective failure or both. Subjective failure was defined as not meeting the minimal clinical important difference for improvement on the UDI (Urogenital Distress Inventory) total score (26.1 points). Objective failure was defined as not achieving 70% improvement on mean incontinence episodes of any type per day or having undergone any additional treatment for persistent urinary symptoms at 12 months postoperative. Logistic regression models for treatment failure were constructed. Independent variables included site and treatment group, and clinical and demographic variables based on bivariate comparisons (P

BACKGROUND AND OBJECTIVE: Pelvic organ prolapse (POP), the herniation of the pelvic organs toward the vaginal opening, is a common pelvic floor disorder (PFD) whose etiology is poorly understood. Traditional methods for evaluating POP are often constrained to external vaginal examination, limited to 2D, or have poor reproducibility. We propose a reliable 3D anatomic coordinate system for standardized 3D assessment of pelvic anatomy using magnetic resonance imaging (MRI). METHODS: The novel 3D anatomic reference system is based on six bony landmarks of the pelvis manually identified in MRI: the ischial spines and the superior and inferior pubic points of the left and right pubic symphysis. The origin of this system is defined as the midpoint of the ischial spines. The reproducibility and applicability of the pelvic coordinate system were evaluated by (1) implementing it in a new method to quantify vaginal position and axis (angulation) in 3D space from MRI segmentations of the vagina and (2) computing the intraclass correlation (ICC) on coordinate system and vaginal measures. The MRI analysis was performed by four non-medically trained observers on five pelvic MRI datasets on approximately five separate occasions. RESULTS: Overall, all bony landmarks had excellent intra-observer reliability and inter-observer reliability (ICC>0.90); intra-observer reliability was moderate-to-good among the vaginal position parameters (0.5

INTRODUCTION AND HYPOTHESIS: Studies have yet to examine the impact of day-of-surgery voiding trials on post-operative urinary retention in women undergoing obliterative and apical suspension procedures for pelvic organ prolapse. Our objective was to evaluate if time to spontaneous void after these procedures is shorter when a voiding trial is performed on the day of surgery compared with our standard practice of post-operative day 1. METHODS: We conducted a randomized, parallel-arm trial in patients undergoing major pelvic floor reconstructive surgery. Women were randomized 1:1 to an early (4 h post-operatively on the day of surgery) or a standard (6 am on post-operative day 1) retrograde voiding trial. RESULTS: A total of 57 women consented. Mean age and BMI were 65 ±11 and 27.9 ± 4.4. Most women had stage III pelvic organ prolapse (77.2%). Groups had similar baseline characteristics. In the intention-to-treat analysis (n = 57), there was no difference in time to spontaneous void in the early versus standard voiding trial groups (15.9 ± 3.8 vs 28.4 ± 3.1 hours, p = 0.081). In the adjusted analysis using mutlivariable linear regression, an early voiding trial decreased the time to spontaneous void (abeta −2.00 h, p = 0.031) when controlling for vaginal packing and stage IV prolapse. In the per-protocol analysis, which excluded 4 patients for crossover, spontaneous void occurred 17 hours faster in the early voiding trial group (14.6 ± 3.7 vs 31.8 ± 2.9 hours; p = 0.022). Early voiding trial patients experienced ambulation sooner and more often than the standard group (p = 0.02). CONCLUSIONS: A day-of-surgery voiding trial did not prolong catheter use after obliterative and apical suspension procedures.

INTRODUCTION AND HYPOTHESIS: New Zealand white rabbits are an inexpensive large-animal model. This study explored the rabbit as a model for mesh-augmented colpopexy using the intra-abdominal vagina. We hypothesized that polypropylene mesh would negatively impact rabbit vaginal smooth muscle (VSM) morphology and contractile function, similar to the nonhuman primate (NHP)—the established model for prolapse mesh evaluation. METHODS: Restorelle was implanted onto the vagina of ten rabbits via lumbar colpopexy after a hysterectomy. Ten rabbits served as sham. Twelve weeks post-implantation, the vagina was excised and VSM morphology and vaginal contractility were assessed. Outcome measures were compared using independent samples t and Mann-Whitney U tests with a Bonferroni correction, where appropriate. Results from the rabbits were compared with published NHP data. RESULTS: Animals had similar age, parity and BMI. VSM was 18% thinner after Restorelle implantation, P = 0.027. Vaginal contractility was 43% decreased in response to 120 mM KCl (P = 0.003), similar to the 46% reduction observed in the NHP vagina implanted with Restorelle (P = 0.027). Three meshes wrinkled in vivo, resulting in dramatic thinning of the underlying vagina in the area of the mesh causing a mesh exposure. CONCLUSIONS: Polypropylene mesh negatively impacts VSM morphology and vaginal contractility in the rabbit, similar to the NHP, suggesting that the rabbit may serve as an alternative large-animal model. The vaginal thinning and appearance of a mesh exposure in the area of a mesh wrinkle suggest the rabbit may also serve as a model for understanding the pathophysiology of mesh exposure.

The use of polypropylene prolapse mesh to treat pelvic organ prolapse has been limited by mesh-related complications. Gynemesh PS mesh, implanted via sacrocolpopexy in rhesus macaques, had a negative impact on the vagina with thinning of vaginal muscularis and decreased vaginal smooth muscle contractility. The negative effect was attenuated when a bioscaffold derived from urinary bladder extracellular matrix was used as a composite with Gynemesh PS.The objective of the study was to further elucidate the impact of Gynemesh PS polypropylene mesh and MatriStem extracellular matrix bioscaffolds on the vaginal smooth muscle in terms of micromorphology of vaginal smooth muscle (muscle bundles and individual myocytes), innervation, and nerve-mediated contractile function following their implantations in a rhesus macaque model via sacrocolpopexy.Thirty-two middle-aged rhesus macaques were randomized to undergo either a sham surgery (sham, n = 8), or the implantation of Gynemesh PS alone (n = 8) vs composite mesh comprised of Gynemesh PS plus 2-ply MatriStem (n = 8) vs 6-ply MatriStem alone (n = 8) via sacrocolpopexy. The graft-vagina complexes were harvested 3 months later. Histomorphometrics of smooth muscle bundles and myocytes were performed by immunofluorescent labeling of alpha smooth muscle actin, caveolin-3 (membrane protein), and cell nuclei followed by confocal imaging. The cross-sectional diameters of smooth muscle bundles and individual myocytes were quantified using images randomly taken in at least 5 areas of each section of sample. Contractile proteins alpha smooth muscle actin and smoothelin were quantified by Western immunoblotting. Nerve density was measured by immunohistochemical labeling of a pan-neuron marker, PGP9.5. Nerve-mediated smooth muscle contractility was quantified using electrical field stimulation. One-way analysis of variance and appropriate post hoc tests were used for statistical comparisons.Compared with sham, the implantation of Gynemesh PS alone resulted in a disorganized smooth muscle morphology with the number of small muscle bundles (cross-sectional diameter less than 20 μm) increased 67% (P = .004) and the myocyte diameter decreased 22% (P.001). Levels of contractile proteins were all decreased vs sham with alpha smooth muscle actin decreased by 68% (P = .009), low-molecular-weight smoothelin by 51% (P = .014), and high-molecular-weight smoothelin by 40% (P = .015). Nerve density was decreased by 48% (P = .03 vs sham) paralleled by a 63% decrease of nerve-mediated contractility (P = .02). Following the implantation of composite mesh, the results of measurements were similar to sham (all P.05), with a 39% increase in the myocyte diameter (P.001) and a 2-fold increase in the level of alpha smooth muscle actin relative to Gynemesh (P = .045). Following the implantation of MatriStem alone, the number of small muscle bundles were increased 54% vs sham (P = .002), while the other parameters were not significantly different from sham (all P.05).The implantation of Gynemesh PS had a negative impact on the structural and functional integrity of vaginal smooth muscle evidenced by atrophic macro- and microscopic muscle morphology, decreased innervation, and impaired contractile property, consistent with a maladaptive remodeling response. The extracellular matrix bioscaffold (MatriStem), when used with Gynemesh PS as a composite (2 ply), attenuated the negative impact of Gynemesh PS; when used alone (6 ply), it induced adaptive remodeling as evidenced by an increased fraction of small smooth muscle bundles with normal contractility.

The pelvic floor plays an integral part in lower urinary tract storage and evacuation. Normal urine storage necessitates that continence be maintained with normal urethral closure and urethral support. The endopelvic fascia of the anterior vaginal wall, its connections to the arcus tendineous fascia pelvis (ATFP), and the medial portion of the levator ani muscles must remain intact to provide normal urethral support. Thus, normal pelvic floor function is required for urine storage. Normal urine evacuation involves a series of coordinated events, the first of which involves complete relaxation of the external urethral sphincter and levator ani muscles. Acquired dysfunction of these muscles will initially result in sensory urgency and detrusor overactivity; however, with time the acquired voiding dysfunction can result in intermittent urine flow and incomplete bladder emptying, progressing to urinary retention in severe cases. This review will start with a discussion of normal pelvic floor anatomy and function. Next various injuries to the pelvic floor will be reviewed. The dysfunctional pelvic floor will be covered subsequently, with a focus on levator ani spasticity and stress urinary incontinence (SUI). Finally, future research directions of the interaction between the pelvic floor and lower urinary tract function will be discussed.

PurposeTo determine the best predictor of the mid urethral sling outcome we calculated the AUC of ROC curves of preoperative parameters, including Valsalva leak point pressure, maximum urethral closure pressure, urinary NTx (N-telopeptide of crosslinked type I collagen) and plasma vitamin D values (D2, D3 and D2 plus D3).Materials and methodsThis was an ancillary study of TOMUS (Trial of Mid-urethral Slings) and the ValUE (Value of Urodynamics Evaluation) trial in which subjects underwent mid urethral sling surgery for stress urinary incontinence. Valsalva leak point pressure and maximum urethral closure pressure were measured in 427 subjects, whereas NTx, vitamin D2, vitamin D3 and vitamin D2 plus D3 levels were obtained from 150, 116, 115 and 116 subjects respectively. Outcome success was defined using identical outcome (subjective and objective) variables for all subjects. ROC curves with corresponding AUC values were compared.ResultsTOMUS and ValUE subjects were significantly different in age, body mass index, UDI (Urogenital Distress Inventory) scores. TOMUS subjects had a lower surgical success rate compared to ValUE subjects (66.3% vs 76.0%, p = 0.03). The AUC values of Valsalva leak point pressure, maximum urethral closure pressure, NTx, and vitamins D2, D3 and D2 plus D3 were 0.542, 0.561, 0.702, 0.627, 0.645 and 0.640, respectively. The AUC of NTx was significantly higher than the AUCs of Valsalva leak point pressure and maximum urethral closure pressure (p = 0.02 and 0.03, respectively).ConclusionsUrinary NTx was the best predictor of the mid urethral sling outcome. This test is not only noninvasive, it is also modifiable. Finding ideal modifiable risk factors prior to mid urethral sling surgery should be subject to future investigations.

OBJECTIVE Some selective estrogen receptor modulators (SERMs) have been associated with increased incidence of urinary incontinence and pelvic organ prolapse. This study explored the effects of five SERMs on the function and matrix components of the vagina and its supportive tissues. METHODS Fifty-six rats were administered SERMs by oral gavage for 8 weeks (n = 8 for each SERM): raloxifene, tamoxifen, idoxifene, bazedoxifene at three different doses, and bazedoxifene with conjugated estrogens. Thirty-two rats were used as controls (n = 8 per group): sham operation (no ovariectomy), ovariectomy only, ovariectomy with vehicle gavage, and 17β-estradiol (subcutaneous). Vaginal supportive tissue complex was tested by uniaxial tensile testing. Total collagen content (hydroxyproline) and glycosaminoglycan content (Blyscan) were measured. RESULTS Ovariectomy significantly decreased the mechanical integrity of the vagina and its supportive tissue complex, with a decrease in ultimate load and stiffness (all P < 0.05). Although 17β-estradiol supplementation maintained these properties similarly to sham operation, none of the SERMs was as effective--particularly idoxifene, bazedoxifene at higher doses, and bazedoxifene with conjugated estrogens (all P < 0.05). In addition, idoxifene and bazedoxifene induced increased total collagen content compared with sham or 17β-estradiol treatment (all P < 0.05). Glycosaminoglycan content did not change significantly. CONCLUSIONS Unlike 17β-estradiol, SERM supplementation does not fully prevent ovariectomy-induced deterioration in the biomechanical properties of the vagina and its supportive tissues, with the effects of idoxifene and bazedoxifene being the least. The paradoxically increased collagen content in these two groups may be related to increased formation of nonfunctional collagen.

Background and objective Strong evidence suggests that pelvic soft tissues soften during pregnancy to facilitate vaginal delivery while protecting against maternal birth injury. We hypothesized that these adaptations likely result in changes to the shape of the pelvic floor. Thus, this study aimed to compare midsagittal pelvic floor shapes from MRIs of nulliparous, gravid, and vaginally parous women using statistical shape modeling. Methods A retrospective study of 22 nulliparous, 29 gravid (vaginally nulliparous), and 18 vaginally parous women who underwent pelvic MRI was performed. The pelvic floor was segmented from pubic symphysis to coccyx as a 2D polyline in the midsagittal plane. Once corresponding landmarks were computed and the variances between them determined by principal component analysis, the principal component scores were calculated for modes that explained variance greater than noise. These became the dependent variables in a MANOVA with univariate ANOVAs, linear regressions, and Benjamini-Hochberg corrections post hoc. Two initial statistical shape analyses were conducted to analyze differences based on gestational age (1st/2nd vs 3rd trimester) and vaginal parity (VP1 vs VP2-4). There were significant differences based on gestational age, but not vaginal parity. Thus, the final statistical shape analysis evaluated pelvic floor shapes of nulliparous, 3rd trimester gravid, and all vaginally parous subjects. Results In the final analysis, six modes described variance—a measure of shape variability—greater than noise. Groups differed significantly for modes 1, 2, and 4 (p Conclusions The shape of the pelvic floor changes significantly during pregnancy and some of those changes are present after vaginal delivery. The fact that the nulliparous and gravid groups differ while the parous is similar to both suggests that some parous women regain their nulliparous shape after pregnancy and delivery while others do not. This indicates that remodeling during pregnancy and/or injury during vaginal delivery can have lasting effects on the pelvic floor.

The use of mesh to treat gynecologic disorders of pelvic organ prolapse and stress urinary incontinence is widespread. While mesh has provided many women relief of their symptoms and relatively good anatomical outcomes, surgeries employing mesh have had significant complications, resulting in the release of public health notifications, the up-classification of these devices, the discontinuation of mesh products by vendors, and multi-district litigation. To date the precise etiology of mesh complications is unknown; however, basic science research investigating the pathogenesis of mesh complications has increased over the past 10–15 years, and potential mechanisms have been identified. The purpose of this chapter is to provide an overview of the ex vivo and in vivo studies that have shed light on our understanding of the factors that contribute to mesh complications. Specifically, the impact of mesh textiles properties and mechanics on the host response will be explored. Additionally, this chapter will summarize the pertinent in vivo animal and human studies that have investigated the host response to polypropylene-based mesh. Although biological meshes have also been used in the treatment of gynecologic disorders, polypropylene urogynecologic meshes will be the main focus of this text. Lastly, the chapter will conclude with a future perspective of basic science research on urogynecologic meshes.

BACKGROUND: Polypropylene mesh is widely used for surgical treatment of pelvic organ prolapse and stress urinary incontinence. While these surgeries demonstrate favorable functional and anatomical outcomes, their use has been limited by complications, the two most common being exposure and pain. Growing evidence suggests T lymphocytes play a critical role in regulating the host response to biomaterials. OBJECTIVES: To define and characterize the T cell response and correlate the response to collagen deposition in fibrotic capsules in mesh tissue complexes removed for the complications of pain versus exposure. STUDY DESIGN: Patients who were scheduled to undergo a surgical excision of mesh for pain or exposure at Magee-Women’s Hospital were offered enrollment. Forty- two mesh-vagina tissue complexes were removed for the primary complaint of exposure (n=24) versus pain (n=18). Twenty-one patients agreed to have an additional vaginal biopsy away from the site of mesh and served as control tissue. T cells were examined via immunofluorescent labeling for cell surface markers CD4+ (T helper), CD8+ (cytotoxic) and foxp3 (T regulatory cell). Frozen sections were stained with H&E for gross morphology and picrosirius red for collagen fiber analysis. Interrupted sodium-dodecyl sulfate gel electrophoresis was used to quantify the content of collagens type I and III, and the collagen III/I ratio. Growth factors TGF-β and CTGF implicated in the development of fibrosis were measured via enzyme-linked immunosorbent assays. Data were analyzed using Student’s t-tests, mixed effects linear regression, and Spearman’s correlation coefficients. RESULTS: Demographic data were not different between groups except for BMI, which was 31.7 for the exposure group and 28.2 for pain (P=0.04). Tissue complexes demonstrated a marked, but highly localized foreign body response. We consistently observed a teardrop shaped fibroma encapsulating mesh fibers in both pain and exposure groups, with the T cells localized within the tip of this configuration away from the mesh-tissue interface. All three T cell populations were significantly increased relative to control - CD4(+) Thelper (P0.7). CONCLUSION: T cells appear to play a critical role in the long-term host response to mesh and may be a central pathway leading to complications. The complexity of this response warrants further investigation and has the potential to broaden our understanding of mesh biology and clinical outcomes.

Objective To evaluate the impact of prolapse meshes on vaginal smooth muscle structure (VaSM) and function, and to evaluate these outcomes in the context of the mechanical and textile properties of the mesh. Design Three months following the implantation of three polypropylene prolapse meshes with distinct textile and mechanical properties, mesh tissue explants were evaluated for smooth muscle contraction, innervation, receptor function, and innervation density. Setting Magee-Womens Research Institute at the University of Pittsburgh. Population Thirty-four parous rhesus macaques of similar age, parity, and pelvic organ prolapse quantification (POP–Q) scores. Methods Macaques were implanted with mesh via sacrocolpopexy. The impact of Gynemesh™ PS (Ethicon; n = 7), Restorelle® (Coloplast; n = 7), UltraPro™ parallel and UltraPro™ perpendicular (Ethicon; n = 6 and 7, respectively) were compared with sham-operated controls (n = 7). Outcomes were analysed by Kruskal–Wallis ANOVA, Mann–Whitney U–tests and multiple regression analysis (P

Exposure following pelvic organ prolapse repair has been observationally associated with wrinkling of the implanted mesh. The purpose of this study was to quantify the impact of variable boundary conditions on the out-of-plane deformations of mesh subjected to tensile loading. Using photogrammetry and surface curvature analyses, deformed geometries were accessed for two commercially available products. Relative to standard clamping methods, the amount of out-of-plane deformation significantly increased when point loads were introduced to simulate suture fixation in-vivo. These data support the hypothesis that regional increases in the concentration of mesh potentially enhance the host’s foreign body response, leading to exposure.

Women with refractory urgency urinary incontinence (ie, unresponsive to behavioral and pharmacological interventions) are treated with onabotulinumtoxinA or sacral neuromodulation.The objective of the study was to compare treatment efficacy and adverse events in women65 and ≥65 years old treated with onabotulinumtoxinA or sacral neuromodulation.This study was a planned secondary analysis of a multicenter, randomized trial that enrolled community-dwelling women with refractory urgency urinary incontinence to onabotulinumtoxinA or sacral neuromodulation treatments. The primary outcome was a change in mean daily urgency urinary incontinence episodes on a bladder diary over 6 months. Secondary outcomes included ≥75% urgency urinary incontinence episode reduction, change in symptom severity/quality of life, treatment satisfaction, and treatment-related adverse events.Both age groups experienced improvement in mean urgency urinary incontinence episodes per day following each treatment. There was no evidence that mean daily urgency urinary incontinence episode reduction differed between age groups for onabotulinumtoxinA (adjusted coefficient, -0.127, 95% confidence interval, -1.233 to 0.979; P = .821) or sacral neuromodulation (adjusted coefficient, -0.698, 95% confidence interval, -1.832 to 0.437; P = .227). Among those treated with onabotulinumtoxinA, women65 years had 3.3-fold greater odds of ≥75% resolution than women ≥65 years (95% confidence interval, 1.56 -7.02). Women65 years had a greater reduction in Overactive Bladder Questionnaire Short Form symptom bother scores compared with women ≥65 years by 7.49 points (95% confidence interval, -3.23 to -11.74), regardless of treatment group. There was no difference between quality of life improvement by age. Women ≥65 years had more urinary tract infections following onabotulinumtoxinA and sacral neuromodulation (odds ratio, 1.9, 95% confidence interval, 1.2-3.3). There was no evidence of age differences in sacral neuromodulation revision/removal or catheterization following onabotulinumtoxinA treatment.Younger women experienced greater absolute continence, symptom improvement, and fewer urinary tract infections; both older and younger women had beneficial urgency urinary incontinence episode reduction, similar rates of other treatment adverse events, and improved quality of life.

Background Parity is the greatest risk factor for the development of pelvic organ prolapse. The normally supported vagina is pulled up and back over the levator ani. Loss of vaginal angulation has been associated with prolapse and may represent injury to the vaginal supportive tissues. Objective We proposed and examined the following hypotheses: (1) pregnancy and delivery impact vaginal support, leading to loss of vaginal angle; (2) vaginal angulation is restored postpartum; and (3) uncomplicated vaginal delivery (VD) is associated with accelerated remodeling of the vaginal fibrillar matrix. Materials and Methods We prospectively enrolled a cohort of nulliparas in the first trimester of pregnancy, and abstracted demographic and delivery data. Metalloproteinase 9 (MMP-9) activity in the vagina was determined in the first and third trimesters and 1 year postpartum using a substrate activity assay. Uncomplicated VD was defined as none of the following: cesarean delivery, forceps or vacuum use, shoulder dystocia, obstetric anal sphincter laceration, or prolonged second-stage labor. Women were grouped dichotomously for comparison based on this definition. A subset of participants underwent transperineal ultrasound. Results We enrolled 173 women with mean age of 25 ± 6 years and a body mass index of 20 ± 7 kg/m2. Of the women, 67% identified as white/Caucasian, 27% black/African American, or 6% Hispanic/Latina. The mean delivery age was 39 ± 3 weeks, with 59% of participants experiencing uncomplicated VD. The MMP-9 median activity (ng/mg protein) was 242.0 (IQR, 18.7, 896.8; n = 157) in the first trimester, 130.8 (IQR, 14.6, 883.8; n = 148) in the third trimester, and 463.5 (IQR, 92.2, 900.0; n = 94) postpartum. The MMP-9 activity increased between the third trimester and 1 year postpartum (P = .006), with no significant difference between MMP-9 values in the first and third trimesters (P = .674). The vaginal angle became less acute from the first to the third trimester, and this change persisted postpartum. The vaginal angulation over the levator plate became more acute between the third trimester and postpartum in women who experienced uncomplicated VD compared to those who did not (−6.4 ± 22.1 degrees vs 17.5 ± 14.8 degrees; P = .017). Higher MMP-9 activity postpartum was associated with uncomplicated VD, with 67% of women in the third tertile achieving uncomplicated VD versus 39% in the first tertile (P = .029). Conclusion Loss of vaginal angulation occurs between trimesters, and women do not recover their baseline resting angle postpartum. MMP-9 activity increases postpartum. Women experiencing uncomplicated VD demonstrate higher postpartum MMP-9 activity and are more likely to have recovered their vaginal angle.

Defining patient characteristics that alter vascular anatomy at the sacrum is critical for avoiding life-threatening bleeding at the time of sacrocolpopexy. We tested the hypothesis that in thinner/older women, the bifurcations of the aorta and inferior vena cava (IVC) are lower relative to S1 resulting in less space accessible for suture/mesh placement, placing this group at increased risk of major vascular injury. In a retrospective cross-sectional study, CT scans were used to make 2D measurements and a 3D model of the aorta/IVC, intervertebral disc space, and bony anatomy using segmentation and modeling software. For analysis, Spearman’s and Pearson’s correlation, Student’s t test and the Mann-Whitney U test were used along with multivariate analysis of variance. Of eligible women who had undergone abdominal/pelvic CT, 107 were included. The median locations of the aortic and IVC bifurcations utilizing 2D analysis were at the inferior L4 and middle L5 vertebral body, respectively. In 10.2% of patients, the IVC was located at the L5-S1 disc space or lower; however, 3D modeling of this space which allowed assessment of the area below the S1 “drop off” showed that the amount of accessible space for suture/mesh placement was not decreased. Utilizing 2D analysis there was no statistically significant independent correlation between age or adiposity and the aortic or IVC bifurcation. Patients who were both elderly and thinner had a lower aortic bifurcation (p = 0.005) and a trend towards a lower IVC bifurcation (p = 0.082). In 10.2% of women, the IVC bifurcation descended at or below the L5-S1 disc space, suggesting that this group of women is at increased risk of major vascular injury. Patients who were both thin and elderly had lower bifurcations, but there was no difference in accessible surface area for suture placement on 3D analysis. 3D modeling improved visualization of the anatomy beyond the S1 “drop off” and may provide a future tool for surgical planning once predictors of high-risk anatomy are defined.

As an alternative to polypropylene mesh, we explored an extracellular matrix (ECM) bioscaffold derived from urinary bladder matrix (MatriStem™) in the repair of vaginal prolapse. We aimed to restore disrupted vaginal support simulating application via transvaginal and transabdominal approaches in a macaque model focusing on the impact on vaginal structure, function, and the host immune response. In 16 macaques, after laparotomy, the uterosacral ligaments and paravaginal attachments to pelvic side wall were completely transected (IACUC# 13081928). 6-ply MatriStem was cut into posterior and anterior templates with a portion covering the vagina and arms simulating uterosacral ligaments and paravaginal attachments, respectively. After surgically exposing the correct anatomical sites, in 8 animals, a vaginal incision was made on the anterior and posterior vagina and the respective scaffolds were passed into the vagina via these incisions (transvaginal insertion) prior to placement. The remaining 8 animals underwent the same surgery without vaginal incisions (transabdominal insertion). Three months post implantation, firm tissue bands extending from vagina to pelvic side wall appeared in both MatriStem groups. Experimental endpoints examining impact of MatriStem on the vagina demonstrated that vaginal biochemical and biomechanical parameters, smooth muscle thickness and contractility, and immune responses were similar in the MatriStem no incision group and sham-operated controls. In the MatriStem incision group, a 41% decrease in vaginal stiffness (P = 0.042), a 22% decrease in collagen content (P = 0.008) and a 25% increase in collagen subtypes III/I was observed vs. Sham. Active MMP2 was increased in both Matristem groups vs. Sham (both P = 0.002). This study presents a novel application of ECM bioscaffolds as a first step towards the rebuilding of vaginal support. Statement of Significance Pelvic organ prolapse is a common condition related to failure of the supportive soft tissues of the vagina; particularly at the apex and mid-vagina. Few studies have investigated methods to regenerate these failed structures. The overall goal of the study was to determine the feasibility of utilizing a regenerative bioscaffold in prolapse applications to restore apical (level I) and lateral (level II) support to the vagina without negatively impacting vaginal structure and function. The significance of our findings is two fold: 1. Implantation of properly constructed extracellular matrix grafts promoted rebuilding of level I and level II support to the vagina and did not negatively impact the overall functional, morphological and biochemical properties of the vagina. 2. The presence of vaginal incisions in the transvaginal insertion of bioscaffolds may compromise vaginal structural integrity in the short term.

Aims The Blaivas–Groutz nomogram defines voiding obstruction in women using Qmax from the NIF and the maximum detrusor pressure (Pdetmax) from the PFS. The aim of this study was to understand the relationship between NIF and PFS maximum flow rates in women with stress incontinence. Methods We analyzed the UDS of 597 women with stress-dominant urinary incontinence. Each subject underwent a NIF and then a PFS. Mixed model was used to test the hypothesis that the relationship between flow rates and voided volume (VV) were similar for NIF and PFS. Results There were 452 subjects with both NIF and PFS studies that met the inclusion criteria and had max flow rate (Qmax) for both NIF and PFS. The mean age was 53. Overall, higher VV were observed during PFS compared to NIF and subjects had higher Qmax with NIF compared to PFS. The relationship between Qmax and VV was significantly different between NIF and PFS (P

OBJECTIVES/SPECIFIC AIMS: Pelvic organ prolapse, a disorder in which the muscles of the pelvic floor are weakened over time, affects over a million women each year in the United States. A quarter of these women undergo a reconstructive procedure, increasingly using polypropylene mesh as mechanical reinforcement to the pelvic floor. However, the number of complications such as chronic pain and mesh erosion/exposure in women with vaginal mesh implants were reported at rates as high as 10%–20%. This indicates a limited understanding of the host response to mesh in vaginal tissue and strategies to reduce these complications. Utilizing a novel surgical technique in New Zealand white rabbits, we implant mesh analogously to human implantation and evaluate changes in the immunologic response at early (14 d) and tissue remodeling outcomes at late stages (90 and 180 d) of implantation. The mesh-tissue complex was removed from each rabbit and processed for histological staining as well as immunolabeling of immune cells, such as macrophages. Extracellular matrix protease assays and mechanical integrity of the tissue also evaluate the overall inflammatory response associated with each implant. METHODS/STUDY POPULATION: Commercially available polypropylene mesh was used to investigate the modulation of the immune response. An adapted radio frequency glow discharge method is used to create a stable negative charge on the surface of the mesh, followed by the sequential deposition of polycationic and polyanionic polymers to provide a stable, conformal, nanoscale coating. It is well known macrophages are characterized on a spectrum ranging from a proinflammatory M1 phenotype to an M2 anti-inflammatory phenotype. Interleukin-4, an immunomodulatory cytokine known to promote the M2 phenotype, is incorporated into the coating to be released in a controlled manner upon implantation. Utilizing a novel surgical technique in New Zealand white rabbits, we implant mesh using the “gold standard” abdominal sacrocolpopexy procedure and evaluate changes in the immunologic response at early (14 d) and tissue remodeling outcomes at late stages (90 and 180 d) of implantation. The procedure begins with an initial hysterectomy removing the uterus followed by creating space along the vaginal wall on both sides between the bladder and the rectum. Two 3×10 cm2 pieces of mesh are secured along both sides of the vaginal wall. The remaining flaps at the top are then secured to a ligament in the sacral/lumbar space, creating the support to the pelvic organs. Upon closing the incision, a partial thickness defect is made in the abdominal wall, and mesh is implanted inside to repair the abdominal muscle. Both of these implantations of mesh allow for the assessment of the immune response in the pelvic area (relevant for prolapse patients) and in the abdominal area (relevant for translation from hernia repair).The mesh-tissue complex was removed from each rabbit and processed for histological staining as well as immunolabeling of immune cells, such as macrophages. Extracellular matrix protease assays and mechanical integrity of the tissue also evaluate the overall inflammatory response associated with each implant. RESULTS/ANTICIPATED RESULTS: The results of this study show that implants into vaginal tissues elicited an increased host inflammatory response at 14 days as compared with those in the abdominal wall. However, at chronic time points the inflammatory response in the vagina was reduced as compared to that in the abdominal cavity. The present study also demonstrates the scale-up of a previous methodology for a nanoscale coating. We present a nanometer thickness, tunable, and uniform coating capable of releasing bioactive interleukin-4. We evaluated the biological functionality of the coated mesh via bioactivity studies and in vivo implantation. An ideal mesh would provide mechanical support to the pelvic floor while decreasing the inflammatory response and increasing integration with the surrounding native tissue. DISCUSSION/SIGNIFICANCE OF IMPACT: We developed an in vivo model clinically relevant to understanding the early host response to mesh in an anatomically relevant area, the vaginal microenvironment. Previous studies have been conducted in a rodent abdominal defect model while other work has been done in a nonhuman primate vaginal model, but the host response is only observed at later time points (>3 mo). Thus, we developed a rabbit model to investigate early responses and a novel coating to actively working towards improved tissue integration.

This study's aim was to determine whether the inclusion of superficial perineal structures in a finite-element simulation of vaginal delivery impacts the pubovisceral muscle and perineal body, two common sites of birth-related injury. The hypothesis, inferred from prevailing literature, was that these structures would have minimal influence (differences less than ±10%). Two models were made using the Visible Human Project's female cadaver to create a rigid, fixed pelvis, musculature held by spring attachments to that pelvis, and a rigid, ellipsoidal fetal head prescribed with an inferior displacement to simulate delivery. Injury site stretch ratios and fetal head and perineal body displacements and angles of progression were compared between the Omitted Model (which excluded the superficial perineal structures as is common practice) and the Included Model (which included them). Included Model stretch ratios were +107%, −9.84% and −14.6% compared to Omitted Model perineal body and right and left pubovisceral muscles, respectively. Included Model peak perineal body inferior displacement was +72.5% greater while similar anterior–posterior displacements took longer to reach. These results refute our hypothesis, suggesting superficial perineal structures impact simulations of vaginal delivery by inhibiting perineal body anterior–posterior displacement, which stretches and inferiorly displaces the perineal body.

Both stress and urge urinary incontinence affect a significant proportion of women, yet the treatment options currently available may lack long-term effectiveness or may be associated with significant adverse events limiting their use. Thus, novel treatment options are needed. Stem cells, with the ability to transform into multiple cell types or to self-renew, have been proposed as a potential treatment option for both stress and urge incontinence. The majority of research has been performed in animal models and has shown that urethral or intradetrusor injection of various types of stem cells improves surrogate markers of incontinence. Although many of these studies have shown promising effects, significant research is still needed before translating these findings into clinical practice.

We measured urinary biomarker levels in women with refractory urgency urinary incontinence and controls at baseline and 6 months after treatment with sacral neuromodulation or intradetrusor injection of onabotulinumtoxinA. We also assessed the association of baseline biomarkers with posttreatment urgency urinary incontinence episodes and overactive bladder symptom bother outcomes.First morning urine samples were collected from consented trial participants and age matched women without urgency urinary incontinence. Biomarkers reflecting general inflammation, neuroinflammation, afferent neurotransmitters and tissue remodeling were measured using standardized enzyme-linked immunosorbent assay and activity assays as appropriate. Symptom bother was assessed by the overactive bladder questionnaire and urgency urinary incontinence episodes were determined by bladder diary. Linear models were used to examine differences in mean biomarker levels and the change in urgency urinary incontinence episodes and symptom bother between baseline and 6 months. Modest evidence of a potential association was represented by p ≤0.01 and p ≤0.004 represented moderate evidence of an association with outcomes.Baseline biomarker levels differed little between cases and controls except tropoelastin (p = 0.001) and N-terminal telopeptide collagen type 1 (p 0.001). Changes in biomarker levels 6 months after intervention included decreases in collagenase (p 0.001) in both treatment groups and increases in interleukin-8 (p = 0.002) and matrix metalloprotease-9 (p0.001) in the onabotulinumtoxinA group. Higher baseline calcitonin gene-related peptide across both treatments (p = 0.007) and nerve growth factor in the onabotulinumtoxinA arm (p = 0.007) were associated with less reduction in overactive bladder symptom bother.Refractory urgency urinary incontinence is a complex condition. These data suggest that matrix remodeling and neuropeptide mediation may be involved in its pathophysiological mechanisms and response to treatment.

Parity is the leading risk factor for the development of pelvic organ prolapse. To assess the impact of pregnancy and delivery on vaginal tissue, researchers commonly use nonhuman primate (NHP) and rodent models. The purpose of this study was to evaluate the ewe as an alternative model by investigating the impact of parity on the ewe vaginal mechanical properties and collagen structure.Mechanical properties of 15 nulliparous and parous ewe vaginas were determined via uniaxial tensile tests. Collagen content was determined by hydroxyproline assay and collagen fiber thickness was analyzed using picrosirius red staining. Outcome measures were compared using Independent samples t or Mann-Whitney U tests. ANOVA (Gabriel's pairwise post-hoc test) or the Welch Alternative for the F-ratio (Games Howell post-hoc test) was used to compare data with previously published NHP and rodent data.Vaginal tissue from the nulliparous ewe had a higher tangent modulus and tensile strength compared with the parous ewe (p 0.025). The parous ewe vagina elongated 42 % more than the nulliparous ewe vagina (p = 0.015). No significant differences were observed in collagen structure among ewe vaginas. The tangent modulus of the nulliparous ewe vagina was not different from that of the NHP or rodent (p = 0.290). Additionally, the tangent moduli of the parous ewe and NHP vaginas did not differ (p = 0.773).Parity has a negative impact on the mechanical properties of the ewe vagina, as also observed in the NHP. The ewe may serve as an alternative model for studying parity and ultimately prolapse development.

Pelvic floor disorders affect up to 24% of adult women in the United States, and many patients with pelvic organ prolapse (POP) choose to undergo surgical repair to improve their quality of life. While a variety of surgical repair approaches and techniques are utilized, including mesh augmentation, there is limited comparative effectiveness and safety outcome data guiding best practice. In conjunction with device manufacturers, federal regulatory organizations, and professional societies, the American Urogynecologic Society developed the Pelvic Floor Disorders Registry (PFDR) designed to improve the quality of POP surgery by facilitating quality improvement and research on POP treatments. The PFDR will serve as a resource for surgeons interested in benchmarking and outcomes data and as a data repository for Food and Drug Administration-mandated POP surgical device studies. Provider-reported clinical data and patient-reported outcomes will be collected prospectively at baseline and for up to 3 years after treatment. All data elements including measures of success, adverse events, and surgeon characteristics were identified and defined within the context of the anticipated multifunctionality of the registry, and with collaboration from multiple stakeholders. The PFDR will provide a platform to collect high-quality, standardized patient-level data from a variety of nonsurgical (pessary) and surgical treatments of POP and other pelvic floor disorders. Data from this registry may be used to evaluate short- and longer-term treatment outcomes, patient-reported outcomes, and complications, as well as to identify factors associated with treatment success and failure with the overall goal of improving the quality of care for women with these conditions.

Mixed urinary incontinence (MUI) can be a challenging condition to manage. We describe the protocol design and rationale for the Effects of Surgical Treatment Enhanced with Exercise for Mixed Urinary Incontinence (ESTEEM) trial, designed to compare a combined conservative and surgical treatment approach versus surgery alone for improving patient-centered MUI outcomes at 12 months. ESTEEM is a multisite, prospective, randomized trial of female participants with MUI randomized to a standardized perioperative behavioral/pelvic floor exercise intervention plus midurethral sling versus midurethral sling alone. We describe our methods and four challenges encountered during the design phase: defining the study population, selecting relevant patient-centered outcomes, determining sample size estimates using a patient-reported outcome measure, and designing an analysis plan that accommodates MUI failure rates. A central theme in the design was patient centeredness, which guided many key decisions. Our primary outcome is patient-reported MUI symptoms measured using the Urogenital Distress Inventory (UDI) score at 12 months. Secondary outcomes include quality of life, sexual function, cost-effectiveness, time to failure, and need for additional treatment. The final study design was implemented in November 2013 across eight clinical sites in the Pelvic Floor Disorders Network. As of 27 February 2016, 433 total/472 targeted participants had been randomized. We describe the ESTEEM protocol and our methods for reaching consensus for methodological challenges in designing a trial for MUI by maintaining the patient perspective at the core of key decisions. This trial will provide information that can directly impact patient care and clinical decision making.

Pelvic organ prolapse is a common condition impacting the quality of life of millions of women worldwide. Although vaginal estrogen is widely used in women with prolapse, little is known regarding estrogen's benefits on the biomechanical properties of vaginal tissue. Here, we aimed to examine the effect of prolapse on the biomechanical properties of the vagina and determine alterations in vaginal mechanics in the presence and absence of hormone therapy (HT).We characterized the viscoelastic properties of vaginal biopsies from age-matched premenopausal women without (n = 12) and with prolapse (n = 8) and postmenopausal women with prolapse on (n = 18) and off HT (n = 9). Utilizing a single-lap shear testing protocol, full-thickness anterior vaginal biopsies were subjected to ±10% shear strain over a range of frequencies (1-90 Hz). This applied energy is either dissipated (viscous) or stored (elastic) as a function of frequency due to compositional or structural differences in the tissue.Prolapsed tissue was more stiff (higher complex modulus) under shear deformation resulting from increases in both elastic (elastic modulus) and viscous (loss modulus) contributions, with non-prolapsed premenopausal women being the least stiff. Postmenopausal women with prolapse currently on HT were the most stiff of all the groups.These data suggest that prolapsed tissue has an increased elastic contribution likely resulting from changes in biochemical constituents, and hormones increase the viscous contribution of prolapsed tissue. Overall, this study design characterized the viscoelastic properties of vaginal biopsies and may be utilized to conduct longitudinal studies to better understand the mechanisms of prolapse development and progression.

AIMS To compare quality of life (QoL) and factors associated with QoL change after retropubic (RMUS) and transobturator midurethral slings (TMUS) using the Incontinence Impact Questionnaire (IIQ) and the International Consultation on Incontinence Questionnaire (ICIQ). METHODS Five hundred ninety-seven women in a multicenter randomized trial of RMUS versus TMUS were examined. The IIQ and the ICIQ were obtained at baseline and at 12 and 24 months. Repeated-measures analysis of variance tested for differences by treatment group over time. Multivariable analysis identified factors associated with QoL change at 12 months postoperative, controlling for treatment group and baseline QoL. RESULTS Improvement in IIQ was associated with the following: treatment success, younger age, improvement in stress urinary incontinence (SUI) symptom severity, and bother (all P < 0.05). Improvement in ICIQ was associated with treatment success, younger age, improvement in SUI symptom severity and bother, lower body mass index, and no reoperation (all P < 0.05). Improvement of the IIQ was stable over time (P = 0.35) for both treatment groups (P = 0.66), whereas the ICIQ showed a small but clinically insignificant decline (P = 0.03) in both treatment groups (P = 0.51). CONCLUSIONS Postoperative QoL was improved after RMUS and TMUS. Measures of QoL functioned similarly, although more surgically modifiable urinary incontinence factors predicted improvement with the IIQ.

The use of polypropylene meshes for surgical repair of pelvic organ prolapse (POP) has been limited by complications, including mesh exposure, encapsulation, and pain. Numerous products are available with a wide array of textile and structural properties. It is thought that complications may be related, in part, to mesh structural properties. However, few descriptions of these properties exists to directly compare products. The aim of this study was to determine the textile and structural properties of five commonly used prolapse mesh products using a ball-burst failure protocol. Porosity, anisotropic index, and stiffness of Gynemesh PS (n = 8), the prototype polypropylene mesh for prolapse repair, was compared with four newer-generation mesh produces: UltraPro (n = 5), SmartMesh (n = 5), Novasilk (n = 5), and Polyform (n = 5). SmartMesh was found to be the most porous, at 78 % ± 1.4 %. This value decreased by 21 % for Gynemesh PS (p

Midurethral slings are increasingly used for the treatment of stress incontinence, but there are limited data comparing types of slings and associated complications.We performed a multicenter, randomized equivalence trial comparing outcomes with retropubic and transobturator midurethral slings in women with stress incontinence. The primary outcome was treatment success at 12 months according to both objective criteria (a negative stress test, a negative pad test, and no retreatment) and subjective criteria (self-reported absence of symptoms, no leakage episodes recorded, and no retreatment). The predetermined equivalence margin was +/-12 percentage points.A total of 597 women were randomly assigned to a study group; 565 (94.6%) completed the 12-month assessment. The rates of objectively assessed treatment success were 80.8% in the retropubic-sling group and 77.7% in the transobturator-sling group (3.0 percentage-point difference; 95% confidence interval [CI], -3.6 to 9.6). The rates of subjectively assessed success were 62.2% and 55.8%, respectively (6.4 percentage-point difference; 95% CI, -1.6 to 14.3). The rates of voiding dysfunction requiring surgery were 2.7% in those who received retropubic slings and 0% in those who received transobturator slings (P=0.004), and the respective rates of neurologic symptoms were 4.0% and 9.4% (P=0.01). There were no significant differences between groups in postoperative urge incontinence, satisfaction with the results of the procedure, or quality of life.The 12-month rates of objectively assessed success of treatment for stress incontinence with the retropubic and transobturator approaches met the prespecified criteria for equivalence; the rates of subjectively assessed success were similar between groups but did not meet the criteria for equivalence. Differences in the complications associated with the two procedures should be discussed with patients who are considering surgical treatment for incontinence. (ClinicalTrials.gov number, NCT00325039.)

Recently, numerous type I macroporous polypropylene vaginal meshes have been introduced into the market with little known of their differences. Seven vaginal meshes were obtained and loaded to failure (n = 5/type). Additional cyclic loading determined permanent deformation with submaximal loading. The load elongation curves demonstrated a bilinear response with lower stiffness (N/mm), followed by higher stiffness. Ascend™ was the stiffest mesh in both regions of the load elongation curve (0.72 and 1.66 N/mm) with the lowest transition to higher stiffness (13.4%). Polyform™ had the highest failure load (53.8 N) while Ultrapro™ had the lowest (7.83 N). Novasilk™ (89.4%) and Ultrapro™ (87.9%) had the highest relative elongations at mesh failure while Ascend™ had the lowest (40.2%). Ascend™ had the least relative elongation after three protocols of cyclic loading (3.0%, 9.8%, and 9.7%). Current vaginal meshes demonstrate marked variation in biomechanical characteristics which may impact the in vivo behavior.