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BACKGROUND: Despite large trials designed to guide management on whether to perform a prophylactic continence procedure at the time of pelvic organ prolapse (POP) repair, it remains unclear if a staged or interval approach confers advantages in treatment of bothersome stress urinary incontinence (SUI) in women without bothersome SUI before their POP repair. OBJECTIVE: The objective of this study was to compare success of concomitant versus interval slings for the prevention/treatment of de novo bothersome SUI after POP repair. STUDY DESIGN: This multicenter retrospective cohort with prospective follow-up enrolled women with minimal or no SUI symptoms who underwent minimally invasive apical surgery for stage 2 or higher POP between 2011 and 2018 and had a concomitant sling placed at the time of POP surgery or an interval sling placed. Prospectively, all patients were administered the Urogenital Distress Inventory Short-Form 6, the Patient Global Impression of Improvement, and questions on reoperation/retreatment and complications. RESULTS: A total of 120 patients had concomitant slings, and 60 had interval slings. There were no differences in the proportion of patients who had intrinsic sphincter deficiency (22% vs 20%), although the concomitant sling group was more likely to have a positive cough stress test result (30% vs 8%, P = 0.006). The interval sling group was more likely to report “yes” to SUI symptoms on Urogenital Distress Inventory Short-Form 6 (3% vs 30%, P = 0.0006) and during their postoperative visit (0% vs 24%, P < 0.0001). There were no differences in surgical complications. CONCLUSIONS: Among women with minimal or no SUI symptoms undergoing prolapse repair, concomitant slings resulted in lower rates of bothersome SUI compared with similar women undergoing interval sling placement.

Surgical proctoring requires increasing resources in growing healthcare systems. In addition, travel has become less safe in the era of COVID-19. This study demonstrates surgeon satisfaction and safety with tele-proctoring in robotic gynecologic surgery. This pilot study assesses surgeon satisfaction and operative outcomes with a novel operative tele-proctoring system with a continuous two-way video-audio feed that allows the off-site surgeon to see the operating room, surgical field, and hands of the robotic surgeon. After thorough system testing, two experienced surgeons underwent tele-proctoring for hospital credentialing, completing 7 total cases. Each completed pre- and post-surveys developed from the Michigan Standard Simulation Experience Scale. Surgical characteristics were compared between tele-proctored cases and 59 historical cases proctored in-person over the last 8 years. Surgeons reported unanimous high satisfaction with tele-proctoring (5 ± 0). There were no major technologic issues. Five of the tele-proctored cases and 35 of controls were hysterectomies. Mean age was 48.2 ± 1.4 years, mean BMI was 29.6 ± 0.9 kg/m2, and mean uterine weight was 152 ± 112.3 g. Two-thirds had prior abdominal surgery (P > 0.1). Tele-proctored hysterectomies were 58 ± 6.5 min shorter than controls (P = 0.001). There were no differences in EBL or complication rates (P > 0.1). Tele-proctoring resulted in high surgeon satisfaction rates with no difference in EBL or complications. Tele-mentoring is a natural extension of tele-proctoring that could provide advanced surgical expertise far beyond where we can physically reach.

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.

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.

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

STUDY OBJECTIVE: To establish face and construct validity for a novel variation of American College of Obstetrics and Gynecology “Flowerpot Model” for transvaginal hysterectomy (TVH) surgical simulation with improved vesicovaginal dissection during surgical education simulation. DESIGN: Cross-sectional face and construct validation study using the “Flowerpot Model.” The vesicovaginal dissection plane was modified to include additional felt and balloon materials to simulate the bladder. SETTING: Single academic center. PARTICIPANTS: Fourteen residents and fellows, postgraduate year (PGY) 2 to 6, subdivided into junior (n = 8) with ≤10 prior TVH surgeries and senior groups (n = 6) with >10 prior TVH surgeries performed. INTERVENTIONS: All subjects watched a brief introductory video and then were filmed simulating a TVH. MEASUREMENTS AND MAIN RESULTS: For face validity, subjects completed an anatomic checklist and pre/post simulation satisfaction survey. For construct validation, 2 independent, blinded expert surgeons (M.A. and J.M.) graded films using the Global Rating Scale of Operative Performance (GRS). Primary outcome was mean GRS between groups. The junior group consisted of PGY 2 to 3 with ≤ 10 prior TVH, median 7.5 (interquartile range [IQR] 6.75) and senior group PGY 3 to 6 with >10 TVH, median 19 (IQR 10) (p

OBJECTIVE The purpose of this analysis is to determine if postoperative opioid usage differs among women randomized to office or phone preoperative counseling for pelvic organ prolapse surgery. METHODS This was a planned exploratory analysis of the Patient Preparedness for Pelvic Organ Prolapse Surgery study, which randomized women to standardized preoperative counseling by office visit or phone call before prolapse surgery. Inclusion criteria were the completion of the assigned counseling intervention and submission of a 7-day postoperative pain and medication diary. Multivariable logistic regression was done to assess the association between counseling method and total opioid use while controlling for variables significant on univariate analysis (surgery type and county of residence). RESULTS There were 84 participants with postoperative data (41 office, 43 phone). Median total number of 5-mg oxycodone tablets used was higher for the office group (5 [interquartile range, 0-10]) than the phone group (0 [interquartile range, 0-2], P = 0.002). On multivariable logistic regression, women who underwent phone counseling were less likely to be in the highest third of opioid use when controlling for surgery type and county of residence (odds ratio, 0.23; P = 0.012; 95% confidence interval, 0.07-0.72). Daily pain scores and nonopioid medication use (nonsteroidal anti-inflammatory medications and acetaminophen) were similar between groups (P > 0.05). CONCLUSIONS Despite similar pain scores, women who received preoperative phone counseling before pelvic organ prolapse surgery had lower opioid utilization than those with office counseling. Further research is needed to determine the optimal method of preoperative counseling and its role in postoperative pain management.

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.

Nicotinic acid (niacin) has been used for decades as an antidyslipidemic drug in man. Its main target is the hydroxy-carboxylic acid receptor HCA2 (GPR109A), a G protein-coupled receptor. Other acids and esters such as methyl fumarate also interact with the receptor, which constituted the basis for the current study. We synthesized a novel series of substituted propenoic acids, such as fumaric acid esters, fumaric acid amides and cinnamic acid derivatives, and determined their affinities for the HCA2 receptor. We observed a rather restricted binding pocket on the receptor with trans-cinnamic acid being the largest planar ligand in our series with appreciable affinity for the receptor. Molecular modeling and analysis of the structure-activity relationships in the series suggest a planar trans-propenoic acid pharmacophore with a maximum length of 8 Å and out-of-plane orientation of the larger substituents.

Persistent viruses, such as cytomegalovirus or human immunodeficiency virus, cause major perturbations of CD8(+) T-lymphocyte subpopulations. To test whether chronic infection with hepatitis B virus (HBV) could also be responsible for such modifications, we analyzed the expression of CD27, CD28, CCR7, and perforin in blood CD8(+) T lymphocytes. In comparison to healthy subjects and patients recovering from acute hepatitis B, chronic hepatitis B patients showed higher percentages of naive CD8(+) T lymphocytes (CD45RA(+)CD27(+)CD28(+)), and lower percentages of intermediately-differentiated CD27(+)CD28(-)CD8(+) T cells. The late differentiated CD45RA(+)CD27(-)CD28(-) subset was also present in a large percentage in some patients, but no statistically significant difference with healthy controls was observed. Removal from the circulation of intermediately-differentiated CD8(+) T lymphocytes may occur during chronic HBV infection, favoring the recruitment of naive cells. This may result in impairment of the generation of functionally-competent memory cells, and an inability to achieve control of HBV replication.

T lymphocyte responses to hepatitis B virus (HBV) core antigen (HBcAg) are vigorous and easily detectable in vitro during recovery from acute hepatitis B but significantly weaker in patients with chronic HBV infection. In contrast, T cell responses to hepatitis B surface antigen (HBsAg) are almost undetectable during infection and even in a substantial fraction of subjects receiving vaccination with HBsAg. The aim of this study was to investigate whether the use of dendritic cells (DCs) in an in vitro assay could increase the detection of HBV-specific T cells in these conditions. Autologous monocyte-derived DCs, compared to direct HBsAg addition to the cultures, increased the stimulation of HBs-specific T cells. These were detected in 73% of healthy subjects who had recently received hepatitis B vaccine and in 43% of patients recovering from acute hepatitis B. Likewise, proliferation in response to DC-presented HBcAg was detected in both CD4(+) and CD8(+) T cells from the majority of chronic hepatitis B patients. A longitudinal evaluation of HBc-specific T cell responses during and after a 1-year treatment with pegylated interferon (IFN)-alpha showed that HBc-specific CD4(+) T cell responses had no correlation with sustained virus suppression whereas CD8(+) T cell responses were more frequently detected in patients able to control HBV replication after therapy interruption. The use of autologous DCs as antigen-presenting cells appears applicable to clinically relevant in vitro evaluation of T cell responses, particularly in those conditions characterized by low frequency of circulating antigen-specific cells and suboptimal in vivo activation. J. Med. Virol. 81:332-339, 2009. (c) 2008 Wiley-Liss, Inc.

Background Treatment with interferon-α (IFN-α) leads to a response in only a minority of patients with chronic hepatitis B virus (HBV) infection, but the reasons for this are poorly understood. It was recently shown that in patients with chronic HBV infection, CD4+CD25+ regulatory T-cells (Treg) can suppress the HBV-specific immune response. We aimed to investigate whether in non-responders to IFN-α therapy Treg contribute to treatment failure by downregulating the HBV-specific T-cell responses. Patients and methods Fourteen patients positive for hepatitis B e antigen received pegylated IFN-α monotherapy for 52 weeks and were followed for 26 weeks. Results Compared with non-responders, responders displayed an increased HBV-specific T-helper cell proliferation. At the start of treatment there was no difference in the frequencies of CD4+CD25+ Treg between responders and non-responders. During therapy, the frequency of CD4+CD25+ Treg increased in non-responders, but not in responders. In contrast to the responders, the non-responders showed a significant increase in the frequency of interleukin-10-producing cells. Treg depletion resulted in increased proliferation capacity, but did not affect the frequency of interleukin-10-producing cells measured during the course of the treatment. Conclusion This study indicates that Treg might have an important role in HBV persistence during and after pegylated IFN-α therapy.

To investigate whether therapy with alpha interferon (IFN-α) induces changes in intrahepatic antigen-presenting cells (APCs), we obtained liver biopsy specimens before, during, and after therapy with IFN-α from chronic hepatitis B patients whose viral load had already been reduced by at least 8 weeks of treatment with lamivudine. HLA-DR, CD1a, and CD83 were not modified by the therapy. The intralobular expression of CD68 on Kupffer cells remained stable, denoting no changes in the number of resident macrophages during IFN-α treatment. In contrast, CD14 was weakly expressed in the absence of IFN-α and was significantly up-regulated during therapy. At the same time, the levels of soluble CD14 and interleukin-10 in plasma increased significantly. In vitro, monocytes maintained in the presence of IFN-α differentiated into macrophages or dendritic cells with higher levels of expression of CD14 than that for the control cultures. During therapy with IFN-α, T-cell infiltration in the portal spaces was reduced, mainly due to a significant decrease in the number of CD8+T cells. These findings show that IFN-α is biologically active on APCs in vivo and in vitro and suggest that this newly described regulatory function, together with the already known inhibitory effects on lymphocytes, may cooperate to reduce inflammation and consequent tissue damage in patients with chronic viral hepatitis.