Cost-effectiveness of pessary therapy versus surgery for symptomatic pelvic organ prolapse: an economic evaluation alongside a randomised non-inferiority controlled trial.

OBJECTIVE: To evaluate the cost-effectiveness of pessary therapy as an initial treatment option compared with surgery for moderate to severe pelvic organ prolapse (POP) symptoms in secondary care from a healthcare and a societal perspective. DESIGN: Economic evaluation alongside a multicentre randomised controlled non-inferiority trial with a 24-month follow-up. SETTING: 21 hospitals in the Netherlands, recruitment conducted between 2015 and 2022. PARTICIPANTS: 1605 women referred to secondary care with symptomatic prolapse stage ≥2 were requested to participate. Of them, 440 women gave informed consent and were randomised to pessary therapy (n=218) or to surgery (n=222) in a 1:1 ratio stratified by hospital. INTERVENTIONS: Pessary therapy and surgery. PRIMARY AND SECONDARY OUTCOME MEASURES: The Patient Global Impression of Improvement (PGI-I), a 7-point scale dichotomised into successful versus unsuccessful, with a non-inferiority margin of -10%; quality-adjusted life-years (QALYs) measured by the EQ-5D-3L; healthcare and societal costs were based on medical records and the institute for Medical Technology Assessment questionnaires. RESULTS: For the PGI-I, the mean difference between pessary therapy and surgery was -0.05 (95% CI -0.14; 0.03) and -0.03 (95% CI -0.07; 0.002) for QALYs. In total, 54.1% women randomised to pessary therapy crossed over to surgery, and 3.6% underwent recurrent surgery. Healthcare and societal costs were significantly lower in the pessary therapy (mean difference=-€1807, 95% CI -€2172; -€1446 and mean difference=-€1850, 95% CI -€2349; -€1341, respectively). The probability that pessary therapy is cost-effective compared with surgery was 1 at willingness-to-pay thresholds between €0 and €20 000/QALY gained from both perspectives. CONCLUSIONS: Non-inferiority of pessary therapy regarding the PGI-I could not be shown and no statistically significant differences in QALYs between interventions were found. Due to significantly lower costs, pessary therapy is likely to be cost-effective compared with surgery as an initial treatment option for women with symptomatic POP treated in secondary care. TRIAL REGISTRATION NUMBER: NTR4883.

Two-Year Preclinical Evaluation of Long-Term Absorbable Poly-4-hydroxybutyrate Scaffold for Surgical Correction of Pelvic Organ Prolapse.

INTRODUCTION AND HYPOTHESIS: Fully absorbable implants may be an alternative to permanent meshes in the correction pf pelvic organ prolapse (POP) as they may reduce adverse events by promoting tissue regeneration and collagen metabolism. This study was aimed at evaluating the long-term host and biomechanical response to a fully absorbable poly-4-hydroxybutyrate (P4HB) scaffold in comparison with polypropylene (PP) mesh. METHODS: Poly-4-hydroxybutyrate scaffold (n = 16) and PP mesh (n = 16) were surgically implanted in the posterior vaginal wall of parous female Dohne Merino sheep. Vaginal explants were evaluated in terms of gross necropsy, host response (immune response, collagen deposition, tissue regeneration), biomechanics, and degradation of P4HB at 12 and 24 months post-implantation. RESULTS: Gross necropsy revealed no infection or fluid collection using P4HB or PP. At 12 months, exposures were observed with both P4HB (3 out of 8) and PP (4 out of 8), whereas at 24 months, exposures were observed only with PP (4 out of 8). The tensile stiffness of the P4HB explants was maintained over time despite complete absorption of P4HB. The collagen amount of the vaginal tissue after P4HB implantation increased over time and was significantly higher than PP at 24 months. P4HB scaffolds exhibited significantly lower myofibroblast differentiation than PP meshes at 24 months. CONCLUSIONS: The P4HB scaffold allowed for gradual load transfer to the vaginal wall and resulted in mechanically self-sufficient tissue. P4HB scaffold had a more favorable host response than PP mesh, with higher collagen content, lower myofibroblastic differentiation, and no exposures at 24 months. P4HB scaffolds have potential as an alternative to permanent implants in treating POP.

The Regenerative Capacity of Tissue-Engineered Amniotic Membranes.

Scaffolds can be introduced as a source of tissue in reconstructive surgery and can help to improve wound healing. Amniotic membranes (AMs) as scaffolds for tissue engineering have emerged as promising biomaterials for surgical reconstruction due to their regenerative capacity, biocompatibility, gradual degradability, and availability. They also promote fetal-like scarless healing and provide a bioactive matrix that stimulates cell adhesion, migration, and proliferation. The aim of this study was to create a tissue-engineered AM-based implant for the repair of vesicovaginal fistula (VVF), a defect between the bladder and vagina caused by prolonged obstructed labor. Layers of AMs (with or without cross-linking) and electrospun poly-4-hydroxybutyrate (P4HB) (a synthetic, degradable polymer) scaffold were joined together by fibrin glue to produce a multilayer scaffold. Human vaginal fibroblasts were seeded on the different constructs and cultured for 28 days. Cell proliferation, cell morphology, collagen deposition, and metabolism measured by matrix metalloproteinase (MMP) activity were evaluated. Vaginal fibroblasts proliferated and were metabolically active on the different constructs, producing a distributed layer of collagen and proMMP-2. Cell proliferation and the amount of produced collagen were similar across different groups, indicating that the different AM-based constructs support vaginal fibroblast function. Cell morphology and collagen images showed slightly better alignment and organization on the un-cross-linked constructs compared to the cross-linked constructs. It was concluded that the regenerative capacity of AM does not seem to be affected by mechanical reinforcement with cross-linking or the addition of P4HB and fibrin glue. An AM-based implant for surgical repair of internal organs requiring load-bearing functionality can be directly translated to other types of surgical reconstruction of internal organs.

Differences in rates of severe perineal trauma between midwife-led and obstetrician-led care in the Netherlands: A nationwide cohort study.

Objective: To investigate trends and rates of severe perineal trauma (SPT), also known as obstetric anal sphincter injury (OASI), between midwife-led and obstetrician-led care in the Netherlands, and factors associated with SPT. Methods: This nationwide cohort study included registry data from 2000 to 2019 (n = 2,169,950) of spontaneous vaginal births of term, live, cephalic, single infants, without a (previous) caesarean section or assisted vaginal birth.First, trends of SPT and episiotomy were shown. Second, differences in SPT rates between midwife- and obstetrician-led care were assessed. Third, associations of care factors with SPT were examined. Multivariable logistic regression analyses were used to determine which factors were important in the associations. All outcomes were stratified for parity. Results: Over time, the SPT incidence increased mainly in midwife-led care and episiotomy rates decreased. Compared to midwife-led care, SPT rates were lower in obstetrician-led care among primiparous women (aOR 0.78; 99 % CI 0.74-0.81) and comparable among multiparous women (aOR 1.04; 99 % CI 0.99-1.10). Among women without epidural analgesia, these differences were smaller for primiparous women (aOR 0.88; 99 % CI 0.84-0.92), but the SPT rate was higher in obstetrician-led care among multiparous women (aOR 1.09; 99 % CI 1.03-1.15). Among women without shoulder dystocia, induction, augmentation, and pain medication, SPT rates were comparable among primiparous women, but higher among multiparous women in obstetrician-led care. In midwife-led care, SPT occurred more often among hospital versus home births. In obstetrician-led care, lower SPT incidences were found among births with epidural analgesia and for multiparous women with induction or augmentation. Conclusions: Among spontaneous vaginal births, induction, augmentation, and epidural analgesia in obstetrician-led care may be an explanatory factor for the higher incidence of SPT among primiparous women in midwife-led care. More research is needed to explain differences in SPT rates and to understand how SPT can be prevented, while maintaining a high intact perineum rate.

An Improved Understanding of the Pathophysiology of Pelvic Organ Prolapse: A 3D In Vitro Model under Static and Mechanical Loading Conditions.

The suboptimal outcomes of pelvic organ prolapse (POP) surgery illustrate the demand for improved therapies. However, their development is hampered by the limited knowledge on the cellular pathophysiology of POP. Current investigations, that are limited to tissues and 2D in vitro models, provide highly inconclusive results on how the extracellular matrix (ECM) metabolism and fibroblasts are affected in POP. This study uses a physiologically relevant 3D in vitro model to investigate the cellular pathophysiology of POP by determining the differences between POP and non-POP fibroblasts on ECM metabolism, proliferation, and fibroblast-to-myofibroblast (FMT) transition. This model, based on the synthetic and biomimetic polyisocyanide hydrogel, enables the incorporation of mechanical loading, which simulates the forces exerted on the pelvic floor. Under static conditions, 3D cultured POP fibroblasts are less proliferative, undergo FMT, and exhibit lower collagen and elastin contents compared to non-POP fibroblasts. However, under mechanical loading, the differences between POP and non-POP fibroblasts are less pronounced. This study contributes to the development of more comprehensive models that can accurately mimic the POP pathophysiology, which will aid in an enhanced understanding and may contribute to improved therapies in the future.

Safety and Efficacy Report for the Use of Poly-4-Hydroxybutyrate as a Retropubic Mid-Urethral Sling (MUS) for Stress Urinary Incontinence: A Prospective 24 Months Follow-Up of New Poly-4-Hydroxybutyrate TephaFlex SUI Bioresorbable MUS.

STUDY OBJECTIVE: To investigate the feasibility and safety of the retropubic mid-urethral sling (MUS) procedure with a resorbable mesh implant made of poly-4-hydroxybutyrate (P4HB). DESIGN: A prospective clinical cohort study with 24 months follow-up. SETTING: A tertiary academic hospital. PATIENTS: Seventeen women with moderate to severe stress urinary incontinence (SUI). INTERVENTIONS: A retropubic MUS procedure with P4HB sling. MEASUREMENTS AND MAIN RESULTS: Seventeen women underwent an uncomplicated MUS procedure with a new sling made of resorbable P4HB. Following safety criteria, there has been no need to stop the study before 24 months' end point. Three serious adverse events were reported during follow-up: (1) inability to void urine after 1 week postsurgery, (2) a hysterectomy and bilateral oophorectomy performed due to a precancerous endometrial lesion at 16 months after initial MUS procedure and (3) exposed mesh with a part of device sheath left behind. These participants underwent an uncomplicated reintervention with no additional and/or permanent harm. Reinterventions because of failure of cure contained 3 second MUS procedures and one admission of urethral bulking agent. Seventy-six percent and 47 percent of patients were objectively cured of SUI at 12 and 24 months, respectively. CONCLUSIONS: Preliminary evidence suggests that a sling made of P4HB can be safely used for MUS procedures and could be an alternative for permanent polypropylene slings in patients that prefer the use of nonpermanent material.

Injectable polyisocyanide hydrogel as healing supplement for connective tissue regeneration in an abdominal wound model.

In pelvic organ prolapse (POP) patients, the uterus, bladder and/or rectum descends into vagina due to weakened support tissues. High recurrence rates after POP surgery suggest an urgent need for improved surgical outcomes. Our aim is to promote connective tissue healing that results in stimulated tissue support functions by surgically applying a hydrogel functionalized with biological cues. We used known vaginal wound healing promoting factors (basic fibroblast growth factor, ß-estradiol, adipose-derived stem cells) in the biomimetic and injectable polyisocyanide (PIC) hydrogel, which in itself induces regenerative vaginal fibroblast behavior. The regenerative capacity of injected PIC hydrogel, and the additional pro-regenerative effects of these bioactive factors was evaluated in abdominal wounds in rabbits. Assessment of connective tissue healing (tensile testing, histology, immunohistochemistry) revealed that injection with all PIC formulations resulted in a statistically significant stiffness and collagen increase over time, in contrast to sham. Histological evaluation indicated new tissue growth with moderate to mild immune activity at the hydrogel - tissue interface. The results suggest that PIC injection in an abdominal wound improves healing towards regaining load-bearing capacity, which encourages us to investigate application of the hydrogel in a more translational vaginal model for POP surgery in sheep.

Creation of a decellularized vaginal matrix from healthy human vaginal tissue for potential vagina reconstruction: experimental studies.

BACKGROUND: When a disorder causes the absence of a healthy, full-size vagina, various neovaginal creation methods are available. Sometimes dilation or stretching of the vaginal cavity is sufficient, but intestinal or dermal flap tissue is generally required. However, different inherent tissue properties cause complications. Therefore, a lost body part should be replaced with a similar material. The use of organ-specific acellular vaginal tissue carries great potential, as its similar architecture and matrix composition make it suitable for vaginal regeneration. METHODS: The authors developed an optimized protocol for decellularization of healthy human vaginal tissue. Resected colpectomy tissue from 12 healthy transgender patients was used. Successful decellularization was confirmed by applying acellular criteria from in-vivo remodeling reports. Suitability as a tissue-mimicking scaffold for vaginal reconstruction was determined by visible structural features, biocompatibility during stretching, and the presence of visible collagen, elastin, laminin, and fibronectin. RESULTS: Histological examination confirmed the preservation of structural features, and minimal cellular residue was seen during fluorescence microscopy, DNA and RNA quantification, and fragment length examination. Biomechanical testing showed decreased peak load (55%, P <0.05), strain at rupture (23%, P <0.01), and ultimate tensile stress (55%, P <0.05) after decellularization, while the elastic modulus (68%) did not decrease significantly. Fluorescence microscopy revealed preserved Fibronectin-I/II/III and Laminin-I/II, while Collagen-I and Ficolin-2B were decreased but mostly retained. CONCLUSIONS: The absence of cellular residue, moderately altered biomechanical extracellular matrix properties, and mostly preserved structural proteins appear to make our decellularized human vaginal matrix a suitable tissue-mimicking scaffold for vagina transplantation when tissue survival through vascularization and innervation are accomplished in the future.

The Microcirculation of Vaginal Tissue in Women with Obstetric Vesicovaginal Fistula and Short-Term Effects of Surgical Repair on Microvascular Parameters.

OBJECTIVES: The objective of the study was to better understand the extent of the ischemic trauma and the effects of surgical repair on the vaginal microcirculation in patients with obstetric vesicovaginal fistula (VVF). DESIGN: In this observational study, we evaluated the vaginal microvasculature surrounding VVF using handheld vital microscopy (HVM) before, during, and 2 weeks after surgical VVF repair. PARTICIPANTS: Seventeen women undergoing VVF repair were included in this study. SETTING: The study was conducted in the Fistula Care Centre in Lilongwe, Malawi. METHODS: We used HVM with incident dark-field imaging to non-invasively visualize the microvasculature of the vaginal tissue surrounding fistulas. The primary outcome was the presence of microvascular flow. Secondary outcomes included angioarchitecture, fistula closure (postoperative dye test), and urinary continence (pad weight test). RESULTS: Microvascular flow was present before, during, and after surgical repair in, respectively, 83.8%, 83.9%, and 93.4% of obtained image sequences. The angioarchitecture was normal in 75.8% of the image sequences before surgery, 69.4% at fistula closure, and 89.1% two weeks after VVF repair. Fourteen (82.4%) patients had a closed fistula after surgical repair. LIMITATIONS: The study was limited by the lack of a control group and the relatively small sample size. CONCLUSION: Although the vaginal microcirculation in women with VVF is compromised, extensive ischemic damage is not observed in the tissue surrounding fistulas. This suggests significant regenerative capacity of the vaginal vasculature in young women, or less extensive ischemic damage than presumed. Following surgical repair, we observed improvement of microcirculatory flow and angioarchitecture, suggesting that surgery is a good option for patients with obstetric VVF.

Vaginal Fibroblast Behavior as a Function of Stiffness Changes in a Polyisocyanide Hydrogel for Prolapse Repair.

There is an urgent need for improved outcomes in the treatment of pelvic organ prolapse (POP). Success of primary surgery relies on the load bearing capacity of plicated connective tissue underneath the vaginal wall, which is compromised due to an altered vaginal fibroblast function and collagen composition. There is an important factor in connective tissue repair that relates to changes in stiffness of the vaginal fibroblast microenvironment, which influences cell activity through cellular mechanosensing. The aim of this study is to investigate the effect of stiffness changes on vaginal fibroblast functions that relate to connective tissue healing in prolapse repair. The substrate stiffness was controlled by changing the polymer concentration in the fibrous and strongly biomimetic polyisocyanide (PIC) hydrogel. We analyzed stiffness during cell culture and assessed the consequential fibroblast proliferation, morphology, collagen deposition, and contraction. Our results show that increasing stiffness coincides with vaginal fibroblast alignment, promotes collagen deposition, and inhibits PIC gel contraction. These findings suggest that the matrix stiffness directly influences vaginal fibroblast functionality. Moreover, we observed a buildup in stiffness and collagen, with an enhanced fibroblast and collagen organization on the PIC-substrate, which indicate an enhanced structural integrity of the hydrogel-cell construct. An improved tissue structure during healing is relevant in the functional repair of POP. Therefore, this study encourages future research in the use of PIC gels as a supplement in prolapse surgery, whereby the hydrogel stiffness should be considered.

Growth Factor Immobilization to Synthetic Hydrogels: Bioactive bFGF-Functionalized Polyisocyanide Hydrogels.

With its involvement in cell proliferation, migration and differentiation basic fibroblast growth factor (bFGF) has great potential for tissue engineering purposes. So far, however, clinical translation of soluble bFGF-based therapies is unsuccessful, because the required effective doses are often supraphysiological, which may cause adverse effects. An effective solution is growth factor immobilization, whereby bFGF retains its bioactivity at increased efficacy. Studied carriers include films, solid scaffolds, and particles, as well as natural and synthetic hydrogels. However, these synthetic hydrogels poorly resemble the characteristics of the native extracellular matrix (ECM). In this work, bFGF is covalently conjugated to the synthetic, but highly biocompatible, polyisocyanide-based hydrogel (PIC-bFGF), which closely mimics the architecture and mechanical properties of the ECM. The growth factor conjugation protocol is straightforward and readily extrapolated to other growth factors or proteins. The PIC-bFGF hydrogel shows a prolonged bioactivity up to 4 weeks although no clear effects on the ECM metabolism are observed. Beyond the future potential of the PIC-bFGF hydrogel toward various tissue engineering applications, this work underlines that simple biological conjugation procedures are a powerful strategy to induce additional bioactivity in 3D synthetic cell culture matrices.

The effect of CO2 laser therapy on vaginal microcirculatory parameters in an animal model for genitourinary syndrome of menopause.

BACKGROUND: Vaginal laser therapy for the treatment of genitourinary syndrome of menopause (GSM) has been introduced to the market with limited (pre)clinical and experimental evidence supporting its efficacy. It is suggested that vaginal laser therapy increases epithelial thickness and improves vascularization, but the underlying biological working mechanism has not been substantiated yet. OBJECTIVE: To evaluate the effects of CO2 laser therapy on vaginal atrophy using noninvasive incident dark field (IDF) imaging in a large animal model for GSM. DESIGN, SETTING, AND PARTICIPANTS: An animal study was conducted between 2018 and 2019 and included 25 Dohne Merino ewes, of which 20 underwent bilateral ovariectomy (OVX) to induce iatrogenic menopause, and 5 did not. The total study duration was 10 months. INTERVENTIONS: Five months after OVX, ovariectomized ewes received monthly applications of CO2 laser (n = 7), vaginal estrogen (n = 7), or no treatment (n = 6) for 3 months. IDF imaging was performed monthly in all animals. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the proportion of image sequences containing capillary loops (angioarchitecture). Secondary outcomes included focal depth (epithelial thickness), and quantitative measures of vessel density and perfusion. Treatment effects were evaluated using ANCOVA and binary logistic regression. RESULTS AND LIMITATIONS: Compared to OVX-only, ewes treated with estrogen demonstrated a higher capillary loops proportion (4% vs. 75%, p < 0.01), and higher focal depth (60 (IQR 60-80) vs. 80 (IQR 80-80) p < 0.05). CO2 laser therapy did not change microcirculatory parameters. As the ewes' vaginal epithelium is thinner than that of humans, it may demand different laser settings. CONCLUSIONS: In a large animal model for GSM, CO2 laser therapy does not affect microcirculatory outcomes related to GSM, whereas vaginal estrogen treatment does. Until more homogeneous and objective evidence about its efficacy is available, CO2 laser therapy should not be adopted into widespread practice for treating GSM.

Vaginal changes after ovariectomy in ewes: A large animal model for genitourinary syndrome of menopause.

OBJECTIVE: To evaluate the effect of iatrogenic menopause on the physiology of the vagina of the ewe and to evaluate if vaginal changes in ewes can be translated to women with genitourinary syndrome of menopause (GSM). METHODS: Preclinical research with Dohne Merino ewes. Iatrogenic menopause was induced by bilateral ovariectomy (OVX). Animals were randomized for surgery, blinded for allocation and outcome assessment. Differences between groups were determined by linear regression analyses at 5 months after OVX. Outcome measures were vaginal epithelial thickness, pH, vaginal maturation value, vaginal maturation index, epithelial glycogen accumulation, content of elastin fibers, collagen, and vascularity. RESULTS: OVX ewes (n = 20) showed epithelial thinning of the vaginal wall from 146 µm to 47 µm (mean, P < 0.001). Furthermore, epithelial glycogen accumulation and vascularity of the vaginal wall significantly decreased (43% and 23%, respectively) as compared with the control group (no intervention; n = 5). No significant differences were found for other outcome measures. CONCLUSION: This study established the ewe as a suitable large animal model for GSM. Furthermore, the similar relevant outcomes in humans and ewes hold great value for future translational research for the evaluation and optimization of different treatment modalities for GSM.

A Clinical Learning Curve Study of Polydimethylsiloxane Urolastic for Stress Urinary Incontinence: Does Safety Improve when Expertise Grow?

OBJECTIVES: The aim of the study was to characterize the learning curve of bulk injection therapy polydimethylsiloxane Urolastic (PDMS-U) for stress urinary incontinence. DESIGN: Secondary analysis from three clinical studies on efficacy and safety outcomes of PDMS-U was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: PDMS-U-certified physicians who performed ≥4 procedures were included. The primary outcome was the number of PDMS-U procedures needed to achieve acceptable failure rates for "complications overall," "urinary retention," and "excision," using the LC-CUSUM method. For the primary outcome, physicians who performed ≥20 procedures were used. For the secondary outcome, logistic and linear regression analysis was used to assess the relationship between number of procedures, complications (complications overall, urinary retention, pain, exposure, excision of PDSM-U), and duration of treatment. RESULTS: In total, 203 PDMS-U procedures were performed by nine physicians. Five physicians were used for the primary outcome. For "complications overall," "urinary retention," and "excision," two physicians reached a level of competence: one at procedure 20 and one at procedure 40. The secondary outcome showed no statistically significant association between procedure number and complications. There was a statistically significant increase in the duration of treatment with more physician experience (mean difference 0.83 min per 10 additional procedures, 95% CI: 0.16-1.48). LIMITATIONS: One limitation is that retrospectively collected data might have underreported the number of complications. Secondly, there was variation in the way the technique was applied between physicians. CONCLUSIONS: Physicians' experience in the PDMS-U procedure did not influence safety outcomes. There was large inter-physician variability and most physicians did not reach acceptable failure rates. There was no relationship between PDMS-U complications and the number of performed procedures.

The Effect of Growth Factors on Vaginal Wound Healing: A Systematic Review and Meta-analysis.

Surgical outcomes of pelvic organ prolapse (POP) surgery are poor, resulting in a 20% recurrence risk. Following the hypothesis that impaired wound healing is the main determinant of recurrent POP, growth factors have the potential to promote wound healing and may improve surgical outcomes. In this study, we systematically reviewed the effect of growth factors on vaginal wound healing in both in vitro and animal studies. For each independent comparison, the standardized mean difference and 95% CI were calculated using the Hedges' g correction. Of the 3858 retrieved studies, seven studies were included, of which six were included in meta-analysis (three in vitro studies and four in vivo studies). In vitro, basic fibroblast growth factor (bFGF) promotes proliferation, differentiation, and collagen types I and III production. Epidermal growth factor stimulates proliferation and connective tissue growth factor promotes Tenascin-C expression. These effects, however, are less pronounced in vivo; only bFGF slightly promotes collagen production. The review shows that growth factors, particularly bFGF, are able to promote vaginal wound healing in vitro. The uncertain in vivo findings suggest that preclinical models should be improved. The ultimate goal is to develop effective growth factor-supplemented therapies that improve surgical outcomes for POP.

Immune activation of vaginal human Langerhans cells increases susceptibility to HIV-1 infection.

Vaginal inflammation increases the risk for sexual HIV-1 transmission but underlying mechanisms remain unclear. In this study we assessed the impact of immune activation on HIV-1 susceptibility of primary human vaginal Langerhans cells (LCs). Vaginal LCs isolated from human vaginal tissue expressed a broad range of TLRs and became activated after exposure to both viral and bacterial TLR ligands. HIV-1 replication was restricted in immature vaginal LCs as only low levels of infection could be detected. Notably, activation of immature vaginal LCs by bacterial TLR ligands increased HIV-1 infection, whereas viral TLR ligands were unable to induce HIV-1 replication in vaginal LCs. Furthermore, mature vaginal LCs transmitted HIV-1 to CD4 T cells. This study emphasizes the role for vaginal LCs in protection against mucosal HIV-1 infection, which is abrogated upon activation. Moreover, our data suggest that bacterial STIs can increase the risk of HIV-1 acquisition in women.

The effect of 12 weeks of estriol cream on stress urinary incontinence post-menopause: A prospective multinational observational study.

OBJECTIVE: To quantitate the changes in stress urinary incontinence (SUI) outcome measures after 12 weeks of vaginal estriol cream in women with stress incontinence. METHODS: A prospective multicentre observational study conducted in tertiary urogynaecology centers. Postmenopausal women with pure SUI or stress predominant mixed urinary incontinence (MUI), not receiving any other treatment for their incontinence were given written instructions regarding digital application of a standard dose of vaginal estriol cream. Outcomes were measured at baseline and 12 weeks. The primary objective outcome was vaginal pH. The primary subjective outcome was the stress domain of the Urogenital Distress Inventory-6 (UDI-6). The secondary objective outcome used was the erect cough stress test. Two quality of life questionnaires and two patient reported outcomes were also included. RESULTS: The 46 postmenopausal recruits had a median age of 62.1 interquartile range (IQR 56.2-65.4). At follow up, the primary subjective outcome SUI domain [UDI-6] significantly improved from 83.3 (IQR 50-100) to 33.3 (33.3-66.7, p ≤ 0.001) as did vaginal pH [from 5.1 (4.9-5.9) to 4.9 (4.6-5.0] p ≤ 0.001; 18/43 patients (42%) were dry on cough stress test. CONCLUSIONS: Twelve weeks of vaginal estriol cream significantly reduced symptoms of stress urinary incontinence in this sample of postmenopausal women.

Non-invasive biomechanical assessment of the prolapsed vaginal wall: an explorative pilot study on cutometry and indentometry.

The clinical assessment of pelvic organ prolapse (POP) and associated treatment strategies is currently limited to anatomical and subjective outcome measures, which have limited reproducibility and do not include functional properties of vaginal tissue. The objective of our study was to evaluate the feasibility of using cutometry and indentometry for non-invasive biomechanical assessment of the vaginal wall in women with POP. Both techniques were applied on the vaginal wall of 20 women indicated for surgical correction of POP stage two or higher. The primary outcome was the measurement success rate. Measurements were considered successful if biomechanical parameters were generated after a maximum of three attempts. Secondary outcomes included acquisition time, number of attempts to obtain a successful measurement, and biomechanical parameters. Measurements were successfully performed on the anterior vaginal wall of 12 women with cystocele and the posterior vaginal wall of eight women with rectocele. The success rate was 100% for both techniques and acquisition time was under 1 minute for all 20 measurements. Tissue fast elasticity of the posterior vaginal wall (rectocele) was significantly higher than that of the anterior vaginal wall (cystocele) and negatively correlated with age (r = - 0.57, P < 0.05). In women with POP, measuring the biomechanical properties of the vaginal wall using cutometry and indentometry is technically feasible. Objective evaluation of biomechanical properties may help to understand the pathophysiology behind surgical outcomes, providing an opportunity for the identification of patients at risk for (recurrent) prolapse, and individualized treatment decisions.

Cost-effectiveness of urethral bulking polydimethylsiloxane-Urolastic® compared with mid-urethral sling surgery for stress urinary incontinence: A two-arm cohort study.

OBJECTIVE: To investigate the cost-effectiveness of urethral bulking polydimethylsiloxane-Urolastic® (PDMS-U) compared with mid-urethral sling (MUS) surgery for stress urinary incontinence (SUI) at 1-year follow-up. DESIGN: Prospective, two-arm cohort study with 2-year follow-up. SETTING: International multicentre. POPULATION: Women with moderate to severe SUI. MAIN OUTCOME MEASURES: Primary outcome was subjective cure (Patient Global Impression of Improvement). SECONDARY OUTCOMES: objective cure (negative cough stress test), Urogenital Distress Inventory (UDI-6), complications and re-interventions. Cost-effectiveness outcomes: total costs, quality-adjusted life year (QALY) using IIQ7-scores (Incontinence Impact Questionnaire) and EQ-5D-5L, incremental cost-effectiveness ratio (ICER) and monetary benefit (adjusted for baseline confounders). RESULTS: In all, 131 PDMS-U and 153 MUS surgery patients were treated. Subjective cure rates for MUS surgery and PDMS-U were, respectively: 101/112 (90%) versus 40/87 (46%), adjusted odds ratio (aOR; for age, body mass index [BMI], severity, type of urinary incontinence and previous SUI procedure) was 4.9. Objective cure rates for MUS surgery and PDMS-U were respectively: 98/109 (90%) versus 58/92 (63%), aOR 5.4. Average total costs for PDMS-U and MUS surgery were €3567 and €6688. ICER for MUS surgery cost €15 598 per IIQ QALY and €37 408 per EQ-5D-5L QALY. With a willingness to pay (WTP) of €25 000, MUS has a 84% chance of being cost-effective using IIQ, whereas PDMS-U has a 99% chance of being cost-effective using EQ-5D-5L. CONCLUSION: MUS surgery is more cost-effective in realising improved disease-specific quality of life (QoL), while PDMS-U is more cost-effective in realising improved generic QoL.

A novel anchoring system for pelvic organ prolapse repair: an observational study.

INTRODUCTION AND HYPOTHESIS: Sacrospinous ligament (SSL) fixation is an effective and widely used vaginal procedure for correcting apical prolapse. The Saffron Fixation System (Coloplast Corp., Minneapolis, MN, USA) is a new anchoring device aimed at facilitating a durable, easy, and short procedure for SSL fixation with the goal of minimizing operative complications. The objective was to demonstrate the efficacy and safety of anchor deployment and suture fixation for pelvic organ prolapse repair using the Saffron Fixation System. METHODS: An observational human cadaver study was conducted to measure the distance between anchor location and anatomical landmarks in the pelvis, and the holding force of the fixated anchors. Anchors were placed in four human cadavers by different implanters. The pull-out force of these anchors was measured to assess efficacy (three cadavers by three implanters) and the distance between anchors and primal vessels and nerves was measured to assess safety (one cadaver by one implanter). RESULTS: Nineteen out of 20 anchors (95%) were correctly placed as judged by independent assessment performed by non-implanting surgeons. Distance between anchors and surrounding nerves and vessels exceeded 10 mm. Mean (SD) pull out-force was 17.9 (5.6) N. CONCLUSION: The innovative anchoring device that was developed appeared to enable precise and solid anchor placement in the SSL. Future clinical studies are needed to explore if the theoretical advantages of this device translate to improved clinical outcomes in comparison with available suturing and anchoring devices.