Structural Basis of Vesicle Formation at the Inner Nuclear Membrane.

Vesicular nucleo-cytoplasmic transport is becoming recognized as a general cellular mechanism for translocation of large cargoes across the nuclear envelope. Cargo is recruited, enveloped at the inner nuclear membrane (INM), and delivered by membrane fusion at the outer nuclear membrane. To understand the structural underpinning for this trafficking, we investigated nuclear egress of progeny herpesvirus capsids where capsid envelopment is mediated by two viral proteins, forming the nuclear egress complex (NEC). Using a multi-modal imaging approach, we visualized the NEC in situ forming coated vesicles of defined size. Cellular electron cryo-tomography revealed a protein layer showing two distinct hexagonal lattices at its membrane-proximal and membrane-distant faces, respectively. NEC coat architecture was determined by combining this information with integrative modeling using small-angle X-ray scattering data. The molecular arrangement of the NEC establishes the basic mechanism for budding and scission of tailored vesicles at the INM.

Late-rising CD4 T cells resolve mouse cytomegalovirus persistent replication in the salivary gland.

Conventional antiviral memory CD4 T cells typically arise during the first two weeks of acute infection. Unlike most viruses, cytomegalovirus (CMV) exhibits an extended persistent replication phase followed by lifelong latency accompanied with some gene expression. We show that during mouse CMV (MCMV) infection, CD4 T cells recognizing an epitope derived from the viral M09 protein only develop after conventional memory T cells have already peaked and contracted. Ablating these CD4 T cells by mutating the M09 genomic epitope in the MCMV Smith strain, or inducing them by introducing the epitope into the K181 strain, resulted in delayed or enhanced control of viral persistence, respectively. These cells were shown to be unique compared to their conventional memory counterparts; producing higher IFNγ and IL-2 and lower IL-10 levels. RNAseq analyses revealed them to express distinct subsets of effector genes as compared to classical CD4 T cells. Additionally, when M09 cells were induced by epitope vaccination they significantly enhanced protection when compared to conventional CD4 T cells alone. These data show that late-rising CD4 T cells are a unique memory subset with excellent protective capacities that display a development program strongly differing from the majority of memory T cells.

Dissecting the cytomegalovirus CC chemokine: Chemokine activity and gHgLchemokine-dependent cell tropism are independent players in CMV infection.

Like all herpesviruses, cytomegaloviruses (CMVs) code for many immunomodulatory proteins including chemokines. The human cytomegalovirus (HCMV) CC chemokine pUL128 has a dual role in the infection cycle. On one hand, it forms the pentameric receptor-binding complex gHgLpUL(128,130,131A), which is crucial for the broad cell tropism of HCMV. On the other hand, it is an active chemokine that attracts leukocytes and shapes their activation. All animal CMVs studied so far have functionally homologous CC chemokines. In murine cytomegalovirus (MCMV), the CC chemokine is encoded by the m131/m129 reading frames. The MCMV CC chemokine is called MCK2 and forms a trimeric gHgLMCK2 entry complex. Here, we have generated MCK2 mutant viruses either unable to form gHgLMCK2 complexes, lacking the chemokine function or lacking both functions. By using these viruses, we could demonstrate that gHgLMCK2-dependent entry and MCK2 chemokine activity are independent functions of MCK2 in vitro and in vivo. The gHgLMCK2 complex promotes the tropism for leukocytes like macrophages and dendritic cells and secures high titers in salivary glands in MCMV-infected mice independent of the chemokine activity of MCK2. In contrast, reduced early antiviral T cell responses in MCMV-infected mice are dependent on MCK2 being an active chemokine and do not require the formation of gHgLMCK2 complexes. High levels of CCL2 and IFN-γ in spleens of infected mice and MCMV virulence depend on both, the formation of gHgLMCK2 complexes and the MCK2 chemokine activity. Thus, independent and concerted functions of MCK2 serving as chemokine and part of a gHgL entry complex shape antiviral immunity and virus dissemination.

Open reading frames M12/M13 jointly contribute to MHV-68 latency.

Murine gammaherpesvirus 68 (MHV-68), a widely used small-animal model for the analysis of gammaherpesvirus pathogenesis, encodes the MHV-68-specific ORFs M12 and M13. The function of M12 and M13 has not been investigated so far. Therefore, we constructed and analysed recombinant MHV-68 with mutations in either M12, M13 or M12/M13. Both the M12 and M13 mutants did not display any phenotype in vitro or in vivo. However, although the M12/13 double mutant showed similar lytic growth in fibroblasts in vitro and in the lungs of infected mice as wild-type MHV-68, it was significantly attenuated in vivo during latency. This phenotype was completely restored in a revertant of the M12/13 double mutant. Thus, it appears that M12 and M13 might have redundant functions that are only revealed if both genes are lacking. The observation that M12/13 have a function during latency not only contributes to the further understanding of the pathogenesis of MHV-68 infection but might also be of interest considering that M12/13 are located at a genomic position similar to that of LMP2A and K15. The latter are important proteins of their respective human gammaherpesviruses EBV and KSHV that contribute to cellular survival, cell activation and proliferation, which was deduced from in vitro studies.

Characterization of M116.1p, a Murine Cytomegalovirus Protein Required for Efficient Infection of Mononuclear Phagocytes.

Broad tissue tropism of cytomegaloviruses (CMVs) is facilitated by different glycoprotein entry complexes, which are conserved between human CMV (HCMV) and murine CMV (MCMV). Among the wide array of cell types susceptible to the infection, mononuclear phagocytes (MNPs) play a unique role in the pathogenesis of the infection as they contribute both to the virus spread and immune control. CMVs have dedicated numerous genes for the efficient infection and evasion of macrophages and dendritic cells. In this study, we have characterized the properties and function of M116, a previously poorly described but highly transcribed MCMV gene region that encodes M116.1p, a novel protein necessary for the efficient infection of MNPs and viral spread in vivo. Our study further revealed that M116.1p shares similarities with its positional homologs in HCMV and RCMV, UL116 and R116, respectively, such as late kinetics of expression, N-glycosylation, localization to the virion assembly compartment, and interaction with gH-a member of the CMVs fusion complex. This study, therefore, expands our knowledge about virally encoded glycoproteins that play important roles in viral infectivity and tropism. IMPORTANCE Human cytomegalovirus (HCMV) is a species-specific herpesvirus that causes severe disease in immunocompromised individuals and immunologically immature neonates. Murine cytomegalovirus (MCMV) is biologically similar to HCMV, and it serves as a widely used model for studying the infection, pathogenesis, and immune responses to HCMV. In our previous work, we have identified the M116 ORF as one of the most extensively transcribed regions of the MCMV genome without an assigned function. This study shows that the M116 locus codes for a novel protein, M116.1p, which shares similarities with UL116 and R116 in HCMV and RCMV, respectively, and is required for the efficient infection of mononuclear phagocytes and virus spread in vivo. Furthermore, this study establishes the α-M116 monoclonal antibody and MCMV mutants lacking M116, generated in this work, as valuable tools for studying the role of macrophages and dendritic cells in limiting CMV infection following different MCMV administration routes.

Sexual Function in Postmenopausal Women With Symptomatic Pelvic Organ Prolapse Treated Either with Locally Applied Estrogen or Placebo: Results of a Double-Masked, Placebo-Controlled, Multicenter Trial.

BACKGROUND: Local estrogen therapy (LET) has beneficial effects on genitourinary atrophy; however it is currently unclear if LET improves sexual function in postmenopausal women with pelvic organ prolapse (POP). AIM: To evaluate if LET vs placebo results in an improved sexual function in postmenopausal women with symptomatic POP. METHODS: We performed a secondary analysis of sexual outcomes of a previous randomized controlled trial comparing LET and placebo in 120 postmenopausal women (60/group) with symptomatic POP stage ≥3 and planned prolapse surgery. Women were randomly assigned to receive local estrogen or placebo cream 6 weeks preoperatively. The effect of therapy vs placebo was assessed with ANOVA with interaction effect of time*group and a multivariable linear regression model was built to assess the impact of different variables on sexual function before therapy. OUTCOMES: We evaluated the sexual function score in sexually active women of our study population using the German Pelvic Floor Questionnaire at recruitment time and again after 6 weeks of treatment. RESULTS: Among 120 randomized women, 66 sexually active women remained for final analysis. There was no significant difference in the change of the sexual function score over time between the treatment groups (difference in changes in score from baseline to 6 weeks for Estrogen group vs control group was -0.110 with 95% CI -0.364 to 0.144) Multivariable analysis showed that no independent risk factor for unsatisfying sexual function score could be identified. CLINICAL IMPLICATIONS: Based on our results, LET has no beneficial effect on sexual function in postmenopausal women with POP. STRENGTHS AND LIMITATIONS: Main strength of our study lies in the study design and in the use of a condition- specific questionnaire. As this is a secondary analysis, this study may be insufficiently powered to identify differences in sexual data between groups. CONCLUSION: LET had no impact on female sexuality in postmenopausal women with POP. Marschalek M-L, Bodner K, Kimberger O, et al. Sexual Function in Postmenopausal Women With Symptomatic Pelvic Organ Prolapse Treated Either with Locally Applied Estrogen or Placebo: Results of a Double-Masked, Placebo-Controlled, Multicenter Trial. J Sex Med 2022;19:1124-1130.

Influence of Human Cytomegalovirus Glycoprotein O Polymorphism on the Inhibitory Effect of Soluble Forms of Trimer- and Pentamer-Specific Entry Receptors.

Human cytomegalovirus (HCMV) envelope glycoprotein complexes, gH/gL/gO trimer and gH/gL/UL128-131 pentamer, are important for cell-free HCMV entry. While soluble NRP2-Fc (sNRP2-Fc) interferes with epithelial/endothelial cell entry through UL128, soluble platelet-derived growth factor receptor α-Fc (sPDGFRα-Fc) interacts with gO, thereby inhibiting infection of all cell types. Since gO is the most variable subunit, we investigated the influence of gO polymorphism on the inhibitory capacities of sPDGFRα-Fc and sNRP2-Fc. Accordingly, gO genotype 1c (GT1c) sequence was fully or partially replaced by gO GT2b, GT3, and GT5 sequences in the bacterial artificial chromosome (BAC) TB40-BAC4-luc background (where luc is luciferase). All mutants were tested for fibroblast and epithelial cell infectivity, for virion content of gB, gH, and gO, and for infection inhibition by sPDGFRα-Fc and sNRP2-Fc. Full-length and partial gO GT swapping may increase epithelial-to-fibroblast ratios due to subtle alterations in fibroblast and/or epithelial infectivity but without substantial changes in gB and gH levels in mutant virions. All gO GT mutants except recombinant gO GT1c/3 displayed a nearly complete inhibition at 1.25 µg/ml sPDGFRα-Fc on epithelial cells (98% versus 91%), and all experienced complete inhibition on fibroblasts (≥99%). While gO GT replacement did not influence sNRP2-Fc inhibition at 1.25 µg/ml on epithelial cells (97% to 99%), it rendered recombinant mutant GT1c/3 moderately accessible to fibroblast inhibition (40%). In contrast to the steep sPDGFRα-Fc inhibition curves (slope of >1.0), sNRP2-Fc dose-response curves on epithelial cells displayed slopes of ∼1.0, suggesting functional differences between these entry inhibitors. Our findings demonstrate that artificially generated gO recombinants rather than the major gO genotypic forms may affect the inhibitory capacities of sPDGFRα and sNRP2 in a cell type-dependent manner.IMPORTANCE Human cytomegalovirus (HCMV) is known for its broad cell tropism, as reflected by the different organs and tissues affected by HCMV infection. Hence, inhibition of HCMV entry into distinct cell types could be considered a promising therapeutic option to limit cell-free HCMV infection. Soluble forms of cellular entry receptor PDGFRα rather than those of entry receptor neuropilin-2 inhibit infection of multiple cell types. sPDGFRα specifically interacts with gO of the trimeric gH/gL/gO envelope glycoprotein complex. HCMV strains may differ with respect to the amounts of trimer in virions and the highly polymorphic gO sequence. In this study, we show that the major gO genotypes of HCMV that are also found in vivo are similarly well inhibited by sPDGFRα. Novel gO genotypic forms potentially emerging through recombination, however, may evade sPDGFRα inhibition on epithelial cells. These findings provide useful additional information for the future development of anti-HCMV therapeutic compounds based on sPDGFRα.

The effectiveness of surgical procedures to prevent post-hysterectomy pelvic organ prolapse: a systematic review of the literature.

INTRODUCTION AND HYPOTHESIS: Hysterectomy is one of the most commonly performed gynecological surgical procedures. One of the long-term risks associated with hysterectomy is the occurrence of pelvic organ prolapse (POP). To prevent post-hysterectomy POP, several suspension procedures are routinely performed at the time of hysterectomy. We performed a systematic review of published data in order to define the most effective surgical procedures for the prevention of post-hysterectomy POP. METHODS: We performed a systematic review of the literature by searching PubMed, the Cochrane Library, EMBASE, Ovid MEDLINE, and clinicaltrials.gov up to 24 May 2020. The search strategy included the keywords hysterectomy, post-hysterectomy, prolapse, colposuspension, culdoplasty, McCall, and combinations thereof. The inclusion criterion was a surgical procedure at the time of hysterectomy to prevent de novo POP. The outcome was incidence of post-hysterectomy POP. RESULTS: Six out of 553 retrieved studies met the methodological criteria for complete analysis. In this review, 719 women aged over 18 years were included. Only 2 studies were designed as prospective trials; however, only 1 compared women undergoing a procedure at the time of hysterectomy with controls. The prevalence of post-hysterectomy prolapse varied from 0% to 39%. CONCLUSION: A systematic review of published literature suggests that performing variations of McCall culdoplasty at the time of hysterectomy might be the most effective prophylactic surgical procedure for preventing post-hysterectomy pelvic organ prolapse.

The N Terminus of Human Cytomegalovirus Glycoprotein O Is Important for Binding to the Cellular Receptor PDGFRα.

The human cytomegalovirus (HCMV) glycoprotein complex gH/gL/gO is required for the infection of cells by cell-free virions. It was recently shown that entry into fibroblasts depends on the interaction of gO with the platelet-derived growth factor receptor alpha (PDGFRα). This interaction can be blocked with soluble PDGFRα-Fc, which binds to HCMV virions and inhibits entry. The aim of this study was to identify parts of gO that contribute to PDGFRα binding. In a systematic mutational approach, we targeted potential interaction sites by exchanging conserved clusters of charged amino acids of gO with alanines. To screen for impaired interaction with PDGFRα, virus mutants were tested for sensitivity to inhibition by soluble PDGFRα-Fc. Two mutants with mutations within the N terminus of gO (amino acids 56 to 61 and 117 to 121) were partially resistant to neutralization. To validate whether these mutations impair interaction with PDGFRα-Fc, we compared binding of PDGFRα-Fc to mutant and wild-type virions via quantitative immunofluorescence analysis. PDGFRα-Fc staining intensities were reduced by 30% to 60% with mutant virus particles compared to wild-type particles. In concordance with the reduced binding to the soluble receptor, virus penetration into fibroblasts, which relies on binding to the cellular PDGFRα, was also reduced. In contrast, PDGFRα-independent penetration into endothelial cells was unaltered, demonstrating that the phenotypes of the gO mutant viruses were specific for the interaction with PDGFRα. In conclusion, the mutational screening of gO revealed that the N terminus of gO contributes to efficient spread in fibroblasts by promoting the interaction of virions with its cellular receptor.IMPORTANCE The human cytomegalovirus is a highly prevalent pathogen that can cause severe disease in immunocompromised hosts. Currently used drugs successfully target the viral replication within the host cell, but their use is restricted due to side effects and the development of resistance. An alternative approach is the inhibition of virus entry, for which understanding the details of the initial virus-cell interaction is desirable. As binding of the viral gH/gL/gO complex to the cellular PDGFRα drives infection of fibroblasts, this is a potential target for inhibition of infection. Our mutational mapping approach suggests the N terminus as the receptor binding portion of the protein. The respective mutants were partially resistant to inhibition by PDGFRα-Fc but also attenuated for infection of fibroblasts, indicating that such mutations have little if any benefit for the virus. These findings highlight the potential of targeting the interaction of gH/gL/gO with PDGFRα for therapeutic inhibition of HCMV.

Murine Cytomegalovirus Glycoprotein O Promotes Epithelial Cell Infection In Vivo.

Cytomegaloviruses (CMVs) establish systemic infections across diverse cell types. Glycoproteins that alter tropism can potentially guide their spread. Glycoprotein O (gO) is a nonessential fusion complex component of both human CMV (HCMV) and murine CMV (MCMV). We tested its contribution to MCMV spread from the respiratory tract. In vitro, MCMV lacking gO poorly infected fibroblasts and epithelial cells. Cell binding was intact, but penetration was delayed. In contrast, myeloid infection was preserved, and in the lungs, where myeloid and type 2 alveolar epithelial cells are the main viral targets, MCMV lacking gO showed a marked preference for myeloid infection. Its poor epithelial cell infection was associated with poor primary virus production and reduced virulence. Systemic spread, which proceeds via infected CD11c+ myeloid cells, was initially intact but then diminished, because less epithelial infection led ultimately to less myeloid infection. Thus, the tight linkage between peripheral and systemic MCMV infections gave gO-dependent infection a central role in host colonization.IMPORTANCE Human cytomegalovirus is a leading cause of congenital disease. This reflects its capacity for systemic spread. A vaccine is needed, but the best viral targets are unclear. Attention has focused on the virion membrane fusion complex. It has 2 forms, so we need to know what each contributes to host colonization. One includes the virion glycoprotein O. We used murine cytomegalovirus, which has equivalent fusion complexes, to determine the importance of glycoprotein O after mucosal infection. We show that it drives local virus replication in epithelial cells. It was not required to infect myeloid cells, which establish systemic infection, but poor local replication reduced systemic spread as a secondary effect. Therefore, targeting glycoprotein O of human cytomegalovirus has the potential to reduce both local and systemic infections.

The role of prescription drugs in female overactive bladder syndrome-A population-wide cohort study.

PURPOSE: Overactive bladder (OAB) syndrome has severe effects on quality of life. Certain drugs are known risk factors for OAB but have not been investigated in a population-wide cohort. The objective of this study was to investigate the role of prescription drugs in the etiology of the OAB. METHODS: Retrospective cohort study using a population-wide database of 4 185 098 OAB-naïve women followed Strengthening the Reporting of Observational Studies in Epidemiology guidelines. We investigated the subscription use of anticholinergic medication and 188 chemical substances, which are suspected triggers for OAB (trigger medications [TMs]). We hypothesized a relationship between the prescription for one or more TM and the prescription for anticholinergic medication against OAB (marker medication [MM]). RESULTS: The use of MM in Austria increased from 2009 to 2012 on average by 0.025 percentage points per year (95% confidence interval [CI]: 0.015-0.036). In December 2012, 1 in 123 women filled a prescription for any MM, equaling an average utilization of 0.84%. The relative risk of filling a prescription for a MM 6 months after filling a prescription for a TM was 2.70 (95% CI: 2.64-2.77). All investigated medication classes showed a higher risk for the prescription for MM. Medication from classes "genitourinary system and sex hormones" and "systemic anti-infectives" caused the highest increase in risk (109% and 89%, respectively). Prescriptions for class "cardiovascular system" caused the lowest increase in the risk (15%). CONCLUSION: Certain prescription medications are a significant risk factor for the need to take anticholinergic medication as a consequence.

Effectiveness of hormones in postmenopausal pelvic floor dysfunction-International Urogynecological Association research and development-committee opinion.

INTRODUCTION AND HYPOTHESIS: There is clear evidence of the presence of estradiol receptors (ERs) in the female lower urinary and genital tract. Furthermore, it is a fact that estrogen deficiency after menopause may cause atrophic changes of the urogenital tract as well as various urinary symptoms. Moreover, the effect of hormone replacement therapy (HRT) on urinary incontinence (UI) symptoms as well as pelvic organ prolapse (POP), anal incontinence (AI) and vulvovaginal symptoms (VVS) is still a matter of debate. This committee opinion paper summarizes the best evidence on influence of sex steroids as well as hormonal treatment (local and systemic) in postmenopausal women with pelvic floor disorders. METHODS: A working subcommittee from the International Urogynecology Association (IUGA) Research and Development Committee was formed. A thorough literature search was conducted and an opinion statement expressed. The literature regarding hormones and pelvic floor disorders was reviewed independently and summarized by the individual members of the sub-committee. RESULTS: The majority of studies reported that vaginal estrogen treatment when compared with placebo has more beneficial effects on symptoms and signs of vaginal atrophy including sensation of burning, dyspareunia and UI symptoms. Definitive evidence on local estrogen application and prolapse treatment or prevention is lacking. A statistically significant increase in risk of worsening of UI as well as development of de novo incontinence was observed with estrogen-only or combination systemic HRT. CONCLUSIONS: In summary, local estrogen seems to be safe and effective in the treatment of VVS and can also improve urinary symptoms in postmenopausal patients with UI, but most of these recommendations correspond to evidence level 2C. The evidence in POP is still scarce but not in favor of benefit. Finally, the duration of local estrogen treatment (LET), optimal dosage, long-term effects and cost-effectiveness compared with current practice are still unknown.

The role of tenascin-X in the uterosacral ligaments of postmenopausal women with pelvic organ prolapse: an immunohistochemical study.

INTRODUCTION AND HYPOTHESIS: Abnormalities of connective tissue structure or its repair mechanism may predispose women to pelvic organ prolapse (POP). We hypothesized that the expression of tenascin-X in the uterosacral ligament of postmenopausal women with symptomatic POP is increased compared with postmenopausal women without POP. Furthermore, we identified clinical risk factors associated with POP in our study population. METHODS: We conducted a retrospective case-control study in which 33 postmenopausal women with symptomatic POP ≥ pelvic organ prolapse quantification system (POP-Q) stage II were matched with 33 postmenopausal women without POP. Studied tissue specimens were taken from hysterectomy specimens, and tenascin-X expression was investigated by immunohistochemistry. The immunohistochemical profile of the uterosacral connective tissue of cases and controls was compared. RESULTS: Tenascin-X was expressed in 94% of POP cases and in 91% of controls. Our study failed to show any statistically significant differences in tenascin-X expression between women with and without POP (p = 0.64). However, tenascin-X was significantly more expressed in cases with severe prolapse (POP-Q stage IV) compared with moderate prolapse stages (POP-Q stage II and III) (p = 0.001). Advanced patient age as well as early menopausal age remained independent risk factors associated with POP in multiple logistic regression analysis (p = 0.001). CONCLUSION: No difference could be demonstrated between tenascin-X expression in patients with or without POP. Tenascin-X does not seem to play a major role in the pathogenesis of POP in postmenopausal women.

Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry.

Herpesvirus gH/gL envelope glycoprotein complexes are key players in virus entry as ligands for host cell receptors and by promoting fusion of viral envelopes with cellular membranes. Human cytomegalovirus (HCMV) has two alternative gH/gL complexes, gH/gL/gO and gH/gL/UL128,130,131A which both shape the HCMV tropism. By studying binding of HCMV particles to fibroblasts, we could for the first time show that virion gH/gL/gO binds to platelet-derived growth factor-α (PDGFR-α) on the surface of fibroblasts and that gH/gL/gO either directly or indirectly recruits gB to this complex. PDGFR-α functions as an entry receptor for HCMV expressing gH/gL/gO, but not for HCMV mutants lacking the gH/gL/gO complex. PDGFR-α-dependent entry is not dependent on activation of PDGFR-α. We could also show that the gH/gL/gO-PDGFR-α interaction starts the predominant entry pathway for infection of fibroblasts with free virus. Cell-associated virus spread is either driven by gH/gL/gO interacting with PDGFR-α or by the gH/gL/UL128,130,131A complex. PDGFR-α-positive cells may thus be preferred first target cells for infections with free virus which might have implications for the design of future HCMV vaccines or anti-HCMV drugs.

Management of complications arising from the use of mesh for stress urinary incontinence-International Urogynecology Association Research and Development Committee opinion.

INTRODUCTION AND HYPOTHESIS: Management of pain or mesh exposure complications after stress incontinence surgery has become a new issue over the last 20 years with the introduction of mesh techniques to treat stress incontinence. There is much debate regarding the incidence of complications and how best to treat them. METHODS: A working subcommittee from the International Urogynecology Association (IUGA) Research and Development (R&D) Committee was formed. An initial document was drafted based on a literature review. The review focused on complications of vaginal mesh inserted for stress incontinence. After evaluation by the entire IUGA R&D Committee revisions were made. The final document represents the IUGA R&D Committee Opinion. RESULTS: The R&D Committee Opinion reviews the literature on the management of complications arising from the use of mesh for stress urinary incontinence. The review concentrated on the assessment and treatment of pain and exposure. CONCLUSIONS: Complications after surgery for stress incontinence using mesh may not be common occurrences for individual surgeons. Complications may be difficult to manage and outcomes are variable. Specialist centres and a multidisciplinary approach may optimise treatment and reporting of outcomes.

Prevalence and risk factors for pelvic floor disorders during early and late pregnancy in a cohort of Austrian women.

PURPOSE: To investigate the prevalence of pelvic floor disorders (PFDs) in a cohort of Austrian women either during their early or late pregnancy and to search for clinical risk factors which correlate with pelvic floor symptoms during pregnancy. METHODS: A prospective study was conducted and 200 pregnant women answered the validated German pelvic floor questionnaire during their first or third trimenon of gestation. Furthermore, a multivariate logistic regression model was used to determine independent risk factors for PFDs after adjusting for confounders. RESULTS: 96/200 (48%) women reported psychological strain in at least 1 of the 4 pelvic floor domains while the remaining 104 women (52%) were asymptomatic. Affected women showed a significant higher BMI, a more frequent positive family history and a higher rate of multiple pregnancies was noted compared to asymptomatic women (p < 0.05). Furthermore, a statistically significant positive correlation could be observed between BMI, smoking and mean bladder score as well as mean prolapse score, signifying more symptom bother from bladder and prolapse in smokers with high BMI. A significant positive correlation was also detected between mean bowel score and parity. In the multivariate model, high BMI (CI 1.013-1.143), positive family history (CI 0.044-0.260) and multiple pregnancies (CI 0.011-0.244) remained independently associated with pelvic floor symptoms (p < 0.05). CONCLUSION: Our results demonstrate that pelvic floor-related quality of life during pregnancy is a prevalent condition which is strongly affected by the expectant mother's weight as well as her family history. In addition, women with multiple pregnancies seem to be at increased risk.

Prolapse surgery versus vaginal pessary in women with symptomatic pelvic organ prolapse: which factors influence the choice of treatment?

OBJECTIVE: To investigate which specific clinical factors influence patients' choice of prolapse treatment. METHODS: This study includes a total of 510 cases with symptomatic pelvic organ prolapse (POP) of stage II or higher requiring prolapse treatment. Patients were divided into surgery and pessary groups according to their own choice and treatment preference. Primary outcome of interest was to define potential clinical parameters, which contribute to surgical treatment decision. RESULTS: A total of 252/510 (49%) women decided for prolapse surgery and 258/510 (51%) cases were treated conservatively with vaginal pessary. Hypertension, COPD as well as polypharmacy were parameters, which were statistically significantly more common in the pessary group compared to the surgically managed cases (p <0.05). On the contrary, women undergoing prolapse surgery were significantly younger and showed more advanced POP-Q (pelvic organ prolapse quantification) stages (p < 0.05). Clinical factors, such as BMI (body mass index), parity, mode of delivery and postmenopausal status, did not differ between the two groups (p > 0.05). Multiple logistic regression analysis revealed that advanced POP-Q stage (p < 0.001) as well as the absence of smoking (p < 0.001) were independent factors associated with surgical treatment decision. CONCLUSION: Women, who favoured prolapse surgery, were younger and in significant better health condition (less hypertension and COPD), but showed a significantly higher POP-Q stage compared to women choosing pessary treatment. Our data indicate that women with higher POP-Q stage and non-smokers tended to decide for prolapse surgery. This information could help in clinical practice to guide patients for the best possible treatment decision and strengthen individual counselling.

Anterior colporrhaphy: a standard operation? Systematic review of the technical aspects of a common procedure in randomized controlled trials.

INTRODUCTION: Anterior colporrhaphy (AC) is considered a standard procedure and is performed all over the world. However, not a single step of the procedure has ever been truly standardized and the rates of failure show a wide range in the literature from 0% up to 92%. The aim of this systematic review was to evaluate the differences in technique and procedure worldwide. METHODS: We performed a systematic literature search up to March 2016 using the MeSH terms "(anterior AND (colporrhaph* or colporhaph* or repair* or cystocel*)" using Preferred Reporting Items for Sytematic Reviews and Meta-Analyses (PRISMA). Only randomized controlled trials (RCT) were included in the systematic review. A 14-point checklist was used to assess the quality of surgery undertaken in each RCT. RESULTS: Forty RCTs from all over the world were included in the review. The indication for AC was urinary incontinence and/or pelvic organ prolapse. A detailed description of colporrhaphy was not provided even in the well-conducted RCTs. The review showed differences in each step of the procedure, in perioperative care, in anesthesia and in surgeon' experience. CONCLUSION: Our results highlight the problems concerning AC with the great range in postoperative outcomes. There is diversity in the anatomical structures used in the repair, in perioperative care and in the procedure itself.

Management of the Perineum during Delivery with the Kiwi Omnicup: Effects of Mediolateral Episiotomy on Anal Sphincter Tears in Nulliparous Women.

AIM: The main objective of this study was to evaluate the association of mediolateral episiotomy with severe perineal trauma during Kiwi omnicup vacuum delivery. METHODS: This retrospective study analyzed all Kiwi omnicup vacuum deliveries between 2010 and 2015 in nulliparous women. Secondary outcomes of interest included frequency of genital tract trauma, outcome of Kiwi extraction and influence on neonatal parameters. RESULTS: A total of 572 nulliparous women who were delivered with the aid of vacuum were analyzed. Successful completion of birth was achieved in 549/572 (96%) resulting in a failure rate of 4%. Out of 572 women, 372 (65%) underwent the Kiwi vacuum delivery system in conjunction with episiotomy. Third- or fourth-degree perineal tears occurred in 38 out of the 572 (6.6%) women and the rate of severe perineal trauma was statistically and significantly lower in women who delivered with the aid of the Kiwi vacuum in conjunction with episiotomy (p = 0.0001). Besides, perineal tears of all degrees, vaginal tears and labial trauma were significantly less common in the Kiwi vacuum delivery system when combined with mediolateral episiotomy (p = 0.0001, p = 0.006, and p = 0.0001, respectively). CONCLUSION: Our data showed that the performance of a mediolateral episiotomy was associated with a decreased risk of severe perineal tears as well as vaginal and labial trauma in Kiwi omnicup vacuum deliveries.

Association of endogenous circulating sex steroids and condition-specific quality of life domains in postmenopausal women with pelvic floor disorders.

OBJECTIVE: To examine the relationship between endogenous sex steroids and various condition-specific quality of life domains in postmenopausal women with pelvic floor disorders. We hypothesized that woman with lowest androgen and estradiol concentrations would report worse scores of quality of life domains. METHODS: Forty-six women with pelvic organ prolapse (POP) and 47 cases with stress urinary incontinence (SUI) answered the validated pelvic floor questionnaire and underwent serum sex steroid measurement. A multivariate logistic regression model was used to determine the association between subjective outcome parameters and serum hormonal levels after adjusting for confounders. RESULTS: Univariate analysis revealed a strong inverse correlation between serum estradiol level (E2) and prolapse domain score (correlation coefficient = 0.005) as well as a significant positive correlation between SHBG level and prolapse domain score (correlation coefficient = 0.019) in cases with POP. Furthermore, the sex domain score showed a significant negative correlation with the androstendion (correlation coefficient = 0.020), DHEAS (correlation coefficient = 0.046) and testosterone level (correlation coefficient = 0.032) in the POP group. In the multivariate model, high serum SHBG (CI: 0.007-0.046) remained independently associated with worse scores in the prolapse domain and low serum DHEAS (CI: - 0.989 to 1.320) persisted as a significant predictor for a worse score in the sex domain. Regarding SUI cases, no association was noted between serum hormonal levels and quality of life related pelvic floor domains (correlation coefficient > 0.05). CONCLUSION: Our results suggest that pelvic floor related quality of life might also be affected by endogenous sex steroids in POP, but not in SUI cases.