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Human papillomavirus (HPV) infection is one of the most common sexually transmitted infections. However, only a small percentage of high-risk (HR) HPV infections progress to cervical precancer and cancer. In this study, we investigated the role of the cervicovaginal microbiome (CVM) in the natural history of HR-HPV. This study was nested within the placebo arm of the Costa Rica HPV Vaccine Trial that included women aged 18-25 years of age. Cervical samples from two visits of women with an incident HR-HPV infection (n = 273 women) were used to evaluate the prospective role of the CVM on the natural history of HR-HPV. We focus specifically on infection clearance, persistence, and progression to cervical intraepithelial neoplasia grade 2 and 3 (CIN2+). The CVM was characterized by amplification and sequencing the bacterial 16S V4 rRNA gene region and the fungal ITS1 region using an Illumina MiSeq platform. OTU clustering was performed using QIIME2. Functional groups were imputed using PICRUSt and statistical analyses were performed using R. At Visit 1 (V1) abundance of Lactobacillus iners was associated with clearance of incident HR-HPV infections (Linear Discriminant Analysis (LDA)>4.0), whereas V1 Gardnerella was the dominant biomarker for HR-HPV progression (LDA>4.0). At visit 2 (V2), increased microbial Shannon diversity was significantly associated with progression to CIN2+ (p = 0.027). Multivariate mediation analysis revealed that the positive association of V1 Gardnerella with CIN2+ progression was due to the increased cervicovaginal diversity at V2 (p = 0.040). A full multivariate model of key components of the CVM showed significant protective effects via V1 genus Lactobacillus, OR = 0.41 (0.22-0.79), V1 fungal diversity, OR = 0.90 (0.82-1.00) and V1 functional Cell Motility pathway, OR = 0.75 (0.62-0.92), whereas V2 bacterial diversity, OR = 1.19 (1.03-1.38) was shown to be predictive of progression to CIN2+. This study demonstrates that features of the cervicovaginal microbiome are associated with HR-HPV progression in a prospective longitudinal cohort. The analyses indicated that the association of Gardnerella and progression to CIN2+ may actually be mediated by subsequent elevation of microbial diversity. Identified features of the microbiome associated with HR-HPV progression may be targets for therapeutic manipulation to prevent CIN2+. ClinicalTrials.gov NCT00128661.

BackgroundBacterial vaginosis (BV), a common condition among reproductive age women is associated with an imbalance of vaginal microbiota composition. It has been implicated in numerous adverse reproductive outcomes and increased risk of sexually transmitted infections. The vaginal ecology varies widely among women from various geographic and ethnic backgrounds. Our study aimed to explore the spectrum of bacterial communities in Indian women with and without BV and the association of individual species with Amsel’s clinical diagnostic criteria.Methods16S rRNA gene PCR and V3-V4 sequencing were performed on vaginal swabs from 38 women with BV (mean age= 30.84 years, Nugent score ≥7) and 16 healthy controls (mean age= 28.25 years, Nugent score≤3). BV was assessed by Amsel’s clinical criteria and confirmed by Nugent scoring of Gram stained vaginal smears. Taxonomic classification was performed using SILVA reference database.ResultsThe vaginal community composition of women with BV was highly heterogeneous and characterized by species diversity and richness. Women with BV harbored high concentrations of Gardnerella vaginalis (>99% women), Atopobium spp (81.6%), Prevotella timonensis (73.7%), Sneathia amnii (73.7%) and Sneathia sanguinegens (63.2%). On the contrary, in healthy women with no evident symptoms of vaginitis, Lactobacillus species dominated the vaginal flora wherein L iners and L gasseri were the two most frequently detected species. Interestingly, L iners was noted in all women, irrespective of their BV status. The presence of Atopobium spp., Sneathia spp., P timonensis and Eggerthella spp., were strongly associated with all four clinical signs defined by Amsel’s criteria.ConclusionLactobacillus species including L iners and L gasseri are the predominant vaginal species found in the vaginal tract of Indian women of reproductive age. A heterogeneous vaginal community marked by the presence of G vaginalis, Sneathia spp., Atopobium spp., Prevotella spp., Eggerthella spp., is associated with BV and its clinical symptoms.

Background: Non–invasive vulvovaginal rejuvenation is a promising option for women who want to restore the appearance and function of the vagina. Vaginal atrophy and vulvovaginal laxity are caused by several circumstances, including ageing, menopause, delivery, and others. Until now, non–invasive vulvovaginal rejuvenation has not been medically indicated, but it is estimated to be the focus of cosmetic dermatology in the future. Discussion: Non–invasive vulvovaginal rejuvenation can be divided into two methods: using energy-based devices and injectables. Carbon dioxide, Erbium:YAG laser and radiofrequency are the commonly used energy-based devices. Injectables most frequently used are hyaluronic acid and platelet–rich plasma. Some additional therapies, such as vaginal bleaching and vaginal tightening, are available to complement the available modalities. Several proposed combination treatments might be used to improve treatment outcomes. Side effects and complications reported are mild, but no consensus has approved its long–term effects. The legal aspect is not to be forgotten during the whole procedure. Conclusion: Further multicenter, double–randomized studies are needed to determine these procedures' safety and efficacy.

Introduction/BackgroundMedical treatment has gained popularity as an alternative treatment option in vaginal intraepithelial neoplasia (VaIN). The aim of this meta-analysis was to ascertain the efficacy and safety of 5-flouorouracil (5-FU) in this context.MethodologyA literature search was conducted throughout the PubMed, EMBASE, SCOPUS, ClinicalTrials.gov, and Cochrane Databases for relevant studies from inception until September 2019. We computed the summary proportions of women treated for VaIN with 5-FU for the outcomes of complete response and recurrence by random-effects meta-analysis. Sub-group analyses were performed to address heterogeneity.Results14 observational studies were included. The studies were of moderate quality. Pooled results from 14 studies enrolling 358 VaIN women rendered a summary proportion of 82.18% (95% CI 69.80% - 88.82%) for the outcome of complete response. Pooled results from six studies enrolling 184 high-grade VaIN women rendered a summary proportion of 77.53% (95% CI, 59.90% - 91.15%) for the outcome of complete response. Pooled results from five studies enrolling 26 VaIN women rendered a summary proportion of 53.92% (95% CI 34.62% - 72.61%) for the outcome of complete response amongst persistent lesions. Pooled results from six studies enrolling 98 VaIN women rendered a summary proportion of 16.42% (95% CI, 7.39% - 28.14%) for the outcome of recurrence. The agent was well tolerated by most women and only few studies reported discontinuation of the treatment owing to severe adverse effects.Conclusion5-FU is seemingly an effective and safe treatment modality in the treatment of VaIN. It can be considered as an alternative conservative treatment option, leading to less aggressive and morbid interventions, especially amongst young women with multifocal lesions. Further studies with longer follow-up will be warranted to further assess its efficacy and safety in this setting.DisclosureNothing to disclose

Introduction/BackgroundThe majority of flaps used in reconstruction of the vulva are local flaps with a random blood supply and consist of the skin and subcutaneous tissue. They include the V-Y advancement flap, the transposition flap and the rhomboid flap. The lotus flap is a transpositional flap with the blood supply from the perineal branches of the internal pudendal artery. It has an axial blood supply at the base and a random blood supply at the tip. It can be 4 times longer than its width and can be rotated more than 90 degrees. The type of flap chosen is based on the size and location of the defect. The V-Y is best for lateral defects, the rhomboid is best for perineal defects and the lotus can be used for anterior lateral or posterior defects.MethodologyThe video will show the defect in the vulva and lower vagina that needs to be covered. It will show the harvesting of the flap, rotating it under the vulva tunnel, preparing the recipient graft site and sewing the graft into place.ResultsThe patient healed primarily. She received 4400 cGy of radiation postop. She did not have stricture or skin breakdown. Photos of the result are shown. She is alive without disease at 2 years.ConclusionThe lotus flap is an excellent flap for reconstruction of the vulva or the lower and mid vagina.DisclosureNothing to disclose

Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development. MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design. We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel [40 mg], or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03). Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy. ClinicalTrials.gov NCT00592124.

Commensal microbiota are well known to play an important role in antiviral immunity by providing immune inductive signals; however, the consequence of dysbiosis on antiviral immunity remains unclear. We demonstrate that dysbiosis caused by oral antibiotic treatment directly impairs antiviral immunity following viral infection of the vaginal mucosa. Antibiotic-treated mice succumbed to mucosal herpes simplex virus type 2 infection more rapidly than water-fed mice, and also showed delayed viral clearance at the site of infection. However, innate immune responses, including type I IFN and proinflammatory cytokine production at infection sites, as well as induction of virus-specific CD4 and CD8 T-cell responses in draining lymph nodes, were not impaired in antibiotic-treated mice. By screening the factors controlling antiviral immunity, we found that IL-33, an alarmin released in response to tissue damage, was secreted from vaginal epithelium after the depletion of commensal microbiota. This cytokine suppresses local antiviral immunity by blocking the migration of effector T cells to the vaginal tissue, thereby inhibiting the production of IFN-γ, a critical cytokine for antiviral defense, at local infection sites. These findings provide insight into the mechanisms of homeostasis maintained by commensal bacteria, and reveal a deleterious consequence of dysbiosis in antiviral immune defense.