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Probiotics are living microbes that provide benefits to the host. The growing data on health promotion, following probiotics administration, increased interest among researchers and pharmaceutical companies. Infections of the lower genital tract in females, caused by a wide range of pathogens, represent one of the main areas for the use of probiotics and postbiotics. Vulvovaginal candidiasis (VVC) affects 75% of women of reproductive age at least once during their lifetime, with 5-8% developing the recurrent form (RVVC). The disease is triggered by the overgrowth of Candida on the vaginal mucosa. Here, in order to establish its probiotic potential in the context of VVC, we evaluated the anti-fungal effects of the spore-producing Bacillus coagulans LMG S-24828 against C. albicans and C. parapsilosis as well as its beneficial effects in counteracting Candida vaginal infection in vitro. Our results show that both live B. coagulans and its Cell-Free Supernatant (CFS) exerted antifungal activity against both fungi. Moreover, live B. coagulans reduced hyphal formation, inhibited C. albicans adhesion to vaginal epithelial cells, showed co-aggregation capacity, and exerted a protective effect on vaginal epithelial cells infected with C. albicans . These data suggest that B. coagulans LMG S-24828 may provide benefits in the context of Candida vaginal infections.

Recent European data show an increase in sexually transmitted infections (STIs), particularly N. gonorrhoeae , among young heterosexuals, surpassing pre-pandemic numbers. Italy's varied local health restrictions during the COVID-19 pandemic likely affected STI management and reporting. To evaluate COVID-19's impact on STI spread in Italy, we analyzed microbiological data from before and during the pandemic in an area with minimal restrictions on clinical services. This retrospective study (2017-2022) included 5503 subjects: 2586 from STI clinics (STD group) and 3687 diagnosed with primary infertility (ART group). Samples were tested for Mycoplasmas / Ureaplasmas , C. trachomatis , N. gonorrhoeae , and T. vaginalis by a multiplex PCR. During the pandemic, overall STI prevalence increased significantly ( p < 0.01). U. parvum was the most frequent microorganism in the STD group (26.1% vs. 23.9%), with a notable increase in women (52.1% vs. 32.7%) ( p < 0.001). C. trachomatis and M. hominis positive rates decreased significantly ( p < 0.001 and p < 0.01, respectively). N. gonorrhoeae cases rose among young people (19-29), predominantly heterosexual, with high ciprofloxacin resistance. In the ART group, U. parvum was the most common infection, particularly in young infertile women ( p = 0.01). This study indicates a notable rise in STIs among young people, including heterosexuals, despite social restrictions. The long-term impact of this trend requires further evaluation.

Candida albicans (C. albicans) can behave as a commensal yeast colonizing the vaginal mucosa, and in this condition is tolerated by the epithelium. When the epithelial tolerance breaks down, due to C. albicans overgrowth and hyphae formation, the generated inflammatory response and cell damage lead to vulvovaginal candidiasis (VVC) symptoms. Here, we focused on the induction of mitochondrial reactive oxygen species (mtROS) in vaginal epithelial cells after C. albicans infection and the involvement of fungal burden, morphogenesis and candidalysin (CL) production in such induction. Bioluminescent (BLI) C. albicans, C. albicans PCA-2 and C. albicans 529L strains were employed in an in vitro infection model including reconstituted vaginal epithelium cells (RVE), produced starting from A-431 cell line. The production of mtROS was kinetically measured by using MitoSOX™ Red probe. The potency of C. albicans to induced cell damage to RVE and C. albicans proliferation have also been evaluated. C. albicans induces a rapid mtROS release from vaginal epithelial cells, in parallel with an increase of the fungal load and hyphal formation. Under the same experimental conditions, the 529L C. albicans strain, known to be defective in CL production, induced a minor mtROS release showing the key role of CL in causing epithelial mithocondrial activation. C. albicans PCA-2, unable to form hyphae, induced comparable but slower mtROS production as compared to BLI C. albicans yeasts. By reducing mtROS through a ROS scavenger, an increased fungal burden was observed during RVE infection but not in fungal cultures grown on abiotic surface. Collectively, we conclude that CL, more than fungal load and hyphae formation, seems to play a key role in the rapid activation of mtROS by epithelial cells and in the induction of cell-damage and that mtROS are key elements in the vaginal epithelial cells response to C. albicans., Competing Interests: The Authors have declared that no competing interests exist., (Copyright: © 2024 Spaggiari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Respiratory infections are common in pregnancy with conflicting evidence supporting their association with neonatal congenital anomalies, especially during the first trimester. We profiled cytokine and chemokine systemic responses in 242 pregnant women and their newborns after SARS-CoV-2 infection, acquired in different trimesters. Also, we tested transplacental IgG passage and maternal vaginal-rectal microbiomes. IgG transplacental passage was evident, especially with infection acquired in the first trimester. G-CSF concentration-involved in immune cell recruitment-decreased in infected women compared to uninfected ones: a beneficial event for the reduction of inflammation but detrimental to ability to fight infections at birth. The later the infection was acquired, the higher the systemic concentration of IL-8, IP-10, and MCP-1, associated with COVID-19 disease severity. All infected women showed dysbiosis of vaginal and rectal microbiomes, compared to uninfected ones. Two newborns tested positive for SARS-CoV-2 within the first 48 h of life. Notably, their mothers had acute infection at delivery. Although respiratory infections in pregnancy are reported to affect babies' health, with SARS-CoV-2 acquired early during gestation this risk seems low because of the maternal immune response. The observed vaginal and rectal dysbiosis could be relevant for neonatal microbiome establishment, although in our series immediate neonatal outcomes were reassuring.

Lactic acid bacteria are considered an inexhaustible source of bioactive compounds; indeed, products from their metabolism are known to have immunomodulatory and anti-inflammatory activity. Recently, we demonstrated that Cell-Free Supernatants (CFS) obtained from Lactobacillus ( L .) acidophilus , Lactiplantibacillus ( L .) plantarum , Lacticaseibacillus ( L .) rhamnosus, and Limosilactobacillus ( L .) reuteri can impair Candida pathogenic potential in an in vitro model of epithelial vaginal infection. This effect could be ascribed to a direct effect of living lactic acid bacteria on Candida virulence and to the production of metabolites that are able to impair fungal virulence. In the present work, stemming from these data, we deepened our knowledge of CFS from these four lactic acid bacteria by performing a metabolomic analysis to better characterize their composition. By using an untargeted metabolomic approach, we detected consistent differences in the metabolites produced by these four different lactic acid bacteria. Interestingly, L. rhamnosus and L. acidophilus showed the most peculiar metabolic profiles. Specifically, after a hierarchical clustering analysis, L. rhamnosus and L. acidophilus showed specific areas of significantly overexpressed metabolites that strongly differed from the same areas in other lactic acid bacteria. From the overexpressed compounds in these areas, inosine from L. rhamnosus returned with the best identification profile. This molecule has been described as having antioxidant, anti-inflammatory, anti-infective, and neuroprotective properties. The biological significance of its overproduction by L. rhamnosus might be important in its probiotic and/or postbiotic activity.

Aims: Epidemiological research has shown relevant differences between sexes in clinical manifestations, severity, and progression of cardiovascular and metabolic disorders. To date, the mechanisms underlying these differences remain unknown. Given the rising incidence of such diseases, gender-specific research on established and emerging risk factors, such as dysfunction of glycaemic and/or lipid metabolism, of sex hormones and of gut microbiome, is of paramount importance. The relationships between sex hormones, gut microbiome, and host glycaemic and/or lipid metabolism are largely unknown even in the homoeostasis status. Yet this knowledge gap would be pivotal to pinpoint to key mechanisms that are likely to be disrupted in disease context., Methods and Results: Here we present the Women4Health (W4H) cohort, a unique cohort comprising up to 300 healthy women followed up during a natural menstrual cycle, set up with the primary goal to investigate the combined role of sex hormones and gut microbiota variations in regulating host lipid and glucose metabolism during homoeostasis, using a multi-omics strategy. Additionally, the W4H cohort will take into consideration another ecosystem that is unique to women, the vaginal microbiome, investigating its interaction with gut microbiome and exploring-for the first time-its role in cardiometabolic disorders., Conclusion: The W4H cohort study lays a foundation for improving current knowledge of women-specific mechanisms in cardiometabolic regulation. It aspires to transform insights on host-microbiota interactions into prevention and therapeutic approaches for personalized health care., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The increasing prevalence of chronic diseases is a driver for emerging big data technologies for healthcare including digital platforms for data collection, systems for active patient engagement and education, therapy specific predictive models, optimized patient pathway models. Powerful bioelectronic medicine tools for data collection, analysis and visualization allow for joint processing of large volumes of heterogeneous data, which in turn can produce new insights about patient outcomes and alternative interpretations of clinical patterns that can lead to implementation of optimized clinical decisions and clinical patient pathway by healthcare professionals.With this perspective, we identify innovative solutions for disease management and evaluate their impact on patients, payers and society, by analyzing their impact in terms of clinical outcomes (effectiveness, safety, and quality of life) and economic outcomes (cost-effectiveness, savings, and productivity).As a result, we propose a new approach based on the main pillars of innovation in the disease management area, i.e. progressive patient care models, patient-centric approaches, bioelectronics for precise medicine, and lean management that, combined with an increase in appropriate private-public-citizen-partnership, leads towards Patient-Centric Healthcare., (© 2023. The Author(s).)

Candida causes an estimated half-billion cases of vulvovaginal candidiasis (VVC) every year. VVC is most commonly caused by Candida albicans , which, in this setting, triggers nonprotective neutrophil infiltration, aggressive local inflammation, and symptomatic disease. Despite its prevalence, little is known about the molecular mechanisms underpinning the immunopathology of this fungal infection. In this study, we describe the molecular determinant of VVC immunopathology and a potentially straightforward way to prevent disease. In response to zinc limitation, C. albicans releases a trace mineral binding molecule called Pra1 (pH-regulated antigen). Here, we show that the PRA1 gene is strongly up-regulated during vaginal infections and that its expression positively correlated with proinflammatory cytokine concentrations in women. Genetic deletion of PRA1 prevented vaginal inflammation in mice, and application of a zinc solution down-regulated expression of the gene and also blocked immunopathology. We also show that treatment of women suffering from recurrent VVC with a zinc gel prevented reinfections. We have therefore identified a key mediator of symptomatic VVC, giving us an opportunity to develop a range of preventative measures for combatting this disease.

It is estimated that the 25-50% of women who are reaching menopause every year report symptoms related to the genitourinary syndrome of menopause (GSM). The symptoms are not due simply to lack of estrogen. One possible contributing cause of symptoms is the vaginal microbiota. The vaginal microbiota is a dynamic entity and plays a critical role in the pathogenic interplay of postmenopausal changes. Treatment of this syndrome depends on the severity and type of the symptoms and on the preferences and expectations of women. As there are many treatment options, therapy should be individualized. While new evidence on the role of Lactobacilli in premenopause is emerging, the role of Lactobacilli is still unclear in GSM and the impact of microbiota on vaginal health remains conflictual. However, some reports show promising data on the effect of probiotic therapy in menopause. In the literature there are few studies and small population samples on the role of an exclusive therapy with Lactobacilli and further data will be mandatory. Studies involving large numbers of patients and different intervention periods will be necessary to obtain evidence of the preventive and curative role of vaginal probiotics.

Background: The rise in antimicrobial resistance means that alternative approaches for the treatment and prevention of urinary tract infection (UTIs) are required., Objective: To evaluate the safety and efficacy of a D-mannose-based dietary supplement (D-mannose, citric acid, prebiotic fibers, Astragalus, and dandelion; DAPAD complex) for the treatment of uncomplicated acute E. coli UTIs., Design, Setting, and Participants: This was a single-center, randomized, double-blind, placebo-controlled trial conducted from April 2021 to October 2021 in Rajalakshmi Hospital and Research Centre (Bangalore, India). The participants were nonmenopausal women with an acute uncomplicated E. coli UTI. UTI was diagnosed according to the presence of at least one urinary symptom and bacteriuria (>100 000 CFU/ml)., Intervention: The DAPAD complex was administered twice a day for 5 d, with phenazopyridine and alkalizing agents as the standard of care (SOC). The control group received placebo with SOC., Outcome Measurements and Statistical Analysis: Subjective (clinical resolution/response) and objective (midstream bacteriuria) outcomes were evaluated at the end of therapy (day 6) and at day 35 of follow-up. Adverse events were recorded. Categorical variables were analyzed using χ 2 and Fisher's exact tests; a p value <0.05 was considered significant., Results and Limitations: Seventy women were enrolled and equally randomized to the two groups. Clinical resolution was higher in the DAPAD group at 6 d (34.3% vs 0%; p < 0.0001) and 35 d from baseline (88.6% vs 20%, p < 0.0001). At day 35, no patients in the DAPAD group had moderate or severe symptoms, whereas 25.7% (nine/35) and 11.4% (four/35) of patients in the placebo group had moderate and severe symptoms, respectively. Bacteriological resolution was also higher in the DAPAD group at day 6 (85.7% vs 14.3%; p < 0.0001) and day 35 (100% vs 40%; p < 0.0001). Three mild adverse events (4.26%) unrelated to the investigated product were recorded, all of which were medically treated., Conclusions: The DAPAD complex dietary supplement is effective and safe for treatment of acute uncomplicated E. coli UTIs., Patient Summary: Our results show that for nonmenopausal women with an uncomplicated Escherichia coli urinary tract infection, those treated with a dietary supplement (containing D-mannose, citric acid, prebiotic fibers, Astragalus, and dandelion) had a higher rate of clinical resolution or response than women who received a placebo., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Vaginal ecosystem is a unique environment where, in physiological conditions, lactobacilli dominate. However, pathogenic microbial species responsible for vaginitis and vaginosis can also harbor vaginal microbiota. To extend our previously published data, we analyzed here both the anti- Candida and anti-inflammatory properties of the vaginal gel formulation, Respecta ® Balance Gel (RBG), commercialized as an adjuvant to treat vaginitis and vaginosis. We evaluated its activity by an in vitro model where a monolayer of A-431 vaginal epithelial cells was infected by Candida albicans in the presence of RBG or the placebo formulation (pRBG). Specifically, we tested the RBG capacity to counteract C. albicans virulence factors and their anti-inflammatory properties. Our results show that, unlike the placebo, RBG reduces C. albicans adhesion, its capacity to form hyphae and C. albicans -induced vaginal cell damage. Interestingly, both RBG and pRBG reduce LPS-induced IL-8 secretion (with RBG being the most effective), demonstrating that also the placebo retains anti-inflammatory properties. From our experimental approach, we highlighted the possible role of farnesol on such effects, but we would like to point out that lactic acid, polydextrose and glycogen too must be relevant in the actual application. In summary, our results show that RBG impairs C. albicans virulence and is able to reduce the inflammation in the vaginal environment, ultimately allowing the establishment of a balanced vaginal ecosystem.

Vulvovaginal candidiasis (VVC) affects nearly 3/4 of women during their lifetime, and its symptoms seriously reduce quality of life. Although Candida albicans is a common commensal, it is unknown if VVC results from a switch from a commensal to pathogenic state, if only some strains can cause VVC, and/or if there is displacement of commensal strains with more pathogenic strains. We studied a set of VVC and colonizing C. albicans strains to identify consistent in vitro phenotypes associated with one group or the other. We find that the strains do not differ in overall genetic profile or behavior in culture media (i.e., multilocus sequence type [MLST] profile, rate of growth, and filamentation), but they show strikingly different behaviors during their interactions with vaginal epithelial cells. Epithelial infections with VVC-derived strains yielded stronger fungal proliferation and shedding of fungi and epithelial cells. Transcriptome sequencing (RNA-seq) analysis of representative epithelial cell infections with selected pathogenic or commensal isolates identified several differentially activated epithelial signaling pathways, including the integrin, ferroptosis, and type I interferon pathways; the latter has been implicated in damage protection. Strikingly, inhibition of type I interferon signaling selectively increases fungal shedding of strains in the colonizing cohort, suggesting that increased shedding correlates with lower interferon pathway activation. These data suggest that VVC strains may intrinsically have enhanced pathogenic potential via differential elicitation of epithelial responses, including the type I interferon pathway. Therefore, it may eventually be possible to evaluate pathogenic potential in vitro to refine VVC diagnosis. IMPORTANCE Despite a high incidence of VVC, we still have a poor understanding of this female-specific disease whose negative impact on women's quality of life has become a public health issue. It is not yet possible to determine by genotype or laboratory phenotype if a given Candida albicans strain is more or less likely to cause VVC. Here, we show that Candida strains causing VVC induce more fungal shedding from epithelial cells than strains from healthy women. This effect is also accompanied by increased epithelial cell detachment and differential activation of the type I interferon pathway. These distinguishing phenotypes suggest it may be possible to evaluate the VVC pathogenic potential of fungal isolates. This would permit more targeted antifungal treatments to spare commensals and could allow for displacement of pathogenic strains with nonpathogenic colonizers. We expect these new assays to provide a more targeted tool for identifying fungal virulence factors and epithelial responses that control fungal vaginitis.

The in utero microbiome hypothesis has been long debated. This hypothesis will change our comprehension of the pioneer human microbiome if proved correct. In 60 uncomplicated pregnancies, we profiled the microbiome of chorionic villi (CV) and amniotic fluids (AF) in relation to maternal saliva, rectum, and vagina and the soluble cytokines cascade in the vagina, CV and AF. In our series, 12/37 (32%) AF and 10/23 (44%) CV tested positive for bacterial DNA. CV and AF harbored bacterial DNA of Streptococcus and Lactobacillus, overlapping that of the matched oral and vaginal niches, which showed a dysbiotic microbiome. In these pregnant women, the immune profiling revealed an immune hyporesponsiveness in the vagina and a high intraamniotic concentration of inflammatory cytokines. To understand the eventual role of bacterial colonization of the CV and AF and the associated immune response in the pregnancy outcome, further appropriate studies are needed. In this context, further studies should highlight if the hematogenous route could justify the spread of bacterial DNA from the oral microbiome to the placenta and if vaginal dysbiosis could favor the likelihood of identifying CV and AF positive for bacterial DNA.

Vulvodynia is a vulvar discomfort that occurs in the absence of any specific, clinically identifiable disorder. Few therapies have shown to be effective for the treatment of vulvodynia. In our recently published study, we tested a drug-free gel in women affected by vulvar vestibulitis. It is a cosmetic gel which acts locally without any metabolic, pharmacological or immunological effect. In order to further promote the validity of this new product, in this manuscript we analyzed the results obtained from the administration of four questionnaires in the same two groups of women affected by PVD and treated with a placebo and the new product. The questionnaires used: Female Sexual Function Index Scoring (FSFI), Female Sexual Distress Scale (FSDS), Hospital Anxiety and Depression Scale (HADS), and health-related quality of life measured by SF-36 (SF-36). The results obtained by this current analysis showed that the new gel has also proven benefits on women's quality of life and sexual function, including improvements in arousal, desire, orgasm and satisfaction.

Introduction: Genitourinary syndrome of menopause (GSM) affects up to 48% of pre-menopause women and up to 90% of menopausal women. Many menopausal women with dyspareunia have significant vestibular tenderness due to oestrogen deficiency, which increases the density of sensory nerve fibres in the vulva and the vagina. For this reason, GSM is recognized as one of the causes of provoked vestibulodynia. Few therapies have proven to be effective for provoked vestibulodynia. Many studies have shown the efficacy of laser CO 2 therapy, proving its cost-effectiveness and safety for vaginal health., Material and Methods: In this article we tested a new non-ablative solid-state laser: Ladylift®. The main difference between Ladylift® and other laser technologies is the use of a non-ablative laser wavelength of 1470 nm, without causing ablative thermal injury on the surface of the mucosa. We enrolled 18 post- menopausal women presenting to a private clinic with GSM symptoms and provoked vulvodynia., Results: The treatment protocol consists of 4 sessions of laser, 2 weeks apart, of the duration of 4 minutes. Benefits to menopause symptoms, reported with a numeric rating scale, and to epithelium trophism reported with the vaginal health index were apparent since the first session. Patients undergoing laser therapy have had evident benefit both from the point of view of pain and from that of vaginal health., Conclusions: All the women tolerated the therapy well without any adverse effects. However, the beneficial effect tended to gradually decrease over time, suggesting the need to perform more therapy sessions., Competing Interests: The authors report no conflict of interest., (Copyright © 2022 Termedia.)

This systematic review and meta-analysis aimed to determine if probiotic supplementation in pregnancy reduced maternal Group B streptococcus (GBS) recto-vaginal colonization in pregnant women at 35-37 weeks of gestation. Electronic databases (i.e., PubMed, MEDLINE, ClinicalTrials.gov, ScienceDirect, and the Cochrane Library) were searched from inception up to February 2022. We included RCTs assessing the effects of probiotic supplementation in pregnancy on GBS recto-vaginal colonization. The primary outcome was GBS-positive recto-vaginal cultures performed at 35-37 weeks of gestation. Secondarily, we evaluated obstetric and short-term neonatal outcomes. A total of 132 publications were identified; 9 full-length articles were reviewed to finally include 5 studies. Probiotic supplementation reduced vaginal GBS colonization: the GBS positive culture rate was estimated at 31.9% (96/301) in the intervention group compared to 38.6% (109/282) in the control group (OR = 0.62, 95% CI 0.40-0.94, I2 4.8%, p = 0.38). The treatment started after 30 weeks of gestation and was more effective in reducing GBS colonization (OR 0.41, 95% CI 0.21-0.78, I2 0%, p = 0.55). Probiotic administration during pregnancy, namely in the third trimester, was associated with a reduced GBS recto-vaginal colonization at 35-37 weeks and a safe perinatal profile. Whether this new strategy could reduce the exposition of pregnant women to significant doses of antibiotics in labor needs to be evaluated in other trials.

Recurrent vulvovaginal candidosis (RVVC) is a chronic, difficult to treat vaginal infection, caused by Candida species, which affects women of all ages and ethnic and social background. A long-term prophylactic maintenance regimen with antifungals is often necessary. In most clinical practice guidelines, oral fluconazole is recommended as the first-line treatment. Although clinical resistance to antifungal agents remains rare, overexposure to azoles may increase the development of fluconazole-resistant C .  albicans strains. In addition, non-albicans Candida species are frequently dose-dependent susceptible or resistant to fluconazole and other azoles, and their prevalence is rising. Available therapeutic options to treat such fluconazole-resistant C. albicans and low susceptibility non- albicans strains are limited. Ten experts from different European countries discussed problematic issues of current RVVC diagnosis and treatment in two audiotaped online sessions and two electronic follow-up rounds. A total of 340 statements were transcribed, summarized, and compared with published evidence. The profile of patients with RVVC, their care pathways, current therapeutic needs, and potential value of novel drugs were addressed. Correct diagnosis, right treatment choice, and patient education to obtain adherence to therapy regimens are crucial for successful RVVC treatment. As therapeutic options are limited, innovative strategies are required. Well- tolerated and effective new drugs with an optimized mechanism of action are desirable and are discussed. Research into the impact of RVVC and treatments on health-related quality of life and sex life is also needed., Competing Interests: GD, IS, JP, PH, FS, JB, JK, JV, BS, and WM are expert consultants to the pharmaceutical industry, including Gedeon Richter. RC is an employee at Gedeon Richter.This study received funding from Gedeon Richter Plc. The funder had the following involvement with the study: design and collection of data, and on the decision to submit the manuscript for publication. Authors led the analysis and interpretation of data, and the writing of the manuscript. All authors declare no other competing interests., (Copyright © 2022 Donders, Sziller, Paavonen, Hay, de Seta, Bohbot, Kotarski, Vives, Szabo, Cepuliené and Mendling.)

Vulvovaginal candidiasis (VVC) is a common clinical condition with symptoms and signs of vaginal inflammation in the presence of Candida species. At least one episode of VVC is experienced in up to 75% of women in the reproductive age group during their lifetime, and 5% to 8% of such women suffer from the chronic form. Most cases of VVC are still caused by C. albicans. However, the incidence of VVC cases by non-albicans Candida (NAC) species, such as C. parapsilosis, is continuously increasing. Despite the prevalence of VVC from NAC, little is known about these species and almost nothing about the mechanisms that trigger the VVC. Lactobacillus spp. are the most widely before represented microorganisms in the vaginal microbiota of healthy women. Here, cell-free supernatants (CFS) obtained from L. acidophilus, L. plantarum, L. rhamnosus, and L. reuteri were assessed for their effect on C. parapsilosis virulence traits. Moreover, we assessed if such an effect persisted even after the removal of the CFS (CFS preincubation effect). Moreover, a transwell coculture system was employed by which the relevant antifungal effect was shown to be attributable to the compounds released by lactobacilli. Our results suggest that lactobacilli can work (i) by reducing C. parapsilosis virulence traits, as indicated by the reduced fungal proliferation, viability, and metabolic activity, and (ii) by improving epithelial resistance to the fungus. Overall, these data suggest that, in the context of the vaginal microbiota, the lactobacilli may play a role in preventing the onset of mucosal C. parapsilosis infection. IMPORTANCE The incidence of VVC by non-albicans Candida (NAC) species, such as C. parapsilosis, is increasing. Treatment failure is common in NAC-VVC because some species are resistant or poorly susceptible to the antifungal agents normally employed. Research on C. parapsilosis's pathogenic mechanisms and alternative treatments are still lacking. C. albicans triggers the VVC by producing hyphae, which favor the loss of epithelial tolerance. Differently, C. parapsilosis only produces pseudohyphae. Hence, different virulence factors may trigger the VVC. Likewise, the therapeutic options could also involve different fungal targets. Substantial in vitro and in vivo studies on the pathogenicity mechanisms of C. parapsilosis are lacking. The data presented here ascribe a novel beneficial role to different Lactobacillus spp., whose CFS provides a postbiotic-like activity against C. parapsilosis. Further studies are needed to unravel the mechanisms involved in the bioactivities of such compounds, to better understand the role of single postbiotics in the CFS.

Background: Provoked vestibulodynia is commonly associated with dyspareunia and affects 7% to 15% of women. This pathology has major implications on sexual function and quality of life, and several types of treatments are available for its management. However, a consensus has not been reached concerning the best treatment of vulvar pain. The aim of this study was to assess the efficacy and safety of a brand-new product, the vulvar emulgel Meclon ® Lenex, for the management of provoked vestibulodynia and non-infective vulvitis., Methods: This was a monocentric, prospective, randomized, double-blind and placebo-controlled study. We enrolled 40 women with provoked vestibulodynia; 20 patients received Meclon ® Lenex, whereas the remaining received a placebo. Each woman was assessed subjectively (through questionnaires) and objectively by evaluating vaginal and vulvar symptoms (Friedrichs criteria and Marinoff dyspareunia grade). We evaluated efficacy, safety, compliance and tolerability of the brand-new product vulvar gel Meclon ® Lenex in provoked vestibulodynia., Results: After administration of Meclon ® Lenex, we evaluated all parameters of the Friedrichs criteria (burning, dyspareunia, erythema, vulvar pain at the 5 o'clock position and 7 o'clock position), as well as the levels of Marinoff dyspareunia. The active treatment showed to be statistically significantly effective ( p value ≤ 0.05) in reducing all symptoms of Friedrichs criteria, vulvar pain and Marinoff dyspareunia., Conclusion: This prospective study showed that Meclon ® Lenex vulvar emulgel revealed an excellent tolerability and compliance, demonstrating to be a safe and effective option in the treatment of provoked vestibulodynia and non-infective vulvitis.

Objective: Urinary tract infections (UTI) among women form a substantial part of medical practice and both patients and medical professionals have an interest in non-antibiotic treatments and preventative measures. This research provides preliminary data on a multi-functional composition, DAPAD, which explored several biologic activities of relevance to UTI., Study Design: This formulation included D-mannose, citric acid, three prebiotic compounds, and extracts of dandelion and astragalus. Studies performed employed 4 bacterial strains that have relevance to UTI including E. coli, Proteus mirabilis, Streptococcus agalactiae and Enterococcus faecalis., Results: Key findings from in vitro studies included: DAPAD at full- and half-strength inhibited growth of all UTI bacteria. Evidence for D-mannose agglutination of E. coli was demonstrated. D-mannose also showed unexpected effects on bacterial membrane integrity with vital staining and modest growth restriction. We did not demonstrate growth inhibition by dandelion or astragalus extracts but the latter showed diminished cytokine elaboration by bladder epithelial cells., Conclusion: DAPAD is a multifunctional composition that may warrant further development as a UTI treatment or preventive if supported by clinical evaluation., Competing Interests: Declaration of Competing Interest The authors declare Z.J., G.S., A.M. and B.L. have no conflict of interest. F.D. serves as scientific advisor to Giellepi S.p.A and was instrumental in providing DAPAD components as stated in the methods section, to our laboratory. F.D. had no direct involvement in data development or interpretation. Employees of Giellepi S.p.A. were not provided a copy of this manuscript prior to submission and had no role in reviewing or interpreting the data., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: This series of articles, titled The Vaginal Microbiome (VMB), written on behalf of the International Society for the Study of Vulvovaginal Disease, aims to summarize the recent findings and understanding of the vaginal bacterial microbiota, mainly regarding areas relevant to clinicians specializing in vulvovaginal disorders., Materials and Methods: A search of PubMed database was performed, using the search terms "vaginal microbiome" with "Candida," "vaginitis," "urinary microbiome," "recurrent urinary tract infections," "sexually transmitted infections," "human immunodeficiency virus," "human papillomavirus," "nonspecific vaginitis," "vulvodynia," and "vulvovaginal symptoms." Full article texts were reviewed. Reference lists were screened for additional articles. The third article in this series describes VMB in various urogenital disorders., Results: Variable patterns of the VMB are found in patients with vulvovaginal candidiasis, challenging the idea of a protective role of lactobacilli. Highly similar strains of health-associated commensal bacteria are shared in both the bladder and vagina of the same individual and may provide protection against urinary tract infections. Dysbiotic VMB increases the risk of urinary tract infection. Loss of vaginal lactic acid-producing bacteria combined with elevated pH, increase the risk for sexually transmitted infections, although the exact protective mechanisms of the VMB against sexually transmitted infections are still unknown., Conclusions: The VMB may constitute a biological barrier to pathogenic microorganisms. When the predominance of lactobacilli community is disrupted, there is an increased risk for the acquisition of various vaginal pathogents. Longitudinal studies are needed to describe the association between the host, bacterial, and fungal components of the VMB., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.)

Objective: This series of articles, titled The Vaginal Microbiome (VMB), written on behalf of the International Society for the Study of Vulvovaginal Disease, aims to summarize the recent findings and understanding of the vaginal bacterial microbiota, mainly regarding areas relevant to clinicians specializing in vulvovaginal disorders., Materials and Methods: A search of PubMed database was performed, using the search terms "vaginal microbiome" with "treatment," "diagnosis," and "research." Full article texts were reviewed. Reference lists were screened for additional articles., Results: The currently available approaches for treating vaginitis or attempting to modulate the VMB are often insufficient. It has traditionally relied on the use of antibiotics, antiseptics, and antifungals. The fifth and last article of this series discusses the new and/or alternative therapeutic modalities. It addresses the role of probiotics, prebiotics and symbiotics, activated charcoal, biofilm disrupting agents, acidifying agents, phage therapy, and the concept of vaginal microbiome transplant. The challenges facing the research of VMB, including the clinical impact of microbiome manipulation, classification, and new diagnostic approaches are discussed., Conclusions: Microbiome research has grown dramatically in recent years, motivated by innovations in technology and decrease in analysis costs. This research has yielded huge insight into the nature of microbial communities, their interactions, and effects with their hosts and other microbes. Further understanding of the bacterial, fungal, phage, and viral microbiomes in combination with host genetics, immunologic status, and environmental factors is needed to better understand and provide personalized medical diagnostics and interventions to improve women's health., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.)

Objective: This series of articles, titled The Vaginal Microbiome, written on behalf of the International Society for the Study of Vulvovaginal Disease, aims to summarize the current findings and understanding of the vaginal bacterial microbiota, mainly regarding areas relevant to clinicians specializing in vulvovaginal disorders., Materials and Methods: A database search of PubMed was performed, using the search terms "vaginal microbiome" (VMB) with "research," "normal," "neonate," "puberty," "adolescent," "menopause," and "ethnicities," as well as "human microbiome project." Full article texts were reviewed. Reference lists were screened for additional articles., Results: In the last 2 decades, many studies applying molecular techniques were performed, intending to characterize the vaginal microbiota. These studies advanced our understanding of how vaginal health is defined. The first article in this series focuses on the advancement of VMB research, technical definitions, the definition of "normal" VMB, and the dynamics of VMB throughout women's lives., Conclusions: Understanding how microorganisms inhabiting the vagina interact with each other and with the host is important for a more complete understanding of vaginal health. The clinical application of microbial community sequencing is in its beginning, and its interpretation regarding practical clinical aspects is yet to be determined., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.)

Objective: This series of articles, titled The Vaginal Microbiome (VMB), written on behalf of the International Society for the Study of Vulvovaginal Disease, aims to summarize the recent findings and understanding of the vaginal bacterial microbiota, mainly regarding areas relevant to clinicians specializing in vulvovaginal disorders., Materials and Methods: A search of PubMed database was performed, using the search terms "vaginal microbiome" with "reproduction," "infertility," "fertility," "miscarriages," "pregnancy" "cervical cancer," "endometrial cancer," and "ovarian cancer." Full article texts were reviewed. Reference lists were screened for additional articles., Results: The fourth article of this series focuses on 2 distinct areas: the role of VMB in various aspects of human reproduction and, in sharp contrast, the association between the VMB and gynecologic malignancies. Several of the negative pregnancy outcomes have been associated with an altered VMB. Dysbiosis is remarkably linked with poor pregnancy outcomes from preconception to delivery. The associations between the microbiome and gynecologic cancers are described., Conclusions: The development of the microbiome research, enabled by molecular-based techniques, has dramatically increased the detection of microorganisms and the understanding of bacterial communities that are relevant to maternal-fetal medicine in health and disease, as well as in gynecological malignancies. Proving causation in cancer is difficult because of the complex interactive nature of potential causative factors. Certain elements of the microbiota have been shown to provoke inflammatory reactions, whereas others produce anti-inflammatory reactions; this balance might be impaired with a change in microbial variety., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.)

Objective: This series of articles, titled The Vaginal Microbiome (VMB), written on behalf of the International Society for the Study of Vulvovaginal Disease, aims to summarize the recent findings and understanding of the vaginal bacterial microbiota, mainly regarding areas relevant to clinicians specializing in vulvovaginal disorders., Materials and Methods: A search of PubMed database was performed, using the search terms "vaginal microbiome" with "dysbiosis," "bacterial vaginosis," "cytolytic vaginosis," "desquamative inflammatory vaginitis," and "aerobic vaginitis." Full article texts were reviewed. Reference lists were screened for additional articles., Results: The second article in this series focuses on vaginal dysbiotic conditions. Dysbiosis is a term describing imbalances in bacterial communities. Given that lactobacillus-dominated microbiota are thought to be the most optimal, vaginal dysbiosis is usually considered as lactobacilli-depleted VMB. Bacterial vaginosis (BV), the most common vaginal dysbiotic condition, is a polymicrobial disorder, considered the leading cause for vaginal discharge in women worldwide. In addition, we review the VMB in other vaginal conditions associated with lactobacilli depletion: desquamative inflammatory vaginitis and aerobic vaginitis. We also discuss the controversial diagnosis of cytolytic vaginosis, related with lactobacilli overgrowth., Conclusions: Bacterial vaginosis displays complex microbiology. The heterogeneity and diversity within the genus Gardnerella may impact the progression of BV. Bacterial biofilms may contribute to the etiology and persistence of BV, and various bacteria may affect its clinical presentation and pathogenicity. Lack of lactobacilli is not always accompanied by an overgrowth of anaerobes., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the ASCCP.)

Many non-prescription preparations intended to treat or alleviate symptoms of vaginal infection are available in American and European markets, but many have scant preclinical or clinical research underpinning. Respecta ® Balance Gel (RBG) is marketed as an adjunct to probiotic treatment and its relevant antimicrobial properties were studied. Key findings with the manufacturer-supplied gel showed reduced turbidity in broth-dilution tests by 50% against Candida albicans and Candida glabrata at RBG concentrations 0.2-0.4% of neat product, respectively. A 50% reduction in turbidity of Escherichia coli , Streptococcus agalactiae , Enterococcus faecalis ranged from 1.6-2.2% and Gardnerella vaginalis was shown by flow cytometry counts to undergo a 50% reduction at 0.3% RBG. Propidium iodide staining indicated a rapid reduction of cell integrity of G. vaginalis almost immediately while after 4 h 45% of E. coli cells were stained. The lactic acid in BHI inhibited bacteria and yeast at concentrations ranging from 0.2-1.8% but inhibition was not solely due to pH since a 1:4 dilution of RBG resulted in a pH near neutral (6.75). Other findings showed biofilm accumulation assessed after 10-days exposure of Candida spp. to RBG and was reduced by an average of one-third (community strains) to one-half (drug-resistant strains). One excipient of the RBG, disodium EDTA, inhibited the growth of bacteria and yeast at concentrations below those present in RBG and may accentuate the activity of the host defense factor, lactoferrin. We conclude that RBG is a potent inhibitor of vaginal microorganisms relevant to vaginitis or intrapartum infections and contains excipients that may contribute to its antimicrobial activity.

Background: An estimated 75% of women will have one episode of vulvovaginal candidiasis (VCC) during their lifetime, and 40-50% of these will experience further episodes. The high incidence of vulvovaginal candidiasis, combined with the problems of azole resistance and toxicity, highlights the necessity for new strategies for the treatment of this condition. In this context, natural compounds represent promising alternatives. Methods: We enrolled, between January 2020 and April 2021, forty women affected by uncomplicated vulvovaginal candidiasis. Women were divided into two groups. In the first group, we treated 20 women with clotrimazole daily administration for six days. In the second group, 20 women were treated with clotrimazole associated with Unilen ® Microbio+, a new product containing Saccharomyces cerevisiae , melatonin, and GLA-14. Women underwent a check at days 15, 30, and 90. A clinical and cultural examination were performed to establish the effect of the treatments on vaginal flora. Results: In the group treated with Unilen ® Microbio+, clinical and microbiological cure at 15 and 30 days was observed in 18 women (90%), compared with 16 women (80%) in the group treated only with clotrimazole. The efficacy of the association between clotrimazole and Unilen ® Microbio+ in these uncomplicated forms was therefore not inferior to the azole treatment alone. Only four women (20%) in the Unilen ® Microbio+ group presented symptomatic recurrences within the 3 months, compared with eight women (40%) in the clotrimazole-only group. Microscopic wet mount analysis at 1 and 3 months demonstrated a significant increase in lactobacillus count and a reduction in the polymorphonucleate cells in the Unilen ® Microbio+ group. Conclusions: Unilen ® Microbio+ supplementation was demonstrated to cure uncomplicated vulvovaginal candidiasis with clotrimazole, reducing recurrence and improving vaginal flora better than clotrimazole treatment alone.

An experimental model of dryness on vaginal mucosa is proposed to assess the efficacy of a new vaginal gel (Respecta ® Hydragel Ref 17031). The dryness model was induced on reconstituted human vaginal epithelium (HVE) by incubating the tissues in modified environmental conditions (R.H. < 50% and T = 40 °C) for 48 h. The products were applied on the 'Dry' HVE models for 24 h (series 48 h + 24 h) in standard culture conditions (37 °C 5% CO 2 ). Their efficacy in counteracting vaginal dryness was assessed and compared to tissues treated with saline solution and cultured in standard culture conditions (negative control) and to untreated tissues incubated in dryness conditions for 48 h and then recovered after 24 h in standard culture conditions (positive control). The products' efficacy was quantified by measuring the following parameters: (1) water flux and direct moisturization by AQP3 immunohistochemical staining, and (2) maintenance of moisturization and elasticity of the mucosa by hyaluronic acid (CD44) immunofluorescence staining. Respecta ® Hydragel demonstrated efficacy in regulating the water flux by inducing AQP3 expression thus determining a positive water balance within the vaginal epithelium. It induced a remodelling of the epithelium morphology with restored trophism compared to the dry HVE control. Furthermore, it demonstrated a significant increase of the expression of CD44, related to hyaluronic acid (HA) distribution in the extracellular matrix. HA has the ability to act on the cellular matrix composition and its renewal compared to the dry HVE control. Through these mechanisms it induces a deep hydration and elasticity of the vaginal mucosa.

The sterile-womb dogma in uncomplicated pregnancy has been lively debated. Data regarding the in utero microbiome environment are based mainly on studies performed at the time of delivery. Aim: To determine whether human placenta and amniotic fluid are populated by a bacterial microbiota in the first and second trimesters of pregnancy. Materials & methods: We analyzed by next-generation sequencing method 24 and 29 samples from chorionic villus sampling (CVS) and amniocentesis (AC), respectively. The V3 region of the 16S rRNA gene was sequenced. Results: 37.5% of CVS and 14% of AC samples showed the presence of bacterial DNA. Conclusion: Our study suggests that bacterial DNA can be identified in the placenta and amniotic fluid during early prenatal life.

Objective: The aim of the present randomized placebo-controlled single-center study was to assess the efficacy and safety of a new vaginal gel (Meclon Idra - Alfasigma) in the treatment of vulvovaginal atrophy (VVA). The gel is composed of sea buckthorn (Hippophaë rhamnoides) oil, aloe vera, 18β-glycyrrhetic acid, hyaluronic acid and glycogen. The study assessed whether the gel can reduce VVA symptoms (vaginal dryness, itching, burning sensation) and improve sexual function in postmenopausal women over 12 weeks., Study Design: Postmenopausal women (n° = 60) reporting VVA symptoms were recruited and randomized in a 1:1 ratio to the gel or placebo. Active vaginal gel or placebo was applied for 14 days and then twice a week for 90 consecutive days., Main Outcome Measure: The Vaginal Health Index (VHI), including vaginal pH, was used to assess changes in objective signs, whereas the self-reported Female Sexual Function Index (FSFI) was used to investigate sexual function., Results: Meclon Idra was effective in reducing vaginal pain, dyspareunia and vaginal pH, with the VHI showing significant improvement at day 90 (P < .0001), and in reducing each VVA symptom (vaginal dryness, vaginal itching, burning sensation) at weeks 2 and 4, and the end of the study (P < .0001). The analysis of FSFI scores showed, after the end of treatment, an improvement of sexual function in the active-treatment group, with a statistically significant increase (P < 0.001) in all domains scores and total score (P < 0.001)., Conclusions: The present single-center randomized clinical trial demonstrated the efficacy, tolerability and safety of 12-week treatment with a new vaginal gel in postmenopausal women with symptoms associated with VVA. Based on this trial, the gel seems to be a valid choice as a single, local agent for relieving VVA symptoms and improving sexual function, and to have good compliance. This trial is registered prospectively with the Clinical Trials Registry - India, number CTRI/2019/05/01911., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Candida albicans overgrowth at various mucosal sites is an ongoing and complex clinical concern involving interactions with indigenous microbiota and therapeutic or preventive measures superimposed on the pathogen-microbiome interaction. In this paper we describe the use of quantitative flow cytometry (specific to the cytometer's sample introduction mechanism) to explore the in vitro interaction between Candida albicans , probiotic lactobacilli and a topical vaginal therapeutic. Our central hypothesis was cytometric measurements of co-cultures of yeast and bacteria could provide a useful method for exploring the dynamics of different microbial species in culture, with and without inhibitors. Two commercial products were used as exemplars for this research, a vaginal antimicrobial gel and two species of probiotic lactobacillus intended or oral administration with crystalline bovine lactoferrin to augment the vaginal gel. The cytometer forward channel height parameter distinguished yeast from bacteria in co-culture experiments in the presence of a vaginal therapeutic gel or components of its formulation including EDTA, glycogen, polydextrose as well as the host defense factor, lactoferrin. Flow cytometry showed lactobacilli influenced yeast counts in co-culture, with the technique lending itself to wide-ranging test conditions including organisms, media composition and screening of various antimicrobials. Key findings: The proprietary vaginal gel augmented the effect of lactobacilli, as did EDTA and lactoferrin. Prebiotic compounds also enhanced Candida inhibition by lactobacilli. Propidium iodide (Fluorescence channel 3) discriminated between necrotic and non-necrotic yeast and bacteria in co-cultures under various culture conditions. This research demonstrates the value of flow cytometry to evaluate the population dynamics of yeast and bacteria in co-culture using a proprietary product and its components. We discuss both the limitations of the current study and describe how methods employed here would be transferrable to the investigation of organisms present in defined cultures or at body sites colonized by fungal species and the effects of therapeutics or probiotics on Candida .

Bacterial vaginosis (BV) affects one-third of reproductive age women, increasing the risk of acquiring sexually transmitted infections (STIs) and posing a risk for reproductive health. The current diagnosis with Gram stain (Nugent Score) identifies a transitional stage named partial BV or intermediate microbiota, raising the problem of how to clinically handle it. We retrospectively analyzed cervicovaginal swabs from 985 immunocompetent non-pregnant symptomaticspp. women (vaginal discharge, burning, itching) by Nugent score and qPCR for BV, aerobic or fungal vaginitis, and STIs ( Mycoplasmas spp., Chlamydia t. , Trichomonas v. , and Neisseria g. ). Nugent scores 0-3 and 7-10 were confirmed in 99.3% and 89.7% cases, respectively, by qPCR. Among Nugent scores 4-6 (partial BV), qPCR identified 46.1% of BV cases, with 37.3% of cases negative for BV, and only 16.7% of partial BV. Gram staining and qPCR were discordant ( p value = 0.0001) mainly in the partial BV. Among the qPCR BV cases, the presence of aerobic vaginitis and STIs was identified, with a significant association ( p < 0.0001) between the STIs and partial BV/overt BV. qPCR is more informative and accurate, and its use as an alternative or in combination with Gram staining could help clinicians in having an overview of the complex vaginal microbiota and in the interpretation of partial BV that can correspond to vaginitis and/or STIs.

Background: Previous outbreaks of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV) have been associated with unfavourable pregnancy outcomes. SARS-CoV-2 belongs to the human coronavirus family, and since this infection shows a pandemic trend it will involve many pregnant women., Aims: This systematic review and meta-analysis aimed to assess the impact of coronavirus disease 19 (COVID-19) on maternal and neonatal outcomes., Sources: PubMed, EMBASE, MedRxiv, Scholar, Scopus, and Web of Science databases were searched up to 8th May 2020. Articles focusing on pregnancy and perinatal outcomes of COVID-19 were eligible. Participants were pregnant women with COVID-19., Content: The meta-analysis was conducted following the PRISMA and MOOSE reporting guidelines. Bias risk was assessed using the Joanna Briggs Institute (JBI) manual. The protocol was registered with PROSPERO (CRD42042020184752). Twenty-four articles, including 1100 pregnancies, were selected. The pooled prevalence of pneumonia was 89% (95%CI 70-100), while the prevalence of women admitted to the intensive care unit was 8% (95%CI 1-20). Three stillbirths and five maternal deaths were reported. A pooled prevalence of 85% (95%CI 72-94) was observed for caesarean deliveries. There were three neonatal deaths. The prevalence of COVID-19-related admission to the neonatal intensive care unit was 2% (95%CI 0-6). Nineteen out of 444 neonates were positive for SARS-CoV-2 RNA at birth. Elevated levels of IgM and IgG Serum antibodies were reported in one case, but negative swab., Implications: Although adverse outcomes such as ICU admission or patient death can occur, the clinical course of COVID-19 in most women is not severe, and the infection does not significantly influence the pregnancy. A high caesarean delivery rate is reported, but there is no clinical evidence supporting this mode of delivery. Indeed, in most cases the disease does not threaten the mother, and vertical transmission has not been clearly demonstrated. Therefore, COVID-19 should not be considered as an indication for elective caesarean section., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: Bromelain is a complex mixture of thiol proteases and other non-proteolytic constituents, commercially extracted primarily from the pineapple stem. Evidence from several in vitro and in vivo studies highlights its excellent bioavailability, lack of side effects, and broad spectrum of medical efficacies, of which the antiphlogistic properties are among the most valuable ones. Bromelain has indeed been employed for the efficient treatment of many inflammatory disorders, ranging from osteoarthritis and inflammatory bowel diseases to cancer-related inflammation., Methods: The aim of the current study was to assess the anti-inflammatory effects of bromelain after gastrointestinal digestion simulated in vitro using stomach, intestinal, and chondrocyte human cellular models (AGS, Caco-2, and SW1353, respectively)., Results: We successfully demonstrated the capability of bromelain to reduce an inflammatory stimulus by reproducing its exposure to the gastro-enteric environment in vitro and assaying its effect in human cell lines derived from stomach, intestinal, and chondrocytes., Conclusion: Consistently with the previously published data, our work underpins the relevance of bromelain in the development of safer and more effective anti-inflammatory therapies.

Infertile couples undergoing the use of assisted reproductive technology are a good study model to evaluate the microbiological signatures affecting reproductive health. We tested vaginal lavages, follicular fluids, embryo culture mediums, and seminal fluids from 47 couples for their microbiome composition and HPV infection. Twenty-five infertile couples were diagnosed with unexplained infertility, whereas 22 were diagnosed with explained infertility. Lactobacilli were dominant in the vaginal lavages of both patient groups, and the most abundant species was L. iners (CST III), which is linked to a decreased fertility rate. Besides this, L. gasseri -which is known to be associated with oocyte DNA fragmentation and decreased sperm mobility-was identified in the seminal fluids, follicular fluids, and embryo culture media of the unexplained infertility group. Prevotella was increased in the seminal fluids of the explained infertility group, along with HPV-positive seminal fluids: an infection commonly associated with infertility, especially male infertility. Prevotella has been described to negatively affect sperm motility. Taken together, these results suggest that the profiling of the reproductive tract microbiome can add new perspectives to human reproduction.

Gastroesophageal reflux disease (GERD) is a common digestive disorder that causes esophagitis and injuries to the esophageal mucosa. GERD symptoms are recurrent during pregnancy and their treatment is focused on lifestyle changes and nonprescription medicines. The aim of this study was to characterize the mechanism of action of a new patented medical device, an oral formulation containing hyaluronic acid, rice extract, and amino acids dispersed in a bioadhesive polymer matrix, by assessing its protective effects in in vitro and ex vivo models of esophageal mucosa damage. Acidic bile salts and pepsin cocktail (BSC) added to CP-A and COLO-680 N esophagus cells were used as an in vitro GERD model to evaluate the binding capacities, anti-inflammatory effects and reparative properties of the investigational product (IP) in comparison to a viscous control. Our results showed that the IP prevents cell permeability and tight junction dysfunction induced by BSC. Furthermore, the IP was also able to down-regulate IL-6 and IL-8 mRNA expression induced by BSC stimulation and to promote tissue repair and wound healing. The results were confirmed by ex vivo experiments in excised rat esophagi through the quantification of Evans Blue permeability assay. These experiments provided evidence that the IP is able to bind to the human esophagus cells, preventing the damage caused by gastroesophageal reflux, showing potential anti-irritative, soothing, and reparative properties., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Intrauterine fetal death (IUFD) is a tragic event and, despite efforts to reduce rates, its incidence remains difficult to reduce. The objective of the present study was to examine the etiological factors that contribute to the main causes and conditions associated with IUFD, over an 11-year period in a region of North-East Italy (Friuli Venezia Giulia) for which reliable data in available., Methods: Retrospective analysis of all 278 IUFD cases occurred between 2005 and 2015 in pregnancies with gestational age ≥ 23 weeks., Results: The incidence of IUFD was 2.8‰ live births. Of these, 30% were small for gestational age (SGA), with immigrant women being significantly over-represented. The share of SGA reached 35% in cases in which a maternal of fetal pathological condition was present, and dropped to 28% in the absence of associated pathology. In 78 pregnancies (28%) no pathology was recorded that could justify IUFD. Of all IUFDs, 11% occurred during labor, and 72% occurred at a gestational age above 30 weeks., Conclusion: The percentage of IUFD cases for which no possible cause can be identified is quite high. Only the adoption of evidence-based diagnostic protocols, with integrated immunologic, genetic and pathologic examinations, can help reduce this diagnostic gap, contributing to the prevention of future IUFDs.

Vulvovaginal atrophy (VVA) has an impact on the quality of life (QoL) of women. This post hoc analysis of the EVES study provides an overview of the QoL in postmenopausal Italian women in relation with VVA severity. We included 1066 women attending menopause/gynaecologic centres. A face-to-face survey (including QoL and sexual life questionnaires), joining an objective gynaecological examination to confirm VVA, were performed. The 65.5% of the participants presented severe vaginal, vulvar and/or urinary symptoms; an 86.9% had an objective confirmed VVA. Women with severe symptoms presented with significantly worse QoL scores than the women without. We found there were moderately significant correlations between vaginal and vulvar symptoms' severity and lower overall DIVA QoL scores (p<.0005, in both cases). Women with a confirmed VVA presented worse QoL scores than women without confirmation. Our data suggest a clear relationship between VVA severity and a decrease in QoL in postmenopausal Italian women.IMPACT STATEMENT What is already known on this subject? Vulvovaginal atrophy (VVA) appears as a common chronic disorder in postmenopausal women that, as soon as the oestrogen levels decrease, becomes a severe condition affecting their quality of life (QoL). What do the results of this study add? We provide new insight about QoL related to VVA severity in Italian postmenopausal women. Our local data demonstrates that QoL in Italian women suffering from menopause is directly related to the severity of vaginal and vulvar symptoms. The same correlation exists for urinary symptoms. QoL is also reduced in patients with an objectively confirmed VVA diagnosis. What are the implications of these findings for clinical practice and/or further research? The implications of our findings involve the need for a better management, not only of the physical aspects of VVA, but also of the non-physical dimensions. Clinicians should ask for the impact of VVA on QoL aspects, making postmenopausal women aware about the possible affected spheres. Medical personnel should conduct future campaigns in the Italian general population, not only in those asking for medical help, to make all women conscious about this silent disorder affecting physical and non-physical dimensions and in order to treat it at early stages.

Vaginal infections are the most prevalent women's health problem. Incompetent diagnosis, inappropriate treatments, and antibiotic resistance are the main causes of the unsatisfactory results of conventional, antimicrobic treatment for these infections. Research has thus been conducted to identify new treatments for these genital diseases. The significant enhancement in our knowledge of vaginal microbiota has permitted the development of new, nonpharmacological strategies for the treatment of vaginal infections that seek to restore the balance of vaginal microflora, as opposed to modifying its components. Among these approaches, bioactive compounds, such as probiotics and nutraceutical proteins (such as lactoferrin), deserve particular attention. The aim of this review is to examine the role of probiotics (mainly Lactobacillus spp.) and lactoferrin as new strategies for counteracting bacterial and fungal vaginal infections.

Regarding bacterial vaginosis (BV), the relevance of the vaginal microbiota to the women's health fulfills a key role, but knowledge gaps regarding aerobic vaginitis (AV) exist. This study aims to characterize vaginal microbiome and its relationship with the local immune mediators, providing an opportunity to define the link between vaginal commensal microorganisms and opportunistic pathogens in the relation of a given vaginal community state type (CST). A total of 90 vaginal samples from Caucasian asymptomatic women of reproductive age (18-40 years) attending the yearly examination and not reporting any vaginal complaints were retrospectively evaluated for microbiome assessment and immune factor dosage. The samples were tested by the Ion Torrent PGM and the Luminex Bio-Plex technologies for the analysis of microbiome and immune factors, respectively. In our study, the CST classification together with the local immune response profiling represented a good predictive indicator of the vaginal health, suggesting that the predominance of a specific Lactobacillus and its relative abundance are pivotal elements to maintain a physiologic status. A vaginal colonization from Bifidobacterium may absolve a protective role similar to that of Lactobacillus , corresponding to a newly identified CST, although studies are needed to better clarify its clinical significance. Moreover, within each CST, a different pattern of inflammation is activated and orchestrated both by the dominant Lactobacillus spp. and by specific non- Lactobacillus bacteria and can give insights into the pathogenic mechanisms. In conclusion, this study contributes to the characterization of vaginal dysbiosis, reshaping this concept by taking into consideration the CST profiling, local immune marker, and immune-microbial network., (Copyright © 2019 De Seta, Campisciano, Zanotta, Ricci and Comar.)

The picture of dynamic interaction between oncogenic viruses and the vaginal bacteria-immune host milieu is incomplete. We evaluated the impact of Polyomaviridae , Papillomaviridae , and Herpesviridae oncoviruses on the vaginal Community State Types (CSTs) and host immune response in reproductive-age women. In our cohort, only Polyomaviridae and Papillomaviridae were detected and were associated with changes in the resident bacteria of CST I and IV ( p < 0.05). Lactobacillus crispatus increased in CST I while Prevotella timonensis and Sneathia sanguinegens increased in CST IV. Conversely, CST II and III showed an alteration of the immune response, with the decrease of Eotaxin, MCP-1, IL-7, IL-9, and IL-15 ( p < 0.05), leading to reduced antiviral efficacy. An efficient viral clearance was observed only in women from CST I, dominated by Lactobacillus crispatus . Our in vivo study begins to address the knowledge gap with respect to the role of vaginal bacteria and immune response in susceptibility to oncoviral infections.

Recently, there are controversial opinions on the presence of Mycoplasmas/Ureaplasmas as colonizers or pathogens, and on the use of a targeted therapy. This study aimed to characterize Mycoplasmas/Ureaplasmas infections in reproductive age women, including the acquisition of sexually transmitted (ST) pathogens and poor birth outcomes. A total of 646 healthy Italian women fulfilled the inclusion criteria including 521 infertile women, 65 pregnant women, and 60 fertile women with identified risk factors and symptomatic for vaginitis/cervicitis. Multiplex and quantitative molecular techniques and direct automatic DNA sequencing were performed to assess the genome structure of Mycoplasma/Ureaplasma species and ST infected pathogens. Ureaplasma parvum serovar 3 represented the predominant colonizer of the urogenital tract of this series and the unique species significantly associated with ST pathogens coinfection (p < 0.01). U. parvum load >10 4 bacteria/ml, suggestive of active infection, has been measured only in asymptomatic high-risk human papillomavirus infected women (24.3%) and in 40% of women with idiopathic infertility. To note, 16% of the follicular fluid from these idiopathic women resulted infected with U. parvum. In conclusion, the present study focused the attention on U. parvum serovar 3 as emerging microorganism in sexually active women that may have the benefit of targeted therapy., (© 2019 Wiley Periodicals, Inc.)

Aim: This study aims to characterize circulating strains to predict their relationship with sexually transmitted microorganisms, Chlamydia trachomatis , HIV, HCV, Treponema pallidum , HPV, Mycoplasmas , in an Italian multiethnic area, which has revealed a recent increase of Neisseria gonorrhoeae first-line antibiotic resistance. Materials & methods: We performed N. gonorrhoeae multiantigen sequence typing and the N. gonorrhoeae sequence typing for antimicrobial resistance. Results: We identified mutations in genes conferring resistance to cephalosporins, macrolides, fluoroquinolones through por and tbpB loci , and we reported new combinations of already known alleles. N. gonorrhoeae resistance to ciprofloxacin was associated with C. trachomatis coinfection. Conclusion: This study's data proved the utility of a routine N. gonorrhoeae molecular characterization to monitor the evolution of antibiotic resistance and to detect the most effective clinical treatment.

Background: Vulvovaginal candidiasis (VVC) is a recurrent vaginal condition in childbearing women., Objectives: The aim of this study was to assess the efficacy of an oral formulation containing Lactobacillus acidophilus GLA-14, Lactobacillus rhamnosus HN001 and bovine lactoferrin on symptoms and recurrence of VVC as adjuvant therapy to topical clotrimazole., Patients/methods: Forty-eight women positive for C. albicans, symptoms of VVC and documented history of recurrences were randomised into 2 groups receiving verum or placebo (2 capsules/day for 5 days followed by 1 capsule/day for additional 10 days) as adjuvant treatment to clotrimazole (induction phase) followed by a maintenance cycle of 6 months (1 capsule/day verum or placebo for 10 consecutive days each month). Symptoms, overall cure rate and recurrence rate were assessed., Results: After clotrimazole therapy, a significant improvement of symptoms was shown in both groups. However, only women treated with probiotics and lactoferrin showed a significant improvement of itching and discharge at 3 and 6 months. During the six-month follow-up, recurrences were significantly less in the intervention group vs placebo (33.3% vs 91.7% after 3 months and 29.2% vs 100% after 6 months)., Conclusions: The results show that the investigated lactobacilli mixture in combination with lactoferrin represents a safe and effective adjuvant approach for reducing symptoms and recurrences of RVVC., (© 2018 Blackwell Verlag GmbH.)

Vasomotor symptoms, particularly hot flushes (HFs), are the most frequently reported symptom by menopausal women. In particular, for young women diagnosed with breast cancer, who experience premature ovarian failure due to cancer treatments, severe HFs are an unsolved problem that strongly impacts on quality of life. The optimal management of HFs requires a personalised approach to identify the treatment with the best benefit/risk profile for each woman. Hormonal replacement therapy (HRT) is effective in managing HFs but it is contraindicated in women with previous hormone-dependent cancer. Moreover, many healthy women are reluctant to take HRT and prefer to manage symptoms with non-hormonal strategies. In this narrative review, we provide an update on the current available non-oestrogenic strategies for HFs management for women who cannot, or do not wish to, take oestrogens. Since isoflavones have oestrogenic properties and it is not known if they can be safely consumed by women with previous hormone-dependent cancer, they were excluded. Selective serotonin reuptake inhibitors/selective serotonin-norepinephrine reuptake inhibitors, as well as other neuroactive agents, some herbal remedies and behavioural strategies are considered., Competing Interests: Anna Maria Paoletti, Francesco De Seta and Stefano Lello declare no conflict of interests. Nicoletta Biglia had a financial relationship (lecturer, member of advisory boards and/or consultant) with Gedeon Richter, Shionogi Limited and Italfarmaco. Rossella E Nappi has a financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer HealthCare, Endoceutics, Gedeon Richter, HRA Pharma, MSD, Novo Nordisk, Pfizer, Shionogi and Teva. Valentina E Bounous had a financial relationship with Italfarmaco S.p.A. (medical writing) and has a financial relationship with Shionogi (medical writing, tables preparation).

Background: Viral infections of the anal/rectal tract of men who have sex with men (MSM) have been poorly studied., Methods: In total, 158 swab samples (81 anal/rectal, 65 throat/oral and 12 urethral) were collected from 126 MSM. DNA was isolated and subjected to real-time PCR assays for the detection of the sexually transmitted (ST) pathogens Chlamydia trachomatis , Neisseria gonorrhoeae and Mycoplasmas ssp , human papillomavirus (HPV) and six human polyomaviruses (HPyVs; JCPyV, BKPyV, Merkel cell PyV⁻MCPyV-, HPyV-6, HPyV-7 and HPyV-9)., Results: C. trachomatis (31/126, 24.6%) and M. genitalium (30/126, 23.8%) were the most frequently detected ST pathogens. Thirty-one/126 (24.6%) patients were positive for at least one HPyV. The significantly ( p < 0.05) prevalent HPyV in the anal tract was MCPyV, which was amplified in 27/81 (33.3%) samples, followed by HPyV-6, which was amplified in 6/81 (7.4%) swabs. Coinfections with MCPyV and C. trachomatis or Mycoplasmas were found in 4/21 (19.0%) and 5/21 (23.8%) anal/rectal swabs, respectively. Three/4 MCPyV- C. trachomatis coinfected patients were symptomatic., Conclusions: Based on the high prevalence of MCPyV in the anal/rectal swabs from MSM patients and on the well-known oncogenic properties of MCPyV, sexual transmission and possible involvement of HPyVs in the pathogenesis of diseases of the anal canal should be further studied.

Bacterial vaginosis (BV) is the most common cause of vaginal discomfort in women. It is characterised by abnormal vaginal microbiota with a depletion of lactobacilli and predominance of anaerobic microorganisms, mainly Gardnerella vaginalis and Atopobium vaginae. Although antibiotics represent an effective therapeutic option in the short-term, recurrent infections still remain a serious problem. Nowadays, evidence exists about the efficacy of probiotics for the management of BV. The aim of the current double blind, randomised clinical trial was to assess the efficacy of a probiotic mixture, including Lactobacillus acidophilus GLA-14 and Lactobacillus rhamnosus HN001, in combination with bovine lactoferrin, as adjuvant therapy to metronidazole in women with recurrent BV. In particular, normalisation of Nugent score, remission of symptoms and recurrences during a six-months follow-up were assessed. 48 adult women received metronidazole (500 mg twice daily) for 7 days and randomly assigned to take simultaneously either probiotics plus lactoferrin or placebo (2 capsules/day for 5 days followed by 1 capsule/day for 10 consecutive days; induction phase). The verum or placebo administration (1 capsule/day for 10 consecutive days) was repeated each month (maintenance phase) during the six months of follow-up starting the first day of menstrual cycle since the menstrual blood increases the vaginal pH and contributes to increase the risk of recurrences. The results showed that symptoms (vaginal discharge and itching), Nugent score and recurrence rate were significantly improved by probiotics mixture in association with lactoferrin. This alternative approach may represent a safe and effective remedy for the restoration of healthy vaginal microbiota in preventing recurrent BV.