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Introduction: Neuroproliferative vestibulodynia (NPV) is suspected in women with entrance dyspareunia, vestibular allodynia, and hyperalgesia, after ruling out other causes. If conservative biopsychosocial treatments in patients with suspected NPV are unsuccessful, vestibulectomy may be an appropriate option. Excised vestibular surgical specimens are sent for routine pathology assessment, including hematoxylin and eosin (H&E) staining. Objective: To review reports of gross and microscopic pathology examinations of excised vestibular specimens from a cohort of patients with NPV and compare immunohistochemical (IHC) staining density between subgroups classified by severity of subepithelial inflammatory infiltrate. Methods: Excised specimens from NPV patients, the 1:00-11:00 region (n = 63) and 12:00 region (n = 54) of the vestibule, were placed in 10% formalin prior to pathology examination. Routine pathology assessment included gross examination and cytological characterization of H&E-stained vestibular tissue for malignancy, viral nuclear changes (in addition to P16 staining), and quality of the vestibular epithelium and subepithelial inflammatory infiltrate. Severity of this infiltrate was classified by the pathologist as mild, mild-moderate, moderate, or severe. Additional vestibular tissue sections were processed for IHC staining for CD117 and PGP9.5, protein markers consistent with mast cells and nerves, respectively. Mast cell counts and immunopositive mean fractional area for CD117 and PGP9.5, separated into subgroups based on severity of subepithelial inflammatory infiltrate, were compared using Kruskal-Wallis test. Results: Gross examinations of the 1:00-11:00 and 12:00 regions of vestibular tissue showed mean dimensions (length, width, thickness) to be 5.8 x 2.1 x 0.6 cm and 1.0 x 0.7 x 0.3 cm, respectively. Microscopic examinations revealed no malignant cells in any specimen and viral nuclear findings were consistent with HPV in 3 specimens. Vestibular tissue was characterized as non-reactive squamous epithelium in 90.5% and 92.6% of specimens for the 1:00-11:00 and 12:00 regions, respectively. Mature lymphocytes were found in the subepithelial stromal infiltrate of 67% of specimens in both the 1:00-11:00 and 12:00 regions. Severity of subepithelial stromal infiltrate was reported as: mild in 67% and 65%; mild-moderate in 5% and 4%; moderate in 14% and 15%; and severe in 14% and 17% of cases for the 1:00-11:00 and 12:00 regions, respectively. Amongst the subgroups categorized by severity of inflammatory infiltrate, there were no significant differences for CD117-immunopositive cell counts or mean fractional area of CD117 and PGP9.5 in the 1:00-11:00 and 12:00 regions. Conclusions: No significant differences were found between subgroups of severity of subepithelial inflammatory infiltrate and IHC data. While routine pathology examination including H&E staining is standard for vestibulectomy specimens, such standardized assessment did not provide any insight into the severe allodynia and hyperalgesia associated with NPV, and further, was not useful for confirmation of the diagnosis of NPV. To better understand NPV, excised vestibular tissue should also be stained for CD117 and PGP9.5. Disclosure: No. [ABSTRACT FROM AUTHOR]

The development of artificial intelligence (AI) in dentistry requires large and well-annotated datasets. However, the availability of public dental imaging datasets remains unclear. This study aimed to provide a comprehensive overview of all publicly available dental imaging datasets to address this gap and support AI development. This observational study searched all publicly available dataset resources (academic databases, preprints, and AI challenges), focusing on datasets/articles from 2020 to 2023, with PubMed searches extending back to 2011. We comprehensively searched for dental AI datasets containing images (intraoral photos, scans, radiographs, etc.) using relevant keywords. We included datasets of >50 images obtained from publicly available sources. We extracted dataset characteristics, patient demographics, country of origin, dataset size, ethical clearance, image details, FAIRness metrics, and metadata completeness. We screened 131,028 records and extracted 16 unique dental imaging datasets. The datasets were obtained from Kaggle (18.8%), GitHub, Google, Mendeley, PubMed, Zenodo (each 12.5%), Grand-Challenge, OSF, and arXiv (each 6.25%). The primary focus was tooth segmentation (62.5%) and labeling (56.2%). Panoramic radiography was the most common imaging modality (58.8%). Of the 13 countries, China contributed the most images (2,413). Of the datasets, 75% contained annotations, whereas the methods used to establish labels were often unclear and inconsistent. Only 31.2% of the datasets reported ethical approval, and 56.25% did not specify a license. Most data were obtained from dental clinics (50%). Intraoral radiographs had the highest findability score in the FAIR assessment, whereas cone-beam computed tomography datasets scored the lowest in all categories. These findings revealed a scarcity of publicly available imaging dental data and inconsistent metadata reporting. To promote the development of robust, equitable, and generalizable AI tools for dental diagnostics, treatment, and research, efforts are needed to address data scarcity, increase diversity, mandate metadata completeness, and ensure FAIRness in AI dental imaging research., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.S. co-founded a startup focusing on dental radiograph analysis using artificial intelligence.

Background and Objectives: Antibodies to myelin oligodendrocyte glycoprotein (MOG-Ab) have recently been reported in patients with encephalitis who do not fulfill criteria for acute disseminated encephalomyelitis (ADEM). We evaluated a cohort of these children and compared them with children with ADEM., Methods: This retrospective, multicenter cohort study comprised consecutive patients <18 years of age with MOG-Ab who fulfilled criteria for autoimmune encephalitis. These patients were stratified into (1) children not fulfilling criteria for ADEM (encephalitis phenotype) and (2) children with ADEM. Clinical/paraclinical data were extracted from the electronic records. Comparisons were made using the Mann-Whitney U test and χ 2 Fisher exact test for statistical analysis., Results: From 235 patients with positive MOG-Ab, we identified 33 (14%) with encephalitis and 74 (31%) with ADEM. The most common presenting symptoms in children with encephalitis were headache (88%), seizures (73%), and fever (67%). Infective meningoencephalitis was the initial diagnosis in 67%. CSF pleocytosis was seen in 79%. Initial MRI brain was normal in 8/33 (24%) patients. When abnormal, multifocal cortical changes were seen in 66% and unilateral cortical changes in 18%. Restricted diffusion was demonstrated in 43%. Intra-attack new lesions were seen in 7/13 (54%). When comparing with children with ADEM, children with encephalitis were older (median 8.9 vs 5.7 years, p = 0.005), were more likely to be admitted to intensive care (14/34 vs 4/74, p < 0.0001), were given steroid later (median 16.6 vs 9.6 days, p = 0.04), and were more likely to be diagnosed with epilepsy at last follow-up (6/33 vs 1/74, p = 0.003)., Discussion: MOG-Ab should be tested in all patients with suspected encephalitis even in the context of initially normal brain MRI. Although exclusion of infections should be part of the diagnostic process of any child with encephalitis, in immunocompetent children, when herpes simplex virus CSF PCR and gram stains are negative, these features do not preclude the diagnosis of immune mediated disease and should not delay initiation of first-line immunosuppression (steroids, IVIG, plasma exchange), even while awaiting the antibody results.

Background: Electrohydraulic shockwave devices have been Food and Drug Administration-cleared for improved blood flow and connective tissue activation and have been used to treat erectile dysfunction (ED). In this study, the main focus was to evaluate improvement in erectile tissue quality after low intensity shockwave therapy (LiSWT)., Methods: A single-blind, sham-controlled, randomized, prospective study, was performed in men with ED naïve to shockwave or radial ballistic pressure wave therapy. Participants were randomized 1:2 to simulated (sham) or active LiSWT treatment. After simulated treatments, participants in the Sham Arm were converted to active LiSWT, while participants initially in the Active Treatment Arm received no further treatment. Assessments were performed at baseline and two follow-up visits. Subjective parameters of erectile function (EF) were assessed by total and EF domain scores of the International Index of Erectile Function (IIEF) and sexual encounter profile (SEP). Objective parameters of penile erection were measurements of hypoechoic areas in images obtained by grayscale ultrasound (GUS) with high resolution 15.4 MHz probe and cavernosal artery peak systolic velocity (PSV) and end diastolic velocity (EDV) by color duplex Doppler ultrasound (DUS). Outcome measures for erectile and urinary function were also obtained., Results: Simulated LiSWT did not significantly change any assessment parameter. Sham Arm participants who converted to active LiSWT had significantly increased mean IIEF total (P=0.02) and IIEF-EF scores that approached statistical significance (P=0.06), relative to baseline. Similarly, at the end of the study, Active Treatment Arm participants had significantly increased mean IIEF total (P=0.02) and IIEF-EF scores that approached statistical significance (P=0.07), relative to baseline. Additionally, at the end of the study, SEP3 success rates (erection lasting long enough for successful intercourse) approached statistical significance when Sham Arm participants were converted to active LiSWT (P=0.08) and reached statistical significance in the Active Treatment Arm (P=0.049). GUS assessments by visual grading were significantly correlated to IIEF-EF score (P=0.002) and were significantly increased relative to baseline in the Active Treatment Arm at follow-up Assessment 1 (P=0.03) and Assessment 2 (P=0.04). The greatest reduction in hypoechoic area after LiSWT occurred in the proximal penile shaft. EDV was also significantly reduced in the Active Treatment Arm at follow-up Assessment 1 (P=0.04) and Assessment 2 (P=0.04). LiSWT also resulted in improved prostate symptom scores, approaching significance in the Active Treatment Arm (P=0.055) with no changes in prostate-specific antigen. Treatment-related adverse events were limited and transient., Conclusions: In this prospective trial, LiSWT was safe and efficacious for erectile symptoms using GUS imaging as a novel, non-invasive method to assess improvements in corporal veno-occlusive function. Improved veno-occlusion and reduced hypoechoic area demonstrated by GUS imaging suggest that LiSWT decreases connective tissue content in penile erectile tissue. Lower urinary tract symptoms also improved with LiSWT., Trial Registration: NCT06600893 on clinicaltrials.gov., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-338/coif). S.W.G. serves on the advisory board of Softwave TRT. I.G. serves on the advisory board of Softwave TRT, on the speaker’s bureau, and is named on a pending patent. These conflicts of interest occurred after completion of the research. The other author has no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background: There are currently no Food and Drug Administration-approved treatments for female sexual arousal disorder (FSAD), which is physiologically analogous to male erectile dysfunction., Aims: The study sought to test the systemic and local genital safety of topical sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD and their sexual partners over a 12-week treatment period., Methods: This was a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream among healthy premenopausal women with FSAD. Safety was assessed by the frequency and incidence of treatment-emergent adverse events (TEAEs) among participants and their sexual partners. Participants recorded the incidence of TEAEs in a daily eDiary (electronic diary). Sexual partners were contacted within 72 hours of each sexual event in which investigational product was used. All participants used placebo cream for 1 month, during a single-blind run-in period, and then if eligible, were randomized 1:1 to sildenafil cream or placebo cream. Participants used their assigned investigational product over a 12-week double-blind dosing period. They attended monthly follow-up visits, in which their eDiary TEAE data were reviewed by the study staff and graded for severity and relationship to study product., Outcomes: The frequency and incidence of TEAEs among participants and their sexual partners., Results: During the 12-week double-blind dosing period, there were 78 TEAEs reported by 29 of 99 sildenafil-assigned participants and 65 TEAEs reported by 28 of 94 placebo-assigned participants (P = .76). All TEAEs were mild or moderate in severity. The most common treatment-related TEAE among active and placebo-assigned participants was application site discomfort. There were no differences in the number of treatment-related TEAEs among sildenafil cream vs placebo cream users (P > .99). Four sildenafil cream participants and 3 placebo cream participants discontinued the study due to TEAEs involving application site discomfort (P > .99). There were 9 TEAEs reported by 7 of 91 sexual partners exposed to sildenafil cream vs 4 TEAEs reported by 4 of 84 sexual partners exposed to placebo cream (P = .54)., Clinical Implications: These data support further clinical development of topical sildenafil cream for the treatment of FSAD., Strengths and Limitations: Safety was assessed among participants and their sexual partners after 1357 and 1160 sexual experiences in which sildenafil cream or placebo cream were used, respectively. The phase 2b study was powered for the primary objectives of efficacy, rather than safety., Conclusion: These data demonstrate that topically applied sildenafil cream was safe and well tolerated by exposed users and their sexual partners., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative symposium dedicated to optimizing sexual function and preserving cardiovascular health. The Fourth Princeton Consensus Conference was convened on March 10-11, 2023, at the Huntington Medical Research Institutes in Pasadena, California. Princeton panels I to III addressed the clinical management of men with erectile dysfunction (ED) who also had cardiovascular disease. Thirteen years since Princeton III, Princeton IV builds on previous foundations in several key areas. Mounting evidence supports the need for providers to treat men with ED as being at risk for cardiac events until proven otherwise. Algorithms for the diagnosis and treatment of ED are updated with new recommendations for coronary artery calcium scoring for advanced cardiovascular risk stratification. Optimization of oral phosphodiesterase type 5 inhibitors in the treatment of men with ED and cardiovascular disease is thoroughly explored, including recent evidence of potential cardioprotective effects of these drugs., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Neuroproliferative vestibulodynia (NPV), a provoked genital pain characterized by severe allodynia and hyperalgesia, is confirmed in excised vestibular tissue by immunohistochemical staining (>8 CD117-positive immunostained cells/100× microscopic field) rather than by hematoxylin and eosin staining., Aim: In this study we sought to assess immunostaining of tissue samples obtained during vestibulectomy surgery and to correlate results with patient outcomes., Methods: Patients (n = 65) meeting criteria for NPV who underwent vestibulectomy during the period from June 2019 through December 2022 formed the study cohort. We performed assessment of pathology of vestibular tissues by use of immunohistochemical staining, including quantitation of mast cells by CD117 (mast cell marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments., Outcomes: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement., Results: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the marker) and nerve fibers by protein gene product (PGP) 9.5 (neuronal marker). We analyzed 725 photomicrographs of immunostained tissue sections (100× and 200×) by manual counting and computer-assisted histometry and correlated these data to clinical assessments., Outcomes: Outcomes included density of CD117 and PGP9.5 immunostaining in the 1:00-11:00 o'clock and 12:00 o'clock vestibular regions, and patient-reported outcomes assessing sexual function, pain, distress, and symptom improvement., Results: All 65 NPV patients (median age 26 years), 45 with lifelong and 20 with acquired NPV, had severe pain documented by PROs and vulvoscopy and had >8 CD117-immunopositive cells/100× microscopic field. Median cell count values were similar in the 1:00-11:00 o'clock and 12:00 vestibular regions (28.5 and 29.5/100× field, respectively). Likewise, the median area of CD117 immunostaining was similar in both regions (0.69% and 0.73%). The median area of PGP9.5 immunostaining was 0.47% and 0.31% in these same regions. Pain scores determined with cotton-tipped swab testing were nominally higher in lifelong vs acquired NPV patients, reaching statistical significance in the 1:00-11:00 o'clock region (P < .001). The median score for the McGill Pain Questionnaire affective subscale dimension was also significantly higher in lifelong vs acquired NPV patients (P = .011). No correlations were observed between hematoxylin and eosin results and density of mast cells or neuronal markers. Of note, 63% of the patient cohort reported having additional conditions associated with aberrant mast cell activity., Clinical Implications: The pathology of NPV is primarily localized to the vestibular epithelial basement membrane and subepithelial stroma with no visible vulvoscopic findings, making clinical diagnosis challenging., Strengths and Limitations: Strengths of this study include the large number of tissues examined with what is to our knowledge the first-ever assessment of the 12:00 vestibule. Major limitations are specimens from a single timepoint within the disease state and lack of control tissues., Conclusions: Performing immunohistochemical staining of excised vestibular tissue with CD117 and PGP9.5 led to histometric confirmation of NPV, indications that NPV is a field disease involving all vestibular regions, validation for patients whose pain had been ignored and who had experienced negative psychosocial impact, and appreciation that such staining can advance knowledge., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Background: In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug-drug interactions, but also a potential cardioprotective effect of these drugs., Aim: In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease., Method: A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus., Outcomes: Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors., Results: An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug-drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non-PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non-PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed., Clinical Implications: Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease., Strengths and Limitations: Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting., Conclusion: The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Introduction: Currently, there are limited accessible and cost-effective biomarkers for preclinical Alzheimer's disease (AD) patients. However, the apolipoprotein E (ApoE) polymorphic alleles can predict if someone is at high (e4), neutral (e3), or low (e2) genetic risk for developing AD. This study analyzed electroencephalogram (EEG) reports from individuals with various ApoE genotypes, aiming to identify EEG changes and patterns that could potentially serve as predictive markers for preclinical AD progression., Methods: Participants aged 64-78 were selected from the patient database at an outpatient neurology clinic. Genotype studies were performed to determine ApoE status, followed by EEG analysis to identify any apparent trends. A case-control design was used, categorizing participants into cases (e2e3, e2e4, e3e4, e4e4) and controls (e3e3). EEG recordings were compared between the groups to identify potential differences in EEG characteristics, including abnormal temporal slowing, frequency, and ApoE genotype association., Results: Among 43 participants, 49% demonstrated evidence of abnormal temporal slowing on EEG. Of these, 48% displayed focal left temporal slowing, and 52% displayed bilateral temporal slowing. The right-sided temporal slowing was not observed. Among participants with abnormal slowing, 95% exhibited theta frequency (4-8 Hz) slowing, while only 4.8% displayed delta frequency (0-4 Hz) slowing. Among participants with the ApoE4 allele, 61.5% demonstrated evidence of abnormal slowing, compared to 43.3% without it. Furthermore, the presence of an ApoE4 allele was associated with a significantly higher proportion of males (54%) compared to those without it (13%) (p=0.009)., Conclusions: Although we did not find a statistically significant difference in temporal EEG slowing among different ApoE genotypes, our findings suggest a potential association between temporal slowing on EEG and the presence of an ApoE4 allele in individuals with preclinical AD. These observations highlight the need for further exploration into the potential influence of the ApoE4 allele on EEG findings and the utility of EEG as a complementary diagnostic tool for AD. Longitudinal studies with large sample sizes are needed to establish the precise relationship between EEG patterns, ApoE genotypes, and AD progression., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Kim et al.)

Background: Prasterone, an intravaginal dyspareunia treatment in menopausal women, improves vaginal health through intracellular conversion of dehydroepiandrosterone into androgens and estrogens. Phase 3 trials for prasterone showed significant improvement in vaginal tissue health and reduction of pain., Aim: To assess vestibular changes with daily use of intravaginal prasterone in menopausal women with moderate to severe dyspareunia., Methods: This open-label prospective pilot study was conducted over 20 weeks. It included 11 menopausal women (median age, 56 years) who were treated daily with intravaginal inserts of 6.5-mg prasterone and assessed monthly. During vulvoscopy, vestibular pain was assessed by cotton-tipped swab testing, and vestibular and vaginal health was independently assessed with the Visual Scale (VS). In addition, vulvoscopic photographs were obtained and assessed via the Vulvoscopic Genital Tissue Appearance (VGTA) scale to evaluate overall genital tissue health. Mean changes from baseline for genital tissue health and pain assessments were analyzed by repeated measures 1-way analysis of variance, followed by a Dunnett post hoc test. Sexual event diaries were completed and adverse events recorded., Outcomes: Outcomes included indices of genital tissue health: pain assessment by cotton-tipped swab testing, VS of the vestibule and vagina, VGTA, and sexual event diary., Results: Aggregate scores from the cotton-tipped swab test progressively improved, reaching statistical significance at week 16, which was maintained through week 20 (-7.27, P  = .019). VS scores significantly improved from baseline by week 4 and were maintained through week 20 for the vestibule (-3.00, P  = .004) and vagina (-4.00, P  = .002). An overall 1607 vulvoscopic photographs were examined; all showed reduction in vestibular erythema and pallor at the end of the study. The mean change from baseline at week 20 for the VGTA score was -7.9 ( P  = .0016). Intercourse associated with pain was reduced from 81.3% of initiated events during the first month of the study to 8.3% during the last month. Sexual activities that were discontinued due to discomfort were reduced from 45.8% to 6.3%. No prasterone-related serious adverse events were reported., Clinical Implications: Prasterone, a safe and effective intravaginal hormone treatment, significantly improves vestibular health parameters., Strengths and Limitations: Strengths are the prospective study design and the use of multiple outcome measures to assess vestibular tissue health and pain associated with sexual activity. Limitations are the small study cohort and use of nonvalidated outcome measures., Conclusion: Our findings suggest that intravaginal prasterone exerts biologic activity on the androgenic endodermal vestibule, as the medication passes from vagina to vestibule, resulting in amelioration of pain associated with sexual activity., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

We report two children with molecularly confirmed mitochondrial disease mimicking Neuromyelitis Optica Spectrum Disorder (NMOSD). The first patient presented at the age of 15 months with acute deterioration following a pyrexial illness with clinical features localising to the brainstem and spinal cord. The second patient presented at 5 years with acute bilateral visual loss. In both cases, MOG and AQP4 antibodies were negative. Both patients died within a year of symptoms onset from respiratory failure. Arriving at an early genetic diagnosis is important for redirection of care and avoiding potentially harmful immunosuppressant therapies.

Background: Data are limited regarding fractional CO2 laser as a nonhormonal treatment for vestibular pain., Aim: We sought to perform what is, to our knowledge, the first multisite prospective randomized, double-blind, sham-controlled clinical trial to assess the safety and efficacy of fractional CO2 laser treatment to the vestibule in women with vestibular pain., Methods: Subjects (n = 70) meeting inclusion/exclusion criteria at each of 3 sites were randomized 2:1 to active or sham (zero energy) fractional CO2 laser treatment using the vestibular probe (SmartXide2 V2LR - MonaLisa Touch, DEKA, Florence, Italy). Subjects in each treatment arm received 3 treatments 4 weeks apart. At the initial follow-up (week 12), subjects were unblinded and those initially assigned to sham started active treatment., Outcomes: Outcome measures included changes from baseline in sexual activity diaries and scores for the Vulvoscopic Genital Tissue Appearance Scale (VGTA), vestibular cotton-tipped swab testing, McGill Pain Questionnaire, Female Sexual Function Index (FSFI), Female Sexual Distress Scale-Revised (FSDS-R), and the O'Leary-Sant voiding and pain indices, the Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI)., Results: After active treatment, VGTA scores significantly improved in 5 parameters. Pain associated with cotton-tipped swab testing was significantly reduced at weeks 4 through 16 (mean change from baseline -0.64 [95% CI, -0.79 to -0.50] and -1.31 [95% CI, -1.46 to -1.16], respectively). FSFI pain domain scores improved significantly at weeks 12 and 16 (mean change from baseline 0.925 [95% CI, 0.10-1.75] and 1.22 [95% CI, 0.40-2.05], respectively). FSFI total scores increased significantly at weeks 12 and 16 (mean change from baseline 6.24 [95% CI, 2.64-9.85] and 4.96 [95% CI, 1.36-8.57], respectively). FSDS-R scores decreased significantly at weeks 12 and 16 (mean change from baseline -5.84 [95% CI, -8.80 to -2.87] and -9.15 [95% CI, -12.11 to -6.18], respectively). ICSI scores decreased significantly at weeks 12 and 16 (mean change from baseline -0.91 [95% CI, -1.65 to -0.18] and -0.754 [95% CI, -1.49 to -0.02], respectively). ICPI scores decreased significantly at week 16 (mean change from baseline -0.99 [95% CI, -1.63 to -0.34]). In contrast, there were no significant changes in outcomes in the sham arm. No serious adverse events occurred., Clinical Implications: Fractional CO2 laser treatment in women with vestibular pain resulted in improvement from baseline in multiple key outcome measures of vestibular health., Strengths and Limitations: Strengths of the study were that it was a multisite prospective randomized double-blind, sham-controlled clinical trial that included multiple measures related to vestibular pain and sexual function. Limitations were the nonvalidated primary outcome measure and limited study cohort., Conclusion: Fractional CO2 laser therapy is a safe and effective nonhormonal treatment for vestibular pain., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This study analyzed the relationship between the lunar phase and the reproductive cycle of Pinctada margaritifera inhabiting Weno Island, Chuuk Lagoon, Micronesia. We measured indicators of maturity (gonadosomatic index [GSI] and sexual maturation-related genes) and investigated changes in the gonadal maturity stages (GMS) of P. margaritifera over lunar cycle. GSI was higher around the full moon. GMS of P. margaritifera were classified as the early gametogenesis stage, ripe and spawning stage, and spent and degenerating stage. A large percentage of oysters was observed in the ripe and spawning stage at the first quarter moon in female and the full moon in male as well as in the spent and degenerating stages at the third quarter moon in both sexes. In addition, the expression of doublesex- and mab-3-related transcription factor 2 (DMRT2) in the male P. margaritifera black-lip pearl oyster was the highest during the full and third quarter moon phases, whereas no difference in expression was observed with the lunar phase in females. In contrast, the expression of vitellogenin (VTG) was the highest in female P. margaritifera during the first and third quarters. No difference in expression was observed according to the lunar phase in males. The results suggest that the lunar phase directly affects the expression of sexually mature gonads in P. margaritifera black-lip pearl oyster., (© 2023 Wiley Periodicals LLC.)

Background: Persistent genital arousal disorder/genitopelvic dysesthesia (PGAD/GPD) is characterized by distressing, abnormal genitopelvic sensations, especially unwanted arousal. In a subgroup of patients with PGAD/GPD, cauda equina Tarlov cyst-induced sacral radiculopathy has been reported to trigger the disorder. In our evaluation of lumbosacral magnetic resonance images in patients with PGAD/GPD and suspected sacral radiculopathy, some had no Tarlov cysts but showed lumbosacral disc annular tear pathology., Aim: The aims were 2-fold: (1) to utilize a novel multidisciplinary step-care management algorithm designed to identify a subgroup of patients with PGAD/GPD and lumbosacral annular tear-induced sacral radiculopathy who could benefit from lumbar endoscopic spine surgery (LESS) and (2) to evaluate long-term safety and efficacy of LESS., Methods: Clinical data were collected on patients with PGAD/GPD who underwent LESS between 2016 and 2020 with at least 1-year follow-up. LESS was indicated because all had lumbosacral annular tear-induced sacral radiculopathy confirmed by our multidisciplinary management algorithm that included the following: step A, a detailed psychosocial and medical history; step B, noninvasive assessments for sacral radiculopathy; step C, targeted diagnostic transforaminal epidural spinal injections resulting in a temporary, clinically significant reduction of PGAD/GPD symptoms; and step D, surgical intervention with LESS and postoperative follow-up., Outcomes: Treatment outcome was based on the validated Patient Global Impression of Improvement, measured at postoperative intervals., Results: Our cohort included 15 cisgendered women and 5 cisgendered men (mean ± SD age, 40.3 ± 16.8 years) with PGAD/GPD who fulfilled the criteria of lumbosacral annular tear-induced sacral radiculopathy based on our multidisciplinary management algorithm. Patients were followed for an average of 20 months (range, 12-37) post-LESS. Lumbosacral annular tear pathology was identified at multiple levels, the most common being L4-L5 and L5-S1. Twenty-two LESS procedures were performed in 20 patients. Overall, 80% (16/20) reported improvement on the Patient Global Impression of Improvement; 65% (13/20) reported improvement as much better or very much better. All patients were discharged the same day. There were no surgical complications., Clinical Implications: Among the many recognized triggers for PGAD/GPD, this subgroup exhibited lumbosacral annular tear-induced sacral radiculopathy and experienced long-term alleviation of symptoms by LESS., Strengths and Limitations: Strengths include long-term post-surgical follow-up and demonstration that LESS effectively treats patients with PGAD/GPD who have lumbosacral annular tear-induced sacral radiculopathy, as established by a multidisciplinary step-care management algorithm. Limitations include the small study cohort and the unavailability of a clinical measure specific for PGAD/GPD., Conclusion: LESS is safe and effective in treating patients with PGAD/GPD who are diagnosed with lumbosacral annular tear-induced sacral radiculopathy., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Introduction: Flibanserin treatment increases sexual desire and satisfying sexual events while decreasing distress in certain women diagnosed with acquired, generalized hypoactive sexual desire disorder (HSDD). Additional aspects of sexual function and the time course of response have not been fully characterized., Aim: To evaluate changes in sexual function assessed by the subdomains of the Female Sexual Function Index (FSFI) in women with HSDD treated with flibanserin., Methods: FSFI data pooled from 3 pivotal flibanserin trials in premenopausal women (flibanserin = 1,165; placebo = 1,203) and FSFI data from one complete flibanserin trial in postmenopausal women (flibanserin = 432; placebo = 463) were subjected to post-hoc analyses. For each FSFI subdomain, least squares mean change from baseline was calculated at each assessment visit (treatment weeks 4, 8, 16, 24) and treatment groups were compared using analysis of covariance. Standardized effect size (Cohen's d) was also determined for each FSFI subdomain., Main Outcome Measure: Changes from baseline in FSFI subdomains., Results: Compared to placebo, both premenopausal (P < .02) and postmenopausal (P < .045) patients in the flibanserin group reported significantly greater increases over baseline in the FSFI subdomain scores of desire, arousal, lubrication, orgasm, and satisfaction. In premenopausal patients, significant improvements were observed at the first assessment of response (week 4) and were maintained through week 24. In postmenopausal patients, significant improvements were observed at week 4 for desire and arousal, while significant improvements in lubrication, orgasm, and satisfaction were observed at week 8. At week 24, excluding the pain subdomain, standardized effect sizes ranged from 0.18 to 0.28 in the premenopausal cohort and 0.12 to 0.29 in the postmenopausal cohort. In both pre- and postmenopausal patients, improvements in pain were smaller and largely undifferentiated between treatment groups., Clinical Implications: While variations in time to response should be taken into consideration, on average, the beneficial impact of flibanserin on overall sexual function occurs within the first month of treatment. The data also suggest that the response to flibanserin is sustained for the duration of treatment., Strengths and Limitations: Sexual function assessments were performed in a large cohort of 2,368 premenopausal women and 895 postmenopausal women. However, the FSFI assesses changes over a 1-month period and time points earlier than 4 weeks could not be assessed., Conclusion: These analyses suggest that assessment of benefit of flibanserin in HSDD should include improvements across all domains of sexual function, not only desire. Simon JA, Clayton AH, Goldstein I, et al. Effects of Flibanserin on Subdomain Scores of the Female Sexual Function Index in Women With Hypoactive Sexual Desire Disorder. Sex Med 2022;10:100570., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of the study was to investigate the effect of bacteriocin-like inhibitory substance (BLIS) from Enterococcus faecium DB1 on cariogenic Streptococcus mutans biofilm. Crystal violet staining, fluorescence, and scanning electron microscopy analyses demonstrated that the BLIS from Enterococcus faecium DB1 (DB1 BLIS) inhibited S. mutans biofilm. When DB1 BLIS was co-incubated with S. mutans , biofilm formation by S. mutans was significantly reduced (p<0.05). DB1 BLIS also destroyed the preformed biofilm of S. mutans . In addition, DB1 BLIS decreased the viability of S. mutans biofilm cells during the development of biofilm formation and in the preformed biofilm. DB1 BLIS significantly decreased the growth of S. mutans planktonic cells. Furthermore, S. mutans biofilm on the surface of saliva-coated hydroxyapatite discs was reduced by DB1 BLIS. Taken together, DB1 BLIS might be useful as a preventive and therapeutic agent against dental caries caused by S. mutans ., Competing Interests: The authors declare no potential conflicts of interest., (© Korean Society for Food Science of Animal Resources.)

Background: The efficacy of flibanserin in treating hypoactive sexual desire disorder (HSDD) is based upon statistically significant improvements in sexual desire, satisfying sexual events, and distress. However, clinically meaningful benefit has not been well characterized., Aim: Evaluate clinically meaningful benefit of flibanserin., Methods: Data were pooled from 3 pivotal trials evaluating flibanserin 100 mg qhs in premenopausal women (flibanserin, n = 1192; placebo, n = 1215). Flibanserin trial data in postmenopausal women (flibanserin, n = 450; placebo, n = 476) were analyzed separately. Clinically meaningful benefit was evaluated by the Patient Global Impression of Improvement (PGI-I). Responders were determined through anchor-based analyses that used the PGI-I for key efficacy endpoints: satisfying sexual events (SSE), desire domain of the Female Sexual Function Index (FSFI-d), and distress associated with decreased sexual desire (FSDS-R13). Odds ratios were calculated to assess effect size and Kaplan-Meier analyses were performed to estimate onset time for treatment benefit., Outcomes: PGI-I, anchor-based analyses for key efficacy endpoints (SSE, FSFI-d, FSDS-R13), odds ratios, onset time for treatment benefit., Results: Based on the PGI-I, more patients reported clinically meaningful benefit with flibanserin treatment versus placebo (49.8% vs 33.6%, premenopausal cohort; 40.5% vs 28.7%, postmenopausal cohort). In anchor-based analyses, responder rates were significantly higher for premenopausal women on flibanserin (46.1%-55.2%) than placebo (34.1%-44.2%) for all 3 key efficacy endpoints (P < .0001). Responder rates for postmenopausal women on flibanserin were higher compared to placebo for SSE (29.8% vs 22.9%; P = .015) and FSFI-d (38.9% vs 26.3%; P = .0001). Odds ratios for key endpoints indicated that premenopausal women were 2.0-2.4 times as likely to be responders with flibanserin treatment compared to placebo. Postmenopausal women were 1.6 times as likely to be responders with flibanserin for FSFI-d. Kaplan-Meier analyses indicated significant separation between flibanserin and placebo for the key endpoints in both premenopausal and postmenopausal cohorts (log-rank tests P < .01) with earlier median response times among patients receiving flibanserin., Clinical Implications: Patient-reported benefit assessments such as the PGI-I capture the patient's perspective and may be a useful approach in assessing overall clinical meaningfulness for sexual dysfunction therapies., Strengths and Limitations: Strengths include a well-powered study with large enrollment, use of validated instruments, and self-assessment of treatment benefit. Limitations include pooling of trial data in premenopausal women with slightly different study designs and use of an endpoint (SSE) indirectly related to HSDD., Conclusion: Assessment of clinically meaningful benefit and additional responder analyses provide further support for flibanserin's efficacy beyond numerical improvements in endpoint measures. Simon JA, Clayton AH, Kim NN, et al. Clinically Meaningful Benefit in Women with Hypoactive Sexual Desire Disorder Treated with Flibanserin. Sex Med 2022;10:100476., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Aim: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with hypoactive sexual desire disorder (HSDD)., Methods: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method., Outcomes: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up., Results: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data., Clinical Implications: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring., Strengths and Limitations: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging., Conclusion: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.

Background: Persistent genital arousal disorder (PGAD), a condition of unwanted, unremitting sensations of genital arousal, is associated with a significant, negative psychosocial impact that may include emotional lability, catastrophization, and suicidal ideation. Despite being first reported in 2001, PGAD remains poorly understood., Aim: To characterize this complex condition more accurately, review the epidemiology and pathophysiology, and provide new nomenclature and guidance for evidence-based management., Methods: A panel of experts reviewed pertinent literature, discussed research and clinical experience, and used a modified Delphi method to reach consensus concerning nomenclature, etiology, and associated factors. Levels of evidence and grades of recommendation were assigned for diagnosis and treatment., Outcomes: The nomenclature of PGAD was broadened to include genito-pelvic dysesthesia (GPD), and a new biopsychosocial diagnostic and treatment algorithm for PGAD/GPD was developed., Results: The panel recognized that the term PGAD does not fully characterize the constellation of GPD symptoms experienced by patients. Therefore, the more inclusive term PGAD/GPD was adopted, which maintains the primacy of the distressing arousal symptoms and acknowledges associated bothersome GPD. While there are diverse biopsychosocial contributors, there is a common underlying neurologic basis attributable to spontaneous intense activity of the genito-pelvic region represented in the somatosensory cortex and its projections. A process of care diagnostic and treatment strategy was developed to guide the clinician, whenever possible, by localizing the symptoms as originating in any of five regions: (i) end organ, (ii) pelvis/perineum, (iii) cauda equina, (iv) spinal cord, and (v) brain. Psychological treatment strategies were considered critical and should be performed in conjunction with medical strategies. Pharmaceutical interventions may be used based on their site and mechanism of action to reduce patients' symptoms and the associated bother and distress., Clinical Implications: The process of care for PGAD/GPD uses a personalized, biopsychosocial approach for diagnosis and treatment., Strengths and Limitations: Strengths and Limitations: Strengths include characterization of the condition by consensus, analysis, and recommendation of a new nomenclature and a rational basis for diagnosis and treatment. Future investigations into etiology and treatment outcomes are recommended. The main limitations are the dearth of knowledge concerning this condition and that the current literature consists primarily of case reports and expert opinion., Conclusion: We provide, for the first time, an expert consensus review of the epidemiology and pathophysiology and the development of a new nomenclature and rational algorithm for management of this extremely distressing sexual health condition that may be more prevalent than previously recognized. Goldstein I, Komisaruk BR, Pukall CF, et al. International Society for the Study of Women's Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD). J Sex Med 2021;18:665-697., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

This study was conducted to investigate the long-term effect of a low fish meal (FM) diet comprising plant-based protein sources (PPS) on changes of gut microbial diversity in olive flounder (Paralichthys olivaceus) over the course of life. Two experimental diets were prepared to contain 74% FM (control) or 52% FM with 22% PPS (30% FM replacement, FM30). Fish were fed one of the two experimental diets for 8 months, and we collected the midgut contents to analyze the gut bacterial community by Illumina MiSeq based on the metagenomic sequences in the V3-V4 regions of 16S rRNA. We found that there were nine dominant phyla, which in turn presented Proteobacteria, Firmicutes, and Actinobacteria as the three major phyla in the gut microbiota of the flounder. At genus level, the dominant genera were Delftia, Prevotella, and Chthoniobacter at the juvenile stage (below 100 g/fish); Chthoniobacter, Bacillus, and Bradyrhizobium at the grower stage (400 g/fish); Chthoniobacter, Bacillus, and Delftia at the subadult stage (800 g/fish); and Lactobacillus and Prevotella at the adult stage (over 1,000 g/fish). The microbial diversity in olive flounders arched from the juvenile and subadult stage and reached a plateau thereafter. The fish fed the FM30 diet significantly had an increased abundance of Lactobacillus and Photobacterium and had less abundance of Prevotella and Paraprevotella than the control. However, the effect of dietary PPS was not significant on total microbial richness, indicating no negative effect as feed sources on the intestinal microbiota in olive flounder. These results indicate that the life stage of olive flounder is more important in modulating intestinal microbiota than is the diet. It could also be concluded that dietary PPS might be used as a potential fish meal alternative without any compromising effects on microbial diversity of olive flounder for long-term feeding., (© 2020 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.)

The occurrence of CD4 helper T cells has already been established for a number of teleost species, though, it has not been possible to analyze these responses at a cellular level due to a large lack of appropriate monoclonal antibodies (mAbs). In the present study, we produced a mAb against olive flounder (Paralichthys olivaceus) CD4-1 lymphocyte to investigate the functional activity of the cells to improve our understanding of the T cell response in this species. This mAb is specifically able to detect CD4-1 lymphocytes in olive flounder proved by immunofluorescence staining and RT-PCR analysis. In flow cytometry analysis, the number of CD4-1-positive lymphocytes was observed to gradually increase from 3 days post infection (dpi) and then reach peak at 7 dpi against two viruses challenge. As a conclusion, both the basic properties of CD4-1 T cells and its response to viral infections in olive flounder are very similar to the helper T cells in terrestrial animals., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction : Hypoactive sexual desire disorder (HSDD) is the most prevalent sexual dysfunction in women, previously managed with off-label therapies. Indicated for premenopausal women, flibanserin is the first FDA-approved medication to treat HSDD. Areas covered : This review summarizes flibanserin's pharmacokinetics, proposed mechanism of action, and safety data in clinical trials with a focus on sedation- and hypotension-related adverse events, and drug interactions with alcohol and antidepressants. Sources included peer-reviewed publications and internal data from the manufacturer. Expert opinion : Flibanserin is a well-tolerated and effective treatment that decreases distress and restores sexual desire to a level that is normative for the individual patient with HSDD. Simplification of a risk mitigation program for flibanserin in the US is likely to increase the number of prescribing clinicians if accompanied with educational efforts to clarify flibanserin's risk-benefit profile. As flibanserin is dosed daily and may be used for a decade or more in the typical premenopausal patient, long-term pharmacovigilance data will be essential. Over time, HSDD will be treated by more nonspecialist health care professionals and flibanserin will likely become established as a significant treatment option along with other medications approved for this indication in the context of a holistic biopsychosocial treatment paradigm.

Introduction: Flibanserin, a treatment for hypoactive sexual desire disorder, carries warnings for increased risk of severe hypotension and syncope when used with alcohol. However, these warnings are not informed by studies that used flibanserin's recommended bedtime dosing because previous alcohol studies assessed flibanserin's safety during the day., Aim: The aim of this study was to assess the effects of ethanol in a real-world context in premenopausal women taking flibanserin at bedtime., Methods: In a randomized, placebo-controlled, double-blind study, 24 healthy premenopausal women (mean age = 34.5 ± 9.9 years; mean body mass index = 25.2 ± 3.4 kg/m 2 ) were dosed with flibanserin or placebo for 3 days to achieve steady-state plasma levels. In a clinical research unit, subjects (n = 22) were provided 2 units of wine (150 mL/unit; 12% ethanol content) or a nonalcoholic beverage with a standardized 3-course evening meal. Flibanserin 100 mg or placebo was administered at bedtime 2.5 hours after the end of the evening meal. On a separate day, subjects were provided the alternative beverage (± alcohol) with the same evening meal and dosed with the same treatment (flibanserin or placebo) at bedtime. After a 5-day washout period, subjects crossed over to the other treatment arm and the protocol was repeated., Main Outcome Measure: Adverse events (AEs) and vital signs were monitored., Results: In the absence of ethanol, headaches and hypotension were the only AEs that occurred in ≥2 subjects after flibanserin dosing (placebo corrected rates were 17.4% and 8.7%, respectively). After ethanol consumption, the rate of hypotension after flibanserin dosing was no greater than with flibanserin or placebo after nonalcoholic beverage consumption. There were no instances of orthostatic hypotension or syncope and no serious AEs or AEs leading to study discontinuation., Conclusion: Flibanserin dosed at bedtime after moderate amounts of alcohol with an evening meal was well-tolerated with no evidence of clinically significant hypotension or syncope. Millheiser L, Clayton AH, Parish SJ, et al. Safety and Tolerability of Evening Ethanol Consumption and Bedtime Administration of Flibanserin in Healthy Premenopausal Female Subjects. Sex Med 2019;7:418-424., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Flibanserin is approved in the United States and Canada for the treatment of acquired, generalized, hypoactive sexual desire disorder in premenopausal women. Sedation-related side effects are among the most prevalent adverse events. Although infrequent, hypotension and syncope remain safety concerns because of possible interaction of flibanserin with alcohol., Aim: To evaluate the impact of the timing of alcohol consumption on flibanserin safety and tolerability., Methods: In this single-center, randomized, double-blind, placebo-controlled, 4-treatment crossover study, 64 healthy premenopausal women (mean age 32.5 ± 8.7 years; range 20‒52 years) received once-daily flibanserin 100 mg or placebo during each of two 10-day treatment periods. Study medication was administered on days 1-3 to achieve steady state. On days 4, 6, 8, and 10, after a standard breakfast, participants consumed 0.4 g/kg ethanol (approximately equivalent to two 5-oz glasses of wine) administered with orange juice 2, 4, or 6 hours before taking study medication or orange juice alone (no ethanol) 2 hours before taking study medication., Outcomes: The primary endpoint was percentage of participants experiencing syncope or orthostatic hypotension-associated adverse events requiring medical intervention. Secondary endpoints included the incidence of hypotension, the incidence of orthostatic hypotension, and rates of adverse events of special interest (syncope, orthostatic hypotension, dizziness, and somnolence)., Results: 1 participant experienced a primary endpoint event (syncope) during treatment with placebo taken 4 hours after ethanol consumption. Within each ethanol dose-timing treatment, there were no statistically significant differences for flibanserin compared with placebo. Rates of hypotension were 53.3-66.7% after flibanserin dosing and 57.4-63.3% after placebo dosing. Rates for orthostatic hypotension were 0.0-5.0% after flibanserin dosing and 1.7-6.6% after placebo dosing., Clinical Implications: Ethanol interaction with flibanserin was not observed in this study., Strengths & Limitations: This study provides information regarding the use of flibanserin after the consumption of moderate amounts of ethanol (0.4 g/kg). However, daytime administration of flibanserin is not consistent with the drug's indicated bedtime dosing., Conclusion: Flibanserin, at steady state taken 2, 4, or 6 hours after 0.4 g/kg of ethanol intake did not increase the incidence of hypotension, orthostatic hypotension, or syncope compared with either flibanserin alone or ethanol alone. Simon JA, Clayton AH, Kingsberg SA, et al. Effects of Timing of Flibanserin Administration Relative to Alcohol Intake in Healthy Premenopausal Women: A Randomized, Double-Blind, Crossover Study. J Sex Med 2019;16:1779-1786., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Flibanserin, a multifunctional serotonin receptor agonist and antagonist, is currently approved in the United States and Canada for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. A post hoc analysis of HSDD clinical trial data found that flibanserin treatment was associated with statistically significant weight loss relative to placebo, even though study patients were not selected for being overweight/obese and were provided no expectation for weight reduction or interventions intended to promote weight loss., Aim: To understand possible mechanisms by which flibanserin may produce weight loss., Methods: A literature review was performed using Medline database for relevant publications on the mechanisms of action by which flibanserin may provide weight loss and the links between sexual function and weight management., Main Outcome Measures: Examination of (i) biopsychosocial factors regulating sexual desire, food intake, and weight regulation; (ii) clinical pharmacology of flibanserin; (iii) neurobiology of brain reward circuitry; and (iv) identification of possible mechanisms common to flibanserin and weight loss., Results: Based on flibanserin clinical trial data, there was no consistent correlation between weight loss and improvement in sexual function, as assessed by HSDD outcome measures. Nausea, a common adverse event associated with flibanserin use, also did not appear to be a contributing factor to weight loss. Hypothetical links between flibanserin treatment and weight loss include modulation of peripheral 5-HT 2A receptors and factors such as improved mood and improved sleep., Conclusion: Mechanisms of flibanserin-induced weight loss have not been well characterized but may involve indirect beneficial effects on peripheral 5-HT 2A receptors and central regulation of mood and sleep. Future research may better elucidate the links between sexual function and weight management and the mechanism(s) by which flibanserin use may result in weight loss. Simon JA, Kingsberg SA, Goldstein I, et al. Weight Loss in Women Taking Flibanserin for Hypoactive Sexual Desire Disorder (HSDD): Insights into Potential Mechanisms. Sex Med Rev 2019;7:575-586., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Genitourinary conditions in women increase in prevalence with age. Androgens are prerequisite hormones of estrogen biosynthesis, are produced in larger amounts than estrogens in women, and decrease throughout adulthood. However, research and treatment for genitourinary complaints have traditionally focused on estrogens to the exclusion of other potential hormonal influences., Aim: To summarize and evaluate the evidence that androgens are important for maintaining genitourinary health in women and that lack of androgenic activity can contribute to the development of symptoms of the genitourinary syndrome of menopause., Methods: The role of androgens in the pathophysiology, diagnosis, and treatment of genitourinary syndrome of menopause was discussed by an international and multidisciplinary panel during a consensus conference organized by the International Society for the Study of Women's Sexual Health. A subgroup further examined publications from the PubMed database, giving preference to clinical studies or to basic science studies in human tissues., Main Outcome Measures: Expert opinion evaluating trophic and functional effects of androgens, their differences from estrogenic effects, and regulation of androgen and estrogen receptor expression in female genitourinary tissues., Results: Androgen receptors have been detected throughout the genitourinary system using immunohistochemical, western blot, ligand binding, and gene expression analyses. Lower circulating testosterone and estradiol concentrations and various genitourinary conditions have been associated with differential expression of androgen and estrogen receptors. Supplementation of androgen and/or estrogen in postmenopausal women (local administration) or in ovariectomized animals (systemic administration) induces tissue-specific responses that include changes in androgen and estrogen receptor expression, cell growth, mucin production, collagen turnover, increased perfusion, and neurotransmitter synthesis., Conclusion: Androgens contribute to the maintenance of genitourinary tissue structure and function. The effects of androgens can be distinct from those of estrogens or can complement estrogenic action. Androgen-mediated processes might be involved in the full or partial resolution of genitourinary syndrome of menopause symptoms in women. Traish AM, Vignozzi L, Simon JA, et al. Role of Androgens in Female Genitourinary Tissue Structure and Function: Implications in the Genitourinary Syndrome of Menopause. Sex Med Rev 2018;6:558-571., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this consensus document is to broaden the perspective on clinical management of genitourinary syndrome of menopause to include androgens., Methods: A modified Delphi method was used to reach consensus among the 14 international panelists representing multiple disciplines and societies., Results: Menopause-related genitourinary symptoms affect over 50% of midlife and older women. These symptoms have a marked impact on sexual functioning, daily activities, emotional well-being, body image, and interpersonal relations. Tissues in the genitourinary system are both androgen and estrogen-dependent. The clitoris, vestibule, including minor and major vestibular glands, urethra, anterior vaginal wall, periurethral tissue, and pelvic floor are androgen-responsive. Historically, treatment of postmenopausal genitourinary symptoms involved both androgens and estrogens. This subsequently gave rise to predominantly estrogen-based therapies. More recently, double-blind, placebo-controlled clinical trials have demonstrated that local vaginal dehydroepiandrosterone improves symptoms in postmenopausal women, including moderate to severe dyspareunia. Limited data suggest that systemic testosterone treatment may improve vaginal epithelial health and blood flow. Open-label studies that have used high doses of intravaginal testosterone in the presence of aromatase inhibitor therapy for breast cancer have resulted in supraphysiological serum testosterone levels, and have been reported to lower vaginal pH, improve the vaginal maturation index, and reduce dyspareunia., Conclusions: Vaginal dehydroepiandrosterone, hypothesized to enhance local production of both androgen and estrogen, is effective for the management of dyspareunia in menopause. Vaginal testosterone offers potential as a treatment for genitourinary syndrome of menopause, but more studies are needed.

The International Society for the Study of Women's Sexual Health process of care (POC) for management of hypoactive sexual desire disorder (HSDD) algorithm was developed to provide evidence-based guidelines for diagnosis and treatment of HSDD in women by health care professionals. Affecting 10% of adult females, HSDD is associated with negative emotional and psychological states and medical conditions including depression. The algorithm was developed using a modified Delphi method to reach consensus among the 17 international panelists representing multiple disciplines. The POC starts with the health care professional asking about sexual concerns, focusing on issues related to low sexual desire/interest. Diagnosis includes distinguishing between generalized acquired HSDD and other forms of low sexual interest. Biopsychosocial assessment of potentially modifiable factors facilitates initiation of treatment with education, modification of potentially modifiable factors, and, if needed, additional therapeutic intervention: sex therapy, central nervous system agents, and hormonal therapy, guided in part by menopausal status. Sex therapy includes behavior therapy, cognitive behavior therapy, and mindfulness. The only central nervous system agent currently approved by the US Food and Drug Administration (FDA) for HSDD is flibanserin in premenopausal women; use of flibanserin in postmenopausal women with HSDD is supported by data but is not FDA approved. Hormonal therapy includes off-label use of testosterone in postmenopausal women with HSDD, which is supported by data but not FDA approved. The POC incorporates monitoring the progress of therapy. In conclusion, the International Society for the Study of Women's Sexual Health POC for the management of women with HSDD provides a rational, evidence-based guideline for health care professionals to manage patients with appropriate assessments and individualized treatments., (Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

In support of a clinical trial in the pediatric population, available nonclinical and clinical data provide input on the study design and safety monitoring considerations. When the existing data are lacking to support the safety of the planned pediatric clinical trial, a juvenile animal toxicity study is likely required. Usually a single relevant species, preferably a rodent, is chosen as the species of choice, while a nonrodent species can be appropriate when scientifically justified. Juvenile toxicology studies, in general, are complicated both conceptually and logistically. Development in young animals is a continuous process with different organs maturing at different rates and time. Structural and functional maturational differences have been shown to affect drug safety. Key points to consider in conducting a juvenile toxicology study include a comparative development of the organ systems, differences in the pharmacokinetics/absorption, distribution, metabolism, excretion (PK/ADME) profiles of the drug between young animal and child, and logistical requirement in the juvenile study design. The purpose of this publication is to note pertinent points to consider when designing and conducting juvenile toxicology studies and to aid in future modifications and enhancements of these studies to enable a superior predictability of safety of medicines in the pediatric population.

Objective: The objective of this study was to determine the next-day residual effects of acute and steady-state nighttime dosing of flibanserin on simulated driving performance and cognitive function in healthy premenopausal women., Methods: In this randomized, double-blind, placebo-controlled, four-way crossover study, 72 subjects were treated with either acute oral doses of placebo, zopiclone 7.5 mg (positive control) or flibanserin 100 mg at bedtime (indicated therapeutic dose), or after chronic nightly oral doses of flibanserin 100 mg for 1 week followed by a single bedtime dose of flibanserin 200 mg (supratherapeutic dose). Simulated driving assessments were conducted 9 hr after dosing and cognitive function tests were administered immediately before or during the driving assessment., Results: Zopiclone increased standard deviation of lateral position (≥3.1 cm; p < .0001) relative to placebo and impaired other parameters previously shown to be sensitive to sedation. No impairment was detected for flibanserin at either dose relative to placebo. Flibanserin 200 mg was similar to the 100-mg dose on cognitive testing and driving performance even though commonly reported adverse events for flibanserin were predictably increased at the higher dose., Conclusions: At both therapeutic and supratherapeutic doses, flibanserin did not impair next-day driving performance and cognitive function compared to placebo., (Copyright © 2017 John Wiley & Sons, Ltd.)