The Role of Vibrators in Women's Pelvic Health: An Alluring Tool to Improve Physical, Sexual, and Mental Health.

INTRODUCTION AND HYPOTHESIS: In limited studies vibrators have been shown to improve sexual function and pelvic floor health; however, there are even fewer studies on the effect of vibrator use on overall genitourinary and mental health. To investigate the effect of regular vibrator use on sexual, genitourinary, and mental health in addition to quality of life. METHODS: We performed a prospective pilot study of women aged 18 to 80 years recruited from a urogynecology clinic. Study participants were instructed to use a vibrator according to the protocol. Sexual function, pelvic floor function, mental health, and pelvic examination were assessed at the initial visit and at 3 months' follow-up using validated questionnaires. RESULTS: Of the 79 participants enrolled in the study, 53 women (66%) completed the study. The mean age of the participants was 54.7 years (range 19-80 years), and the majority of participants were white (n = 59, 74.7%), post-menopausal (n = 48, 60.8%), and not receiving systemic (n = 63, 79.7%) or local (n = 63, 79.7%) hormone therapy. Sexual function significantly improved over time (p = 0.002), whereas the rate of bothersome pelvic organ prolapse symptoms and pain scores significantly decreased (p = 0.034 and 0.0008 respectively). Rates of urge urinary incontinence decreased although this was not statistically significant (p = 0.059). There was a significant improvement in the gross appearance of lichen sclerosus lesions (p = 0.025) and in the severity of vaginal atrophy (p = 0.018). Rates of depression were significantly decreased (p = 0.011). CONCLUSIONS: Vibrator use was associated with improved sexual, genitourinary, and mental health.

A Proactive, Systematic Approach to Building the Capacity of Technical Assistance Providers.

Technical assistance (TA) is a major capacity building strategy used by the government sector to promote health outcomes in the United States. However, there is minimal literature about how to develop TA provider capacities. This article describes a systematic and proactive approach for developing TA provider capacity, referred to as Technical Assistance for Technical Assistance Providers (TAFTAP), which draws on three implementation science frameworks (Interactive Systems Framework for Dissemination and Implementation, Getting To Outcomes, and R = MC2). We present an application of TAFTAP within a federal agency providing a readiness-informed TA approach to health departments of states, territories, and tribal areas implementing comprehensive tobacco prevention control programs. Pilot data suggest that TAFTAP is a promising approach for improving the quality of TA delivery. At the end of the 2-year project period, TAFTAP recipients provided generally positive qualitative feedback about the support they received. They chose to sustain the readiness-informed TA by incorporating it into a future funding announcement. Downstream state-level TA grantee recipients reported positive outcomes (e.g., accelerated progress, enjoying more one-on-one time with TA providers) from receiving the TA innovation from TAFTAP recipients. We suggest that funding agencies and training and TA centers consider this approach to bolster the capacity and motivation of TA providers for downstream benefit to health and human services staff and their clients. Practical steps for employing TAFTAP to advance health outcomes are included in this article.

Training programme for community service providers who support adults with intellectual disabilities: A systematic quantitative literature review of single-case research.

BACKGROUND: Research on training direct support professionals to address challenging behaviour exhibited by adults with intellectual disabilities is essential in generating effective training approaches for this sector. This systematic review's objective was to evaluate the effects of training types and whether specific training delivery components influenced outcomes. METHODS: Following PRISMA (2020) guidelines, 16 single-case design studies were included that directly evaluated behaviour change of service providers training for adults with intellectual disabilities in community settings. Study quality was assessed using Horner et al. (Exceptional Children, 2005, 71(2), 165-180) criteria. The database searched included Academic Search Complete, CINAHL, Embase, ERIC, Psych Info, and Web of Science. RESULTS: Descriptive analysis of effect size outcomes suggested that all training types were associated with improved outcomes. Further, in situ training was associated with improved service provider performance. Interestingly, feedback was associated with poorer service provider performance. CONCLUSIONS: We provide possible explanations for this surprising outcome and propose future research.

A model for fostering community capacity to support adults with intellectual disabilities who engage in challenging behaviour: A scoping review.

Developmental support agencies support many adults with intellectual disabilities in the community. Unfortunately, these adults often exhibit high rates of challenging behaviour, which present significant pressures on these service providers. Agencies need to develop effective means of increasing their capacity to provide quality support. Previous systematic reviews found that training staff in positive behaviour supports can improve outcomes; however, the factors facilitating training's effects, long-term effectiveness, and outcomes for service users have yet to be determined. We conducted a scoping review of 98 journal articles and book chapters to develop a model for fostering capacity development drawing from Organizational Behaviour Management and Knowledge Translation theories. Some relevant factors include features of the inner and outer organizational contexts, training approaches (e.g., behavioural skills training & in-situ coaching), ongoing support and feedback. This model may lead to more effective and enduring treatment programs and improved support for adults with intellectual disabilities.

Supracervical Hysterectomy Is Protective against Mesh Complications after Minimally Invasive Abdominal Sacrocolpopexy: A Population-Based Cohort Study of 12,189 Patients.

PURPOSE: Although minimally invasive (robotic or laparoscopic) abdominal sacrocolpopexy (MISC) has become the new gold standard for durable pelvic organ prolapse repair after the vaginal mesh controversy, current literature is limited. Our objective was to study reoperation for mesh complications after MISC. MATERIALS AND METHODS: All women undergoing MISC in California from January 2012 to December 2018 were identified from Office of Statewide Health Planning and Development data sets using appropriate ICD-9/10 (International Classification of Diseases 9th/10th Revision) and CPT® (Current Procedural Terminology) codes. Univariate and multivariable analyses were performed to assess associations between patient demographics, surgical details and our primary outcomes: rates of reoperation for a mesh complication. RESULTS: Of 12,189 women undergoing MISC 8,398 (68.9%) had concomitant hysterectomy. Total hysterectomy (TH) and supracervical hysterectomy (SCH) were performed in 5,027 (41.2%) and 3,371 (27.6%) cases, respectively. Reoperation rates for mesh complications were lower after SCH vs TH (overall: 0.7%, mean followup time 1,111 days vs 3.1%, mean followup time 1,095 days, p <0.001; subcohort with at least 4 years of followup: 2.1% vs 8.9%, p <0.001). Additionally, mesh complication rates were higher even if TH was performed remotely, as compared to concomitant SCH (5.2% vs 0.7%, p <0.001). The increased risk for reoperation due to mesh complications after TH was preserved on multivariable analysis (OR 4.20, 95% CI 2.72‒6.50, p <0.001). CONCLUSIONS: Concomitant TH at time of MISC is associated with a significantly higher rate of mesh complication as compared to SCH. The increased risk of a mesh complication associated with TH is present even if the TH was performed prior to the MISC.

Cytokine induced 3-D organotypic psoriasis skin model demonstrates distinct roles for NF-κB and JAK pathways in disease pathophysiology.

Psoriasis vulgaris is an inflammatory skin disease that affects 2%-3% of the population worldwide. One of the major challenges in discovering novel therapies is the poor translatability of animal models to human disease. Therefore, it is imperative to develop human preclinical models of psoriasis that are amenable to pharmacological intervention. Here, we report a 3-D reconstituted human epidermis (RHE) culture system treated with cytokines commonly associated with psoriasis (TNFα, IL-17A and IL-22) that reproduced some key features of the human disease. The effects on epidermal morphology, gene transcription and cytokine production, which are dysregulated in psoriasis were assessed. Certain morphological features of psoriatic epidermis were evident in cytokine-stimulated RHEs, including hypogranulosis and parakeratosis. In addition, RHEs responded to a cytokine mix in a dose-dependent manner by expressing genes and proteins associated with impaired keratinocyte differentiation (keratin 10/K10, loricrin), innate immune responses (S100A7, DEFB4, elafin) and inflammation (IL-1α, IL-6, IL-8, IL-10, IL-12/23p40, IL-36γ, GM-CSF and IFNγ) typical of psoriasis. These disease-relevant changes in morphology, gene transcription and cytokine production were robustly attenuated by pharmacologically blocking TNFα/IL-17A-induced NF-κB activation with IKK-2 inhibitor IV. Conversely, inhibition of IL-22-induced JAK1 signalling with ABT-317 strongly attenuated morphological features of the disease but had no effect on NFκB-dependent cytokine production, suggesting distinct mechanisms of action by the cytokines driving psoriasis. These data support the use of cytokine-induced RHE models for identifying and targeting keratinocyte signalling pathways important for disease progression and may provide translational insights into novel keratinocyte mechanisms for novel psoriasis therapies.

Physician Interpretation of Data of Uncertain Clinical Utility in Oncology Prescription Drug Promotion.

BACKGROUND: Little is known about how physicians interpret data displays that depict preliminary or exploratory clinical data in physician-targeted sales aids for oncology drugs. Using three factorial experiments, we examined whether disclosures of data limitations and clinical uncertainty adequately communicate the limitations and practical utility of this type of data. SUBJECTS, MATERIALS, AND METHODS: The studies used a 2 (disclosure of data limitations: technical, nontechnical) × 2 (disclosure of clinical uncertainty: present, absent) + 1 (control: no disclosure) between-subjects experimental design to examine the impact of disclosures as they relate to presentations of preliminary or exploratory data in promotional communications for oncology products. In each experiment, we randomized oncologists and primary care physicians with oncology experience to view one version of a two-page sales aid. Following this exposure, physicians completed a web-based survey. The design was replicated in three concurrently conducted experiments using sales aids for different fictitious oncology drugs, each featuring one of three common data displays: a forest plot (n = 495), a Kaplan-Meier curve (n = 504), or a bar chart (n = 532). RESULTS: Results provide initial evidence that in some contexts disclosures can improve understanding of the clinical utility of certain information about a drug and the limitations of results presented in a data display. Disclosures can also temper perceptions of how much evidence is presented that supports a conclusion that the drug is an appropriate treatment. In terms of the language used in the disclosure of data limitations, physicians in all three experiments strongly preferred the nontechnical disclosures. CONCLUSION: The findings from the three experiments in this study suggest that disclosures have the potential to increase relevant knowledge, but more research is needed to establish best practice recommendations for using disclosures to convey contextual information relevant for interpreting data displays in promotional communications. IMPLICATIONS FOR PRACTICE: This article reports the results from three large, online experimental studies that address a growing concern that drug companies often share favorable clinical trial results with physicians in promotional materials that lack important context for physicians to interpret the data. This series of studies investigates whether strategic use of two types of disclosures (disclosure of data limitations and a disclosure of clinical uncertainty) improves understanding and reduces misinterpretations among physicians. The results from these studies help identify communication factors that impact how physicians critically appraise preliminary or exploratory clinical trial data to inform policy and regulatory efforts.

Mycoplasma and Ureaplasma Molecular Testing Does Not Correlate with Irritative or Painful Lower Urinary Tract Symptoms.

PURPOSE: For patients with persistent irritative lower urinary tract symptoms, such as dysuria and urinary frequency, evaluation for the atypical organisms Ureaplasma and Mycoplasma has been a common part of care. However, these species are genitourinary colonizers and have not been established as causative pathogens in chronic lower urinary tract symptoms. We therefore sought to evaluate diagnostic testing patterns for Ureaplasma and Mycoplasma and characterize the associations of these bacteria with irritative lower urinary tract symptoms using molecular detection techniques. MATERIALS AND METHODS: Ureaplasma/Mycoplasma testing patterns for 2019 were assessed using an anonymized data repository. Clean catch urine specimens (179) were collected prospectively from female and male patients with and without irritative lower urinary tract symptoms. Quantitative polymerase chain reaction evaluated urinary Ureaplasma and Mycoplasma DNA concentrations, while next-generation sequencing assessed the relative abundance of Ureaplasma and Mycoplasma within the urinary bacterial population. RESULTS: Ureaplasma/Mycoplasma testing was common, with 575 tests performed in 2019 in our community hospital system. In our cohort, Ureaplasma and Mycoplasma were identified in similar proportions in symptomatic and asymptomatic subjects: 25% of female controls and 27% of females with lower urinary tract symptoms and 9.5% of asymptomatic males and 3.3% of men with symptoms (p=0.87 and p=0.91 for females and males, respectively). Regression analysis revealed that both abundance and concentrations of Mycoplasmataceae correlated negatively with a range of irritative lower urinary tract symptoms, including dysuria and urethral pain. CONCLUSIONS: A statistically significant negative correlation of Ureaplasma/Mycoplasma levels with a variety of lower urinary tract symptoms suggests that polymerase chain reaction-based Mycoplasmataceae detection has little diagnostic benefit in assessment of chronic irritative urinary symptoms.

Fear and Frustration among Women with Recurrent Urinary Tract Infections: Findings from Patient Focus Groups.

PURPOSE: We investigated the perspectives of women suffering from recurrent urinary tract infections using patient focus group discussions with an emphasis on patient attitudes toward the current prevention and treatment of urinary tract infection episodes. MATERIALS AND METHODS: Twenty-nine women with recurrent urinary tract infections were recruited from a tertiary urology practice to participate in one of 6 focus groups. Participants were asked questions related to urinary tract infection knowledge, prevention strategies, treatment and impact on quality of life. Grounded theory methods were used to analyze focus group transcripts and identify preliminary themes that describe patient attitudes toward current management strategies for recurrent urinary tract infections. RESULTS: The median age of participants was 46 years (range 20-81). The majority were Caucasian and held a college degree. The 7 preliminary themes identified during discussions fell into 2 categories: 1) negative impacts of taking antibiotics for prevention and treatment of recurrent urinary tract infections, and 2) resentment of the medical profession regarding their management of recurrent urinary tract infections. From the preliminary themes, the emergent concepts of "fear" and "frustration" became evident. CONCLUSIONS: Focus group discussions of women with recurrent urinary tract infections suggest that many women are fearful of the adverse effects of antibiotics and are frustrated with the medical profession for not addressing their fears and optimizing antibiotic stewardship. There is a need for physicians to modify management strategies to address these concerns and to devote more research efforts to improving the nonantibiotic options for prevention and treatment of recurrent urinary tract infections, as well as management strategies that better empower patients.

Histologic progression of acne inversa/hidradenitis suppurativa: Implications for future investigations and therapeutic intervention.

Since first recognized in 1839, the pathogenesis of acne inversa (AI) has undergone repeated revisions. Although there is agreement that AI involves occlusion of hair follicles with subsequent inflammation and the formation of tracts, the histologic progression of this disease still requires refinement. The objective of this study was to examine the histologic progression of AI based on the examination of a large cohort of punch biopsies and excisional samples that were examined first by hematoxylin and eosin staining. The most informative of these samples were step-sectioned and stained by immunohistochemistry for epithelial and inflammatory markers. Based on this examination, the following observations were made: 1) AI arises from the epithelium of the infundibulum of terminal and vellus hairs; 2) These form cysts and epithelial tendrils that extend into soft tissue; 3) Immunohistochemical staining demonstrates the epithelium of AI is disordered with infundibular and isthmic differentiation and de novo expression of stem cell markers; 4) The inflammatory response in AI is heterogeneous and largely due to cyst rupture. The conclusions of this investigation were that AI is an epithelial-driven disease caused by infiltrative, cyst forming tendrils and most of the inflammation is due to cyst rupture and release of cornified debris and bacteria. Cyst rupture often occurs below the depths of punch biopsy samples indicating their use for analysis may give an incomplete picture of the disease. Finally, our data suggest that unless therapies inhibit tendril development, it is unlikely they will cause prolonged treatment-induced remission in AI.

Thermal stress induces a positive phenotypic and molecular feedback loop in zebrafish embryos.

Aquatic organisms must cope with both rising and rapidly changing temperatures. These thermal changes can affect numerous traits, from molecular to ecological scales. Biotic stressors are already known to induce the release of chemical cues which trigger behavioural responses in other individuals. In this study, we infer whether fluctuating temperature, as an abiotic stressor, may similarly induce stress-like responses in individuals not directly exposed to the stressor. To test this hypothesis, zebrafish (Danio rerio) embryos were exposed for 24 h to fluctuating thermal stress, to medium in which another embryo was thermally stressed before ("stress medium"), and to a combination of these. Growth, behaviour, expression of molecular markers, and of whole-embryo cortisol were used to characterise the thermal stress response and its propagation between embryos. Both fluctuating high temperature and stress medium significantly accelerated development, by shifting stressed embryos from segmentation to pharyngula stages, and altered embryonic activity. Importantly, we found that the expression of sulfide:quinone oxidoreductase (SQOR), the antioxidant gene SOD1, and of interleukin-1ß (IL-1ß) were significantly altered by stress medium. This study illustrates the existence of positive thermal stress feedback loops in zebrafish embryos where heat stress can induce stress-like responses in conspecifics, but which might operate via different molecular pathways. If similar effects also occur under less severe heat stress regimes, this mechanism may be relevant in natural settings as well.

R = MC2 readiness building process: A practical approach to support implementation in local, state, and national settings.

Effective implementation of evidence-based interventions is a persistent challenge across community settings. Organizational readiness - or, the motivation and collective capacity of an entity to adopt and sustain an innovation - is important to facilitate implementation. Drawing on the R = MC2 readiness framework, we developed a readiness building process to tailor support for implementation. The process is composed of the following stages: assessment, feedback and prioritization, and strategize. In this article, we describe the application of the readiness building process through three case examples representing interventions at different ecological levels: local, state, and national. The case examples illuminate challenges and practical considerations for using the readiness building process, including the significance of on-going leadership engagement and collaboration between support system and delivery system staff. To further the research and practice of implementation readiness, we suggest examining the impact of readiness building on implementation outcomes and developing an empirically-informed repository of change management strategies matched to readiness constructs.

Re-evaluation of birth trends and pregnancy complications among female urologists: Have we made any progress?

AIMS: Females are becoming surgeons at ever-increasing rates and doing so while many have or wish to have children. This study follows up on a 2007 effort to study the problems and conditions such women faced. We ask here if these challenges are different after a decade that included changes in working rules. METHODS: A survey was sent to all female American Board of Urology diplomates. Birth trends, pregnancy complications, infertility service requirements, and satisfaction were evaluated in respondents (n = 183) and compared to the previous survey of female urologists who completed residency before August 2007 as well as Center for Disease Control data. RESULTS: Seventy-six physicians completed the survey who were residents before 2007, while 107 replied who experienced residency after. The first group's average age was 50.2 and the second's 38.3. Overall, these women gave birth 6 to 7 years later than the US mean. Complications did not decrease, infertility occurred at similar levels, and both were higher than US norms. Length of maternity leave correlated with respondents' level of overall satisfaction. The most positive responses came from those with more than 8 weeks off (P = .002). CONCLUSIONS: Women practicing in urology gave birth later, had greater fertility issues, used assisted reproductive technology (ART) more and reported a higher level of at least one complication during pregnancy than American women overall. Changes in hours and awareness of this issue have not made giving birth a healthier event for these physicians. Further investigation into factors other than work hours is needed.

Disentangling Complex Inheritance Patterns of Plant Organellar Genomes: An Example From Carrot.

Plant mitochondria and plastids display an array of inheritance patterns and varying levels of heteroplasmy, where individuals harbor more than 1 version of a mitochondrial or plastid genome. Organelle inheritance in plants has the potential to be quite complex and can vary with plant growth, development, and reproduction. Few studies have sought to investigate these complicated patterns of within-individual variation and inheritance using experimental crosses in plants. We carried out crosses in carrot, Daucus carota L. (Apiaceae), which has previously been shown to exhibit organellar heteroplasmy. We used mitochondrial and plastid markers to begin to disentangle the patterns of organellar inheritance and the fate of heteroplasmic variation, with special focus on cases where the mother displayed heteroplasmy. We also investigated heteroplasmy across the plant, assaying leaf samples at different development stages and ages. Mitochondrial and plastid paternal leakage was rare and offspring received remarkably similar heteroplasmic mixtures to their heteroplasmic mothers, indicating that heteroplasmy is maintained over the course of maternal inheritance. When offspring did differ from their mother, they were likely to exhibit a loss of the genetic variation that was present in their mother. Finally, we found that mitochondrial variation did not vary significantly over plant development, indicating that substantial vegetative sorting did not occur. Our study is one of the first to quantitatively investigate inheritance patterns and heteroplasmy in plants using controlled crosses, and we look forward to future studies making use of whole genome information to study the complex evolutionary dynamics of plant organellar genomes.

Quantitative ligand and receptor binding studies reveal the mechanism of interleukin-36 (IL-36) pathway activation.

IL-36 cytokines signal through the IL-36 receptor (IL-36R) and a shared subunit, IL-1RAcP (IL-1 receptor accessory protein). The activation mechanism for the IL-36 pathway is proposed to be similar to that of IL-1 in that an IL-36R agonist (IL-36α, IL-36ß, or IL-36γ) forms a binary complex with IL-36R, which then recruits IL-1RAcP. Recent studies have shown that IL-36R interacts with IL-1RAcP even in the absence of an agonist. To elucidate the IL-36 activation mechanism, we considered all possible binding events for IL-36 ligands/receptors and examined these events in direct binding assays. Our results indicated that the agonists bind the IL-36R extracellular domain with micromolar affinity but do not detectably bind IL-1RAcP. Using surface plasmon resonance (SPR), we found that IL-1RAcP also does not bind IL-36R when no agonist is present. In the presence of IL-36α, however, IL-1RAcP bound IL-36R strongly. These results suggested that the main pathway to the IL-36R·IL-36α·IL-1RAcP ternary complex is through the IL-36R·IL-36α binary complex, which recruits IL-1RAcP. We could not measure the binding affinity of IL-36R to IL-1RAcP directly, so we engineered a fragment crystallizable-linked construct to induce IL-36R·IL-1RAcP heterodimerization and predicted the binding affinity during a complete thermodynamic cycle to be 74 µm The SPR analysis also indicated that the IL-36R antagonist IL-36Ra binds IL-36R with higher affinity and a much slower off rate than the IL-36R agonists, shedding light on IL-36 pathway inhibition. Our results reveal the landscape of IL-36 ligand and receptor interactions, improving our understanding of IL-36 pathway activation and inhibition.

IL-36 receptor antagonistic antibodies inhibit inflammatory responses in preclinical models of psoriasiform dermatitis.

Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by cytokines/chemokines from skin cells. Among skin-derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is limited data showing crosstalk between the IL-23 and IL-36 pathways in PV. Herein, potential attenuation of skin inflammation in the IL-23-induced mouse model of psoriasiform dermatitis by functional inhibition of IL-36 receptor (IL-36R) was interrogated. Anti-mouse IL-36R monoclonal antibodies (mAbs) were generated and validated in vitro by inhibiting IL-36α-induced secretion of CXCL1 from NIH 3T3 cells. Antibody target engagement was demonstrated by inhibition of CXCL1 production in a novel acute model of IL-36α systemic injection in mice. In addition, anti-IL-36R mAbs inhibited tissue inflammation and inflammatory gene expression in an IL-36α ear injection model of psoriasiform dermatitis demonstrating engagement of the target in the ear skin. To elucidate the possible role of IL-36 signalling in IL-23/Th17 pathway, the ability of anti-IL-36R mAbs to inhibit skin inflammation in an IL-23 ear injection model was assessed. Inhibiting the IL-36 pathway resulted in significant attenuation of skin thickening and psoriasis-relevant gene expression. Taken together, these data suggest a role for IL-36 signalling in the IL-23/Th17 signalling axis in PV.

A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.

Perilipin 2 (PLIN2) is a lipid-droplet protein that is up-regulated in alcoholic steatosis and associated with hepatic accumulation of ceramides, bioactive lipids implicated in alcoholic liver disease pathogenesis. The specific role of ceramide synthetic enzymes in the regulation of PLIN2 and promotion of hepatocellular lipid accumulation is not well understood. We examined the effects of pharmacologic ceramide synthesis inhibition on hepatic PLIN2 expression, steatosis, and glucose and lipid homeostasis in mice with alcoholic steatosis and in ethanol-incubated human hepatoma VL17A cells. In cells, pharmacologic inhibition of ceramide synthase reduced lipid accumulation by reducing PLIN2 RNA stability. The subtype ceramide synthase (CerS)6 was specifically up-regulated in experimental alcoholic steatosis in vivo and in vitro and was up-regulated in zone 3 hepatocytes in human alcoholic steatosis. In vivo ceramide reduction by inhibition of de novo ceramide synthesis reduced PLIN2 and hepatic steatosis in alcohol-fed mice, but only de novo synthesis inhibition, not sphingomyelin hydrolysis, improved glucose tolerance and dyslipidemia. These findings implicate CerS6 as a novel regulator of PLIN2 and suggest that ceramide synthetic enzymes may promote the earliest stage of alcoholic liver disease, alcoholic steatosis.-Williams, B., Correnti, J., Oranu, A., Lin, A., Scott, V., Annoh, M., Beck, J., Furth, E., Mitchell, V., Senkal, C. E., Obeid, L., Carr, R. M. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.

Robot-assisted laparoscopic sacrocolpopexy with autologous fascia lata: technique and initial outcomes.

INTRODUCTION AND HYPOTHESIS: Pelvic reconstructive surgery is increasingly being performed with autologous grafts to avoid complications of synthetic mesh and improve the durability of a native tissue repair. Autologous fascia lata (AFL) provides a reliable source of robust connective tissue to improve surgical outcomes. We present our technique and initial experience with performing robotic sacrocolpopexy (RSC) augmented with AFL. METHODS: A retrospective review was conducted of patients who underwent RSC with AFL between January 2015 and November 2017. Outcomes evaluated include recurrence of prolapse on physical examination, prolapse symptoms, urinary incontinence, patient satisfaction based on the Patient Global Impression of Improvement (PGI-I) and complications. RESULTS: Twelve patients were identified with a median age of 68 years (range, 46-77 years) at the time of RSC with AFL. Eleven patients had a history of prior sling and/or vaginal mesh. The median operative time was 225 min (177-302 min). There were no intra- or postoperative complications. After a median follow-up of 14.7 months (5.7 to 39 months), the median PGI-I response was 2 (range, 1-3, very much to a little better). No recurrent or persistent apical prolapse was observed. Three patients (25%) reported recurrence of sensation of a vaginal bulge, which were all due to anterior vaginal wall prolapse. CONCLUSIONS: RSC can be performed with AFL and should be considered in patients with a history of mesh complications. Overall patient satisfaction was high. While these short-term outcomes are encouraging, further studies are needed to assess long-term durability of anatomic results.

Design of Aminobenzothiazole Inhibitors of Rho Kinases 1 and 2 by Using Protein Kinase†A as a Structure Surrogate.

We describe the design, synthesis, and structure-activity relationships (SARs) of a series of 2-aminobenzothiazole inhibitors of Rho kinases (ROCKs) 1 and 2, which were optimized to low nanomolar potencies by use of protein kinase A (PKA) as a structure surrogate to guide compound design. A subset of these molecules also showed robust activity in a cell-based myosin phosphatase assay and in a mechanical hyperalgesia in vivo pain model.

Development of an excitatory kisspeptin projection to the oxytocin system in late pregnancy.

KEY POINTS: Oxytocin release from the posterior pituitary gland stimulates uterine contraction during birth but the central mechanisms that activate oxytocin neurones for birth are not well characterized. We found that that kisspeptin fibre density around oxytocin neurones increases in late-pregnant rats. These kisspeptin fibres originated from hypothalamic periventricular nucleus neurones that upregulated kisspeptin expression in late pregnancy. Oxytocin neurones were excited by central kisspeptin administration in late-pregnant rats but not in non-pregnant rats or early- to mid-pregnant rats. Our results reveal the emergence of a new excitatory kisspeptin projection to the oxytocin system in late pregnancy that might contribute to oxytocin neurone activation for birth. ABSTRACT: The hormone oxytocin promotes uterine contraction during parturition. Oxytocin is synthesized by magnocellular neurones in the hypothalamic supraoptic and paraventricular nuclei and is released into the circulation from the posterior pituitary gland in response to action potential firing. Systemic kisspeptin administration increases oxytocin neurone activity to elevate plasma oxytocin levels. Here, immunohistochemistry revealed that rats on the expected day of parturition (day 21 of gestation) had a higher density of kisspeptin-positive fibres in the perinuclear zone surrounding the supraoptic nucleus (which provides dense glutamatergic and GABAergic innervation to the supraoptic nucleus) than was evident in non-pregnant rats. Retrograde tracing showed the kisspeptin projections to the perinuclear zone originated from the hypothalamic periventricular nucleus. Quantitative RT-PCR showed that kisspeptin receptor mRNA, Kiss1R mRNA, was expressed in the perinuclear zone-supraoptic nucleus and that the relative Kiss1R mRNA expression does not change over the course of pregnancy. Finally, intracerebroventricular administration of kisspeptin increased the firing rate of oxytocin neurones in anaesthetized late-pregnant rats (days 18-21 of gestation) but not in non-pregnant rats, or in early- or mid-pregnant rats. Taken together, these results suggest that kisspeptin expression is upregulated in the periventricular nucleus projection to the perinuclear zone of the supraoptic nucleus towards the end of pregnancy. Hence, this input might activate oxytocin neurones during parturition.