S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3.

Cytosolic DNA-mediated activation of the transcription factor IRF3 is a key event in host antiviral responses. Here we found that infection with DNA viruses induced interaction of the metabolic checkpoint kinase mTOR downstream effector and kinase S6K1 and the signaling adaptor STING in a manner dependent on the DNA sensor cGAS. We further demonstrated that the kinase domain, but not the kinase function, of S6K1 was required for the S6K1-STING interaction and that the TBK1 critically promoted this process. The formation of a tripartite S6K1-STING-TBK1 complex was necessary for the activation of IRF3, and disruption of this signaling axis impaired the early-phase expression of IRF3 target genes and the induction of T cell responses and mucosal antiviral immunity. Thus, our results have uncovered a fundamental regulatory mechanism for the activation of IRF3 in the cytosolic DNA pathway.

Psychometric Evaluation and Adaptation of the Five-Factor Sexual Satisfaction Scale (SSS-W) for Use in Men: The Sexual Satisfaction Scale (SSS).

The Sexual Satisfaction Scale for Women (SSS-W) is a psychometrically sound, widely used instrument for assessing sexual satisfaction and distress in women. Because the majority of scale items are gender nonspecific, numerous researchers have adapted this scale for use in male samples. The goal of the current study was to assess the reliability and validity of a slightly modified version of the SSS-W in a male sample (N = 268). A Confirmatory Factor Analysis of five previously established factors provided evidence for consistency of internal structure in men. The adapted scale (SSS) exhibited acceptable test-retest reliability, as well as evidence for validity based on relationships with theoretically predicted variables. Taken together, there is evidence to suggest that the SSS may be a reliable and valid psychometric tool for the measurement of sexual satisfaction and distress in both men and women.

History of Sexual Assault as a Predictor of Response to a Self-Guided Online Program for Sexual Desire and Arousal Difficulties in Women.

Sexual Interest/Arousal Disorder (distressing, long-lasting impairments in sexual desire and/or arousal) is common in women, but few have access to efficacious psychotherapies, including cognitive-behavioral therapy (CBT) and mindfulness-based therapy (MBT). eSense, an online program meant to maximize treatment access, has been shown to be a feasible, satisfactory, and potentially efficacious intervention. However, subpopulations such as sexual assault survivors may find the program less usable or efficacious. The current study compared women with and without a history of sexual assault (SA) regarding their ability to use and benefit from eSense. Forty-four women (22 with a history of SA; M age = 34.20 years) used eSense (CBT or MBT) and completed validated self-report scales of sexual function, sexual distress, treatment satisfaction, and homework compliance. A history of SA did not predict differences in attrition or changes in clinical outcomes. Exploratory analyses suggested that women with a history of SA reported slightly higher difficulty completing homework assignments, but also slightly higher treatment satisfaction. These preliminary results suggest that eSense may be usable and helpful for women with a history of SA. We discuss ways to maximize the acceptability and efficacy of online programs for women with a history of SA.

Feasibility of a cognitive behavioral online intervention for women with Sexual Interest/Arousal Disorder.

OBJECTIVES: Difficulties with sexual desire and arousal are common in women, but most lack access to effective treatment such as cognitive-behavioral therapy (CBT). eSense is a recently created online CBT intervention for sexual difficulties with promising evidence of usability. The current study assessed the feasibility of women completing the full eSense CBT program without guidance. METHODS: Eleven women with Sexual Interest/Arousal Disorder completed eSense and provided feedback via semi-structured interviews. RESULTS: Participants reported high satisfaction with eSense's functionality, improved knowledge about sexuality, greater awareness of their thought patterns, and better perspective around their sexual difficulties. Despite some difficulty completing homework, participants exhibited statistically significant pre-post improvements in sexual desire (d = 1.04), sexual arousal (d = 1.83), sexual satisfaction (d = 1.35), and sexual distress (d = 1.79). CONCLUSION: The findings add to the growing evidence that self-guided online interventions are feasible and potentially efficacious in treating female sexual dysfunction.

Feasibility of a Brief Online Psychoeducational Intervention for Women With Sexual Interest/Arousal Disorder.

BACKGROUND: Low sexual desire and arousal are the most common sexual concerns in women, but most women lack access to effective treatment such as cognitive behavioral therapy. Web-based psychological interventions, which are economical, private, easily accessible, and potentially effective, may increase the reach of evidence-based treatment. AIM: To determine the feasibility of translating cognitive behavioral therapy for the most common female sexual dysfunction, Female Sexual Interest/Arousal Disorder, into an online format. The present study examined the feasibility of an introductory psychoeducational module of eSense, an online program currently being developed that is based on existing empirically supported in-person treatments, which delivers content to the user in a visually appealing and interactive manner. METHODS: Sixteen cisgender women (M age = 31.9) with female sexual arousal/interest disorder worked through a pilot module of eSense inperson at a sexual health laboratory. OUTCOMES: Qualitative semistructured interviews and online questionnaires were used to assess participants' experiences of usability of the platform, clarity/relevance of the content, satisfaction with the experience, and any changes in clinical outcomes of sexual function and distress. RESULTS: Participants reported a high level of satisfaction with the website's functionality and presentation. They reported greater knowledge, felt validated and more hopeful, and were eager to continue the remaining modules. Participants also reported notable prepost improvements in sexual desire, arousal, and satisfaction. CLINICAL IMPLICATIONS: Initial user-experience assessment may represent a method of simultaneously improving online interventions and providing therapeutic education to participants. STRENGTHS & LIMITATIONS: This is one of the first studies, to our knowledge, to test a graphics-rich, interactive online intervention for sexual difficulties that does not require direct contact with expert providers or support groups. Limitations include the high level of education, motivation, and technical fluency of the sample and the potentially confounding effect of the researcher's presence during interviews. Because this was a feasibility study, the sample size was small, and no control group was included, limiting conclusions about efficacy and generalizability. CONCLUSION: The format of eSense appears to be feasible and usable, lending support to the growing evidence that it is possible to take in-person therapeutic interventions online. Zippan N, Stephenson KR, Brotto LA, Feasibility of a Brief Online Psychoeducational Intervention for Women With Sexual Interest/Arousal Disorder. J Sex Med 2020;17:2208-2219.

Statistical Mediators of the Association Between Mindfulness and Sexual Experiences in Men with Impaired Sexual Function.

Mindfulness-based therapy has shown promise as a treatment for female sexual dysfunction and has the potential to be an efficacious treatment for male sexual dysfunction. However, there has been little empirical evidence regarding the mechanisms through which mindfulness may improve sexual experiences, especially for men. Recent theoretical reviews have suggested potential mediators that may explain the beneficial effects of mindfulness on symptoms of male sexual dysfunction, including reduced avoidance of sex, reduced distraction during sex, and/or reduced activation of negative sexual schemas. We attempted an initial statistical test of these factors as potential mediators of the association between trait mindfulness and multiple sexual outcomes (sexual function, sexual satisfaction, and sexual distress) using a cross-sectional correlational design. A total of 163 men with self-reported current impairments in one or more aspects of sexual function completed self-report scales using a secure online survey. Bivariate correlations indicated that mindfulness was significantly associated with sexual satisfaction, sexual distress, and premature ejaculation, but not other aspects of sexual function. Sexual avoidance statistically mediated the link between mindfulness and sexual satisfaction, both distraction and activation of negative schemas statistically mediated the link between mindfulness and premature ejaculation, and all three factors statistically mediated the link between mindfulness and sexual distress. These results generally supported previous theoretical work and have implications for future treatment outcome research.

Separate roles of IL-6 and oncostatin M in mouse macrophage polarization in vitro and in vivo.

Arginase-1 (Arg-1)-expressing M2-like macrophages are associated with Th2-skewed immune responses, allergic airway pathology, ectopic B16 melanoma cancer growth in murine models, and can be induced by Oncostatin M (OSM) transient overexpression in vivo. Here, we compare OSM to the gp130-cytokine IL-6 in mediating macrophage polarization, and find that IL-6 overexpression alone (Ad vector, AdIL-6) did not induce Arg-1 protein in mouse lungs at day 7, nor ectopic melanoma tumor growth at day 14, in contrast to overexpression of OSM (AdOSM). AdOSM elevated levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid, whereas AdIL-6 did not. Bone marrow-derived macrophages respond with Arg-1 enzymatic activity to M2 stimuli (IL-4/IL-13), which was further elevated in combination with IL-6 stimulation; however, OSM or LIF had no detectable activity in vitro. Arg-1 mRNA expression induced by AdOSM was attenuated in IL-6-/- and STAT6-/- mice, suggesting requirements for both IL-6 and IL-4/IL-13 signaling in vivo. Ectopic B16 tumor burden was also reduced in IL-6-/- mice. Thus, OSM induces Arg-1+ macrophage accumulation indirectly through elevation of Th2 cytokines and IL-6 in vivo, whereas IL-6 acts directly on macrophages but requires a Th2 microenvironment, demonstrating distinct roles for OSM and IL-6 in M2 macrophage polarization.

Why Is Impaired Sexual Function Distressing to Men? Consequences of Impaired Male Sexual Function and Their Associations With Sexual Well-Being.

INTRODUCTION: According to theoretical models of sexual dysfunction, the complex association between male sexual function and subjective sexual well-being (ie, sexual satisfaction and distress) may be partially mediated by specific "consequences" of impaired function, but little research has assessed the frequency of specific consequences or their association with well-being. AIM: To pilot a scale assessing consequences of impaired male sexual function, and test whether specific consequences (eg, disruption of sexual activity, negative partner responses) mediated the association between sexual function and well-being. METHODS: 166 men in sexually active heterosexual relationships completed self-report measures. A majority of men self-identified as experiencing impaired sexual function in the past month. MAIN OUTCOME MEASURE: Sexual Satisfaction Scale, International Index of Erectile Function, and Measure of Sexual Consequences. RESULTS: 17 specific consequences were reported with at least moderate frequency and were rated at least somewhat distressing. A factor analysis suggested 3 distinct categories of consequences: barrier to sex and pleasure, negative partner emotional responses, and impaired partner sexual function. These factors and the overall scale exhibited acceptable internal and test-retest reliability and each was significantly associated with multiple facets of sexual function and well-being. Frequency of sexual consequences significantly mediated the association between sexual function and well-being, with the strongest and most consistent indirect effects being found for the barrier to sex and pleasure factor. CLINICAL IMPLICATIONS: Consequences of impaired sexual function on one's sexual experiences may be an important maintaining factor of sexual dysfunction and reduction in these consequences may represent a mechanism of action for psychological treatments. STRENGTH AND LIMITATIONS: Strengths included a relatively large sample with a diverse range of sexual function and well-being, as well as modern statistical analyses to assess factor structure and mediation effects. Limitations included the use of self-report scales with limited independent evidence of validity and reliability for use with male samples, as well as the cross-sectional methods that preclude strong conclusions regarding causal relationships. CONCLUSION: Sexual consequences represent potential maintaining factors of male sexual dysfunction and may represent key targets of cognitive behavioral treatments. Stephenson KR, Truong L, Shimazu L. Why is impaired sexual function distressing to men? Consequences of impaired male sexual function and their associations with sexual well-being. J Sex Med 2018;15:1336-1349.

Statistical and Epistemological Issues in the Evaluation of Treatment Efficacy of Pharmaceutical, Psychological, and Combination Treatments for Women's Sexual Desire Difficulties.

We were grateful to receive responses from Leonore Tiefer, Anita Clayton and Robert Pyke, and Richard Balon and Robert Segraves, to our commentary (Brotto et al., 2016 ) on Pyke and Clayton ( 2015 ). These commentaries raise a number of substantive statistical and epistemological issues relating to the evaluation of treatment efficacy in pharmaceutical, psychological, and combination treatments for sexual desire difficulties and caution researchers to remain mindful of sources of bias as we do the science. In what follows, we discuss each of these issues in turn in hopes of encouraging our field to adopt the highest possible standards when carrying out and interpreting treatment outcome research.

Changes in Mindfulness and Posttraumatic Stress Disorder Symptoms Among Veterans Enrolled in Mindfulness-Based Stress Reduction.

OBJECTIVES: The current study assessed associations between changes in 5 facets of mindfulness (Acting With Awareness, Observing, Describing, Non-Reactivity, and Nonjudgment) and changes in 4 posttraumatic stress disorder (PTSD) symptom clusters (Re-Experiencing, Avoidance, Emotional Numbing, and Hyperarousal symptoms) among veterans participating in mindfulness-based stress reduction (MBSR). METHOD: Secondary analyses were performed with a combined data set consisting of 2 published and 2 unpublished trials of MBSR conducted at a large Veterans Affairs hospital. The combined sample included 113 veterans enrolled in MBSR who screened positive for PTSD and completed measures of mindfulness and PTSD symptoms before and after the 8-week intervention. RESULTS: Increases in mindfulness were significantly associated with reduced PTSD symptoms. Increases in Acting With Awareness and Non-Reactivity were the facets of mindfulness most strongly and consistently associated with reduced PTSD symptoms. Increases in mindfulness were most strongly related to decreases in Hyperarousal and Emotional Numbing. CONCLUSIONS: These results extend previous research, provide preliminary support for changes in mindfulness as a viable mechanism of treatment, and have a number of potential practical and theoretical implications.

Further Validation of the Female Sexual Function Index: Specificity and Associations With Clinical Interview Data.

Female sexual function is a multi-faceted psychophysiological construct. The Female Sexual Function Index (FSFI) is considered a "gold standard" self-report instrument that assesses the various aspects of sexual function. However, researchers have recently proposed potential limitations of the FSFI, highlighting the need for continued validation research. The aims of the current analyses were (a) to assess the correlations between FSFI scores and information regarding specific rates of functional impairment gained via clinical interview; and (b) to assess the specificity of FSFI subscale scores in reflecting corresponding aspects of sexual function (e.g., whether the Sexual Desire subscale reflects sexual desire specifically rather than sexual arousal, orgasm, etc.). The participants were 97 sexually active women who reported impairments in sexual function. Clinical interview data exhibited moderate-to-strong correlations with FSFI scores. Additionally, FSFI subscales generally exhibited adequate specificity in terms of reflecting their corresponding aspects of sexual function more strongly than other aspects. The results generally supported the validity of the FSFI. Implications for the measurement and conceptualization of female sexual function are discussed.

Heterosexual Women's Causal Attributions Regarding Impairment in Sexual Function: Factor Structure and Associations with Well-Being.

Theory and interventions for female sexual dysfunction typically emphasize the role of cognitions, including the perceived causes of impaired sexual function (causal attributions). Although causal attributions have been extensively studied in the context of mood disorders and relational distress, research in the area of sexual dysfunction has been limited. The current study explored the factor structure of women's causal attributions regarding their impaired sexual function and the association between these attributions and multiple indicators of subjective well-being. Women in heterosexual relationships reporting current impairments in sexual function (N = 147) completed self-report scales assessing 13 distinct causal attributions, sexual function, and subjective well-being. Results suggested moderately reliable patterns of attributions regarding responsibility (e.g., self vs. partner), specificity to sexual activity, and the degree to which women could effectively address the causes of their difficulties. Beliefs that impaired sexual function was the fault of one's self or one's partner, caused by wider issues in the relationship, and difficult to effectively address were generally associated with lower well-being over and above severity of functional impairment. These findings support multiple theories of sexual dysfunction, and highlight the potential importance of cognitive factors in understanding and treating female sexual dysfunction.

Human coronavirus OC43 nucleocapsid protein binds microRNA 9 and potentiates NF-κB activation.

The human coronavirus OC43 is a major contributor to the common cold worldwide, though due to its low mortality rate, little research has focused on this human pathogen. The nucleocapsid is an essential structural protein with conserved functions across the coronavirus family. While a multitude of studies have examined nucleocapsid function, none have described the effects of OC43 nucleocapsid on the transcription factor NF-κB. We report that the nucleocapsid protein of OC43 causes potentiation of NF-κB activation. This prolonged activation is the direct result of the ability of the nucleocapsid to bind RNA, specifically microRNA 9 (miR-9), which is a negative regulator of NF-κB. This previously undescribed interaction between virus and host is a potential mechanism of immune evasion in RNA viruses.

Why is impaired sexual function distressing to women? The primacy of pleasure in female sexual dysfunction.

INTRODUCTION: Recent research has highlighted a complex association between female sexual function and subjective distress regarding sexual activity. These findings are difficult to explain given limited knowledge as to the mechanisms through which impaired sexual function causes distress. AIM: The current study assessed whether a number of specific consequences of impaired sexual function, including decreased physical pleasure, disruption of sexual activity, and negative partner responses, mediated the association between sexual function and distress. METHODS: Eighty-seven women in sexually active relationships reporting impairments in sexual function completed validated self-report measures and daily online assessments of sexual experiences. MAIN OUTCOME MEASURES: Participants completed the Sexual Satisfaction Scale for Women, the Female Sexual Function Index, and the Measure of Sexual Consequences. RESULTS: Results suggested that decreased physical pleasure and disruption of sexual activity, but not partner responses, statistically mediated the association between sexual function and distress. CONCLUSION: Sexual consequences represent potential maintaining factors of sexual dysfunction that are highly distressing to women. Results are discussed in the context of theoretical models of sexual dysfunction and related treatments.

The conditional importance of sex: exploring the association between sexual well-being and life satisfaction.

Leaders in the field of sexuality have called for additional research examining the link between sexual well-being and life satisfaction in women in order to expand knowledge regarding the important consequences of a satisfying sex life. Participants in the present study were sexually active women reporting a wide range of sexual difficulties who completed an in-person interview, validated self-report measures, and daily online assessments for 4 weeks. Sexual well-being was related to life satisfaction both cross-sectionally and within individuals over time. In addition, high relational satisfaction and low attachment anxiety served as protective factors, decreasing the degree to which unsatisfying sexual experiences were associated with decreases in life satisfaction. These results extend previous findings by confirming a strong association between sexual well-being and overall life satisfaction within individuals over time. The strength of this association is moderated by a number of intra- and interpersonal factors. Implications for healthcare providers are discussed.

Maraba virus as a potent oncolytic vaccine vector.

The rhabdovirus Maraba has recently been characterized as a potent oncolytic virus. In the present study, we engineered an attenuated Maraba strain, defined as MG1, to express a melanoma-associated tumor antigen. Its ability to mount an antitumor immunity was evaluated in tumor-free and melanoma tumor-bearing mice. Alone, the MG1 vaccine appeared insufficient to prime detectable adaptive immunity against the tumor antigen. However, when used as a boosting vector in a heterologous prime-boost regimen, MG1 vaccine rapidly generated strong antigen-specific T-cell immune responses. Once applied for treating syngeneic murine melanoma tumors, our oncolytic prime-boost vaccination protocol involving Maraba MG1 dramatically extended median survival and allowed complete remission in more than 20% of the animals treated. This work describes Maraba virus MG1 as a potent vaccine vector for cancer immunotherapy displaying both oncolytic activity and a remarkable ability to boost adaptive antitumor immunity.

Maraba MG1 virus enhances natural killer cell function via conventional dendritic cells to reduce postoperative metastatic disease.

This study characterizes the ability of novel oncolytic rhabdoviruses (Maraba MG1) to boost natural killer (NK) cell activity. Our results demonstrate that MG1 activates NK cells via direct infection and maturation of conventional dendritic cells. Using NK depletion and conventional dendritic cells ablation studies in vivo, we established that both are required for MG1 efficacy. We further explored the efficacy of attenuated MG1 (nonreplicating MG1-UV(2min) and single-cycle replicating MG1-Gless) and demonstrated that these viruses activate conventional dendritic cells, although to a lesser extent than live MG1. This translates to equivalent abilities to remove tumor metastases only at the highest viral doses of attenuated MG1. In tandem, we characterized the antitumor ability of NK cells following preoperative administration of live and attenuated MG1. Our results demonstrates that a similar level of NK activation and reduction in postoperative tumor metastases was achieved with equivalent high viral doses concluding that viral replication is important, but not necessary for NK activation. Biochemical characterization of a panel of UV-inactivated MG1 (2-120 minutes) revealed that intact viral particle and target cell recognition are essential for NK cell-mediated antitumor responses. These findings provide mechanistic insight and preclinical rationale for safe perioperative virotherapy to effectively reduce metastatic disease following cancer surgery.

A pilot trial of telephone-based collaborative care management for PTSD among Iraq/Afghanistan war veterans.

BACKGROUND: Collaborative care and care management are cornerstones of Primary Care-Mental Health Integration (PC-MHI) and have been shown to reduce depressive symptoms. Historically, the standard of Veterans Affairs (VA) collaborative care was referring patients with posttraumatic stress disorder (PTSD) to specialty care. Although referral to evidence-based specialty care is ideal, many veterans with PTSD do not receive such care. To address this issue and reduce barriers to care, VA currently recommends veterans with PTSD be offered treatment within PC-MHI as an alternative. The current project outlines a pilot implementation of an established telephone-based collaborative care model-Translating Initiatives for Depression into Effective Solutions (TIDES)-adapted for Iraq/Afghanistan War veterans with PTSD symptoms (TIDES/PTSD) seen in a postdeployment primary care clinic. MATERIALS AND METHODS: Structured medical record extraction and qualitative data collection procedures were used to evaluate acceptability, feasibility, and outcomes. RESULTS: Most participants (n=17) were male (94.1%) and white (70.6%). Average age was 31.2 (standard deviation=6.4) years. TIDES/PTSD was successfully implemented within PC-MHI and was acceptable to patients and staff. Additionally, the total number of care manager calls was positively correlated with number of psychiatry visits (r=0.63, p<0.05) and amount of reduction in PTSD symptoms (r=0.66, p<0.05). Overall, participants in the pilot reported a significant reduction in PTSD symptoms over the course of the treatment (t=2.87, p=0.01). CONCLUSIONS: TIDES can be successfully adapted and implemented for use among Iraq/Afghanistan veterans with PTSD. Further work is needed to test the effectiveness and implementation of this model in other sites and among veterans of other eras.

Assessing the association between childhood sexual abuse and adult sexual experiences in women with sexual difficulties.

Self-report instruments for assessing sexual well-being in women with sexual difficulties have not to date been explicitly validated among women with a history of childhood sexual abuse (CSA). Given an extensive literature suggesting psychological differences between women with and without a history of CSA, it is possible that sexual well-being has a different meaning for these groups. Without validated scales, it is difficult to evaluate the impact of early sexual trauma on adult sexuality. The present study assessed whether the factor structure of widely used measures of sexual well-being were consistent across women experiencing sexual difficulties, with and without an abuse history, and to estimate effect sizes for the statistical effect of CSA on sexual well-being in this population. A sample of women with and without a history of CSA (N = 238) completed the Female Sexual Function Index and the Sexual Satisfaction Scale for Women. Structural equation models indicated generally consistent factor structures across groups, suggesting good construct validity. Effect size estimates indicated medium to large (0.53-0.72) effects of CSA on sexual well-being for women with sexual difficulties. These findings support and extend research regarding the potential effects of CSA that may inform treatment for this population.

Arthroscopic irrigation and debridement in the treatment of septic arthritis after anterior cruciate ligament reconstruction.

PURPOSE: To systematically review the literature and characterize the success and failure rates of arthroscopic irrigation and debridement (I & D) in the treatment of septic arthritis after anterior cruciate ligament (ACL) reconstructions. We also aimed to identify which variables affected the failure rate. METHODS: Five databases (MEDLINE, Ovid, Medscape, Web of Science, and Google Scholar) were screened for clinical studies involving the treatment of septic arthritis after ACL reconstruction with arthroscopic I & D. A full-text review of eligible studies was conducted. Inclusion and exclusion criteria were applied to the searched studies. Failure of I & D was defined as the need for graft removal or revision ACL reconstructive surgery because of infection. Data from the selected studies were combined for statistical analyses to elucidate factors associated with the success or failure. RESULTS: We identified 11 eligible studies involving 90 patients. These studies described the results of 90 arthroscopic I & D procedures with an overall success rate of 85.6%. Repeated I & D was necessary in 34.5% of patients. Removal of the graft with or without subsequent revision ACL reconstruction was reported in 13 (14.4%) cases. Statistical analysis showed that cases involving Staphylococcus aureus (P = .053), 2 or more I & D procedures (P = .029), and allografts (P < .0001) were at greater risk of failure. CONCLUSIONS: Arthroscopic I & D with graft retention is an effective treatment for patients with septic arthritis after ACL reconstruction. Factors affecting the failure rate may include graft choice and organism virulence. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies.