A Non-Randomized Comparison of Online and In-Person Formats of the Canadian Androgen Deprivation Therapy Educational Program: Impacts on Side Effects, Bother, and Self-Efficacy.

Although Androgen Deprivation Therapy (ADT) is effective in controlling prostate cancer (PCa) and increasing survival, it is associated with a myriad of side effects that cause significant morbidity. Previous research has shown that PCa patients starting on ADT are neither fully informed nor well-equipped to manage the breadth of ADT's side effects. The ADT Educational Program (a 1.5 h interactive class plus a book) was developed as an evidence-based resource for patients dealing with ADT. Our aim here was to compare the efficacy of an online version of the class with a previously assessed in-person version of the class. Using mixed MANOVAs within a non-randomized comparison design, we assessed: (1) changes in patients' experiences of self-efficacy to manage and bother associated with side effects approximately 10 weeks after attending a class, and (2) potential differences in these variables between online and in-person class formats. Side effect bother decreased from pre- to post-class but did not differ between in-person (n = 94) and online (n = 137) class cohorts. While self-efficacy to manage side effects was slightly higher post-class in both cohorts, the increase was not statistically significant. Average self-efficacy ratings were significantly higher among in-person versus online class participants (p < 0.05; ηp2 = 0.128). Both online and in-person classes are associated with a significant reduction in the severity of side effect bother reported by PCa patients, suggesting non-inferiority of online versus in-person formats. Online classes offer greater accessibility to the program for patients outside the reach of in-person classes, increasing the availability of the program to more PCa patients and family members across Canada.

Patient Reported Sexual Adaptation Following Prostate Cancer Treatment: An Analysis of Related Variables and Sexual Outcomes Associated with Sexual Adaptation Styles.

Sexual concerns after prostate cancer (PCa) treatment are high. Flexible coping is a crucial element to maintaining sexual activity after PCa and improves adaptation outcomes. We aimed to identify potential sexual adaptation styles reported by men following PCa treatment, and to assess relationships among associated variables and outcomes. Individuals (n = 223) with PCa treatment history (e.g., radical prostatectomy [n = 165, 74.0%], external beam radiation [n = 83, 37.2%], hormone/androgen deprivation therapy [n = 83, 37.2%]), completed an online survey assessing sexual variables and processes of sexual adaptation. Using a combination of inductive and deductive coding, open-ended responses were thematically analyzed and grouped into sexual adaptation styles. Factors potentially associated with sexual adaptation styles (e.g., age, perceived partner involvement, co-morbidities, relationship duration, time since PCa treatment, desire for physical affection, depression, relationship adjustment) were tested using multinomial logistic regression. Outcomes of sexual well-being (sexual distress, sexual bother, sexual satisfaction) and relationship adjustment were compared against each sexual adaptation style using a multivariate analysis of variance. Sexual activity status and satisfaction with the adaptation process was assessed across the sexual adaptation styles using a chi-square analysis and post-hoc tests. Two distinct categories were identified: those who had Adapted (n = 185) and those who had Not Adapted (n = 38). Four sexual adaptation styles emerged in the adapted category: Relationship Renegotiation (n = 53) and Sexual Renegotiation (n = 47), which were couples-focused styles, and Acceptance/Resignation (n = 34) and Masturbation/Erection (n = 48), which were individual-focused styles. Participants who could not be categorized as one style, but rather met several, were identified as Mixed (n = 3). Higher rates of depression, lower relationship adjustment, lack of sexual activity, and greater dissatisfaction with the adaptation process were observed for Not Adapted participants. Participants engaged in any type of adaptation style fared better than those who had Not Adapted. Couples-focused styles tended to emphasize renegotiation, including a changed perspective on the expression of the relationship. Perceived direct engagement of the partner facilitated adaptation and emphasized engagement with flexible coping, either through redefining priorities or ways of being sexual. Individual-focused styles emphasized pre-cancer erectile function, and either aimed to return to capacity for penetrative sexual activity or accepted its inaccessibility and largely an abandonment of partnered sexual activity.

A Proposal for the Comprehensive Care of Men on Androgen Deprivation Therapy: Recommendations From the Multidisciplinary Prostate Cancer 360 Working Group.

INTRODUCTION: To promote comprehensive care of patients throughout the androgen deprivation therapy (ADT) prescribing process, the Prostate Cancer 360 (PC360) Working Group developed monitoring and management recommendations intended to mitigate or prevent ADT-associated adverse events. METHODS: The PC360 Working Group included 14 interdisciplinary experts with a dedicated clinical interest in prostate cancer and ADT management. The working group defined challenges associated with ADT adverse event management and then collaboratively developed comprehensive care recommendations intended to be practical for ADT prescribers. RESULTS: The PC360 Working Group developed both overarching recommendations for ADT adverse event management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle). The working group recommends an interdisciplinary, team-based approach wherein the ADT prescriber retains an oversight role for ADT management while empowering patients and their primary and specialty care providers to manage risk factors. The PC360 recommendations also emphasize the importance of proactive patient education that involves partners or other support providers. Recommended monitoring and assessment tools, risk factor management, and patient counseling points are also included for the 5 identified domains, with an emphasis on lifestyle and behavioral interventions that can improve quality of life and reduce the risk for ADT-associated complications. CONCLUSIONS: Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, psychological health. Patient education and primary care provider involvement should begin prior to ADT initiation and continue throughout treatment to improve patient and partner quality of life.

Sexual satisfaction in prostate cancer: a multi-group comparison study of treated patients, patients under active surveillance, patients with negative biopsy, and controls.

PURPOSE: Erectile function changes after prostate cancer (PCa) treatment are well documented, but less understood is the relative impact of prostate biopsy and active surveillance on sexual well-being. It is unknown whether potential negative impacts are exclusive to patients who have been treated for PCa, or whether the diagnosis itself or the experience of biopsy may also impact sexual well-being. Sexual satisfaction is an important yet understudied indicator of sexual well-being in this population. This study examines sexual satisfaction and its predictors across several comparison groups to explore relative impact. METHODS: At baseline and 12 months, questionnaire data was collected in four samples: (1) following PCa treatment, (2) active surveillance, (3) negative prostate biopsy result, and (4) controls receiving no biopsy or treatment. Predictors assessed included group, erectile function, communication style, and partner involvement. RESULTS: Sexual satisfaction declined in the active treatment group, no changes were observed in active surveillance or non-PCa control, and improvements were observed in the biopsy group. Predictors of sexual satisfaction over and above erectile function included restrictive communication (i.e. protective buffering) and perceived partner involvement. For higher levels of erectile function, a higher perceived degree of partner involvement was protective of sexual satisfaction. CONCLUSION: Sexual satisfaction is an important indicator of sexual well-being and is negatively impacted following PCa treatment, but not active surveillance or prostate biopsy. IMPLICATIONS FOR CANCER SURVIVORS: Communication and partner involvement are potentially modifiable factors to be considered for intervention and may promote sexual satisfaction following PCa treatment. Patients experiencing negative biopsy, who note lower sexual satisfaction may experience improved satisfaction with time, and those under active surveillance who worry about sexual satisfaction may find reassurance from these results.

Increased intestinal permeability and downregulation of absorptive ion transporters Nhe3, Dra, and Sglt1 contribute to diarrhea during Clostridioides difficile infection.

BACKGROUND & AIM: Clostridioides difficile infection (CDI) is the leading cause of hospital-acquired diarrhea and pseudomembranous colitis. Two protein toxins, TcdA and TcdB, produced by C. difficile are the major determinants of disease. However, the pathophysiological causes of diarrhea during CDI are not well understood. Here, we investigated the effects of C. difficile toxins on paracellular permeability and apical ion transporters in the context of an acute physiological infection. METHODS: We studied intestinal permeability and apical membrane transporters in female C57BL/6J mice. Üssing chambers were used to measure paracellular permeability and ion transporter function across the intestinal tract. Infected intestinal tissues were analyzed by immunofluorescence microscopy and RNA-sequencing to uncover mechanisms of transporter dysregulation. RESULTS: Intestinal permeability was increased through the size-selective leak pathway in vivo during acute CDI in a 2-day-post infection model. Chloride secretory activity was reduced in the cecum and distal colon during infection by decreased CaCC and CFTR function, respectively. SGLT1 activity was significantly reduced in the cecum and colon, accompanied by ablated SGLT1 expression in colonocytes and increased luminal glucose concentrations. SGLT1 and DRA expression was ablated by either TcdA or TcdB during acute infection, but NHE3 was decreased in a TcdB-dependent manner. The localization of key proteins that link filamentous actin to the ion transporters in the apical plasma membrane was unchanged. However, Sglt1, Nhe3, and Dra were drastically reduced at the transcript level, implicating downregulation of ion transporters in the mechanism of diarrhea during CDI. CONCLUSIONS: CDI increases intestinal permeability and decreases apical abundance of NHE3, SGLT1, and DRA. This combination likely leads to dysfunctional water and solute absorption in the large bowel, causing osmotic diarrhea. These findings provide insights into the pathophysiological mechanisms underlying diarrhea and may open novel avenues for attenuating CDI-associated diarrhea.

Implementation of individually tailored treatment plans in a group-based intervention for women with mixed vulvo-vaginal and sexual health concerns following cancer treatment: A feasibility study.

PURPOSE: This study evaluated a professionally-led, group-based vulvo-vaginal and sexual health (VSH) workshop for women diagnosed with cancer. The study goals were to: (1) implement and assess a novel group intervention for diverse VSH concerns; (2) explore post-workshop changes in symptom bother, motivation to use VSH treatments, and frequency of VSH treatment use; (3) examine post-workshop changes in sexual well-being. METHODS: A group-based educational workshop to address a variety of VSH concerns was developed and implemented. During the workshop, participants created an individualized treatment plan by selecting from various VSH treatment options presented. Treatment plan follow-ups were administered online at one-, two-, and three-months post-workshop. At baseline and three-month follow-up, participants completed online questionnaires to assess self-reported vulvo-vaginal symptoms, sexual function, sexual distress, and use of VSH strategies. RESULTS: 195 participants (age 20-81) attended workshops over a 2.5-year period. Individualized treatment plans were effectively completed by most participants (92%). Preliminary results show decreases in bother severity associated with VSH concerns post-workshop, stabilizing after 2 months. At three-month follow-up, participants reported increased use of VSH treatment strategies. Sexual satisfaction, sexual distress, and emotional impact of vulvovaginal symptoms also improved. CONCLUSIONS: Workshop attendance was associated with increased uptake of VSH treatment strategies and improvements in several parameters of sexual well-being. Findings indicate that individualized treatment plans can be implemented effectively in a group setting and that a one-time, group-based educational workshop can meaningfully impact VSH-related behavior change, reduce vulvo-vaginal symptom bother and promote sexual well-being in patients with diverse VSH concerns.

Functional HIV-1/HCV cross-reactive antibodies isolated from a chronically co-infected donor.

Despite prolific efforts to characterize the antibody response to human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) mono-infections, the response to chronic co-infection with these two ever-evolving viruses is poorly understood. Here, we investigate the antibody repertoire of a chronically HIV-1/HCV co-infected individual using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq). We identify five HIV-1/HCV cross-reactive antibodies demonstrating binding and functional cross-reactivity between HIV-1 and HCV envelope glycoproteins. All five antibodies show exceptional HCV neutralization breadth and effector functions against both HIV-1 and HCV. One antibody, mAb688, also cross-reacts with influenza and coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We examine the development of these antibodies using next-generation sequencing analysis and lineage tracing and find that somatic hypermutation established and enhanced this reactivity. These antibodies provide a potential future direction for therapeutic and vaccine development against current and emerging infectious diseases. More broadly, chronic co-infection represents a complex immunological challenge that can provide insights into the fundamental rules that underly antibody-antigen specificity.

Feasibility and Acceptability of a Group-Based Mindfulness Intervention for Sexual Interest/Arousal Disorder Following Breast Cancer Treatment.

This study aimed to assess feasibility and preliminary efficacy of an 8-week Mindfulness-Based Cognitive Therapy (MBCT) group program to treat Sexual Interest/Arousal Disorder (SIAD) in women following breast cancer (BrCa) treatment. Thirty women participated, of whom 67% (n = 20) attended at least 6 of 8 group sessions. Feedback indicated the program was relevant and valuable; minor modifications were suggested to further address survivorship concerns. Results of pre-post questionnaires demonstrated significant improvements in sexual distress and sexual interest/desire, with large effect sizes. Results support the feasibility and preliminary efficacy of an 8-week MBCT program among women following breast cancer treatment.

Sidestream Smoke Extracts from Harm-Reduction and Conventional Camel Cigarettes Inhibit Osteogenic Differentiation via Oxidative Stress and Differential Activation of intrinsic Apoptotic Pathways.

Epidemiological studies suggest cigarette smoking as a probable environmental factor for a variety of congenital anomalies, including low bone mass, increased fracture risk and poor skeletal health. Human and animal in vitro models have confirmed hypomineralization of differentiating cell lines with sidestream smoke being more harmful to developing cells than mainstream smoke. Furthermore, first reports are emerging to suggest a differential impact of conventional versus harm-reduction tobacco products on bone tissue as it develops in the embryo or in vitro. To gather first insight into the molecular mechanism of such differences, we assessed the effect of sidestream smoke solutions from Camel (conventional) and Camel Blue (harm-reduction) cigarettes using a human embryonic stem cell osteogenic differentiation model. Sidestream smoke from the conventional Camel cigarettes concentration-dependently inhibited in vitro calcification triggered by high levels of mitochondrially generated oxidative stress, loss of mitochondrial membrane potential, and reduced ATP production. Camel sidestream smoke also induced DNA damage and caspase 9-dependent apoptosis. Camel Blue-exposed cells, in contrast, invoked only intermediate levels of reactive oxygen species insufficient to activate caspase 3/7. Despite the absence of apoptotic gene activation, damage to the mitochondrial phenotype was still noted concomitant with activation of an anti-inflammatory gene signature and inhibited mineralization. Collectively, the presented findings in differentiating pluripotent stem cells imply that embryos may exhibit low bone mineral density if exposed to environmental smoke during development.

Openness to Using an External Penile Prosthesis for Maintaining Sexual Intimacy by Individuals with Erectile Dysfunction: A Cross-Sectional Study.

INTRODUCTION: Erectile dysfunction (ED) can lead to reduced sexual intimacy in men. The external penile prosthesis (EPP) is a device to help them participate in penetrative sex. AIM: We investigate factors that may affect the willingness of individuals with ED to try an EPP and explore how the EPP could be presented most effectively to such patients to enhance their willingness to try an EPP. METHODS: Recruitment for this cross-sectional study occurred in-person and online. 147 participants (60.0 ± 14.3 years old; all experiencing self-reported ED) completed a survey containing both validated measures and questions specific to this study. The survey was open to English-speakers over the age of 18 who self-reported experiencing ED. MAIN OUTCOME MEASURE: The primary outcome was participants' willingness to try an EPP based on their level of knowledge about using the EPP. Secondary outcomes included the influence of the sexual function, sexual distress, ED history, age, relationship duration, sexual flexibility on willingness to try an EPP. We also collected feedback from participants' on how and where they would like to be introduced to the EPP option. RESULTS: Most participants indicated a preference for being introduced to the EPP after trying some ED treatments (51.0%). Participants did not have strong preference regarding the setting where they were informed about the EPP. The majority however preferred having a sexual health therapist/counsellor (28.6%) or physician (25.9%) as the person introducing the EPP to them. Participants' willingness to try the EPP increased with more information about the EPP presented to them (P < .001). Personalization of the EPP to match one's own penis was preferred by 38.7% of participants. Referring to this aid as an 'external penile prosthesis' was significantly more preferred over alternative labels, such as a "belted prosthetic phallus" or "strap-on dildo" (Ps < .001 for both). Multiple regression analyses showed that only sexual script flexibility was associated with the initial willingness to try an EPP (P < .01). CLINICAL IMPLICATIONS: Clinicians should consider presenting the EPP to men with ED, who desire maintaining penetrative sexual intercourse with their partners. STRENGTH AND LIMITATIONS: This is the first study to explore factors influencing the willingness to try an EPP. Further research is needed to establish the efficacy of EPPs for maintaining sexual activity and satisfaction in the real-life setting. CONCLUSION: This study informs clinicians about effective ways to introduce the EPP to patients with ED who wish to maintain insertive/receptive sex. Fu F, Duthie CJ, Wibowo E, et al. Openness to Using an External Penile Prosthesis for Maintaining Sexual Intimacy by Individuals with Erectile Dysfunction: A Cross-Sectional Study. Sex Med 2022;10:100559.

Single-cell profiling of the antigen-specific response to BNT162b2 SARS-CoV-2 RNA vaccine.

RNA-based vaccines against SARS-CoV-2 have proven critical to limiting COVID-19 disease severity and spread. Cellular mechanisms driving antigen-specific responses to these vaccines, however, remain uncertain. Here we identify and characterize antigen-specific cells and antibody responses to the RNA vaccine BNT162b2 using multiple single-cell technologies for in depth analysis of longitudinal samples from a cohort of healthy participants. Mass cytometry and unbiased machine learning pinpoint an expanding, population of antigen-specific memory CD4+ and CD8+ T cells with characteristics of follicular or peripheral helper cells. B cell receptor sequencing suggest progression from IgM, with apparent cross-reactivity to endemic coronaviruses, to SARS-CoV-2-specific IgA and IgG memory B cells and plasmablasts. Responding lymphocyte populations correlate with eventual SARS-CoV-2 IgG, and a participant lacking these cell populations failed to sustain SARS-CoV-2-specific antibodies and experienced breakthrough infection. These integrated proteomic and genomic platforms identify an antigen-specific cellular basis of RNA vaccine-based immunity.

High-Throughput B Cell Epitope Determination by Next-Generation Sequencing.

Development of novel technologies for the discovery of human monoclonal antibodies has proven invaluable in the fight against infectious diseases. Among the diverse antibody repertoires elicited by infection or vaccination, often only rare antibodies targeting specific epitopes of interest are of potential therapeutic value. Current antibody discovery efforts are capable of identifying B cells specific for a given antigen; however, epitope specificity information is usually only obtained after subsequent monoclonal antibody production and characterization. Here we describe LIBRA-seq with epitope mapping, a next-generation sequencing technology that enables residue-level epitope determination for thousands of single B cells simultaneously. By utilizing an antigen panel of point mutants within the HIV-1 Env glycoprotein, we identified and confirmed antibodies targeting multiple sites of vulnerability on Env, including the CD4-binding site and the V3-glycan site. LIBRA-seq with epitope mapping is an efficient tool for high-throughput identification of antibodies against epitopes of interest on a given antigen target.

Efficient discovery of SARS-CoV-2-neutralizing antibodies via B cell receptor sequencing and ligand blocking.

Although several monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been approved for coronavirus disease 2019 (COVID-19) therapy, development was generally inefficient, with lead generation often requiring the production and testing of numerous antibody candidates. Here, we report that the integration of target-ligand blocking with a previously described B cell receptor-sequencing approach (linking B cell receptor to antigen specificity through sequencing (LIBRA-seq)) enables the rapid and efficient identification of multiple neutralizing mAbs that prevent the binding of SARS-CoV-2 spike (S) protein to angiotensin-converting enzyme 2 (ACE2). The combination of target-ligand blocking and high-throughput antibody sequencing promises to increase the throughput of programs aimed at discovering new neutralizing antibodies.

Pelvic Organ Prolapse Takes Up Space in the Bedroom: A Mixed Method Exploration of the Circular Sexual Response Cycle in Women With Pelvic Organ Prolapse.

OBJECTIVE: Pelvic organ prolapse (POP) is a multidimensional reproductive health issue, which negatively affects women's sexual well-being. Using the circular sexual response cycle as a framework, we sought to evaluate women's sexual experiences living with POP. METHODS: Measures of genital self-image, sexual distress, sexual satisfaction, and sexual function were administered before conducting semistructured interviews. Participants were 16 heterosexual partnered women seeking surgical and nonsurgical treatment for symptomatic POP. RESULTS: Standardized questionnaires indicated normal genital self-image, sexual satisfaction, and sexual function; however, sexual distress scores exceeded normal cutoffs. Eight themes emerged, including reasons for having sex, willingness to initiate and sexual receptivity, contextual factors, sexual stimuli, sexual arousal, responsive desire, outcomes, and spontaneous sexual desire. In contrast to quantitative findings, themes demonstrated sexual difficulty. Women with POP mainly engage in sex out of obligation and report reduced sexual initiation and receptiveness, as well as a negative impact on genital self-image. Pelvic organ prolapse was perceived to adversely affect subjective arousal, responsive desire, and spontaneous desire, despite intact physiological arousal. Difficulty experiencing subjective arousal was profound and seemed to be limited by preoccupation with POP. Sexual satisfaction and rewards were diminished after POP, including orgasmic capacity. Rewarding motivators to engage in sex were seldom discussed and often overshadowed by experiencing guilt and obligation related to sex. CONCLUSIONS: The circular sexual response cycle largely fit participants' experiences; however, POP inhibits subjective arousal, which prevents responsive desire for many. Patients may need better support to cope with preoccupation with POP, indicating that addressing the psychosocial symptoms of POP should be prioritized.

Potent neutralization of SARS-CoV-2 variants of concern by an antibody with an uncommon genetic signature and structural mode of spike recognition.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages that are more transmissible and resistant to currently approved antibody therapies poses a considerable challenge to the clinical treatment of coronavirus disease (COVID-19). Therefore, the need for ongoing discovery efforts to identify broadly reactive monoclonal antibodies to SARS-CoV-2 is of utmost importance. Here, we report a panel of SARS-CoV-2 antibodies isolated using the linking B cell receptor to antigen specificity through sequencing (LIBRA-seq) technology from an individual who recovered from COVID-19. Of these antibodies, 54042-4 shows potent neutralization against authentic SARS-CoV-2 viruses, including variants of concern (VOCs). A cryoelectron microscopy (cryo-EM) structure of 54042-4 in complex with the SARS-CoV-2 spike reveals an epitope composed of residues that are highly conserved in currently circulating SARS-CoV-2 lineages. Further, 54042-4 possesses uncommon genetic and structural characteristics that distinguish it from other potently neutralizing SARS-CoV-2 antibodies. Together, these findings provide motivation for the development of 54042-4 as a lead candidate to counteract current and future SARS-CoV-2 VOCs.