Restriction of Viral Replication, Rather than T Cell Immunopathology, Drives Lethality in Murine Norovirus CR6-Infected STAT1-Deficient Mice.

Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that regulate the virome remain largely unknown. In this study, we used colonization with the model commensal murine norovirus (MNV; strain CR6) to interrogate host-directed mechanisms of viral regulation, and we show that STAT1 is a central coordinator of both viral replication and antiviral T cell responses. In addition to restricting CR6 replication to the intestinal tract, we show that STAT1 regulates antiviral CD4+ and CD8+ T cell responses and prevents systemic viral-induced tissue damage and disease. Despite altered T cell responses that resemble those that mediate lethal immunopathology in systemic viral infections in STAT1-deficient mice, depletion of adaptive immune cells and their associated effector functions had no effect on CR6-induced disease. However, therapeutic administration of an antiviral compound limited viral replication, preventing virus-induced tissue damage and death without impacting the generation of inflammatory antiviral T cell responses. Collectively, our data show that STAT1 restricts MNV CR6 replication within the intestinal mucosa and that uncontrolled viral replication mediates disease rather than the concomitant development of dysregulated antiviral T cell responses in STAT1-deficient mice. IMPORTANCE The intestinal microbiota is a collection of bacteria, archaea, fungi, and viruses that colonize the mammalian gut. Coevolution of the host and microbiota has required development of immunological tolerance to prevent ongoing inflammatory responses against intestinal microbes. Breakdown of tolerance to bacterial components of the microbiota can contribute to immune activation and inflammatory disease. However, the mechanisms that are necessary to maintain tolerance to viral components of the microbiome, and the consequences of loss of tolerance, are less well understood. Here, we show that STAT1 is integral for preventing escape of a commensal-like virus, murine norovirus CR6 (MNV CR6), from the gut and that in the absence of STAT1, mice succumb to infection-induced disease. In contrast to the case with other systemic viral infections, mortality of STAT1-deficient mice is not driven by immune-mediated pathology. Our data demonstrate the importance of host-mediated geographical restriction of commensal-like viruses.

Sexual rehabilitation recommendations for prostate cancer survivors and their partners from a biopsychosocial Prostate Cancer Supportive Care Program.

PURPOSE: This study aimed to highlight the biopsychosocial recommendations provided to prostate cancer survivors and their partners during sexual rehabilitation. METHODS: Retrospective analysis of a prospectively maintained patient database was conducted for visits between 2013 and 2019. The sexual health rehabilitation action plan (SHRAP) is a standardized 29-item list of biopsychosocial recommendations. The frequency of biopsychosocial recommendations provided to patients via their SHRAPs was assessed. RESULTS: Among 913 patients, across 2671 appointments, nearly 74% of patients underwent radical prostatectomy. Other treatments included combination therapy (surgery, radiation, and/or androgen deprivation therapy (ADT)) (13%), radiation (external beam radiation or brachytherapy) (5%), and active surveillance (2%). Each patient had a median of 2 (SD 2.06) appointments and received a mean of 10.0 (SD 3.9) recommendations at each visit. Educational recommendations (penile rehabilitation, orgasmic guidelines, and climacturia management) were provided in 84% of visits followed by psychosexual recommendations (pleasure-focused, dedicated time, simmering, sexual aids, and sensate focus) in 71% of all appointments. The top recommendations (total n, frequency of recommendation) were penile rehabilitation (2253, 84%), pleasure-focus (1887, 71%), phosphodiesterase inhibitors (1655, 62%), clinical counselor (1603, 60%), vacuum erectile device (1418, 53%) and intracavernosal injections (1383, 52%). CONCLUSIONS: Biopsychosocial programs are evolving to be a key part of prostate cancer survivorship. This study's insight suggests that prostate cancer survivors require education around their sexual consequences and psychosexual counseling alongside proven biomedical strategies for erectile dysfunction. IMPLICATIONS FOR CANCER SURVIVORS: Cancer survivorship programs should integrate educational and psychosocial strategies alongside biological strategies for prostate cancer survivors and their partners.

The effects of Y chromosome microdeletions on in vitro fertilization outcomes, health abnormalities in offspring and recurrent pregnancy loss.

Male factor infertility accounts for approximately 50% of all infertility evaluations. A common cause of severe oligozoospermia and azoospermia is Y chromosome microdeletions (YCMs). Men with these genetic microdeletions must typically undergo assisted reproductive technology (ART) procedures to obtain paternity. In this review, we performed a thorough and extensive search of the literature to summarize the effects of YCMs on in vitro fertilization (IVF) outcomes, health abnormalities in offspring and recurrent pregnancy loss (RPL). The PubMed database was searched using specific search terms and papers were identified using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Sperm retrieval amongst men with complete AZFa and/or AZFb deletions is extremely rare and thus data on ARTs is largely unavailable. In AZFc-deleted men undergoing assisted reproduction, the collective fertilization rate (FR) is 59.8%, the clinical pregnancy rate is 28.6% and the live birth rate is 23.4%. When successful, the YCM is always transmitted to the male offspring and the deletion size either remains unchanged or widens. YCMs generally result in decreased fertilization, clinical pregnancy and live birth rates compared to men with intact Y chromosomes during ART interventions. There is a minimal or absent association of YCMs with abnormalities in the offspring or RPL.

Histology and sperm retrieval among men with Y chromosome microdeletions.

In this review of Y chromosome microdeletions, azoospermia factor (AZF) deletion subtypes, histological features and microTESE sperm retrieval rates are summarized after a systematic literature review. PubMed was searched and papers were identified using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Approximately half of infertile couples have a male factor contributing to their infertility. One of the most common genetic etiologies are Y chromosome microdeletions. Men with Y chromosome microdeletions may have rare sperm available in the ejaculate or undergo surgical sperm retrieval and subsequent intracytoplasmic sperm injection to produce offspring. Azoospermia or severe oligozoospermia are the most common semen analysis findings found in men with Y chromosome microdeletions, associated with impaired spermatogenesis. Men with complete deletions of azoospermia factor a, b, or a combination of any loci have severely impaired spermatogenesis and are nearly always azoospermic with no sperm retrievable from the testis. Deletions of the azoospermia factor c or d often have sperm production and the highest likelihood of a successful sperm retrieval. In men with AZFc deletions, histologically, 46% of men demonstrate Sertoli cell only syndrome on biopsy, whereas 38.2% have maturation arrest and 15.7% have hypospermatogenesis. The microTESE sperm retrieval rates in AZFc-deleted men range from 13-100% based on the 32 studies analyzed, with a mean sperm retrieval rate of 47%.

Clinic Utilization and Characteristics of Patients Accessing a Prostate Cancer Supportive Care Program's Sexual Rehabilitation Clinic.

Prostate cancer (PC) treatment leads to impairment of sexual function. The Prostate Cancer Supportive Care (PCSC) Program's Sexual Rehabilitation clinic (SRC) assists patients and their partners with sexual recovery using a biopsychosocial approach to rehabilitation. This study characterizes patients seen in the SRC between July 2013-1 July 2019. Data was retrospectively abstracted from clinic records. In total, 965 patients were seen over 3391 appointments during the study period. Median age (standard deviation (SD)) was 66 years (SD = 7.1), 82.0% were partnered, yet 81.7% attended appointments alone. 88.0% were treated with surgery, 5.1% with brachytherapy, 3.7% with external beam radiation (EBRT), 1.8% with combined brachytherapy and EBRT, and 1.4% with androgen deprivation therapy. In total, 708 patients (73.4%) attended ≥1 follow-up appointment. Median time (SD) between end of prostate cancer treatment to first SRC appointment was 270 days (range 0-7766). The mean (SD) self-reported overall sexual satisfaction (extracted from International Index of Erectile Function-5 (IIEF-5)) significantly increased both with erectile aids (1.69 (SD = 1.52) to 2.26 (SD = 1.66), p < 0.001, n = 148) and without erectile aids (1.71 (SD = 1.44) to 2.35 (SD = 1.57), p < 0.001, n = 235). This study provides guidance for further investigation to refine treatment, wait-times, support, and/or resource offerings in this type of program.