Fosfomycin Trometamol for the Prevention of Infectious Complications After Prostate Biopsy: A Consensus Statement by an International Multidisciplinary Group.

CONTEXT: Transrectal ultrasound-guided prostate biopsy (TRPB) has been a standard of care for diagnosing prostate cancer but is associated with a high incidence of infectious complications. OBJECTIVE: To achieve an expert consensus on whether fosfomycin trometamol provides adequate prophylaxis in TRPB and discuss its role as prophylaxis in transperineal prostate biopsy (TPPB). EVIDENCE ACQUISITION: An international multidisciplinary group of experts convened remotely to discuss how to best use fosfomycin in various clinical settings and patient situations. Six statements related to prostate biopsy and the role of fosfomycin were developed, based on literature searches and relevant clinical experience. EVIDENCE SYNTHESIS: Consensus was reached for all six statements. The group of experts was unanimous regarding fosfomycin as a preferred candidate for antimicrobial prophylaxis in TRPB. Fosfomycin potentially also meets the requirements for empiric prophylaxis in TPPB, although further clinical studies are needed to confirm or refute its utility in this setting. There is a risk of bias due to sponsorship by a pharmaceutical company. CONCLUSIONS: Antimicrobial prophylaxis is mandatory in TRPB, and fosfomycin trometamol is an appropriate candidate due to low rates of resistance, a good safety profile, sufficient prostate concentrations, and demonstrated efficacy in reducing the risk of infectious complications following TRPB. PATIENT SUMMARY: Patients undergoing transrectal ultrasound-guided prostate biopsy (TRPB) have a high risk of infectious complications, and antimicrobial prophylaxis is mandatory. However, increasing antimicrobial resistance, as well as safety concerns with fluoroquinolones, has restricted the number of antimicrobial options. Fosfomycin trometamol meets the requirements for a preferred antimicrobial in the prophylaxis of TRPB.

The human memory T cell compartment changes across tissues of the female reproductive tract.

Memory CD4 T cells in tissues fulfill numerous functions that are critical for local immune homeostasis and protection against pathogens. Previous studies have highlighted the phenotypic and functional heterogeneity of circulating and tissue-resident memory CD4 T cells across different human tissues such as skin, lung, liver, and colon. Comparatively little is known in regard to memory CD4 T cells across tissues of the female reproductive tract (FRT). We examined CD4 T cells in donor-matched vaginal, ecto- and endocervical tissues, which differ in mucosal structure and exposure to external environmental stimuli. We hypothesized that this could be reflected by tissue-specific differences in the memory CD4 T cell compartment. We found differences in CD4 subset distribution across these tissues. Specifically, CD69+CD103+ CD4 T cells were significantly more abundant in vaginal than cervical tissues. In contrast, the transcriptional profiles of CD4 subsets were fairly conserved across FRT tissues. CD69+CD103+ CD4 T cells showed a TH17 bias independent of tissue niche. Our data suggest that FRT tissues affect T cell subset distribution but have limited effects on the transcriptome of each subset. We discuss the implications for barrier immunity in the FRT.

Mechanisms of Endogenous HIV-1 Reactivation by Endocervical Epithelial Cells.

Pharmacological HIV-1 reactivation to reverse latent infection has been extensively studied. However, HIV-1 reactivation also occurs naturally, as evidenced by occasional low-level viremia ("viral blips") during antiretroviral treatment (ART). Clarifying where blips originate from and how they happen could provide clues to stimulate latency reversal more effectively and safely or to prevent viral rebound following ART cessation. We studied HIV-1 reactivation in the female genital tract, a dynamic anatomical target for HIV-1 infection throughout all disease stages. We found that primary endocervical epithelial cells from several women reactivated HIV-1 from latently infected T cells. The endocervical cells' HIV-1 reactivation capacity further increased upon Toll-like receptor 3 stimulation with poly(I·C) double-stranded RNA or infection with herpes simplex virus 2 (HSV-2). Notably, acyclovir did not eliminate HSV-2-induced HIV-1 reactivation. While endocervical epithelial cells secreted large amounts of several cytokines and chemokines, especially tumor necrosis factor alpha (TNF-α), CCL3, CCL4, and CCL20, their HIV-1 reactivation capacity was almost completely blocked by TNF-α neutralization alone. Thus, immunosurveillance activities by columnar epithelial cells in the endocervix can cause endogenous HIV-1 reactivation, which may contribute to viral blips during ART or rebound following ART interruption.IMPORTANCE A reason that there is no universal cure for HIV-1 is that the virus can hide in the genome of infected cells in the form of latent proviral DNA. This hidden provirus is protected from antiviral drugs until it eventually reactivates to produce new virions. It is not well understood where in the body or how this reactivation occurs. We studied HIV-1 reactivation in the female genital tract, which is often the portal of HIV-1 entry and which remains a site of infection throughout the disease. We found that the columnar epithelial cells lining the endocervix, the lower part of the uterus, are particularly effective in reactivating HIV-1 from infected T cells. This activity was enhanced by certain microbial stimuli, including herpes simplex virus 2, and blocked by antibodies against the inflammatory cytokine TNF-α. Avoiding HIV-1 reactivation could be important for maintaining a functional HIV-1 cure when antiviral therapy is stopped.

A pro-inflammatory CD8+ T-cell subset patrols the cervicovaginal tract.

The immune system of the cervicovaginal tract (CVT) must balance immunosurveillance and active immunity against pathogens with maintenance of tolerance to resident microbiota and to fetal and partner antigens for reproductive purposes. Thus, we predicted that CVT immunity is characterized by distinctive features compared to blood and other tissue compartments. Indeed, we found that CVT CD8+ T-cells had unique transcriptional profiles, particularly in their cytokine signature, compared to that reported for CD8+ T-cells in other tissue sites. Among these CVT CD8+ T-cells, we identified a CD69- CD103- subset that was characterized by reduced migration in response to tissue-exit signals and higher pro-inflammatory potential as compared to their blood counterpart. These inflammatory mucosal CD8+ T-cells (Tim) were increased in frequency in the CVT of individuals with chronic infection, pointing to a potential role in perpetuating inflammation. Our findings highlight the specialized nature of immunity within the CVT and identify Tim cells as potential therapeutic targets to tame tissue inflammation upon chronic infection.

Cryopreservation of human mucosal tissues.

BACKGROUND: Cryopreservation of leukocytes isolated from the cervicovaginal and colorectal mucosa is useful for the study of cellular immunity (see Hughes SM et al. PLOS ONE 2016). However, some questions about mucosal biology and sexually transmitted infections are better addressed with intact mucosal tissue, for which there is no standard cryopreservation protocol. METHODS AND FINDINGS: To find an optimal preservation protocol for mucosal tissues, we tested slow cooling (1°C/min) with 10% dimethylsulfoxide (designated "cryopreservation") and fast cooling (plunge in liquid nitrogen) with 20% dimethylsulfoxide and 20% ethylene glycol ("vitrification"). We compared fresh and preserved human cervicovaginal and colorectal tissues in a range of assays, including metabolic activity, human immunodeficiency virus infection, cell phenotype, tissue structure by hematoxylin-and-eosin staining, cell number and viability, production of cytokines, and microbicide drug concentrations. Metabolic activity, HIV infectability, and tissue structure were similar in cryopreserved and vitrified vaginal tissues. However, vitrification led to poor cell recovery from the colorectal mucosa, with 90% fewer cells recovered after isolation from vitrified colorectal tissues than from cryopreserved. HIV infection rates were similar for fresh and cryopreserved ectocervical tissues, whereas cryopreserved colorectal tissues were less easily infected than fresh tissues (hazard ratio 0.7 [95% confidence interval 0.4, 1.2]). Finally, we compared isolation of cells before and after cryopreservation. Cell recoveries were higher when cells were isolated after freezing and thawing (71% [59-84%]) than before (50% [38-62%]). Cellular function was similar to fresh tissue in both cases. Microbicide drug concentrations were lower in cryopreserved explants compared to fresh ones. CONCLUSIONS: Cryopreservation of intact cervicovaginal and colorectal tissues with dimethylsulfoxide works well in a range of assays, while the utility of vitrification is more limited. Cell yields are higher from cryopreserved intact tissue pieces than from thawed cryopreserved single cell suspensions isolated before freezing, but T cell functions are similar.

Training surgical residents: the current Canadian perspective.

BACKGROUND: Numerous constraints may limit the practical experience of surgical residents. Current research supports a need for structured curricula, skills acquisition, and feedback outside the operating room (OR) and formal assessment of technical skills. We examined the current state of surgical skill teaching and evaluation for Canadian residents across surgical specialties. METHODS: One hundred twenty-three surveys were mailed to surgical residency program directors of all 17 Canadian medical schools. Nine surgical specialties were identified. Program demographics, details of surgical skill teaching methods, and several surgical skill assessment modalities used from admission to graduation were surveyed. Obstetrics and Gynecology (ObGyn) survey results were compared with other surgical specialties. RESULTS: Seventy surveys (57%) from 15 medical schools (88%) were returned. All specialties were represented in responses. ObGyn residents had fewer surgical training months per year than other residents (4.9 versus 8.5 months; p = 0.001). The most common teaching method was didactic lectures (86%; 95% confidence interval [CI], 75%-93%) for all programs. Inanimate and/or animate skills laboratories and didactic lectures were equally used by 90% (95% CI, 55%-100%) of ObGyn programs. Virtual reality simulators for procedure-specific surgical skills ranked low at 30% (95% CI, 7%-65%) use in ObGyn programs. Most programs had a dedicated space to teach and practice skills outside the OR. Assessment, feedback, and determination of surgical competence were most commonly performed via subjective evaluation by surgical mentors. Forty percent of ObGyn programs versus 76% of other programs used a local program-specific surgical training curriculum (p = 0.054). Most program directors who did not have access to a standard training curriculum wished to have one implemented. CONCLUSIONS: Lectures and subjective evaluations are the most common educational tools in Canadian surgical residencies. Despite the availability of validated surgical teaching and evaluation tools remote from the OR, standard training curricula are not the norm in Canadian ObGyn residency programs.

A psychoeducational intervention for sexual dysfunction in women with gynecologic cancer.

Treatment of early-stage cervical and endometrial cancer has been associated with significant sexual difficulties in at least half of women following hysterectomy. Despite the fact that women report such sexual side effects to be the most distressing aspect of their cancer treatment, evidence-based treatments for Female Sexual Arousal Disorder (FSAD), the most common sexual symptom in this group, do not exist. We developed and pilot tested a brief, three session psychoeducational intervention (PED) targeting FSAD in 22 women with early-stage gynecologic cancer. The PED consisted of three, 1-h sessions that combined elements of cognitive and behavioral therapy with education and mindfulness training. Women completed questionnaires and had a physiological measurement of genital arousal at pre- and post-PED (sessions 1 and 4) and participated in a semi-structured interview (session 4) during which their feedback on the PED was elicited. There was a significant positive effect of the PED on sexual desire, arousal, orgasm, satisfaction, sexual distress, depression, and overall well-being, and a trend towards significantly improved physiological genital arousal and perceived genital arousal. Qualitative feedback indicated that the PED materials were very user-friendly, clear, and helpful. In particular, women reported the mindfulness component to be most helpful. These findings suggest that a brief 3-session PED can significantly improve aspects of sexual response, mood, and quality of life in gynecologic cancer patients, and has implications for establishing the components of a psychological treatment program for FSAD.

A comprehensive women's health care center: are gynecologists offering primary care?

OBJECTIVE: The purpose of this study was to compare patient characteristics and diagnoses in a comprehensive Women's Health Care Clinic between gynecologists and internal medicine physicians. STUDY DESIGN: This retrospective cohort study evaluated International Classification of Diseases, 9th Revision, codes that were recorded between January 1, 2001, and January 4, 2004, at the Women's Health Care Clinic. We compared demographics and prevalence of diagnosis codes for patients who were seen by obstetricians/gynecologists and internal medicine physicians and compared these data with national survey statistics. A sampling of charts was reviewed for coding verification. RESULTS: We analyzed 13,462 visits at the Women's Health Care Clinic. Patients who were seen by internists were older, had greater racial diversity, and had more gender-nonspecific medical disorders (hypertension, depression). Gynecologists saw more specific women's health problems (P < .05). The diagnoses of menstrual disorders, menopause, pelvic pain, and abnormal cytologic findings within the Women's Health Care Clinic follow closely with the national ambulatory survey data. CONCLUSION: Within this multispecialty Women's Health Care Clinic, internal medicine physicians are practicing primary care and obstetricians/gynecologists are providing specialty care.

A six-year study of surgical teaching and skills evaluation for obstetric/gynecologic residents in porcine and inanimate surgical models.

OBJECTIVE: This study was undertaken to evaluate an ongoing teaching and objective surgical skills testing program for obstetric/gynecologic residents in a laboratory setting, and assess the impact on residents of having 4 years of a surgical laboratory curriculum. STUDY DESIGN: From 1997 through 2002, we conducted surgical skills training sessions for all obstetric/gynecologic residents, using both inanimate and animal (porcine) models. Once a year we tested each resident on 12 structured surgical bench tasks. At the end of each year, we conducted formal objective structured assessment of technical skills (OSATS) with all residents attempting multiple surgical procedures. We compared residents who had 4 years of laboratory training with those who started residency earlier and had only 1 or 2 years of the new curriculum. We also compared residents' own performance from year to year and cohort performance by resident year. RESULTS: PGY3 and PGY4s who had 4 years of surgical laboratory training did significantly better on bench laboratory skills than PGY3 and PGY4s with fewer years of training sessions (total scores of 48.8 vs 30.3, P < .001). However, no significant improvement in surgical procedures as measured by global OSATS was found. When comparing residents' own performance between the beginning and the end of 1 year, global OSATS scores improved significantly on laparoscopic salpingotomy (P < .001) and open oophorectomy (P < .001). For the cohort of PGY4s completing 4 years of laboratory training, average global OSATS scores showed statistically significant improvement (PGY1, PGY2 < PGY3 < PGY4, P < .001). CONCLUSION: Residents who completed the 4-year curriculum showed significantly better technical skills on bench tasks but not on OSATS compared with those with less training. Resident surgical skills evaluated by OSATS significantly improve over time both individually and as a cohort by resident year.

Self-assessment of resident surgical skills: is it feasible?

OBJECTIVE: The purpose of this study was to examine obstetrics and gynecology residents' self-assessment of proficiency on a variety of surgical bench procedures and to compare their ratings with those ratings of trained faculty observers who used instruments that have been shown to be reliable and valid. STUDY DESIGN: As part of a 6-station Objective Structured Assessment of Technical Skills, 74 residents at 5 institutions estimated their overall open and laparoscopic skill level before the testing. After completing each station, residents evaluated their overall and global skills performance. RESULTS: Residents rated their proficiency higher on open skills than on laparoscopic skills. Task-specific, overall, and global assessments were correlated significantly with the faculty ratings (P < .001). Residents tended to rate themselves lower than did faculty on almost all measures; even those residents with poor skills indicated that they were aware of their deficiencies. Overall and global self-assessments increased with each resident level, which indicated good construct validity. CONCLUSION: Residents can rate their overall open and laparoscopic skills, task-specific performance, and global skills with good reliability and validity. Although they tended to score themselves lower than did faculty observers, the correlations are high (ie, residents who give themselves a higher score tended to receive a higher score from faculty, and vice versa). One of the concerns about self-assessment is that residents with poor skills might not be aware of their deficiencies. We did not find that to be the case. Therefore, when residents work on self-directed exercises, task-specific and global checklists can be used for both learning and self-assessment.

Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms.

The repeat region of DC-SIGNR (CD209L) is polymorphic on the genomic level, and, in a separate study, we observed a correlation between the DC-SIGNR genotype and HIV-1 susceptibility during sexual contact. However, previous investigations using immunohistochemistry failed to detect membrane-bound DC-SIGNR on cells in the genital and rectal mucosa. We therefore explored the presence of DC-SIGNR in these compartments with a more sensitive limiting dilution RT-PCR, which also allowed for quantification of alternatively spliced mRNA isoforms. DC-SIGN (CD209) and DC-SIGNR mRNA transcript isoforms were found in all 12 vaginal and two rectal biopsies obtained from 14 healthy individuals. For DC-SIGNR, we detected significantly more isoform than full-length transcripts (mean copy numbers/mug RNA: 602 vs 26; P=0.0009). Four mucosal samples lacked full-length DC-SIGNR transcripts entirely. Cloning and sequencing of DC-SIGNR mRNA in three additional individuals revealed a diverse repertoire of DC-SIGNR isoforms, many of which encoded for proteins predicted to be soluble and secreted. Indeed, in one vaginal sample, we detected only soluble isoforms. In conjunction with our prior observation that the DC-SIGNR genotype has an effect on HIV-1 transmission in vivo, these findings emphasize that DC-SIGNR, in addition to DC-SIGN, should be considered as a cofactor in sexual HIV-1 transmission. Soluble isoforms, in particular, may modulate the efficiency of viral transmission and dissemination.

Complications from transvaginal pubovaginal slings using bone anchor fixation.

OBJECTIVES: To evaluate the history and management of complications from transvaginally placed pubovaginal slings using bone anchor fixation. METHODS: During a 3-year period, 10 patients were referred to us for complications related to transvaginally placed pubovaginal slings using bone anchor fixation. RESULTS: The patient age ranged from 42 to 73 years. All women had a vaginally introduced bone anchor sling for stress urinary incontinence. The presenting symptoms after surgery included fever, pain, and difficulty ambulating in 1; pain and/or vaginal dyspareunia with discharge in 5; pain or dyspareunia alone in 2; and vaginal discharge alone in 2 patients. Two patients ultimately developed bone lesions on radiologic studies consistent with osteomyelitis. Six patients developed sinus drainage tracts associated with granulation tissue from at least one bone anchor that was unresponsive to outpatient management. One of the patients with pain alone had a permanent suture extending into the bladder neck. Nine patients underwent surgery, of whom five had resolution of their presenting complaint. Four of these patients were continent at last follow-up. CONCLUSIONS: Transvaginally placed pubovaginal slings using bone anchors can be associated with serious complications that may be intractable to common therapies. This knowledge may enable practitioners who use this technique to better counsel their patients regarding these significant complications.

Relationship between patient report and physician assessment of urinary incontinence severity.

OBJECTIVE: The purpose of this study was to determine the relationship between patient report and physician assessment of urinary incontinence severity and to compare these assessments to a validated severity instrument. STUDY DESIGN: A sequential sample of 153 women with urinary incontinence was enrolled over 12 months. Patients completed a detailed health questionnaire that included a medical comorbidity scale, 12-item short-form health survey (SF-12) the incontinence quality of life instrument, the PRIME-MD patient health questionnaire, and a patient incontinence severity assessment. The patient incontinence severity assessment is a single question that asks the patient to rate the severity of her incontinence symptoms on a 5-point Likert scale (range: 1 [mild] to 5 [severe]). After the physicians completed a detailed history, a physical examination, and a review of a 3-day voiding diary, they assigned a physician incontinence severity assessment score. The physician incontinence severity assessment is a physician rating of the severity of the patient's incontinence on a 5-point Likert scale (range: 1 [mild] to 5 [severe]). A validated severity index was computed and used for comparison. This is a multiplicative index that is based on frequency (4 levels) and amount of leakage (2 levels), which yields an index value of 1 to 8. Spearman correlation coefficients were calculated for patient incontinence severity assessment, the physician incontinence severity assessment scores, and the severity index values. Chi-square tests were used to determine differences between patient incontinence severity assessment and physician incontinence severity assessment ratings. RESULTS: Spearman correlation coefficients for patient incontinence severity assessment and physician incontinence severity assessment were 0.62 (P <.001), for patient incontinence severity assessment and the severity index was 0.61 (P <.001), and for physician incontinence severity assessment and the severity index was 0.66 (P <.001). Agreement between patient assessment and physician assessment for different severity levels on the patient incontinence severity assessment and physician incontinence severity assessment are provided. CONCLUSION: There is a high correlation between patient report and physician assessment of urinary incontinence severity. Both patient reports (patient incontinence severity assessment) and physician assessments (physician incontinence severity assessment) correlate well with a validated severity index. The agreement between patient and physician ratings is very high for mild incontinence but decreases as incontinence severity progresses.

Posterior vaginal wall defects and their relation to measures of pelvic floor neuromuscular function and posterior compartment symptoms.

OBJECTIVE: The purpose of this study was to describe the pelvic floor neuromuscular function and posterior compartment symptoms in patients with posterior vaginal wall prolapse. STUDY DESIGN: Two hundred twenty-seven women who were referred to a urogynecology and urology clinic were enrolled prospectively. Each patient completed a health history questionnaire and standardized physical examination that specifically graded uterovaginal prolapse according to the pelvic organ prolapse quantification system. RESULTS: Sixty-nine women had a pelvic organ prolapse quantification system point (most dependent portion of the posterior vaginal wall during straining as measured from the hymeneal ring) of < or =-1. Older age, a history of hysterectomy, a genital hiatus of >3 cm (48% vs 24%; P =.002), and perineal descent of > or =2 cm (14% vs 5%; P =.042) were significantly more common in women with posterior vaginal prolapse. When women with posterior prolapse and symptomatic complaints were compared with asymptomatic women with prolapse, a perineal descent of > or =2 cm (21% vs 0%; P =.004) was significantly more common in the symptomatic group. CONCLUSION: Pelvic floor neuromuscular function should be related to posterior vaginal prolapse and symptoms; however, only perineal descent appears associated strongly with both symptoms and prolapse in this population.

Hormonal manipulation in women with chronic, cyclic irritable bladder symptoms and pelvic pain.

OBJECTIVE: Chronic, painful bladder symptoms are diagnostic and therapeutic challenges for urologists and gynecologists. The aims of this study were to evaluate women with menstrual cycle-related changes in their interstitial cystitis symptoms, to treat them with hormonal manipulation, and to follow them long term. STUDY DESIGN: The cases of women who were referred to a tertiary care center with interstitial cystitis and menstrual cycle exacerbation of symptoms were evaluated in a retrospective study. Fifteen women had undergone laparoscopy that was followed immediately by cystoscopy and bladder hydrodistension. Patients were then treated with leuprolide acetate or oral contraceptive pills. RESULTS: Patient age ranged from 23 to 48 years. The duration of symptoms ranged from 1 to 26 years. Ten patients (67%) had findings of both interstitial cystitis and peritoneal endometriosis. Five of 15 patients (33%) had interstitial cystitis, but no endometriosis was found. Symptoms improved for 8 of 9 women who were treated with leuprolide acetate and for 5 of 6 women who were treated with oral contraceptive pills. Patients were followed up for an average of 55 months. CONCLUSION: Diagnostic laparoscopy should be considered together with hydrodistension of the bladder for women with pelvic pain and irritative bladder symptoms that are exacerbated premenstrually. Endometriosis is often present in patients with these complex symptoms. This is the first report of hormonal treatment for chronic, cyclic irritative bladder symptoms; improvement appears to occur even when endometriosis is not identified by laparoscopy.

Surgical skills assessment: a blinded examination of obstetrics and gynecology residents.

OBJECTIVE: We have previously shown that objective structured assessment of technical skills (OSATS) is an innovative, reliable, and valid method of assessing surgical skills. Our goal was to establish the feasibility, reliability, and validity of our surgical skills assessment instrument when administered in a blinded fashion. STUDY DESIGN: A 7-station OSATS was administered to 16 obstetric and gynecology residents from Madigan Army Medical Center. The test included laparoscopic (salpingostomy, intracorporeal knot, and ligation of vessels with clips) and open abdominal procedures (subcuticular closure, bladder neck suspension, enterotomy repair, and abdominal wall closure). All tasks were performed with lifelike surgical models. Residents were timed and assessed at each station with 3 methods of scoring: task-specific checklist, global rating scale, and pass/fail grade. Each resident was evaluated by one examiner blinded as to the postgraduate year level and one examiner who had previously worked with the resident. RESULTS: Assessment of construct validity (the ability to distinguish between resident levels) found significant differences on the checklist, global rating scale, and pass/fail grade by residency level for both blinded and unblinded examiners. Reliability indices calculated with Cronbach's alpha were.82 for the checklists and.93 for the global rating scale. Overall interrater reliability between blinded and unblinded examiners was 0.95 for global rating scale and ranged from 0.74 to 0.97 for the checklists. The cost to administer the exam for the 16 residents was approximately $1000. CONCLUSIONS: OSATS administered in either a blinded or unblinded fashion can assess residents' surgical skills with a high degree of reliability and validity. This study provides further evidence that OSATS can be used to establish surgical competence.