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.

Washington State Surgeon Perspectives on Quality Measures in the Surgical Care of Stress Urinary Incontinence in Women.

INTRODUCTION: No consensus exists on outcomes that define high quality care in female stress urinary incontinence management. A working group of surgeons from diverse health care settings in Washington State who treat stress urinary incontinence was convened through a state level quality collaborative. Preliminary questions were developed and focus groups conducted to obtain surgeon input and perspectives on stress urinary incontinence surgery quality measures to guide future research. METHODS: Washington State surgeons who perform sling surgery were recruited via email. Focus groups were convened via teleconference using preliminary questions as discussion points. Participants were surgeons from a variety of locations and practice types. Focus groups were led by a trained moderator, recorded and transcribed verbatim, and qualitatively analyzed using inductive content analysis. RESULTS: Eight urologists and 6 gynecologists from 5 academic, 4 private practice and 5 hospital based settings participated in 3 focus groups. The 4 emergent concepts derived, were a perceived need to individualize rather than standardize the management approach to recurrent and persistent stress urinary incontinence, a need to establish and validate shared decision making tools for synthetic mesh procedures, a need to define risk factors and treatment strategies for unique populations, including those with mixed urinary incontinence, younger patients and those with concomitant prolapse, and an enthusiasm to identify practical and clinically meaningful quality measures. CONCLUSIONS: Focus groups with clinical experts on quality of stress urinary incontinence care identified several priority topics for future study. Further work is needed to refine research prioritization on this important area of women's health.

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.

Stress Urinary Incontinence Surgery in Washington State Before and After Introduction of the Mesh Midurethral Sling.

OBJECTIVES: Mesh midurethral slings (MUSs) are safe, effective treatments for female stress urinary incontinence (SUI), but many companies have ceased production because of controversies surrounding transvaginal mesh. To determine if introduction of MUS has increased the complication rate associated with SUI surgery, we compared women undergoing SUI surgery in the MUS era to those who had surgery prior its introduction. METHODS: This was a retrospective cohort study of a statewide hospital discharge database. Stress urinary incontinence surgeries from 1987 to 1996 and 2007 to 2013 were identified using International Classification of Diseases, Ninth Revision codes. RESULTS: A total of 30,723 SUI surgeries were performed during the study periods. After 2006, slings accounted for 91.8% of SUI surgeries. Patients were older (54.5 vs 53.0 years, P < 0.001) and sicker (22.6% vs 9.7% had ≥1 comorbid condition, P < 0.0001). Blood transfusion was more common in the MUS era (1.2% vs 0.4%, P < 0.001) however, other complications were either similar between groups or less common in the MUS era including 30-day readmission (2.5% vs 2.4%, P = 0.543), reoperation for urinary retention (0.1% vs 0.2%, P < 0.0375), and wound infection (0.1% vs 0.5%, P < 0.001), despite more concomitant prolapse surgeries (69.0 vs 26.9%, P < 0.001) and hysterectomies (53.0 vs 35.4%, P < 0.001) in the MUS era. Hospital stays were shorter after 2006 (1.0 vs 3.0 days, P < 0.001), and fewer women required reoperation for SUI within 2 years (0.5% vs 1.8%, P < 0.001). CONCLUSIONS: Following introduction of MUS, women who underwent SUI surgery were slightly older with more medical comorbidities yet did not appear to experience increased surgical complications. Fewer women underwent reoperation for recurrent SUI, and hospital stays were shorter, suggesting an improvement in care. This study supports the continued availability and use of MUSs.

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.

Provision of Reproductive Healthcare to Women with Disabilities: A Survey of Obstetrician-Gynecologists' Training, Practices, and Perceived Barriers.

Purpose: The purpose of this study was to document current awareness, attitudes, and training regarding the care of women with disabilities by obstetrician-gynecologists (ob-gyns) and explore barriers that may explain observed discrepancies in care. Methods: One thousand ob-gyns, including 500 members of the Collaborative Ambulatory Research Network (CARN), were surveyed on practice accessibility, training, awareness, barriers, beliefs, comfort, challenges, practices, contraceptive counseling, and preconception/pregnancy counseling. Results: CARN, 49.0%, and non-CARN, 19.4%, members completed the survey for an overall response rate of 33.9%. Most respondents indicated feeling "somewhat" (57.5%) or "very" (21.9%) aware of the special healthcare needs of women with disabilities. Only 17.2%, however, received any information or training on the provision of healthcare to women with disabilities. Eighty-one percent agreed somewhat or strongly that women with disabilities are less likely to receive comprehensive reproductive healthcare. Respondents who provided contraceptive counseling (94.3%) initiated it with women of reproductive age who did not have a disability more frequently than those who had a disability. Finally, only 19.3% felt "definitely" adequately equipped to manage the pregnancies of women with disabilities. Conclusion: Women with disabilities require reproductive healthcare no less than women without disabilities; however, the evidence consistently identifies disparities. This study suggests that while ob-gyn providers are aware of these issues, they lack adequate training and resources to provide equal care.

Benefits and Barriers to Teaching Medical Students in an Ob-Gyn Clinic.

INTRODUCTION: As the US health-care system has evolved over the past decade, access to obstetric care in rural communities has declined, and there has been a challenge in retaining obstetrics and gynecology (OB-GYN) providers to train the next generation of physicians. The current pilot study sought to identify the factors that influence faculty who train medical students within the field of OB-GYN with the hope of influencing recruitment and retention of providers for the future. METHODS: Clinical OB-GYN faculty within the University of Washington School of Medicine regional medical education program were surveyed about practice patterns and beliefs regarding medical student training as part of a pilot study on provider recruitment and retention. RESULTS: Fifty-seven eligible respondents completed the survey. Most (88.9%) reported their hospitals encourage student participation in patient care. Students in their practices participate in many aspects of patient care, including conducting exams (96.2%) and participating in the operating room (94.3%). The majority found the rewarding aspects of teaching medical students to be intellectual stimulation (90.9%), continuing the tradition of medical teaching (87.5%), and the intrinsic satisfaction of teaching (83.6%). Challenging aspects of teaching included reduced reimbursement (40%) and the student/workload (63.6%). DISCUSSION: Medical student education continues to rely on a generation's medical professionals to impart their knowledge to the next. We hope that with a better understanding of the benefits of participation and minimization of the challenges, we can perpetuate this tradition despite the uncertainty in our health-care system.

New Partner Recruitment to Rural Versus Urban Ob-Gyn Practices: A Survey of Practicing Ob-Gyns.

PURPOSE: The purpose of this pilot study was to investigate the recruitment efforts of practicing obstetrics and gynecology (ob-gyns) from rural and urban practices. METHOD: The authors surveyed practicing ob-gyns from 5 states in the Pacific Northwest in 2016 about their background, practice setting, practice profile, partner recruitment, and retention. RESULTS: Seventy-three patients completed the study (53.2% response rate). Thirty-seven percent of respondents work in an urban practice and 43% have a rural practice, with the remainder in a suburban setting. A majority of the respondents attempted to recruit a new partner in the past 5 years. Respondents were most interested in experience and diversity in new recruits. Urban respondents, however, were more interested in hiring those with specialized skills (χ2 = 7.842, P = .02) than rural providers who were more interested in partners familiar with their community (χ2= 7.153, P = .03). Reasons most often cited to leave their practice were reimbursement, limited social/marital options, and workload, other than rural providers who more often also cited lack of access to specialty care (χ2= 13.256, P = .001). Rural providers were more likely to cite marital and family status as an advantage to recruitment, whereas urban and suburban providers were more often neutral. CONCLUSIONS: Reduced access to care has led to significant health disparities for women living in rural communities. Understanding which providers are most likely to be successful in these settings might help preserve access as our health-care systems evolves.

Attitudes and Beliefs Regarding the Utility of Robotically Assisted Gynecologic Surgery Among Practicing Gynecologists.

While use of robotic-assisted surgery has increased rapidly, little is known about the attitudes and beliefs of practicing gynecologists regarding the utility of the technology. We surveyed a large sample of gynecologists to examine their attitudes and beliefs about the benefits, utility, and factors driving use of robotic-assisted gynecologic surgery. A 51-item survey was mailed to 600 fellows or junior fellows of the American College of Obstetricians and Gynecologists. The survey included questions on use of robotic surgery, decision-making, and beliefs regarding the technology. Responses were stratified based on whether the respondent used robotic surgery or not. A total of 310 responses were received including 27.8% who used robotic surgery in their practices. Hysterectomy was the most commonly performed procedure. Opinions about the use and effectiveness of robotic procedures varied based on whether an individual was a robot user. Eighty-two percentage of robot users and 21% of nonrobot users believed robotic surgery provided benefits over laparoscopic (p < .0001). Among both groups, the ability to increase access to minimally invasive surgery and marketing were believed to be the greatest drivers of use of robotic surgery. Attitudes and beliefs about the effectiveness of robotic gynecologic surgery are highly variable among clinicians.

Obstetricians and gynecologists' opinions about the Affordable Care Act and their expectations about how it will impact their practice.

As the primary healthcare providers for women, obstetrician-gynecologists' (OB/GYNs) experiences with and opinions about the Affordable Care Act (ACA) are important to understand. An online survey was sent to 1000 randomly selected OB/GYNs who were members of the American College of Obstetricians and Gynecologists (ACOG) in 2014. Of those, 523 opened the email and 163 responded (31% participation rate). Data were collected August 2014-October 2014 and analyzed in 2015-2016. Support for the ACA was widely distributed, with the largest subset of the sample (about 21%) in the "very supportive" category. Opinions of the ACA were more supportive than they were in a previous study conducted in 2011. When given a list of possible positive and negative impacts of the ACA on their practice, roughly 1 in 5 reported that the ACA increased work-related stress (28%), decreased total profits (22%), and lowered career satisfaction (22%), whereas 8.6% reported that the ACA increased quality of care. Around half of the providers thought that their newly insured patients would have the same level of education (42%) and numeric ability (55%) as their current patients. Almost all respondents (87%) indicated that it is at least slightly important for patients to understand their numeric likelihood of risk (such as numeric risk information from medications, treatments, and other procedures you might prescribe) -31% think it is extremely important and 44% think it is moderately important.

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.

Intrauterine air embolism associated with a rectovaginal fistula in a pregnant woman.

BACKGROUND: Previous case reports have reported maternal and fetal mortality in pregnancies complicated by air emboli induced by various mechanisms. CASE: A 33-year-old multiparous woman with a known rectovaginal fistula presented with symptoms of placental abruption. She subsequently was found to have a large intrauterine air embolus. The patient was treated successfully to term by continuously draining the vaginal air with a Malecot catheter. CONCLUSION: We describe a rare case of an intrauterine air embolism during pregnancy caused by a rectovaginal fistula. Prompt recognition of air within the uterine myometrium and subchorionic space during ultrasonography led to the diagnosis and successful treatment of a potentially fatal complication by using an intravaginal Malecot catheter to release the trapped air.

Training the next generation of minimally invasive surgeons.

A paradigm shift is occurring in the educational approach to surgical procedures. A variety of pressures are forcing the initial education of surgeons of all disciplines out of the operating department and into simulation. Fortunately, increasing evidence suggests that surgeons can learn many fundamental skills and specific procedures with simulators. Evidence also supports the expectation that surgeons trained in simulation laboratories initially perform better in the operating department than those who are not. Minimally invasive procedures lend themselves to simulation particularly well. Currently, many different models are available for training and improvement in skills are seen with both low- and high-fidelity models. Developing an effective curriculum principally requires a commitment to the concept, and the time and space, for residents to learn and practice. Although many questions remain about how to optimally apply and evaluate the educational tools being developed, it appears certain that surgical simulation, in some form, is the educational paradigm of the present and future.

Incidence of recurrent pelvic organ prolapse 10 years following primary surgical management: a retrospective cohort study.

We conducted this study to estimate the rate of, and identify risk factors for, recurrent pelvic organ prolapse (POP) following primary surgical repair. The study consisted of a retrospective cohort study of 142 women who underwent primary surgical management of POP in 1993 and were followed up to 10 years. Prolapse severity was graded using an established classification system of clinical descriptors. Hazard ratios (HR) for recurrent POP were determined using Cox regression. 36 recurrent cases were identified (recurrence rate: 3.7 per 100 woman-years). A cystocele was the most frequent element of primary (87%) and recurrent (72%) prolapse. No predictors of the likelihood of recurrence were identified, though recurrence was somewhat more common among women with a history of two or fewer vaginal deliveries vs three or more (HR = 1.6; 95% confidence interval = 0.81-3.3). Recurrent POP following surgical management is common. Our ability to predict recurrence is limited.

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.

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.

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.