Aging modifies endometrial dendritic cell function and unconventional double negative T cells in the human genital mucosa.

BACKGROUND: Immune function in the genital mucosa balances reproduction with protection against pathogens. As women age, genital infections, and gynecological cancer risk increase, however, the mechanisms that regulate cell-mediated immune protection in the female genital tract and how they change with aging remain poorly understood. Unconventional double negative (DN) T cells (TCRαß + CD4-CD8-) are thought to play important roles in reproduction in mice but have yet to be characterized in the human female genital tract. Using genital tissues from women (27-77 years old), here we investigated the impact of aging on the induction, distribution, and function of DN T cells throughout the female genital tract. RESULTS: We discovered a novel site-specific regulation of dendritic cells (DCs) and unconventional DN T cells in the genital tract that changes with age. Human genital DCs, particularly CD1a + DCs, induced proliferation of DN T cells in a TFGß dependent manner. Importantly, induction of DN T cell proliferation, as well as specific changes in cytokine production, was enhanced in DCs from older women, indicating subset-specific regulation of DC function with increasing age. In human genital tissues, DN T cells represented a discrete T cell subset with distinct phenotypical and transcriptional profiles compared to CD4 + and CD8 + T cells. Single-cell RNA and oligo-tag antibody sequencing studies revealed that DN T cells represented a heterogeneous population with unique homeostatic, regulatory, cytotoxic, and antiviral functions. DN T cells showed relative to CD4 + and CD8 + T cells, enhanced expression of inhibitory checkpoint molecules and genes related to immune regulatory as well as innate-like anti-viral pathways. Flow cytometry analysis demonstrated that DN T cells express tissue residency markers and intracellular content of cytotoxic molecules. Interestingly, we demonstrate age-dependent and site-dependent redistribution and functional changes of genital DN T cells, with increased cytotoxic potential of endometrial DN T cells, but decreased cytotoxicity in the ectocervix as women age, with implications for reproductive failure and enhanced susceptibility to infections respectively. CONCLUSIONS: Our deep characterization of DN T cell induction and function in the female genital tract provides novel mechanistic avenues to improve reproductive outcomes, protection against infections and gynecological cancers as women age.

Opioid use after laparoscopic hysterectomy: prescriptions, patient use, and a predictive calculator.

BACKGROUND: In the setting of America's opioid epidemic, judicious postoperative opioid prescribing is important. Gynecologists lack standard guidelines about postoperative opioid prescriptions. OBJECTIVES: The objectives of the study were to describe opioid prescribing practices by a group of minimally invasive gynecologic surgeons, to measure postoperative opioid use after minimally invasive hysterectomy, and to identify preoperative factors that could predict whether a patient will be a low or high postoperative opioid user. STUDY DESIGN: This was a prospective survey-based study including 125 women undergoing laparoscopic hysterectomy for benign indications at 2 community teaching hospitals. Patients were preoperatively surveyed about demographics, past medical history, and current and expected pain scores and were screened for anxiety, depression, and pain catastrophizing. At 1 and 2 weeks after surgery, patients were surveyed about their pain and pain medication use. RESULTS: Ninety-eight percent of patients were prescribed an opioid for acute postoperative pain. The median opioid prescription was for 150 morphine milligram equivalents, equivalent to 20 tablets of oxycodone 5 mg, while median patient postoperative use was 37.5 morphine milligram equivalents, equivalent to 5 tablets of oxycodone 5 mg. Ninety percent of patients had leftover opioids at 2 weeks after surgery, and most leftover opioids were stored in an unsecure location. Preoperative factors that were most strongly correlated with postoperative opioid use included a history of chronic pelvic pain or endometriosis, preoperative opioid use, anxiety, depression, pain catastrophizing, preoperative pain score, anticipated postoperative pain score, and anticipated postoperative pain medication needs. A predictive calculator was developed based on these factors to help identify patients who are likely to be a high opioid user (defined as taking greater than 112.5 morphine milligram equivalents) or a low opioid user (defined as taking 37.5 morphine milligram equivalents or less). CONCLUSION: On average, surgeons prescribed 4 times the amount of opioids than was needed for patients undergoing laparoscopic hysterectomy for acute postoperative pain control. Individualizing patients' opioid prescriptions based on preoperative risk factors could help reduce excess prescription opioids.

Determining a Learning Curve for Contained Hand Tissue Extraction: Perioperative Outcomes and Operative Time.

STUDY OBJECTIVE: To compare the operative time of contained hand tissue extraction with power morcellation and to quantify the learning curve required to develop this skill. DESIGN: A retrospective cohort study (Canadian Task Force classification II-3). SETTING: Lahey Hospital and Medical Center, a suburban academic tertiary care center serving a broad base of patients. PATIENTS: Eighty-eight women undergoing laparoscopic hysterectomy requiring morcellation or tissue extraction from 2012 through 2015. INTERVENTIONS: Power morcellation before the institution's ban on power morcellation and contained hand tissue extraction instituted in a response to the ban. MEASUREMENTS AND MAIN RESULTS: Data were collected to compare the operative time and perioperative outcomes of morcellation before discontinuation of the power morcellator and after adaptation of a contained hand tissue extraction protocol. The data were then used to determine a learning curve for the new procedure. Eighty-eight consecutive cases of laparoscopic hysterectomy requiring morcellation were identified during the study duration, with 46 patients undergoing power morcellation and 42 undergoing hand tissue extraction. The 2 groups were similar overall in body mass index (28.9 vs 29.5, p = .70), prior laparoscopy (28% vs 21%, p = .46) or laparotomy (39% vs 21%, p = .07), removal of the cervix (56% vs 86%, p < .01), and uterine weight (581 vs 628 g, p = .56). The hand tissue extraction group had an average operating room time of 170 minutes compared with 154 minutes (p = .08) for the power morcellation group. The 2 surgeons performed 32 and 10 hand tissue extractions, respectively, with a decrease in 0.7 and 3 minutes per case, respectively, over the course of 7 months (p = .3 and .6, respectively). CONCLUSION: Contained hand tissue extraction was similar to power morcellation in the total operative time. The learning curve of surgeons performing contained hand tissue extraction showed a nonsignificant trend toward improvement in the operative time with an increasing number of cases.

Contained tissue extraction using power morcellation: prospective evaluation of leakage parameters.

BACKGROUND: Safe tissue removal is a challenge for minimally invasive procedures such as myomectomy, supracervical hysterectomy, or total hysterectomy of a large uterine specimen. There is concern regarding disruption or dissemination of tissue during this process, which may be of particular significance in cases of undetected malignancy. Contained tissue extraction techniques have been developed in an effort to mitigate morcellation-related risks. OBJECTIVE: The objective of the study was to quantify perioperative outcomes of contained tissue extraction using power morcellation, specifically evaluating parameters of tissue or fluid leakage from within the containment system. STUDY DESIGN: This was a study including a multicenter prospective cohort of adult women who underwent minimally invasive hysterectomy or myomectomy using a contained power morcellation technique. Blue dye was applied to the tissue specimen prior to removal to help identify cases of fluid or tissue leakage from within the containment system. RESULTS: A total of 76 patients successfully underwent the contained power morcellation protocol. Mean time for the contained morcellation procedure was 30.2 minutes (±22.4). The mean hysterectomy specimen weight was 480.1 g (±359.1), and mean myomectomy specimen weight was 239.1 g (±229.7). The vast majority of patients (73.7%) were discharged home the same day of surgery. Final pathological diagnosis was benign in all cases. Spillage of dye or tissue was noted in 7 cases (9.2%), although containment bags were intact in each of these instances. CONCLUSION: Findings are consistent with prior work demonstrating the feasibility of contained tissue extraction; however, further refinement of this technique is warranted.

Aging dysregulates neutrophil extracellular trap formation in response to HIV in blood and genital tissues.

Women acquire HIV through sexual transmission, with increasing incidence in women >50 years old. Identifying protective mechanisms in the female genital tract (FGT) is important to prevent HIV-acquisition in women as they age. Human genital and blood neutrophils inactivate HIV by releasing neutrophil extracellular traps (NETs), an innate protective mechanism against HIV-infection. However, how NET formation is triggered by HIV in different tissues and whether this mechanism is affected by aging remain unknown. We demonstrate that the mechanisms that trigger NET release in response to HIV are different in blood and genital tissues, and that NET release decreases with aging. In blood neutrophils, HIV stimulation independently activated calcium pathways and endosomal TLR8, but aging reduced calcium responses, resulting in delayed NET release. In contrast, calcium responses were absent in genital neutrophils and NET release was triggered preferentially through TLR8 activation, but aging impaired this pathway. HIV induced NET formation through non-lytic pathways in blood and FGT neutrophils, except for a small subset of NETs that incorporated annexin V and lactoferrin predominantly in blood, suggesting proinflammatory and lytic NET release. Our findings demonstrate that blood neutrophils cannot model genital neutrophil responses which has important implications to understanding protection against HIV acquisition.

Cancer Screening in Women.

Advancements in cancer screening techniques have allowed for earlier detection of cancer at premalignant or early stages of disease. Several organizations have guidelines for screening strategies for breast, cervical, colon, and lung cancer. Ovarian cancer remains the deadliest cancer of the female reproductive tract; however, guidelines have yet to be shown effective in identifying ovarian cancer at earlier stages. It is important that providers familiarize themselves with up-to-date screening strategies in women at average risk and at increased risk of disease. The provider's role in guiding patients toward screening programs and counseling regarding risk reduction is one of the most important.

Bilateral Bell palsy as a presenting sign of preeclampsia.

BACKGROUND: Bell palsy is a facial nerve neuropathy that is a rare disorder but occurs at higher frequency in pregnancy. Almost 30% of cases are associated with preeclampsia or gestational hypertension. Bilateral Bell palsy occurs in only 0.3%-2.0% of cases of facial paralysis, has a poorer prognosis for recovery, and may be associated with a systemic disorder. CASE: We describe a case of a 24-year-old primigravid woman with a twin gestation at 35 weeks diagnosed initially with bilateral facial palsy and subsequently with preeclampsia. She then developed partial hemolysis, elevated liver enzymes, and low platelet count syndrome, prompting the diagnosis of severe preeclampsia, and was delivered. CONCLUSION: Bilateral facial palsy is a rare entity in pregnancy that may be the first sign of preeclampsia and suggests increased severity of disease, warranting close monitoring.

Suture compared with staple skin closure after cesarean delivery: a randomized controlled trial.

OBJECTIVE: To compare the incidence of wound complications between suture and staple skin closure after cesarean delivery. METHODS: This prospective, randomized clinical trial conducted at three hospitals in the United States between 2010 and 2012 included women undergoing cesarean delivery at 23 weeks of gestation or greater through a low-transverse skin incision. Women were randomized to closure of the skin incision with suture or staples after stratifying by body mass index and primary compared with repeat cesarean delivery. The primary outcome was incidence of wound complications, predefined as a composite of infection, hematoma, seroma, separation of 1 cm or longer, or readmission for wound complications. Analysis was according to the intention-to-treat principle; results were stratified by randomization group and adjusted for hospital by including it as a covariate. RESULTS: A total of 746 women were randomized, 370 to suture and 376 to staple closure. The median gestational age was 39 weeks. Fifty-eight women (7.8%) had wound complications-4.9% in the suture group and 10.6% in the staple group (adjusted odds ratio [OR] 0.43, 95% confidence interval [CI] 0.23-0.78); this was largely the result of the decreased incidence of wound separation in the respective groups (1.6% compared with 7.4%; adjusted OR 0.20, 95% CI 0.07-0.51). CONCLUSIONS: Suture closure of the skin incision at cesarean delivery is associated with a 57% decrease in wound complications compared with staple closure. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT01211600. LEVEL OF EVIDENCE: I.