Investigating Racial Disparities in Drug Prescriptions for Patients with Endometriosis.

Background: Endometriosis is a chronic disease with a long time to diagnosis and several known comorbidities that requires a range of treatments including of pain management and hormone-based medications. Racial disparities specific to endometriosis treatments are unknown. Objective: We aim to investigate differences in patterns of drug prescriptions specific to endometriosis management in Black and White patients prior to diagnosis and after diagnosis of endometriosis and compare these differences to racial disparities established in the general population. Study Design: We conduct a retrospective cohort study using observational health data from the IBM MarketScan® Multi-state Medicaid dataset. We identify a cohort of endometriosis patients consisting of women between the ages of 15 and 49 with an endometriosis-related surgical procedure and a diagnosis code for endometriosis within 30 days of this procedure. Cohort is further restricted to patients with at least 3 years of continuous observation prior to diagnosis.We identify a non-endometriosis cohort of women between the ages of 15 and 49 with no endometriosis diagnosis and at least 1 year of continuous observation. We compare prevalence of prescriptions across selected drug classes for Black vs. White endometriosis patients. We further examine prevalence differences in the non-endometriosis cohort and prevalence differences pre- and post-diagnosis in the endometriosis cohort. Results: The endometriosis cohort comprised 16,372 endometriosis patients (23.3% Black, 66.0% White). Of the 28 drug classes examined, 17 were prescribed significantly less in Black patients compared to 21 in non-endometriosis cohort (n=3,663,904), and 4 were prescribed significantly more in Black patients compared to 6 in the non-endometriosis cohort. Of the 17 drugs prescribed more often in White patients, 16 have larger disparities pre-diagnosis than post-diagnosis. Conclusions: Our analysis identified significant differences in medication prescriptions between White and Black patients with endometriosis, notably in hormonal treatments, pain management, and treatments for common endometriosis co-morbidities. Racial disparities in drug prescriptions are well established in healthcare, and better understanding these disparities in the specific context of chronic reproductive conditions and chronic pain is important for increasing equity in drug prescription practices.

Global endometrial DNA methylation analysis reveals insights into mQTL regulation and associated endometriosis disease risk and endometrial function.

Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.

Endometriosis in the era of precision medicine and impact on sexual and reproductive health across the lifespan and in diverse populations.

Endometriosis is a common estrogen-dependent disorder wherein uterine lining tissue (endometrium) is found mainly in the pelvis where it causes inflammation, chronic pelvic pain, pain with intercourse and menses, and infertility. Recent evidence also supports a systemic inflammatory component that underlies associated co-morbidities, e.g., migraines and cardiovascular and autoimmune diseases. Genetics and environment contribute significantly to disease risk, and with the explosion of omics technologies, underlying mechanisms of symptoms are increasingly being elucidated, although novel and effective therapeutics for pain and infertility have lagged behind these advances. Moreover, there are stark disparities in diagnosis, access to care, and treatment among persons of color and transgender/nonbinary identity, socioeconomically disadvantaged populations, and adolescents, and a disturbing low awareness among health care providers, policymakers, and the lay public about endometriosis, which, if left undiagnosed and under-treated can lead to significant fibrosis, infertility, depression, and markedly diminished quality of life. This review summarizes endometriosis epidemiology, compelling evidence for its pathogenesis, mechanisms underlying its pathophysiology in the age of precision medicine, recent biomarker discovery, novel therapeutic approaches, and issues around reproductive justice for marginalized populations with this disorder spanning the past 100 years. As we enter the next revolution in health care and biomedical research, with rich molecular and clinical datasets, single-cell omics, and population-level data, endometriosis is well positioned to benefit from data-driven research leveraging computational and artificial intelligence approaches integrating data and predicting disease risk, diagnosis, response to medical and surgical therapies, and prognosis for recurrence.

Uterine Artery Embolization for Symptomatic Adenomyosis: Proceedings from a Society of Interventional Radiology Foundation Research Consensus Panel.

Adenomyosis poses an important diagnostic and therapeutic challenge in women's health because of a variety of clinical/imaging presentations and frequent coexistence with other benign gynecologic conditions. In recent years, uterine artery embolization (UAE) for the treatment of adenomyosis has shown encouraging and favorable outcomes and long-term symptom improvement. To expand the current understanding of adenomyosis pathophysiology, imaging diagnostic criteria, and treatment outcomes, the Society of Interventional Radiology Foundation gathered a multidisciplinary Research Consensus Panel with experts from diverse backgrounds. The topics addressed were centered around the following: (i) the clinical presentation and imaging findings to diagnose adenomyosis; (ii) the currently available medical, interventional, and surgical treatment options; and (iii) existing literature for and experiences with UAE in symptomatic disease. The panel acknowledged that before the pursuit of a clinical trial, it would be necessary to first evaluate the imaging criteria for adenomyosis and correlate them with pathology and symptoms to establish a noninvasive imaging classification system. Second priority was given to the development of a quality of life questionnaire to assess patient outcomes following treatment. The third priority was the performance of a prospective clinical trial comparing UAE with medical therapy, which would help establish UAE in the treatment algorithm and societal guidelines for symptomatic adenomyosis.

Rethinking Disparities in Minimally Invasive Myomectomy: Identifying Drivers of Disparate Surgical Approach to Myomectomy Between African American and White Women.

STUDY OBJECTIVE: To identify drivers of disparities among patients undergoing surgical management of myomas when stratified by self-identified patient race. DESIGN: This is a retrospective institutional review board-approved chart review of all patients who underwent a myomectomy at a large academic center. Surgical approach to myomectomy was classified as abdominal, laparoscopic, or robotic-assisted laparoscopic. Myoma burden was quantified preoperatively using uterine volume, intraoperatively by number of myomas listed on operative report, and postoperatively by myoma weight from pathology reports. SETTING: A large tertiary care hospital containing a comprehensive myoma treatment center. PATIENTS: A total of 265 white patients and 121 African American patients who underwent a myomectomy between January 2012 and October 2018 were included in the study population. INTERVENTIONS: Abdominal, laparoscopic, and robotic-assisted myomectomy. Laparoscopic and robotic-assisted myomectomy were classified as minimally invasive myomectomy. Multivariable logistic regression models and a propensity score matching algorithm were used to match African American (AA) women and white women for myoma burden. MEASUREMENTS AND MAIN RESULTS: A total of 386 women were included in the study. AA women (31%; n = 121) had higher myoma burden than white women by preoperative imaging (AA: 36% with 3 or more myomas; white: 19% with 3 or more myomas; p <.01) and operative report (>8 AA: 31% vs white 13%; p <.01). Despite this, AA women underwent minimally invasive myomectomy at similar rates as compared with white women when adjusted for myoma burden, body mass index, preoperative hematocrit, hypertension, and surgical indication (adjusted odds ratio 1.3; 95% confidence interval, 0.8-2.2 myomas; p <.01). Sensitivity analysis using propensity score matching found similar results. CONCLUSION: In this population, AA women had a higher myoma burden than white women. When matched for myoma burden, however, there was no statistically significant difference between rates of minimally invasive myomectomy and abdominal myomectomy. This finding was consistent when controlling for myoma burden measured by preoperative, intraoperative, or postoperative methods of measurement. Further studies are needed to better characterize this disparity at other hospitals and to investigate ways to increase access and equity among patients undergoing minimally invasive myomectomy.

m6A RNA Methylation Regulators Contribute to Eutopic Endometrium and Myometrium Dysfunction in Adenomyosis.

Adenomyosis is a prevalent, estrogen-dependent uterine disorder wherein endometrial cells are abnormally present in the myometrium and are surrounded by hyperplastic/hypertrophic smooth muscle. Its etiology is unclear, although endometrial cell invasion into the myometrium has been postulated. RNA methylation, particularly N6-methyladenosine (m6A), plays an important role in regulating various physiological processes and invasive disorders. The goal of this in silico and lab-based experimental study was to explore a possible role for m6A in adenomyosis. Gene expression profiles of both the endometrium and myometrium of women with adenomyosis (cases) and without disease (controls) were obtained from the publicly available Gene Expression Omnibus (GEO) database. In the endometrium, STRING database analysis revealed that METTL3 functions as a "hub" gene of m6A RNA methylation regulators, and the genes involved in m6A regulation, including METTL3, FTO, ZC3H13, and YTHDC1 expression, were significantly decreased in cases versus controls. Functional, co-expression, and correlational analyses of endometrium from cases versus controls revealed decreased total m6A levels, induced by METTL3, and the downstream elevated insulin-like growth factor-1(IGF1) and D-Dopachrome Tautomerase (DDT), with the latter two having known functions in epithelial proliferation and cell migration, which are important processes in the pathogenesis of adenomyosis in endometrium. m6A RNA methylation regulators, including RBM15/15B, ALKBH5, FTO, YTHDF1/2, KIAA1429, HNRNPC, METTL3, ZC3H13, and YTHDC2, were also differentially expressed in the myometrium from cases versus controls. We validated decreased total m6A levels and differential expression of m6A RNA methylation regulators in the myometrium of patients with adenomyosis using qRT-PCR, immunohistochemistry and tissues available from our biorepository. Possible target genes, including cadherin 3(CDH3), sodium channelß-subunit 4 (SCN4B), and placenta-specific protein 8 (PLAC8), which are involved in cell adhesion, muscle contraction and immune response in the myometrium of adenomyosis patients were also validated. Thus, through extensive public database mining and validation of select genes, this study, for the first time, implicates m6A and its methylation regulators in the pathogenesis of adenomyosis. Follow on functional studies are anticipated to elucidate mechanisms involving m6A and its regulators and down-stream effectors in the pathogenesis of this enigmatic reproductive disorder and potentially identify druggable targets to control its associated symptoms.

Intraoperative tranexamic acid to decrease blood loss during myomectomy: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Myomectomy is associated with a significant risk of hemorrhage. Tranexamic acid is a synthetic lysine derivative with antifibrinolytic activity used in other surgical disciplines to reduce blood loss during surgery. However, its utility in gynecologic surgery is not well understood. OBJECTIVE: This study aimed to determine the effect of early administration of intravenous tranexamic acid on perioperative bleeding and blood transfusion requirements in women undergoing myomectomy. STUDY DESIGN: This study was a double-blinded, randomized, placebo-controlled trial conducted in an academic teaching hospital. Women with symptomatic fibroids thought to be at risk for large intraoperative blood loss who met the following criteria were included in the study: (1) at least 1 fibroid ≥10 cm, (2) any intramural or broad ligament fibroid ≥6 cm, and/or (3) at least 5 total fibroids based on preoperative imaging. Patients were randomized to receive a single intravenous bolus injection of tranexamic acid 15 mg/kg (intervention group) versus an intravenous bolus injection of saline of equivalent volume (placebo group) 20 minutes before the initial surgical incision. Perioperative bleeding was defined by measuring intraoperative estimated blood loss, change between pre- and postoperative hemoglobin, and frequency of blood transfusions. Estimated blood loss was calculated by combining the blood volume collected within the suction canister and the weight of used sponges. The 2 groups were compared for age; body mass index; perioperative hemoglobin and hematocrit; perioperative blood loss; duration of surgery; blood transfusion requirements; and the number, total weight, and volume of myomas removed. RESULTS: A total of 60 patients (30 per arm) were enrolled into the study between March 1, 2015, and January 29, 2018. Age, body mass index, baseline hemoglobin and/or hematocrit, number and total weight of myomas removed, and size of myomas did not differ between arms. Of 60 patients, 32 (53%) had laparoscopic myomectomy, 24 (40%) had robotic myomectomy, and 4 (7%) had laparotomy. Median estimated blood loss was 200 mL for the tranexamic acid group and 240 mL for the placebo group (P=.88). There was no difference in median duration of surgery (165 vs 164 minutes; P=.64) or change in perioperative hemoglobin (1.00 vs 1.1 g/dL; P=.64). Patients in the tranexamic acid group did not require blood transfusions; however, 4 patients (13.3%) in the placebo group (P=.11) required blood transfusions. CONCLUSION: Intravenous administration of tranexamic acid in patients undergoing laparoscopic or robotic myomectomies was not associated with decreased blood loss.

Predictors of Prolonged Operative Time for Robotic-Assisted Laparoscopic Myomectomy: Development of a Preoperative Calculator for Total Operative Time.

STUDY OBJECTIVE: To develop a preoperative calculator to predict the total operative time (TOT) for robotic-assisted laparoscopic myomectomy (RALM). DESIGN: Retrospective cross-sectional study. SETTING: University medical center. PATIENTS: Women who underwent RALM performed by 3 high-volume surgeons at a single institution between January 2014 and December 2017. INTERVENTIONS: Demographic characteristics, indication for surgery, surgical history, myoma burden on imaging, and TOT were collected. RALM operative time was classified as <3 hours, 3 to 5 hours, and >5 hours. We identified preoperative characteristics predictive of increased operative time and developed a preoperative calculator to estimate TOT. MEASUREMENTS AND MAIN RESULTS: A total of 126 women underwent RALM during the study period, with a mean TOT of 213 minutes ± 66 minutes. The mean total weight of myomas removed was 264 g ± 236 g, and mean largest myoma diameter was 8.5 cm ± 2.6 cm. Overall, mean number of myomas removed was 2.5 ± 2.4, and estimated blood loss (EBL) was 215 ± 212 mL. Five patients (4.0%) received a blood transfusion, and 4 patients (3.2%) underwent conversion to laparotomy. Preoperative factors significantly associated with TOT included patient age, personal history of diabetes mellitus, uterine volume, number of myomas, number of myomas >3 cm, diameter of the dominant myoma, and surgeon experience. The mean uterine volume was 282 cm3 for procedures with a TOT <3 hours, 461 cm3 for procedures with a TOT of 3 to 5 hours, and 532 cm3 for procedures with a TOT >5 hours (p = .004). Body mass index, personal history of hypertension, previous abdominal/pelvic surgery, surgical indication, location of dominant myoma (anterior, posterior, or fundal) and classification of dominant myoma (submucosal, intramural, subserosal, or other) were not associated with TOT. Our preoperative calculator correctly predicted TOT category in 88% of the patients and estimated TOT within a 1-hour margin in 80% of patients. CONCLUSION: RALM is becoming a more popular surgical approach for the management of uterine myomas. Preoperative radiographic evaluation and a thorough patient history may enhance patient counseling and surgical planning. Uterine volume and myoma number and size appear to be more predictive of TOT compared with myoma location.

The menstrual cycle and blood loss during laparoscopic myomectomy.

INTRODUCTION: Operative morbidity of laparoscopic myomectomy largely relates to the potential for intraoperative blood loss. We sought to determine whether blood loss varies according to the menstrual cycle. MATERIAL AND METHODS: A retrospective study of 268 women who underwent a laparoscopic myomectomy from 2007 to 2012. Patients were categorized into five menstrual groups: follicular phase, luteal phase, oligomenorrheic or amenorrheic on hormonal therapy, postmenopausal or other. Patient and procedure characteristics were compared for the follicular phase group, luteal phase group, and hormonal therapy group. The estimated blood loss was compared across the five groups using a regression model. RESULTS: A total of 268 women underwent a laparoscopic myomectomy: 108 (40.3%) were in the follicular phase, 92 (34.3%) were in the luteal phase, 44 (16.4%) were on hormonal therapy, nine (3.4%) were postmenopausal, and 15 (5.6%) could not be classified. Baseline patient characteristics were similar between the groups with the exception of endometriosis. Geometric mean estimated blood loss was 91.9 mL in the follicular phase group, 108.7 mL in the luteal phase group, 114.1 mL in the hormonal therapy group, and 39.8 mL in the postmenopausal group. There was no significant difference in the geometric mean estimated blood loss when comparing the follilcuar phase, luteal phase, and hormonal phase groups (p = 0.41). Upon adjusted multivariable analysis of all five menstrual groups, there was also no difference in estimated blood loss. CONCLUSIONS: Intraoperative blood loss during laparoscopic myomectomy does not vary significantly with the phase of the menstrual cycle.

Minimally Invasive Hysterectomy for Uteri Greater Than One Kilogram.

BACKGROUND AND OBJECTIVES: To assess the feasibility and safety of minimally invasive hysterectomy for uteri >1 kg. METHODS: Clinical and surgical characteristics were collected for patients in an academic tertiary care hospital. Included were patients who underwent minimally invasive hysterectomy by 1 of 3 fellowship-trained gynecologists from January 1, 2009, to July 1, 2015 and subsequently had confirmed uterine weights of 1 kg or greater on pathology report. Both robotic and conventional laparoscopic procedures were included. RESULTS: During the study period, 95 patients underwent minimally invasive hysterectomy with confirmed uterine weight over 1 kg. Eighty-eight percent were performed with conventional laparoscopy and 12.6% with robot-assisted laparoscopy. The median weight (range) was 1326 g (range, 1000-4800). The median estimated blood loss was 200 mL (range, 50-2000), and median operating time was 191 minutes (range, 75-478). Five cases were converted to laparotomy (5.2%). Four cases were converted secondary to hemorrhage and one secondary to extensive adhesions. There were no conversions after 2011. Intraoperative transfusion was given in 6.3% of cases and postoperative transfusion in 6.3% of cases. However, after 2013, the rate of intraoperative transfusion decreased to 1.0% and postoperative transfusion to 2.1%. Of the 95 cases, there were no cases with malignancy. CONCLUSIONS: This provides the largest case series of hysterectomy over 1 kg completed by a minimally invasive approach. Our complication rate improved with experience and was comparable to other studies of minimally invasive hysterectomy for large uteri. When performed by experienced surgeons, minimally invasive hysterectomy for uteri >1 kg can be considered feasible and safe.

Transferability of Virtual Reality, Simulation-Based, Robotic Suturing Skills to a Live Porcine Model in Novice Surgeons: A Single-Blind Randomized Controlled Trial.

STUDY OBJECTIVE: To assess whether a robotic simulation curriculum for novice surgeons can improve performance of a suturing task in a live porcine model. DESIGN: Randomized controlled trial (Canadian Task Force classification I). SETTING: Academic medical center. PATIENTS: Thirty-five medical students without robotic surgical experience. INTERVENTIONS: Participants were enrolled in an online session of training modules followed by an in-person orientation. Baseline performance testing on the Mimic Technologies da Vinci Surgical Simulator (dVSS) was also performed. Participants were then randomly assigned to the completion of 4 dVSS training tasks (camera clutching 1, suture sponge 1 and 2, and tubes) versus no further training. The intervention group performed each dVSS task until proficiency or up to 10 times. A final suturing task was performed on a live porcine model, which was video recorded and blindly assessed by experienced surgeons. The primary outcomes were Global Evaluative Assessment of Robotic Skills (GEARS) scores and task time. The study had 90% power to detect a mean difference of 3 points on the GEARS scale, assuming a standard deviation (SD) of 2.65, and 80% power to detect a mean difference of 3 minutes, assuming an SD of 3 minutes. MEASUREMENTS AND MAIN RESULTS: There were no differences in demographics and baseline skills between the 2 groups. No significant differences in task time in minutes or GEARS scores were seen for the final suturing task between the intervention and control groups, respectively (9.2 [2.65] vs 9.9 [2.07] minutes, p = .406; and 15.37 [2.51] vs 15.25 [3.38], p = .603). The 95% confidence interval for the difference in mean task times was -2.36 to .96 minutes and for mean GEARS scores -1.91 to 2.15 points. CONCLUSIONS: Live suturing task performance was not improved with a proficiency-based virtual reality simulation suturing curriculum compared with standard orientation to the da Vinci robotic console in a group of novice surgeons.

Feasibility, Safety, and Prediction of Complications for Minimally Invasive Myomectomy in Women With Large and Numerous Myomata.

OBJECTIVE: To assess perioperative outcomes and identify predictors of complications for minimally invasive surgery (MIS) myomectomy in a cohort of women with large and numerous myomata. DESIGN: Case-control study (Canadian Task Force classification II-2). SETTING: Academic tertiary care medical center. PATIENTS: Women undergoing MIS myomectomy performed by 3 high-volume surgeons between April 2011 and December 2014. INTERVENTIONS: Characteristics were compared between women who experienced complications and those who did not. Factors predictive of complications were then identified. MEASUREMENTS AND MAIN RESULTS: A total of 221 women underwent an MIS myomectomy, 47.5% via a laparoscopic approach and 52.5% via robotic surgery. The mean ± SD specimen weight was 408.1 ± 384.9 g, uterine volume was 586.1 ± 534.1 cm3, dominant myoma diameter was 9.6 ± 5.1 cm, and number of myomata removed was 4.5 ± 4.1. The most common complications were hemorrhage >1000 mL (8.6%) and blood transfusion (4.1%). The conversion rate was 1.8%. A dominant myoma diameter of ≥12 cm and a uterine volume of ≥750 cm3 increased the odds of complications (odds ratio [OR], 7.44; 95% confidence interval [CI], 2.03-31.84; p = .004 and OR, 6.15; 95% CI, 1.55-30.02; p = .014 respectively). A receiver operating characteristic curve considering dominant myoma diameter and uterine volume had an area under the curve of 0.81. A combination of dominant myoma diameter of ≥10 cm and uterine volume of 600 cm3 predicted complications with 79% sensitivity and 79% specificity. CONCLUSION: Our cohort had large and numerous myomata with high specimen weights, but complications were comparable to those reported in previous studies of MIS myomectomy with less complex pathology. Hemorrhage and transfusion accounted for the majority of complications, and a combination of dominant myoma diameter and uterine volume was predictive of complications. Both factors can be easily defined before surgery and may be used to guide patient counseling, referrals, and implementation of preventative measures for hemorrhage and transfusion.

Comparison of methods of morcellation: manual versus power.

INTRODUCTION: With the growing controversy surrounding power morcellation (PM), other approaches must be examined so that women may still benefit from minimally invasive gynecologic surgeries. In this study we sought to compare power morcellation to manual morcellation through mini-laparotomy or vaginally. MATERIALS AND METHODS: Retrospective cohort study carried out at an urban teaching hospital including 274 women who underwent a minimally invasive myomectomy or hysterectomy, requiring morcellation for tissue extraction. Surgical outcomes were compared between PM, manual morcellation through mini-laparotomy (MMM) and manual morcellation through the vagina (MMV). Primary outcome measured was operative time. Secondary outcomes were intraoperative and postoperative complications. RESULTS: Compared with PM, MMM was associated with shorter operative time for hysterectomy, (140.5 min vs. 164.2 min, p = 0.05). Intraoperative and postoperative complications were similar among groups. There were four postoperative complications in the MMV group, one related to blood transfusion and three related to postoperative vaginal cuff and pelvic infections. CONCLUSION: Compared with PM, MMM is associated with shorter operative time during hysterectomies. Intraoperative and postoperative complications were similar among groups.

Systematic review of laparoscopic surgery in low- and middle-income countries: benefits, challenges, and strategies.

BACKGROUND: Laparoscopy may prove feasible to address surgical needs in limited-resource settings. However, no aggregate data exist regarding the role of laparoscopy in low- and middle-income countries (LMICs). This study was designed to describe the issues facing laparoscopy in LMICs and to aggregate reported solutions. METHODS: A search was conducted using Medline, African Index Medicus, the Directory of Open Access Journals, and the LILACS/BIREME/SCIELO database. Included studies were in English, published after 1992, and reported safety, cost, or outcomes of laparoscopy in LMICs. Studies pertaining to arthroscopy, ENT, flexible endoscopy, hysteroscopy, cystoscopy, computer-assisted surgery, pediatrics, transplantation, and bariatrics were excluded. Qualitative synthesis was performed by extracting results that fell into three categories: advantages of, challenges to, and adaptations made to implement laparoscopy in LMICs. PRISMA guidelines for systematic reviews were followed. RESULTS: A total of 1101 abstracts were reviewed, and 58 articles were included describing laparoscopy in 25 LMICs. Laparoscopy is particularly advantageous in LMICs, where there is often poor sanitation, limited diagnostic imaging, fewer hospital beds, higher rates of hemorrhage, rising rates of trauma, and single income households. Lack of trained personnel and equipment were frequently cited challenges. Adaptive strategies included mechanical insufflation with room air, syringe suction, homemade endoloops, hand-assisted techniques, extracorporeal knot tying, innovative use of cheaper instruments, and reuse of disposable instruments. Inexpensive laboratory-based trainers and telemedicine are effective for training. CONCLUSIONS: LMICs face many surgical challenges that require innovation. Laparoscopic surgery may be safe, effective, feasible, and cost-effective in LMICs, although it often remains limited in its accessibility, acceptability, and quality. This study may not capture articles written in languages other than English or in journals not indexed by the included databases. Surgeons, policymakers, and manufacturers should focus on plans for sustainability, training and retention of providers, and regulation of efforts to develop laparoscopy in LMICs.

New Success With Microbicides and Pre-Exposure Prophylaxis for Human Immunodeficiency Virus (HIV): Is Female-Controlled Prevention the Answer to the HIV Epidemic?

Women who cannot negotiate condom use with their partners, often due to socioeconomic factors and sexual abuse, have no means of preventing themselves from acquiring the human immunodeficiency virus (HIV). There is a need to develop HIV-preventive methods initiated and controlled by women. Microbicides and other pre-exposure prophylaxis may help fill that need. Although two decades of research on broad-spectrum microbicides have generally been disappointing, recent trials with HIV-specific agents have yielded promising initial results. A new era of clinical research involves novel biochemical prevention methods, including HIV-specific vaginal microbicides and oral antiretroviral chemoprophylaxis drugs (pre-exposure prophylaxis; PrEP) that may help provide more control for women.

NKG2D is a costimulatory receptor for human naive CD8+ T cells.

In humans, all alpha beta CD8+ T cells express NKG2D, but in mouse, it is only expressed by activated and memory CD8+ T cells. We purified human naive CD8+ T cells to show that NKG2D serves as a costimulatory receptor for TCR induced Ca2+ mobilization and proliferation. The resulting effector cells are skewed toward a type 1 phenotype and produce high levels of IFN-gamma and TNF-alpha. NKG2D ligands, MHC class I chain-related (MIC)A, MICB, and UL16-binding proteins are expressed on the proliferating cells and NKG2D is down-regulated. The addition of the homeostatic cytokines IL-7 and IL-15 to the culture medium not only enhances proliferation but also counteracts the down-regulation of NKG2D, more so than the addition of IL-2. These results indicate that NKG2D can regulate the priming of human naive CD8+ T cells, which may provide an alternative mechanism for potentiating and channeling the immune response.