Multiprong control of glioblastoma multiforme invasiveness: blockade of pro-inflammatory signaling, anti-angiogenesis, and homeostasis restoration.

Glioblastoma multiforme (GBM) is the most invasive type of glial tumor with poor overall survival, despite advances in surgical resection, chemotherapy, and radiation. One of the main challenges in treating GBM is related to the tumor's location, complex and heterogeneous biology, and high invasiveness. To meet the demand for oxygen and nutrients, growing tumors induce new blood vessels growth. Antibodies directed against vascular endothelial growth factor (VEGF), which promotes angiogenesis, have been developed to limit tumor growth. Bevacizumab (Avastin), an anti-VEGF monoclonal antibody, is the first approved angiogenesis inhibitor with therapeutic promise. However, it has limited efficacy, likely due to adaptive mutations in GBM, leading to overall survival compared to the standard of care in GBM patients. Molecular connections between angiogenesis, inflammation, oxidative stress pathways, and the development of gliomas have been recognized. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the converging dysregulation of signaling pathways. While most GBM clinical trials focus on "anti-angiogenic" modalities, stimulating inflammation resolution is a novel host-centric therapeutic avenue. The selective therapeutic possibilities for targeting the tumor microenvironment, specifically angiogenic and inflammatory pathways expand. So, a combination of agents aiming to interfere with several mechanisms might be beneficial to improve outcomes. Our approach might also be combined with other therapies to enhance sustained effectiveness. Here, we discuss Suramab (anti-angiogenic), LAU-0901 (a platelet-activating factor receptor antagonist), Elovanoid (ELV; a novel lipid mediator), and their combination as potential alternatives to contain GBM growth and invasiveness.

Endometriosis is a chronic systemic disease: clinical challenges and novel innovations.

Endometriosis is a common disease affecting 5-10% of women of reproductive age globally. However, despite its prevalence, diagnosis is typically delayed by years, misdiagnosis is common, and delivery of effective therapy is prolonged. Identification and prompt treatment of endometriosis are essential and facilitated by accurate clinical diagnosis. Endometriosis is classically defined as a chronic, gynaecological disease characterised by endometrial-like tissue present outside of the uterus and is thought to arise by retrograde menstruation. However, this description is outdated and no longer reflects the true scope and manifestations of the disease. The clinical presentation is varied, the presence of pelvic lesions is heterogeneous, and the manifestations of the disease outside of the female reproductive tract remain poorly understood. Endometriosis is now considered a systemic disease rather than a disease predominantly affecting the pelvis. Endometriosis affects metabolism in liver and adipose tissue, leads to systemic inflammation, and alters gene expression in the brain that causes pain sensitisation and mood disorders. The full effect of the disease is not fully recognised and goes far beyond the pelvis. Recognition of the full scope of the disease will facilitate clinical diagnosis and allow for more comprehensive treatment than currently available. Progestins and low-dose oral contraceptives are unsuccessful in a third of symptomatic women globally, probably as a result of progesterone resistance. Oral gonadotropin-releasing hormone (GnRH) antagonists constitute an effective and tolerable therapeutic alternative when first-line medications do not work. The development of GnRH antagonists has resulted in oral drugs that have fewer side-effects than other therapies and has allowed for rapid movement between treatments to optimise and personalise endometriosis care. In this Review, we discuss the latest understanding of endometriosis as a systemic disease with multiple manifestations outside the parameters of classic gynaecological disease.

Seven days of statin treatment improves nitric-oxide mediated endothelial-dependent cutaneous microvascular function in women with endometriosis.

INTRODUCTION: Endometriosis is associated with systemic inflammation and increased risk of cardiovascular disease (CVD). Endothelial dysfunction is one of the first manifestations of CVD but is unexplored in women with endometriosis. HMG-CoA-reductase inhibitors (statins) exert potent anti-inflammatory effects, and have been proposed as an adjunctive therapy in women with endometriosis. We hypothesized that microvascular endothelial function would be impaired in otherwise healthy women with endometriosis mediated by reduced nitric oxide (NO)-dependent dilation and that short term statin administration would improve endothelial function. METHODS: In 8 healthy control (HC: 33 ± 9 yr) and 8 women with endometriosis (EN: 34 ± 9 yr), laser-Doppler flux (LDF) was measured continuously during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (Ach: 10-10-10-1 M) alone and in combination with the NO synthase inhibitor (L-NAME: 0.015 M). 6 EN repeated the microdialysis experiment following 7 days of oral atorvastatin treatment (10 mg). Cutaneous vascular conductance was calculated (CVC = LDF*mmHg-1) and normalized to site-specific maximum (28 mM sodium nitroprusside, 43 °C). The NO-dependent dilation was calculated as the difference between the areas under the dose response curves. RESULTS: Ach-induced vasodilation was blunted in women with endometriosis (main effect p < 0.01), indicating impaired endothelial function. NO-dependent vasodilation was also reduced in women with endometriosis (HC: 217 ± 120.3 AUC vs. EN: 88 ± 97 AUC, p = 0.03). Oral atorvastatin improved Ach-induced (main effect p < 0.01) and NO-dependent (295 ± 153 AUC; p = 0.05) vasodilation in women with endometriosis. CONCLUSION: Microcirculatory endothelium-dependent vasodilation is impaired in women with endometriosis, mediated in part by reductions in NO. Short-term oral atorvastatin improved endothelium-dependent vasodilation, suggesting that statin therapy may be a viable intervention strategy to mitigate accelerated CVD risk in women with endometriosis.

Tofacitinib alters STAT3 signaling and leads to endometriosis lesion regression.

Endometriosis is a widespread gynecologic condition affecting up to 15% of women of reproductive age. The Janus kinase/signal transducer and activator of transcription (JAK/STAT3) pathway is upregulated in endometriosis and is a therapeutic target. Here we sought to determine the effect of Tofacitinib, a JAK inhibitor in widespread clinical use, on JAK/STAT signaling in endometriosis and lesion growth. Endometriosis was surgically induced in C57BL/6 mice using homologous uterine horn transplantation. Lesions were allowed to form over 4 weeks followed by Tofacitinib (10 mg/kg) or vehicle administered by oral gavage over 4 weeks. Tofacitinib treatment in vivo led to endometriosis lesion regression and reduced adhesion burden compared to vehicle treatment. In vitro studies on Ishikawa cells showed that Tofacitinib reduced hypoxia-inducible factor 1α and vascular endothelial growth factor mRNA levels at 12 and 24 h. Western blot analysis showed that Tofacitinib effectively reduced STAT3 phosphorylation in Ishikawa cells and human primary stromal and epithelial cells from eutopic endometrium of patients with and without endometriosis. This study suggests that the inhibition of JAK/STAT signaling using Tofacitinib may be a viable method for the treatment of endometriosis.

The Diagnostic Criteria for Chronic Endometritis: A Survey of Pathologists.

While acute endometritis is a reasonably well-defined entity of ascending infection and attendant active inflammation, chronic endometritis is less well defined. As part of a broad effort to define and refine the diagnostic criteria and management of the disease, we conducted a survey of pathologists to understand the variability in diagnostic criteria and implications of the diagnosis of nonspecific, nonobstetric chronic endometritis. Members of national and international professional pathology societies were surveyed utilizing anonymous electronic surveys designed to examine diagnostic criteria, etiological understanding and treatment implications of a pathologic diagnosis of nonspecific, nonobstetric chronic endometritis. There was substantial variability among pathologists in the diagnostic criteria used for making a diagnosis of nonspecific, nonobstetric chronic endometritis, with 28.5% of pathologists using the presence of a single plasma cell for making the diagnosis. There was additional variability in the use of special stains, reporting in the presence of coexisting lesions and the hormonal stage of the endometrium. There were no differences between generalists and specialists in the diagnostic criteria used, except the significantly greater likelihood of specialists making the diagnosis in gestational endometrium. The substantial variability in diagnostic criteria for nonspecific, nonobstetric chronic endometritis among pathologists, including among gynecologic pathologists, has the potential to confound the management of patients. Standardization of diagnostic criteria for chronic endometritis is essential to understand the implications of the diagnosis.

Accurate diagnosis of endometriosis using serum microRNAs.

BACKGROUND: Endometriosis, a chronic disease that afflicts millions of women worldwide, has traditionally been diagnosed by laparoscopic surgery. This diagnostic barrier delays identification and treatment by years, resulting in prolonged pain and disease progression. Development of a noninvasive diagnostic test could significantly improve timely disease detection. We tested the feasibility of serum microRNAs as diagnostic biomarkers of endometriosis in women with gynecologic disease symptoms. OBJECTIVE: The objective of the study was to validate the use of a microRNA panel as a noninvasive diagnostic method for detecting endometriosis. STUDY DESIGN: This was a prospective study evaluating subjects with a clinical indication for gynecological surgery in an academic medical center. Serum samples were collected prior to surgery from 100 subjects. Women were selected based on the presence of symptoms, and laparoscopy was performed to determine the presence or absence of endometriosis. The control group was categorized based on absence of visual disease at the time of surgery. Circulating miRNAs, miR-125b-5p, miR-150-5p, miR-342-3p, miR-451a, miR-3613-5p, and let-7b, were measured in serum by quantitative real-time polymerase chain reaction in a blinded fashion without knowledge of disease status. Receiver-operating characteristic analysis was performed on individual microRNAs as well as combinations of microRNAs. An algorithm combining the expression values of these microRNAs, built using machine learning with a random forest classifier, was generated to predict the presence or absence of endometriosis on operative findings. This algorithm was then tested in an independent data set of 48 previously identified subjects not included in the training set (24 endometriosis and 24 controls) to validate its diagnostic performance. RESULTS: The mean age of women in the study population was 34.1 and 36.9 years for the endometriosis and control groups, respectively. Control group subjects displayed varying pathologies, with leiomyoma occurring the most often (n = 39). Subjects with endometriosis had significantly higher expression levels of 4 serum microRNAs: miR-125b-5p, miR-150-5p, miR-342-3p, and miR-451a. Two serum microRNAs showed significantly lower levels in the endometriosis group: miR-3613-5p and let-7b. Individual microRNAs had receiver-operating characteristic areas under the curve ranging from 0.68 to 0.92. A classifier combining these microRNAs yielded an area under the curve of 0.94 when validated in the independent set of subjects not included in the training set. Analysis of the expression levels of each microRNA based on revised American Society of Reproductive Medicine staging revealed that all microRNAs could distinguish stage I/II from control and stage III/IV from control but that the difference between stage I/II and stage III/IV was not significant. Subgroup analysis revealed that neither phase of the menstrual cycle or use of hormonal medication had a significant impact on the expression levels in the microRNAs used in our algorithm. CONCLUSION: This is the first report showing that microRNA biomarkers can reliably differentiate between endometriosis and other gynecological pathologies with an area under the curve >0.9 across 2 independent studies. We validated the performance of an algorithm based on previously identified microRNA biomarkers, demonstrating their potential to detect endometriosis in a clinical setting, allowing earlier identification and treatment. The ability to diagnose endometriosis noninvasively could reduce the time to diagnosis, surgical risk, years of discomfort, disease progression, associated comorbidities, and health care costs.

Effects of bazedoxifene/conjugated estrogens on reproductive endocrinology and reproductive tract ultrasonographic appearance in premenopausal women: a preliminary study.

Bazedoxifene (BZA) paired with conjugated estrogens (CE) is the first tissue selective estrogen receptor complex (TSEC) approved by the United States Food and Drug Administration for the treatment of menopausal symptoms. Clinical trials in menopausal women and in premenopausal murine models of endometriosis have demonstrated safety and efficacy, however, the impact of BZA/CE on premenopausal women is not known. Here we report a case series study in premenopausal women assessing effects of BZA/CE on reproductive hormones, and uterine/ovarian ultrasonographic appearance. After one monitoring cycle, five subjects underwent daily administration of BZA/CE (20 mg/0.45 mg) for 12 weeks, and were followed for 4 weeks after treatment. Uterine/ovarian morphology was assessed with ultrasound, and endocrinologic function with ovulation prediction kits and serum assessment of reproductive hormones throughout the menstrual cycle. All subjects demonstrated an LH surge on the medication; interestingly there was a significant decrease in luteinizing hormone level during treatment compared to posttreatment values. BZA/CE was well-tolerated in premenopausal women and did not induce clinically relevant reproductive hormone changes, endometrial alterations, or abnormal ovarian folliculogenesis.

Managing Menopause by Combining Evidence With Clinical Judgment.

Menopause occurring before the age of 40 harbors unique challenges as well as lifetime burden resulting from premature deprivation from ovarian hormones, primarily estrogen. Cessation of ovarian function before age 40 is considered premature (ovarian insufficiency), whereas if occurring before age 45, it is deemed "early." Early/premature menopause may be idiopathic, medically, or surgically induced. Regardless of the cause, for such women, menopausal hormone therapy is truly replacement and should continue until at least the average age of menopause. Hormone therapy offers the benefit of symptom control, and prevention of health consequences associated with premature loss of ovarian hormones.

Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) - protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids.

INTRODUCTION: Uterine fibroids affect 30%-77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications such as adhesions negatively impacting fertility. Existing medical therapies, such as oral contraceptives, gonadotropin hormone-releasing hormone (GnRH) analogues and GnRH antagonists, can manage fibroid symptoms but are not fertility friendly. This study addresses the pressing need for non-hormonal, non-surgical treatment options for women with fibroids desiring pregnancy. Previous preclinical and clinical studies have shown that epigallocatechin gallate (EGCG) effectively reduces uterine fibroid size. We hypothesise that EGCG from green tea extract will shrink fibroids, enhance endometrial quality and increase pregnancy likelihood. To investigate this hypothesis, we initiated a National Institute of Child Health and Human Development Confirm-funded trial to assess EGCG's efficacy in treating women with fibroids and unexplained infertility. METHODS AND ANALYSIS: This multicentre, prospective, interventional, randomised, double-blinded clinical trial aims to enrol 200 participants with fibroids and unexplained infertility undergoing intrauterine insemination (IUI). Participants will be randomly assigned in a 3:1 ratio to two groups: green tea extract (1650 mg daily) or a matched placebo, combined with clomiphene citrate-induced ovarian stimulation and timed IUI for up to four cycles. EGCG constitutes approximately 45% of the green tea extract. The primary outcome is the cumulative live birth rate, with secondary outcomes including conception rate, time to conception, miscarriage rate, change in fibroid volume and symptom severity scores and health-related quality of life questionnaire scores. ETHICS AND DISSEMINATION: The FRIEND trial received approval from the Food and Drug adminstration (FDA) (investigational new drug number 150951), the central Institutional Review Board (IRB) at Johns Hopkins University and FRIEND-collaborative site local IRBs. The data will be disseminated at major conferences, published in peer-reviewed journals and support a large-scale clinical trial. TRIAL REGISTRATION NUMBER: NCT05364008.

Assessing the Hepatic Safety of Epigallocatechin Gallate (EGCG) in Reproductive-Aged Women.

A similar abstract of the interim analysis was previously published in Fertility and Sterility. EPIGALLOCATECHIN GALLATE (EGCG) FOR TREATMENT OF UNEXPLAINED INFERTILITY ASSOCIATED WITH UTERINE FIBROIDS (PRE-FRIEND TRIAL): EARLY SAFETY ASSESSMENT. Uterine fibroids are the most common cause of unexplained infertility in reproductive-aged women. Epigallocatechin gallate (EGCG), a green tea catechin, has demonstrated its ability to shrink uterine fibroids in prior preclinical and clinical studies. Hence, we developed an NICHD Confirm-funded trial to evaluate the use of EGCG for treating women with fibroids and unexplained infertility (FRIEND trial). Prior to embarking on that trial, we here conducted the pre-FRIEND study (NCT04177693) to evaluate the safety of EGCG in premenopausal women. Specifically, our aim was to assess any adverse effects of EGCG alone or in combination with an ovarian stimulator on serum liver function tests (LFTs) and folate level. In this randomized, open-label prospective cohort, participants were recruited from the FRIEND-collaborative clinical sites: Johns Hopkins University, University of Chicago, University of Illinois at Chicago, and Yale University. Thirty-nine women, ages ≥18 to ≤40 years, with/without uterine fibroids, were enrolled and randomized to one of three treatment arms: 800 mg of EGCG daily alone, 800 mg of EGCG daily with clomiphene citrate 100 mg for 5 days, or 800 mg of EGCG daily with Letrozole 5 mg for 5 days. No subject demonstrated signs of drug induced liver injury and no subject showed serum folate level outside the normal range. Hence, our data suggests that a daily dose of 800 mg of EGCG alone or in combination with clomiphene citrate or letrozole (for 5 days) is well-tolerated and is not associated with liver toxicity or folate deficiency in reproductive-aged women.

Chronic endometritis: A prevalent yet poorly understood entity.

OBJECTIVE: To examine the prevalent understanding of and management approaches to chronic endometritis among obstetricians/gynecologists. METHODS: In a cross-sectional observational study, 262 members of national and international professional obstetrician/gynecologist societies were surveyed via anonymous electronic survey that investigated knowledge of the pathophysiology, diagnostic criteria, clinical implications, and treatment strategies for chronic endometritis. Statistical analyses of results were performed using Fisher's exact tests, chi square tests and odds ratios with 95% confidence intervals. A two-sided P < 0.05 was deemed statistically significant. RESULTS: Responses identified a concerning spectrum of deficiencies in the understanding of the pathophysiology of chronic endometritis, in awareness of clinical presentation of chronic endometritis, and in the understanding of methodology/ies that allow diagnosis of chronic endometritis. Heterogeneities in management approaches to chronic endometritis were apparent. CONCLUSION: Our findings underscore a need for targeted efforts to gain clarity on chronic endometritis and to establish evidence-based consensus for good clinical practice. In the absence of a clear understanding of chronic endometritis diagnosis, we posit that the prevalent inconsistencies are likely inflicting unquantified and underappreciated burdens on patients and healthcare systems. We propose consideration for a task force to examine existing literature and create standards for good practice for a prevalent condition.

A North Star for Gerontology: Using the Threshold Concept Framework to Transform Ageism Education.

Threshold concepts are fundamental to the learning process and are said to transform the way we view and understand the world around us. Although a new framework to gerontology, the threshold concept framework has been utilized in many fields inside (e.g., psychology, social work) and outside (e.g., clinical and research settings) of academia. This framework facilitates understanding learning, exposing expert blind spots, and designing curricula for complex concepts that are challenging to learn. For decades gerontologists have grappled with ageism and its dire consequences including unemployment, negative health outcomes, and rationing of health care. Education is one of, if not the most, powerful tools to combat ageism. This article demonstrates the utility of the threshold concept framework for gerontologists by conceptualizing ageism as a threshold concept. The purpose of this article is to provide an innovative approach to education on complex gerontological topics in different clinical, research, and educational settings using ageism as a primary example of a threshold concept in gerontology.

Pre-IVF treatment with a GnRH antagonist in women with endometriosis (PREGNANT): study protocol for a prospective, double-blind, placebo-controlled trial.

INTRODUCTION: Infertility is a common complication of endometriosis. While in vitro fertilisation-embryo transfer (IVF) successfully treats endometriosis-associated infertility, there is some evidence that pregnancy rates may be diminished in women seeing fertility treatment for endometriosis-associated infertility compared with other etiologies of infertility. The use of gonadotropin releasing hormone (GnRH) agonist prior to IVF has been suggested to improve success, however studies have been small and rarely reported live birth rates. Recent approval of an oral GnRH antagonist for endometriosis provides a novel option for women with endometriosis who are undergoing IVF. There have been no studies on the efficacy of GnRH antagonists for the treatment of endometriosis-related infertility. METHODS AND ANALYSIS: This study is a multicentre, prospective, randomised, double-blind, placebo-controlled trial to study the efficacy of GnRH antagonist pretreatment for women with endometriosis who are undergoing IVF. A total of 814 patients with endometriosis undergoing fertility treatment will be enrolled and randomised 1:1 into two groups: elagolix 200 mg two times per day or placebo for 8 weeks, prior to undergoing IVF. All participants will then undergo IVF treatment per local protocols. The primary outcome is live birth. Secondary outcomes include oocyte number, fertilisation rate, embryo morphology and implantation rates, as well as rates of known endometriosis-related obstetrical outcomes (pregnancy-induced hypertension, antepartum haemorrhage, caesarean delivery and preterm birth). ETHICS AND DISSEMINATION: The PREGnant trial was approved by the Institutional Review Board at Johns Hopkins University. Results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04173169.

Hormone Therapy in Menopause: Concepts, Controversies, and Approach to Treatment.

Hormone therapy (HT) is an effective treatment for menopausal symptoms, including vasomotor symptoms and genitourinary syndrome of menopause. Randomized trials also demonstrate positive effects on bone health, and age-stratified analyses indicate more favorable effects on coronary heart disease and all-cause mortality in younger women (close proximity to menopause) than in women more than a decade past menopause. In the absence of contraindications or other major comorbidities, recently menopausal women with moderate or severe symptoms are appropriate candidates for HT. The Women's Health Initiative (WHI) hormone therapy trials-estrogen and progestin trial and the estrogen-alone trial-clarified the benefits and risks of HT, including how the results differed by age. A key lesson from the WHI trials, which was unfortunately lost in the posttrial cacophony, was that the risk:benefit ratio and safety profile of HT differed markedly by clinical characteristics of the participants, especially age, time since menopause, and comorbidity status. In the present review of the WHI and other recent HT trials, we aim to provide readers with an improved understanding of the importance of the timing of HT initiation, type and route of administration, and of patient-specific considerations that should be weighed when prescribing HT.

Combined Therapy With Avastin, a PAF Receptor Antagonist and a Lipid Mediator Inhibited Glioblastoma Tumor Growth.

Glioblastoma multiforme (GBM) is an aggressive, highly proliferative, invasive brain tumor with a poor prognosis and low survival rate. The current standard of care for GBM is chemotherapy combined with radiation following surgical intervention, altogether with limited efficacy, since survival averages 18 months. Improvement in treatment outcomes for patients with GBM requires a multifaceted approach due to the dysregulation of numerous signaling pathways. Recently emerging therapies to precisely modulate tumor angiogenesis, inflammation, and oxidative stress are gaining attention as potential options to combat GBM. Using a mouse model of GBM, this study aims to investigate Avastin (suppressor of vascular endothelial growth factor and anti-angiogenetic treatment), LAU-0901 (a platelet-activating factor receptor antagonist that blocks pro-inflammatory signaling), Elovanoid; ELV, a novel pro-homeostatic lipid mediator that protects neural cell integrity and their combination as an alternative treatment for GBM. Female athymic nude mice were anesthetized with ketamine/xylazine, and luciferase-modified U87MG tumor cells were stereotactically injected into the right striatum. On post-implantation day 13, mice received one of the following: LAU-0901, ELV, Avastin, and all three compounds in combination. Bioluminescent imaging (BLI) was performed on days 13, 20, and 30 post-implantation. Mice were perfused for ex vivo MRI on day 30. Bioluminescent intracranial tumor growth percentage was reduced by treatments with LAU-0901 (43%), Avastin (77%), or ELV (86%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 72, 92, and 96%, respectively. Additionally, tumor reduction was confirmed by MRI on day 30, which shows a decrease in tumor volume by treatments with LAU-0901 (37%), Avastin (67%), or ELV (81.5%), individually, by day 30 compared to saline treatment. In combination, LAU-0901/Avastin, ELV/LAU-0901, or ELV/Avastin had a synergistic effect in decreasing tumor growth by 69, 78.7, and 88.6%, respectively. We concluded that LAU-0901 and ELV combined with Avastin exert a better inhibitive effect in GBM progression than monotherapy. To our knowledge, this is the first study that demonstrates the efficacy of these novel therapeutic regimens in a model of GBM and may provide the basis for future therapeutics in GBM patients.

Emergency Department Characteristics and Capabilities in Quito, Ecuador.

Background: Emergency care is an essential part of a health system. Ecuador has recognized emergency medicine as a specialty and has two emergency medicine residency training programs. However, little has been published about emergency department characteristics and capabilities in Ecuador. Objective: We described the characteristics and capabilities of emergency departments (EDs) in Quito, Ecuador, in 2017, using the National Emergency Department Inventory (NEDI) survey. Methods: The 23-item survey included questions pertaining to ED characteristics, including: visit volume, physical and administrative structure, clinical capabilities, technological resources, and consult personnel availability. This study included all EDs in Quito operating 24 hours/day, 7 days/week, and serving all patients seeking care. One representative from each ED was asked to complete the survey based on calendar year 2017. Findings: Thirty EDs met the inclusion criteria, and 26 completed the survey (87% response). The median number of ED beds was 17 (range 2-61). Median annual visit volume was 22,580 (range 1,680 to 129,676). All but two EDs provided care for both children and adults. Cardiac monitors were available in 88% of EDs, CT scanners in 68%, and rooms for respiratory isolation in 31%. Most EDs could manage patients with general medicine (92%), general surgery (92%), and gynecology (88%) emergencies 24/7. Fewer were able to provide hand surgery (45%) and dental (28%) care 24/7. Typical length of stay was 1-6 hours in 65% and >6 hours in 31% of EDs. Half of EDs reported operating at full capacity and 27% reported operating over their capacity. When compared to private EDs, government EDs (public and social security) had a higher mean number of visits per year (50,090 government vs. 13,968 private, p < 0.001), higher mean number of ED beds (36 government vs. 9 private, p = 0.002), and higher length of stay (58% of patient stays > 6 hours in government EDs vs. 86% of patient stays 1-6 hours in private EDs, p = 0.009). Conclusions: EDs in Quito varied widely with respect to annual visit volume, ability to treat different pathologies 24/7, and resources. Most EDs are functioning at or over capacity, and a substantial number have long lengths of stay. Further research and investment in emergency care could help increase the capacity and efficiency of EDs in Ecuador.

A step towards the automation of intracytoplasmic sperm injection: real time confirmation of mouse and human oocyte penetration and viability by electrical resistance measurement.

OBJECTIVE: To evaluate if oocyte penetration and viability can be confirmed by an electrical resistance increase. Automated (robotic) intracytoplasmic sperm injection (ICSI) requires confirmation of oolemma penetration before sperm injection. Visual assessment using image processing algorithms have been developed but remain unreliable. We hypothesized that an increase in electrical resistance upon oolemma piercing during ICSI can serve as an objective tool to confirm oocyte penetration and viability. DESIGN: Experimental study. SETTING: Research laboratory in an academic center. PATIENTS/ANIMALS: Oocytes from female mice and women undergoing oocyte retrieval procedure. INTERVENTION: Oolemma piercing attempts with the ICSI pipette were performed by advancing the pipette towards mature (metaphase II) oocytes collected from 6 to 12-week-old mice and immature (germinal vesicle stage and metaphase I) oocytes donated by women who underwent oocyte retrieval. Electrical resistance was measured using a conventional electrophysiological setup that includes an electrical resistance meter and two electrical wires located in the lumina of the holding and ICSI pipettes. MAIN OUTCOME MEASURE(S): The measure of interest was the change in electrical resistance (ΔR) before and after advancing the ICSI pipette in an attempt to penetrate an oocyte. The experiments of resistance measurements were done in 3 steps: Step 1 (proof of concept), penetrated vs. non-penetrated mouse oocytes. Step 2, mouse oocytes with visually intact oolemma vs. fragmented mouse oocytes. Step 3, human oocytes with visually intact oolemma vs. fragmented human oocytes. For each group, median and range (in parenthesis) of ΔR were determined in MΩ. Mann-Whitney test was performed to compare the two groups in each step. RESULTS: In Step 1, the penetrated mouse oocytes showed a statistically significant resistance increase compared to the non-penetrated ones (n = 20, median ΔR = 7.79 [2.57 - 106.00] vs. n = 15, median ΔR = 0.10 [-0.06 - 0.69], respectively. In Step 2, the mouse oocytes with visually intact oolemma showed a statistically significant resistance increase compared to the fragmented ones (n = 45, median ΔR = 6.5 [0.1 - 191.7] vs. n = 13, median ΔR = 0.1 [-0.3 - 2.2], respectively. In Step 3, the human oocytes with visually intact oolemma showed a statistically significant resistance increase compared to the fragmented ones (n = 96, median ΔR = 1.92 [-0.05 - 6.70] vs. n = 17, median ΔR = 0.11 [0.00 - 0.30], respectively. CONCLUSIONS: An electrical resistance increase can serve as a reliable tool to confirm oocyte penetration and viability, independent of optical visualization. Following further validation and safety assessment, this technology can potentially be integrated into manual and robotic ICSI systems.

Bazedoxifene-Conjugated Estrogens for Treating Endometriosis.

BACKGROUND: Endometriosis is a gynecologic disorder affecting 6-10% of reproductive-aged women. First-line therapies are progestin-based regimens; however, failure rates are high, often requiring alternative hormonal agents, each with unfavorable side effects. Bazedoxifene with conjugated estrogens is approved for treatment of menopausal symptoms, and use in animal studies has demonstrated regression of endometriotic lesions. As such, it represents a potential treatment option for endometriosis. CASE: A patient with stage III endometriosis referred for management of dysmenorrhea and cyclic pelvic pain was treated with 20 mg bazedoxifene and 0.45 mg conjugated estrogens daily for more than 6 months. She noted resolution of pelvic pain. There were no abnormal effects on hormonal, uterine, or ovarian parameters. CONCLUSION: Bazedoxifene with conjugated estrogens may be an effective alternative to traditional endometriosis treatment options.

Progesterone Receptor Status Predicts Response to Progestin Therapy in Endometriosis.

Context: Progestin-based therapy is the first-line treatment for managing endometriosis-associated pain. However, response to progestins is currently variable and unpredictable. Predictive markers for response to progestin-based therapy would allow for a personalized approach to endometriosis treatment. Objective: We hypothesize that progesterone receptor (PR) levels in endometriotic lesions determine response to progestin-based therapy. Design: Retrospective cohort study. Setting: Academic center. Patients: Fifty-two subjects with histologically confirmed endometriosis and a previous documented response to hormonal therapy were included. Interventions: Immunohistochemistry was performed on sections of endometriotic lesions using a rabbit polyclonal IgG for detection of PR-A/B. Main Outcome Measures: The Histo (H)-score was used for quantifying PR status. Response to progestin-based therapies was determined from review of the electronic medical record. Results: H-score was higher in responders compared with nonresponders. Subjects were categorized into three groups: high (H-score > 80, n = 7), medium (H-score 6 to 80, n = 28), and low (H-score ≤ 5, n = 17) PR status. The threshold of PR > 80 was associated with a 100% positive predictive value. The threshold of PR < 5 was associated with a 94% negative predictive value. Conclusion: PR status is strongly associated with response to progestin-based therapy. Receptor status in endometriosis could be used to tailor hormonal-based regimens after surgery, and negate trialing progestin-based therapy to determine resistance. Ascertainment of PR status may allow for a novel, targeted, precision-based approach to treating endometriosis.

Bazedoxifene/conjugated estrogens in combination with leuprolide for the treatment of endometriosis.

Bazedoxifene/conjugated estrogens can be used with leuprolide as effective add-back therapy in premenopausal women with endometriosis without unwanted stimulation of the breasts, CNS (Central Nervous System), or endometrium. Bazedoxifene/conjugated estrogens may be an effective progestin-free alternative to traditional add-back therapies.