Introduction to Preclinical Evidence from Animal Models of Endometriosis.

Endometriosis, the presence and growth of uterine endometrial glandular epithelial and stroma cells outside the uterine cavity, causes pain and infertility in women and girls of reproductive age. As randomized, double-blinded, controlled studies of endometriosis in women are impractical and at times ethically prohibitive, animal models for endometriosis arose as an important adjunct to gain mechanistic insights into the etiology and pathophysiological mechanisms of this perplexing disorder. A more thorough understanding of endometriosis in women may help develop novel noninvasive diagnostics, classification systems, therapeutic regimes, and even preventative methods for the management of endometriosis. This chapter is intended to introduce a brief historical background, biological and epidemiological aspects, the major symptoms, the effects of endocrine-disrupting chemicals, and an example of an epigenetic factor of endometriosis in women.

Identifying Mechanisms of Endometriosis-Associated Reduced Fecundity in a Rat Model: Novel Insights toward Understanding Human Infertility.

The existence of endometriosis has been known since at least the nineteenth century, yet the lack of understanding of causes of infertility and therefore inadequate treatment approaches in endometriosis creates a significant challenge in reproductive medicine. Women worldwide suffer not only pain and infertility but also economical, societal, and physiological burdens. Studies of reproductive events in women are difficult to conduct due to a host of confounding personal and environmental factors and ethically limited due to the very nature of working with reproductive tissues and cells, especially embryos. Animal models are a viable adjunct to study mechanisms causing human reproductive anomalies and infertility in endometriosis. This chapter discusses reproductive anomalies causing infertility in endometriosis and well-established animal models which help decipher the problems and lead to heretofore unknown nonsurgical, nonhormonal methods to manage endometriosis in women. In addition, studies of effects of developmental exposure to endometriosis are revealing for the first time, in both female and male offspring, transgenerational subfertility in a rat model providing insights into the familial nature of endometriosis and possible epigenetic involvement.

Prehospital amputation: An experimental comparison of techniques.

OBJECTIVE: Prehospital limb amputation is a rare but potentially life-saving intervention. When patients cannot be extricated due to limb entrapment or have hemodynamic compromise that precludes a prolonged extrication, they may benefit from an emergent prehospital amputation. The objective was to experimentally compare three prehospital amputation techniques on porcine legs. METHODS: The three techniques studied were a scalpel with a Gigli saw, a hacksaw, and a reciprocating saw. For the first technique, a scalpel was used to make a circumferential incision in the soft tissue and a Gigli wire saw to cut through the bone. The second and third techniques only used a saw and did not require soft tissue incision with a scalpel. Three providers including an emergency medicine physician, a paramedic, and a medical student performed three amputations of each technique, resulting in twenty-seven total amputations. The primary outcome was amputation time. Secondary outcomes were rate of instrument malfunction and cleanliness of cut. RESULTS: The primary outcome of amputation time was different between techniques. The Gigli saw technique took 32.86 ± 16.53 s (mean ± SD), hacksaw technique 6.28 ± 0.76 s, and reciprocating saw technique 2.84 ± 0.40 s. There were no differences in amputation time between participants for a given amputation technique. The Gigli saw technique had an instrument malfunction on 3/9 trials which was distinct from the other techniques. Differences in cleanliness of cut were nonsignificant. CONCLUSIONS: Prehospital limb amputation with a hacksaw or reciprocating saw may result in faster completion of the time-sensitive procedure with fewer instrument malfunctions.

Differential Regulation of Human and Mouse Myometrial Contractile Activity by FSH as a Function of FSH Receptor Density.

Previous studies from our laboratory revealed that the follicle-stimulating hormone receptor (FSHR) is expressed at low levels in nonpregnant human myometrium and that it is up-regulated in pregnant term nonlaboring myometrium; however, the physiological relevance of these findings was unknown. Herein, we examined signaling pathways stimulated by FSH in immortalized uterine myocytes expressing recombinant FSHR at different densities and showed that cAMP accumulation is stimulated in all cases but that inositol phosphate accumulation is stimulated only at high FSHR densities. Because an increase in cAMP quiets myometrial contractile activity but an increase in 1,4,5-triphosphoinositol stimulates contractile activity, we hypothesized that FSHR density dictates whether FSH quiets or stimulates myometrial contractility. Indeed, in human and mouse nonpregnant myometrium, which express low levels of FSHR, application of FSH resulted in a quieting of contractile activity. In contrast, in pregnant term nonlaboring myometrium, which expresses higher levels of FSHR, application of FSH resulted in increased contractile activity. Examination of pregnant mouse myometrium from different stages of gestation revealed that FSHR levels remained low throughout most of pregnancy. Accordingly, through mid-gestation, the application of FSH resulted in a quieting of contractile activity. At Pregnancy Day (PD) 16.5, FSHR was up-regulated, although not yet sufficiently to mediate stimulation of contractility in response to FSH. This outcome was not observed until PD 19.5, when FSHR was further up-regulated. Our studies describe a novel FSHR signaling pathway that regulates myometrial contractility, and suggest that myometrial FSHR levels dictate the quieting vs. stimulation of uterine contractility in response to FSH.

FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice.

Expression and function of the follicle-stimulating hormone receptor (FSHR) in females were long thought to be limited to the ovary. Here, however, we identify extragonadal FSHR in both the human female reproductive tract and the placenta, and test its physiological relevance in mice. We show that in nonpregnant women FSHR is present on: endothelial cells of blood vessels in the endometrium, myometrium, and cervix; endometrial glands of the proliferative and secretory endometrium; cervical glands and the cervical stroma; and (at low levels) stromal cells and muscle fibers of the myometrium. In pregnant women, placental FSHR was detected as early as 8-10 wk of gestation and continued through term. It was expressed on: endothelial cells in fetal portions of the placenta and the umbilical cord; epithelial cells of the amnion; decidualized cells surrounding the maternal arteries in the maternal decidua; and the stromal cells and muscle fibers of the myometrium, with particularly strong expression at term. These findings suggest that FSHR expression is upregulated during decidualization and upregulated in myometrium as a function of pregnancy. The presence of FSHR in the placental vasculature suggests a role in placental angiogenesis. Analysis of genetically modified mice in which Fshr is lacking in fetal portions of the placenta revealed adverse effects on fetoplacental development. Our data further demonstrate FSHB and CGA mRNAs in placenta and uterus, consistent with potential local sources of FSH. Collectively, our data suggest heretofore unappreciated roles of extragonadal FSHR in female reproductive physiology.

Opioid Overdose Patients in Central Missouri, United States, Have High Rates of Hepatitis C Infection and Limited Testing History.

BACKGROUND: Cases of newly identified hepatitis C virus (HCV) infection increased 3.8-fold between 2010 and 2017 due to increasing injection drug use. Furthermore, multiple HIV outbreaks have been attributed to injection drug use. This retrospective cohort study assessed the prevalence of and testing history for HIV and HCV among opioid overdose patients in the emergency department. METHODS: Each encounter including an opioid overdose at three emergency departments between January 2021 and May 2022 was reviewed. Emergency department note, most recent primary care note, and laboratory results from January 2000 to May 2022 were reviewed for the history of HIV and HCV testing. Fisher's exact test was used to identify associations of HIV and HCV status with age or gender. RESULTS: There were 134 encounters for 120 patients. A total of 72 were male and 48 were female. A total of 48 had a history of HCV testing. A total of 54 had a history of HIV testing. A total of 20 tested positive for HCV antibodies. One tested positive for HIV. Eight had detectable HCV viral loads, six had undetectable HCV viral loads, and six had no quantitative testing. One had a detectable HIV viral load. A total of 16.7% of both males and females had a history of a positive HCV test. Females were more likely to have ever received an HCV test compared to males (p=0.013, odds ratio (OR)=.68 (confidence interval (CI): 1.293-5.836)). Patients aged 55-64 were more likely to test positive than any other age group (p=0.018, OR=3.889 (CI: 1.391-11.81)), and were the least likely to be untested (p=0.037, OR=0.1905 (CI: 0.03914-0.9334)). CONCLUSION: There is a substantial burden of HCV among opioid overdose patients in central Missouri, United States, emergency departments, particularly among male patients and those aged 55-64. Universal HCV screening for individuals being observed following an overdose could detect many undiagnosed HCV infections.

Football Saturday: are collegiate football stadiums adequately prepared to handle spectator emergencies?

BACKGROUND: Mass gatherings are a commonly occurring event, especially on college campuses. Any mass gathering gives rise to possible small- or large-scale emergencies. Mass gathering medicine is an integral part of emergency medical services (EMS). An assessment was performed to see if collegiate stadiums possess capabilities for advanced medical care when emergencies arise among attendees. METHODS: A standardized survey was sent by a single researcher to all National Collegiate Athletic Association (NCAA) Division I programs regarding medical services they currently have in place at their stadiums during Saturday football games. A follow-up inquiry was made at each local community office of emergency management (OEM) to confirm responses or obtain missing data. RESULTS: Only 21.5% (N.=17) of stadium facilities reported having physicians solely dedicated to the care of fans and other support staff. Most stadiums (N.=70, 88.6%) offered ALS services for their fans, with the remaining ALS services provided by paramedics (N.=46, 58.2%) or registered nurses (N.=7, 8.9%). The remaining stadiums only offered BLS services (N.=6, 7.6%) or basic first aid (N.=3, 3.8%). One stadium offered athletic trainer services to its fan in addition to the ALS care. CONCLUSIONS: Given the potential for a large influx of patients at sporting events, almost all stadiums have some degree of prehospital emergency care on site. More than a 10% of stadiums lacked ALS services and very few stadiums have physicians on site. Many stadiums were unaware of the resources available during these events. The ability to have ALS services on site who can provide rapid, advanced care to spectators is important due to likely delays in 911 response. At a minimum ALS services should be available within the stadium with consideration of physician coverage as well.

Walking time to nearest public automated external defibrillator for out-of-hospital cardiac arrest in a major U.S. city.

Background: How frequently out-of-hospital cardiac arrest (OHCA) occurs within a reasonable walking distance to the nearest public automated external defibrillator (AED) has not been well studied. Methods: As Kansas City, Missouri has a comprehensive city-wide public AED registry, we identified adults with an OHCA in Kansas City during 2019-2022 in the Cardiac Arrest Registry to Enhance Survival. Using AED location data from the registry, we computed walking times between OHCAs and the nearest registered AED using the Haversine formula, a mapping algorithm to calculate walking distance in miles from one location to another. Results were stratified by OHCA location (home vs. public) and by whether the patient received bystander cardiopulmonary resuscitation (CPR). Results: Of 1,522 OHCAs, 1,291 (84.8%) occurred at home and 231 (15.2%) in public. Among at-home OHCAs, 634 (49.1%) received bystander CPR and no patients had an AED applied even as 297 (23.0%) were within a 4-minute walk to the closest public AED. Among OHCAs in public, 108 (46.8%) were within a 4-minute walk to the closest public AED. For public OHCAs within a 4-minute walk, bystanders applied an AED in 13 (12.0%) of these cases and in 24.5% (13/53) of those who received bystander CPR. Conclusion: In one U.S. city with a publicly available AED registry, there were no instances in which a bystander accessed a public AED for an OHCA at home. For OHCAs in public, nearly half occurred within a 4-minute walk to the closest AED but bystander use of an AED was low.

Physical therapy in the Emergency Department: A prospective cohort study from an Alternatives to Opioids program.

Objective: Musculoskeletal pain complaints are common in the emergency department (ED). The objective of this study was to determine the impact of physical therapy (PT) in the ED on pain and ED return. Methods: A prospective cohort study was performed with those presenting to the ED or Urgent Care at a single academic center for musculoskeletal pain between November 2020 and December 2022. All patients were referred to outpatient PT. During business hours, PT was available to begin treatment in the ED. Long-term follow-up was performed using the electronic health records. Statistical analyses included descriptive and non-parametric pairwise comparisons, Fisher's exact test, and multiple logistic regression. Results: A total of 974 patients were included in the study with 553 completing optional surveys. Back pain was most common. Pain was reduced at ED discharge for all patients, but pain was significantly improved if patients saw PT in the ED. Patients in the ED were less likely to keep their outpatient PT appointments than others, but importantly, patients who saw PT in the ED were less likely to return to the ED for the same complaint up to 1 year later. Those who kept PT appointments were likely to establish or maintain healthcare outside emergency services later. Conclusions: Initiating PT in this ED reduces pain at ED discharge. However, patients who utilized PT were more likely to later utilize health care resources outside of emergency services. Those who saw PT in this ED were less likely to return to the ED for the same complaint up to 1 year later.

TIMP1 contributes to ovarian anomalies in both an MMP-dependent and -independent manner in a rat model.

Ovulatory dysfunction occurs in women with endometriosis, yet the mechanisms are unknown. We have shown that endometriotic lesions synthesize and secrete tissue inhibitor of metalloproteinase (TIMP) 1 into the peritoneal cavity in humans and a rat model of endometriosis, where excess TIMP1 localizes in the ovarian theca in endometriosis and modulating peritoneal TIMP1 alters ovarian dynamics. Here, we evaluated whether mechanisms whereby excessive peritoneal fluid TIMP1 negatively impacts ovarian function are matrix metalloproteinase (MMP)-dependent and/or MMP-independent actions. Rats were treated with a mutated TIMP1 without MMP inhibitory function (Ala-TIMP1), wild-type TIMP1 (rTIMP1), or PBS. Rats treated with Ala-TIMP1 or rTIMP1 had fewer antral follicles, fewer new corpora lutea, and the presence of luteinized unruptured follicle syndrome compared with PBS rats. Ala-TIMP1 and rTIMP1 differentially caused downstream changes in gene expression and protein localization related to ovulation, as measured by whole-genome microarray with quantitative real-time PCR validation and immunohistochemistry. More vascular endothelial growth factor and FN were expressed and localized in ovaries of Ala-TIMP1-treated rats compared to rTIMP1- and PBS-treated rats inferring MMP-independent functions. Less caspase 3 localized in ovaries of rTIMP1 compared with the other two groups, and was thus dependent on MMP action. Furthermore, after coimmunoprecipitation, more CD63 was bound to TIMP1 in ovaries of rats treated with Ala-TIMP1 than in rTIMP1-treated rats, providing evidence for another MMP-independent mechanism of ovulatory dysfunction. We predict that MMP-dependent and MMP-independent events are involved in improper fortification of the follicular wall through multiple mechanisms, such as apoptosis inhibition, extracellular matrix components and angiogenesis. Collectively, excessive peritoneal TIMP1 causes changes in ovarian dynamics, both dependently and independently of MMP inhibition.

Cellular and molecular basis for endometriosis-associated infertility.

Endometriosis is a gynecological disease characterized by the presence of endometrial glandular epithelial and stromal cells growing in the extra-uterine environment. The disease afflicts 10%-15% of menstruating women causing debilitating pain and infertility. Endometriosis appears to affect every part of a woman's reproductive system including ovarian function, oocyte quality, embryo development and implantation, uterine function and the endocrine system choreographing the reproductive process and results in infertility or spontaneous pregnancy loss. Current treatments are laden with menopausal-like side effects and many cause cessation or chemical alteration of the reproductive cycle, neither of which is conducive to achieving a pregnancy. However, despite the prevalence, physical and psychological tolls and health care costs, a cure for endometriosis has not yet been found. We hypothesize that endometriosis causes infertility via multifaceted mechanisms that are intricately interwoven thereby contributing to our lack of understanding of this disease process. Identifying and understanding the cellular and molecular mechanisms responsible for endometriosis-associated infertility might help unravel the confounding multiplicities of infertility and provide insights into novel therapeutic approaches and potentially curative treatments for endometriosis.

CPR in correctional facilities: a missed opportunity?

In the incarcerated population, the largest ethnic and racial group is Black people. Heart disease is known as the leading causes of death in the United States which can lead to cardiac arrest. Layperson cardiopulmonary resuscitation (CPR) has been shown to provide a benefit and increase likelihood of return of spontaneous circulation (ROSC). Recent research shows that in witnessed out of hospital cardiac arrests, the likelihood of receiving bystander CPR was found to be less among Black or Hispanic people when compared to White persons. One neglected area for layperson CPR training are these correctional facilities. This population is known to have higher rates of diabetes, high blood pressure and coronary artery disease, all of which contribute to an increased risk of acute coronary syndrome.A search was performed of the NEMSIS database. When comparing witnessed cardiac arrest, incidents without bystander interventions occurred more frequently than expected if the arrest was witnessed by a family member or other lay person. These interventions included bystander CPR or AED placement with or without defibrillation.The data presented shows that there is an unmet need of additional lay person CPR training in correctional facilities which could be implemented for little cost.

Diversity begets diversity: Factors contributing to emergency medicine residency gender diversity.

BACKGROUND: Although the number of women entering medical school and emergency medicine (EM) residencies has increased, female physicians are still proportionally underrepresented in EM. The goal of this study was to determine if there was a relationship between resident gender and program leadership gender. METHODS: A survey of residency leadership and residents was completed, and multivariate factor analysis was performed. RESULTS: It was found that 31% of program directors (PDs) were women, along with 42% of associate PDs, 48% of assistant PDs, 36% of residents, and 48% of chief residents. The strongest correlation between female residents and program leadership was between female residents and female assistant PDs (0.25). Female residents were also strongly correlated with female chief residents (0.40). CONCLUSIONS: Although we cannot determine the direction of causation, moving forward, programs looking to increase their female resident cohort should consider focusing efforts around increasing representation at the program leadership and chief resident level.

Effect of Ketamine on Cardiovascular Function During Procedural Sedation of Adults.

INTRODUCTION:  Ketamine is commonly used in emergency department procedural sedation. Mild to moderate transient increases in blood pressure, heart rate, and cardiac output are common due to ketamine causing an increase in sympathetic activity. There is a concern that these physiological changes could result in an increased myocardial oxygen demand that may exacerbate underlying cardiac disease. METHODS:  Convenience sample of patients older than 50 years receiving ketamine for procedural sedation in the emergency department was used (n = 31). Patients were selected to receive ketamine based on provider discretion. Primary outcome was incidence of new myocardial ischemia apparent on an electrocardiogram (ECG). ECGs were obtained prior to sedation and during the sedation approximately one minute after administration of ketamine. ECGs were reviewed by a board-certified emergency medicine physician and a board-certified cardiologist. RESULTS:  New onset ischemia was found in 9.7% (3/31) of ECGs. Of these, one was in a patient who had previously received ketamine without evidence of ischemia on the repeat ECG. There were no statistically significant differences between the groups. Evidence of ischemia on ECG did not impact patient disposition. CONCLUSIONS:  Ketamine is a useful medication in procedural sedation; however, careful attention should be made in patient selection when ketamine is the desired agent. Consideration might be made in using the lowest possible dose of ketamine to obtain adequate sedation in order to hopefully lessen the occurrence of ECG changes suggestive of myocardial ischemia. Based on this small sample, single-site study, no evidence of statistically or clinically significant ischemia was seen with the use of ketamine for procedural sedation. Ketamine remains a safe medication option in adults undergoing procedural sedation.

Neutralizing TIMP1 restores fecundity in a rat model of endometriosis and treating control rats with TIMP1 causes anomalies in ovarian function and embryo development.

Human and rat endometriotic lesions synthesize and secrete tissue inhibitor of metalloproteinase 1 (TIMP1). More TIMP1 localizes in the ovarian theca in an established rat model for endometriosis (Endo) when compared to surgical controls (Sham). We hypothesized that endometriotic TIMP1 secreted into peritoneal fluid (PF) negatively affects ovarian function and embryogenesis by altering the balance of matrix metalloproteinases (MMPs) and TIMPs. Three experiments were performed modulating TIMP1 in vitro and in vivo to investigate ovarian and embryonic anomalies. The first experiment demonstrated control embryos treated in vitro with endometriotic PF concentrations of TIMP1 developed abnormally. In the second experiment where TIMP1 was modulated in vivo, TIMP1-treated Sham rats had fewer zygotes, ovarian follicles, and corpora lutea (CLs) and poorer embryo quality and development, which is analogous to the findings in Endo rats. Importantly, Endo rats treated with a TIMP1 function-blocking antibody had zygote, follicle, and CL numbers and embryo quality similar to Sham rats. In addition, more TIMP1 inhibitory activity was found in ovaries from Endo and TIMP1-treated Sham rats than in ovaries from Sham or TIMP1 antibody-treated Endo rats. In experiment three, control rats (no surgery) treated with Endo PF had fewer follicles and CLs and increased TIMP1 localization in the ovarian theca whereas treatment with Endo PF stripped of TIMP1 or with Sham PF had no effect, providing further evidence that endometriotic TIMP1 sequesters in the ovary and inhibits MMPs necessary for ovulation. Collectively, these results showed that excessive TIMP1 was deleterious to ovulation and embryo development. Thus, novel TIMP1-modulating therapies may be developed to alleviate infertility in women with endometriosis.

Leftover narcotic analgesics among emergency department patients and methods of disposal.

OBJECTIVE: Given the increase in narcotic addiction and diversion, understanding how patients use their opioid prescriptions and store or dispose of any remainders is important. We set out to determine the frequency in which patients had leftover opioid quantities from prescriptions received in the emergency department (ED). In addition, we sought to describe patients' reasons for taking or not taking all of their prescribed medications and their strategies to manage and/or dispose of any excess or leftovers. METHODS: This cross-sectional study took place at an academic center in an urban environment in mid-Missouri with an annual emergency department volume of 55,000 patients. Potential participants were identified using a patient discharge prescription log and consisted of adult patients who received opioid prescriptions. A single researcher recruited participants via phone and invited them to participate in the study by completing a short phone survey. RESULTS: The discharge log included 301 patient encounters; of those, 170 potential participants were successfully contacted by phone and 89 agreed to participate in the survey. A majority of the participants indicated that they did not take the full prescription amount. Only 4.1% of participants disposed of their leftover opioids according to U.S. Food and Drug Administration recommendations. Those who did not dispose of their leftover opioids most frequently stored their remaining medication in a medicine cabinet or box, and a majority (77%) indicated that this storage location was unlocked. CONCLUSIONS: A majority of patients discharged from the emergency department have leftover opioids, and almost all of these leftover medications were not disposed of or stored in compliance with US Food and Drug Administration recommendations. Future research to determine what interventions could increase proper storage and disposal of leftover opioids is recommended.

Use of Emergency Department Pharmacists in Emergency Medicine Resident Milestone Assessment.

INTRODUCTION: The use of competency-based milestones for emergency medicine (EM) was mandated by the Accreditation Council for Graduate Medical Education in 2013. However, clinical competency committees (CCC) may lack diverse, objective data to assess these new competencies. To remedy the lack of objective data when assessing the pharmacotherapy sub-competency (PC5) we introduced a unique approach that actively involves departmental clinical pharmacists in determining the milestone level achieved by the resident. METHODS: Our pharmacists assess the pharmacotherapy knowledge of the residents through multiple methods: direct observation of orders, communication with the residents while performing patient care within the emergency department (ED), and real-time chart review. This observation occurs informally on a daily basis in the ED and is incorporated into the routine work of the pharmacist. The pharmacists use the PC5 sub-competency as their standard evaluation tool in this setting to keep all assessments consistent. RESULTS: Since our residency program introduced pharmacist assessment of resident pharmacotherapy knowledge, the CCC has conducted seven biannual meetings. Of the 120 separate PC5 sub-competency assessments made during those meetings there was 100% agreement between the pharmacist's assessment and the CCC's final assessment of the trainee. A survey of the CCC members concluded that the pharmacists' assessments were useful and aided in accurate resident evaluation. CONCLUSION: The use of ED pharmacists in assessing the pharmacotherapy sub-competency provides important information used in resident assessment of the PC5 milestone.