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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.

ObjectiveWe describe our Fall 2020 study of college students’ COVID-19 related behaviors, attitudes, and antibody test results.ParticipantsThe study included 1,446 randomly selected and self-enrolled undergraduate and graduate students from a midwestern university.MethodsAn online survey was distributed to a sample of students, between September and December 2020. A sub-group also participated in a SARS-CoV-2 antibody blood draw.ResultsNearly half of students reported a prior COVID-19 test with 22% indicating a positive test, which represents an 11% positivity rate across all student participants. Of those who participated in antibody testing, 15.1% tested positive for SARS-CoV-2 antibodies. Seventy-seven percent of participants said they would get vaccinated. One-third of students reported moderate to severe generalized anxiety disorder and 13% reported moderate to severe depression.ConclusionsThis study informed campus decisions in Fall 2020. The importance of effective public health messaging on campus should continue in the future.

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.

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.

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.

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.

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.

By mediating estrogen synthesis and follicular growth in response to FSH, the ovarian FSH receptor (FSHR) is essential for female fertility. Indeed, ovarian stimulation via administration of FSH to women with infertility is part of the primary therapeutic intervention used in assisted reproductive technology. In physiological and therapeutic contexts, current dogma dictates that once ovulation has occurred, FSH/FSHR signaling is no longer required for successful pregnancy outcomes. However, a continued role for FSH during pregnancy is suggested by recent studies demonstrating extraovarian FSHR in the female reproductive tract. Furthermore, functional roles for FSHR in placenta and in uterine myometrium have now been demonstrated. In placenta, vascular endothelial FSHR of fetal vessels within the chorionic villi (human) or labyrinth (mouse) mediate angiogenesis, and it has further been shown that deletion of placental Fshr in mice has deleterious effects on pregnancy. In uterine myometrium, changes in the densities of FSHR in muscle fiber and stroma in the nonpregnant state, early pregnancy, and term pregnancy differentially regulate contractile activity, suggesting that signaling through myometrial FSHR may contribute to the quieting of contractile activity required for successful implantation and that the temporal upregulation of the FSHR at term pregnancy may be required for the appropriate timing of parturition. In addition, extraovarian expression of mRNAs encoding the glycoprotein hormone α subunit and the FSH β subunit has been demonstrated, suggesting that these novel aspects of extraovarian FSH/FSHR signaling during pregnancy may be mediated by locally synthesized FSH.

It has been shown in both human and mouse placentas that follicle stimulating hormone receptor (FSHR) is expressed in fetal vascular endothelium. There are conflicting reports, however, on the role of FSH to stimulate angiogenesis in vitro in cultured endothelial cells from umbilical veins. Therefore, in this study we undertook an in vivo approach utilizing Fshr null mice to definitively address this question. In the context where all pregnant dams have identical Fshr genotypes, we generated fetuses and associated fetal portions of placenta that were Fshr wt or Fshr null and analyzed angiogenesis within the placental labyrinths. Quantitative morphometric analyses of placentas obtained at mid-gestation revealed that the percentage of the placenta composed of labyrinth is significantly decreased in Fshr null placentas relative to wt placentas. Furthermore, data presented demonstrate that within the Fshr null labyrinths, fetal vessel angiogenesis was significantly reduced relative to wt labyrinths. The results obtained with this combination of in vivo and genetic approaches conclusively demonstrate that signaling through endothelial FSHR does indeed stimulate angiogenesis and that placental Fshr is essential for normal angiogenesis of the fetal placental vasculature.

Context: The FSH receptor (FSHR) is traditionally thought to play a role in female reproductive physiology solely within the context of ovarian FSHR. However, FSHR is also expressed in endothelial cells of the placental vasculature and human umbilical cord vessels, suggesting additional facets of female reproduction regulated by extragonadal FSHR. Objective: We sought to determine the functional role of FSHR on human umbilical cord endothelial cells (HUVECs), hypothesizing that activation of the FSHR would stimulate angiogenesis. Design: The ability of FSH to stimulate several angiogenic processes in HUVECs was determined. Setting: This was a laboratory-based study using commercially prepared HUVECs. Results: Tube formation, wound healing, cell migration, cell proliferation, nitric oxide production, and cell survival were stimulated in response to FSH. Quantitative comparisons between HUVECs incubated with maximally stimulatory concentrations of FSH vs vascular endothelial growth factor (VEGF), a well-characterized angiogenic factor, revealed that FSH is as efficacious as VEGF in promoting angiogenic processes. FSH did not provoke increased secretion of VEGF by HUVECs, suggesting the direct stimulation of angiogenic processes by FSH in endothelial cells. In contrast to gonadal cells, the FSHR on HUVECs did not mediate an FSH-stimulated increase in cAMP. However, increased phosphorylation of AKT in response to FSH was observed, suggesting that FSH stimulation of HUVEC FSHR stimulates the PI3K/AKT signaling pathway. Conclusions: Our studies reveal a novel role for FSHR in female reproductive physiology. Its ability to promote angiogenesis in placental endothelial cells suggests that the FSHR may have an influential role in pregnancy.

Endometriosis-associated infertility manifests itself via multiple, poorly understood mechanisms. Our goal was to characterize signaling pathways, between peritoneal endometriotic lesions and the ovary, leading to failed ovulation. Genome-wide microarray analysis comparing ovarian tissue from an in vivo endometriosis model in the rat (Endo) with controls (Sham) identified 22 differentially expressed genes, including transiently expressed early growth response factor 1 (Egr1). The Egr1 regulates gene requisites for ovulation. The Egr1 promoter is responsive to tumor necrosis factor-alpha (TNF-α) signaling. We hypothesized that altered expression of ovarian EGR1 is induced by elevated peritoneal fluid TNF-α which is upregulated by the presence of peritoneal endometriosis. Endo rats, compared to controls, had more peritoneal fluid TNF-α and quantitative, spatial differences in Egr1 mRNA and EGR1 protein localization in follicular compartments. Interactions between elevated peritoneal fluid TNF-α and overexpression of follicular Egr1/EGR1 expression may affect downstream protease pathways impeding ovulation in endometriosis. Preliminary studies identified similar patterns of EGR1 protein localization in human ovaries from women with endometriosis and compared to those without endometriosis.

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.

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.

The cause of reduced fecundity in women with endometriosis is unknown. Expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) by both ectopic and eutopic endometrium reportedly has a role in the pathogenesis of endometriosis. We hypothesize that anomalous endometriotic TIMP protein synthesis, secretion, and localization also cause reproductive pathologies resulting in reduced fecundity. An established rat model for endometriosis (Endo) compared with nonendometriotic controls (Shams) was used to investigate reduced fecundity in endometriosis. Comparing Endo and Sham rats, Endo rats had altered ovarian dynamics, including fewer ovarian follicles and corpora lutea with luteinized unruptured follicles. Furthermore, in vivo anomalies in postovulatory oocyte structure and preimplantation embryo development, including misaligned chromosomes, nuclear and cytoplasmic fragmentation, and delayed or arrested cleavage, as well as spontaneous abortions, were found only in Endo rats. A causative role for TIMP1 in these phenomena is supported by our findings that Endo rats have more TIMP1 in their peritoneal fluid as detected by ELISA and more TIMP1 immunolocalization in the theca of antral follicles as measured by computer-assisted morphometric analysis. These data suggest that in endometriosis the accumulation of TIMP1 disrupts the normal MMP/TIMP enzymatic milieu in the peritoneal cavity and negatively affects ovarian dynamics, oocyte quality, and preimplantation embryo development, thereby decreasing fecundity. Most intriguingly, daughters of Endo rats that had no experimental interventions exhibited these same reproductive abnormalities. We predict that developmental exposure to endometriosis leads to permanent epigenetic changes in subsequent generations.

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.

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.

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.