Philip D. Anderson

International perspectives on emergency department crowding.

The maturation of emergency medicine (EM) as a specialty has coincided with dramatic increases in emergency department (ED) visit rates, both in the United States and around the world. ED crowding has become a public health problem where periodic supply and demand mismatches in ED and hospital resources cause long waiting times and delays in critical treatments. ED crowding has been associated with several negative clinical outcomes, including higher complication rates and mortality. This article describes emergency care systems and the extent of crowding across 15 countries outside of the United States: Australia, Canada, Denmark, Finland, France, Germany, Hong Kong, India, Iran, Italy, The Netherlands, Saudi Arabia, Catalonia (Spain), Sweden, and the United Kingdom. The authors are local emergency care leaders with knowledge of emergency care in their particular countries. Where available, data are provided about visit patterns in each country; however, for many of these countries, no national data are available on ED visits rates or crowding. For most of the countries included, there is both objective evidence of increases in ED visit rates and ED crowding and also subjective assessments of trends toward higher crowding in the ED. ED crowding appears to be worsening in many countries despite the presence of universal health coverage. Scandinavian countries with robust systems to manage acute care outside the ED do not report crowding is a major problem. The main cause for crowding identified by many authors is the boarding of admitted patients, similar to the United States. Many hospitals in these countries have implemented operational interventions to mitigate crowding in the ED, and some countries have imposed strict limits on ED length of stay (LOS), while others have no clear plan to mitigate crowding. An understanding of the causes and potential solutions implemented in these countries can provide a lens into how to mitigate ED crowding in the United States through health policy interventions and hospital operational changes.

Isolation of Epiblast Stem Cells from Preimplantation Mouse Embryos

Pluripotent stem cells provide a platform to interrogate control elements that function to generate all cell types of the body. Despite their utility for modeling development and disease, the relationship of mouse and human pluripotent stem cell states to one another remains largely undefined. We have shown that mouse embryonic stem (ES) cells and epiblast stem cells (EpiSCs) are distinct, pluripotent states isolated from pre- and post-implantation embryos respectively. Human ES cells are different than mouse ES cells and share defining features with EpiSCs, yet are derived from pre-implantation human embryos. Here we show that EpiSCs can be routinely derived from pre-implantation mouse embryos. The preimplantation-derived EpiSCs exhibit molecular features and functional properties consistent with bona fide EpiSCs. These results provide a simple method for isolating EpiSCs and offer direct insight into the intrinsic and extrinsic mechanisms that regulate the acquisition of distinct pluripotent states.

Nkx3.1 and Myc crossregulate shared target genes in mouse and human prostate tumorigenesis

Cooperativity between oncogenic mutations is recognized as a fundamental feature of malignant transformation, and it may be mediated by synergistic regulation of the expression of pro- and antitumorigenic target genes. However, the mechanisms by which oncogenes and tumor suppressors coregulate downstream targets and pathways remain largely unknown. Here, we used ChIP coupled to massively parallel sequencing (ChIP-seq) and gene expression profiling in mouse prostates to identify direct targets of the tumor suppressor Nkx3.1. Further analysis indicated that a substantial fraction of Nkx3.1 target genes are also direct targets of the oncoprotein Myc. We also showed that Nkx3.1 and Myc bound to and crossregulated shared target genes in mouse and human prostate epithelial cells and that Nkx3.1 could oppose the transcriptional activity of Myc. Furthermore, loss of Nkx3.1 cooperated with concurrent overexpression of Myc to promote prostate cancer in transgenic mice. In human prostate cancer patients, dysregulation of shared NKX3.1/MYC target genes was associated with disease relapse. Our results indicate that NKX3.1 and MYC coregulate prostate tumorigenesis by converging on, and crossregulating, a common set of target genes. We propose that coregulation of target gene expression by oncogenic/tumor suppressor transcription factors may represent a general mechanism underlying the cooperativity of oncogenic mutations during tumorigenesis.

Pim1 kinase is required to maintain tumorigenicity in MYC-expressing prostate cancer cells

PIM1 kinase and MYC are commonly co-expressed in human prostate cancer and synergize to induce rapidly progressing prostate cancer in mouse models. Deficiency of the Pim kinase genes is well tolerated in vivo, suggesting that PIM1 inhibition might offer an attractive therapeutic modality for prostate cancer, particularly for MYC-expressing tumors. Here we examine the molecular consequences of Pim1 and MYC overexpression in the prostate as well as the effects of depleting Pim1 in prostate carcinoma cells with high levels of MYC. Overexpression of Pim1 in the mouse prostate induces several pro-tumorigenic genetic programs including cell cycle genes and Myc-regulated genes before the induction of any discernible pathology. Pim1 depletion by RNA interference in mouse and human prostate cancer cells decreased cellular proliferation, survival, Erk signaling and tumorigenicity even when MYC levels were not significantly altered. These results indicate that PIM1 may be necessary to maintain tumorigenicity, and further support efforts aimed at developing PIM1 inhibitors for prostate cancer therapy.

The globalization of emergency medicine and its importance for public health

Emergency medicine (EM) is a global discipline that provides secondary disease prevention and is also a tool for primary prevention. It is a horizontally integrated system of emergency care consisting of access to EM care; provision of EM care in the community and during transportation of patients; and provision of care at the receiving facility or hospital emergency department. EM can offer many tools to improve public health. These tools include primary disease prevention; interventions for addressing substance abuse and interpersonal violence; education about safety practices; epidemiological surveillance; enrolment of patients in clinical research trials focusing on acute interventions; education and clinical training of health-care providers; and participation in local and regional responses to natural and man-made disasters. Public health advocates and health policy-makers can benefit from the opportunities of EM and can help overcome its challenges. Advocating the establishment and recognition of the specialty of EM worldwide can result in benefits for health-care education, help in incorporating the full scope of EM care into the system of public health, and expand the capabilities of EM for primary and secondary prevention for the benefit of the health of the public.

PIM Kinase Inhibitor AZD1208 for Treatment of MYC-Driven Prostate Cancer

BACKGROUND PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence. METHODS A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5-11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with χ(2) test. Students t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided. RESULTS AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3 ± 39% (P < .001), decreased cellular proliferation by 46 ± 14% (P = .016), and increased apoptosis by 326 ± 170% (P = .039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients. CONCLUSIONS PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation.

NFI transcription factors interact with FOXA1 to regulate prostate-specific gene expression

Androgen receptor (AR) action throughout prostate development and in maintenance of the prostatic epithelium is partly controlled by interactions between AR and forkhead box (FOX) transcription factors, particularly FOXA1. We sought to identity additional FOXA1 binding partners that may mediate prostate-specific gene expression. Here we identify the nuclear factor I (NFI) family of transcription factors as novel FOXA1 binding proteins. All four family members (NFIA, NFIB, NFIC, and NFIX) can interact with FOXA1, and knockdown studies in androgen-dependent LNCaP cells determined that modulating expression of NFI family members results in changes in AR target gene expression. This effect is probably mediated by binding of NFI family members to AR target gene promoters, because chromatin immunoprecipitation (ChIP) studies found that NFIB bound to the prostate-specific antigen enhancer. Förster resonance energy transfer studies revealed that FOXA1 is capable of bringing AR and NFIX into proximity, indicating that FOXA1 facilitates the AR and NFI interaction by bridging the complex. To determine the extent to which NFI family members regulate AR/FOXA1 target genes, motif analysis of publicly available data for ChIP followed by sequencing was undertaken. This analysis revealed that 34.4% of peaks bound by AR and FOXA1 contain NFI binding sites. Validation of 8 of these peaks by ChIP revealed that NFI family members can bind 6 of these predicted genomic elements, and 4 of the 8 associated genes undergo gene expression changes as a result of individual NFI knockdown. These observations suggest that NFI regulation of FOXA1/AR action is a frequent event, with individual family members playing distinct roles in AR target gene expression.

Learning by internal medicine residents: differences and similarities of perceptions by residents and faculty.

AbstractOBJECTIVE: To learn about what enhances or hinders learning in postgraduate medical education. DESIGN AND PARTICIPANTS: Through the use of critical incident interviews, 20 internal medicine residents and 20 attending physicians/faculty were asked to describe specific situations where resident learning had occurred and where it had not occurred. SETTING: A large teaching hospital in the Midwest. MEASUREMENTS AND MAIN RESULTS: Factors positively associated with learning were mentioned frequently (faculty involvement, interaction, and reflection in discussion), and others only rarely (knowing outcomes of effort, resident reading) by both the faculty and the residents. Others were mentioned more often by the residents (feeling relaxed) or by the faculty (technical rationality)! CONCLUSIONS: Residents and attendings do not always agree as to what facilitates resident learning. Recognizing actions that residents believe facilitate learning may help faculty more effectively promote resident learning. Because of the similarities of resident training across the country, the results from this study can be applied to other programs.

Genetic factors on mouse chromosome 18 affecting susceptibility to testicular germ cell tumors and permissiveness to embryonic stem cell derivation

Despite strong heritability, little is known about the genetic control of susceptibility to testicular germ cell tumors (TGCT) in humans or mice. Although the mouse model of spontaneous TGCTs has been extensively studied, conventional linkage analysis has failed to locate the factors that control teratocarcinogenesis in the susceptible 129 family of inbred strains. As an alternative approach, we used both chromosome substitution strains (CSS) to identify individual chromosomes that harbor susceptibility genes and a panel of congenic strains derived from a selected CSS to determine the number and location of susceptibility variants on the substituted chromosome. We showed that 129-Chr 18(MOLF) males are resistant to spontaneous TGCTs and that at least four genetic variants control susceptibility in males with this substituted chromosome. In addition, early embryonic cells from this strain fail to establish embryonic stem cell lines as efficiently as those from the parental 129/Sv strain. For the first time, 129-derived genetic variants that control TGCT susceptibility and fundamental aspects of embryonic stem cell biology have been localized in a genetic context in which the genes can be identified and functionally characterized.

Core Curricular Elements for Fellowship Training in International Emergency Medicine

OBJECTIVES The objective was to describe the common educational goals, curricular elements, and methods of evaluation used in international emergency medicine (IEM) fellowship training programs currently. IEM fellowship programs have been developed to provide formal training for emergency physicians (EPs) interested in pursuing careers in IEM. Those fellowships are variable in scope, objectives, and duration. Previously published articles have suggested a general curriculum structure for IEM fellowships. METHODS A search of MEDLINE, EMBASE, and CINAHL databases from 1950 to June 2008 was performed, combining the terms international, emergency medicine, and fellowship. Online curricula and descriptive materials from IEM fellowships listed by the Society for Academic Emergency Medicine (SAEM) were reviewed. Knowledge and skill areas common to multiple programs were organized in discrete categories. IEM fellowship directors were contacted for input and feedback. RESULTS Eight articles on IEM fellowships were identified. Two articles described a general structure for fellowship curriculum. Sixteen of 20 IEM fellowship programs had descriptive materials posted online. These information sources, plus input from seven fellowship program directors, yielded the following seven discrete knowledge and skill areas: 1) emergency medicine systems development, 2) humanitarian relief, 3) disaster management, 4) public health, 5) travel and field medicine, 6) program administration, and 7) academic skills. CONCLUSIONS While IEM fellowships vary with regard to objectives and structure, this article presents an overview of the current focus of IEM fellowship training curricula that could serve as a resource for IEM curriculum development at individual institutions.