Search

Though the exact causes of systemic lupus erythematosus (SLE) remain unknown, exposure to ultraviolet (UV) light is one of the few well-known triggers of cutaneous inflammation in SLE. However, the precise cell types which contribute to the early cutaneous inflammatory response in lupus, and the ways that UV dosing and interferons modulate these findings, have not been thoroughly dissected. Here, we explore these questions using the NZM2328 spontaneous murine model of lupus. In addition, we use iNZM mice, which share the NZM2328 background but harbor a whole-body knockout of the type I interferon (IFN) receptor, and wild-type BALB/c mice. 10-13-week-old female mice of each strain were treated with acute (300 mJ/cm 2 x1), chronic (100 mJ/cm 2 daily x5 days), or no UVB, and skin was harvested and processed for bulk RNA sequencing and flow cytometry. We identify that inflammatory pathways and gene signatures related to myeloid cells - namely neutrophils and monocyte-derived dendritic cells - are a shared feature of the acute and chronic UVB response in NZM skin greater than iNZM and wild-type skin. We also verify recruitment and activation of these cells by flow cytometry in both acutely and chronically irradiated NZM and WT mice and demonstrate that these processes are dependent on type I IFN signaling. Taken together, these data indicate a skewed IFN-driven inflammatory response to both acute and chronic UVB exposure in lupus-prone skin dominated by myeloid cells, suggesting both the importance of type I IFNs and myeloid cells as therapeutic targets for photosensitive patients and highlighting the risks of even moderate UV exposure in this patient population., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Macrophage transition from an inflammatory to reparative phenotype after tissue injury is controlled by epigenetic enzymes that regulate inflammatory gene expression. We have previously identified that the histone methyltransferase SETDB2 in macrophages drives tissue repair by repressing NF-κB-mediated inflammation. Complementary ATAC-Seq and RNA-Seq of wound macrophages isolated from mice deficient in SETDB2 in myeloid cells revealed that SETDB2 suppresses the inflammatory gene program by inhibiting chromatin accessibility at NF-κB-dependent gene promoters. We found that STAT3 was required for SETDB2 expression in macrophages, yet paradoxically, it also functioned as a binding partner of SETDB2 where it repressed SETDB2 activity by inhibiting its interaction with the NF-κB component, RELA, leading to increased RELA/NF-κB-mediated inflammatory gene expression. Furthermore, RNA-Seq in wound macrophages from STAT3-deficient mice corroborated this and revealed STAT3 and SETDB2 transcriptionally coregulate overlapping genes. Finally, in diabetic wound macrophages, STAT3 expression and STAT3/SETDB2 binding were increased. We have identified what we believe to be a novel STAT3/SETDB2 axis that modulates macrophage phenotype during tissue repair and may be an important therapeutic target for nonhealing diabetic wounds.

Macrophage (Mφ) plasticity is critical for normal wound repair; however, in type 2 diabetic wounds, Mφs persist in a low-grade inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome activity has been shown in diabetic wound Mφs; however, the molecular mechanisms regulating NLRP3 expression and activity are unclear. Here, we identified that diabetic wound keratinocytes induce Nlrp3 gene expression in wound Mφs through IL-1 receptor-mediated signaling, resulting in enhanced inflammasome activation in the presence of pathogen-associated molecular patterns and damage-associated molecular patterns. We found that IL-1α is increased in human and murine wound diabetic keratinocytes compared with nondiabetic controls and directly induces Mφ Nlrp3 expression through IL-1 receptor signaling. Mechanistically, we report that the histone demethylase, JMJD3, is increased in wound Mφs late post-injury and is induced by IL-1α from diabetic wound keratinocytes, resulting in Nlrp3 transcriptional activation through an H3K27me3-mediated mechanism. Using genetically engineered mice deficient in JMJD3 in myeloid cells (Jmjd3f/flyz2Cre+), we demonstrate that JMJD3 controls Mφ-mediated Nlrp3 expression during diabetic wound healing. Thus, our data suggest a role for keratinocyte-mediated IL-1α/IL-1R signaling in driving enhanced NLRP3 inflammasome activity in wound Mφs. These data also highlight the importance of cell cross-talk in wound tissues and identify JMJD3 and the IL-1R signaling cascade as important upstream therapeutic targets for Mφ NLRP3 inflammasome hyperactivity in nonhealing diabetic wounds., (© 2024 by the American Diabetes Association.)

Immune cell-mediated inflammation is important in normal tissue regeneration but can be pathologic in diabetic wounds. Limited literature exists on the role of CD4+ T cells in normal or diabetic wound repair; however, the imbalance of CD4+ Th17/Tregs has been found to promote inflammation in other diabetic tissues. Here, using human tissue and murine transgenic models, we identified that the histone methyltransferase Mixed-lineage-leukemia-1 (MLL1) directly regulates the Th17 transcription factor RORγ via an H3K4me3 mechanism and increases expression of Notch receptors and downstream Notch signaling. Furthermore, we found that Notch receptor signaling regulates CD4+ Th cell differentiation and is critical for normal wound repair, and loss of upstream Notch pathway mediators or receptors in CD4+ T cells resulted in the loss of CD4+ Th cell differentiation in wounds. In diabetes, MLL1 and Notch-receptor signaling was upregulated in wound CD4+ Th cells, driving CD4+ T cells toward the Th17 cell phenotype. Treatment of diabetic wound CD4+ T cells with a small molecule inhibitor of MLL1 (MI-2) yielded a significant reduction in CD4+ Th17 cells and IL-17A. This is the first study to our knowledge to identify the MLL1-mediated mechanisms responsible for regulating the Th17/Treg balance in normal and diabetic wounds and to define the complex role of Notch signaling in CD4+ T cells in wounds, where increased or decreased Notch signaling both result in pathologic wound repair. Therapeutic targeting of MLL1 in diabetic CD4+ Th cells may decrease pathologic inflammation through regulation of CD4+ T cell differentiation.

Long-standing hypertension (HTN) affects multiple organ systems and leads to pathologic arterial remodeling, which is driven largely by smooth muscle cell (SMC) plasticity. Although genome wide association studies (GWAS) have identified numerous variants associated with changes in blood pressure in humans, only a small percentage of these variants actually cause HTN. In order to identify relevant genes important in SMC function in HTN, we screened three separate human GWAS and Mendelian randomization studies to identify SNPs located within non-coding gene regions, focusing on genes encoding epigenetic enzymes, as these have been recently identified to control SMC fate in cardiovascular disease. We identified SNPs rs62059712 and rs74480102 in the promoter of the human JMJD3 gene and show that the minor C allele increases JMJD3 transcription in SMCs via increased SP1 binding to the JMJD3 promoter. Using our novel SMC-specific Jmjd3-deficient murine model ( Jmjd3 flox/flox Myh11 CreERT ), we show that loss of Jmjd3 in SMCs results in HTN, mechanistically, due to decreased EDNRB expression and a compensatory increase in EDNRA expression. As a translational corollary, through single cell RNA-sequencing (scRNA-seq) of human arteries, we found strong correlation between JMJD3 and EDNRB expression in SMCs. Further, we identified that JMJD3 is required for SMC-specific gene expression, and loss of JMJD3 in SMCs in the setting of HTN results in increased arterial remodeling by promoting the SMC synthetic phenotype. Our findings link a HTN-associated human DNA variant with regulation of SMC plasticity, revealing therapeutic targets that may be used in the screening and/or personalized treatment of HTN.

Plasmacytoid dendritic cells (pDCs) are first responders to tissue injury, where they prime naive T cells. The role of pDCs in physiologic wound repair has been examined, but little is known about pDCs in diabetic wound tissue and their interactions with naive CD4+ T cells. Diabetic wounds are characterized by increased levels of inflammatory IL-17A cytokine, partly due to increased Th17 CD4+ cells. This increased IL-17A cytokine, in excess, impairs tissue repair. Here, using human tissue and murine wound healing models, we found that diabetic wound pDCs produced excess IL-6 and TGF-β and that these cytokines skewed naive CD4+ T cells toward a Th17 inflammatory phenotype following cutaneous injury. Further, we identified that increased IL-6 cytokine production by diabetic wound pDCs is regulated by a histone demethylase, Jumonji AT-rich interactive domain 1C histone demethylase (JARID1C). Decreased JARID1C increased IL-6 transcription in diabetic pDCs, and this process was regulated upstream by an IFN-I/TYK2/JAK1,3 signaling pathway. When inhibited in nondiabetic wound pDCs, JARID1C skewed naive CD4+ T cells toward a Th17 phenotype and increased IL-17A production. Together, this suggests that diabetic wound pDCs are epigenetically altered to increase IL-6 expression that then affects T cell phenotype. These findings identify a therapeutically manipulable pathway in diabetic wounds.

Background: Pulmonary contusion (PC) is common in severely traumatized patients and can lead to respiratory failure requiring mechanical ventilation (MV). Ventilator-induced lung injury (VILI) might aggravate lung damage. Despite underrepresentation of trauma patients in trials on lung-protective MV, results are extrapolated to these patients, potentially disregarding important pathophysiological differences., Methods: Three MV protocols with different positive end-expiratory pressure (PEEP) levels: ARDSnetwork lower PEEP (ARDSnet-low), ARDSnetwork higher PEEP (ARDSnet-high), and open lung concept (OLC) were applied in swine for 24 hours following PC. Gas exchange, lung mechanics, quantitative computed tomography, and diffuse alveolar damage (DAD) score were analyzed. Results are given as median (interquartile range) at 24 hours. Statistical testing was performed using general linear models (group effect) over all measurement points and pairwise Mann-Whitney U tests for DAD., Results: There were significant differences between groups: PEEP ( p < 0.0001) ARDSnet-low (8 [8-10] cmH 2 O), ARDSnet-high (12 [12-12] cmH 2 O), OLC (21 [20-22] cmH 2 O). The fraction of arterial partial pressure of oxygen and inspired oxygen fraction ( p = 0.0016) was lowest in ARDSnet-low (78 (73-111) mm Hg) compared with ARDSnet-high (375 (365-423) mm Hg) and OLC (499 (430-523) mm Hg). The end-expiratory lung volume (EELV) differed significantly ( p < 0.0001), with highest values in OLC (64% [60-70%]) and lowest in ARDSnet-low (34% [24-37%]). Costa's surrogate for mechanical power differed significantly ( p < 0.0001), with lowest values for ARDSnet-high (73 [58-76]) compared with OLC (105 [108-116]). Diffuse alveolar damage was lower in ARDSnet-high compared with ARDSnet-low (0.0007)., Conclusion: Progression to ARDS, 24 hours after PC, was mitigated by OLC and ARDSnet-high. Both concepts restored EELV. ARDSnet-high had the lowest mechanical power surrogate and DAD. Our data suggest, that ARDSnet-high restored oxygenation and functional lung volume and reduced physiological and histological surrogates for VILI. ARDSnet-low generated unfavorable outcomes, such as loss of EELV, increased mechanical power and DAD after PC in swine. The high respiratory rate in the OLC may blunt favorable effects of lung recruitment., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

This Policy Resource and Education Paper (PREP) from the American College of Emergency Physicians (ACEP) discusses the use of high-sensitivity cardiac troponin (hs-cTn) in the emergency department setting. This brief review discusses types of hs-cTn assays as well as the interpretation of hs-cTn in the setting of various clinical factors such as renal dysfunction, sex, and the important distinction between myocardial injury versus myocardial infarction. In addition, the PREP provides one possible example of an algorithm for the use of a hs-cTn assay in patients in whom the treating clinician is concerned about potential acute coronary syndrome., (© 2023 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Macrophage plasticity is critical for normal tissue repair following injury. In pathologic states such as diabetes, macrophage plasticity is impaired, and macrophages remain in a persistent proinflammatory state; however, the reasons for this are unknown. Here, using single-cell RNA sequencing of human diabetic wounds, we identified increased JMJD3 in diabetic wound macrophages, resulting in increased inflammatory gene expression. Mechanistically, we report that in wound healing, JMJD3 directs early macrophage-mediated inflammation via JAK1,3/STAT3 signaling. However, in the diabetic state, we found that IL-6, a cytokine increased in diabetic wound tissue at later time points post-injury, regulates JMJD3 expression in diabetic wound macrophages via the JAK1,3/STAT3 pathway and that this late increase in JMJD3 induces NFκB-mediated inflammatory gene transcription in wound macrophages via an H3K27me3 mechanism. Interestingly, RNA sequencing of wound macrophages isolated from mice with JMJD3-deficient myeloid cells (Jmjd3 f/f Lyz2 Cre+ ) identified that the STING gene (Tmem173) is regulated by JMJD3 in wound macrophages. STING limits inflammatory cytokine production by wound macrophages during healing. However, in diabetic mice, its role changes to limit wound repair and enhance inflammation. This finding is important since STING is associated with chronic inflammation, and we found STING to be elevated in human and murine diabetic wound macrophages at late time points. Finally, we demonstrate that macrophage-specific, nanoparticle inhibition of JMJD3 in diabetic wounds significantly improves diabetic wound repair by decreasing inflammatory cytokines and STING. Taken together, this work highlights the central role of JMJD3 in tissue repair and identifies cell-specific targeting as a viable therapeutic strategy for nonhealing diabetic wounds., (© 2022. The Author(s).)

Pulmonary embolism (PE) remains a common and important clinical condition that cannot be accurately diagnosed on the basis of signs, symptoms, and history alone. The diagnosis of PE has been facilitated by technical advancements and multidetector CT pulmonary angiography, which is the major diagnostic modality currently used. Ventilation and perfusion scans remain largely accurate and useful in certain settings. MR angiography can be useful in some clinical scenarios and lower-extremity ultrasound can substitute by demonstrating deep vein thrombosis; however, if negative, further studies to exclude PE are indicated. In all cases, correlation with the clinical status, particularly with risk factors, improves not only the accuracy of diagnostic imaging but also overall utilization. Other diagnostic tests have limited roles. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer-reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer-reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2022 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Wound repair following acute injury requires a coordinated inflammatory response. Type I IFN signaling is important for regulating the inflammatory response after skin injury. IFN-κ, a type I IFN, has recently been found to drive skin inflammation in lupus and psoriasis; however, the role of IFN-κ in the context of normal or dysregulated wound healing is unclear. Here, we show that Ifnk expression is upregulated in keratinocytes early after injury and is essential for normal tissue repair. Under diabetic conditions, IFN-κ was decreased in wound keratinocytes, and early inflammation was impaired. Furthermore, we found that the histone methyltransferase mixed-lineage leukemia 1 (MLL1) is upregulated early following injury and regulates Ifnk expression in diabetic wound keratinocytes via an H3K4me3-mediated mechanism. Using a series of in vivo studies with a geneticall y engineered mouse model (Mll1fl/fl K14cre-) and human wound tissues from patients with T2D, we demonstrate that MLL1 controls wound keratinocyte-mediated Ifnk expression and that Mll1 expression is decreased in T2D keratinocytes. Importantly, we found the administration of IFN-κ early following injury improves diabetic tissue repair through increasing early inflammation, collagen deposition, and reepithelialization. These findings have significant implications for understanding the complex role type I IFNs play in keratinocytes in normal and diabetic wound healing. Additionally, they suggest that IFN may be a viable therapeutic target to improve diabetic wound repair.

The outpatient treatment of select emergency department patients with acute pulmonary embolism (PE) or deep vein thrombosis (DVT) has been shown to be safe, cost effective and associated with high patient satisfaction. Despite this, outpatient PE and DVT treatment remains uncommon. To address this, the American College of Emergency Physicians assembled a multidisciplinary team of content experts to provide evidence-based recommendations and practical advice to help clinicians safely treat patients with low-risk PE and DVT without hospitalization. The emergency clinician must stratify the patient's risk of clinical decompensation due to their PE or DVT as well as their risk of bleeding due to anticoagulation. The clinician must also select and start an anticoagulant and ensure that the patient has access to the medication in a timely manner. Reliable follow-up is critical, and the patient must also be educated about signs or symptoms that should prompt a return to the emergency department. To facilitate access to these recommendations, the consensus panel also created 2 web-based "point-of-care tools.", Competing Interests: CK: Grants from Janssen, Diagnostica Stago, Siemens Healthcare Diagnostics, Grifols; Consulting: Boston Scientific. DRV: Grants from Janssen. AMM: Grants from Janssen. RPR: Grants from Janssen and BMS; Consulting/Advisory Board: Janssen, BMS, Dova, Inari. AMC: grants from Janssen, Diagnostica Stago, Siemens (to institution). JH‐N: Grants from Janssen, National Institutes of Health/National Heart, Lung, and Blood Institute. K12HL 133310‐01. SJW: Grants from Janssen., (© 2021 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Non-healing wounds in Type 2 Diabetes (T2D) patients represent the most common cause of amputation in the US, with an associated 5-year mortality of nearly 50%. Our lab has examined tissue from both T2D murine models and human wounds in order to explore mechanisms contributing to impaired wound healing. Current published data in the field point to macrophage function serving a pivotal role in orchestrating appropriate wound healing. Wound macrophages in mice and patients with T2D are characterized by a persistent inflammatory state; however, the mechanisms that control this persistent inflammatory state are unknown. Current literature demonstrates that gene regulation through histone modifications, DNA modifications, and microRNA can influence macrophage plasticity during wound healing. Further, accumulating studies reveal the importance of cells such as adipocytes, infiltrating immune cells (PMNs and T cells), and keratinocytes secrete factors that may help drive macrophage polarization. This review will examine the role of macrophages in the wound healing process, along with their function and interactions with other cells, and how it is perturbed in T2D. We also explore epigenetic factors that regulate macrophage polarization in wounds, while highlighting the emerging role of other cell types that may influence macrophage phenotype following tissue injury., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Remediation is an important component of residency training that ensures residents are progressing toward competency and unsupervised practice. There is literature describing educators' attitudes about remediation; however, little is known about residents' perspectives regarding peers who are struggling and remediation. Understanding this perspective is critical to supporting struggling residents and developing successful remediation programs., Objective: The objective of this study was to describe residents' perspectives on peers who are struggling and remediation processes within graduate medical education programs., Methods: In 2015, we conducted focus groups of residents in a multi-institutional exploratory qualitative study designed to investigate resident perspectives on remediation. Focus groups included questions on identification of residents who are struggling, reasons residents face difficulty in training, attitudes toward remediation, and understanding of the remediation process. Using conventional content analysis, we analyzed the focus group data to discover common themes., Results: Eight focus groups were performed at 3 geographically distinct institutions. A total of 68 residents participated, representing 12 distinct medical specialties. Four major themes emerged from the participants' discussion: lack of transparency, negative stigma, overwhelming emotions, and a need for change., Conclusions: Resident perspectives on remediation are affected by communication, culture, and emotions. The resident participants called for change, seeking greater understanding and transparency about what it means to struggle and the process of remediation. The residents also believed that remediation can be embraced and normalized., Competing Interests: Conflict of interest: The authors declare they have no competing interests.

Background: Didactic lectures remain common in medical education. Many faculty physicians do not receive formal training on public presentations or leading instructional sessions. Coaching has emerged in medical education with the potential to positively impact skills. We sought to evaluate a novel, national faculty peer-coaching program created to improve lecture presentation skills and foster career development., Methods: This was a mixed-methods study of participant and faculty perceptions after completing the Council of Residency Directors in Emergency Medicine Academy Coaching Program. Participants completed an online evaluative survey consisting of multiple choice and Likert-type items. Program coaches participated in semistructured interviews. Descriptive statistics were reported for survey data. Thematic qualitative analysis by two independent reviewers was performed on interview data., Results: During 2012 to 2017, a total of 30 participants and 11 coaches from 37 residency programs across the United States engaged in the program. Twenty-four (80%) participants completed the survey. Eight (73%) coaches participated in semistructured interviews. Data were collected between October and December 2018. The mean ± SD numbers of national presentations participants had given before and after the coaching program were 6.92 ± 7.68 and 16.42 ± 15.43, respectively. Since their coaching, most participants (87.5%) have been invited to give a lecture at another institution. Many participants felt that the program improved their lecture evaluations, public speaking, ability to engage an audience, and professional development. Almost all (92%) would recommend the program to a colleague. The coaches perceived multiple benefits including improved skills, self-reflection, networking, career advancement, and personal fulfillment. Suggestions for improvement included improved administrative processes, more clear expectations, increased marketing, and increased participant and coach engagement., Conclusion: Participants and coaches perceived multiple benefits from this novel, national faculty coaching program. With identification of the success, challenges, and suggestions for improvement, others may benefit as they develop coaching programs in medical education., Competing Interests: The authors have no potential conflicts to disclose., (© 2021 by the Society for Academic Emergency Medicine.)

This clinical policy from the American College of Emergency Physicians is a revision of the 2009 "Clinical Policy: Critical Issues in the Management of Adult Patients Presenting to the Emergency Department With Community-Acquired Pneumonia." A writing subcommittee conducted a systematic review of the literature to derive evidence-based recommendations to answer the following clinical questions: (1) In the adult emergency department patient diagnosed with community-acquired pneumonia, what clinical decision aids can inform the determination of patient disposition? (2) In the adult emergency department patient with community-acquired pneumonia, what biomarkers can be used to direct initial antimicrobial therapy? (3) In the adult emergency department patient diagnosed with community-acquired pneumonia, does a single dose of parenteral antibiotics in the emergency department followed by oral treatment versus oral treatment alone improve outcomes? Evidence was graded and recommendations were made based on the strength of the available data., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Chronic macrophage inflammation is a hallmark of type 2 diabetes (T2D) and linked to the development of secondary diabetic complications. T2D is characterized by excess concentrations of saturated fatty acids (SFA) that activate innate immune inflammatory responses, however, mechanism(s) by which SFAs control inflammation is unknown. Using monocyte-macrophages isolated from human blood and murine models, we demonstrate that palmitate (C16:0), the most abundant circulating SFA in T2D, increases expression of the histone demethylase, Jmjd3. Upregulation of Jmjd3 results in removal of the repressive histone methylation (H3K27me3) mark on NFκB-mediated inflammatory gene promoters driving macrophage-mediated inflammation. We identify that the effects of palmitate are fatty acid specific, as laurate (C12:0) does not regulate Jmjd3 and the associated inflammatory profile. Further, palmitate-induced Jmjd3 expression is controlled via TLR4/MyD88-dependent signaling mechanism, where genetic depletion of TLR4 (Tlr4 -/- ) or MyD88 (MyD88 -/- ) negated the palmitate-induced changes in Jmjd3 and downstream NFκB-induced inflammation. Pharmacological inhibition of Jmjd3 using a small molecule inhibitor (GSK-J4) reduced macrophage inflammation and improved diabetic wound healing. Together, we conclude that palmitate contributes to the chronic Jmjd3-mediated activation of macrophages in diabetic peripheral tissue and a histone demethylase inhibitor-based therapy may represent a novel treatment for nonhealing diabetic wounds., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Blunt cardiac injuries range from myocardial concussion (commotio cordis) leading to fatal ventricular arrhythmias to myocardial contusion, cardiac chamber rupture, septal rupture, pericardial rupture, and valvular injuries. Blunt injuries account for one-fourth of the traumatic deaths in the United States. Chest radiography, transthoracic echocardiography, CT chest with and without contrast, and CT angiography are usually appropriate as the initial examination in patients with suspected blunt cardiac injury who are both hemodynamically stable and unstable. Transesophageal echocardiography and CT heart may be appropriate as examination in patients with suspected blunt cardiac injuries. This publication of blunt chest trauma-suspected cardiac injuries summarizes the literature and makes recommendations for imaging based on the available data and expert opinion. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment., (Copyright © 2020 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

This clinical policy from the American College of Emergency Physicians addresses key issues in opioid management in adult patients presenting to the emergency department. A writing subcommittee conducted a systematic review of the literature to derive evidence-based recommendations to answer the following clinical questions: (1) In adult patients experiencing opioid withdrawal, is emergency department-administered buprenorphine as effective for the management of opioid withdrawal compared with alternative management strategies? (2) In adult patients experiencing an acute painful condition, do the benefits of prescribing a short course of opioids on discharge from the emergency department outweigh the potential harms? (3) In adult patients with an acute exacerbation of noncancer chronic pain, do the benefits of prescribing a short course of opioids on discharge from the emergency department outweigh the potential harms? (4) In adult patients with an acute episode of pain being discharged from the emergency department, do the harms of a short concomitant course of opioids and muscle relaxants/sedative-hypnotics outweigh the benefits? Evidence was graded and recommendations were made based on the strength of the available data., (Copyright © 2020 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout ( Mll1 f/f Lyz2 Cre+ ), we determined that MLL1 drives Tlr4 expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the Tlr4 promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either Tlr4 ( Tlr4 -/- ) or myeloid-specific Tlr4 (Tlr4 f/f Lyz2 Cre+ ) resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation., (Copyright © 2020 by The American Association of Immunologists, Inc.)

A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines, such as TNF-α. Previous studies have shown that an altered epigenetic program directs diabetic macrophages toward a proinflammatory phenotype, contributing to a sustained inflammatory phase. Males absent on the first (MOF) is a histone acetyltransferase (HAT) that has been shown be a coactivator of TNF-α signaling and promote NF-κB-mediated gene transcription in prostate cancer cell lines. Based on MOF's role in TNF-α/NF-κB-mediated gene expression, we hypothesized that MOF influences macrophage-mediated inflammation during wound repair. We used myeloid-specific Mof-knockout (Lyz2Cre Moffl/fl) and diet-induced obese (DIO) mice to determine the function of MOF in diabetic wound healing. MOF-deficient mice exhibited reduced inflammatory cytokine gene expression. Furthermore, we found that wound macrophages from DIO mice had elevated MOF levels and higher levels of acetylated histone H4K16, MOF's primary substrate of HAT activity, on the promoters of inflammatory genes. We further identified that MOF expression could be stimulated by TNF-α and that treatment with etanercept, an FDA-approved TNF-α inhibitor, reduced MOF levels and improved wound healing in DIO mice. This report is the first to our knowledge to define an important role for MOF in regulating macrophage-mediated inflammation in wound repair and identifies TNF-α inhibition as a potential therapy for the treatment of chronic inflammation in diabetic wounds.

Context: Situativity theory posits that learning and the development of clinical reasoning skills are grounded in context. In case-based teaching, this context comes from recreating the clinical environment, through emulation, as with manikins, or description. In this study, we sought to understand the difference in student clinical reasoning abilities after facilitated patient case scenarios with or without a manikin., Methods: Fourth-year medical students in an internship readiness course were randomized into patient case scenarios without manikin (control group) and with manikin (intervention group) for a chest pain session. The control and intervention groups had identical student-led case progression and faculty debriefing objectives. Clinical reasoning skills were assessed after the session using a 64-question script concordance test (SCT). The test was developed and piloted prior to administration. Hospitalist and emergency medicine faculty responses on the test items served as the expert standard for scoring., Results: Ninety-six students were randomized to case-based sessions with ( n  = 48) or without ( n  = 48) manikin. Ninety students completed the SCT (with manikin n  = 45, without manikin n  = 45). A statistically significant mean difference on test performance between the two groups was found ( t  = 3.059, df = 88, p  = .003), with the manikin group achieving higher SCT scores., Conclusion: Use of a manikin in simulated patient case discussion significantly improves students' clinical reasoning skills, as measured by SCT. These results suggest that using a manikin to simulate a patient scenario situates learning, thereby enhancing skill development., Competing Interests: Conflict of InterestThe authors declare that they have no conflict of interest., (© International Association of Medical Science Educators 2020.)

This clinical policy from the American College of Emergency Physicians addressed key issues in the evaluation and management of adult patients presenting to the emergency department with acute headache. A writing subcommittee conducted a systematic review of the literature to derive evidence-based recommendations to answer the following clinical questions: (1) In the adult emergency department patient presenting with acute headache, are there risk-stratification strategies that reliably identify the need for emergent neuroimaging? (2) In the adult emergency department patient treated for acute primary headache, are nonopioids preferred to opioid medications? (3) In the adult emergency department patient presenting with acute headache, does a normal noncontrast head computed tomography scan performed within 6 hours of headache onset preclude the need for further diagnostic workup for subarachnoid hemorrhage? (4) In the adult emergency department patient who is still considered to be at risk for subarachnoid hemorrhage after a negative noncontrast head computed tomography, is computed tomography angiography of the head as effective as lumbar puncture to safely rule out subarachnoid hemorrhage? Evidence was graded and recommendations were made based on the strength of the available data., (Copyright © 2019 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Ultraviolet (UV) light is a known trigger of skin and possibly systemic inflammation in systemic lupus erythematosus (SLE) patients. Although type I interferons (IFN) are upregulated in SLE skin after UV exposure, the mechanisms to explain increased UVB-induced inflammation remain unclear. This paper compares the role of type I IFNs in regulating immune cell activation between wild-type and lupus-prone mice following UVB exposure. 10-week old female lupus-prone (NZM2328), wild-type (BALB/c) and iNZM mice (lack a functional type I IFN receptor on NZM2328 background) were treated on their dorsal skin with 100 mJ/cm 2 of UVB for 5 consecutive days. Following UVB treatment, draining lymph node cell populations were characterized via flow cytometry and suppression assays; treated skin was examined for changes in expression of type I IFN genes. Only NZM2328 mice showed an increase in T cell numbers and activation 2 weeks post UVB exposure. This was preceded by a significant increase in UVB-induced type I IFN expression in NZM2328 mice compared to BALB/c mice. Following UVB exposure, both BALB/c and iNZM mice demonstrated an increase in functional T regulatory (T Reg ) cells; however, this was not seen in NZM2328 mice. These data suggest a skewed UVB-mediated T cell response in lupus-prone mice where activation of T cells is enhanced secondary to a type I IFN-dependent suppression of T Reg cells. Thus, we propose type I IFNs are important for UVB-induced inflammation in lupus-prone mice and may be an effective target for prevention of UVB-mediated flares., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: The objective of this study was to review and critically appraise the medical education literature pertaining to a flipped-classroom (FC) education model, and to highlight influential papers that inform our current understanding of the role of the FC in medical education., Methods: A search of the English-language literature querying Education Resources Information Center (ERIC), PsychINFO, PubMed, and Scopus identified 296 papers related to the FC using either quantitative, qualitative, or review methods. Two reviewers independently screened each category of publications using previously established exclusion criteria. Eight reviewers then independently scored the remaining 54 publications using either a qualitative, quantitative, or review-paper scoring system. Each scoring system consisted of nine criteria and used parallel metrics that have been previously used in critical appraisals of education research., Results: A total of 54 papers (33 quantitative, four qualitative, and 17 review) on FC met a priori criteria for inclusion and were critically appraised and reviewed. The top 10 highest scoring articles (five quantitative studies, two qualitative studies, and three review papers) are summarized in this article., Conclusion: This installment of the Council of Emergency Medicine Residency Directors (CORD) Academy Critical Appraisal series highlights 10 papers that describe the current state of literature on the flipped classroom, including an analysis of the benefits and drawbacks of an FC approach, practical implications for emergency medicine educators, and next steps for future research., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

Autoimmune disease is 4 times more common in women than men. This bias is largely unexplained. Female skin is "autoimmunity prone," showing upregulation of many proinflammatory genes, even in healthy women. We previously identified VGLL3 as a putative transcription cofactor enriched in female skin. Here, we demonstrate that skin-directed overexpression of murine VGLL3 causes a severe lupus-like rash and systemic autoimmune disease that involves B cell expansion, autoantibody production, immune complex deposition, and end-organ damage. Excess epidermal VGLL3 drives a proinflammatory gene expression program that overlaps with both female skin and cutaneous lupus. This includes increased B cell-activating factor (BAFF), the only current biologic target in systemic lupus erythematosus (SLE); IFN-κ, a key inflammatory mediator in cutaneous lupus; and CXCL13, a biomarker of early-onset SLE and renal involvement. Our results demonstrate that skin-targeted overexpression of the female-biased factor VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease that is strikingly similar to SLE. This work strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity.

Introduction: Didactic lectures remain fundamental in academic medicine; however, many faculty physicians do not receive formal training in instructional delivery. In order to design a program to instill and enhance lecture skills in academic emergency medicine (EM) physicians we must first understand the gap between the current and ideal states., Methods: In 2012 the Council of Emergency Medicine Residency Directors (CORD) Academy for Scholarship designed a novel coaching program to improve teaching skills and foster career development for medical educators based on literature review and known teaching observation programs. In order to inform the refinement of the program, we performed a needs assessment of participants. Participants' needs and prior teaching experiences were gathered from self-reflection forms completed prior to engaging in the coaching program. Two independent reviewers qualitatively analyzed data using a thematic approach., Results: We analyzed data from 12 self-reflection forms. Thematic saturation was reached after nine forms. Overall inter-rater agreement was 91.5%. We categorized emerging themes into three domains: participant strengths and weaknesses; prior feedback with attempts to improve; and areas of desired mentorship. Several overlapping themes and subthemes emerged including factors pertaining to the lecturer, the audience/learner, and the content/delivery., Conclusion: This study identified several areas of need from EM educators regarding lecture skills. These results may inform faculty development efforts in this area. The authors employed a three-phase, novel, national coaching program to meet these needs., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

Ultraviolet (UV) light is an important environmental trigger for systemic lupus erythematosus (SLE) patients, yet the mechanisms by which UV light impacts disease are not fully known. This review covers evidence in both human and murine systems for the impacts of UV light on DNA damage, apoptosis, autoantigen exposure, cytokine production, inflammatory cell recruitment, and systemic flare induction. In addition, the role of the circadian clock is discussed. Evidence is compared in healthy individuals and SLE patients as well as in wild-type and lupus-prone mice. Further research is needed into the effects of UV light on cutaneous and systemic immune responses to understand how to prevent UV-light mediated lupus flares.

Systemic lupus erythematosus is an autoimmune disease characterized by increased type I IFNs, autoantibodies, and inflammatory-mediated multiorgan damage. TLR7 activation is an important contributor to systemic lupus erythematosus pathogenesis, but the mechanisms by which type I IFNs participate in TLR7-driven pathologic conditions remain uncertain. In this study, we examined the requirement for type I IFNs in TLR7-stimulated lupus nephritis. Lupus-prone NZM2328, INZM (which lack a functional type I IFN receptor), and NZM2328 IL-1β -/- mice were treated at 10 wk of age on the right ear with R848 (TLR7 agonist) or control (DMSO). Autoantibody production and proteinuria were assessed throughout treatment. Multiorgan inflammation was assessed at the time of decline in health. Renal infiltrates and mRNA expression were also examined after 14 d of treatment. Both NZM2328 and INZM mice exhibited a decline in survival after 3-4 wk of R848 but not vehicle treatment. Development of splenomegaly and liver inflammation were dependent on type I IFN. Interestingly, autoantibody production, early renal infiltration of dendritic cells, upregulation of IL-1β, and lupus nephritis occurred independent of type I IFN signaling. Development of TLR7-driven lupus nephritis was not abolished by the deletion of IL-1β. Thus, although IFN-α is sufficient to induce nephritis acceleration, our data emphasize a critical role for IFN-independent signaling in TLR7-mediated lupus nephritis. Further, despite upregulation of IL-1β after TLR7 stimulation, deletion of IL-1β is not sufficient to reduce lupus nephritis development in this model., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Background: We aimed to identify foundational non-clinical attributes expected of medical school graduates to be successful in residency., Methods: We conducted a three-round modified Delphi study with snowball sampling of experienced medical educators. In Round 1, respondents rated 28 attributes identified from a literature search. Additional attributes were proposed through invited comments. In Round 2, respondents expressed their agreement with advanced attribute definitions and examples. Consensus on final definitions and examples was obtained in Round 3., Results: Sixty-four percent (105/163) of invited educators participated in Round 1. There was broad representation of educational focus (undergraduate, graduate, and continuing medical education) and field of practice (primary care, sub-specialty, medical, and surgical). Thirteen attributes were advanced to Round 2. Ninety-seven of 105 (92%) respondents participated in Round 2, with greater than 92% agreement for all attributes. Three pairs were consolidated. In Round 3, 88% (85/97) of educators expressed greater than 92% agreement about definitions and representative examples. The final 10 foundational attributes are: communication skills, critical thinking, emotional intelligence, ethical behavior, intellectual curiosity, organizational skills, resilience, self-improvement, teamwork, and vocational commitment., Conclusion: Through a consensus-building process of medical educators, we identified and defined 10 foundational non-clinical attributes for a medical student's successful transition to residency.

Introduction: The American College of Emergency Physicians (ACEP) and the Council of Emergency Medicine Residency Directors (CORD) were invited to contribute to the 2016 Accreditation Council for Graduate Medical Education's (ACGME) Second Resident Duty Hours in the Learning and Working Environment Congress . We describe the joint process used by ACEP and CORD to capture the opinions of emergency medicine (EM) educators on the ACGME clinical and educational work hour standards, formulate recommendations, and inform subsequent congressional testimony., Methods: In 2016 our joint working group of experts in EM medical education conducted a consensus-based, mixed-methods process using survey data from medical education stakeholders in EM and expert iterative discussions to create organizational position statements and recommendations for revisions of work hour standards. A 19-item survey was administered to a convenience sample of 199 EM residency training programs using a national EM educational listserv., Results: A total of 157 educational leaders responded to the survey; 92 of 157 could be linked to specific programs, yielding a targeted response rate of 46.2% (92/199) of programs. Respondents commented on the impact of clinical and educational work-hour standards on patient safety, programmatic and personnel costs, resident caseload, and educational experience. Using survey results, comments, and iterative discussions, organizational recommendations were crafted and submitted to the ACGME., Conclusion: EM educators believe that ACGME clinical and educational work hour standards negatively impact the learning environment and are not optimal for promoting patient safety or the development of resident professional citizenship., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

Due to a miscommunication during the process of transferring this manuscript from our editorial team to Production, the Members of the American College of Emergency Physicians Clinical Policies Committee (Oversight Committee) were not properly indexed in PubMed. This has now been corrected online. The publisher would like to apologize for any inconvenience caused., (Copyright © 2017 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Introduction: During residency, some trainees require the identification and remediation of deficiencies to achieve the knowledge, skills and attitudes necessary for independent practice. Given the limited published frameworks for remediation, we characterize remediation from the perspective of educators and propose a holistic framework to guide the approach to remediation., Methods: We conducted semistructured focus groups to: explore methods for identifying struggling residents; categorize common domains of struggle; describe personal factors that contribute to difficulties; define remediation interventions and understand what constitutes successful completion. Data were analyzed through conventional content analysis., Results: Nineteen physicians across multiple specialties and institutions participated in seven focus groups. Thirteen categories emerged around remediation. Some themes addressed practical components of remediation, while others reflected barriers to the process and the impact of remediation on the resident and program. The themes were used to inform development of a novel holistic framework for remediation., Conclusions: The approach to remediation requires comprehensive identification of individual factors impacting performance. The intervention should not only include a tailored learning plan but also address confounders that impact likelihood of remediation success. Our holistic framework intends to guide educators creating remediation plans to ensure all domains are addressed.

Background: Training in innovation and entrepreneurship (I&E) in medical education has become increasingly prevalent among medical schools to train students in complex problem solving and solution design., Objective: We aim to characterize I&E education in US allopathic medical schools to provide insight into the features and objectives of this growing field., Design: I&E programs were identified in 2016 via structured searches of 158 US allopathic medical school websites. Program characteristics were identified from public program resources and structured phone interviews with program directors. Curricular themes were identified via thematic analysis of program resources, and themes referenced by >50% of programs were analyzed., Results: Thirteen programs were identified. Programs had a median age of four years, and contained a median of 13 students. Programs were led by faculty from diverse professional backgrounds, and all awarded formal recognition to graduates. Nine programs spanned all four years of medical school and ten programs required a capstone project. Thematic analysis revealed seven educational themes (innovation, entrepreneurship, technology, leadership, healthcare systems, business of medicine, and enhanced adaptability) and two teaching method themes (active learning, interdisciplinary teaching) referenced by >50% of programs., Conclusions: The landscape of medical school I&E programs is rapidly expanding to address newfound skills needed by physicians due to ongoing changes in healthcare, but programs remain relatively few and small compared to class size. This landscape analysis is the first review of I&E in medical education and may contribute to development of a formal educational framework or competency model for current or future programs., Abbreviations: AAMC: American Association of Medical Colleges; AMA: American Medical Association; I&E: Innovation and entrepreneurship.

Gene delivery using recombinant adeno-associated virus (rAAV) has emerged to the forefront demonstrating safe and effective phenotypic correction of diverse diseases including hemophilia B and Leber's congenital amaurosis. In addition to rAAV's high efficiency of transduction and the capacity for long-term transgene expression, the safety profile of rAAV remains unsoiled in humans with no deleterious vector-related consequences observed thus far. Despite these favorable attributes, rAAV vectors have a major disadvantage preventing widespread therapeutic applications; as the AAV capsid is the smallest described to date, it cannot package "large" genomes. Currently, the packaging capacity of rAAV has yet to be definitively defined but is approximately 5 kb, which has served as a limitation for large gene transfer. There are two main approaches that have been developed to overcome this limitation, split AAV vectors, and fragment AAV (fAAV) genome reassembly (Hirsch et al., Mol Ther 18(1):6-8, 2010). Split rAAV vector applications were developed based upon the finding that rAAV genomes naturally concatemerize in the cell post-transduction and are substrates for enhanced homologous recombination (HR) (Hirsch et al., Mol Ther 18(1):6-8, 2010; Duan et al., J Virol 73(1):161-169, 1999; Duan et al., J Virol 72(11):8568-8577, 1998; Duan et al., Mol Ther 4(4):383-391, 2001; Halbert et al., Nat Biotechnol 20(7):697-701, 2002). This method involves "splitting" the large transgene into two separate vectors and upon co-transduction, intracellular large gene reconstruction via vector genome concatemerization occurs via HR or nonhomologous end joining (NHEJ). Within the split rAAV approaches there currently exist three strategies: overlapping, trans-splicing, and hybrid trans-splicing (Duan et al., Mol Ther 4(4):383-391, 2001; Halbert et al., Nat Biotechnol 20(7):697-701, 2002; Ghosh et al., Mol Ther 16(1):124-130, 2008; Ghosh et al., Mol Ther 15(4):750-755, 2007). The other major strategy for AAV-mediated large gene delivery is the use of fragment AAV (fAAV) (Dong et al., Mol Ther 18(1):87-92, 2010; Hirsch et al., Mol Ther 21(12):2205-2216, 2013; Lai et al., Mol Ther 18(1):75-79, 2010; Wu et al., Mol Ther 18(1):80-86, 2010). This strategy developed following the observation that the attempted encapsidation of transgenic cassettes exceeding the packaging capacity of the AAV capsid results in the packaging of heterogeneous single-strand genome fragments (<5 kb) of both polarities (Dong et al., Mol Ther 18(1):87-92, 2010; Hirsch et al., Mol Ther 21(12):2205-2216, 2013; Lai et al., Mol Ther 18(1):75-79, 2010; Wu et al., Mol Ther 18(1):80-86, 2010). After transduction by multiple fAAV particles, the genome fragments can undergo opposite strand annealing, followed by host-mediated DNA synthesis to reconstruct the intended oversized genome within the cell. Although, there appears to be growing debate as to the most efficient method of rAAV-mediated large gene delivery, it remains possible that additional factors including the target tissue and the transgenomic sequence factor into the selection of a particular approach for a specific application (Duan et al., Mol Ther 4(4):383-391, 2001; Ghosh et al., Mol Ther 16(1):124-130, 2008; Hirsch et al., Mol Ther 21(12):2205-2216, 2013; Trapani et al., EMBO Mol Med 6(2):194-211, 2014; Ghosh et al., Hum Gene Ther 22(1):77-83, 2011). Herein we discuss the design, production, and verification of the leading rAAV large gene delivery strategies.

Wolf SJ. You're the flight surgeon: lateral epicondylitis. Aerosp Med Hum Perform. 2015; 86(12):1077-1080.

Systemic lupus erythematosus is clinically characterized by episodes of flare and remission. In patients, cutaneous exposure to ultraviolet light has been proposed as a flare trigger. However, induction of flare secondary to cutaneous exposure has been difficult to emulate in many murine lupus models. Here, we describe a system in which epidermal injury is able to trigger the development of a lupus nephritis flare in New Zealand Mixed (NZM) 2328 mice. 20-week old NZM2328 female mice underwent removal of the stratum corneum via duct tape, which resulted in rapid onset of proteinuria and death when compared to sham-stripped littermate control NZM2328 mice. This was coupled with a drop in serum C3 concentrations and dsDNA antibody levels and enhanced immune complex deposition in the glomeruli. Recruitment of CD11b(+)CD11c(+)F4/80(high) macrophages and CD11b(+)CD11c(+)F4/80(low) dendritic cells was noted prior to the onset of proteinuria in injured mice. Transcriptional changes within the kidney suggest a burst of type I IFN-mediated and inflammatory signaling which is followed by upregulation of CXCL13 following epidermal injury. Thus, we propose that tape stripping of lupus-prone NZM2328 mice is a novel model of lupus flare induction that will allow for the study of the role of cutaneous inflammation in lupus development and how crosstalk between dermal and systemic immune systems can lead to lupus flare., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cancer cells possess unique characteristics such as invasiveness, the ability to undergo epithelial-mesenchymal transition, and an inherent stemness. Cell morphology is altered during these processes and this is highly dependent on actin cytoskeleton remodeling. Regulation of the actin cytoskeleton is, therefore, important for determination of cell fate. Mutations within the TP53 (tumor suppressor p53) gene leading to loss or gain of function (GOF) of the protein are often observed in aggressive cancer cells. Here, we highlight the roles of p53 and its GOF mutants in cancer cell invasion from the perspective of the actin cytoskeleton; in particular its reorganization and regulation by cell adhesion molecules such as integrins and cadherins. We emphasize the multiple functions of p53 in the regulation of actin cytoskeleton remodeling in response to the extracellular microenvironment, and oncogene activation. Such an approach provides a new perspective in the consideration of novel targets for anti-cancer therapy.

Background: Atelectasis can provoke pulmonary and non-pulmonary complications after general anaesthesia. Unfortunately, there is no instrument to estimate atelectasis and prompt changes of mechanical ventilation during general anaesthesia. Although arterial partial pressure of oxygen (PaO2) and intrapulmonary shunt have both been suggested to correlate with atelectasis, studies yielded inconsistent results. Therefore, we investigated these correlations., Methods: Shunt, PaO2 and atelectasis were measured in 11 sheep and 23 pigs with otherwise normal lungs. In pigs, contrasting measurements were available 12 hours after induction of acute respiratory distress syndrome (ARDS). Atelectasis was calculated by computed tomography relative to total lung mass (Mtotal). We logarithmically transformed PaO2 (lnPaO2) to linearize its relationships with shunt and atelectasis. Data are given as median (interquartile range)., Results: Mtotal was 768 (715-884) g in sheep and 543 (503-583) g in pigs. Atelectasis was 26 (16-47) % in sheep and 18 (13-23) % in pigs. PaO2 (FiO2 = 1.0) was 242 (106-414) mmHg in sheep and 480 (437-514) mmHg in pigs. Shunt was 39 (29-51) % in sheep and 15 (11-20) % in pigs. Atelectasis correlated closely with lnPaO2 (R2 = 0.78) and shunt (R2 = 0.79) in sheep (P-values<0.0001). The correlation of atelectasis with lnPaO2 (R2 = 0.63) and shunt (R2 = 0.34) was weaker in pigs, but R2 increased to 0.71 for lnPaO2 and 0.72 for shunt 12 hours after induction of ARDS. In both, sheep and pigs, changes in atelectasis correlated strongly with corresponding changes in lnPaO2 and shunt., Discussion and Conclusion: In lung-healthy sheep, atelectasis correlates closely with lnPaO2 and shunt, when blood gases are measured during ventilation with pure oxygen. In lung-healthy pigs, these correlations were significantly weaker, likely because pigs have stronger hypoxic pulmonary vasoconstriction (HPV) than sheep and humans. Nevertheless, correlations improved also in pigs after blunting of HPV during ARDS. In humans, the observed relationships may aid in assessing anaesthesia-related atelectasis.

p53 (aka TP53) is a powerful tumor suppressor, and oncogenic transformation is induced when the ability of p53 to suppress tumorigenesis is compromised. p53 not only prevents tumorigenesis, but also tumor progression, that is, local invasion and distant metastasis. Recently, we showed that cytoplasmic p53 prevents RAS-driven invasion via alteration of actin cytoskeleton remodeling. This follows modulation of mitochondrial integrity. The transcriptional activity of p53 has been restored using small molecules; however, their success as cancer therapies is largely dependent on the status of downstream targets of p53. It is therefore important to elucidate the role of these downstream targets in p53 regulated tumor progression. With the recently described mechanism of tumor suppression highlighting a role of p53's downstream targets in the regulation of actin cytoskeleton dynamics and lamellipodia formation, we suggest that potential therapeutic targets may be revealed within this mechanism that can be exploited in anticancer therapy.

Purpose: Little is known about the purpose and value of the fourth year of medical school from the perspective of medical students. In this study, the authors systematically explored the year's purpose and value as determined by students., Method: In April 2011, the authors conducted semistructured focus groups with graduating fourth-year students at the University of Colorado School of Medicine to understand their perspectives on the purpose of the fourth year. Using results of a thematic analysis of the focus group data, the authors developed and administered a 10-item questionnaire to all graduating fourth-year medical students in May 2011. Questionnaire data were analyzed using descriptive statistics and exploratory factor analysis., Results: A total of 17 students participated in two focus groups. Six themes related to the purpose of the fourth year emerged from the focus group data: career development and preparation, pursuing personal interests, career identification, exploration of diverse practice settings, influence of emotion, and flexibility and individualization. The questionnaire was completed by 134 of 148 students (91% response rate). Factor analysis of the questionnaire data identified five factors: strengthening one's residency application, developing skills, pursuing personal interests, exploring diverse practice settings, and identifying a career., Conclusions: Medical students uniformly identified the fourth year of medical school as having purpose and value, but their views on the fourth year's purpose differed. This finding underscores the importance of the individualization of the fourth year. Students' perspectives should inform any decisions made about modifying fourth-year curricula and structure.