Emergency medicine residency pathways for MD/PhD trainees: A national cross-sectional study of physician-scientist training programs.

Background: Combined clinical and research training is common in residency programs outside emergency medicine (EM), and these pathways are particularly valuable for combined MD/PhD graduates planning to pursue a career as a physician-scientist. However, EM departments may not know what resources to provide these trainees during residency to create research-focused, productive, future faculty, and trainees may not know which programs support their goal of becoming a physician-scientist in EM. The objective of this study was to describe research training and resources available to MD/PhD graduates in EM residency training with a focus on dedicated research pathways. Methods: This study was a cross-sectional inventory conducted through an electronic survey of EM residency program directors. We sought to identify dedicated MD/PhD research training pathways, with a focus on both resources and training priorities. Descriptive statistics were used to summarize survey responses. Results: We collected 192 survey responses (69.6% response rate). Among respondents, 41 programs (21.4%) offered a research pathway/track, 52 (27.4%) offered a research fellowship, 22 (11.5%) offered both a residency research pathway/track and a research fellowship, and two (1.0%) offered a dedicated EM physician-scientist training pathway. Most programs considered research a priority and were enthusiastic about interviewing applicants planning a research career, but recruitment of physician-scientist applicants was not generally prioritized. Conclusions: Some EM residency programs offer combined clinical and mentored research training for prospective physician-scientists, and nearly all residency programs considered research important. Future work will focus on improving the EM physician-scientist pipeline by optimizing pathways available to trainees during residency and fellowship.

Resident Synovial Macrophages in Synovial Fluid: Implications for Immunoregulation in Infectious and Inflammatory Arthritis.

Objectives: Resident synovial macrophages (RSM) provide immune sequestration of the joint space and are likely involved in initiation and perpetuation of the joint-specific immune response. We sought to identify RSM in synovial fluid (SF) and demonstrate migratory ability, in additional to functional changes that may perpetuate a chronic inflammatory response within joint spaces. Methods: We recruited human patients presenting with undifferentiated arthritis in multiple clinical settings. We used flow cytometry to identify mononuclear cells in peripheral blood and SF. We used a novel transwell migration assay with human ex-vivo synovium obtained intra-operatively to validate flow cytometry findings. We used single cell RNA-sequencing (scRNA-seq) to further identify macrophage/monocyte subsets. ELISA was used to evaluate the bone-resorption potential of SF. Results: We were able to identify a rare population of CD14dim, OPG+, ZO-1+ cells consistent with RSM in SF via flow cytometry. These cells were relatively enriched in the SF during infectious processes, but absolutely decreased compared to healthy controls. Similar putative RSM were identified using ex vivo migration assays when MCP-1 and LPS were used as migratory stimulus. scRNA-seq revealed a population consistent with RSM transcriptionally related to CD56+ cytotoxic dendritic cells and IDO+ M2 macrophages. Conclusion: We identified a rare cell population consistent with RSM, indicating these cells are likely migratory and able to initiate or coordinate both acute (septic) or chronic (autoimmune or inflammatory) arthritis. RSM analysis via scRNA-seq indicated these cells are M2 skewed, capable of antigen presentation, and have consistent functions in both septic and inflammatory arthritis.

Modulation of Macrophage Redox and Apoptotic Processes to Leishmania infantum during Coinfection with the Tick-Borne Bacteria Borrelia burgdorferi.

Canine leishmaniosis (CanL) is a zoonotic disease caused by protozoan Leishmania infantum. Dogs with CanL are often coinfected with tick-borne bacterial pathogens, including Borrelia burgdorferi in the United States. These coinfections have been causally associated with hastened disease progression and mortality. However, the specific cellular mechanisms of how coinfections affect microbicidal responses against L. infantum are unknown. We hypothesized that B. burgdorferi coinfection impacts host macrophage effector functions, prompting L. infantum intracellular survival. In vitro experiments demonstrated that exposure to B. burgdorferi spirochetes significantly increased L. infantum parasite burden and pro-inflammatory responses in DH82 canine macrophage cells. Induction of cell death and generation of mitochondrial ROS were significantly decreased in coinfected DH82 cells compared to uninfected and L. infantum-infected cells. Ex vivo stimulation of PBMCs from L. infantum-seronegative and -seropositive subclinical dogs with spirochetes and/or total Leishmania antigens promoted limited induction of IFNγ. Coexposure significantly induced expression of pro-inflammatory cytokines and chemokines associated with Th17 differentiation and neutrophilic and monocytic recruitment in PBMCs from L. infantum-seropositive dogs. Excessive pro-inflammatory responses have previously been shown to cause CanL pathology. This work supports effective tick prevention and risk management of coinfections as critical strategies to prevent and control L. infantum progression in dogs.

Early Changes in Cement-Bone Fixation Using a Novel Rat Knee Replacement Model.

Trabecular resorption from interdigitated regions between cement and bone has been found in postmortem-retrieved knee replacements, but the viability of interdigitated bone, and the mechanism responsible for this bone loss is not known. In this work, a Sprague-Dawley (age 12 weeks) rat knee replacement model with an interdigitated cement-bone interface was developed. Morphological and cellular changes in the interdigitated region of the knee replacement over time (0, 2, 6, or 12 weeks) were determined for ovariectomy (OVX) and Sham OVX treatment groups. Interdigitated bone volume fraction (BV/TV) increased with time for Sham OVX (0.022 BV/TV/wk) and OVX (0.015 BV/TV/wk) group, but the rate of increase was greater for the Sham OVX group (p = 0.0064). Tissue mineral density followed a similar increase with time in the interdigitated regions. Trabecular resorption, when it did occur, started at the cement border with medullary-adjacent bone in the presence of osteoclasts. There was substantial loss of viable bone (~80% empty osteocyte lacunae) in the interdigitated regions. Pre-surgical fluorochrome labels remained in the interdigitated regions, and did not diminish with time, indicating that the bone was not remodeling. There was also some evidence of continued surface mineralization in the interdigitated region after cementing of the knee, but this diminished over time. Statement of clinical significance: Interdigitated bone with cement provides mechanical stability for success of knee replacements. Improved understanding of the fate of the interdigitated bone over time could lead to a better understanding of the loosening process and interventions to prevent loss of fixation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2163-2171, 2019.

Peri-Implant Distribution of Polyethylene Debris in Postmortem-Retrieved Knee Arthroplasties: Can Polyethylene Debris Explain Loss of Cement-Bone Interlock in Successful Total Knee Arthroplasties?

BACKGROUND: Loss of mechanical interlock between cement and bone with in vivo service has been recently quantified for functioning, nonrevised, cemented total knee arthroplasties (TKAs). The cause of interlocking trabecular resorption is not known. The goal of this study is to quantify the distribution of PE debris at the cement-bone interface and determine if polyethylene (PE) debris is locally associated with loss of interlock. METHODS: Fresh, nonrevised, postmortem-retrieved TKAs (n = 8) were obtained en bloc. Laboratory-prepared constructs (n = 2) served as negative controls. The intact cement-bone interface of each proximal tibia was embedded in Spurr's resin, sectioned, and imaged under polarized light to identify birefringent PE particles. PE wear particle number density was quantified at the cement-bone interface and distal to the interface, and then compared with local loss of cement-bone interlock. RESULTS: The average PE particle number density for postmortem-retrieved TKAs ranged from 8.6 (1.3) to 24.9 (3.1) particles/mm2 (standard error) but was weakly correlated with years in service. The average particle number density was twice as high as distal (>5mm) to the interface compared to at the interface. The local loss of interlock at the interface was not related to the presence, absence, or particle density of PE. CONCLUSION: PE debris can migrate extensively along the cement-bone interface of well-fixed tibial components. However, the amount of local bone loss at the cement-bone interface was not correlated with the amount of PE debris at the interface, suggesting that the observed loss of trabecular interlock in these well-fixed TKAs may be due to alternative factors.