Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response.

IgE is an ancient and conserved immunoglobulin isotype with potent immunological function. Nevertheless, the regulation of IgE responses remains an enigma, and evidence of a role for IgE in host defense is limited. Here we report that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress surveillance by γδTCR+ intraepithelial lymphocytes that resulted in class switching to IgE in B cells and the accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific variable-diversity-joining (VDJ) rearrangements with unique characteristics of the complementarity-determining region CDRH3. This endogenous IgE response, via the IgE receptor FcεRI, provided protection against epithelial carcinogenesis, and expression of the gene encoding FcεRI in human squamous-cell carcinoma correlated with good disease prognosis. These data indicate a joint role for immunosurveillance by T cells and by B cells in epithelial tissues and suggest that IgE is part of the host defense against epithelial damage and tumor development.

Human dermal CD14⁺ cells are a transient population of monocyte-derived macrophages.

Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⁺ CLEC9A⁺ DCs and CD1c⁺ DCs are murine CD103⁺ DCs and CD64⁻ CD11b⁺ DCs. In addition, human tissues also contain CD14⁺ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⁺ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14⁺ monocytes and dermal CD14⁺ cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⁺ cells are CD11b⁺ CD64⁺ monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system.

Causes and predictors of failed same-day home discharge following primary hip and knee total joint arthroplasty: a Canadian perspective.

PURPOSE: Same-day home (SDH) discharge in total joint arthroplasty (TJA) has increased in popularity in recent years. The objective of this study was to evaluate the causes and predictors of failed discharges in planned SDH patients. METHODS: A consecutive cohort of patients who underwent total knee (TKA) or total hip arthroplasty (THA) that were scheduled for SDH discharge between 01 April 2019 and 31 March 2021 were retrospectively reviewed. Patient demographics, causes of failed discharge, perioperative variables, 30-day readmissions and 6-month reoperation rates were collected. Multivariate regression analysis was undertaken to identify independent predictors of failed discharge. RESULTS: The cohort consisted of 527 consecutive patients. 101 (19%) patients failed SDH discharge. The leading causes were postoperative hypotension (20%) and patients who were ineligible for the SDH pathway (19%). 2 individual surgeons, later operative start time (OR 1.3; 95% CI, 1.15-1.55; p = 0.001), ASA class IV (OR 3.4; 95% CI, 1.4-8.2; p = 0.006) and undergoing a THA (OR 2.0; 95% CI, 1.2-3.1, p = 0.004) were independent predictors of failed SDH discharge. No differences in age, BMI, gender, surgical approach or type of anaesthetic were found (p > 0.05). The 30-day readmission or 6-month reoperation were similar between groups (p > 0.05). CONCLUSIONS: Hypotension and inappropriate patient selection were the leading causes of failed SDH discharge. Significant variability existed between individual surgeons failed discharge rates. Patients undergoing a THA, classified as ASA IV or had a later operative start time were all more likely to fail SDH discharge.

Assessment of Emergency Medicine Resident Performance in a Pediatric In Situ Simulation Using Multi-Source Feedback.

Introduction Multi-source feedback (MSF) is an evaluation method mandated by the Accreditation Council for Graduate Medical Education (ACGME). The Queen's Simulation Assessment Tool (QSAT) has been validated as being able to distinguish between resident performances in a simulation setting. The QSAT has also been demonstrated to have excellent MSF agreement when used in an adult simulation performed in a simulation lab. Using the QSAT, this study sought to determine the degree of agreement of MSF in a single pediatric (Peds) simulation case conducted in situ in a Peds emergency department (ED). Methods This Institutional Review Board-approved study was conducted in a four-year emergency medicine residency. A Peds resuscitation case was developed with specific behavioral anchors on the QSAT, which uses a 1-5 scale in each of five categories: Primary Assessment, Diagnostic Actions, Therapeutic Actions, Communication, and Overall Assessment. Data was gathered from six participants for each simulation. The lead resident self-evaluated and received MSF from a junior peer resident, a fixed Peds ED nurse, a random ED nurse, and two faculty (one fixed, the other from a dyad). The agreement was calculated with intraclass correlation coefficients (ICC). Results The simulation was performed on 35 separate days over two academic years. A total of 106 MSF participants were enrolled. Enrollees included three faculty members, 35 team leaders, 34 peers, 33 ED registered nurses (RN), and one Peds RN; 50% of the enrollees were female (n=53). Mean QSAT scores ranged from 20.7 to 23.4. A fair agreement was demonstrated via ICC; there was no statistically significant difference between sources of MSF. Removing self-evaluation led to the highest ICC. ICC for any single or grouped non-faculty source of MSF was poor. Conclusion Using the QSAT, the findings from this single-site cohort suggest that faculty must be included in MSF. Self-evaluation appears to be of limited value in MSF with the QSAT. The degree of MSF agreement as gathered by the QSAT was lower in this cohort than previously reported for adult simulation cases performed in the simulation lab. This may be due to either the pediatric nature of the case, the location of the simulation, or both.

C3 Drives Inflammatory Skin Carcinogenesis Independently of C5.

Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium by UVR or chemical carcinogens. There is growing evidence that the complement system is involved in cancer immune surveillance; however, its role in cSCC remains unclear. Here, we show that complement genes are expressed in tissue from patients with cSCC, and C3 activation fragments are present in cSCC biopsies, indicating complement activation. Using a range of complement-deficient mice in a two-stage mouse model of chemically-induced cSCC, where a subclinical dose of 7,12-dimethylbenz[a]anthracene causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate promotes the outgrowth of these cells, we found that C3-deficient mice displayed a significantly reduced tumor burden, whereas an opposite phenotype was observed in mice lacking C5aR1, C5aR2, and C3a receptor. In addition, in mice unable to form the membrane attack complex, the tumor progression was unaltered. C3 deficiency did not affect the cancer response to 7,12-dimethylbenz[a]anthracene treatment alone but reduced the epidermal hyperplasia during 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Collectively, these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or membrane attack complex.

Assessment of Emergency Medicine Resident Performance in an Adult Simulation Using a Multisource Feedback Approach.

INTRODUCTION: The Accreditation Council for Graduate Medical Education (ACGME) specifically notes multisource feedback (MSF) as a recommended means of resident assessment in the emergency medicine (EM) Milestones. High-fidelity simulation is an environment wherein residents can receive MSF from various types of healthcare professionals. Previously, the Queen's Simulation Assessment Tool (QSAT) has been validated for faculty to assess residents in five categories: assessment; diagnostic actions; therapeutic actions; interpersonal communication, and overall assessment. We sought to determine whether the QSAT could be used to provide MSF using a standardized simulation case. METHODS: Prospectively after institutional review board approval, residents from a dual ACGME/osteopathic-approved postgraduate years (PGY) 1-4 EM residency were consented for participation. We developed a standardized resuscitation after overdose case with specific 1-5 Likert anchors used by the QSAT. A PGY 2-4 resident participated in the role of team leader, who completed a QSAT as self-assessment. The team consisted of a PGY-1 peer, an emergency medical services (EMS) provider, and a nurse. Two core faculty were present to administer the simulation case and assess. Demographics were gathered from all participants completing QSATs. We analyzed QSATs by each category and on cumulative score. Hypothesis testing was performed using intraclass correlation coefficients (ICC), with 95% confidence intervals. Interpretation of ICC results was based on previously published definitions. RESULTS: We enrolled 34 team leader residents along with 34 nurses. A single PGY-1, a single EMS provider and two faculty were also enrolled. Faculty provided higher cumulative QSAT scores than the other sources of MSF. QSAT scores did not increase with team leader PGY level. ICC for inter-rater reliability for all sources of MSF was 0.754 (0.572-0.867). Removing the self-evaluation scores increased inter-rater reliability to 0.838 (0.733-0.910). There was lesser agreement between faculty and nurse evaluations than from the EMS or peer evaluation. CONCLUSION: In this single-site cohort using an internally developed simulation case, the QSAT provided MSF with excellent reliability. Self-assessment decreases the reliability of the MSF, and our data suggest self-assessment should not be a component of MSF. Use of the QSAT for MSF may be considered as a source of data for clinical competency committees.