Cone-beam CT-based Navigation With Augmented Fluoroscopy of the Airways for Image-guided Bronchoscopic Biopsy of Peripheral Pulmonary Nodules: A Prospective Clinical Study.

BACKGROUND: Cone-beam computed tomography (CBCT) and augmented fluoroscopy (AF), in which intraprocedural CBCT data is fused with fluoroscopy, have been utilized as a novel image-guidance technique for biopsy of peripheral pulmonary lesions. The aim of this clinical study is to determine the safety and diagnostic performance of CBCT-guided bronchoscopy with advanced software tools for procedural planning and navigational guidance with AF of the airways for biopsy of peripheral pulmonary nodules. METHODS: Fifty-two consecutive subjects were prospectively enrolled in the AIRWAZE study (December 2018 to October 2019). Image-guided bronchoscopic biopsy procedures were performed under general anesthesia with specific ventilation protocols in a hybrid operating room equipped with a ceiling-mounted C-arm system. Procedural planning and image-guided bronchoscopy with CBCT and AF were performed using the Airwaze investigational device. RESULTS: A total of 58 pulmonary lesions with a median size of 19.0 mm (range 7 to 48 mm) were biopsied. The overall diagnostic yield at index procedure was 87.9% (95% CI: 77.1%-94.0%). No severe adverse events related to CBCT-guided bronchoscopy, such as pneumothorax, bleeding, or respiratory failure, were observed. CONCLUSION: CBCT-guided bronchoscopic biopsy with augmented fluoroscopic views of the airways and target lesion for navigational guidance is technically feasible and safe. Three-dimensional image-guided navigation biopsy is associated with high navigational success and a high diagnostic yield for peripheral pulmonary nodules.

Instruments to measure the ability to self-reflect: A systematic review of evidence from workplace and educational settings including health care.

INTRODUCTION: Self-reflection has become recognised as a core skill in dental education, although the ability to self-reflect is valued and measured within several professions. This review appraises the evidence for instruments available to measure the self-reflective ability of adults studying or working within any setting, not just health care. MATERIALS AND METHODS: A systematic review was conducted of 20 electronic databases (including Medline, ERIC, CINAHL and Business Source Complete) from 1975 to 2017, supplemented by citation searches. Data were extracted from each study and the studies graded against quality indicators by at least two independent reviewers, using a coding sheet. Reviewers completed a utility analysis of the assessment instruments described within included studies, appraising their reported reliability, validity, educational impact, acceptability and cost. RESULTS: A total of 131 studies met the inclusion criteria. Eighteen were judged to provide higher quality evidence for the review and three broad types of instrument were identified, namely: rubrics (or scoring guides), self-reported scales and observed behaviour. CONCLUSIONS: Three types of instrument were identified to assess the ability to self-reflect. It was not possible to recommend a single most effective instrument due to under reporting of the criteria necessary for a full utility analysis of each. The use of more than one instrument may therefore be appropriate dependent on the acceptability to the faculty, assessor, student and cost. Future research should report on the utility of assessment instruments and provide guidance on what constitutes thresholds of acceptable or unacceptable ability to self-reflect, and how this should be managed.

Soluble CD14, CD163, and CD27 biomarkers distinguish ART-suppressed youth living with HIV from healthy controls.

OBJECTIVE: To define inflammatory pathways in youth living with HIV infection (YLWH), assessments of biomarkers associated with lymphocyte and macrophage activation, vascular injury, or bone metabolism were performed in YLWH in comparison with healthy controls (HC). DESIGN: Longitudinal multicenter study comparing biomarkers in YLWH suppressed on antiretroviral therapy (ART), those with ongoing viral replication, and HC were compared using single blood samples obtained at end of study. METHODS: Twenty-three plasma proteins were measured by ELISA or multiplex assays. Principal component analysis (PCA) was used to define contributions of individual biomarkers to define outcome groups. RESULTS: The study cohort included 129 predominantly African American, male participants, 21-25 years old at entry. Nine biomarkers of lymphocyte and macrophage activation and cardiovascular injury differed between HC and YLWH. Significant positive correlations were identified between lymphocyte and macrophage activation biomarkers among HC and YLWH. Correlations distinct to YLWH were predominantly between biomarkers of macrophage and vascular inflammation. PCA of outcome groups showed HC and suppressed YLWH clustering together for lymphocyte activation biomarkers, whereas macrophage activation markers showed all YLWH clustering distinct from HC. Cardiovascular biomarkers were indistinguishable across groups. Averaged variable importance projection to assess single biomarkers that maximally contribute to discriminate among outcome groups identified soluble CD27, CD14, and CD163 as the 3 most important with TNFα and LPS also highly relevant in providing separation. CONCLUSIONS: Soluble inflammatory and lymphocyte biomarkers sufficiently distinguish YLWH from HC. Persistent macrophage activation biomarkers may provide a means to monitor consequences of HIV infection in fully suppressed YLWH.

Chewing gum vs. ibuprofen in the management of orthodontic pain, a multi-centre randomised controlled trial - the effect of anxiety.

OBJECTIVES: Pain is a common side effect of orthodontic treatment. An objective of this study, part of a large previously reported RCT on pain and analgesic use, was to determine the effect of anxiety on perceived pain and use of analgesia. METHODS: 1000 patients aged 11-17 years, undergoing upper and lower fixed appliance treatment in nine hospital departments were recruited into this two-arm parallel design randomised controlled trial. One arm was given sugar-free chewing gum and the other arm ibuprofen for pain relief. Neither the clinicians nor patients were blinded to assignment. In addition to recording pain experience and analgesic use for 3 days following appliance placement and first archwire change, each patient recorded their level of anxiety immediately following the fitting of the appliance and the first archwire change. RESULTS: 419 chewing gum group (84%) and 407 ibuprofen group (83%) questionnaires were returned following appliance placement, and 343 chewing gum group (70%) and 341 ibuprofen group (71%) questionnaires were returned following the first archwire change. The mean anxiety scores following fitting of the appliance and first archwire change were 2.7 (SD 2.1) and 1.6 (SD 1.8), respectively. There were weak but significant positive associations between anxiety scores and pain scores. Multi-level modelling produced a coefficient for anxiety of 0.23 (95% CI 0.17-0.28) for appliance placement, suggesting a small rise (0.23) on the 11-point pain scale for a one-point increase on the corresponding anxiety scale. Following archwire change, the corresponding coefficient was 0.32 (0.24-0.39). For ibuprofen use, again simple analyses suggested a relationship with anxiety. Multi-level logistic modelling produced an odds ratio for ibuprofen use of 1.11 (95% CI 1.07-1.15) at appliance placement and 1.21 (1.10-1.33) at the first archwire change. There was a 10-20% increase in the odds of using ibuprofen for each one-point increase on the anxiety scale. No such relationship was found between anxiety and chewing gum use. There were no adverse effects or harms reported during the trial. Approvals were granted by the Research Ethics Committee (08/H0106/139), R&D and MHRA (Eudract 2008-005522-36) and the trial was registered on the ISRCTN (79884739) and NIHR (6631) portfolios. Support was provided by the British Orthodontic Society Foundation. CONCLUSIONS: There was a weak positive correlation between anxiety reported and pain experienced following both the initial fitting of the fixed appliances and at the subsequent archwire change. Patients that were more anxious tended to take more ibuprofen for their pain relief.

Protease-Activated Receptor 1 Enhances Poly I:C Induction of the Antiviral Response in Macrophages and Mice.

The coagulation cascade is activated during viral infections as part of the host defense system. Coagulation proteases activate cells by cleavage of protease-activated receptors (PARs). Recently, we reported that the activation of PAR-1 enhanced interferon (IFN)ß and CXCL10 expression in cardiac fibroblasts and in the hearts of mice infected with Coxsackievirus B3. In this study, we used the double-stranded RNA mimetic polyinosinic:polycytidylic acid (poly I:C) to induce an antiviral response in macrophages and mice. Activation of PAR-1 enhanced poly I:C induction of IFNß and CXCL10 expression in the murine macrophage cell line RAW264.7, bone-marrow derived mouse macrophages (BMM) and mouse splenocytes. Next, poly I:C was used to induce a type I IFN innate immune response in the spleen and plasma of wild-type (WT) and PAR-1-/- mice. We found that poly I:C treated PAR-1-/- mice and WT mice given the thrombin inhibitor dabigatran etexilate exhibited significantly less IFNß and CXCL10 expression in the spleen and plasma than WT mice. These studies suggest that thrombin activation of PAR-1 contributes to the antiviral response in mice.

What is the truth behind the smile?

A number of arguments surround orthodontics and orthodontic treatment and this article aims to discuss the current thinking and evidence base associated with these controversies.

Which professional (non-technical) competencies are most important to the success of graduate veterinarians? A Best Evidence Medical Education (BEME) systematic review: BEME Guide No. 38.

BACKGROUND: Despite the growing prominence of professional (non-technical) competencies in veterinary education, the evidence to support their importance to veterinary graduates is unclear. AIM: To summarize current evidence within the veterinary literature for the importance of professional competencies to graduate success. METHODS: A systematic search of electronic databases was conducted (CAB Abstracts, Web of Science, PubMed, PsycINFO, ERIC, Australian and British Education Index, Dissertations & Theses) from 1988 to 2015 and limited to the veterinary discipline (veterinar* term required). Evidence was sought from consensus-based competence frameworks, surveys of stakeholder perceptions, and empirical evidence linked to relevant outcomes (e.g. employability, client satisfaction or compliance). Data extraction was completed by two independent reviewers and included a quality assessment of each source. RESULTS: Fifty-two sources were included in the review, providing evidence from expert frameworks (10 sources), stakeholder perceptions (30 sources, including one from the previous category), and empirical research (13 sources). Communication skills were the only competency to be well-supported by all three categories of evidence. Other competencies supported by multiple sources of empirical evidence include empathy, relationship-centered care, self-efficacy, and business skills. Other competencies perceived to be relatively more important included awareness of limitations, professional values, critical thinking, collaboration, and resilience. CONCLUSIONS: This review has highlighted the comparatively weak body of evidence supporting the importance of professional competencies for veterinary graduate success, with the exception of communication skills. However we stress this is more indicative of the scarcity of high-quality veterinary-based education research in the field, than of the true priority of these competencies.

Δ(9)-Tetrahydrocannabinol (THC) enhances lipopolysaccharide-stimulated tissue factor in human monocytes and monocyte-derived microvesicles.

BACKGROUND: Immunomodulatory effects in humans of Δ(9-)Tetrahydrocannabinol (THC), the psychoactive component of marijuana are controversial. Tissue factor (TF), the activator of the extrinsic coagulation cascade, is increased on circulating activated monocytes and is expressed on microvesicles released from activated monocytes during inflammatory conditions, which perpetuate coagulopathies in a number of diseases. In view of the increased medicinal use of marijuana, effects of THC on human monocytes and monocyte-derived microvesicles activated by lipopolysaccharide (LPS) were investigated. FINDINGS: Peak levels of TF procoagulant activity developed in monocytes or microvesicles 6 h following LPS treatment and were unaltered by THC. After 24 h of LPS stimulation, TF activity declined in control-treated or untreated cells and microvesicles, but persisted with THC treatment. Peak TF protein occurred within 6 h of LPS treatment independent of THC; by 24 h, TF protein declined to almost undetectable levels without THC, but was about 4-fold greater with THC. Steady-state TF mRNA levels were similar up to 2 h in the presence of LPS with or without THC, while 10-fold greater TF mRNA levels persisted over 3-24 h with THC treatment. Activation of MAPK or NF-κB pathways was unaltered by THC treatment and inflammatory cytokine IL-6 levels were unchanged. In contrast, TNF and IL-8 levels were enhanced by 20-50 %. CONCLUSIONS: THC enhances TF expression in activated monocytes resulting in elevated procoagulant activity. Marijuana use could potentiate coagulopathies in individuals with chronic immune activation such as HIV-1 infection or inflammatory bowel disease.

Δ(9)-Tetrahydrocannabinol treatment during human monocyte differentiation reduces macrophage susceptibility to HIV-1 infection.

The major psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), also acts to suppress inflammatory responses. Receptors for THC, CB1, CB2, and GPR55, are differentially expressed on multiple cell types including monocytes and macrophages, which are important modulators of inflammation in vivo and target cells for HIV-1 infection. Use of recreational and medicinal marijuana is increasing, but the consequences of marijuana exposure on HIV-1 infection are unclear. Ex vivo studies were designed to investigate effects on HIV-1 infection in macrophages exposed to THC during or following differentiation. THC treatment of primary human monocytes during differentiation reduced HIV-1 infection of subsequent macrophages by replication competent or single cycle CCR5 using viruses. In contrast, treatment of macrophages with THC immediately prior to or continuously following HIV-1 exposure failed to alter infection. Specific receptor agonists indicated that the THC effect during monocyte differentiation was mediated primarily through CB2. THC reduced the number of p24 positive cells with little to no effect on virus production per infected cell, while quantitation of intracellular viral gag pinpointed the THC effect to an early event in the viral life cycle. Cells treated during differentiation with THC displayed reduced expression of CD14, CD16, and CD163 and donor dependent increases in mRNA expression of selected viral restriction factors, suggesting a fundamental alteration in phenotype. Ultimately, the mechanism of THC suppression of HIV-1 infection was traced to a reduction in cell surface HIV receptor (CD4, CCR5 and CXCR4) expression that diminished entry efficiency.

PAR-1 contributes to the innate immune response during viral infection.

Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3-induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1(-/-) mice expressed reduced levels of IFN-ß and CXCL10 during the early phase of infection compared with Par1(+/+) mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-ß and CXCL10 expression. Par1(-/-) mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1(+/+) mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-ß expression and contributes to the innate immune response during single-stranded RNA viral infection.

The HIV-1 protease inhibitor nelfinavir activates PP2 and inhibits MAPK signaling in macrophages: a pathway to reduce inflammation.

The HIV-1 PI NFV has off-target effects upon host enzymes, including inhibition of the 20S proteasome, resulting in activation of PP1. HIV-1-associated monocyte/macrophage activation, in part a result of systemically elevated levels of microbial products including LPS, is associated with risk of mortality, independent of viremia or CD4 T cell loss. This study tested the hypothesis that activation of protein phosphatases by NFV would reduce activation of monocytes/macrophages through dephosphorylation of signal transduction proteins. NFV uniquely blocked LPS-induced production by human monocyte-derived macrophages of the inflammatory cytokines TNF and IL-6, as well as sCD14. Although NFV failed to modulate NF-κB, NFV treatment reduced phosphorylation of AKT and MAPKs. Inhibition of PP2 with okadaic acid blocked the anti-inflammatory effect of NFV, whereas the PP1 inhibitor calyculin A failed to counter the anti-inflammatory effects of NFV. For in vivo studies, plasma sCD14 and LPS were monitored in a cohort of 31 pediatric HIV-1 patients for over 2 years of therapy. Therapy, including NFV, reduced sCD14 levels significantly compared with IDV or RTV, independent of ΔLPS levels, VL, CD4 T cell frequency, or age. The hypothesis was supported as NFV induced activation of PP2 in macrophages, resulting in disruption of inflammatory cell signaling pathways. In vivo evidence supports that NFV may offer beneficial effects independent of antiviral activity by reducing severity of chronic innate immune activation in HIV-1 infection.

Tumor-derived tissue factor activates coagulation and enhances thrombosis in a mouse xenograft model of human pancreatic cancer.

Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In the present study, we analyzed tissue factor (TF) expression in 4 different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that 2 of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Only TF-positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti-human TF Ab. Of the 2 TF-positive lines, only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly, < 5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor-bearing and control mice in an inferior vena cava stenosis model. The results of the present study using a xenograft mouse model suggest that tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis.

Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin.

Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor-deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex.

Tissue factor in health and disease.

Tissue Factor (TF) is a crucial initiator of the extrinsic coagulation cascade. TF is expressed on cells which are normally sequestered from blood. However, upon injury TF is exposed to the blood resulting in activation of the coagulation cascade. TF dependent generation of coagulation proteases also initiates intracellular signaling through protease activated receptors. Pathologic TF expression is found in patients with a number of different diseases. This review will describe the roles of TF in health and disease as well as discuss approaches to reduce pathologic TF expression.

Anthracycline treatment of the human monocytic leukemia cell line THP-1 increases phosphatidylserine exposure and tissue factor activity.

INTRODUCTION: Cancer associated thrombosis is a well-recognized phenomenon that results in considerable patient morbidity and mortality. Malignancy conveys an increased risk for thrombosis and chemotherapy further elevates this risk. The pathophysiological mechanisms underlying this process remain poorly defined. MATERIALS AND METHODS: A human acute monocytic leukemia cell line (THP-1) was treated with commonly used anthracycline chemotherapeutics at concentrations similar to those found in the plasma of cancer patients. Cells were analyzed for tissue factor (TF) mRNA, protein, and activity. Microparticle (MP) TF activity was also measured. Phosphatidylserine (PS) exposure on cells and MPs was analyzed by flow cytometry. PS levels on MPs was also evaluated in an annexin V capture assay. RESULTS: Anthracycline treatment of THP-1 cells resulted in a concentration-dependent increase in cellular TF activity without a change in TF protein, which was associated with increased PS exposure on the cell surface and apoptosis. The increase in TF activity was abolished by annexin V or lactadherin indicating that PS exposure was required. Anthracycline treatment of THP-1 cells also increased the number of TF-positive MPs. CONCLUSION: Treatment of THP-1 cells with anthracyclines induces apoptosis and increases cellular TF activity. The increased activity required an increase in exposure of PS. Additionally, anthracyclines increase the release of TF-positive MPs from THP-1 cells. We propose that the increase in cellular TF activity in circulating leukemic cells, combined with increased numbers of TF-positive MPs, may contribute to thrombosis in cancer patients receiving chemotherapy.

Effect of PAR-2 Deficiency in Mice on KC Expression after Intratracheal LPS Administration.

Protease activated receptors (PAR) have been shown to play a role in inflammation. PAR-2 is expressed by numerous cells in the lung and has either proinflammatory, anti-inflammatory, or no effect depending on the model. Here, we examined the role of PAR-2 in a model of LPS-induced lung inflammation. We found that PAR-2-deficient mice had significantly less KC expression in bronchial lavage fluid compared with wild-type mice but there was no difference in MIP-2 or TNF-α expression. We also found that isolated alveolar and resident peritoneal macrophages lacking PAR-2 showed a similar deficit in KC after LPS stimulation without differences in MIP-2 or TNF-α. Infiltration of neutrophils and macrophages into the lung following LPS administration was not affected by an absence of PAR-2. Our results support the notion that PAR-2 plays a role in LPS activation of TLR4 signaling in macrophages.

Monocytic microparticles activate endothelial cells in an IL-1ß-dependent manner.

Microparticles (MPs) are shed from activated and dying cells. They can transmit signals from cell to cell, locally or at a distance through the circulation. Monocytic MPs are elevated in different diseases, including bacterial infections. Here, we investigated how monocytic MPs activate endothelial cells. We found that MPs from lipopolysaccharide (LPS)-treated THP-1 monocytic cells bind to and are internalized by human endothelial cells. MPs from LPS-treated THP-1 cells, but not untreated cells, induced phosphorylation of ERK1/2, activation of the nuclear factor-κB pathway and expression of cell adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. Similar results were observed using MPs from LPS-treated peripheral blood mononuclear cells. We next investigated the mechanism by which monocytic MPs activated endothelial cells and found that they contain IL-1ß and components of the inflammasome, including apoptosis-associated speck-like protein containing a CARD, caspase-1, and NLRP3. Importantly, knockdown of NLRP3 in THP-1 cells reduced the activity of the MPs and blockade of the IL-1 receptor on endothelial cells decreased MP-dependent induction of cell adhesion molecules. Therefore, monocytic MPs contain IL-1ß and may amplify inflammation by enhancing the activation of the endothelium.

MPs or ICs?

In this issue of Blood, György and colleagues used multiple methods to characterize cell-derived microparticles (MPs) in the plasma and synovial fluid of arthritis patients and discovered that MPs and immune complexes (ICs) have overlapping biophysical properties.

Increased hematopoietic cells in the mertk-/- mouse peritoneal cavity: a result of augmented migration.

The peritoneal cavity is recognized as an important site for autoreactive B cells prior to their transit to other immune tissues; however, little is known of the genes that may regulate this process. Mice lacking the receptor tyrosine kinase, Mertk, display a lupus-like autoimmune phenotype with splenomegaly and high autoantibodies titers. In this study, we investigate whether Mertk regulates the composition of peritoneal cells that favor an autoimmune phenotype. We found an increase in the number of macrophages, dendritic cells (DCs), plasmacytoid DCs, T cells, and B cells in the peritoneal cavity of mertk-/- mice when compared with wild-type mice. This disparity in cell numbers was not due to changes in cell proliferation or cell death. In adoptive transfer experiments, we showed an increase in migration of labeled donor cells into the mertk-/- peritoneal cavity. In addition, bone marrow chimeric mice showed hematopoietic-derived factors were also critical for T cell migration. Consistent with this migration and the increase in the number of cells, we identified elevated expression of CXCL9, its receptor CXCR3, and IL-7R on peritoneal cells from mertk-/- mice. To corroborate the migratory function of CXCR3 on cells, the depletion of CXCR3 donor cells significantly reduced the number of adoptively transferred cells that entered into the peritoneum of mertk-/- mice. This control of peritoneal cells numbers correlated with autoantibody production and was exclusively attributed to Mertk because mice lacking other family members, Axl or Tyro 3, did not display dysregulation in peritoneal cell numbers or the autoimmune phenotype.