Repair of a fistula between the aorta and right ventricular outflow tract secondary to infective endocarditis of a unicuspid aortic valve and previously repaired ventricular septal defect.

BACKGROUND: Infective endocarditis of the aortic valve can result in a wide range of destructive pathology beyond the valve leaflets and annulus which require careful surgical planning to provide appropriate debridement and reconstruction. Failure to do so can result in a failure of surgical treatment, recurrent infection and cardiac failure with concomitant high morbidity and mortality. CASE REPORT: We describe the case of a 45-year-old male with previous patch repair of a ventricular septal defect, who was diagnosed with sub-acute bacterial endocarditis of the native aortic valve and developed a new fistula from the aorta to the right ventricular outflow tract which. This was managed surgically. CONCLUSION: This unique case highlights another spectrum of infective endocarditis with a unique approach to repair and management.

Precise endoballoon positioning for High-Risk sternal re-entry in an ascending aortic pseudoaneurysm with patent coronary grafts.

Redo cardiac surgery can present a unique set of challenges even to the experienced surgeon. Although outcomes have steadily improved in the modern era; if an intraoperative adverse event occurs, there is a 5% incidence of mortality and 19% incidence of myocardial infarction, stroke or death. Overall, the modern incidence of mortality at reoperation varies but be segregated into low and higher risk cohorts depending on the planning computed tomography imaging and risk to substernal structures on re-entry. Patients with ascending aortic or root pseudoaneurysms represent a particularly difficult subset of high-risk patients requiring reoperative cardiac surgery due to the danger of exsanguination and air embolization. The gold standard for management of such cases remains the use of deep hypothermic circulatory arrest (DHCA) to achieve safe re-entry in such cases however this can result in unpredictable DHCA duration depending on the degree of pericardial adhesions. We report a case of aortic pseudoaneurysm in a patient with patent coronary grafts managed using an endoballoon precisely positioned relative to the proximal anastomoses resulting in a safe surgical re-entry and shorter DHCA time.

The moderating role of sleep duration on momentary relations between negative affect and loss-of-control eating in children and adolescents.

OBJECTIVE: Loss-of-control (LOC) eating is associated with eating disorders and obesity, and thus it is imperative to understand its momentary risk factors in order to improve intervention efforts. Negative affect has been proposed as a momentary risk factor for LOC eating, but the evidence for its effects in children and adolescents is mixed. Short sleep duration (which is very common in youth), may be one variable that moderates the relation between negative affect and subsequent LOC eating. As such, we aimed to examine the moderating role of within-person sleep duration on the momentary relations between negative affect and subsequent LOC eating. METHOD: We recruited children (N = 30) with overweight/obesity ages 8-14, who completed a 2-week ecological momentary assessment protocol assessing negative affect and LOC eating several times per day, while also wearing a sleep actigraphy device and completing sleep diaries. RESULTS: Consistent with hypotheses, within-person sleep duration moderated the next-day momentary relation between within-person negative affect and LOC eating, such that shorter sleep duration strengthened the positive relation between negative affect and loss-of-control eating. CONCLUSIONS: Results suggest that, in children and adolescents, fluctuations in sleep duration may influence susceptibility to losing control over eating after experiencing negative affect. Future research should further investigate other metrics of sleep disturbance as they relate to emotion regulation and LOC eating. Such research will set the stage for augmenting paediatric interventions to better target maintenance factors for LOC eating.

Urinary interleukin-9 in youth with type 1 diabetes mellitus.

AIMS: Interleukin-9 (IL-9) attenuates podocyte injury in experimental kidney disease, but its role in diabetic nephropathy is unknown. We sought to relate urinary IL-9 levels to the release of podocyte-derived extracellular vesicles (EVs) in youth with type 1 diabetes. We related urinary IL-9 levels to clinical variables and studied interactions between urinary IL-9, vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) on urinary albumin/creatinine ratio (ACR) a functional measure of podocyte injury. METHODS: We performed an analysis of urine samples and clinical data from a cohort of youth with type 1 diabetes (n = 53). Cytokines were measured using a Luminex platform (Eve Technologies), and nanoscale flow cytometry was employed to quantify urinary podocyte-derived EVs. All urinary measures were normalized to urinary creatinine. RESULTS: Mean age was 14.7 ± 1.6 years, and the mean time from diagnosis was 6.7 ± 2.9 years. Mean HbA1c was 70.3 ± 13.9 mmol/mol, mean ACR was 1.3 ± 1.9 mg/mmol, and mean eGFR was 140.3 ± 32.6 ml/min/1.73 m2. IL-9 was inversely related to podocyte EVs (r = - 0.56, p = 0.003). IL-9 was also inversely related to blood glucose, HbA1C and eGFR (r = - 0.44, p = 0.002; r = - 0.41, p = 0.003; r = - 0.49, p < 0.001, respectively) and positively correlated with systolic BP (r = 0.30, p = 0.04). There was a significant interaction between IL-9, EVs and ACR (p = 0.0143), and the relationship between IL-9 and ACR depended on VEGF (p = 0.0083), TNFα (p = 0.0231) and IL-6 levels (p = 0.0178). CONCLUSIONS: IL-9 is associated with podocyte injury in early type 1 diabetes, and there are complex interactions between urinary IL-9, inflammatory cytokines and ACR.

Examining the forgotten valve: outcomes of tricuspid valve surgery, a 15-year experience.

BACKGROUND: We have entered an era of renewed interest in novel approaches to surgical intervention and minimally invasive and transcatheter technique. With an aging population, isolated tricuspid valve regurgitation incidence is rising; however, referral for surgical intervention remains low. AIMS: We undertook this retrospective review to assess outcomes and challenges associated with tricuspid valve intervention. METHODS: A comprehensive retrospective review of all patients undergoing tricuspid valve intervention in our institution between 2004 and 2018 was carried out. RESULTS: A total of 259 patients who underwent a tricuspid intervention between 2004 and 2018 were identified. Of those, 229 underwent a repair and 30 underwent a replacement. Median survival for repair was 3124 days, and replacement was 2294 days. In-patient mortality was 12% for those undergoing repair and 7% for the replacement patients. Of those undergoing redo tricuspid valve intervention, eight patients (61.5%) were alive at most recent follow-up. Eight patients required intraoperative pacemakers, 2 required postoperative pacemakers. Of those who had intraoperative epicardial pacing systems placed, 5 of the 8 remained pacing dependent on most recent follow up. CONCLUSION: Beyond technical challenges, decision making regarding pacemaker requirement requires further exploration. Redo tricuspid valve surgery carries a significant mortality risk and consideration should be given to earlier intervention in this context.

Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC.

PIM kinases are constitutively active proto-oncogenic serine/threonine kinases that play a role in cell cycle progression, metabolism, inflammation and drug resistance. PIM kinases interact with and stabilize p53, c-Myc and parallel signaling pathway PI3K/Akt. This study evaluated PIM kinase expression in NSCLC and in response to PI3K/mTOR inhibition. It investigated a novel preclinical PI3K/mTOR/PIM inhibitor (IBL-301) in vitro and in patient-derived NSCLC tumor tissues. Western blot analysis confirmed PIM1, PIM2 and PIM3 are expressed in NSCLC cell lines and PIM1 is a marker of poor prognosis in patients with NSCLC. IBL-301 decreased PIM1, c-Myc, pBAD and p4EBP1 (Thr37/46) and peIF4B (S406) protein levels in-vitro and MAP kinase, PI3K-Akt and JAK/STAT pathways in tumor tissue explants. IBL-301 significantly decreased secreted pro-inflammatory cytokine MCP-1. Altered mRNA expression, including activated PIM kinase and c-Myc, was identified in Apitolisib resistant cells (H1975GR) by an IL-6/STAT3 pathway array and validated by Western blot. H1975GR cells were more sensitive to IBL-301 than parent cells. A miRNA array identified a dysregulated miRNA signature of PI3K/mTOR drug resistance consisting of regulators of PIM kinase and c-Myc (miR17-5p, miR19b-3p, miR20a-5p, miR15b-5p, miR203a, miR-206). Our data provides a rationale for co-targeting PIM kinase and PI3K-mTOR to improve therapeutic response in NSCLC.

The Role of Glomerular Epithelial Injury in Kidney Function Decline in Patients With Diabetic Kidney Disease in the TRIDENT Cohort.

INTRODUCTION: Although diabetic kidney disease (DKD) is responsible for more than half of all chronic and end-stage kidney disease (ESKD), the association of light (LM) and electron microscopic (EM) structural changes with clinical parameters and prognosis in DKD is incompletely understood. METHODS: This is an interim analysis of 62 patients diagnosed with biopsy-confirmed DKD from the multicenter TRIDENT (Transformative Research in Diabetic Nephropathy) study. Twelve LM and 8 EM descriptors, representing changes in glomeruli, tubulointerstitium, and vasculature were analyzed for their relationship with clinical measures of renal function. Patients were followed every 6 months. RESULTS: Multivariable linear regression analysis revealed that estimated glomerular filtration rate (eGFR) upon enrollment correlated the best with interstitial fibrosis. On the other hand, the rate of kidney function decline (eGFR slope) correlated the most with glomerular lesions including global glomerulosclerosis and mesangiolysis. Unbiased clustering analysis based on histopathologic data identified 3 subgroups. The first cluster, encompassing subjects with the mildest histologic lesions, had the most preserved kidney function. The second and third clusters had similar degrees of kidney dysfunction and structural damage, but differed in the degree of glomerular epithelial cell and podocyte injury (podocytopathy DKD subtype). Cox proportional hazard analysis showed that subjects in cluster 2 had the highest risk to reach ESKD (hazard ratio: 17.89; 95% confidence interval: 2.13-149.79). Glomerular epithelial hyperplasia and interstitial fibrosis were significant predictors of ESKD in the multivariate model. CONCLUSION: The study highlights the association between fibrosis and kidney function and identifies the role of glomerular epithelial changes and kidney function decline.

A study of the immune infiltrate and patient outcomes in esophageal cancer.

OBJECTIVES: Cancer patient outcomes and selection for novel therapies are heavily influenced by the immune contexture of the tumor microenvironment. Esophageal cancer is associated with poor outcomes. In contrast to colorectal cancer, where the immunoscore is increasingly used in prognostic staging, little is known about the immune cell populations in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (SCC), and their clinical significance. METHODS: Tissue microarrays were constructed from resected tumor tissue of 72 EAC patients and 23 SCC patients. Immunohistochemical staining of CD3, CD8, CD56, CD68, CD45RO, CD69, IFN-γ, IL-10, IL-4, IL-17, TGF-ß, FOXP3 and CD107a was performed. Positivity was examined in both the stromal and epithelial compartments. Statistical analysis was performed to identify differences in immune cell infiltration and functional phenotypes between cancer subtypes and tissue compartments. RESULTS: This study identified that esophageal tumors are enriched with CD45RO+ and CD8+ cells and such positivity is significantly higher in SCC compared with EAC. Furthermore, the expression of CD45RO positively correlates with that of CD8 within the tumors of both patient cohorts, suggesting a dominance of memory cytotoxic T cells. This is supported by strong positivity of degranulation marker CD107a in the stromal compartment of EAC and SCC tumors. Cytokine staining revealed a mixed pro- and anti-inflammatory profile within EAC tumors. CONCLUSIONS: Esophageal tumors are enriched with memory cytotoxic T cells. Applying these measurements to a larger cohort will ascertain the clinical utility of assessing specific lymphocyte infiltrates in EAC and SCC tumors with regards to future immunotherapy use, patient prognosis and outcomes.

Permanent pacemaker implantation rates following cardiac surgery in the modern era.

AIMS: The aim of this study was to evaluate the incidence of permanent pacemaker (PPM) implantation after cardiac surgery in our institution and investigate risk factors for PPM dependency to provide patients with accurate incidence figures at the time of consent for surgery. METHODS: Data was collected retrospectively from a single tertiary institution from October 2018 to April 2019 inclusive of 403 patients. Incidence of PPM implantation after various cardiac operations was evaluated. A univariate analysis was carried out to identify the independent risk factors related to PPM implantation. RESULTS: Ten patients required a PPM (2.48%). The most common indication for PPM implantation post-cardiac surgery was complete heart block (N = 7, 70%) followed by bradycardia/pauses (N = 2, 20%) and sick sinus syndrome (N = 1, 10%). PPM implantation after coronary artery bypass graft (CABG) surgery was the lowest (0.63%), while combined CABG and valve operations had the highest incidence (5.97%). Independent risk predictors for PPM implantation included female gender (p = 0.03), rheumatic heart disease (p = 0.008), pulmonary hypertension (p = 0.01), redo operations (p = 0.002), mitral valve procedures (p = 0.001), tricuspid valve procedures (p = 0.0003) and combined mitral and tricuspid valve procedures (p = 0.0001). Average length of intensive care unit (ICU)/high-dependency unit (HDU) stay was significantly prolonged for patients who required a PPM post-cardiac surgery. CONCLUSION: As clinicians, it can be challenging to provide our patients with accurate information on the risk of PPM implantation relative to their operation. A unit-specific data may be a more accurate method of informing our patients on this risk.

Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10 Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with PDCD10 mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of Pdcd10, but not Krit1, in gut epithelial cells. Loss of gut epithelial Pdcd10 results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of Pdcd10 in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.

A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy.

BACKGROUND: Median sternotomy has been the most commonly used approach for thymectomy to date. Recent advances in video-assisted thoracoscopic surgery (VATS) and robotic access with CO2 insufflation techniques have allowed more minimally invasive approaches. However, prior reviews have not compared robotic to both open and VATS thymectomy. METHODS: A systematic review was conducted in accordance with the PRISMA guidelines using PubMed, Embase and Scopus databases. Original research articles comparing robotic to VATS or to open thymectomy for myasthenia gravis, anterior mediastinal masses, or thymomas were included. Meta-analyses were performed for mortality, operative time, blood loss, transfusions, length of stay, conversion to open, intraoperative and postoperative complication rates, and positive/negative margin rates. RESULTS: Robotic thymectomy is a valid alternative to the open approach; advantages include: reduced blood loss [weighted mean difference (WMD): -173.03, 95% confidence interval (95% CI): -305.90, -40.17, P=0.01], fewer postoperative complications (odds ratio: 0.37, 95% CI: 0.22, 0.60, P<0.00001), a shorter hospital stay (WMD: -2.78, 95% CI: -3.22, -2.33, P<0.00001), and a lower positive margin rate (relative difference: -0.04, 95% CI: -0.07, -0.01, P=0.01), with comparable operative times (WMD: 6.73, 95% CI: -21.20, 34.66, P=0.64). Robotic thymectomy was comparable with the VATS approach; both have the advantage of avoiding median sternotomy. CONCLUSIONS: While randomized controlled studies are required to make definitive conclusions, current data suggests that robotic thymectomy is superior to open surgery and comparable to a VATS approach. Long-term follow-up is required to further delineate oncological outcomes.

Epstein-Barr virus latent gene EBNA-1 genetic diversity among transplant patients compared with patients with infectious mononucleosis.

INTRODUCTION: As a step toward evaluating the association between Epstein-Barr virus genetic diversity and post-transplant lymphoproliferative disorder (PTLD), we conducted a preliminary study to compare the genetic diversity of the EBNA-1 gene among transplant patients and patients with infectious mononucleosis (IM). METHODS: We sequenced the EBNA-1 gene in blood samples from study subjects using Sanger methodology. The sequences were aligned with a reference strain and compared with publicly available sequences. RESULTS: We analyzed 33 study samples and 25 publicly available sequences along with the reference strain B95-8. The evaluable samples were from sixteen patients with IM (median age 14.0 years, range 2-24) and 17 transplant patients. There were six children without PTLD (median age 1.93 years, range 0.79-7.46) and 11 who developed PTLD (median age 5.67 years, range 0.96-17.45). A predominant EBNA-1 variant (P-thr) was identified across the study groups. Differences were observed between the samples from the IM patients compared with the transplant samples. CONCLUSION: The predominant EBNA-1 strain is in contrast to reports of the predominant strain in North America. The results suggest differences between the EBNA-1 strains among the study groups. Further studies will examine the relationship between EBNA-1 strains and PTLD occurrence and outcomes.

A systematic review and meta-analysis of robotic versus open and video-assisted thoracoscopic surgery approaches for lobectomy.

OBJECTIVES: A number of meta-analytical and database studies have sought to compare open, video-assisted thoracoscopic surgery (VATS) and robotic operative approaches to lobectomy, often with conflicting results. Our objective was to perform a comprehensive review of these meta-analytical and database studies published to date. METHODS: A systematic review was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines using the PubMed and Scopus databases. Primary outcome was short-term mortality, and secondary outcomes were operative time, blood loss or transfusion rate, hospital stay, conversions, lymph node yield and complications. Meta-analyses of the primary and secondary outcomes were performed. RESULTS: Robotic lobectomy is a valid alternative to the VATS approach and is superior to the open approach with respect to complications [OR 0.67, 95% CI 0.58-0.76, P < 0.00001] and duration of hospital stay (WMD -1.4, 95% CI -1.96-0.85, P < 0.00001). It is inferior to both VATS and open with respect to operative duration (robotic vs. VATS; WMD 4.98, 95% CI 2.61-7.36, P < 0.001, robotic vs. open WMD 65.56, 95% CI 53.66-77.46, P < 0.00001). Robotic approach is superior with respect to 30-day mortality compared to VATS (OR 0.61, 95% CI 0.45-0.83, P = 0.001 and open approaches (OR 0.53, 95% CI 0.33-0.85, P = 0.008). CONCLUSIONS: This is the largest published systematic review and meta-analysis to date qualifying the robotic lobectomy as a reasonable alternative to VATS and open surgery. Short-term survival is superior in the robotic cohorts. No definitive conclusions on long-term outcomes can be drawn until a randomized controlled trial comparing approaches is conducted.

Limax Nd:YAG laser-assisted thoracoscopic resection of pulmonary metastases; a single centre's initial experience.

INTRODUCTION: Pulmonary metastasectomy and indeed redo-pulmonary metastasectomy are now commonly performed thoracic surgical procedures. The air-sealant, haemostatic, and necrotic properties of the KLS Martin Limax Nd:YAG laser at 1.318 µm make it an ideal tool for limited lung resection such as metastasectomy. We present our initial experience of thoracoscopic laser metastasectomy. METHODS: We reviewed data from the first seven patients in our unit to undergo thoracoscopic laser metastasectomy, in particular, patient age, gender, primary malignancy, primary treatment, complications, length of stay (LOS), and final histopathology. All procedures were performed using a two- or three-port thoracoscopic technique with some lesions requiring CT-guided wire localisation. A single drain was inserted via the camera port site and was removed upon confirmation that there was no air leak. RESULTS: Seven patients underwent thoracoscopic laser wedge metastasectomy of eight lesions in our centre between February 2017 and October 2017. The median age was 61 years. The primary disease was colorectal carcinoma in five cases, eccrine carcinoma in one case, and high-grade uterine leiomyosarcoma in one case. Only one patient had a prolonged air leak in the other six cases; the drain was removed on post-operative day 1. The median post-operative LOS was 1 day. All patients had confirmed metastatic disease with clear resection margins on histopathology. CONCLUSION: In our early experience, thoracoscopic laser wedge metastasectomy is a safe and efficient method for performance of pulmonary metastasectomy. We experienced a low complication rate and a short post-operative stay.

Long-term outcomes following partial atrioventricular septal defect (AVSD) repair in Ireland.

BACKGROUND: We describe the long-term results of partial atrioventricular septal defect (AVSD) repair in a single centre encompassing a 22-year period. Described are rates of survival, reoperation and complications. METHODS: We performed a retrospective review of 556 patients undergoing AVSD repair to identify the 51 patients who underwent partial AVSD repair in Our Lady's Children's Hospital, Crumlin, Ireland, between 1993 and 2015 with long-term follow-up where available. RESULTS: A total of 29 (56.8%) of patients were male and mean age at operation was 3.32 years. Mean weight was 13.2 kg. Trisomy 21 was present in 29 (56.8%). Five patients (9.6%) had undergone prior surgery. Mean cardiopulmonary bypass time was 89 ± 36 min and mean aortic cross-clamp time was 57 ± 28 min. One patient underwent partial AVSD repair and concomitant tracheal resection and extracorporeal membrane oxygenation decannulation. One patient was managed with suture atrial septal defect (ASD) closure, the remainder with patch repair of ASD and mitral cleft closure. The length of hospital stay was 9 ± 5 days. Median follow-up was 6.06 years (IQR, 1.65-10.2 years). There were no early mortalities. One patient died 1 year following surgery (1.9%). One patient required reoperation at an interval of 2 years for severe mitral regurgitation (1.9%). CONCLUSIONS: Short- and long-term survival following partial AVSD repair in Ireland revealed excellent results compared with other published series. Reoperation incidence also compared excellently with other reports published in the literature.

Length of Stay Beyond Medical Readiness in Neurosurgical Patients: A Prospective Analysis.

BACKGROUND: In an era of growing healthcare costs, there is increased pressure on medical care providers to discharge patients once they are medically fit. However, it is not uncommon for patients to stay beyond medical readiness (BMR). OBJECTIVE: To analyze the frequency with which patients remain in the hospital BMR. METHODS: A prospective cohort analysis utilizing a database maintained between 2014 and 2015 included 718 adults admitted to the neurosurgical service. The attending for admitted patients was asked on a daily basis as to whether the patient was medically cleared for discharge. Standard statistical analyses were performed. RESULTS: Of the 718 patients, 105 (14.6%) remained in the hospital BMR. Of the patients who presented with a spinal pathology, 17.8% had a length of stay (LOS)-BMR compared to 13.9% who presented with cerebrovascular pathologies and 14.8% who presented with a brain tumor. The average LOS-BMR was 1.8 d. Only 7.7% of patients who were discharged home had an LOS-BMR compared to 30.7% of patients who were discharged to a skilled nursing facility or rehabilitation center (P < .001). In logistic regression, a physical therapy consultation and discharge to a specialized nursing facility were both associated with a longer LOS (average 2.4 d longer, P < .001, and 6.2 d longer, P = .028, respectively). However, neither was associated with an LOS-BMR. CONCLUSION: LOS-BMR is an important process engineering concept within neurosurgery that represents a potential area for improvement to maximize limited healthcare resources. A sizeable portion of neurosurgical patients remained in the hospital BMR.

Programmed cell removal by calreticulin in tissue homeostasis and cancer.

Macrophage-mediated programmed cell removal (PrCR) is a process essential for the clearance of unwanted (damaged, dysfunctional, aged, or harmful) cells. The detection and recognition of appropriate target cells by macrophages is a critical step for successful PrCR, but its molecular mechanisms have not been delineated. Here using the models of tissue turnover, cancer immunosurveillance, and hematopoietic stem cells, we show that unwanted cells such as aging neutrophils and living cancer cells are susceptible to "labeling" by secreted calreticulin (CRT) from macrophages, enabling their clearance through PrCR. Importantly, we identified asialoglycans on the target cells to which CRT binds to regulate PrCR, and the availability of such CRT-binding sites on cancer cells correlated with the prognosis of patients in various malignancies. Our study reveals a general mechanism of target cell recognition by macrophages, which is the key for the removal of unwanted cells by PrCR in physiological and pathophysiological processes.