Implementation of a formal sleep center-based screening protocol for primary aldosteronism in patients with obstructive sleep apnea.

BACKGROUND: There is a bidirectional association between primary aldosteronism and obstructive sleep apnea, with evidence suggesting that the treatment of primary aldosteronism can reduce obstructive sleep apnea severity. Current guidelines recommend screening for primary aldosteronism in patients with comorbid hypertension and obstructive sleep apnea, identifying potential candidates for treatment. However, emerging data suggest current screening practices are unsatisfactory. Moreover, data regarding the true incidence of primary aldosteronism among this population are limited. This study aimed to assess the primary aldosteronism screening rate among patients with obstructive sleep apnea and hypertension at our institution and estimate the prevalence of primary aldosteronism among this population. METHODS: Sleep studies conducted at our institution between January and September 2021 were retrospectively reviewed. Adult patients with a sleep study diagnostic of obstructive sleep apnea (respiratory disturbance index ≥5) and a diagnosis of hypertension were included. Patient medical records were reviewed and laboratory data of those with biochemical screening for primary aldosteronism were assessed by an experienced endocrinologist. Screening rates were compared before and after initiation of a screening protocol in accordance with the 2016 Endocrine Society guidelines. RESULTS: A total of 1,005 patients undergoing sleep studies were reviewed; 354 patients had comorbid obstructive sleep apnea and hypertension. Patients were predominantly male (67%), with a mean age of 58 years (standard deviation = 12.9) and mean body mass index of 34 (standard deviation = 8.1). The screening rate for primary aldosteronism among included patients was 19% (n = 67). The screening rate was significantly higher after initiation of a dedicated primary aldosteronism screening protocol (23% vs 12% prior; P = .01). Fourteen screens (21%) were positive for primary aldosteronism, whereas 45 (67%) were negative and 8 (12%) were indeterminate. Four had prior abdominal cross-sectional imaging, with 3 revealing an adrenal adenoma. Compared with patients without primary aldosteronism, patients with positive primary aldosteronism screens were more likely to have a history of hypokalemia (36% vs 4.4%; P = .002). The frequency of hyperlipidemia, diabetes mellitus, and left ventricular hypertrophy did not differ between patients with positive versus negative screens. CONCLUSION: Current screening practices for primary aldosteronism among patients with comorbid obstructive sleep apnea and hypertension are suboptimal. Patients evaluated at sleep centers may represent an optimal population for screening, as the prevalence of primary aldosteronism among this cohort appears high.

Increasing age is associated with worse outcomes in elderly patients with severe liver injury.

While the incidence of geriatric trauma continues to increase, outcomes following severe blunt liver injury (BLI) are unknown. We sought to investigate independent predictors of mortality among elderly trauma patients with severe BLI. A retrospective study of the NTDB (2014-15) identified patients with isolated, high-grade BLI. Patients were stratified into two groups, non-elderly (<65 years) and elderly (≥65 years), and then two management groups: operative within 24 h of admission and non-operative. Demographics and outcomes were compared. Multivariable logistic regression was used to estimate association with mortality. A total of 1133 patients met our inclusion criteria. 107 patients required surgery and 1011 patients were managed non-operatively. Age was independently associated with mortality (AOR 1.04, p < .001). For patients <65 years, need for operative intervention was associated with a 55 times greater likelihood of death (AOR 55.1, p < .001). In patients ≥65 years, operative intervention was associated with a 122 times greater likelihood of death (AOR 122.09, p = .005). Age is independently associated with mortality in patients with high grade BLI.

Is trauma center designation associated with disparities in discharge to rehabilitation centers among elderly patients with Traumatic Brain Injury?

BACKGROUND: We sought to evaluate the role of trauma center designation in the association of race and insurance status with disposition to rehabilitation centers among elderly patients with Traumatic Brain Injury (TBI). METHODS: The National Trauma Data Bank (2014-2015) was used to identify elderly (age ≥ 65) patients with isolated moderate to severe blunt TBI who survived to discharge. Race, insurance status, and outcomes were stratified by trauma center designation and compared. RESULTS: 3,292 patients met the inclusion criteria. Black patients were 1.5 times less likely (AOR 0.64, p = 0.01) and Latino patients were 1.7 times less likely (AOR 0.58, p = 0 0.007) to be discharged to rehabilitation centers as compared with White patients. Asian patients at Level I hospitals were more likely to be discharged to rehabilitation centers if they had private vs. non-private insurance (42.9% versus 12.7%, p = 0.01). CONCLUSION: Black and Latino patients were less likely to be discharged to rehabilitation centers compared to White patients. The etiology of these disparities deserves further study.

Improving Operating Room Turnover Time in a New York City Academic Hospital via Lean.

BACKGROUND: Prolonged operating room turnover time erodes patient and employee satisfaction and value. METHODS: Lean and value stream mapping was applied to three operating room teams at an academic health center in New York City, and a solution called Performance Improvement Team (PIT Crew) was piloted. RESULTS: Overall, 10% of operating room turnover steps were considered nonvalued and were eliminated, and 25% of previously sequential steps were performed synchronously. Seven institutional dogmas were eliminated, and three hospital policies were changed. After 35 pilot turnovers, median operating room turnover time improved from 37 minutes (range, 26 to 167 minutes) in historic matched controls to 14 minutes (range, 10 to 45 minutes, p < 0.0001) for the PIT Crew. Cost of the PIT Crew was $1,298 daily, and estimated return on investment was $19,500 per day. CONCLUSIONS: Lean and value stream mapping identifies nonvalued steps in operating room turnover and affords opportunities for efficiency. Once institutional rules and dogma are changed, culture and workflow improve and turnover time substantially improves. This process adds cost but is profitable. Scalability and sustainability are under further study, as is the "halo effect" on the culture in other non-PIT Crew operating rooms.

A Quest for Optimization of Postoperative Triage After Major Surgery.

INTRODUCTION: Innovative strategies to reduce costs while maintaining patient satisfaction and improving delivery of care are greatly needed in the setting of rapidly rising health care expenditure. Intensive care units (ICUs) represent a significant proportion of health care costs due to their high resources utilization. Currently, the decision to admit a patient to the ICU lacks standardization because of the lack of evidence-based admission criteria. The objective of our research is to develop a prediction model that can help the physician in the clinical decision-making of postoperative triage. MATERIALS AND METHODS: Our group identified a list of index events that commonly grants admission to the ICU independently of the hospital system. We analyzed correlation among 200 quantitative and semiquantitative variables for each patient in the study using a decision tree modeling (DTM). In addition, we validated the DTM against explanatory models, such as bivariate analysis, multiple logistic regression, and least absolute shrinkage and selection operator. RESULTS: Unlike explanatory modeling, DTM has several unique strengths: tree models are easy to interpret, the analysis can examine hundreds of variables at once, and offer insight into variable relative importance. In a retrospective analysis, we found that DTM was more accurate at predicting need for intensive care compared with current clinical practice. DISCUSSION: DTM and predictive modeling may enhance postoperative triage decision-making. Future areas of research include larger retrospective analyses and prospective observational studies that can lead to an improved clinical practice and better resources utilization.

Can we downstage locally advanced pancreatic cancer to resectable? A phase I/II study of induction oxaliplatin and 5-FU chemoradiation.

BACKGROUND: Half of patients with pancreatic adenocarcinoma (PC) present with regionally advanced disease. This includes borderline resectable and locally advanced unresectable tumors as defined by current NCCN guidelines for resectability. Chemoradiation (CH-RT) is used in this setting in attempt to control local disease, and possibly downstage to resectable disease. We report a phase I/II trial of a combination of 5FU/Oxaliplatin with concurrent radiation in patients presenting with borderline resectable and locally advanced unresectable pancreatic cancer. METHODS: Patients with biopsy-proven borderline resectable or locally advanced unresectable PC were eligible. Chemotherapy included continuous infusion 5FU (200 mg/m2) daily and oxaliplatin weekly for 5 weeks in dose escalation cohorts, ranging from 30 to 60 mg/m2. Concurrent radiation therapy consisted of 4,500 cGy in 25 fractions (180 cGy/fx/d) followed by a comedown to the tumor and margins for an additional 540 cGy ×3 (total dose 5,040 cGy in 28 fractions). Following completion of CH-RT, patients deemed resectable underwent surgery; those who remained unresectable for cure but did not progress (SD, stable disease) received mFOLFOX6 ×6 cycles. Survival was calculated using Kaplan-Meier analysis. End-points of the phase II portion were resectability and overall survival. RESULTS: Overall, 24 subjects (15 men and 9 women, mean age 64.5 years) were enrolled between June 2004 and December 2009 and received CH-RT. Seventeen patients were enrolled in the Phase I component of the study, fifteen of whom completed neoadjuvant therapy. Reasons for not completing treatment included grade 3 toxicities (1 patient) and withdrawal of consent (1 patient). The highest dose of oxaliplatin (60 mg/m2) was well tolerated and it was used as the recommended phase II dose. An additional 7 patients were treated in the phase II portion, 5 of whom completed CH-RT; the remaining 2 patients did not complete treatment because of grade 3 toxicities. Overall, 4/24 did not complete CH-RT. Grade 4 toxicities related to initial CH-RT were observed during phase I (n=2, pulmonary embolism and lymphopenia) and phase II (n=3, fatigue, leukopenia and thrombocytopenia). Following restaging after completion of CH-RT, 4 patients had progressed (PD); 9 patients had SD and received additional chemotherapy with mFOLFOX6 (one of them had a dramatic response after two cycles and underwent curative resection); the remaining 7 patients (29.2%) were noted to have a response and were explored: 2 had PD, 4 had SD, still unresectable, and 1 patient was resected for cure with negative margins. Overall 2 patients (8.3%) in the study received curative resection following neoadjuvant therapy. Median overall survival for the entire study population was 11.4 months. Overall survival for the two resected patients was 41.7 and 21.6 months. CONCLUSIONS: Combined modality treatment for borderline resectable and locally advanced unresectable pancreatic cancer with oxaliplatin, 5FU and radiation was reasonably well tolerated. The majority of patients remained unresectable. Survival data with this regimen were comparable to others for locally advanced pancreas cancer, suggesting the need for more novel approaches.

MRI-Based Apparent Diffusion Coefficient for Predicting Pathologic Response of Rectal Cancer After Neoadjuvant Therapy: Systematic Review and Meta-Analysis.

OBJECTIVE: The purpose of this study was to assess the use of apparent diffusion coefficient (ADC) during DWI for predicting complete pathologic response of rectal cancer after neoadjuvant therapy. MATERIALS AND METHODS: A systematic review of available literature was conducted to retrieve studies focused on the identification of complete pathologic response of locally advanced rectal cancer after neoadjuvant chemoradiation, through the assessment of ADC evaluated before, after, or both before and after treatment, as well as in terms of the difference between pretreatment and posttreatment ADC. Pooled mean pretreatment ADC, posttreatment ADC, and Δ-ADC (calculated as posttreatment ADC minus pretreatment ADC divided by pretreatment ADC and multiplied by 100) in complete responders versus incomplete responders were calculated. For each parameter, we also pooled sensitivity and specificity and calculated the area under the summary ROC curve. RESULTS: We found 10 prospective and eight retrospective studies. Overall, pathologic complete response was observed in 22.2% of patients. Pooled mean pretreatment ADC in complete responders was 0.84 × 10-3 mm2/s versus 0.89 × 10-3 mm2/s in incomplete responders (p = 0.33). Posttreatment ADC values were 1.51 × 10-3 mm2/s and 1.29 × 10-3 mm2/s, in complete and incomplete responders, respectively (p = 0.00001). The Δ-ADC percentages were also significantly higher in complete responders than in incomplete responders (59.7% vs 29.7%, respectively, p = 0.016). Pooled sensitivity, specificity, and AUC were 0.743, 0.755, and 0.841 for pretreatment ADC; 0.800, 0.737, and 0.782 for posttreatment ADC; and 0.832, 0.806, and 0.895 for Δ-ADC. CONCLUSION: Use of ADC during DWI is a promising technique for assessment of results of neoadjuvant treatment of rectal cancer.

Surgical clerkship or medical clerkship first: Does it make a difference?

INTRODUCTION: This study compares NBME surgical clerkship scores of students who completed their medicine clerkship before their surgical clerkship with the performance of those who had not previously completed their medical clerkship. METHODS: The study included 815 New York University School of Medicine students from the years 2014-2018 (571 students took medicine first, while 244 took surgery first). Performance on the surgical clerkship was assessed using the NBME SHELF examination. Statistical comparisons were performed via 2-tailed, independent-samples, unequal-variance t-tests. RESULTS: Mean NBME surgical SHELF scores of the students who had previously taken medicine were significantly higher than students who had not (mean 78.6 vs. 73.5, p < 0.001). Students who had solely medicine (as their first clerkship) before surgery also performed significantly better (mean 78.8 vs. 73.5, p < 0.001). Students who completed surgery later in the year did not perform better on the surgical SHELF, so long as both surgical clerkship cohorts had completed medicine. CONCLUSION: Students who completed their core medical clerkship prior to their surgical clerkship scored significantly better on the NBME surgical SHELF examination.

Predictors and Prognostic Implications of Perioperative Chemotherapy Completion in Gastric Cancer.

BACKGROUND: Perioperative chemotherapy in gastric cancer is increasingly used since the "MAGIC" trial, while clinical practice data outside of trials remain limited. We sought to evaluate the predictors and prognostic implications of perioperative chemotherapy completion in patients undergoing curative-intent gastrectomy across multiple US institutions. METHODS: Patients who underwent curative-intent resection of gastric adenocarcinoma between 2000 and 2012 in eight institutions of the US Gastric Cancer Collaborative were identified. Patients who received preoperative chemotherapy were included, while those who died within 90 days or with unknown adjuvant chemotherapy status were excluded. Predictors of chemotherapy completion and survival were identified using multivariable logistic regression and Cox proportional hazards. RESULTS: One hundred sixty three patients were included (median age 63.3, 36.8% female). The postoperative component of perioperative chemotherapy was administered in 112 (68.7%) patients. Factors independently associated with receipt of adjuvant chemotherapy were younger age (odds ratio (OR) 2.73, P = 0.03), T3 tumors (OR 14.3, P = 0.04), lymph node metastasis (OR 5.82, P = 0.03), and D2 lymphadenectomy (OR 4.12, P = 0.007), and, inversely, postoperative complications (OR 0.25, P = 0.008). Median overall survival (OS) was 25.1 months and 5-year OS was 36.5%. Predictors of OS were preexisting cardiac disease (hazard ratio (HR) 2.7, 95% CI 1.13-6.46), concurrent splenectomy (HR 4.11, 95% CI 1.68-10.0), tumor stage (reference stage I; stage II HR 2.62; 95% CI 0.99-6.94; stage III HR 4.86, 95% CI 1.81-13.02), and D2 lymphadenectomy (HR 0.43, 95% CI 0.19-0.95). After accounting for these factors, adjuvant chemotherapy administration was associated with improved OS (HR 0.33, 95% CI 0.14-0.82). CONCLUSION: Completion of perioperative chemotherapy was successful in two thirds of patients with gastric cancer and was independently associated with improved survival.

Factor VIII elevation may contribute to portomesenteric vein thrombosis after laparoscopic sleeve gastrectomy: a multicenter review of 40 patients.

BACKGROUND: Portomesenteric vein thrombosis (PMVT) has been increasingly reported after laparoscopic sleeve gastrectomy (LSG). Factor VIII (FVIII) is a plasma sialoglycoprotein that plays an essential role in hemostasis. There is increasing evidence that FVIII elevation constitutes a clinically important risk factor for venous thrombosis. OBJECTIVES: To report the prevalence of FVIII elevation as well as other clinical characteristics in a multicenter series of patients who developed PMVT after LSG. SETTING: University hospitals. METHODS: A retrospective review was conducted of all patients that developed PMVT after laparoscopic bariatric surgery from 2006 to 2016 at 6 high-volume bariatric surgery centers. RESULTS: Forty patients who developed PMVT postoperatively, all after LSG, were identified. During this timeframe, 25,569 laparoscopic bariatric surgery cases were performed, including 9749 LSG (PMVT incidence after LSG = .4%). Mean age and body mass index were 40 years (18-65) and 43.4 kg/m2 (35-59.7), respectively. Abdominal pain was the most common (98%) presenting symptom. Of patients, 92% had a hematologic abnormality identified, and of these, FVIII elevation was the most common (76%). The vast majority (90%) was successfully managed with therapeutic anticoagulation alone. A smaller number of patients required small bowel resection (n = 2) and surgical thrombectomy (n = 1). There were no mortalities. CONCLUSIONS: A high index of clinical suspicion and prompt diagnosis/treatment of PMVT usually leads to favorable outcomes. FVIII elevation was the most common (76%) hematologic abnormality identified in this patient cohort. Further studies are needed to determine the prevalence of FVIII elevation in patients seeking bariatric surgery.

Minimally Invasive Management of Ectopic Pancreas.

BACKGROUND: The management of ectopic pancreas is not well defined. This study aims to determine the prevalence of symptomatic ectopic pancreas and identify those who may benefit from treatment, with a particular focus on robotically assisted surgical management. METHODS: Our institutional pathology database was queried to identify a cohort of ectopic pancreas specimens. Additional clinical data regarding clinical symptomatology, diagnostic studies, and treatment were obtained through chart review. RESULTS: Nineteen cases of ectopic pancreas were found incidentally during surgery for another condition or found incidentally in a pathologic specimen (65.5%). Eleven patients (37.9%) reported prior symptoms, notably abdominal pain and/or gastrointestinal bleeding. The most common locations for ectopic pancreas were the duodenum and small bowel (31% and 27.6%, respectively). Three out of 29 cases (10.3%) had no symptoms, but had evidence of preneoplastic changes on pathology, while one harbored pancreatic cancer. Over the years, treatment of ectopic pancreas has shifted from open to laparoscopic and more recently to robotic surgery. CONCLUSIONS: Our experience is in line with existing evidence supporting surgical treatment of symptomatic or complicated ectopic pancreas. In the current era, minimally invasive and robotic surgery can be used safely and successfully for treatment of ectopic pancreas.

Midclerkship feedback in the surgical clerkship: the "Professionalism, Reporting, Interpreting, Managing, Educating, and Procedural Skills" application utilizing learner self-assessment.

BACKGROUND: The Liaison Committee on Medical Education requires midclerkship formative (low stakes) feedback to students regarding their clinical skills. Student self-assessment is not commonly incorporated into this evaluation. We sought to determine the feasibility of collecting and comparing student self-assessment with that of their preceptors using an iPad application. These student self-ratings and preceptor ratings are jointly created and reviewed as part of a face-to-face midclerkship feedback session. METHODS: Using our iPad application for Professionalism, Reporting, Interpreting, Managing, Educating, and Procedural Skills ("PRIMES"), students answer 6 questions based on their self-assessment of performance at midclerkship. Each skill is rated on a 3-point scale (beginning, competent, and strong) with specific behavioral anchors. The faculty preceptors then complete the same PRIMES form during the face-to-face meeting. The application displays a comparison of the 2 sets of ratings, facilitating a discussion to determine individualized learning objectives for the second half of the clerkship. RESULTS: A total of 209 student-preceptor pairs completed PRIMES ratings. On average, student-preceptor ratings were in agreement for 38% of the time. Agreement between students and preceptors was highest for Professionalism (70%) and lowest for Procedural Skills (22%). On average, 60% of student-preceptor ratings did not agree. Students rated themselves lower than preceptors 52% of the time, while only 8% of students rated themselves higher than their preceptors' ratings (this difference is significant at the P value <.05 level). CONCLUSIONS: This study demonstrates the value of using the PRIMES framework to incorporate surgery clerkship students' self-assessment into formative face-to-face midclerkship feedback sessions with their preceptors with the goal to improve performance during the second half of the clerkship.

Professionalism Training For Surgical Residents: Documenting the Advantages of a Professionalism Curriculum.

OBJECTIVES: Professionalism education is a vital component of surgical training. This research attempts to determine whether an annual, year-long professionalism curriculum in a large surgical residency can effectively change professionalism attitudes. SUMMARY OF BACKGROUND DATA: The ACGME mandated 6 competencies in 2003. The competencies of Professionalism and Interpersonal/Professional Communication Skills had never been formally addressed in surgical resident education in the past. METHODS: A professionalism curriculum was developed focusing on specific resident professionalism challenges: admitting mistakes, effective communication with colleagues at all levels, delivering the news of an unexpected death, interdisciplinary challenges of working as a team, the cultural challenge of obtaining informed consent through an interpreter, and the stress of surgical practice on you and your family. These professionalism skills were then evaluated with a 6-station Objective Structured Clinical Examination (OSCE). Identical OSCE scenarios were administered to 2 cohorts of surgical residents: in 2007 (before instituting the professionalism curriculum in 2008) and again in 2014. Surgical residents were rated by trained Standardized Patients according to a behaviorally anchored professionalism criteria checklist. RESULTS: An analysis of variance was conducted of overall OSCE professionalism scores (% well done) as the dependent variable for the 2 resident cohorts (2007 vs 2014). The 2007 residents received a mean score of 38% of professionalism items "well done" (SD 9%) and the 2014 residents received a mean 59% "well done" (SD 8%). This difference is significant (F = 49.01, P < .001). CONCLUSIONS: Professionalism education has improved surgical resident understanding, awareness, and practice of professionalism in a statistically significant manner from 2007 to 2014. This documented improvement in OSCE performance reflects the value of a professionalism curriculum in the care of the patients we seek to serve.

Stage-Specific Prognostic Effect of Race in Patients with Resectable Gastric Adenocarcinoma: An 8-Institution Study of the US Gastric Cancer Collaborative.

BACKGROUND: Gastric cancer constitutes a major public health problem. This study sought to evaluate the relevance of race in gastric cancer and its prognostic effect in the overall outcomes of patients with gastric adenocarcinoma. STUDY DESIGN: Patients who underwent curative intent resection of gastric adenocarcinoma in 8 institutions of the US Gastric Cancer Collaborative were included, from 2000 to 2012. Nonparametric descriptive statistics were used to evaluate characteristics of standard demographic data. Multivariate Cox proportional hazards regression was used to identify factors associated with recurrence-free survival and overall survival. RESULTS: There were 1,077 patients included in the study, the majority of whom were of Caucasian race (n = 698, 68%), followed by African-American (n = 164, 15%), Asian (n = 132, 12%), Hispanic (n = 34, 3.2%), and other (n = 49, 4.5%). Clinicopathologic data were similarly distributed among the 5 groups. Mean follow-up was 27.1 months. By multivariate, stage-specific analysis, Asian race was a significant predictor of recurrence (all stages hazard ratio [HR] 0.45 95% CI [0.23, 0.97], p = 0.041) and of overall survival (all stages HR 0.35 95% CI [0.18, 0.68], p = 0.002). Recurrence-free survival was significantly increased in the Asian population compared with the non-Asian population (25th percentile: 38.6 vs 17.7 months, p = 0.0096), as was overall median survival (141 vs 38.8 months, p < 0.001). CONCLUSIONS: Patients of Asian race undergoing curative gastrectomy for gastric adenocarcinoma appear to have a better prognosis stage for stage. Further studies are required to elucidate the underlying etiology of this phenomenon.

Fatal Falls in New York City: An Autopsy Analysis of Injury Patterns.

INTRODUCTION: Falls from heights are an important cause of unintentional fatal injury. We investigated the relationship between the characteristics of fatal falls and resulting injury patterns. MATERIALS AND METHODS: We reviewed prospectively collected data from the Office of Chief Medical Examiner in New York City between 2000 and 2010. Data included fall height, work or non-work related, use of safety equipment, intentionality, specific organ injuries, and death on impact. The primary outcome was organ injury based on fall height. RESULTS: Higher falls were associated with hemorrhage as well as rib and various organ injuries. Organ injury pattern did not differ based on work status. The presence of equipment misuse or malfunction was associated with more deaths upon impact. Victims of falls from 200 ft or higher were 11.59 times more likely to die on impact than from lower than 25 ft. CONCLUSIONS: Fall height and work-related falls were significantly associated with death on impact. This is a public health issue, as 13% of falls were work related and 4% of falls were due to improper use of safety equipment. Some work-related falls are potentially preventable with proper safety equipment use. Understanding patterns of injury may play a role in prevention and management of survivors in the acute period.

Mincle suppresses Toll-like receptor 4 activation.

Regulation of Toll-like receptor responses is critical for limiting tissue injury and autoimmunity in both sepsis and sterile inflammation. We found that Mincle, a C-type lectin receptor, regulates proinflammatory Toll-like receptor 4 signaling. Specifically, Mincle ligation diminishes Toll-like receptor 4-mediated inflammation, whereas Mincle deletion or knockdown results in marked hyperresponsiveness to lipopolysaccharide in vitro, as well as overwhelming lipopolysaccharide-mediated inflammation in vivo. Mechanistically, Mincle deletion does not up-regulate Toll-like receptor 4 expression or reduce interleukin 10 production after Toll-like receptor 4 ligation; however, Mincle deletion decreases production of the p38 mitogen-activated protein kinase-dependent inhibitory intermediate suppressor of cytokine signaling 1, A20, and ABIN3 and increases expression of the Toll-like receptor 4 coreceptor CD14. Blockade of CD14 mitigates the increased sensitivity of Mincle(-/-) leukocytes to Toll-like receptor 4 ligation. Collectively, we describe a major role for Mincle in suppressing Toll-like receptor 4 responses and implicate its importance in nonmycobacterial models of inflammation.

Dectin-1 Regulates Hepatic Fibrosis and Hepatocarcinogenesis by Suppressing TLR4 Signaling Pathways.

Dectin-1 is a C-type lectin receptor critical in anti-fungal immunity, but Dectin-1 has not been linked to regulation of sterile inflammation or oncogenesis. We found that Dectin-1 expression is upregulated in hepatic fibrosis and liver cancer. However, Dectin-1 deletion exacerbates liver fibro-inflammatory disease and accelerates hepatocarcinogenesis. Mechanistically, we found that Dectin-1 protects against chronic liver disease by suppressing TLR4 signaling in hepatic inflammatory and stellate cells. Accordingly, Dectin-1(-/-) mice exhibited augmented cytokine production and reduced survival in lipopolysaccharide (LPS)-mediated sepsis, whereas Dectin-1 activation was protective. We showed that Dectin-1 inhibits TLR4 signaling by mitigating TLR4 and CD14 expression, which are regulated by Dectin-1-dependent macrophage colony stimulating factor (M-CSF) expression. Our study suggests that Dectin-1 is an attractive target for experimental therapeutics in hepatic fibrosis and neoplastic transformation. More broadly, our work deciphers critical cross-talk between pattern recognition receptors and implicates a role for Dectin-1 in suppression of sterile inflammation, inflammation-induced oncogenesis, and LPS-mediated sepsis.