Faculty Bibliography

BACKGROUND: Patients with type 2 diabetes (T2D) and body mass index (BMI)<35 may benefit from metabolic surgery. The soluble form of the receptor for advanced glycation end products (sRAGE) may identify patients at greater chance for T2D remission. OBJECTIVES: To study long-term outcomes of patients with T2D and BMI 30-35 treated with metabolic surgery or medical weight management (MWM) and search for predictors of T2D remission. SETTING: University METHODS: Retrospective review of the original cohort, including patients who crossed over from MWM to surgery. Repeated-measures linear models were used to model weight loss (%WL), change in glycated hemoglobin (HbA1C) and association with baseline sRAGE. RESULTS: Fifty-seven patients with T2D and BMI 30-35 were originally randomly assigned to metabolic surgery versus MWM. Mean BMI and HbA1C was 32.6% and 7.8%, respectively. A total of 30 patients underwent surgery (19 sleeves, 8 bypasses, 3 bands). Three-year follow-up in the surgery group and MWM group was 75% and 86%, respectively. Surgery resulted in higher T2D remission (63% versus 0%; P<.001) and lower HbA1C (6.9% versus 8.4%; P<.001) for up to 3 years. There was no difference in %WL in those with versus those without T2D remission (21.7% versus 20.6%, P = .771), suggesting that additional mechanisms other than %WL play an important role for the studied outcome. Higher baseline sRAGE was associated with greater change in HbA1C and greater %WL after surgery (P< .001). CONCLUSION: Metabolic surgery was effective in promoting remission of T2D in 63% of patients with BMI 30-35; higher baseline sRAGE predicted T2D remission with surgery. Larger-scale randomly assigned trials are needed in this patient population.

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.

BACKGROUND: Trauma is a leading cause of death and disability in the United States (US). This analysis describes trends and annual changes in in-hospital trauma morbidity and mortality; evaluates changes in age and gender specific outcomes, diagnoses, causes of injury, injury severity and surgical procedures performed; and examines the role of teaching hospitals and Level 1 trauma centres in the care of severely injured patients. METHODS: We conducted a retrospective descriptive and analytic epidemiologic study of an inpatient database representing 20,659,684 traumatic injury discharges from US hospitals between 2000 and 2011. The main outcomes and measures were survey-adjusted counts, proportions, means, standard errors, and 95% confidence intervals. We plotted time series of yearly data with overlying loess smoothing, created tables of proportions of common injuries and surgical procedures, and conducted survey-adjusted logistic regression analysis for the effect of year on the odds of in-hospital death with control variables for age, gender, weekday vs. weekend admission, trauma-centre status, teaching-hospital status, injury severity and Charlson index score. RESULTS: The mean age of a person discharged from a US hospital with a trauma diagnosis increased from 54.08 (s.e.=0.71) in 2000 to 59.58 (s.e.=0.79) in 2011. Persons age 45-64 were the only age group to experience increasing rates of hospital discharges for trauma. The proportion of trauma discharges with a Charlson Comorbidity Index score greater than or equal to 3 nearly tripled from 0.048 (s.e.=0.0015) of all traumatic injury discharges in 2000 to 0.139 (s.e.=0.005) in 2011. The proportion of patients with traumatic injury classified as severe increased from 22% of all trauma discharges in 2000 (95% CI 21, 24) to 28% in 2011 (95% CI 26, 30). Level 1 trauma centres accounted for approximately 3.3% of hospitals. The proportion of severely injured trauma discharges from Level 1 trauma centres was 39.4% (95% CI 36.8, 42.1). Falls, followed by motor-vehicle crashes, were the most common causes of all injuries. The total cost of trauma-related inpatient care between 2001 and 2011 in the US was $240.7 billion (95% CI 231.0, 250.5). Annual total US inpatient trauma-related hospital costs increased each year between 2001 and 2011, more than doubling from $12.0 billion (95% CI 10.5, 13.4) in 2001 to 29.1 billion (95% CI 25.2, 32.9) in 2011. CONCLUSIONS: Trauma, which has traditionally been viewed as a predicament of the young, is increasingly a disease of the old. The strain of managing the progressively complex and costly care associated with this shift rests with a small number of trauma centres. Optimal care of injured patients requires a reappraisal of the resources required to effectively provide it given a mounting burden.

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.

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.

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.