INTRODUCTION:Low creatinine to cystatin-C ratio (Cr/Cys-C) may be a biomarker for low-muscle mass. Furthermore, low Cr/Cys-C is associated with decreased overall survival (OS), but to date, has not been examined in patients with renal cell carcinoma (RCC). Our objective is to evaluate associations between low Cr/Cys-C ratio and OS and recurrence-free survival (RFS) in patients with RCC treated with nephrectomy. METHODS:We performed a retrospective review of patients with RCC treated with nephrectomy. Patients with end-stage renal disease and less than 1-year follow up were excluded. Cr/Cys-C was dichotomized at the median for the cohort (low vs. high). OS and RFS for patients with high versus low Cr/Cys-C were estimated with the Kaplan-Meier method, and associations with the outcomes of interest were modeled using Cox proportional Hazards models. Associations between Cr/Cys-C and skeletal muscle mass were assessed with correlations and logistic regression. RESULTS:A total of 255 patients were analyzed, with a median age of 64. Median (IQR) Cr/Cys-C was 1 (0.8-1.2). Low Cr/Cys-C was associated with age, female sex, Eastern Cooperative Oncology Group Performance Status ≥1, TNM stage, and tumor size. Kaplan-Meier and Cox regression analysis demonstrated an association between low Cr/Cys-C and decreased OS (HR = 2.97, 95%CI, 1.12-7.90, P =0.029) and RFS (HR = 3.31, 95%CI, 1.26-8.66, P = .015). Furthermore, a low Cr/Cys-C indicated a 2-3 increase in risk of radiographic sarcopenia. CONCLUSIONS:Lower Cr/Cys-C is associated with inferior oncologic outcomes in RCC and, pending validation, may have utility as a serum biomarker for the presence of sarcopenia in patients with RCC treated with nephrectomy.

Abstract Introduction and Objective: Patients with kidney cancer experience higher rates of depression compared with other cancer subtypes. Inflammation has been shown to contribute to depression associated with malignancy. Here, we assess the association between preoperative C-reactive protein (CRP) and major depression, as screened by the eight-item Patient Health Questionnaire (PHQ-8) depression scale, in patients undergoing nephrectomy for nonmetastatic renal cell carcinoma (RCC). Methods: Retrospective review of prospectively administered PHQ-8 surveys in patients who underwent nephrectomy for nonmetastatic RCC was conducted. Patients with available PHQ-8 within 180 days before and after surgery were included. The association of major depressive symptoms on preoperative PHQ-8 and clinical improvement on postoperative survey with patient/tumor characteristics and CRP levels was determined by the generalized chi-square test for categorical variables and analysis of variance for continuous variables. Multivariable logistic regression was used to analyze variables associated with major depression on PHQ-8 and postoperative survey improvement. Results: Two hundred forty-five patients were analyzed. Most were male (66%). Median age and body mass index were 65 and 28.9 kg/m2, respectively. 64.5% of patients were White, and 29.0% were Black. 30.2% had an elevated CRP (≥10 mg/L). 45 (18.4%) patients screened positive for major depressive symptoms on PHQ-8 (≥10 points). Patients with elevated CRP were more likely to have positive preoperative depression screening (odds ratio [OR] 2.66, 95% CI 1.08–6.52, P = .033) but had higher probability of demonstrating meaningful change on PHQ-8 after nephrectomy (OR 3.50, 95% CI 1.04–11.85, P = .044). Conclusion: In nonmetastatic RCC, patients with elevated preoperative CRP had higher scoring for major depressive symptoms on PHQ-8 and were more likely to demonstrate clinical improvement in depressive symptomatology after nephrectomy.

BACKGROUND Injury Severity Score (ISS) is a widely used metric for trauma research and center verification; however, it does not account for age-related physiologic parameters. We hypothesized that a novel age-based injury severity metric would better predict mortality. METHODS Adult patients (≥18 years) sustaining blunt trauma (BT) or penetrating trauma (PT) were abstracted from the 2010 to 2016 National Trauma Data Bank. Admission vitals, Glasgow Coma Scale, ISS, mechanism, and outcomes were analyzed. Patients with incomplete/non-physiologic vital signs were excluded. For each age: (1) a cut point analysis was used to determine the ISS with the highest specificity and sensitivity for predicting mortality and (2) a linear discriminant analysis was performed using ISS, ISS greater than 16, Trauma and Injury Severity Score, and Revised Trauma Scale to compare each scoring system’s mortality prediction. A novel injury severity metric, the trauma component score (TCS), was developed for each age using significant ( p < 0.05) variables selected from Abbreviated Injury Scale scores, Glasgow Coma Scale, vital signs, and gender. Receiver operator curves were developed and the areas under the curve were compared between the TCS and other systems. RESULTS There 777,794 patients studied (BT, 91.1%; PT, 8.9%). Blunt trauma patients were older (53.6 ± 21.3 years vs. 34.4 ± 13.8 years), had higher ISS scores (11.1 ± 8.5 vs. 8.5 ± 8.9), and lower mortality (2.9% vs. 3.4%) than PT patients ( p < 0.05). When assessing the entire PT and BT cohort the optimal ISS cut point was 16. The optimal ISS was between 20 and 25 for BT younger than 70 years. For those older than 70 years, the optimal BT ISS steadily declined as age increased PT’s cut point was 16 or less for all ages assessed. When the injury metrics were compared by area under the curve, our novel TCS more accurately predicted mortality across all ages in both BT and PT ( p < 0.001). CONCLUSION Injury Severity Score is a poor mortality predictor in older patients and those sustaining penetrating trauma. The age-based TCS is a superior metric for mortality prediction across all ages. LEVEL OF EVIDENCE Clinical outcomes, Level IV.

BACKGROUND The equivalent Injury Severity Score (ISS) cutoffs for severe trauma vary between adult (ISS, >16) and pediatric (ISS, >25) trauma. We hypothesized that a novel injury severity prediction model incorporating age and mechanism of injury would outperform standard ISS cutoffs. METHODS The 2010 to 2016 National Trauma Data Bank was queried for pediatric trauma patients. Cut point analysis was used to determine the optimal ISS for predicting mortality for age and mechanism of injury. Linear discriminant analysis was implemented to determine prediction accuracy, based on area under the curve (AUC), of ISS cutoff of 25 (ISS, 25), shock index pediatric adjusted (SIPA), an age-adjusted ISS/abbreviated Trauma Composite Score (aTCS), and our novel Trauma Composite Score (TCS) in blunt trauma. The TCS consisted of significant variables (Abbreviated Injury Scale, Glasgow Coma Scale, sex, and SIPA) selected a priori for each age. RESULTS There were 109,459 blunt trauma and 9,292 penetrating trauma patients studied. There was a significant difference in ISS (blunt trauma, 9.3 +/- 8.0 vs. penetrating trauma, 8.0 +/- 8.6; p < 0.01) and mortality (blunt trauma, 0.7% vs. penetrating trauma, 2.7%; p < 0.01). Analysis of the entire cohort revealed an optimal ISS cut point of 25 (AUC, 0.95; sensitivity, 0.86; specificity, 0.95); however, the optimal ISS ranged from 18 to 25 when evaluated by age and mechanism. Linear discriminant analysis model AUCs varied significantly for each injury metric when assessed for blunt trauma and penetrating trauma (penetrating trauma-adjusted ISS, 0.94 +/- 0.02 vs. ISS 25, 0.88 +/- 0.02 vs. SIPA, 0.62 +/- 0.03; p < 0.001; blunt trauma-adjusted ISS, 0.96 +/- 0.01 vs. ISS 25, 0.89 +/- 0.02 vs. SIPA, 0.70 +/- 0.02; p < 0.001). When injury metrics were assessed across age groups in blunt trauma, TCS and aTCS performed the best. CONCLUSION Current use of ISS in pediatric trauma may not accurately reflect injury severity. The TCS and aTCS incorporate both age and mechanism and outperform standard metrics in mortality prediction in blunt trauma.

The family of Notch proteins plays a key role in cell fate determination. Additionally, Notch proteins regulate critical functions of the endothelium, as well as other recruited supporting cells, in concert with other pathways. Despite significant advances in the field and extensive studies focused on elucidating this pathway, many questions remain regarding Notch activation and its upstream/downstream effects, with vascular biology constituting one area of particular interest. Here, we provide a brief description of the components and functions of the Notch pathway in vasculature, followed by a detailed compilation of recommended methods of evaluation in vitro and in vivo. We provide a rationale for key elements when choosing different approaches and controls, strengths and limitations, and essential considerations when providing a meaningful interpretation of results. Our aim is to describe a careful approach to assessing Notch function in endothelial cells, based on underlying principles, with the overall goal of obtaining physiologically relevant information that will enhance our understanding of this pathway and its role in vascular biology.

Keskey, Robert MD; Lynn Allen, Debra MSN; Turney Cone, Jennifer MD, MHS; Lam, Adam MD; Biermann, Henry BS; Wilson, Kenneth MD, FACS; Olweston Rogers, Selwyn MD, MPH, FACS; Hampton, David A. MD, MEng Author Information

Staphylococcus aureus infection is one of the leading causes of morbidity in hospitalized patients in the United States, an effect compounded by increasing antibiotic resistance. The secreted agent hemolysin alpha toxin (Hla) requires the receptor A Disintegrin And Metalloproteinase domain-containing protein 10 (ADAM10) to mediate its toxic effects. We hypothesized that these effects are in part regulated by Notch signaling, for which ADAM10 activation is essential. Notch proteins function in developmental and pathological angiogenesis via the modulation of key pathways in endothelial and perivascular cells. Thus, we hypothesized that Hla would activate Notch in vascular cells. Human umbilical vein endothelial cells were treated with recombinant Hla (rHla), Hla-H35L (genetically inactivated Hla), or Hank’s solution (HBSS), and probed by different methods. Luciferase assays showed that Hla (0.01 µg/mL) increased Notch activation by 1.75 ± 0.5-fold as compared to HBSS controls (p < 0.05), whereas Hla-H35L had no effect. Immunocytochemistry and Western blotting confirmed these findings and revealed that ADAM10 and γ-secretase are required for Notch activation after inhibitor and siRNA assays. Retinal EC in mice engineered to express yellow fluorescent protein (YFP) upon Notch activation demonstrated significantly greater YFP intensity after Hla injection than controls. Aortic rings from Notch reporter mice embedded in matrix and incubated with rHla or Hla-H35L demonstrate increased Notch activation occurs at tip cells during sprouting. These mice also had higher skin YFP intensity and area of expression after subcutaneous inoculation of S. aureus expressing Hla than a strain lacking Hla in both EC and pericytes assessed by microscopy. Human liver displayed strikingly higher Notch expression in EC and pericytes during S. aureus infection by immunohistochemistry than tissues from uninfected patients. In sum, our results demonstrate that the S. aureus toxin Hla can potently activate Notch in vascular cells, an effect which may contribute to the pathobiology of infection with this microorganism.