Citations

AbstractObjectivesChest pain is a common complaint to emergency departments (EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin (MR‐proADM) in prediction of mortality and major adverse cardiac events (MACE).MethodsThis was a subanalysis of the CHOPIN study, a 16‐center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6‐month all‐cause mortality and the secondary endpoint was 30‐day and 6‐month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure.ResultsMR‐proADM performed similarly to troponin (cTnI; c‐statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR‐proADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6‐month mortality risk versus 0.9% risk for those in the bottom nine deciles (p < 0.0001). MR‐proADM, history of coronary artery disease (CAD), and hypertension were predictors of short‐term MACE, while history of CAD, hypertension, cTnI, and MR‐proADM were predictors of long‐term MACE.ConclusionsIn patients with chest pain, MR‐proADM predicts mortality and MACE in all‐comers with chest pain and has similar prediction in those with a noncardiac diagnosis. This exploratory analysis is primarily hypotheses‐generating and future prospective studies to identify its utility in risk stratification should be considered.

Abstract Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC). Experimental Design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses. Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m2 with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P. Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation. Clin Cancer Res; 21(15); 3420–7. ©2015 AACR.

AbstractClinical research ethics consultation services have been established across academic health centers over the past decade. This paper presents the results of collaboration within the CTSA consortium to develop a standard approach to the collection of research ethics consultation information to serve as a foundation for quality improvement, education, and research efforts. This approach includes categorizing and documenting descriptive information about the requestor, research project, the ethical question, the consult process, and describing the basic structure for a consult note. This paper also explores challenges in determining how to share some of this information between collaborating institutions related to concerns about confidentially, data quality, and informatics. While there is much still to be learned to improve the process of clinical research ethics consultation, these tools can advance these efforts, which, in turn, can facilitate the ethical conduct of research.

Findings suggest that more intensive efforts than audit and feedback will be required to improve the quality of psychosocial care, and that greater recognition of problems with emotional well-being may tax the ability of practices to link patients with appropriate services.

Circadian rhythm dysfunction is linked to many diseases, yet pathophysiological roles in articular cartilage homeostasis and degenerative joint disease including osteoarthritis (OA) remains to be investigated in vivo. Here, we tested whether environmental or genetic disruption of circadian homeostasis predisposes to OA‐like pathological changes. Male mice were examined for circadian locomotor activity upon changes in the light:dark (LD) cycle or genetic disruption of circadian rhythms. Wild‐type (WT) mice were maintained on a constant 12 h:12 h LD cycle (12:12 LD) or exposed to weekly 12 h phase shifts. Alternatively, male circadian mutant mice ( Clock Δ19 or Csnk1e tau mutants) were compared with age‐matched WT littermates that were maintained on a constant 12:12 LD cycle. Disruption of circadian rhythms promoted osteoarthritic changes by suppressing proteoglycan accumulation, upregulating matrix‐degrading enzymes and downregulating anabolic mediators in the mouse knee joint. Mechanistically, these effects involved activation of the PKCδ‐ERK‐RUNX2/NFκB and β‐catenin signaling pathways, stimulation of MMP‐13 and ADAMTS‐5, as well as suppression of the anabolic mediators SOX9 and TIMP‐3 in articular chondrocytes of phase‐shifted mice. Genetic disruption of circadian homeostasis does not predispose to OA‐like pathological changes in joints. Our results, for the first time, provide compelling in vivo evidence that environmental disruption of circadian rhythms is a risk factor for the development of OA‐like pathological changes in the mouse knee joint. J. Cell. Physiol. 230: 2174–2183, 2015. © 2015 Wiley Periodicals, Inc.