Cassette Notes

https://orc.library.atu.edu/atu_cass065/1013/thumbnail.jp

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Endotoxin tolerance in sepsis: concentration-dependent augmentation or inhibition of LPS-stimulated macrophage TNF secretion by LPS pretreatment

We previously showed that macrophages (MPhi) pretreated with bacterial endotoxin (lipopolysaccharide [LPS]) develop an altered state of LPS-responsiveness--"LPS tolerance": LPS tolerance was associated with inhibition of tumor necrosis factor (TNF) release and decreased extracellular signal-regulated kinase and p38 kinase activation when MPhi were restimulated with LPS. However, the concentration of LPS used for pretreatment (most frequently 10 ng/mL) may be much higher than LPS concentrations observed in patients. Therefore, in the current study we examined the effect of lower and higher pretreatment LPS concentrations on subsequent LPS-stimulated MPhi responses. RAW 264.7 MPhi-like cells were pretreated in vitro (PreRx) for 24 hours in medium or a range of LPS concentrations (0 ng/mL, 1 ng/mL, 10 ng/mL, or 100 ng/mL of E. coli 0111B4 LPS). Culture medium was discarded after 24 hours and MPhi were restimulated with LPS (0 ng/mL, 1 ng/mL, 10 ng/mL or 100 ng/mL). Three different lots of LPS (Sigma) were used. Supernatant TNF secretion at 3 hour was measured using enzyme-linked immunosorbent assay (pg/mL +/- SEM). Statistics by Chi-square and student's t test. Pretreatment with 100 ng/mL of LPS profoundly inhibited TNF release at all LPS restimulation concentrations (p < 0.05 vs. Medium PreRx). In contrast, very low dose LPS pretreatment (1 ng/mL) significantly augmented TNF release versus medium (p < 0.05). There was no further augmentation observed when even lower doses of LPS (0.1 ng/mL) were used for pretreatment. Similar results were obtained with three different lots E. coli 0111B4 LPS or using LPS from E. coli 0127B8. Prior exposure of MPhi to bacterial ligands alters MPhi cytokine production in response to subsequent LPS-stimulated activation. This modulated MPhi response is critically dependent on the concentration of LPS pretreatment

A qualitative metasynthesis of the experience of fatigue across five chronic conditions

Context Fatigue is a symptom reported by patients with a variety of chronic conditions. However, it is unclear whether fatigue is similar across conditions. Better understanding its nature could provide important clues regarding the mechanisms underlying fatigue and aid in developing more effective therapeutic interventions to decrease fatigue and improve quality of life. Objectives To better understand the nature of fatigue, we performed a qualitative metasynthesis exploring patients' experiences of fatigue across five chronic noninfectious conditions: heart failure, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, and chronic obstructive pulmonary disease. Methods We identified 34 qualitative studies written in the last 10 years describing fatigue in patients with one of the aforementioned conditions using three databases (Embase, PubMed, and CINAHL). Studies with patient quotes describing fatigue were synthesized, integrated, and interpreted. Results Across conditions, patients consistently described fatigue as persistent overwhelming tiredness, severe lack of energy, and physical weakness that worsened over time. Four common themes emerged: running out of batteries, a bad life, associated symptoms (e.g., sleep disturbance, impaired cognition, and depression), and feeling misunderstood by others, with a fear of not being believed or being perceived negatively. Conclusion In adults with heart failure, multiple sclerosis, rheumatoid arthritis, chronic kidney disease, and chronic obstructive pulmonary disease, we found that fatigue was characterized by severe energy depletion, which had negative impacts on patients' lives and caused associated symptoms that exacerbated fatigue. Yet, fatigue is commonly misunderstood and inadequately acknowledged

Acquisition of Portal Venous Circulating Tumor Cells From Patients With Pancreaticobiliary Cancers by Endoscopic Ultrasound

Background & AimsTumor cells circulate in low numbers in peripheral blood; their detection is used predominantly in metastatic disease. We evaluated the feasibility and safety of sampling portal venous blood via endoscopic ultrasound (EUS) to count portal venous circulating tumor cells (CTCs), compared with paired peripheral CTCs, in patients with pancreaticobiliary cancers (PBCs).MethodsIn a single-center cohort study, we evaluated 18 patients with suspected PBCs. Under EUS guidance, a 19-gauge EUS fine needle was advanced transhepatically into the portal vein and as many as four 7.5-mL aliquots of blood were aspirated. Paired peripheral blood samples were obtained. Epithelial-derived CTCs were sorted magnetically based on expression of epithelial cell adhesion molecules; only those with a proper morphology and found to be CD45 negative and positive for cytokeratins 8, 18, and/or 19 and 4′,6-diamidino-2-phenylindole were considered to be CTCs. For 5 samples, CTCs also were isolated by flow cytometry and based on CD45 depletion. ImageStream was used to determine the relative protein levels of P16, SMAD4, and P53. DNA was extracted from CTCs for sequencing of select KRAS codons.ResultsThere were no complications from portal vein blood acquisition. We detected CTCs in portal vein samples from all 18 patients (100%) vs peripheral blood samples from only 4 patients (22.2%). Patients with confirmed PBCs had a mean of 118.4 ± 36.8 CTCs/7.5 mL portal vein blood, compared with a mean of 0.8 ± 0.4 CTCs/7.5 mL peripheral blood (P < .01). The 9 patients with nonmetastatic, resectable, or borderline-resectable PBCs had a mean of 83.2 CTCs/7.5 mL portal vein blood (median, 62.0 CTCs/7.5 mL portal vein blood). In a selected patient, portal vein CTCs were found to carry the same mutations as those detected in a metastatic lymph node and expressed similar levels of P16, SMAD4, and P53 proteins.ConclusionsIt is feasible and safe to collect portal venous blood from patients undergoing EUS. We identified CTCs in all portal vein blood samples from patients with PBCs, but less than 25% of peripheral blood samples. Portal vein CTCs can be used for molecular characterization of PBCs and share features of metastatic tissue. This technique might be used to study the pathogenesis and progression of PBCs, as well as a diagnostic or prognostic tool to stratify risk of cancer recurrence or developing metastases

Poppensiek, George C.

Also available as a printed booklet and from the Dean of Faculty website https://theuniversityfaculty.cornell.edu/Memorial Statement for George C. Poppensiek, who died in 2015. The memorial statements contained herein were prepared by the Office of the Dean of the University Faculty of Cornell University to honor its faculty for their service to the university