The seasonal cycle of energetics from the GLAS/UMD climate GCM

The annual cycle of atmospheric energetics from a 2-year integration of the GLAS/UMD Climate GCM is computed and compared to results from the European Centre analyses of the GWE year, and to previously published results on a global basis. All calculations are done in the mixed space-time domain. The main conclusions are: (1) the seasonal cycle of today's eddy kinetic energy (in both hemispheres), and of the transient eddy available potential energy and the potential-to-kinetic energy conversions (mean and eddy) in the Northern Hemisphere are well simulated by the GCM; (2) the GCM's tendency to have anomalously large mean u-winds at upper levels in high latitudes leads to excessive wintertime values of mean kinetic and available potential energies, and causes distortions in the GCM latitude-height distribution of kinetic energy and of many of the conversions; (3) the eddy conversion of available potential-to-kinetic energy obtained from the ageostrophic wind in these analyses; and (4) the conversions in the Southern Hemisphere are not well simulated by the GCM, although the observations are somewhat questionable

An intercomparison of intraseasonal variability in general circulation models and observations

Low frequency oscillations appearing in three GCM seasonal cycle integrations are compared with the analyses of the European Center for Medium Range Weather Forecasting (ECMWF). All three models have the same resolution: 4 deg latitude by 5 deg longitude, with 9 levels. The dominant phase speeds and the differential vertical structure of the heating profiles in the GCMs are in general agreement with current theory involving the positive feedback between latent heating and moist static stability. All three GCMs fail to capture the detailed evolution in the different stages of the development and decay of the oscillation. The results suggest that an improvement in the boundary layer moisture processes may be crucial for a better simulation of the oscillation

Circulation Regimes: Chaotic Variability versus SST-Forced Predictability

Abstract The circulation regimes in the Pacific–North American region are studied using the NCEP–NCAR reanalyses for the 18-winter period (1981/82–1998/99; NCEP18) and for the 54-winter period (1948/49–2001/02; NCEP54). The sampling properties of the regimes are estimated using very large ensembles (of size 55) of winter simulations made for the NCEP18 period with the atmospheric general circulation model of the Center for Ocean–Land–Atmosphere Studies, forced by observed SST and sea ice. The regimes are identified using a modified version of the k-means method. From the NCEP54 dataset a set of four clusters was found [i.e., the Alaskan ridge (AR), Arctic low (AL), Pacific trough (PT), and the Arctic high (AH)], which are significant (vis-à-vis a multinormal background), and more reproducible (within randomly chosen half-length samples) than would be expected from a multinormal process. The frequency of occurrence of the PT (AH) has increased (decreased) significantly during the past two decades. The PT cluster obtained from NCEP18 dataset more closely resembles the El Niño–forced seasonal mean pattern of recent decades than it does the traditional PNA. The GCM simulates the AR, AL, and PT clusters (but not the AH). The simulated AR and PT patterns have errors (cf. the NCEP18 results), which are outside the range of internal variability. The simulated frequency of occurrence agrees with the NCEP18 results within sampling variability. The differences in cluster properties of the PT and AR regimes between the NCEP18 and NCEP54 datasets are due to changes in SST forcing, not sampling error. Year-to-year changes in the frequency of occurrence of the PT, AL, and AR clusters in the simulations and the NCEP18 dataset are generally consistent with each other

Dose-Reduced Busulfan, Cyclophosphamide, and Autologous Stem Cell Transplantation for Human Immunodeficiency Virus–Associated Lymphoma: AIDS Malignancy Consortium Study 020

AbstractIntensive chemotherapy for human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) has resulted in durable remissions in a substantial proportion of patients. High-dose chemotherapy and autologous stem cell transplantation (AuSCT), moreover, has resulted in sustained complete remissions in selected patients with recurrent chemosensitive disease. Based on a favorable experience with dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT for older patients with non-HIV–associated aggressive lymphomas, an AIDS Malignancy Consortium multicenter trial was undertaken using the same dose-reduced busulfan and cyclophosphamide preparative regimen with AuSCT for recurrent HIV-associated NHL and HL. Of the 27 patients in the study, 20 received an AuSCT. The median time to achievement of an absolute neutrophil count (ANC) of ≥ 0.5×109/L was 11 days (range, 9-16 days). The median time to achievement of an unsupported platelet count of ≥ 20×109/L was 13 days (range, 6-57 days). One patient died on day +33 posttransplantation from hepatic veno-occlusive disease (VOD) and multiorgan failure. No other fatal regimen-related toxicity occurred. Ten of 19 patients (53%) were in complete remission at the time of their day +100 post-AuSCT evaluation. Of the 20 patients, 10 were alive and event-free at a median of 23 weeks post-AuSCT. Median overall survival (OS) was not reached by 13 of the 20 patients alive at the time of last follow-up. This multi-institutional trial demonstrates that a regimen of dose-reduced high-dose busulfan, cyclophosphamide, and AuSCT is well tolerated and is associated with favorable disease-free survival (DFS) and OS probabilities for selected patients with HIV-associated NHL and HL

CD28 and the Tyrosine Kinase Lck Stimulate Mitogen-Activated Protein Kinase Activity in T Cells via Inhibition of the Small G Protein Rap1

Proliferation of T cells via activation of the T-cell receptor (TCR) requires concurrent engagement of accessory costimulatory molecules to achieve full activation. The best-studied costimulatory molecule, CD28, achieves these effects, in part, by augmenting signals from the TCR to the mitogen-activated protein (MAP) kinase cascade. We show here that TCR-mediated stimulation of MAP kinase extracellular-signal-regulated kinases (ERKs) is limited by activation of the Ras antagonist Rap1. CD28 increases ERK signaling by blocking Rap1 action. CD28 inhibits Rap1 activation because it selectively stimulates an extrinsic Rap1 GTPase activity. The ability of CD28 to stimulate Rap1 GTPase activity was dependent on the tyrosine kinase Lck. Our results suggest that CD28-mediated Rap1 GTPase-activating protein activation can help explain the augmentation of ERKs during CD28 costimulation

SPOTS: signaling protein oligomeric transduction structures are early mediators of death receptor–induced apoptosis at the plasma membrane

Fas (CD95, APO-1, TNFRSF6) is a TNF receptor superfamily member that directly triggers apoptosis and contributes to the maintenance of lymphocyte homeostasis and prevention of autoimmunity. Although FADD and caspase-8 have been identified as key intracellular mediators of Fas signaling, it is not clear how recruitment of these proteins to the Fas death domain leads to activation of caspase-8 in the receptor signaling complex. We have used high-resolution confocal microscopy and live cell imaging to study the sequelae of early events in Fas signaling. These studies have revealed a new stage of Fas signaling in which receptor ligation leads to the formation of surface receptor oligomers that we term signaling protein oligomerization transduction structures (SPOTS). Formation of SPOTS depends on the presence of an intact Fas death domain and FADD but is independent of caspase activity. Analysis of cells expressing Fas mutations from patients with the autoimmune lymphoproliferative syndrome (ALPS) reveals that formation of SPOTS can be disrupted by distinct mechanisms in ALPS

A pragmatic study exploring the prevention of delirium among hospitalized older hip fracture patients: Applying evidence to routine clinical practice using clinical decision support

Delirium occurs in up to 65% of older hip fracture patients. Developing delirium in hospital has been associated with a variety of adverse outcomes. Trials have shown that multi-component preventive interventions can lower delirium rates. The objective of this study was to implement and evaluate the effectiveness of an evidence-based electronic care pathway, which incorporates multi-component delirium strategies, among older hip fracture patients. We conducted a pragmatic study using an interrupted time series design in order to evaluate the use and impact of the intervention. The target population was all consenting patients aged 65 years or older admitted with an acute hip fracture to the orthopedic units at two Calgary, Alberta hospitals. The primary outcome was delirium rates. Secondary outcomes included length of hospital stay, in-hospital falls, in-hospital mortality, new discharges to long-term care, and readmissions. A Durbin Watson test was conducted to test for serial correlation and, because no correlation was found, Chi-square statistics, Wilcoxon test and logistic regression analyses were conducted as appropriate. At study completion, focus groups were conducted at each hospital to explore issues around the use of the order set. During the 40-week study period, 134 patients were enrolled. The intervention had no effect on the overall delirium rate (33% pre versus 31% post; p = 0.84). However, there was a significant interaction between study phase and hospital (p = 0.03). Although one hospital did not experience a decline in delirium rate, the delirium rate at the other hospital declined from 42% to 19% (p = 0.08). This difference by hospital was mirrored in focus group feedback. The hospital that experienced a decline in delirium rates was more supportive of the intervention. Overall, post-intervention there were no significant differences in mean length of stay (12 days post versus 14 days pre; p = 0.74), falls (6% post versus 10% pre; p = 0.43) or discharges to long-term care (6% post versus 13% pre; p = 0.20). Translation of evidence-based multi-component delirium prevention strategies into everyday clinical care, using the electronic medical record, was not found to be effective at decreasing delirium rates among hip facture patients

Core competencies in the science and practice of knowledge translation: description of a Canadian strategic training initiative

<p>Abstract</p> <p>Background</p> <p>Globally, healthcare systems are attempting to optimize quality of care. This challenge has resulted in the development of implementation science or knowledge translation (KT) and the resulting need to build capacity in both the science and practice of KT.</p> <p>Findings</p> <p>We are attempting to meet these challenges through the creation of a national training initiative in KT. We have identified core competencies in this field and have developed a series of educational courses and materials for three training streams. We report the outline for this approach and the progress to date.</p> <p>Conclusions</p> <p>We have prepared a strategy to develop, implement, and evaluate a national training initiative to build capacity in the science and practice of KT. Ultimately through this initiative, we hope to meet the capacity demand for KT researchers and practitioners in Canada that will lead to improved care and a strengthened healthcare system.</p

Comparison of sedation strategies for critically ill patients:A protocol for a systematic review incorporating network meta-analyses

Abstract Background Sedatives and analgesics are administered to provide sedation and manage agitation and pain in most critically ill mechanically ventilated patients. Various sedation administration strategies including protocolized sedation and daily sedation interruption are used to mitigate drug pharmacokinetic limitations and minimize oversedation, thereby shortening the duration of mechanical ventilation. At present, it is unclear which strategy is most effective, as few have been directly compared. Our review will use network meta-analysis (NMA) to compare and rank sedation strategies to determine their efficacy and safety for mechanically ventilated patients. Methods We will search the following from 1980 to March 2016: Ovid MEDLINE, CINAHL, Embase, PsycINFO, and Web of Science. We will also search the Cochrane Library, gray literature, and the International Clinical Trials Registry Platform. We will use a validated randomized control trial search filter to identify studies evaluating any strategy to optimize sedation in mechanically ventilated adult patients. Authors will independently extract data from eligible studies in duplicate and complete the Cochrane Risk of Bias tool. Our outcomes of interest include duration of mechanical ventilation, time to first extubation, ICU and hospital length of stay, re-intubation, tracheostomy, mortality, total sedative and opioid exposure, health-related quality of life, and adverse events. To inform our NMA, we will first conduct conventional pair-wise meta-analyses using random-effects models. Where appropriate, we will perform Bayesian NMA using WinBUGS software. Discussion There are multiple strategies to optimize sedation for mechanically ventilated patients. Current ICU guidelines recommend protocolized sedation or daily sedation interruption. Our systematic review incorporating NMA will provide a unified analysis of all sedation strategies to determine the relative efficacy and safety of interventions that may not have been compared directly. We will provide knowledge users, decision makers, and professional societies with ranking of multiple sedation strategies to inform future sedation guidelines. Systematic review registration PROSPERO CRD4201603748