NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands ...(the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1-6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12-US21; a genetic arrangement, which is suggestive of an 'accordion' expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:This study aims to explore the relationship between team-leadership skills and quality of cardiopulmonary resuscitation in an adult cardiac-arrest simulation. Factors affecting ...team-leadership skills were also assessed.
DESIGN:Forty advanced life-support providers leading a cardiac arrest team in a standardized cardiac-arrest simulation were videotaped. Background data were collected, including age (in yrs), sex, whether they had received any leadership training in the past, whether they were part of a professional group, the most recent advanced life-support course (in months) they had undergone, advanced life-support instructor/provider status, and whether they had led in any cardiac arrest situation in the preceding 6 months.
MEASUREMENTS AND MAIN RESULTS:Participants were scored using the Cardiac Arrest Simulation test score and Leadership Behavior Description Questionnaire for leadership skills. Process-focused quality of cardiopulmonary resuscitation data were collected directly from manikin and video recordings. Primary outcomes were complex technical skills (measured as Cardiac Arrest Simulation test score, preshock pause, and hands-off ratio). Secondary outcomes were simple technical skills (chest-compression rate, depth, and ventilation rate). Univariate linear regressions were performed to examine how leadership skills affect quality of cardiopulmonary resuscitation and bivariate correlations elicited factors affecting team-leadership skills.Teams led by leaders with the best leadership skills performed higher quality cardiopulmonary resuscitation with better technical performance (R = 0.75, p < .001), shorter preshock pauses (R = 0.18, p < .001), with lower total hands-off ratio (R = 0.24, p = .01), and shorter time to first shock (R = 0.14, p = .02). Leadership skills were not significantly associated with more simple technical skills such as chest-compression rate, depth, and ventilation rate. Prior training in team leader skills was independently associated with better leadership behavior.
CONCLUSIONS:There is an association between team leadership skills and cardiac arrest simulation test score, preshock pause, and hands off ratio. Developing leadership skills should be considered an integral part of resuscitation training.
Objectives This study sought to determine the effects of a p38 mitogen-activated protein kinase inhibitor, losmapimod, on vascular inflammation, by18 F-fluorodeoxyglucose (FDG) positron emission ...tomography/computed tomography imaging. Background The p38 mitogen-activated protein kinase cascade plays an important role in the initiation and progression of inflammatory diseases, including atherosclerosis. Methods Patients with atherosclerosis on stable statin therapy (n = 99) were randomized to receive losmapimod 7.5 mg once daily (lower dose LD), twice daily (higher dose HD) or placebo for 84 days. Vascular inflammation was assessed by FDG positron emission tomography/computed tomography imaging of the carotid arteries and aorta; analyses focused on the index vessel (the artery with the highest average maximum tissue-to-background ratio TBR at baseline). Serum inflammatory biomarkers and FDG uptake in visceral and subcutaneous fat were also measured. Results The primary endpoint, change from baseline in average TBR across all segments in the index vessel, was not significantly different between HD and placebo (ΔTBR: −0.04 95% confidence interval CI: −0.14 to +0.06, p = 0.452) or LD and placebo (ΔTBR: −0.02 95% CI: −0.11 to +0.06, p = 0.579). However, there was a statistically significant reduction in average TBR in active segments (TBR ≥1.6) (HD vs. placebo: ΔTBR: −0.10 95% CI: −0.19 to −0.02, p = 0.0125; LD vs. placebo: ΔTBR: −0.10 95% CI: −0.18 to −0.02, p = 0.0194). The probability of a segment being active was also significantly reduced for HD when compared with placebo (OR: 0.57 95% CI: 0.41 to 0.81, p = 0.002). Within the HD group, reductions were observed in placebo-corrected inflammatory biomarkers including high-sensitivity C-reactive protein (% reduction: −28% 95% CI: −46 to −5, p = 0.023) as well as FDG uptake in visceral fat (ΔSUV: −0.05 95% CI: −0.09 to −0.01, p = 0.018), but not subcutaneous fat. Conclusions Despite nonsignificant changes for the primary endpoint of average vessel TBR, HD losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. These results suggest a systemic anti-inflammatory effect. (A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging; NCT00633022 )
OBJECTIVE:To evaluate the effect of implementing real-time audiovisual feedback with and without postevent debriefing on survival and quality of cardiopulmonary resuscitation quality at in-hospital ...cardiac arrest.
DESIGN:A two-phase, multicentre prospective cohort study.
SETTING:Three UK hospitals, all part of one National Health Service Acute Trust.
PATIENTS:One thousand three hundred and ninety-five adult patients who sustained an in-hospital cardiac arrest at the study hospitals and were treated by hospital emergency teams between November 2009 and May 2013.
INTERVENTIONS:During phase 1, quality of cardiopulmonary resuscitation and patient outcomes were measured with no intervention implemented. During phase 2, staff at hospital 1 received real-time audiovisual feedback, whereas staff at hospital 2 received real-time audiovisual feedback supplemented by postevent debriefing. No intervention was implemented at hospital 3 during phase 2.
MEASUREMENTS AND MAIN RESULTS:The primary outcome was return of spontaneous circulation. Secondary endpoints included other patient-focused outcomes, such as survival to hospital discharge, and process-focused outcomes, such as chest compression depth. Random-effect logistic and linear regression models, adjusted for baseline patient characteristics, were used to analyze the effect of the interventions on study outcomes. In comparison with no intervention, neither real-time audiovisual feedback (adjusted odds ratio, 0.62; 95% CI, 0.31–1.22; p = 0.17) nor real-time audiovisual feedback supplemented by postevent debriefing (adjusted odds ratio, 0.65; 95% CI, 0.35–1.21; p = 0.17) was associated with a statistically significant improvement in return of spontaneous circulation or any process-focused outcome. Despite this, there was evidence of a system-wide improvement in phase 2, leading to improvements in return of spontaneous circulation (adjusted odds ratio, 1.87; 95% CI, 1.06–3.30; p = 0.03) and process-focused outcomes.
CONCLUSIONS:Implementation of real-time audiovisual feedback with or without postevent debriefing did not lead to a measured improvement in patient or process-focused outcomes at individual hospital sites. However, there was an unexplained system-wide improvement in return of spontaneous circulation and process-focused outcomes during the second phase of the study.
Each year, more than 1.5 million health care professionals receive advanced life support (ALS) training.
To determine whether a blended approach to ALS training that includes electronic learning ...(e-learning) produces outcomes similar to those of conventional, instructor-led ALS training.
Open-label, noninferiority, randomized trial. Randomization, stratified by site, was generated by Sealed Envelope (Sealed Envelope, London, United Kingdom). (International Standardized Randomized Controlled Trial Number Register: ISCRTN86380392)
31 ALS centers in the United Kingdom and Australia.
3732 health care professionals recruited between December 2008 and October 2010.
A 1-day course supplemented with e-learning versus a conventional 2-day course.
The primary outcome was performance in a cardiac arrest simulation test at the end of the course. Secondary outcomes comprised knowledge- and skill-based assessments, repeated assessment after remediation training, and resource use.
440 of the 1843 participants randomly assigned to the blended course and 444 of the 1889 participants randomly assigned to conventional training did not attend the courses. Performance in the cardiac arrest simulation test after course attendance was lower in the electronic advanced life support (e-ALS) group compared with the conventional advanced life support (c-ALS) group; 1033 persons (74.5%) in the e-ALS group and 1146 persons (80.2%) in the c-ALS group passed (mean difference, -5.7% 95% CI, -8.8% to -2.7%). Knowledge- and skill-based assessments were similar between groups, as was the final pass rate after remedial teaching, which was 94.2% in the e-ALS group and 96.7% in the c-ALS group (mean difference, -2.6% CI, -4.1% to 1.2%). Faculty, catering, and facility costs were $438 per participant for electronic ALS training and $935 for conventional ALS training.
Many professionals (24%) did not attend the courses. The effect on patient outcomes was not evaluated.
Compared with conventional ALS training, an approach that included e-learning led to a slightly lower pass rate for cardiac arrest simulation tests, similar scores on a knowledge test, and reduced costs.
National Institute of Health Research and Resuscitation Council (UK).
Abstract Background The use of cardiac arrest educational debriefing has been associated with improvements in cardiopulmonary resuscitation (CPR) quality and patient outcome. The practical challenges ...associated with delivering some debriefing approaches may not be generalisable to the UK health setting. The aim of this study was to evaluate the deliverability and effectiveness of three cardiac arrest debriefing approaches that were tailored to UK working practice. Methods We undertook a before/after study at three hospital sites. During the post-intervention period of the study, three cardiac arrest educational debriefing models were implemented at study hospitals (one model per hospital). To evaluate the effectiveness of the interventions, CPR quality and patient outcome data were collected from consecutive adult cardiac arrest events attended by the hospital cardiac arrest team. The primary outcome was chest compression depth. Results Between November 2011 and July 2014, 1198 cardiac arrest events were eligible for study inclusion (782 pre-intervention; 416 post-intervention). The quality of CPR was high at baseline. During the post-intervention period, cardiac arrest debriefing interventions were delivered to 191 clinicians on 344 occasions. Debriefing interventions were deliverable in practice, but were not associated with a clinically important improvement in CPR quality. The interventions had no effect on patient outcome. Conclusion The delivery of these cardiac arrest educational debriefing strategies was feasible, but did not have a large effect on CPR quality. This may be attributable to the high-quality of CPR being delivered in study hospitals at baseline. Trial registration ISRCTN39758339.
Summary Introduction CPR feedback/prompt devices are being used increasingly to guide CPR performance in clinical practice. A potential limitation of these devices is that they may fail to measure ...the amount of mattress compression when CPR is performed on a bed. The aim of this study is to quantify the amount of mattress compression compared to chest compression using a commercially available compression sensor (Q-CPR, Laerdal, UK). A secondary aim was to evaluate if placing a backboard beneath the victim would alter the degree of mattress compression. Methods CPR was performed on a manikin on the floor and on a bed with a foam or inflatable mattress with and without a backboard. Chest and mattress compression depths were measured by an accelerometer placed on the manikin's chest (total compression depth) and sternal–spinal (chest) compression by manikin sensors. Results Feedback provided by the accelerometer device led to significant under compression of the chest when CPR was performed on a bed with a foam 26.2 (2.2) mm or inflatable mattress 32.2 (1.16) mm. The use of a narrow backboard increased chest compression depth by 1.9 mm (95% CI 0.1–3.7 mm; P = 0.03) and wide backboard by 2.6 mm (95% CI 0.9–4.5 mm; P = 0.013). Under compression occurred as the device failed to compensate for compression of the underlying mattress, which represented 35–40% of total compression depth. Conclusion The use of CPR feedback devices that do not correct for compression of an underlying mattress may lead to significant under compression of the chest during CPR.
Summary Introduction Previous studies have documented poor quality CPR during real life resuscitation attempts. This study investigated whether poor quality CPR during advanced life support training ...could be contributing to poor performance in clinical practice. Methods Observational study of quality of CPR during advanced life support training courses before and after the implementation of the European Resuscitation Council Guidelines 2005 into the ALS course. The quality of chest compressions were downloaded from a manikin and direct observations of no-flow time; pre-shock pauses were recorded. Results 94 cardiac arrest simulations were studied (46 before implementation of Guidelines 2005 and 48 after). Delays in starting CPR, inadequate compression depth, prolonged interruptions of chest compressions and excessive pre-shock pauses were identified. The introduction of Guidelines 2005 resulted in improvements in the number of compressions given per minute and a reduction in no-flow time and duration of pre-shock pauses, but overall the quality of CPR performed during the ALS course remained poor. There was little evidence of performance improving over successive simulations as the course progressed. Conclusion The implementation of Guidelines 2005 into the ALS course appear to have improved the process of CPR by reducing no-flow time during simulated CPR. However, the quality of CPR during ALS training remains sub-optimal. Delays in starting CPR, inadequate compression depth, excessive interruptions in chest compressions and prolonged pre-shock pauses mirror observations from clinical practice. Strategies to improve CPR performance during ALS training should be explored and potentially may result in improvements in clinical practice.
Abstract Purpose Chest compressions are often performed at a variable rate during cardiopulmonary resuscitation (CPR). The effect of compression rate on other chest compression quality variables ...(compression depth, duty-cycle, leaning, performance decay over time) is unknown. This randomised controlled cross-over manikin study examined the effect of different compression rates on the other chest compression quality variables. Methods Twenty healthcare professionals performed 2 min of continuous compressions on an instrumented manikin at rates of 80, 100, 120, 140 and 160 min−1 in a random order. An electronic metronome was used to guide compression rate. Compression data were analysed by repeated measures ANOVA and are presented as mean (SD). Non-parametric data was analysed by Friedman test. Results At faster compression rates there were significant improvements in the number of compressions delivered (160(2) at 80 min−1 vs. 312(13) compressions at 160 min−1 , P < 0.001); and compression duty-cycle (43(6)% at 80 min−1 vs. 50(7)% at 160 min−1 , P < 0.001). This was at the cost of a significant reduction in compression depth (39.5(10) mm at 80 min−1 vs. 34.5(11) mm at 160 min−1 , P < 0.001); and earlier decay in compression quality (median decay point 120 s at 80 min−1 vs. 40 s at 160 min−1 , P < 0.001). Additionally not all participants achieved the target rate (100% at 80 min−1 vs. 70% at 160 min−1 ). Rates above 120 min−1 had the greatest impact on reducing chest compression quality. Conclusions For Guidelines 2005 trained rescuers, a chest compression rate of 100–120 min−1 for 2 min is feasible whilst maintaining adequate chest compression quality in terms of depth, duty-cycle, leaning, and decay in compression performance. Further studies are needed to assess the impact of the Guidelines 2010 recommendation for deeper and faster chest compressions.
The aim of this study was to define which measure of microvascular best predicts the extent of left ventricular (LV) infarction.
Microvascular injury after ST-segment elevation myocardial infarction ...(STEMI) is an important determinant of outcome. Several invasive measures of the microcirculation at primary percutaneous coronary intervention (PPCI) have been described. One such measure is zero-flow pressure (Pzf), the calculated pressure at which coronary flow would cease.
In 34 STEMI patients, Pzf, hyperemic microvascular resistance (hMR), and index of microcirculatory resistance (IMR) were derived using thermodilution flow/pressure and Doppler flow/pressure wire assessment of the infarct-related artery following PPCI. The extent of infarction was determined by blinded late gadolinium enhancement on cardiac magnetic resonance at 6 months post-PPCI. Infarction of ≥24% total LV mass was used as a categorical cutoff in receiver-operating characteristic curve analysis.
Pzf was superior to both hMR and IMR for predicting ≥24% infarction area under the curve: 0.94 for Pzf versus 0.74 for hMR (p = 0.04) and 0.54 for IMR (p = 0.003). Pzf ≥42 mm Hg was the optimal cutoff value, offering 100% sensitivity and 73% specificity. Patients with Pzf ≥42 mm Hg also had a lower salvage index (61.3 ± 8.1 vs. 44.4 ± 16.8, p = 0.006) and 6-month ejection fraction (62.4 ± 3.6 vs. 49.9 ± 9.6, p = 0.002). In addition, there were significant direct relationships between Pzf and troponin area under the curve (rho = 0.55, p = 0.002), final infarct mass (rho = 0.75, p < 0.0001), percentage of LV infarction and percent transmurality of infarction (rho = 0.77 and 0.74, respectively, p < 0.0001), and inverse relationships with myocardial salvage index (rho = -0.53, p = 0.01) and 6-month ejection fraction (rho = -0.73, p = 0.0001).
Pzf measured at the time of PPCI is a better predictor of the extent of myocardial infarction than hMR or IMR. Pzf may provide important prognostic information at the time of PPCI and merits further investigation in clinical studies with relevant outcome measures.
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