Abstract Objective To evaluate adverse outcomes after elective aortic arch surgery performed at higher or lower temperatures (24.0°C-28.0°C vs 20.1°C-23.9°C) within the wide range of moderate ...hypothermia. Methods Over a 9-year period, a total of 665 patients underwent elective proximal (n = 479) or total (n = 186) arch replacement with moderate hypothermia and antegrade cerebral perfusion. Circulatory arrest was initiated at an actual temperature of 20.1°C to 23.9°C in the lower-temperature group (n = 334; 223 proximal, 111 total) and at 24.0°C to 28.0°C in the higher-temperature group (n = 331; 256 proximal, 75 total). Composite adverse outcome was defined as operative mortality or persistent neurologic event or persistent hemodialysis at discharge. Multivariate logistic regression analysis was used to model adverse outcome. In addition to the actual temperature, a new, balanced variable, “predicted temperature,” was analyzed to eliminate surgeon bias. We used this variable in a propensity score–matching analysis to validate the multivariate analysis results. Results A composite adverse outcome occurred in 7.2% of cases. Operative mortality was 5.1%. The rate of postoperative persistent neurologic deficits was 2.4%. No significant differences were found between the lower– and higher–predicted temperature groups within the moderate hypothermia range in the propensity score–matching analysis. The higher–actual temperature group had a lower rate of ventilator support at >48 hours ( P = .036) and less need for tracheostomy ( P = .023). Packed red blood cell transfusion and previous coronary artery bypass independently predicted composite adverse outcome ( P = .0053 and .0002, respectively), operative mortality ( P = .0051 and .0041), and postoperative stroke ( P = .045 and .048). Cardiopulmonary bypass time independently predicted composite outcome ( P = .0005), operative mortality ( P < .0001), ventilatory support for >48 hours ( P < .0001), and renal dysfunction ( P = .0005). Conclusions In elective proximal or total arch surgery, higher temperatures (≥24.0°C-28.0°C) within the wide range of moderate hypothermia (20.1°C-28°C) are safe and, compared with colder temperatures, not associated with significantly different rates of composite and adverse outcomes.
Objective Selective antegrade cerebral perfusion (ACP) during hypothermic circulatory arrest (HCA) provides cerebral protection during aortic arch surgery. However, the ideal temperature for HCA ...during ACP remains unknown. Clinical outcomes were compared in patients who underwent moderate (nasopharyngeal temperature, ≥20°C) versus deep (nasopharyngeal temperature, <20°C) HCA with ACP during aortic arch repair. Methods By using a prospectively maintained clinical database, we analyzed data from 221 consecutive patients who underwent aortic arch replacement with HCA and ACP between December 2006 and May 2009. Seventy-eight patients underwent deep hypothermia (mean lowest temperature, 16.8°C ± 1.7°C) and 143 patients underwent moderate hypothermia (mean, 22.9°C ± 1.4°C) before systemic circulatory arrest was initiated. Multivariate stepwise logistic and linear regressions were performed to determine whether depth of hypothermia independently predicted postoperative outcomes and blood-product use. Results Compared with moderate hypothermia, deep hypothermia was associated independently with a greater risk of in-hospital death (7.7% vs 0.7%; odds ratio OR, 9.3; 95% confidence interval CI, 1.1-81.6; P = .005) and 30-day all-cause mortality (9.0% vs 2.1%; OR, 4.7; 95% CI, 1.2-18.6; P = .02), and with longer cardiopulmonary bypass time (154 ± 62 vs 140 ± 46 min; P = .008). Deep hypothermia also was associated with a higher incidence of stroke, although this association was not statistically significant (7.6% vs 2.8%; P = .073; OR, 4.3; 95% CI, 0.9-12.5). No difference was seen in acute kidney injury, blood product transfusion, or need for surgical re-exploration. Conclusions Moderate hypothermia with ACP is associated with lower in-hospital and 30-day mortality, shorter cardiopulmonary bypass time, and fewer neurologic sequelae than deep hypothermia in patients who undergo aortic arch surgery with ACP.
Blood stream infection (BSI) and acute GVHD (aGVHD) are serious complications of hematopoietic SCT (HSCT). We hypothesized that the two events were not independent of one another. We studied (1) ...associations between BSI and aGVHD; and (2) the impact of BSI and/or aGVHD on death within 100 days after HSCT, using a retrospective cohort analysis. Risk factor analysis was carried out using multivariable Cox proportional hazards analyses. Of 211 patients who underwent allogeneic HSCT from January 2000 to December 2005 (58% of whom underwent reduced intensity transplantation), 82 (39%) developed BSI. In 49 patients (23%), grade (gr) 2-4 aGVHD occurred. Early BSI was independently associated with an increased occurrence of subsequent aGVHD gr 2-4. CMV seropositivity was independently associated with decreased occurrence of aGVHD. aGVHD gr 2-4 independently predicted subsequent first BSI. Both BSI and aGVHD gr 2-4 were significant independent predictors of death within 100 days after HSCT. There is a strong, independent association between BSI and aGVHD. Potential explanations include the elaboration of cytokines during BSI favoring the development of aGVHD and/or the immunosuppressive treatment of aGVHD favoring the development of BSI. Future studies should be directed at the mechanistic investigations of this association.
Abstract Background In the PROTECT AF (Watchman Left Atrial Appendage Closure Technology for Embolic Protection in Patients With Atrial Fibrillation) trial that evaluated patients with nonvalvular ...atrial fibrillation (NVAF), left atrial appendage (LAA) occlusion was noninferior to warfarin for stroke prevention, but a periprocedural safety hazard was identified. Objectives The goal of this study was to assess the safety and efficacy of LAA occlusion for stroke prevention in patients with NVAF compared with long-term warfarin therapy. Methods This randomized trial further assessed the efficacy and safety of the Watchman device. Patients with NVAF who had a CHADS2 (congestive heart failure, hypertension, age >75 years, diabetes mellitus, and previous stroke/transient ischemic attack) score ≥2 or 1 and another risk factor were eligible. Patients were randomly assigned (in a 2:1 ratio) to undergo LAA occlusion and subsequent discontinuation of warfarin (intervention group, n = 269) or receive chronic warfarin therapy (control group, n = 138). Two efficacy and 1 safety coprimary endpoints were assessed. Results At 18 months, the rate of the first coprimary efficacy endpoint (composite of stroke, systemic embolism SE, and cardiovascular/unexplained death) was 0.064 in the device group versus 0.063 in the control group (rate ratio 1.07 95% credible interval (CrI): 0.57 to 1.89) and did not achieve the prespecified criteria noninferiority (upper boundary of 95% CrI ≥1.75). The rate for the second coprimary efficacy endpoint (stroke or SE >7 days’ postrandomization) was 0.0253 versus 0.0200 (risk difference 0.0053 95% CrI: –0.0190 to 0.0273), achieving noninferiority. Early safety events occurred in 2.2% of the Watchman arm, significantly lower than in PROTECT AF, satisfying the pre-specified safety performance goal. Using a broader, more inclusive definition of adverse effects, these still were lower in PREVAIL (Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trial than in PROTECT AF (4.2% vs. 8.7%; p = 0.004). Pericardial effusions requiring surgical repair decreased from 1.6% to 0.4% (p = 0.027), and those requiring pericardiocentesis decreased from 2.9% to 1.5% (p = 0.36), although the number of events was small. Conclusions In this trial, LAA occlusion was noninferior to warfarin for ischemic stroke prevention or SE >7 days’ post-procedure. Although noninferiority was not achieved for overall efficacy, event rates were low and numerically comparable in both arms. Procedural safety has significantly improved. This trial provides additional data that LAA occlusion is a reasonable alternative to warfarin therapy for stroke prevention in patients with NVAF who do not have an absolute contraindication to short-term warfarin therapy.
Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of African ancestry (AA) experience the disease more severely and with an ...increased co-morbidity burden compared to European ancestry (EA) populations. We hypothesize that the disparities in disease prevalence, activity, and response to standard medications between AA and EA populations is partially conferred by genomic influences on biological pathways. To address this, we applied a comprehensive approach to identify all genes predicted from SNP-associated risk loci detected with the Immunochip. By combining genes predicted via eQTL analysis, as well as those predicted from base-pair changes in intergenic enhancer sites, coding-region variants, and SNP-gene proximity, we were able to identify 1,731 potential ancestry-specific and trans-ancestry genetic drivers of SLE. Gene associations were linked to upstream and downstream regulators using connectivity mapping, and predicted biological pathways were mined for candidate drug targets. Examination of trans-ancestral pathways reflect the well-defined role for interferons in SLE and revealed pathways associated with tissue repair and remodeling. EA-dominant genetic drivers were more often associated with innate immune and myeloid cell function pathways, whereas AA-dominant pathways mirror clinical findings in AA subjects, suggesting disease progression is driven by aberrant B cell activity accompanied by ER stress and metabolic dysfunction. Finally, potential ancestry-specific and non-specific drug candidates were identified. The integration of all SLE SNP-predicted genes into functional pathways revealed critical molecular pathways representative of each population, underscoring the influence of ancestry on disease mechanism and also providing key insight for therapeutic selection.
AbstractPurposeThe goal of this study was to assess the long-term safety and efficacy of mepolizumab in patients with the most severe eosinophilic asthma. MethodsThis multicenter, open-label, ...long-term, Phase IIIb study (COSMEX COSMOS Extension; 201312/NCT02135692) enrolled patients from the 52-week, open-label extension study COSMOS (A Study to Determine Long-term Safety of Mepolizumab in Asthmatic Subjects) that previously enrolled patients from the double-blinded, placebo-controlled Phase III studies MENSA (Mepolizumab as Adjunctive Therapy in Patients with Severe Asthma) and SIRIUS (Steroid Reduction with Mepolizumab Study). To enter COSMEX, patients had to have life-threatening/seriously debilitating asthma before entering MENSA or SIRIUS and to have completed these previous studies with demonstrated improvement while receiving mepolizumab. In COSMEX, patients received mepolizumab 100 mg subcutaneously every 4 weeks as add-on therapy for up to 172 weeks. Primary endpoints were adverse event frequency and exacerbation rate per year; also assessed were forced expiratory volume in 1 s, Asthma Control Questionnaire-5 score, and daily oral corticosteroid (OCS) use. FindingsOf the 340 patients enrolled, 339 received mepolizumab; median treatment duration within this extension study was 2.2 years, equating to 718 patient-years of additional exposure. No new safety signals were identified. Patients receiving mepolizumab throughout this study and previous studies had lasting reductions in exacerbation rate and daily OCS use and improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire-5 score. In COSMEX, the on-treatment exacerbation rate (95% CI) was 0.93 (0.81–1.06) event/year for clinically significant exacerbations, 0.13 (0.10–0.18) event/year for exacerbations requiring hospitalization/emergency department visit, and 0.07 (0.05–0.10) event/year for exacerbations requiring hospitalization. In patients requiring systemic/oral corticosteroids with ≥128 weeks of continuous enrollment across SIRIUS, COSMOS, and COSMEX, mepolizumab maintained the median daily OCS dose at 1.3–2.8 mg during COSMEX, with additional patients no longer requiring OCS after extended mepolizumab treatment. ImplicationsThis study indicates that long-term mepolizumab treatment is well tolerated and associated with sustained clinical benefits in patients with severe eosinophilic asthma. ClinicalTrials.gov identifier: NCT02135692.
Topical hemostatic agents are used in conjunction with conventional procedures to reduce blood loss. They are often used in cardiothoracic surgery, which is particularly prone to bleeding risks. ...Variation in their use exists because detailed policy and practice guidelines reflecting the current medical evidence have not been developed to promote best surgical practice in this setting. To address this need, the Society for the Advancement of Blood Management convened an International Hemostatic Expert Panel. This article reviews the available literature and sets out evidence-based recommendations for the use of topical hemostatic agents in cardiothoracic surgery.
The flare of radiation from the tidal disruption and accretion of a star can be used as a marker for supermassive black holes that otherwise lie dormant and undetected in the centres of distant ...galaxies. Previous candidate flares have had declining light curves in good agreement with expectations, but with poor constraints on the time of disruption and the type of star disrupted, because the rising emission was not observed. Recently, two 'relativistic' candidate tidal disruption events were discovered, each of whose extreme X-ray luminosity and synchrotron radio emission were interpreted as the onset of emission from a relativistic jet. Here we report a luminous ultraviolet-optical flare from the nuclear region of an inactive galaxy at a redshift of 0.1696. The observed continuum is cooler than expected for a simple accreting debris disk, but the well-sampled rise and decay of the light curve follow the predicted mass accretion rate and can be modelled to determine the time of disruption to an accuracy of two days. The black hole has a mass of about two million solar masses, modulo a factor dependent on the mass and radius of the star disrupted. On the basis of the spectroscopic signature of ionized helium from the unbound debris, we determine that the disrupted star was a helium-rich stellar core.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives This study sought to evaluate the clinical impact of intraprocedural stent thrombosis (IPST), a relatively new endpoint. Background In the prospective, double-blind, active-controlled ...CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST. Methods An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment at any time during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee. Results IPST developed in 89 patients (0.8%), including 35 of 5,470 (0.6%) and 54 of 5,469 (1.0%) patients in the cangrelor and clopidogrel arms, respectively (odds ratio: 0.65; 95% confidence interval: 0.42 to 0.99; p = 0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction MI, ischemia-driven revascularization, or new-onset out-of-laboratory stent thrombosis Academic Research Consortium) at 48 h and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, respectively; p < 0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points. Conclusions In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous adenosine diphosphate antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 h and 30 days. (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention PCI CHAMPION PHOENIX; NCT01156571 )
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