Search

Background: Many patients with acute ST-segment elevation myocardial infarction (STEMI) are admitted to emergency departments (EDs) of centres without percutaneous coronary intervention (PCI) facilities. The 2012 European Society of Cardiology guidelines recommend transfer to a PCI centre with a "door in - door out" (DI-DO) time≤30min., Purpose: To report DI-DO times in a registry of patients with acute STEMI., Methods: The RESeau des Urgences CORonarienne (RESUCOR) is a permanent registry of patients admitted with acute STEMI in 16 hospitals in the north French Alps since 2002. In patients admitted to a non-PCI centre, the DI-DO times were split into "diagnostic time" (from admission to transfer decision) and "logistical time" (from transfer decision to discharge)., Results: Of 2081 patients included in the registry from 2012 to 2014, 493 were admitted directly into an ED (254 PCI centre and 239 non-PCI centre). Of those admitted into an ED of a non-PCI centre, 228 were immediately transferred to a PCI centre (76 treated with thrombolysis and 132 with primary PCI). The proportions of patients with DI-DO≤30min and median (interquartile range [IQR]) DI-DO times are reported in the Table 1. Median (IQR) DIDO times were 90.5 (69-118) min for patients treated with thrombolysis and 88 (62-147) min for primary PCI., Conclusions: DI-DO times were longer than recommended. Efforts to decrease these delays are required. Transfer with a non-PCI centre ambulance is preferable., (Copyright © 2016. Published by Elsevier SAS.)

In the emergency department, the management of patients with pulmonary embolism depends on the early mortality risk. Outpatient care is possible in low-risk patients. We present the existing scores and the strategy proposed by the North Alps Emergency Network, which uses the simplified PESI score (Pulmonary Embolism Severity Index) to select those low-risk patients, candidates for early discharge., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Elderly patients are at high risk of ischaemic and bleeding events. Platelet function monitoring offers the possibility to individualise antiplatelet therapy to improve the therapeutic risk-benefit ratio. We aimed to assess the effect of platelet function monitoring with treatment adjustment in elderly patients stented for an acute coronary syndrome., Methods: We did this multicentre, open-label, blinded-endpoint, randomised controlled superiority study at 35 centres in France. Patients aged 75 years or older who had undergone coronary stenting for acute coronary syndrome were randomly assigned (1:1), via a central interactive voice-response system based on a computer-generated permuted-block randomisation schedule with randomly selected block sizes, to receive oral prasugrel 5 mg daily with dose or drug adjustment in case of inadequate response (monitoring group) or oral prasugrel 5 mg daily with no monitoring or treatment adjustment (conventional group). Randomisation was stratified by centre. Platelet function testing was done 14 days after randomisation and repeated 14 days after treatment adjustment in patients in the monitoring group. Study investigators and patients were not masked to treatment allocation, but allocation was concealed from an independent clinical events committee responsible for endpoint adjudication. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, urgent revascularisation, and Bleeding Academic Research Consortium-defined bleeding complications (types 2, 3, or 5) at 12 months' follow-up. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01538446., Findings: Between March 27, 2012, and May 19, 2015, we randomly assigned 877 patients to the monitoring group (n=442) or the conventional group (n=435). The primary endpoint occurred in 120 (28%) patients in the monitoring group compared with 123 (28%) patients in the conventional group (hazard ratio [HR], 1·003, 95% CI 0·78-1·29; p=0·98). Rates of bleeding events did not differ significantly between groups., Interpretation: Platelet function monitoring with treatment adjustment did not improve the clinical outcome of elderly patients treated with coronary stenting for an acute coronary syndrome. Platelet function testing is still being used in many centres and international guidelines still recommend platelet function testing in high-risk situations. Our study does not support this practice or these recommendations., Funding: Eli Lilly and Company, Daiichi Sankyo, Stentys, Accriva Diagnostics, Medtronic, and Fondation Coeur et Recherche., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Reestablishment of competent regulatory pathways has emerged as a strategy to reduce the severity of graft-versus-host disease (GVHD), and recalibrate the effector and regulatory arms of the immune system. However, clinically feasible, cost-effective strategies that do not require extensive ex vivo cellular manipulation have remained elusive. In the current study, we demonstrate that inhibition of the interleukin-27p28 (IL-27p28) signaling pathway through antibody blockade or genetic ablation prevented lethal GVHD in multiple murine transplant models. Moreover, protection from GVHD was attributable to augmented global reconstitution of CD4 + natural regulatory T cells (nTregs), CD4 + induced Tregs (iTregs), and CD8 + iTregs, and was more potent than temporally concordant blockade of IL-6 signaling. Inhibition of IL-27p28 also enhanced the suppressive capacity of adoptively transferred CD4 + nTregs by increasing the stability of Foxp3 expression. Notably, blockade of IL-27p28 signaling reduced T-cell-derived-IL-10 production in conventional T cells; however, there was no corresponding effect in CD4 + or CD8 + Tregs, indicating that IL-27 inhibition had differential effects on IL-10 production and preserved a mechanistic pathway by which Tregs are known to suppress GVHD. Targeting of IL-27 therefore represents a novel strategy for the in vivo expansion of Tregs and subsequent prevention of GVHD without the requirement for ex vivo cellular manipulation, and provides additional support for the critical proinflammatory role that members of the IL-6 and IL-12 cytokine families play in GVHD biology., (© 2016 by The American Society of Hematology.)

Background: No randomized study has investigated the value of optical coherence tomography (OCT) in optimizing the results of percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndromes., Methods: We conducted a multicenter, randomized study involving 240 patients with non-ST-segment elevation acute coronary syndromes to compare OCT-guided PCI (use of OCT pre- and post-PCI; OCT-guided group) to fluoroscopy-guided PCI (angiography-guided group). The primary end point was the functional result of PCI assessed by the measure of post PCI fractional flow reserve. Secondary end points included procedural complications and type 4a periprocedural myocardial infarction. Safety was assessed by the rate of acute kidney injury., Results: OCT use led to a change in procedural strategy in 50% of the patients in the OCT-guided group. The primary end point was improved in the OCT-guided group, with a significantly higher fractional flow reserve value (0.94±0.04 versus 0.92±0.05, P=0.005) compared with the angiography-guided group. There was no significant difference in the rate of type 4a myocardial infarction (33% in the OCT-group versus 40% in the angiography-guided group, P=0.28). The rates of procedural complications (5.8%) and acute kidney injury (1.6%) were identical in each group despite longer procedure time and use of more contrast medium in the OCT-guided group. Post-PCI OCT revealed stent underexpansion in 42% of patients, stent malapposition in 32%, incomplete lesion coverage in 20%, and edge dissection in 37.5%. This led to the more frequent use of poststent overdilation in the OCT-guided group versus the angiography-guided group (43% versus 12.5%, P<0.0001) with lower residual stenosis (7.0±4.3% versus 8.7±6.3%, P=0.01)., Conclusions: In patients with non-ST-segment elevation acute coronary syndromes, OCT-guided PCI is associated with higher postprocedure fractional flow reserve than PCI guided by angiography alone. OCT did not increase periprocedural complications, type 4a myocardial infarction, or acute kidney injury., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01743274., (© 2016 American Heart Association, Inc.)

Damage to the gastrointestinal tract is a major cause of morbidity and mortality in graft-versus-host disease (GVHD) and is attributable to T cell-mediated inflammation. In this work, we identified a unique CD4+ T cell population that constitutively expresses the β2 integrin CD11c and displays a biased central memory phenotype and memory T cell transcriptional profile, innate-like properties, and increased expression of the gut-homing molecules α4β7 and CCR9. Using several complementary murine GVHD models, we determined that adoptive transfer and early accumulation of β2 integrin-expressing CD4+ T cells in the gastrointestinal tract initiated Th1-mediated proinflammatory cytokine production, augmented pathological damage in the colon, and increased mortality. The pathogenic effect of this CD4+ T cell population critically depended on coexpression of the IL-23 receptor, which was required for maximal inflammatory effects. Non-Foxp3-expressing CD4+ T cells produced IL-10, which regulated colonic inflammation and attenuated lethality in the absence of functional CD4+Foxp3+ T cells. Thus, the coordinate expression of CD11c and the IL-23 receptor defines an IL-10-regulated, colitogenic memory CD4+ T cell subset that is poised to initiate inflammation when there is loss of tolerance and breakdown of mucosal barriers.

Objective: Fall-related visits to emergency departments (EDs) are common among older individuals. We aimed to assess effectiveness of a healthcare intervention program for the management of elderly patients admitted to EDs after a fall., Methods: Using a before-after observation method, we investigated ED healthcare staff practices related to fall-related injuries in 2010 (period 1) and 2012 (period 2) in 13 centers participating in the Northern French Alps Emergency Network. Following the identification of initial weaknesses, several information and training tools were introduced between the two periods to improve patient management. All individuals aged 75 years or over who presented to an ED after a fall were included in the study. We reviewed the completeness and quality of medical records during both periods and compared the rate of clinical-paraclinical check-ups performed, geriatric evaluation/assessment in the ED, and the 1-month recurrence of visits to the ED for the same reason., Results: During period 1, a total of 2,425 falls were recorded, while 2,684 were reported in period 2. The 2012 medical charts contained significantly more information about risk factors than those of 2010. An electrocardiogram (64% vs. 53%; p < 0.001), biologic check-up (65% vs. 57%; p < 0.001), balance, orthostatic hypotension, and cognitive impairment tests were more often performed in 2012. There was no change in the hospitalization rate, although short-duration hospitalization in the ED was more frequent in 2012. Geriatrists were more often consulted by patients in 2012 (18% vs. 13%; p < 0.001) and more involved in ED evaluation and hospitalization. The intervention program had a beneficial impact on the fall recurrence rate (n = 29 [3.6%] in period 1 and n = 17 [2.0%] in period 2; odds ratio = 0.52; p = 0.037), which significantly decreased between 2010 and 2012., Conclusions: The intervention program was associated with a decrease of fall recurrence. Further efforts should be made in EDs to ensure a sustained level of satisfactory and long-lasting management of the elderly., (© 2016 by the Society for Academic Emergency Medicine.)

Introduction: Allogeneic hematopoietic stem cell transplantation (alloHSCT) offers potential curative treatment for a wide range of malignant and nonmalignant hematological disorders. However, its success may be limited by post-transplant acute graft-versus-host disease (aGVHD), a systemic syndrome in which donor's immune cells attack healthy tissues in the immunocompromised host. aGVHD is one of the main causes of morbidity and mortality after alloHSCT. Despite standard GVHD prophylaxis regimens, aGVHD still develops in approximately 40-60% of alloHSCT recipients., Areas Covered: In this review, after a brief summary of current knowledge on the pathogenesis of aGVHD, the authors review the current combination of a calcineurin inhibitor with an antimetabolite with or without added anti-thymocyte globulin (ATG) and emerging strategies for GVHD prevention., Expert Opinion: A new understanding of the involvement of cytokines, intracellular signaling pathways, epigenetics and immunoregulatory cells in GVHD pathogenesis will lead to new standards for aGVHD prophylaxis allowing better prevention of severe aGVHD without affecting graft-versus-tumor effects.

Background: The minimalist immediate mechanical intervention (MIMI) strategy aims to restore normal anterograde flow in the culprit artery (by using manual thrombectomy or small-sized balloon predilation) and to defer potential stent implantation. This study evaluated the applicability and midterm clinical results of the MIMI strategy for ST-elevation myocardial infarction (STEMI) management., Methods: This observational study included consecutive patients admitted for ongoing STEMI (<24 hours' evolution) at 1 institution between June 2010 and June 2013. Revascularization was performed at the physician's discretion. We compared retrospectively "intentional immediate stenting" (standard technique) and "intentional delayed stenting" (MIMI technique)., Results: Twenty percent of the 279 included patients were treated with the MIMI strategy. These patients were significantly younger and were more frequently men and smokers compared with patients who underwent the standard procedure. The rate of acute reocclusion of the culprit artery related to STEMI in the MIMI group was 1.8%. Drug-eluting stents were used more frequently in the MIMI group (52% vs 27% in the standard group; P < 0.001). The culprit lesion was stented less frequently in the patients treated with MIMI compared with patients in the other group (28.5% vs 9%; P < 0.001). The 1-year actuarial survival free from major adverse cardiovascular events was higher in the MIMI group than in the standard group (96.3% ± 1.8% vs 83.8% ± 2.5%; P = 0.01)., Conclusions: The MIMI strategy can be applied in selected patients with STEMI. In our centre, this strategy is associated with less systematic culprit lesion stenting and more implantation of drug-eluting stents. However, this needs to be evaluated further in a randomized trial., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Introduction and Aims: Recent years have witnessed increased attention to how cannabis use impacts the use of other psychoactive substances. The present study examines the use of cannabis as a substitute for alcohol, illicit substances and prescription drugs among 473 adults who use cannabis for therapeutic purposes., Design and Methods: The Cannabis Access for Medical Purposes Survey is a 414-question cross-sectional survey that was available to Canadian medical cannabis patients online and by hard copy in 2011 and 2012 to gather information on patient demographics, medical conditions and symptoms, patterns of medical cannabis use, cannabis substitution and barriers to access to medical cannabis., Results: Substituting cannabis for one or more of alcohol, illicit drugs or prescription drugs was reported by 87% (n = 410) of respondents, with 80.3% reporting substitution for prescription drugs, 51.7% for alcohol, and 32.6% for illicit substances. Respondents who reported substituting cannabis for prescription drugs were more likely to report difficulty affording sufficient quantities of cannabis, and patients under 40 years of age were more likely to substitute cannabis for all three classes of substance than older patients., Discussion and Conclusions: The finding that cannabis was substituted for all three classes of substances suggests that the medical use of cannabis may play a harm reduction role in the context of use of these substances, and may have implications for abstinence-based substance use treatment approaches. Further research should seek to differentiate between biomedical substitution for prescription pharmaceuticals and psychoactive drug substitution, and to elucidate the mechanisms behind both. [Lucas P, Walsh Z, Crosby K, Callaway R, Belle-Isle L, Kay B, Capler R, Holtzman S. Substituting cannabis for prescription drugs, alcohol, and other substances among medical cannabis patients: The impact of contextual factors. Drug Alcohol Rev 2016;35:326-333]., (© 2015 Australasian Professional Society on Alcohol and other Drugs.)

Background: Mineralocorticoid receptor antagonists (MRA) improve outcome in the setting of post-myocardial infarction (MI) heart failure (HF)., Objectives: The study sought to assess the benefit of an early MRA regimen in acute MI irrespective of the presence of HF or left ventricular (LV) dysfunction., Methods: We randomized 1,603 patients to receive an MRA regimen with a single intravenous bolus of potassium canrenoate (200 mg) followed by oral spironolactone (25 mg once daily) for 6 months in addition to standard therapy or standard therapy alone. The primary outcome of the study was the composite of death, resuscitated cardiac arrest, significant ventricular arrhythmia, indication for implantable defibrillator, or new or worsening HF at 6-month follow-up. Key secondary/safety outcomes included death and other individual components of the primary outcome and rates of hyperkalemia at 6 months., Results: The primary outcome occurred in 95 (11.8%) and 98 (12.2%) patients in the treatment and control groups, respectively (hazard ratio [HR]: 0.97; 95% confidence interval [CI]: 0.73 to 1.28). Death occurred in 11 (1.4%) and 17 (2.1%) patients in the treatment and control groups, respectively (HR: 0.65; 95% CI: 0.30 to 1.38). In a non-pre-specified exploratory analysis, the odds of death were reduced in the treatment group (3 [0.5%] vs. 15 [2.4%]; HR: 0.20; 95% CI: 0.06 to 0.70) in the subgroup of ST-segment elevation MI (n = 1,229), but not in non-ST-segment elevation MI (p for interaction = 0.01). Hyperkalemia >5.5 mmol/l(-1) occurred in 3% and 0.2% of patients in the treatment and standard therapy groups, respectively (p < 0.0001)., Conclusions: The study failed to show the benefit of early MRA use in addition to standard therapy in patients admitted for MI. (Aldosterone Lethal effects Blockade in Acute myocardial infarction Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up; NCT01059136)., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In countries where a single public emergency telephone number is not in operation, different emergency telephone numbers corresponding to multiple dispatch centres (police, fire, emergency medical service) may create confusion for the population about the most appropriate service to call. In particular, out-of-hospital cardiac arrest (OHCA) requires a prompt and effective response. We compare two different dispatch systems on OHCA patient survival at 30 days in a national system with multiple emergency telephone numbers., Methods: We conducted an observational retrospective study of 6871 patients aged 18 years or older with presumed OHCA of cardiac origin between 2005 and 2013 in three counties of the Northern French Alps region. One county had a single dispatch centre combining medical and fire emergencies, and two had multiple dispatch centres. Propensity score matching analyses were performed to compare patient survival at 30 days., Results: A total of 2257 emergency calls for OHCA were managed by a single dispatch centre and 4614 by a multiple dispatch centre. A single dispatch centre was associated with an increase in survival (adjusted odds ratio [OR] for all patients: 1.7; 95 % confidence interval [CI] = 1.3-2.2; p <0.001; adjusted OR for propensity-matched patients: 2.0; 95 % CI = 1.2-3.4; p = 0.012)., Conclusions: A single dispatch centre was associated with a markedly improved increase of survival among OHCA patients at 30 days in a system with several emergency telephone numbers.

Aims: Angiography has limited value for identifying the causes of stent thrombosis (ST). We studied a large cohort of patients by optical coherence tomography (OCT) to explore ST characteristics and mechanisms., Methods and Results: A prospective multicentre registry was screened for patients with confirmed ST. Optical coherence tomography was performed after initial intervention to the culprit lesion (in 69% of cases in a deferred procedure). Stent thrombosis was classified as acute (AST), sub-acute (SAST), late (LST), and very late (VLST). Optical coherence tomography records were analysed in a central core lab. The analysis included 120 subjects aged 61.7 [51.4-70.7]; 89% male. Very late ST was the clinical presentation in 75%, LST in 6%, SAST in 15%, and AST in 4% of patients. Bare metal stents (BMS) were used in 39%, drug-eluting stents (DES) in 59% and bioresorbable vascular scaffolds in 2% of the cases. Optical coherence tomography identified an underlying morphological abnormality in 97% of cases, including struts malapposition (34%), neoatherosclerotic lesions (22%), major stent underexpansion (11%), coronary evagination (8%), isolated uncovered struts (8%), edge-related disease progression (8%), and neointimal hyperplasia (4%). Ruptured neoatherosclerotic lesions were more frequent with BMS than with DES (36 vs. 14%, P = 0.005), whereas coronary evaginations were more frequent with DES than with BMS (12 vs. 2%, P = 0.04). LST + VLST were mainly related to malapposition (31%) and neoatherosclerosis (28%), while prominent mechanisms for AST + SAST were malapposition (48%) and underexpansion (26%)., Conclusion: In patients with confirmed ST, OCT imaging identified an underlying morphological abnormality in 97% of cases., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Delayed stent implantation after restoration of normal epicardial flow by a minimalist immediate mechanical intervention aims to decrease the rate of distal embolization and impaired myocardial reperfusion after percutaneous coronary intervention. We sought to confirm whether a delayed stenting (DS) approach (24-48 hours) improves myocardial reperfusion, versus immediate stenting, in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention., Methods and Results: In the prospective, randomized, open-label minimalist immediate mechanical intervention (MIMI) trial, patients (n=140) with ST-segment-elevation myocardial infarction ≤12 hours were randomized to immediate stenting (n=73) or DS (n=67) after Thrombolysis In Myocardial Infarction 3 flow restoration by thrombus aspiration. Patients in the DS group underwent a second coronary arteriography for stent implantation a median of 36 hours (interquartile range 29-46) after randomization. The primary end point was microvascular obstruction (% left ventricular mass) on cardiac magnetic resonance imaging performed 5 days (interquartile range 4-6) after the first procedure. There was a nonsignificant trend toward lower microvascular obstruction in the immediate stenting group compared with DS group (1.88% versus 3.96%; P=0.051), which became significant after adjustment for the area at risk (P=0.049). Median infarct weight, left ventricular ejection fraction, and infarct size did not differ between groups. No difference in 6-month outcomes was apparent for the rate of major cardiovascular and cerebral events., Conclusions: The present findings do not support a strategy of DS versus immediate stenting in patients with ST-segment-elevation infarction undergoing primary percutaneous coronary intervention and even suggested a deleterious effect of DS on microvascular obstruction size., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01360242., (© 2016 American Heart Association, Inc.)

Background: Takotsubo cardiomyopathy (TTC) is a rare condition characterized by a sudden temporary weakening of the heart. TTC can mimic acute myocardial infarction and is associated with a minimal release of myocardial biomarkers in the absence of obstructive coronary artery disease., Aims: To provide an extensive description of patients admitted to hospital for TTC throughout France and to study the management and outcomes of these patients., Methods: In 14 non-academic hospitals, we collected clinical, electrocardiographic, biological, psychological and therapeutic data in patients with a diagnosis of TTC according to the Mayo Clinic criteria., Results: Of 117 patients, 91.5% were women, mean ± SD age was 71.4 ± 12.1 years and the prevalence of risk factors was high (hypertension: 57.9%, dyslipidaemia: 33.0%, diabetes: 11.5%, obesity: 11.5%). The most common initial symptoms were chest pain (80.5%) and dyspnoea (24.1%). A triggering psychological event was detected in 64.3% of patients. ST-segment elevation was found in 41.7% of patients and T-wave inversion in 71.6%. Anterior leads were most frequently associated with ST-segment elevation, whereas T-wave inversion was more commonly associated with lateral leads, and Q-waves with septal leads. The ratio of peak B-type natriuretic peptide (BNP) or N-terminal prohormone BNP (NT-proBNP) level to peak troponin level was 1.01. No deaths occurred during the hospital phase. After 1 year of follow-up, 3 of 109 (2.8%) patients with available data died, including one cardiovascular death. Rehospitalizations occurred in 17.4% of patients: 2.8% due to acute heart failure and 14.7% due to non-cardiovascular causes. There was no recurrence of TTC., Conclusions: This observational study of TTC included primarily women with atherosclerotic risk factors and mental stress. T-wave inversion was more common than ST-segment elevation. There were few adverse cardiovascular outcomes in these patients after 1-year follow-up., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Data on regional variations in the characteristics, management and early outcome of patients admitted with ST-elevation myocardial infarction (STEMI) in France are limited. We used data from the FAST-MI 2010 registry to determine whether regional specificities existed, dividing the French territory into 6 larger geographical regions. Variations in the patients' characteristics were found, partly related to regional variations in demography. Acute reperfusion strategy showed more use of primary percutaneous coronary intervention in the greater Paris area, compared to other regions, which would be expected owing to geography and local availability of catheterization laboratories. Overall, however, in-hospital management showed more similarities than differences across regions. Complications, and in particular in-hospital mortality, did not differ significantly among regions., (Copyright © 2015. Published by Elsevier SAS.)

Background: Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling., Methods: In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume., Results: A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups., Conclusions: In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).

Introduction: The northern French Alps emergency network (RENAU) manages emergent care and patient treatment pathways in a three-county area in the French Alps. The aim of the study was to describe the pediatric activity in mobile intensive care units (MICUs)., Method: This retrospective observational study was conducted from 1 January to 31 December 2012. Data were obtained from patients' medical records in seven representative MICUs of the RENAU. Consecutive patients between 1 month and 18 years of age were enrolled., Results: During the study period, MICUs carried out 11,951 primary transports and 3087 secondary transfers. A total of 1325 patients were enrolled: 1087 primary transports and 238 secondary transfers. In primary interventions, 531 (48.9%) patients were managed for a trauma, 118 (11%) children were discharged and stayed home, 427 (39.9%) underwent an intravenous cannulation and 27 (2.5%) on-scene intubation. A pediatrician was in charge of 64 (26.9%) secondary transfers. Among 1649 (18%) mountain rescues, 296 (18.7%) involved a child., Conclusion: Emergency physicians in MICUs are involved with children's prehospital care and need dedicated materiel and special training., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients., Methods: CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow ≤1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1:1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in the minutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction., Results: Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015., Conclusions: The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aims: We investigated the feasibility of thrombus quantification by frequency-domain optical coherence tomography (FD-OCT) methods in patients with highly thrombotic acute coronary syndrome (ACS) treated by deferred stenting strategy., Methods and Results: Patients were suitable for inclusion if they presented (i) an ACS that was successfully revascularized by manual thrombo-aspiration and (ii) a large residual thrombus on coronary angiography and initial FD-OCT analysis. These patients underwent a second procedure including FD-OCT analysis after several days of optimal antithrombotic therapy. Serial area measurements within the athero-thrombotic culprit lesion were performed to evaluate the OCT-thrombus score, volume, and length. Sixteen patients (88% men/age = 59.3 ± 4.1 years/94% STEMI) were included in the study. The mean delay between OCT analyses was 3.9 ± 0.3 day. No adverse event was observed during this interval. We observed a reduction of thrombus burden between the two analyses, as assessed by the significant reductions in OCT-thrombus score (22.3 ± 2.6 vs. 10.3 ± 1.3, P < 0.001), OCT-thrombus volume (9.6 ± 2.3 vs. 3.6 ± 0.9 mm(3), P = 0.003), and OCT-thrombus length (11.1 ± 1.4 vs. 7.4 ± 0.8 mm, P = 0.01). The percentages of OCT-thrombus score and volume reduction were highly correlated with the inter-OCT analyses delay (respectively ρ = 0.65 and ρ = 0.84, P < 0.01 for both)., Conclusion: FD-OCT assessment of thrombus volume in selected ACS patients is feasible, safe, and could allow clot regression monitoring in vivo., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: Many studies have suggested that longer duration of cardiac monitoring is suitable for the detection of occult paroxysmal atrial fibrillation (AF) after stroke; however, most studies involved patients aged≥65years - a population with a high stroke rate., Aims: To assess the incidence of paroxysmal AF in unselected young patients presenting with stroke., Methods: We included consecutive patients aged<60years with a stroke diagnosis on magnetic resonance imaging. Aetiological screening included clinical history and examination, and biological and cardiac tests. Patients were included if they had no history of AF and if a 24-hour electrocardiogram recording detected no AF or atrial flutter. Patients wore the SpiderFlash(®) monitor for 21days after discharge from hospital. The primary outcome was detection of paroxysmal AF episodes lasting>30seconds during monitoring. The secondary outcome was detection of paroxysmal AF episodes lasting<30seconds and any arrhythmia during monitoring., Results: Among the 56 patients included (mean age 48±9years), 39 had cryptogenic stroke (CS) and 17 had stroke of known cause (SKC). Cardiac monitoring was achieved in 54 patients (37 CS, 17 SKC); one CS patient had a paroxysmal AF episode lasting>30seconds and one CS patient had a paroxysmal AF episode lasting<30seconds (versus no patients in the SKC group). Two CS patients and one SKC patient presented numerous premature atrial complexes. Non-sustained ventricular tachycardia was detected in one CS patient., Conclusion: This prospective observational study showed a low rate of paroxysmal AF among young patients presenting with stroke, on the basis of 21-day cardiac monitoring. This result highlights the need to identify patients who would benefit from such long monitoring., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Factors secreted by tumor cells shape the local microenvironment to promote invasion and metastasis, as well as condition the premetastatic niche to enable secondary-site colonization and growth. In addition to this secretome, tumor cells have increased abundance of growth-promoting receptors at the cell surface. We found that the tyrosine phosphatase PTPN14 (also called Pez, which is mutated in various cancers) suppressed metastasis by reducing intracellular protein trafficking through the secretory pathway. Knocking down PTPN14 in tumor cells or injecting the peritoneum of mice with conditioned medium from PTPN14-deficient cell cultures promoted the growth and metastasis of breast cancer xenografts. Loss of catalytically functional PTPN14 increased the secretion of growth factors and cytokines, such as IL-8 (interleukin-8), and increased the abundance of EGFR (epidermal growth factor receptor) at the cell surface of breast cancer cells and of FLT4 (vascular endothelial growth factor receptor 3) at the cell surface of primary lymphatic endothelial cells. We identified RIN1 (Ras and Rab interactor 1) and PRKCD (protein kinase C-δ) as binding partners and substrates of PTPN14. Similar to cells overexpressing PTPN14, receptor trafficking to the cell surface was inhibited in cells that lacked PRKCD or RIN1 or expressed a nonphosphorylatable RIN1 mutant, and cytokine secretion was decreased in cells treated with PRKCD inhibitors. Invasive breast cancer tissue had decreased expression of PTPN14, and patient survival was worse when tumors had increased expression of the genes encoding RIN1 or PRKCD. Thus, PTPN14 prevents metastasis by restricting the trafficking of both soluble and membrane-bound proteins., (Copyright © 2015, American Association for the Advancement of Science.)

Background: European guidelines for ST-segment elevation myocardial infarction (STEMI) encourage healthcare networks to increase rates of, and decrease delays to, reperfusion. We examined the impact of training primary care physicians (PCPs) to use equipment for pre-hospital management of STEMI patients in remote areas., Methods and Results: A network for cardiac emergencies was set up in the French Northern Alps in 2002 and a registry of STEMI patients has been kept since. In 2005, 24 local volunteer PCPs were trained and equipped with electrocardiograms, fibrinolysis kits, and automated external defibrillators to deal with cardiac emergencies in remote areas (>30-minute ambulance travelling time). In this study, when the central call dispatcher received a telephone call from a patient in a remote area reporting chest pain with a high probability of STEMI, the dispatcher sent a mobile intensive care unit (MICU) with an emergency physician on board and asked the local PCP, if available, to manage the patient while awaiting arrival of the MICU. Patients in whom the diagnosis of STEMI was confirmed were taken by MICU to an interventional cardiology hospital. We report on patients who received care from a PCP before arrival of the MICU. Between 2005 and 2010, 4,015 patients were enrolled in the registry; 180 patients were located in a remote area, of whom 140 were in an area covered by a participating PCP. Of the 62 patients attended by a PCP before MICU arrival, 27 received thrombolysis and eight patients with ventricular tachycardia/fibrillation were shocked with an automated external defibrillator by the PCP. Mean times from telephone call to thrombolysis were shorter when the patient was attended by a PCP (45.0 ± 25.5 vs 62.4 ± 23.4 min without intervention; p = 0.003). STEMI diagnosis without contraindication to thrombolysis was confirmed in 26 of 27 patients treated as such by PCPs and 1 patient was diagnosed with a Tako-Tsubo syndrome., Conclusion: PCP care of STEMI patients located in isolated areas appears efficient, with high rates of resuscitation and thrombolysis and a shorter delay to reperfusion., (© The European Society of Cardiology 2014.)

Purpose: Mild therapeutic hypothermia (TH) is recommended as soon as possible after the return of spontaneous circulation to improve outcomes after out-of-hospital cardiac arrest (OHCA). Preclinical data suggest that the benefit of TH could be increased if treatment is started during cardiac arrest. We aimed to study the impact of intra-arrest therapeutic hypothermia (IATH) on neurological injury and inflammation following OHCA., Methods: We conducted a 1:1 randomized, multicenter study in three prehospital emergency medical services and four critical care units in France. OHCA patients, irrespective of the initial rhythm, received either an infusion of cold saline and external cooling during cardiac arrest (IATH group) or TH started after hospital admission (hospital-cooling group). The primary endpoint was neuron-specific enolase (NSE) serum concentrations at 24 h. Secondary endpoints included IL-6, IL-8, and IL-10 concentrations, and clinical outcome., Results: Of the 245 patients included, 123 were analyzed in the IATH group and 122 in the hospital-cooling group. IATH decreased time to reach temperature ≤ 34 °C by 75 min (95% CI: 4; 269). The rate of patients admitted alive to hospital was not different between groups [IATH n = 41 (33%) vs. hospital cooling n = 36 (30%); p = 0.51]. Levels of NSE and inflammatory biomarkers were not different between groups [median NSE at 24 h: IATH 96.7 μg/l (IQR: 49.9-142.8) vs. hospital cooling 97.6 μg/l (IQR: 74.3-142.4), p = 0.64]. No difference in survival and cerebral performance were found at 1 month., Conclusions: IATH did not affect biological markers of inflammation or brain damage or clinical outcome.

Background: Multiple myeloma (MM) is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM) effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT) remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD)., Methods and Results: Balb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor) or autologous (Balb/cJ donor) transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vβ spectratyping analysis identified Vβ families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vβ families within CD4 T cells were associated exclusively with either GvM or GvHD responses., Conclusions: We successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vβ spectratyping, we also demonstrated the presence of GvM unique responses potentially associated with the curative capacity of this immunotherapeutic approach.

Background: International guidelines have recommendations for selecting the type of reperfusion (fibrinolysis or angioplasty) in the setting of ST-segment elevation myocardial infarction (STEMI), and suggest that emergency-care networks adapt these recommendations according to the local environment., Aim: To assess the proportions of STEMI patients treated with fibrinolysis or angioplasty in accordance with regional guidelines., Method: Observational study based on a permanent registry of patients with STEMI of <12h duration in an emergency network in the French North Alps (Isère, Savoie, Haute-Savoie) from January 2009 to December 2012., Results: The registry included 2620 patients. Reperfusion was given in 2425/2620 (93%) of patients. Reperfusion type was in accordance with recommendations in 1567/2620 (60%) patients. Guideline-recommended fibrinolysis and angioplasty were performed in 47% (656/1385) and 79% (911/1149) respectively, of patients. In multivariable analysis, variables independently associated with guideline-recommended reperfusion were: an age < 65 years (OR 1.60; 95%CI 1.33-1.90), being managed in Haute-Savoie versus Isère or Savoie (OR 1.38; 95%CI 1.12-1.71), an arterial tension < 100mmHg (OR 1.73; 95%CI 1.27-2.35), a cardiogenic shock (OR 0.50; 95%CI 0.30-0.84), a pacemaker or left bundle branch block (OR 0.49; 95%CI 0.28-0.88), and an initial management outside the network (followed by treatment in an interventional centre in the network) (OR 0.62; 95%CI 0.40-0.94). Patients initially treated by mobile intensive care units were more often reperfused in accordance with recommendations when admitted < 3 (versus ≥ 3) h following symptom onset (adjusted OR 2.05; 95% CI 1.61-2.59), while those initially treated by in-hospital emergency units were less often reperfused in accordance with recommendation when treated < 3h following symptom onset (adjusted OR 0.67; 95% CI 0.46-0.97). In-hospital major adverse cardiac events (9.1% vs. 8.5%) and in-hospital mortality (6.4% vs. 5.1%) were not significantly different between patients reperfused in accordance with (versus not) recommendations., Conclusions: Forty percent of patients with STEMI were not reperfused with fibrinolysis or angioplasty in accordance with regional guidelines. Characterization of this population should allow us to improve guideline adherence., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Background: Elderly patients are at high risk for both ischemic and bleeding events. Platelet monitoring offers the opportunity to individualized antiplatelet therapy to optimize the therapeutic risk/benefit ratio., Study Design: The ANTARCTIC study is designed to demonstrate the superiority of a strategy of platelet function monitoring with dose and drug adjustment in patients initially on prasugrel 5 mg as compared with a more conventional strategy using prasugrel 5 mg without monitoring and without adjustment (Conventional Treatment Arm) to reduce the primary end point evaluated 1 year after stent percutaneous coronary intervention in elderly patients presenting with an acute coronary syndrome (ACS). ANTARCTIC is a multicenter, prospective, open-label study with 2 parallel arms. A total of 852 elderly patients (≥ 75 years) undergoing stent percutaneous coronary intervention for ACS are to be enrolled. The primary end point is the time to first occurrence of cardiovascular death, myocardial infarction, stroke, definite stent thrombosis, urgent revascularization, and bleeding complications (Bleeding Academic Research Consortium definition 2, 3, or 5). Platelet function analyses will be performed 14 days after randomization and repeated 14 days later in patients who require a change in treatment., Conclusion: ANTARCTIC is a nationwide, prospective, open-label study testing a strategy of platelet function monitoring with dose and drug adjustment to reduce ischemic and bleeding complications in elderly ACS patients undergoing coronary stenting., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Colonoscopy remains the gold standard for colorectal cancer screening. Many barriers to the procedure exist including the possibility of abdominal discomfort that may occur with insufflation. Carbon dioxide (CO2), which is rapidly absorbed in the blood stream, is an alternate method used to distend the lumen during colonoscopy. The goal of this study was to compare patient discomfort, abdominal girth, and recovery time in 2 groups of patients randomized to CO2 versus room air insufflation during colonoscopy. Using a Wong-Baker score, we found statistical difference in postprocedural discomfort levels (CO2 Group: 1.15 ± 2.0 vs. room air: 0.41 ± 0.31, p = .015) and a significantly greater increase in abdominal girth over CO2 immediately postprocedure (room air: 1.06 ± 1.29 inches vs. CO2: 0.56 ± 0.73 inches, p = .054) girth immediately postprocedure; however, recovery time was similar between the 2 study arms (CO2: 9.1 ± 16.2 minutes vs. room air: 10.2 ± 18.6 minutes, p = .713). Further studies are needed to determine whether CO2 is cost-effective and improves patient satisfaction with colonoscopy.

Background: There is increased interest in the therapeutic potential of cannabis in recent decades. Canada, the Netherlands, Israel and some states in the United States have developed programs to allow access to cannabis for therapeutic purposes (CTP). In Canada, enrollment in the federal CTP program represents fewer than 5% of the estimated users of CTP. The discrepancy between the number of Canadians who report using CTP and the rate of utilization of the federal CTP program suggests the existence of barriers to access to this program., Methods: In the present study we employ a health services analytical framework to examine barriers to access to CTP among 628 current CTP users. We define barriers to access as areas of poor fit between clients and services. We use five dimensions of accommodation, accessibility, availability, affordability, and acceptability to examine access to CTP., Results: Our findings reveal that it is difficult for Canadians to find a physician to support their application to access CTP. Accessing CTP from unauthorized sources was common; only 7% of respondents accessed CTP exclusively from authorized sources. Access to CTP was positively associated with the presence of medical cannabis dispensaries, which were not included in the regulatory regime. Access to CTP varied by medical condition and general quality of health. Affordability of CTP was a substantial barrier to access., Conclusions: Strategies need to be developed to encourage scientific inquiry into CTP and address the barriers to access to CTP and the stigma and controversy that surround CTP and strain patient-physician relationships., (Copyright © 2014. Published by Elsevier B.V.)

Background: Individualizing antiplatelet therapy after platelet function testing did not improve outcome after coronary stenting in the Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting (ARCTIC) study. Whether results are different during the phase of secondary prevention starting after hospital discharge, when periprocedural events have been excluded, is unknown., Methods and Results: In ARCTIC, 2440 patients were randomized before coronary stenting to a strategy of platelet function monitoring (VerifyNow P2Y12/aspirin point-of-care assay) with drug adjustment in suboptimal responders to antiplatelet therapy or to a conventional strategy without monitoring and without drug or dose changes. We performed a landmark analysis starting at the time of hospital discharge evaluating the primary end point of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization through 1 year. After discharge, the primary end point occurred in 8.6% of patients in the monitoring arm and 7.9% in the conventional arm (hazard ratio, 1.105; 95% confidence interval, 0.835-1.461; P=0.48). Stent thrombosis or urgent revascularization occurred in 4.4% and 4.5% in the monitoring and conventional arms, respectively (P=0.99). There was no difference for any of the other ischemic end points. Major bleeding event rates were 1.8% in the monitoring arm and 2.8% in the conventional arm (P=0.11), whereas major or minor bleeding event rates were 2.3% and 3.4%, respectively (P=0.10)., Conclusions: Detection of platelet hyper-reactivity by platelet function testing in patients undergoing coronary stenting with further therapeutic adjustment does not reduce ischemic recurrences after intervention. On-treatment platelet hyperreactivity cannot be considered as a risk factor requiring intervention for secondary prevention after percutaneous coronary revascularization., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00827411., (© 2014 American Heart Association, Inc.)

Background: Although primary percutaneous coronary intervention (pPCI) is the preferred reperfusion method for ST-segment-elevation myocardial infarction, it remains difficult to implement in many areas, and fibrinolytic therapy is still widely used., Methods and Results: We assessed 5-year mortality in patients with ST-segment-elevation myocardial infarction from the French Registry of Acute ST-Elevation or Non-ST Elevation Myocardial Infarction (FAST-MI) 2005 according to use and type of reperfusion therapy. Of 1492 patients with ST-segment-elevation myocardial infarction with a first call ≤12 hours from onset, 447 (30%) received fibrinolysis (66% prehospital; 97% with subsequent angiography, 84% with subsequent PCI), 583 (39%) had pPCI, and 462 (31%) received no reperfusion. Crude 5-year survival was 88% for the fibrinolytic-based strategy, 83% for pPCI, and 59% for no reperfusion. Adjusted hazard ratios for 5-year death were 0.73 (95% confidence interval, 0.50-1.06) for fibrinolysis versus pPCI, 0.57 (95% confidence interval, 0.36-0.88) for prehospital fibrinolysis versus pPCI, and 0.63 (95% confidence interval, 0.34-0.91) for fibrinolysis versus pPCI beyond 90 minutes of call in patients having called ≤180 minutes from onset. In propensity score-matched populations, however, survival rates were not significantly different for fibrinolysis and pPCI, both in the whole population (88% lysis, 85% pPCI) and in the population seen early (87% fibrinolysis, 85% pPCI beyond 90 minutes from call)., Conclusions: In a real-world setting, on a nationwide scale, a pharmaco-invasive strategy constitutes a valid alternative to pPCI, with 5-year survival at least equivalent to that of the reference reperfusion method., Clinical Trial Registration Url: www.clinicaltrials.gov. Unique identifier: NCT00673036.

Background: High-sensitivity troponin (HS-TnT) combined with copeptin have been proposed to expedite the diagnostic exclusion of acute myocardial infarction. The Global Registry of Acute Coronary Events (GRACE) has been validated and recommended by the European Society of Cardiology as a prognostic score in the management of acute coronary syndrome (ACS) without ST-segment elevation (non-ST+) on the electrocardiogram. Our study examined whether a low GRACE score (<108) combined with negative HS-TnT (<14 ng/L) and copeptin (<14 pmol/L) reliably exclude the diagnosis of non-ST+ ACS, including non-ST-segment elevation myocardial infarction and unstable angina., Methods: This observational, prospective study included patients presenting with chest pain lasting <6 hours, consistent with non-ST+ ACS. Blood was collected early for measurements of copeptin and HS-TnT. The negative predictive value of combined copeptin, HS-TnT, and GRACE score was calculated in the diagnosis of non-ST+ ACS. The thresholds of positivity were 14 ng/L for HS-TnT, 14 pmol/L for copeptin and 108 for the GRACE score., Results: Among 247 patients retained in the analysis, the diagnosis of ACS was made in 50 (20.4%), including 39 non-ST-segment elevation myocardial infarction and 11 unstable angina. The negative predictive value of combined HS-TnT, copeptin and GRACE score was 99%., Conclusion: A negative copeptin associated with a negative HS-TnT in a patient presenting with a low GRACE score expedited the diagnostic exclusion of non-ST+ ACS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Dual antiplatelet therapy, comprising aspirin and clopidogrel, is recommended in patients undergoing coronary stenting to avoid the occurrence of stent thrombosis and others ischaemic events. Interindividual response to clopidogrel varies, however, with poor response associated with an increased risk of ischaemic events. New assays are available for testing aspirin and clopidogrel response routinely at the bedside., Aim: To evaluate the prognostic value of testing antiplatelet response in an intermediate-risk population undergoing stent implantation., Methods: We prospectively assessed clopidogrel and aspirin response using the VerifyNow assay at the time of coronary stenting in 1001 patients who presented with stable coronary disease or non-ST-segment elevation acute coronary syndrome. The main ischaemic endpoint was the composite of definite and probable stent thrombosis, cardiovascular death or spontaneous myocardial infarction at one year. The safety endpoint was major bleeding., Results: Overall, 36.0% of patients had high on-clopidogrel platelet reactivity (OCR) and 8.6% had high on-aspirin platelet reactivity (OAR). The main ischaemic composite endpoint occurred in 3.9% of patients with high vs. 2.3% of patients with normal OCR (hazard ratio 1.66, 95% confidence interval 0.78-3.54; P=0.18). Definite or probable stent thrombosis occurred in 1.1% of patients with high vs. 0.3% of patients with normal OCR (P=0.86). There was no significant difference in ischaemic endpoints according to OAR and there was no difference in rates of major bleeding between patients with high versus normal on-treatment platelet reactivity., Conclusions: On-treatment platelet reactivity was not associated with 1-year ischaemic or bleeding events in an intermediate-risk population undergoing stent implantation., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Objectives: To evaluate practices for the protection from radiation of patients during coronary angiography (CA) and percutaneous coronary intervention (PCI), and to update reference values for the main radiation dose parameters., Background: Few multicenter data from large populations exist on radiation doses to patients during CA and PCI., Methods: RAY'ACT is a multicenter, nationwide French survey, with retrospective analysis of radiation parameters routinely registered in professional software from 33,937 CAs and 27,826 PCIs performed at 44 centers from January 1, through December 31, 2010., Results: Kerma-area product (KAP) was registered in 91.7% (44/48) of centers and in 91.5% of procedures for CA (median, 27.2 Gy·cm(2) , interquartile range [IQR], 15.5-45.2) and 91.1% for PCI (median, 56.8 Gy·cm(2) , IQR, 32.8-94.6). Fluoroscopy time was registered in 87.5% (42/48) of centers and in 83.1% of procedures (median, 3.7 min, IQR, 2.3-6.3 for CA; 10.3 min, 6.7-16.2 for PCI). Variability across centers was high. Old equipment and routine left ventriculography were more common and number of registered frames and frame rate were higher in centers delivering high doses. The radial route was associated with lower doses than the femoral route (median KAP 26.8 Gy·cm(2) [15.1-44.25] vs. 28.1 [16.4-46.9] for CA, respectively; and 55.6 Gy·cm(2) [32.2-92.1] vs. 59.4 [24.6-99.9] for PCI, respectively; P < 0.01)., Conclusions: This survey showed a very high rate of compliance with dose registration during CA and PCI in French nonacademic hospitals. Updated diagnostic reference values are established for the main dose parameters (KAP, 45 Gy·cm(2) for CA, 95 Gy·cm(2) for PCI)., (Copyright © 2013 Wiley Periodicals, Inc.)

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Despite major advances in the understanding of GVHD pathogenesis, standard GVHD prophylaxis regimens continue to be based on the combination of a calcineurin inhibitor with an antimetabolite, while first line treatments still rely on high-dose corticosteroids. Further, no second line treatment has emerged thus far in acute or chronic GVHD patients who failed to respond with corticosteroid treatment. After briefly reviewing current standards of GVHD prevention and treatment, this article will discuss recent approaches that might change GVHD prophylaxis/treatment for decades to come, with a special focus on recently developed immunoregulatory strategies based on infusion of mesenchymal stromal or regulatory T-cells, or injection of low-dose interleukin-2.

Background: We investigated the ability of clinical-grade enriched human regulatory T cells (Treg) to attenuate experimental xenogeneic graft-versus-host disease (GVHD) induced by peripheral blood mononuclear cells (PBMNCs; autologous to Treg) infusion in NSG mice, as well as verified their inability to induce xenogeneic GVHD when infused alone., Study Design and Methods: Human Treg were isolated from peripheral blood apheresis products with a cell separation system (CliniMACS, Miltenyi Biotec GmbH) using a two-step procedure (simultaneous CD8 and CD19 depletion followed by CD25-positive selection) in six independent experiments with six different healthy volunteer donors. Sublethally (2.5 Gy) irradiated NSG mice were given 2 × 10(6) cytapheresis (PBMNC) product cells intravenously (IV) without (PBMNC group) or with 1 × 10(6) Treg (PBMNC + Treg group), while other NSG mice received 2 × 10(6) enriched Treg alone (also in IV; Treg group)., Results: The first five procedures were successful at obtaining a relatively pure Treg population (defined as >50%), while the sixth procedure, due to a technical problem, was not (Treg purity, 42%). Treg cotransfusion significantly delayed death from xenogeneic GVHD in the first five experiments, (p < 0.0001) but not in the sixth experiment. Importantly, none of the mice given enriched Treg alone (Treg group) experienced clinical signs of GVHD, while, interestingly, the CD4+ cells found in these mice 26 days after transplantation were mainly conventional T cells (median CD25+FoxP3+ cells among human CD4+ total cells were only 2.1, 3.1, and 12.2% in spleen, marrow, and blood, respectively)., Conclusions: Infusion of clinical-grade enriched Treg delayed the occurrence of xenogeneic GVHD without inducing toxicity in this murine model., (© 2013 American Association of Blood Banks.)

Background: There is no large report of the impact of fractional flow reserve (FFR) on the reclassification of the coronary revascularization strategy on individual patients referred for diagnostic angiography., Methods and Results: The Registre Français de la FFR (R3F) investigated 1075 consecutive patients undergoing diagnostic angiography including an FFR investigation at 20 French centers. Investigators were asked to define prospectively their revascularization strategy a priori based on angiography before performing the FFR. The final revascularization strategy, reclassification of the strategy by FFR, and 1-year clinical follow-up were prospectively recorded. The strategy a priori based on angiography was medical therapy in 55% and revascularization in 45% (percutaneous coronary intervention, 38%; coronary artery bypass surgery, 7%). Patients were treated according to FFR in 1028/1075 (95.7%). The applied strategy after FFR was medical therapy in 58% and revascularization in 42% (percutaneous coronary intervention, 32%; coronary artery bypass surgery, 10%). The final strategy applied differed from the strategy a priori in 43% of cases: in 33% of a priori medical patients, in 56% of patients undergoing a priori percutaneous coronary intervention, and in 51% of patients undergoing a priori coronary artery bypass surgery. In reclassified patients treated based on FFR and in disagreement with the angiography-based a priori decision (n=464), the 1-year outcome (major cardiac event, 11.2%) was as good as in patients in whom final applied strategy concurred with the angiography-based a priori decision (n=611; major cardiac event, 11.9%; log-rank, P=0.78). At 1 year, >93% patients were asymptomatic without difference between reclassified and nonreclassified patients (Generalized Linear Mixed Model, P=0.75). Reclassification safety was preserved in high-risk patients., Conclusion: This study shows that performing FFR during diagnostic angiography is associated with reclassification of the revascularization decision in about half of the patients. It further demonstrates that it is safe to pursue a revascularization strategy divergent from that suggested by angiography but guided by FFR.

The secretome is the collection of all macromolecules secreted by a cell, and is a vital aspect of cell-cell communication in eukaryotes. In cancer, tumour cells often display secretomes with altered composition compared to the normal tissue from which they are derived. These changes can contribute to the acquisition and maintenance of the recognised hallmarks of cancer. In addition, evidence is emerging for a more sophisticated role for the tumour secretome in cancer, with significant implications for malignant disease progression. In this review, we highlight recent advances in our understanding of factors contributing to secretome alterations in cancer, including genetic mutations, microRNA-based regulation and the influence of the tumour microenvironment. The contribution of secreted factors in maintenance and function of cancer stem cells, and of tumour-derived factors in specification of a pre-metastatic niche are also discussed. Collectively, evidence from the current literature suggests that the tumour secretome, consisting of factors derived from cancer stem cells, non-stem cells and the surrounding stroma, plays a deterministic role in cancer progression, and may constitute a key therapeutic target in many cancers. This article is part of a Special Issue entitled: An Updated Secretome., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The authorized and unauthorized use of cannabis for therapeutic purposes (CTP) has increased dramatically in recent years, and physicians have called for further research to better clarify the parameters of effective and appropriate use. We report findings from a large cross-sectional study of the use of CTP in Canada and compare use across medical conditions and across authorized and unauthorized users., Methods: We examined cannabis use history, medical conditions and symptoms, patterns of current use of CTP, modes of access and perceived effectiveness among 628 self-selected Canadians consumers of CTP. Participants were recruited from medical cannabis dispensaries and from organizations that assist users of CTP., Results: Patients reported using cannabis to treat multiple symptoms, with sleep, pain, and anxiety being the most common. Cannabis was perceived to provide effective symptoms relief across medical conditions. Patterns of use were also consistent across medical conditions. Notable differences were observed with regard to modes of access., Conclusion: Across medical conditions respondents reported using cannabis to effectively address diverse symptoms. Results indicate a substantial disconnect between the therapeutic use of cannabis and research on the risks and benefits of such use; particularly with regard to the anxiolytic and sedative use of cannabis. Authorized and unauthorized users exhibited few meaningful differences with regard to medical conditions and patterns of use, but faced substantial differences regarding access., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Homelessness and drug use often overlap and the harms of substance use are exacerbated by homelessness. Responding to the twin problems of homelessness and substance use is an important aspect of strategies to end homelessness. The introduction and development of ten year plans to end homelessness in North America heralds a new era of systemic responses to homelessness. Central to many of these plans is the adoption of 'Housing First' as a policy response. Housing First focuses directly on housing people regardless of current patterns of substance use. As such, harm reduction is a key principle of Housing First. In this paper, we examine Housing First as an example of the integration of housing and harm reduction and then put forth a community level policy framework to further promote the integration of harm reduction as part of a response to homelessness. Drawing on Rhodes' risk environment framework and current evidence of Housing First and harm reduction, we describe four key policy areas for action: (1) social inclusion policies; (2) adequate and appropriate supply of housing; (3) on demand harm reduction services and supports and (4) systemic and organizational infrastructure. We conclude by identifying areas for future research., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background Aims: Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation caused by donor T cells reacting against host tissues. Previous studies have suggested that mesenchymal stromal cells (MSCs) could exert potent immunosuppressive effects., Methods: The ability of human bone marrow derived MSCs to prevent xenogeneic GVHD in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice and in NOD/SCID/interleukin-2Rγ(null) (NSG) mice transplanted with human peripheral blood mononuclear cells (PBMCs) was assessed., Results: Injection of 200 × 10(6) human PBMCs intraperitoneally (IP) into sub-lethally (3.0 Gy) irradiated NOD/SCID mice also given anti-asialo GM1 antibodies IP 1 day prior and 8 days after transplantation induced lethal xenogeneic GVHD in all tested mice. Co-injection of 2 × 10(6) MSCs IP on day 0 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs. Similarly, injection of 30 × 10(6) human PBMCs IP into sub-lethally (2.5 Gy) irradiated NSG mice induced a lethal xenogeneic GVHD in all tested mice. Injection of 3 × 10(6) MSCs IP on days 0, 7, 14 and 21 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs., Conclusions: Injection of MSCs did not prevent xenogeneic GVHD in these two humanized mice models., (Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Aims: To conduct a meta-analysis of studies comparing immediate versus delayed stenting in populations where primary percutaneous coronary intervention (PCI) or early invasive revascularisation was the initial mode of reperfusion., Methods and Results: We identified five non-randomised studies and one randomised trial for a total of 590 patients in studies comparing immediate to delayed stenting in populations where primary PCI or early invasive revascularisation was the initial mode of reperfusion. In non-randomised studies, delayed stenting was associated with a reduction of procedure-related angiographic events (OR=0.13, 95% credible interval [CrI]: 0.03- 0.36). No differences were observed in the rates of major bleeding (OR=0.81, 95% CrI: 0.01-13.42) and major adverse cardiac events (OR=0.40, 95% CrI: 0.09-1.91), between delayed and immediate stenting. In one randomised trial, delayed stenting was associated with a reduction in myocardial infarction during hospitalisation (39% vs. 60%; relative risk [RR]=0.55, 95% confidence interval [CI]: 0.39-0.80). None of the patients assigned to delayed stenting experienced a major adverse cardiac event in the interval between the initial angiogram and the stenting., Conclusions: Delayed stent implantation is associated with better angiographic outcomes. Randomised trials are required to assess whether delayed stenting translates into better long-term cardiac outcomes.

Background: The prevalence of hypertension in the Sub-Saharan Africa region is increasing as a manifestation of the epidemiological transition, and this fact will oblige these countries to mobilize significant resources. World Bank estimates cheaper to prevent cardiovascular disease than to treat people once these diseases are established suggesting the need to know the prevalence of hypertension in order to allow prevention programs in our population. However, data in Togolese populations are rare. The purpose of the present study was to determine the prevalence of high blood pressure and its risk factors in Lomé., Methods: We performed a cross-sectional survey among 2002 unselected respondents of the municipality of Lomé in May 2011. A questionnaire has been filled about family history of hypertension, habits and practices that affect hypertension on behalf of each respondent and anthropometric data and blood pressure has been measured., Results: The prevalence of high blood pressure was 36.7% (34.6% of male vs. 38.4% of female, OR=0.85; 95%CI=0.7-1.02; P=0.08); 42.4% of the hypertensive respondents have been diagnosed at the screening. Blood pressure was positively correlated to the age (SBP: r=+0.46; P=0.001; DBP: r=+0.36; P<0.001), the body mass index (SBP: r=+0.7; P<0.001; DBP: r=+0.89; P<0.001) and waist circumference (SBP: r=+0.28; P<0.001; DBP: r=+0.3; P<0.001). There was a significant relationship between arterial hypertension and obesity (OR=1.65; 95%CI=1.47-1.84; P=0.003), salt consumption (OR=1.4; 95%CI=1.13-1.72; P<0.001) and oral contraception (OR=2.1; 95%CI=1.29-3.43; P=0.002)., Conclusion: There was a high prevalence and low awareness of arterial hypertension in the municipality of Lomé with a female prevalence. This affection was correlated to age, salt consumption and obesity. This study raises the need for accentuating the prevention in our poor populations which are unable to face adverse outcomes which can occur., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background: Patients' responses to oral antiplatelet therapy are subject to variation. Bedside monitoring offers the opportunity to improve outcomes after coronary stenting by individualizing therapy., Methods: We randomly assigned 2440 patients scheduled for coronary stenting at 38 centers to a strategy of platelet-function monitoring, with drug adjustment in patients who had a poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment. The primary end point was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation. For patients in the monitoring group, the VerifyNow P2Y12 and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2 to 4 weeks later., Results: In the monitoring group, high platelet reactivity in patients taking clopidogrel (34.5% of patients) or aspirin (7.6%) led to the administration of an additional bolus of clopidogrel, prasugrel, or aspirin along with glycoprotein IIb/IIIa inhibitors during the procedure. The primary end point occurred in 34.6% of the patients in the monitoring group, as compared with 31.1% of those in the conventional-treatment group (hazard ratio, 1.13; 95% confidence interval [CI], 0.98 to 1.29; P=0.10). The main secondary end point, stent thrombosis or any urgent revascularization, occurred in 4.9% of the patients in the monitoring group and 4.6% of those in the conventional-treatment group (hazard ratio, 1.06; 95% CI, 0.74 to 1.52; P=0.77). The rate of major bleeding events did not differ significantly between groups., Conclusions: This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting, as compared with standard antiplatelet therapy without monitoring. (Funded by Allies in Cardiovascular Trials Initiatives and Organized Networks and others; ARCTIC ClinicalTrials.gov number, NCT00827411.).

With femoral access, bivalirudin decreases risks of major bleeding after percutaneous coronary intervention (PCI) and provides better net clinical benefit compared to unfractionated heparin (UFH) plus planned glycoprotein IIb/IIIa inhibitors. Whether this benefit exists compared to UFH monotherapy is less clear. We performed a systematic review and meta-analysis to compare outcomes in patients undergoing transfemoral PCI with UFH or bivalirudin. Randomized trials (n = 3) and observational studies (n = 13) comparing bivalirudin to UFH monotherapy were reviewed. Primary outcomes were 30-day rates of major adverse cardiovascular events (MACEs) including death, myocardial infarction (MI), urgent revascularization, as well as all-cause mortality, MI, major bleeding, and blood transfusion. We collected data from 16 studies involving 32,492 patients undergoing PCI. Most observational studies were performed in the United States, whereas all randomized trials were done in Europe. Compared to UFH monotherapy, bivalirudin was associated with similar risk of MACEs (odds ratios [OR] 0.92, 95% confidence interval [CI] 0.75 to 1.12), a substantial 45% relative decrease in major bleeding (OR 0.55, 95% CI 0.43 to 0.72), and a trend in the decrease of transfusion (OR 0.87, 95% CI 0.70 to 1.08). A decrease in mortality was seen in observational studies (OR 0.62, 95% CI 0.45 to 0.85) but remained inconclusive in randomized trials (OR 0.63, 95% CI 0.20 to 2.01). MI rate was similar with the 2 anticoagulants. In conclusion, in patients undergoing transfemoral PCI, the benefit of bivalirudin over UFH monotherapy is driven by a significant decrease in major bleeding with similar rates of MACE. As PCI practice moves toward other bleeding-avoidance strategies such as the radial approach, future studies should focus on the interaction between anticoagulant strategy and access-site choice., (Copyright © 2012 Elsevier Inc. All rights reserved.)