Summary Background Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its ...use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. Methods In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5–20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00402597. Findings Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios HRs 2·21 95% CI 1·25–3·91 for 5 mg, 3·35 2·31–4·87 for 10 mg, 3·60 2·32–5·58 for 15 mg, and 5·06 3·45–7·42 for 20 mg doses; p<0·0001). Rates of the primary efficacy endpoint were 5·6% (126/2331) for rivaroxaban versus 7·0% (79/1160) for placebo (HR 0·79 0·60–1·05, p=0·10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 3·9% vs 62/1160 5·5%; HR 0·69, 95% CI 0·50–0·96, p=0·0270). The most common adverse event in both groups was chest pain (248/2309 10·7% vs 118/1153 10·2%). Interpretation The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. Funding Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.
The Paris Agreement calls for global warming to be limited to 1.5-2 °C. For the first time, this study investigates how different regional heatwave characteristics (intensity, frequency and duration) ...are projected to change relative to increasing global warming thresholds. Increases in heatwave days between 4-34 extra days per season are projected per °C of global warming. Some tropical regions could experience up to 120 extra heatwave days/season if 5 °C is reached. Increases in heatwave intensity are generally 0.5-1.5 °C above a given global warming threshold, however are higher over the Mediterranean and Central Asian regions. Between warming thresholds of 1.5 °C and 2.5 °C, the return intervals of intense heatwaves reduce by 2-3 fold. Heatwave duration is projected to increase by 2-10 days/°C, with larger changes over lower latitudes. Analysis of two climate model ensembles indicate that variation in the rate of heatwave changes is dependent on physical differences between different climate models, however internal climate variability bears considerable influence on the expected range of regional heatwave changes per warming threshold. The results of this study reiterate the potential for disastrous consequences associated with regional heatwaves if global mean warming is not limited to 2 degrees.
Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition ...and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming "uncontrolled" or that remains "uncontrolled" despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.
Using MHO numerical simulations in a three-dimensional spherical geometry, we model the loss of confinement and eruption of a flux rope emerging quasi-statically Into a preexisting coronal arcade ...field. Our numerical experiments investigated two distinct mechanisms that led to the eruption of the flux rope. In one case, the overlying arcade field declines with height slowly such that the emerging flux rope remains confined until its self-relative magnetic heliclty normalized by the square of the rope's flux reaches -1.4 and the flux rope becomes significantly kinked. The kinking motion causes rotation of the tube to an orientation that makes it easier for it to rupture through the arcade field, leading to an eruption. In the second case, the overlying field declines more rapidly with height, and the emerging flux rope is found to lose equilibrium and erupt via the torus instability when its self-relative magnetic helicity normalized by the square of its flux is only approximately -0.63, before it becomes kinked. The values of the total relative magnetic helicity of the entire coronal magnetic field (including both the flux rope and the arcade field) normalized by the square of the total magnetic flux are, on the other hand, of similar magnitudes for the two cases when the eruption takes place. We compare and contrast the eruptive properties and the posteruption states resulting from the two cases.
Ferroptosis is an iron-dependent, oxidative cell death, and is distinct from apoptosis, necrosis and autophagy. In this study, we demonstrated that lysosome disrupting agent, siramesine and a ...tyrosine kinase inhibitor, lapatinib synergistically induced cell death and reactive oxygen species (ROS) in MDA MB 231, MCF-7, ZR-75 and SKBr3 breast cancer cells over a 24 h time course. Furthermore, the iron chelator deferoxamine (DFO) significantly reduced cytosolic ROS and cell death following treatment with siramesine and lapatinib. Furthermore, we determined that FeCl3 levels were elevated in cells treated with siramesine and lapatinib indicating an iron-dependent cell death, ferroptosis. To confirm this, we treated cells with a potent inhibitor of ferroptosis, ferrastatin-1 that effectively inhibited cell death following siramesine and lapatinib treatment. The increase levels of iron could be due to changes in iron transport. We found that the expression of transferrin, which is responsible for the transport of iron into cells, is increased following treatment with lapatinib alone or in combination with siramesine. Knocking down of transferrin resulted in decreased cell death and ROS after treatment. In addition, ferroportin-1 (FPN) is an iron transport protein, responsible for removal of iron from cells. We found its expression is decreased after treatment with siramesine alone or in combination with lapatinib. Overexpression FPN resulted in decreased ROS and cell death whereas knockdown of FPN increased cell death after siramesine and lapatinib treatment. This indicates a novel induction of ferroptosis through altered iron regulation by treating breast cancer cells with a lysosome disruptor and a tyrosine kinase inhibitor.
Treatment outcomes in younger patients with acute myeloid leukemia (AML) have improved, but optimization and new combinations are needed. We assess three combinations in induction and consolidation.
...Younger untreated patients with AML (median age, 49 years; range, 0 to 73 years) were randomly allocated to two induction courses of daunorubicin and cytarabine (DA) with or without etoposide (ADE; n = 1983) or ADE versus fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-Ida; n = 1268), and to amsacrine, cytarabine, etoposide, and then mitoxantrone/cytarabine (MACE-MidAC) or high-dose cytarabine (n = 1,445) 3 g/m(2) or 1.5 g/m(2) (n = 657) in consolidation, and finally to a fifth course (cytarabine) or not (n = 227).
Overall remission rates were similar for DA versus ADE (84% v 86%; P = .14) and ADE versus FLAG-Ida (86% v 85%; P = .7), with more course 1 remissions after FLAG-Ida (77%) reducing relapse (38% v 55%; P < .001) and improving relapse-free survival (45% v 34%; P = .01), overall and in subgroups, but with increased myelosuppression, reducing participation in the consolidation randomization. Overall outcomes were similar between MACE/MidAc and high-dose cytarabine (1.5/3.0 g/m(2)), but cytarabine required less supportive care. MACE/MidAc was superior for high-risk patients. A fifth course provided no benefit. The outcome for recipients of only two FLAG-Ida courses were not different from that with DA/ADE with consolidation.
FLAG-Ida is an effective remission induction treatment, with a high complete remission rate after course 1 and reduced relapse. Consolidation with MACE/MidAc is similar overall to high-dose cytarabine, but superior in high-risk patients. Cytarabine at 1.5 g/m(2) is equivalent to a 3 g/m(2) dose. A fifth course is unnecessary. In patients receiving FLAG-Ida (two courses) and cytarabine (two courses), 8-year survival was 63% for patients with intermediate-risk and 95% for those with favorable-risk disease.
Asthma is a serious health problem throughout the world. During the past two decades, many scientific advances have improved our understanding of asthma and ability to manage and control it ...effectively. However, recommendations for asthma care need to be adapted to local conditions, resources and services. Since it was formed in 1993, the Global Initiative for Asthma, a network of individuals, organisations and public health officials, has played a leading role in disseminating information about the care of patients with asthma based on a process of continuous review of published scientific investigations. A comprehensive workshop report entitled "A Global Strategy for Asthma Management and Prevention", first published in 1995, has been widely adopted, translated and reproduced, and forms the basis for many national guidelines. The 2006 report contains important new themes. First, it asserts that "it is reasonable to expect that in most patients with asthma, control of the disease can and should be achieved and maintained," and recommends a change in approach to asthma management, with asthma control, rather than asthma severity, being the focus of treatment decisions. The importance of the patient-care giver partnership and guided self-management, along with setting goals for treatment, are also emphasised.
Summary
The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of ...consolidation chemotherapy. 504 children (<16 years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten‐year event‐free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate 32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00 and disease‐free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care.
We demonstrate the partial expulsion of a three-dimensional magnetic flux rope, in which an upper, escaping rope is separated from a lower, surviving rope by cusped, reconnecting loop field lines. We ...use the three-dimensional magnetohydrodynamic model recently presented by Fan, extended to examine the erupting rope's end state. As in that work, the modeled flux rope in spherical coordinates erupts when enough twist has emerged to induce a loss of equilibrium. After multiple reconnections at current sheets that form during the eruption, the rope breaks in two, so that only a part of it escapes. We consider the details of how this separation occurs and discuss the observational significance of such a partially expelled flux rope for partially erupting filaments and re-forming X-ray sigmoids.
We present the results of MHD simulations in the low- beta regime of the evolution of the three-dimensional coronal magnetic field as an arched, twisted magnetic flux tube emerges into a preexisting ...coronal potential magnetic arcade. We find that the line-tied emerging flux tube becomes kink-unstable when a sufficient amount of twist is transported into the corona. For an emerging flux tube with a left-handed twist (which is the preferred sense of twist for active region flux tubes in the northern hemisphere), the kink motion of the tube and its interaction with the ambient coronal magnetic field lead to the formation of an intense current layer that displays an inverse- S shape, consistent with the X-ray sigmoid morphology preferentially seen in the northern hemisphere. The position of the current layer in relation to the lower boundary magnetic field of the emerging flux tube is also in good agreement with the observed spatial relations between the X-ray sigmoids and their associated photospheric bipolar magnetic regions. We argue that the inverse- S-shaped current layer formed is consistent with being a magnetic tangential discontinuity limited by numerical resolution and thus may result in the magnetic reconnection and significant heating that causes X-ray sigmoid brightenings.
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