Natalizumab in acute ischemic stroke (ACTION II): a randomized, placebo-controlled trial

OBJECTIVE: We evaluated the effect of two doses of natalizumab on functional outcomes in acute ischemic stroke (AIS) patients. METHODS: In this double-blind phase 2b trial, AIS patients aged 18-80 years with National Institutes of Health Stroke Scale scores of 5-23 from 53 US and European sites were randomized 1:1:1 to receive a single dose of 300 or 600 mg intravenous natalizumab or placebo, with randomization stratified by treatment window (≤9 or >9 to ≤24 hours from patient's last known normal state). The primary endpoint was a composite measure of excellent outcome (modified Rankin Scale score ≤1 and Barthel Index score ≥95) at day 90 assessed in all patients receiving a full dose. Sample size was estimated from a Bayesian model; p values were not used for hypothesis testing. RESULTS: An excellent outcome was less likely with natalizumab than with placebo (natalizumab 300 mg or 600 mg odds ratio 0.60; 95% confidence interval 0.39-0.93). There was no effect modification by time to treatment or use of thrombolysis/thrombectomy. For natalizumab 300 mg, 600 mg, or placebo, there were no differences in incidence of adverse events (90%, 92%, and 92%, respectively), serious adverse events (26%, 33%, and 21%, respectively), or deaths (7%, 5%, and 6%, respectively). CONCLUSIONS: Natalizumab administered ≤24 hours after AIS did not improve patient outcomes. CLINICALTRIALSGOV IDENTIFIER: NCT02730455 CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with AIS, an excellent outcome was less likely in patients treated with natalizumab than with placebo

Effects of alteplase for acute stroke on the distribution of functional outcomes: a pooled analysis of 9 trials

Background—Thrombolytic therapy with intravenous alteplase within 4.5 hours of ischemic stroke onset increases the overall likelihood of an excellent outcome (no, or nondisabling, symptoms). Any improvement in functional outcome distribution has value, and herein we provide an assessment of the effect of alteplase on the distribution of the functional level by treatment delay, age, and stroke severity. Methods—Prespecified pooled analysis of 6756 patients from 9 randomized trials comparing alteplase versus placebo/open control. Ordinal logistic regression models assessed treatment differences after adjustment for treatment delay, age, stroke severity, and relevant interaction term(s). Results—Treatment with alteplase was beneficial for a delay in treatment extending to 4.5 hours after stroke onset, with a greater benefit with earlier treatment. Neither age nor stroke severity significantly influenced the slope of the relationship between benefit and time to treatment initiation. For the observed case mix of patients treated within 4.5 hours of stroke onset (mean 3 hours and 20 minutes), the net absolute benefit from alteplase (ie, the difference between those who would do better if given alteplase and those who would do worse) was 55 patients per 1000 treated (95% confidence interval, 13–91; P=0.004). Conclusions—Treatment with intravenous alteplase initiated within 4.5 hours of stroke onset increases the chance of achieving an improved level of function for all patients across the age spectrum, including the over 80s and across all severities of stroke studied (top versus bottom fifth means: 22 versus 4); the earlier that treatment is initiated, the greater the benefit

Predictions for p+p+Pb Collisions at sNN=5\sqrt{s_{NN}} = 5 TeV: Comparison with Data

Predictions made in Albacete {\it et al} prior to the LHC $p+$Pb run at $\sqrt{s_{NN}} = 5$ TeV are compared to currently available data. Some predictions shown here have been updated by including the same experimental cuts as the data. Some additional predictions are also presented, especially for quarkonia, that were provided to the experiments before the data were made public but were too late for the original publication are also shown here.Comment: 55 pages 35 figure

Heavy-flavour and quarkonium production in the LHC era: from proton-proton to heavy-ion collisions

This report reviews the study of open heavy-flavour and quarkonium production in high-energy hadronic collisions, as tools to investigate fundamental aspects of Quantum Chromodynamics, from the proton and nucleus structure at high energy to deconfinement and the properties of the Quark-Gluon Plasma. Emphasis is given to the lessons learnt from LHC Run 1 results, which are reviewed in a global picture with the results from SPS and RHIC at lower energies, as well as to the questions to be addressed in the future. The report covers heavy flavour and quarkonium production in proton-proton, proton-nucleus and nucleus-nucleus collisions. This includes discussion of the effects of hot and cold strongly interacting matter, quarkonium photo-production in nucleus-nucleus collisions and perspectives on the study of heavy flavour and quarkonium with upgrades of existing experiments and new experiments. The report results from the activity of the SaporeGravis network of the I3 Hadron Physics programme of the European Union 7th Framework Programme

Hard diffractive quarkonium hadroproduction at high energies

We present a study of heavy quarkonium production in hard diffractive process by the Pomeron exchange for Tevatron and LHC energies. The numerical results are computed using recent experimental determination of the diffractive parton density functions in Pomeron and are corrected by unitarity corrections through gap survival probability factor. We give predictions for single as well as central diffractive ratios. These processes are sensitive to the gluon content of the Pomeron at small Bjorken-x and may be particularly useful in studying the small-x physics. They may also be a good place to test the different available mechanisms for quarkonium production at hadron colliders.Comment: 7 pages, 3 figures, 1 table. Final version to be published in European Physical Journal

Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes

Background In the Netherlands, a screening programme was set up in 1994 in order to identify all patients with familial hypercholesterolaemia (FH). After 15 years of screening, we evaluated the geographical distribution, possible founder effects and clinical phenotype of the 12 most prevalent FH gene mutations. Methods Patients who carried one of the 12 most prevalent mutations, index cases and those identified between 1994 and 2009 through the screening programme and whose postal code was known were included in the study. Low-density lipoprotein cholesterol (LDL-C) levels at the time of screening were retrieved. The prevalence of identified patients in each postal code area was calculated and visualised in different maps. Results A total of 10,889 patients were included in the study. Mean untreated LDL-C levels ranged from 4.4 to 6.4 mmol/l. For almost all mutations, a region of high prevalence could be observed. In total, 51 homozygous patients were identified in the Netherlands, of which 13 true homozygous for one of the 12 most prevalent mutations. The majority of them were living in high-prevalence areas for that specific mutation. Conclusions Phenotypes with regard to LDL-C levels varied between the 12 most prevalent FH mutations. For most of these mutations, a founder effect was observed. Our observations can have implications with regard to the efficiency of molecular screening and physician's perception of FH and to the understanding of the prevalence and distribution of homozygous patients in the Netherland

Spin physics and TMD studies at A Fixed-Target ExpeRiment at the LHC (AFTER@LHC)

We report on the opportunities for spin physics and Transverse-Momentum Dependent distribution (TMD) studies at a future multi-purpose fixed-target experiment using the proton or lead ion LHC beams extracted by a bent crystal. The LHC multi-TeV beams allow for the most energetic fixed-target experiments ever performed, opening new domains of particle and nuclear physics and complementing that of collider physics, in particular that of RHIC and the EIC projects. The luminosity achievable with AFTER@LHC using typical targets would surpass that of RHIC by more that 3 orders of magnitude in a similar energy region. In unpolarised proton-proton collisions, AFTER@LHC allows for measurements of TMDs such as the Boer-Mulders quark distributions, the distribution of unpolarised and linearly polarised gluons in unpolarised protons. Using the polarisation of hydrogen and nuclear targets, one can measure transverse single-spin asymmetries of quark and gluon sensitive probes, such as, respectively, Drell-Yan pair and quarkonium production. The fixed-target mode has the advantage to allow for measurements in the target-rapidity region, namely at large x^uparrow in the polarised nucleon. Overall, this allows for an ambitious spin program which we outline here.Comment: 6 pages, 4 figures, 1 table, LaTeX. Proceedings of the Fourth International Workshop on Transverse Polarisation Phenomena in Hard Processes (Transversity 2014), 9-13 June, 2013, Chia, Ital

The Impact of Timing and Mode of Entry on Successor Development and Successful Succession

Family businesses frequently are disrupted by the process of succession of leadership and ownership. This article focuses on causes of conflict and how to manage success after siblings have entered the business.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Life After Succession in the Family Business: Is It Really the End of Problems?

The succession processes in family business are well chronicled in the business literature. Most of the research focuses on the process of transferring power within the business-family. What has not been as closely examined is the after-succession environment that exists when the management and leadership of the family business are passed on to the next generation. This article addresses that organizational climate and the potential for additional problems in the business-family if post-succession issues are not identified and addressed and suggests some steps that will be helpful in producing complete succession success.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline