Assembly of Recombinant Israeli Acute Paralysis virus capsids

The dicistrovirus Israeli Acute Paralysis Virus (IAPV) has been implicated in the worldwide decline of honey bees. Studies of IAPV and many other bee viruses in pure culture are restricted by available isolates and permissive cell culture. Here we show that coupling the IAPV major structural precursor protein ORF2 to its cognate 3C-like processing enzyme results in processing of the precursor to the individual structural proteins in a number of insect cell lines following expression by a recombinant baculovirus. The efficiency of expression is influenced by the level of IAPV 3C protein and moderation of its activity is required for optimal expression. The mature IAPV structural proteins assembled into empty capsids that migrated as particles on sucrose velocity gradients and showed typical dicistrovirus like morphology when examined by electron microscopy. Monoclonal antibodies raised to recombinant capsids were configured into a diagnostic test specific for the presence of IAPV. Recombinant capsids for each of the many bee viruses within the picornavirus family may provide virus specific reagents for the on-going investigation of the causes of honeybee loss

Statistical analysis plan for the ‘Efficacy of Nitric Oxide in Stroke’ (ENOS) trial

High blood pressure is common during the acute phase of stroke and is associated with a poor outcome. However, the management of high blood pressure remains unclear. The ‘Efficacy of Nitric Oxide in Stroke’ trial tested whether transdermal glyceryl trinitrate, a nitric oxide donor that lowers blood pressure, is safe and effective in improving outcome after acute stroke. Efficacy of Nitric Oxide in Stroke is an international multicenter, prospective, randomized, single-blind, blinded endpoint trial, with funding from the UK Medical Research Council. Patients with acute ischemic stroke or intracerebral hemorrhage and systolic blood pressure 140–220 mmHg were randomized to glyceryl trinitrate or no glyceryl trinitrate and, where relevant, to continue or stop prestrike antihypertensive therapy. The primary outcome is shift in modified Rankin Scale at three-months. Patients or relatives gave written informed (proxy) consent, and all sites had research ethics approval. Analyses will be done by intention to treat. This paper and attachment describe the trial’s statistical analysis plan, developed prior to unblinding of date. The statistical analysis plan contains design and methods for analyses, and unpopulated tables and figures for the two primary publications and some secondary publications. The database will be locked in late February 2014 in preparation for presentation of the results in May 2014. The data from the trial will improve the precision of the estimates of the overall treatment effects (efficacy and safety) of results from completed trials of blood pressure management in acute stroke, and provide the first large-scale randomized evidence on transdermal glyceryl trinitrate, and of continuing (vs. stopping) prestroke antihypertensive medications, in acute stroke

Publication Bias in Reports of Animal Stroke Studies Leads to Major Overstatement of Efficacy

Publication bias confounds attempts to use systematic reviews to assess the efficacy of various interventions tested in experiments modelling acute ischaemic stroke, leading to a 30% overstatement of efficacy of interventions tested in animals

Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2)

Background Human neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute—chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study. Methods We undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2–13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation. Findings Twenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures. Interpretation Administration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials. Funding ReNeuron, Innovate UK (application no 32074-222145). Trial registration number EudraCT Number: 2012-003482-1

An improvement of the Berry--Esseen inequality with applications to Poisson and mixed Poisson random sums

By a modification of the method that was applied in (Korolev and Shevtsova, 2009), here the inequalities $$\rho(F_n,\Phi)\le\frac{0.335789(\beta^3+0.425)}{\sqrt{n}}$$ and $$\rho(F_n,\Phi)\le \frac{0.3051(\beta^3+1)}{\sqrt{n}}$$ are proved for the uniform distance $\rho(F_n,\Phi)$ between the standard normal distribution function $\Phi$ and the distribution function $F_n$ of the normalized sum of an arbitrary number $n\ge1$ of independent identically distributed random variables with zero mean, unit variance and finite third absolute moment $\beta^3$. The first of these inequalities sharpens the best known version of the classical Berry--Esseen inequality since $0.335789(\beta^3+0.425)\le0.335789(1+0.425)\beta^3<0.4785\beta^3$ by virtue of the condition $\beta^3\ge1$, and 0.4785 is the best known upper estimate of the absolute constant in the classical Berry--Esseen inequality. The second inequality is applied to lowering the upper estimate of the absolute constant in the analog of the Berry--Esseen inequality for Poisson random sums to 0.3051 which is strictly less than the least possible value of the absolute constant in the classical Berry--Esseen inequality. As a corollary, the estimates of the rate of convergence in limit theorems for compound mixed Poisson distributions are refined.Comment: 33 page

Biomass burning, land-cover change, and the hydrological cycle in Northern sub-Saharan Africa

The Northern Sub-Saharan African (NSSA) region, which accounts for 20%–25%of the global carbon emissions from biomass burning, also suffers from frequent drought episodes and other disruptions to the hydrological cycle whose adverse societal impacts have been widely reported during the last several decades. This paper presents a conceptual framework of the NSSA regional climate system components that may be linked to biomass burning, as well as detailed analyses of a variety of satellite data for 2001–2014 in conjunction with relevant model-assimilated variables. Satellite fire detections in NSSA show that the vast majority (\u3e75%) occurs in the savanna and woody savanna land-cover types. Starting in the 2006–2007 burning season through the end of the analyzed data in 2014, peak burning activity showed a net decrease of 2–7%/yr in different parts of NSSA, especially in the savanna regions. However, fire distribution shows appreciable coincidence with land-cover change. Although there is variable mutual exchange of different land cover types, during 2003–2013, cropland increased at an estimated rate of 0.28%/yr of the total NSSA land area,with most of it (0.18%/yr) coming from savanna.During the last decade, conversion to croplands increased in some areas classified as forests and wetlands, posing a threat to these vital and vulnerable ecosystems. Seasonal peak burning is anticorrelated with annual water-cycle indicators such as precipitation, soil moisture, vegetation greenness, and evapotranspiration, except in humid West Africa (5°–10° latitude),where this anti-correlation occurs exclusively in the dry season and burning virtually stops when monthly mean precipitation reaches 4 mm d−1. These results provide observational evidence of changes in land-cover and hydrological variables that are consistent with feedbacks from biomass burning in NSSA, and encourage more synergistic modeling and observational studies that can elaborate this feedback mechanism

Therapeutic potential of transdermal glyceryl trinitrate in the management of acute stroke

The nitric oxide donor, glyceryl trinitrate (GTN), is a candidate treatment for the management of acute stroke with haemodynamic and potential reperfusion and neuroprotective effects. When administered as a transdermal patch during the acute and subacute phases after stroke, GTN was safe, lowered blood pressure, maintained cerebral blood flow, and did not induce cerebral steal or alter functional outcome. However, when given within 6 h of stroke onset, GTN reduced death and dependency (odds ratio 0.52; 95% confidence interval 0.34–0.78), death, disability, cognitive impairment and mood disturbance, and improved quality of life (data from two trials, n = 312). In a pooled analysis of four studies (n = 186), GTN reduced between-visit systolic blood pressure variability over days 1–7 compared with no GTN (mean difference -2.09; 95% confidence interval -3.83 to -0.35; p = 0.019). The efficacy of GTN given in the ultra-acute/pre-hospital setting is currently being assessed and, if found to be beneficial, the implications for hyperacute stroke practice are significant. Here, we discuss the evidence to date, potential mechanisms of action and future possibilities, including unanswered questions, for the therapeutic potential of GTN in acute stroke