Safety and efficacy of dimethyl fumarate in ALS: randomised controlled study

Objective Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro-inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS. Methods Phase-2, double-blind, placebo-controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin-receptor p75 and quality of life. Results A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS-R score was not significantly different at week 36 (−1.12 [−3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least-squares mean: (0.84 [−0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups. Interpretation Dimethyl fumarate, in combination with riluzole, was safe and well-tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS

Phase 2 randomized placebo controlled double blind study to assess the efficacy and safety of tecfidera in patients with amyotrophic lateral sclerosis (TEALS Study)

Background: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disorder of the human motor system. Neuroinflammation appears to be an important modulator of disease progression in ALS. Specifically, reduction of regulatory T cell (Treg) levels, along with an increase in pro-inflammatory effector T cells, macrophage activation and upregulation of co-stimulatory pathways have all been associated with a rapid disease course in ALS. Autologous infusion of expanded Tregs into sporadic ALS patients, resulted in greater suppressive function, slowing of disease progression and stabilization of respiratory function. Tecfidera (dimethyl fumarate) increases the ratio of anti-inflammatory (Treg) to proinflammatory T-cells in patients with relapsing remitting multiple sclerosis and rebalances the regulatory: inflammatory axis towards a neuroprotective phenotype. Consequently, the aim of this study was to assess the efficacy, safety, and tolerability of Tecfidera in sporadic ALS. Methods: The study is an investigator led Phase 2 multi-center, randomized, placebo controlled, double blind clinical trial assessing the efficacy and safety of Tecfidera in patients with sporadic ALS. The study duration is 40 weeks, with a 36-week study period and end of study visit occurring at 40 weeks or at early termination/withdrawal from study. The TEALS study has been registered with the Australian and New Zealand Clinical Trials registry (ANZCTR) under the trials registration number ACTRN12618000534280 and has been approved by the Human Research Ethics Committee and Research Governance Office at the lead site (Westmead Hospital) with the ethics number HREC/17/WMEAD/353. The participating sites have obtained site specific ethics and governance approvals from the local institution. Results: The primary endpoint is slowing of disease progression as reflected by the differences in the ALS Functional Rating Score-Revised (ALSFRS-R) score at Week 36. The secondary endpoints will include effects in survival, lower motor neuron function, respiratory function, quality of life and safety. Conclusion: This Phase 2 multi-center, randomized, placebo controlled, double blind clinical trial will provide evidence of efficacy and safety of Tecfidera in sporadic ALS

The Layer 0 Inner Silicon Detector of the D0 Experiment

This paper describes the design, fabrication, installation and performance of the new inner layer called Layer 0 (L0) that was inserted in the existing Run IIa Silicon Micro-Strip Tracker (SMT) of the D0 experiment at the Fermilab Tevatron collider. L0 provides tracking information from two layers of sensors, which are mounted with center lines at a radial distance of 16.1 mm and 17.6 mm respectively from the beam axis. The sensors and readout electronics are mounted on a specially designed and fabricated carbon fiber structure that includes cooling for sensor and readout electronics. The structure has a thin polyimide circuit bonded to it so that the circuit couples electrically to the carbon fiber allowing the support structure to be used both for detector grounding and a low impedance connection between the remotely mounted hybrids and the sensors.Comment: 28 pages, 9 figure

Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1

Background Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. Methods The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with ‘omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). Results SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10−6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10−3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression. Conclusions These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings

Modelling spectral and timing properties of accreting black holes: the hybrid hot flow paradigm

The general picture that emerged by the end of 1990s from a large set of optical and X-ray, spectral and timing data was that the X-rays are produced in the innermost hot part of the accretion flow, while the optical/infrared (OIR) emission is mainly produced by the irradiated outer thin accretion disc. Recent multiwavelength observations of Galactic black hole transients show that the situation is not so simple. Fast variability in the OIR band, OIR excesses above the thermal emission and a complicated interplay between the X-ray and the OIR light curves imply that the OIR emitting region is much more compact. One of the popular hypotheses is that the jet contributes to the OIR emission and even is responsible for the bulk of the X-rays. However, this scenario is largely ad hoc and is in contradiction with many previously established facts. Alternatively, the hot accretion flow, known to be consistent with the X-ray spectral and timing data, is also a viable candidate to produce the OIR radiation. The hot-flow scenario naturally explains the power-law like OIR spectra, fast OIR variability and its complex relation to the X-rays if the hot flow contains non-thermal electrons (even in energetically negligible quantities), which are required by the presence of the MeV tail in Cyg X-1. The presence of non-thermal electrons also lowers the equilibrium electron temperature in the hot flow model to <100 keV, making it more consistent with observations. Here we argue that any viable model should simultaneously explain a large set of spectral and timing data and show that the hybrid (thermal/non-thermal) hot flow model satisfies most of the constraints.Comment: 26 pages, 13 figures. To be published in the Space Science Reviews and as hard cover in the Space Sciences Series of ISSI - The Physics of Accretion on to Black Holes (Springer Publisher

The velocity potential and the interacting force for two spheres moving perpendicularly to the line joining their centers

The velocity potential around two spheres moving perpendicularly to the line joining their centers is given by a series of spherical harmonics. The appropriateness of the truncation is evaluated by determining the residual normal surface velocity on the spheres. In evaluating the residual normal velocity, a recursive procedure is constructed to evaluate the spherical harmonics to reduce computational effort and truncation error as compared to direct transformation or numerical integration. We estimate the lift force coefficient for touching spheres to be 0.577771, compared to the most accurate earlier estimate of 0.51435 by Miloh (1977).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42701/1/10665_2004_Article_BF00127479.pd

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02