Background
Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal ...antibody directed against aggregated soluble and insoluble forms of amyloid beta.
Objectives
We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease.
Design
EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease.
Setting
These studies involved 348 sites in 20 countries.
Participants
Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study.
Intervention
Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks.
Measurements
The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints.
Results
EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo 95% CI, -0.69 to -0.09; P=.012; 22% decrease) but not in ENGAGE (difference of 0.03, 95% CI, -0.26 to 0.33; P=.833; 2% increase). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema.
Conclusions
Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose-and time-dependent reduction in pathophysiological markers of Alzheimer’s disease was observed in both trials.
High-energy muons can travel large thicknesses of matter. For underground neutrino and cosmic ray detectors the energy loss of muons has to be known accurately for simulations. In this article the ...next-to-leading order correction to the average energy loss of muons through bremsstrahlung is calculated using a modified Weizsäcker–Williams method. An analytical parametrisation of the numerical results is given.
In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis AFFIRM study), involving 942 patients with relapsing multiple sclerosis (MS), ...natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study.
The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years.
Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients.
Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.
To evaluate the safety and tolerability of natalizumab when added to glatiramer acetate (GA) in patients with relapsing multiple sclerosis. The primary outcome assessed whether this combination would ...increase the rate of development of new active lesions on cranial MRI scans vs GA alone.
This phase 2, randomized, double-blind, placebo-controlled study included patients aged 19 to 55 years who were treated with GA for at least 1 year before randomization and experienced at least one relapse during the previous year. Patients received IV natalizumab 300 mg (n = 55) or placebo (n = 55) once every 4 weeks plus GA 20 mg subcutaneously once daily for < or = 20 weeks.
The mean rate of development of new active lesions was 0.03 with combination therapy vs 0.11 with GA alone (p = 0.031). Combination therapy resulted in lower mean numbers of new gadolinium-enhancing lesions (0.6 vs 2.3 for GA alone, p = 0.020) and new/newly enlarging T2-hyperintense lesions (0.5 vs 1.3, p = 0.029). The incidence of infection and infusion reactions was similar in both groups; no hypersensitivity reactions were observed. One serious adverse event occurred with combination therapy (elective hip surgery). With the exception of an increase in anti-natalizumab antibodies with combination therapy, laboratory data were consistent with previous clinical studies of natalizumab alone.
The combination of natalizumab and glatiramer acetate seemed safe and well tolerated during 6 months of therapy.
Underground cosmic-ray experiments, including very large volume neutrino telescopes, depend on a precise description of the interaction cross sections of muons, which can travel large distances ...before reaching the detector. High-energy muons lose their energy almost exclusively via four processes: ionization, electron-positron pair production, bremsstrahlung and inelastic interaction with nuclei. At low energies, ionization is the dominant process, while above energies of about a TeV, the three other processes dominate the energy loss. We discuss the uncertainties of the cross sections of the energy loss processes used in the simulation chain of current very large volume neutrino telescopes and review recent theoretical improvements.
PROPOSAL is a Monte Carlo simulation library, usable both in C++ and via a python wrapper, used to describe the propagation of highly energetic particles. Originally designed to provide a precise ...description of muon and tau propagation, recent updates introduced both photon propagation as well as a more precise implementation of electron and positron propagation. Due to its modular code structure, the user can either use the complete propagation routine provided by PROPOSAL to easily simulate all secondaries created during particle propagation or extract individual parts of the propagation routine to use them in specific applications. Examples of applications of PROPOSAL are its usage in the simulation chain of the IceCube Neutrino Observatory as well as its implementation as an electromagnetic shower model in the upcoming eighth version of the extensive air shower simulation framework CORSIKA. This talk provides a general overview of the functionalities and possibilities of PROPOSAL.
This placebo-controlled, randomized trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab (an α
4
integrin antagonist) in all the primary and secondary outcome ...measures. After two years, the probability of sustained progression of disability was 17 percent with natalizumab and 29 percent with placebo. Fatigue and allergic reaction were more common among patients receiving natalizumab.
This trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab in all the primary and secondary outcome measures. In this trial, natalizumab in combination with interferon was more effective than interferon alone. Progressive multifocal leukoencephalopathy developed in two patients. In this systematic evaluation for PML in patients who received natalizumab in clinical trials, no additional cases were identified.
Relapsing multiple sclerosis is characterized by the intermittent development of inflammatory lesions in the brain and spinal cord, resulting in plaques of demyelination and axonal loss. Lymphocyte migration across the blood–brain barrier is thought to be an important early step in the formation of lesions.
1
The interaction of α
4
β
1
integrin, a protein on the surface of lymphocytes, with vascular-cell adhesion molecule 1 (VCAM-1), which is expressed on the surface of vascular endothelial cells in brain and spinal cord blood vessels, mediates the adhesion and migration of lymphocytes in areas of inflammation.
2
–
6
Furthermore, the interaction of α . . .
Muons are the dominant event signature for neutrino telescopes like IceCube and they are the main background for neutrino searches. Furthermore, they are used to investigate extended air showers. In ...both cases, the stochasticity of the muon propagation plays a key role in the data extraction step and an accurate understanding, even of the edge cases, is crucial. The main process driving stochastic losses for TeV scale muons is bremsstrahlung. In this paper, a feasibility study is presented to measure the cross section of stochastic losses using neutrino-induced muons. The simulation study is based on the propagation of muons using the Monte-Carlo library PROPOSAL. For different reconstruction methods and resolutions, the energy loss distribution for different muon energies is used to estimate the sensitivity to measure the bremsstrahlung cross section. Two further systematic parameters, the detection efficiency, which scales the amount of detected light, and the spectral index are also estimated to analyze their correlation to the estimated bremsstrahlung normalization. The statistics of the simulated dataset correspond to 10 years of up-going muon neutrino data in IceCube.
Visual dysfunction is one of the most common causes of disability in multiple sclerosis (MS). The Multiple Sclerosis Functional Composite (MSFC), a new clinical trial outcome measure, does not ...currently include a test of visual function.
To examine contrast letter acuity as a candidate visual function test for the MSFC.
Binocular contrast letter acuity testing (Sloan charts) was performed in a subgroup of participants from the International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial (IMPACT Substudy) and in MS patients and disease-free control subjects from a cross-sectional study of visual outcome measures (Multiple Sclerosis Vision Prospective cohort MVP cohort). High-contrast visual acuity was measured in both studies; MVP cohort participants underwent additional binocular testing for contrast sensitivity (Pelli-Robson chart), color vision (D-15 desaturated test), and visual field (Esterman test, Humphrey Field Analyzer II).
Contrast letter acuity (Sloan charts, p < 0.0001, receiver operating characteristic curve analysis) and contrast sensitivity (Pelli-Robson chart, p = 0.003) best distinguished MS patients from disease-free control subjects in the MVP cohort. Correlations of Sloan chart scores with MSFC and Expanded Disability Statue Scale (EDSS) scores in both studies were significant and moderate in magnitude, demonstrating that Sloan chart scores reflect visual and neurologic dysfunction not entirely captured by the EDSS or MSFC.
Among clinical measures, contrast letter acuity (Sloan charts) and contrast sensitivity (Pelli-Robson chart) demonstrate the greatest capacity to identify binocular visual dysfunction in MS. Sloan chart testing also captures unique aspects of neurologic dysfunction not captured by current EDSS or MSFC components, making it a strong candidate visual function test for the MSFC.
ARIA (for acetylcholine receptor-inducing activity), a protein purified on the basis of its ability to stimulate acetylcholine receptor (AChR) synthesis in cultured myotubes, is a member of the ...neuregulin family and is present at motor endplates. This suggests an important role for neuregulins in mediating the nerve-dependent accumulation of AChRs in the postsynaptic membrane. Nerve-muscle synapses have now been analyzed in neuregulin-deficient animals. Mice that are heterozygous for the deletion of neuregulin isoforms containing an immunoglobulin-like domain are myasthenic. Postsynaptic AChR density is significantly reduced, as judged by the decrease in the mean amplitude of spontaneous miniature endplate potentials and bungarotoxin binding. On the other hand, the mean amplitude of evoked endplate potentials was not decreased, due to an increase in the number of quanta released per impulse, a compensation that has been observed in other myasthenic states. Thus, the density of AChRs in the postsynaptic membrane depends on immunoglobulin-containing neuregulin isoforms throughout the life of the animal.
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