Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Comparison of Sirtuin 3 Levels in ALS and Huntington’s Disease—Differential Effects in Human Tissue Samples vs. Transgenic Mouse Models

Neurodegenerative diseases are characterized by distinct patterns of neuronal loss. In amyotrophic lateral sclerosis (ALS) upper and lower motoneurons degenerate whereas in Huntington’s disease (HD) medium spiny neurons in the striatum are preferentially affected. Despite these differences the pathophysiological mechanisms and risk factors are remarkably similar. In addition, non-neuronal features, such as weight loss implicate a dysregulation in energy metabolism. Mammalian sirtuins, especially the mitochondrial NAD+ dependent sirtuin 3 (SIRT3), regulate mitochondrial function and aging processes. SIRT3 expression depends on the activity of the metabolic master regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a modifier of ALS and HD in patients and model organisms. This prompted us to systematically probe Sirt3 mRNA and protein levels in mouse models of ALS and HD and to correlate these with patient tissue levels. We found a selective reduction of Sirt3 mRNA levels and function in the cervical spinal cord of end-stage ALS mice (superoxide dismutase 1, SOD1G93A). In sharp contrast, a tendency to increased Sirt3 mRNA levels was found in the striatum in HD mice (R6/2). Cultured primary neurons express the highest levels of Sirt3 mRNA. In primary cells from PGC-1α knock-out (KO) mice the Sirt3 mRNA levels were highest in astrocytes. In human post mortem tissue increased mRNA and protein levels of Sirt3 were found in the spinal cord in ALS, while Sirt3 levels were unchanged in the human HD striatum. Based on these findings we conclude that SIRT3 mediates the different effects of PGC-1α during the course of transgenic (tg) ALS and HD and in the human conditions only partial aspects Sirt3 dysregulation manifest

THE UN COMMITTEE ON THE RIGHTS OF THE CHILD’S GENERAL COMMENT ON THE DIGITAL ENVIRONMENT

For too long, child rights advocates knew little about the internet while internet governance experts knew little about children’s rights. In March 2021, the UN Committee on the Rights of the Child (CRC) adopted General Comment 25 (GC25) on children’s rights in relation to the digital environment. A General Comment is an authoritative document which sets out how states should implement the UN Convention on the Rights of the Child (UNCRC) in specific contexts, such as the digital environment. Like the Convention itself, General Comment 25 needs to apply in wealthier and poorer nations, to governments of all political stripes, and for all children whatever their abilities or circumstances. It has to balance the provision of guidance on a very broad range of issues with adequate depth, so as to be meaningfully applied. And it has to shore up children’s rights today, while also anticipating the risks of harm and the potential benefits associated with future developments in the technological environment. A major cross-sector and international collaborative effort was required to ensure GC25 could achieve its aims. To inform the process, the drafting team coordinated an international public consultation, receiving unprecedented numbers of submissions; consulted with 50 experts from across jurisdictions; and conducted consultations with over 700 children in 27 countries. This process surfaced deep theoretical dilemmas and disagreements, as well as diverse practical challenges for implementing meaningful and actionable digital policy. For the child rights advocates uncertain exactly how to realize rights online as offline, GC25 provides a mandate and agenda. For policymakers uncertain where children fit into ongoing debates over internet governance, GC25 provides explanation and direction. For the public keen for children to thrive in a digital world, no longer ‘canaries in the coal mine,’ GC25 provides the road map for states to generate improvements. For 1000+ children consulted around the world, and the one in three internet users under 18 for whom they spoke, GC25 reflects their views on a matter that affects them greatly. But it is easier to say that rights offline also apply online than it is to achieve this in practice. On publication, GC25 was recognized by OECD, United Nations Broadband Commission for Sustainable Development Goals, ECPAT (the Global Partnership to End Violence Against Children), International Telecommunication Union, UNESCO, WeProtect Global Alliance, World Childhood Foundation USA, World Health Organization and the European Commission. However, it is states rather than regional or other bodies who are the primary duty bearers bound to implement the Convention and its General Comments under international law. GC25 landed on the desk of every government in the world, and they must ensure that all duty bearers within their jurisdiction meet their responsibilities to children’s rights – including businesses and others whose activities significantly impact on children. Introduced and chaired by members of the GC25 drafting team responsible for the international consultations among stakeholders and children, this panel discusses ongoing efforts to interpret and implement GC25. Conceiving the child as a limit case for policy development, and recognising that, far from abstract legal principles, children’s rights come to life at the level of children’s everyday experiences, the panel will reflect on the difficulties of generating policy guidance to protect and uphold children’s rights in a digital age. It highlights the particular challenges for communication policy and law, including generating the evidence base and meaningful participation from children regarding child online protection policy in Zimbabwe (paper 1), aligning state with regional policies in Europe so as to provide a coordinated and rights-respecting framework for internet governance (paper 2), reconciling parents’ responsibilities with children’s rights regarding privacy in the US (paper 3), and translating child rights-respecting initiatives into designing digital products and services used by children (paper 4). While four papers cannot capture the full range of issues that arise in relation to children’s rights in the digital environment, the panel represents perspectives from three very different continents which contrasting approaches both to children and to internet governance. Through their commonalities and differences, the panel will seek to open a dialogue that represents diverse experiences across cultures and contexts, including the struggles and possible contestation that UN initiatives can occasion. A respondent to all four papers will reflect on the challenges of promoting coordination and implementing child rights-respecting governance in contexts of global inequality and conflict. Building on his role as expert advisor to the United Nations, he will suggest a framework for advancing the recommendations of General Comment internationally, before opening up the discussion for participation among the chairs, panellist and delegates

Lipidomic and Metallomic Alteration of Caenorhabditis elegans after Acute and Chronic Manganese, Iron, and Zinc Exposure with a Link to Neurodegenerative Disorders

Parkinson’s disease (PD) progresses with the loss of dopaminergic neurons in the substantia nigra pars compacta region of the brain. The superior mechanisms and the cause of this specific localized neurodegeneration is currently unknown. However, experimental evidence indicates a link between PD progression and reactive oxygen species with imbalanced metal homeostasis. Wild-type Caenorhabditis elegans exposed to redox-active metals was used as the model organism to study cellular response to imbalanced metal homeostasis linked to neurodegenerative diseases. Using modern hyphenated techniques such as capillary electrophoresis coupled to inductively coupled plasma mass spectrometry and ultrahigh-performance liquid chromatography mass spectrometry, alterations in the lipidome and metallome were determined in vivo. In contrast to iron, most of the absorbed zinc and manganese were loosely bound. We observed changes in the phospholipid composition for acute iron and manganese exposures, as well as chronic zinc exposure. Furthermore, we focused on the mitochondrial membrane alteration due to its importance in neuronal function. However, significant changes in the inner mitochondrial membrane by determination of cardiolipin species could only be observed for acute iron exposure. These results indicate different intracellular sites of local ROS generation, depending on the redox active metal. Our study combines metallomic and lipidomic alterations as the cause and consequence to enlighten intracellular mechanisms in vivo, associated with PD progression. The mass spectrometry raw data have been deposited to the MassIVE database (https://massive.ucsd.edu) with the identifier MSV000090796 and 10.25345/C51J97C8F

Pyroclastic dune bedforms: macroscale structures and lateral variations. Examples from the 2006 pyroclastic currents at Tungurahua (Ecuador).

Pyroclastic currents are catastrophic flows of gas and particles triggered by explosive volcanic eruptions. For much of their dynamics, they behave as particulate density currents and share similarities with turbidity currents. They occasionally deposit dune bedforms with peculiar lamination patterns, from what is thought to represent the dilute, low concentration, and fluid-turbulence supported end member of the pyroclastic currents. Here, we present a high resolution dataset of sediment plates (lacquer peels) with several closely spaced lateral profiles representing sections through single pyroclastic bedforms from the August 2006 eruption of Tungurahua (Ecuador). Most of the sedimentary features contain backset bedding and preferential stoss-face deposition. From the ripple scale (few cm) to the largest dune bedform scale (several m length), similar patterns of erosive-based backset beds are evidenced. Recurrent trains of sub-vertical truncations on the stoss side of structures reshape and steepen the bedforms. In contrast, sporadic coarse-grained lenses and lensoidal layers flatten bedforms by filling troughs. The coarsest (clasts up to 10 cm), least sorted and massive structures still exhibit lineation patterns that follow the general backset bedding trend. The stratal architecture exhibits strong lateral variations within tens of centimeters, with very local truncations both in flow-perpendicular and flow-parallel direction. We infer that the bedforms' sedimentary patterns result from four formation mechanisms: "differential draping", "slope-influenced saltation", "truncative bursts", and "granular-based events". Whereas most of the literature makes a straightforward link between backset bedding and Froude-supercritical flows, we reconsider this interpretation. Indeed, features that would be diagnostic of subcritical dunes, antidunes, and "chute and pools" can be found on the same horizon and in a single bedform, only laterally separated by short distances (10s of cm). Our data stress the influence of the pulsating and highly turbulent nature of the currents and the possible role of coherent flow structures such as Görtler vortices. Backset bedding is interpreted here as a consequence of a very high sedimentation environment of weak and waning currents that interact with the pre-existing morphology. Quantification of near-bed flow velocities are made via comparison with wind tunnel experiments. We estimate that shear velocities of ca. 0.30 m.s-1 (equivalent to pure wind velocity of 6 to 8 m.s-1 at 10 cm above the bed) could emplace the constructive bedsets, whereas the truncative phases would result from bursts with impacting wind velocities of at least 30-40 m.s-1