A phase 3 multicenter, prospective, open-label efficacy and safety study of immune globulin (human) 10% caprylate/chromatography purified in patients with myasthenia gravis exacerbations

Background: Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Exacerbations may involve increasing bulbar weakness and/or sudden respiratory failure, both of which can be critically disabling. Management of MG exacerbations includes plasma exchange and intravenous immunoglobulin (IVIG); they are equally effective, but patients experience fewer side effects with IVIG. The objective of this study was to assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with MG exacerbations. Methods: This prospective, open-label, non-controlled 28-day clinical trial was conducted in adults with MG Foundation of America class IVb or V status. Subjects received IGIV-C 2 g/kg over 2 consecutive days (1 g/kg/day) and were assessed for efficacy/safety on Days 7, 14, 21, and 28. The primary efficacy endpoint was the change from Baseline in quantitative MG (QMG) score to Day 14. Secondary endpoints of clinical response, Baseline to Day 14, included at least a 3-point decrease in QMG and MG Composite and a 2-point decrease in MG-activities of daily living (MG-ADL). Results: Forty-nine subjects enrolled. The change in QMG score at Day 14 was significant (p < 0.001) in the Evaluable (-6.4, n = 43) and Safety (-6.7, n = 49) populations. Among evaluable subjects, Day 14 response rates were 77, 86, and 88% for QMG, MG Composite, and MG-ADL, respectively. IGIV-C showed good tolerability with no serious adverse events. Conclusions: The results of this study show that IGIV-C was effective, safe, and well tolerated in the treatment of MG exacerbations

Neuropeptide AF and FF modulation of adipocyte metabolism. Primary insights from functional genomics and effects on beta-adrenergic responsiveness.

The presence of a neuropeptide AF and FF receptor (NPFF-R2) mRNA in human adipose tissue (Elshourbagy, N. A., Ames, R. S., Fitzgerald, L. R., Foley, J. J., Chambers, J. K., Szekeres, P. G., Evans, N. A., Schmidt, D. B., Buckley, P. T., Dytko, G. M., Murdock, P. R., Tan, K. B., Shabon, U., Nuthulaganti, P., Wang, D. Y., Wilson, S., Bergsma, D. J., and Sarau, H. M. (2000) J. Biol. Chem. 275, 25965-25971) suggested these peptides, principally recognized for their pain modulating effects, may also impact on adipocyte metabolism, an aspect that has not been explored previously. Our aim was thus to obtain more insights into the actions of these peptides on adipocytes, an approach initially undertaken with a functional genomic assay. First we showed that 3T3-L1 adipocytes express both NPFF-R1 and NPFF-R2 transcripts, and that NPAF binds adipocyte membranes with a nanomolar affinity as assessed by surface plasmon resonance technology. Then, and following a 24-h treatment with NPFF or NPAF (1 microm), we have measured using real-time quantitative reverse transcriptase-PCR the mRNA steady state levels of already well characterized genes involved in key pathways of adipose metabolism. Among the 45 genes tested, few were modulated by NPFF ( approximately 10%) and a larger number by NPAF ( approximately 27%). Interestingly, NPAF increased the mRNA levels of beta2- and beta3-adrenergic receptors (AR), and to a lesser extent those of beta1-ARs. These variations in catecholamine receptor mRNAs correlated with a clear induction in the density of beta2- and beta3-AR proteins, and in the potency of beta-AR subtype-selective agonists to stimulate adenylyl cyclase activity. Altogether, these data show that NPFF-R1 and NPFF-R2 are functionally present in adipocytes and suggest that besides their well described pain modulation effects, NPAF and to a lesser extent NPFF, may have a global impact on body energy storage and utilization

Epistemic policy networks in the European Union’s CBRN risk mitigation policy

This paper offers insights into an innovative and currently flagship approach of the European Union (EU) to the mitigation of chemical, biological, radiological, and nuclear (CBRN) risks. Building on its long-time experience in the CBRN field, the EU has incorporated methods familiar to the students of international security governance: it is establishing regional networks of experts and expertise. CBRN Centers of Excellence, as they are officially called, aim to contribute to the security and safety culture in different parts of Africa, the Middle East, South East Asia, and South East Europe, in the broadly construed CBRN area. These regional networks represent a modern form of security cooperation, which can be conceptualized as an epistemic policy networks approach. It offers flexibility to the participating states, which have different incentives to get involved. At the same, however, the paper identifies potential limitations and challenges of epistemic policy networks in this form

Efficacy and safety of rozanolixizumab in moderate to severe generalized myasthenia gravis : a phase 2 randomized control trial

OBJECTIVE: To explore the clinical efficacy and safety of subcutaneous (SC) rozanolixizumab, an anti-neonatal Fc receptor humanized monoclonal antibody, in patients with generalized myasthenia gravis (gMG). METHODS: In this phase 2a, randomized, double-blind, placebo-controlled, 2-period, multicenter trial (NCT03052751), patients were randomized (1:1) in period 1 (days 1-29) to 3 once-weekly (Q1W) SC infusions of rozanolixizumab 7 mg/kg or placebo. In period 2 (days 29-43), patients were re-randomized to either rozanolixizumab 7 mg/kg or 4 mg/kg (3 Q1W SC infusions), followed by an observation period (days 44-99). Primary endpoint was change from baseline to day 29 in Quantitative Myasthenia Gravis (QMG) score. Secondary endpoints were change from baseline to day 29 in MG-Activities of Daily Living (MG-ADL) and MG-Composite (MGC) scores and safety. RESULTS: Forty-three patients were randomized (rozanolixizumab 21, placebo 22 [period 1]). Least squares (LS) mean change from baseline to day 29 for rozanolixizumab vs placebo was as follows: QMG (LS mean -1.8 vs -1.2, difference -0.7, 95% upper confidence limit [UCL] 0.8; p = 0.221; not statistically significant), MG-ADL (LS mean -1.8 vs -0.4, difference -1.4, 95% UCL -0.4), and MGC (LS mean -3.1 vs -1.2, difference -1.8, 95% UCL 0.4) scores. Efficacy measures continued to improve with rozanolixizumab 7 mg/kg in period 2. The most common adverse event in period 1 was headache (rozanolixizumab 57%, placebo 14%). CONCLUSION: Whereas change from baseline in QMG was not statistically significant, the data overall suggest rozanolixizumab may provide clinical benefit in patients with gMG and was generally well tolerated. Phase 3 evaluation is ongoing (NCT03971422). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with gMG, rozanolixizumab is well-tolerated, but did not significantly improve QMG score

Toward a Regulatory Pathway for the Use of in Silico Trials in The Ce Marking of Medical Devices

In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing

The Manipulative Complexity of Lower Paleolithic Stone Toolmaking

Early stone tools provide direct evidence of human cognitive and behavioral evolution that is otherwise unavailable. Proper interpretation of these data requires a robust interpretive framework linking archaeological evidence to specific behavioral and cognitive actions.Here we employ a data glove to record manual joint angles in a modern experimental toolmaker (the 4(th) author) replicating ancient tool forms in order to characterize and compare the manipulative complexity of two major Lower Paleolithic technologies (Oldowan and Acheulean). To this end we used a principled and general measure of behavioral complexity based on the statistics of joint movements.This allowed us to confirm that previously observed differences in brain activation associated with Oldowan versus Acheulean technologies reflect higher-level behavior organization rather than lower-level differences in manipulative complexity. This conclusion is consistent with a scenario in which the earliest stages of human technological evolution depended on novel perceptual-motor capacities (such as the control of joint stiffness) whereas later developments increasingly relied on enhanced mechanisms for cognitive control. This further suggests possible links between toolmaking and language evolution

Prognostic value of microvessel density in stage II and III colon cancer patients:a retrospective cohort study

Background Microvessel density (MVD), as a derived marker for angiogenesis, has been associated with poor outcome in several types of cancer. This study aimed to evaluate the prognostic value of MVD in stage II and III colon cancer and its relation to tumour-stroma-percentage (TSP) and expression of HIF1A and VEGFA. Methods Formalin-fixed paraffin-embedded (FFPE) colon cancer tissues were collected from 53 stage II and 54 (5-fluorouracil-treated) stage III patients. MVD was scored by digital morphometric analysis of CD31-stained whole tumour sections. TSP was scored using haematoxylin-eosin stained slides. Protein expression of HIF1A and VEGFA was determined by immunohistochemical evaluation of tissue microarrays. Results Median MVD was higher in stage III compared to stage II colon cancers (11.1% versus 5.6% CD31-positive tissue area, p <0.001). High MVD in stage II patients tended to be associated with poor disease free survival (DFS) in univariate analysis (p = 0.056). In contrast, high MVD in 5FU-treated stage III patients was associated with better DFS (p = 0.006). Prognostic value for MVD was observed in multivariate analyses for both cancer stages. Conclusions MVD is an independent prognostic factor associated with poor DFS in stage II colon cancer patients, and with better DFS in stage III colon cancer patients treated with adjuvant chemotherapy

Exact Speedup Factors and Sub-Optimality for Non-Preemptive Scheduling

Fixed priority scheduling is used in many real-time systems; however, both preemptive and non-preemptive variants (FP-P and FP-NP) are known to be sub-optimal when compared to an optimal uniprocessor scheduling algorithm such as preemptive earliest deadline first (EDF-P). In this paper, we investigate the sub-optimality of fixed priority non-preemptive scheduling. Specifically, we derive the exact processor speed-up factor required to guarantee the feasibility under FP-NP (i.e. schedulability assuming an optimal priority assignment) of any task set that is feasible under EDF-P. As a consequence of this work, we also derive a lower bound on the sub-optimality of non-preemptive EDF (EDF-NP). As this lower bound matches a recently published upper bound for the same quantity, it closes the exact sub-optimality for EDF-NP. It is known that neither preemptive, nor non-preemptive fixed priority scheduling dominates the other, in other words, there are task sets that are feasible on a processor of unit speed under FP-P that are not feasible under FP-NP and vice-versa. Hence comparing these two algorithms, there are non-trivial speedup factors in both directions. We derive the exact speed-up factor required to guarantee the FP-NP feasibility of any FP-P feasible task set. Further, we derive the exact speed-up factor required to guarantee FP-P feasibility of any constrained-deadline FP-NP feasible task set

Lymph Node Negative Colorectal Cancers with Isolated Tumor Deposits Should Be Classified and Treated As Stage III

BACKGROUND: The prognostic role of pericolic or perirectal isolated tumor deposits (ITDs) in node-negative colorectal cancer (CRC) patients is unclear. Rules to define ITDs as regional lymph node metastases changed in subsequent editions of the TNM staging without substantial evidence. Aim of this study was to investigate the correlation between ITDs and disease recurrence in stage II and III CRC patients. MATERIALS AND METHODS: The medical files of 870 CRC patients were reviewed. Number, size, shape, and location pattern of all ITDs in node-negative patients were examined in relation to involvement of vascular structures and nerves. The correlation between ITDs and the development of recurrent disease was investigated. RESULTS: Disease recurrence was observed in 50.0% of stage II patients with ITDs (13 of 26), compared with 24.4% of stage II patients without ITDs (66 of 270) (P <.01). Disease-free survival of ITD-positive stage II patients was comparable with that of stage III patients. Also within stage III, more recurrences were observed in ITD-positive patients compared with ITD-negative patients (65.1 vs. 39.1%, respectively). No correlation was found between size of ITDs and disease recurrence. More recurrences were seen in patients with irregularly shaped ITDs compared with patients with 1 or more smooth ITDs present. CONCLUSIONS: Because of the high risk of disease recurrence, all node-negative stage II patients with ITDs, regardless of size and shape, should be classified as stage III, for whom adjuvant chemotherapy should be considere