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

Cytokine Detection and Modulation in Acute Graft vs. Host Disease in Mice

A murine model for acute lethal graft vs. host disease (GVHD) was used to study the role that a number of cytokines play in the development of lethal GVHD. In this study we focused on the role of IL-1, IL-2, IL-4, IL-6, IFN-γ and TNF-α. Lethally irradiated (C57BL × CBA)F1 mice were reconstituted either with 107 allogeneic BALB/c spleen cells or with a similar number of syngeneic cells, as a control. A significant rise in serum levels of IL-6, TNF-α and IFN-γ levels was found in allogeneically reconstituted mice. This is in contrast to the syngeneic control group in which no rise was seen. Serum IL-2 and IL-4 levels were below the detection limit. In the supernatant of Con A stimulated spleen cells from allogeneically reconstituted mice IL-6, IFN-γ and TNF-α concentrations were increased. The expression of mRNA for cytokines as detected by reverse transcription PCR was studied in spleen cells. In the allogeneic reconstituted mice the mRNA expression of IL-1α, IL-2, IL-6, IFN-γ and TNF-α displayed faster kinetics compared with that in syngeneic reconstituted mice. The effect of treatment with recombinant cytokines, antibodies to cytokines and to cytokine receptors on the development of GVHD was investigated. Administration of recombinant IL-2 to allogeneically reconstituted mice strongly increased the morbidity and mortality whereas injection of IL-1α and TNF-α did not influence survival. Administration of antibodies against IL-2 or the IL-2 receptor decreased the morbidity and mortality. Anti-IL-6, anti-IFN-γ, and anti-TNF-α mAB, on the other hand, did not affect the morbidity and mortality of GVHD. The results of this study suggest successive waves of cytokine-secreting cell populations consistent with the induction of an inflammatory response in the development of acute GVH disease

Optimization of the photon path length probability density function-simultaneous (PPDF-S) method and evaluation of CO 2 retrieval performance under dense aerosol conditions

The photon path length probability density function-simultaneous (PPDF-S) algorithm is effective for retrieving column-averaged concentrations of carbon dioxide (XCO 2 ) and methane (XCH 4 ) from Greenhouse gases Observing Satellite (GOSAT) spectra in Short Wavelength InfraRed (SWIR). Using this method, light-path modification attributable to light reflection/scattering by atmospheric clouds/aerosols is represented by the modification of atmospheric transmittance according to PPDF parameters. We optimized PPDF parameters for a more accurate XCO 2 retrieval under aerosol dense conditions based on simulation studies for various aerosol types and surface albedos. We found a more appropriate value of PPDF parameters referring to the vertical profile of CO 2 concentration as a measure of a stable solution. The results show that the constraint condition of a PPDF parameter that represents the light reflectance effect by aerosols is sufficiently weak to affect XCO 2 adversely. By optimizing the constraint, it was possible to obtain a stable solution of XCO 2 . The new optimization was applied to retrieval analysis of the GOSAT data measured in Western Siberia. First, we assumed clear sky conditions and retrieved XCO 2 from GOSAT data obtained near Yekaterinburg in the target area. The retrieved XCO 2 was validated through a comparison with ground-based Fourier Transform Spectrometer (FTS) measurements made at the Yekaterinburg observation site. The validation results showed that the retrieval accuracy was reasonable. Next, we applied the optimized method to dense aerosol conditions when biomass burning was active. The results demonstrated that optimization enabled retrieval, even under smoky conditions, and that the total number of retrieved data increased by about 70%. Furthermore, the results of the simulation studies and the GOSAT data analysis suggest that atmospheric aerosol types that affected CO 2 analysis are identifiable by the PPDF parameter value. We expect that we will be able to suggest a further improved algorithm after the atmospheric aerosol types are identified. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.Russian Science Foundation: 18-11-00024Acknowledgments: The v3.0 ACOS/OCO-2 absorption coefficient (ABSCO) tables, used for the calculation of gas absorption coefficients, were provided by NASA and the ACOS/OCO-2 project. Vyacheslav Zakharov, Konstantin Gribanov, and Nikita Rokotyan thank the Russian Science Foundation for support of their research under the framework of grant 18-11-00024

Impact of a Novel Adaptive Optimization Algorithm on 30-Day Readmissions Evidence From the Adaptive CRT Trial

AbstractObjectivesThis study investigated the impact of the Medtronic AdaptivCRT (aCRT) (Medtronic, Mounds View, Minnesota) algorithm on 30-day readmissions after heart failure (HF) and all-cause index hospitalizations.BackgroundThe U.S. Hospital Readmission Reduction Program, which includes a focus on HF, reduces Medicare inpatient payments when readmissions within 30 days of discharge exceed a moving threshold based on national averages and hospital-specific risk adjustments. Internationally, readmissions within 30 days of any discharge may attract reduced or no payment. Recently, cardiac resynchronization therapy (CRT) devices equipped with the aCRT algorithm allowing automated ambulatory device programming were introduced. The Adaptive CRT trial demonstrated the algorithm’s safety and comparable outcome against a rigorous echocardiography-based optimization protocol.MethodsWe analyzed data from the Adaptive CRT trial, which randomized patients undergoing CRT defibrillation on a 2:1 basis to aCRT (n = 318) or to CRT with echocardiographic optimization (Echo, n = 160) and followed up these patients for a mean of 20.2 months (range: 0.2 to 31.3 months). Logistic regression with generalized estimating equation methodology was used to compare the proportion of patients hospitalized for HF and for all causes who had a readmission within 30 days.ResultsFor HF hospitalizations, the 30-day readmission rate was 19.1% (17 of 89) in the aCRT group and 35.7% (15 of 42) in the Echo group (odds ratio: 0.41; 95% confidence interval [CI]: 0.19 to 0.86; p = 0.02). For all-cause hospitalization, the 30-day readmission rate was 14.8% (35 of 237) in the aCRT group compared with 24.8% (39 of 157) in the Echo group (odds ratio: 0.54; 95% CI: 0.31 to 0.94; p = 0.03). The risk of readmission after HF or all-cause index hospitalization with aCRT was also significantly reduced beyond 30 days.ConclusionsUse of the aCRT algorithm is associated with a significant reduction in the probability of a 30-day readmission after both HF and all-cause hospitalizations. (Adaptive Cardiac Resynchronization Therapy Study [aCRT]; NCT00980057

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

Diabetic Neuropathy: A cross-sectional study of the relationships among tests of neurophysiology

OBJECTIVE — To determine the relationships among large, small, and autonomic fiber neurophysiological measures in a cross-sectional study of patients with diabetes. RESEARCH DESIGN AND METHODS — We assessed 130 individuals: 25 healthy subjects and 105 subjects with diabetes. Subjects were classified by the presence or absence of neuropathy by physical examination. All subjects underwent autonomic testing, nerve conduc-tion studies, quantitative sensory testing, and nerve-axon reflex vasodilation in addition to quantifiable neurological examination and symptom scores. Correlation and cluster analysis were used to determine relationships between and among different neurophysiological testing parameters. RESULTS — Results of neurophysiological tests were abnormal in patients with clinical evi-dence of diabetic neuropathy compared with results in healthy control subjects and in those without neuropathy (P 0.01, all tests). The correlations among individual tests varied widely, both within (r range0.5–0.9, NS to0.001) and between test groups (r range0.2–0.5, NS to0.01). A two-step hierarchical cluster analysis revealed that neurophysiological tests do not aggregate by typical “small, ” “large, ” or “autonomic ” nerve fiber subtypes

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