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Determining the success of antitrypanosomal therapy for Chagas disease is challenging, particularly in the chronic phase of the disease, because seropositivity persists for a long time after successful antitrypanosomal treatment and is known to be related to the duration of Trypanosoma cruzi infection. Seroconversion to negative by two or more conventional serologic tests is the currently accepted measure of efficacy, and studies suggest no significant change in seropositivity if left untreated. However, there is no guidance for industry on how to establish the effectiveness of drugs intended for the treatment of Chagas disease. Due to the lack of validated sensitive, specific, easy-to-use markers that allow early monitoring of the efficacy of antitrypanosomal treatment in an efficient manner, we used seroreduction measured by two conventional enzyme-linked immunosorbent assays in addition to the currently accepted criterion for what constitutes a cure, seroconversion to negative, as a surrogate parameter for efficacy in a Phase III pediatric trial with nifurtimox. The measures for confirmation of the antitrypanosomal efficacy of nifurtimox were discussed with US FDA. In this perspective article, we present our experiences obtained from a pediatric study on Chagas disease with an established drug using a surrogate efficacy parameter in addition to the established criterion for a cure.

Abstract Muon spin rotation with low‐energy muons (LE‐µSR) is a powerful nuclear method where electrical and magnetic properties of surface‐near regions and thin films can be studied on a length scale of ≈200 nm. This study shows the potential of utilizing low‐energy muons for a depth‐resolved characterization of oxide‐semiconductor interfaces, i.e., for silicon (Si) and silicon carbide (4H‐SiC). The performance of semiconductor devices relies heavily on the quality of the oxide‐semiconductor interface; thus, investigation of defects present in this region is crucial to improve the technology. Silicon dioxide (SiO2) deposited by plasma‐enhanced chemical vapor deposition (PECVD) and grown by thermal oxidation of the SiO2‐semiconductor interface are compared with respect to interface and defect formation. The nanometer depth resolution of LE‐µSR allows for a clear distinction between the oxide and semiconductor layers, while also quantifying the extension of structural changes caused by the oxidation of both Si and SiC. The results demonstrate that LE‐µSR can reveal unprecedented details on the structural and electronic properties of the thermally oxidized SiO2‐semiconductor interface.

BackgroundMeasurement of the success of antitrypanosomal treatment for Chagas disease is difficult, particularly in the chronic phase of the disease, because anti-Trypanosoma cruzi antibodies persist in serum for prolonged periods. We studied the effects of nifurtimox administered by two different treatment regimens on the T. cruzi calcium-binding flagellar protein F29 in children diagnosed with Chagas disease measured using an enzyme-linked immunosorbent assay (ELISA) technique (ELISA F29).Methods and principal findingsIn a phase 3, randomized, double-blind, parallel-group, historically controlled study (ClinicalTrials.gov NCT02625974), blood samples obtained from children diagnosed with Chagas disease and treated with nifurtimox for either 60 days or 30 days were analyzed using an ELISA with an F29 recombinant protein as the antigen, as well as conventional serological tests (recombinant ELISA and indirect hemagglutination assay). In an exploratory approach, serological response to nifurtimox treatment was evaluated for 4 years post-treatment. In both treatment groups, the number of patients with negative ELISA F29 values increased over the period of observation. The incidence rate of negative seroconversion using ELISA F29 was 22.94% (95% CI: 19.65%, 26.63%) in the 60-day treatment group and 21.64% (95% CI: 17.21%, 26.86%) in the 30-day treatment group. In the subpopulation of patients who tested seropositive for F29 before nifurtimox treatment, 88 patients (67.7%) in the 60-day regimen and 39 patients (59.1%) in the 30-day regimen were F29 seronegative at 4 years post-treatment. All patients who had a positive ELISA F29 test at baseline and seroconverted to negative measured by conventional serology reached seronegativity in ELISA F29 earlier than in conventional serology.ConclusionsThe results demonstrate a serological response to treatment with nifurtimox measured by the ELISA F29 test in children diagnosed with Chagas disease. The F29-based ELISA can be considered a potential early marker of response to antitrypanosomal therapy for Chagas disease.Trial registrationClinicalTrials.gov NCT02625974.

One of the main challenges in realizing 4H–SiC (silicon carbide)-based bipolar devices is the improvement of minority carrier lifetime in as-grown epitaxial layers. Although Z1/2 has been identified as the dominant carrier lifetime limiting defect, we report on B-related centers being another dominant source of recombination and acting as lifetime limiting defects in 4H–SiC epitaxial layers. Combining time-resolved photoluminescence (TRPL) measurement in near band edge emission and 530 nm, deep level transient spectroscopy, and minority carrier transient spectroscopy (MCTS), it was found that B related deep levels in the lower half of the bandgap are responsible for killing the minority carriers in n-type, 4H–SiC epitaxial layers when the concentration of Z1/2 is already low. The impact of these centers on the charge carrier dynamics is investigated by correlating the MCTS results with temperature-dependent TRPL decay measurements. It is shown that the influence of shallow B acceptors on the minority carrier lifetime becomes neutralized at temperatures above ∼422 K. Instead, the deep B related acceptor level, known as the D-center, remains active until temperatures above ∼570 K. Moreover, a correlation between the deep level concentrations, minority carrier lifetimes, and growth parameters indicates that intentional nitrogen doping hinders the formation of deep B acceptor levels. Furthermore, tuning growth parameters, including growth temperature and C/Si ratio, is shown to be crucial for improving the minority carrier lifetime in as-grown 4H–SiC epitaxial layers.

Nifurtimox is indicated in Chagas disease but determining its effectiveness in chronic disease is hindered by the length of time needed to demonstrate negative serological conversion. We manually reviewed long-term follow-up data from hospital records of patients with chronic Chagas disease (N = 1,497) in Argentina diagnosed during 1967-1980. All patients were aged ≥18 years at diagnosis and were either treated with nifurtimox (n = 968) or received no antitrypanosomal treatment (n = 529). The primary endpoint was negative seroconversion (the "event"), defined as a change from positive to negative in the serological or parasitological laboratory test used at diagnosis. Time to event was from baseline visit to date of endpoint event or censoring. The effectiveness of nifurtimox versus no treatment was estimated with Cox proportional hazard regression using propensity scores with overlap weights to calculate the hazard ratio and 95% confidence interval. The nifurtimox group was younger than the untreated group (mean, 32.4 vs. 40.3 years), with proportionally fewer females (47.9% vs. 60.1%), and proportionally more of the nifurtimox group than the untreated group had clinical signs and symptoms of Chagas disease at diagnosis (28.9% vs. 14.0%). Median maximum daily dose of nifurtimox was 8.0 mg/kg/day (interquartile range [IQR]: 8.0-9.0) and median treatment duration was 44 days (IQR: 1-90). Median time to event was 2.1 years (IQR: 1.0-4.5) for nifurtimox-treated and 2.4 years (IQR: 1.0-4.2) for untreated patients. Accounting for potential confounders, the estimated hazard ratio (95% confidence interval) for negative seroconversion was 2.22 (1.61-3.07) favoring nifurtimox. Variable treatment regimens and follow-up duration, and an uncommonly high rate of spontaneous negative seroconversion, complicate interpretation of this epidemiological study, but with the longest follow-up and largest cohort analyzed to date it lends weight to the benefit of nifurtimox in adults with chronic Chagas disease. Trial registration: The study protocol was registered at ClinicalTrials.gov: NCT03784391.

Nifurtimox is a recommended treatment for Chagas disease, but data from treated children are limited. We investigated the efficacy, safety and tolerability of nifurtimox administered as divisible, dispersible 30 mg and 120 mg tablets in children with Chagas disease. In this blinded, controlled study conducted January 2016-July 2018, 330 patients aged

Broadband electromagnetic (EM) modeling increases in importance for virtual prototyping of advanced power electronics systems (PES), enabling a more accurate prediction of fast switching converter operation and its impact on energy conversion efficiency and EM interference. With the aim to predict and reduce an adverse impact of parasitics on the dynamic performance of fast switching power semiconductor devices, the circuit-oriented EM modeling based on the extraction of equivalent lumped R-L-C-G circuits is frequently selected over the Finite Element Method (FEM)-based EM modeling, mainly due to its lower computational complexity. With requirements for more accurate virtual prototyping of fast-switching PES, the modeling accuracy of the equivalent-RLCG-circuit-based EM modeling has to be re-evaluated. In the literature, the equivalent-RLCG-circuit-based EM techniques are frequently misinterpreted as the quasi-static (QS) 3-D Partial Element Equivalent Circuit (PEEC) method, and the observed inaccuracies of modeling HF effects are attributed to the QS field assumption. This paper presents a comprehensive analysis on the differences between the QS 3-D PEEC-based and the equivalent-RLCG-circuit-based EM modeling for simulating the dynamics of fast switching power devices. Using two modeling examples of fast switching power MOSFETs, a 3-D PEEC solver developed in-house and the well-known equivalent-RLCG-circuit-based EM modeling tool, ANSYS Q3D, are compared to the full-wave 3-D FEM-based EM tool, ANSYS HFSS. It is shown that the QS 3-D PEEC method can model the fast switching transients more accurately than Q3D. Accordingly, the accuracy of equivalent-RLCG-circuit-based modeling approaches in the HF range is rather related to the approximations made on modeling electric-field induced effects than to the QS field assumption.

A short, convergent, and asymmetric synthesis of the epicoccin core was achieved using a phosphite-promoted one-step condensation of a complex proline-type amino acid. Key features of the assembly of this amino acid were a double-bond isomerization/vinylation/ring-closing metathesis strategy as well as an efficient, highly diastereoselective [2 + 2] cycloaddition of a ketene to an enecarbamate, derived from l-pyroglutamic acid. [ABSTRACT FROM AUTHOR]