A measurement of the spectrum of cosmic ray electrons between 20 MeV and 4 BeV in 1968 - Further evidence for extensive time variations of this component

Cosmic ray electron intensity and spectrum measurements between 20 MeV and 4 BeV - 196

An embedding technique for the solution of reaction-fiffusion equations on algebraic surfaces with isolated singularities

In this paper we construct a parametrization-free embedding technique for numerically evolving reaction-diffusion PDEs defined on algebraic curves that possess an isolated singularity. In our approach, we first desingularize the curve by appealing to techniques from algebraic geometry.\ud We create a family of smooth curves in higher dimensional space that correspond to the original curve by projection. Following this, we pose the analogous reaction-diffusion PDE on each member of this family and show that the solutions (their projection onto the original domain) approximate the solution of the original problem. Finally, we compute these approximants numerically by applying the Closest Point Method which is an embedding technique for solving PDEs on smooth surfaces of arbitrary dimension or codimension, and is thus suitable for our situation. In addition, we discuss the potential to generalize the techniques presented for higher-dimensional surfaces with multiple singularities

Boceprevir in combination with HIV protease inhibitors in patients with advanced fibrosis-altered drug-drug interactions?

In HIV/HCV co-infected patients improved treatment outcomes have been reported for the HCV protease inhibitors (PIs) boceprevir (BOC) and telaprevir (TVR), reaching SVR rates of up to 70% in pilot trials. Due to complex drug-drug-interactions triple therapy is substantially limited in HIV/HCV-coinfected individuals. Co-administration of BOC with the commonly available HIV PIs has been reported not only to decrease the level of BOC but also to lead to relevant decreases in the respective HIV PI. Here, we report on two patients who received BOC-containing HCV triple therapy in combination with a HIV PI. Patient 1 was on darunavir 800 mg/ritonavir 100 mg once-daily mono-therapy. Using FibroScan a liver stiffness of 34 kPa suggested liver cirrhosis prior to start of HCV triple therapy. At week 5 of HCV triple therapy darunavir trough concentration was measured in the reference range with 3777 ng/ml (reference trough concentration 2400–4600 ng/ml). HCV-RNA became negative at week 10 and HIV-RNA was below detection limit (<40 copies/ml) at all times. Patient 2 was on a simplified FTC qd and fos-amprenavir 700 mg/ritonavir 100 mg bid regimen. Liver disease had also progressed to liver cirrhosis, confirmed in FibroScan, with a liver stiffness of 32 kPa. At week 8 of HCV triple therapy fos-amprenavir trough level was measured in the normal reference range with 1699 ng/ml (reference trough concentration 750–2500 ng/ml). At week 11 HCV-RNA was <12 IU/ml and HIV viral load was below detection limit of <40 copies/ml at all times. Our clinical data suggest that in patients with advanced liver disease possibly drug levels of HIV PIs which are coadministered with BOC may be within the normal range. In order to better understand the true amount of drug interactions between BOC and commonly used HIV PIs in HIV/HCV-coinfected patients with more advanced liver fibrosis, urgently more PK studies are required to make HCV triple therapy accessible for a wider number of HIV/HCV-coinfected patients in desperate need of these drugs

Transmission of Human Immunodeficiency Virus I Drug Resistance - a Case Report. What are the Clinical Implications?

The success of first-line antiretroviral therapy can be challenged by the acquisition of primary drug resistance. Here we report a case where baseline genotypic resistance testing detected resistance conferring nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-associated mutations, but no primary mutations for protease inhibitor (PI). Subsequent PI-based HAART with boosted saquinavir led to virological treatment success with persistently undetectable viral load. After treatment simplification from saquinavir to an atazanavir based PI-therapy and no change in backbone therapy rapid virological breakthrough occurred. Retrospective analysis displayed preexisting gag cleavage site mutations which may have reduced the genetic barrier in a clinical relevant manner in combination with the already existing NRTI resistance mutations. Alternatively, this effect could be explained with a different antiviral potency for the respective PIs used

From C-3PO to HAL: Opening The Discourse About The Dark Side of Multi-Modal Social Agents

The increasing prevalence of communicative agents raises questions about human-agent communication and the impact of such interaction on people's behavior in society and human-human communication. This workshop aims to address three of those questions: (i) How can we identify malicious design strategies - known as dark patterns - in social agents?; (ii) What is the necessity for and the effects of present and future design features, across different modalities and social contexts, in social agents?; (iii) How can we incorporate the findings of the first two questions into the design of social agents? This workshop seeks to conjoin ongoing discourses of the CUI and wider HCI communities, including recent trends focusing on ethical designs. Out of the collaborative discussion, the workshop will produce a document distilling possible research lines and topics encouraging future collaborations

Avoiding Pitfalls in Comparison of Activity and Selectivity of Solid Catalysts for Electrochemical HMF Oxidation

Electrocatalytic oxidation of 5-hydroxymethylfurfural (HMF) offers a renewable approach to produce the value-added platform chemical 2,5-furandicarboxylic acid (FDCA). The key for the economic viability of this approach is to develop active and selective electrocatalysts. Nevertheless, a reliable catalyst evaluation protocol is still missing, leading to elusive conclusions on criteria for a high-performing catalyst. Herein, we demonstrate that besides the catalyst identity, secondary parameters such as materials of conductive substrates for the working electrode, concentration of the supporting electrolyte, and electrolyzer configurations have profound impact on the catalyst performance and thus need to be optimized before assessing the true activity of a catalyst. Moreover, we highlight the importance of those secondary parameters in suppressing side reactions, which has long been overlooked. The protocol is validated by evaluating the performance of free-standing Cu-foam, and CuCoO modified with NaPO2H2 and Ni, which were immobilized on boron-doped diamond (BDD) electrodes. Recommended practices and figure of merits in carefully evaluating the catalyst performance are proposed. © 2021 The Authors. Published by The Chemical Society of Japan & Wiley-VCH Gmb

Cell-Mediated Immune Predictors of Vaccine Effect on Viral Load and CD4 Count in a Phase 2 Therapeutic HIV-1 Vaccine Clinical Trial.

In a placebo-controlled trial of the peptide-based therapeutic HIV-1 p24 <sup>Gag</sup> vaccine candidate Vacc-4x, participants on combination antiretroviral therapy (cART) received six immunizations over 18weeks, followed by analytical treatment interruption (ATI) between weeks 28 and 52. Cell-mediated immune responses were investigated as predictors of Vacc-4x effect (VE) on viral load (VL) and CD4 count during ATI. All analyses of week 28 responses and fold-changes relative to baseline considered per-protocol participants (Vacc-4x:placebo=72:32) resuming cART after week 40. Linear regression models with interaction tests were used. VE was estimated as the Vacc-4x-placebo difference in log <sub>10</sub> -transformed VL (VE <sup>VL</sup> ) or CD4 count (VE <sup>CD4</sup> ). A lower fold-change of CD4+ T-cell proliferation was associated with VE <sup>CD4</sup> at week 48 (p=0.036, multiplicity adjusted q=0.036) and week 52 (p=0.040, q=0.080). A higher fold-change of IFN-γ in proliferation supernatants was associated with VE <sup>VL</sup> at week 44 (p=0.047, q=0.07). A higher fold-change of TNF-α was associated with VE <sup>VL</sup> at week 44 (p=0.045, q=0.070), week 48 (p=0.028, q=0.070), and week 52 (p=0.037, q=0.074). A higher fold-change of IL-6 was associated with VE <sup>VL</sup> at week 48 (p=0.017, q=0.036). TNF-α levels (>median) were associated with VE <sup>CD4</sup> at week 48 (p=0.009, q=0.009). These exploratory analyses highlight the potential value of investigating biomarkers in T-cell proliferation supernatants for VE in clinical studies