The Magnetic Electron Ion Spectrometer (MagEIS) Instruments Aboard the Radiation Belt Storm Probes (RBSP) Spacecraft

This paper describes the Magnetic Electron Ion Spectrometer (MagEIS) instruments aboard the RBSP spacecraft from an instrumentation and engineering point of view. There are four magnetic spectrometers aboard each of the two spacecraft, one low-energy unit (20–240 keV), two medium-energy units (80–1200 keV), and a high-energy unit (800–4800 keV). The high unit also contains a proton telescope (55 keV–20 MeV). The magnetic spectrometers focus electrons within a selected energy pass band upon a focal plane of several silicon detectors where pulse-height analysis is used to determine if the energy of the incident electron is appropriate for the electron momentum selected by the magnet. Thus each event is a two-parameter analysis, an approach leading to a greatly reduced background. The physics of these instruments are described in detail followed by the engineering implementation. The data outputs are described, and examples of the calibration results and early flight data presented

Treatment initiation for parkinson's disease in Australia 2013-2018 : a nation-wide study

Background Guidelines highlight the importance of an individualized approach to treatment initiation for Parkinson's disease. Our aim was to investigate initiation of anti-Parkinson medication in Australia from 2013-2018, and to determine factors predicting choice of initial treatment. Methods Cohort of new-users (N = 4,887) of anti-Parkinson medication aged >= 40 years were identified from a 10% random representative sample of national medication dispensing data from July-2013 to June-2018. Changes in treatment initiation were examined across the whole cohort and stratified by age and sex. Results Treatment initiation was most frequent with levodopa followed by non-ergot dopamine agonists (DAs) and anticholinergics. Two thirds initiated with levodopa across the study period. Initiation with non-ergot DAs increased from 22 to 27% (rate ratio, RR 1.23, 95% confidence interval, CI 1.02-1.47) and initiation with anticholinergics decreased from 6.9% to 2.4% (RR 0.34, 95% CI 0.21-0.55) from 2013-2018. Among persons aged >= 65 years, one third of women and one fourth of men initiated on levodopa. Among women aged = 65 years, consistent with current guidelines. Whilst the value of levodopa sparing strategies is unclear, treatment initiation with DA has become increasingly common relative to levodopa among women but not among men aged < 65 years.Peer reviewe

Report from the 5th cardiovascular outcome trial (CVOT) summit

The 5th Cardiovascular Outcome Trial (CVOT) Summit was held in Munich on October 24th-25th, 2019. As in previous years, this summit served as a reference meeting for in-depth discussions on the topic of recently completed and presented CVOTs. This year, focus was placed on the CVOTs CAROLINA, CREDENCE, DAPA-HF, REWIND, and PIONEER-6. Trial implications for diabetes management and the impact on new treatment algorithms were highlighted for diabetologists, cardiologists, endocrinologists, nephrologists, and general practitioners. Discussions evolved from CVOTs to additional therapy options for heart failure (ARNI), knowledge gained for the treatment and prevention of heart failure and diabetic kidney disease in populations with and without diabetes, particularly using SGLT-2 inhibitors and GLP-1 receptor agonists. Furthermore, the ever increasing impact of CVOTs and substances tested for primary prevention and primary care was discussed. The 6th Cardiovascular Outcome Trial Summit will be held in Munich on October 29th-30th, 2020 (https://www.cvot.org)

Varicellovirus UL 49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP

Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms

Advancing therapy in suboptimally controlled basal insulin-treated type 2 diabetes:Clinical outcomes with iGlarLixi versus premix BIAsp 30 in the SoliMix randomized controlled trial

OBJECTIVE: To directly compare the efficacy and safety of a fixed-ratio combination, of insulin glargine 100 units/mL and the glucagon-like peptide 1 receptor agonist lixisenatide (iGlarLixi), with those of a premix insulin analog, biphasic aspart insulin 30 (30% insulin aspart and 70% insulin aspart protamine) (BIAsp 30) as treatment advancement in type 2 diabetes suboptimally controlled on basal insulin plus oral antihyperglycemic drugs (OADs). RESEARCH DESIGN AND METHODS: In SoliMix, a 26-week, open-label, multicenter study, adults with suboptimally controlled basal insulin–treated type 2 diabetes (HbA(1c) ≥7.5% and ≤10%) were randomized to once-daily iGlarLixi or twice-daily BIAsp 30. Primary efficacy end points were noninferiority in HbA(1c) reduction (margin 0.3%) or superiority in body weight change for iGlarLixi versus BIAsp 30. RESULTS: Both primary efficacy end points were met: after 26 weeks, baseline HbA(1c) (8.6%) was reduced by 1.3% with iGlarLixi and 1.1% with BIAsp 30, meeting noninferiority (least squares [LS] mean difference −0.2% [97.5% CI −0.4, −0.1]; P < 0.001). iGlarLixi was also superior to BIAsp 30 for body weight change (LS mean difference −1.9 kg [95% CI −2.3, −1.4]) and percentage of participants achieving HbA(1c) <7% without weight gain and HbA(1c) <7% without weight gain and without hypoglycemia (all P < 0.001). iGlarLixi was also superior versus BIAsp 30 for HbA(1c) reduction (P < 0.001). Incidence and rates of American Diabetes Association level 1 and 2 hypoglycemia were lower with iGlarLixi versus BIAsp 30. CONCLUSIONS: Once-daily iGlarLixi provided better glycemic control with weight benefit and less hypoglycemia than twice-daily premix BIAsp 30. iGlarLixi is a more efficacious, simpler, and well-tolerated alternative to premix BIAsp 30 in suboptimally controlled type 2 diabetes requiring treatment beyond basal insulin plus OAD therapy. VIDEO 1: [Figure: see text] [Figure: see text

A CD8+ T cell immune evasion protein specific to Epstein-Barr virus and its close relatives in Old World primates

γ1-Herpesviruses such as Epstein-Barr virus (EBV) have a unique ability to amplify virus loads in vivo through latent growth-transforming infection. Whether they, like α- and β-herpesviruses, have been driven to actively evade immune detection of replicative (lytic) infection remains a moot point. We were prompted to readdress this question by recent work (Pudney, V.A., A.M. Leese, A.B. Rickinson, and A.D. Hislop. 2005. J. Exp. Med. 201:349–360; Ressing, M.E., S.E. Keating, D. van Leeuwen, D. Koppers-Lalic, I.Y. Pappworth, E.J.H.J. Wiertz, and M. Rowe. 2005. J. Immunol. 174:6829–6838) showing that, as EBV-infected cells move through the lytic cycle, their susceptibility to EBV-specific CD8+ T cell recognition falls dramatically, concomitant with a reductions in transporter associated with antigen processing (TAP) function and surface human histocompatibility leukocyte antigen (HLA) class I expression. Screening of genes that are unique to EBV and closely related γ1-herpesviruses of Old World primates identified an early EBV lytic cycle gene, BNLF2a, which efficiently blocks antigen-specific CD8+ T cell recognition through HLA-A–, HLA-B–, and HLA-C–restricting alleles when expressed in target cells in vitro. The small (60–amino acid) BNLF2a protein mediated its effects through interacting with the TAP complex and inhibiting both its peptide- and ATP-binding functions. Furthermore, this targeting of the major histocompatibility complex class I pathway appears to be conserved among the BNLF2a homologues of Old World primate γ1-herpesviruses. Thus, even the acquisition of latent cycle genes endowing unique growth-transforming ability has not liberated these agents from evolutionary pressure to evade CD8+ T cell control over virus replicative foci

Bovine Herpesvirus Type 1 (BHV-1) UL49.5 Luminal Domain Residues 30 to 32 Are Critical for MHC-I Down-Regulation in Virus-Infected Cells

Bovine herpesvirus type 1 (BHV-1) UL49.5 inhibits transporter associated with antigen processing (TAP) and down-regulates cell-surface expression of major histocompatibility complex (MHC) class I molecules to promote immune evasion. We have constructed a BHV-1 UL49.5 cytoplasmic tail (CT) null and several UL49.5 luminal domain mutants in the backbone of wild-type BHV-1 or BHV-1 UL49.5 CT- null viruses and determined their relative TAP mediated peptide transport inhibition and MHC-1 down-regulation properties compared with BHV-1 wt. Based on our results, the UL49.5 luminal domain residues 30–32 and UL49.5 CT residues, together, promote efficient TAP inhibition and MHC-I down-regulation functions. In vitro, BHV-1 UL49.5 Δ30–32 CT-null virus growth property was similar to that of BHV-1 wt and like the wt UL49.5, the mutant UL49.5 was incorporated in the virion envelope and it formed a complex with gM in the infected cells