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Particle acceleration and loss in the million electron Volt (MeV) energy range (and above) is the least understood aspect of radiation belt science. In order to measure cleanly and separately both the energetic electron and energetic proton components, there is a need for a carefully designed detector system. The Relativistic Electron-Proton Telescope (REPT) on board the Radiation Belt Storm Probe (RBSP) pair of spacecraft consists of a stack of high-performance silicon solid-state detectors in a telescope configuration, a collimation aperture, and a thick case surrounding the detector stack to shield the sensors from penetrating radiation and bremsstrahlung. The instrument points perpendicular to the spin axis of the spacecraft and measures high-energy electrons (up to ∼20 MeV) with excellent sensitivity and also measures magnetospheric and solar protons to energies well above E =100 MeV. The instrument has a large geometric factor ( g =0.2 cm 2  sr) to get reasonable count rates (above background) at the higher energies and yet will not saturate at the lower energy ranges. There must be fast enough electronics to avert undue dead-time limitations and chance coincidence effects. The key goal for the REPT design is to measure the directional electron intensities (in the range 10 −2 –10 6 particles/cm 2  s sr MeV) and energy spectra (Δ E / E ∼25 %) throughout the slot and outer radiation belt region. Present simulations and detailed laboratory calibrations show that an excellent design has been attained for the RBSP needs. We describe the engineering design, operational approaches, science objectives, and planned data products for REPT.

The Lunar Dust Experiment (LDEX) is an in situ dust detector onboard the Lunar Atmosphere and Dust Environment Explorer (LADEE) mission. It is designed to characterize the variability of the dust in the lunar exosphere by mapping the size and spatial distributions of dust grains in the lunar environment as a function of local time and the position of the Moon with respect to the magnetosphere of the Earth. LDEX gauged the relative contributions of the two competing dust sources: (a) ejecta production due to the continual bombardment of the Moon by interplanetary micrometeoroids, and (b) lofting of small grains from the lunar surface due to plasma-induced near-surface electric fields.

Background: COPD patients suffer from respiratory symptoms and limitations in daily life. We aimed to characterize the impact of disease on overall health, daily life, and perceived well-being in COPD outpatients. Methods: We conducted a national, cross-sectional study among pulmonologists and general practitioners (GPs). The St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Inclusion criteria were a physician's diagnosis of COPD and age [greater than or equal to]40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded. Results: Sixty-seven pulmonologists and 6 GPs enrolled 1175 COPD patients. Two hundred forty-eight of those did not fulfill GOLD criteria for COPD ([FEV.sub.1]/FVC <0.7) and 77 were excluded due to missing data. Finally, 850 patients (62.8% men; mean age 66.2 [+ or -] 0.3 (SE) years; mean [FEV.sub.1]%pred. 51.5 [+ or -] 0.6 (SE)) were analyzed. Last year, 55.4% reported at least one exacerbation, and 12.7% were hospitalized for COPD exacerbation. Mean SGRQ-C total score was 43.1 [+ or -] 0.83 (SE) and mean component scores for symptoms, activity and impacts were 55.6, 55.4 and 30.5, respectively. Half of the patients (50.3%) reported not being able to do any sports and 78.7% stated that their respiratory symptoms did not allow them doing anything they would like to do. In patients with less severe COPD ([FEV.sub.1]pred [greater than or equal to]50% and non-frequent exacerbations), global health status was overrated, ie, estimated as better by the physician than by the patient, while it was underrated in more severe COPD. Conclusion: In Austria, the burden of disease in COPD outpatients tends to be underestimated in patients with milder airway obstruction and less exacerbations and overestimated in patients with more severe airway obstruction and frequent exacerbations. Our finding suggests that validated assessment of global health status might decrease these differences of perception. Keywords: chronic obstructive pulmonary disease, limitations, quality of life, St. Georges Respiratory Questionnaire

COPD exacerbations are associated with worsening clinical outcomes and increased healthcare costs, despite use of optimal medical therapy. A novel bronchoscopic therapy, targeted lung denervation (TLD), which disrupts parasympathetic pulmonary innervation of the lung, has been developed to reduce clinical consequences of cholinergic hyperactivity and its impact on COPD exacerbations. The AIRFLOW-2 study assessed the durability of safety and efficacy of TLD additive to optimal drug therapy compared to sham bronchoscopy and optimal drug therapy alone in subjects with moderate-to-severe, symptomatic COPD two years post randomization. TLD was performed in COPD patients (FEV 30-60% predicted, CAT≥10 or mMRC≥2) in a 1:1 randomized, sham-controlled, double-blinded multicenter study (AIRFLOW-2) using a novel lung denervation system (Nuvaira, Inc., USA). Subjects remained blinded until their 12.5-month follow-up visit when control subjects were offered the opportunity to undergo TLD. A time-to-first-event analysis on moderate and severe and severe exacerbations of COPD was performed. Eighty-two subjects (FEV 41.6±7.4% predicted, 50.0% male, age 63.7±6.8 yrs, 24% with prior year respiratory hospitalization) were randomized. Time-to-first severe COPD exacerbation was significantly lengthened in the TLD arm (p=0.04, HR=0.38) at 2 years post-TLD therapy and trended towards similar attenuation for moderate and severe COPD exacerbations (p=0.18, HR=0.71). No significant changes in lung function or SGRQ-C were found 2 years post randomization between groups. In a randomized trial, TLD demonstrated a durable effect of significantly lower risk of severe AECOPD over 2 years. Further, lung function and quality of life remained stable following TLD. NCT02058459.

Inappropriate activation of the NOTCH signaling pathway, for example, by activating mutations, contributes to the pathogenesis of various human malignancies. Here, we demonstrate that aberrant expression of an essential NOTCH coactivator of the Mastermind-like (MAML) family provides an alternative mechanism to activate NOTCH signaling in human lymphoma cells. We detected high-level MAML2 expression in several B cell-derived lymphoma types, including classical Hodgkin lymphoma (cHL) cells, relative to normal B cells. Inhibition of MAML-protein activity by a dominant negative form of MAML or by small hairpin RNAs targeting MAML2 in cHL cells resulted in downregulation of the NOTCH target genes HES7 and HEY1 , which we identified as overexpressed in cHL cells, and in reduced proliferation. Furthermore, a NOTCH gene-expression signature in cHL cells confirmed their cell-autonomous NOTCH activity. Finally, in line with the essential role of MAML proteins for assembly and activity of the NOTCH transcriptional complex (NTC), we show that MAML-derived small-peptide constructs block NOTCH activity and disrupt NTC formation in vitro . These data strongly suggest direct targeting of the NTC as treatment strategy for NOTCH-dependent malignancies.

The Student Dust Counter (SDC) experiment of the New Horizons Mission is an impact dust detector to map the spatial and size distribution of dust along the trajectory of the spacecraft across the solar system. The sensors are thin, permanently polarized polyvinylidene fluoride (PVDF) plastic films that generate an electrical signal when dust particles penetrate their surface. SDC is capable of detecting particles with masses m >10 −12 g, and it has a total sensitive surface area of about 0.1 m 2 , pointing most of the time close to the ram direction of the spacecraft. SDC is part of the Education and Public Outreach (EPO) effort of this mission. The instrument was designed, built, tested, integrated, and now is operated by students.

Purpose: The accurate delivery of intensity modulated radiotherapy (IMRT), volumetric‐modulated arc therapy (VMAT) and conformal head and neck (H&N) radiotherapy (RT) relies on patient stabilisation. With the multitude of products and variations available, it is imperative to investigate which product or combination of products offer the most optimal immobilisation. This quality improvement paper investigates the feasibility of using Posifix® (Civco Medical Solutions, Iowa, USA) headrests compared with Silverman® (Civco Medical Solutions, Iowa, USA) headrests in H&N RT stabilisation. This investigation is based on the hypothesis that foam Posifix® headrests may improve stabilisation and reproducibility as compared with the rigid plastic cast moulds of Silverman® headrests. Methods: A retrospective group of 12 consecutive patients (six Silverman® and six Posifix®) were used to evaluate the accuracy of positioning from planning to treatment. In the assessment, 204 treatment portal images were matched to planning digitally reconstructed radiographs (DRR). The resultant shifts were documented for anterior/posterior and lateral films. For all three directions; left/right, anterior/posterior and superior/inferior (x, y and z) set‐up deviations from the planning DRR were measured and averaged. A change in patient position by removal or addition of plastic spacers (shims) was collated from the treatment set‐up sheet. Results: A total of 33 shifts of ≥ 3 mm were required for Silverman® headrests compared with 11 for Posifix® headrests. Total shim adjustments made were 10 and 0 for Silverman® and Posifix® headrests respectively. Conclusion: Using Posifix® headrests reduced shifts of ≥ 3 mm and patient set‐up adjustments. As a result, Posifix® headrests have been implemented as part of the department's protocol for head and neck patient positioning.

Using design patterns is claimed to improve programmer productivity and software quality. Such improvements may manifest both at construction time (in faster and better program design) and at maintenance time (in faster and more accurate program comprehension). The paper focuses on the maintenance context and reports on experimental tests of the following question: does it help the maintainer if the design patterns in the program code are documented explicitly (using source code comments) compared to a well-commented program without explicit reference to design patterns? Subjects performed maintenance tasks on two programs ranging from 360 to 560 LOC including comments. The experiments tested whether pattern comment lines (PCL) help during maintenance if patterns are relevant and sufficient program comments are already present. This question is a challenge for the experimental methodology: A setup leading to relevant results is quite difficult to find. We discuss these issues in detail and suggest a general approach to such situations. A conservative analysis of the results supports the hypothesis that pattern-relevant maintenance tasks were completed faster or with fewer errors if redundant design pattern information was provided. The article provides the first controlled experiment results on design pattern usage and it presents a solution approach to an important class of experiment design problems for experiments regarding documentation.

Symptoms of depression, pain and limitations in physical activity may affect quality of life in COPD patients independent from their respiratory burden. We aimed to analyze the associations of these factors in outpatients with COPD in Austria in a stable phase of disease. We conducted a national, cross-sectional study among patients with COPD. For depression, the Patient Health Questionnaire-9 (PHQ-9) and for respiratory symptoms the St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) were used along with 10-point scales for physical activity and pain. After exclusion of 211 patients due to non-obstructive spirometry or missing data, 630 patients (62.5% men; mean age 66.8 ± 8.6 (SD) years; mean FEV %pred. 54.3 ± 16.5 (SD)) were analyzed. Of these, 47% reported one or more exacerbations in the previous year, 10.4% with hospitalization. A negative depression score was found in 54% and a score suggesting severe depression (PHQ-9 score ≥ 15) in 4.7%. In a multivariate linear regression model, self-reported pain, dyspnea, and number of exacerbations were predictors for higher PHQ-9-scores. A negative pain score was found in 43.8%, and a score suggesting severe pain in 2.9% (8-10 points of 10-point scale). Patients reporting severe pain were more often female, had more exacerbations, and reported more respiratory and depressive symptoms, a lower quality of life, and less physical activity. About 46% of patients rated their physical activity as severely impaired. These patients were significantly older, had more exacerbations, concomitant heart disease, a higher pain and depression score, and a lower quality of life (SGRQ-C - total score and all subscores). In Austria, nearly half of stable COPD outpatients reported symptoms of depression, which were associated with lower levels of self-reported physical activity, more pain, and respiratory symptoms. The associations were particularly strong for depression with SGRQ-C.