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The ultraviolet spectrograph instrument on the Juno mission (Juno-UVS) is a long-slit imaging spectrograph designed to observe and characterize Jupiter’s far-ultraviolet (FUV) auroral emissions. These observations will be coordinated and correlated with those from Juno’s other remote sensing instruments and used to place in situ measurements made by Juno’s particles and fields instruments into a global context, relating the local data with events occurring in more distant regions of Jupiter’s magnetosphere. Juno-UVS is based on a series of imaging FUV spectrographs currently in flight—the two Alice instruments on the Rosetta and New Horizons missions, and the Lyman Alpha Mapping Project on the Lunar Reconnaissance Orbiter mission. However, Juno-UVS has several important modifications, including (1) a scan mirror (for targeting specific auroral features), (2) extensive shielding (for mitigation of electronics and data quality degradation by energetic particles), and (3) a cross delay line microchannel plate detector (for both faster photon counting and improved spatial resolution). This paper describes the science objectives, design, and initial performance of the Juno-UVS.

The Lyman Alpha Mapping Project (LAMP) is a far-ultraviolet (FUV) imaging spectrograph on NASA’s Lunar Reconnaissance Orbiter (LRO) mission. Its main objectives are to (i) identify and localize exposed water frost in permanently shadowed regions (PSRs), (ii) characterize landforms and albedos in PSRs, (iii) demonstrate the feasibility of using natural starlight and sky-glow illumination for future lunar surface mission applications, and (iv) characterize the lunar atmosphere and its variability. As a byproduct, LAMP will map a large fraction of the Moon at FUV wavelengths, allowing new studies of the microphysical and reflectance properties of the regolith. The LAMP FUV spectrograph will accomplish these objectives by measuring the signal reflected from the night-side lunar surface and in PSRs using both the interplanetary HI Lyman- α sky-glow and FUV starlight as light sources. Both these light sources provide fairly uniform, but faint, illumination. With the expected LAMP sensitivity, by the end of the primary 1-year LRO mission, the SNR for a Lyman- α albedo map should be >100 in polar regions >1 km 2 , providing useful FUV constraints to help characterize subtle compositional and structural features. The LAMP instrument is based on the flight-proven Alice series of spectrographs flying on the Rosetta comet mission and the New Horizons Pluto mission. A general description of the LAMP instrument and its initial ground calibration results are presented here.

Aims/hypothesisWe aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA1c.MethodsThe PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m2, 30–70 years of age, and prediabetes (HbA1c 39–47 mmol/mol [5.7–6.4%]) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%).ResultsOne hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% [95% CI 0.7, 30.8], p = 0.042) and a small, non-significant, reduction in the exercise group (15.3% [95% CI −1.2, 29.1], p = 0.067), whereas MAGE was unchanged in the metformin group (0.1% [95% CI −16.1, 19.4], p = 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9; p = 0.041) lower in the dapagliflozin group and 15.4% (95% CI −1.1, 29.1; p = 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% [95% CI −14.8, 22.5], p = 0.815). One serious adverse event occurred in the control group (lung cancer).Conclusions/interpretationTreatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain.Trial registrationClinicalTrials.gov NCT02695810FundingThe study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS

ObjectiveFindings from individual anterior cruciate ligament reconstruction (ACLR) registry studies are impactful, but how various registries from different countries compare with different patient populations and surgical techniques has not been described. We sought to describe six ACLR registry cohorts to understand variation across countries.MethodsFive European registries and one US registry participated. For each registry, all primary ACLR registered between registry establishment through 31December 2014 were identified. Descriptive statistics included frequencies, proportions, medians and IQRs. Revision incidence rates following primary ACLR were computed.Results101 125 ACLR were included: 21 820 in Denmark, 300 in Luxembourg, 17 556 in Norway, 30 422 in Sweden, 2972 in the UK and 28 055 in the US. In all six cohorts, males (range: 56.8%–72.4%) and soccer injuries (range: 14.1%–42.3%) were most common. European countries mostly used autografts (range: 93.7%–99.7%); allograft was most common in the US (39.9%). Interference screw was the most frequent femoral fixation in Luxembourg and the US (84.8% and 42.9%), and suspensory fixation was more frequent in the other countries (range: 43.9%–75.5%). Interference was the most frequent tibial fixation type in all six cohorts (range: 64.8%–98.2%). Three-year cumulative revision probabilities ranged from 2.8% to 3.7%.ConclusionsSimilarities in patient demographics and injury activity were observed between all cohorts of ACLR. However, graft and fixation choices differed. Revision rates were low. This work, including >100 000 ACLR, is the most comprehensive international description of contemporary practice to date.

Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC.

Prostate cancer (PCa) is a leading cause of cancer-related deaths and is driven by aberrant androgen receptor (AR) signalling. For this reason, androgen deprivation therapies (ADTs) that suppress androgen-induced PCa progression either by preventing androgen biosynthesis or via AR signalling inhibition (ARSi) are common treatments. The N6-methyladenosine (m6A) RNA modification is involved in regulating mRNA expression, translation, and alternative splicing, and through these mechanisms has been implicated in cancer development and progression. RNA-m6A is dynamically regulated by the METTL3 RNA methyltransferase complex and the FTO and ALKBH5 demethylases. While there is evidence supporting a role for aberrant METTL3 in many cancer types, including localised PCa, the wider contribution of METTL3, and by inference m6A, in androgen signalling in PCa remains poorly understood. Therefore, the aim of this study was to investigate the expression of METTL3 in PCa patients and study the clinical and functional relevance of METTL3 in PCa. It was found that METTL3 is aberrantly expressed in PCa patient samples and that siRNA-mediated METTL3 knockdown or METTL3-pharmacological inhibition significantly alters the basal and androgen-regulated transcriptome in PCa, which supports targeting m6A as a novel approach to modulate androgen signalling in PCa.

Purpose To investigate whether the prediction of post-treatment HbA 1c levels can be improved by adding an additional biomarker of the glucose metabolism in addition to baseline HbA 1c . Methods We performed an exploratory analysis based on data from 112 individuals with prediabetes (HbA 1c 39–47 mmol) and overweight/obesity (BMI ≥ 25 kg/m 2 ), who completed 13 weeks of glucose-lowering interventions (exercise, dapagliflozin, or metformin) or control (habitual living) in the PRE-D trial. Seven prediction models were tested; one basic model with baseline HbA 1c as the sole glucometabolic marker and six models each containing one additional glucometabolic biomarker in addition to baseline HbA 1c . The additional glucometabolic biomarkers included: 1) plasma fructosamine, 2) fasting plasma glucose, 3) fasting plasma glucose × fasting serum insulin, 4) mean glucose during a 6-day free-living period measured by a continuous glucose monitor 5) mean glucose during an oral glucose tolerance test, and 6) mean plasma glucose × mean serum insulin during the oral glucose tolerance test. The primary outcome was overall goodness of fit ( R 2 ) from the internal validation step in bootstrap-based analysis using general linear models. Results The prediction models explained 46–50% of the variation ( R 2 ) in post-treatment HbA1c with standard deviations of the estimates of ~2 mmol/mol. R 2 was not statistically significantly different in the models containing an additional glucometabolic biomarker when compared to the basic model. Conclusion Adding an additional biomarker of the glucose metabolism did not improve the prediction of post-treatment HbA 1c in individuals with HbA 1c -defined prediabetes.

This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). The study population consisted of patients aged ≥40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for \"ever use\" of roflumilast, compared to \"never use\", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among \"current users\" in Germany (HR: 0.93, 95% CI: 0.88-0.98), Norway (HR: 0.77, 95% CI: 0.67-0.87), and Sweden (HR: 0.80, 95% CI: 0.73-0.88). There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.

Starting from six regional climate change scenarios, nitrogen leaching from arable-soil, water discharge, and nitrogen retention was modeled in the Rönneå catchment. Additionally, biological response was modeled in the eutrophic Lake Ringsjön. The results are compared with similar studies on other catchments. All scenarios gave similar impact on water quality but varied in quantities. However, one scenario resulted in a different transport pattern due to less-pronounced seasonal variations in the hydrology. On average, the study shows that, in a future climate, we might expect: i) increased concentrations of nitrogen in the arable root zone (+50%) and in the river (+13%); ii) increased annual load of nitrogen from land to sea (+22%) due to more pronounced winter high flow; moreover, remote areas in the catchment may start to contribute to the outlet load; iii) radical changes in lake biochemistry with increased concentrations of total phosphorus (+50%), total nitrogen (+20%), and planktonic algae such as cyanobacteria (+80%).

IntroductionThe primary aim of this study is to compare the efficacy of three short-term glucose-lowering interventions (exercise, metformin and dapagliflozin) on glycaemic variability in overweight or obese men and women with elevated diabetes risk (ie, prediabetes, defined as haemoglobin A1c (HbA1c)39–47 mmol/mol / 5.7%–6.4%). The secondary aims are to investigate the effects of the interventions on body composition and cardiometabolic risk factors.Methods and analysisThe Pre-D Trial is an investigator-initiated, randomised, controlled, parallel, open-label, superiority trial. The study aims to assign 120 participants in a 1:1:1:1 ratio to receive one of four interventions for 13 weeks: (1) dapagliflozin (10 mg once daily); (2) metformin (850 mg twice daily); (3) exercise (interval training, 5 days a week, 30 min per session); or (4) control (lifestyle advice). After the 13 weeks of intervention, a follow-up period of 13 weeks will follow to study the long-term effects of the interventions. The primary endpoint is reduction from baseline to end-of treatment (13 weeks) in mean amplitude of glycaemic excursions measured by continuous glucose monitoring. The secondary endpoints include concomitant changes in various measures of glucose metabolism, body weight, cardiorespiratory fitness, blood pressure, plasma lipids, objectively measured physical activity and dietary intake.Ethics and disseminationThe study protocol has been approved by the Ethics Committee of the Capital Region and the Danish Medicines Agency. Approval of data and biobank storage has been obtained from the Danish Data Protection Board. The study will be carried out according to the Declaration of Helsinki and to the regulations for good clinical practice. The results from this trial will allow a number of research questions concerning the effect of exercise versus dapagliflozin or metformin in HbA1c-defined prediabetes to be addressed.Trial registrationNCT02695810