The MURALES survey: III. Completing the MUSE observations of 37 3C low-z radio galaxies

Galaxie

The MURALES survey: V. Jet-induced star formation in 3C 277.3 (Coma A)

Interstellar matter and star formatio

Categorizing Different Approaches to the Cosmological Constant Problem

We have found that proposals addressing the old cosmological constant problem come in various categories. The aim of this paper is to identify as many different, credible mechanisms as possible and to provide them with a code for future reference. We find that they all can be classified into five different schemes of which we indicate the advantages and drawbacks. Besides, we add a new approach based on a symmetry principle mapping real to imaginary spacetime.Comment: updated version, accepted for publicatio

Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged ≥18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G→A (Gly168Ser) in the GLP1R (0·08% [95% CI 0·04–0·12] or 0·9 mmol/mol lower reduction in HbA1c per serine, p=6·0 × 10−5) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6·7 × 10−8), largely driven by rs140226575G→A (Thr370Met; 0·25% [SE 0·06] or 2·7 mmol/mol [SE 0·7] greater HbA1c reduction per methionine, p=5·2 × 10−6). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6–11%) than in White European populations. Combining these two genes identified 4% of the population who had a 30% greater reduction in HbA1c than the 9% of the population with the worse response. Interpretation: This genome-wide pharmacogenomic study of GLP-1 receptor agonists provides novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants might benefit from earlier initiation of GLP-1 receptor agonists. Funding: Innovative Medicines Initiative and the Wellcome Trus

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Measurement of projectile trajectory in dielectric target with micropower-impluse radar

The micropower-impulse radar has been adapted for non-intrusive tracking of projectiles in dielectric targets. The main application of this technique is intended to be the validation of continuum mechanics simulation codes and material models used in the study of the interaction between high-velocity penetrators and concrete targets. Two experiments have been conducted in which a gun-launched 90-mm-diameter projectile was fired at velocities of 160 and 230 m/s into a cubical box filled with dry sand and tracked with the micropower-impulse radar. The system was adjusted so that a 2-m range in sand was divided into 511 timing intervals, which were swept every 0.1 ms. As the projectile took approximately 40 ms to come to rest this meant that there were 400measurements of its position. The CALE continuum mechanics simulation was used to model the projectile motion in the target, and close agreement was found with the measured trajectory

Association between the primary biliary cirrhosis specific anti-sp100 antibodies and recurrent urinary tract infection

Background and aims. Recurrent urinary tract infections (rUTI) have been suggested to be involved in the induction of anti-mitochondrial antibodies (AMA), the serological hallmark of primary biliary cirrhosis (PBC), in view of the presence of AMA in rUTI women without liver disease and conversely of a high prevalence of rUTI in women with PBC. This prompted us to investigate whether PBC-specific anti-nuclear antibodies (ANA) to sp100, gp210 and lamin B receptor (LBR) antigens may also be related to rUTI. Methods and subjects. PBC-specific ANA reactivities were investigated in 20 women with rUTI but without liver disease, some of whom were AMA-seropositive; 40 women with PBC, with or without rUTI; and 104 pathological and 23 healthy controls. Results. Among the women with rUTI but without liver disease, 8 (80%) of 10 AMA-positive women reacted with sp100 compared with none of the 10 AMA-negative women. Among the PBC patients, 14 (74%) of 19 with rUTI and 1 (4.8%) of the 21 without rUTI reacted with sp100. None of the rUTI women without liver disease reacted with gp210 or LBR. None of 127 pathological and healthy controls had PBC-specific ANA reactivity. Conclusions. Anti-sp100 reactivity strongly correlates with AMA seropositivity in rUTI women, with or without evidence of primary biliary cirrhosis. These findings provide additional support to the notion that E. coli infection is involved in the induction of PBC-specific autoimmunity. Additional factors must be involved in the progression to overt autoimmune disease. (C) 2003 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved