Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer's disease: the MADE Phase II, three-arm RCT

Background: Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives: The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design: A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting: Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants: Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention: Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures: Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results: Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p < 0.0001), mainly because of gastrointestinal symptoms (p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations: Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions: Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work: The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies

Making Landscape Decisions to Meet Net Zero Carbon: Pathways that consider ethics, socio-ecological diversity, and landscape functions.

Landscapes are an integral part of the net-zero challenge; not only are they carbonstores but they constitute the environments upon which humans develop their livelihoods,interact and shape their cultures.This report focuses on three key landscape types (agricultural, peatlands and forests), andthe associated practices and impacts with particular relevance to the net zero carbonagenda.We have brought together perspectives from natural and social science, humanities, and thearts to understand and evaluate how modern landscapes can absorb the impact of potentialzero-carbon policies

Randomised, double-blind, multicentre, mixed-methods, dose-escalation feasibility trial of mirtazapine for better treatment of severe breathlessness in advanced lung disease (BETTER-B feasibility)

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. New treatments are required for severe breathlessness in advanced disease. We conducted a randomised feasibility trial of mirtazapine over 28 days in adults with a modified medical research council breathlessness scale score ≥3. Sixty-four patients were randomised (409 screened), achieving our primary feasibility endpoint of recruitment. Most patients had COPD or interstitial lung disease; 52 (81%) completed the trial. There were no differences between placebo and mirtazapine in tolerability or safety, and blinding was maintained. Worst breathlessness ratings at day 28 (primary clinical activity endpoint) were, 7.1 (SD 2.3, placebo) and 6.3 (SD 1.8, mirtazapine). A phase III trial of mirtazapine is indicated. Trial registration: ISRCTN 32236160; European Clinical Trials Database (EudraCT no: 2015-004064-11)

Modelling Herschel observations of infrared-dark clouds in the Hi-GAL survey

We demonstrate the use of the 3D Monte Carlo radiative transfer code PHAETHON to model infrared-dark clouds (IRDCs) that are externally illuminated by the interstellar radiation field (ISRF). These clouds are believed to be the earliest observed phase of high-mass star formation, and may be the high-mass equivalent of lower-mass prestellar cores. We model three different cases as examples of the use of the code, in which we vary the mass, density, radius, morphology and internal velocity field of the IRDC. We show the predicted output of the models at different wavelengths chosen to match the observing wavebands of Herschel and Spitzer. For the wavebands of the long- wavelength SPIRE photometer on Herschel, we also pass the model output through the SPIRE simulator to generate output images that are as close as possible to the ones that would be seen using SPIRE. We then analyse the images as if they were real observations, and compare the results of this analysis with the results of the radiative transfer models. We find that detailed radiative transfer modelling is necessary to accurately determine the physical parameters of IRDCs (e.g. dust temperature, density profile). This method is applied to study G29.55+00.18, an IRDC observed by the Herschel Infrared Galactic Plane survey (Hi-GAL), and in the future it will be used to model a larger sample of IRDCs from the same survey.Comment: MNRAS accepted, High resolution paper available at http://www.astro.cardiff.ac.uk/pub/Dimitrios.Stamatellos/Publications.htm

Isolated starless cores in IRDCs in the Hi-GAL survey

In a previous paper we identified cores within infrared dark clouds (IRDCs). We regarded those without embedded sources as the least evolved, and labelled them starless. Here we identify the most isolated starless cores and model them using a three-dimensional, multi-wavelength, Monte Carlo, radiative transfer code. We derive the cores' physical parameters and discuss the relation between the mass, temperature, density, size and the surrounding interstellar radiation field (ISRF) for the cores. The masses of the cores were found not to correlate with their radial size or central density. The temperature at the surface of a core was seen to depend almost entirely on the level of the ISRF surrounding the core. No correlation was found between the temperature at the centre of a core and its local ISRF. This was seen to depend, instead, on the density and mass of the core.Comment: 12 pages + appendix, 12 figures, 4 tables. Only a sample of images in Appendix A is given due to size restrictions. Accepted by MNRA

Pharmacovigilance in hospice/palliative care: the net immediate and short-term effects of dexamethasone for anorexia

Objectives Loss of appetite is prevalent in palliative care and distressing for patients and families. Therapies include corticosteroids or progestogens. This study explores the net effect of dexamethasone on anorexia. Methods Prospective data were collected when dexamethasone was started for anorexia as part of routine care. The National Cancer Institute’s Common Toxicity Criteria for Adverse Events (NCICTCAE) Likert scales assessed severity of anorexia and immediate and short-term harms at 2 time points: baseline and 7 days. Results This study (41 sites, 8 countries) collected data (July 2013 to July 2014) from 114 patients (mean age 71 (SD 11), 96% with cancer). Median Australian-modified Karnofsky Performance Scale was 50% (range 20–70). Mean baseline NCICTCAE anorexia score was 2.7 (SD 0.6; median 3). 6 patients died by day 7. Of 108 evaluable patients, 74 (68.5%; 95% CI 59.0% to 76.7%) reported ≥1 reduction anorexia scores by day 7, of whom 30 were 0. Mean dexamethasone dose on day 7 was 4.1 mg/day (SD 3.4; median 4; range 0–46 mg). 24 patients reported ≥1 harms (32.4% CI 22.6% to 44.1%; insomnia n=10, depression n=7, euphoria n=7 and hyperglycaemia n=7). Of 24 patients with no benefit, 10 reported ≥1 harms. Conclusions This study shows positive and negative effects of 7 days of dexamethasone as an appetite stimulant in patients with advanced life-limiting illnesses. Identifying clinicodemographic characteristics of people most at risk of harms with no benefit is a crucial next step. Longer term follow-up will help to understand longer term and cumulative harms

The initial conditions for stellar protocluster formation

Context. Galactic plane surveys of pristine molecular clouds are key for establishing a Galactic-scale view of star formation. For this reason, an unbiased sample of infrared dark clouds in the 10◦ < |l| < 65◦, |b| < 1◦ region of the Galactic plane was built using Spitzer 8 µm extinction. However, intrinsic fluctuations in the mid-infrared background can be misinterpreted as foreground clouds. Aims. The main goal of this study is to disentangle real clouds in the Spitzer Dark Cloud (SDC) catalogue from artefacts due to fluctuations in the mid-infrared background. Methods. We constructed H2 column density maps at ∼1811 resolution using the 160 µm and 250 µm data from the Herschel Galactic plane survey Hi-GAL. We also developed an automated detection scheme that confirms the existence of a SDC through its association with a peak on these Herschel column density maps. Detection simulations, along with visual inspection of a small sub-sample of SDCs, have been performed to get more insight into the limitations of our automated identification scheme. Results. Our analysis shows that 76(±19)% of the catalogued SDCs are real. This fraction drops to 55(±12)% for clouds with angular diameters larger than ∼1 arcmin. The contamination of the PF09 catalogue by large spurious sources reflects the large uncertainties associated to the construction of the 8 µm background emission, a key stage in identiying SDCs. A comparison of the Herschel confirmed SDC sample with the BGPS and ATLASGAL samples shows that SDCs probe a unique range of cloud properties, reaching down to more compact and lower column density clouds than any of these two (sub-)millimetre Galactic plane surveys. Conclusions. Even though about half of the large SDCs are spurious sources, the vast majority of the catalogued SDCs do have a Herschel counterpart. The Herschel-confirmed sample of SDCs offers a unique opportunity to study the earliest stages of both low- and high-mass star formation across the Galaxy

Cores in Infra-Red Dark Clouds (IRDCs) seen in the Hi-GAL survey between l = 300{\deg} and l = 330{\deg}

We have used data taken as part of the Herschel infrared Galactic Plane survey (Hi-GAL) to study 3171 infrared-dark cloud (IRDC) candidates that were identified in the mid-infrared (8 {\mu}m) by Spitzer (we refer to these as 'Spitzer-dark' regions). They all lie in the range l=300 - 330 \circ and |b| 6 1 \circ. Of these, only 1205 were seen in emission in the far-infrared (250-500 {\mu}m) by Herschel (we call these 'Herschel-bright' clouds). It is predicted that a dense cloud will not only be seen in absorption in the mid-infrared, but will also be seen in emission in the far-infrared at the longest Herschel wavebands (250-500 {\mu}m). If a region is dark at all wavelengths throughout the mid-infrared and far-infrared, then it is most likely to be simply a region of lower background infrared emission (a 'hole in the sky'). Hence, it appears that previous surveys, based on Spitzer and other mid-infrared data alone, may have over-estimated the total IRDC population by a factor of 2. This has implications for estimates of the star formation rate in IRDCs in the Galaxy.We studied the 1205 Herschel-bright IRDCs at 250 {\mu}m, and found that 972 of them had at least one clearly defined 250-{\mu}m peak, indicating that they contained one or more dense cores. Of these, 653 (67 per cent) contained an 8-{\mu}m point source somewhere within the cloud, 149 (15 per cent) contained a 24-{\mu}m point source but no 8-{\mu}m source, and 170 (18 per cent) contained no 24-{\mu}m or 8-{\mu}m point sources. We use these statistics to make inferences about the lifetimes of the various evolutionary stages of IRDCs.Comment: 7 pages (+26 in appendices). Accepted for publication in MNRA