Active Galactic Nuclei at the Crossroads of Astrophysics

Over the last five decades, AGN studies have produced a number of spectacular examples of synergies and multifaceted approaches in astrophysics. The field of AGN research now spans the entire spectral range and covers more than twelve orders of magnitude in the spatial and temporal domains. The next generation of astrophysical facilities will open up new possibilities for AGN studies, especially in the areas of high-resolution and high-fidelity imaging and spectroscopy of nuclear regions in the X-ray, optical, and radio bands. These studies will address in detail a number of critical issues in AGN research such as processes in the immediate vicinity of supermassive black holes, physical conditions of broad-line and narrow-line regions, formation and evolution of accretion disks and relativistic outflows, and the connection between nuclear activity and galaxy evolution.Comment: 16 pages, 5 figures; review contribution; "Exploring the Cosmic Frontier: Astrophysical Instruments for the 21st Century", ESO Astrophysical Symposia Serie

ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19

Background Consistent with fulminant endothelial cell activation, elevated plasma von Willebrand factor (VWF) antigen levels have been reported in patients with COVID-19. The multimeric size and function of VWF are normally regulated through A Disintegrin And Metalloprotease with ThrombSpondin Motif type 1 motif, member 13 (ADAMTS-13)--mediated proteolysis. Objectives This study investigated the hypothesis that ADAMTS-13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection contributing to the observed microvascular thrombosis. Patients and Methods Patients with COVID-19 (n = 23) were recruited from the Beaumont Hospital Intensive Care Unit (ICU) in Dublin. Plasma VWF antigen, multimer distribution, ADAMTS-13 activity, and known inhibitors thereof were assessed. Results We observed markedly increased VWF collagen-binding activity in patients with severe COVID-19 compared to controls (median 509.1 versus 94.3 IU/dl). Conversely, plasma ADAMTS-13 activity was significantly reduced (median 68.2 IU/dl). In keeping with an increase in VWF:ADAMTS-13 ratio, abnormalities in VWF multimer distribution were common in patients with COVID-19, with reductions in high molecular weight VWF multimers. Terminal sialylation regulates VWF susceptibility to proteolysis by ADAMTS-13 and other proteases. We observed that both N- and O-linked sialylation were altered in severe COVID-19. Furthermore, plasma levels of the ADAMTS-13 inhibitors interleukin-6, thrombospondin-1, and platelet factor 4 were significantly elevated. Conclusions These findings support the hypothesis that SARS-CoV-2 is associated with profound quantitative and qualitative increases in plasma VWF levels, and a multifactorial down-regulation in ADAMTS-13 function. Further studies will be required to determine whether therapeutic interventions to correct ADAMTS-13-VWF multimer dysfunction may be useful in COVID-microvascular thrombosis and angiopathy

Serum magnesium and calcium levels in relation to ischemic stroke : Mendelian randomization study

ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 7 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 7 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype

Complex speech-language therapy interventions for stroke-related aphasia: the RELEASE study incorporating a systematic review and individual participant data network meta-analysis

Background: People with language problems following stroke (aphasia) benefit from speech and language therapy. Optimising speech and language therapy for aphasia recovery is a research priority. Objectives: The objectives were to explore patterns and predictors of language and communication recovery, optimum speech and language therapy intervention provision, and whether or not effectiveness varies by participant subgroup or language domain. Design: This research comprised a systematic review, a meta-analysis and a network meta-analysis of individual participant data. Setting: Participant data were collected in research and clinical settings. Interventions: The intervention under investigation was speech and language therapy for aphasia after stroke. Main outcome measures: The main outcome measures were absolute changes in language scores from baseline on overall language ability, auditory comprehension, spoken language, reading comprehension, writing and functional communication. Data sources and participants: Electronic databases were systematically searched, including MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Linguistic and Language Behavior Abstracts and SpeechBITE (searched from inception to 2015). The results were screened for eligibility, and published and unpublished data sets (randomised controlled trials, non-randomised controlled trials, cohort studies, case series, registries) with at least 10 individual participant data reporting aphasia duration and severity were identified. Existing collaborators and primary researchers named in identified records were invited to contribute electronic data sets. Individual participant data in the public domain were extracted. Review methods: Data on demographics, speech and language therapy interventions, outcomes and quality criteria were independently extracted by two reviewers, or available as individual participant data data sets. Meta-analysis and network meta-analysis were used to generate hypotheses. Results: We retrieved 5928 individual participant data from 174 data sets across 28 countries, comprising 75 electronic (3940 individual participant data), 47 randomised controlled trial (1778 individual participant data) and 91 speech and language therapy intervention (2746 individual participant data) data sets. The median participant age was 63 years (interquartile range 53–72 years). We identified 53 unavailable, but potentially eligible, randomised controlled trials (46 of these appeared to include speech and language therapy). Relevant individual participant data were filtered into each analysis. Statistically significant predictors of recovery included age (functional communication, individual participant data: 532, n = 14 randomised controlled trials) and sex (overall language ability, individual participant data: 482, n = 11 randomised controlled trials; functional communication, individual participant data: 532, n = 14 randomised controlled trials). Older age and being a longer time since aphasia onset predicted poorer recovery. A negative relationship between baseline severity score and change from baseline (p < 0.0001) may reflect the reduced improvement possible from high baseline scores. The frequency, duration, intensity and dosage of speech and language therapy were variously associated with auditory comprehension, naming and functional communication recovery. There were insufficient data to examine spontaneous recovery. The greatest overall gains in language ability [14.95 points (95% confidence interval 8.7 to 21.2 points) on the Western Aphasia Battery-Aphasia Quotient] and functional communication [0.78 points (95% confidence interval 0.48 to 1.1 points) on the Aachen Aphasia Test-Spontaneous Communication] were associated with receiving speech and language therapy 4 to 5 days weekly; for auditory comprehension [5.86 points (95% confidence interval 1.6 to 10.0 points) on the Aachen Aphasia Test-Token Test], the greatest gains were associated with receiving speech and language therapy 3 to 4 days weekly. The greatest overall gains in language ability [15.9 points (95% confidence interval 8.0 to 23.6 points) on the Western Aphasia Battery-Aphasia Quotient] and functional communication [0.77 points (95% confidence interval 0.36 to 1.2 points) on the Aachen Aphasia Test-Spontaneous Communication] were associated with speech and language therapy participation from 2 to 4 (and more than 9) hours weekly, whereas the highest auditory comprehension gains [7.3 points (95% confidence interval 4.1 to 10.5 points) on the Aachen Aphasia Test-Token Test] were associated with speech and language therapy participation in excess of 9 hours weekly (with similar gains notes for 4 hours weekly). While clinically similar gains were made alongside different speech and language therapy intensities, the greatest overall gains in language ability [18.37 points (95% confidence interval 10.58 to 26.16 points) on the Western Aphasia Battery-Aphasia Quotient] and auditory comprehension [5.23 points (95% confidence interval 1.51 to 8.95 points) on the Aachen Aphasia Test-Token Test] were associated with 20–50 hours of speech and language therapy. Network meta-analyses on naming and the duration of speech and language therapy interventions across language outcomes were unstable. Relative variance was acceptable (< 30%). Subgroups may benefit from specific interventions. Limitations: Data sets were graded as being at a low risk of bias but were predominantly based on highly selected research participants, assessments and interventions, thereby limiting generalisability. Conclusions: Frequency, intensity and dosage were associated with language gains from baseline, but varied by domain and subgroup. Future work: These exploratory findings require confirmatory study designs to test the hypotheses generated and to develop more tailored speech and language therapy interventions. Study registration: This study is registered as PROSPERO CRD42018110947. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 28. See the NIHR Journals Library website for further project information. Funding was also provided by The Tavistock Trust for Aphasia

Equipping for risk: Lessons learnt from the UK shale-gas experience on assessing environmental risks for the future geoenergy use of the deep subsurface

Summary findings are presented from an investigation to improve understanding of the environmental risks associated with developing an unconventional-hydrocarbons industry in the UK. The EQUIPT4RISK project, funded by UK Research Councils, focused on investigations around Preston New Road (PNR), Fylde, Lancashire, and Kirby Misperton Site A (KMA), North Yorkshire, where operator licences to explore for shale gas by hydraulic fracturing (HF) were issued in 2016, although exploration only took place at PNR. EQUIPT4RISK considered atmospheric (greenhouse gases, air quality), water (groundwater quality) and solid-earth (seismicity) compartments to characterise and model local conditions and environmental responses to HF activities. Risk assessment was based on the source-pathway-receptor approach. Baseline monitoring of air around the two sites characterised the variability with meteorological conditions, and isotopic signatures were able to discriminate biogenic methane (cattle) from thermogenic (natural-gas) sources. Monitoring of a post-HF nitrogen-lift (well-cleaning) operation at PNR detected the release of atmospheric emissions of methane (4.2 ± 1.4 t CH4). Groundwater monitoring around KMA identified high baseline methane concentrations and detected ethane and propane at some locations. Dissolved methane was inferred from stable-isotopic evidence as overwhelmingly of biogenic origin. Groundwater-quality monitoring around PNR found no evidence of HF-induced impacts. Two approaches for modelling induced seismicity and associated seismic risk were developed using observations of seismicity and operational parameters from PNR in 2018 and 2019. Novel methodologies developed for monitoring include use of machine learning to identify fugitive atmospheric methane, Bayesian statistics to assess changes to groundwater quality, a seismicity forecasting model seeded by the HF-fluid injection rate and high-resolution monitoring of soil-gas methane.The project developed a risk-assessment framework, aligned with ISO 31000 risk-management principles, to assess the theoretical combined and cumulative environmental risks from operations over time. This demonstrated the spatial and temporal evolution of risk profiles: seismic and atmospheric impacts from the shale-gas operations are modelled to be localised and short-lived, while risk to groundwater quality is longer-term