Atmospheric Cerenkov astronomy of cataclysmic variables & other potential gamma ray sources

Recent developments in the application of the atmospheric Cerenkov technique to 7-ray astronomy are reviewed here. These include new methods of signal to noise enhancement and the increasing diversity of stellar systems positively identified as Very High Energy 7-ray sources. Four Cataclysmic Variable systems were observed using the University of Durham Atmospheric Cerenkov telescopes during the course of 1990 and 1991. The statistical analysis performed in the search for a 7-ray signal, above a threshold energy of approximately 0-4 TeV, from three of these objects, H0253+193, EF Eridani and VW Hydri, is described here. The results of this brief survey are discussed in the context of current ideas as to the mechanisms by which Very High Energy 7-rays may be emitted from accreting binary star systems of this type. The analysis techniques applied to Cataclysmic Variable data were extended to an x-ray binary system, Sgr X-7. For comparison, the analysis of data recorded on two radio pulsars, PSR 1855+09 and PSR 1509-58, having more accurately known pulse signatures than the accreting systems is also described here, together with that of the globular cluster 47 Tucanae, which may emit a steady 7-ray flux; an upper limit is placed upon the level of Very High Energy 7-ray emission from this object. Extension of the Very High Energy 7-ray source catalogue will require a further improvement beyond the current signal to noise ratios of atmospheric Cerenkov telescopes. Some features characteristic of the atmospheric Cerenkov emission triggered by Very High Energy 7-rays as opposed to other cosmic ray particles, which could be exploited in an attempt to reduce interference from the latter, are reviewed. The first attempt to obtain directional information from the relative time of arrival of a Cerenkov flash at the telescopes at the University of Durham Southern Hemisphere site, and thus isolate an anisotropic 7-ray flux is reported here

Stellar intensity interferometry: Experimental steps toward long-baseline observations

Experiments are in progress to prepare for intensity interferometry with arrays of air Cherenkov telescopes. At the Bonneville Seabase site, near Salt Lake City, a testbed observatory has been set up with two 3-m air Cherenkov telescopes on a 23-m baseline. Cameras are being constructed, with control electronics for either off- or online analysis of the data. At the Lund Observatory (Sweden), in Technion (Israel) and at the University of Utah (USA), laboratory intensity interferometers simulating stellar observations have been set up and experiments are in progress, using various analog and digital correlators, reaching 1.4 ns time resolution, to analyze signals from pairs of laboratory telescopes.Comment: 12 pages, 3 figur

Very-high energy gamma-ray astronomy: A 23-year success story in high-energy astroparticle physics

Very-high energy (VHE) gamma quanta contribute only a minuscule fraction - below one per million - to the flux of cosmic rays. Nevertheless, being neutral particles they are currently the best "messengers" of processes from the relativistic/ultra-relativistic Universe because they can be extrapolated back to their origin. The window of VHE gamma rays was opened only in 1989 by the Whipple collaboration, reporting the observation of TeV gamma rays from the Crab nebula. After a slow start, this new field of research is now rapidly expanding with the discovery of more than 150 VHE gamma-ray emitting sources. Progress is intimately related with the steady improvement of detectors and rapidly increasing computing power. We give an overview of the early attempts before and around 1989 and the progress after the pioneering work of the Whipple collaboration. The main focus of this article is on the development of experimental techniques for Earth-bound gamma-ray detectors; consequently, more emphasis is given to those experiments that made an initial breakthrough rather than to the successors which often had and have a similar (sometimes even higher) scientific output as the pioneering experiments. The considered energy threshold is about 30 GeV. At lower energies, observations can presently only be performed with balloon or satellite-borne detectors. Irrespective of the stormy experimental progress, the success story could not have been called a success story without a broad scientific output. Therefore we conclude this article with a summary of the scientific rationales and main results achieved over the last two decades.Comment: 45 pages, 38 figures, review prepared for EPJ-H special issue "Cosmic rays, gamma rays and neutrinos: A survey of 100 years of research

Genetic variants of HvCbf14 are statistically associated with frost tolerance in a European germplasm collection of Hordeum vulgare

Two quantitative trait loci (Fr-H1 and Fr-H2) for frost tolerance (FT) have been discovered on the long arm of chromosome 5H in barley. Two tightly linked groups of CBF genes, known to play a key role in the FT regulatory network in A. thaliana, have been found to co-segregate with Fr-H2. Here, we investigate the allelic variations of four barley CBF genes (HvCbf3, HvCbf6, HvCbf9 and HvCbf14) in a panel of European cultivars, landraces and H. spontaneum accessions. In the cultivars a reduction of nucleotide and haplotype diversities in CBFs compared with the landraces and the wild ancestor H. spontaneum, was evident. In particular, in cultivars the loss of HvCbf9 genetic variants was higher compared to other sequences. In order to verify if the pattern of CBF genetic variants correlated with the level of FT, an association procedure was adopted. The pairwise analysis of linkage disequilibrium (LD) among the genetic variants in four CBF genes was computed to evaluate the resolution of the association procedure. The pairwise plotting revealed a low level of LD in cultivated varieties, despite the tight physical linkage of CBF genes analysed. A structured association procedure based on a general liner model was implemented, including the variants in CBFs, of Vrn-H1, and of two reference genes not involved in FT (α-Amy1 and Gapdh) and considering the phenotypic data for FT. Association analysis recovered two nucleotide variants of HvCbf14 and one nucleotide variant of Vrn-H1 as statistically associated to FT

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Cross-scale habitat structure driven by coral species composition on tropical reefs

The availability of habitat structure across spatial scales can determine ecological organization and resilience. However, anthropogenic disturbances are altering the abundance and composition of habitat-forming organisms. How such shifts in the composition of these organisms alter the physical structure of habitats across ecologically important scales remains unclear. At a time of unprecedented coral loss and homogenization of coral assemblages globally, we investigate the inherent structural complexity of taxonomically distinct reefs, across fve ecologically relevant scales of measurement (4–64cm). We show that structural complexity was infuenced by coral species composition, and was not a simple function of coral cover on the studied reefs. However, inter-habitat variation in structural complexity changed with scale. Importantly, the scales at which habitat structure was available also varied among habitats. Complexity at the smallest, most vulnerable scale (4cm) varied the most among habitats, which could have inferences for as much as half of all reef fshes which are small-bodied and refuge dependent for much of their lives. As disturbances continue and species shifts persist, the future of these ecosystems may rely on a greater concern for the composition of habitat-building species and prioritization of particular confgurations for protection of maximal cross-scale habitat structural complexity

Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R): a randomised, parallel-arm, open-label, phase 4 trial

Background From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19. Methods TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464). Findings Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62–1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88–2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group. Interpretation Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570