Ultra High Energy Cosmic Rays from Sequestered X Bursts

Assuming that there is no GZK (Greisen-Zatsepin-Kuzmin) cut-off and that super-GZK cosmic rays correlate with AGN (Active Galactic Nuclei) at cosmological distances, it is speculated that a relic superheavy particle (X) has its lifetime enhanced by sequestration in an extra dimension. This sequestration is assumed to be partially liberated by proximity of merging supermassive black holes in an AGN, temporarily but drastically reducing the lifetime, thus stimulating an X burst. Based on sequestration of the decay products of X, a speculative explanation of the observed $\gamma/N$ ratio is proposed.Comment: 12 pages LaTe

Recovery of the Historical SN1957D in X-rays with Chandra

SN1957D, located in one of the spiral arms of M83, is one of the small number of extragalactic supernovae that has remained detectable at radio and optical wavelengths during the decades after its explosion. Here we report the first detection of SN1957D in X-rays, as part of a 729 ks observation of M83 with \chandra. The X-ray luminosity (0.3 - 8 keV) is 1.7 (+2.4,-0.3) 10**37 ergs/s. The spectrum is hard and highly self-absorbed compared to most sources in M83 and to other young supernova remnants, suggesting that the system is dominated at X-ray wavelengths by an energetic pulsar and its pulsar wind nebula. The high column density may be due to absorption within the SN ejecta. HST WFC3 images resolve the supernova remnant from the surrounding emission and the local star field. Photometry of stars around SN1957D, using WFC3 images, indicates an age of less than 10**7 years and a main sequence turnoff mass more than 17 solar masses. New spectra obtained with Gemini-South show that the optical spectrum continues to be dominated by broad [O III] emission lines, the signature of fast-moving SN ejecta. The width of the broad lines has remained about 2700 km/s (FWHM). The [O III] flux dropped precipitously between 1989 and 1991, but continued monitoring shows the flux has been almost constant since. In contrast, radio observations over the period 1990-2011 show a decline rate inf the flux proportional to t**-4, far steeper than the rate observed earlier, suggesting that the primary shock has overrun the edge of a pre-SN wind.Comment: 28 pages, including 3 tables and 7 figures, accepted for publication in Ap

Observability of Earth-skimming Ultra-high Energy Neutrinos

Neutrinos with energies above 10^8 GeV are expected from cosmic ray interactions with the microwave background and are predicted in many speculative models. Such energetic neutrinos are difficult to detect, as they are shadowed by the Earth, but rarely interact in the atmosphere. Here we propose a novel detection strategy: Earth-skimming neutrinos convert to charged leptons that escape the Earth, and these leptons are detected in ground level fluorescence detectors. With the existing HiRes detector, neutrinos from some proposed sources are marginally detectable, and improvements of two orders of magnitude are possible at the proposed Telescope Array.Comment: 4 pages, 3 figure

Population pharmacokinetics of subcutaneous C1-inhibitor for prevention of attacks in patients with hereditary angioedema

Background: Long-term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma-derived C1-esterase inhibitor (C1-INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention. Objective: To characterize the population pharmacokinetics of C1-INH (SC) (HAEGARDA \uae ; CSL Behring) in healthy volunteers and HAE patients, and assess the variability and influence of covariates on pharmacokinetics. Methods: C1-INH functional activity data obtained after administration of various C1-INH (intravenous; IV) and C1-INH (SC) doses from 1 study in healthy volunteers (n = 16) and 2 studies in subjects with HAE (n = 108) were pooled to develop a population pharmacokinetic model (NONMEM v7.2). Pharmacokinetic parameters derived from steady-state simulations based on the final model were also evaluated. Results: C1-INH functional activity following C1-INH (SC) administration was described by a linear one-compartment model with first-order absorption and elimination, with inter-individual variability in all parameters tested. The mean population bioavailability of C1-INH (SC), and pharmacokinetic parameters for clearance (CL), volume of distribution, and absorption rate were estimated to be ~43%, 1.03 mL/hour/kg, 0.05 L/kg and 0.0146 hour 121 , respectively. The effect of bodyweight on CL of C1-INH functional activity was included in the final model, estimated to be 0.74. Steady-state simulations of C1-INH functional activity vs time profiles in 1000 virtual HAE patients revealed higher minimum functional activity (C trough ) levels after twice-weekly dosing with 40 IU/kg (~40%) and 60 IU/kg (~48%) compared with 1000 IU IV (~30%). Based on the population pharmacokinetic model, the median time to peak concentration was ~59 hours and the median apparent plasma half-life was ~69 hours. Conclusions and Clinical Relevance: Twice-weekly bodyweight-adjusted dosing of C1-INH (SC) exhibits linear pharmacokinetics and dose-dependent increases in C trough levels at each dosing interval. In this analysis, SC dosing led to maintenance of higher C trough levels than IV dosing

TeV Particle Astrophysics II: Summary comments

A unifying theme of this conference was the use of different approaches to understand astrophysical sources of energetic particles in the TeV range and above. In this summary I review how gamma-ray astronomy, neutrino astronomy and (to some extent) gravitational wave astronomy provide complementary avenues to understanding the origin and role of high-energy particles in energetic astrophysical sources.Comment: 6 pages, 4 figures; Conference summary talk for "TeV Particle Astrophysics II" at University of Wisconsin, Madison, 28-31 August 200

Searching the Footprint of WIMPZILLAs

We constrain mass, lifetime and contribution of a very slowly decaying Ultra Heavy Dark Matter (UHDM) by simulating the cosmological evolution of its remnants. Most of interactions which participate in energy dissipation are included in the numerical solution of the Boltzmann equation. Cross-sections are calculated either analytically or by using PYTHIA Monte Carlo program. This paper describes in detail our simulation. To show the importance of the distribution of matter in constraining WIMPZILLA characteristics, we consider two extreme cases: a homogeneous universe, and a local halo with uniform distribution. We show that in a homogeneous universe, the decay of UHDM with a mass \sim 10^15 GeV and a lifetime \sim a few times \tau_0 the age of the Universe, can not explain the flux of observed Ultra High Energy Cosmic Rays (UHECRs). This shows the importance of nearby sources, notably galactic halo. In a uniform clump with an over-density of \sim 200 extended to 100 kpc or more, the lifetime must be \sim 10 - 100 \tau_0 or the contribution in the DM must be proportionally smaller. We also compare our calculation with observed gamma-rays at E \sim 10^11 eV by EGRET and CASA-MIA limit at E \sim 10^15 eV. They are compatible with a UHDM with relatively short lifetime.Comment: 27 pages, 9 figures. New results with better energy resolution close to GZK cutoff. Text slightly modifie

Hereditary angioedema: New therapeutic options for a potentially deadly disorder

Although the biochemistry of hereditary angioedema (HAE) is fairly well understood today, the lag in diagnosis of a decade or more suggests that clinicians have low awareness of this disease. This lag in diagnosis and hence treatment certainly stems from the rarity and complexity of the presentation which can be easily mistaken for allergic and non-allergic reactions alike. The symptoms of the disease include acute swelling of any or multiple parts of the body. The attacks may be frequent or rare, and they may vary substantially in severity, causing stomach discomfort or periorbital swelling in mild cases and hypovolemic shock due to abdominal fluid shift or asphyxiation in the most severe cases. Given that these patients are at significant risk for poor quality of life and death, greater awareness of this disease is needed to ensure that newly available, effective medications are used in these patients. These new medications represent significant advances in HAE therapy because they are targeted at the plasma cascades implicated in the pathophysiology of this disease. The clinical presentation of HAE, overlapping symptoms with other angioedemas, and available therapies are reviewed

Efficacy and safety of Vilobelimab (IFX-1), a novel monoclonal anti-C5a antibody, in patients with early severe sepsis or septic shock — a randomized, placebo-controlled, double-blind, multicenter, phase IIa Trial (SCIENS Study)

IMPORTANCE:. Anaphylatoxin C5a, a proinflammatory complement split product, plays a central role in mediating organ dysfunction. OBJECTIVES:. This phase II clinical trial was conducted to study safety, tolerability, pharmacokinetics, and pharmacodynamics of vilobelimab, a recombinant monoclonal antibody against C5a, in patients with severe sepsis or septic shock. DESIGN:. Multicenter, randomized, and placebo-controlled study. SETTING AND PARTICIPANTS:. Eleven multidisciplinary ICUs across Germany. Adult patients with severe sepsis or septic shock and with early onset of infection-associated organ dysfunction. MAIN OUTCOMES AND MEASURES:. Patients were randomly assigned in a ratio of 2:1 to three subsequent dosing cohorts for IV vilobelimab or placebo receiving either 2 × 2 mg/kg (0 and 12 hr), 2 × 4 mg/kg (0 and 24 hr), and 3 × 4 mg/kg (0, 24, and 72 hr). Co-primary endpoints were pharmacodynamics (assessed by C5a concentrations), pharmacokinetics (assessed by vilobelimab concentrations), and safety of vilobelimab. Preliminary efficacy was evaluated by secondary objectives. RESULTS:. Seventy-two patients were randomized (16 patients for each vilobelimab dosing cohort and eight patients for each placebo dosing cohort). Vilobelimab application was associated with dosing dependent decrease in C5a compared with baseline (p < 0.001). Duration of C5a decrease increased with more frequent dosing. Membrane attack complex lysis capacity measured by 50% hemolytic complement was not affected. Vilobelimab was well tolerated with similar safety findings in all dose cohorts. No vilobelimab-specific adverse events emerged. For vilobelimab-treated patients, investigators attributed less treatment-emergent adverse events as related compared with placebo. Dosing cohorts 2 and 3 had the highest ICU-free and ventilator-free days. There was no difference in mortality, vasopressor-free days, or renal replacement therapy-free days between the groups. CONCLUSIONS AND RELEVANCE:. Administration of vilobelimab in patients with severe sepsis and septic shock selectively neutralizes C5a in a dose-dependent manner without blocking formation of the membrane attack complex and without resulting in detected safety issues. The data warrant further investigation of C5a inhibition in sepsis

Proceedings from the Inaugural American Initiative in Mast Cell Diseases (AIM) Investigator Conference

The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. The overarching goal of this meeting was to establish a Pan-American organization of physicians and scientists with multidisciplinary expertise in mast cell disease. To serve this unmet need, AIM envisions a network where basic, translational, and clinical researchers could establish collaborations with both academia and biopharma to support the development of new diagnostic methods, enhanced understanding of the biology of mast cells in human health and disease, and the testing of novel therapies. In these AIM proceedings, we highlight selected topics relevant to mast cell biology and provide updates regarding the recently described hereditary alpha-tryptasemia. In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy and anaphylaxis in mast cell disorders, and the clinical and biologic heterogeneity of the more indolent forms of mastocytosis. Because mast cell disorders are relatively rare, AIM hopes to achieve a coordination of scientific efforts not only in the Americas but also in Europe by collaborating with the well-established European Competence Network on Mastocytosis.The research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) (award no. R13TR002722 to J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank The Mast Cell Disease Society, Inc (TMS), a national 501c3 nonprofit, for their partnership and support of AIM, for patient-centered research, and for sponsoring international physicians at this inaugural meeting. J.G. expresses gratitude for the support of the Charles and Ann Johnson Foundation, the staff of the Stanford Mastocytosis Center, and the Stanford Cancer Institute Innovation Fund. M.C., J.J.L., and D.D.M. are supported in part by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH. D.F.D. is supported by the Asthma and Allergic Diseases Cooperative Research Centers Opportunity Fund (award no. U19AI07053 from the NIH). P.V. has been supported by the Austrian Science Fund (FWF) (grant nos. F4701-B20, F4704-B20, and P32470-B)