Safety of biologics approved for the treatment of rheumatoid arthritis and other autoimmune diseases: a disproportionality analysis from the FDA Adverse Event Reporting System (FAERS)

Introduction: The molecular and pharmacological complexity of biologic disease-modifying antirheumatic drugs used for the management of rheumatoid arthritis (RA) favors the occurrence of adverse drug reactions (ADRs), which should be constantly monitored in post-marketing safety studies. Objective: The aim of this study was to identify signals of disproportionate reporting (SDR) of clinical relevance related to the use of biologic drugs approved for RA and other autoimmune diseases. Methods: All suspected ADRs registered in the FDA Adverse Event Reporting System between January 2003 and June 2016 were collected. The reporting odds ratio was used as a measure of disproportionality to identify possible SDRs related to biologics. Those involving important medical events and designated medical events (DME) were prioritized. Results: In total, 2602 SDRs were prioritized. The most commonly reported were ‘Infections and infestations’ (32.2%) and ‘Neoplasms benign, malignant, and unspecified’ (20.4%), and were mainly related to use of infliximab (25.3%, p < 0.001, and 28.8%, p = 0.002, respectively). Sixty-three signals involving DMEs were identified, most of which were related to rituximab (n = 27), and were mainly due to ‘blood disorders’. Amongst the DMEs detected for more than one biologic, ‘intestinal perforation’ and ‘pulmonary fibrosis’ were related to most of them. Conclusions: The results of this study highlight possible safety issues associated with biologics, whose relationship should be more thoroughly investigated. Our results contribute to future research on the identification of clinically relevant risks associated with these drugs, and may help contribute to their rational and safe use

Surgical approach in correction of a crack in the gnathotheca of a black swan (Cygnus atratus, Latham, 1790) - First case report

ABSTRACT The black swan (Cygnus atratus, LATHAM, 1790) is a bird kept as an ornamental in zoos. Because of their long beaks they tend to have a reserved prognosis in musculoskeletal disorders such as beak trauma, secondary to skull bone fractures, presenting irreversible lesions. The aim of this report is present a clinical surgical innovation in the repair of a black swan’s gnathotheca fissure with the application of non-conventional materials used. It was observed that one of the swans kept in a zoo display area had difficulty feeding, with associated weight loss. It was observed tissue loss and a lacerative lesion in the caudal sublingual region of its beak. The lesion was corrected by a separate simple suture in the cranial region of the beak and with a x-clamping using steel surgical wire and the application of dental resin in the distal region to perform a sustentation bridge in the beak end-gap. After 12 days, the animal was able to feed again and remained perfectly adapted to the restoration, reestablishing the anatomical and physiological function of its beak

Hydrogen sulfide inhibits preoptic prostaglandin E2 production during endotoxemia

AbstractHydrogen sulfide (H2S) is a gaseous neuromodulator endogenously produced in the brain by the enzyme cystathionine β-synthase (CBS). We tested the hypothesis that H2S acts within the anteroventral preoptic region of the hypothalamus (AVPO) modulating the production of prostaglandin (PG) E2 (the proximal mediator of fever) and cyclic AMP (cAMP). To this end, we recorded deep body temperature (Tb) of rats before and after pharmacological modulation of the CBS–H2S system combined or not with lipopolysaccharide (LPS) exposure, and measured the levels of H2S, cAMP, and PGE2 in the AVPO during systemic inflammation. Intracerebroventricular (icv) microinjection of aminooxyacetate (AOA, a CBS inhibitor; 100pmol) did not affect basal PGE2 production and Tb, but enhanced LPS-induced PGE2 production and fever, indicating that endogenous H2S plays an antipyretic role. In agreement, icv microinjection of a H2S donor (Na2S; 260nmol) reduced the LPS-induced PGE2 production and fever. Interestingly, we observed that the AVPO levels of H2S were decreased following the immunoinflammatory challenge. Furthermore, fever was associated with decreased levels of AVPO cAMP and increased levels of AVPO PGE2. The LPS-induced decreased levels of cAMP were reduced to a lesser extent by the H2S donor. The LPS-induced PGE2 production was potentiated by AOA (the CBS inhibitor) and inhibited by the H2S donor. Our data are consistent with the notion that the gaseous messenger H2S synthesis is downregulated during endotoxemia favoring PGE2 synthesis and lowering cAMP levels in the preoptic hypothalamus

A new ghost cell/level set method for moving boundary problems:application to tumor growth

In this paper, we present a ghost cell/level set method for the evolution of interfaces whose normal velocity depend upon the solutions of linear and nonlinear quasi-steady reaction-diffusion equations with curvature-dependent boundary conditions. Our technique includes a ghost cell method that accurately discretizes normal derivative jump boundary conditions without smearing jumps in the tangential derivative; a new iterative method for solving linear and nonlinear quasi-steady reaction-diffusion equations; an adaptive discretization to compute the curvature and normal vectors; and a new discrete approximation to the Heaviside function. We present numerical examples that demonstrate better than 1.5-order convergence for problems where traditional ghost cell methods either fail to converge or attain at best sub-linear accuracy. We apply our techniques to a model of tumor growth in complex, heterogeneous tissues that consists of a nonlinear nutrient equation and a pressure equation with geometry-dependent jump boundary conditions. We simulate the growth of glioblastoma (an aggressive brain tumor) into a large, 1 cm square of brain tissue that includes heterogeneous nutrient delivery and varied biomechanical characteristics (white matter, gray matter, cerebrospinal fluid, and bone), and we observe growth morphologies that are highly dependent upon the variations of the tissue characteristics—an effect observed in real tumor growth

Quality control in blood irradiation

Irradiation is a technique used in hemotherapy to functionally inactivateviable lymphocytes, in cellular blood components, to reduce the risk of Transfusion-associated Graft-versus-Host Disease (AT-GVHD), is rare but letal. One way to avoid it is to irradiate blood componentes in situations such as: intrauterine transfusion, newborns, patients receiving immunosuppressive therapy in bone marrow transplantation. Thus, it is extremely important that blood component is irradiated and, above all, ensure that the minimum dose is 25 Gy.The blood policy in Brazil is implemented through laws and normative decrees, giving rise to a legal system that underpins the actions of hemotherapy services. In order to correct verify absorbed doses and the quality assurance process as well as the safety for the irradiator operators we describe in this paper a several of physical measurements that is mandatory to support a physicist to evaluate the quality assurance during and after the irradiation process. The results obtained from this physical measurements  provided a guarantee of proper radiation dose used in hemotherapy as well as methods and procedures applied to protect the patient, employees and general public due to procedure of blood irradiation accordling the Technical Regulation of Hemotherapy Procedures of the National Health Surveillance Agency (ANVISA) and safety regulations by National Nuclear Energy Commission (CNEN)

Measurement of prompt D0^{0} and D‾\overline{D}0^{0} meson azimuthal anisotropy and search for strong electric fields in PbPb collisions at root SNN\sqrt{S_{NN}} = 5.02 TeV

The strong Coulomb field created in ultrarelativistic heavy ion collisions is expected to produce a rapiditydependent difference (Av2) in the second Fourier coefficient of the azimuthal distribution (elliptic flow, v2) between D0 (uc) and D0 (uc) mesons. Motivated by the search for evidence of this field, the CMS detector at the LHC is used to perform the first measurement of Av2. The rapidity-averaged value is found to be (Av2) = 0.001 ? 0.001 (stat)? 0.003 (syst) in PbPb collisions at ?sNN = 5.02 TeV. In addition, the influence of the collision geometry is explored by measuring the D0 and D0mesons v2 and triangular flow coefficient (v3) as functions of rapidity, transverse momentum (pT), and event centrality (a measure of the overlap of the two Pb nuclei). A clear centrality dependence of prompt D0 meson v2 values is observed, while the v3 is largely independent of centrality. These trends are consistent with expectations of flow driven by the initial-state geometry. ? 2021 The Author. Published by Elsevier B.V. This is an open access article under the CC BY licens

Performance of the CMS Level-1 trigger in proton-proton collisions at √s = 13 TeV

At the start of Run 2 in 2015, the LHC delivered proton-proton collisions at a center-of-mass energy of 13\TeV. During Run 2 (years 2015–2018) the LHC eventually reached a luminosity of 2.1× 10$^{34}$ cm$^{-2}$s$^{-1}$, almost three times that reached during Run 1 (2009–2013) and a factor of two larger than the LHC design value, leading to events with up to a mean of about 50 simultaneous inelastic proton-proton collisions per bunch crossing (pileup). The CMS Level-1 trigger was upgraded prior to 2016 to improve the selection of physics events in the challenging conditions posed by the second run of the LHC. This paper describes the performance of the CMS Level-1 trigger upgrade during the data taking period of 2016–2018. The upgraded trigger implements pattern recognition and boosted decision tree regression techniques for muon reconstruction, includes pileup subtraction for jets and energy sums, and incorporates pileup-dependent isolation requirements for electrons and tau leptons. In addition, the new trigger calculates high-level quantities such as the invariant mass of pairs of reconstructed particles. The upgrade reduces the trigger rate from background processes and improves the trigger efficiency for a wide variety of physics signals