Effectiveness of delayed-release dimethyl fumarate on patient-reported outcomes and clinical measures in patients with relapsing-remitting multiple sclerosis in a real-world clinical setting : PROTEC

Background: Patient-reported outcomes (PRO) and clinical outcomes give a broad assessment of relapsing-remitting multiple sclerosis (RRMS) disease. Objective: The aim is to evaluate the effectiveness of delayed-release dimethyl fumarate (DMF) on disease activity and PROs in patients with RRMS in the clinic. Methods: PROTEC, a phase 4, open-label, 12-month observational study, assessed annualized relapse rate (ARR), proportion of patients relapsed, and changes in PROs. Newly diagnosed and early MS (≤3.5 EDSS and ≤1 relapse in the prior year) patient subgroups were evaluated. Results: Unadjusted ARR at 12 months post-DMF versus 12 months before DMF initiation was 75% lower (0.161 vs. 0.643, p < 0.0001) overall (n = 1105) and 84%, 77%, and 71% lower in newly diagnosed, ≤3.5 EDSS, and ≤1 relapse subgroups, respectively. Overall, 88% of patients were relapse-free 12 months after DMF initiation (84%, newly diagnosed; 88%, ≤3.5 EDSS; 88%, ≤1 relapse). PRO measures for fatigue, treatment satisfaction, daily living, and work improved significantly over 12 months of DMF versus baseline. Conclusion: At 12 months after versus 12 months before DMF initiation, ARR was significantly lower, the majority of patients were relapse-free, and multiple PRO measures showed improvement (overall and for subgroups), suggesting that DMF is effective based on clinical outcomes and from a patient perspective. Clinical trial: A Study Evaluating the Effectiveness of Tecfidera (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC), NCT01930708, https://clinicaltrials.gov/ct2/show/NCT01930708

Pulmonary thromboembolism in AIDS patient with chronic venous insufficiency, pulmonary tuberculosis and breast cancer: a case report and pathophysiology review Tromboembolismo pulmonar em uma paciente com AIDS com insuficiência venosa profunda, tuberculose pulmonar e câncer de mama: relato de um caso e revisão da fisiopatologia

Recent literature reports thrombotic episodes occurring in patients with HIV infection associated with other abnormalities including neoplasms and infections predisposing to a hypercoagulable state. We report a 47-year-old woman who developed pulmonary thromboembolism in association with HIV infection, pulmonary tuberculosis and breast cancer. She was treated with rifampin, isoniazid, pyrazinamide; heparin, phenprocoumon, zidovudine, lamivudine and efavirenz. Acid fast bacilli were visualized in a sputum smear and three months after, Mycobacterium tuberculosis was isolated from lymph node biopsy during a episode of immune reconstitution. The isolated mycobacteria showed sensitivity to all first-line drugs. HIV infection, breast cancer and pulmonary tuberculosis have several mechanisms that induce hypercoagulable state and can lead to thromboembolic complications. Pulmonary thromboembolism in this patient was a diagnostic challenge because of all the other severe diseases that she experienced at the same time.<br>Publicações recentes relatam episódios trombóticos em pacientes infectados pelo HIV associados a outras condições que incluem neoplasias e infecções que predispõem para um estado de hipercoagulabilidade. Relata-se o caso de uma paciente de 47 anos portadora do HIV que desenvolveu tromboembolismo pulmonar, tuberculose pulmonar e câncer de mama. Foi tratada com rifampicina, isoniazida, pirazinamida, heparina, femprocumona, zidovudina, lamivudina e efavirenz. Bacilos ácido-álcool-resistentes foram observados no exame de escarro e três meses depois foi isolado o Mycobacterium tuberculosis da biópsia de linfonodo durante um episódio de reconstituição imune. A micobactéria isolada demonstrou sensibilidade a todas as drogas anti-tuberculosas de primeira linha. A infecção pelo HIV, o câncer de mama e a tuberculose pulmonar possuem vários mecanismos que induzem um estado de hipercoagulabilidade e que podem produzir complicações tromboembólicas incluindo o TEP nos pacientes com AIDS. O TEP nesta paciente foi um desafio diagnóstico, considerando todas as outras doenças graves que apresentou simultaneamente

Viral pathogenesis, modulation of immune receptor signaling and treatment.

During the co-evolution of viruses and their hosts, the latter have equipped themselves with an elaborate immune system to defend themselves from the invading viruses. In order to establish a successful infection, replicate and persist in the host, viruses have evolved numerous strategies to counter and evade host antiviral immune responses as well as exploit them for productive viral replication. These strategies include those that target immune receptor transmembrane signaling. Uncovering the exact molecular mechanisms underlying these critical points in viral pathogenesis will not only help us understand strategies used by viruses to escape from the host immune surveillance but also reveal new therapeutic targets for antiviral as well as immunomodulatory therapy. In this chapter, based on our current understanding of transmembrane signal transduction mediated by multichain immune recognition receptors (MIRRs) and the results of sequence analysis, we discuss the MIRR-targetingviral strategies of immune evasion and suggest their possible mechanisms that, in turn, reveal new points of antiviral intervention. We also show how two unrelated enveloped viruses, human immunodeficiency virus and human cytomegalovirus, use a similar mechanism to modulate the host immune response mediated by two functionally different MIRRs-T-cell antigen receptor and natural killer cell receptor, NKp30. This suggests that it is very likely that similar general mechanisms can be or are used by other viral and possibly nonviral pathogens

Imaging individual barium atoms in solid xenon for barium tagging in nEXO

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. Double-β-decay involves the simultaneous conversion of two neutrons into two protons, and the emission of two electrons and two neutrinos; the neutrinoless process, although not yet observed, is thought to involve the emission of the two electrons but no neutrinos. The search for neutrinoless-double-β-decay probes fundamental properties of neutrinos, including whether or not the neutrino and antineutrino are distinct particles. Double-β-decay detectors are large and expensive, so it is essential to achieve the highest possible sensitivity with each study, and removing spurious contributions (‘background’) from detected signals is crucial. In the nEXO neutrinoless-double-β-decay experiment, the identification, or ‘tagging’, of the 136 Ba daughter atom resulting from the double-β decay of 136 Xe provides a technique for discriminating background. The tagging scheme studied here uses a cryogenic probe to trap the barium atom in a solid xenon matrix, where the barium atom is tagged through fluorescence imaging. Here we demonstrate the imaging and counting of individual barium atoms in solid xenon by scanning a focused laser across a solid xenon matrix deposited on a sapphire window. When the laser irradiates an individual atom, the fluorescence persists for about 30 seconds before dropping abruptly to the background level—a clear confirmation of one-atom imaging. Following evaporation of a barium deposit, the residual barium fluorescence is 0.16 per cent or less. Our technique achieves the imaging of single atoms in a solid noble element, establishing the basic principle of barium tagging for nEXO11Nsciescopu

Reflectivity and PDE of VUV4 Hamamatsu SiPMs in liquid xenon

© 2020 IOP Publishing Ltd and Sissa Medialab. Understanding reflective properties of materials and photodetection efficiency (PDE) of photodetectors is important for optimizing energy resolution and sensitivity of the next generation neutrinoless double beta decay, direct detection dark matter, and neutrino oscillation experiments that will use noble liquid gases, such as nEXO, DARWIN, DarkSide-20k, and DUNE . Little information is currently available about reflectivity and PDE in liquid noble gases, because such measurements are difficult to conduct in a cryogenic environment and at short enough wavelengths. Here we report a measurement of specular reflectivity and relative PDE of Hamamatsu VUV4 silicon photomultipliers (SiPMs) with 50 μm micro-cells conducted with xenon scintillation light (∼175 nm) in liquid xenon. The specular reflectivity at 15ˆ incidence of three samples of VUV4 SiPMs is found to be 30.4±1.4%, 28.6±1.3%, and 28.0±1.3%, respectively. The PDE at normal incidence differs by ±8% (standard deviation) among the three devices. The angular dependence of the reflectivity and PDE was also measured for one of the SiPMs. Both the reflectivity and PDE decrease as the angle of incidence increases. This is the first measurement of an angular dependence of PDE and reflectivity of a SiPM in liquid xenon11Nsciescopu

Characterization of the Hamamatsu VUV4 MPPCs for nEXO

© 2019 Elsevier B.V.In this paper we report on the characterization of the Hamamatsu VUV4 (S/N: S13370-6152) Vacuum Ultra-Violet (VUV) sensitive Multi-Pixel Photon Counters (MPPC)s as part of the development of a solution for the detection of liquid xenon scintillation light for the nEXO experiment. Various MPPC features, such as: dark noise, gain, correlated avalanches, direct crosstalk and Photon Detection Efficiency (PDE) were measured in a dedicated setup at TRIUMF. MPPCs were characterized in the range 163K≤T≤233K. At an over voltage of 3.1±0.2 V and at T=163K we report a number of Correlated Avalanches (CAs) per pulse in the 1μs interval following the trigger pulse of 0.161±0.005. At the same settings the Dark-Noise (DN) rate is 0.137±0.002Hz/mm2. Both the number of CAs and the DN rate are within nEXO specifications. The PDE of the Hamamatsu VUV4 was measured for two different devices at T=233K for a mean wavelength of 189±7nm. At 3.6±0.2 V and 3.5±0.2 V of over voltage we report a PDE of 13.4±2.6% and 11±2%, corresponding to a saturation PDE of 14.8±2.8% and 12.2±2.3%, respectively. Both values are well below the 24% saturation PDE advertised by Hamamatsu. More generally, the second device tested at 3.5±0.2 V of over voltage is below the nEXO PDE requirement. The first one instead yields a PDE that is marginally close to meeting the nEXO specifications. This suggests that with modest improvements the Hamamatsu VUV4 MPPCs could be considered as an alternative to the FBK-LF Silicon Photo-Multipliers for the final design of the nEXO detector11sciescopu