Long-term adherence to IFN beta-1a treatment when using rebismart1device in patients with relapsing-remitting multiple sclerosis

The effectiveness of disease-modifying drugs in the treatment of multiple sclerosis is associated with adherence. RebiSmart® electronic device provides useful information about adherence to the treatment with subcutaneous (sc) interferon (IFN) ß-1a (Rebif®). The aim of the study was to determine long-term adherence to this treatment in patients with relapsing- remitting multiple sclerosis (RRMS). This retrospective multicentre observational study analysed 258 patients with RRMS who were receiving sc IFN ß-1a (Rebif®) treatment by using RebiSmart® until replacement (36 months maximum lifetime) or treatment discontinuation. Adherence was calculated with data (injection dosage, time, and date) automatically recorded by RebiSmart®. Patients in the study had a mean age of 41 years with a female proportion of 68%. Mean EDSS score at start of treatment was 1.8 (95% CI, 1.6-1.9). Overall adherence was 92.6%(95% CI, 90.6-94.5%). A total of 30.2% of patients achieved an adherence rate of 100%, 80.6% at least 90%, and only 13.2% of patients showed a suboptimal adherence (<80%). A total of 59.9% of subjects were relapse-free after treatment initiation. Among 106 subjects (41.1%) who experienced, on average, 1.4 relapses, the majority were mild (40.6%) or moderate (47.2%). Having experienced relapses from the beginning of the treatment was the only variable significantly related to achieving an adherence of at least 80% (OR = 3.06, 1.28-7.31). Results of this study indicate that sc IFN ß-1a administration facilitated by RebiSmart® could lead to high rates of adherence to a prescribed dose regimen over 36 months

PP2A ligand ITH12246 protects against memory impairment and focal cerebral ischemia in mice

ITH12246 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8] naphthyridine-3-carboxylate) is a 1,8-naphthyridine described to feature an interesting neuroprotective profile in in vitro models of Alzheimer's disease. These effects were proposed to be due in part to a regulatory action on protein phosphatase 2A inhibition, as it prevented binding of its inhibitor okadaic acid. We decided to investigate the pharmacological properties of ITH12246, evaluating its ability to counteract the memory impairment evoked by scopolamine, a muscarinic antagonist described to promote memory loss, as well as to reduce the infarct volume in mice suffering phototrombosis. Prior to conducting these experiments, we confirmed its in vitro neuroprotective activity against both oxidative stress and Ca2+ overload-derived excitotoxicity, using SH-SY5Y neuroblastoma cells and rat hippocampal slices. Using a predictive model of blood-brain barrier crossing, it seems that the passage of ITH12246 is not hindered. Its potential hepatotoxicity was observed only at very high concentrations, from 0.1 mM. ITH12246, at the concentration of 10 mg/kg i.p., was able to improve the memory index of mice treated with scopolamine, from 0.22 to 0.35, in a similar fashion to the well-known Alzheimer's disease drug galantamine 2.5 mg/kg. On the other hand, ITH12246, at the concentration of 2.5 mg/kg, reduced the phototrombosis-triggered infarct volume by 67%. In the same experimental conditions, 15 mg/kg melatonin, used as control standard, reduced the infarct volume by 30%. All of these findings allow us to consider ITH12246 as a new potential drug for the treatment of neurodegenerative diseases, which would act as a multifactorial neuroprotectant.Peer Reviewe

Factor structure and measurement invariance across various demographic groups and over time for the phq-9 in primary care patients in spain

The Patient Health Questionnaire (PHQ-9) is a widely-used screening tool for depression in primary care settings. The purpose of the present study is to identify the factor structure of the PHQ-9 and to examine the measurement invariance of this instrument across different sociodemographic groups and over time in a sample of primary care patients in Spain. Data came from 836 primary care patients enrolled in a randomized controlled trial (PsicAP study) and a subsample of 218 patients who participated in a follow-up assessment at 3 months. Confirmatory factor analysis (CFA) was used to test one- and two-factor structures identified in previous studies. Analyses of multiple-group invariance were conducted to determine the extent to which the factor structure is comparable across various demo- graphic groups (i.e., gender, age, marital status, level of education, and employment situa- tion) and over time. Both one-factor and two-factor re-specified models met all the pre- established fit criteria. However, because the factors identified in the two-factor model were highly correlated (r = .86), the one-factor model was preferred for its parsimony. Multi-group CFA indicated measurement invariance across different demographic groups and across time. The present findings suggest that physicians in Spain can use the PHQ-9 to obtain a global score for depression severity in different demographic groups and to reliably monitor changes over time in the primary care setting

PhoP: A Missing Piece in the Intricate Puzzle of Mycobacterium tuberculosis Virulence

Inactivation of the transcriptional regulator PhoP results in Mycobacterium tuberculosis attenuation. Preclinical testing has shown that attenuated M. tuberculosis phoP mutants hold promise as safe and effective live vaccine candidates. We focused this study to decipher the virulence networks regulated by PhoP. A combined transcriptomic and proteomic analysis revealed that PhoP controls a variety of functions including: hypoxia response through DosR crosstalking, respiratory metabolism, secretion of the major T-cell antigen ESAT-6, stress response, synthesis of pathogenic lipids and the M. tuberculosis persistence through transcriptional regulation of the enzyme isocitrate lyase. We also demonstrate that the M. tuberculosis phoP mutant SO2 exhibits an antigenic capacity similar to that of the BCG vaccine. Finally, we provide evidence that the SO2 mutant persists better in mouse organs than BCG. Altogether, these findings indicate that PhoP orchestrates a variety of functions implicated in M. tuberculosis virulence and persistence, making phoP mutants promising vaccine candidates

Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

8 figuras, 2 tablasBackground Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. Methodology/Principal Findings We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. Conclusion/Significance The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDPThis work has been supported by grants from Ministry of Education and Science (SAF2007-61701, SAF2010-15700, SAF2011-28603), Fundación Eugenio Rodríguez Pascual, and Basque Government (Saiotek program 2008–2009). NE holds a fellowship of the JAE predoctoral program of the CSICPeer reviewe

The Next White (NEW) detector

[EN] Conceived to host 5 kg of xenón at a pressure of 15 bar in the ¿ducial volume,the NEXTWhite (NEW)apparatus is currently the largest high pressure xenon gas TPC using electroluminescent ampli¿cation in the world. It is also a 1:2 scale model of the NEXT-100 detector scheduled to start searching for ßß0¿ decays in 136Xe in 2019. Both detectors measure the energy of the event using a plane of photomultipliers located behind a transparent cathode. They can also reconstruct the trajectories of charged tracks in the dense gas of the TPC with the help of a plane of silicon photomultipliers located behind the anode. A sophisticated gas system, common to both detectors, allows the high gas purity needed to guarantee a long electron lifetime. NEXT-White has been operating since October 2017 at the Canfranc Underground Laboratory (LSC), in Spain. This paper describes the detector and associated infrastructures.The NEXT Collaboration acknowledges support from the following agencies and institutions: the European Research Council (ERC) under the Advanced Grant 339787-NEXT; the European Union's Framework Programme for Research and Innovation Horizon 2020 (2014-2020) under the Marie Sklodowska-Curie Grant Agreements No. 674896, 690575 and 740055; the Ministerio de Economia y Competitividad of Spain under grants FIS2014-53371-C04, the Severo Ochoa Program SEV-2014-0398 and the Maria de Maetzu Program MDM-2016-0692; the GVA of Spain under grants PROMETEO/2016/120 and SEJI/2017/011; the Portuguese FCT and FEDER through the program COMPETE, projects PTDC/FIS-NUC/2525/2014 and UID/FIS/04559/2013; the U.S. Department of Energy under contract numbers DE-AC02-07CH11359 (Fermi National Accelerator Laboratory), DE-FG02-13ER42020 (Texas A&M), DE-SC0017721 (University of Texas at Arlington), and DE-AC02-06CH11357 (Argonne National Laboratory); and the University of Texas at Arlington. We also warmly acknowledge the Laboratorio Nazionale di Gran Sasso (LNGS) and the Dark Side collaboration for their help with TPB coating of various parts of the NEXT-White TPC. Finally, we are grateful to the Laboratorio Subterraneo de Canfranc for hosting and supporting the NEXT experiment.Monrabal, F.; Gomez-Cadenas, JJ.; Toledo Alarcón, JF.; Laing, A.; Álvarez-Puerta, V.; Benlloch-Rodriguez, JM.; Carcel, S.... (2018). The Next White (NEW) detector. Journal of Instrumentation. 13:1-35. https://doi.org/10.1088/1748-0221/13/12/P12010S13513Nygren, D. (2009). High-pressure xenon gas electroluminescent TPC for 0-ν ββ-decay search. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 603(3), 337-348. doi:10.1016/j.nima.2009.01.222Gómez Cadenas, J. J., Álvarez, V., Borges, F. I. G., Cárcel, S., Castel, J., Cebrián, S., … Dias, T. H. V. T. (2014). Present Status and Future Perspectives of the NEXT Experiment. Advances in High Energy Physics, 2014, 1-22. doi:10.1155/2014/907067Martín-Albo, J., Muñoz Vidal, J., Ferrario, P., Nebot-Guinot, M., Gómez-Cadenas, J. J., … Cárcel, S. (2016). Sensitivity of NEXT-100 to neutrinoless double beta decay. Journal of High Energy Physics, 2016(5). doi:10.1007/jhep05(2016)159Álvarez, V., Borges, F. I. G., Cárcel, S., Castel, J., Cebrián, S., Cervera, A., … Díaz, J. (2013). Initial results of NEXT-DEMO, a large-scale prototype of the NEXT-100 experiment. Journal of Instrumentation, 8(04), P04002-P04002. doi:10.1088/1748-0221/8/04/p04002Álvarez, V., Borges, F. I. G., Cárcel, S., Castel, J., Cebrián, S., Cervera, A., … Díaz, J. (2013). Operation and first results of the NEXT-DEMO prototype using a silicon photomultiplier tracking array. Journal of Instrumentation, 8(09), P09011-P09011. doi:10.1088/1748-0221/8/09/p09011Álvarez, V., Borges, F. I. G. M., Cárcel, S., Castel, J., Cebrián, S., Cervera, A., … Díaz, J. (2013). Near-intrinsic energy resolution for 30–662keV gamma rays in a high pressure xenon electroluminescent TPC. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 708, 101-114. doi:10.1016/j.nima.2012.12.123Ferrario, P., Laing, A., López-March, N., Gómez-Cadenas, J. J., Álvarez, V., … Cebrián, S. (2016). First proof of topological signature in the high pressure xenon gas TPC with electroluminescence amplification for the NEXT experiment. Journal of High Energy Physics, 2016(1). doi:10.1007/jhep01(2016)104López-March, N. (2017). Sensitivity of the NEXT-100 detector to neutrinoless double beta decay. Journal of Physics: Conference Series, 888, 012243. doi:10.1088/1742-6596/888/1/012243Álvarez, V., Borges, F. I. G., Cárcel, S., Cebrián, S., Cervera, A., Conde, C. A. N., … Esteve, R. (2013). Ionization and scintillation response of high-pressure xenon gas to alpha particles. Journal of Instrumentation, 8(05), P05025-P05025. doi:10.1088/1748-0221/8/05/p05025Gehman, V. M., Seibert, S. R., Rielage, K., Hime, A., Sun, Y., Mei, D.-M., … Moore, D. (2011). Fluorescence efficiency and visible re-emission spectrum of tetraphenyl butadiene films at extreme ultraviolet wavelengths. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 654(1), 116-121. doi:10.1016/j.nima.2011.06.088Sanguino, P., Balau, F., Botelho do Rego, A. M., Pereira, A., & Chepel, V. (2016). Stability of tetraphenyl butadiene thin films in liquid xenon. Thin Solid Films, 600, 65-70. doi:10.1016/j.tsf.2016.01.006Silva, C., Pinto da Cunha, J., Pereira, A., Chepel, V., Lopes, M. I., Solovov, V., & Neves, F. (2010). Reflectance of polytetrafluoroethylene for xenon scintillation light. Journal of Applied Physics, 107(6), 064902. doi:10.1063/1.3318681Christophorou, L. G. (1988). Insulating gases. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 268(2-3), 424-433. doi:10.1016/0168-9002(88)90550-5Vijh, A. K. (1985). Relative electric strengths and polarizabilities of gaseous dielectrics. Materials Chemistry and Physics, 12(3), 287-296. doi:10.1016/0254-0584(85)90098-7Rebel, B., Hall, C., Bernard, E., Faham, C. H., Ito, T. M., Lundberg, B., … Wang, H. (2014). High voltage in noble liquids for high energy physics. Journal of Instrumentation, 9(08), T08004-T08004. doi:10.1088/1748-0221/9/08/t08004Cebrián, S., Pérez, J., Bandac, I., Labarga, L., Álvarez, V., Azevedo, C. D. R., … Cárcel, S. (2017). Radiopurity assessment of the energy readout for the NEXT double beta decay experiment. Journal of Instrumentation, 12(08), T08003-T08003. doi:10.1088/1748-0221/12/08/t08003Lung, K., Arisaka, K., Bargetzi, A., Beltrame, P., Cahill, A., Genma, T., … Yoshizawa, Y. (2012). Characterization of the Hamamatsu R11410-10 3-in. photomultiplier tube for liquid xenon dark matter direct detection experiments. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 696, 32-39. doi:10.1016/j.nima.2012.08.052Rodríguez, J., Toledo, J., Esteve, R., Lorca, D., & Monrabal, F. (2015). The front-end electronics for the 1.8-kchannel SiPM tracking plane in the NEW detector. Journal of Instrumentation, 10(01), C01025-C01025. doi:10.1088/1748-0221/10/01/c01025Carena, F., Carena, W., Chapeland, S., Chibante Barroso, V., Costa, F., Dénes, E., … von Haller, B. (2014). The ALICE data acquisition system. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 741, 130-162. doi:10.1016/j.nima.2013.12.015Martoiu, S., Muller, H., Tarazona, A., & Toledo, J. (2013). Development of the scalable readout system for micro-pattern gas detectors and other applications. Journal of Instrumentation, 8(03), C03015-C03015. doi:10.1088/1748-0221/8/03/c03015Toledo, J., Muller, H., Esteve, R., Monzó, J. M., Tarazona, A., & Martoiu, S. (2011). The Front-End Concentrator card for the RD51 Scalable Readout System. Journal of Instrumentation, 6(11), C11028-C11028. doi:10.1088/1748-0221/6/11/c11028Esteve, R., Toledo, J., Rodríguez, J., Querol, M., & Álvarez, V. (2016). Readout and data acquisition in the NEXT-NEW Detector based on SRS-ATCA. Journal of Instrumentation, 11(01), C01008-C01008. doi:10.1088/1748-0221/11/01/c01008Esteve, R., Toledo, J., Monrabal, F., Lorca, D., Serra, L., Marí, A., … Mora, F. (2012). The trigger system in the NEXT-DEMO detector. Journal of Instrumentation, 7(12), C12001-C12001. doi:10.1088/1748-0221/7/12/c12001Herzenberg, A. (1969). Attachment of Slow Electrons to Oxygen Molecules. The Journal of Chemical Physics, 51(11), 4942-4950. doi:10.1063/1.1671887Huk, M., Igo-Kemenes, P., & Wagner, A. (1988). Electron attachment to oxygen, water, and methanol, in various drift chamber gas mixtures. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 267(1), 107-119. doi:10.1016/0168-9002(88)90635-3Novella, P., Palmeiro, B., Simón, A., Sorel, M., Adams, C., … Zuzel, G. (2018). Measurement of radon-induced backgrounds in the NEXT double beta decay experiment. Journal of High Energy Physics, 2018(10). doi:10.1007/jhep10(2018)112Saldanha, R., Grandi, L., Guardincerri, Y., & Wester, T. (2017). Model independent approach to the single photoelectron calibration of photomultiplier tubes. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 863, 35-46. doi:10.1016/j.nima.2017.02.086Simón, A., Felkai, R., Martínez-Lema, G., Monrabal, F., González-Díaz, D., Sorel, M., … Álvarez, V. (2018). Electron drift properties in high pressure gaseous xenon. Journal of Instrumentation, 13(07), P07013-P07013. doi:10.1088/1748-0221/13/07/p07013Martínez-Lema, G., Morata, J. A. H., Palmeiro, B., Botas, A., Ferrario, P., Monrabal, F., … Para, A. (2018). Calibration of the NEXT-White detector using 83mKr decays. Journal of Instrumentation, 13(10), P10014-P10014. doi:10.1088/1748-0221/13/10/p1001

Gaia Focused Product Release: Radial velocity time series of long-period variables

The third Gaia Data Release (DR3) provided photometric time series of more than 2 million long-period variable (LPV) candidates. Anticipating the publication of full radial-velocity (RV) in DR4, this Focused Product Release (FPR) provides RV time series for a selection of LPVs with high-quality observations. We describe the production and content of the Gaia catalog of LPV RV time series, and the methods used to compute variability parameters published in the Gaia FPR. Starting from the DR3 LPVs catalog, we applied filters to construct a sample of sources with high-quality RV measurements. We modeled their RV and photometric time series to derive their periods and amplitudes, and further refined the sample by requiring compatibility between the RV period and at least one of the $G$, $G_{\rm BP}$, or $G_{\rm RP}$ photometric periods. The catalog includes RV time series and variability parameters for 9\,614 sources in the magnitude range $6\lesssim G/{\rm mag}\lesssim 14$, including a flagged top-quality subsample of 6\,093 stars whose RV periods are fully compatible with the values derived from the $G$, $G_{\rm BP}$, and $G_{\rm RP}$ photometric time series. The RV time series contain a mean of 24 measurements per source taken unevenly over a duration of about three years. We identify the great most sources (88%) as genuine LPVs, with about half of them showing a pulsation period and the other half displaying a long secondary period. The remaining 12% consists of candidate ellipsoidal binaries. Quality checks against RVs available in the literature show excellent agreement. We provide illustrative examples and cautionary remarks. The publication of RV time series for almost 10\,000 LPVs constitutes, by far, the largest such database available to date in the literature. The availability of simultaneous photometric measurements gives a unique added value to the Gaia catalog (abridged)Comment: 36 pages, 38 figure

Gaia Early Data Release 3 Acceleration of the Solar System from Gaia astrometry

Context. Gaia Early Data Release 3 (Gaia EDR3) provides accurate astrometry for about 1.6 million compact (QSO-like) extragalactic sources, 1.2 million of which have the best-quality five-parameter astrometric solutions. Aims. The proper motions of QSO-like sources are used to reveal a systematic pattern due to the acceleration of the solar systembarycentre with respect to the rest frame of the Universe. Apart from being an important scientific result by itself, the acceleration measured in this way is a good quality indicator of the Gaia astrometric solution. Methods. Theeffect of the acceleration was obtained as a part of the general expansion of the vector field of proper motions in vector spherical harmonics (VSH). Various versions of the VSH fit and various subsets of the sources were tried and compared to get the most consistent result and a realistic estimate of its uncertainty. Additional tests with the Gaia astrometric solution were used to get a better idea of the possible systematic errors in the estimate. Results. Our best estimate of the acceleration based on Gaia EDR3 is (2.32 +/- 0.16) x 10(-10) m s(-2) (or 7.33 +/- 0.51 km s(-1) Myr-1) towards alpha = 269.1 degrees +/- 5.4 degrees, delta = -31.6 degrees +/- 4.1 degrees, corresponding to a proper motion amplitude of 5.05 +/- 0.35 mu as yr(-1). This is in good agreement with the acceleration expected from current models of the Galactic gravitational potential. We expect that future Gaia data releases will provide estimates of the acceleration with uncertainties substantially below 0.1 mu as yr(-1).Peer reviewe