Audiovestibular manifestations in patients with ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory disease of unknown origin affecting up to 1% of the population. Little is known about audiovestibular impairment in patients with AS, especially the presence of cochleovestibular dysfunction in these patients. To investigate audiovestibular manifestations in AS, we studied a series of 50 consecutive patients who fulfilled the modified New York diagnostic criteria for AS and 44 matched controls. Individuals with history of cardiovascular disease, cerebrovascular complications, peripheral artery disease, renal insufficiency, syphilis, Meniere and other vestibular syndromes, infections involving the inner ear, barotrauma, or in treatment with ototoxic drugs were excluded. Most patients with AS were men (80%). The mean age at the time of study was 52.5 years, and mean age at the onset of symptoms was 34.4 years. Twenty-nine (58%) patients showed abnormal hearing loss in the audiogram compared to only 8 (18%) controls (p < 0.001). Values of audiometric tests (pure-tone average and speech reception threshold) yielded significant differences between patients and controls (p < 0.001). It is noteworthy that the audiogram shape disclosed a predominant pattern of high-frequency sensorineural hearing loss in AS patients (50%) compared to controls (18%) (p = 0.002). Also, AS patients exhibited abnormal vestibular tests more commonly than controls. AS patients had an increased frequency of head-shaking nystagmus (20%) compared to controls (0%) (p < 0.001). Moreover, patients (26%) showed a significantly increased frequency of abnormal caloric test compared to controls (0%) (p < 0.001). Finally, a significantly increased frequency of abnormal clinical test of sensory integration and balance with a predominant vestibular loss pattern was observed in patients (36%) compared to controls (5%) (p < 0.001). In conclusion, the current study demonstrates strong evidence for inner ear compromise in patients with AS

New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial

Background: Current treatment for Chagas disease with the only available drugs, benznidazole or nifurtimox, has substantial limitations, including long treatment duration and safety and tolerability concerns. We aimed to evaluate the efficacy and safety of new benznidazole monotherapy regimens and combinations with fosravuconazole, in the treatment of Chagas disease. Methods: We did a double-blind, double-dummy, phase 2, multicentre, randomised trial in three outpatient units in Bolivia. Adults aged 18–50 years with chronic indeterminate Chagas disease, confirmed by serological testing and positive qualitative PCR results, were randomly assigned (1:1:1:1:1:1:1) to one of seven treatment groups using a balanced block randomisation scheme with an interactive response system. Participants were assigned to benznidazole 300 mg daily for 8 weeks, 4 weeks, or 2 weeks, benznidazole 150 mg daily for 4 weeks, benznidazole 150 mg daily for 4 weeks plus fosravuconazole, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, or placebo, with a 12-month follow-up period. The primary endpoints were sustained parasitological clearance at 6 months, defined as persistent negative qualitative PCR results from end of treatment, and incidence and severity of treatment-emergent adverse events, serious adverse events, and adverse events leading to treatment discontinuation. Primary efficacy analysis was based on the intention-to-treat and per-protocol populations and secondary efficacy analyses on the per-protocol population. Safety analyses were based on the as-treated population. Recruitment is now closed. This trial is registered with ClinicalTrials.gov, NCT03378661. Findings: Between Nov 30, 2016, and July 27, 2017, we screened 518 patients, and 210 were enrolled and randomised. 30 patients (14%) were assigned to each treatment group. All 210 randomised patients were included in the intention-to-treat population, and 190 (90%) were included in the per-protocol population. In the intention-to-treat analysis, only one (3%) of 30 patients in the placebo group had sustained parasitological clearance at 6 months of follow-up. Sustained parasitological clearance at 6 months was observed in 25 (89%) of 28 patients receiving benznidazole 300 mg daily for 8 weeks (rate difference vs placebo 86% [95% CI 73–99]), 25 (89%) of 28 receiving benznidazole 300 mg daily for 4 weeks (86% [73–99]), 24 (83%) of 29 receiving benznidazole 300 mg daily for 2 weeks (79% [64–95]), 25 (83%) of 30 receiving benznidazole 150 mg daily for 4 weeks (80% [65–95]), 23 (85%) of 28 receiving benznidazole 150 mg daily for 4 weeks plus fosravuconazole (82% [67–97]), and 24 (83%) of 29 receiving benznidazole 300 mg weekly for 8 weeks plus fosravuconazole (79% [64–95]; p<0·0001 for all group comparisons with placebo). Six patients (3%) had ten serious adverse events (leukopenia [n=3], neutropenia [n=2], pyrexia, maculopapular rash, acute cholecystitis, biliary polyp, and breast cancer), eight had 12 severe adverse events (defined as interfering substantially with the patient's usual functions; elevated alanine aminotransferase [n=4], elevated gamma-glutamyltransferase [n=2], elevated aspartate aminotransferase [n=1], neutropenia [n=3], leukopenia [n=1], and breast cancer [n=1]), and 15 (7%) had adverse events that led to treatment discontinuation (most of these were in the groups who received benznidazole 300 mg daily for 8 weeks, benznidazole 300 mg once per week for 8 weeks plus fosravuconazole, and benznidazole 150 mg daily for 4 weeks plus fosravuconazole). No adverse events leading to treatment discontinuation were observed in patients treated with benznidazole 300 mg daily for 2 weeks or placebo. There were no treatment-related deaths. Interpretation: Benznidazole induced effective antiparasitic response, regardless of treatment duration, dose, or combination with fosravuconazole, and was well tolerated in adult patients with chronic Chagas disease. Shorter or reduced regimens of benznidazole could substantially improve treatment tolerability and accessibility, but further studies are needed to confirm these results. Funding: Drugs for Neglected Diseases initiative (DNDi). Translation: For the Spanish translation of the abstract see Supplementary Materials section.Fil: Torrico, Faustino. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; Bolivia. Universidad Mayor de San Simón; BoliviaFil: Gascón, Joaquim. Instituto de Salud Global de Barcelona; España. Universidad de Barcelona; EspañaFil: Barreira, Fabiana. DNDi Latin America; BrasilFil: Blum, Bethania. DNDi Latin America; BrasilFil: Almeida, Igor C. University of Texas at El Paso; Estados UnidosFil: Alonso Vega, Cristina. DNDi Latin America; Brasil. Instituto de Salud Global de Barcelona; EspañaFil: Barboza, Tayná. DNDi Latin America; BrasilFil: Bilbe, Graeme. Drugs For Neglected Diseases Initiative; SuizaFil: Correia, Erika. DNDi Latin America; BrasilFil: Garcia, Wilson. Universidad Mayor de San Simón; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente ; BoliviaFil: Ortiz, Lourdes. Universidad Autónoma Juan Misael Saracho; Bolivia. Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente; BoliviaFil: Parrado, Rudy. Universidad Mayor de San Simón; BoliviaFil: Ramirez Gomez, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; ArgentinaFil: Ribeiro, Isabela. Drugs For Neglected Diseases Initiative; SuizaFil: Strub Wourgaft, Nathalie. Drugs For Neglected Diseases Initiative; SuizaFil: Vaillant, Michel. Luxembourg Institute Of Health; LuxemburgoFil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. DNDi Latin America; Brasi

Erratum: Search for photons with energies above 1018 eV using the hybrid detector of the Pierre Auger Observatory

1 Exposure calculation Due to a mistake in the numerical integration following eq. (6.2) of the original article [1], the exposure shown in figure 5 of the original article was incorrect. The correct exposure is shown in figure 1. 2 Upper limits on the integral photon flux and fraction The incorrect exposure affects the calculation of the upper limits on the integral photon flux following eq. (6.1) of the original article. The correct values for the upper limits are 0.038, 0.010, 0.009, 0.008 and 0.007 km−2 sr−1 yr−1 for threshold energies of 1, 2, 3, 5 and 10 EeV. The correct values for the upper limits on the integral photon fraction subsequently derived are 0.14 %, 0.17 %, 0.42 %, 0.86 % and 2.9 % for the same threshold energies. 3 Author list The author list of this erratum also corrects a mistake made in the original article, where F. Zuccarello was missing and Z. Zong was listed twice.Fil: Aab, A.. Radboud Universiteit Nijmegen; Países BajosFil: Abreu, P.. Instituto Superior Tecnico; PortugalFil: Aglietta, M.. Istituto Nazionale di Astrofisica; Italia. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Al Samarai, I.. Laboratoire de Physique Nucléaire Et de Hautes Energies; FranciaFil: Albuquerque, I. F. M.. Universidade de Sao Paulo; BrasilFil: Allekotte, Ingomar. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; ArgentinaFil: Almela, A.. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; Argentina. Universidad Tecnológica Nacional; ArgentinaFil: Alvarez Castillo, J.. Universidad Nacional Autónoma de México; MéxicoFil: Alvarez-Muñiz, J.. Universidad de Santiago de Compostela; EspañaFil: Anastasi, G. A.. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Anchordoqui, Luis A.. City University of New York; Estados UnidosFil: Andrada, B.. Comisión Nacional de Energía Atómica. Centro Atómico Constituyentes; ArgentinaFil: Andringa, S.. Instituto Superior Tecnico; PortugalFil: Aramo, C.. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Arqueros, F.. Universidad Complutense de Madrid; EspañaFil: Arsene, N.. University of Bucharest; RumaniaFil: Asorey, Hernán Gonzalo. Universidad Industrial Santander; Colombia. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Assis, P.. Instituto Superior Tecnico; PortugalFil: Aublin, J.. Laboratoire de Physique Nucléaire Et de Hautes Energies; FranciaFil: Avila, G.. Observatorio Pierre Auger And Comisión Nacional de Energía Atómica; Argentina. Observatorio Pierre Auger; ArgentinaFil: Badescu, A. M.. University Politehnica Of Bucharest; RumaniaFil: Balaceanu, A.. “Horia Hulubei” National Institute for Physics and Nuclear Engineering; RumaniaFil: Barreira Luz, R. J.. Instituto Superior Tecnico; PortugalFil: Beatty, J. J.. Ohio State University; Estados UnidosFil: Becker, K. H.. Bergische Universität Wuppertal; AlemaniaFil: Bellido, J.A.. University of Adelaide; AustraliaFil: Berat, C.. Université Grenoble Alpes; FranciaFil: Bertaina, M. E.. Università di Torino; Italia. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Bertou, Xavier Pierre Louis. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sciutto, Sergio Juan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; Argentin

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Combined fit of spectrum and composition data as measured by the Pierre Auger Observatory

We present a combined fit of a simple astrophysical model of UHECR sources to both the energy spectrum and mass composition data measured by the Pierre Auger Observatory. The fit has been performed for energies above 5⋅1018 eV, i.e.~the region of the all-particle spectrum above the so-called "ankle" feature. The astrophysical model we adopted consists of identical sources uniformly distributed in a comoving volume, where nuclei are accelerated through a rigidity-dependent mechanism. The fit results suggest sources characterized by relatively low maximum injection energies, hard spectra and heavy chemical composition. We also show that uncertainties about physical quantities relevant to UHECR propagation and shower development have a non-negligible impact on the fit results.Fil: Aab, A.. Radboud Universiteit Nijmegen; Países BajosFil: Abreu, P.. Universidade de Lisboa; PortugalFil: Aglietta, M.. Istituto Nazionale di Astrofisica; ItaliaFil: Al Samarai, I.. Universite de Paris VI. Institut des Nanosciences de Paris; Francia. Centre National de la Recherche Scientifique; FranciaFil: Albuquerque, I. F. M.. Universidade de Sao Paulo; BrasilFil: Allekotte, Ingomar. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro | Universidad Nacional de Cuyo. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro; ArgentinaFil: Almela, Daniel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Alvarez Castillo, J.. Universidad Nacional Autónoma de México; MéxicoFil: Alvarez Muñiz, J.. Universidad de Santiago de Compostela; EspañaFil: Anastasi, G. A.. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Anchordoqui, Luis A.. City University of New York; Estados UnidosFil: Andrada, Betiana Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Andringa, S.. Universidade Nova de Lisboa; PortugalFil: Aramo, C.. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Arqueros, F.. Universidad Complutense de Madrid; EspañaFil: Arsene, N.. University of Bucharest; RumaniaFil: Asorey, Hernán Gonzalo. Comisión Nacional de Energía Atómica. Gerencia del Área de Energía Nuclear. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro | Universidad Nacional de Cuyo. Instituto Balseiro. Archivo Histórico del Centro Atómico Bariloche e Instituto Balseiro; Argentina. Universidad Industrial de Santander; ColombiaFil: Assis, P.. Universidade de Lisboa; PortugalFil: Aublin, J.. Université Paris 6; Francia. Université Paris 7; Francia. Centre National de la Recherche Scientifique; FranciaFil: Avila, G.. Observatorio Pierre Auger; ArgentinaFil: Badescu, A. M.. Observatorio Pierre Auger; ArgentinaFil: Balaceanu, A.. “Horia Hulubei” National Institute for Physics and Nuclear Engineering; RumaniaFil: Luz Barreira, R. J.. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Beatty, J. J.. Ohio State University; Estados UnidosFil: Figueira, Juan Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Platino, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Wundheiler, Brian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Wahlberg, Hernan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Mollerach, Maria Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Biermann, P. L.. Max-Planck-Institut f¨ur Radioastronomie; Alemani

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment

Imago & mirabilia : les formes del prodigi a la Mediterrània medieval

Hem organitzat el present volum a partir de tres àmbits que, sense cap pretensió totalitzadora ni teòrica, mostrin la vivacitat del prodigi medieval i la riquesa de la seva exploració. El primer àmbit és el titulat Geografies. El sagrat i el profà tracen una topografia del meravellós que omple la geografia d'indrets singulars, escenaris de tota mena de prodigis, alguns de remots o d'altres encara avinents. La tradicional història sagrada i l'heterogeni santoral, la literatura i els tractats pseudo-científics de l'antiguitat, les cròniques de viatgers i pelegrins o la mateixa cartografia, tot contribueix a fixar els indrets de la meravella com a lieux de mémoire. En efecte, el meravellós també respon a una topografia, a uns espais concrets on es troba, es reconeix i es difon; una memòria precisa on tothora són recordades les mirabilia. El segon àmbit del volum és Objectes. A l'edat mitjana, relíquies, objectes valuosos, rars o exòtics van ser buscats amb afany i els van creure portadors de virtuts prodigioses o reminiscències de criatures tan llunyanes com fabuloses. Presents a les corts, als tresors d'església o a les llars benestants, van esdevenir formes tangibles del sobrenatural. Alguns de procedents de l'Orient cristià van assolir una remarcable dimensió llegendària. I molts d'ells van desvetllar una arkhaiología, una «història de les coses antigues», amb la qual es va anar acompanyant l'objecte prodigiós d'una llegenda que reverberava la seva condició meravellosa i remota. Per últim, el tercer àmbit és Relats. Les narracions escrites i també els relats visuals van ser vehicles fonamentals per a la formació i la difusió del prodigi a l'edat mitjana. Les diverses formes de la meravella troben en la literatura profana o en l'hagiogràfica uns potents mitjans d'expressió i de la seva concreció. Cròniques, novel·les i relats hagiogràfics són portaveus de successos extraordinaris, i la seva enunciació o visualització és causa d'estupor. Miracle, llegenda i aventura esdevenen presències constants en la literatura i en les arts figuratives medievals

A search for ultra-high-energy photons at the Pierre Auger Observatory exploiting air-shower universality

The Pierre Auger Observatory is the most sensitive detector to primary photons with energies above ∼0.2 EeV. It measures extensive air showers using a hybrid technique that combines a fluorescence detector (FD) with a ground array of particle detectors (SD). The signatures of a photon-induced air shower are a larger atmospheric depth at the shower maximum (X$_{max}$) and a steeper lateral distribution function, along with a lower number of muons with respect to the bulk of hadron-induced background. Using observables measured by the FD and SD, three photon searches in different energy bands are performed. In particular, between threshold energies of 1-10 EeV, a new analysis technique has been developed by combining the FD-based measurement of X$_{max}$ with the SD signal through a parameter related to its muon content, derived from the universality of the air showers. This technique has led to a better photon/hadron separation and, consequently, to a higher search sensitivity, resulting in a tighter upper limit than before. The outcome of this new analysis is presented here, along with previous results in the energy ranges below 1 EeV and above 10 EeV. From the data collected by the Pierre Auger Observatory in about 15 years of operation, the most stringent constraints on the fraction of photons in the cosmic flux are set over almost three decades in energy

Study on multi-ELVES in the Pierre Auger Observatory

Since 2013, the four sites of the Fluorescence Detector (FD) of the Pierre Auger Observatory record ELVES with a dedicated trigger. These UV light emissions are correlated to distant lightning strikes. The length of recorded traces has been increased from 100 μs (2013), to 300 μs (2014-16), to 900 μs (2017-present), to progressively extend the observation of the light emission towards the vertical of the causative lightning and beyond. A large fraction of the observed events shows double ELVES within the time window, and, in some cases, even more complex structures are observed. The nature of the multi-ELVES is not completely understood but may be related to the different types of lightning in which they are originated. For example, it is known that Narrow Bipolar Events can produce double ELVES, and Energetic In-cloud Pulses, occurring between the main negative and upper positive charge layer of clouds, can induce double and even quadruple ELVES in the ionosphere. This report shows the seasonal and daily dependence of the time gap, amplitude ratio, and correlation between the pulse widths of the peaks in a sample of 1000+ multi-ELVES events recorded during the period 2014-20. The events have been compared with data from other satellite and ground-based sensing devices to study the correlation of their properties with lightning observables such as altitude and polarity