Monitoring dynamics of human adenovirus disassembly induced by mechanical fatigue

The standard pathway for virus infection of eukaryotic cells requires disassembly of the viral shell to facilitate release of the viral genome into the host cell. Here we use mechanical fatigue, well below rupture strength, to induce stepwise disruption of individual human adenovirus particles under physiological conditions, and simultaneously monitor disassembly in real time. Our data show the sequence of dismantling events in individual mature (infectious) and immature (noninfectious) virions, starting with consecutive release of vertex structures followed by capsid cracking and core exposure. Further, our experiments demonstrate that vertex resilience depends inextricably on maturation, and establish the relevance of penton vacancies as seeding loci for virus shell disruption. The mechanical fatigue disruption route recapitulates the adenovirus disassembly pathway in vivo, as well as the stability differences between mature and immature virionsWe acknowledge funding by grants from the Ministry of Science and Innovation of Spain, PIB2010US-00233, FIS2011-29493, Consolider CSD2010-00024 and CAM project and the Comunidad de Madrid No. S2009/MAT-1467 to P. J. P.; BFU2010-16382/BMC to C.S.M.; and FIS2011-16090-E to C.S.M. and P.J.P. S.J.F acknowledges funding from the National Institutes of Health, USA (GM037705 and AI1058172). A.J.P.-B. holds a Juan de la Cierva postdoctoral contract from the Ministry of Science and Innovation of Spain; A.O.-E. and R.M.-C. are recipients of predoctoral fellowships from the Ministry of Education and the Instituto de Salud Carlos III of Spain, respectivel

Structure and uncoating of immature adenovirus

Maturation via proteolytical processing is a common trait in the viral world, and is often accompanied by large conformational changes and rearrangements in the capsid. The adenovirus protease has been shown to play a dual role in the viral infectious cycle: (a) in maturation, as viral assembly starts with precursors to several of the structural proteins, but ends with proteolytically processed versions in the mature virion; and (b) in entry, because protease-impaired viruses have difficulties in endosome escape and uncoating. Indeed, viruses that have not undergone proteolytical processing are not infectious. We present the 3D structure of immature adenovirus particles, as represented by the thermosensitive mutant Ad2 ts1 grown under nonpermissive conditions, and compare it with the mature capsid. Our 3DEM maps at subnanometer resolution indicate that adenovirus maturation does not involve large scale conformational changes in the capsid. Difference maps reveal the location of unprocessed peptides pIIIa and pVI and help to define their role in capsid assembly and maturation. An intriguing difference appears in the core, indicating a more compact organization and increased stability of the immature cores. We have further investigated these properties by in vitro disassembly assays. Fluorescence and electron microscopy experiments reveal differences in the stability and uncoating of immature viruses, both at the capsid and core levels, as well as disassembly intermediates not previously imaged.This work was supported by grants from the Ministerio de Ciencia e Innovación of Spain (BFU2007-60228 to C.S.M. and BIO2007-67150-C03-03 to R.M.), the Comunidad Autónoma de Madrid and Consejo Superior de Investigaciones Científicas (CCG08-CSIC/SAL-3442 to C.S.M.) and the National Institutes of Health (5R01CA111569 to D.T.C., R0141599 to W.F.M. and GM037705 to S.J.F.). R.M.-C. is a recipient of a PFIS fellowship from the Instituto de Salud Carlos III of Spain. A.J.P.-B. holds a CSIC JAE-Doc postdoctoral position, partially funded by the European Social FundPeer reviewe

Respuestas de oyentes y expertos musicales a una encuesta para valorar la percepción musical en salas de conciertos, auditorios y teatros

Para valorar la percepción musical en salas de concierto se diseñó una encuesta de 58 preguntas en la que cada una se valoraba de 0 a 5 puntos. A esta encuesta han respondido 1057 personas entre público en general y expertos musicales, sin formación especializada en acústica, tras la audición de un concierto en alguno de los 14 auditorios, salas de conciertos y teatros ubicados en diferentes comunidades de nuestro país (8 en el sur y 6 en levante). El análisis de las respuestas obtenidas ha mostrado que la fluctuación de la valoración media de cada una de las preguntas de la encuesta en una sala es un patrón que se repite aproximadamente en todas las salas estudiadas, formando una banda de aproximadamente 1 punto de variación en cada respuesta que contiene a todas las salas. Los límites de esta banda indicarían los extremos de respuesta subjetiva asociada a las salas de conciertos.Ponencia presentada en el Encuentro Ibérico de Acústica. EAA Symposium. Gandía(España). 2006.In order to evaluate the quality of the musical perception in concert halls, a survey with 58 items was designed in which each question was valued from 0 to 5 points. This survey has been replied by 1057 people between general public and musical experts without any specialized formation in acoustics, after the audition of a concert in any of the 14 auditoriums, concert hall or theatres, located in different regions of our country (8 in the south and 6 in the east). The analysis has shown that the fluctuation of the mean valuation of each question of the survey in a determined room is a pattern that is repeated approximately in all of the studied spaces, forming a band of approximately 1 variation point in each answer and that contains to all rooms. The limits of this band would indicate the ends of the subjective response associated to concert halls

Elaboration process of a subjective response test from listeners and Musical experts, as a tool of evaluation of the musical perception in Concerts halls, auditoria and theatres

In order to tackle the study related to the requirements for musical audition in concert halls, some measurements and analyses of objective acoustic parameters have been made. However, the subjective evaluation of the sensation that the values of these acoustic parameters have on the listeners, can only be shown by means of a questionnaire that listeners have to answer. Such questionnaire has been formulated in an understandable way and the questions are directly or indirectly related to the abovementioned parameters. The aim of the present article is to present the elaboration process of a test of subjective response addressed to the general public and to some musical experts who have no special skills on acoustics. This study has been made in 13 auditoria, concert rooms and theatres distributed in different Autonomous Regions of Spain.Para abordar el estudio de las exigencias para la audición musical en salas de conciertos se realiza la medida y análisis de parámetros acústicos objetivos. Sin embargo, la valoración subjetiva de la sensación que unos u otros valores de esos parámetros acústicos producen en la audiencia, sólo puede ponerse de manifiesto a través de las respuestas de los oyentes a una encuesta cuyas preguntas, formuladas de manera comprensible, estén relacionadas, directa o indirectamente, con dichos parámetros acústicos. El objeto de este artículo es presentar el proceso de elaboración de un test de respuesta subjetiva dirigido al público en general y a expertos musicales pero sin formación especializada en acústica. Este estudio se ha realizado en 13 auditorios, salas de conciertos y teatros repartidos en diferentes Comunidades Autónomas de nuestro país. Ponencia presentada al Encuentro Ibérico de Acústica. EAA Symposium. Gandía (España). 200

Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial

Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone (Rd), there are not phase III trials confirming these results. In this phase III trial, 286 patients with MM ineligible for ASCT received Rd with or without clarithromycin until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). With a median follow-up of 19 months (range, 0-54), no significant differences in the median PFS were observed between the two arms (C-Rd 23 months, Rd 29 months; HR 0.783, p = 0.14), despite a higher rate of complete response (CR) or better in the C-Rd group (22.6% vs 14.4%, p = 0.048). The most common G3-4 adverse events were neutropenia [12% vs 19%] and infections [30% vs 25%], similar between the two arms; however, the percentage of toxic deaths was higher in the C-Rd group (36/50 [72%] vs 22/40 [55%], p = 0.09). The addition of clarithromycin to Rd in untreated transplant ineligible MM patients does not improve PFS despite increasing the ?CR rate due to the higher number of toxic deaths in the C-Rd arm. Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results. The trial was registered in clinicaltrials.gov with the name GEM-CLARIDEX: Ld vs BiRd and with the following identifier NCT02575144. The full trial protocol can be accessed from ClinicalTrials.gov. This study received financial support from BMS/Celgene

Effectiveness of Motivational Interviewing in improving lipid level in patients with dyslipidemia assisted by general practitioners: Dislip-EM study protocol

<p>Abstract</p> <p>Background</p> <p>The non-pharmacological approach to cholesterol control in patients with hyperlipidemia is based on the promotion of a healthy diet and physical activity. Thus, to help patients change their habits, it is essential to identify the most effective approach. Many efforts have been devoted to explain changes in or adherence to specific health behaviors. Such efforts have resulted in the development of theories that have been applied in prevention campaigns, and that include brief advice and counseling services. Within this context, Motivational Interviewing has proven to be effective in changing health behaviors in specific cases. However, more robust evidence is needed on the effectiveness of Motivational Interviewing in treating chronic pathologies -such as dyslipidemia- in patients assisted by general practitioners. This article describes a protocol to assess the effectiveness of MI as compared with general practice (brief advice), with the aim of improving lipid level control in patients with dyslipidemia assisted by a general practitioner.</p> <p>Methods/Design</p> <p>An open, two-arm parallel, multicentre, cluster, controlled, randomized, clinical trial will be performed. A total of 48-50 general practitioners from 35 public primary care centers in Spain will be randomized and will recruit 436 patients with dyslipidemia. They will perform an intervention based either on Motivational Interviewing or on the usual brief advice. After an initial assessment, follow-ups will be performed at 2, 4, 8 and 12 months. Primary outcomes are lipid levels (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides) and cardiovascular risk. The study will assess the degree of dietary and physical activity improvement, weight loss in overweight patients, and adherence to treatment guidelines.</p> <p>Discussion</p> <p>Motivational interview skills constitute the primary strategies GPs use to treat their patients. Having economical, simple, effective and applicable techniques is essential for primary care professionals to help their patients change their lifestyle and improve their health. This study will provide scientific evidence on the effectiveness of Motivational interviewing, and will be performed under strict control over the data collected, ensuring the maintenance of therapeutic integrity.</p> <p>Trials Registration</p> <p>ClinicalTrials.gov (<a href="http://www.clinicaltrials.gov/ct2/show/NCT01282190">NCT01282190</a>).</p

Diet quality index as a predictor of treatment efficacy in overweight and obese adolescents: The EVASYON study

Background & aim: A diet quality index (DQI) is a tool that provides an overall score of an individual''s dietary intake when assessing compliance with food-based dietary guidelines. A number of DQIs have emerged, albeit their associations with health-related outcomes are debated. The aim of the present study was to assess whether adherence to dietary intervention, and the overall quality of the diet, can predict body composition changes. Methods: To this purpose, overweight/obese adolescents (n = 117, aged: 13–16 years; 51 males, 66 females) were recruited into a multi-component (diet, physical activity and psychological support) family-based group treatment programme. We measured the adolescents’ compliance and body composition at baseline and after 2 months (intensive phase) and 13 months (extensive phase) of follow-up. Also, at baseline, after 6 months, and at the end of follow-up we calculated the DQI. Results: Global compliance with the dietary intervention was 37.4% during the intensive phase, and 14.3% during the extensive phase. Physical activity compliance was 94.1% at 2-months and 34.7% at 13months and psychological support compliance were growing over the intervention period (10.3% intensive phase and 45.3% during extensive phase). Adolescents complying with the meal frequency criteria at the end of the extensive phase had greater reductions in FMI z-scores than those did not complying (Cohen''s d = 0.53). A statistically significant association was observed with the diet quality index. DQI-A variation explained 98.1% of BMI z-score changes and 95.1% of FMI changes. Conclusions: We conclude that assessment of changes in diet quality could be a useful tool in predicting body composition changes in obese adolescents involved in a diet and physical activity intervention programme backed-up by psychological and family support

Epidemiology and cost of herpes zoster and postherpetic neuralgia among patients treated in primary care centres in the valencian community of Spain

<p>Abstract</p> <p>Background</p> <p>Data on the epidemiology and costs related to herpes zoster (HZ) and postherpetic neuralgia (PHN) in Spain are scarce; therefore, studies are needed to evaluate the epidemiological and economic impact of HZ and its most common complication, PHN. The present study aimed to estimate the clinical and economic burden of HZ and PHN in Valencia (Spain).</p> <p>Methods</p> <p>We prospectively analyzed the burden of HZ and PHN and their attributable costs in patients from 25 general practices in the Autonomous Community of Valencia serving 36,030 persons aged > 14 years. All patients with a clinical diagnosis of HZ who attended these centers between December 1^st2006 and November 30^th2007 were asked to participate. Patients included were followed for 1 year.</p> <p>Results</p> <p>Of the 130 cases of HZ followed up, continued pain was experienced by 47.6% (95% confidence interval (CI) = 35.6-56.7%) at 1 month after rash onset, by 14.5% (95% CI = 7.8-1.2%) at 3 months, by 9.0% (95% CI = 3.7-14.3%) at 6 months, and by 5.9% (95% CI = 1.5-10.3%) at 12 months. The percentage of patients with PHN increased with age, from 21.4% (95% CI = 8.3-40) in patients < 50 years to 59.2% (95% CI = 44.4-74) in patients ≥ 70 years. The estimated total cost for the 130 HZ cases during the follow-up period was €49,160 ($67,349). Mean cost per patient was €378 (range 53-2,830) ($517, range 73-3,877).</p> <p>Conclusions</p> <p>This study shows that PHN is a relatively common complication of HZ and that both conditions combined give rise to a significant clinical and economic burden for patients and providers.</p

Effectiveness and Safety of the Sequential Use of a Second and Third Anti-TNF Agent in Patients with Inflammatory Bowel Disease: Results from the Eneida Registry

Background: The effectiveness of the switch to another anti-tumor necrosis factor (anti-TNF) agent is not known. The aim of this study was to analyze the effectiveness and safety of treatment with a second and third anti-TNF drug after intolerance to or failure of a previous anti-TNF agent in inflammatory bowel disease (IBD) patients. Methods: We included patients diagnosed with IBD from the ENEIDA registry who received another anti-TNF after intolerance to or failure of a prior anti-TNF agent. Results: A total of 1122 patients were included. In the short term, remission was achieved in 55% of the patients with the second anti-TNF. The incidence of loss of response was 19% per patient-year with the second anti-TNF. Combination therapy (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.8-3; P < 0.0001) and ulcerative colitis vs Crohn''s disease (HR, 1.6; 95% CI, 1.1-2.1; P = 0.005) were associated with a higher probability of loss of response. Fifteen percent of the patients had adverse events, and 10% had to discontinue the second anti-TNF. Of the 71 patients who received a third anti-TNF, 55% achieved remission. The incidence of loss of response was 22% per patient-year with a third anti-TNF. Adverse events occurred in 7 patients (11%), but only 1 stopped the drug. Conclusions: Approximately half of the patients who received a second anti-TNF achieved remission; nevertheless, a significant proportion of them subsequently lost response. Combination therapy and type of IBD were associated with loss of response. Remission was achieved in almost 50% of patients who received a third anti-TNF; nevertheless, a significant proportion of them subsequently lost response

She\u27s So Bubbly

We introduce the Automatic Learning for the Rapid Classification of Events (ALeRCE) broker, an astronomical alert broker designed to provide a rapid and self-consistent classification of large etendue telescope alert streams, such as that provided by the Zwicky Transient Facility (ZTF) and, in the future, the Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST). ALeRCE is a Chilean-led broker run by an interdisciplinary team of astronomers and engineers working to become intermediaries between survey and follow-up facilities. ALeRCE uses a pipeline that includes the real-time ingestion, aggregation, cross-matching, machine-learning (ML) classification, and visualization of the ZTF alert stream. We use two classifiers: a stamp-based classifier, designed for rapid classification, and a light curve–based classifier, which uses the multiband flux evolution to achieve a more refined classification. We describe in detail our pipeline, data products, tools, and services, which are made public for the community (see https://alerce.science). Since we began operating our real-time ML classification of the ZTF alert stream in early 2019, we have grown a large community of active users around the globe. We describe our results to date, including the real-time processing of 1.5 × 10⁸ alerts, the stamp classification of 3.4 × 10⁷ objects, the light-curve classification of 1.1 × 10⁶ objects, the report of 6162 supernova candidates, and different experiments using LSST-like alert streams. Finally, we discuss the challenges ahead in going from a single stream of alerts such as ZTF to a multistream ecosystem dominated by LSST